CONNECTIVE TISSUE DISEASE
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.
SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
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
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 319-2, p. 2727, in HPIM-18)
• 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 antinuclear antibodies (ANA); antihistone antibodies may be present, but antibodies to dsDNA and hypocomplementemia are uncommon. Most pts improve following withdrawal of offending drug.
EVALUATION
• 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 ANA subtypes (antibodies to dsDNA, ssDNA, Sm, Ro, La, 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
Made in the presence of four or more published criteria (Table 319-3, p. 2728, in HPIM-18).
TREATMENT Systemic Lupus Erythematosus
Choice of therapy is based on type and severity of disease manifestations. Goals are to control acute, severe flares and to develop maintenance strategies whereby symptoms are suppressed to an acceptable level. Treatment choices depend on (1) whether disease is life-threatening or likely to cause organ damage; (2) whether manifestations are reversible; and (3) the best approach to prevent complications of disease and treatment (Fig. 319-2, p. 2729, and Table 319-5, p. 2732, in HPIM-18).
CONSERVATIVE THERAPIES FOR NON-LIFE-THREATENING DISEASE
• NSAIDs (e.g., ibuprofen 400–800 mg three to four times a day). Must consider renal, GI, and cardiovascular complications.
• Antimalarials (hydroxychloroquine 400 mg/d)—may improve constitutional, cutaneous, articular manifestations. Ophthalmologic evaluation required before and during Rx to rule out ocular toxicity.
• Belimumab (10 mg/kg IV at weeks 0, 2, 4 then monthly). B lymphocyte stimulator (BLyS)-specific inhibitor. Should not be used in severe SLE such as nephritis or CNS disease and limited to pts with mild to moderate active disease.
TREATMENTS FOR LIFE-THREATENING SLE
• Systemic glucocorticoids.
• Cytotoxic/immunosuppressive agents—added to glucocorticoids to treat serious SLE.
1. Cyclophosphamide—administered as IV pulse 500–750 mg/M2 IV × 6 months followed by maintenance with mycophenolate mofetil or azathioprine. European studies have found cyclophosphamide 500 mg every 2 weeks for 6 doses may be effective, but it remains unclear whether these data will apply to U.S. populations.
2. Mycophenolate mofetil—2–3 g/d; efficacy data limited to nephritis. A higher proportion of black pts appear to respond to mycophenolate mofetil compared with cyclophosphamide.
3. Azathioprine—may be effective but is slower in inducing therapeutic response.
RHEUMATOID ARTHRITIS (RA)
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; 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
EVALUATION
• Hx and physical exam with careful examination of all joints.
• Rheumatoid factor (RF) is present in >66% of pts; its presence correlates with severe disease, nodules, extraarticular 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. Chest x-ray should be obtained.
DIAGNOSIS
Not difficult in pts with typical established disease. May be confusing early. Classification criteria were updated in 2010 (Table 321-1, p. 2745, in HPIM-18).
DIFFERENTIAL DIAGNOSIS
Gout, SLE, psoriatic arthritis, infectious arthritis, osteoarthritis, sarcoid.
TREATMENT Rheumatoid Arthritis
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 (Table 321-2, HPIM-18, pp. 2748–2749). All RA therapies have individual toxicities, with many requiring pretreatment screening and monitoring.
• Pt education on disease, joint protection.
• Physical and occupational therapy—strengthen periarticular muscles, consider assistive devices.
• Aspirin or NSAIDs.
• Intra-articular glucocorticoids.
• Systemic glucocorticoids.
• Disease-modifying antirheumatic drugs (DMARDs)—e.g., methotrexate, hydroxychloroquine, sulfasalazine, leflunomide.
• Biologic therapies.
• TNF modulatory agents (etanercept, infliximab, adalimumab, golimumab, certolizumab)—effective at controlling RA in many pts and can slow the rate of progression of radiographic joint damage and decrease disability; carry potential for serious infection and individual toxicities.
• Abatacept (CTLA4-Ig)—inhibits T cell activation, can be given with or without methotrexate.
• Rituximab—a chimeric antibody directed to CD20 that depletes mature B cells, is approved for refractory RA.
• Tocilizumab—humanized monoclonal antibody directed against the IL-6 receptor.
• Anakinra—an IL-1 receptor antagonist approved for RA but rarely used in RA due to only modest clinical efficacy.
• Surgery—may be considered for severe functional impairment due to deformity.
SYSTEMIC SCLEROSIS (SCLERODERMA, SSC)
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
• Pulmonary—fibrosis, pulmonary 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; associated with better prognosis; a subset of limited SSc has features of CREST syndrome (calcinosis, Raynaud’s, esophageal dysmotility, sclerodactyly, telangiectasias).
EVALUATION
• Hx and physical exam 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 323-3, HPIM-18, p. 2760)
• Radiographs: CXR, barium swallow if indicated, hand x-rays may show distal tuft resorption and calcinosis.
• Additional studies: ECG, echo, PFT, consider skin biopsy.
TREATMENT Systemic Sclerosis
• Education regarding warm clothing, smoking cessation, antireflux measures.
• Calcium channel blockers (e.g., nifedipine) useful for Raynaud’s phenomenon. Other agents with potential benefit include sildenafil, losartan, nitroglycerin paste, fluoxetine, bosentan, digital sympathectomy.
• ACE inhibitors—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 and survival in pts with alveolitis.
• Epoprostenol (prostacyclin) and bosentan (endothelin-1 receptor antagonist)—may improve cardiopulmonary hemodynamics in pts with pulmonary hypertension.
MIXED CONNECTIVE TISSUE DISEASE (MCTD)
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.
TREATMENT Mixed Connective Tissue Disease
Few published data. Treat based on manifestations with similar approach to that used if feature occurred in SLE/SSc/polymyositis/RA.
SJÖGREN’S SYNDROME
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.
CLINICAL MANIFESTATIONS
• Constitutional—fatigue
• 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
EVALUATION
• 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 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 exam—unstimulated salivary flow, dental exam.
• 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 324-5, HPIM-18, p. 2772).
TREATMENT Sjögren’s Syndrome
• Regular follow-up with dentist and ophthalmologist.
• Dry eyes—artificial tears, ophthalmic lubricating ointments, local stimulation with cyclic adenosine monophosphate or cyclosporine drops.
• Xerostomia—frequent sips of water, sugarless candy.
• Pilocarpine or cevimeline—may help sicca manifestations.
• Hydroxychloroquine—may help arthralgias.
• Glucocorticoids—not effective for sicca Sx but may have role in treatment of extraglandular manifestations.
ANTIPHOSPHOLIPID ANTIBODY SYNDROME (APS)
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 320-2 in HPIM-18, p. 2737). 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 partial thromboplastin time, 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.
TREATMENT Antiphospholipid Antibody Syndrome
• After first thrombotic event, warfarin for life to achieve an INR 2.5–3.5.
• Pregnancy morbidity prevented by heparin with aspirin 80 mg daily. IV immunoglobulins (IVIG) may also prevent pregnancy loss. Glucocorticoids are ineffective.
• For CAPS, consider IVIG, anti-CD20 and use of antithrombotics such as fondaparinux or rivaroxaban.
For a more detailed discussion, see Hahn BH: Systemic Lupus Erythematosus, Chap. 319, p. 2724; Shah A, St. Clair EW: Rheumatoid Arthritis, Chap. 321, p. 2738; Varga J: Systemic Sclerosis (Scleroderma) and Related Disorders, Chap. 323, p. 2757; Moutsopoulos HM, Tzioufas AG: Sjögren’s Syndrome, Chap. 324, p. 2770; and Moutsopoulos HM, Vlachoyiannopoulos PG: Antiphospholipid Antibody Syndrome, Chap. 320, p. 2736, in HPIM-18.