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Harrison’s Manual of Medicine



Connective Tissue Disease
Systemic Lupus Erythematosus (SLE)
Rheumatoid Arthritis (RA)
Systemic Sclerosis (Scleroderma, SSc)
Mixed Connective Tissue Disease (MCTD)
Sjögren’s Syndrome

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 certain distinct clinical entities may be defined, manifestations may vary considerably from one pt to the next, and overlap of clinical features between and among specific diseases is common.
DEFINITION AND PATHOGENESIS   Disease of unknown etiology in which tissues and cells are damaged by deposition of pathogenic 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   90% of cases are women, usually of child-bearing age; more common in blacks than whites. Course of disease is often one of 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


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. Features are predominantly constitutional, joint, and pleuropericardial; CNS and renal disease are rare. All pts have antinuclear antibodies (ANA); antihistone antibodies may be present, but antibodies to dsDNA and hypocomplementemia are uncommon. Most pts improve following withdrawal of offending drug.

Hx and physical exam

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

Appropriate radiographic studies


Consideration of renal biopsy if evidence of glomerulonephritis
DIAGNOSIS   Made in the presence of four or more published criteria (Table 311-3, p. 1925, in HPIM-15).

Choice of therapy is based on type and severity of disease manifestations (Fig. 159-1). Goals are to control acute, severe flares and to develop maintenance strategies where symptoms are suppressed to an acceptable level. The toxicity of therapy must always be considered. Useful agents include:

FIGURE 159-1. Algorithm for the treatment of SLE, GC, glucocorticoids; high-dose GC, methylprednisolone 1000 mg, IV, qd × 3, then 1 to 2 mg/kg prednisone per day orally, cytotox, cytotoxic drugs such as cyclophosphamide (Cy) and azathioprine (Aza); qod, alternate day therapy.

NSAIDs (e.g., ibuprofen 400–800 mg tid–qid).

Antimalarials(hydroxychloroquine 400 mg/d)—may improve constitutional, cutaneous, articular manifestations. Ophthalmologic evaluation required before and during Rx to rule out ocular toxicity.

Systemic glucocorticoids—may be necessary for life-threatening or severely disabling manifestations.

Cytotoxic agents—beneficial in active glomerulonephritis; may be required for severe disease not successfully controlled by acceptable doses of steroids.
1.   Cyclophosphamide—most effective and most toxic; administered as IV pulse 10–15 mg/kg every 4 weeks. Daily oral dosing 1.5–2.5 (mg/ kg)/d can also be used but has a greater risk of urinary bladder toxicity.
2.   Azathioprine 2–3 (mg/kg)/d—indicated in pts who cannot take cyclophosphamide.
3.   Mycophenolate mofetil 1000 mg bid—may be considered in selected pts.

Anticoagulation may be indicated in pts with thrombotic complications.

DEFINITION AND PATHOGENESIS   A chronic multisystem disease of unknown etiology characterized by persistent inflammatory synovitis, usually involving peripheral joints in a symmetric fashion. Although cartilaginous destruction, bony erosions, and joint deformity are hallmarks, the course of RA can be 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 ~0.8% of the population; women affected 3 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; PIP and 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, episcleritis, scleritis

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

Cardiac—pericarditis, myocarditis

Neurologic—myelopathies secondary to cervical spine disease, entrapment, vasculitis.

Hx and physical exam with careful examination of all joints.

Rheumatoid factor is present in 85% of pts; its presence correlates with severe disease, nodules, extraarticular features.

Other laboratories: CBC, ESR.

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

Radiographs—juxtaarticular osteopenia, joint space narrowing, marginal erosions. CXR should be obtained.
DIAGNOSIS   Not difficult in pts with typical established disease. May be confusing early. New criteria are more sensitive and specific (Table 312-1, p. 1934, in HPIM-15).
Differential Diagnosis   Gout, SLE, psoriatic arthritis, infectious arthritis, osteoarthritis, sarcoid.

Goals: lessen pain, reduce inflammation, improve/maintain function, prevent long-term joint damage, control of systemic involvement. Increasing trend to treat RA more aggressively earlier in disease course (Fig. 159-2).

FIGURE 159-2. Algorithm for the medical management of rheumatoid arthritis. CSI, Cox-2 selective inhibitors; DMARD, disease-modifying antirheumatic drug; TNF-a, tumor necrosis factor a.

Pt education on disease, joint protection

Physical and occupational therapy—strengthen periarticular muscles, consider assistive devices.

Aspirin or NSAIDs (including Cox-2 selective inhibitors, which may have less GI toxicity).

Intrarticular glucocorticoids.

Systemic glucocorticoids.

Disease-modifying antirheumatic drugs (DMARDs)—e.g., methotrexate; oral or IM gold salts; hydroxychloroquine; sulfasalazine; D-penicillamine. Each agent has individual toxicities—pt education and monitoring required. Have been used in combination but with increased toxicity.

TNF-a neutralizing agents—consider in pts with moderate to severely active RA or DMARD-unresponsive disease.

Immunosuppressive therapy—e.g., azathioprine, leflunomide, cyclosporine, and cyclophosphamide. Generally reserved for pts who have failed DMARDs.

Surgery—may be considered for severe functional impairment due to deformity.

DEFINITION AND PATHOGENESIS   Multisystem disorder characterized by inflammatory, vascular, and fibrotic changes of skin and various internal organ systems (chiefly GI tract, lungs, heart, and kidney). Pathogenesis unclear; involves immunologic mechanisms leading to vascular endothelial damage and activation of fibroblasts.

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

Pulmonary—fibrosis, pulmonary hypertension, alveolitis.

Cardiac—pericarditis, cardiomyopathy, conduction abnormalities

Renal—hypertension; renal crisis/failure (leading cause of death).
Two main subsets can be identified:
1.   Diffuse cutaneous scleroderma—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 scleroderma or CREST syndrome (calcinosis, Raynaud’s, esophageal dysmotility, sclerodactyly, telangiectasias)—skin involvement limited to face and extremity distal to elbows; associated with better prognosis.

Hx and physical exam with particular attention to blood pressure (heralding feature of renal disease).

Laboratories: ESR, ANA (anticentromere pattern associated with CREST), specific antibodies may include antitopoisomerase I (Scl-70), UA

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

Additional studies: ECG, consider skin biopsy.


Education regarding warm clothing, smoking cessation, antireflux measures

Calcium channel blockers (e.g., nifedipine) useful for Raynaud’s phenomenon

ACE inhibitors (e.g., captopril)—particularly important for controlling hypertension and limiting progression of renal disease.

Antacids, H2 antagonists, omeprazole, and metoclopramide may be useful for esophageal reflux.

D-Penicillamine—controversial benefit to reduce skin thickening and prevent organ involvement; no advantages to using doses >125 mg every other day.

Glucocorticoids—no efficacy in slowing progression of SSc; indicated for inflammatory myositis or pericarditis; high doses early in disease may be associated with development of renal crisis.

Cyclophosphamide—improves lung function outcomes and survival in pts with alveolitis.

Epoprostenol—may improve cardiopulmonary hemodynamics in pts with pulmonary hypertension.

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.
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 rheumatoid factor in 50% of pts.
EVALUATION   Similar to that for SLE and SSc.

Little published data. Treat based upon manifestations with similar approach to that used if feature occurred in SLE/SSc/polymyositis/RA.

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.


Sicca symptoms—keratoconjunctivitis sicca (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.

Hx and physical exam—with special attention to oral, ocular, lymphatic exam and presence of other autoimmune disorders.

Presence of autoantibodies is a hallmark of disease (ANA, RF, anti-Ro, anti- La)

Other laboratories—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 exam—unstimulated salivary flow, dental exam.

Labial salivary gland biopsy—demonstrates lymphocytic infiltration and destruction of glandular tissue.
DIAGNOSIS   Criteria often include: KCS, xerostomia, (+) serologic features of autoimmunity. Positive lip biopsy considered necessary in some series—should be performed in setting of objective KCS/xerostomia with negative serologies.


Regular follow-up with dentist and ophthalmologist.

Symptomatic relief of dryness with artificial tears, ophthalmic lubricating ointments, nasal saline sprays, frequent sips of water, sugarless candy, moisturizing skin lotions.

Pilocarpine—may help sicca manifestations.

Hydroxychloroquine—may help arthralgias.

Glucocorticoids—not effective for sicca Sx but may have role in treatment of extraglandular manifestations.

DEFINITION   Polymyositis is a condition of presumed autoimmune etiology in which the skeletal muscle is damaged by an inflammatory process dominated by lymphocytic infiltration. Dermatomyositis is characterized by skin changes accompanying or preceding muscle weakness and inflammatory myopathy.

Group I: Primary idiopathic polymyositis—female:male 2:1.

Group II: Primary idiopathic dermatomyositis—skin changes may precede or follow muscle changes.

Group III: Dermatomyositis (or polymyositis) associated with neoplasia— malignancy may precede or follow onset of myositis by up to 2 years; commonly associated malignancies: lung, ovary, breast, GI tract, myeloproliferative disorders.

Group IV: Childhood dermatomyositis (or polymyositis) associated with vasculitis—vasculitis may involve skin and visceral organs.

Group V: Polymyositis (or dermatomyositis) associated with collagen-vascular disease—RA, scleroderma, SLE, MCTD most frequently associated.

Proximal muscle weakness—difficulty climbing stairs, combing hair, arising from chair

Weakness of neck flexors—unable to raise head from pillow

Muscle pain or tenderness

Dysphagia—25% at presentation

Dyspnea—respiratory impairment in 5%, interstitial lung disease in 10%

Cardiac disturbances—conduction defects, tachyarrhythmias, cardiomyopathy.

Systemic symptoms—fever, malaise, weight loss, arthralgias, Raynaud’s phenomenon.
Physical Examination

Muscle weakness proximal > distal

Skin lesions: localized or diffuse erythema, maculopapular eruption, scaling eczematoid dermatitis, exfoliative dermatitis, classic lilac-colored (heliotrope) rash on eyelids, nose, cheeks, forehead, trunk, extremities, nailbeds, knuckles (Gottron rash)

Subcutaneous calcification—see especially in childhood disease

Complete evaluation is important to look for features suggestive of neoplasm or other connective tissue diseases.

CPK, aldolase, SGOT, SGPT, LDH usually elevated.

In setting of very high CPK, check urine myoglobin and renal function.

Autoantibodies—anti-Jo-1 seen in 50% of pts with polymyositis and 15% with dermatomyositis, other antibodies may be seen in association with other connective tissue diseases.

ECG abnormal in 5–10% cases at presentation.

EMG—abnormal in 40% of cases; short-duration, low-amplitude polyphasic units on voluntary activation and increased spontaneous activity with fibrillations, complex repetitive discharges, and positive sharp waves.

MRI—may identify sites of muscle involvement and guide biopsy location.

Skeletal muscle pathology—patchy process; inflammatory cells, destruction of muscle fibers with a phagocytic reaction, and perivascular inflammatory cell infiltration. The presence of perifascicular atrophy is diagnostic of dermatomyositis.

Search for underlying malignancies—extent of search for occult neoplasm in dermatomyositis depends on the clinical circumstances. Tumors usually uncovered by abnormal history and exam and not through extensive blind searches. When malignancy is not apparent, consider complete annual physical exam with pelvic, breast, and rectal examination, urinalysis, CBC, blood chemistries, and CXR.
DIAGNOSIS   Diagnosis strongly suggested by presence of muscle weakness, elevation of CK, abnormal EMG. Pts with dermatomyositis who have skin rash may not require muscle biopsy. In polymyositis, biopsy usually needed to make a firm diagnosis and rule out other myopathies.
DIFFERENTIAL DIAGNOSIS   Metabolic myopathies, infectious myositis, toxic or drug-induced myopathies, neuromuscular disorders, endocrine and electrolyte disorders, myositis associated with sarcoidosis, polymyalgia rheumatica, eosinophilia myalgia syndrome.
Inclusion Body Myositis   The most common inflammatory myopathy in pts ³50. Weakness and atrophy occur in distal muscles. Characteristic appearance on muscle biopsy. Resistant to immunosuppressive therapies.

Goal is to improve muscle strength improving function in activities of daily living. When strength improves, CK falls but the reverse is not always true. Therapy should be directed to improving muscle strength, not solely on lowering CK level.

Prednisone 1–2 (mg/kg)/day, tapered after strength improves and CK declines. The onset of steroid-induced myopathy may complicate therapy.

Cytotoxic agents: should be considered for severe disease, inadequate response to steroids, relapsing disease, steroid-induced complications. Methotrexate 7.5–15 mg/week, azathioprine 2.5–3.5(mg/kg)/day, mycophenolate mofetil, cyclophosphamide 1–2(mg/kg)/d reported to be beneficial but have significant side effects.

Intravenous immunoglobulin—may bring about short-lived improvement in some pts.

Physical therapy


For a more detailed discussion, see Hahn BH: Systemic Lupus Erythematosus, Chap. 311, p. 1922; Lipsky PE: Rheumatoid Arthritis, Chap. 312, p. 1928; Gilliland BC: Systemic Sclerosis (Scleroderma), Chap. 313, p. 1937; Moutsopoulos HM: Sjögren’s Syndrome, Chap. 314, p. 1947; Dalakas MC Jr: Polymyositis, Dermatomyositis, and Inclusion Body Myositis, Chap. 382, p. 2524, in HPIM-15.


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