Rheumatoi

d arthritis

Elias
xwatsal
(MMed)
 Introduction

 RA is a chronic, systemic inflammatory

disorder characterized by chronic
symmetrical polyarthritis causing cartilage
destruction, bone erosions and changes in
joint intergrity.
 Progressive joint destruction and
deformity leads to variable degrees of
incapacitation.
 F:M=2-3:1 40-60 years old
Rheumatoid arthritis
Epidemiology of RA
 Pathology

 Rheumatoid factors (RF) are antibodies with

specificity for antigenic determinates on the Fc
portion of IgG. Currently, the most popular notion that
RF arise as antibodies to ―altered‖autologous IgG.
 Synovitis edema, cell proliferation
 Rheumatoid pannus, a vascular granulation tissue
composed of proliferation fibroblasts, numerous small
blood vessels, and various inflammatory cells.
 Vasculitis a widespread necrotizing arteritis of small
and medium sized arteries
 Rheumatoid Arthritis:
Key Features
• Symptoms >6 weeks’ duration
• Often lasts the remainder of the patient’s life

• Inflammatory synovitis
• Palpable synovial swelling

• Morning stiffness >1 hour, fatigue

• Symmetrical and polyarticular (>3 joints)

• Typically involves wrists, MCP, and PIP joints

• Typically spares certain joints

• Thoracolumbar spine

• DIPs of the fingers and IPs of the toes

 Rheumatoid Arthritis:
Key features
• May have nodules: subcutaneous or periosteal at
pressure points
• Rheumatoid factor
• 45% positive in first 6 months

• 85% positive with established disease

• Not specific for RA, high titer early is a bad

sign
• Marginal erosions and joint space narrowing on
x-ray

Adapted from Arnett, et al. Arth Rheum. 1988;31:315–324.

Rheumatoid Arthritis: PIP Swelling
 Swelling is confined to
the area of the joint
capsule
 Synovial thickening
feels like a firm
sponge
 Rheumatoid Arthritis:
Ulnar Deviation and MCP Swelling
 An across-the-room
diagnosis
 Prominent ulnar
deviation in the right
hand
 MCP and PIP swelling
in both hands
 Synovitis of left wrist
Xrays
 Clinical Course of RA
Severity of Arthritis
4
Type 1
3
Type 2
2 Type 3
1
0
0 0.5 1 2 3 4 6 8 16
Years

Type 1 = Self-limited—5% to 20%

Type 2 = Minimally progressive—5% to 20%
Type 3 = Progressive—60% to 90%

Pincus. Rheum Dis Clin North Am. 1995;21:619.

 Rheumatoid Arthritis: Typical Course
• Damage occurs early in most patients
• 50% show joint space narrowing or erosions in
the first 2 years
• By 10 years, 50% of young working patients
are disabled
• Death comes early
• Multiple causes

• Compared to general population

• Women lose 10 years, men lose 4 years

Pincus, et al. Rheum Dis Clin North Am. 1993;19:123–151.

Rheumatoid Arthritis
Caplan syndrome
 Laboratory findings
 Anemia of moderate degree,
 Thrombocytosis
 ESR 
 C-reactive protein 
 RF 70% but not specific
 Synovial fluid analysis: PMNs predorminate
 Radiology Bony decalcification adjacent to the
involved joints and not just degenerative changes
 Rheumatoid nodules
 Proposed 1987 Revised American Rheumatism
Association Criteria for Rheumatoid Arthritis
4/7
 Morning stiffness for at least one hour and present for at
least 6 weeks
 Swelling of three or more joints for at least 6 weeks
 Swelling of wrist, metacarpophalangeal or proximal
interphalangeal joints for six or more weeks
 Symmetric joint swelling
 Hand roentgenogram changes typical rheumatoid arthritis
that must include erosions or unequivocal bony decalci-
fication
 Rheumatoid nodules
 serum rheumatoid factor positive in less than 5% of
normals
 Radiographic changes on hands erosions and bony
decalcifications
 Rheumatoid Arthritis:
Treatment Principles
 Confirm the diagnosis
 Determine where the patient stands in the
spectrum of disease
 When damage begins early, start aggressive
treatment early
 Use the safest treatment plan that matches the
aggressiveness of the disease
 Monitor treatment for adverse effects
 Monitor disease activity, revise Rx as needed
 Critical Elements of a Treatment Plan:
Assessment
• Assess current activity
• Morning stiffness, synovitis, fatigue, ESR

• Document the degree of damage

• ROM and deformities

• Joint space narrowing and erosions on x-ray

• Functional status

• Document extra-articular manifestations

• Nodules, pulmonary fibrosis, vasculitis

• Assess prior Rx responses and side effects

 Critical Elements of a Treatment Plan:
Therapy
• Education
• Build a cooperative long-term relationship

• Exercise/physiotherapy
• ROM, conditioning, and strengthening exercises

• Medications
• Analgesic and/or anti-inflammatory
• Immunosuppressive, cytotoxic, and biologic
• Balance efficacy and safety with activity
 Rheumatoid Arthritis:
Drug Treatment Options
• NSAIDs
• Symptomatic relief, improved function

• No change in disease progression

• Low-dose prednisone (10 mg qd)

• May substitute for NSAID

• Used as bridge therapy

• If used long term, consider prophylactic

treatment for osteoporosis
• Intra-articular steroids
• Useful for flares
Paget. Primer on Rheum Dis. 11th edition. 1997:168.
 Rheumatoid Arthritis:
Treatment Options
• Disease modifying drugs (DMARDs)
• Minocycline

• Modest effect, may work best early

• Sulfasalazine, hydroxychloroquine

• Moderate effect, low cost

• Intramuscular gold

• Slow onset, decreases progression, rare

remission
• Requires close monitoring

Alarcon. Rheum Dis Clin North Am. 1998;24:489–499.

Paget. Primer on Rheum Dis. 11th edition. 1997:168.
 Rheumatoid Arthritis:
Treatment Options (cont’d)
• Immunosuppressive drugs
• Methotrexate

• Most effective single DMARD

• Good benefit-to-risk ratio

• Azathioprine

• Slow onset, reasonably effective

• Cyclophosphamide

• Effective for vasculitis, less so for arthritis

• Cyclosporine

• Superior to placebo, renal toxicity

Paget. Primer on Rheum Dis. 11th edition. 1997:168.
 Treatment Options—Combinations
2-Year Outcome  Methotrexate,
90 hydroxychloroquine,
Percent With 50% ACR Response

80 and sulfasalazine
70
 Superior to any one or
60
two alone for ACR
50
50% improvement
40
30
response and
20
maintenance of the
10
response
0  Side effects no greater
Triple SSZ+ MTX
RX HCQ
 Treatment Options
• Step-down prednisone with sulfasalazine and
low-dose methotrexate*
• Superior to sulfasalazine in early disease*

• Methotrexate + hydroxychloroquine or
methotrexate + cyclosporine†
• May have additive beneficial effects†

*Boers, et al. Lancet. 1997;350:309–318.

†Stein, et al. Arth Rheum. 1997;40:1721–1723.
 New Treatment Options DMARDs
• Leflunomide
• Pyrimidine inhibitor

• Effect and side effects similar to those of MTX

• Etanercept
• Soluble TNF receptor, blocks TNF

• Rapid onset, quite effective in refractory

patients in short-term trials and in combination
with MTX
• Injection site reactions, long-term effects
unknown, expensive
Rozman. J Rheumatol. 1998;53:27–32.
Moreland. Rheum Dis Clin North Am. 1998;24:579–591.
 Rheumatoid Arthritis: Monitoring
Treatment With DMARDs
• These drugs need frequent monitoring
• Blood, liver, lung, and kidney are frequent sites of
adverse effects
• Interval of laboratory testing varies with the drug
• 4- to 8-week intervals are commonly needed

• Most patients need to be seen 3 to 6 times a year

 Rheumatoid Arthritis:
Adverse Effects of DMARDs
Drug Hem Liver Lung Renal Infect Ca Other
HCQ + - - - - - Eye
SSZ + + + - - - GI Sx
Gold ++ - + ++ - - Rash
MTX + + ++ - ++ ? Mucositis
AZA ++ + - - ++ + Pancreas
PcN ++ + + ++ - - SLE, MG
Cy +++ - - - +++ +++ Cystitis
CSA + ++ - +++ ++ + HTN
TNF* - - - - ? ? Local
Lef* ++ ++ - - ? ?
*Long-term data not available.
Adapted from Paget. Primer on Rheum Dis. 11th edition. 1997:168.
Rheumatoid Arthritis

Case Management
 Rheumatoid Arthritis: Case 1
 34-year-old woman with 5-year history of RA
 Morning stiffness = 30 minutes
 Synovitis: 1+ swelling of MCP, PIP, wrist, and
MTP joints
 Normal joint alignment
 Rheumatoid factor positive
 No erosions seen on x-rays
 Rheumatoid Arthritis: Case 1 (cont’d)
• Assessment
• Current activity—mild

• No sign of damage after 5 years

• Type 2 minimally progressive course

• Treatment
• NSAID + safer, less potent drugs, eg,

• Hydroxychloroquine, minocycline, or
sulfasalazine
• Education + ROM, conditioning, and
strengthening exercises
 Rheumatoid Arthritis: Case 2
 34-year-old woman with 1-year history of RA
 Morning stiffness = 90 minutes
 Synovitis: 1+ to 2+ swelling of MCP, PIP, wrist,
knee, and MTP joints
 Normal joint alignment
 RF positive
 Small erosions of the right wrist and two MCP
joints seen on x-rays
 Rheumatoid Arthritis: Case 2 (cont’d)
Early erosion at the tip of the ulnar styloid
 Rheumatoid Arthritis: Case 2 (cont’d)
How fast is joint damage progressing?
A. Soft-tissue swelling,
no erosions
B. Thinning of the cortex
on the radial side and
minimal joint space
narrowing
C. Marginal erosion at
the radial side of the
metacarpal head with
joint space narrowing
ACR Clinical Slide Collection, 1997.
 Rheumatoid Arthritis: Case 2 (cont’d)
• Assessment of case 2
• Moderate disease activity

• Many joints involved

• Clear radiologic signs of joint destruction early

in disease course
• Type 3 progressive course

• Treatment should be more aggressive

• NSAID, MTX, SSZ, and hydroxychloroquine
would be a good choice
 Rheumatoid Arthritis: Case 3
• 34-year-old woman with 3-year history of RA
• Morning stiffness = 3 hours

• 2 to 3+ swelling of MCP, PIP, wrist, elbow,

knee, and MTP joints
• Ulnar deviation, swan neck deformities,
decreased ROM at wrists, nodules on elbows
• RF positive, x-rays show erosions of wrists and
MCP joints bilaterally
• Currently on low-dose prednisone + MTX, SSZ,
and hydroxychloroquine
 Rheumatoid Arthritis: Case 3 (cont’d)
• Assessment
• Very active disease in spite of aggressive
combination therapy
• Evidence of extensive joint destruction

• Treatment options are many

• Step-down oral prednisone, 60 mg qd tapered
to 10 mg qd over 5 weeks, can be used for
immediate relief of symptoms
• Use other cytotoxics or cyclosporine

• Consider TNF inhibitor or leflunomide

 Rheumatoid Arthritis:
Treatment Plan Summary
• A variety of treatment options are available
• Treatment plan should match
• The current disease activity

• The documented and anticipated pace of joint

destruction
• Consider a rheumatology consult to help design a
treatment plan
Rheumatoid Arthritis

Potential Complications
 RA: Case 1
 68-year-old woman with 3-year history of RA
 She presents with 4 weeks of increasing fatigue,
dizziness, dyspnea, and anorexia
 Her joint pain and stiffness are mild and
unchanged
 Managed with ibuprofen and hydroxychloroquine
until 4 months ago, when a flare caused a switch
to piroxicam and prednisone
 RA: Case 1 (cont’d)
 Past history: Peptic ulcer 10 years ago and mild
hypertension
 Exam shows a thin, pale apathetic woman with
Temp 98.4ºF, BP 110/65, pulse 110 bpm
 Symmetrical 1+ synovitis of the wrist, MCP, PIP,
and MTP joints
 Exam of the heart, lungs, and abdomen is
unremarkable
 Case 1 (cont’d)
 What system must you inquire more
about today?
A. Cardiovascular
B. Neuropsychological
C. Endocrine
D. Gastrointestinal
 Case 1 (cont’d)

 NSAID gastropathy can be fatal

 RA: Case 1 (cont’d)
• Clues of impending disaster
• High risk for NSAID gastropathy

• Presentation suggestive of blood loss

• Pale, dizzy, weak

• Tachycardia, low blood pressure

• No evidence of flare in RA to explain recent

symptoms of increased fatigue
 NSAID Gastropathy
 Gastric ulcers are more common than duodenal
ulcers
 No reliable warning signs
 80% of serious events occur without prior
symptoms
 Risk of hospitalization for NSAID ulcers in RA is
2.5 to 5.5 times higher than general population
 107,000 patients are hospitalized and 16,000
deaths occur annually in the US because of
NSAID-induced gastrointestinal complications

Singh. Am J Med. 1998;105(suppl B):31S–38S.

Know the Risk Factors for NSAID Ulcers
 Older age
 Prior history of peptic ulcer or GI symptoms with
NSAIDs
 Concomitant use of prednisone
 NSAID dose: More prostaglandin suppression =
greater risk of serious events
 Disability level: The sicker the patient the higher
the risk

Singh. Am J Med. 1998;105(suppl B):31S–38S.

 NSAID Gastropathy: Treatment
• Acute bleed or perforation
• Stop NSAID

• Endoscopy or surgery

• Start omeprazole IV or Po

• Ulcer without bleed or perforation, and needs or

wants continued NSAID
• Omeprazole 20 mg qd—76% healed

• Misoprostol 200 µg qid—71% healed

Hawkey. N Engl J Med. 1998;338:727–734.

 NSAID Gastropathy: Prevention
• Avoid the problem
• Stop the NSAID and use alternative treatment
• Low-dose prednisone

• Use a selective cyclooxygenase-2 inhibitor

 Differential Expression of COX-1 and COX-2
Cyclooxygenase (COX) enzymes are a key step in
prostaglandin production
COX-1 COX-2
Housekeeping Inducible
most tissues immune system,
stomach ovary, amniotic fluid,
platelets bone, kidney,
kidney
colorectal tumors
Inducible
Housekeeping
macrophages
brain, kidney

Furst. Rheum Grand Rounds. 1998;1:1.

Needleman, et al. J Rheumatol. 1997;24(suppl 49):6–8.
 Selective COX-2 Suppression:
A Potentially Elegant Solution
• Traditional NSAIDs at full therapeutic doses inhibit
both enzymes
• Most have greater effect on COX-1 than COX-2

• The new drugs are highly selective for COX-2

• >300-fold more effective against COX-2

• This difference allows

• Major reduction in COX-2 production of

proinflammatory PGs
• Sparing of COX-1–produced housekeeping
PGs
Vane, Botting. Am J Med. 1998;104(suppl 3A):2S–8S.
 NSAID Gastropathy: Prevention
• Short-term (1 to 4 weeks) clinical studies with
COX-2 inhibitor in patients with OA and RA*
• Significant control of arthritis symptoms
• Fewer endoscopic ulcers
• No effect on platelet aggregation or
bleeding time
• Insufficient data to determine risk of serious
events or safety in high-risk populations
• Celecoxib and rofecoxib and meloxicam
approved
NSAID Gastropathy: Prevention (cont’d)
• Counteract the problem
• Misoprostol
• Reduction of serious events by 40%

• Results best with 200 µg qid

• Side effects: diarrhea and uterine cramps

• Avoid if pregnancy risk is present

• Omeprazole
• Recent studies show 72% to 78% reduction in
all ulcers when used for primary prevention at
20 mg qd
Scheiman, Isenberg. Am J Med. 1998;105(suppl 5A):32S–38S.
Hawkey. Am J Med. 1998;104(suppl 3A):67S–74S.
 NSAID Gastropathy: Key Points
• Keep it in mind
• Know the risk factors
• The best way to treat it is to prevent it
• Avoid it: Use acetaminophen, salsalate, or a
selective COX-2 inhibitor
• Counteract it: Omeprazole or misoprostol

• Antacids and H2 blockers are not the answer

• May mask symptoms but do not prevent
serious events
 Case 2
 You are doing a preop physical for a routine
cholecystectomy on a 43-year-old woman with
RA since age 20.
 No other medical problems. Current meds:
NSAID, low-dose prednisone, MTX, and HCQ
 General physical exam normal
 MS exam, extensive deformities, mild synovitis
 In addition to routine tests, what test should be
ordered before surgery?
 Subluxation of C1 on C2
Don’t Miss It

RA can cause asymptomatic instability of the neck

Manipulation under anesthesia can cause spinal cord injury
 Clues for C1-C2 Subluxation
• Long-standing rheumatoid arthritis or JRA
• May have NO symptoms
• C2-C3 radicular pain in the neck and occiput
• Spinal cord compression
• Quadriparesis or paraparesis

• Sphincter dysfunction

• Sensory deficits

• TIAs secondary to compromise of the vertebral

arteries

Anderson. Primer on Rheum Dis. 11th edition. 1997:161.

 Rheumatoid Arthritis:
Special Considerations on Preop Exam
• C1-C2 subluxation
• Cricoarytenoid arthritis with adductor spasm of
the vocal cords and a narrow airway
• Pulmonary fibrosis
• Risk for GI bleeding
• Need for stress steroid coverage
• Discontinue NSAIDs several days preop
• Discontinue methotrexate 1 to 2 weeks preop
• Cover with analgesic meds or if necessary
short-term, low-dose steroid if RA flares
 Case 3
 52-year-old man with destructive RA treated with
NSAID and low-dose prednisone. MTX started 4
months ago, now 15 mg/wk
 Presents with 3-week history of fever, dry cough,
and increasing shortness of breath
 Exam: Low-grade fever, fine rales in both lungs,
normal CBC and liver enzymes, low albumin,
diffuse interstitial infiltrates on chest x-ray
 Case 3 (cont’d)
 What would you do?
A. Culture, treat with antibiotic for bacterial
pneumonia
B. Culture, give cough suppressant for viral
pneumonia and watch
C. Give oral steroid for hypersensitivity
pneumonitis and stop methotrexate
D. Give a high-dose oral pulse of steroid
and increase methotrexate for
rheumatoid lung
 DMARDs Have a Dark Side
 DMARDs have a dark side
 Methotrexate may cause serious problems
Lung
Liver
Bone marrow
 look out for toxicity with all the DMARDs
 Methotrexate Lung
• Dry cough, shortness of breath, fever
• Most often seen in the first 6 months of MTX
treatment
• Diffuse interstitial pattern on x-ray
• Bronchoalveolar lavage may be needed to rule
out infection
• Acute mortality = 17%; 50% to 60% recur with
retreatment, which carries the same mortality
• Risk factors: older age, RA lung, prior use of
DMARD, low albumin, diabetes

Kremer, et al. Arth Rheum. 1997;40:1829–1837.

 Etiology

 Genetic factors HLA-DR4

 Infection
Pathology