1.

DIAGNOSTIC STRATEGY IN RHEUMATOLOGY

BACKGROUND

MAIN SYNDROMES

Joint syndrome
• Inflammatory arthritis
• Osteoarthritis
The main reason the patients address to the rheumatologist is joint pain. The first
thing we have to do is to identify the source of pain – is it articular or not? The
joint pain has the following characteristics:
• it is present in all degrees/movements of the joint
• the intensity is similar in active and passive mobilization, causing limited
range of motion
• it is localized (normally alongside the margins of the joints)
• the presence of crepitus, heat, swelling or effusion are additional clues to
confirm a the joint involvement
The pattern of the pain, initially can discriminate between a degenerative disorder
versus an inflammatory one. The pain can be: mechanical or inflammatory.
In the mechanical model the pain augments during mobilization and usually its
intensity is increased at the end of the day. The pain is reduced at rest, and the
patient will confess the presence of a pain – free position. Stiffness appears after
rest (2-3) and don’t last, ceasing in a few minutes (< 15).
The inflammatory pattern is characterized by pain at rest, usually during the night
and early morning, morning stiffness that last minutes (>30) to hours. The
intensity decreases during and after exercise.
In chronic conditions the pain’s pattern might be mixed: mechanical and
inflammatory.
The onset of the pain is important. In inflammatory model the onset is quick –
hours to week, as for the mechanical pain the patient will confirm an increasing of
the pain over the years – the onset is insidious, chronic.
It is not mandatory in inflammatory pattern to associate all the Celsius signs.
Redness might be lacking in 50% of the patients with septic arthritis and can be
present in gout and psoriatic arthritis. The articular swelling is a sign of an
inflamed, engorged synovium. It is firm, uniform spindle shape (due to the
limitation imposed by the capsule), globular in superficial joints and has a rubbery
consistency. Effusion may be associated.
Patterns of inflammatory joint disease
When evaluating a patient we are evaluating a patient with articular involvement
we must consider the following:
1. number of joints involve
• monoarthritis: one single joint involved
• oligoarthritis: 2 to 4 joints involved
• polyarthritis: 5 or more joints involved
2. the type of the onset
• acute: onset in hours or days
• chronic: onset over weeks or months
3. the site affected
• proximal: arthritis mainly involves large joints, i.e, proximal to the
wrist or ankle, and the spine
• distal: the arthritis mainly involves the small joints of the hands and
feet, with or without the wrist and ankle
4. the evolution of pain
• symmetrical: affects approximately the same joint groups of each
side of the body
• asymmetrical: there is no relationship between the joints involved
on either side of the body
• persistent: once it has set, the arthritis persists over the time
• recurrent: episodes or crisis of arthritis separated by symptom-
free intervals
• additive: the affected joints are added progressively
• migratory: the inflammatory process flits from one joint to another
5. the association with other manifestations
• systemic manifestations
 • inflammatory low back pain

Monoarthritis
Acute monoarthritis. It is mandatory to exclude a sepsis when dealing with
inflammatory monoarthritis. Classically it is characterized by rapid onset, redness
and swelling in a single joint. Aspiration or/and biopsy of synovial fluid is required
in order to confirm the diagnosis.
Gout is the most common cause of acute monoarthritis. The sudden onset, at night
involves the first metatarsophalangeal joint. The joint is typically swollen, bright
red, hot and extremely tender. Systemic symptoms such fever and malaise could
be present. The pattern of pain is recurrent. In time other joints are affected, the
pattern becoming polyarticular.
The following disorders can start as monoarthritis:
• reactive arthritis
• post-traumatic synovitis
• pseudo-gout
• bacterial endocarditis
• psoriatic arthritis
Chronic monoarthritis (weeks to months)
• synovial biopsy is required for diagnosis
• infections are the common causes (brucella, mycobacterium, Lyme disease,
others),
• crystal induced arthritis
• juvenile idiopathic arthritis
• reactive arthritis
• seronegative spondyloarhropathy
• sarcoidosis
Differential diagnosis with non-inflammatory conditions:
• osteoarthritis,
• recurrent hidrarthrosis
• osteonecrosis
• reflex sympathetic dystrophy
 • neuropathic (Carchot’s) joints
• tumors - villonodular synovitis

Polyarthritis
Chronic symmetrical additive peripheral polyarthritis
• common affected – small joints of the hands and feet
• no inflammatory low back pain
• rheumatoid arthritis
• connective tissue diseases:
➢ systemic lupus
➢ primary Sjögren’s syndrome
➢ polymyositis
➢ mixed connective tissue disease
• psoriatic arthritis
• chondrocalcinosis
• gout
• viral arthritis
Chronic, asymmetrical oligo/polyarthritis
• asymmetrical arthritis, affecting proximal or distal joints
• common, but not mandatory – dactilitis
• psoriatic arthritis
• hand osteoarthritis
• seronegative spondylarthropathies:
➢ ankylosing spondylitis,
➢ inflammatory bowel disease
• chronic sarcoid arthropathy
Proximal oligoarthritis
• seronegative spondylarthropathies
• rheumatoid arthritis
• juvenile idiopathic arthritis
Polyarthritis with systemic manifestations
• connective tissue diseases - eg. systemic lupus erythematosus (+
 photosensitivity, livedo reticularis, alopecia, ulcers etc.)
• Still’s disease
• reactive arthritis
Acute oligo -or polyarthritis
• oligo- or polyarthritis
• fever
• recent infection
• reactive arthritis
• systemic lupus erythematosus
• dermatomyositis
• Behcet’s disease
• rheumatoid arthritis
Inflammatory low back pain
• specific for seronegative spondylarthropathies:
➢ ankylosing spondylitis
➢ psoriatic arthritis
➢ Reiter’s syndrome,
➢ spondylitis of inflammatory bowel disease
➢ Behçet’s disease
• infectious or aseptic discitis
Patterns of degenerative joint disease
• ageing related
• most common sites: hip, knee, spine
• no specific cause – “primary osteoarthritis”
• nodal osteoarthritis – typical osteoarthritis

Regional Syndromes

• a unique muscle area is affected

• the pain can be:
➢ periarticular (eg. shoulders, elbows). Pain is more increased in active
motion compare to passive one. Also, it is exacerbated in certain positions
 that induce compression of the structure (rotator cuff tendonitis). Passive
movement is not limited, because the structure involved remains at rest
during passive motion.
➢ articular (forefeet, knees) – pain at motion (active or passive). Passive
motion is limited due to swelling or structural damage. The joint is tender
accompanied by crepitus, swelling, effusion and articular heat.
➢ neurogenic – compression or irritation of nerve roots or peripheral nerves.
Pain is described as a sensation of burning, numbness, electric shock,
tingling.
➢ reffered – symptoms are felt at distance from their anatomical origin.

Generalized pain syndrome

• pain is diffuse, migratory, worse after exercise

• the specific disorder is fibromyalgia
• other conditions: rheumatoid arthritis, systemic lupus erythematosus,
Sjögren’s syndrome, polymyalgia rheumatica, ankylosing spondylitis,
polymyositis, hypothyroidism, hypoparathyroidism,polyneuropathy

Neck/Low back pain

• pain has a mechanical rhythm with certain exception (see table one)
• pain can be reffered

• lymphadenopathy, thyroiditis and meningitis represent important non-rheumatic causes of neck

pain.
• The
• possibility of referred pain, from the heart, lung apex and shoulder must be kept in mind.

“RED FLAGS”
Back pain with inflammatory rhythm Sacroiliitis
Localized pain Spondylodiscitis
Nocturnal pain
Metastases
Visceral or constitutional symptoms
Osteoporotic fracture
Onset before age 30 or after 50
 Pain at movement in all directions Neurogenic pain
History of neoplasm Referred pain
Risk or evidence of osteoporosis
Interspinous ligamentitis
Neurological manifestations

Table 1. Low back pain - alarm signals

Bone syndrome

The pain is:

• deep,
• diffuse,
• continuous pain
• unrelated to movement
• most common affected: proximal limbs, pelvis, spine
• metastatic tumors
• metabolic bone disease

Osteoporosis syndrome

• related with the osteoporosis risk factors:

• smoking
• alcohol
• sedentary life style
• family history of osteoporosis
• history of fractures
• late menarche
• early menopaise
• hyperparathyroidism
• liver disease
• malabsortion
Muscle syndrome

• typically characterized by: proximal muscle weakness and atrophy

• most common disorders: polymyositis, dermatomyositis, inclusion-body
myositis
• pay attention at patietnt’s drugs intake: glucocorticoids, statins, fibrates,
colchicine, cyclosporine
• always perform a neurological exam – to exclude non-inflammatory
disorders such as: myasthenia gravis, spinal muscle atrophies, storage
diseases, myotonic diseases

Systemic syndrome

The autoimmune inflammatory diseases are associating extra-articular

manifestations. Some of them are common, nonspecific those are the
constitutional manifestations (fever, weight loss, severe fatigue) others are
specific (eg. serositis – SLE, muscular weakness – myositis etc.).

Paediatric syndromes

“Children are not just little adults.”

The enquiry is similar with the adult’s one. The physical exam is different from the
adult patients. The child can be uncooperative and shy. The majority of symptoms
in children are confined to a single joint area and are caused by minor deformities,
growth abnormalities or trauma. Generalized pain is also relatively common. The
musculoskeletal symptoms and signs associated with major rheumatic or
systemic conditions are less common.

TAKE HOME MESSAGES

Out rule all the malignancies and TB diagnosis before considering a rheumatologic
disorder
References:
1. West S, Rheumatology Secrets second edition, ed. Hanley  Belfus, 2002,
695: 12-22
2. Bijlisma WJJ, Eular Compendium on Rheumatic Diseases, BMJ Publishing
Group, 2009, 824: 1-12

2. IMMUNOLOGY AND THE RHEUMATIC DISEASES

GENERAL TERMS

Immune system is a coordinated system of cells, tissues, and soluble molecules

that constitute the body’s defense against invasion by non-self entities, including
infectious, inert agents and tumor cells.
The immune system plays 4 key roles:
1. Recognition: detect infection or harm
2. Effector: contain and eliminate infection
3. Regulation: control activity to avoid damage to the body

4. Memory: remember exposure; react immediately and strongly upon re-
exposure
Tolerance – the normal non-reactivity of the immune system towards harmless
antigens.
Self-non-self discrimination/ harmful-harmless discrimination – is the to
distinguish between harmless components of the body (self) and components
such as commensal bacteria, food, and the potential pathogens (foreign agents).
Autoimmunity – reactivity towards self.
Imunological tolerance – mechanism that keep auto-aggressive pathways in
check.
Immune complexes – antigen binding to antibodies and/or complement either
in circulation or specific tissues.
Molecular mimicry – the antigenically cross-reactivity of an antigen from a
microbe with a self antigen leading to a response from the immunity system
against the microbe and the self antigen, causing disease (eg. Guillain-Barré
syndrome).

INNATE IMMUNITY

Innate immunity is a system that can discriminate between molecules expressed

by the infectious agents and their hosts. Rarely causes direct damage to the host.

Innate immunity
• Nonspecific
• All the time
• Immediate but general protection
• Activates adaptive immune response
• Does not improve with repeated exposure to pathogen

Components of innate immunity

Macrophage:
• antigen presentation
• activation of bactericidal activity
• phagocytosis
Dendritic cells:
• antigen presentation
• antigen uptake in the periphery
Neutrophil:
• activation of bactericidal activity
• phagocytosis
Myeloid cells (mast cells, basophils, eosinophils):
• release histamine granules and other pro-inflammatory mediators
• kill antibody-coated parasites
Natural Killer cells:
 • kill virus-infected cells by releasing lytic granules
Complement:
• soluble proteins that form a complex to destroy microorganism.
Complement components have immunologic activity individually and in
activation cascade leading to a polymer formed by C5, C6, C7, C8, and C9
(the membrane attack complex or MAC) and thus in lysis of target cell
membranes. MAC is involved in host defence against Neisseria infection.
The complement is involved in opsonisation and phagocytosis (C3) and
also increases vascular permeability by a direct stimulation of mast cells
and basophils, releasing histamine. Deficiency of certain components (C1,
C4, C2) is increased in autoimmune diseases secondary to impaired
clearance of immune complexes. It acts as “anaphylatoxin” and it is
chemotactic (C3a and C5a) for phagocytic neutrophils.
• Three pathways are involved in activation of the complement:
1. Classical – the binding of IgM and IgG to antigen forming immune
complexes activating C1 sequences. Other molecules can activate this
pathway such as: C reactive protein, C4 nephritic factor and serum amyloid
P.
2. Alternative – is characterized by the absence of antibody, being activated
by the lipopolysaccharide on microbial cell surfaces.
3. Lectin – mannan – binding lectin is secreted by the liver and binds to
microbial ligands. These activates the associated proteases and lead to
complement activation by the cleavage of C4.
Cytokines:
• proteins secreted by cells that affects the behavior of nearby cells bearing
appropiate receptors

ADAPTIVE IMMUNITY

Adaptive immunity can cause damage (by recruiting components and

augmenting the functions of innate immunity) and death to the host. This is due
to the fact that the antigens expressed by the pathogens recognised by the
adaptive immunity are not so different from the host’s own molecules. So, the
antigen receptors of the adaptive system cannot be preselected to recognize only-
pathogen expressed antigens.
Adaptive immunity
• Develops in response to an infection
• Protective against specific pathogens
• Leverages components of the innate response
• Develops memory, colide may provide lifelong immunity to reinfection
with the same pathogen

Components of adaptive immunity

T cells:
• according to their antigen specificity (function), T lymphocytes are
divided in 2 major classes CD4+ T cells and CD8+ T cells.
• CD4+ T cells – helper T cells – orchestrate and regulate immune responses.
There are 4 subsets of helper T cells: Th1, Th2, Th 17 and Treg cells.
• Th1 cells: help for cytotoxic T cell, help for B cells (instruct B cells to
develop into plasma cells, opsonisation of antibodies), help for macrophage
activation
• Th2 cells: help for B cells (barrier antibodies), help for “alternative
macrophage activation”
• Th 17 cells: help for acute inflammation (recruitment of neutrophils)
• Treg cells: suppress the responses of other cells (eg. dendritic cells and/or
other lymphocites)
• CD8+ T cells – cytotoxic T cells – kill cells infected with viruses or other
intracellular pathogens
TCR – T cell receptor – antigen receptor conferring antigen specificity to
the T cell. T cells can’t recognize free soluble antigen. They need the T cell
receptor, only binding to antigen linked to MHC (major histocompatibility
complex) molecule on the surface of the antigen-presenting cell (APC).
• T cell activation requires 2 signals:
1. Implication of the T cell receptor by the antigen/MHC complex
2. Direct interaction between co stimulatory cell surface molecules on
the antigen presenting cell and T cell. Except for CTLA4-/B7 interactions,
 all the other co stimulatory pairs are upregullating the T cells. Also, CTLA-
4 has a higher affinity than CD28 to B7. Biologic treatments have been
developed to interfere with these interactions in order to treat
autoimmune diseases.
Lacking one of the signals will lead to apoptosis.
MHC – is a group of genes located on human chromosome 6. 2 Types of
MHC are most encountered:
• Class I MHC – expressed on the surface of all nucleated cells.
• Class II MHC – expressed on antigen presenting cells.
B cells:
• antigen presentation
• produce antibodies in response to antigens
• cytokine secretion
Antibodies:
• bind the antigens to neutralize them or to facilitate destruction of
microorganisms. The antibodies are active participants in immune and
inflammatory responses by: coating and neutralising invading organism,
activating the complement (IgM, IgG) and improving the phagocytosis by
opsonisation.
• The major classes of antibodies are:
G – IgG – fixes the complement. It is found in serum and penetrates the
tissues.
A – IgA – it is involved in host defence at mucosal surfaces (sites of antigen
entry).
M – IgM - fixes the complement. It is the first antibodie as response to the
antigen. It is involved in host defence against blood – borne antigens.
E – IgE – binds to the surface of mast cells and basophils – releasing
histamine when cross-linked. It is involve din host defence against
parasites.
Cytokines:
• proteins secreted by cells that affects the behavior of nearby cells bearing
appropiate receptors. Cytokines regulate many biological processes,
including inflammatory and immune responses. The complex network of
 cytokines balances pro-inflammatory and anti-inflammatory effects. An
imbalance between pro and anti-inflammatory cytokines or the
uncontrolled production of cytokines can result in inflammatory disease.
• Pro – inflammatory cytokines: Il-1, TNF, Il-6, IFN, Il-17, Il-18, TGF, IL-
8, GM-CSF and other chemokines.
• Anti – inflammatory cytokines: Il-4, Il-10, monoclonal antibody to TNF,
Il-1RA etc.

Autoimmune diseases can result from activation of adaptive immune responses

against intrinsic (harmless) components of the host itself or against extrinsic
(non-infectious, foreign) agents from the environment. The mechanisms causing
the damage are mediated by:
• antibodies
• large immune complexes
• T cells that abnormally activate macrophages
• cytotoxic T cells
In autoimmune diseases we are dealing with a defective mechanism of tolerance
induction. Others mechanisms are involved as well, such as:
• activation of autoreactive B cells
• secretion of antibodies against the normal components – autoantibodies.
So a cytotoxic effect is induced and the consequence will be the tissue
damage (mediated by the cells that interact with the autoantibodies).
Another way is to block the binding of molecules to their receptors – the
direct inhibition of the normal function of the cells of the body (eg.
myasthenia gravis: the autoantibody blocks the transmission of the nerve
impulses to muscles such leading to progressive paralysis)
• production of immune complexes (IC); the fail of removing the IC can
lead to inflammation preventing normal functioning of certain organs (eg.
kidney damage in systemic lupus erythematosus)
• induction of T cells – mediated responses against self antigens, such
activating the main mediators of damage – the cytotoxic T cells or
macrophages. This response is encountered in insulin-dependent (Type I)
diabetes.
So the previous paragraph outline the four main types of the immune responses
as described by Gell and Coombs. According to them we can classify the immune
related diseases as:
1. Diseases caused by IgE antibodies (Type I: allergic hypersensitivity)
IgE antibodies cause allergy and anaphylaxis by acting through mast cells.
Treatment of less severe reactions includes anti-histamines and non-
steroidal anti-inflammatory drugs.
2. Diseases caused by antibody-dependent modulation of function
(Type II: cytotoxic hypersensitivity)
IgG and IgM can modulate cell function directly, by killing the cell (eg.
haemolytic anaemia) or by blocking or stimulating receptors (eg.
myasthenia gravis).
3. Diseases mediated by immune complexes (Type III: hypersensitivity)
Immune complexes can cause acute inflammation locally or systemically
(eg. SLE or Farmer’s lung).
4. Diseases caused by cell-mediated immune responses (Type IV:
delayed – type hypersensitivity)
Cell – mediated (antibody - independent) immunopathology is usually due
to Th1 – biased responses involving cytotoxic CD8 T cells and/or activated
macrophages (eg. type I diabetes or contact sensitivity)

Sensitisation
 Immediate hypersensitivity:
rapid (acute) inflammation
minutes to hours

Fig. 2.1 Immediate and delayed – type Delayed hypersensitivity:

slow onset (chronic)
hypersensitivity reactions (adapted from inflammation over days

MacPherson  Austyn)
Immediate hypersensitivity consists in a very rapidly inflammatory response
(minutes to hours) in a person that has been sensitized to a particular antigen and
is challenged with the same antigen (eg. allergy, Farmer’s lung). It only occurs in
cases with pre-formed antibody.
Delayed hypersensitivity takes 24 to 48 h to occur. The delayed response is due
to time taken to reactivate and expand memory cells, but the response in fact is
accelerated relative to the primary T cell response that occurs during
sensitization.

IMMUNE BASED THERAPIES

Antigen - based therapies

The most common antigen – based therapy is vaccination (eg. stimulate protective
immunity against an infectious disease). Antigens are used to decrease or alter the
immune response. How? By inducing tolerance antigen unresponsiveness in
trigerring suppressive mechanism mediated by regulatory T (Treg) (eg. treatment
of allergies). Antigens can be used to reduce specific immune responses
(desensitization).
Vaccination against cancer and infectious
disease
AG +
AG - Desensitization for allergies

Fig. 2.2 Antigen – based vaccines (adapted from MacPherson  Austyn)

Antibody – based therapies

Antibodies are used to block the activity of certain molecules such as cytokines or
to inhibit or deplete cell populations expressing specific molecules. (eg.
rheumatoid arthritis – anti TNF therapies). The depletion of antibodies that
cause damage (eg. plasmapheresis) is another therapeutically option (eg.
vasculitis).

Passive vaccination against autoimmune and infectious

Ab diseases
+
 Therapeutic antibodies for autoimmune diseases, cancer and
Ab
- transplant

Fig. 2.3 Antibody – based therapies (adapted from MacPherson  Austyn)

Adoptive cell – based therapies

In chronic infections and tumours, antigen-specific lymphocytes or dendritic cells
(DCs) can be transferred to stimulate or modulate ongoing responses. Treg have
been used to suppress transplant rejection and experimentally used for the
treatment of autoimmune diseases.

Immunotherapy against cancer and chronic infectious diseases

T Cells
DC +++
Treg Immunotherapy for autoimmune diseases and prevention of transplant

_____ rejection

Fig. 2.4 Cell – based therapies (adapted from MacPherson  Austyn)

Immunosuppresive drugs
They were developed mainly for their anti-inflammatory effects in order to
control autoimmune diseases and to prevent transplant rejection. They can
interfere with key intracellular signalling pathways in cells such as T cells.

Cytokine therapy
The management is relying in the potency and selectivity of cytokines. Initially,
the drugs developed were aiming the cancer and chronic infections such as
hepatitis B and C (eg. type I interferons – IFNs, Il-2). Growth factors can be used
to mobilise cells (eg. neutrophils) from the bone marrow when their number is
reduced.

TAKE HOME MESSAGES

• Two signals are needed for the T cells to be activated.

• Autoimmune diseases are characterized by defective mechanisms of
tolerance induction.
 • Four main immune responses are known: type I: allergic hypersensitivity,
type II: cytotoxic hypersensitivity, type III: hypersensitivity, type IV:
delayed – type hypersensitivity.
• Immune based therapies are used in order ameliorate the outcome of
autoimmune diseases and also to suppress their side effects.

References :

3. MacPherson G, Austyn J, Exploring Immunology – Concepts and Evidence,

ed. Wiley Black, 2012, 351: 259-298
4. West S, Rheumatology Secrets second edition, ed. Hanley  Belfus, 2002,
695: 12-22

3. RHEUMATOID ARTHRITIS

DEFINITION

Rheumatoid Arthritis (RA) is a chronic, inflammatory, systemic, autoimmune

disorder affecting primarily cartilage and bone of small and middle-sized joints.

The course of disease is highly variable, ranging from mild cases with non-erosive,
even sometimes spontaneously remitting disease,to severe, rapidly progressive
and destructive RA. Recent analysis of genetic risk factors,autoantibody responses
and therapeutic studies suggests, however, that clinical RA might consist of
pathogenetically distinct subgroups, and that different treatment strategies
should be applied to patients within these groups.

RA is considered an autoimmune disease, implying breakdown of immunological

tolerance towards self at a given point in a patient’s life. The trigger initiating this
breakdown is so far unknown.
CLASSIFICATION OF RA

1. Auto antibodies:
• ACPA positive RA
• ACPA negative RA

• RF positive RA
• RF negative RA (better prognosis, better survival, less extra-articular
manifestations)

2. The onset
• Very early RA
• Early RA
• Chronic RA

EPIDEMIOLOGY

RA affects approximately 0.5-1% of European and North-American adults.

Prevalence is estimated as 3.3 to 10.7 per 103 cases (South Europe - USA).
Annual incidence rates are estimated to be 16.5 to 38 cases (per 105) in Southern
Europe and USA,
Women are more frequently affected than men (a ratio of 0.3).

PATHOGENESIS

Witebsky postulated that a disease must fulfill three criteria to be considered

autoimmune in nature:
1) the presence of autoantibodies or a cell-mediated immune response against an
autoantigen

The presence of rheumatoid factor (RF), an autoantibody, targeting the Fc-part of

human IgG in the blood of the RA patients, is a prove for the first postulate. They
form immune complexes activating complement in the joint leading to release of
chemotactic factors (recruiters of effectors cell in the joint) and increased vascular
permeability.

The autoantibody most likely directly related to RA-pathogenesis, targets proteins

containing the atypical amino-acid citrullin. Citrullination is a process by which
arginine residues in a given protein are posttranslationally modified in the
presence of relatively high calcium-concentrations by an enzyme called PAD
(peptidyl arginine deiminase). Citrullination means degradation of intracellular
proteins during apoptosis. New anti-citrullinated protein antibodies (ACPA, anti-
CCP) are directed against the citrullinated fillagrin. The ACPA are present in about
50% of the patients with RA.

2) the autoantigen is known (is usually known, demonstrating pathogenetic

relevance of the respective autoantibody has proven far more difficult)

3) a similar disease can be initiated in animals based on an analogous immune

response (4). (hard to be proven)

Factors involved in the pathogenesis of RA

1. Genetic factors

Fifty percent of the variation in prevalence of RA is caused by genetic factors.

(proven by the concordance rates in monozygotic twins).

The most relevant genetic factor is the shared epitope. Is found in HLA class II
molecules on chromosomal location 6p21.3. Several HLA-DRB1 molecules (*0101,
*0102,*0401, *0404, *0405, *0408, *1001 and *1402) share a common amino acid
sequence at position 70-74 in the third hypervariable region of the DRβ1-chain.
This sequence consists of glutamineleucine-arginine-alanine-alanine (QKRAA),
QRRAA or RRRAA. The shared epitope is implicated in the binding of a putative
arthritogenic peptide. The amino acids at position 70 and 71 flanking positions
72-74 (RAA) seem to modulate the T cell response, thus influencing the risk
conferred by the shared epitope to the development of RA.

2.The Environmental Factors

• factors promoting citrullination of proteins
• triggers of innate immunity

Infections:
• Mycobacteria,
• Epstein-Barr Virus,
• Parvovirus B19 etc.

Smoking confers an increased risk for the development of RA (ACPA positive RA,
and a more severe evolution of RA). Smoking induces an anti-citrullin specific
immune response by inducing apoptosis and subsequently citrullination in
alveolar cells.

Coffee consumption is associated with ACPA positive RA.

Alcohol seemed to have a protective effect on the development of ACPA-positive

RA.

High body-mass index is related with ACPA-negative RA.

Other (presumed) risk factors:

• mineral oils (e.g. motor oils, hydraulic oils etc.) was found to be a risk
factor for ACPA-positive RA in males in a Swedish cohort.
• sex hormones and reproductive factors (female predominance)
• pregnancy

The immune system in RA

The trigger of the immunological tolerance breakdown in RA, is still unknown.

Known facts:
• the synovium in RA is infiltrated by T cells, B cells, mast cells, neutrophils,
 monocytes
• the T and B lymphocytes, the mast cells, the neutrophils and monocytes
proliferate and produce proinflammatory cytokines/chemokines (eg. Il1,
Il6, TNFα, IFN-Υ etc.) in the synovium
• additional effector cells are recruited alongside with vascular growth
factors
• the vascular growth factors promote neovascularisation and vascular
leakage
• the synovial fibroblasts and osteoclasts are activated, thus promoting the
degradation of the bone and cartilage
• the T cells – MHS class II (the effectors that recognize the autoantigen as
foreign) are activated via antigen presenting cells (eg. dendritic cells, B
cells)
• in RA the regulatory T cells (Treg) are incapable of controlling the
activation and reactivation of the effectors cells (also T cells)
• the myth: RA was considered a Th1-mediated autoimmune disease- was
due to the lack of Th2
• Th1 cell – correlates with proinflammatory cytokines: Il1, Il6, Il12, IFNΥ
and TNF α – the main activator of monocytes
• Th2 cell – correlates with noninflammatory cytokines: Il2, Il4, Il10
• the newcomers: Il 23, Il 17, Th 17
• Il 12 shares a common subunit with Il 23
• Il 23 is found in sera, synovial fluid and synovial biopsy
• Il 23 is one of the drivers of Il 17 production
• Il 17 is an activator of macrophages, thus leading to production of
proinflammatory cytokines such as TNFα
• Th 17 – Il 17, TNFα, Il 6, Il 22, GM-CSF
• B – cells roles:
➢ cytokine production (Il6, TNF, IL10)
➢ antigen presenting cells
➢ modulation of T cell responses
➢ autoantibody production
 • Mast cells – involved in driving local synovial inflammation
• Monocytes/macrophages roles:
➢ strong phagocytic activity,
➢ antigen presentation,
➢ secretion of proinflammatory cytokines,
➢ expression of Fc-receptors responsive to (auto-) antibodies
➢ expression of immune complexes,
➢ complement activation and regulation,
➢ fibroblast activation
➢ tissue degradation
➢ remodeling
➢ toll like receptor (TLR) expression
• The fibroblast and osteoclasts roles:
➢ the destruction of cartilage and bone
➢ the degradation of cartilage is due to the synovial fibroblast
➢ the bone degradation is due to the osteoclasts
➢ the degradation of cartilage is due to the secretion of matrix
metalloproteinases (MMPs) - MMP-1, -3, -13, -14 and - 15 and cathepsins
B, K, L.
• Osteoclastogenesis, is the differentiation of osteoclasts from precursor
cells.
• Osteoclastogenesis requires M-CSF and the presence of an osteoclast
differentiation factor (ODF).
• the ODF is similar /identical with RANKL (receptor activator of NKkB
ligand), osteoprotegrin ligend (OPG-L) and TRANCE (TNF related
activation induce cytokine).
• RANKL is present in RA patients.
• RANKL is expressed by T cells, synovial fibroblast and neutrophils.
• Osteoclastogenesis is down regulated by the Th1 cells (IFNΥ), the Th2 cells
(IL4, Il10), Il12 and Il18.

CLINICAL MANIFESTATIONS
The onset of the disease:
• acute
• subacute
• insidious and gradual (the most common)

B symptoms:
• low grade fever
• fatigue (loss of energy)
• weight loss

Common symptoms:
• pain (typical - small joints involvement)
• small joints swelling
• stiffness (morning and after resting stiffness that lasts more than 30
minutes)

Other symptoms:
• extra-articular manifestations (pleuritis, pericarditis etc.)

Joints involvement:
• symmetrical
• mono, oligoarthritis – less common
• poliarthritis – more common
• joints first invoved - swelling of the proximal interphalangeal
(PIP) joints, the metacarpophalangeal (MCP) joints, the wrists and the
metatarsophalangeal (MTP) joints
• the DIP joints are not usually part of the clinical tableau (differential
diagnose with psoriatic arthritis)
Common deformities of the joints:
• Fusiform swelling (spindle shape fingers) – synovitis of PIP joints
• Swan-neck deformity – contraction of the flexors of the MCPs, the flexor
contraction of the MCP joint, hyperextension of PIP, flexion of DIP joint
 • Boutonniere deformity – flexion of the PIP, hyperextension of the DIP
joints
• Ulnar deviation of fingers
• subluxations of MCPs
• “Piano key” ulnar head secondary to destruction of the ulnar collateral
ligament
• Claw/hammer toe – inflammation of the MTP joints with subluxation of
the metatarsal heads.

The dorsal and the lombar spine are not usually involved in RA.
Thirty to fifty patients with RA are complaining of the cervical spine. The C1-C2
is the most commonly involved level. The pattern of the cervical spine
involvement is:
C1-C2 subluxation - (atlantoaxial) subluxation
• anterior subluxation is caused by synovial proliferation around the
odontoid process and the C1 arch, thus leading to the rupture of the alar
and transverse ligaments. It is more than 3 mm between the arch of C1 and
the odontoid of C2. The ris of spinal cord compression is when the anterior
atlanto-odontoid interval is more than 9mm or the posterior atlanto-
odontoid interval is less than 14 mm.
• vertical subluxation - is the result of collapse of the lateral articulations
between C1-C2. The odontoid impinge the brainstem.
• lateral
• posterior
C1-2 impactions – destructions between the occipitoatlantal and atlantoaxial
joints.
Subaxial involvement – the C2-C3, C3-C4 facets and intervertebral disks are
involved.

Tenosynovitis, bursitis and carpal tunnel syndrome may be the first

manifestations of RA.

Extraarticular manifestations in RA
Pulmonary manifestations
a. Pleural disease – pleural effusion, pleurisy
Pleural effusion is characterized by:
• cellular exudates
• high protein levels
• high lactate dehydrogenase levels
• low glucose levels
• low ph (infections)
b. Nodules
Its can be solitary or multiple. Its can resolve spontaneously or cavitate.
Caplan’s syndrome equals coil miners with RA and pulmonary rheumathoid
nodules.
c. Interstitial pulmonary fibrosis (IPF) – fibrosing alveolitis
Is characterized by dyspnea, Velcro rales and primary fibrosis (lower lobes). A
rapid progression of IPF is called Hamman-Rich syndrome.
d. Bronchiolitis obliterans (BO) – Attention to the side effects of
Penicilamine!!! Patients are complaining of dyspnea. It can be visualized
hyperinflated chest x-rays and small airways obstruction on pulmonary
function test.
e. Bronchiolitis obliterans with organizing pneumonia (BOOP)
f. Nonspecific interstitial pneumonitis (NSIP)

Cardiac manifestations
a. Pericarditis – can lead to pain, tamponade (rare), constriction (uncommon)
b. Nodules – valvular problems, conduction abnormalities
c. Coronary arteritis – myocardial infarction
d. Myocarditis – congestive heart failure

Ocular manifestations
a. episcleritis
b. scleritis
c. retinal nodules
 d. choroid nodules

Dermatologic manifestations
a. vasculitis
Types of vasculitis in RA:
• Leukocytoclastic vasculitis (inflammation of postcapillary venules)–
palpable purpura
• Small arteriolar vasculitis – infarcts of digit pulp + distal sensorial
neuropathy (vasculitis of vasa nervorum)
• Medium vessel vasculitis – livedo reticularis, visceral arteritis +
mononeuritis multiplex
• Pioderma gangrenosum
b. subcutaneous nodules
c. palmar erythema

Neuromuscular manifestations
a. mononeuritis multiplex
b. peripheral neuropathy
c. entrapment neuropathy – median nerve (carpal tunnel), posterior tibial
nerve (tarsal tunnel), ulnar nerve (cubital tunnel), radial nerve –
interosseous branch

Hematologic manifestations
a. Felty’s syndrome – splenomegaly, leukopenia
b. Lymphomas
c. Large granular lymphocyte syndrome

Others
Sjögren’s syndrome
Amyloidosis – AA associated amyloidosis – poor controlled RA – nephrotic
syndrome

Miscellaneous manifestations:
Palindromic rheumatism – affects the large joints, lasts a few hours, days and
remits spontaneously.
RS3PE syndrome – acute severe onset of symmetrical synovitis of the small joints
of the hands, wrists and flexors sheats plus pitting edema of the dorsum of the
hand (“boxing glove” hand). Ussually affects 70 years old Caucasian males. All
patients are RF negative.

LABORATORY FINDINGS

1. Inflammatory markers
• ESR (erythrocyte sedimentation rate) elevated
• CRP (C-reactive protein) elevated
2. Antibodies
• RF (rheumatoid factor) – is a series of antibodies that recognize the
Fc portion of an IgG molecule as it’s antigen. Isotypes of RF: IgG, IgA,
IgM, IgE.
• anti - CCP antibodies
• ANA (antinuclear antibodies)
3. thrombocytosis – active disease
4. leucocytosis – active disease
5. low levels of hemoglobin - anemia
6. serum iron – low levels – acute phase reaction
7. ferritin – high levels – acute phase reaction
8. serum albumin – low levels – negative acute phase reactant
9. Synovial fluid is characterized by:
• inflammatory pattern
• WBC (white blood cells) 5000-50.000/mm3
• > 50% of PMN’s
• elevated protein level
• low glucose level
• negative cultures
 • no crystals

IMAGISTIC FINDINGS

Radiographic features of RA – ABCDE’S

Conventional radiography is still the golden standard in RA.
A – Alignment, abnormal, no ankylosis
B – Bones – periarticular (juxta-articular) osteoporosis, no osteophytes or
periostitis
C – Cartilage – uniform joint space loss in weight bearing joints, no cartilage or soft
tissue cacification
D – Deformities – boutonniere, swan neck, ulnar deviation – symmetrical
distribution
E - Erosions, marginal
S – Soft tissue swelling, nodules without calcifications

Ultrasound in RA
It is an extension of the clinical exam. It can show the synovitis of the involved
joints, erosions (at an early stage of the disease) and tendinitis/tenosynovitis.

MRI can depict the erosions of the wrist and fingers earlier than ultrasound. The
marrow edema shown in MRI is not a patognomonic sign in RA. It reveals only a
site of inflammation.

CLASSIFICATION CRITERIA

The 2010 American College of Rheumatology/European League Against

Rheumatism classification criteria for rheumatoid arthritis

Target population (Who should be tested?):

Patients who
1) have at least 1 joint with definite clinical synovitis (swelling)
2) with the synovitis not better explained by another disease
Classification criteria for RA (score-based algorithm: add score of categories A–D;
a score of ≥ 6/10 is needed for classification of a patient as having definite RA)

A. Joint involvement
1 large joint 0
2 to 10 large joints 1
1 to 3 small joints (with or without involvement of large joints) 2
4 to10 small joints (with or without involvement of large joints) 3
>10 joints (at least 1 small joint) 5

B. Serology (at least 1 test result is needed for classification)

Negative RF and negative ACPA 0
Low-positive RF or low-positive ACPA 2
High-positive RF or high-positive ACPA 3

C. Acute-phase reactants (at least 1 test result is needed for classification)

Normal CRP and normal ESR 0
Abnormal CRP or abnormal ESR 1

D. Duration of symptoms
< 6 weeks 0
≥ 6 weeks 1

DIFFERENTIAL DIAGNOSES

1. Osteoarthritis/ hand osteoarthritis

2. Psoriatic arthritis
3. Spondylarthopathies
4. Polymyalgia rheumatica with peripheral arthritis
5. Reactive arthritis
6. Acute sarcoid athropathy (Löfgren’s syndrome)
7. Systemic Lupus Erythematosus
 8. Other connective tissue diseases
9. Gout (tophi)
10. Amyloidosis
11. Sarcoidosis
12. Xanthoma
13. Rheumatic Fever

DISEASE ASSESSMENT

The activity of the disease can be quantified by different indexes. The most
common used are:

Disease Activity Score - DAS 28 consists of: 28-swollen joint counts (28-SJC) and
28-tender joint counts (28-TJC) in addition to patient global assessments of
disease activity on a visual analogue scale (VAS) and erythrocyte sedimentation
rate (ESR) or CRP (C reactive protein).

Simplified Disease Activity Index (SDAI) includes 28-SJC and 28-TJC, patient and
investigator global assessments of disease activity on a VAS and C-reactive protein
(CRP).

Clinical Disease Activity Index (CDAI) is the SDAI without the lab assessment.

PROGNOSTIC MARKERS
The known predictors of structural damage are: RF, anti-CCP antibodies, acute
phase reactants, the erosive disease.
The mortality predictors are: extraarticular manifestations, comorbidities, age,
physical status, education, RF.
The major cause of death among RA patients is cardiovascular and
cerebrovascular diseases. Male sex and age at disease onset have been found to
predict both the occurrence of cardiovascular events and death. Alongside with
the cardiovascular events an increased moratlity is due to disease activity, age,
level of education, comorbidities and corticotherapy.
TREATMENT

DMARD – “disease modifying” drug that has a positive impact on radiological

outcome of joint damage (erosions and joint space narrowing).

The front line DMARDs are:

• Methotrexate – MTX
• Sulfasalazine – SSZ
• Hydroxycloroquine – HCQ
• Leflunomide

The less used DMARDs are:

• Azathioprine – AZA
• Gold
• Minocycline
• Ciclosporin
• D- Penicillamine – D-Pen

The benefits of DMARDs are:

• Control of sign and symptoms – joint involvement
• Improvement of functional status
• Improvement of quality of life
• Retardation of radiographic evidence of erosions

TREATMENT OBJECTIVES – EARLY REMISSION

 number of swollen and tender joints

 morning stiffness
 synovitis
 fatigue
 acute phase reaction
A. NON BIOLOGIC DMARDS – first line of treatment

1. Methotrexate (MTX) is the golden standard of the therapy in RA. Methotrexate

proved to be efficient on radiographic progression. It inhibits the:
• pyrimidinie synthesis – (DNA)
• de novo purine synthesis – (DNA, RNA)
• the depletion of tetrahydrofolate (protein synthesis, RNA, DNA)
MTX is:
• absorbed rapidly, completely after dosage not exceeding 30mg/m2
• postabsortion 50-70% bounds to plasma protein (albumin)
• transported via an active carrier-mediated system into the hepatic cells
beeing converted to MTX polyglutamate
• 80-90% renal excrete
•  % biliary excreation

Dose: 20-25 mg/ w orally, parentally (EVP, sc, im)

Predisposing factors for toxicity:

• increased dose
• Prolonged exposure
• Advanced age
• Renal insufficiency
• Concomitant use of other antifolates
• Liver fibrosis – rare (monitoring- AST, ALT; no liver biopsy)

Hypersensitivity do not correlate with:

• Cumulative dose
• Age
• Way of administration

Risk is due to:

 • Age
• Diabetes
• Previously lung disease
• ≠ Pneumocystis jerovici pneumonia
SMOKING – is not a risk factor for MTX treatment.
Side effects:
• 3% - leucopenie, trombocytopenia, megaloblastic anaemia, pancytopenia
• Subcutaneous rheumatoid nodules
• MTX is teratogenic – no - pregnancy (appropiate contraceptive measures)

2. Leflunomide is an izoxazole derivate. It’s active metabolite is malonitrilamide

A77 1726.
It inhibits the de novo pirimidine synthesis, thus inhibiting the proliferative and
anti-inflammatory effects.
It suppresses the TNF α induced cellular responses.
It inhibits the MMP (matrix metalloproteinases) and the osteoclasts.
T1/2 is 15 days.

Dose: 20mg/day po; in remission the dose is 10mg/day po.

Wash out – cholestiramine 3x8g/d 11 days.
No wash out – 2 years.

Contraindication:
• Obstructive biliary disease
• Liver disease
• Viral hepatitis
• Severe immunodeficiency
• Rifampicin treatment

Side effects:
• Diarrhoea
• Alopecia
 • Rash
• Leucopenia
• Hepatotoxicity
• Hypertention
• teratogenic/fetal death

3. Sulfasalazine ia a 5 aminosalicylic acid derivate.It is metabolised via colonic

intestinal flora. It’s active metabolites are: sulfapyridine, 5-amino-salicylic acid (5-
ASA).

Dose: 2-3 g/day.

Side effects
• Gastrointestinal
• Central nervous system toxicity – headache; dizziness
• 4-5% rash
• myelosuppresion !!!
• fever + rash+ abnormal liver function – viral illness

4. The antimalarial agents - Hydroxicloroquine (HCQ), Cloroquine (CQ) are 4

– aminoquinoline derivatives. Its absorbed from the gastrointestinal tract.

Dose: the onset 1200mg/d then 400mg/d.

Retinal toxicity :
• HCQ > 6.5 mg/kg/w
• CQ > 3mg/kg/w
• More than 10 years of treatment
• Impaired renal or liver function
• Age > 60 years old
• Obesity
• Macular degeneration
 • History – previously antimalarial drugs
• Rarely – myopathy (HCQ)

5. Cyclosporin is a fungal peptide with immunosuppressive properties. Inhibits

the proliferation and activation of T cells and the secretion of the proinflammatory
cytokines. The efficiency of Cyclosporin was proven in association with MTX.

Side effects
• Hypertrichosis
• Tremor
• Gum hyperplasia
• Hypertension
• Dose related with the loss of renal function

Dose: 2.5 mg/kgc –increased with 0.5-0.75 mg/kgc

6. Other DMARDS
Azathioprine (Imuran)
• Immunossupresor
• Mielossupresion
• Risk of lymphoma, non-melanoma skin cancer
• Hepatotoxicity
D-Penicillamin
• Tetracycline derivates – inhibits metalloproteinase activity involved in
joint destruction
• Adjunctive therapy in early RA

B. BIOLOGIC DMARDS – second line of treatment

a. Anti TNFα
• Infliximab
• Etanercept
• Adalimumab
 • Golimumab
• Certolizumab
b. LyB - anti CD 20
• Rituximab
c.Co-stimulation
• Abatacept
d. Il-1
• Anakinra
e.Il6
• Tocilizumab

a. Anti TNFα
1. INFLIXIMABUM (REMICADE)
It is a human murine chimeric antibody.
Dose: 3 mg/kgc PEV 0-2-6-8 weeks afterwards increasing the dose (if not LDA or
remmission) till 10mg/kgc.
2. ETANERCEP (ENBREL)
It is a recombinant TNFα receptor fused to a human Fc molecule creating a TNFα
binding agent.
Dose: 50mg sc weekly.
3. ADALIMUMABUM (HUMIRA)
It is a human antiTNFα antibody.
Dose: 40mg sc bimonthly.
4. GOLIMUMABUM (SIMPONI) similar with Infliximab but it is given once monthly
sc.
5. CERTOLIZUMABUM (CYMZIA) is a humanised pegylate antiTNFα antibody.
Dose:
• 2, 4 week 400mg (2x200mg)
• 400mg monthly .
B. RITUXIMAB (MABTHERA) is a monoclonal chimeric (huminised and murine
sequences) anti CD20 antibody.
C. TOCILIZUMAB (RoActemra) is an inhibitor of IL 6 receptor.
Dose: 4mg/kgc lunar PEV
D. ANAKINRA is a recombinant Il 1 antagonist.
E. ABATACEPT (ORENCIA) is a soluble recombinant fully human protein that
comprises the extracellular domain of CTLA4 and the Fc portion of the IgG1
molecule that has been modified to prevent complement activation.

C. NON DMARD therapies

Glucocorticosteroids
• Prednisolone – the most used
• Dexamethasone

Pleiotropic effects:
• Immunosupressive effects
• Anti-inflammatory effects
• Rapid and effective mode of action
• Adm.: per os, PEV (pulse therapy), ia – thumb rule (no > 4 adm. at the same
joint/year; metilprednisolone, triamcinolone + derivates)

Dose: low - 10 mg/d, high 10-30mg/d

NSAIDS + COXIBS
• Pathophysiological mechanisms
Nociceptive pain:
• Inflammation
• OA
Non-nociceptive pain due to sensitization:
• Secondary fibromyalgia
Neuropathic pain:
• Carpian tunnel syndrome

EULAR evaluation:
• Gastrointestinal
• Cardiovascular
 • Renal

TAKE HOME MESSAGES

RA is an independent risk factor for cardiovascular disease.

In patients with early RA, anti-CCP antibody positivity is an excellent predictor for
the outcome of the disease.
Not all destructive polyarthritis is rheumatoid or psoriatic arthritis.
Remission or low disease activity are the target in RA.

References:
1. Bijlisma WJJ, Eular Compendium on Rheumatic Diseases, BMJ Publishing
Group, 2009, 824: 61-91
2. West S., Rheumatology Secrets, 14: 117-128, Hanley and Belfus, 2002, 695:
117-127
3. Schellekens,G.A., de Jong,B.A., van den Hoogen,F.H., van de Putte,L.B., and
van Venrooij,W.J. 1998. Citrulline is an essential constituent of antigenic
determinants recognized by rheumatoid arthritis-specific autoantibodies.
J.Clin.Invest 101:273-281.
4. Girbal-Neuhauser,E., Durieux,J.J., Arnaud,M., Dalbon,P., Sebbag,M.,
Vincent,C., Simon,M., Senshu,T., Masson-Bessiere,C., Jolivet-Reynaud,C. et
al. 1999. The epitopes targeted by the rheumatoid arthritis-associated
antifilaggrin autoantibodies are posttranslationally generated on various
sites of (pro)filaggrin by deimination of arginine residues. J.Immunol.
162:585-594.
5. van Gaalen,F., Ioan-Facsinay,A., Huizinga,T.W., and Toes,R.E. 2005. The
devil in the details: the emerging role of anticitrulline autoimmunity in
rheumatoid arthritis. J.Immunol. 175:5575-5580.
6. Kuhn,K.A., Kulik,L., Tomooka,B., Braschler,K.J., Arend,W.P., Robinson,W.H.,
and Holers,V.M. 2006. Antibodies against citrullinated proteins enhance
tissue injury in experimental autoimmune arthritis. J.Clin.Invest 116:961-
973.
7. Astorga,G.P. and Williams,R.C., Jr. 1969. Altered reactivity in mixed
 lymphocyte culture of lymphocytes from patients with rheumatoid
arthritis. Arthritis Rheum. 12:547-554.

4. SJÖGREN’S SYNDROME

DEFINITION

The Sjögren’s syndrome (SS) is a systemic autoimmune disease, characterized by

lymphocytic infiltrates of salivary and tear’s glands leading to ocular and mouth
dryness, and by autoantibody secretion.

“European American consensus group criteria” (EACG) stated that the presence of
an objective immunological abnormality, either focal lymphocytic infiltrates in
minor salivary glands achieving a focus score of 1 or more, or anti SSA/SSB
autoantibody secretion can outline the diagnosis of SS.

Classification
1. Primary Sjögren's syndrome, pSS: no underline cause.
2. Secondary Sjögren’s syndrome:
• rheumatoid arthritis
• systemic lupus erythematosus
• inflammatory myositis
• systemic sclerosis
• autoimmune thyroiditis
• primary biliary cirrhosis

EPIDEMIOLOGY

• common disease
• 0,1% to 0,4% of the general adult population
 • the second most frequent systemic autoimmune disease after rheumatoid
arthritis
• female to male ratio at least 9:1
• the age peak of the disease occurs after menopause in the mid-50s

PATHOGENESIS

Pathogenesis – first step

• undesirable epithelial cell surface exposure of endogenous
ribonucleoproteins like SS-A, SS-B, normally hidden from the immune
system, in apoptotic blebs, or exosomes
• recruitment of plasmacytoid dendritic cells
• activation of innate immunity and interferon pathways
• BAFF secretion by dendritic cells, some salivary gland B and T
lymphocytes, and epithelial salivary and lachrymal cells.
• activation of adaptive immunity
• autoantibody secretion in patients with predisposing genetic factors
• persistent activation due to immune complexes
• anti-SSA/SSB might complex with double-stranded RNAs (Y-RNA) or
single-stranded RNA and drive the continuous stimulation of interferon-
producing cells through their Fc and Toll-like receptors.
• the persistent activation of the interferon pathways might thus be related
to a vicious circle, in which the environment interacts with genetic factors
(HLA-DR associated production of autoantibodies and subsequent
formation of immune complexes with self RNA) to drive the mutually co-
stimulatory innate and adaptive immune response.
Pathogenesis – second step
• Glandular hypofunction rather than glandular destruction is observed
• Glandular dysfunction in SS could result from immune mediated inhibition
of secretory processes rather than from glandular destruction
• Apoptosis of the salivary gland epithelial cells has been shown to be a rare
event.
 • Patients with pSS with disabling objective dryness retain large amounts
(30-50%) of histological normal salivary gland tissue.
• This residual tissue is functional in vitro and can be stimulated in vivo in
patients with pSS using systemic sialogogues.
• inhibition of neurotransmitter release by cytokines (IL-1, TNF- α)
• enhanced breakdown of acetylcholine by increased levels of cholinesterase
in pSS
• blockade of M3 receptors by antimuscarinic autoantibodies
• altered NO production and intracellular calcium mobilization
• altered fluid movement due to abnormal distribution of aquaporins (AQP)

Presumed trigger factors

Genetic factors
• HLA gene polymorphisms actually predispose to a pattern of autoantibody
secretion.
• DR15 is associated with anti-SSA antibodies only.
• DR3 is associated with anti-SSA and anti-SSB antibodies together.
Environmental factors (viruses)
• EBV (Ebstein Bar Virus)
• Retroviruses
• Hepatitis C virus (HCV)
• Enteroviruses – coxsackie
Hormonal factors
• Women are more affected between the 4th and the 6th decade
• The development of autoimmune exocrinopathy in oestrogen-deficient or
aromatase-knockout mice was noticed.
• Oestrogens and androgens regulate the lachrymal film and have
immunomodulatory functions, notably on B cells.

CLINICAL MANIFESTATIONS

Main symptoms:
 • dryness - sicca symptoms
• fatigue - common but are usually not associated with B symptoms (fever,
night sweats and weight loss). The presence of lymphoma should be
suspected if B symptoms are found.

• pain - articular and muscular pain - polyarthralgias (tender joints without

swelling) or less frequently to nonerosive polysynovitis.

Common complications
• Dry mouth: dental caries, loss of teeth, oral candidiasis
• Dry eyes: keratoconjunctivitis sicca, corneal abrasions, keratitis filiformis.
In rare cases, corneal perforations might threaten the visual prognosis.
• Parotid gland swelling (often painless), which might raise the possibility of
salivary lymphoma. MRI or parotid ultrasound can be helpful to
differentiate glandular swelling from lymphoma.
• Raynaud’s phenomenon is a common complication of SS.
• Peripheral nerve involvement of various pathogenic mechanisms
(vasculitis, cryoglobulinemia, lymphocytic infiltrates, auto-antibodies),
often purely sensory, less frequently sensory-motor. The most frequent
involvement concerns the trigeminal nerve.
• Palpable purpura is often associated with hypergammaglobulinemia or
cryoglobulinemia.
• Skin biopsy is not helpful to determine the cause of purpura, since it reveals
nonspecific leukocytoclastic vasculitis.
• Lymphadenopathy – raised the suspicion of lymphoma.
• Myositis, frequently, is subclinical or mild.
• Depression and anxiety are frequent in patients with pSS and might be
related, at least in part, to the disabling chronic symptoms of dryness, pain
and fatigue.

Severe complications
Lymphomas are the most severe complications of the disease.
Clinical predictive factors
• persistent purpura or skin vasculitis
• leg ulcers
• persistent enlargement of salivary glands, liver and spleen, or lymph nodes
• previous parotid irradiation
• peripheral neuropathy

Biological predictive factors

• presence of monoclonal immunoglobulin or urinary monoclonal light
chains of immunoglobulins
• recent decrease of previously high gammaglobulin levels
• disappearance of previously positive autoantibodies
• increased levels of β2-microglobulin
• low complement levels independently of the presence of cryoglobulins
• decreased CD4 to CD8 ratio
Pulmonary involvement:
• lymphocytic interstitial pneumonitis – FIBROSIS
• pSS – dyspnoea:
➢ arterial gasometry,
➢ measurement of carbon monoxide diffusing capacity,
➢ thin section thorax CT
➢ broncho-alveolar lavage with flow cytometry analysis
• Pneumonitis # lymphoma
➢ CT - pleurisy, pulmonary nodules or lymph node enlargement –are
clues for lymphoma
Renal involvement
Interstitial nephritis
• The most frequent
• Secondary to interstitial lymphocytic infiltrates
• Often revealed by distal renal tubular acidosis,
• Hypokalaemia and/or hypophosphatemia
• Renal failure is very infrequent in this setting
Glomerulonephritis
• Very rare
• Often associated with cryoglobulinemia and vasculitis
• Associated with increased morbidity and mortality
• Requires early diagnosis and therapeutic management
Nervous system
• sensory neuropathy related to damage to dorsal root and Gasserian
ganglia.
• Sensory-motor polyneuropathy and mononeuritis multiplex - vasculitis or
cryoglobulinemia.
• Symptomatic central nervous system - mimicking multiple sclerosis.
Gastro-intestinal complications
• pancreatitis,
• mild atrophic gastritis
• small bowel involvement
Cardiac complications
• myocarditis, less frequently pericarditis
• pulmonary hypertension + interstitial pneumonitis

LABORATORY FINDINGS

Biological inflammatory syndrome is usually absent or mild (C reactive

protein most often normal) but ESR is often increased because of the frequent
presence of polyclonal hypergammaglobulinemia.
Causes of hypergammaglobulinemia:
• Chronic parasitosis (Leishmaniasis..)
• HIV infection
• Chronic hepatitis (cirrhosis, primary biliary cirrhosis, autoimmune
hepatitis)
• Sarcoidosis
• Chronic bacterial infections (endocarditis….)
• Sjögren’s syndrome
 • Systemic lupus erythematosus –
• Lymphoproliferations (Castleman’s disease etc.)

Cytopenia is the most most frequently lymphopenia, but also thrombocytopenia

and neutropenia are present.

Hypokalemia, hyperchloremic acidosis might reveal distal renal tubular acidosis.

Type II or III cryoglobulinemia may be present. Cryoglobulinemia is associated

with decreased C4 levels by consumption. Complement levels may be decreased,
especially C4. This low C4 level may be either genetically determined or secondary
to consumption (immune complexes or cryoglobulinemia).

The presence of SSA/SSB autoantibodies is associated with higher incidence of

non-exocrine manifestations and severe complications.
Antibodies present in SS:
• RF
• antinuclear antibodies (ANA) - indirect immunofluorescence
• anti-SS-A/Ro antibodies
• anti-SS-B/La antibodies
• Anti-fodrin antibodies – research field
• Antibodies against acetylcholine muscarinic receptor M3
• Antibodies against ICA 69
3 groups of patients.:
• 1/3 without anti-SS-A or SS-B (but then mandatory positive salivary
gland biopsy),
• 1/3 with anti-SS-A antibodies alone
• 1/3 with anti-SS-A and anti-SS-B antibodies

Minor salivary gland biopsy

It is mandatory. The biopsy of the glands is performed on the endo - buccal border
of the lower lip after local anaesthesia.
The presence of dense lymphocytic aggregates, associated with acinar rare faction
and widening of salivary ducts is to be seen in SS disease.
An average « focus score » is determined based on survey of at least 4 informative
lobules. A focus is a cluster of at least 50 lymphocytes on a 4mm2 surface.
The minor salivary gland biopsy sample is considered as a diagnostic criteria
when the focus score is > 1.

DIAGNOSIS

European American Consensusal Group Criteria

1. Ocular symptoms (at least one present)

• Persistent, troublesome dry eyes every day for longer than 3 months
• Recurrent sensation of sand or gravel in the eyes
• Use of a tear substitute more than three times a day
2. Oral symptoms (at least one present)
• Feeling of dry mouth every day for at least 3 months
• Recurrent feeling of swollen salivary glands as an adult
• Need to drink liquids to aid in swallowing dry foods
3. Objective evidence of dry eyes (at least one present)
• Schirmer test ≤5 mm/5mn
• Van Bijsterveld score ≥4 (after green lissamin test)
4. Objective evidence of salivary-gland involvement (at least one present)
• Salivary-gland scintigraphy
• Parotid sialography
• Unstimulated salivary flow (≤1·5 mL per 15 min, ≤ 0,1 ml/mn)
5. Histological features
• Positive minor-salivary-gland biopsy sample (focus score >1: this refers to
a cluster of 50 or more lymphocytes per lobule when at least four lobules
are assessed)
6. Autoantibodies
• Presence of antibodies to SS-A (Ro) or to SS-B (La)
Classification of primary Sjögren's syndrome requires four of six criteria,
including a positive minor salivary gland biopsy sample or antibody to SS-
A/SS-B, - or three of the four objective criteria (criteria 3 to 6)

Classification of secondary Sjögren's syndrome requires an established

connective-tissue disease and one sicca symptom (criteria 1 or 2) plus two
objective tests for dry mouth and eyes at the time of presentation.

Exclusions include previous radiotherapy to the head and neck, lymphoma,

sarcoidosis, graft-versus-host disease, and infection with hepatitis C virus, or HIV,
use of anticholinergic drugs.

TREATMENT

The drug management is mainly symptomatic.

DRYNESS
No efficacy proven – the first drugs used for dryness - bromhexine and
anetholtrithion.
Efficacy on salivary, and to a lesser extent, tear secretion:
Pilocarpin hydrochloride (SALAGENR) - an advised dosage between 10 to 30 mg
per day.
Cevimeline hydrochloride (EVOXACR) is a newer muscarinic agonist, more
selective for M3 receptors - 30 mg 3 times daily for 12 weeks.
Others:
• Tear substitutes
• Lubricating ointments and methylcellulose inserts
• Collagen plugs or electrocautery - occlusion of the punctae lacrimales
• Topical Cyclosporine collyrium (0.05%) – ocular dryness
• Environmental measures - avoidance of hot air heating systems, or
excessive air conditioning, use of a humidifier
• Sugar-free chewing gums, regular water drinking, salivary substitutes
• Local flour preparations - flour chewing gum or lozenges
PAIN/FATIGUE
 • Simple analgesics – acetaminophen
• Non steroidal anti-inflammatory drugs
• A short course of low-dose corticosteroid
• Benzodiazepines, such as clonazepam, or low dosages of tricyclic
antidepressants, like amitriptyline 15-20 mg/day,or anticonvulsants, like
pregabalin might be helpful to alleviate neuropathic or fibromyalgic pain.
• Serotonin reuptake inhibitors or presynaptic α2-antagonists (mirtazepin)
- depressive patients.
• Aerobic exercise (Nordic walking)

IMMUNOMODULATORY DRUGS
Hydroxychloroquine - improves features of immunologic hyper-reactivity. It is
used on patients with:
• palpable purpura
• hypergammaglobulinemia
• refractory polyarthralgias or polysynovitis
Methotrexate, 10 to 15 mg/week on patients with polysynovitis (not
polyarthralgias) refractory to hydroxychloroquine.
Azathioprine is used on systemic involvement.
Leflunomide - improved fatigue, cutaneous vasculitis and led to a decrease of IgG.
Mycophenolate sodium resulted in significant reduction of
hypergammaglobulinemia and rheumatoid factor.

THE MANAGEMENT OF COMPLICATIONS

Oral candidiasis - worsen sicca symptoms!!!
• Oral amphotericin B
• Fluconazole
Lymphoid interstitial pneumonitis
• Corticosteroids - 0,5 to 1 mg/kg
• Cyclophosphamide or azathioprine
Mononeuritis multiplex
• Corticosteroids - 0,5 to 1 mg/kg
 • Cyclophosphamide or azathioprine - necrotizing vasculitis
Isolated trigeminal neuralgia
• Analgesics - clonazepam,
• low-dose corticosteroids (0,25 to 0,5 mg/kg)
Purely sensitive and sensory-motor neuropathies
• Symptomatic treatment (amitriptyline, clonazepam, pregabalin)
Central nervous system vasculitis
• corticosteroids
• azathioprine or cyclophosphamide
Tubulo-interstitial nephropathy with renal function impairment
• corticosteroids
• azathioprine or cyclophosphamide
Complete distal renal tubular acidosis or kidney stone formation
• bicarbonate or citrate
Painful parotid gland swelling
• corticosteroids (0,25 to 0,5 mg/kg/day)for a short duration (10 to 15
days)
• azathioprine or exceptionally chlorambucil - a few months
Localized low-grade lymphoma affecting exocrine glands – WAIT AND
WATCH POLICY!!!
Disseminated lymphoma - chemotherapy regimen should be adapted to the
histological grade
• Rituximab in pSS - related lymphomas, alone in low-grade lymphomas, or
in combination with:
• Cyclophosphamide
• Doxorubicin
• Vincristine
• Prednisone (CHOP) in diffuse large B-cell lymphomas.

TAKE HOME MESSAGES

• Patients with primary SS are at increased risk for lymphoma.

 • Purpura, hypocomplementenemia, and cryoglobulinemia are three key
prognostic factors for adverse outcome in primary SS.
• Treatment in SS is symptomatic.

References:
1. Bijlisma WJJ, Eular Compendium on Rheumatic Diseases, BMJ Publishing
Group, 2009, 824: 314-328
2. Vitali C, Bombardieri S, et al, Classifications criteria for Sjogren’s
syndrome: a revised version of the European criteria proposed by the
American-European Consensus Group, Ann Rheum Dis, 2002: 61:554-8
3. Haneji N., Nakamura T., Takio K., et al. 1997. Identification of α-fodrin as a
candidate autoantigen in primary Sjögren's syndrome. Science 276 : 604-
607.
4. Witte T., Matthias T., Arnett F.C., et al. 2000. IgA and IgG autoantibodies
against α-fodrin as markers for Sjögren’s syndrome. J Rheumatol 27 : 2617-
2620.
5. Kuwana M., Okano T., Ogawa Y., Kaburaki J., Kawakami Y. 2001.
Autoantibodies to the amino-terminal fragment of β-fodrin expressed in
glandular epithelial cells in patients with Sjögren’s syndrome. J Immunol
167 : 5449-5456.
6. Nordmark G, Alm GV, Ronnblom L. 2006. Mechanisms of Disease: primary
Sjogren's syndrome and the type I interferon system. Nat Clin Pract
Rheumatol 2:262-9
7. Dawson LJ, Fox PC, Smith PM. 2006. Sjogren’s syndrome-the non-
apoptotic model of glandular hypofunction. Rheumatology.2006;45:792-8.
8. Theander E, Henriksson G, Ljungberg 0, et al. 2006. Lymphoma and other
malignancies in primary Sjogren's syndrome: a cohort study on cancer
incidence and lymphoma predictors. Ann Rheum Dis.65 : 796-803.
 9. Mariette X. Current and potential treatments for primary Sjogren's
syndrome. Joint Bone Spine 2002 ;69:363-6
10. Mavragani CP, Moutsopoulos NM, Moutsopoulos HM. 2006. The
management of Sjogren's syndrome. Nat Clin Pract Rheumatol. 2:252-61.
11. Ramos-Casals M, Tzioufas AG, Font J. 2005. Primary Sjogren's syndrome:
new clinical and therapeutic concepts. Ann Rheum Dis.64:347-54
12. Baecklkund E, Iliadou A, Askling J et al. 2006. Association of chronic
inflammation, not its treatment, with increased lymphoma risk in
rheumatoid arthritis. Arthritis Rheum; 54:692-701.
13. Askling J, Fored CM, Baecklund E, et al. 2005. Haematopoietic
malignancies in rheumatoid arthritis: lymphoma risk and characteristics
after exposure to tumour necrosis factor antagonists. Ann Rheum Dis 64:
1414-20.
14. Stone JH, A Clinician’s Pearls and Myths in Rheumatology, Springer 2009,
493: 23-26, ISBN: 978-1-84800-933-2

5. SYSTEMIC LUPUS ERYTHEMATOSUS

DEFINITION
Systemic lupus erythematosus is a multisystemic disease of unknown etiology
with protean clinical and laboratory manifestations and a variable course and
prognostic.

EPIDEMIOLOGY

Incidence of lupus is variable depending on:

• Studied population
Age
Genre - women are more affected than men.
Race - The afro-american race is three times more affected than the Caucasian
race.
Ethnic affiliation
Duration of the study
• EC: 3.3-4.8
• USA: 1.8-7.6
The onset of the disease is between 15-40 years old (fertile period).
The F: M ratio is 9:1.
Prevalence of the disease is characterized by:
➢ Variability
➢ Type of report
➢ Social-economical factors
• EC: 12.5-28
• USA: 14.6-50

PATHOGENESIS

1.Apoptosis (inefficient apoptosis)

Autoantigens are released by necrotic as well as apoptotic cells. Defects in the
clearance of apoptotic cells may lead to aberrant uptake by macrophages which
then present the previously intracellular antigens to T and B cells thus driving the
autoimmune process.
2.Cytokine model
Signature of IFN - the over-expression of the type I interferon pathway in patients
with lupus.
Genetic risk factor: Haplotype 5 (IRF5) of IFN
3. Genetic factors - genetic susceptibility to lupus is inherited. An interval on the
long arm of chromosome - cr. 1 – 1q23-24, is linked to lupus.
A single nucleotide polymorphism (SNP) within the programmed cell death 1 gene
(PDCD1) is associated with the development of lupus in both European and
Mexican populations.
4. Environmental factors
Sunlight exposure – the most common trigger.
Exposure to mercury, mixing pesticides.
EBV – Epstein Barr virus (90%)
• ↑ cells
• ↑ viral load
5. Hormones
Exogenous estrogens involvement in SLE:
• Risk 1.9 x ↑
• Onset of flares
Contraceptive pills and anticardiolipin antibodies are associated with risk of
thrombosis. The risk is present even if the anticardiolipin antibodies are missing,
in a lupus patient.

CLINICAL MANIFESTATIONS

1. General manifestations – the “B” symptoms

• malaise
• fatigue – active lupus
• fever
• weight loss
2. Skin manifestations
• lupus- specific lesions
• acute
 • days to weeks – photosensitivity
• pruritic or painful
• commonly accompanied by other inflammatory manifestations
➢ malar “butterfly rash” – non transient
➢ generalized erythema
➢ bullous lupus erythematosous – neck, axilla, inguinal
• subacute
• non-fixed, non-scarring, exacerbating, remitting
• occur in sun-exposed area
• may be generalized
➢ annular – polycyclic
➢ psoriasiform – papulosquamous
• chronic lupus
• starts as erythematous papules or plaque with scaling becoming
thick and adherent with a hypopigmented central area
➢ localized discoid – absence of systemic manifestations
➢ generalized discoid associated with systemic features
➢ lupus profundus – panniculitis plus skin lession
• lupus – non-specific lesions
• vasculitis
• livedo reticularis
• oral lesions
• panniculitis – deep, firm nodule
• urticarial lesions – mucous membrane lesions – mouth, vagina,
nasal septal erosions (vasculitis), often chronic
• non-scarring alopecia –common in lupus, may be induced by drugs
such as cytotoxic drugs or corticosteroids
3. Arthritis/arthralgia – the most common presenting manifestations of SLE
• any joint may be affected
• typically – small joints of the hand, wrists and knees
• asymmetric
• typically not erosive
 • mild synovial thikening
• tenosynovitis – early manifestation
• subluxations initially reversible (hands)
• late lupus – hook-like erosions similar with the erosions described
in post-rheumatic fever Jaccoud’s syndrome
• 2 complications: septic arthritis and osteonecrosis (later stages of
lupus)
4. Myositis
• secondary to joint inflammation
• secondary to drugs – corticosteroids, antimalars
• muscle atrophy + mononuclear cell infiltrate
5. Renal disease
• renal failure
• advanced nephrotic syndrome
• always ask for urine analysis and serum creatinine
• renal biopsy – diagnosis and treatment regimens – lupus nephritis
• Lupus nephritis classification:
• First class
• Normal
• Second class
• Mesangial nephritis
• Third class
• Focal proliferative glomerulonephritis
• Forth class
• Diffuse proliferative glomerulonephritis
• Fifth class
• Membraneous nephropathy
• Sixth class
• Advanced sclerosing glomerulonephritis
6. Neuropsychiatric manifestations
• Neurologic manifestation
• stroke syndrome
 • seizures – grand mal, petit mal, focal, temporal lobe
• headache
• transverse myelitis
• cranial neuropathy
• peripheral neuropathy
• movement disorder
• Psychiatric manifestations
• psychosis
• organic brain syndrome
• psychoneurosis
• neurocognitive dysfunction
7. Serositis
• pleuritis – usually small, occasionally massive
• frequently bilateral
• often seen in aged patients or drug induced lupus
• infections must be ruled out
• fluid is an exudate with glucose concentrate normal (pay attention
in RA the levels of glucose are low)
• the wight blood cells are moderately increased:
• acute settings – neutrophils
• chronic settings – lymphocytes
• pericarditis – most common presentation of heart involvement
• pericardial rub plus chest pain – often absent
• cardiac tamponade is rare
• pericardial fluid pattern: leukocytosis with a high percentage of
neutrophils, complement activity may be present, increased ANA
concentrations, positive LE cells
• large p[ericardial effusions if associated with uremia
8. Pulmonary involvement
• pleuritis
• pneumonitis – acute or chronic
 • Acute pneumonitis – fever, dyspnea, cough, occasionally
hemoptysis. The pulmonary infiltrates are associated with other
lupus manifestations.
• Chronic pneumonitis presents as a diffuse interstitial lung disease,
characterized by dyspnea on exertion, non-productive cough and
basilar rales.
• pulmonary hemorrhage – presents with cough and hemoptysis. It
is secondary to pulmonary vasculitis.
• pulmonary embolism
• pulmonary hypertension – dyspnea
• normal chest radiograph
• patients are mildly hypoxic and have a restrictive pattern on
pulmonary function test
• carbon dioxide diffusion capacity is reduce
• Raynaud’s phenomenon is frequently present
• shrinking lung syndrome – unexplained dyspnea, small lung
volumes with restrictive pulmonary function studies and an
elevated diapragm. Responds to acute treatment with
corticosteroids.
9. Cardiac involvement
• myocarditis - suspected if arrhythmias or conduction defects
present with unexplained cardiomegaly with or without congestive
heart failure or an unexplained tachycardia
• endocarditis – non-bacterial vegetations can be found up to 60%
of patients with lupus. Vegetations may vary for small to large.
Acute and subacute endocarditis may occur so prophylactic
antibiotics for surgical procedures are advisible.
• coronary heart disease – manifestation of atherosclerosis
(generalized).
10. Gastrointestinal involvement
• diffuse abdominal pain
• anorexia
 • nausea
• vomiting
• pseudo-obstruction presentation – diffuse peritonitis, bowel
vasculitis, pancreatitis or inflammatory bowel disease
• ascites may become chronic – painless, associated with other lupus
symptoms
• other manifestations: esophageal disease, liver disease (active
hepatitis, hepatomegaly)
11. Reticuloendothelial system involvement
• lymphadenopathy – non-specific feature of lupus, is common. The
nodes are: soft, non-tender and vary in size. The nodes
demonstrated reactive hyperplasia.
• spleen – “onion skin lesions” – periarterial fibrosis –
pathognomonic for lupus. Hypotheses: the hypersaturation of
reticuloendothelial system leads to prolonged circulations of
immune complexes and their tissue deposition. It was found in
lupus patients – spleen atrophy or splenic lymphoma.

The clinical course of the SLE can be divided in five patterns:

1. classic lupus
• at least 4 ACR criteria present
2. drug induced lupus
• no previous history of lupus
• develops after drug exposure
• Drug’s lupus inducers:
➢ positive drug’s association: chlorpromazine, methyldopa,
hydralazine, procainamide, isoniazid
➢ possibly drug’s association: dilasntin, penicillamine, minocycline,
quinidine
➢ questionable drug’s association: gold salts, grisofulvin, infliximab,
certain antibiotics
3. late stage lupus
• more than 5 years duration
 • prognostic is due to its long term complications, not really the
disease flares
• chronic morbidity: end-stage renal disease, dialysis,
transplantation, osteonecrosis, atherosclerosis, venous syndromes,
pulmonary emboli, neuropsychiatric dysfunction, shrinking lung
syndrome
4. latent lupus
• constellation of clinical manifestations suggestive for SLE
• less than 4 ACR criteria presents
• not a classical pattern for lupus
5. anti-phospolipid syndrome

Predictors of renal disease:

• ethnicity
• histopathological findings:
➢ tubular atrophy
➢ diffuse proliferative glomerulonephritis
• duration of glomerulonephritis signs for more than 6 months before biopsy
• serum creatinine greater than 140mol/L

LABORATORY FINDINGS

• Hematologic abnormalities
• Cytopenia is pathognomonic in lupus.
• anemia – different etiologies: secondary to chronic inflammatory disease,
renal insufficiency, blood loss, drugs. The most significant is the
autoimmune hemolytic anemia caused by the autoantibodies directed
against RBC antigens, detected by Coombs’ test. Sometimes the test is
negative. EVANS SYNDROME – hemolitic anemia + thrombocytopenia.
• leucopenia
• lymphopenia
• thrombocytopenia
 • Serological manifestations
• Ds DNA atb. are associated with:
➢ ↑nefropathy
➢ ↑hemolitic anemia
➢ ↑fever
➢ ↓thrombosis
➢ ↓sicca sdr.
• anti-SM atb.
• anti-SSa, anti-Ro: neonatal lupus, photosensitivity, Sjogren’s syndrome
• anti-SSb, anti-La: neonatal lupus, Sjogren’s syndrome
• anti-RNP: overlap syndrome
• anti-histone antibodies – druged induced lupus
• RF
• aPL IgG, IgM (Cardiolipin/β 2 –GPI) - miscarriage/clots
• LA
• .Complement deficiency – CH50, C3 and C4. Be attentive because the
complement components are not stable at room temperature so due to
improper sample handling low CH50 titers may be found with normal C3
or C4.
• usually in early manifestations of an active lupus disease the C1, C4, C2 and
C3 are involved.
• Other findings:
• prolonged partial prothrombine time
• positive Coomb’s test
• a false-positive Venereal Disease Research Laboratories (VDRL) test for
syphilis
• elevated erythrocyte sedimentation rate
• CRP – usually negative; elevated in infections or in patients with
predisposition to coronary artery disease

IMAGISTIC FINDINGS
There are non specific imagistic findings in SLE.

CLASSIFICATION CRITERIA

New Classification Criteria – SLICC (Systemic Lupus International

Collaborating Clinics group) 2012
Clinical
1.Acute cutaneous
2.Chronic cutaneous
3.Oral ulcers
4.Alopecia
5.Synovitis
6.Serositis
7.Renal involvement
8.Neuralgia
9.Haemolytic anaemia
10.Leukopenia/lymphopenia
11.Thrombocytopenia
Immunological
1.ANA
2.Anti ds-DNA
3.Anti Sm
4.APA
5.Low complement
6.Direct Coombs’ test
LUPUS – at least one clinical and immunologic criteria or biopsy proven lupus
nephritis + anti ds-DNA or ANA

ACR revised Lupus Classification Criteria

1. Malar rash: Fixed erythema, flat or raised, over the malar eminences, tending
to spare the nasolabial folds.
2. Discoid rash: Erythematous raised patches with adherent keratotic scaling and
follicular plugging; atrophic scarring occurs in older lesions.
3. Photosensitivity: Skin rash as a result of unusual reaction to sunlight, by
patient history or physician observation.
4. Oral ulcers: Oral or nasopharyngeal ulceration, usually painless, observed by
a physician.
5. Arthritis: Non-erosive arthritis involving two or more peripheral joints,
characterised by tenderness, swelling or effusion.
6. Serositis:
a. Pleuritis: convincing history of pleuritic pain or rub heard by a physician or
evidence of pleural effusion or
b. Pericarditis: documented by ECG or rub or evidence of pericardial effusion
7. Renal disorder
a. Persistent proteinuria >0.5 g per day or >3+ if quantitation is not performed or
b. Cellular casts: may be red cell, haemoglobin, granular tubular, or mixed
8. Neurological disorder
a. Seizures: in the absence of off ending drugs or known metabolic derangements
(eg, uraemia,acidosis, or electrolyte imbalance) or
b. Psychosis: in the absence of off ending drugs or known metabolic derangements
(eg, uraemia, acidosis, or electrolyte imbalance)
9. Hematologic disorder
a. Hemolytic anaemia with reticulocytosis, or
b. Leucopenia: <4000/mm3, or
c. Lymphopenia: <1500/mm3, or
d. Thrombocytopenia: <100 000/mm3 in the absence of off ending drugs
10. Immunologic disorder
a. Anti-DNA: antibody to native DNA in abnormal titre, or
b. Anti-Sm: presence of antibody to Sm nuclear antigen, or
c. Positive finding of antiphospholipid antibodies based on:
(1) an abnormal serum concentration of IgG or IgM anticardiolipin antibodies, (2)
a positive test result for lupus anticoagulant using a standard method, or
(3) a false positive serologic test for syphilis known to be positive for at least 6
months and confirmed by Treponema pallidum immobilisation or fl uorescent
treponemal antibody absorption test.
11. Antinuclear antibody: An abnormal titre of antinuclear antibody by
immunofluorescence or an equivalent assay at any point in time and in the
absence of drugs known to be associated with ‘drug-induced lupus’ syndrome.

Lupus- at least 4 criteria should be present.

TREATMENT

The treatment in lupus is aiming:

• remission
• maintaining remission
• management of comorbidities
The management of lupus patient is determined by the clinical manifestations, the
experience of the physiscian and also the co-morbidities associated. Usually we
are dealing with an immunosuppresive pattern.
The most used immunosuppressive therapy pattern is:
Arthritis
Methotrexate
Leflunomide
Renal involvement
Cyclophosphamide
Mycophenolite mofetil
Azathioprine
Rituximab
Cutaneous lupus
Hydroxycloroquine
Methotrexate – second line agent
Mycophenolite mofetil – second line agent
Discoid lupus
Thalidomide – less used due its toxicity: neuropathy, teratogenicity, premature
gonodal failure, thrombosis.
CNS involvement
Methotrexate
Azathioprine – vasculitis
Cyclophosphomide

Corticosteroids, alongside with antimalars are the most common treatment in

lupus. They are used for the induction, the maintenance of remission and in flares.
The doses are different according with the protocols, but in the latest years using
the minimal successful dose of corticosteroids have been a target (due to side
effects).
A low dose of corticosteroids is considered less than 10mg/day, a moderate one
0.2-0.5 mg/kg/day and a high dose is represented by 0.5-1 gm/kg/day.

TAKE HOME MESSAGES

• SLE occurs mostly in women during their reproductive years.

• Lupus can complicate a pregnancy, even if the disease itself is not active.

SLE’s flares Preeclampsia/eclampsia

Any time during pregnanacy Not before the 20th week of gestation
Rash Pathologically brisk reflexes
Arthritis Clonus
Serositis Elevated serum levels of hepatic
transaminases
Fever HELLP syndrome – 3rd trimester
Less common increased serum acid Increased serum uric acid level
levels
Active urine sediment Decreased urine calcium
concentrations

• Most of SLE flares are due to noncompliance.

• Immunosuppressive drug regimens in SLE are selected according to the
organ involved. The treatment in lupus is a patterned one.
• Less GC
• Early switch
 • Prevention of cardiovascular disease
• Prevention of other comorbidities
• Prolonged maintenance of immunosupression
• Plaquenil “poisoning”
• Unmasking non-compliance to therapy

References:
1. Stone JH, A Clinician’s Pearls and Myths in Rheumatology, Springer 2009,
493: 23-26
2. Bijlisma WJJ, Eular Compendium on Rheumatic Diseases, BMJ Publishing
Group, 2009, 824: 257-279
6. ANTIPHOSPHOLIPID SYNDROME

DEFINITION

Antiphospholipid syndrome (APS) is a disorder characterized by a

hypercoagulability state – recurrent arterial and venous thromboses and
pregnancy loss.

EPIDEMIOLOGY

It is a disease of young adult (20 -40 years old). The females are more affected.
The prevalence of primary APL is less than 0.5%.
1. Primary APS – no autoimmune disorder association.
2. Secondary APS – association with other autoimmune disorder (eg, SLE)
3. Catastrophic APS – multiorgan failure due to acute thrombotic
microangiopathy associating a high mortality rate.

PATHOGENESIS

The pathogenesis of APS is not completely known. It is known the fact that the
antiphospholipid antibodies affect coagulation and thrombosis by:
 • upragulating tromboxane A2 and glycoprotein 2b-3a via binding to
platelets
• binding to endothelial cells, monocytes will increase the levels of tissue
factors and the adhesion molecules
• activating the complement and such initiating an inflammatory cascade
that would lead to thrombosis

CLINICAL MANIFESTATIONS

Clinical pattern differs according with the blood vessels involved. Usually the most
common findings are:
• Venous thrombosis
• Arterial thrombosis
• Pregnancy loss
• Thrombocytopenia
Other manifestations:
Skin: livedo reticularis, Raynaud’s phenomenon
Obstetric: HELLP syndrome (hemolysis, elevated liver enzymes, low platelet
count), pre-eclampsia, eclampsia
Neurologic: stroke, myasthenia gravis, transverse myelopathy
Pulmonary: pulmonary embolus, pulmonary hypertension
Cardiovascular: myocardial infarction, intracardiac thrombosis
Renal: hypertension, renal insufficiency
Hematologic: haemolytic anemia
Musculoskeletal: deep venous thrombosis, avascular necrosis
Endocrine: adrenal insufficiency
LABORATORY FINDINGS

Three types of assays are available to detect APL:

1. the LAC (lupus anticoagulant)
2. the aCL antibodies anti--2gpl antibodies (anticardiolipin antibodies)
3. the anti--2gpl antibodies (anti--2 antiglicoprotein antibodies)
Other tests:
 • complete blood count
• blood chemistries – liver and renal dysfunction

IMAGISTIC FINDINGS

CT/MRI – assess damage and guide management.

CLASSIFICATION

Research criteria for defining the antiphospholipid syndrome (2006

International Society on Thrombosis and Haemostasis)

Clinical criteria

1. Vascular thrombosis
One or more clinical episodes of arterial, venous or small vessel thrombosis
2. Pregnancy morbidity
(a) One or more unexplained deaths of a morphologically normal fetus at or
beyond the 10th week of gestation
(b) One or more pre-term births of a morphologically normal neonate before the
34th week of gestation because of: (i) eclampsia or severe pre-eclampsia or (ii)
recognized features of placental insufficiency
(c) Three or more unexplained consecutive spontaneous miscarriages before the
10th week of gestation, with maternal anatomic orhormonal abnormalities and
paternal and maternal chromosomal causes excluded

Laboratory criteria

1. Lupus anticoagulant (LA) present in plasma, on two or more occasions at least

12 weeks apart
2. Anticardiolipin (aCL) antibody of immunoglobulin (Ig)G and/or IgM isotype in
serum or plasma, present in medium or high titre (i.e. >40GPL units or MPL units,
or > the 99th centile), on two or more occasions, at least 12 weeks apart
3. Anti-b2–glycoprotein I antibody of IgG and/or IgM isotype in serum or plasma
(in titre >the 99th centile), present on two or more occasions at least 12 weeks
apart

Antiphospholipid antibody syndrome (APS) is present if at least one of the

clinical criteria and one of the laboratory criteria are met.

TREATMENT

Goal:
• prevention of thrombosis.
Primary prophylaxis – (aCL positive patients without previous thrombosis,
obstetric patients)
• Aspirin 325mg PO daily
• Hydroxycloroquine 400mg PO daily – protective against future
thrombosis
Secondary prophylaxis – (APS patients with at least one thrombotic event) –
long - term intensive anticoagulation is required based on the type of the
thrombotic event.
Venous event
• Unfractioned heparin followed by warfarin with a goal of international
normalized ratio (INR) of 2.5 (range 2 to 3) – first thrombotic event.
• Do not stop medications in the first 6 months. The risk of recurrence is high.
The consensus is to treat indefinitely with anticoagulants.
• In recurrent venous thrombosis the high anticoagulation is
recommended – INR 3 to 4 or warfarin with INR 2 to 3 plus aspirin. If
unstable INR it is recommended to switch to low-molecular weight
heparin.
Arterial event – the cerebral circulation is mostly involved (stroke, transient
ischemic attacks). The treatment used is:
• Aspirin 325mg PO daily
• Warfarin
Pregnancy morbidity prevention – the treatment of pregnant women with fetal
loss and aCL antibodies is controversial.
• Aspirin 81 mg daily should be started when attempting conception
 • Heparin (unfractionated or low molecular weight) should be started
when intrauterine pregnancy is confirmed. Both should be discontinued
in the third trimester.
• Unfractionated heparin – 5000-10.000 units q12h
• Low molecular weight heparin – enoxaparin 1mg/kg or 40-80 mg,
dalteparin 5000 units, nadroparin 3800 units – once daily.
Catastrophic APS
It is a disorder characterized by multiorgan failure due to small-vessel occlusion
developing simultaneously or < 1 week. Histopathololgy confirms the occlusion in
at least one tissue or organ. The mortality is high.
• treatment of precipitating factors (eg. SLE flares, infection etc.)
• 7 to 10 days or longer anticoagulation with iv heparin
• high-dose steroids for 3 or more days
• IV immune globulin – 0.4gm/kg body weight daily for 4 to 5 days or
plasma exchange for at least 3 to 5 days
Other therapeutical options:
• cyclophosphomide – in patients with secondary APL
• rituximab – in patients with thrombocytopenia or autoimmune
haemolytic anemia
• smoking cessation
• avoidance of supplemental estrogens
• controlling hypertension
• controlling diabetes

TAKE HOME MESSAGES

In APS, previous thrombosis is the strongest predictor of future events.

Anticoagulation in a patient with APS should be lifelong.

References:
3. Stone JH, A Clinician’s Pearls and Myths in Rheumatology, Springer 2009,
493: 173-180
4. Kahl Leslie, Rheumatology Subspecialty Consult, Lippincott, Wiliams and
Wilkins 2012, 422: 329-355, ISBN: 978-1-4511-1412-5
7. VASCULITIS

DEFINITION

Autoimmune systemic vasculitis represents a heterogenous group with a

common pattern: inflammation followed by the necrosis of the vascular wall.

EPIDEMIOLOGY

• disease’s definitions vary, data are different based on the definitions used
• the incidence of primary systemic vasculitis is approximately 20 cases per
million

PATHOGENESIS

The inflammation of the blood vessels due to different factors unknown (primary
vasculitis) or known (secondary vasculitis) will lead to blood vessel damage as
thickening of vessel wall and attenuation of vessel wall. The thickening of vessel
wall will provoke luminal narrowing or occlusion leading to tissue or organ
ischemia. The attenuation of vessel wall as vessel wall thinning will lead to
aneurysm formation or disruption of the vessel wall with hemorrhage into tissue.
Known inducer factors:
• infection – (mediated through a type III or immune-complex reaction
where the antigens are the infectious agents)
➢ HIV
➢ B and C hepatitis (mediated by the production of cryoglobulins, C hepatitis
– genetic predisposition: association with HLA-B8 and DR3 markers)
➢ cytomegalovirus
 ➢ herpes simplex
➢ fungi
➢ staphylococcus, streptococcus
➢ mycoplasma
• drugs
➢ sulfonamides
➢ penicillin (by conjugating to serum proteins and mediating immune-
complex vasculitis as in type III hypersensitivity reactions)
➢ allopurinol
➢ thiazides
➢ hydantoins
➢ aspirin
➢ propylthiouracil (appear to induce antibody production, specifically
antineutrophil cytoplasmic antibodies (ANCA))
➢ minocycline
• malignancy – less common (abnormal production of proteins, leading to
formation of immune complexes, which bind antigens on vessel walls.
Molecular mimicry – cell surface antigens may be similar in both neoplastic
and endothelial cells, and apoptosis may lead to the development of
vasculitis.)

CLINICAL MANIFESTATIONS

1. Constitutional symptoms – any vasculitis

• fever
• fatigue
• weight loss
• anorexia
• malaise
2. Renal manifestations
• Glomerulonephritis - Microscopic polyangiitis, Wegener's granulomatosis,
cryoglobulinemia, Churg-Strauss vasculitis, Henoch-Schönlein purpura
 • Ischemic renal failure - Polyarteritis, Takayasu's arteritis; less commonly,
Churg-Strauss vasculitis and Wegener's granulomatosis
3. Pulmonary manifestations
• Pulmonary hemorrhage - Microscopic polyangiitis, Wegener's
granulomatosis
• Pulmonary infiltrates or cavities - Churg-Strauss vasculitis, microscopic
polyangiitis
4. Neurologic manifestations
• Peripheral neuropathy - Polyarteritis, Churg-Strauss vasculitis, Wegener's
granulomatosis, cryoglobulinemia
• Stroke - Giant cell arteritis, SLE-associated vasculitis
5. Cutaneous manifestations
• Palpable purpura – any vasculitis except the giant cell arteritis and
Takayasu’s arteritis
• Skin ulcers - Polyarteritis, Churg-Strauss vasculitis, Wegener's
granulomatosis, hypersensitivity vasculitis
• Gangrene in an extremity - Polyarteritis, Churg-Strauss vasculitis,
Wegener's granulomatosis
6. Gastrointestinal tract manifestations
• Abdominal pain or mesenteric ischemia - Henoch-Schönlein purpura,
polyarteritis, Churg-Strauss vasculitis

• Gastrointestinal bleeding - Henoch-Schönlein purpura, polyarteritis, Churg-

Strauss vasculitis

LABORATORY FINDINGS

1. Inflammatory syndrome
• Chronic anemia + trombocytosis/ neutrophilia + eosinophilia
• ESR ↑ 100mm + CRP >10mg/dl – absence of bacterial infections and
paranoplastic syndrome
• Albumine ↓
2. Organic involvement (elevated)
 • Creatinine
• Urea
• Liver enzymes
• CK
3. Immune complexes depot
• RF - never positive in primary vasculitis
• ANA - never positive in primary vasculitis
• RF + cryoglobulinemia – bacterial endocarditis
• AAN + SLE, Sjogren sdr.
• Cryoglobuline + -hepatitis C
• •C3,C4 ↓ - cryoglobulinemia, PAN (25%), hypersensitivity vasculitis
4. ANCA + (antineutrophil cytoplasmatic antibodies)
• c-ANCA (serine proteinase 3): WG with systemical involvement (90%)
• p-ANCA (anti myeloperoxidase): Churg- Strauss sdr., mycroscopic
polyangeitis

IMAGISTIC FINDINGS

• Pulmonary X ray - granuloma

• Sinus X Ray - granuloma
• Doppler US - Giant Cell Arteritis
• Cranial MRI - demielinisation
• Angio MRI - aorta (thickness, stenosis)-Takayasu’s Arteritis, Giant Cell
Arteritis
• CT scan – abdominal - granuloma
• PET CT – aorta, subclavia - Takayasu’s Arteritis, Giant Cell Arteritis
• Angiography:
➢ Abdominal (celiac br., sup. Mesenteric artery, renal arteries a.) – PAN
➢ Aortic Arch – Takayasu’s Arteritis, Giant Cell Arteritis
➢ Limbs – Buerger disease
➢ Cerebral – isolating angiitis CNS
• Biopsy
 Common sites Less common sites
Skin Testicle
Sural nerve Rect
Temporal artery Liver
Muscle Heart
Kidney Brain
Lungs Sinus

• BAL

CLASSIFICATION CRITERIA

1. Classification of the Vasculitic Syndromes According to Vessel size and

ANCA

Dominant Vessel Primary Secondary

Large arteries Giant cell arteritis Aortitis associated
Takayasu’s arteritis with RA, infection
(e.g. syphilis,TB)
Medium arteries Classical PAN Hepatitis B
Kawasaki disease associated PAN
Small vessels and medium Wegener’s Vasculitis secondary
arteries granulomatosis* to Rheumatoid
Churg-Strauss syndrome* Arthritis, Systemic
Microscopic polyangiitis* Lupus
Erythematosus,
Sjögren’s syndrome,
Drugs, Infection (e.g
HIV)
Small vessels Henoch-Schonlein purpura Drugs
Cryoglobulinaemia Hepatitis C
Cutaneous associated
leucocytoclastic angiitis Infection

* ANCA positive vasculitis

2. ACR 1990 CRITERIA (most common used for clinical intentions)
LARGE VESSELS
1.Giant cell arteritis /Horton’s headache/Temporal arteritis/Cranial
Arteritis (3 out of 5 )
 • Age > 50
• New headache – recent onset or new localisation
• Temporal artery tenderness or decreased temporal pulse
• ESR > 50mm
• HP: necrotising arteritis, mononuclear infiltration or granulomatous
inflammation
2. Takayasu’s Arteritis
• Age<40
• Claudications of the limbs (upper limbs)
•  brachial arterial pulse
• BP difference > 10 mmHg between the 2 limbs
• Bruit over subclavian arteries or aorta
• Arteriographic narrowing or occlusion of the entire aorta, its proximal
branches, or large arteries in the proximal upper or lower extremities
MEDIUM VESSELS
1. PAN (Polyarteritis Nodosa)
•  Weight > 4kg.
• Livedo reticularis
• Pain/testicular tenderness
• Myalgias
• Mononeuropathy/polineuropathy
• dBP > 90mmHg
•  urea or creatinine (BUN)
• Markers for B hepatitis
• Arteriographic modifications: aneurysms, oclussion
• HP: granulocytes or granulocytes and mononuclear leucocytes in the artery
wall
2. Kawasaki’s Disease (5 out of 6)
Presence of at least five of six conditions:
• Fever for five days or more
• Bilateral conjunctival injection without exudate
• Polymorphous exanthem
Changes in lips and mouth:
• Reddened, dry, or cracked lips
• Strawberry tongue
• Diffuse redness of oral or pharyngeal mucosa
Changes in extremities:
• Reddening of palms or soles
• Indurative oedema of hands or feet
• Desquamation of skin of hands, feet, and groin (in convalescence)
• Cervical lymphadenopathy:
• More than 15 mm in diameter, usually unilateral, single, non-purulent,
and painful
SMALL VESSELS
Immune complexes associations:
1. Henoch Schonlein’s purpura
• age < 20
• palpable purpura
• acute abdominal pain
• HP: granulocytes in the walls of the arterioles and venules
2. Hypersensibilisation vasculitis
• age > 16
• history: medication – precipitating factor
• palpable purpura
• maculopapular rash
• HP: granulocytes in a perivascular or extravascular location
ANCA POSITIVE VASCULITIS
1. Granulomatosis with poliangiitis/ Wegener’s granulomatosis
• hematuria
• Rx: nodules, cavitaties, infiltrations
• Oral and nasals ulcers
• HP: granulomatosis inflammation
2.Granulomatosis with eosinophylia/ Churg Strauss Syndrome
• Asthma
 • Eozinophilia > 10%
• mononeuropathy (multiplex), polineuropathy
• Pulmonary infiltrates
• Paranasal sinus abnormality
• HP: Extravascular eosinophils

Chapel Hill’s Classification – nomenclature classification

LARGE VESSELS
1.Giant cell arteritis /Horton’s headache/Temporal arteritis/Cranial
Arteritis
• Age > 50
• Temporal artery
• Rheumatic polimyalgia
• The involvement of AO and its main branches (external branches of
carotid)
2.Takayasu’s Arteritis
• Age < 50
• Granulomatosis inflammation - AO and its main branches

MEDIUM VESSELS
1.PAN
• Necrotising inflammation of the medium and small arteries, without
glomerulonefritis or vasculitis
2. Kawasaki’s Disease
• Involvement of large, medium, small vessels + subcutaneous lymphatic
nodules
• Coronary artery – frequently involved
• Children
SMALL VESSELS
1.Granulomatis with polyangiitis
• Granulomatosis inflammation of the respiratory airways + necrotising
vasculitis of small vessels or medium vessels
 • Necrotising glomerulonephritis – frequent
2.Eosynophilic granulomatosis with polyangiitis/ Alergic granulomatosis
• Granulomatosis inflammation of the respiratory airways + necrotising
vasculitis of small vessels or medium vessels
• Asthma
• Eosynophilia
3.Mycroscopic polyangiiis
• Necrotising vasculitis
• ,  immune deposits
• Necrotising arteritis – medium and small vessels involvement
• Necrotising glomerulonephritis – frequent
• Pulmonary capilaritis – frequent
3. Classification criteria for systemic rheumatoid vasculitis
The presence in a patient with RA of one or more of the following:
• Mononeutitis multiplex or acute peripheral neuropathy
• Peripheral gangrene
• Biopsy evidence of acute necrotizing arteritis plus systemic illness
• Deep cutaneous ulcers or active extra-articular manifestations (pleurisy,
scleritis, pericarditis etc.) if associated with typical infarcts or vasculitis
(biopsy)

TREATMENT

Objectives:
• Identifications and elimination of the onset factor (drugs)
• Treatment of co-diseases (AB-miocarditis, IFNα, VIDARABINA, LAMIVUDINA
hep. B and C)
• Anti-inflammatory and immunosuppressive therapy
•Prevention of complications: infections, osteoporosis, atherosclerosis (BP, lipids-
monitor)
Induction therapy:
 Dominant vessels Corticosteroids Cyclophosphamide Others
involved alone + Corticosteroids

Large arteries ++ - +
Medium arteries + ++ ++*
Small vessels and medium + +++ +
arteries
Small vessels + +/- ++
*plasmapheresis, anti viral therapy , iv Ig
• Rituximab (ANCA positive vasculitis)
Maintain therapy:
• Methotrexate
• Azathioprine

TAKE HOME MESSAGES

Prognostic is determined by the FFS (FIVE FACTOR SCORE):

• proteinuria > 1g/day
• creatinine > 140umol/day
• cardiomiopathy
• gastrointestinal involvement
• CNS complications
FFS > 2 - increased mortality
There is not specific treatment in vasculitis.

References:
5. Stone JH, A Clinician’s Pearls and Myths in Rheumatology, Springer 2009,
493: 201-238
6. Bijlisma WJJ, Eular Compendium on Rheumatic Diseases, BMJ Publishing
Group, 2009, 824: 329-340
8. MYOSITIS

DEFINITION
Polimyiositis (PM) and or dermatomyositis (DPM) are part of a heterogeneous group of
disorders called idiopathic inflammatory myopathies (IIM) characterised by
progressive symmetrical muscle weakness, fatigue, decreased muscle endurance and
chronic inflammation of striated muscles.

Other inflammatory muscle diseases – part of IIM:

• inclusion body myositis
• eosinophilic myositis
• giant cell myositis
• focal/localised myositis
• myopathies secondary to infections, drugs, toxins

Classification proposed by Bohan and Peter:

• adult polymyositis
• adult dermatomyositis
• childhood DM (less often PM)
• PM/DM associated with connective tissue disorders
• PM/DM associated with malignancy
• amyopathic DM

EPIDEMIOLOGY

• the annual incidence is 2-10 cases/million

• bimodal peak age: one peak at 10-15 years of age, the second peak at 45-55
years
• the Afro-American race is more affected than the white race – a ratio of 5:1
(adult polymyositis) and 3:1 (adult dermatomyositis)
• the overall female to male ratio is 2.5-3:1

PATHOGENESIS

ETIOLOGY:
1. Environmental factors
• drugs: statins, fibrates, lipid-lowering agents, nicotinic acid, colchicine,
antimalarials, AZT (azathioprine), alcohol, glucocorticoids, cocaine
• exposure to UV light
• infections: bacterial (Streptococcus, Staphylococcus, Borrelia burgdorferi),
parasitic (Toxoplasma, Trichinella, Taenia, Trypanosoma cruzi), viral (HIV,
adenovirus, influenza)
2. Genetic factors
• genetic predisposition – the occurrence in monozygotic twins (the human
leukocyte antigen – HLA DQA1*0501 locus – the strongest known risk factor
and HLA-DRB1*0301, ) and first – degree relatives (the IIM occurs four times
more frequently)
• non-HLA genetic risk factors – gene regulating cytokines and its receptors
(interleukin 1 – IL 1, tumor necrosis factor α - TNFα)
3. Malignancies
• DM’s patients – a greater risk of malignancy (haematological malignancies –
lymphoma, lung, ovary, breast, colon cancer)
• cause: an hypotheses – chronic inflammation

The immune mechanisms are involved in the pathogenesis of IMM. The presence
of T lymphocytes as well as the involvement of B cells – detected autoantibodies
support the previous hypotheses.

Three major mechanism were considered having a role in the development of

chronic muscle inflammation, muscle weakness and muscle fatigue:

1. the direct effects of infiltrating leukocytes, mainly T lymphocytes and

macrophages on muscle cells – cytotoxicity
2. the indirect effects of molecules from the immune system (eg. cytokines) on
muscle metabolism and function
3. the involvement of microvessels and improper microcirculation – acquired
metabolic disturbances and reduced muscle function
 CLINICAL MANIFESTATIONS

• constitutional: fatigue (IMM), fever (juvenile dermatomyositis, the

antisynthetase syndrome), weight loss (systemic illness, associated malignancy,
poor caloric intake due to striated muscle dysfunction or esophageal
dysmotility).

• musculoskeletal: arthralgias/arthritis; proximal, symmetrical muscle weakness

around the shoulder/pelvic girdles and neck flexors – subacute or insidious
onset, muscle fatigue, decreased muscle endurance. Ocular and facial motor
weakness is unusual.

• skin: heliotrope (lilac-colored) rash - (purple to erythematous rash affecting the

eyelids, malar region, forehead and nasolibial folds); Gottron’s papules – purple
to reythematous flat or raised lesions over the interphalangeal regions of the
fingers; V-sign rash – confluent erythematous rash over the anterior chest and
neck; shawl-sign rash – erythematous rash over the shoulders and proximal
arms; mechanic’s hands – cracking and fissuring of the skin of the finger pads;
nailfold abnormalities – periungual erythema, dilated capillary loops, cuticular
overgrowth; subcutaneous calcifications – juvenile form of DM

• pulmonary: dyspnea – non-parenchymal involvement (ventilatory muscle

weakness, cardiac disfunction), interstitial lung disease (diffuse alveolar
damage, non-specific interstitial pneumonitis, usual interstitial pneumonitis,
organizing pneumonias – cryptogenic organizing pneumonia), pulmonary
hypertention, alveolar hemorrhage, pneumomediastinum, infections, drug
induced (eg. methotrexate)

• gastrointestinal: esophageal dysmotility, intestinal perforation due to vasculitic

(juvenile DM)
• cardiac: dysrhythmias, conduction blocks, myocarditis, pericardial tamponade
(unusual)

• vascular: vasculitis – livedo reticularis, skin ulcerations (juvenile DM), Raynaud’s

phenomenon, tender dermal and/or subcutaneous nodules, periungual infarcts,
digital ulcerations

• kidney: acute tubular necrosis with renal failure related to myoglobinuria, IgA
nephropathy, membranous nefropathy – unusual

• miscellaneous: retinopathy, retinal vasculitis, macroglossia, hyposalivation,

increased prevalence of dental caries, weak masticatory force, progressive
multifocal leukoencephalopathy

LABORATORY FINDINGS

Muscle biopsy is the golden standard for the diagnosis of IMM. In 90% a
degenerative/regenerative pattern is described. In 80% of cases, chronic
inflammatory cells in the perivascular and interstitial areas surrounding
myofibrils are present as well as lymphocytic invasion of non - necrotic fibers
considered pathognomonic of polymyositis. Other cells may be present such as:
histiocytes, plasma cells, eosinophils and polymorphonuclear leukocytes. In
chronic myositis the muscle tissue is replaced by fat and fibrous connective tissue
and macrophages are phagocytosing necrotic fibers.

EMG (electromyography) – myopathic motor unit potentials with or without

spontaneous, complex, repetitive discharges, fibrillations, positive sharp waves,
short duration, low-amplitude, complex (polyphasic) potential on contractions. It
is a sensitive but non specific method of evaluating muscle inflammation.

It is recommended to perform the EMG and the muscle biopsy in different sites
(eg. EMG performed in the contralateral muscle chosen for muscle biopsy).
 Serum muscle enzymes
• serum CK – the most reliable enzyme test
• aldolase
• aspartate and alanine aminotransferases
• lactate dehydrogenase
• serum myoglobin – useful marker of muscle damage, cleared by the kidney
• urinary levels of markers of muscle damage – creatine, choline-containing
metabolites, betaine, citrate – juvenile myositis

Serum autoantibodies
Are usefull in defining clinically homogenous subsets of patients.
90% of cases the antinuclear and anticytoplasmatic antibodies are detected. Some
of these antibodies are specific ones for myositis (MSAs).
• Anti-Jo-1 directed against histidyl-t-RNA synthetases – the synthetases
syndrome: a severe myositis with multiple exacerbations.
• Antibodies to signal recognition particle (anti-SRP) – target a ribonucleoprotein
involved in translocation.
• Anti-Mi-2 – associated with rash of dermatomyositis and a good response to
immunosupression and patients with PM.
• Anti-PM-Scl –antinucleolar antibody that identifies a subset of patients with
myositis who often have features of systemic slerosis.
• Anti-Ku antibody – scleroderma overlap

Associations of clinical abnormalities with myositis-specific autoantibodies

Antisynthetase

• arthritis
• mechanic’s hands
• interstitial lung disease
• fever
 Anti-SRP (signal recognition particle)

• myalgias
• acute severe muscle weakness
• cardiac involvement

Anti-Mi-2

• classic dermatomyositis
• V - sign rash
• shawl - sign rash
• cuticular overgrowth

IMAGISTIC FINDINGS

Magnetic resonance imaging (MRI)

• shows the site of biopsy
• distinguishe between chronic active from chronic inactive myositis
• confirm amyopathic dermatomyositis
• document myositis or a disease flare in pts. with normal CK, EMG or biopsy

Magnetic resonance spectroscopy (MRS) – bioenergetics of normal and abnormal

muscle.

Ultrasound – blood flow, calcifications.

CT – calcifications, atrophy (quantify).

CLASSIFICATION CRITERIA
 Bohan and Peter criteria for diagnosis of polymyositis and dermatomyositis:

Individual criteria:
1. symmetrical (bilateral but not necessarily equal involvement) proximal muscle
weakness
2. muscle biopsy – evidence of myositis (perivascular and endomysial
inflammation with muscle fiber necrosis and regeneration). PM – endomysial
infiltration, the majority of the cells are cytotoxic CD8+ T cells. DPM –
perivascular and perifascicular infiltration regions, the CD4+ T cells overcast the
B cells and perifascicular atrophy is diagnostic of DM.
3. increase in serum levels of skeletal muscle enzymes (creatine kinase - CK,
aldolase, aspartate aminotransferase - ALT, alanine aminotransferase - AST,
lactate dehydrogenase - LH)
4. specific electromyographic pattern (myopathic motor unit potentials with short
duration and low amplitude)
5. typical skin rash of dermatomyositis (eg. Gottron’s papules/sign, heliotrope
rash)

Diagnostic criteria:
PM
• definite: all 1-4
• probable: any 3 of 1-4
• possible: any 2 of 1-4

DPM
• definite: 5 plus any 3 of 1-4
• probable: 5 plus any 2 of 1-4
• possible: 5 plus any 1 of 1-4

DIFFERENTIAL DIAGNOSIS
1. Neuromuscular disorders
• denervating conditions (eg. amyotrophic lateral sclerosis)
• neuromuscular junction disorders (eg. myasthenia gravis, Eaton-Lambert
syndrome)
• muscular dystrophies (eg. Duchenne’s)
2. Endocrine disorders
• hypothyroidism
• hyperthyroidism
• acromegaly
• Addison’s disease
• Cushing’s disease
3. Metabolic myopathies
• sarcoidosis
• electrolyte disorders (hypo/hypercalcemia, hypokalemia,
hypophosphatemia)
• mitochondrial myopathies
• nutritional disorders (vitamin D and E deficiencies, malabsortion)
• glycogen storage diseases (eg. acid maltase deficiency, McArdle’s or
myophosphorylase deficiency)
• abnormalities of lipidic metabolism (eg. carnitine deficiency)
4. Infectious myositis
• bacterial (Streptococcus, Staphylococcus, Borrelia burgdorferi), parasitic
(Toxoplasma, Trichinella, Taenia, Trypanosoma cruzi), viral (HIV, adenovirus,
influenza)
5. Drug and toxic induced myopathies
• acute and chronic alcoholism, penicillamine, clofibrate, cloroquine, emetine,
statins, fibrates, lipid-lowering agents, nicotinic acid, colchicine,
antimalarials, AZT (azathioprine), glucocorticoids, cocaine
6. Miscellaneous
• organic failure: liver failure, uremia
• acute rhabdomyolysis
• carcinomatous neuromyopathy
 • other rheumatic disorders: polymyalgia rheumatica, fibromyalgia syndrome,
systemic vasculitis etc.

PROGNOSIS
• similar 5-year survival in patients with idiopathic PM/DM and in those with
associated tissue diseases .85%
• anti-Mi-2, anti-PM-Scl – very good prognosis (5 year survival 95%)
• anti-SRP – the worst prognostic marker (5 year survival 30%)

TREATMENT

Treatment of PM and DM should be tailored to the individual patient and the initial
approach and monitoring of the disease may vary from case to case. The activity and the
severity of the disease should be evaluated before the initiation of the treatment.

A. Drug therapy

1. Corticosteroids

Corticosteroids are still the mainstay of treatment in most cases of PM/DM despite
their side effects.
Daily oral corticosteroids – according to Oddis and Medsger the following regimen
should achieve more prolonged control of the disease:
• maintain an initial divided dose of prednisone 1mg/kg/day for at least 1month
and until CK returns to normal
• reduce the prednisone dose by 25 % monthly to a maintainance dose of 5-
10mg/day
Pulse corticosteroids – 1 g in total daily for 3 days or methyl-prednisolone
15mg/kg – in severe, acute myositis followed by high dose oral corticosteroids;
justify in life threatening disease such as dysphagia (high risk of aspiration),
myocardial involvement, active alveolitis.
 Corticoids side-effects – osteoporosis (vertebral collapse), osteonecrosis – Calcium
supplements and vitamin D, eventually bisphosphonates; hypertention,
hyperglycemia, fat redistribution, cataract, propensity for infections.

2. Cytotoxic drugs
The classic approach to the use of cytotoxic drugs involved:
• lack of response to high-dose corticosteroids
• occurrence of unacceptable corticosteroids side – effects
• difficulty in reducing high-dose corticosteroids because of flares

The new approach to the use of cytotoxic drugs involves an earlier combination
(corticosteroids and cytotoxic drug).

Methotrexate – first choice among immunosuppressive drugs. It started with 10-

15mg/weeks and increased till 50mg/week iv or oral dose. Take notice to
methotrexate induced pneumonitis in pts. with rapidly progressing alveolitis.

Cyclophosphamide (CYC) – 1 to 2mg/kg/day, usually not exceeding 150mg/day;

pulse iv CYC – overlaps or lung involvement

Cyclosporin – 2 to 3.5 mg/kg/day – successful in not responding to methotrexate

therapy pts.

Other cytotoxic drugs

• mofetil mycophenolate
• chlorambucil
• flutarabine

Other therapeutic modalities

• intravenous γ – globulin
• anti-tumor necrosis factor antibodies
• B-cell targeted therapy
• total body irradiation
 • plasmapheresis

B. Rehabilitation
The rehabilitation management should be tailored to the individual’s needs,
according to the following:
• age
• type of myositis
• predicted outcome
• stage of the disease (acute, recovery, chronic)
• degree of muscle weakness and joint involvement
• accompanying diseases and/or systemic manifestations
• the patient’s work status anf lifestyle
• support systems available to the patients

Acute phase
• exercise – passive range of motion exercises, stretching
• massage and heat treatment in painful muscles
• fit with an appropiate collar for neck support
• occupational therapy
• patient education
• regular evaluations
• nurses education

Early recovery
• exercise – muscle re-education, active assisted range of motion exercises,
isometrics
• work on improving truncal balance and strength
• occupational therapy
• job retraining
• assess vocational abilities
• energy conservation strategy
• as enzymes decrease, increase the isometric exercise program to 6 contractions
of each muscle group daily; pool therapy with range of motion and stretching
exercises

Late recovery and chronic phase

• exercise – isotonics (low weight, 2-4 kg), pool or dry land; aerobic exercise
(starting at 156 min sessions, increasing to 30 min sessions, three weekly) at
60%V02 (ergonometer or pool)

TAKE HOME MESSAGES

Muscle inflammation in the setting of a normal CK activity level is more likely in

DM than in PM.
Patients with amyopathic DM should be screened for malignancies.
DM is not polymyositis with a rash.

References:
7. Stone JH, A Clinician’s Pearls and Myths in Rheumatology, Springer 2009,
493: 167-172
8. Bijlisma WJJ, Eular Compendium on Rheumatic Diseases, BMJ Publishing
Group, 2009, 824: 297-313
9. SYSTEMIC SCLEROSIS

DEFINITION

Systemic sclerosis is an autoimmune disease characterized clinically mainly by the

thickening of skin due to extracellular matrix accumulation (e.g. collagen in skin
and viscera) associating fibrotic ateriosclerosis and specific autoantibodies such
as anticentromere and anti-Scl-70 (antitopoisomerase).
1. LOCALIZED SCLERODERMA
•Morphea
•Linear scleroderma
•En coup de sabre
2. SYSTEMIC SCLEROSIS
•Diffuse cutaneous systemic sclerosis
•Limited cutaneous systemic sclerosis
•Overlap syndromes (AR< LES< DPM/PM)
CREST syndrome – a form of limited systemic sclerosis
Calcinosis
Raynaud’s phenomenon
Esophageal dysmotility
Sclerodactyly
Telangiectasias

EPIDEMIOLOGY

Incidence and prevalence – vary according to:

➢ Definition of cases
➢ Time period
➢ Country
➢ Patients’ survival
The children and the males under 30 years old, are rarely affected by the disease,
Ratio female: male is 3-5 to 1. Women are more common affected between 30 and
50 years range.
The incidence noted was 20-cases/million populations per year.

PATHOGENESIS

The clinical tableau of the disease is probably due to the following mechanisms:
1. vascular damage – microcirculation
2. immune system activation/inflammation - autoimmunity
3. fibrosis – abnormal accumulation of extracellular matrix components.
It is not yet understand the way the immune system is involved, but it is presumed
that it initiates and propagates the inflammatory process causing the vascular
damage and the tissue fibrosis. The vascular involvement is characterized by
arterial vasospasm, smooth muscle hyperactivity, intimal proliferation and
vascular occlusion. Fibrosis is the most characteristic finding but the process of
internal damage is complex and as exemplification in systemic sclerosis the
involvement of gastrointestinal tract is described more often as a striking smooth
muscle atrophy and a limited fibrosis.
Different trigger factors have been incriminated such as:
1. Environmental factors
Exposure to organic solvents and toxins
• Aromatic hydrocarbons-toluene, benzene
• Aliphatic hydrocarbons
➢ Chlorinated – trichloroethylene, perhlorethylene
➢ Nonchlorinated –naphta-n-hexane, hexachloroethane
Epoxy resins
Drugs – bleomycin, pentazocine
Appetite supressants
Vinyl chloride
Silica dust – gold miners
Rapeseed oil contaminated with aniline dye – Spain 1981
Contaminated L-tryptophan
Silicone – breast implants (controversial)
2. Microchimerism - CMV
3. Latent vital infection may trigger autoimmunity by a molecular mimicry
mechanism
4. Genetic predisposition – unclear
•Familiar clustering of the disease – first degree relatives more prevalent
•HLA-DR1 – limited scleroderma, anticentromere antibody
•HLA-DR5 – diffuse scleroderma, anti-topoisomerase antibody

CLINICAL MANIFESTATIONS

1. Skin thickening associated with loss of sweat glands and hair loss. It begins
on the fingers and hands.If the thickening initially is localized elsewhere a
 differential diagnosis with eosinophilic fasciitis and other forms of
scleroderma should be considered.
2. Raynaud’s phenomenon – a vasomotor disturbance, self-limited and
reversible, manifested by colour changes: pallor, cyanosis, erythema.
Feature Primary Raynaud’s Systemic sclerosis
Sex F:M 4:1 F:M 3:1
Age at onset Puberty 25 years or older
Frequency < 5 per day > 5-10 attacks per day
Precipitants Cold, emotional stress Cold
Ischemic injury Absent Present
Other vasomotor Yes Yes
phenomena
ANA Absent Present
Anticentromere Absent Present
antibody
Anti-Scl-70 antibody Absent Present
Platelet activation (in Absent Present
vivo)
Abnormal capillaroscopy Absent Present

3. Calcinosis of the hands, periarticular tissue and over bony prominences.

They are firm, irregular, nontender. In evolution they can become inflamed,
infected or ulcerated. They may discharge a chalky white material.
4. Teleangiectases are dilated arterioles, cappilaries and venules. They are
oval or polygonal and tend to affect the face, lips, oral mucosa and hands. If
the GI tract is involved, they can bleed leading to iron deficiency anemia. It
is a clinical manifestation more related with limited systemic sclerosis.
5. Paroxistic hematoma of the digits – asymptomatic and disappears after 2-
3 days. It is suggestive for diffuse form of systemic sclerosis.
6. Esophageal hypomotility. There are a few steps that would lead to an
affected GI tract such as:
1.Neural dysfunction
2.Smooth muscle atrophy
 3.Fibrosis of the muscle
7. Arthritis or arthralgias
8. Myopathy
9. Pulmonary fibrosis – interstitial lung disease. For many years the patients
can be asymptomatic. The onset is insidious with exertional dyspnea, and
later with rest dyspnea, easy fatigability, exertional non-productive cough.
Clinical signs: early inspiratory fine or Velcro crackles. Pleuretic chest pain
is rare.
10. Pulmonary hypertention – insidious onset of exertional dyspnea, which can
rapidely become dyspnea at rest with pedal edema. Clinical signs:
increased pulmonic component of the second heart sound (P2), right
ventricular gallops, pulmonic or tricuspid insufficiency murmur, jugular
venous distention and pedal edema associated with lower lobes interstitial
fibrosis.
11. Congestive heart failure
12. Renal crisis –the most deadly SS complication. It is characterized by acute
onset of nephropathy and urinary syndrome such as: proteinuria,
azotemia, nephrotic syndrome, maligne HT. It can be triggered by
corticosteroids, so the minimal dose is required in the management of SS.
The hints for the renal crisis are:
• Symptomes < 1 year
• Raynaud’s phenomenon– absent or recent onset
• Fatigability – acute onset
• Loss of weight
• Polyarthritis
• Puffy hands
• Carpal Tunnel Syndrome
• Tendons lesions
• Progression of skin thickening
• Anti-topoisomerase I and ARN polymeraza III
13. Tendon friction rubs – early systemic sclerosis.

LABORATORY FINDINGS
Immunological findings
Autoantibodies – risk stratification:
Centromere
• lcSSc,
• isolated PAH
• bad gut disease
Topoisomerase-1
• interstitial lung disease
• dcSSc
• renal crisis

RNA pol I, III

• renal crisis
• dcSSc
Fibrillarin
• pulmonary hypertension,
• myositis
PM-Scl
• myositis
Th/To
• lcSSc with respiratory involvement

Esophageal dysmotility:

IMAGISTIC FINDINGS

HRCT will help in defining the pattern and the extent of parenchymal lung disease.
Lesions described in SS:
• amorphous or reticular appearance – inflammation or fine fibrosis, hard to
assess
• associated features: pulmonary arterial trunk diameter, oesophageal
dilatation, cystic change, bronchiectasis, UIP or NSIP pattern
To be further assessed:
Echocardiography: - eg. tricuspid gradient to be measured
Pulmonary function test - DLCO
Cardiac Questionnaire: - dyspnoea, cardiac problems
Cardiac catheterisation
Capillaroscopy: - nailfold capillary abnormalities of capillary drop out and/or
dilattion.
Doppler arteriography: obstruction, involvement of the walls of radial, ulnar
arteries
Biopsy of the finger: subintimal hiperplasia of the arterio-venous anastomosis
Manometry – esophageal dysmotility – rare used.
Cine-esophagraphy - esophageal dysmotility.
Barium swallon - esophageal dysmotility .
Endoscopy – reflux esophagitis, Barret’s esophagus, strictures – lower esophageal
area, watermelon stomach – gastric antral venous ectasia.

CLASSIFICATION CRITERIA

The American College of Rheumatology (ACR) – preliminary criteria

MAJOR CRITERIA
Scleroderma proximal to the metacarpophalangeal or metatarsophalangeal joints
MINOR CRITERIA
Sclerodactyly
Digital pitting scars
Bibasilar pulmonary fibrosis
1 Major + 2 minor criteria – definitive SS
+ abnormal capillary microscopy, dilated capillaries, avascular areas at the nail
beds
+ anti-centromere antibodies

Diffuse systemic sclerosis - dcSSc

• Skin involvement 1 year after the Raynaud’s phenomenon onset
• Early pulmonary involvement
 • Renal failure
• GI involvement
• Cardiac involvement
• Autoantibodies: Topo1 or RNA POL I,II,III

Limited systemic sclerosis - lcSSc

• Years for the onset of Raynaud’s phenomenon
• Skin involvement – hands, face, lower limbs
• Late onset of pulmonary hypertension +/- pulmonary interstitial
involvement, teleangiectasia, calcinosis, GI involvement
• Antibodies: ACA (70-80%)
• Capillary dilatation, no stenosis

TREATMENT

The treatment is symptomatic and according with the type of systemic sclerosis.

symptomatic
management of co-
morbidities:
lcSSc therapy: vascular
Raynaud's, GI
involvement,
calcinosis etc.

therapy: vascular
treatment of sevre organ-
SS dcSSc immunosuppresive - based complications
antifibrotic

therapy of the overlap features: arthritis,

overlap lupus, myositis

Fig. 1. Management of systemic sclerosis

1. Pulmonary fibrosis
Potential immunomodulatory strategies

• Methotrexate
• Cyclophosphamide – lung fibrosis, alveolitis.
• Azathioprine – maintenanace therapy
• Mycophenolate mofetil – lung fibrosis
• Stem cell transplant (autologous/allogeneic)
• Tacrolimus, rapamycin

• Biological agents – Rituximab - refractory or progressive lung disease,

Abatacept, Basiliximab – lung fibrosis

• Oral tolerance to type I collagen
• Hyperimmune caprine serum

Rigorous anti-reflux therapy

• PPI, H2 antagonist, prokinetic

Other interventions

• N-acetyl cysteine po 600mg tds

• Oxygen – intermittent or long term low flow
• Identification and treatment of pulmonary hypertension

2. Pulmonary hypertension treatment

Endothelin receptor antagonists (p.o.):

• Bosentan – licensed also for digital ulcers
• Ambrisentan
• Macitentan
Fig. 2. Endothelin receptor antagonists

Selective phosphodiesterase inhibitors (p.o.):

• Sildenafil
• Tadalafil
• Riociguat – guanylate cyclase agonist

Fig. 3. Selective phosphodiesterase inhibitors

Prostacyclin analogues (i.v., s.c., inh.):

• Epoprostenol
• Treprostinil
• Iloprost
Fig. 4. Prostacyclin analogues

3. Treatment and prevention of digital vasculopathy in SSc

Pulmonary hypertension treatment

• Parenteral prostacyclin
• Bosentan
• PDE5 inhibitors
• Angiotensin axis – (ACEi) ARB
Statin

Antithrombotic therapy

• Clopidogrel, aspirin
• LMW heparin

Surgical approaches
• Radical microarteriolysis
• Botulinum toxin injection

Raynaud’s therapy
• Oral vasodilators, SSRI
• Topical GTN microemulsion

TAKE HOME MESSAGES

Do not overdose glucocorticosteroids (no more than 10mg daily) due to the risk
of renal crisis.

Anticentromere antibody, an autoantibody associated with good survival,

virtually never occurs in diffuse SSc.

The interstitial lung disease in SSc usually occurs at the bases.

Scleroderma renal crisis may be the first manifestations of SSc.

References:
9. Stone JH, A Clinician’s Pearls and Myths in Rheumatology, Springer 2009,
493: 151-160
10. Bijlisma WJJ, Eular Compendium on Rheumatic Diseases, BMJ Publishing
Group, 2009, 824: 290-296

10. SERONEGATIVE SPONDYLARTHRITIDES (SpAs)

DEFINITION

The spondyloarthritides (SpA) are a group of clinically, inflammatory disorders

characterized by the absence of rheumatoid factor. They comprise ankylosing
spondylitis (AS), reactive arthritis (ReA), arthritis/spondylitis associated with
psoriasis – psoriatic arthritis (PsA), and arthritis/spondylitis associated with
inflammatory bowel disease – enteropathic arthritis.
 Undifferentiated SpA

Juvenial
SpA Psoriatic arthritis

Crohn's Disease Ankylosing spondylitis

Ulcerative colitis

Reactive arthritis Acute uveitis

Fig. 1. Concept of Spondyloarthritis (SpA)

EPIDEMIOLOGY

• SpAs occur in about 2% of the general population

• The frequency of HLA-B27 in general population is 10% and in patient
population with SpA ranges 50% up to 95%
• SpAs occur in just over 10% of HLA-B27 positive people
• SpAs are often associated with HLA-B27

PATHOGENESIS

SpAs are immune-mediated diseases. This is supported by:

• the association with HLA-B27
• the presence of TNF - 

CLINICAL MANIFESTATIONS

• inflammatory low back pain, spinal stiffness, alternating buttock pain

- SpAs
 • sacroiliitis - SpAs
• enthesitis - SpAs
• oligoarticular arthritis - SpAs
• dactylitis (sausage digits) – inflammation at tendon insertions and
tendon sheats in fingers and toes with joint space involvement – PsA, ReA
• uveitis - SpAs
• conjunctivitis – ReA
• psoriasis – salmon-colored hyperkeratotic scaling plaques on extensor
surfaces – PsA,
• nail changes: pitting, splinter hemorrhages, nail bed hyperkeratosis, oil-
drop discoloration, onycholisis – PsA, ReA
• infectious diarrhea – ReA
• urethritis or cervicitis – ReA
• painless oral ulcers – ReA
• sterial pyuria/dysuria – ReA
• circinate balanitis – ReA
• keratoderma blennorrhagicum – ReA
• cardiac involvement – aortic insufficiency – SA, ReA
• erythema nodosum – CD, UC
• pyoderma gangrenosum – CD, UC
LABORATORY FINDINGS

• ESR, CRP – elevated in active disease

• HLA-B27 – ASAS criteria for diagnosis (only 10%)
• anti-CCP antibodies can be present in PsA – evolution factor
• serological tests- high false negative results – not usually used in clinical
practice

IMAGISTIC FINDINGS

Plain radiography :
 • Anterior-posterior radiographs of the SI joints – bilateral sacroillitis
(AS, CD, UC), asymmetrical sacroillitis (PsA, ReA)
Grading of radiographic sacroiliitis:
➢ Grade 0: normal.
➢ Grade 1: suspicious changes.
➢ Grade 2: minimal abnormality—small localised areas with erosion or
sclerosis, without alteration in the joint width.
➢ Grade 3: unequivocal abnormality—moderate or advancedsacroiliitis
with one or more of: erosions, evidence of sclerosis, widening, narrowing,
or partial ankylosis.
➢ Grade 4: severe abnormality—total ankylosis.
• Spine’s radiography – ankylosis of the spine with syndesmophytes
(osseous attachments to ligaments) – bamboo appearance
• Joint radiographs: pencil in cup erosions (PsA), fluffy erosions (ReA) lysis
of terminal phalanges, periostitis, new bone growth in the distal joints, new
bone growth at site of enthesitis (SpAs)
MRI (T1, STIR):
• bone marrow oedema and fat infiltration (early AS)
• vertebral corner erosion (AS)
Active inflammatory lesions (STIR/post-gadolinium T1):
• bone marrow oedema (osteitis)
• capsulitis
• synovitis
• enthesitis
Chronic inflammatory lesions (normally T1):
• sclerosis
• erosions
• fat deposition
• bony bridges/ankylosis

CLASSIFICATION CRITERIA

ASAS criteria for classification of axial spondyloarthritis (to be applied in

patients with chronic back pain and age at onset of back pain < 45 years)
A. Sacroiliitis on imaging (MRI’s sacroiliitis or New York radiographic criteria
for sacroiliitis – grade 2 bilateral or grade ¾ unilateral) plus at least 1 *SpA
features
or
B. HLA-B27 plua at least 2 other *SpA features

*SpA features:
• inflammatory back pain
• arthritis
• enthesitis
• uveitis
• dactylitis
• psoriasis
• Crohn’s/colitis
• good response to NSAIDs
• family history for SpA
• HLA-B27
• elevated CRP

AS is an inflammatory arthritis characterized by low back pain, stiffness of the

spine, sacroiliitis and occasionally associating oligoarticular arthritis, enthesitis
and uveitis.
AS can be:
• axial AS – sacroillitis and linflammatory low back pain
• peripheral AS – polyarthritis or oligoarthritis

PsA is an inflammatory arthritis that is associated with psoriasis.

PsA can present as:
• asymmetric oligoarthritis – at least 5 joints involved
• symmetric polyarthritis – symmetrical involvement of the small joints
(dd with RA)
 • spondyloarthropaty – sacroillitis, spondylitis
• distal arthritis – involves the distat interphalangeal (DIP) joints
• arthritis mutilans – destructive arthritis
•
CLASSIFICATION OF PSORIATIC ARTHRITIS (CASPAR)
CRITERIA
Inflammatory joint disease + at least 3 points from the following
Current psoriasis 2 points
Personal history of psoriasis 1 point
Family history of psoriasis 1 point
Psoriatic nail distrophy 1 point
Negative test for RA 1 point
Current dactylitis 1 point
History of dactylitis 1 point
Rx evidence of juxtaarticulat new bone formation 1 point

ReA is a sterile inflammatory disorder characterized by arthritis, uveitis and

conjunctivitis. There are no specific classification criteria for ReA. (see clinical
manifestations)

Enteropathic arthritis – Crohn’s disease (CD) and ulcerative colitis:

• Type I – peripheral, pauciarticular arthritis: is non-deforming,
asymmetric, migratory, associated with active bowel disease
• Type II – peripheral, polyarticular arthritis: is not associated with
active bowel disease
• Type III – axial disease: is not associated with active bowel disease. It is
characterized by inflammatory low back pain and sacroiliitis.

TREATMENT

The treatment is aiming for the symptoms and forms of manifestations articular -
axial or peripheral or extraarticular.
DRUG THERAPY
Axial involvement
• NSAIDs – first line treatment
• TNF -  agents (eg. infliximab, golimumab, adalimumab, etanercept)
Peripheral involvement
• sulfasalazine – first line treatment
• methotrexate – first line treatment
• azathioprine – (PsA)
• TNF -  agents (eg. infliximab, adalimumab, etanercept)
• Alefacept (T cell modulator) plus methotrexate – PsA
• Ustekinumab (Interleukin 12/23 antagonist) - PsA
Limited joint involvement
• intra-articular and topical steroids
Circinate balanitis and keratoderma blennorrhagicum
• topical steroids
Skin involvement
• topical agents: retinoids (acitretin), photochemotherapy/ultraviolet B
(PUVA/UVB) (PsA)
• no immunosuppresion after phototherapy due to the risk of skin cancers
(eg. melanoma) (PsA)
• Cyclosporin (PsA)
NON DRUG THERAPY
• physical therapy and exercise (respiratory and postural training) –
limitation of pain and increasing of mobility
• quit smoking – predictor of worse outcome
• surgery (AS, CD, UC) – total hip arthroplasty, spinal fusion (subluxation),
wedge osteotomies (severe flexion deformities)

TAKE HOME MESSAGES

It is mandatory to refer to a rheumatologist a patient with a chronic back pain (at

least 3 months from the onset) and one or ore of the following:
• inflammatory back pain
• HLA-B27 positivity
• sacroiliitis on imaging
• refractory peripheral arthritis
References:
11. Stone JH, A Clinician’s Pearls and Myths in Rheumatology, Springer 2009,
493: 23-26, ISBN: 978-1-84800-933-2
12. Kahl Leslie, Rheumatology Subspecialty Consult, Wolter Kluwer,
Lippincott, Williams and Wilkins, 422: 160-193
11. OSTEOARTHRITIS

DEFINITION

Osteoarthritis (OA) is a multidimensional disease that affects all anatomical

structures in the joints, especially the cartilage and subchondral bone, producing
progressive functional deterioration.
Synonims for OA:
• Hypertrophic arthritis
• Degenerative joint disease
• Degenerative disc disease
• Generelized osteoarthritis (Kellgren’s syndrome)

EPIDEMIOLOGY

• the most common osteoarticular disease

• prevalence increases with age
Primary OA
• Women > Men
• Increased age
• Symptomatic OA 2-3% overall population
• Symptomatic knee OA – 11% (> 65 years old)
• Symptomatic hip OA – 5% (> 65 years old)
• Radiographic evidence: 50-80% > 65 years old
Secondary OA
 • Known etiologic factor
• Different joint distribution

PATHOGENESIS

OA risk factors include mechanical, genetic and biochemical factors.

Risk factors for primary OA
• age
• gender – females are more affected than males
• high bone mass – pts. with osteoporosis are less likely to develop OA
• obesity - the effect of excess weight on overloading joints (knee, hip)
during weight-bearing activities, will cause cartilage breakdown and
damage to ligaments and other structures
• overused joint/mechanical factors – joints exposed to repetitive use
• genetic – mutations in genes encoding for matrix proteins lead to
premature OA
Risk factors for secondary OA
• hemarthrosis – secondary to trauma, diseases with defect coagulation.
Persistent and recurrent blood in the synovial fluid will lead to cartilage
destruction.
• metabolic diseases – acromegaly, Paget’s disease, Cushing’s syndrome,
crystalline arthropaties, amyloidosis.
• damaged joints
• neuropathic joints – diabetes – foot, ankle and spine are involved,
syringomyelia involves the elbows and shoulders, the knees are involved
in tabes dorsalis.

Pathogenesis involves all joint tissues including cartilage, bone, synovium,

ligamentous capsular structures, and surrounding muscle. It is characterized
structurally by active bone remodeling, degradation of articular cartilage, and
synovial inflammation resulting in loss of joint function and angular deformity or
malalignment. OA is thought to be also a cytokine-driven disease. (see figure
below)
 Small proteins mediators
Cytokines

Chemical signaling or
“cross-talk” among involved tissues

Inflammation – synovium
Remodeling subchondral bone
Enzyme activation
Extracellular matrix degradation

CLINICAL MANIFESTATIONS

• Joint pain
• Crepitus
• Stiffness after immobility
• Limitation of motion
• Deformity
• Chronic disability

LABORATORY FINDINGS

• Erythrocyte sedimentation rate (ESR) - normal limits.

• Rheumatoid Factor is negative.
 • Antinuclear antibodies (ANA) are not present.
• Synovial fluid:
➢ High viscosity with good string sign
➢ Color is clear and yellow
➢ White blood cells typically < 1000-2000/mm3
➢ No crystals and negative cultures

IMAGISTIC FINDINGS

Xray changes – ABCDES

A – no ankylosis, alignment may be abnormal
B – bone mineralization is normal, bony subchondral sclerosis, bony spurs
(osteophytes)
C – no calcifications in cartilage, irregular cartilage space narrowing
D – deformities of Heberden’s/Bouchard’s nodes, distribution: typical joints
involvement
E – no erosions (erosive arthritis – “Gull wing” sign)
S – slow progression over years, vacuum sign, no specific nail or soft tissue
abnormalities

CLASSIFICATION CRITERIA

Primary or idiopathic:
• localized form – one or two joint group involved - hands (erosive,
inflammatory; DIP, PIP, 1st CMC joints); feet (1st MTP joint), hip, knee, spine
• generalized form – three or more joint groups involved associated with
Heberden’s or Bouchard’s nodes - Kellgren’s syndrome
Secondary - involves atypical joints such as: metacarpophalangeal joints, wrists,
ankles, shoulders, elbows.
Erosive or inflammatory OA affects the DIP and PIP joints of the hand with
negative RF or anti-CCP antibodies.
American College of Rheumatology (ACR) radiologic and clinical criteria for
HAND osteoarthritis (OA)
Clinical
1. Hand pain, aching or stiffness for most days or prior months
2. Hard tissue enlargement of two or more of 10 selected joints*
3. Metacarpophalangeal joints swelling in two or more joints
4. Hard tissue enlargement of two or more distal interphalangeal joints
5. Deformity of two or more of 10 selected hand joints*
OA if the items 1, 2, 3, 4 or 1, 2, 3, 5 are present.
* Ten selected joints include bilateral second and third interphalangeal proximal
joints, second and third proximal interphalangeal joints, and first
carpometacarpal joint.

American College of Rheumatology (ACR) radiologic and clinical criteria for

knee osteoarthritis (OA)
Clinical
1. Knee pain for most days or prior months
2. Crepitus on active joint motion
3. Morning stiffness lasting 30 minutes or less
4. Age 38 years or older
5. Bony enlargement of the knee on examination
OA if the items 1, 2, 3, 4 or 1, 2, 5 or 1, 4, 5 are present.
Clinical and radiographic
1. Knee pain for most days or prior months
2. Osteophytes at joint margins on radiographs
3. Synovial fluid typical of OA (laboratory)
4. Age 40 years or older
5. Crepitus on active joint motion
6. Morning stiffness lasting 30 minutes or less
OA if the items 1, 2 or 1, 3, 5, 6 or 1, 4, 5, 6 are present.

American College of Rheumatology (ACR) radiologic and clinical criteria for

hip osteoarthritis (OA)
1. Hip pain for most days or prior months
2. ESR of less than 20 mm at the 1st hour
3. Femoral or acetabular osteophytes on radiographs
4. Hip joint space narrowing on radiographs
OA if the items 1, 2, 3 or 1, 2 ,4 or 1, 3, 4 are present.

TREATMENT

OA’s treatment is multimodal – a combination of non pharmacological procedures

combined with drug therapy.

Objectives:

• patient education and information access

• pain relief

• optimization of function

• beneficial modification of the OA process

NON-PHARMACOLOGICAL MANAGEMENT
• Weight loss
• Patient education
• Rest of affected joints
• Exercise for muscle strengthening and aerobic conditions:
• Improvement of pain and joint function
• A state of psychological well-being
• No weight-bearing exercise – affects the articular cartilage and
subchondral bone
• Swimming
• Shock-absorbing insoles
• Hydrotherapy
• Superficial heat and cold
 • Paraffin baths for hands
• Splinting (knee sleeves, CMC splints)
• Ambulatory aids (canes, crutches, walkers)
• Heel wedges, knee wedges to un weight medical compartment of knee
• Cervical collar
• Cervical traction or distraction
• Transcutaneous electrical nerve stimulator (TENS)
• Total joint replacement (hip, knee) – indications:
1. Severe pain unresponsive to medical therapy
2. Loss of joint function
Predictive factors for physical therapy success:
➢ 1 joint affected (pain)
➢ Age ≤ 58 years old
➢ VAS (pain) ≥ 6/10
➢ 40 m SPWT ≤ 25.9 sec.
➢ Onset ≤ 1 year

PHARMACOLOGICAL TREATMENT
• Acetaminophen
• NSAIDs
• Opiods
• Corticosteroids injections
• Hyaluronic acid injections

OA – FUTURE THERAPIES
• Metalloproteinase inhibitors – tetracycline's derivates (the inhibition of
collagenase, stromelysin – can slow the progression of osteoarthritis)
• Cartilage growth factors
• In vitro grown cartilage – repair of cartilage
• Erosive arthritis – MTX (in use)

TAKE HOME MESSAGES

OA is not an old person’s disease.

Risk factors for OA can be modified.

References:
13. Stone JH, A Clinician’s Pearls and Myths in Rheumatology, Springer 2009,
493: 23-26, ISBN: 978-1-84800-933-2
14.
13. ADULT STILL DISEASE

DEFINITION

Adult Still’s Disease (ASD) is a rare, systemic, inflammatory, autoimmune disorder

characterised by polyarthritis, high spiking fevers and salmon-colored,
evanescent rash.
It is part of the group of “auto inflammatory syndromes” – familial Mediterranean
fever, Muckle – Wells syndrome, characterized by: amyloidosis, malarial fever and
urticarial rash.

EPIDEMIOLOGY

ASD is a rare disorder. The incidence reported differs from continent to continent.
A bimodal peak at ages 15-25 and 36-46 was reported. No discrimination found
regarding the involvement of male or female gender.

PATHOGENESIS

The aetiology of ADS is unknown. It is a IL-1 mediated disease. Elevated serum

levels of IL-1, IL-18, IL-6, TNF were found in active untreated patients with ASD.
Triggers presumably involved are: rubella, Epstein Barr virus, cytomegalovirus,
parvovirus B19, cocksakievirus B4, mumps, hepatitis B and C, human herpes virus,
Chlamydia pneumoniae, Mycoplasma pneumoniae, Borrelia burgdorferii, Yersinia
enterocolitica, Brucella abortus.

CLINICAL MANIFESTATIONS

12. Fever – the most important diagnostic criteria

• dramatic, sudden onset
• remittent
• mimics septic pattern
• fever spikes –“double quotidian” pattern, can occur any time in the
24 h period (usually in the late afternoon or early evening)
• exceeds 390C
• last under 4 hours
13. Rash
• small salmon-pink, maculopaupar eruptions
• affects the trunk and extremities involved
• disapear during the night
• coincident with a fever spike
• dermatoraphism is not specific
14. Arthritis
• may be absent in the initial stages of ADS
• mild
• oligoarticular
• transient
• no swelling
• no synovitis
15. Myalgia
• may be severe
• inflammatory myopathy is rare
• serum creatinine kinase and aldolase slightly elevated
 16. Pharyngitis
• is often the initial symptom – severe sore throat and difficulty
swallowing
• no evidence of tonsillar, laryngeal or tracheal inflammation
17. Other manifestations:
• abnormal liver functions – hepatitis
• reactive hemophagocytic syndrome - pancytopenia
• splenomegaly
• cervical lymph nodes
• pleural effusions
• pericarditis

The clinical course of the ASD can be divided in three patterns:

6. chronic articular pattern
• persistent active disease
• severe, destructive arthritis
7. self-limiting or monophasic pattern
• single disease episode
• systemic symptoms: fever, rash, serositis, hepato/splenomegaly
8. intermittent or polycyclic systemic pattern
• recurrent disease flares
• systemic symptoms

Predictors of chronic disease:

• rash
• polyarthritis
• involvement of shoulders and hips

LABORATORY FINDINGS

ASD is a seronegative disease. It is lacking positivity for rheumatoid factor (RF) or

antinuclear antibody (ANA).
 • high levels of erytrocyte sedimentation rate (ESR) and C reactive
protein (CRP)
• leucocytosis (WBC > 15x109/l)
• predominance of granulocytes
• normocytic, normochromic anemia
• reactive trombocytosis
• pancytopenia (reactive hemophagocytic syndrome ) –
recommended immunosuppressive treatment
• intravascular coagulation
• high levels of transaminases, lactate dehydrogenase,  -
glutamyltransferase
• increased levels of bilirubin
• elevated serum ferritin – disease activity
• decreased levels of glycosylated ferritin

IMAGISTIC FINDINGS

No radiographic manifestations are specific for ASD. It may presents with:

• joint space narrowing (eg. carpal joint space)
• joint erosions
• rapid destruction of the hip or knee – arthroplasty

CLASSIFICATION CRITERIA

Yamaguchi criteria (93.5% sensitivity) – diagnosis of ASD – presence of 5 criteria

or more, at least 2 major criteria present.

Major criteria
• fever of at least 390C, intermittent, lasting one week or longer arthralgias
or arthritis, lasting two weaks or longer
• typical rash
 • leukocytosis (10,000/L or greater), with 80% or more granulocytes

Minor criteria
• sore throat
• hepatomegaly or splenomegaly
• abnormal liver functions (elevated levels of aminotransferases and lactate
dehydrogenase)
• recent onset of significant lymphadenopathy
• negative tests for RF and ANA

Exclusion criteria
• malignancies
• infections
• other rheumatic conditions

TREATMENT

The management of ASD aims the organ involvement and the disease severity.
NSAIDS and Aspirin
• fever
• arthritis
Glucocorticoids
• all patterns of disease
• arthritis – Prednisone 0.5 to 1mg/kg/day
• pulses in flares
Immunomodulating drugs – anecdotic results
• Methotrexate
• Sulfasalazine
• Cyclosporine
Intravenous immunoglobulin – chronic pattern
On study:
IL-1 receptor antagonist – Anakinra
Anti Il-6 – MRA
Anti-tumour necrosis factor alpha – Infliximab, Etanercept

TAKE HOME MESSAGES

• The pattern of fever is the most important diagnostic criteria for ASD.
• Primary renal involvement does not occur in ASD. It is useful in
differentiating ASD from lupus, vasculitis or malignancies.
• Increased serum levels of Il-1, Il-6, TNF  means fever, high acute phase
protein production and leucocytosis.
• ASD is typically seronegative.
• There are not diagnostic tests for ASD.

References:
15. Stone JH, A Clinician’s Pearls and Myths in Rheumatology, Springer 2009,
493: 23-26, ISBN: 978-1-84800-933-2
16. xxx
14. SARCOIDOSIS

DEFINITION

Sarcoidosis is a systemic inflammatory disorder characterized by the presence of

noncaseating granulomatous inflammation in involved organs. The lungs, eyes,
skin, joints, lymph nodes, and upper respiratory tract are usually affected.

EPIDEMIOLOGY

The incidence and prevalence of sarcoidosis is characterized by heterogeneity. It

appears to be 3 to 4 times more common in Afro Americans than Caucasians. The
female gender is more affected than the male one. The highest prevalence was
noted in northern Europe with a peak between 20 and 40 years of age.
PATHOGENESIS

The aetiology of sarcoidosis is unknown. The following factors (presumably

triggers/antigens) were noted in studies aiming the cause of sarcoidosis:
• infectious agents: Mycobacterium tuberculosis, Propionibacterium acnes,
Human herpes virus. – following transplantation ( eg. bone marrow, stem
cell, cardiac)
• Kveim-Siltzbach reagent
• genetic background: angiotensin converting enzyme genotypes, HLA-
B12,13, 27, 35; HLA-DR3,4,5
• CD4+/CD8+ T cells – the Th1/Th2 balance plays an important role in the
organisation of granulomas, the auto-resolution and/or progression of the
disease.
• Cytokines – Il-2 (proliferation or redistribution of the activated
lymphocytes population and B – cell differentiation ), Il-6, Il-8 (disease
process), Il-15 (CD4+ T cell proliferation), Il-12, Il-18 (stimulate IFN-)

The characteristic of sarcoidosis is the non-caseating granuloma that can be found

in any organ. Sarcoidosis is mediated primarily by the CD4+ T cells (T helper cells
– Th1). The initial lesion, at the level of the lung, is alveolitis. So beside the CD4+ T
cells, the alveolar macrophages (inflammation!!!) produce and express pro-
inflammatory cytokines such as: Il-12, Il-18, IFN-, TNF .
The granuloma is characterized by:
• central – epitheliod cells, activated monocytes-macrophages, and
multinucleated giant cells
• periphery – suppressor CD8+ T cells (Th2)
It is presumed that the extrapulmonary manifestations in sarcoidosis are due to
the migration of activated T cells through the blood and lymphatic vessels to other
tissues.

CLINICAL MANIFESTATIONS
1. Pulmonary involvement
• 90% of cases
• 50% detected incidentally 0 chest radiography – hilar adenopathy
• cough
• dyspnea
• chest pain
• wheezing (may be present)
• self limited
• spontaneous remission
2. Extrathoracic manifestations
• cutaneous involvement: erythema nodosum, subcutaneous
nodules, plaques, paules, lupus pernio
• ocular involvement: uveal tract, lacrimal gland and conjunctiva;
optic neuritis, pars planis (attention!!! – differential diagnoses with
multiple sclerosis); uveitis is the most common ophthalmologic
manifestation
• arthralgia/arthritis, tenosynovitis, myopathies
• unilateral facial nerve palsy
• heart involvement: pericarditis, left ventricular dysfunctions,
arrhythmias
• hepatomegaly
• diabetes mellitus – hypothalamic-pituitary axis involved
• vasculitis
3. Lofgren’s syndrome is characterized by:
• hilar adenopathy
• acute arthritis/arthralgias
• erythema nodosum
• Caucasians
• women
• typically involves the ankles and knees
• also associates: fever, myalgia and weight loss
• excellent response to corticotherapy
 • 90% remission rate
4. Heefordt’s syndrome:
• anterior uveitis (iridocyclitis or iritis)
• parotid gland enlargement
• facial palsy
• fever

LABORATORY FINDINGS

• elevated ESR (non specific)

• hypergammaglobulinemia
• anemia – secondary to chronicity
• leukopenia, lymphopenia, eosinophilia, thrombocytopenia is rare
• elevated angiotensin converting enzyme (ACE) – is normal in acute
sarcoidosis
• hypercalciuria, hypercalcemia – consequence of enhance production of
1,25 – dihydrocholecalciferol due to elevated levels of ACE
• serum alkaline phosphatase might be elevated – hepatic involvement

IMAGISTIC FINDINGS

Chest radiographic stages

Stage 0
• normal
Stage 1
• bilateral hilar adenopathy
Stage 2
• bilateral hilar adenopathy with pulmonary infiltrates
Stage 3
• pulmonary infiltrates with lung insufficiency
Chest High Resolution Computed Tomography (HRCT) – the lesions are
localised in the mid-upper zones of the lungs:
• lymphadenopathy (hilar and mediastinal)
• nodules
• fibrosis
• ground glass phenomenon
• cysts
• parenchymal masses or bands
• thickening of the bronchovascular bundles

Bone radiography - bone lesions usually occurs in the proximal and middle
phalanges:
• cystic bone lesions (more cystic than sclerotic)
• lytic bone lesions – heads
• sclerotic lesions
• focal bone lesions
• osteopenia/osteoporosis

Pulmonary function tests

• restrictive pattern -  diffusing capacity for carbon monoxide
• sometimes – obstructive pattern – endobronchial sarcoidosis

Bronchoalveolar lavage (BAL)

• reduce number of CD8+ T cells
• elevated CD4 to CD8 ratio
• lymphocytosis is not specific
• neutrophils > 2% or eosinophils > 1% - usually is not sarcoidosis!!!

DIAGNOSIS

It is suggested if the following are present:

• clinical and imagistic manifestations
 • biopsy – non-caseating granuloma
• exclusions of other diseases such as: tuberculosis, Crohn’s disease,
lymphomas, bacterial, viral, parasitic or fungal infections etc.

Prognosis is negative influenced by:

• Afro American race
• onset after 40 years old
• lupus pernio (be attentive – it may be tuberculosis: TB)
• chronic uveitis
• chronic hypercalcaemia
• nephrocalcinosis
• progressive pulmonary involvement
• nasal mucosal involvement
• cystic bone lesions
• neurosarcoidosis
• cardiac involvement

TREATMENT

The management of sarcoidoisis depends on the clinical manifestations – lung or

extrapulmonary symptoms.

Pulmonary involvement treatment

Indications:
• progressive radiographic changes
• deterioration of lung function
• worsening of pulmonary symptoms

Medications:

Corticosteroids – are used for its suppressing effects on inflammatory response.

It is believed to reduce the progression of fibrosis and acts on pulmonary
sarcoidosis as well. There are not stipulated protocols concerning the dose of
corticosteroids in pulmonary sarcoidosis. The oral therapy can be started with 0.5
to 1 mg/kg ideal body weight for 4 to 6 weaks and after that tapered by 5 to 10mg
every 4 to 8 weeks until the maintenance dose is reached (0.25mg/kg ideal body
weight – for 6 to 12 months).

Immunosuppresive drugs
In case of a non response to corticosteroids the following drugs may be used:
• Azathioprine
• Cyclophosphamide
• Chlorambucil
• Cyclosporine

Lung transplantation – end stage pulmonary fibrosis.

Extrapulmonary involvement treatment

Indications:
• resistant symptomatic disease
• resistant ophthalmic manifestations
• progressive chronic pulmonary disease
• neurosarcoidosis
• cardiac involvement
• hypercalcemia
• bone and joint destruction

Medications:

Corticosteroids – similar doses as in pulmonary involevement.

Methotrexate (MTX) is used as a substitute for corticosteroids in acute

sarcoidosis (except pulmonary manifestations). MTX is often associated with liver
fibrosis and progressive interstitial lung changes (especially in sarcoidosis).
Colchicine can be effective for acute arthritis.

Antimalars (chloroquine/hydroxichloroquine) – cutaneous and/or

musculoskeletal disease (+/- low dose of methotrexate).

Immunosuppresive drugs
In case of a non response to corticosteroids the following drugs may be used:
• Azathioprine – cutaneous disease
• Cyclophosphamide – cardiac and neurosarcoidosis

TAKE HOME MESSAGES

• Sarcoidosis is characterized by a non-caseating granuloma, that can affect

any organ.
• The most common manifestations are pulmonary involvemet – hilar
adenopathy (bilateral) and anterior uveitis.
• An increase CD4 to CD8 ratio in BAL fluid strongly supports the diagnosis
of sarcoidosis.
• ACE can be normal in acute sarcoidosis.
• Corticosteroids are the cornerstone therapy for active sarcoidosis.

References:
17. 1. Stone JH, A Clinician’s Pearls and Myths in Rheumatology, Springer
2009, 493: 23-26, ISBN: 978-1-84800-933-2
18. xxx

15. BEHÇET’S DISEASE

DEFINITION
Behçet’s Syndrome (BS) is a systemic inflammatory disease characterized by oral
aphthae, genital ulceration and hypopyon uveitis.

EPIDEMIOLOGY

• affects every age group

• onset on third decade
• rare in Northern Europe, Northern Asia, Africa, Australia, Americas
• patterned by The Silk Route – Middle and Farr East in common involved

PATHOGENESIS AND HYSTOPATHOLOGY

The pathogenesis is unknown. But it was noted:

• an evidence for a genetic predisposition
• HLA-B51 has been the most consistently reported HLA association
• both innate and adaptive immune systems are involved in the pathogenesis
The histopathology of the BS lesions is not characterized by a certain pattern. All
the vessels are involved, but only some of the probes would be characterized by
immune complex deposition.

CLINICAL MANIFESTATIONS

Skin and mucosa manifestations

• oral ulcers - first disease manifestation; affect lips, gingiva, cheeks, and
tongue. they are multiple, oval or round. Healing is in 15 days without
scarring. Tobacco is a protective factor for those type of canker sores.
• genital ulcers - usually located on the scrotum in males and on the major
and minor labiae in females . They are larger, deeper, less recurrent and
resistant to healing than oral ulcers.
• scar
• papulopustular lesions – similar to ordinary acne. They are found on face,
upper chest and back.
• erythema nodosum
 • pathergy reaction – non-specific hyperreactivity in response to minor
trauma.
• superficial thrombophebitis – more common in males, similar to erythema
nodosum
• Sweet’s Syndrome - acute febrile neutrophilic dermatosis — is
characterized by fever and painful skin lesions on arms, neck, face and
back.
Eye symptoms
• hypopyon – pus in anterior segment
• acute anterior uveitis (good prognosis) - bilateral
• pan-uveitis (poor prognosis) rare associating retinal vasculitis - bilateral
• blindness - if no treatment applied
• cataract
• optic atrophy
• macular degeneration
• posterior synechia
• rare: conjunctivitis, corneal ulcerations, scleritis.
Neurological involvement - a cause of high morbidity and mortality. Two
patterns are described.
1. Parenchymal (80%)
• isolated spinal cord lesions
• hemispheric involvement
• peripheral neuropathy (rare)
• isolated cerebellar involvement (rare)
• aseptic meningitis (rare)
2. Non-parenchymal (20%)
• dural sinus thrombosis
• intracranial arterial occlusions (rare)
• dissections (rare)
• aneurysms (rare)
Major vessels involvement - late onset, usually after eye involvement. It is
uncommon.
 • deep vein thrombosis
• arteritis with occlusion and/or pseudo-aneurysms;
• microaneurysms
Cardiac disease - uncommon
• pericarditis
• valve lesions
• coronary artery involvement
• intracardiac thrombi
Pulmonary Involvement
• haemoptysis associated with pulmonary arterial aneurysm;
• pulmonary artery occlusion;
• pleural involvement uncommon;
• interstitial involvement very rare
Gastrointestinal involvement
• severe abdominal pain;
• ulcerative lesions at any level but mainly in the ileocaecal region;
• mild GI symptoms should not be associated with BS
Joint involvement
• no sacroiliac joints or spine involvement
• deformity and erosions rare
• monarthritis – most frequently,
• oligoarticular or polyarticular involving - may be symmetrical (knees most
affected); intermittent - resolving in 2-4 weeks or chronic and continuous.

LABORATORY FINDINGS

• mild anemia
• neutrophilic leucocytosis
• the erythrocyte sedimentation (ESR) rate – may be elevated
 • the C-reactive protein (CRP) may be moderatly elevatedn - erythema
nodosum and acute thrombophlebitis
• RF - absent
• antinuclear antibodies - absent
• anti-neutrophil cytoplasmic antibodies (ANCA) are usually negative
• BS with gastrointestinal involvement - high levels of Anti-Saccharomyces
Cerevisiae Antibodies (ASCA)
• cerebrospinal fluid (CSF): protein is elevated; neutrophil or lymphocyte
predominance or a mixed pattern is observed alohgside with 1-2
oligoclonal bands. It is a poor prognosis sign.

IMAGISTIC FINDINGS

• MRI – neurological manifestations

• CT – GI pulmonary changes
• X Ray – cardiac and pulmonary changes
• Doppler US – vascular manifestations

DIAGNOSIS CRITERIA

International Study Group Criteria for diagnosis of Behçet’s Disease

Manifestation Definition
Recurrent oral Minor apthous, major aphthous or herpetiform ulcers
ulceration observed by a physician or reported reliably by patient
Recurrent at least three times in one 12-month period
plus any 2 of the following findings
Recurrent genital Recurrent genital aphthous ulceration or sacrring,
ulceration observed by a physician or reported reliably by patient
Anterior uveitis, posterior uveitis, or cells in vitreous on
Eye lesions
slit-lamp examination; or retainal vasculitis observed by
qualified physician (ophthalmologist)
 Erythema nodosum-like lesions observed by a physician
or reported reliably by patient, pseudofolliculitis or
Skin lesions
papulopustular lesions; or acneiform nodules observed
by a physician in postadolescent patients not receiving
corticosteroids
Test interpreted as positive by a physician at 24-48 hours,
Positive pathergy
performed with oblique insertion of a 20-gauge or
test
smaller needle under sterile conditions

TREATMENT

The treatment is based on the signs and symptoms of the patient. Due to the fact
that young males have a poor prognosis (highest morbidity and mortality), its’s
management should be more aggressive.
Drug’s management of the:
1. Skin and mucosa manifestations
• topical glucocorticoids
• depot glucocorticoids
• colchicine - genital ulcers and erythema nodosum (female patients)
• systemic therapy – azathioprine
• antibiotics – penicillin
• TNF- blockers - etanercept
2. Eye symptoms
• azathioprine
• cyclosporine A
• TNF- blockers
• interferon - 
3. Neurological involvement
• cyclosporine A
• glucorticosteroids iv/ po
• methotrexate
 4. Major vessels involvement
• monthly pulses of cyclophosphamide combined with prednisolone
5. Cardiac disease
• glucocorticosteroids
6. Pulmonary Involvement
• no drug prove efficacy
7. Gastrointestinal involvement
• thalidomide
• TNF- blockers
• sulphasalazine - anecdotal
8. Joint involvement
• colchicine
• oral prednisolone
• interferon - 

TAKE HOME MESSAGES

Oral ulcers are usually the first and most persistent clinical feature of BS.

Uveitis is a bilateral panuveitis. Eye disease are a major source of morbidity.

BS is not a connective tissue disorder.

If the central nervous system white matter is involved it is mandatory to elude a

multiple sclerosis.

References:
19. Stone JH, A Clinician’s Pearls and Myths in Rheumatology, Springer 2009,
493: 23-26, ISBN: 978-1-84800-933-2
20. xxx