Seminars 5th year
Prof. J. Horák
RHEUMATOLOGY (1)
Rheumatoid Arthritis (RA)
It can affect various organs but predominantly involves the synovial
tissues of joints. HLA-D4 is present in 60 -70%. An unknown antigen
may initiate the rheumatoid process. HLA-DR1 is found in most HLADR4 -negative patients.
Pathogenesis: membrane proliferation and ultimate erosion of articular
cartilage and subchondral bone. Specific antigenic stimulation of
susceptible T-lymphocytes bearing the appropriate MHC molecules. This
results in both T and B cell proliferation, stimulation of blood vessel
proliferation in the synovial membrane, accumulation of inflammatory
cells, synovial cell proliferation, and development of a rapidly growing
and invasive pannus.
Clin: RA affects about 1.5% of most populations. Women in the
childbearing years are affected three times more frequently than males.
Classification Criteria for Rheumatoid Arthritis
1. Morning stiffness (>1 hour)
2. Soft tissue swelling of three or more joints
3. Soft tissue swelling of hand joints
4. Symmetric swelling (soft tissue)
5. Subcutaneous nodules
6. Serum rheumatoid factor
7. Erosions and/or periarticular osteopenia, in hand or wrist joints, seen
on radiograph
The small joints of the hands and feet are the most common articulations
affected. Initially, the synovitis of the PIP joints results in fusiform
swelling associated with warmth, erythema, pain, and limitation of
motion.
Permanent deformities: in the feet subluxation of the heads of the MTPs;
in the hands volar subluxation of the MCP joints and ulnar deviation of
the fingers.
The wrist joints are commonly affected: tenosynovitis of the dorsa of the
wrists, interosseous muscle atrophy and diminished movement due to
articular destruction and/or bony ankylosis. Volar synovitis → carpal
tunnel syndrome.
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Seminars 5th year
Prof. J. Horák
Chronic synovitis of the elbows, shoulders, hips, knees, and/or ankles
creates special secondary disorders:
- elbow- flexion contracture, loss of supination and pronation
- shoulder - limitation of shoulder mobility, dislocation, and chronic
pain
- knee - hypertrophy of the gastrocnemius-semimembranous bursa
(Baker's cyst) of the popliteal fossa.
Th:
objectives - to relieve pain, reduce inflammation, avoid side effects,
preserve or restore function, maintain lifestyle.
 an ongoing educational program (balanced rest and exercise, physical
and occupational therapy)
 pharmacologic therapy - initiated with NSAIDs (consider side effects)
 antimalarials (hydroxychloroquine) - ocular toxicity: corneal deposits,
macular pigmentation, field defects.
 gold salts - appear to alter macrophage function. Doses 25 - 50
mg/week i.m. Hematologic, dermatologic, and renal side effects.
 penicillamine - its effects are slow in expression, significant toxicity
on the bone marrow and the kidneys.
 immunosuppressive agents such as azathioprine, cyclophosphamide,
chlorambucil, and methotrexate are effective particularly in severe RA.
Esp. methotrexate is very effective and relatively free of toxicity. The
oral dose begins at 7.5 mg one time per week.
 corticosteroids are beneficial in the therapy of acute flare, but their
long-term use is not warranted as they neither cure nor alter the natural
course of the disease
Systemic Lupus Erythematosus (SLE)
cause: unknown
production of autoantibodies → immunologically mediated tissue injury
of several organ systems
periods of remissions and acute or chronic relapse
common causes of death: renal failure, hemorrhage, infection, pulmonary
disease, and vasculitis. The 10-year survival rate ~ 90%.
Peak incidence of onset between the ages of 16 and 55 years, more
frequent in women.
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Prof. J. Horák
Etiology and Pathogenesis
Immune hyperactivity → production of numerous autoantibodies.
Environmental agents such as drugs or ultraviolet light can trigger the
disease. Inherited predisposition to SLE is important in some persons.
SLE = immune complex disorder; ANA (antinuclear antibodies) and antidsDNA (anti-double stranded DNA) react with antigens in the circulation
or the glomerulus → complement fixation → release of chemotactic
factors and release of mediators of inflammation from leukocytes →
irreversible organ damage. Autoantibodies may be produced against
erythrocytes, platelets, and lymphocytes.
Typical histologic lesions:
 „onion-skin lesions“ found in arteries of the spleen, which consist of
concentric layers of fibrosis surrounding the vessel;
 Libman-Sacks verrucous endocarditis – vegetations on heart valves;
 hematoxylin bodies - globular masses of bluish, dense, homogeneous
material seen on hematoxylin and eosin stain; they can be found in all
organs, are identical to the inclusion bodies of the LE cells and
probably represent the interaction of antibodies to nucleoprotein
Subsets of lupus
Idiopathic
systemic
discoid
subacute cutaneous (ANA negative)
late-onset
Drug-induced
90% of patients with discoid LE have disease limited to the skin.
Late-onset SLE – presentation after age 50; accounts for approximately
15% of all cases.
Neonatal lupus is rare. It appears to be a complication of maternal
antibodies transferred through the placenta. Shortly after birth, infants
develop typical dicoid lesions with exposure to UV light. However, very
few of these infants develop SLE later in life.
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Prof. J. Horák
Criteria for Classification of SLE
criteria
definition
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
3. Photosensitivity
skin rash as a result of unusual reaction to
sunlight
4. Oral ulcers
oral or nasopharyngeal ulceration, usually
painless
5. Arthritis
nonerosive arthritis involving two or more
peripheral joints
6. Serositis
pleuritis or pericarditis
7. Renal disorder
persistent proteinuria > 0.5 g/day or cellular
casts
8. Neurologic disorder
seizures or psychosis
9. Hematologic
hemolytic anemia with reticulocytosis or
disorders
leukopenia < 4000/mm3 or
lymphopenia < 1500/ mm3 or
thrombocytopenia < 100000/ mm3
10. Immunologic
disorders
positive LE cell preparation or
anti-DNA antibody or
anti-SM antibody or
false-positive serologic test for syphilis
11. Antinuclear antibody
Drugs with association to SLE: hydralazine, procainamide,
chlorpromazine, methyldopa, INH. Renal and CNS involvement is
uncommon. The symptoms are usually mild and reversible when the drug
is stopped.
Clin: periods of exacerbation are followed by remission or inactive
disease. Frequent nonspecific symptoms: fatigue, fever, weight loss,
arthralgia/myalgia.
Arthritis is typically symmetric and involves small joints of hands,
wrists, and feet. Deformities similar to rheumatoid arthritis develop
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in ~ 10% of patients. Rheumatoid nodules and rheumatoid factors may be
present.
Raynaud’s phenomenon may result in digital gangrene.
Conjunctivitis, episcleritis, or keratoconjunctivitis occur in ~ 20% of
patients.
Abdominal pain may be a manifestation of serositis, mesenteric arteritis,
or pancreatitis or may be secondary to visceral perforation.
Acute pneumonitis with or without pulmonary hemorrhage.
Renal involvement occurs in ~ 50% of patients: proteinuria, hypertension,
hematuria, red blood cell casts are found in active disease.
Neuropsychiatric manifestations: depression and psychosis are frequent,
impairment of orientation, memory, or cognition.
Cardiac manifestation: pericarditis in up to 30% of patients, myocarditis
→ tachycardia, ST-T wave changes, congestive heart failure, and
cardiomegaly. Valvular lesions (the mitral and aortic valve) may occur.
Verrucous endocarditis is present at autopsy in nearly all patients with
cardiac involvement. Coronary arteritis, thrombosis, or premature
atherosclerosis secondary to corticosteroid use may lead to myocardial
infarction.
Hematologic abnormalities: normochromic normocytic anemia,
hemolytic anemia (sometimes Coombs’ positive), leukopenia (usually
lymphopenia), and thrombocytopenia.
Antibodies to clotting factors: the most common is the lupus
anticoagulant (an antiphospholipid antibody) → prolonged APTT.
However, it is associated with thrombotic disease and not with bleeding.
False-positive tests for syphilis are found in up to 25% of patients.
Oral contraceptives containing estrogen derivatives may lead to an
exacerbation of SLE.
Lab.: high-titer autoantibodies directed against nuclear components
(ANA). Anemia, leukopenia, hypergammaglobulinemia, proteinuria,
leukocyturia, low serum complement.
Th: aim – relieving symptoms, suppressing inflammation, and preventing
future pathology. UV light should be avoided in photosensitive patients.
Hypertension should be treated aggressively. Estrogen is useful for its
benefit regarding coronary artery disease and osteoporosis. Renal biopsy
is needed to determine appropriate therapy and prognosis.
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Prof. J. Horák
Pharmacotherapy:
- NSAIDs for arthralgias, mild arthritis, pleurisy, pericarditis, myalgias,
and headaches;
- corticosteroids to control the inflammatory response to prevent endorgan damage. Doses > 60 mg/day of prednisone may be necessary
for brief periods;
- antimalarials are used for dermatologic and musculoskeletal
manifestations (retinal toxicity);
- azathioprine may be useful in moderate renal disease, intractable skin
disease or arthritis;
- cyclophosphamide (daily oral or monthly pulse i.v.) combined with
corticosteroids is commonly used to treat proliferative types of
nephritis.
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