Chapter 158: Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Other Connective Tissue Diseases

DEFINITION

Heterogeneous disorders that share certain common features, including inflammation of skin, joints, and other structures rich in connective tissue; as well as altered patterns of immunoregulation, including production of autoantibodies and abnormalities of cell-mediated immunity. While distinct clinical entities can be defined, manifestations may vary considerably from one pt to the next, and overlap of clinical features between and among specific diseases can occur.

DEFINITION AND PATHOGENESIS

Disease of unknown etiology in which tissues and cells undergo damage mediated by tissue-binding autoantibodies and immune complexes. Genetic, environmental, and sex hormonal factors are likely of pathogenic importance. T- and B-cell hyperactivity, production of autoantibodies with specificity for nuclear antigenic determinants, and abnormalities of T-cell function occur.

CLINICAL MANIFESTATIONS

Approximately 90% of pts are women, usually of child-bearing age; more common in blacks than whites. Course of disease is often characterized by periods of exacerbation and relative quiescence. May involve virtually any organ system and have a wide range of disease severity. Common features include:

• Constitutional: fatigue, fever, malaise, weight loss

• Cutaneous: rashes (especially malar “butterfly” rash), photosensitivity, vasculitis, alopecia, oral ulcers

• Arthritis: inflammatory, symmetric, nonerosive

• Hematologic: anemia (may be hemolytic), neutropenia, thrombocytopenia, lymphadenopathy, splenomegaly, venous or arterial thrombosis

• Cardiopulmonary: pleuritis, pericarditis, myocarditis, endocarditis. Pts are also at increased risk of myocardial infarction usually due to accelerated atherosclerosis.

• Nephritis: classification is primarily histologic (Table 378-2, p. 2127, in HPIM-19)

• GI: peritonitis, vasculitis

• Neurologic: organic brain syndromes, seizures, psychosis, cerebritis

Drug-Induced Lupus

A clinical and immunologic picture similar to spontaneous SLE may be induced by drugs; in particular: procainamide, hydralazine, isoniazid, chlorpromazine, methyldopa, minocycline, anti-TNF agents. Features are predominantly constitutional, joint, and pleuropericardial; CNS and renal disease are rare. All pts have ANAs; antihistone antibodies may be present, but antibodies to dsDNA and hypocomplementemia are uncommon. Most pts improve following withdrawal of offending drug.

EVALUATION

• History and physical examination

• Presence of ANA is a cardinal feature, but a (+) ANA is not specific for SLE. Laboratory assessment should include: CBC, ESR, ANA and ANA subtypes (antibodies to dsDNA, ssDNA, Sm, anti-Ro/SS-A, anti-La/SS-B, histone), complement levels (C3, C4, CH50), serum immunoglobulins, VDRL, PT, PTT, anticardiolipin antibody, lupus anticoagulant, urinalysis.

• Appropriate radiographic studies

• ECG

• Consideration of renal biopsy if evidence of glomerulonephritis

DIAGNOSIS

Classification criteria used to confirm SLE in studies can provide a basis in individual patients for estimating the probability that a disease is SLE. Four or more published criteria carry a 93% specificity and 92% sensitivity for SLE (Table 378-3, p. 2127, in HPIM-19).

DEFINITION AND PATHOGENESIS

A chronic multisystem disease of unknown etiology characterized by persistent inflammatory synovitis, usually involving peripheral joints symmetrically. Although cartilaginous destruction, bony erosions, and joint deformity are hallmarks, the course of RA can be quite variable. An association with HLA-DR4 has been noted; both genetic and environmental factors may play a role in initiating disease. The propagation of RA is an immunologically mediated event in which joint injury occurs from synovial hyperplasia; lymphocytic infiltration of synovium; and local production of cytokines and chemokines by activated lymphocytes, macrophages, and fibroblasts.

CLINICAL MANIFESTATIONS

RA occurs in 0.5–1.0% of the population; women affected three times more often than men; prevalence increases with age, onset most frequent in fourth and fifth decades.

Articular Manifestations

Typically a symmetric polyarthritis of peripheral joints with pain, tenderness, and swelling of affected joints; morning stiffness is common; proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints frequently involved; joint deformities may develop after persistent inflammation.

Extraarticular Manifestations

• Cutaneous: rheumatoid nodules, vasculitis

• Pulmonary: nodules, interstitial disease, bronchiolitis obliterans–organizing pneumonia (BOOP), pleural disease, Caplan’s syndrome [sero (+) RA associated with pneumoconiosis]

• Ocular: keratoconjunctivitis sicca (KCS), episcleritis, scleritis

• Hematologic: anemia, Felty’s syndrome (splenomegaly and neutropenia)

• Cardiac: pericarditis, myocarditis

• Neurologic: myelopathies secondary to cervical spine disease, entrapment, vasculitis

EVALUATION

• History and physical examination with careful examination of all joints.

• Rheumatoid factor (RF) is present in >66% of pts; its presence correlates with severe disease, nodules, extra-articular features.

• Antibodies to cyclic citrullinated protein (anti-CCP) have similar sensitivity but higher specificity than RF; may be most useful in early RA; presence most common in pts with aggressive disease with a tendency for developing bone erosions.

• Other laboratory data: CBC, ESR.

• Synovial fluid analysis: useful to rule out crystalline disease, infection.

• Radiographs: juxta-articular osteopenia, joint space narrowing, marginal erosions. CXR should be obtained.

DIAGNOSIS

Not difficult in pts with typical established disease. May be confusing early. Classification criteria were updated in 2010 (Table 380-1, p. 2143, in HPIM-19).

DIFFERENTIAL DIAGNOSIS

Gout, SLE, psoriatic arthritis, infectious arthritis, osteoarthritis, sarcoid.

DEFINITION AND PATHOGENESIS

Systemic sclerosis (SSc) is a multisystem disorder characterized by thickening of the skin (scleroderma) and distinctive involvement of multiple internal organs (chiefly GI tract, lungs, heart, and kidney). Pathogenesis unclear; involves immunologic mechanisms leading to vascular endothelial damage and activation of fibroblasts.

CLINICAL MANIFESTATIONS

• Cutaneous: edema followed by fibrosis of the skin (chiefly extremities, face, trunk); telangiectasis; calcinosis; Raynaud’s phenomenon

• Arthralgias and/or arthritis

• GI: esophageal hypomotility; intestinal hypofunction, gastric antral vascular ectasia (GAVE)

• Pulmonary: interstitial lung disease, pulmonary arterial hypertension, alveolitis

• Cardiac: pericarditis, cardiomyopathy, conduction abnormalities

• Renal: hypertension; renal crisis/failure

Two distinct subsets can be identified:

1. Diffuse cutaneous SSc: rapid development of symmetric skin thickening of proximal and distal extremity, face, and trunk. At high risk for development of visceral disease early in course.

2. Limited cutaneous SSc: often have long-standing Raynaud’s phenomenon before other features appear; skin involvement limited to fingers (sclerodactyly), extremity distal to elbows, and face; generally associated with better prognosis but can be associated with pulmonary arterial hypertension; a subset of limited SSc has features of CREST syndrome (calcinosis, Raynaud’s, esophageal dysmotility, sclerodactyly, telangiectasias).

EVALUATION

• History and physical examination with particular attention to blood pressure (heralding feature of renal disease).

• Laboratories: ESR, ANA (anticentromere pattern associated with limited SSc), specific antibodies may include antitopoisomerase I (Scl-70), (UA). An increased range of autoantibodies correlating with specific clinical features have become recognized (Table 382-3, HPIM-19, p. 2157).

• Radiographs: CXR, barium swallow if indicated, hand x-rays may show distal tuft resorption and calcinosis.

• Additional studies: ECG, echo, PFT, consider skin biopsy.

DEFINITION

Syndrome characterized by a combination of clinical features similar to those of SLE, SSc, polymyositis, and RA; unusually high titers of circulating antibodies to a nuclear ribonucleoprotein (RNP) are found. It is controversial whether MCTD is a truly distinct entity or a subset of SLE or SSc.

CLINICAL MANIFESTATIONS

Raynaud’s phenomenon, polyarthritis, swollen hands or sclerodactyly, esophageal dysfunction, pulmonary fibrosis, inflammatory myopathy. Renal involvement occurs in about 25%. Laboratory abnormalities include high-titer ANAs, very high titers of antibody to RNP, positive RF in 50% of pts.

EVALUATION

Similar to that for SLE and SSc.

DEFINITION

An immunologic disorder characterized by progressive lymphocytic destruction of exocrine glands most frequently resulting in symptomatic eye and mouth dryness; can be associated with extraglandular manifestations; predominantly affects middle-age females; may be primary or secondary when it occurs in association with other autoimmune diseases. Lymphoma can occur in 6% with glandular MALT being most common.

CLINICAL MANIFESTATIONS

• Constitutional: fatigue

• Sicca symptoms: KCS and xerostomia

• Dryness of other surfaces: nose, vagina, trachea, skin

• Extraglandular features: arthralgia/arthritis, Raynaud’s, lymphadenopathy, interstitial pneumonitis, vasculitis (usually cutaneous), nephritis, lymphoma

EVALUATION

• History and physical examination: with special attention to oral, ocular, lymphatic examination and presence of other autoimmune disorders.

• Presence of autoantibodies is a hallmark of disease (ANA, RF, anti-Ro/SS-A, anti-La/SS-B).

• Other laboratory tests: ESR; CBC; renal, liver, and thyroid function tests; serum protein electrophoresis (SPEP) (hypergammaglobulinemia or monoclonal gammopathy common); UA.

• Ocular studies: to diagnose and quantitate KCS; Schirmer’s test, Rose bengal staining.

• Oral examination: unstimulated salivary flow, dental examination.

• Labial salivary gland biopsy: demonstrates lymphocytic infiltration and destruction of glandular tissue.

DIAGNOSIS

International classification criteria based on clinical and laboratory features have been established (Table 383-5, HPIM-19, p. 2168).

DEFINITION

Autoantibody-mediated acquired thrombophilia characterized by recurrent arterial or venous thromboses and/or pregnancy morbidity in the presence of autoantibodies against phospholipid (PL)-binding plasma proteins. Can occur alone (primary) or in association with another autoimmune disease (secondary).

CLINICAL MANIFESTATIONS

Consist of vascular thrombotic features and pregnancy morbidity (Table 379-2 in HPIM-19, p. 2135). Catastrophic APS (CAPS) is rapidly progressive thromboembolic disease involving three or more organ systems that can be life threatening.

EVALUATION

Laboratory examination of clotting parameters to include PTT, kaolin clotting time, dilute Russell viper venom test, antibodies directed against cardiolipin, β₂ glycoprotein, prothrombin. Antibodies should be measured on two occasions 12 weeks apart.

DIAGNOSIS

Suggested by the presence of at least one clinical and one laboratory feature.