HARRISON

BASED

MEDICINE PYQs

RHEUMATOLOGY

STRUCTURED BY
DR. VISHAL GABALE
 INDEX
Sl.No. Unit Name Page No
1. Acute Rhematic Fever– Dec 20, Dec 18 1
2. Ankylosing Spondylosis– April 23, Dec 21, June 20, Dec 18, June 17, 10
16
3. Anti Phospholipid Antibody Syndrome – Oct 23, June 16 18
4. Articular and Non – Articular Pain– Dec 20 22
5. Fibromyalgia – June 22 23
6. Gout – June 20, Dec 18, June 18 29
7. IgG4-Related Disease (IgG4-RD) – 21 32
8. Inclusion Body Myosistis– June 22 38
9. Lupus Nephritis– June 21, Dec 17 43
10. Osteoarthritis – 18 48
11. Psoriatic Arthritis – Dec 20 56
12. Rhematoid Arthritis – Dec 22, 21, Dec 20, Dec 19, June 19, Dec 18, 61
June 18, Dec 16, June 15, Dec 14
13. Sarcoidosis– Dec 21, June 20, Dec 15 74
14. Systemic Lupus Erythematosus – June 22, 21, Dec 20, Dec 19, Dec 85
18, Dec 17
15. Systemic Sclerosis– Oct 23, June 22, Dec 21, June 19 100
16. Takayasu Arteritis (TA) – Dec 17 123
17. Vasculitis – Dec 22, June 21, Dec 20, June 20, Dec 17, June 125

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 Acute Rhematic Fever
– Dec 20, Dec 18
ARF and RHD remain prevalent in many developing countries.
RHD: Continues to be the most common cause of acquired heart disease in children and a
major cause of morbidity and mortality in adults.

Global Statistics:
 Estimated 29.7 to 43.1 million people affected by RHD worldwide.
 Over 300,000 deaths annually.
 95% of ARF cases and RHD deaths occur in developing countries, with high rates in sub-
Saharan Africa, Pacific nations, Australasia, and South and Central Asia.

Pathogenesis and Risk Factors

 Pathogenetic Pathway:
o Exposure: Group A Streptococcus exposure followed by pharyngeal or skin
infection.
o Development: Progression from ARF-to-ARF recurrences and eventual RHD with its
complications.
o Risk Factors: A range of risk factors contribute to the development and progression
of these diseases.

 Interventions:
o Developing Countries: Lack of coordinated, register-based RHD control programs.
o Affluent Countries: Better control of risk factors and interventions.

Epidemiology
 Acute Rheumatic Fever (ARF):
o Age Group: Mainly affects children aged 5-14 years.
o Recurrent Episodes: More common in adolescents and young adults, but rare in
those over 30 years old.

 Rheumatic Heart Disease (RHD):

o Prevalence: Peaks between ages 25 and 40 years.
o Gender Distribution: No clear gender association for ARF; however, RHD affects
females more frequently, sometimes up to twice as often as males.

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PATHOGENESIS OF ACUTE RHEUMATIC FEVER
(ARF)
Organism Factors
 Causative Agent:
o Group A Streptococci: ARF is primarily triggered by upper respiratory tract infections
with group A Streptococci (GAS).
o M-Serotypes: Traditionally associated M-serotypes include types 1, 3, 5, 6, 14, 18, 19,
24, 27, and 29. However, recent evidence shows many more M-serotypes can be
rheumatogenic.
o Rheumatogenic Motifs: Not all serotypes associated with ARF have "rheumatogenic
motifs," which are specific patterns found in some but not all serotypes.

 Skin Infections:
o Role in Pathogenesis: Evidence suggests that skin infections with GAS also play a
role in the development of ARF.

 Other Streptococci:
o Groups C and G: The role of group C and G streptococci in ARF remains unclear.

Host Factors
 Susceptibility:
o Population Prevalence: Approximately 3–6% of any population is susceptible to ARF,
with this proportion being relatively consistent across different populations.

 Genetic and Familial Factors:

o Familial Clustering: There is evidence of familial clustering of ARF cases and higher
concordance in monozygotic twins (44%) compared to dizygotic twins (12%).
o Heritability: Recent estimates place the heritability of ARF at around 60%.

 Immunologic Determinants:
o HLA Class II Alleles:
 Susceptibility: HLA-DR7 and HLA-DR4 alleles are associated with increased
susceptibility to ARF.
 Protection: HLA-DR5, HLA-DR6, HLA-DR51, HLA-DR52, and HLA-DQ alleles
are linked to protection against ARF.
o Tumor Necrosis Factor Alpha (TNF-α): Polymorphisms at the TNF-α locus (TNF-α-
308 and TNF-α-238) are associated with ARF susceptibility.
o Mannose-Binding Lectin: High levels of circulating mannose-binding lectin have
been linked to ARF susceptibility.

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 o Toll-Like Receptors: Variants in Toll-like receptors may also play a role in
susceptibility.

 Genomic Studies:
o Recent Discoveries: Genome-wide association studies have identified associations
with the HLA region (particularly HLA-DQA1 to HLA-DQB1) and the
immunoglobulin heavy chain locus, indicating genetic factors involved in ARF
susceptibility.

CLINICAL FEATURES OF ACUTE RHEUMATIC

FEVER (ARF)
Latent Period and Preceding Infection
 Latent Period: Approximately 3 weeks (1–5 weeks) between the group A streptococcal
infection and ARF symptoms.
 Exceptions: Chorea and indolent carditis can have a prolonged latent period of up to 6
months.
 Preceding Infection: Many patients report a prior sore throat, but the infection is often
subclinical; confirmed through streptococcal antibody testing.

Clinical Features
1. Polyarthritis:
o Prevalence: Present in 60–75% of cases.
o Characteristics: Migratory, affecting large joints (knees, ankles, hips, elbows),
asymmetrical, and often severe.
o Response to Treatment: Highly responsive to NSAIDs. Persistent symptoms after
starting NSAIDs are unlikely due to ARF.

2. Carditis:
o Prevalence: Affects 50–75% of patients.
o Involvement: Endocardium, pericardium, or myocardium may be affected.
o Valvular Damage: Mitral valve is commonly affected, sometimes along with the aortic
valve. Isolated aortic valve involvement is rare.
o Long-Term: May progress to rheumatic heart disease (RHD), with symptoms such as
mitral and/or aortic regurgitation. Myocardial inflammation may cause electrical
conduction issues, leading to P-R interval prolongation (first-degree AV block).

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3. Chorea:
o Prevalence: Varies between <2% to 30%.
o Characteristics: Often occurs in isolation, primarily in females, with choreiform
movements affecting the head and upper limbs. May include emotional lability or
obsessive-compulsive traits.
o Resolution: Movements usually resolve within 6 weeks but can last up to 6 months.
Associated with carditis in more than 50% of cases.

4. Skin Manifestations:
o Erythema Marginatum: Pink macules with a spreading serpiginous edge, transient
and usually located on the trunk.
o Subcutaneous Nodules: Painless, mobile lumps (0.5–2 cm) over bony prominences.
Appears 2–3 weeks after disease onset and lasts for a few days to 3 weeks. Commonly
associated with carditis.

5. Other Features:
o Fever: Common in ARF, typically high-grade (≥39°C), but low-grade fever can
occur. Elevated acute-phase reactants are also present.

Evidence of Preceding Group A Streptococcal Infection

 Serologic Tests: Anti-streptolysin O (ASO) and anti-DNase B (ADB) titers are used, as
throat swabs or rapid antigen tests may be negative.

WORLD HEART FEDERATION CRITERIA FOR

ECHOCARDIOGRAPHIC DIAGNOSIS OF
RHEUMATIC HEART DISEASE (RHD)
Definite RHD (Any of the following A, B, C, or D):
 (A) Pathologic Mitral Regurgitation (MR): Requires at least two morphologic features
of RHD in the mitral valve.
 (B) Mitral Stenosis (MS): Mean gradient ≥4 mmHg (Note: Exclude congenital mitral
valve anomalies).
 (C) Pathologic Aortic Regurgitation (AR): Requires at least two morphologic features of
RHD in the aortic valve (Note: Exclude bicuspid aortic valve and dilated aortic root).
 (D) Borderline Disease: Presence of borderline findings in both the mitral and aortic
valves.

Borderline RHD (Any of the following A, B, or C):

 (A) Mitral Valve: At least two morphologic features of RHD without pathologic MR or
MS.

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 (B) Pathologic MR: Presence of mitral regurgitation with evidence of pathology.
 (C) Pathologic AR: Presence of aortic regurgitation with evidence of pathology.

Normal Echocardiographic Findings (All of the following A, B, C,

and D):
 (A) Physiologic MR: Mitral regurgitation that does not meet all four Doppler criteria.
 (B) Physiologic AR: Aortic regurgitation that does not meet all four Doppler criteria.
 (C) Isolated Morphologic Feature of Mitral Valve: e.g., valvular thickening, without
associated pathologic stenosis or regurgitation.
 (D) Morphologic Feature of Aortic Valve: e.g., valvular thickening, without associated
pathologic stenosis or regurgitation.

Definitions of Pathologic Regurgitation and Morphologic Features of

RHD
 Pathologic Mitral Regurgitation (MR):
o Seen in at least two views.
o In at least one view: jet length ≥2 cm; peak velocity ≥3 m/s; pansystolic jet present in
at least one envelope.

 Pathologic Aortic Regurgitation (AR):

o Seen in at least two views.
o In at least one view: jet length ≥1 cm; peak velocity ≥3 m/s; pandiastolic jet present in
at least one envelope.

 Morphologic Features of RHD in the Mitral Valve:

o Anterior leaflet thickening ≥3 mm (age-specific).
o Chordal thickening.
o Restricted leaflet motion.
o Excessive leaflet tip motion during systole.

 Morphologic Features of RHD in the Aortic Valve:

o Irregular or focal thickening.
o Coaptation defect.
o Restricted leaflet motion.
o Prolapse.

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DIAGNOSIS CRITERIA
For All Patient Populations with Evidence of Preceding Group A Streptococcal
Infection
 Initial ARF: Diagnosis requires either:
o 2 Major Manifestations, or
o 1 Major and 2 Minor Manifestations

 Recurrent ARF: Diagnosis requires either:

o 2 Major Manifestations, or
o 1 Major and 2 Minor Manifestations, or
o 3 Minor Manifestations

TREATMENT OF ACUTE RHEUMATIC FEVER

General Management
 Monitoring: Follow patients closely to confirm diagnosis, manage heart failure, and
initiate preventive measures. Use echocardiography to assess carditis severity and perform
other relevant tests.
 Symptomatic Treatment: ARF treatment is primarily symptomatic, with no proven
intervention to alter the development or severity of rheumatic heart disease (RHD) aside
from managing heart failure.

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Antibiotics
 Drug of Choice: Penicillin.
o Oral: Phenoxymethyl penicillin, 500 mg (250 mg for children ≤27 kg) twice daily, or
amoxicillin, 50 mg/kg (maximum, 1 g) daily for 10 days.
o IM Injection: Benzathine penicillin G, 1.2 million units (600,000 units for children
≤27 kg) as a single dose.

Salicylates and NSAIDs

 Aspirin:
o Dose: 50–60 mg/kg per day, up to 80–100 mg/kg per day (4–8 g/d in adults) in 4–5
divided doses.
o Monitoring: Watch for salicylate toxicity (nausea, vomiting, tinnitus) and adjust
dosage as needed.
o Duration: High doses for 1–2 weeks, then reduced to 50–60 mg/kg per day for 2–4
weeks. Recurrent symptoms may require brief resumption of high doses.

 Naproxen:
o Dose: 10–20 mg/kg per day.
o Advantage: Safer than aspirin and allows twice-daily dosing.

Congestive Heart Failure

 Glucocorticoids:
o Controversial Use: Evidence is mixed; recent studies may not reflect current practices.
o Dose: Prednisone or prednisolone, 1–2 mg/kg per day (maximum, 80 mg), for a few
days to 3 weeks.

Management of Heart Failure

 Refer to detailed protocols in Chapter 258.

Bed Rest
 Current Practice: Limited to cases with active arthritis, arthralgia, or heart failure. Gradual
mobilization is recommended once symptoms are controlled.

Chorea
 Medication:
o Mild Cases: Manage with a calm environment.
o Severe Cases: Carbamazepine or sodium valproate preferred over haloperidol.
o Corticosteroids: Prednisone or prednisolone at 0.5 mg/kg daily, with gradual tapering
as symptoms improve.

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 IVIG:
o Use: Consider only for severe chorea refractory to other treatments.
o Evidence: Mixed; no proven benefit for carditis.

PREVENTION OF ACUTE RHEUMATIC FEVER

(ARF)
Primary Prevention
 Goal: Prevent the initial occurrence of ARF by targeting group A streptococcal infections.

 Strategies:
o Antibiotic Prophylaxis: Timely treatment of group A streptococcal sore throat with
penicillin (as detailed for ARF treatment). Effective if commenced within 9 days of
onset.
 Oral Penicillin: Phenoxymethyl penicillin, 500 mg (250 mg for children ≤27 kg)
twice daily or amoxicillin, 50 mg/kg (maximum, 1 g) daily for 10 days.
 IM Penicillin: Benzathine penicillin G, 1.2 million units (600,000 units for children
≤27 kg) as a single dose.
o Resource-Limited Settings: Use clinical algorithms to identify higher likelihood cases
of group A streptococcal pharyngitis or treat all patients with sore throat with penicillin.
o Skin Infections: Treat group A streptococcal skin infections (e.g., impetigo) as they
are associated with ARF.

Secondary Prevention
 Goal: Prevent recurrences of ARF and progression to rheumatic heart disease (RHD) in
patients who have already had ARF.

 Prophylaxis:
o Benzathine Penicillin G:
 Dosage: 1.2 million units (or 600,000 units for children ≤27 kg) every 4 weeks.
 Increased Risk: Consider every 3 weeks or even every 2 weeks for high-risk
individuals.
o Oral Penicillin V:
 Dosage: 250 mg twice daily.
 Note: Less effective compared to benzathine penicillin G.
o Erythromycin (for penicillin-allergic patients):
 Dosage: 250 mg twice daily.

 Duration:
o Factors Influencing Duration:
 Time Since Last Episode: Longer durations reduce recurrence risk.

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  Age: Older age is associated with lower recurrence risk.
 Severity of RHD: Severe RHD may require extended prophylaxis.

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 Ankylosing Spondylosis
– April 23, Dec 21, June 20,
Dec 18, June 17, 16
 Axial Spondyloarthritis (axSpA) encompasses inflammatory disorders affecting the axial
skeleton, often involving peripheral joints and extraarticular structures.
 Radiographic Axial Spondyloarthritis (r-axSpA): Characterized by significant
radiographic damage of the sacroiliac joints, previously known as AS.
 Nonradiographic Axial Spondyloarthritis (nr-axSpA): Similar clinical presentation
without significant radiographic sacroiliitis; some may develop significant radiographic
changes over time.

Epidemiology:
 Prevalence: AS affects ~0.17% of adults in 20 countries, with axSpA prevalence being 1.3
to 2-fold higher than AS.
 HLA-B27: Strongly associated with AS; present in 80-90% of patients. The prevalence of
HLA-B27 is 6% in North American whites, 80-90% in AS patients.

 Genetics:
o B27: Major genetic factor, contributing ~20% of susceptibility.
o Additional non-HLA alleles: 115 SNPs contribute another ~7-8%.
o nr-axSpA: Lower HLA-B27 prevalence compared to AS, with a higher proportion of
females. Genetically more heterogeneous.

Family and Twin Studies:

 Prevalence in B27+ Adults: 1-6% in the general population, 10-30% among first-degree
relatives of AS probands.
 Twin Concordance: Approximately 65% in identical twins.

CLINICAL MANIFESTATIONS OF ANKYLOSING

SPONDYLITIS (AS)
Onset and Symptoms:
 Age of Onset: Typically late adolescence or early adulthood; median age in the mid-
twenties. Symptoms can start after age 40 in about 5% of cases.

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 Initial Symptoms: Pain (sharp or dull), insidious onset, deep in the lower lumbar or gluteal
region. Accompanied by morning stiffness lasting up to a few hours, improving with
activity and returning after inactivity.
 Pain Pattern: Becomes persistent and bilateral within a few months. Nocturnal pain may
cause the patient to wake and move around.

Associated Findings:
 Bony Tenderness: Reflects enthesitis or osteitis, with common sites including costosternal
junctions, spinous processes, iliac crests, greater trochanters, ischial tuberosities, tibial
tubercles, and heels.
 Hip and Shoulder Arthritis: Affects 25-35% of patients, with severe isolated hip arthritis
or bony chest pain sometimes being the initial presentation. Symptomatic hip disease may
dominate, especially in juvenile-onset cases.
 Peripheral Arthritis: Usually asymmetric and can occur at any point in the disease course.
 Neck Pain and Stiffness: May occur later or be dominant if cervical spine involvement is
present.
 Chest Pain: Common at any stage; can be mistaken for cardiovascular disease.

Juvenile Spondyloarthritis:
 Presentation: Predominantly peripheral arthritis and enthesitis, with axial symptoms
developing later.

Physical Findings:
 Loss of Spinal Mobility: Limitation of anterior and lateral flexion, extension of the lumbar
spine, and chest expansion.
 Pain and Tenderness: In sacroiliac joints, posterior spinous processes, and other bony
areas.
 Modified Schober Test: Measures lumbar spine flexion. Normal increase is ≥2 cm.
 Chest Expansion: Measured between maximal inspiration and forced expiration. Normal
expansion is ≥2.5 cm.
 Lateral Bending: Measured by the distance the middle finger travels down the leg with
maximal lateral bending. Normal is >10 cm.
 Hip and Shoulder Involvement: Limitation or pain with motion if these joints are
involved.

Disease Progression Indicators:

 Clinical Measures: Loss of height, limitation of chest expansion and spinal flexion,
increasing occiput-to-wall distance.
 Radiographic Progression: Presence of syndesmophytes, high inflammatory markers, and
smoking are predictive. Early hip involvement and adolescent onset may correlate with
worse prognosis.

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 Sex Differences: Women often progress less to total spinal ankylosis but may have higher
prevalence of peripheral arthritis.

Complications:
 Spinal Fracture: Can occur with minor trauma due to the rigid, osteoporotic spine; the
lower cervical spine is most commonly affected. Risk of fractures is >10% over a lifetime,
with possible spinal cord injury and pseudoarthrosis leading to pain and neurologic issues.

 Extraarticular Manifestations:
o Acute Anterior Uveitis: Affects up to 50% of patients, often unilateral, causing pain,
photophobia, and accommodation issues. Risk of cataracts and secondary glaucoma.
o Inflammatory Bowel Disease (IBD): Occurs in up to 60% of patients, with overt IBD
in 5-10%.
o Psoriasis: Present in about 10% of patients.
o SAPHO Syndrome: Includes skin manifestations such as acne fulminans or
hidradenitis suppurativa.
o Cardiovascular Issues: Increased risk of ischemic heart disease and aortic
insufficiency, sometimes with heart block.
o Other Rare Complications: Cauda equina syndrome, upper pulmonary lobe fibrosis,
prostatitis, and rarely amyloidosis.

Disease Management:
 Assessment Tools:
o BASDAI: Bath Ankylosing Spondylitis Disease Activity Index.
o ASDAS: Ankylosing Spondylitis Disease Activity Score.
o BASFI: Bath Ankylosing Spondylitis Functional Index.
o ASAS Health Index: Assesses impairment of function and health.

Laboratory Findings:
 HLA-B27: Present in 75–90% of patients across most ethnic groups. Not diagnostic alone
but supports the diagnosis.
 Inflammatory Markers: Erythrocyte sedimentation rate (ESR) and C-reactive protein
(CRP) are often elevated but not consistently.
 Anemia: Mild anemia may be observed.
 Alkaline Phosphatase: Elevated in severe disease cases.
 Serum IgA: Commonly elevated.
 Autoantibodies: Rheumatoid factor, anti-cyclic citrullinated peptide (CCP), and
antinuclear antibodies (ANAs) are generally absent unless associated with another
condition. ANAs may appear with anti-TNF therapy.
 CD8+ T Cells: Circulating levels may be low.
 Matrix Metalloproteinase 3: Serum levels correlate with disease activity.

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 Synovial Fluid: From peripheral joints is typically non-specifically inflammatory.
 Chest Wall Motion: Restricted, leading to decreased vital capacity, though ventilatory
function is usually well-maintained.

Radiographic Findings:
 Sacroiliitis: Diagnosis of AS involves advanced radiographic sacroiliitis, usually
symmetric. Early changes include blurring of the cortical margins, followed by erosions
and sclerosis. Progression leads to "pseudowidening" of the joint space and eventual
ankylosis.
 Lumbar Spine: Progression can lead to loss of lordosis, osteitis of anterior vertebral body
corners, erosion, and new bone formation ("squaring" or "barreling" of vertebral bodies).
Marginal syndesmophytes form bony bridges connecting successive vertebral bodies.
 Non-Radiographic Axial Spondyloarthritis (nr-axSpA): A minority of patients with nr-
axSpA develop radiographic sacroiliitis within a decade, and even fewer show spinal
changes.

MRI Findings:
 Early Detection: MRI is crucial for early diagnosis, especially in nr-axSpA. Standard
protocols for low back pain have low sensitivity for ax-SpA and may give false negatives.
 Active Sacroiliitis: Best visualized with dynamic MRI using semicoronal slices with fat
saturation, T2-weighted turbo spin-echo, short tau inversion recovery (STIR), or T1-
weighted images with contrast.
 Bone Marrow Edema: Indicates inflammation but is not specific to spondyloarthritis.
Erosions are better detected on T1-weighted images.
 Optimal MRI: Requires high suspicion, appropriate protocols, and collaboration between
radiologists and clinicians.

Bone Mineral Density:

 Dual-Energy X-Ray Absorptiometry (DXA): Detects reduced bone mineral density, with
a lateral projection of the L3 vertebral body to avoid falsely elevated readings due to spinal
ossification.

DIAGNOSIS OF AXIAL SPONDYLOARTHRITIS

(AX-SPA)
Challenges in Diagnosis:
1. Prevalence: Only a minority of back pain patients have ax-SpA.
2. Clinical Expertise: Early diagnosis often relies on clinical evaluation and MRI, requiring
expertise.

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3. Patient Behavior: Young individuals with symptoms may not seek medical care.
4. Radiographic Limitations: Early or mild cases may be missed if relying solely on
radiographic sacroiliitis.

ASAS Classification Criteria for ax-SpA (Table 362-1):

 Developed for research, not as strict diagnostic criteria.
 Applicable to individuals with:
o Back Pain: Duration ≥3 months.
o Age of Onset: <45 years.
o MRI: Active sacroiliac joint inflammation is considered equivalent to radiographic
sacroiliitis.

Diagnostic Features of Inflammatory Back Pain (IBP):

 Age of Onset: <40 years.
 Onset: Insidious.
 Exercise: Improvement with exercise.
 Rest: No improvement with rest.
 Night Pain: Pain at night with improvement upon rising.
 Morning Stiffness: >30 minutes.
 Night Awakening: Awakening from back pain during the second half of the night.
 Alternating Buttock Pain: Common.

Suspicion and Diagnosis:

 Two or More Features: Suspect IBP.
 Four or More Features: Consider presumptively diagnostic of ax-SpA.

Differential Diagnosis:
1. Mechanical or Degenerative Causes: More common than ax-SpA; may show less
clustering of SpA features.
2. Infectious Causes: Spondylitis, spondylodiskitis, or sacroiliitis.
3. Tumors: Primary or metastatic.
4. Ochronosis: May resemble AS.
5. Diffuse Idiopathic Skeletal Hyperostosis (DISH):
o Occurs in middle age or older, usually asymptomatic.
o Shows "flowing wax" appearance of calcified ligaments.
o Intervertebral disk spaces are preserved; sacroiliac and facet joints appear normal.

6. Hyperparathyroidism:
o Both primary and secondary can cause subchondral bone resorption around SI joints.
o Radio-graphically, joints appear widened and ill-defined, but without joint space
narrowing.

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TREATMENT
1. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):
 First-Line Therapy: NSAIDs are used to reduce pain, tenderness, and improve
mobility.
 Efficacy: Continuous high-dose NSAID therapy may slow radiographic progression in
high-risk patients.
 Many patients may have persistent symptoms despite NSAID use, necessitating
biologic therapy.

2. Biologic Therapy:
 Anti-TNF Agents: Effective in managing ax-SpA by reducing disease activity and
improving both objective and subjective indicators.
o Infliximab: Chimeric human/mouse anti-TNF monoclonal antibody.
 Dosage: 5 mg/kg intravenously; repeat at 2 weeks, 6 weeks, then every 6-8
weeks.
o Etanercept: Soluble p75 TNF receptor–IgG fusion protein.
 Dosage: 50 mg subcutaneously once weekly.
o Adalimumab: Human anti-TNF monoclonal antibody.
 Dosage: 40 mg subcutaneously biweekly.
o Golimumab: Human anti-TNF monoclonal antibody.
 Dosage: 50 mg subcutaneously every 4 weeks.
o Certolizumab Pegol: Humanized mouse anti-TNF monoclonal antibody.
 Dosage: 200 mg subcutaneously biweekly or 400 mg every 4 weeks.

 Response:
o Clinical Improvement: Significant reductions in morning stiffness, pain, spinal
mobility, peripheral joint swelling, CRP, ESR, and bone mineral density.
o MRI Findings: Substantial resolution of bone marrow edema, enthesitis, and joint
effusions.
o Effectiveness: About 50% of patients achieve a ≥50% reduction in the Bath
Ankylosing Spondylitis Disease Activity Index (BASDAI).
o Predictors of Response: Younger age, shorter disease duration, higher baseline
inflammatory markers, and lower baseline functional disability.
 Response in nr-axSpA: Generally similar to AS.

3. Safety and Side Effects:

 Increased Risk:
o Serious infections, including disseminated tuberculosis.
o Hypersensitivity reactions (infusion/injection site).
o Anti-TNF-induced psoriasis.
o Rare cases of SLE, hematologic disorders (e.g., pancytopenia), demyelinating
disorders, exacerbation of congestive heart failure, and severe liver disease.

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  Malignancy: No overall increase in malignancy risk, but isolated cases of hematologic
malignancies reported.

4. Pre-Treatment Requirements:
 Screening: Test for latent tuberculosis (TB) and hepatitis B; treat if positive.
 Contraindications: Active infection or high infection risk, multiple sclerosis, history
of hematologic malignancy, SLE, or related autoimmunity.
 Pregnancy/Breast-Feeding: Not contraindicated with precautions; minimal
transplacental transfer with certolizumab pegol. Infants exposed to anti-TNF in utero
should avoid live vaccines before 6 months.

5. Switching Therapy:
 Second-Line Anti-TNF Agents: May be effective if there was initial response to the
first agent that was lost.

1. Interleukin-17 (IL-17) Inhibitors:

 Secukinumab: Human monoclonal antibody targeting IL-17A.
o Dosage: 150 mg subcutaneously weekly for 4 weeks, then every 4 weeks.
 Ixekizumab: Humanized monoclonal antibody targeting IL-17A.
o Dosage: Initiate with two 80 mg injections, followed by 80 mg every 4 weeks.

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  Efficacy: Similar to anti-TNF agents; effective in patients who failed or could not
tolerate anti-TNF therapy and those naïve to biologic therapy. Effective in nr-axSpA as
well.
 Precautions: Monitor for infection risks similar to anti-TNF agents. Additional
concern for exacerbation of underlying inflammatory bowel disease (IBD).

2. Interleukin-23 (IL-23) Inhibitors:

 Ustekinumab and Risankizumab: Target IL-23 but have shown no efficacy in AS.
They are effective in psoriatic arthritis.

3. Non-Biologic Disease-Modifying Antirheumatic Drugs (DMARDs):

 Sulfasalazine: Effective for peripheral arthritis in doses of 2–3 g/day.
 Methotrexate: Not beneficial in AS.
 Oral Glucocorticoids: No documented therapeutic role in AS.

4. Janus Kinase (JAK) Inhibitors:

 Tofacitinib, Upadacitinib, and Filgotinib: Show efficacy in AS, reducing
inflammation observable on MRI. Ongoing clinical trials are assessing their
effectiveness further.
 Precautions: Infection risks similar to anti-TNF agents, with additional concern for
herpes zoster.

5. Surgical Interventions:
 Total Hip Arthroplasty: Commonly indicated for severe hip joint arthritis, providing
significant relief of pain and stiffness.
 Spinal Surgery: Rarely indicated, but may benefit patients with extreme spinal flexion
deformities or atlantoaxial subluxation.

6. Management of Uveitis:
 Local Treatments: Local glucocorticoids and mydriatic agents are often effective.
 Systemic Treatments: Systemic glucocorticoids, immunosuppressive drugs, or anti-
TNF therapy may be required.
 Anti-TNF Therapy: Can reduce the frequency of uveitis attacks in ax-SpA.
Adalimumab is FDA-approved for intermediate, posterior, or panuveitis.
 Anti-IL-17A Agents: Not directly studied for SpA-associated uveitis; clinical trials
with secukinumab showed no increased incidence of uveitis.

7. Spinal Manipulation:
 Avoidance: Strongly discouraged due to risks, particularly in patients with osteoporosis
or structural spinal lesions.

8. Osteoporosis Management:
 Approach: Similar to that for primary osteoporosis; specific data for AS are lacking.

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17
 Anti Phospholipid Antibody
Syndrome – Oct 23, June 16
An autoantibody-mediated acquired thrombophilia characterized by recurrent arterial or
venous thrombosis and/or pregnancy morbidity. It predominantly affects females and can occur
as a primary condition or secondary to autoimmune diseases like systemic lupus erythematosus
(SLE).

Major Autoantibodies in APS

 Antibodies against Phospholipids (PLs): Target negatively charged phospholipids such
as cardiolipin, phosphocholine, and phosphatidylserine.
 Antibodies against β2-Glycoprotein I (β2-GPI): Directed against the plasma protein β2-
GPI which interacts with negatively charged PLs.
 Lupus Anticoagulant (LA): Prolongs clotting times in vitro without correction by normal
plasma.

Diagnostic Tests
 Antibodies against Cardiolipin (aCL): Detected using ELISA with cardiolipin as the
antigen.
 Antibodies against β2-GPI (anti-β2-GPI): Detected using ELISA with β2-GPI as the
antigen.
 Lupus Anticoagulant (LA): Detected via assays such as activated partial thromboplastin
time (aPTT), Kaolin clotting time (KCT), and Dilute Russell viper venom test (DRVVT).

Epidemiology
 Incidence: ~5 cases per 100,000 persons per year.
 Prevalence: Estimated at 40–50 per 100,000 in the general population.

Pathogenesis
 Triggers: Infections, oxidative stress, and physical stresses can induce anti-PL antibodies
in individuals with a genetic predisposition.
 Mechanism: Anti-PL antibodies bind to endothelial cells, leading to thrombus formation
and activation of coagulation.

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18
Clinical Manifestations:
1. Venous Thrombosis:
o Superficial or Deep Vein Thrombosis (DVT): Primarily in lower extremities, may
lead to pulmonary embolism.
o Pulmonary Arterial Thrombosis: Causes pulmonary hypertension.
o Inferior Vena Cava Thrombosis: Can result in Budd-Chiari syndrome.
o Cerebral Venous Thrombosis: Symptoms include intracranial hypertension and
retinal vein thrombosis.

2. Arterial Thrombosis:
o Brain: Migraines, cognitive dysfunction, transient ischemic attacks, stroke, and retinal
artery occlusion.
o Extremities: Ischemic leg ulcers, digital gangrene, avascular bone necrosis.
o Other Arteries: Myocardial infarction, renal artery stenosis, glomerular lesions,
infarcts of spleen, pancreas, and adrenals.

3. Livedo Reticularis:
o A purplish, lace-like discoloration of the skin caused by venule swelling and capillary
obstruction.

4. Libman-Sacks Endocarditis:
o Small vegetations on heart valves, characterized by platelet-fibrin microthrombi
surrounded by fibroblasts and macrophages.

5. Glomerular Involvement:
o Acute Phase: Thrombotic microangiopathy in glomerular capillaries.
o Chronic Phase: Fibrous intima hyperplasia, arteriolar occlusions, and focal cortical
atrophy.

6. Pregnancy Morbidity:
o Recurrent miscarriages, intrauterine growth retardation, preeclampsia, eclampsia, and
preterm birth.

7. Premature Atherosclerosis:
o Accelerated vascular damage and early onset of atherosclerosis.

8. Musculoskeletal Manifestations:
o Bone necrosis, arthralgia/arthritis, bone marrow necrosis, muscle infarction,
nontraumatic fractures, osteoporosis.

9. Laboratory Findings:
o Coombs-positive hemolytic anemia and thrombocytopenia.

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Diagnosis:
o Consider APS in cases of thrombosis, cerebral vascular accidents in individuals <55 years,
or pregnancy morbidity with livedo reticularis or thrombocytopenia.

o Clinical Criteria:
1. Vascular Thrombosis: One or more episodes of arterial, venous, or small vessel
thrombosis.
2. Pregnancy Morbidity:
 One or more unexplained deaths of a morphologically normal fetus ≥10 weeks
gestation.
 One or more premature births of a morphologically normal neonate <34 weeks due
to eclampsia, severe preeclampsia, or placental insufficiency.
 Three or more unexplained consecutive spontaneous abortions before 10 weeks
gestation.

o Laboratory Criteria:
1. Lupus Anticoagulant (LA).
2. Anticardiolipin Antibodies (aCL).
3. Anti-β2-Glycoprotein I Antibodies (anti-β2-GPI).
 Criteria must be met on two occasions 12 weeks apart.

 Differential Diagnosis:
o Other Causes of Thrombophilia: Exclude inherited or acquired causes.
o Coombs-Positive Hemolytic Anemia and Thrombocytopenia: Differentiate from
APS-related findings.
o Other Conditions with Livedo Reticularis:
 Vascular Wall Disorders: Atherosclerosis, polyarteritis nodosa, SLE,
cryoglobulinemia, lymphomas.
 Vascular Lumen Disorders: Myeloproliferative disorders, hypercholesterolemia,
other thrombophilia causes.

Treatment of Antiphospholipid Syndrome (APS)

1. General Management Based on Thrombotic Events:
 After a First Thrombotic Event:
o Vitamin K Antagonists (VKAs): Lifelong therapy to maintain an International
Normalized Ratio (INR) of:
 Venous Thrombosis: INR 2.0–3.0.
 Arterial Thrombosis: INR 3.0–4.0, or INR 2.0–3.0 with low-dose aspirin
(LDA, 75–100 mg daily).
 Direct Oral Thrombin Inhibitors:
o Generally avoided due to increased risk of arterial events, particularly in patients
with triple positivity or previous arterial thrombosis.

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20
 o Considered with extreme caution if VKAs are contraindicated or ineffective.

2. Management During Pregnancy:

 History of Obstetric APS:
o Combination Treatment:
 Low-Dose Aspirin (LDA).
 Prophylactic dose of Low-Molecular-Weight Heparin (LMWH).

 Thrombotic APS During Pregnancy:

o Combination Treatment:
 LDA.
 Therapeutic dose of LMWH.

 Recurrent Obstetric Complications:

o Consider increasing LMWH dose (from prophylactic to therapeutic) or adding oral
hydroxychloroquine (400 mg/day) or Intravenous Immunoglobulin (IVIg) (400
mg/kg/day for 5 days).

3. Asymptomatic Individuals or High-Risk SLE Patients:

 Prophylactic Treatment:
o Low-Dose Aspirin (LDA): Recommended if there is a high-risk anti-PL profile but
no previous thrombotic event or pregnancy morbidity.
 Nonpregnant Women with APS-Related Obstetric Complications:
o Treatment with LDA: To reduce the risk of subsequent thrombotic events.

4. Catastrophic Antiphospholipid Syndrome (CAPS):

 Initial Management:
o Combination therapy with:
 Glucocorticoids.
 Heparin.
 Plasma Exchange or Intravenous Immunoglobulin (IVIG).

 Refractory CAPS:
o Alternative Therapies:
 B-cell Depletion (e.g., Rituximab).
 Complement Inhibition (e.g., Eculizumab).

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Articular and Non – Articular Pain
– Dec 20
Articular Structures: Include synovium, synovial fluid, articular cartilage, intraarticular
ligaments, joint capsule, and juxtaarticular bone.

Nonarticular (Periarticular) Structures: Include supportive extraarticular ligaments,

tendons, bursae, muscle, fascia, bone, nerve, and overlying skin.

Articular Pain Characteristics:

 Deep or diffuse pain.
 Limited range of motion on both active and passive movement.
 May present with swelling, crepitation, instability, locking, or deformity.

Nonarticular Pain Characteristics:

 Pain on active but not passive movement.
 Often shows point or focal tenderness.
 May radiate or be associated with specific movements or positions.
 Rarely presents with swelling, crepitus, instability, or deformity.

Distinguishing between articular and nonarticular pain is challenging but essential for accurate
diagnosis and management of musculoskeletal conditions.

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 Fibromyalgia – June 22
 Fibromyalgia (FM): A chronic condition characterized by widespread musculoskeletal
pain and tenderness. It is primarily a pain syndrome but also includes associated symptoms
such as fatigue, unrefreshing sleep, cognitive dysfunction, anxiety, and depression.
 Associated Conditions: Patients with FM often have other pain and fatigue-related
syndromes, including chronic fatigue syndrome, temporomandibular disorder, chronic
headaches, irritable bowel syndrome, and pelvic pain syndromes.
 Pathophysiology: Central nervous system dysfunction is believed to play a key role in
maintaining pain and other core symptoms of FM.

Epidemiology
 Prevalence: Approximately 2% worldwide, with a higher prevalence in women (~4%)
compared to men (<1%).
 Gender Distribution: In clinical settings, FM is diagnosed much more frequently in
women than men, with a ratio of about 9:1.
 Global Consistency: Prevalence is consistent across different world regions and
socioeconomic classes, though cultural factors may influence whether patients seek
medical attention for FM symptoms.

CLINICAL MANIFESTATIONS OF FIBROMYALGIA

(FM)
Pain and Tenderness
 Pain Distribution: Patients often describe experiencing "pain all over," typically above
and below the waist, on both sides of the body, and involving the axial skeleton (neck, back,
or chest).
 Pain Characteristics: The pain is poorly localized, difficult to ignore, severe in intensity,
and impacts functional capacity. For FM diagnosis, pain should be present most of the day
on most days for at least 3 months.
 Tenderness and Sensitivity: Patients exhibit increased sensitivity to pain, detectable
through clinical methods such as pressure from a blood pressure cuff or skin roll tenderness.
Traditional tender-point examinations involve applying pressure to specific
musculotendinous sites, but newer diagnostic criteria emphasize clinical symptoms over
tender points.
 Peripheral Pain Generators: FM patients often have other conditions that trigger
widespread pain, such as arthritis, bursitis, tendinitis, neuropathies, joint hypermobility,

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 and scoliosis. These conditions need to be distinguished from FM itself, which may arise
as a consequence of these comorbidities.

Neuropsychological Symptoms
 Common Symptoms: Fatigue, stiffness, sleep disturbances, cognitive dysfunction,
anxiety, and depression are prevalent in FM patients.
 Fatigue: Frequently reported and exacerbated by exercise or unaccustomed activity.
 Sleep Disturbances: Patients often have trouble falling asleep, staying asleep, and
experience early-morning awakenings, leading to unrefreshed mornings. Conditions like
restless legs syndrome, sleep-disordered breathing, and sleep apnea may also be present.
 Cognitive Dysfunction: Includes difficulties with attention, concentration, word retrieval,
and short-term memory loss, although processing speed remains age-appropriate.
 Mood Disorders: Anxiety and depression are common, with the lifetime prevalence of
mood disorders in FM patients approaching 80%. Screening for major depressive disorders
is essential as FM shares neurobiologic pathways with mood disorders.

Overlapping Syndromes
 Chronic Overlapping Pain Syndromes: FM is often grouped with conditions like
headaches, facial/jaw pain, regional myofascial pain, and arthritis, due to the tendency of
these syndromes to coexist. Visceral pain involving the gastrointestinal tract, bladder, and
pelvic or perineal region is also common.

Comorbid Conditions
 While FM affects about 2% of the general population, its prevalence rises to 10–30%
among patients with degenerative or inflammatory rheumatic disorders. Chronic infectious,
metabolic, or psychiatric conditions can mimic or trigger FM by acting as peripheral pain
generators, which may alter central pain-processing pathways.
 It's important for clinicians to differentiate between ongoing peripheral pain from the
comorbid condition and FM-related central pain processes.
 Treatment should focus on central pain mechanisms when FM is identified, characterized
by widespread pain, neuropsychological symptoms, or tenderness that extends beyond the
primary condition.

Psychosocial Considerations
 Stress and Symptom Onset: FM symptoms often begin or worsen during periods of
perceived stress, reflecting the interaction between central stress physiology, anxiety, and
pain-processing pathways.

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24
 Impact of Trauma: A significant proportion of FM patients have a history of exposure to
interpersonal violence or trauma, which may contribute to symptom severity. In cases
where posttraumatic stress disorder (PTSD) is present, appropriate treatment options
should be considered.

Functional Impairment
 Evaluation of Impact: FM symptoms can significantly impair physical, mental, and social
functioning. Assessing the extent of functional impairment is crucial for setting treatment
goals and measuring the success of management strategies.

Differential Diagnosis
 Musculoskeletal Pain: Given the broad differential diagnosis for musculoskeletal pain,
clinicians must consider a range of conditions. Inflammatory causes of widespread pain
should be identifiable through specific history, physical examination, and laboratory or
radiographic tests.

Laboratory and Radiographic Testing in Fibromyalgia (FM)

 Routine Testing: Laboratory and radiographic tests generally return normal results in FM
patients without comorbidities. Therefore, the primary focus of diagnostic testing is to rule
out other conditions or identify potential pain generators or comorbidities.
 Sparing Use of Imaging: Radiographic testing should be limited and primarily used for
diagnosing inflammatory arthritis. MRI of the spine is discouraged unless there are clear
signs of inflammatory spine disease or neurologic symptoms.

Common Conditions in Differential Diagnosis

 Inflammatory Conditions:
o Polymyalgia rheumatica
o Inflammatory arthritis (e.g., rheumatoid arthritis, spondyloarthritides)
o Connective tissue diseases (e.g., systemic lupus erythematosus, Sjögren’s syndrome)

 Infectious Diseases:
o Hepatitis C
o HIV infection
o Lyme disease
o Parvovirus B19 infection
o Epstein-Barr virus infection

 Noninflammatory Conditions:
o Degenerative joint/spine/disk disease
o Myofascial pain syndromes

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25
 o Bursitis, tendinitis, repetitive strain injuries

 Endocrine Disorders:
o Hypothyroidism or hyperthyroidism
o Hyperparathyroidism

 Neurologic Diseases:
o Multiple sclerosis
o Neuropathic pain syndromes

 Psychiatric Disorders:
o Major depressive disorder

 Drug-Induced Conditions:
o Statins
o Aromatase inhibitors

Recommended Laboratory and Radiographic Testing

 Routine Tests:
o Erythrocyte Sedimentation Rate (ESR) or C-Reactive Protein (CRP): To rule out
inflammation.
o Complete Blood Count (CBC): To check for any hematologic abnormalities.
o Thyroid-Stimulating Hormone (TSH): To assess thyroid function.

 Tests Guided by History and Physical Examination:

o Complete Metabolic Panel: To evaluate metabolic status.
o Antinuclear Antibody (ANA): To screen for connective tissue diseases.
o Anti-SSA (Anti–Sjögren’s Syndrome A) and Anti-SSB: To evaluate for Sjögren’s
syndrome.
o Rheumatoid Factor and Anti–Cyclic Citrullinated Peptide (Anti-CCP): To assess
for rheumatoid arthritis.
o Creatine Phosphokinase (CPK): To detect muscle damage.
o Viral and Bacterial Serologies: Such as hepatitis C, HIV, and Lyme disease
serologies.
o Spine and Joint Radiographs: To evaluate structural abnormalities in cases of
suspected inflammatory arthritis.

TREATMENT OF FIBROMYALGIA (FM)

Nonpharmacologic Treatment
1. Patient Education:
o Educate patients about the genetics, triggers, and physiology of FM to alleviate anxiety.

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26
 o Emphasize the goal of improving function and quality of life rather than eliminating
pain.
o Discourage illness behaviors like frequent physician visits, and promote behaviors that
enhance function.

2. Physical Conditioning:
o Encourage starting with low levels of aerobic exercise, progressing slowly but
consistently.
o Physical activity and exercise are crucial, with supervised or water-based programs
recommended for inactive patients.
o Strength Training: Consider adding after achieving aerobic fitness goals.
o TENS: Can reduce movement-evoked pain and fatigue.
o Meditative Movement Therapies: Qigong, yoga, or Tai Chi may be beneficial.
o Other Physical Therapies: Acupuncture and hydrotherapy may also be considered.
o Exercise Benefits: Reduces tenderness and improves self-efficacy.

3. Cognitive-Behavioral Strategies:
o Focus on improving sleep hygiene and reducing illness behaviors.

Pharmacologic Approaches
1. Comorbid Condition Management:
o Treat any comorbid conditions that may trigger FM symptoms.
o Clearly explain the treatment goals for each medication to the patient.
o Note: Glucocorticoids and NSAIDs may help with inflammatory triggers but are not
effective for FM-specific symptoms.

2. Targeting Pain Pathways:

o The most successful treatments target afferent or descending pain pathways.

3. Medications with Demonstrated Effectiveness:

o Tramadol: An opioid with mild serotonin-noradrenaline reuptake inhibitor activity;
has shown some efficacy in FM.
o Avoid Strong Opioids: These have no demonstrated efficacy in FM and may worsen
symptoms and function.

4. Single-Agent Treatments:
o Combination Effect: Use single agents that can treat multiple symptoms (e.g., pain
and sleep disturbances).
o Examples:
 Cyclobenzaprine: Offers both analgesic and sleep-promoting effects.
 Sedating Antidepressants: Amitriptyline for combined pain and sleep issues.
 Alpha-2-Delta Ligands: Gabapentin and pregabalin for pain and sleep.

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27
  For Pain with Fatigue, Anxiety, or Depression:
 Duloxetine or Milnacipran: Both offer analgesic and antidepressant/anxiolytic
effects.

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28
 Gout – June 20, Dec 18, June 18
Pathogenesis:
 Hyperuricemia: Key factor in gout, resulting from an increased body pool of urate.
 Monosodium Urate (MSU) Crystals: Chronic hyperuricemia leads to supersaturation and
deposition of MSU crystals in joints and connective tissue, triggering gout.
 Species Specificity: Humans, due to the loss of uricase, are the only mammals to develop
gout spontaneously.
 Risk Factors: Includes obesity, Western diet, alcohol consumption, sedentary lifestyle, and
use of diuretics.
 Comorbidities: Often associated with cardiovascular-metabolic issues like obesity,
hypertension, type 2 diabetes, myocardial infarction, stroke, and urate nephrolithiasis.

Clinical Manifestations:
 Acute Gout Flares: Initial presentation involves intense pain in a single joint, commonly
the first metatarsophalangeal joint (podagra), followed by tarsal joints, ankles, and knees.
Flares typically start at night and subside in 1-2 weeks.
 Chronic Gouty Arthritis: Develops after years of untreated gout, characterized by
ongoing synovitis, subcutaneous tophi, joint deformity, and bony destruction.
 Gender and Age: Gout primarily affects middle-aged to elderly men and postmenopausal
women. Women with gout are often elderly, with comorbid conditions like osteoarthritis,
hypertension, or mild renal insufficiency, and often on diuretics.
 Triggers: Purine-rich foods, alcohol, diuretics, trauma, and certain medical conditions like
heart failure and respiratory hypoxia.

Laboratory Diagnosis:
 Joint Aspiration: Needle aspiration of the affected joint or tophaceous deposits is the gold
standard for confirming gout diagnosis.
 MSU Crystals: Identified in synovial fluid during flares; appear as needle-shaped,
negatively birefringent crystals under polarized light.
 Synovial Fluid Analysis: During an acute flare, the fluid is cloudy due to high leukocyte
count (5,000–75,000/μL). The fluid may become thick or pasty with large crystal deposits.
 Coexistence with Infection: Always consider the possibility of bacterial infection
alongside MSU crystals, necessitating synovial fluid staining and culture.
 Serum Urate Levels: May be normal or low during an acute flare due to cytokine-induced
uricosuria (e.g., IL-6). Historical or post-flare serum urate levels can be elevated and are
key for diagnosis and treatment planning.

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29
Radiographic Features:
 Advanced Gout: Cystic changes, well-defined erosions with sclerotic margins, and
overhanging bony edges on plain radiographs are characteristic.
 Early Diagnosis: Musculoskeletal ultrasound can reveal the double-contour sign (MSU
deposition over articular cartilage).
 Dual-Energy CT: Identifies MSU crystals by their specific chemical composition,
providing a definitive diagnosis.

TREATMENT
Acute Gout Care
 Nonpharmacologic Measures: Rest and ice pack application can help reduce symptoms.

 Anti-inflammatory Drugs:
o NSAIDs: Commonly used in patients without complicating comorbidities. Effective
doses include indomethacin (25–50 mg tid), naproxen (500 mg bid), ibuprofen (800 mg
tid), and celecoxib (800 mg followed by 400 mg 12 hours later, then 400 mg bid).
o Colchicine: Effective when administered early; low-dose regimen preferred (1.2 mg
initially, followed by 0.6 mg after 1 hour, with additional doses depending on response).
Dose adjustment is necessary for patients with renal disease or when used with P-
glycoprotein or CYP3A4 inhibitors.
o Glucocorticoids: Can be given orally (e.g., prednisone 30–50 mg/day, tapered) or via
intra-articular injection for polyarticular gout.
o Anakinra, an IL-1β inhibitor, is an option when other treatments fail.

Urate-Lowering Therapy
 Corrects chronic hyperuricemia, prevent recurrent flares, and eliminate tophi by
maintaining serum urate levels below the subsaturation point (<5–6 mg/dL).
 Initiated in patients with recurrent flares, subcutaneous tophi, chronic gouty arthritis, or
uric acid stones.
 First-line Drug:
o Allopurinol: Xanthine oxidase inhibitor, starting dose 100 mg/day (adjusted for CKD),
titrated up to 800 mg/day. Risks include SCARs (e.g., Stevens-Johnson syndrome),
especially in patients with CKD or those carrying the HLA-B*5801 allele.

 Alternative Options:
o Febuxostat: Another xanthine oxidase inhibitor, safer in CKD patients, and an option
for HLA-B*5801 carriers.
o Uricosurics: Probenecid (250 mg bid, titrated up) is effective in patients with good
renal function. Benzbromarone is an option in CKD (not available in the U.S.).
o Pegloticase: For patients intolerant to or unresponsive to other treatments.

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30
 Considerations: Urate-lowering drugs should generally not be initiated during active
flares. Start therapy during the resolution phase or after a flare, with anti-inflammatory
prophylaxis to prevent paradoxical flares associated with rapid urate reduction

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31
 IgG4-Related Disease
(IgG4-RD) – 21
IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition that often presents
with tumefactive lesions (tumor like mass) and can affect almost any organ system.
Commonly involved organs include the pancreas, biliary tree, major salivary glands, periorbital
tissues, kidneys, lungs, lymph nodes, and retroperitoneum.
Less commonly, IgG4-RD may affect the meninges, aorta, prostate, thyroid, pericardium, and
skin, while involvement of the brain, joints, bone marrow, and bowel mucosa is rare.

Pathological Features:
 Lymphoplasmacytic Infiltrate: Characterized by a high percentage of IgG4-positive
plasma cells.
 Storiform Fibrosis: A unique pattern of fibrosis resembling a woven mat.
 Obliterative Phlebitis: A tendency to target and obliterate blood vessels, especially veins.
 Eosinophilia: Mild to moderate tissue eosinophilia is often present.

ORGAN MANIFESTATIONS OF IGG4-RELATED

DISEASE (IGG4-RD):
Orbits and Periorbital Tissues:
 Painless eyelid or periocular tissue swelling
 Orbital pseudotumor, dacryoadenitis, dacryocystitis
 Orbital myositis, mass lesions extending into the pterygopalatine fossa, infiltration along
the trigeminal nerve

Ears, Nose, and Sinuses:

 Allergic phenomena: nasal polyps, asthma, allergic rhinitis, peripheral eosinophilia
 Nasal obstruction, rhinorrhea, anosmia, chronic sinusitis
 Occasional bone-destructive lesions

Salivary Glands:
 Submandibular and/or parotid gland enlargement (bilateral submandibular gland
involvement is more common)
 Sometimes involves minor salivary glands

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32
Meninges:
 Headache, radiculopathy, cranial nerve palsies
 Mass lesions, MRI shows thickening and enhancement of dura

Hypothalamus and Pituitary:

 Anterior pituitary hormone deficiency, central diabetes insipidus, or both
 Imaging: thickened pituitary stalk, mass formation on the stalk, pituitary gland swelling

Lymph Nodes:
 Generalized lymphadenopathy or localized disease near affected organs
 Lymph nodes are typically 1–2 cm in diameter and nontender

Thyroid Gland:
 Riedel’s thyroiditis
 Fibrosing variant of Hashimoto’s thyroiditis

Lungs:
 Asymptomatic finding on lung imaging, or symptoms like cough, hemoptysis, dyspnea,
pleural effusion, or chest discomfort
 Associated with parenchymal lung involvement, pleural disease
 Four main lung syndromes: inflammatory pseudotumor, paravertebral mass, central airway
disease, localized/diffuse interstitial pneumonia

Aorta:
 Asymptomatic radiologic finding, or surprise finding during elective aortic surgery
 Aortic dissection, lymphoplasmacytic aortitis, periaortitis, periarteritis, inflammatory
abdominal aneurysm

Retroperitoneum:
 Backache, lower abdominal pain, lower extremity edema, hydronephrosis from ureteral
involvement
 Classic radiologic appearance: periaortic inflammation extending to iliac vessels

Kidneys:
 Tubulointerstitial nephritis, membranous glomerulonephritis (minority)
 Asymptomatic tumoral lesions, often multiple and bilateral
 Renal involvement strongly associated with hypocomplementemia

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33
Pancreas:
 Type 1 autoimmune pancreatitis: mild abdominal pain, weight loss, acute obstructive
jaundice
 Mimics pancreatic adenocarcinoma, often presents with acute glucose intolerance
 Imaging: "sausage-shaped pancreas" or segmental pancreatic enlargement

Biliary Tree and Liver:

 Obstructive jaundice, weight loss, steatorrhea, abdominal pain, new-onset diabetes mellitus
 Mimics primary sclerosing cholangitis and cholangiocarcinoma

Other Organs:
 Gallbladder, liver (mass), breast (pseudotumor), prostate (prostatism)
 Pericardium (constrictive pericarditis), mesentery (sclerosing mesenteritis)
 Mediastinum (fibrosing mediastinitis), skin (erythematous or flesh-colored papules)
 Peripheral nerve (perineural inflammation)

SEROLOGIC FINDINGS IN IGG4-RELATED

DISEASE (IGG4-RD):
Serum IgG4 Concentrations:
 Elevated Serum IgG4: Most patients with IgG4-RD have elevated serum IgG4 levels,
which can vary widely. Some patients may have levels 30-40 times the upper limit of
normal, particularly those with multi-organ involvement.
 Normal Serum IgG4: Approximately 30% of patients have normal serum IgG4 levels
despite classic histopathologic and immunohistochemical findings. These patients usually
have less extensive organ involvement.
 Retroperitoneal Fibrosis: Patients with IgG4-related retroperitoneal fibrosis often has
normal serum IgG4 levels, likely due to advanced fibrosis by the time of diagnosis.

Correlation with Disease Activity:

 Imperfect Correlation: Serum IgG4 levels do not perfectly correlate with disease activity
or the need for treatment. Levels usually decrease rapidly with therapy but may not
normalize completely.
 Persistent Elevation: Clinical remission can occur even with persistently elevated serum
IgG4 levels. However, rising serum IgG4 levels post-treatment may indicate a risk of
relapse and the need for re-treatment.

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34
 Relapses: Clinical relapses can occur despite normal IgG4 concentrations.

Measurement and Challenges:

 Nephelometry Assays: Serum IgG4 is typically measured by nephelometry assays.
 Prozone Effect: Extremely high serum IgG4 levels can cause the prozone effect, leading
to spuriously low IgG4 values. This can mask the presence of significant disease, especially
in patients at high risk for multi-organ involvement and end-organ damage.
 Correction: The prozone effect can be corrected by diluting the serum sample before
testing. This should be considered when clinical features strongly suggest IgG4-RD, but
serologic testing shows normal IgG4 levels.

Pathology of IgG4-Related Disease (IgG4-RD):

1. Lymphoplasmacytic Infiltrate:
o Dense infiltrate of lymphocytes and plasma cells.
o Typically organized in a storiform (basket weave) pattern.
o Often encased in a distinctive type of fibrosis.

2. Storiform Fibrosis:
o Characterized by fibroblasts and strands of fibrosis surrounding the lymphoplasmacytic
infiltrate.
o The pattern is consistent across various organs affected by IgG4-RD, including the
pancreas, kidneys, lungs, and salivary glands.

3. Obliterative Phlebitis:
o Tendency to involve veins, which is a hallmark of IgG4-RD.
o Arterial involvement (obliterative arteritis) is less common but may occur, particularly
in the lungs.

4. Eosinophilic Infiltrate:
o Mild to moderate infiltration of eosinophils is typically observed.
o Some biopsy samples, especially from long-standing cases, are rich in eosinophils.

5. Lymphoid Follicles and Germinal Centers:

o Frequently observed, with B cells organized in germinal centers.
o Plasma cells, staining for CD19, CD138, and IgG4, radiate from these germinal centers.
o T cells, predominantly CD4+, are diffusely distributed and are the most abundant cell
type.

6. Fibrosis:
o As the disease progresses, tissue fibrosis predominates, especially in chronic cases.

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35
 o In the acellular phase of fibrosis, the IgG4
IgG ratio and the pattern of fibrosis are more critical for diagnosis than the number of IgG4-
positive cells.

Immunohistochemical Confirmation:
 IgG4 Staining:
o IgG4-positive plasma cells are predominant but can be found along with plasma cells
containing other immunoglobulin subclasses.
o The number of IgG4-positive cells can be quantified either by counting the number per
high-power field (HPF) or by calculating the IgG4
IgG ratio.
o Immunohistochemical confirmation is necessary for diagnosis, particularly in the later
stages when fibrosis is prominent.

Uncommon Histopathologic Features (Mitigate Against IgG4-RD

Diagnosis):
 Intense Neutrophilic Infiltration.
 Leukocytoclasis.
 Granulomatous Inflammation.
 Multinucleated Giant Cells.
 Fibrinoid Necrosis

Treatment
 Vital Organ Involvement: Requires aggressive treatment due to the risk of serious organ
dysfunction, such as end-stage liver disease, renal atrophy, aortic dissection, and permanent
pancreatic impairment.
 Some IgG4-RD manifestations, like asymptomatic lymphadenopathy, may not require
immediate treatment. Regular monitoring is essential as serious organ involvement may
develop over time.

First-Line Therapy:
 Glucocorticoids:
o Initial Regimen: Prednisone, starting at 40 mg/day, tapering to 5 mg/day within 2-3
months.
o Response: Typically, rapid and significant, but prolonged steroid-free remissions are
uncommon.
o Risks: High risk of steroid-induced morbidity, especially in middle-aged to elderly
patients with baseline comorbidities.

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Second-Line Therapy:
 Rituximab:
o Indications: Used for relapsing or glucocorticoid-resistant disease, or as a first-line
therapy in patients at high risk for glucocorticoid toxicity.
o Dosage: Two doses of 1 g IV, 15 days apart.
o Effects: Swift decline in serum IgG4 concentrations and potential modulation of T-cell
function, particularly CD4+ cytotoxic T cells.

Emerging Therapies:
 Targeted Approaches:
o Bruton's Tyrosine Kinase Inhibition.
o CD19+ B Lymphocyte Depletion.
o SLAM-F7 Targeting: Affects both B lymphocytes and CD4+ cytotoxic T cells, both
implicated in IgG4-RD pathophysiology.

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 Inclusion Body Myosistis
– June 22
Introduction
Inclusion Body Myositis (IBM) is an inflammatory muscle disease characterized by
progressive muscle weakness and atrophy. It is the most common acquired muscle disease in
individuals over 50 years of age. IBM has a distinctive clinical presentation, laboratory
findings, and histopathological features that help differentiate it from other inflammatory
myopathies such as polymyositis (PM) and dermatomyositis (DM).

Clinical Features
 Age and Gender Prevalence:
o Typically manifests in individuals over the age of 50.
o Slightly more common in men than in women.

 Pattern of Muscle Weakness:

o Slowly progressive weakness and muscle atrophy are hallmark features.
o Early involvement of specific muscle groups:
 Upper Limbs: Wrist and finger flexors, particularly affecting grip strength and fine
motor skills.
 Lower Limbs: Quadriceps muscles, leading to difficulties in climbing stairs, rising
from chairs, and frequent falls.
o Asymmetry: Unlike other myopathies, weakness in IBM is often asymmetric,
affecting one side more than the other.

 Dysphagia:
o Difficulty in swallowing (dysphagia) is common and can occasionally be the
presenting symptom.
o May lead to complications such as aspiration pneumonia and significant weight loss.

 Progression:
o The disease progresses slowly over years.
o Mobility Impact: On average, patients may require the use of a wheelchair or scooter
within approximately 10-15 years from symptom onset.

 Malignancy Risk:
o Unlike some other inflammatory myopathies, there is no known increased risk of
malignancy associated with IBM.

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38
LABORATORY FEATURES
 Creatine Kinase (CK) Levels:
o CK levels may be normal or only mildly elevated, usually less than 10 times the
normal upper limit.

 Autoantibodies:
o Presence of anti-cytosolic 5′-nucleotidase 1A (cN-1A) antibodies in one-third to
more than two-thirds of patients.
 These antibodies serve as a highly specific diagnostic biomarker for IBM among
patients with myopathy.

 Immunological Findings:
o Detection of an abnormal population of large granular lymphocytes via flow
cytometry.
o Altered CD4/CD8 ratio with an increased CD8 count, indicating immune system
involvement.

 Electromyography (EMG):
o Needle EMG may show large-amplitude, long-duration motor unit potentials.
 These findings can mimic neurogenic patterns but actually reflect the chronic
nature of the myopathy.

 Muscle MRI:
o Imaging may reveal a predilection for involvement of specific muscles:
 Upper Limbs: Flexor digitorum profundus.
 Lower Limbs: Vastus medialis and lateralis muscles.
 Sparing: Rectus femoris muscle is often spared, aiding in differential diagnosis.

HISTOPATHOLOGY AND PATHOGENESIS

 Muscle Biopsy Findings:
o Endomysial Inflammatory Infiltrates:
 Predominantly composed of CD8+ T cells and macrophages.
 These cells surround and invade non-necrotic muscle fibers.

o MHC Class I Expression:

 Increased MHC-1 expression on the sarcolemma of muscle fibers.

o Rimmed Vacuoles:
 Presence of rimmed vacuoles within muscle fibers.
 These may not be present in 20–30% of biopsies, necessitating additional
diagnostic methods.

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 o Inclusions:
 Beta-sheet misfolded proteins (amyloid) inclusions detectable via p62
immunostaining.
 Standard Congo red staining may not effectively reveal these inclusions.

o Mitochondrial Abnormalities:
 Presence of ragged red fibers and cytochrome oxidase (COX)-negative fibers
indicating mitochondrial dysfunction.

 Pathogenesis:
o The exact cause remains poorly understood, but several mechanisms are implicated:
 Autoimmune Components:
 The presence of specific autoantibodies and T-cell-mediated muscle fiber
invasion suggest an autoimmune attack on muscle tissue.
 Protein Misfolding and Aggregation:
 Chronic inflammation may lead to abnormal protein synthesis and
degradation, resulting in protein aggregation and muscle fiber degeneration.
 Endoplasmic Reticulum (ER) Stress and Autophagy:
 Markers of ER stress and impaired autophagy pathways are observed, similar
to other refractory autoimmune diseases.

TREATMENT
Currently, there is no effective cure or disease-modifying treatment for IBM. Management
focuses on symptomatic relief and maintaining functional abilities through supportive
therapies.
1. Physical Therapy
 Goals:
o Preserve muscle strength and flexibility.
o Improve balance and coordination to reduce the risk of falls.
o Maintain mobility and independence for as long as possible.

 Interventions:
o Customized exercise programs including:
 Strength training: Utilizing low-resistance exercises tailored to individual
capability.
 Aerobic conditioning: Low-impact activities such as walking, swimming, or
cycling to enhance cardiovascular fitness.
 Flexibility exercises: Stretching routines to prevent contractures and maintain
joint range of motion.
o Assistive Devices:
 Use of canes, walkers, orthotic supports, and eventually wheelchairs or
scooters as needed to aid mobility and safety.

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 o Fall Prevention Strategies:
 Training in safe movement techniques and home modifications to reduce
environmental hazards.

2. Occupational Therapy
 Goals:
o Facilitate independence in daily living activities (e.g., dressing, eating, personal
hygiene).
o Adapt home and work environments to accommodate physical limitations.

 Interventions:
o Energy conservation techniques: Teaching patients how to pace activities and
prioritize tasks to manage fatigue.
o Adaptive equipment: Recommending and training in the use of tools such as
modified utensils, button hooks, and reachers.
o Hand function support: Exercises and splints to maintain hand dexterity and
strength, crucial due to early involvement of hand muscles.

3. Speech and Swallowing Therapy

 Goals:
o Address dysphagia to prevent complications like aspiration and ensure adequate
nutrition.
 Interventions:
o Swallowing assessments: Evaluate the extent and nature of swallowing difficulties.
o Swallowing exercises: Strengthen muscles involved in swallowing and improve
coordination.
o Dietary modifications:
 Adjusting food textures and liquid consistencies to facilitate safer swallowing.
 Feeding strategies: Training in specific techniques, such as chin-tuck
maneuver during swallowing.
o Alternative Feeding Methods:
 In severe cases, consideration of enteral feeding methods (e.g., gastrostomy
tubes) to maintain nutrition.
o Surgical Interventions:
 Esophageal dilation: To alleviate obstruction and improve swallowing in
selected patients.
 Cricopharyngeal myotomy: Surgical procedure to cut the upper esophageal
sphincter muscle, enhancing passage of food.

4. Supportive Care and Monitoring

 Regular Assessments:
o Ongoing monitoring of muscle strength, functional abilities, and nutritional
status.

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 o Early identification and management of complications such as respiratory
insufficiency or severe dysphagia.
 Psychosocial Support:
o Providing emotional support and counseling to patients and families coping with
chronic disease progression.
o Support groups and community resources to connect with others facing similar
challenges.
 Research and Clinical Trials:
o Encouraging participation in clinical trials exploring new therapeutic options.
o Staying informed about emerging treatments and management strategies.

5. Pharmacologic Interventions
 Limited Efficacy:
o Traditional immunosuppressive and immunomodulatory therapies (e.g.,
corticosteroids, methotrexate, IVIG) have generally shown limited to no benefit in
IBM.
 Symptomatic Medications:
o Pain management: Use of analgesics to manage discomfort associated with muscle
weakness.
o Experimental Therapies:
 Ongoing research into antimyostatin agents, monoclonal antibodies, and
other novel therapeutics aimed at modifying disease progression.
 Clinical trials are essential to evaluate the efficacy and safety of these potential
treatments.

PROGNOSIS
 Disease Course:
o IBM is a chronic and progressively debilitating disease.
o Functional Decline: Gradual loss of muscle strength leads to increased dependence on
assistive devices and support for daily activities.

 Response to Treatment:
o IBM is typically refractory to immunotherapies, distinguishing it from other
inflammatory myopathies that may respond to such treatments.
o The focus is on symptomatic management and maintaining quality of life.

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 Lupus Nephritis
– June 21, Dec 17
Affects 30% of SLE patients at diagnosis, more common in Blacks, Asians, and Hispanics.

Pathophysiology:
Caused by deposition of immune complexes (DNA and anti-DNA), activating complement
cascade leading to damage, leukocyte infiltration, activation of procoagulant factors, and
cytokine release.

Immune Deposits: Can occur in mesangial, subendothelial, and/or subepithelial spaces.

Clinical Manifestations: Proteinuria is most common; other signs include hematuria,
hypertension, varying degrees of renal failure, and active urine sediment with red blood cell
casts.
Anti-dsDNA antibodies that fix complement correlate best with the presence of renal disease.
Hypocomplementemia is common in patients with acute lupus nephritis (70–90%), and
declining complement levels may herald a flare.
A kidney biopsy should be performed in most patients with renal involvement to establish the
histologic subtype, which guides therapy.

WHO Classification of Lupus Nephritis:

Outlined in 1974, modified in 2004; forms the basis for modern treatment recommendations.
 Class I Nephritis:
o Normal glomerular histology with minimal mesangial deposits.
o Minimal renal manifestation and normal renal function.
o Nephrotic syndrome is rare.
o Excellent prognosis, generally no therapy needed.

 Class II Nephritis:
o Mesangial immune complexes with mesangial proliferation.
o Minimal renal manifestation and normal renal function.
o Excellent prognosis, generally no therapy needed.

 Class III Nephritis:

o Focal lesions involving <50% of glomeruli with proliferation or scarring.
o Variable course with hematuria, proteinuria, active urinary sediment, nephrotic
syndrome, hypertension, and decreased GFR.

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 o Mild cases respond well to steroids; <5% progress to renal failure over 5 years.
o Severe cases have a worse prognosis and require similar treatment to Class IV.

 Class IV Nephritis:
o Diffuse lesions with >50% of glomeruli involved and proliferative endocapillary
lesions.
o Subtypes: Segmental (IV-S) and Global (IV-G).
o High anti-DNA antibody titers, low serum complement, hematuria, red blood cell casts,
proteinuria, hypertension, and decreased renal function.
o 50% of patients have nephrotic-range proteinuria.
o Presence of crescents on biopsy often indicates a rapidly progressive decline in renal
function.

Class V Membranous Nephritis:

 Characterized by thickened basement membranes with diffuse subepithelial immune
deposits.
 Can occur alongside Class III or IV lesions, sometimes referred to as mixed membranous
and proliferative nephritis.
 Managed like Class IV.
 60% present with nephrotic syndrome or lesser proteinuria; risk of renal vein thrombosis
and other thrombotic complications.
Presence of antiphospholipid antibodies can lead to glomerular microthromboses and
thrombotic microangiopathy, worsening prognosis despite anticoagulant therapy.

Class VI Sclerotic Nephritis:

 Defined by global sclerosis of nearly all glomerular capillaries.

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44
Treatment and Prognosis of Lupus Nephritis:
 Prognosis and Remission:
o Class IV-S lesions have a worse prognosis than Class IV-G.
o Achieving remission (near-normal renal function and proteinuria ≤330 mg/dL/day)
leads to excellent renal outcomes.

Managing life-threatening and proliferative forms of lupus nephritis

(LN):
1. Systemic Glucocorticoids:
o Initial Treatment: High-dose glucocorticoids are crucial for severe, inflammatory
manifestations. Options include:
 Oral: 0.5–1 mg/kg per day of prednisone.
 Intravenous (IV): 500–1000 mg of methylprednisolone sodium succinate daily for
3 days.
o Transition: After the initial high-dose phase (4–6 weeks), taper the dose as rapidly as
possible to ≤7.5 mg/day of prednisone or equivalent for maintenance.

2. Current Practices:
o High-Dose Therapy Duration: Modern guidelines recommend using high doses of
glucocorticoids for much shorter periods (4–6 weeks) compared to older practices.
o Long-Term Management: Many patients require years of low-dose glucocorticoid
maintenance therapy. Regular attempts to reduce glucocorticoid doses are advised to
minimize long-term side effects.

3. Adverse Effects:
o Long-term glucocorticoid use is associated with significant adverse effects, including
infections, hyperglycemia, hypertension, and osteoporosis.

4. Alternative Therapies:
o Mycophenolate Mofetil and Rituximab: An open trial showed promising results for
treating lupus nephritis with mycophenolate mofetil plus rituximab without
maintenance daily glucocorticoids. However, the general applicability of this approach
is still uncertain.

Combination Therapy:
 Glucocorticoids are essential in all treatment regimens for severe lupus nephritis.

 Cytotoxic/Immunosuppressive Agents:
o Cyclophosphamide: An alkylating agent effective for induction, particularly for
patients with ISN grade III or IV disease. It reduces progression to end-stage renal
disease (ESRD) and death. Two regimens are used:

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  High-Dose: 500–1000 mg/m² body surface area IV monthly for 6 months.
 Low-Dose: 500 mg IV every 2 weeks for 6 doses, followed by maintenance therapy.
o Mycophenolate Mofetil (MMF): A lymphocyte-specific inhibitor of purine synthesis,
similar to cyclophosphamide in efficacy for induction therapy but with different toxicity
profiles. Particularly effective in African American and Latin American patients.
o Azathioprine: A purine analogue, may be less effective and associated with more
frequent flares.

Effectiveness and Tolerability:

 MMF: Effective in induction and has fewer severe side effects compared to
cyclophosphamide. Common side effects include diarrhea.
 Cyclophosphamide: Associated with higher rates of amenorrhea, leukopenia, and nausea.
The risk of severe infections and death is similar to that with MMF.
 Comparison: Studies show similar long-term outcomes (death or ESRD) between high-
dose and low-dose cyclophosphamide regimens.

Newer Approaches:
 Triple Therapy: Combination of MMF, calcineurin inhibitors (tacrolimus or voclosporin),
and glucocorticoids has shown better short-term responses compared to MMF or
cyclophosphamide plus glucocorticoids alone. Complete renal responses were observed in
41% of patients on triple therapy versus 21% on double therapy.
 Calcineurin Inhibitors: Effective but nephrotoxic. Should be used for no more than 12
months and possibly discontinued after 6 months if no improvement is seen.

Prevention of Ovarian Failure:

 Leuprolide: A gonadotropin-releasing hormone agonist can reduce the risk of ovarian
failure associated with high-dose cyclophosphamide.

Maintenance Therapy:
 Mycophenolate Mofetil (MMF) and Azathioprine are similarly effective and safer than
Cyclophosphamide.
 MMF has shown superiority over Azathioprine in maintaining renal function and survival
after induction therapy.
 High serum creatinine levels and high chronicity scores on renal biopsy are associated
with poor response to these therapies.
 Maintenance therapy with MMF (1.5–2 g daily) or Azathioprine (1–2.5 mg/kg daily)
reduces SLE flares.

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46
Pregnancy Considerations:
 Medications like MMF, Cyclophosphamide, Methotrexate, and Calcineurin Inhibitors can
harm the fetus and should be avoided for at least 3 months before conception.
 Azathioprine is considered safer during pregnancy, but prescreening for TMPT enzyme
deficiency is advised due to risk of bone marrow suppression.

Treatment for Membranous Nephritis (INS Class V):

 Treatment is less defined for those with pure membranous changes.
 Some experts recommend immunosuppression only if proteinuria is nephrotic. ACE
inhibitors or ARBs are recommended.
 Combination therapies, including glucocorticoids and various immunosuppressants, are
effective in reducing proteinuria. Long-term renal function preservation remains
controversial.

Long-term Outcomes:
 Cyclophosphamide or MMF shows good improvement in about 60% of patients over 1–
2 years.
 Adding a Calcineurin Inhibitor improves response rates and delays flares, but many
patients will experience flares within 5 years and may progress to ESRD.
 Outcomes tend to be better in whites compared to African Americans.

Other Therapies:
 Leflunomide may suppress disease activity but is not well-established for nephritis.
 Methotrexate is more suited for arthritis and dermatitis, not nephritis.
 Hydroxychloroquine is recommended for most SLE patients to prolong survival and
reduce damage.
 ACE inhibitors or ARBs are crucial for patients with significant proteinuria (>500 mg
daily).

Biologic Therapies:
 Rituximab (anti-CD20) shows efficacy in patients resistant to standard therapies but is not
consistently superior to placebo in trials.
 Obinutuzumab, a more potent anti-CD20 monoclonal antibody, is under fast-track review
by the FDA.
 Belimumab, approved for lupus nephritis, reduces renal damage significantly when
combined with MMF and glucocorticoids.
 Telitacicept, targeting BAFF and APRIL growth factors, is also under fast-track review by
the FDA; phase 3 trial data are awaited.

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 Osteoarthritis – 18
 OA is the most common type of arthritis.
 Highly prevalent in the elderly and a leading cause of disability.
 Rising in occurrence due to aging populations and increasing obesity.

Commonly Affected Joints:

 Hip, knee, first metatarsal phalangeal joint (MTP), cervical and lumbosacral spine.
 In the hands: distal and proximal interphalangeal joints and the base of the thumb.

Spares Certain Joints:

 Wrist, elbow, and ankle are usually spared.

Evolutionary Perspective:
 Joints like the thumb base and knees/hips are prone to OA due to evolutionary design for
four-limbed movement.
 Ankle joints might be spared due to articular cartilage resistance to loading stresses.

Definition and Pathology:

 OA is defined as joint failure involving pathologic changes in all joint structures.
 Characterized by hyaline articular cartilage loss, subchondral bone sclerosis, osteophyte
growth, stretching of the articular capsule, synovitis, and muscle weakness.
 In the knees, meniscal degeneration is part of OA.
 Joint injury often triggers OA, particularly when protective mechanisms fail

Joint protective mechanisms and their failure:

1. Joint Protective Mechanisms:
o Joint Capsule and Ligaments: Limit joint excursion and fix the range of motion,
protecting against excessive movement.
o Synovial Fluid: Reduces friction between articulating cartilage surfaces, aided by
hyaluronic acid and lubricin, a mucinous glycoprotein. Lubricin's concentration
decreases after joint injury and in synovial inflammation.
o Mechanoreceptors: Located in ligaments, overlying skin, and tendons, they provide
feedback to muscles and tendons, helping them adjust tension to protect joints during
movement.
o Muscles and Tendons: Minimize focal stress on joints by contracting to decelerate
joints before impact and distribute impact across the joint surface.

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2. Failure of Joint Protectors:
o Increases the risk of joint injury and osteoarthritis (OA).
o Examples:
 Sectioning of sensory nerves to joints in animals leads to rapid OA development
after joint injury.
 Charcot's arthropathy in humans develops when minor joint injuries occur alongside
peripheral neuropathy.
 Rupture of ligaments is a known cause of early OA development.

Joint environment contributing to osteoarthritis (OA):

1. Local Joint Environment:
o Anatomic Abnormalities:
 Abnormalities like congenital dysplasia, Legg-Perthes disease, and slipped capital
femoral epiphysis can lead to OA in later life, with severity influencing the age of
onset.
 Femoroacetabular impingement in adolescence can cause hip pain and increase the
risk of hip OA later.
 Major injuries (e.g., fractures through the joint surface, avascular necrosis) create
anatomic irregularities, increasing OA risk.
 Ligamentous and fibrocartilaginous structure tears (e.g., meniscus, labrum) can lead
to premature OA.
o Malalignment:
 Varus (bowlegged) alignment increases the risk of cartilage loss in the medial knee
compartment.
 Valgus (knock-kneed) alignment predisposes to cartilage loss in the lateral knee
compartment.
 Malalignment leads to increased focal stress on cartilage, damaging both cartilage
and subchondral bone.
o Quadriceps Muscle Weakness: Increases the risk of painful knee OA.

2. Systemic Factors Affecting Joint Vulnerability:

o Increased Bone Density: High bone density is associated with a higher risk of OA and
the formation of osteophytes.
o Age, Gender, Genetics: Increased age, female gender, and genetic susceptibility also
play significant roles in the development of OA.
o Nutritional Factors: Influence joint vulnerability.

3. Loading Factors:
o Obesity: A significant risk factor due to increased load on joints.
o Injurious Physical Activities: Activities that stress joints increase OA risk or its
progression.

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4. Combined Influence:
o Both local joint vulnerability and systemic factors, combined with loading factors,
contribute to the development and progression of OA

LOADING FACTORS CONTRIBUTING TO

OSTEOARTHRITIS (OA):
Obesity:
1. Impact on Joints:
o During single-leg stance, 3 to 6 times the body weight is transmitted across the knee.
o Increased body weight significantly raises the force on weight-bearing joints, especially
the knee, during activities like walking.

2. Risk Factor for OA:

o Obesity is a potent risk factor for the development of knee OA and, to a lesser extent,
hip OA.
o The risk is higher in women, with a linear relationship between weight and disease risk.
o Weight loss in women can reduce the risk of developing symptomatic OA.
o Obesity not only increases the likelihood of developing OA but also exacerbates pain
in those already affected.

3. Mechanism:
o The primary mechanism by which obesity influences OA development is through
increased joint loading, leading to more severe pain in obese individuals.

Repeated Use of Joint and Exercise:

1. Occupational Use:
o Long-term repetitive use of joints in occupations, such as farming and mining, increases
the risk of OA in specific joints like the hip, knees, and spine.
o Jobs requiring regular knee bending, lifting, or carrying heavy loads are associated with
a high rate of knee OA.
o Muscle exhaustion during long workdays may diminish the muscles' ability to protect
joints, leading to OA.

2. Leisure Time Physical Activities:

o Exercise is generally recommended, and most studies do not show a consistent
association between exercise and OA risk in the general population.
o Individuals with pre-existing joint injuries, such as major knee injuries, are at increased
risk of OA progression from activities like running.
o Elite runners have a higher risk of knee and hip OA compared to non-runners.

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50
 o Recreational runners are not at an increased risk of knee OA but may have a modestly
increased risk of hip OA.

Pathology of Osteoarthritis (OA)

1. Cartilage Changes:
 Early Stage:
o Surface Fibrillation and Irregularity: Cartilage initially shows surface damage.
o Focal Erosions: Small, localized areas of cartilage erosion develop, extending
deeper into the underlying bone as the disease progresses.
 Progression:
o Expanding Cartilage Loss: Erosions spread, but the disease remains focal with
uneven cartilage loss across the joint.
o Chondrocyte Activity: Chondrocytes undergo mitosis and form clusters. Despite
their increased metabolic activity, the net effect is proteoglycan depletion, leading
to further cartilage damage.
o Proteoglycan Depletion and Collagen Damage: Loss of proteoglycans and
damage to collagen matrix leads to cartilage swelling due to water retention,
reducing its resilience to loading and increasing vulnerability to further injury.

2. Subchondral Bone Changes:

 Bone Remodeling: As cartilage is lost, subchondral bone undergoes thickening due to
increased activity of osteoclasts and osteoblasts stimulated by growth factors and
cytokines.
 Bone Trauma: Joint loading can cause microtrauma, leading to bone remodeling and
small areas of osteonecrosis.
 Osteophyte Formation: At the joint margins, near areas of cartilage loss, osteophytes
(bony outgrowths) form. These start as cartilage outgrowths that ossify with
neurovascular invasion.

3. Synovium Changes:
 Synovial Inflammation: The synovium, normally a single discontinuous layer, can
become edematous and inflamed in OA. Macrophages infiltrate, and synovial cells
proliferate, leading to the production of inflammatory cytokines that further damage
cartilage.
 Cytokine Production: Inflammatory cytokines and alarmins produced by the
synovium stimulate chondrocytes to secrete enzymes that accelerate matrix destruction.

4. Capsule Changes:
 The joint capsule becomes stretched, edematous, and may develop fibrosis,
contributing to joint stiffness and pain.

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5. Crystals in Advanced OA:
 Calcium Crystals: Basic calcium phosphate and calcium pyrophosphate dihydrate
crystals are often found in joints with end-stage OA. Their presence may trigger
synovial inflammation and nociceptive stimulation, though their exact role in cartilage
pathology is unclear.

6. Joint-Specific Pathology:
 In severe OA of the hand, cartilage erosions often occur in the center of the joint due to
bony pressure from the opposite side.

Clinical Features of Osteoarthritis (OA)

1. Joint Pain:
o Early Stages: Pain is primarily activity-related, occurring during or just after joint use
and resolving gradually. Examples include knee or hip pain while climbing stairs or
hand pain during cooking.
o Progression: Pain becomes more constant, eventually occurring even at rest or during
the night. Early on, pain episodes are often triggered by overuse, such as after a long
run in a person with knee OA.

2. Stiffness:
o Typically, joint stiffness occurs but is usually brief, lasting less than 30 minutes in the
morning.

3. Mechanical Symptoms:
o Buckling: Common in the knees due to muscle weakness or internal derangement (e.g.,
anterior cruciate ligament or meniscal tears).
o Catching or Locking: These symptoms are often related to internal derangement and
may need further evaluation if they follow an acute injury.
o Pain with Knee Flexion: Particularly from the patellofemoral compartment, evident
during activities like stair climbing or rising from a chair.

4. Differential Diagnosis:
o Chronic Knee Pain in Adults Over 45: OA is the most common cause, but other
conditions like inflammatory arthritis (indicated by prolonged morning stiffness and
involvement of multiple joints) or bursitis (e.g., anserine or trochanteric bursitis) must
be considered.
o Hip Pain: Loss of internal rotation on passive movement can suggest OA, while lateral
hip pain often indicates trochanteric bursitis.

5. Physical Examination:
o Focus on identifying whether tenderness is localized over the joint line or outside it,
which may point to conditions like bursitis.

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Laboratory and Imaging Studies:
o Blood Tests: Generally not indicated unless there are signs suggestive of inflammatory
arthritis.
o Synovial Fluid Analysis: Useful if the white count is over 1,000/μL, pointing towards
inflammatory arthritis, gout, or pseudogout.
o Imaging: X-rays and MRIs are not routinely indicated for diagnosing OA. Imaging should
be reserved for cases where pain and physical findings are atypical or if symptoms persist
despite standard treatment. Radiographs may be normal in early OA, and MRI findings
often do not correlate with the severity of symptoms or warrant a change in therapy.

Treatment
The primary goals in treating osteoarthritis (OA) are to alleviate pain and minimize loss of
physical function. A comprehensive approach is often needed, involving both physical and
pharmacologic modalities tailored to the severity of the condition.

1. Physical Management Modalities

 Altering Joint Load:
o Avoid activities that exacerbate pain and overload the joint.
o Strengthen and condition muscles around the joint to optimize function and reduce
joint stress.
o Unload the joint using braces, splints, or assistive devices like canes or crutches.

 Weight Loss:
o Central to managing OA, particularly in weight-bearing joints like the knees and
hips. Even modest weight loss can significantly reduce joint pain and improve
function.
 Exercise:
o A key component in managing OA, aimed at reducing pain and improving physical
function.
o Aerobic and Resistance Training: Focuses on strengthening muscles that support
the joint.
o Low-Impact Exercises: Water aerobics and water resistance training are often
better tolerated than high-impact activities.
o Adherence: Long-term adherence is challenging; reinforcement by healthcare
providers and use of technology can improve compliance.
 Correction of Malalignment:
o Addressing varus-valgus malalignment (knee misalignment) through bracing or
surgical interventions can relieve pain and prevent disease progression.
o Patellar braces or taping can help with patellofemoral pain, though effectiveness
varies.

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  Acupuncture and Radiofrequency Ablation:
o Acupuncture may provide modest pain relief, though its effects may largely be due
to placebo.
o Radiofrequency ablation offers potential pain relief for refractory joint pain, but its
long-term safety remains uncertain.

2. Targeted Treatment for Specific Joints

 Knee OA:
o Focused treatments due to more extensive evaluation and research.
o Exercise and weight management are especially emphasized.

 Hand OA:
o Splinting can minimize pain by limiting motion, particularly at the base of the
thumb.
 Hip OA:
o Similar principles apply, but specific approaches like addressing internal hip
rotation loss are important.

3. Considerations for Treatment

 Patient Education and Self-Management:
o Educate patients about the nature of OA and the importance of self-management
strategies.
 Use of Assistive Devices:
o Canes, crutches, and walkers can help unload joints and improve mobility.

4. Pharmacotherapy:
o Typically reserved for patients with ongoing, disabling pain and should be combined
with physical modalities for optimal results.

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RHEUMATOLOGY
55
 Psoriatic Arthritis – Dec 20
 Typically occurs in individuals with psoriasis.
 Affected Areas: Distal interphalangeal (DIP) joints of fingers, spine, sacroiliac joints.
 Familial Aggregation: Significant family history noted.

Pathology:
 Synovial Inflammation: Resembles RA but with less hyperplasia and cellularity.
 Vascular Pattern: Greater and more tortuous than in RA.
 Enthesitis: Prominent, with histology similar to other forms of spondyloarthritis (SpA).

Pathogenesis:
 Immunopathogenic Mechanisms: Shares mechanisms with psoriasis.

 Synovium Features:
o Lining layer hyperplasia.
o Infiltration by T cells, B cells, macrophages, and NK receptor–expressing cells.
o Neutrophil proliferation and angiogenesis.

 Clonal T-Cell Subpopulations: Present in both synovium and skin.

 Role of Dendritic Cells: Plasmacytoid dendritic cells are implicated.

 Key Cytokines:
o IL-23/17 Pathway: Critical drivers of PsA.
o Other Cytokines: IL-1β, 2, 6, 8, 10, 12, 13, 15, 17A; interferon γ; myeloid-related
protein (S100A8/A9).

 Bone Remodeling:
o Increased osteoclastic precursors in peripheral blood.
o Upregulation of RANKL in the synovial lining layer.
o Correlation with serum levels of TNF, RANKL, leptin, and omentin.

CLINICAL FEATURES
Onset and Frequency:
 Psoriasis Precedes Joint Disease: In ~70% of cases.
 Joint Disease Precedes Psoriasis: In ~15% of cases, presenting diagnostic challenges.
 Typical Onset: Usually in the fourth or fifth decade (average age 37), but can start in
childhood or late in life.

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 Gender Distribution: Almost equal in men and women, though disease patterns may vary
by sex.

Disease Patterns:
 Wright and Moll's Classification:
1. Arthritis of DIP Joints: Occurs in ~5% of cases; often accompanied by nail changes.
2. Asymmetric Oligoarthritis: Affects ~30% of patients, involving large joints (e.g.,
knee) and smaller joints with dactylitis.
3. Symmetric Polyarthritis: Found in ~40% of patients; similar to RA but with PsA-
specific features.
4. Axial Involvement: ~5% of patients; resembles AS but with more neck and less
thoracolumbar involvement.
5. Arthritis Mutilans: Severe, destructive form with "telescoping" of digits and possible
ankylosis.

 Simpler Classification:
1. Oligoarthritis
2. Polyarthritis
3. Axial Arthritis

Common Clinical Features:

 Nail Changes: Frequent in PsA patients, including pitting, horizontal ridging, onycholysis,
yellowish discoloration, and dystrophic hyperkeratosis.
 Dactylitis: Present in >30% of patients.
 Enthesitis: Common, often not apparent on physical exam.
 Shortening of Digits: Due to osteolysis, more common than in RA.
 Fibrous and Bony Ankylosis: Greater tendency than in RA.
 "Ray" Distribution: Involvement of all joints of a single finger or toe.

Other Manifestations:
 Back and Neck Pain: Common.
 Eye Involvement: 7–33% of patients may experience conjunctivitis or uveitis, often
chronic and bilateral.
 Heart Involvement: Similar prevalence of aortic valve insufficiency and heart block as in
AS.

Disease Outcome:
 Severity: Can be as crippling and fatal as severe RA.
 Remissions: Temporary in many patients.
 Erosive Disease: Develops in the majority, with progressive deformity and disability
common.

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 Increased Mortality: Some studies show significantly higher mortality compared to the
general population.

HIV-Associated PsA:
 Severity: Severe arthritis with enthesitis, dactylitis, and rapid joint destruction.
 Axial Involvement: Very rare.
 Response to Antiretroviral Therapy: Effective in preventing or managing PsA.

Laboratory Findings:
 ESR and CRP: Elevated in ~30% of patients.
 Rheumatoid Factor (RF) and ANAs: Low titers may be present in some patients.
 Anti-CCP Antibodies: Found in about 10% of patients.
 Uric Acid: May be elevated with extensive psoriasis.
 HLA-B27: Present in 50–70% of patients with axial disease; ≤20% in those with only
peripheral involvement.

Radiographic Findings:
 Peripheral PsA:
o DIP Involvement: Classic "pencil-in-cup" deformity.
o Marginal Erosions: Adjacent bony proliferation ("whiskering").
o Small-Joint Ankylosis: Including osteolysis and telescoping of digits.
o Periostitis: Proliferative new bone at sites of enthesitis.
o "Ray" Distribution: Joint involvement of an entire digit.

 Axial PsA:
o Asymmetric Sacroiliitis: Less symmetric than AS.
o Facet Joint Arthritis: Less common compared to AS.
o Syndesmophytes: Nonmarginal, bulky, "comma"-shaped; fewer and less delicate than
in AS.
o Fluffy Hyperperiostosis: On anterior vertebral bodies.
o Cervical Spine Involvement: Severe, with potential atlantoaxial subluxation.
o Paravertebral Ossification: Less thoracolumbar spine involvement.

 Imaging Modalities:
o Ultrasound and MRI: Effective for demonstrating enthesitis and tendon sheath
effusions. MRI studies show sacroiliitis in ~35% of patients, correlated with restricted
spinal movement.

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Diagnosis:
 CASPAR Criteria (Classification Criteria for Psoriatic Arthritis):
o Points System: Requires ≥3 points from the following categories + inflammatory
articular disease (joint, spine, or entheseal)
1. Current Psoriasis or History: 2 points for current psoriasis; 1 point for a personal
or family history of psoriasis.
2. Typical Psoriatic Nail Dystrophy: 1 point (e.g., onycholysis, pitting,
hyperkeratosis).
3. Negative Rheumatoid Factor: 1 point.
4. Dactylitis: Current or history recorded by a rheumatologist (1 point).
5. Radiographic Evidence: Juxtaarticular new bone formation in hand or foot (1
point).

 Diagnosis Challenges:
o Psoriasis Preceding Arthritis: Often helps in diagnosis.
o Undiagnosed or Obscure Psoriasis: Can complicate diagnosis.
o Differential Diagnosis: Includes other forms of arthritis like osteoarthritis, gout,
multicentric reticulohistiocytosis, and inflammatory osteoarthritis. Radiography aids in
distinguishing these conditions and differentiating PsA from idiopathic AS.

 Koebner Phenomenon: Psoriatic skin lesions may arise at sites of skin trauma, which
might occur more frequently in PsA.

Treatment
1. Biologic Agents:
 Anti-TNF Agents:
o Examples: Adalimumab, etanercept, infliximab, golimumab, certolizumab.
o Efficacy: Dramatic resolution of both arthritis and skin lesions; beneficial for long-
standing disease resistant to other therapies.
o Considerations: May trigger or exacerbate psoriasis (e.g., palmoplantar pustular
psoriasis); however, therapy can sometimes continue.
 IL-23/IL-17 Pathway Antagonists:
o IL-17A Monoclonal Antibodies:
 Examples: Secukinumab, ixekizumab.
o IL-23/IL-12p40 Monoclonal Antibody:
 Example: Ustekinumab.
o IL-23 (p19 subunit) Monoclonal Antibodies:
 Examples: Guselkumab, risankizumab, tildrakizumab.
o Efficacy: Comparable to or superior to anti-TNF agents for PsA and psoriasis.

 Apremilast:
o Mechanism: Oral phosphodiesterase-4 inhibitor.

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 o Efficacy: Effective for psoriasis and PsA; not as effective as biologics but has a
better safety profile.
o Considerations: Not recommended for patients with radiographically evident joint
damage or axial involvement.
 Tofacitinib:
o Mechanism: Oral JAK inhibitor.
o Efficacy: Comparable to anti-TNF agent adalimumab.
o Current Status: Approved for PsA; other JAK inhibitors are under investigation.

2. Traditional Treatments:
 Methotrexate:
o Dosage: 15–25 mg/week.
o Efficacy: Moderate efficacy for psoriasis and PsA; commonly used when biologics
are not required.
o Considerations: Requires regular monitoring.

 Other Agents:
o Cyclosporine: Effective for psoriasis and reported benefits for PsA.
o Retinoic Acid Derivatives: Effective for psoriasis; potential benefits for PsA.
o Psoralens Plus Ultraviolet A (PUVA) Light: Effective for psoriasis; limited
benefit for PsA.
o Leflunomide: Pyrimidine synthetase inhibitor with modest benefit for PsA and
psoriasis.

3. Monitoring and Special Considerations:

 Monitoring: Regular monitoring required for all treatments, especially biologics and
immunosuppressive agents.
 HIV-Associated PsA: Immunosuppressive therapy may be used cautiously if HIV
infection is well controlled.

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 Rhematoid Arthritis
– Dec 22, 21, Dec 20, Dec 19, June 19, Dec 18,
June 18, Dec 16, June 15, Dec 14
Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology,
characterized by symmetric polyarthritis and is the most common form of chronic
inflammatory arthritis.
Early and aggressive diagnosis and treatment are crucial to prevent articular cartilage and bone
destruction, as well as functional disability.
RA can lead to various extraarticular manifestations such as fatigue, subcutaneous nodules,
lung involvement, pericarditis, peripheral neuropathy, vasculitis, and hematologic
abnormalities.
Significant progress has been made in understanding the disease-related genes, environmental
interactions, and molecular pathways involved in RA pathogenesis, leading to new biologic
and targeted synthetic disease-modifying therapies.

Clinical features of rheumatoid arthritis (RA):

1. Incidence and Age: The incidence of RA increases between 25 and 55 years of age,
plateaus until 75, and then decreases.
2. Presenting Symptoms: RA typically presents with joint, tendon, and bursa inflammation.
Patients often experience early morning joint stiffness lasting over an hour, which improves
with physical activity.
3. Initial Joint Involvement: The earliest affected joints are usually the small joints of the
hands and feet. The pattern of joint involvement can be monoarticular, oligoarticular (≤4
joints), or polyarticular (>5 joints), often in a symmetric distribution.
4. Undifferentiated Inflammatory Arthritis: Some patients may present with too few
affected joints to be classified as RA. These patients with undifferentiated arthritis are more
likely to develop RA if they have more tender and swollen joints, test positive for
rheumatoid factor (RF) or ACPA, and exhibit higher physical disability scores.
5. Common Joint Involvement: Once RA is established, the wrists, metacarpophalangeal
(MCP), and proximal interphalangeal (PIP) joints are most frequently involved. Flexor
tendon tenosynovitis is common, leading to decreased range of motion, reduced grip
strength, and potential tendon rupture.
6. Deformities: Chronic inflammation can cause irreversible joint deformities such as:
o Ulnar deviation from MCP joint subluxation.
o Swan-neck deformity (PIP hyperextension, DIP flexion).
o Boutonnière deformity (PIP flexion, DIP hyperextension).

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 o Z-line deformity (MCP subluxation, IP joint hyperextension).

7. Additional Joint Involvement: Inflammation in the ulnar styloid and extensor carpi
ulnaris tendon can cause "piano-key movement" of the ulnar styloid. Metatarsophalangeal
(MTP) joint involvement is an early feature, while ankle and midtarsal inflammation
leading to flat feet may occur later.
8. Atlantoaxial Involvement: Involvement of the cervical spine's atlantoaxial region can lead
to compressive myelopathy and neurologic dysfunction. Atlantoaxial subluxation is now
less common, occurring in less than 10% of patients.
9. Spinal Involvement: Unlike spondyloarthritides, RA rarely affects the thoracic and lumbar
spine.
10. Extraarticular Manifestations: Up to 40% of RA patients may develop extraarticular
manifestations, sometimes even before arthritis onset. Common manifestations include
subcutaneous nodules, secondary Sjögren’s syndrome, interstitial lung disease (ILD),
pulmonary nodules, and anemia. Smoking, early physical disability, and positive serum RF
or ACPA are risk factors for extraarticular disease.

Constitutional Symptoms
 Common Symptoms: Weight loss, fever, fatigue, malaise, depression, and cachexia reflect
high inflammation levels.
 Fever Consideration: A fever >38.3°C (101°F) during the disease course may indicate
systemic vasculitis or infection.

Nodules
 Subcutaneous nodules occur in 30–40% of RA patients, especially those with high disease
activity, a positive rheumatoid factor (RF), and joint erosions.
 Characteristics: Nodules are firm, non-tender, and adhere to periosteum, tendons, or
bursae, commonly developing in areas subject to trauma (e.g., forearm, sacral
prominences).
 They may also occur in the lungs, pleura, pericardium, and peritoneum.
 Complications: Nodules are usually benign but can lead to infection, ulceration, and
gangrene. Accelerated growth may occur with long-term methotrexate use.

Sjögren’s Syndrome
 Secondary Sjögren’s syndrome, defined by dry eyes (keratoconjunctivitis sicca) or dry
mouth (xerostomia), occurs in about 10% of RA patients.

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Pulmonary Manifestations
 Pleuritis: The most common pulmonary manifestation, causing pleuritic chest pain,
dyspnea, and pleural effusions (exudative with monocytes and neutrophils).

 Interstitial Lung Disease (ILD):

o Symptoms: Dry cough and progressive shortness of breath.
o Risk Factors: Associated with cigarette smoking and higher disease activity.
o Prevalence: Up to 12% of RA patients, diagnosed by high-resolution CT showing
infiltrative opacification or ground-glass opacities.
o Types: Usual Interstitial Pneumonia (UIP) with honeycomb changes and Nonspecific
Interstitial Pneumonia (NSIP) with bilateral ground-glass opacities.
o Prognosis: ILD in RA has a poor prognosis but responds better to immunosuppressive
therapy compared to idiopathic pulmonary fibrosis.

 Pulmonary Nodules: Common in RA, can be solitary or multiple.

 Caplan's Syndrome: A rare subset of pulmonary nodulosis associated with silica
exposure.
 Other Pulmonary Disorders: Respiratory bronchiolitis and bronchiectasis are less
commonly associated with RA.

Cardiac Manifestations
 Pericarditis: The most frequent cardiac manifestation, though clinical symptoms occur in
<10% of patients. Pericardial involvement can be detected in up to 50% of cases by
echocardiogram or autopsy.
 Asymptomatic Pericardial Effusions: Found in up to 20% of RA patients on
echocardiography.
 Cardiomyopathy: Can result from myocarditis, coronary artery disease, or diastolic
dysfunction, often subclinical.
 Valvular Abnormalities: Mitral regurgitation is the most common, occurring more
frequently in RA patients than in the general population.

Vasculitis
 Typically occurs in patients with long-standing RA, positive RF or anti-CCP antibodies,
and hypocomplementemia.
 Incidence: Has decreased to less than 1% of RA patients.
 Cutaneous Signs: Include petechiae, purpura, digital infarcts, gangrene, livedo reticularis,
and severe ulcerations.
 Treatment: Vasculitic ulcers may require immunosuppressive therapy and possibly skin
grafting.
 Neuropathies: Sensory-motor polyneuropathies, such as mononeuritis multiplex, may
present with numbness, tingling, or focal muscle weakness.

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Hematologic Manifestations
 Anemia: Normochromic, normocytic anemia is common, correlating with inflammation
levels (CRP, ESR).
 Platelet Counts: May be elevated as an acute-phase reactant.
 Thrombocytopenia: Rarely immune-mediated in RA.
 Felty’s Syndrome: Characterized by neutropenia, splenomegaly, and nodular RA, seen in
less than 1% of patients, more common in severe RA.
 T-cell Large Granular Lymphocyte Leukemia (T-LGL): May present similarly to
Felty’s syndrome with neutropenia and splenomegaly but can develop early in RA.
 Leukopenia: Rare outside of these conditions and often drug-induced.

Lymphoma
 Increased Risk: RA patients have a two- to fourfold increased risk of lymphoma,
particularly diffuse large B-cell lymphoma.
 Risk Factors: High disease activity or Felty’s syndrome increases lymphoma risk.

Associated Conditions
 Cardiovascular Disease: Leading cause of death in RA patients, with higher incidences of
coronary artery disease, carotid atherosclerosis, and heart failure compared to the general
population. Elevated inflammatory markers increase cardiovascular risk.
 Osteoporosis: RA patients have nearly double the incidence of osteoporosis compared to
healthy individuals, with a high prevalence in postmenopausal women. Inflammatory
responses contribute to bone loss, particularly in cortical bone. Glucocorticoid use and
immobility further exacerbate osteoporosis. Hip fractures in RA patients are significant
predictors of increased disability and mortality.

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PATHOLOGY
The development of rheumatoid arthritis (RA) involves a complex interaction between genetic
predisposition and environmental factors, leading to immune system dysregulation,
particularly within the synovial joints.

Immune Activation in RA
1. Genetic and Environmental Triggers: Individuals with genetic susceptibility to RA may
experience environmental triggers that activate the immune system, specifically synovial
T-cells.

2. T-Cell Activation:
o Antigen-Presenting Cells (APCs) activate CD4+ T-cells via two signals:
 Signal 1: Interaction between T-cell receptors (TCR) and class II MHC-peptide
complexes on APCs.
 Signal 2: Co-stimulation through the CD28-CD80/86 pathway.
o Toll-Like Receptors (TLRs) may further activate APCs within the joint, amplifying
the immune response.

3. T-Cell Differentiation:
o Activated CD4+ T-cells differentiate into TH1 and TH17 cells, each with distinct
cytokine profiles.
o These T-cells activate B-cells, some of which become plasma cells that produce
autoantibodies like rheumatoid factors (RFs) and anti–cyclic citrullinated peptides
(CCP).

4. Immune Complex Formation:

o Immune complexes formed by RFs and anti-CCP antibodies activate the complement
pathway, leading to increased inflammation within the joint.

Inflammation and Bone Erosion

1. Proinflammatory Cytokines:
o T effector cells stimulate synovial macrophages (M) and fibroblasts (SF) to produce
proinflammatory cytokines, including tumor necrosis factor α (TNF-α).
o TNF-α plays a pivotal role by:
 Upregulating adhesion molecules on endothelial cells, facilitating leukocyte
migration into the joint.
 Inducing the production of other cytokines like IL-1, IL-6, and granulocyte-
macrophage colony-stimulating factor (GM-CSF).

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2. Bone Erosion:
o TNF-α disrupts the balance between bone formation and destruction by upregulating
dickkopf-1 (DKK-1), which inhibits the Wnt signaling pathway crucial for
osteoblastogenesis (bone formation).
o TNF-α also promotes osteoclastogenesis (bone resorption) but requires additional
factors, such as:
 Macrophage colony-stimulating factor (M-CSF) and RANKL (Receptor
Activator of Nuclear Factor-κB Ligand).
 RANKL, primarily from stromal cells, synovial fibroblasts, and T-cells, binds to
RANK on osteoclast precursors (Pre-OC), leading to osteoclast activation and bone
erosion.
 Osteoprotegerin (OPG) acts as a decoy receptor for RANKL, thus inhibiting
osteoclastogenesis and preventing bone loss.

Key Molecules Involved

 TNF-α: Central to inflammation and bone erosion.
 DKK-1: Inhibits Wnt signaling, reducing bone formation.
 RANK/RANKL: Critical for osteoclast differentiation and bone resorption.
 OPG: Inhibits RANKL, protecting against bone loss.

DIAGNOSIS
The diagnosis of rheumatoid arthritis (RA) primarily relies on clinical assessment, supported
by laboratory and radiographic findings. The 2010 ACR-EULAR classification criteria aim to
improve the early detection of RA, facilitating timely initiation of disease-modifying therapies

Clinical Diagnosis
 Signs and Symptoms: The diagnosis of RA is based on the presence of chronic
inflammatory arthritis, characterized by joint pain, swelling, and stiffness, particularly in
the hands, wrists, and feet.
 Duration of Symptoms: Unlike older criteria, the 2010 criteria do not require symptoms
to be present for more than 6 weeks, allowing for earlier diagnosis.

2010 ACR-EULAR Classification Criteria

 Scoring System: The criteria assign a score from 0 to 10, with a score of ≥6 indicating
definite RA.

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 Key Changes:
o The inclusion of a positive test for anti-citrullinated peptide antibodies (ACPA),
which is more specific for RA than rheumatoid factor (RF).
o Exclusion of features like rheumatoid nodules or radiographic joint damage, which are
less common in early RA.

Laboratory and Radiographic Findings

 Seropositivity: Approximately 75% of RA patients are seropositive, meaning they test
positive for RF and/or ACPA.
 Seronegative RA: The remaining 25% of RA patients are seronegative, lacking these
antibodies.

Differential Diagnosis
 Primary Sjögren's Syndrome: Often presents with polyarthralgia and mild synovitis,
similar to RA, and can test positive for RF.
 Spondyloarthropathies: Conditions like psoriatic arthritis or enteropathy-associated
arthritis may mimic RA but can be differentiated by sacroiliitis and other features, along
with the presence of psoriasis or inflammatory bowel disease.
 Polymyalgia Rheumatica (PMR): May resemble RA in elderly patients, though RA
usually affects the wrists, hands, ankles, and feet.
 RS3PE Syndrome: Characterized by distal limb pitting edema, which is uncommon in RA
and responds well to low-dose prednisone.
 Chronic Tophaceous Gout: Can mimic severe RA; tophi may be mistaken for rheumatoid
nodules.
 Hepatitis C-Related Arthropathy: Often involves small joints of the hands and is
associated with a positive RF but generally lacks ACPA.

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Laboratory Features
1. Inflammatory Markers:
o Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP): These
nonspecific markers are often elevated in RA, reflecting systemic inflammation.

2. Rheumatoid Factor (RF):

o IgM RF is the most commonly measured isotype.
o Found in ~75% of RA patients, but its presence is not exclusive to RA and can occur
in other conditions like Sjögren's syndrome, systemic lupus erythematosus (SLE),
chronic infections, and even in 1–5% of healthy individuals.

3. Anti-Cyclic Citrullinated Peptide (anti-CCP) Antibodies:

o Sensitivity is similar to RF, but specificity is higher (up to 95%).
o Positive anti-CCP is a strong indicator of RA and can help differentiate it from other
forms of arthritis.
o Both RF and anti-CCP have prognostic value, with anti-CCP particularly associated
with worse outcomes.

4. Other Autoantibodies:
o Antinuclear Antibodies (ANAs): Present in about 30% of RA patients.
o Antineutrophil Cytoplasmic Antibodies (ANCAs): Occasionally found, especially p-
ANCAs, but RA patients generally do not test positive for anti-MPO or anti-PR3
antibodies.

Synovial Fluid Analysis

 Synovial Fluid WBC Count: Typically between 5,000 and 50,000 WBC/μL, indicative of
an acute inflammatory state.
 Predominant Cell Type: Neutrophils are the main cells found in the synovial fluid.
 Clinical Utility: Helps confirm inflammatory arthritis and exclude other conditions like
infection or crystal-induced arthritis (gout, pseudogout).

Joint Imaging
1. Plain Radiography:
o Initial Finding: Periarticular osteopenia (though subtle on plain films).
o Other Findings: Soft tissue swelling, symmetric joint space loss, subchondral erosions,
especially in the wrists, hands (MCPs and PIPs), and feet (MTPs).
o Advanced RA: May show severe joint destruction, subluxation, and collapse.

2. MRI:
o Sensitivity: Superior for detecting early signs of RA such as synovitis, joint effusions,
and bone marrow edema.

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68
 o Predictive Value: Bone marrow edema on MRI can predict future erosions.
o Limitations: High cost and limited availability restrict routine use.

3. Ultrasound:
o Erosions and Synovitis: Detects more erosions than plain radiography and can identify
synovitis with increased vascularity.
o Advantages: Portable, no radiation exposure, and relatively inexpensive compared to
MRI.
o Dependence on Expertise: The effectiveness of ultrasound relies heavily on the skill
of the sonographer.

TREATMENT OF RHEUMATOID ARTHRITIS

Clinical Disease Activity and Treatment Decisions
 Disease Activity Indices: Clinical disease activity, reflecting the burden of inflammation,
is key in guiding treatment. Tools such as ACR improvement criteria, DAS, SDAI, CDAI,
and RAPID3 help assess and monitor this activity.

Therapeutic Developments
1. Methotrexate: Emerged as the first-line disease-modifying antirheumatic drug (DMARD)
for early RA.
2. Biologic DMARDs: Highly efficacious biologics can be used alone or combined with
methotrexate.
3. Combination DMARD Therapy: Proven superior to methotrexate alone, often necessary
to control disease.

Categories of RA Medications
1. NSAIDs:
o Role: Once central, now adjunctive for symptom control.
o Action: Inhibit COX-1 and COX-2, providing analgesic and anti-inflammatory effects.
o Limitations: Chronic use is limited due to risks like gastritis, peptic ulcers, and renal
impairment.

2. Glucocorticoids:
o Rapid Disease Control: Low to moderate doses are used until DMARDs take full
effect.
o Acute Flares: A short burst (1-2 weeks) can manage exacerbations.
o Chronic Use: Low doses (5–10 mg/d of prednisone) may control disease when
DMARDs are insufficient but should be minimized due to risks like osteoporosis.
o Severe Extraarticular RA: High doses may be needed for severe manifestations, such
as interstitial lung disease (ILD).

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 o Intraarticular Injections: Triamcinolone acetonide can control inflammation in a few
joints, ensuring infection is excluded first.
Osteoporosis Prevention: Chronic prednisone increases osteoporosis risk.
Bisphosphonates, teriparatide, or denosumab may be used based on patient-specific risk
factors.

Important Considerations
 Chronic Glucocorticoid Therapy: Avoid long-term use when possible; consider
osteoporosis prophylaxis if needed.
 NSAID Use with Glucocorticoids: Increases the risk of peptic ulcer disease, though
guidelines for prophylaxis are not well established.

DMARDS FOR RHEUMATOID ARTHRITIS

Conventional DMARDs
1. Methotrexate:
 Role: First-line DMARD and the anchor drug in most combination therapies.
 Mechanism: Stimulates adenosine release, providing anti-inflammatory effects.
 Administration: Given weekly, either orally or subcutaneously, often with folic acid
to reduce side effects.

2. Leflunomide:
 Mechanism: Inhibits pyrimidine synthesis.
 Use: Effective as monotherapy or in combination with methotrexate.

3. Hydroxychloroquine:
 Role: Used for early, mild disease or as adjunctive therapy.
 Limitation: Does not delay radiographic disease progression.
 Dosage: Typically 5 mg/kg to minimize retinal toxicity.

4. Sulfasalazine:
 Role: Reduces radiographic disease progression, used similarly to hydroxychloroquine.

 Others: Drugs like minocycline, gold salts, penicillamine, azathioprine, and cyclosporine
have been used in RA treatment but are less common now due to inconsistent efficacy and
toxicity concerns.

Biologic DMARDs
 Overview: Biologics have transformed RA treatment, particularly by targeting cytokines
and cell-surface molecules.

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 Key Agents:
1. TNF Inhibitors:
 Role: The first biologics approved for RA treatment.
2. Anakinra:
 Mechanism: IL-1 receptor antagonist.
 Limitation: Offers modest benefits compared to other biologics, now rarely used.
3. Abatacept, Rituximab, Tocilizumab:
 Newest: These represent the latest advancements in biologic therapy for RA.

DOSES
1. Hydroxychloroquine (HCQ)
 Dose: 200–400 mg/day (orally)
 Side Effects: Retinal toxicity (dose-dependent, rare at doses ≤5 mg/kg), gastrointestinal
discomfort, rash, headache.

2. Sulfasalazine
 Dose: 1–3 g/day (orally) in divided doses
 Side Effects: Gastrointestinal distress, rash, reversible oligospermia, headache,
hepatotoxicity, bone marrow suppression.

3. Methotrexate
 Dose: 7.5–25 mg/week (orally, subcutaneously, or intramuscularly)
 Side Effects: Hepatotoxicity, bone marrow suppression, mucositis, pneumonitis,
increased risk of infections, gastrointestinal symptoms.

4. Leflunomide
 Dose: 20 mg/day (orally)
 Side Effects: Hepatotoxicity, gastrointestinal symptoms, alopecia, hypertension, bone
marrow suppression, increased risk of infections.

5. TNF-alpha Inhibitors
 Adalimumab
o Dose: 40 mg every other week (subcutaneously)
o Side Effects: Injection site reactions, increased risk of infections (including TB),
lupus-like syndrome, demyelinating disorders, malignancy risk.
 Golimumab
o Dose: 50 mg once a month (subcutaneously)
o Side Effects: Similar to adalimumab; increased risk of infections, malignancy.

 Certolizumab
o Dose: 400 mg every other week for 3 doses, then 200 mg every other week
(subcutaneously)

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 o Side Effects: Injection site reactions, infections, lupus-like syndrome,
demyelinating disorders, malignancy risk.
 Etanercept
o Dose: 50 mg once a week (subcutaneously)
o Side Effects: Injection site reactions, infections, heart failure, lupus-like syndrome,
demyelinating disorders, malignancy risk.
 Infliximab
o Dose: 3–10 mg/kg every 4–8 weeks (intravenously)
o Side Effects: Infusion reactions, infections, lupus-like syndrome, demyelinating
disorders, heart failure, malignancy risk.

6. Abatacept
 Dose: 500–1000 mg based on weight every 4 weeks (intravenously) or 125 mg/week
(subcutaneously)
 Side Effects: Headache, infections, infusion reactions, malignancy risk, possible
exacerbation of COPD.

7. Anakinra
 Dose: 100 mg/day (subcutaneously)
 Side Effects: Injection site reactions, increased risk of infections, neutropenia,
headache.

8. Rituximab
 Dose: 1000 mg twice, 2 weeks apart, then repeated every 24 weeks (intravenously)
 Side Effects: Infusion reactions, infections (including PML),
hypogammaglobulinemia, reactivation of hepatitis B, cardiac arrhythmias.

9. Janus Kinase Inhibitors (Tofacitinib, Baricitinib)

 Dose:
o Tofacitinib: 5 mg twice daily or 11 mg once daily (extended-release) (orally)
o Baricitinib: 2–4 mg once daily (orally)
 Side Effects: Increased risk of infections, thrombosis, gastrointestinal perforation, liver
enzyme elevations, lipid elevations, malignancy risk.

10. IL-6 Inhibitors (Tocilizumab, Sarilumab)

 Tocilizumab
o Dose: 4–8 mg/kg every 4 weeks (intravenously) or 162 mg once weekly
(subcutaneously)
o Side Effects: Infections, neutropenia, thrombocytopenia, liver enzyme elevations,
lipid abnormalities, gastrointestinal perforation.
 Sarilumab
o Dose: 200 mg every 2 weeks (subcutaneously)

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 o Side Effects: Similar to tocilizumab, including infections, liver enzyme elevations,
lipid abnormalities.

Treatment of Extraarticular Manifestations

1. RA-ILD (Rheumatoid Arthritis-Associated Interstitial Lung Disease)
o Treatment:
 Corticosteroids: High doses are often used to control inflammation.
 Immunosuppressive Agents: Azathioprine, mycophenolate mofetil, and rituximab
can be used as adjunctive treatments.
o Caution: Some DMARDs like methotrexate and leflunomide can exacerbate
pulmonary toxicity, making careful management necessary.

Management Considerations for Pregnancy

1. General Approach
o Symptom Management: Up to 75% of female RA patients experience symptom
improvement during pregnancy but may have flares post-delivery.
o Medications:
 Safe Options: Low doses of prednisone, hydroxychloroquine, and sulfasalazine are
generally considered safe.
 Contraindicated: Methotrexate and leflunomide are contraindicated due to
teratogenicity.
 Biologics: Experience is limited; many patients discontinue them during pregnancy.
They are generally considered safe through the second trimester, but controlling
disease activity is crucial.

Management in Elderly Patients

1. Considerations
o Treatment Aggressiveness: RA may present after age 60, but treatment might be less
aggressive due to concerns about increased toxicity.
o Drug Safety: Conventional DMARDs and biologics are effective and generally safe
for older patients, but caution is needed due to comorbidities.
o Renal Function: Aging leads to decreased renal function, which can affect the
metabolism of NSAIDs and DMARDs like methotrexate.
 Methotrexate: Usually not prescribed if serum creatinine >2 mg/dL. Dosages may
need adjustment for renal impairment.

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 Sarcoidosis
– Dec 21, June 20, Dec 15
Definition:
 Sarcoidosis is an inflammatory condition characterized by noncaseating granulomas
affecting multiple organs, particularly the lungs, liver, skin, and eyes.
 Diagnosis requires involvement in at least two organs, and other causes of granulomas must
be ruled out, such as infections, malignancies, or environmental exposures.

Etiology:
 The cause of sarcoidosis remains unknown, but it is thought to involve an environmental
trigger in genetically susceptible individuals.
 Infectious agents, such as Propionibacterium acnes and Mycobacterium tuberculosis
proteins, have been implicated in triggering the disease.
 Environmental exposures to insecticides, mold, and certain occupational hazards are
associated with increased risk.
 The disease may represent a specific immune response to various agents rather than a single
cause.

PATHOPHYSIOLOGY AND
IMMUNOPATHOGENESIS
Granuloma Formation:
 The hallmark of sarcoidosis is the formation of noncaseating granulomas, which result from
a local accumulation of inflammatory cells, particularly in the lungs.
 Initial Inflammatory Response: Bronchoalveolar lavage (BAL) studies indicate an early
influx of T helper cells and activated monocytes in the affected areas.

Antigen Presentation:
 Antigen-Presenting Cells (APCs): These cells present an unidentified antigen to T helper
cells via the HLA-CD4 complex. Specific HLA haplotypes (e.g., HLA-DRB1*1101) are
linked to an increased risk of sarcoidosis and may influence clinical outcomes.
 T Cell Activation: Upon antigen recognition, T cells activate and release cytokines like
IL-2. Macrophages release interferon-γ (IFN-γ) and tumor necrosis factor (TNF), which are
crucial for sustaining the inflammatory response.

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Cytokine Release and Granuloma Formation:
 The interaction between macrophages and T helper cells leads to a cascade of cytokine
release, forming granulomas.
 Cytokines Involved:
o IL-2: Released by T cells.
o IFN-γ and TNF: Released by macrophages, promoting granuloma maintenance.

Disease Progression and Chronicity:

 Resolution vs. Chronic Disease: Granulomas may resolve spontaneously or persist,
leading to chronic sarcoidosis in about 20% of patients. Chronic sarcoidosis is associated
with elevated levels of IL-8, IL-17, CXCL9, and excessive TNF production in inflamed
areas.
 Genetic Factors: Certain gene signatures are linked to severe forms of the disease,
affecting the heart, nervous system, and lungs.

HIV and Sarcoidosis:

 Sarcoidosis is rare in patients with advanced, untreated HIV due to the lack of helper T
cells.
 However, sarcoidosis can become unmasked when HIV-infected individuals receive
antiretroviral therapy, which restores their immune function.

Löfgren’s Syndrome:
 A specific form of sarcoidosis characterized by erythema nodosum and hilar adenopathy,
often with periarticular arthritis.
 Prognosis: Löfgren’s syndrome generally has a favorable prognosis, with over 90% of
patients experiencing disease resolution within 2 years.
 HLA-DRB1*03 Association: In Scandinavian patients, the presence of HLA-DRB1*03 is
strongly associated with disease resolution, highlighting a genetic influence on the disease
course. However, the applicability of these findings to other populations remains uncertain.

CLINICAL MANIFESTATIONS OF SARCOIDOSIS

General Presentation:
 Sarcoidosis presents with a wide spectrum of clinical manifestations, ranging from
asymptomatic cases to severe organ failure.
 Approximately one-third of patients may be asymptomatic, especially in countries where
routine chest X-rays are performed, detecting 20–30% of pulmonary cases incidentally.

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Common Symptoms:
 Respiratory Symptoms: The most common presenting symptoms include cough and
dyspnea, often developing over 2-4 weeks. Due to their nonspecific nature, diagnosis may
be delayed, sometimes up to a year, until a chest X-ray suggests sarcoidosis.
 Cutaneous and Ocular Symptoms: Skin and eye involvement are also frequent. Skin
lesions, although often nonspecific, can lead to an earlier diagnosis compared to pulmonary
disease. Eye disease, particularly in African Americans and women under 40, is another
common manifestation.
 Constitutional Symptoms: Fatigue is the most common nonspecific symptom, along with
fever, night sweats, and weight loss. These are often unrecognized as related to sarcoidosis
until the disease resolves.

Organ Involvement:
 The frequency of organ involvement varies, with lungs being the most commonly affected
organ (over 90% of cases), followed by skin, eyes, and nervous system involvement.

Lung Involvement:
 Chest X-ray Findings: Lung involvement is often detected through chest X-rays, which
may show bilateral hilar adenopathy. The Scadding staging system classifies lung
involvement from Stage 1 (hilar adenopathy) to Stage 4 (fibrosis).
 CT scan: Although more sensitive, CT scans are generally reserved for specific cases, such
as those with pulmonary fibrosis. CT features of sarcoidosis include peribronchial
thickening and subpleural reticular nodular changes.
 Lung Function Tests: Sarcoidosis can cause restrictive lung disease, with a decrease in
lung volumes and diffusion capacity (DLCO). Obstructive lung disease, reflected by a
reduced FEV1/FVC ratio, is present in about half of the patients. Cough is common, often
due to airway involvement and obstruction.
 Pulmonary Arterial Hypertension (PAH): PAH is reported in at least 5% of sarcoidosis
patients and is more common in those with end-stage fibrosis. Up to 50% of symptomatic
patients may have PAH, which can respond to treatment, warranting evaluation in
persistently dyspneic patients.

Skin Involvement in Sarcoidosis

 Skin involvement is observed in over one-third of sarcoidosis patients.

 Classic Cutaneous Lesions:

o Erythema Nodosum: A transient rash, often associated with hilar adenopathy and
uveitis (Löfgren’s syndrome). More common in women and certain demographic

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 groups, including whites and Puerto Ricans. In contrast, lupus pernio is more prevalent
among African Americans.
o Maculopapular Lesions: These are the most common chronic cutaneous manifestation
of sarcoidosis. Initially appearing as purplish indurated papules, they can become
confluent and infiltrate large skin areas. They may fade in color and induration with
treatment. A skin biopsy of these noncaseating granulomas can confirm the diagnosis
of sarcoidosis.
o Lupus Pernio: A chronic, diagnostic form of sarcoidosis that affects the bridge of the
nose, areas beneath the eyes, and the cheeks. It is a more severe and specific skin
manifestation.
o Other Lesions: Hyper- and hypopigmentation, keloid formation, and subcutaneous
nodules can also occur.

Eye Involvement in Sarcoidosis

 Common Manifestations:
o Anterior Uveitis: The most common ocular manifestation.
o Posterior Segment Inflammation: Including retinitis and pars planitis, affecting over
a quarter of patients. Symptoms may include photophobia, blurred vision, and increased
tearing, but some patients remain asymptomatic while still having active inflammation.

 Complications: Asymptomatic ocular sarcoidosis can progress to blindness if untreated.

Chronic sarcoidosis often leads to sicca (dry eyes) due to prior lacrimal gland involvement,
requiring lubricants like natural tears.
 Screening: All sarcoidosis patients should undergo a dedicated ophthalmologic
examination to prevent severe complications.

Liver Involvement in Sarcoidosis

 Liver granulomas can be identified in over half of sarcoidosis patients through biopsies,
though liver function tests detect involvement in only 20–30% of cases.

 Common Abnormalities:
o Alkaline Phosphatase Elevation: The most common liver function abnormality,
consistent with an obstructive pattern.
o Transaminase Elevation: Elevated transaminases are also possible.
o Elevated Bilirubin: Indicates more advanced liver disease.

 Clinical Significance: Only about 5% of patients exhibit significant liver symptoms

requiring treatment, typically due to hepatomegaly or intrahepatic cholestasis leading to
portal hypertension. Symptoms can include ascites and esophageal varices.
 Management: Liver transplant is rarely necessary, as even patients with sarcoidosis-
induced cirrhosis may respond to systemic therapy.

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Bone Marrow and Spleen Involvement in Sarcoidosis
 Bone Marrow:
o Common Manifestations: Lymphopenia is the most common hematologic issue,
caused by lymphocyte sequestration into inflamed areas. Anemia occurs in about 20%
of patients, while leukopenia is less common.
o Bone Marrow Examination: Granulomas are found in about one-third of patients.

 Spleen:
o Prevalence: Splenomegaly is detected in 5–10% of patients, but splenic biopsy reveals
granulomas in 60% of cases.
o Imaging: CT scans can be specific for sarcoidosis involvement of the spleen.

 Clinical Significance: Both bone marrow and spleen involvement are more common in
African Americans than whites. Although these manifestations rarely necessitate therapy,
splenectomy may be indicated for massive symptomatic splenomegaly or profound
pancytopenia.

Calcium Metabolism in Sarcoidosis

 Hypercalcemia and/or hypercalciuria occur in about 10% of sarcoidosis patients, more
common in whites than African Americans and in men.
 Mechanism: Increased production of 1,25-dihydroxyvitamin D by granulomas leads to
increased intestinal absorption of calcium, causing hypercalcemia with suppressed
parathyroid hormone (PTH) levels.
 Management: Serum calcium levels should be measured during the initial evaluation and
repeated during times of increased sunlight exposure (e.g., summer). Patients with a history
of renal calculi should have a 24-hour urine calcium measurement, especially if calcium
supplements are considered.

Renal Disease in Sarcoidosis

 Direct kidney involvement occurs in less than 5% of sarcoidosis patients and can lead to
nephritis. However, hypercalcemia is the most common cause of sarcoidosis-associated
renal disease.
 Complications: In 1–2% of sarcoidosis patients, acute renal failure may develop due to
hypercalcemia. Treatment with glucocorticoids and other therapies often improves but does
not usually completely resolve renal dysfunction.

Nervous System Involvement in Sarcoidosis

 Neurologic disease affects 5–10% of sarcoidosis patients and occurs equally across all
ethnic groups. Any part of the central or peripheral nervous system can be involved.

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 MRI Findings: Granulomatous inflammation is often visible on MRI with gadolinium
enhancement. However, MRI can sometimes be negative due to small lesions or the effects
of systemic therapy.
 CSF Findings: Lymphocytic meningitis with a mild increase in protein is common, with
normal or low CSF glucose levels.

 Common Neurologic Manifestations:

o Cranial Nerve Involvement: Includes seventh nerve paralysis (which can mimic
Bell’s palsy), basilar meningitis, myelopathy, and anterior hypothalamic disease with
diabetes insipidus.
o Optic Neuritis: Often requires long-term systemic therapy and can be associated with
both anterior and posterior uveitis.
o Seizures and Cognitive Changes: These are other possible manifestations.

 Differential Diagnosis: Differentiating neurosarcoidosis from multiple sclerosis can be

challenging, particularly with optic neuritis and multiple enhancing white matter
abnormalities on MRI. Meningeal enhancement, hypothalamic involvement, and
extraneurologic disease (e.g., pulmonary or skin involvement) suggest neurosarcoidosis.

Cardiac Involvement in Sarcoidosis

 Cardiac involvement varies by race, with over 25% of Japanese sarcoidosis patients
developing cardiac disease, compared to only 5% of patients in the United States and
Europe. There is no racial predilection between whites and African Americans.
 Clinical Presentation: Cardiac sarcoidosis typically presents as congestive heart failure or
cardiac arrhythmias. Granulomatous infiltration of the heart muscle can lead to severe
dysfunction, with left ventricular ejection fractions dropping below 10%. Despite this,
systemic therapy can sometimes improve ejection fractions.
 Arrhythmias: Can occur due to diffuse or patchy granulomatous infiltration. Heart block
may occur if the AV node is affected. Ventricular arrhythmias and ventricular tachycardia
are common causes of death. Arrhythmias are best detected using 24-hour ambulatory
monitoring, although electrophysiology studies may be negative.
 Diagnosis: Routine ECG and echocardiography are used for screening. Confirmation of
cardiac sarcoidosis is typically done with MRI or PET scanning.
 Treatment: Ablation therapy is generally ineffective due to the multifocal nature of
ventricular arrhythmias. Patients with significant arrhythmias may benefit from an
implanted defibrillator, which has reduced death rates. Systemic therapy can help treat
arrhythmias, but malignant arrhythmias can still occur, particularly within six months of
starting treatment or during medication tapering.

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Musculoskeletal System Involvement in Sarcoidosis
 Direct granulomatous involvement of bone and muscle is documented in about 10% of
sarcoidosis patients via radiography (X-ray, MRI, PET scan, or gallium scan) or biopsy.
 Symptoms: A larger percentage of patients report myalgia and arthralgia, which are similar
to symptoms seen in other inflammatory diseases and chronic infections like
mononucleosis. Fatigue is often overwhelming and may be linked to small peripheral nerve
fiber disease in sarcoidosis.

Other Organ Involvement in Sarcoidosis

 Rare Organ Involvement: Sarcoidosis rarely affects the breast, testes, ovary, or stomach.
A mass in these areas requires biopsy to rule out cancer or other diseases. In breast
sarcoidosis, granulomas are more likely than breast cancer, but routine screening like
mammography is still recommended, especially as women age and the risk of breast cancer
increases.

Complications of Sarcoidosis
 Sarcoidosis is typically a self-limited and non-life-threatening disease, but organ-
threatening complications can occur, leading to blindness, paraplegia, or renal failure.
 Mortality: Death occurs in about 5% of patients seen in sarcoidosis referral clinics, usually
due to lung, cardiac, neurologic, or liver involvement. Respiratory failure with elevated
right atrial pressure is a poor prognostic sign.
 Lung Complications: Can include infections like mycetoma, which may lead to massive
bleeding. The use of immunosuppressive agents increases the risk of serious infections.

LABORATORY FINDINGS IN SARCOIDOSIS

Biochemical Markers:
 Serum Angiotensin-Converting Enzyme (ACE) Levels:
o Can assist in diagnosing sarcoidosis, though sensitivity and specificity are somewhat
low.
o Elevated ACE Levels:
 Reported in 60% of patients with acute sarcoidosis.
 Found in 20% of patients with chronic sarcoidosis.
 Mild elevations can occur in conditions like diabetes.
o Significant Elevations (>50% of the upper limit of normal):
 Seen in conditions like sarcoidosis, leprosy, Gaucher’s disease, hyperthyroidism,
and disseminated granulomatous infections (e.g., miliary tuberculosis).
o ACE Inhibitors (e.g., lisinopril):
 Can lead to very low ACE levels due to interference with the assay.

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Imaging Studies:
 Chest Roentgenogram:
o Most common tool for assessing lung involvement in sarcoidosis.
o Classifies lung involvement into four stages:
 Stage 1 and 2: Characterized by hilar and paratracheal adenopathy.

 CT scan:
o Used increasingly to evaluate interstitial lung disease.
o Presence of adenopathy and nodular infiltrate may suggest sarcoidosis but is not
specific.
o Adenopathy greater than 2 cm in short axis favors a diagnosis of sarcoidosis over other
interstitial lung diseases, such as idiopathic pulmonary fibrosis.

 PET Scan:
o Replacing gallium-67 scanning for identifying areas of granulomatous disease in the
chest and other parts of the body.
o Useful in cardiac sarcoidosis assessment, identifying hypermetabolic activity from
granulomas.

 MRI:
o Valuable for assessing extrapulmonary sarcoidosis, particularly in the brain, heart, and
bone.
o Gadolinium enhancement highlights areas of inflammation.
o May reveal asymptomatic lesions.
o Changes in MRI can resemble those seen in malignancy and infection, sometimes
necessitating biopsy for accurate diagnosis.

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Prognosis of Sarcoidosis
 Overall Mortality:
o Approximately 5%.
o Mortality is associated with advanced pulmonary fibrosis, pulmonary hypertension, and
significant loss of lung function.

 Outcome Factors:
o Advanced Disease: Poor outcomes are more likely in patients with advanced disease
or those with irreversible fibrotic changes.
o Pulmonary Fibrosis: >20% fibrosis on chest CT or DLCO <50% indicates worse
prognosis.
o Pulmonary Hypertension: Correlates with increased mortality.

 Mortality Trends:
o Increased in the U.S. and England over the past 20 years.
o The reasons are unclear but may include greater awareness, chronic disease recognition,
or more use of immunosuppressive therapy.

Disease Course:
 Acute Sarcoidosis:
o Often resolves within 2–5 years.
o Characterized by the granulomatous phase of the disease.

 Chronic Sarcoidosis:
o May not resolve within 2–5 years.
o Risk factors for chronic disease include:
 Fibrosis on Chest Imaging: Indicates advanced disease.
 Lupus Pernio: Chronic skin lesions.
 Bone Cysts: Presence of cystic changes.
 Cardiac or Neurologic Involvement: Except isolated seventh nerve paralysis.
 Renal Calculi: Due to hypercalciuria.

 Predictive Factors:
o Need for Glucocorticoids:
 Patients requiring glucocorticoids within the first 6 months of presentation have
>50% chance of chronic disease.
 Less than 10% of patients who do not require systemic therapy in the first 6 months
develop chronic disease.

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TREATMENT OF SARCOIDOSIS
Treatment Indications:
o For organ- or life-threatening disease, including involvement of the eye, heart, or nervous
system.

 Improve Quality of Life:

o For patients with symptomatic disease affecting daily living.
o Care must be taken to avoid toxicity from treatment that might outweigh the benefits.

Medications:
 Glucocorticoids:
o First-Line Treatment: Prednisone is commonly used.
o Dosage: Higher doses may be used for neurosarcoidosis; lower doses for cutaneous
disease.
o Toxicity: Long-term use may lead to significant side effects; hence, steroid-sparing
alternatives are considered.

 Steroid-Sparing Agents:
o Antimalarials:
 Hydroxychloroquine: Effective for skin disease.
 Minocycline: Useful for cutaneous sarcoidosis.
o Cytotoxic Agents:
 Methotrexate: Widely studied; works in about two-thirds of patients; less toxic
compared to azathioprine.
 Azathioprine: Effective but associated with more toxicity compared to
methotrexate.
 Leflunomide, Mycophenolate, Cyclophosphamide: Other options.
o Cytokine Modulators:
 Thalidomide, Pentoxifylline: Used in limited cases.

 Biologic Agents:
o Anti-TNF Agents:
 Infliximab: Significant improvement in lung function; higher risk of tuberculosis
reactivation. Effective in chronic pulmonary disease.
 Golimumab: No significant difference from placebo in chronic pulmonary disease.
 Etanercept: Limited role as a steroid-sparing agent; not as effective as infliximab.
 Adalimumab: Effective at higher doses, similar to its role in Crohn’s disease.

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Monitoring and Management:
 Dosage and Monitoring:
o Regular monitoring is essential for managing toxicity and assessing effectiveness.
o Guidelines for dosage and monitoring vary based on the medication and disease
manifestation.

 Considerations:
o Risk of Reactivation: Especially for anti-TNF agents.
o Newer Agents: The role of newer therapies is still being defined, but they highlight the
importance of TNF as a treatment target.

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 Systemic Lupus Erythematosus
– June 22, 21, Dec 20, Dec 19, Dec 18, Dec 17
DEFINITION
Systemic lupus erythematosus (SLE) is an autoimmune disease in which organs and cells
undergo damage initially mediated by tissue-binding autoantibodies and immune complexes

Pathogenesis
Increased production of immunogenic nucleic acids and self-antigens drives autoimmunity,
leading to activation of innate immunity, autoantibodies, and T cells.
Genetic and Environmental Interactions: Genes, environment, and epigenetic changes
contribute to increased autophagy, antigen presentation, NETosis, and autoantibody formation.
This results in pathogenic T and B cells with ineffective regulatory networks.
Genetic Susceptibility: Certain genes (e.g., HLA, PTPN) confirmed through genome-wide
association studies increase susceptibility to SLE and lupus nephritis.
Epigenetics: Epigenetic changes play a significant role in B cell dysfunction and are influenced
by environmental triggers.
Immune Responses: Abnormal immune responses generate pathogenic autoantibodies and
immune complexes, leading to tissue deposition, complement activation, cytokine release,
inflammation, and irreversible organ damage.
Key Immune Components: Involvement of complement components (C1q, C3), dendritic
cells, and cytokines (IL, MCP) is critical in the disease process.

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Important antibodies in systemic lupus erythematosus (SLE) and their
clinical utility:

PATHOLOGY
Skin Biopsy in SLE:
 Deposition of Ig at the dermal-epidermal junction (DEJ), injury to basal keratinocytes, and
T lymphocyte-dominated inflammation at DEJ and around blood vessels/dermal
appendages.
 Clinical: Ig deposition can also occur in clinically unaffected skin.
 Markers: Expression of IFN-regulated cytokines/chemokines, and IFN-producing
plasmacytoid dendritic cells (pDCs) and keratinocytes.
 Specificity: Patterns suggest SLE but are not specific to dermatologic SLE.

Renal Biopsy in SLE (Lupus Nephritis):

 Pattern and severity of injury guide diagnosis and therapy.
 Activity/Chronicity: "A" for active and "C" for chronic changes indicate disease
reversibility potential.
 Classification emphasizes glomerular disease but also considers tubular interstitial and
vascular disease, as well as chronicity scores.
 Treatment Recommendations:
 Aggressive immunosuppression for class III, IV, and class V with III/IV.
 No treatment for class I, II, or extensive irreversible changes (class VI).
 2019 EULAR/ACR Criteria: Class III or IV renal histology with antinuclear
autoantibodies is sufficient for SLE diagnosis.

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Vascular and Lymph Node Histology:
 Vasculitis: Leukocytoclastic vasculitis is common; patterns can indicate active disease but
are not SLE-specific.
 Lymph Node Biopsy: Shows nonspecific diffuse chronic inflammation, usually performed
to rule out infection or malignancy.

DIAGNOSIS
Classification Systems:
 2012 SLICC Criteria:
o Requires ≥4 well-documented criteria, with at least one clinical and one immunologic
criterion.
o Specificity: 97%, Sensitivity: 84%.
o Easier for individual patient evaluation.

 2019 EULAR/ACR Criteria:

o Requires a positive ANA (≥1:80 by immunofluorescence) and a total score of ≥10.
o Specificity: 97%, Sensitivity: 93%.
o More current and likely to be used in future clinical studies.
o Clinical manifestations are weighted

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Autoantibodies:
 ANA: Positive in >98% of patients during the course of the disease.
o Repeated negative ANA tests by immunofluorescence suggest that the diagnosis is
unlikely to be SLE unless other autoantibodies are present.
 Anti-dsDNA and Anti-Sm: High-titer IgG antibodies are specific for SLE and support the
diagnosis in the presence of compatible clinical manifestations.
 Multiple Autoantibodies: Presence without clinical symptoms does not confirm SLE
diagnosis but indicates an increased risk.

Systemic manifestations of SLE:

 SLE can initially involve one or several organ systems, with additional manifestations
appearing over time.
 Autoantibodies: Most characteristic autoantibodies are present when clinical symptoms
appear.
 Systemic Symptoms: Fatigue and myalgias/arthralgias are common. Severe cases may
present with fever, prostration, weight loss, and anemia.

 Disease Course:
o 85% of patients have ongoing active disease or annual flares.
o Permanent complete remissions are rare (<5%).
o Treatment target is remission on therapy or low disease activity.

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Musculoskeletal Manifestations:
 Polyarthritis: Intermittent, affecting hands, wrists, and knees, with soft tissue swelling and
tenderness.
 Joint Deformities: Occur in 10% of patients, often reducible.
 Erosions: Rare on x-rays, but ultrasound may detect them in 10-50% of patients. "Rhupus"
(overlap of RA and SLE) may be present.
 Ischemic Necrosis of Bone (INB): Consider if persistent pain occurs in a single joint
without active SLE signs, especially in glucocorticoid-treated patients.

 Myositis: Characterized by muscle weakness, elevated creatine kinase, MRI findings, and
muscle necrosis/inflammation on biopsy.
o Myalgias without frank myositis are more common.
o Glucocorticoid or antimalarial therapy-related muscle weakness should be
differentiated from active disease.

Cutaneous Manifestations:
 Lupus Dermatitis: Can be classified as acute, subacute, or chronic.
o Discoid Lupus Erythematosus (DLE): Most common chronic dermatitis, with scaly,
hyperpigmented erythematous rims and depigmented, atrophic centers. DLE is
disfiguring, particularly on the face and scalp. Only 5% of DLE patients have SLE, but
20% of SLE patients may have DLE.
o Acute SLE Rash: Photosensitive, slightly raised erythema, commonly on the cheeks
and nose (butterfly rash), ears, chin, neck, chest, upper back, and extensor surfaces of
the arms. It may worsen with systemic disease flares.
o Subacute Cutaneous Lupus Erythematosus (SCLE): Presents as scaly red patches
or annular lesions, with extreme photosensitivity and commonly associated with anti-
Ro (SS-A) antibodies.
o Other Rashes: Include recurring urticaria, lichen planus-like dermatitis, bullae, and
panniculitis (lupus profundus).

 Mucosal Ulcerations: Small ulcerations on the oral or nasal mucosa, resembling aphthous
ulcers, which may or may not be painful.

Renal Manifestations:
 Nephritis is one of the most serious manifestations of SLE, being a leading cause of
mortality along with infection in the first decade of disease.
 Regular urinalysis is essential in SLE patients due to often asymptomatic nephritis.
 Renal Biopsy: Recommended for any SLE patient with clinical evidence of nephritis, as it
guides therapy decisions.
 Histologic Classification: Lupus nephritis is classified primarily by histology, especially
using the ISN/RPS classification.

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 Clinical Indicators:
o Microscopic Hematuria and Proteinuria: Common in dangerous proliferative forms
(ISN III and IV), with >500 mg/24 h proteinuria.
o Nephrotic Syndrome: Develops in about half of the patients with proliferative
glomerular damage.
o Hypertension: Common in severe cases.
o Prognosis: ~20% of patients with diffuse proliferative glomerulonephritis (DPGN) in
the U.S. may develop ESRD or die within 10 years.

 Membranous Glomerulopathy: About 20% of patients with proteinuria have this without
proliferative changes; their prognosis is better, but treatment parallels that of proliferative
diseases.

Nervous System Manifestations:

 CNS and peripheral nervous system involvement can be a major cause of morbidity and
mortality in SLE.

 Diagnostic Approach:
o Primary SLE vs. Other Causes: Determine if symptoms are due to SLE or another
condition like infection or drug side effects.
o Diffuse vs. Vascular Disease: Identify whether the CNS involvement is diffuse
(requiring immunosuppression) or due to vascular occlusive disease (requiring
anticoagulation).

 Common CNS Manifestations:

o Cognitive Dysfunction: Includes memory and reasoning difficulties; it is the most
common diffuse CNS manifestation.
o Headaches: Severe headaches may indicate an SLE flare, while milder ones may mimic
migraines or tension headaches.
o Seizures: Can occur in SLE, often requiring both antiseizure and immunosuppressive
treatments.
o Psychosis: May be due to SLE or glucocorticoid-induced, with the latter resolving after
reducing or stopping glucocorticoids.
o Myelopathy: Requires rapid and aggressive immunosuppressive therapy, often with
high-dose glucocorticoids.

Cardiac Manifestations:
 Pericarditis: The most common cardiac issue, generally responding well to anti-
inflammatory treatment. It rarely progresses to tamponade.

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 Myocarditis and Fibrinous Endocarditis (Libman-Sacks Endocarditis):
o Myocarditis: Can lead to left ventricular dysfunction and heart failure, with lupus
patients having a 2.7-fold increased risk of heart failure.
o Endocarditis: Can cause valvular insufficiencies (especially mitral and aortic valves)
and embolic events.
o Arrhythmias: Common among SLE patients.

 SLE patients are at higher risk due to accelerated atherosclerosis, likely from chronic
inflammation, immune attack, and oxidative damage.

Hematologic Manifestations:
 Anemia: Most commonly normochromic normocytic, reflecting chronic disease.
Hemolysis can occur rapidly and severely, requiring high-dose glucocorticoid therapy.
 Leukopenia: Common, typically involving lymphopenia rather than granulocytopenia.
This rarely leads to infections or requires treatment.
 Thrombocytopenia: May be recurrent. If platelet counts are above 40,000/μL and there is
no abnormal bleeding, treatment may not be necessary. Severe cases often respond to high-
dose glucocorticoids, but recurrent or prolonged cases may require additional therapies like
rituximab, platelet growth factors, or splenectomy.

Gastrointestinal Manifestations:
 Nausea, vomiting, diarrhea, and diffuse abdominal pain can occur during SLE flares. Liver
enzyme elevations (AST and ALT) are common with active SLE and usually improve with
glucocorticoid therapy.
 Vasculitis: Intestinal vasculitis can be life-threatening, with risks of perforation, ischemia,
bleeding, and sepsis. Aggressive treatment with high-dose glucocorticoids is necessary for
control, with additional immunosuppression required if recurrence occurs.

Ocular Manifestations:
 Sicca Syndrome and Conjunctivitis: Common but generally not vision-threatening.
 Retinal vasculitis and optic neuritis can lead to blindness within days to weeks. These
conditions require aggressive immunosuppression, although the effectiveness is not well-
established.

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LABORATORY TESTS IN SYSTEMIC LUPUS
ERYTHEMATOSUS (SLE)
Autoantibody Testing
 Antinuclear Antibodies (ANA): Positive in >95% of SLE patients, often from the onset
of symptoms. Negative ANA is rare in adults and may be associated with other
autoantibodies like anti-Ro or anti-DNA.
 Anti-dsDNA: Specific for SLE, with ~60% sensitivity. Levels may rise before a flare,
especially in nephritis or vasculitis, and often correlate with decreased complement levels
(C3, C4).
 Anti-Sm: Specific for SLE but does not correlate with disease activity.
 Antiphospholipid Antibodies: Not specific to SLE but indicate increased risk for clotting
events, thrombocytopenia, and fetal loss. Tests include anticardiolipin, anti-β2-
glycoprotein, and lupus anticoagulant.
 Anti-Ro/SS-A: Predictive value for neonatal lupus, sicca syndrome, and subacute
cutaneous lupus erythematosus (SCLE).
 Anti-C1q: Associated with active lupus nephritis, though not specific or sensitive for SLE.

Standard Diagnostic Tests

 Complete Blood Count (CBC): Detects anemia, leukopenia, and thrombocytopenia.
 Urinalysis: Identifies hematuria and proteinuria, which are important in diagnosing renal
involvement.

Monitoring Disease Course

 Organ Involvement: Regular tests like urinalysis, hemoglobin levels, platelet counts, and
serum creatinine/albumin levels help monitor disease flares and organ damage.

 Markers of Disease Activity:

o Anti-DNA and Anti-C1q Levels: Fluctuate with disease activity, particularly in
nephritis.
o Complement Levels (C3): Decreasing levels may indicate an impending flare.
o Emerging Markers: Research is ongoing for new markers like BLyS, TWEAK,
NGAL, and MCP-1, though none are universally accepted yet.

Cardiovascular Risk
 Given the increased risk of atherosclerosis in SLE, it is recommended to follow guidelines
for cardiovascular risk management, including cholesterol testing and considering SLE as
an independent risk factor similar to diabetes mellitus

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MANAGEMENT OF SYSTEMIC LUPUS
ERYTHEMATOSUS (SLE)
Goals of Treatment
 SLE has no cure, and complete, sustained remissions are rare.

 Low-Level Disease Activity (LLDAS): Aim for LLDAS, meaning mild symptoms
managed with the lowest possible doses of medications.
o LLDAS Criteria:
1. SLEDAI-2K Score ≤4: The Systemic Lupus Erythematosus Disease Activity
Index-2K (SLEDAI-2K) is a widely used measure of disease activity. Scores >3
reflect clinically active disease.
2. No New Lupus Activity: Compared with the previous visit.
3. Physician’s Global Assessment ≤1: On a scale of 0–3.
4. Prednisone Dose ≤7.5 mg/day: To minimize steroid-related side effects.
5. Stable Doses of Antimalarials/Immunosuppressives: Well-tolerated doses should
be maintained.

Long-Term Outcomes
 LLDAS Achievement: Achieved in 50–80% of patients, with ~30% maintaining LLDAS
for 2 or more years. This is associated with significantly less organ damage and a better
quality of life.

 Therapeutic Strategy:
1. Acute Flares: Induce improvement.
2. Maintenance: Use strategies to suppress symptoms to an acceptable level and prevent
organ damage.
3. Chronic Prednisone: Taper to the lowest dose possible, ideally ≤7.5 mg/day.

CONSERVATIVE THERAPIES FOR

MANAGEMENT OF NON-LIFE-THREATENING
SLE
Analgesics and Antimalarials
1. NSAIDs:
o Uses: Effective for arthritis and arthralgias.
o Risks:
 Increased risk of NSAID-induced aseptic meningitis, elevated serum transaminases,
hypertension, and renal dysfunction.

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  Higher risk of myocardial infarction, especially with COX-2 inhibitors.
o Acetaminophen can be used for pain control but may be less effective than NSAIDs.
Relative hazards compared to low-dose glucocorticoid therapy are not well established.

2. Antimalarials:
o Hydroxychloroquine: Reduces disease symptoms, prolongs survival, and reduces
accrual of tissue damage, including renal damage.
 Optimal Dosage: Aim for hydroxychloroquine blood level of ≥750 ng/mL. Doses
should be reduced after response is achieved.
 Retinal Toxicity: Occurs in ~6% of patients after cumulative doses of 1000 g
(approximately 5 years). Annual ophthalmologic examinations are recommended.
o Chloroquine and Quinacrine: Alternatives to hydroxychloroquine with similar
effects.

3. Dehydroepiandrosterone (DHEA):
o Use: Reduces activity of mild disease.
o Considerations: Evaluate effectiveness on a case-by-case basis.

Biologics
1. Belimumab (Anti-Baff):
o Effective for persistent disease activity and fatigue despite standard therapies.
o Indicators for Use: Most effective in patients with robust clinical activity (SLEDAI-
2K score of ≥10), positive anti-DNA, and low serum complement.

2. Anifrolumab (Anti-IFN Type 1 Receptor):

o Highly effective in patients with lupus dermatitis.

Lupus Dermatitis Management

1. Topical Treatments:
o Sunscreens: Essential for protection from UV exposure.
o Topical Glucocorticoids: For inflammation control.
o Topical Tacrolimus: Alternative for dermatitis.

2. Systemic Treatments:
o Systemic Glucocorticoids: For severe or unresponsive cases.
o Additional Agents: Mycophenolate mofetil, azathioprine, methotrexate, or
belimumab.

3. Anifrolumab: Particularly effective for lupus dermatitis when conventional treatments are
insufficient.

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Drugs in SLE

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Pregnancy in Systemic Lupus Erythematosus (SLE):
1. Fertility and Pregnancy Outcomes:
o Fertility rates in men and women with SLE are generally normal.
o Women with SLE face an increased risk of fetal loss (2-3 times higher).

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 o Higher risks of fetal demise are associated with high disease activity, antiphospholipid
antibodies (especially lupus anticoagulant), hypertension, and active nephritis.

2. Disease Management:
o Systemic glucocorticoids can help suppress disease activity, but care must be taken
with their use during pregnancy.
o 11-β-dehydrogenase 2, a placental enzyme, deactivates glucocorticoids more
effectively than dexamethasone or betamethasone, so fluorinated steroids should be
avoided during pregnancy.
o Potential adverse effects of prenatal glucocorticoids (especially betamethasone) include
low birth weight, CNS developmental abnormalities, and a predisposition to adult
metabolic syndrome.

3. Medication Safety Categories:

o FDA Category "Fetal Risk Cannot Be Ruled Out": Hydroxychloroquine,
belimumab, cyclosporine.
o FDA Category "May Cause Fetal Harm": Rituximab, azathioprine,
cyclophosphamide, tacrolimus, voclosporin.
o FDA Category "Fetal Risk Has Been Demonstrated" or "Avoid in Pregnancy":
Methotrexate, mycophenolate.

4. Recommended Treatment:
o Hydroxychloroquine and, if needed, prednisone/prednisolone at the lowest effective
doses for the shortest duration.
o Azathioprine may be added if disease activity is not adequately controlled with
hydroxychloroquine and glucocorticoids.
o Breastfeeding: Medications may pass into breast milk; consider not breastfeeding if
treatment is required.

5. Antiphospholipid Syndrome:
o For patients with antiphospholipid antibodies and previous fetal losses, heparin
(usually low-molecular-weight) plus low-dose aspirin significantly increases live birth
rates.
o Aspirin alone is less effective compared to heparin-plus-aspirin.
o Warfarin is teratogenic and direct oral anticoagulants are generally avoided due to lack
of safety data.

6. Anti-Ro Antibodies:
o Antibodies to Ro can cause neonatal lupus, including rash and/or congenital heart
block. Cardiac manifestations can be severe and life-threatening.
o Hydroxychloroquine can reduce the risk of heart block in subsequent pregnancies if
the mother is anti-Ro-positive.
o Dexamethasone may help prevent progression of heart block if detected in utero.

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7. Pregnancy Management:
o Most women with SLE tolerate pregnancy well without disease flares.
o A small proportion may experience severe flares requiring aggressive glucocorticoid
therapy or early delivery.

1. Antiphospholipid Syndrome (APS) in SLE:

 SLE patients with venous or arterial clotting, repeated fetal losses, and at least two
positive antiphospholipid antibody tests are diagnosed with APS.
 Anticoagulation:
o Warfarin:
 INR target of 2.0–2.5 for one episode of venous clotting.
 INR target of 3.0–3.5 for recurring clots or arterial clotting, especially in the
CNS.
o Direct Oral Anticoagulants: Not effective and not recommended in APS.

2. Microvascular Thrombotic Crisis:

 Includes Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic-Uremic
Syndrome (HUS), characterized by hemolysis, thrombocytopenia, and microvascular
thrombosis in multiple organs.
 Management:
o Plasma Exchange/Plasmapheresis: Often life-saving.
o Glucocorticoids: Recommended alongside plasmapheresis.
o Rituximab/Eculizumab: Used in refractory cases; Eculizumab inhibits C5.
o Cytotoxic Drugs: No evidence of benefit.

3. Lupus Dermatitis:
 Sun Protection: Minimize UV exposure using SPF 30+ sunscreens and protective
clothing.
 Topical Treatments:
o Glucocorticoids: Effective and relatively safe.
o Antimalarials: Hydroxychloroquine is commonly used.
 Additional Therapies:
o Methotrexate, Azathioprine, Mycophenolate: May be effective in some cases.
o Belimumab, Anifrolumab: Can be effective for resistant cases.
 Systemic Treatments:
o Retinoic Acid: Effective but has severe potential side effects (including fetal
abnormalities); stringent reporting required.
 For Severe or Therapy-Resistant Dermatitis:
o Topical Tacrolimus: Caution due to potential malignancy risk.
o Systemic Dapsone or Thalidomide/Lenalidomide: Effective but with significant
side effects (e.g., fetal deformities, peripheral neuropathy).

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Drugs commonly associated with drug-induced lupus (DIL):
1. Procainamide
2. Disopyramide
3. Propafenone
4. Hydralazine
5. ACE Inhibitors (e.g., Enalapril, Lisinopril)
6. Beta Blockers (e.g., Metoprolol, Atenolol)
7. Propylthiouracil
8. Chlorpromazine
9. Lithium
10. Carbamazepine
11. Phenytoin
12. Isoniazid
13. Minocycline
14. Nitrofurantoin
15. Sulfasalazine
16. Hydrochlorothiazide
17. Lovastatin
18. Simvastatin
19. Biologics (e.g., Inhibitors of IFNs, TNF inhibitors)

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 Systemic Sclerosis
– Oct 23, June 22, Dec 21, June 19
An orphan disease with unknown aetiology, complex pathogenesis, and variable clinical
presentations. It often has a progressive course, significant disability, and high mortality.
SSc patients show variability in skin involvement, organ complications, disease progression,
treatment response, severity, and survival.
Early stages involve inflammation; later stages show vascular and visceral organ fibrosis and
dysfunction.
Skin Involvement: Thickened and indurated skin (scleroderma) is a hallmark of SSc, but
similar skin changes can occur in other conditions.

Subtypes:
 Diffuse Cutaneous SSc (dcSSc): Extensive skin induration starting at fingers
(sclerodactyly) and moving proximally. Early progressive skin disease, interstitial lung
disease (ILD), and sometimes acute renal involvement.
 Limited Cutaneous SSc (lcSSc): Raynaud’s phenomenon precedes sclerodactyly, with
skin involvement limited to fingers, distal limbs, and face. The trunk is spared. Associated
with CREST syndrome (Calcinosis, Raynaud’s, Esophageal dysmotility, Sclerodactyly,
Telangiectasia) and late complications like PAH, hypothyroidism, Sjogren’s, and primary
biliary cirrhosis.
 SSc Sine Scleroderma: Raynaud’s and SSc features without skin thickening; relatively
benign.

Incidence and Prevalence:

 SSc is sporadic, worldwide, and affects all races.
 Incidence and prevalence vary by region, influenced by case definition, environmental
exposures, and genetic factors.
 Female predominance (4.6:1), particularly during childbearing years, decreasing post-
menopause.
 First-degree relatives have a 13-fold increased risk.
 Onset typically at 65–74 years in women; earlier onset and worse prognosis in blacks, with
more diffuse cutaneous disease and ILD.

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Environmental and Occupational Exposures:
 The exact cause of SSc is unknown, but environmental factors are believed to play a major
role due to the modest genetic contribution. Potential environmental triggers include
infectious agents, occupational exposures, dietary factors, lifestyle, and drug exposures.

 Infectious Agents: Possible pathogenic roles have been suggested for:

o Viruses: Parvovirus B19, Epstein-Barr virus (EBV), and cytomegalovirus (CMV).
o Fungus: Rhodotorula glutinis.

 Toxic Epidemic Syndromes:

o Toxic Oil Syndrome: An epidemic in Spain linked to contaminated rapeseed oil,
presenting features similar to SSc.
o Eosinophilia-Myalgia Syndrome (EMS): An epidemic in the U.S. linked to L-
tryptophan-containing dietary supplements.
o Nephrogenic Systemic Fibrosis: Associated with gadolinium contrast material in
individuals with compromised renal function undergoing MRI.

 Occupational Exposures: Substances tentatively linked with SSc include:

o Particulate Silica (Quartz)
o Polyvinyl Chloride
o Epoxy Resins
o Welding Fumes
o Organic Solvents and Aromatic Hydrocarbons: Including paint thinners, toluene,
xylene, and trichloroethylene.

 Epigenetic Modifications: Environmental exposures may cause cell-specific stable and

heritable epigenetic modifications, such as DNA methylation and histone modification,
which may drive pathogenic alterations in gene expression. These modifications are
potentially reversible, representing targets for therapy.

 Drugs Linked to SSc-like Illnesses:

o Bleomycin
o Pentazocine
o Cocaine
o Appetite Suppressants: Associated with pulmonary arterial hypertension (PAH).
o Immune Checkpoint Inhibitors: PD-1 blockers used in cancer therapy.
o Radiation Therapy: Linked to the de novo onset of SSc and exacerbation of
preexisting SSc.

 Other Exposures:
o Silicone Breast Implants: Initially suspected to be linked with SSc, but large-scale
epidemiologic studies found no evidence of increased prevalence.

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 o Cigarette Smoking: Unlike in rheumatoid arthritis, smoking does not increase the risk
of SSc.

Pathogenesis:
 Overview: SSc pathogenesis involves environmental triggers that cause epigenetic changes
in genetically predisposed individuals, leading to changes in gene expression and the
behavior of multiple cell types.

 Cardinal Pathomechanistic Processes:

1. Diffuse Microangiopathy
2. Inflammation and Autoimmunity
3. Visceral and Vascular Fibrosis: Affecting multiple organs.

 Disease Progression:
o Early Stages: Dominated by autoimmunity and reversible vascular reactivity.
o Later Stages: Characterized by fibrosis and atrophy.

Pathogenesis of systemic sclerosis (SSc):

 Vascular Insult: In genetically predisposed individuals, an initial vascular insult triggers
functional and structural vascular changes associated with inflammation and autoimmunity.
 Immune Response: The early immune response activates and differentiates fibroblasts,
leading to sustained pathological fibrogenesis.
 Fibrosis and Tissue Damage: This fibroblast activity results in irreversible tissue damage,
progressive fibrosis, and ultimately, organ failure.
 Tissue Ischemia: Vascular damage causes tissue ischemia, further driving progressive
fibrosis and atrophy.

 Key Factors and Processes:

o Ab: Antibody
o CTGF: Connective tissue growth factor
o ECM: Extracellular matrix
o EndoMT: Endothelial-mesenchymal transition
o GIT: Gastrointestinal tract
o IFN: Interferon
o IL: Interleukin
o PDGF: Platelet-derived growth factor
o TGF-β: Transforming growth factor β
o TLR: Toll-like receptor

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Pathology of systemic sclerosis (SSc):
 Widespread Microangiopathy: The hallmark of SSc across all organ systems is
fibroproliferative vasculopathy, which involves capillary loss and obliteration.
 Perivascular Inflammation: In the early stages, perivascular inflammatory cell infiltrates,
including T and B lymphocytes, activated monocytes, macrophages, and mast cells, can be
detected in multiple organs.

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 Noninflammatory Obliterative Microangiopathy: In the late stages of the disease,
noninflammatory obliterative microangiopathy is prominent in organs such as the heart,
lungs, kidneys, and gastrointestinal tract.
 Fibrosis: SSc is characterized by significant fibrosis, which affects the skin, lungs,
cardiovascular system, gastrointestinal tract, tendon sheaths, perifascicular tissue around
skeletal muscle, and certain endocrine organs like the thyroid gland.
 Collagen and Matrix Accumulation: The excessive buildup of collagens and other
structural matrix macromolecules leads to a disruption of normal tissue architecture,
ultimately resulting in impaired function and organ failure.

Clinical features of systemic sclerosis (SSc):

 Systemic Involvement: SSc is a systemic disease that can affect virtually any organ.
 Subsets and Endophenotypes: Although SSc is often classified into diffuse cutaneous
(dcSSc) and limited cutaneous (lcSSc) subsets, the disease is complex, with multiple
distinct endophenotypes that have characteristic manifestations, trajectories, and outcomes.
 Overlap Syndromes: Patients may present with features of SSc along with another
autoimmune disease such as polymyositis, Sjögren's syndrome, polyarthritis, autoimmune
liver disease, or systemic lupus erythematosus (SLE).

INITIAL CLINICAL PRESENTATION:

Diffuse Cutaneous Systemic Sclerosis (dcSSc):
 Raynaud’s Phenomenon: The interval between the onset of Raynaud’s phenomenon and
other manifestations is typically brief (weeks to months).
 Early Signs: Soft tissue swelling, puffy fingers, and pruritus are early signs, occurring
during the inflammatory "edematous" phase.
 Skin Involvement: The skin becomes diffusely hyperpigmented, with the face, fingers,
and distal limbs being affected first. The disease progresses from an edematous phase to a
fibrotic phase with skin induration, hair loss, reduced skin oil production, and decreased
sweating.
 Joint and Muscle Involvement: There may be arthralgias, muscle weakness, fatigue, and
decreased joint mobility. Progressive flexion contractures of the fingers and stiffness in
joints (wrists, elbows, knees, and ankles) may occur due to fibrosis.
 Internal Organ Involvement: The first 4 years from onset is critical, with rapidly evolving
lung and renal damage. If organ failure does not occur during this phase, the disease may
stabilize.

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Limited Cutaneous Systemic Sclerosis (lcSSc):
 Raynaud’s Phenomenon: The interval between Raynaud’s phenomenon and other disease
manifestations can be prolonged, often years.
 Course: The course is more indolent compared to dcSSc.
 Common Manifestations: GERD, cutaneous telangiectasia, ischemic digital ulcers, and
soft tissue calcifications may develop over time.
 Rare Complications: Scleroderma renal crisis, significant ILD, and tendon friction rubs
are rare. However, PAH and overlap with conditions like keratoconjunctivitis sicca,
polyarthritis, cutaneous vasculitis, and biliary cirrhosis can develop, even years after
disease onset.

Raynaud’s Phenomenon in Systemic Sclerosis (SSc):

 Raynaud’s phenomenon is the most common extracutaneous complication of SSc,
characterized by episodic vasoconstriction primarily affecting the fingers and toes, and
occasionally the tip of the nose and earlobes.
 Triggers: These episodes are typically triggered by cold, emotional stress, and vibration.

 Phases:
1. Pallor: The initial phase due to vasoconstriction.
2. Cyanosis: Caused by ischemia of variable duration.
3. Hyperemia: Occurs spontaneously or with rewarming, reflecting reperfusion.

Primary vs. Secondary Raynaud’s Phenomenon:

 Primary Raynaud’s Disease:
o Occurs without any underlying condition and is an exaggerated physiological response
to cold.
o Common in the general population (up to 5%).
o Typically presents with no associated tissue necrosis or ulceration.
o Negative ANA test is common.
o Often has a family history of Raynaud’s phenomenon.

 Secondary Raynaud’s Phenomenon:

o Occurs in association with SSc, other connective tissue diseases, hematologic and
endocrine disorders, occupational exposures, and some medications (e.g., beta-
blockers, cisplatin, bleomycin).
o More severe with frequent, prolonged, and painful episodes.
o Complications include ischemic digital ulcers and potential loss of digits.
o Typically presents at an older age compared to primary Raynaud’s.

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Diagnostic Tools:
 Nailfold Capillaroscopy:
o Used to differentiate between primary and secondary Raynaud’s phenomenon.
o Primary Raynaud’s Disease: Shows evenly spaced, parallel vascular loops.
o Secondary Raynaud’s Phenomenon: Displays distorted capillaries with widened and
irregular loops, dilated lumen, microhemorrhages, and areas of vascular dropout.

SKIN FEATURES IN SYSTEMIC SCLEROSIS (SSC):

 Hallmark: Bilateral symmetrical skin thickening, beginning in the fingers and progressing
proximally, is a distinguishing feature of SSc.

Initial Signs:
 Diffuse Tanning: Early sign, even without sun exposure.
 Vitiligo-like Hypopigmentation: May occur in dark-skinned individuals.
 Salt-and-Pepper Appearance: Resulting from pigment loss sparing the perifollicular
areas, commonly seen on the scalp, upper back, and chest.

Progressive Changes:
 Dermal Sclerosis: Leads to hair loss, decreased sweating, xerosis (dryness), and itching.
Transverse creases on the dorsum of fingers may disappear.

 Contractures and Fibrosis:

o Fingers: Fixed flexion contractures reduce hand mobility, leading to muscle atrophy.
o Wrists, Elbows, Knees: Fibrosis causes fixed contractures in these joints.
o Neck: Thick ridges and firm adherence of skin to the underlying platysma muscle can
interfere with neck extension.

Facial Features:
 Mauskopf Appearance: Characterized by taut, shiny skin, loss of wrinkles, and
expressionless facies due to reduced mobility of the eyelids, cheeks, and mouth.
 Microstomia: Reduced oral aperture, interfering with eating and oral hygiene.
 Nose: Beak-like, pinched appearance.
 Late-Stage: Skin becomes thin, atrophic, and tethered to subcutaneous fat. Prominent
perioral radial furrowing (rhytides) and thinning of the lips are common.

Vascular Manifestations:
 Telangiectasia: Dilated skin capillaries (2–20 mm in diameter) frequently appear on the
face, hands, lips, and oral mucosa. The number of telangiectasias correlates with the
severity of microvascular disease, including pulmonary arterial hypertension (PAH).

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 Chronic Ulcerations: Occur at extensor surfaces of proximal interphalangeal joints, volar
pads of the fingertips, and bony prominences like elbows and malleoli, often painful and
slow-healing, with potential for secondary infections and osteomyelitis.
 Acro-Osteolysis: Resorption of terminal phalanges associated with ischemic soft tissue
loss at the fingertips, leading to fixed digital "pits."

Calcinosis Cutis:
 Occurrence: Found in up to 40% of patients, particularly those with long-standing anti-
centromere antibody-positive lcSSc.
 Nature: Composed of calcium hydroxyapatite crystals, these dystrophic calcifications vary
in size and can be visualized on radiographs or dual-energy CT.
 Locations: Finger pads, palms, extensor surfaces of the forearms, olecranon, and
prepatellar bursae are common sites.
 Complications: Large deposits may cause pain, nerve compression, and ulceration, leading
to secondary infections. Paraspinal sheet calcifications can cause neurologic complications.

PULMONARY FEATURES IN SYSTEMIC

SCLEROSIS (SSC):
1. Interstitial Lung Disease (ILD):
 ILD can be detected in up to 65% of SSc patients via high-resolution computed
tomography (HRCT), with clinically significant ILD developing in 16–43% of cases.
 Risk Factors:
o Male sex
o African-American race
o Diffuse skin involvement
o Severe gastroesophageal reflux
o Presence of topoisomerase-I (Scl-70) autoantibodies
o Low forced vital capacity (FVC) or diffusing capacity for carbon monoxide (DLCO) at
initial presentation
 Clinical Course: The most rapid progression occurs within the first 3–5 years of
disease, with FVC potentially declining by 30% annually.
 Symptoms: Subtle and slowly progressive, including exertional dyspnea, fatigue,
reduced exercise tolerance, and chronic dry cough. Physical examination may reveal
fine inspiratory "Velcro" crackles at the lung bases.
 Diagnosis:
o Pulmonary Function Testing (PFT): Shows restrictive ventilatory defect and
reduced DLCO.

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 o Imaging: HRCT is more sensitive than chest radiography and typically shows
lower lobe subpleural reticular opacities, ground-glass opacifications, traction
bronchiectasis, and possibly honeycomb changes.
o Bronchoalveolar Lavage (BAL): May show inflammatory cells but is not useful
for SSc diagnosis.
o Lung Biopsy: Indicated only for atypical imaging findings; the histologic pattern
may predict ILD progression.

2. Pulmonary Arterial Hypertension (PAH):

 PAH develops in 8–12% of SSc patients, often as a late complication and can occur in
isolation or with ILD.
 Mean pulmonary artery pressure ≥20 mmHg with pulmonary capillary wedge pressure
≤15 mmHg and pulmonary vascular resistance >3 Wood units.
 Clinical Course: PAH often progresses to right heart failure, with a 3-year survival
rate of less than 50% if untreated.
 Risk Factors:
o Limited cutaneous disease
o Older age at disease onset
o High number of cutaneous telangiectasias

o Presence of centromere, U3-RNP (fibrillarin), and B23 antibodies

 Symptoms: Initially asymptomatic, progressing to exertional dyspnea, reduced
exercise capacity, angina, near-syncope, and signs of right-sided heart failure.
 Diagnosis:
o Physical Examination: May reveal tachypnea, a loud pulmonic component of S2,
murmurs, right ventricular heave, elevated jugular venous pressure, and edema.
o Doppler Echocardiography: Non-invasive screening method; elevated pulmonary
artery systolic pressure >40 mmHg or tricuspid regurgitation jet velocities >3 m/s
suggest PAH.
o Pulmonary Function Testing (PFT): Reduced DLCO may indicate PAH.
o Cardiac Catheterization: Required to confirm PAH diagnosis, assess severity,
rule out other causes, and provide prognostic parameters.
o Serum NT-proBNP: Correlates with PAH presence, severity, and survival but is
not specific for PAH.

3. Other Pulmonary Complications:

 Aspiration Pneumonitis: Related to chronic gastroesophageal reflux.
 Pulmonary Hemorrhage: Can occur due to endobronchial telangiectasia.

 Other Conditions:
o Obliterative bronchiolitis
o Pleural reactions
o Restrictive physiology due to chest wall fibrosis
o Spontaneous pneumothorax

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 o Drug-induced lung toxicity
 Lung Cancer: Increased incidence in SSc patients.

Gastrointestinal Involvement in Systemic Sclerosis (SSc):

 Up to 90% of SSc patients experience gastrointestinal (GI) involvement, which can affect
any part of the GI tract. This is common in both limited and diffuse cutaneous SSc.
 Pathology: GI involvement is characterized by fibrosis, smooth muscle atrophy, and
obliterative small vessel vasculopathy throughout the GI tract, leading to significant
impacts on quality of life, malnutrition, and mortality.

1. Upper Gastrointestinal Tract Involvement:

 Oral and Oropharyngeal Manifestations:
o Decreased Oral Aperture: Interferes with dental hygiene.
o Periodontal Disease: Loss of the periodontal ligament leads to teeth loosening.
o Xerostomia: Along with a shortened frenulum and mandibular condyle resorption,
causes significant distress.
 Gastroesophageal Reflux Disease (GERD):
o Symptoms: Heartburn, regurgitation, and dysphagia due to reduced lower
esophageal sphincter pressure, diminished esophageal motility, and delayed gastric
emptying.
o Exacerbating Factors: Calcium channel blockers and phosphodiesterase inhibitors
used for Raynaud’s phenomenon may worsen reflux.
o Manometry: Abnormal esophageal motility is common, even in asymptomatic
patients.
o Complications:
 Extraesophageal Manifestations: Hoarseness, cough, and chronic
microaspiration, which can worsen ILD.
 Esophageal Dilation: Associated with ILD severity.
 Endoscopy: Used to rule out infections like Candida and herpes, and to detect
complications like esophageal strictures and Barrett’s esophagus, which
increases the risk of adenocarcinoma.
 Gastroparesis:
o Symptoms: Early satiety, abdominal distention, and aggravated reflux.
o Gastric Antral Vascular Ectasia (GAVE): Also known as "watermelon stomach,"
presents with recurrent GI bleeding and chronic anemia.

2. Lower Gastrointestinal Tract and Anorectal Involvement:

 Malabsorption and Malnutrition:
o Impaired Motility: Leads to malabsorption, chronic diarrhea, and bacterial
overgrowth.

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 o Nutrient Deficiencies: Fat and protein malabsorption, vitamin B12 and D
deficiencies, potentially exacerbated by pancreatic insufficiency.
 Intestinal Pseudo-Obstruction:
o Symptoms: Acute abdominal pain, nausea, vomiting, and signs of acute intestinal
obstruction on radiography.
o Differentiation: Must be distinguished from mechanical obstruction, as pseudo-
obstruction responds to supportive care.
 Colonic Involvement:
o Symptoms: Constipation, sigmoid volvulus, fecal incontinence, GI bleeding from
telangiectasias, and rectal prolapse.
o Complications: In late-stage SSc, wide-mouth sacculations or diverticula in the
colon can cause perforation and bleeding.
 Pneumatosis Cystoides Intestinalis: A rare condition involving air trapping in the
bowel wall, potentially leading to benign pneumoperitoneum.

3. Liver Involvement:
 Primary Biliary Cirrhosis (PBC): Although rare, PBC can occur in SSc, particularly
in patients with limited cutaneous disease.

4. Microbiota Changes:
 Fecal Microbiota: Studies show a reduction in protective butyrate-producing bacteria
in SSc, which may promote a pro-inflammatory intestinal environment.

RENAL INVOLVEMENT IN SYSTEMIC

SCLEROSIS (SSC):
Scleroderma Renal Crisis (SRC):
 Occurs in <15% of SSc patients, typically within 4 years of disease onset. It can be the
presenting manifestation of SSc.
 Prognosis: Historically, short-term survival was <10% before the advent of angiotensin-
converting enzyme (ACE) inhibitors. Outcomes have significantly improved with modern
treatments.

Pathogenesis:
 Vascular Changes: Obliterative vasculopathy of renal arcuate and interlobular arteries
leads to decreased renal blood flow.
 Vicious Cycle: Vasospasm causes reduced blood flow, increased renin and angiotensin II
generation, further renal vasoconstriction, and accelerated hypertension.

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Risk Factors:
 Demographics: African-American race, male sex.
 Disease Characteristics: Diffuse or progressive skin involvement.
 Autoantibodies: Up to 50% of patients with SRC have antibodies to anti-RNA polymerase
III. Patients with anti-centromere antibodies are less likely to develop SRC.

Clinical Presentation:
 Hypertension: Accelerated hypertension (>150/90 mmHg) with progressive oliguric renal
insufficiency. ~10% of patients may have normal blood pressure, which is associated with
poorer outcomes.
 Symptoms: Headache, blurred vision, congestive heart failure, and pulmonary edema may
accompany elevated blood pressure.
 Laboratory Findings:
o Hematology: Moderate thrombocytopenia, microangiopathic hemolysis (fragmented
red blood cells).
o Urinalysis: Mild proteinuria, granular casts, microscopic hematuria.
o Renal Function: Progressive oliguric renal failure typically develops over several
days.

Diagnosis and Differentiation:

 Misdiagnosis: Can be mistaken for thrombotic thrombocytopenic purpura (TTP) or other
forms of thrombotic microangiopathy.

 Diagnostic Aids:
o Renal Biopsy: Helps differentiate from TTP and assesses for vascular thrombosis and
glomerular ischemic collapse.
o Serum Testing: Measurement of von Willebrand factor-cleaving protease activity can
aid in diagnosis.

Management and Outcomes:

 Blood Pressure Monitoring: High-risk patients with early-stage SSc should monitor blood
pressure daily.
 Glucocorticoids: Use of prednisone is associated with SRC; it should be used cautiously
and at low doses (<10 mg/d) in high-risk patients.

 Prognostic Indicators:
o Initial Creatinine: Oliguria or creatinine >3 mg/dL at presentation indicates poor
prognosis.
o Renal Biopsy: Vascular thrombosis and glomerular ischemic collapse predict poor
outcomes.

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Other Renal Complications:
 Asymptomatic Renal Impairment: Can occur in up to 50% of SSc patients, often
associated with other vascular manifestations, and rarely progresses to end-stage renal
failure.
 Other Glomerulonephritis Types:
o Crescentic Glomerulonephritis: May be linked to myeloperoxidase-specific
antineutrophil cytoplasmic antibodies (ANCAs).
o Membranous Glomerulonephritis: May occur in patients treated with D-
penicillamine.

CARDIAC INVOLVEMENT IN SYSTEMIC

SCLEROSIS (SSC):
 Cardiac involvement is detected in 10–50% of SSc patients using sensitive diagnostic tools.
It is more frequent in diffuse cutaneous SSc (dcSSc) compared to limited cutaneous SSc
(lcSSc).
 Clinical Impact: Cardiac involvement may be primary or secondary to pulmonary arterial
hypertension (PAH), interstitial lung disease (ILD), or renal issues, and is associated with
poor outcomes.

Types of Cardiac Involvement:

1. Pericardial Involvement:
o Manifestations: Pericarditis, pericardial effusions, constrictive pericarditis, and rarely,
cardiac tamponade.

2. Myocardial Involvement:
o Fibrosis: Patchy myocardial fibrosis due to microvascular involvement, vasospasm,
and ischemia-reperfusion injury.
o Function: Results in systolic or diastolic left ventricular dysfunction, which can
progress to overt heart failure.

3. Endocardial Involvement:
o Conduction System: Fibrosis may lead to heart block. Other arrhythmias include
premature ventricular contractions, atrial fibrillation, and supraventricular tachycardia.

4. Acute or Subacute Myocarditis:

o Diagnosis: Best assessed by cardiac MRI or endomyocardial biopsy.

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Diagnostic Tools:
 Echocardiography: Conventional echocardiography has low sensitivity for preclinical
cardiac involvement.

 Advanced Modalities:
o Tissue Doppler Echocardiography (TDE): Assesses myocardial function.
o Cardiac MRI: Evaluates myocardial fibrosis and function.
o Nuclear Imaging (SPECT): Assesses myocardial perfusion.

 Biomarkers: NT-proBNP levels may indicate cardiac involvement, especially in SSc-

PAH.

Musculoskeletal Complications:
1. Joint and Tendon Involvement:
o Carpal Tunnel Syndrome: May present as an early disease manifestation.
o Arthralgia and Stiffness: Prominent in early disease, with progressive joint mobility
impairment.
o Contractures: Fixed contractures at proximal interphalangeal joints and wrists, with
large joint contractures in dcSSc. Tendon friction rubs are associated with increased
risk for renal and cardiac complications.

2. Muscle Weakness:
o Causes: Deconditioning, disuse atrophy, malnutrition, inflammation, and fibrosis.
o Late-Stage Myopathy: Chronic noninflammatory myopathy with atrophy and fibrosis,
mildly elevated muscle enzymes.

3. Bone Involvement:
o Acro-Osteolysis: Loss of distal tufts of phalanges.
o Osteolysis: Can also affect ribs and distal clavicles, and resorption of mandibular
condyles may cause bite difficulties.

Less Recognized Disease Manifestations:

1. Sicca Complex:
o Symptoms: Dry eyes and dry mouth.
o Biopsy Findings: Fibrosis of minor salivary glands, not focal lymphocytic infiltration
seen in primary Sjögren’s syndrome.

2. Thyroid Issues:
o Hypothyroidism: Common, especially in lcSSc, due to Graves’ or Hashimoto’s
disease.

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3. Neurological Involvement:
o Trigeminal Neuropathy: Unilateral or bilateral sensory neuropathy.

4. Erectile Dysfunction:
o Cause: Vascular insufficiency and fibrosis of corporeal smooth muscle.
o Impact: Poor response to medical therapy and affects sexual performance in women as
well.

5. Pregnancy:
o Risks: Higher risk of adverse fetal outcomes and worsening cardiopulmonary
involvement. New onset of scleroderma renal crisis can occur during pregnancy.

Cancer Risk:
 Increased Risk: Epidemiological studies suggest increased cancer risk in SSc.
o Associated Cancers: Lung cancer and esophageal adenocarcinoma are linked to long-
standing ILD or GERD.
o Paraneoplastic Syndrome: SSc may act as a paraneoplastic syndrome, particularly in
patients with autoantibodies to RNA polymerase III, where it may be triggered by an
antitumor immune response.

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LABORATORY EVALUATION AND BIOMARKERS
IN SYSTEMIC SCLEROSIS (SSC):
Anemia Types:
1. Microcytic Anemia:
o Recurrent GI bleeding (e.g., GAVE), chronic esophagitis.

2. Macrocytic Anemia:
o Folate and vitamin B12 deficiency due to small-bowel bacterial overgrowth or
malabsorption, or due to drugs like methotrexate.

3. Microangiopathic Hemolytic Anemia:

o Characteristics: Mechanical fragmentation of red blood cells in microvessels coated
with fibrin or platelet thrombi, a hallmark of scleroderma renal crisis.

4. Erythrocyte Sedimentation Rate (ESR):

o Typical Findings: Generally normal in SSc. An elevated ESR may indicate coexisting
myositis or malignancy.

Autoantibodies:
1. Antinuclear Antibodies (ANA):
o Presence: Detected in almost all SSc patients.

2. Anti-Topoisomerase I (Scl-70) Antibodies:

o Association: Increased risk of interstitial lung disease (ILD) and poor outcomes.

3. Anti-Centromere Antibodies:
o Association: Pulmonary arterial hypertension (PAH); infrequently associated with
significant cardiac, pulmonary, or renal involvement.

4. Antibodies Indicated by Immunofluorescence Patterns:

o Nucleolar Pattern: May indicate antibodies to U3-RNP (fibrillarin), Th/To, or PM/Scl.
o Speckled Pattern: Indicates antibodies to RNA polymerase III, associated with
increased risk of scleroderma renal crisis and malignancy.

Diagnosis, Staging, and Monitoring:

1. Diagnosis:
o Clinical Grounds: Based on clinical presentation and skin findings.
o Diagnostic Criteria: Highly specific and sensitive for SSc; skin induration with
characteristic patterns and visceral organ manifestations.

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2. Early-Stage Diagnosis:
o Challenges: Initial symptoms may be nonspecific, and Raynaud’s phenomenon may
be absent.
o Initial Symptoms: May include upper extremity edema and puffy fingers.
o Misdiagnosis: May be confused with arthritis, SLE, myositis, or undifferentiated
connective tissue disease.

3. SSc-Specific Autoantibodies:
o Diagnostic Certainty: High degree of certainty when paired with Raynaud’s
phenomenon, fingertip ulcerations, telangiectasia, distal esophageal dysmotility, ILD,
PAH, or accelerated hypertension with renal failure.

4. Screening and Monitoring:

o Initial Screening: Patients with new diagnosis of SSc should be screened for ILD.
o Regular Monitoring: Pulmonary function should be monitored regularly for several
years to assess progression.

MANAGEMENT OF SYSTEMIC SCLEROSIS (SSC):

General Principles:
 No Significant Disease-Altering Therapies: While no treatment has been shown to
significantly alter the natural history of SSc, interventions can alleviate symptoms, slow
organ damage, and reduce disability.

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 Precision Medicine Approach: Care should be tailored to each patient's unique needs,
involving:
o Prompt and accurate diagnosis
o Patient subclassification and risk stratification
o Early recognition of organ-based complications
o Regular monitoring and adjusting therapy
o Patient education and empowerment

 Multidisciplinary Approach: Coordination with various specialists is crucial for

comprehensive management.

Disease-Modifying Therapy:
1. Immunosuppressive Agents:
o Glucocorticoids: Alleviate stiffness and aching but do not alter progression of skin or
internal organ involvement. Risk of scleroderma renal crisis limits use.
o Cyclophosphamide: Effective for SSc-associated ILD, with potential benefits in
pulmonary function and skin induration. Associated with significant toxicities.
o Methotrexate: Modest effect on skin involvement.
o Mycophenolate Mofetil: Improves skin induration and ILD; well-tolerated.
o Tocilizumab: Monoclonal antibody targeting IL-6 receptor, beneficial for skin and
lung involvement.
o Rituximab: Monoclonal antibody against CD20, with some support in trials.
o Other Agents: Limited evidence for cyclosporine, azathioprine, hydroxychloroquine,
thalidomide, and rapamycin. Intensive immune ablation with HSCT has shown durable
remission but is associated with high morbidity, mortality, and cost.

2. Antifibrotic Therapy:
o D-Penicillamine: Previous studies suggested benefit, but recent trials did not show a
difference in skin involvement.
o Nintedanib: Tyrosine kinase inhibitor that slows loss of lung function in SSc-ILD.

3. Vascular Therapy:
o Raynaud’s Phenomenon:
 Preventive Measures: Dress warmly, minimize cold exposure.
 Medications: Extended-release calcium channel blockers (e.g., amlodipine,
nifedipine), diltiazem, and angiotensin II receptor blockers (e.g., losartan).
 Adjunctive Therapies: α1-adrenergic blockers (e.g., prazosin), phosphodiesterase-
5 inhibitors (e.g., sildenafil), topical nitroglycerin, and IV prostaglandins.
 For Ischemic Ulcers: Endothelin-1 receptor antagonist bosentan; digital
sympathectomy and botulinum type A (Botox) for severe ischemia.
o Platelet Aggregation Prevention: Low-dose aspirin and dipyridamole.

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4. Cardiac Complications:
o Rate Control: Nondihydropyridine calcium channel blockers for atrial arrhythmias;
carvedilol for improving myocardial perfusion and systolic function.
o Avoidance: Selective beta blockers (e.g., metoprolol) may precipitate vasospasm.

Monitoring and Follow-Up:

 Regular Monitoring: For disease progression, new complications, and response to
therapy.
 Patient Education: Empower patients with knowledge about complications, therapeutic
options, and ongoing management.

TREATMENT OF SYSTEMIC SCLEROSIS (SSC)-

ASSOCIATED INTERSTITIAL LUNG DISEASE
(ILD):
Management of ILD:
 Identification of High-Risk Patients:
o Risk Factors for Progression: Male sex, older age at onset, progressive skin
involvement, and myocardial disease.
o Perform pulmonary function tests (PFTs) every 6 months. Serial HRCT imaging is
generally not recommended.

 Treatment Options:
o Cyclophosphamide: Administered orally or intravenously for 6–12 months. It can
slow the decline in lung function and improve respiratory symptoms, but it has a higher
risk of side effects.
o Mycophenolate Mofetil: Effective in slowing lung function decline and improving
symptoms. Better tolerated compared to cyclophosphamide.
o Nintedanib: An antifibrotic agent recently approved for SSc-associated ILD. Its
efficacy and optimal duration are still under investigation.
o Lung Transplantation: Considered in cases with progressive ILD despite medical
therapy. GERD is a significant concern as it may contribute to organ rejection.
Recurrence of SSc-ILD in transplanted lungs has not been reported.

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MANAGEMENT OF GASTROINTESTINAL
COMPLICATIONS:
Oral Care:
 Regular Dental Care: Essential due to common oral problems such as decreased oral
aperture, decreased saliva production, gum recession, and periodontal disease.

Gastroesophageal Reflux (GERD):

 Lifestyle Modifications:
o Elevate the head of the bed.
o Eat frequent small meals.
o Avoid alcohol, caffeine, known reflux triggers, and large meals before bedtime.

 Medications:
o Proton Pump Inhibitors (PPIs): May need to be given in high doses to reduce acid
reflux.
o Prokinetic Agents: Metoclopramide, erythromycin, and domperidone can be used but
may have side effects.

 Botulinum Toxin: Can help with impaired gastric emptying.

 Antireflux Procedures: Nissen fundoplication should generally be avoided due to the risk
of secondary achalasia.

GAVE (Gastric Antral Vascular Ectasia):

 Treatment: Endoscopic ablation using laser or argon plasma photocoagulation, though
recurrences are common.

Small Intestinal Complications:

 Small Bowel Bacterial Overgrowth: Causes bloating, diarrhea, and malabsorption. Short
courses of broad-spectrum antibiotics like metronidazole, erythromycin, or rifaximin can
be effective.
 Small Bowel Hypomotility: Octreotide may improve symptoms, but pseudo-obstruction
can be challenging to manage.

Fecal Incontinence:
 Management Options: Antidiarrheal medications, biofeedback, sphincter augmentation,
and sacral neuromodulation can be considered.

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Malnutrition:
 Assessment: Routine evaluation for potential malnutrition is necessary, and enteral feeding
or decompression via percutaneous gastrostomy or jejunostomy may be required in severe
cases.

TREATMENT OF PULMONARY ARTERIAL

HYPERTENSION (PAH) IN SYSTEMIC SCLEROSIS
(SSC):
Screening and Diagnosis:
 Regular Screening: Given the poor prognosis and asymptomatic nature until advanced
stages, screen SSc patients at initial evaluation and periodically thereafter.

Treatment Options:
 Initial Therapies:
o Endothelin-1 Receptor Antagonists: Bosentan.
o Phosphodiesterase-5 Inhibitors: Sildenafil.

 Recent Additions:
o Riociguat: A soluble guanylate cyclase stimulator that increases nitric oxide
production.
o Selexipag: A selective IP prostacyclin receptor agonist that improves PAH symptoms
and survival.

 Adjunctive Medications:
o Diuretics: To manage fluid retention.
o Digoxin: For heart failure symptoms.
o Supplemental Oxygen: Prescribed for documented hypoxemia to avoid secondary
pulmonary vasoconstriction.

 Advanced Therapies:
o Prostacyclin Analogues:
 Epoprostenol and Treprostinil can be administered by continuous IV, SC
infusion, or nebulized inhalations.
o Combination Therapy: Often necessary, using agents from different classes to act
additively or synergistically.

 Lung Transplantation: Considered for patients with PAH unresponsive to medical

therapy. Two-year survival rates (64%) are comparable to idiopathic ILD or PAH.

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MANAGEMENT OF SCLERODERMA RENAL
CRISIS:
Preventive Measures:
 High-risk patients should monitor blood pressure daily and report significant changes.
 Avoid nephrotoxic drugs and use glucocorticoids only if necessary and at low doses.

Treatment:
 Initial Therapy: Immediate hospitalization and prompt initiation of short-acting ACE
inhibitors to rapidly normalize blood pressure.

 Additional Agents: If hypertension persists, consider:

o Angiotensin II Receptor Blockers
o Calcium Channel Blockers
o Endothelin-1 Receptor Blockers
o Prostacyclins
o Direct Renin Inhibitors
o Eculizumab: May be considered due to evidence of intrarenal complement activation.

 Dialysis and Transplantation:

o Dialysis: Required in up to two-thirds of cases; renal replacement therapy can often be
discontinued in 30-50% of patients.
o Kidney Transplantation: Appropriate for those unable to discontinue dialysis after 2
years. Survival rates are comparable to other diseases, with rare recurrence of renal
crisis.

SKIN CARE:
Management Strategies:
 Inflammatory Symptoms: Controlled with antihistamines and short-term low-dose
glucocorticoids.
 Skin Induration: Managed with cyclophosphamide and methotrexate, though effects are
modest.

 Skin Care:
o Use hydrophilic ointments and bath oils to combat dryness.
o Regular skin massage is beneficial.

 Telangiectasia: Treated with pulsed dye laser for cosmetic concerns.

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Digital Ulcerations:
 Protection and Healing: Use occlusive dressings.
 Infections: Treated with topical antibiotics and surgical debridement.

Calcific Deposition:
 Potential Treatments: Minocycline, bisphosphonates, topical or IV sodium thiosulfate
(STS).
 Additional Approaches: Carbon dioxide laser treatment, extracorporeal shock-wave
lithotripsy, and surgical high-speed microdrilling.

Treatment of Musculoskeletal Complications:

 Arthralgia and Joint Stiffness:
o NSAIDs: For short-term relief.
o Methotrexate and Low-Dose Glucocorticoids: For persistent symptoms.

 Physical and Occupational Therapy: Effective in preventing loss of musculoskeletal

function and joint contractures; should be initiated early.

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 Takayasu Arteritis (TA) – Dec 17
1. Definition:
 Takayasu Arteritis: An inflammatory and stenotic disease primarily affecting medium-
and large-sized arteries, with a notable predilection for the aortic arch and its branches.

2. Incidence and Prevalence:

 Incidence: 1.2–2.6 cases per million annually.
 Demographics: Most prevalent in adolescent girls and young women. More common
in Asia but not restricted by race or geography.

3. Pathology and Pathogenesis:

 Affected Arteries: Primarily the aortic arch and its branches; the pulmonary artery may
also be involved.
 Histology: Characterized by panarteritis with inflammatory mononuclear cell infiltrates
and occasional giant cells. Features include intimal proliferation, fibrosis, scarring,
vascularization of the media, and disruption of the elastic lamina.
 Vasa Vasorum: Often involved.
 Immune Mechanisms: Suspected but not fully understood; circulating immune
complexes have been found, but their pathogenic role is unclear.

4. Clinical and Laboratory Manifestations:

 General Symptoms: Malaise, fever, night sweats, arthralgias, anorexia, weight loss.
These can precede vascular symptoms.
 Vascular Symptoms: Pulses may be absent, especially in the subclavian arteries.
Hypertension occurs in 32–93% of patients and can lead to renal, cardiac, or cerebral
complications.
 Laboratory Findings: Elevated ESR and/or CRP, mild anemia, and elevated
immunoglobulin levels.

Diagnosis:
 Clinical Clues: Decreased or absent peripheral pulses, blood pressure discrepancies,
arterial bruits, particularly in young women.
 Imaging: Arteriography shows irregular vessel walls, stenosis, poststenotic dilation,
aneurysm formation, occlusion, and increased collateral circulation. Magnetic resonance or
computed tomography arteriography is used to assess the extent and severity of disease.
 Histological Differentiation: IgG4-related disease can cause aortitis and periaortitis but is
differentiated by dense lymphoplasmacytic infiltrate with IgG4-positive plasma cells,
storiform fibrosis, and obliterative phlebitis.

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Treatment:
 Survival Rate: Varies widely; 5-year mortality rates range from 0 to 35%. Disease-related
mortality typically arises from congestive heart failure, cerebrovascular events, myocardial
infarction, aneurysm rupture, or renal failure.

 Medical Management:
o Glucocorticoids: 40–60 mg of prednisone per day can alleviate symptoms but does not
consistently improve survival.
o Methotrexate: Up to 25 mg per week can be effective in refractory cases or when
glucocorticoids cannot be tapered.
o Anti-TNF Therapies: Results have been encouraging but not confirmed by
randomized trials.
o Abatacept: Examined but did not show added benefit beyond glucocorticoids.
o Tocilizumab: Showed secondary benefits in studies, but the utility is still under
evaluation.

 Surgical Management: Aggressive surgical or arterioplastic interventions for stenosed

vessels improve outcomes by reducing stroke risk, correcting hypertension due to renal
artery stenosis, and improving blood flow. Surgery is generally undertaken once the
inflammatory process is well-controlled with medical therapy.

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 Vasculitis – Dec 22, June 21,
Dec 20, June 20, Dec 17, June
Antineutrophil Cytoplasmic Antibodies (ANCA)
1. ANCA Categories:
 Cytoplasmic ANCA (cANCA):
o Staining Pattern: Diffuse, granular cytoplasmic staining.
o Major Antigen: Proteinase-3 (29-kDa neutral serine proteinase).
o Associated Disease: Over 90% of patients with active granulomatosis with
polyangiitis (GPA) have detectable cANCA antibodies.
 Perinuclear ANCA (pANCA):
o Staining Pattern: Localized perinuclear or nuclear staining.
o Major Antigen: Myeloperoxidase.
o Other Targets: Elastase, cathepsin G, lactoferrin, lysozyme,
bactericidal/permeability-increasing protein.
o Associated Diseases: Microscopic polyangiitis (MPA), eosinophilic
granulomatosis with polyangiitis (EGPA, Churg-Strauss), isolated necrotizing
crescentic glomerulonephritis, and GPA. pANCA patterns not due to anti-
myeloperoxidase antibodies are associated with various nonvasculitic conditions.

2. Pathogenesis:
 Antibody Role: The exact role of ANCA in disease pathogenesis is unclear. Potential
mechanisms include:
o Neutrophil Priming: TNF-α and IL-1 can translocate proteinase-3 and
myeloperoxidase to the cell membrane, making them accessible to ANCA. This
interaction may lead to neutrophil degranulation and reactive oxygen species
production.
o Endothelial Cell Damage: ANCA-activated neutrophils can adhere to and damage
endothelial cells.
o Proinflammatory Cytokine Release: ANCA activation induces the release of
cytokines like IL-1 and IL-8.
o Experimental Evidence: Adoptive transfer experiments in genetically engineered
mice support a pathogenic role of ANCA.
 Contradictory Evidence:
o Disease Occurrence Without ANCA: GPA can occur without detectable ANCA.
o Antibody Titers and Disease Activity: ANCA levels do not always correlate with
disease activity or severity.
o Persistent ANCA Levels: High ANCA levels can persist even during disease
remission.

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3. Clinical Relevance:
 Diagnostic Use: ANCA testing is valuable for diagnosing and distinguishing ANCA-
associated vasculitides but is not always indicative of disease activity or progression.
 Monitoring: Persistent ANCA levels do not necessarily reflect active disease and may
remain elevated long after remission.

GRANULOMATOSIS WITH POLYANGIITIS (GPA)

OVERVIEW
Definition:
 Granulomatosis with Polyangiitis (GPA) is a form of vasculitis characterized by:
o Granulomatous inflammation affecting the upper and lower respiratory tracts.
o Glomerulonephritis.
o Possible involvement of small arteries and veins with disseminated vasculitis.
o Can occur at any age; ~15% of cases are in those <19 years old, but it is rare before
adolescence. Mean age of onset is around 40 years.

Pathology and Pathogenesis:

 Histopathology:
o Vasculitis: Necrotizing vasculitis affecting small arteries and veins.
o Granulomas: Can be intravascular or extravascular.
o Lung Involvement: Typically presents as multiple, bilateral, nodular cavitary
infiltrates. Biopsy often shows necrotizing granulomatous vasculitis.
o Upper Airway: Involves inflammation, necrosis, and granuloma formation, sometimes
with vasculitis.
o Renal Involvement: Initially presents as focal and segmental glomerulitis, which can
progress to rapidly progressive crescentic glomerulonephritis. Granulomas are rare in
renal biopsies, and immune complex deposition is not observed.

 Immunopathogenesis:
o Immune Response: Likely involves an aberrant cell-mediated immune response to an
antigen that enters or resides in the upper airway.
o Associations: Chronic nasal carriage of Staphylococcus aureus is associated with a
higher relapse rate but not directly implicated in disease pathogenesis.
o Cytokine Profile:
 Increased secretion of IFN-γ and TNF-α.
 Elevated IL-12 production by monocytes.
 Unbalanced TH1-type T-cell cytokine pattern.

 ANCA Role:
o A high percentage of patients develop ANCA (antineutrophil cytoplasmic antibodies).

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 o ANCA may play a role in the pathogenesis of GPA.

CLINICAL AND LABORATORY MANIFESTATIONS

OF GRANULOMATOSIS WITH POLYANGIITIS
(GPA)
Upper Airways (95% of patients):
 Symptoms:
o Paranasal sinus pain
o Nasal discharge (purulent or bloody)
o Nasal mucosal ulceration

 Complications:
o Nasal septal perforation leading to saddle nose deformity
o Serous otitis media from eustachian tube blockage
o Subglottic stenosis causing airway obstruction (~16% of patients)

Pulmonary Involvement (85–90% of patients):

 Symptoms:
o Cough
o Hemoptysis
o Dyspnea
o Chest discomfort

 Asymptomatic Cases: Up to 30% of patients may be asymptomatic.

 Complications:

Eye Involvement (52% of patients):

 Conditions:
o Conjunctivitis
o Dacryocystitis
o Episcleritis
o Scleritis
o Granulomatous sclerouveitis
o Ciliary vessel vasculitis
o Retroorbital mass lesions causing proptosis

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Skin Lesions (46% of patients):
 Types:
o Papules
o Vesicles
o Palpable purpura
o Ulcers
o Subcutaneous nodules

 Biopsy Findings: Vasculitis, granuloma, or both

Cardiac Involvement (8% of patients):

 Conditions:
o Pericarditis
o Coronary vasculitis
o Rarely, cardiomyopathy

Nervous System Manifestations (23% of patients):

 Conditions:
o Cranial neuritis
o Mononeuritis multiplex
o Rarely, cerebral vasculitis and/or granuloma

Renal Disease (77% of patients):

 Presentation:
o Mild glomerulitis with proteinuria, hematuria, and red blood cell casts
o Progression to rapidly progressive renal failure if untreated

General Symptoms:
 Malaise
 Weakness
 Arthralgias
 Anorexia
 Weight loss
 Fever (may indicate disease activity or secondary infection)

Laboratory Findings:
 Elevated:
o Erythrocyte sedimentation rate (ESR)
o C-reactive protein (CRP)

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 Other Findings:
o Mild anemia
o Leukocytosis
o Mild hypergammaglobulinemia (particularly IgA)
o Mildly elevated rheumatoid factor
o Thrombocytosis as an acute-phase reactant

 ANCA:
o Positive antiproteinase-3 ANCA in ~90% of active cases
o Sensitivity drops to ~60–70% in the absence of active disease
o Antimyeloperoxidase ANCA may be present in some cases (~20% may lack ANCA)

Venous Thrombotic Events:

 Increased incidence of deep-vein thrombosis or pulmonary emboli
 Routine anticoagulation is not recommended, but vigilance for signs of thrombotic events
is advised.

TREATMENT OF GRANULOMATOSIS WITH

POLYANGIITIS (GPA)
Induction Therapy:
 Glucocorticoids:
o Standard Regimen: Prednisone 1 mg/kg per day for the first month, then tapering
gradually.
o Reduced-Dose Regimen: Found to be noninferior to standard dosing with a lower rate
of serious infections.
o Methylprednisolone: 1000 mg daily for 3 days in life-threatening cases.

 Immunosuppressive Agents:
o Cyclophosphamide: Dramatically improved outcomes; marked improvement in >90%
of patients, complete remission in 75%, and 5-year survival in >80%.
o Alternative Agents: For patients with contraindications or intolerances to
cyclophosphamide, options include rituximab or methotrexate, depending on the
disease severity and patient factors.

Maintenance Therapy:
 Glucocorticoids: Continued at lower doses, tapering further over time.

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 Immunosuppressive Agents:
o Cyclophosphamide: For severe cases; typically switched to a less toxic agent like
azathioprine or methotrexate for maintenance.
o Rituximab: May be used as an alternative or in patients with relapsing disease.
o Azathioprine or Methotrexate: Common choices for maintenance therapy, depending
on individual patient factors.

Management of Relapse:
 Assessment: Relapse should be based on objective evidence of disease activity, ruling out
infections, medication toxicity, or chronic sequelae.
 Treatment: Reinduction of remission is usually achieved with the same agents used for
initial treatment, potentially with adjustments based on previous responses and side effects.

Additional Considerations:
 ANCA Monitoring: Rising ANCA levels alone are not predictive of relapse and should
not lead to increased immunosuppressive therapy.
 Renal Failure: Patients with irreversible renal failure who achieve remission may benefit
from renal transplantation.

Cyclophosphamide for induction in severe disease

 Cyclophosphamide:
o Oral Cyclophosphamide: 2 mg/kg/day combined with glucocorticoids.
 Dose Adjustment: Consider reduction in renal insufficiency.
o Intravenous (IV) Cyclophosphamide: 15 mg/kg per infusion, every 2 weeks initially,
then every 3 weeks.
 Comparative Outcomes: Similar remission rates to oral cyclophosphamide with
lower cumulative dose and less leukopenia, but relapse rate was higher (19% for IV
vs. 9% for daily oral).
 Concerns: Lack of routine blood count monitoring in some studies.

 Rituximab:
o Dosage: 375 mg/m² weekly for 4 weeks combined with glucocorticoids.
o Effectiveness: Comparable to cyclophosphamide in inducing remission; superior in
relapsing cases.
o Advantages: Avoids cyclophosphamide’s bladder toxicity and infertility risks.
o Considerations: Choice depends on disease severity, relapse status, and patient-
specific factors such as fertility concerns.

 Preferred Regimen for Severe Disease: Daily cyclophosphamide and glucocorticoids are
favored for rapidly progressive glomerulonephritis or pulmonary hemorrhage requiring
mechanical ventilation.

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2. Remission Maintenance:
 Cyclophosphamide:
o Duration: Discontinue after 3–6 months.
o Switch to Maintenance Therapy: Options include rituximab, azathioprine,
methotrexate, or mycophenolate mofetil.
 Maintenance Medications:
o Rituximab: 500 mg every 6 months (after initial induction).
 Effectiveness: Lower relapse rate compared to azathioprine.
o Azathioprine: 2 mg/kg/day.
o Methotrexate: 15 mg/week, increased by 2.5 mg every 2 weeks up to 20–25
mg/week.
 Effectiveness: Similar relapse and toxicity rates compared to azathioprine.
o Mycophenolate Mofetil: 1000 mg twice daily.
 Considerations: Higher relapse rate compared to azathioprine.

 Optimal Duration of Maintenance Therapy:

o Glucocorticoids: Prednisone 5 mg/day versus discontinuation after 6–9 months is
debated.
o Azathioprine, Methotrexate, Mycophenolate Mofetil: Typically used for at least
2 years. Long-term therapy may be needed for patients with significant organ
damage or frequent relapses.
o Rituximab: Duration beyond 2 years remains uncertain; needs individual
assessment.
 Relapse Risk: Higher when maintenance therapy is discontinued; tapering over 6-12
months may be considered.

Remission Induction of Non-Severe Granulomatosis with Polyangiitis

(GPA)
1. Induction Therapy for Non-Severe Disease:
 Methotrexate: Used in combination with glucocorticoids for inducing remission in
non-severe cases.
 Mycophenolate Mofetil: Another option combined with glucocorticoids.
 Cyclophosphamide: Generally, not recommended for non-severe GPA.

2. Other Biologic Agents and Small Molecule Inhibitors:

 Abatacept:
o Status: Promising results in a pilot study for non-severe relapsing disease, but more
research is needed.
 Etanercept:
o Status: Not effective in sustaining remission and should not be used for GPA.
 Belimumab:
o Status: No additional benefit when used with azathioprine for maintenance.

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  Avacopan:
o Function: C5a receptor inhibitor.
o Effectiveness: Demonstrated higher sustained remission rates compared to
prednisone with similar serious adverse event rates in a randomized trial.
o Use: Promising for reducing glucocorticoid use in ANCA-associated vasculitis.

3. Trimethoprim-Sulfamethoxazole (TMP-SMX):
 Effectiveness: May be beneficial for sinonasal involvement but should not be used
alone for active disease involving other organs.
 Studies: Showed decreased relapses in upper airway disease but no difference in major
organ relapses.

4. Organ-Specific Treatment:
 Sinus Disease:
o Management: Focus on local care, including moisturization and humidification.
 Subglottic Stenosis:
o Management: Best managed with non-medical interventions such as dilation and
glucocorticoid injection.

Microscopic Polyangiitis (MPA)

1. Definition:
 Microscopic Polyangiitis: A necrotizing vasculitis affecting small vessels (capillaries,
venules, or arterioles) with minimal or no immune complex deposition.
 Differentiation: Distinguished from granulomatosis with polyangiitis (GPA) by the
absence of granulomatous inflammation.

2. Incidence and Prevalence:

 Incidence: 3–5 cases per 100,000 people.
 Age of Onset: Mean age is approximately 57 years.
 Gender: Slightly more common in males.

3. Pathology and Pathogenesis:

 Vessel Involvement: Predominantly affects capillaries, venules, and small- to medium-
sized arteries.
 Immunohistochemistry: Shows minimal immunoglobulin deposition, suggesting a
lack of immune-complex involvement.
 ANCA Association: High association with ANCA, particularly anti-myeloperoxidase
(MPO) antibodies, which may play a role in disease pathogenesis.

4. Clinical and Laboratory Manifestations:

 Common Symptoms: Fever, weight loss, musculoskeletal pain. Disease onset can be
gradual or acute.

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  Renal Involvement: Glomerulonephritis occurs in at least 79% of patients and can
progress rapidly to renal failure.
 Pulmonary Involvement: Hemoptysis may indicate alveolar hemorrhage, present in
about 12% of cases.
 Other Manifestations: Mononeuritis multiplex, gastrointestinal tract, and cutaneous
vasculitis. Upper airway disease and pulmonary nodules suggest GPA rather than MPA.
 Laboratory Findings: Elevated ESR and/or CRP, anemia, leukocytosis,
thrombocytosis. ANCA present in 75% of patients, with anti-MPO antibodies being
predominant.

5. Diagnosis:
 Criteria: Based on histologic evidence of vasculitis or pauci-immune
glomerulonephritis with clinical features of multisystem disease. Tissue biopsy remains
crucial for diagnosis, especially in cases without clear clinical evidence.

6. Treatment:
 Survival Rate: The 5-year survival rate for treated MPA is 74%.
 Treatment Approach: Similar to that for GPA, including:
o Induction Therapy: Typically involves glucocorticoids combined with
cyclophosphamide or rituximab.
o Maintenance Therapy: Options include rituximab, azathioprine, methotrexate, or
mycophenolate mofetil.
 Relapse: Observed in about 34% of patients, with management tailored to the site and
severity of the relapse.

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