Pulmonary Manifestations of Connective Tissue Diseases
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Richard Meehan, MD
Head, Division of Rheumatology,
Associate Professor of Medicine
National Jewish Medical and Research Center
Associate Clinical Professor of Medicine-Rheumatology Division
University of Colorado Denver
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Introduction
Multiple systemic autoimmune illnesses frequently exhibit pulmonary manifestations as their initial manifestation or during the course of disease progression. Among the more common are:
• Rheumatoid arthritis (RA)
• Diffuse or limited systemic sclerosis (dSSc, lSSc)
• Polymyositis/dermatomyositis (PM/DM)
• Systemic lupus erythematosus (SLE)
• Sjögren’s syndrome (SS)
• Ankylosing spondylitis (AS)
• Relapsing polychondritis (RP)
Others include systemic vasculitis such as Wegener’s granulomatosis, Goodpasture’s disease, and polyarteritis nodosa. These patients may exhibit a variety of pulmonary manifestations of connective tissue disease, as outlined in Table 1.
Since patients with significant arthritis, weakness, and fatigue have impaired mobility, they often do not appreciate exertional breathlessness until significant loss of functional capacity has occurred. In fact, abnormalities on routine chest X-ray may be the first recognized feature of associated pulmonary involvement. It is also not uncommon that the first manifestation of a systemic connective tissue disease will be pulmonary symptoms or chest X-ray abnormalities.
Clinical Presentation
Case Study
A 61-year-old woman was referred to National Jewish Medical and Research Center’s Interstitial Lung Disease service for treatment of idiopathic pulmonary fibrosis (IPF). Her symptoms included slowly progressive exertional breathlessness and a non-productive cough of two to three years duration. A prior video-assisted thoracoscopic surgery (VATS) biopsy was interpreted as IPF. However, since her cough and dyspnea improved on glucocorticoid therapy and recurred as the prednisone dosage was tapered, she was referred to Rheumatology to rule out an associated connective tissue disease. On review of systems, she reported worsening ocular and oral dryness but denied adenopathy, exocrine gland swelling, weight loss, fevers, rashes, chest pain, arthralgias, or joint swelling. Family history was negative for connective tissue disease. She was only receiving 20 mg prednisone daily, alendronate sodium (70 mg weekly), vitamins, and oxygen. Her past medical history was unremarkable. Her physical examination was remarkable only for erythematosus conjunctiva and inspiratory crackles in the lower quarter of posterior lung.
...a careful review of systems may yield valuable clues to an underlying systemic connective tissue disease.
The most common symptoms of parenchyma lung injury associated with interstitial lung disease (ILD) are progressive exertional breathlessness and a nonproductive cough. Pleuritic type chest pain or non-chest wall pain that is influenced by position is suggestive of pleural or pericardial disease, especially if accompanied by constitutional symptoms such as fever and worsening rheumatic complaints. Dyspnea, wheezing, nocturnal coughing, and chest tightness could also indicate airway disease as manifestations of RP or bronchiolitis obliterans (BO) associated with RA, Sjögren’s syndrome, or SLE. A recent onset of severe and refractory adult asthma could be a manifestation of Churg-Strauss disease, especially in the setting of eosinophilia, vasculitis rash, neuropathy, or renal disease. Transient pulmonary infiltrates that are culture negative on bronchoscopy and improve with glucocorticoid therapy are suggestive of bronchiolitis obliterans with organizing pneumonia (BOOP). Some patients exhibit a rapid deterioration with a fulminant course characterized by multiple alveolar infiltrates and progressive hypoxemia due to acute interstitial pneumonitis (AIP), or a pulmonary hemorrhage syndrome associated with SLE, or a systemic vasculitis. Physicians should obtain an appropriate environmental and drug exposure history to exclude other lung diseases that can mimic connective tissue disease; these include drug-induced injury (radiation, methotrexate, bleomycin, amiodarone, sulfasalazine, gold, d-penicillamine, etc), hypersensitivity pneumonitis, berylliosis, and silicosis.
In patients who present with pulmonary disease, a careful review of systems may yield valuable clues to an underlying systemic connective tissue disease. The presence of new onset or worsening Raynaud’s, tight skin, telangiectasias, and reflux symptoms may indicate systemic sclerosis (SSc). Since 90% of dSSc patients exhibit Raynaud’s, its absence is helpful in excluding that diagnosis.
Progressive painless proximal muscle weakness or dysphagia are usual features of inflammatory myopathies including PM or DM. One must always exclude hypothyroidism and glucocorticoid-induced myopathy, which can mimic inflammatory myopathies. Some dermatomyositis patients may exhibit the classic “Heliotrope” (lilac-colored) periorbital rash or Gottron’s papules, which are erythematous scaling lesions over the dorsum of the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints in the hands even in the absence of weakness. Another subset of patients with the “anti-synthetase syndrome” exhibits more aggressive lung disease and may have Raynaud’s, fever, arthritis, and “mechanic’s hands.” The palmar surfaces of these patients exhibit roughened and fissured texture in the absence of repetitive trauma. Approximately one-third of patients with PM or DM may present with ILD before the onset of skin or muscle manifestations.
SLE patients may give a history of prior serositis, photosensitivity or malar rash, alopecia, recurrent oral ulcers and prior thromboembolic complications (deep vein thrombosis, pulmonary emboli, multiple spontaneous abortions), or severe arthralgias with appropriate serologic abnormalities. Progressive ocular and oral dryness, especially if unrelated to medications and associated with parotid/lacrimal gland enlargement or adenopathy, are commonly seen among Sjögren’s syndrome patients.
The physical examination can provide multiple objective features of an underlying connective tissue disease. Fine “Velcro” inspiratory rales that are loudest at the bases are typical of interstitial lung disease, whereas pleural or pericardial rubs may be noted in serositis. Elevated neck veins, prolonged or fixed split P2, and peripheral edema suggest pulmonary arterial hypertension. A careful examination of the skin may reveal classic features of SSc, including telangiectasias, narrowed oral aperture, sclerodactyly, calcinosis, tapering of the digit tips, or healed ulcerations. SLE patients may exhibit a malar rash, livedo reticularis, palpable purpura, or an erythematosus rash between the MCP and PIP joints. Oral dryness and associated parotid or lacrimal gland enlargement and adenopathy are seen among patients with long standing Sjögren’s syndrome. However, ocular dryness is a common complaint among elderly patients and those on multiple medications in the absence of immunologically mediated exocrine gland dysfunction. Most patients with RA have symmetrical synovial distention involving the MCPs, PIPs, metatarsophalangeals (MTPs) and/or wrists, but classic deformities such as ulnar drift, joint subluxation, and swan-neck and boutonniere deformities or nodules are features of longstanding aggressive or inadequately treated disease. In contrast to RA, bone proliferation and angulation deformities limited to the DIPs, PIPs, and carpal-metacarpalphalangeal (C-MCP) joints are common features of non-inflammatory degenerative arthritis (osteoarthritis). Collapse of the nasal cartilage may be seen with RP or Wegener’s granulomatosis, whereas stridor and swelling associated with erythema of the ear cartilage are seen exclusively in RP.
Diagnostic Evaluation
Case, continued
This patient had a Schirmer’s test that was very abnormal, resulting in 0 mm of wetting after 5 minutes in each eye. Despite a negative antinuclear antibody (ANA), a Ro (SSA) titer was ordered; it was elevated at 103 units (normal <20). Normal or negative laboratory studies included: La (SSB), anti-SCL-70, C3, C4, serum protein electrophoresis, cryoglobulins, hepatitis C antibody, HBsAg, rheumatoid factor (RF), ESR 21, chemistry profile, CBC, and urinalysis. A sublabial lip biopsy was not performed due the high likelihood of false negative results associated with her prednisone therapy.
Physiologic testing revealed: FVC, 2.06 L (54% of predicted); FEV1, 1.7 L (60% of predicated) with a 14% improvement during bronchodilator challenge; FVC/FEV1 ratio, 83%; TLC (total lung capacity), 3.42 L (64% of predicted); RV (residual volume), 0.91L (72% of predicted); DLCO corrected for alveolar volume, 4.0 mL/min/mm Hg/L (80% of predicted) consistent with a mixed physiologic abnormality. ABG revealed pH 7.47, PCO2 30.5 mm Hg, PO2 72.3 mm Hg, and alveolar-arterial oxygen gradient of 14.6 mmHg. She had a normal exercise tolerance, achieving 105 watts (98% of predicted), whereas VO2 uptake was 67% of predicted. Her heart rate and blood pressure responses were normal, but ventilation was abnormal but not limiting. Alveolar ventilation rose from 10.2 to 46.5 L/min, and respiratory rate increased from 13 to 32 breaths/min with dead space falling from 41 to 31% at maximum exercise. Tidal volume recruitment was limited, rising from 0.795 to 1.44 L. On room air, PO2 fell from 68 to 58 mm Hg with an increase in the alveolar-arterial oxygen gradient from 13.5 to 32.4 mm Hg and a normal lactate threshold.
HRCT of her chest revealed subpleural reticular opacification in all five lobes with some ground glass opacities without honeycombing. Pulmonary arteries were of normal caliber, and there was no adenopathy or esophageal abnormality.
Initial evaluation of patients with ...significant pulmonary symptoms should include a chest X-ray, spirometry, and pulse oximetry while walking.
Pathologic review of her VATS biopsy obtained 3 years earlier revealed a homogeneous interstitial fibrosing process in a diffuse and bronchocentric distribution. Lymphocytes and plasma cells were seen within regions of interstitial fibrosis, and macrophages and multinucleated cells were seen within some air spaces. Scattered foci of organizing pneumonia and pleural thickening with mild vascular changes were also noted. The overall changes were consistent with nonspecific interstitial pneumonitis (NSIP).
Initial evaluation of patients with connective tissue disease who display significant pulmonary symptoms should include a chest X-ray, spirometry, and pulse oximetry while walking. If infectious or drug-induced illness is not the cause or the condition is not improving, additional diagnostic studies should be considered, including complete spirometry that includes lung volumes, diffusing capacity of the lung for carbon monoxide (DLCO), and bronchodilator challenge and a HRCT of the chest. Echocardiography should be performed on all patients at risk for pulmonary artery hypertension (PAH), including those with SSc and SLE. PAH should be suspected in patients whose DLCO is lower than expected based upon spirometry values and changes on the HRCT. Exercise-induced PAH should be considered in patients with exertional breathlessness and significant desaturation during exercise. An echocardiogram can provide useful additional information regarding underlying left ventricular systolic and diastolic function, and evidence of pericardial disease. Pericardial effusions may be clinically silent in SSc and SLE patients. Severity of dry eye symptoms can be quantified and documented with a Schirmer’s test as was obtained in our patient suspected of having Sjögren’s syndrome; <5 mm of wetting after 5 minutes is abnormal. An ophthalmologist can use rose bengal staining to confirm keratoconjunctivitis sicca that is severe enough to damage the corneal epithelium. A minor salivary gland biopsy on the inside of the lip can easily demonstrate lymphocytic infiltration of the salivary gland. Changes consistent with Sjögren’s syndrome include a lymphocyte focus score of >1 per 4 mm2 of glandular tissue. (A focus is an aggregate of >50 lymphocytes.) This lymphocytic infiltration typical of Sjögren’s syndrome represents histologic evidence of an autoimmune exocrinopathy and may be present early in the disease before extensive and irreversible destruction of the gland is evident by fibrosis. Most patients with SSc will have classic findings on nailfold capillary microscopy examination; these include dilated capillary loops, tortuosity, and/or dropout. A barium swallow is ordered to evaluate dysmotility due to SSc or PM/DM and should be considered if there is evidence of aspiration or an abnormal esophagus on HRCT of the chest. Fluoroscopic examination of diaphragmatic function may be necessary in some patients with PM/DM or SLE if spirometry values suggest hypoventilation consistent with the “shrinking lung syndrome” of SLE.
If patients have evidence of pulmonary hypertension, one should consider sleep studies to exclude obstructive sleep apnea. A ventilation perfusion lung scan (V/Q scan) should be considered to exclude multiple pulmonary emboli, especially if the patient has antiphospholipid antibodies or evidence of prior thromboembolic episodes.
X-rays of the hands and feet can confirm classic RA erosions or demonstrate calcinosis seen in the limited (lSSc) disorder of CREST syndrome (calcinosis, Raynaud’s, esophageal dysmotility, sclerodactyly, and telangiectasis). An MRI of the hands may reveal subtle evidence of synovitis or erosions not visible on standard bone films of patients with mild or early RA.
Laboratory studies should be tailored by the clinical suspicion of an associated connective tissue disease.
Laboratory studies should be tailored by the clinical suspicion of an associated connective tissue disease. In addition to a full chemistry panel, patients suspected of having a connective tissue disease associated-ILD should have a complete blood count (CBC), urinalysis, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), the muscle enzymes creatine kinase (CK) and aldolase, rheumatoid factor (RF), antinuclear antibody (ANA), and an ANA profile [Smith antigen (Sm), double-stranded DNA (dsDNA), ribonucleoprotein (RNP), Ro (SSA), La (SSB), and anti-centromere antibodies (ACA)]. SSA and SSB antibodies should be ordered separately if Sjögren’s syndrome is suspected even in the absence of a positive ANA, as was the case in our patient. Additional tests could also include:
• Anti-SCL-70 (topoisomerase I, a DNA-binding protein sensitive to nucleases) frequently seen in dSSC patients with ILD
• Anti-Jo-1 (an anti aminoacyl-tRNA synthetase antibody seen in 20-50% of PM/DM patients)
• Anti-Mi-2 antibody (seen in 5-10% of PM/DM patients)
• Cytoplasmic and perinuclear antineutrophilic cytoplasmic antibodies (C-ANCA; P-ANCA). C-ANCAs are commonly observed in Wegener’s granulomatosis and microscopic polyarteritis, while P-ANCAs are frequently positive in patients with microscopic polyarteritis, Churg-Strauss vasculitis, or pauci-immune glomerulonephritis, and occasionally seen with ulcerative colitis, autoimmune liver disease, and chronic infections.
- PR3 (anti-proteinase-3 antibodies) is a more specific test for Wegener’s granulomatosis.
- MPO (anti-myeloperoxidase antibodies) is a more specific test for microscopic polyangiitis.
• Antibodies to hepatitis C virus, an HIV test, and a hepatitis B surface antigen (HBsAg) test should be obtained before beginning immunosuppressive therapy.
• Antiphospholipid antibodies (anticardiolipin or beta-2 glycoprotein-1 antibodies, Russell’s viper venom time [RVVT)], and rapid plasma reagin [RPR] test)
• Complement (C3 and C4) levels and cryoglobulins, especially if SLE or vasculitis is suspected. Complement components may be reduced due to accelerated consumption or increased as acute phase reactants.
• Serum protein electrophoresis may reveal evidence of a systemic inflammatory disease (polyclonal increase in immunoglobulins and alpha1 and alpha2 zones) or may suggest multiple myeloma.
5% percent of normal women will have a positive ANA ... and the incidence of false positive RF tests approaches 25% in normal individuals >70 years
One must not interpret positive lab results as confirmatory evidence of connective tissue disease-related ILD. Five percent of normal women will have a positive ANA using the common HEp-2 (human epithelial tumor) cell line at a titer of < 1:160, and the incidence of false positive RF tests approaches 25% in normal individuals >70 years of age. Some antibodies, however, have greater disease specificity, as they are rarely observed among healthy control subjects. For example, positive ACA antibodies are commonly seen among patients with lSSc, especially those with CREST syndrome, whereas anti-SCL 70 antibodies are usually observed among patients with dSSc. A nucleolar-staining pattern on ANA testing is common among SSC patients; this may indicate anti-SCL-70 or anti-Th/To antibodies.
Among the most valuable of tests that suggest connective tissue disease-related ILD are HRCT results. Characteristic findings may include ground glass opacification and early fibrosis with or without honeycombing in a peripheral and basilar predominance. Severity of fibrosis, which usually represents irreversible changes, is easy to document and can be monitored to document disease progression and/or response to therapy. Air trapping and bronchial wall thickening are features of bronchiolitis obliterans (BO), and thin-walled cystic changes may be features of Sjögren’s syndrome. Pleural thickening usually indicates prior serositis, and evidence of esophageal disease suggestive of SSc is routinely apparent as dilation and/or thickening. Enlarged pulmonary arteries suggest pulmonary hypertension.
Fiberoptic bronchoscopy with lavage is most helpful to obtain cultures to exclude atypical mycobacterial infections, and it may be helpful in diagnosing eosinophilic syndromes, sarcoidosis, and beryllium disease. Some investigators have utilized lavage cell counts and differential analysis to suggest active alveolitis. However, video-assisted thoracoscopic (VATS) or open lung biopsy is often performed to confidently diagnose the type of underlying lung disease.
Management and Treatment Options
Case, continued
Our initial recommendation for a disease-modifying, glucocorticoid-sparing agent was azathioprine. However, due to intolerance to azathioprine, the patient received cyclophosphamide with a gradual dose escalation from 50 to 150 mg per day. After receiving 150 mg daily for one year, her symptoms and spirometry values improved significantly, despite a lowered daily prednisone maintenance dose of 10 mg and no evidence of drug toxicity.
Life-threatening acute intersitial pneumonia or pulmonary hemorrhage usually require high-dose glucocorticoids, such as 250 mg q 6 hours of methylprednisolone sodium succinate injection (Solu-Medrol®) for 72 hours. It is imperative to first exclude underlying infection. Daily oral cyclophosphamide is probably the most effective therapy for progressive ILD secondary to SSc, RA, and polymyositis, especially if ground glass opacification is noted on HRCT. Cyclophosphamide therapy is However, many patients have mild or nonprogressive fibrosis on imaging studies; controlling their underlying non-pulmonary manifestations may be adequate with a less toxic drug than cyclophosphamide. Physicians must always balance the adverse effects of immunosuppressive and cytotoxic therapy with the morbidity or increased mortality of inadequately treated disease.
Alternative agents that are usually less toxic than cyclophosphamide include azathioprine, leflunomide, cyclosporine, and mycophenolate mofetil. Short courses of glucocorticoid may be adequate for serositis or recurrent BOOP. Patients with suspected pulmonary hypertension may need referral to a cardiologist for right heart catheterization and documentation of PAH and testing for vascular responsiveness. Unfortunately, correlation between estimated pulmonary artery systolic pressures obtained by echocardiogram and right ventricular systolic pressure (RVSP) measured during right heart catheterization are often poor. Nocturnal oxygen therapy and calcium channel blocker therapy (such as long-acting nifedipine preparations) are often utilized in mild disease, whereas patients with severe pulmonary hypertension (WHO functional class III or IV) have improved functional outcome with bosentan or epoprostenol. Many specialists also favor anticoagulation with warfarin in patients with moderate to severe PAH. All patients with risk factors for osteoporosis or those receiving >7.5 mg prednisone for 3 months should have a baseline dual energy X-ray absorptiometry (DEXA) study to determine bone mineral density. Those with T-scores <1.5 SD should consider antiresorptive therapy with a weekly bisphosphonate such as alendronate or risedronate in addition to 1,500 mg of calcium and 800 IU of vitamin D daily. Intravenous bisphosphonate therapy with pamidronate should be considered for patients with significant esophageal disease to reduce the risk of complications.
The goal of therapy in ILD associated with connective tissue disease is to halt the progression of irreversible lung damage,
Patients with connective tissue disease with significant pulmonary disease are best managed jointly by their pulmonologist and rheumatologist using objective parameters to monitor disease progression and responsiveness to therapy. Therefore, baseline and sequential spirometry, dlco, oximetry (at rest and with activity) values and periodic HRCT scans are needed in addition to monitoring of symptoms. The goal of therapy in ILD associated with connective tissue disease is to halt the progression of irreversible lung damage, whereas the treatment goal in other patients may be to prevent recurrent pleurisy or hospitalizations. A multidisciplinary approach is usually needed to correctly diagnose and manage these challenging patients. A high index of suspicion for significant pulmonary disease among patients with connective tissue disease is necessary if intervention is to impact the high morbidity and reduce premature death or need for transplantation.
Suggestions for Further Reading
Ascherman DP. Pulmonary complications of inflammatory myopathy. Curr Rheumatol Rep. 2002;4:409-413.
Franquet T. High-resolution CT of lung disease related to collagen vascular disease. Radiol Clin North Am. 2001;39:1171-1187
King TE. Connective tissue disease. Schwarz MI, King TE, Eds. Interstitial Lung Disease. Hamilton BC Decker, Inc; Philadelphia, 1998.
Lamblin C, Bergoin C, Saelens T, Wallaert B. Interstitial lung diseases in collagen vascular diseases. Eur Respir J Suppl. 2001;32:69s-80s.
Lomeo RM, Cornella RJ, Schabel SI, Silver RM. Progressive systemic sclerosis sine scleroderma presenting as pulmonary interstitial fibrosis. Am J Med. 1998;87:525-527.
Veeraraghavan S, Nicholson AG, Wells AU. Lung fibrosis: new classifications and therapy. Curr Opin Rheumatol. 2001;13:500-504.
White B, Moore WC, Wigley FM, Xiao HQ, Wise RA. Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis. Ann Intern Med. 2000;132:947-954.
