Connective Tissue disorders

Connective Tissue disorders

Heterogenous disorders with common features:
inflammation of skin, joints, and other structures rich in connective tissue alteration of immunoregulation
production of autoantibodies and abnormalities of cell-mediated immunity

Outlines
Rheumatoid Arthritis Sjogrens Syndrome Systemic Lupus Erythematosus Progressive Systemic Sclerosis Ankylosing Spondylitis Reiters Syndrome Psoriatic Arthritis

Rheumatoid Arthritis

Rheumatoid Arthritis
A chronic multisystem disease of unknown etiology, characterized by persistent inflammatory synovitis ( usually involving peripheral joints in a symmetric fashion)

Rheumatoid Arthritis
Etiology
Prevalence
Genetic: association with HLA-DR4 Environmental factors also plays a role 0.8% of population women affected 3 times more often than men prevalence increased with age onset: more frequent in fourth and fifth decades

Pathology

Immunologically mediated event:

Synovial hyperplasia, lymphocytic infiltration of synovium Local production of cytokines and chemokines

HLA
Human Leukocyte Antigen Any one of 4 genetic markers on ch. 6 HLA-A,B,C,D ( several alleles on each) Associated certain diseases HLA is also used to assess tissue compatibility WBC are used for testing

Rheumatoid Arthritis Clinical manifestations

1.Articular manifestations
Symmetric polyarthritis of peripheral joints with pain, tenderness and swelling of affected joints Morning stiffness ( > 30 min) or after prolonged inactivity Proximal interphalangeal joints (PIP) and metacarpophalangeal joints (MCP) Metatarsophalangeal joints( MP), wrists, elbows and ankles Joint deformities

Rheumatoid Arthritis - Clinical manifestations

Extra-articular manifestations
Cutaneous- subcutaneous rheumatoid nodules, vasculitis ( leg ulcers) Pulmonary- nodules, interstitial disease, bronchiolitis, pleural disease Ocular-scleritis Hematologic- anemia, splenomegaly and neutropenia ( Feltys syndrome, 1-2%) Cardiac- pericarditis, myocarditis Neurologic- myelopathies secondary to cervical spine disease Fever ( low grade)

Feltys syndrome
Hypersplenism occurring in R.A. Manifested by:
Splenomegaly, leukopenia, frequent infection

Cause: unknown

Fever of Unknown Origin

Infection Autoimmune disease Malignancy

Rheumatoid Nodule

Rheumatoid Arthritis
Diagnosis
Physical exam with careful exam of all joints CBC: anemia Rheumatoid factor: 85% ESR elevation ( 90%) Synovial fluid analysis: rule out infection Radiograph ( X-ray)

( RF correlated with severe disease, nodules, extraarticular features)

juxta-articular osteopenia, joint space narrowing, marginal erosions Only soft tissue swelling without bony change in 1st months of disease

Rheumatoid Arthritis

Rheumatoid Arthritis
Typical erosion Narrowing joint space juxta-articular osteopenia

Rheumatoid Arthritis
Criteria for rheumatoid arthritis ( any four of the following)
Morning stiffness > 1h ( > 6month) Arthritis of three or more joints Arthritis of hand joints Symmetrical arthritis Rheumatoid nodule Serum rheumatoid factor Radiographic changes

 Treatment

Rheumatoid Arthritis
Physical therapy Aspirin or NSAIDs Intra-articular glucocorticoids Systemic glucocorticoids Disease-modifying antirheumatic drugs (DMARD)

Immunosuppressive therapy

Methotrexate: block folate reduction ( toxicity of BM, liver, kidney) Gold salts: ineffective ( pancytopenia,hepatitis) Hydroxychloroquine ( anti-malarial) Sulfasalazine ( anti-inflammation) D-penicillamine Azathioprine, cyclosporine, cyclophosphamide ( for pts failing DMARD)

Sjogrens Syndrome

Sjogrens Syndrome
A chronic, systemic inflammatory disorder of unknown cause, characterized by dryness of the mouth, eyes and other mucous membranes (and often associated with rheumatic disorders sharing certain autoimmune features)

Sjogrens Syndrome (SS)

Epidemiology
An association between HLA-DR3 antigens and primary SS Prevalence: RA> Sjogrens syndrome > SLE Atrophy of secretory epithelium of lacrimal glands causing dryness of cornea and conjuntiva Lymphocyte infiltration

Pathology

Sjogrens Syndrome
Classification: Primary SS (Sicca syndrome)
Affect only eyes or mouth

Secondary SS
Generalized collagen vascular disease

Sjogrens Syndrome
Symptoms and Signs (secondary SS)
Arthritis (33%)
Similar distribution to RA; but joint S/S are milder and rarely destruction

Parotid glands enlargement and saliva diminished (in 1/3)

Firm, fluctuating sized, mild tender Inhibit chewing and swallowing and promote tooth decay

Dryness of skin and mucous membranes of nose, throat, bronchi and vagina Dryness of respiratory tract -> lung infection GI effects ( dysphagia) Chronic hepatobiliary disease and pancreatitis

Sjogrens Syndrome
Diagnosis
Eye is tested for dryness
Schirmer test measures the quantity of tears A young person moistens 15mm of each paper strip; SS patients moisten < 5mm in 5 min

Salivary gland evaluation: sialography

radiography of the salivary tract after injection of a radiopaque substance

Biopsy RF present in >70% ESR elevated in 70% Anemia (1/3); Leukopenia (1/4)

Sjogrens Syndrome
Prognosis and Treatment
Related to the associated connective tissue disorder No specific treatment for basic process Local manifestations: treated symptomatically Connective tissue involvement:
Usually mild and chronic Corticosteriods and immunosuppressive drugs indicated only occasionally

Systemic Lupus Erythematosus (SLE)

Systemic Lupus Erythematosus

Disease of unknown etiology in which tissues are damaged by deposition of autoantibodies and immune complexes

Systemic Lupus Erythematosus

Epidemiology
Genetic Environmental Sex hormone:

More often in blacks than in whites May involve any organ system and have a wide range of disease severity

90% are women (usually of child- bearing age) After menopause, flare is rare

 Clinical manifestations
Constitutional Cutaneous Arthritis-

SLE

fatigue, fever, malaise, weight loss rashes ( malar butterfly rash) Photosensitivity, vasculitis, alopecia, oral ulcers (inflammatory, symmetric, nonerosive, 90% pts before other S/S) anemia, leukopenia (<4,000), thrombocytopenia( <100,000) lymphadenopathy, splenomegaly, venous or arterial thrombosis pleuritis, pericarditis, myocarditis, endocarditis peritonitis, vasculitis seizures, psychosis, cerebritis

Hematologic-

Cardiopulmonary Nephitis GI-

Neurologic-

Systemic Lupus Erythematosus Diagnostic Criteria: 4/11 ( 1982 revised criteria )

Malar rash Discoid rash Photosensitivity Oral ulcer Arthritis Serositis
Renal disorder Neurologic disorder Hematologic disorder Immunologic disorder Antinuclear antibody

Mucocutaneous lesions

Systemic Lupus Erythematosus Classification

Spontaneous SLE Drug- induced lupus

Systemic Lupus Erythematosus- Evaluation

History and physical exam ANA(+)
A cardinal feature, >98%, screening for SLE, but not specific for SLE

Anti-DS DNA antibody: more specific for SLE CBC ESR Complement levels: low level in C3,C4 Urinalysis Radiographic studies

Immune Complex
Circulating Antigens -> Ab produced to attack Ag-> Immune complex formed in blood Immune complex deposit in tissues (e.g. glomeruli or blood vessels ) -> Complement activated-> Tissue injury

Systemic Lupus Erythematosus-Drug- induced lupus

A clinical and immunologic picture similar to spontaneous SLE may be induced by drugs Clinical features:
procainamide, hydralazine, isoniazid, cholorpromazine, methyldopa Constitutional Joint Pleuropericardial (CNS and renal disease are rare)

Lab

Prognosis

ANA (+) in all pts Antihistone antibodies may be present Antibody to dsDNA and hypocomplementemia are uncommon Most pts improve following withdrawal of offending drug

Systemic Lupus Erythematosus

Treatment
Goals: control acute, severe flares 1.NSAIDs 2.Antimalarials
Develop maintenance strategies

3.Systemic glucocorticoids

Hydroxycholoroquine; improve constitutional, cutaneous, articular manifestations, but ophthalmologic evaluation due to ocular toxicity for life-threatening or severely disabling manifestations Needed in doses of 40 mg/d or more during severe flares, tapered to low doses 10-15mg/d during disease inactivity cyclophosphamide, azathioprine indicated in thrombotic complications

4.Cytotoxic agents : 5.Anticoagulation

Systemic Lupus Erythematosus

Prognosis
The more severe the disease, the greater the risk of drug-induced complications, which increase morbidity and mortality Flares are rare after menopause. Infections have become the leading cause of death

Late onset SLE occur and difficult to diagnose 10-yr survival in most developed countries is > 95%