Microscopic polyangiitis (MPA) may present with a syndrome that resembles idiopathic pulmonary fibrosis (IPF). We describe an MPA patient with the clinical presentation of a “pulmonary-muscle” syndrome in which interstitial lung disease antedated the onset of myopathy. Identification of vasculitis on muscle biopsy was instrumental in recognizing clinical, radiographic, and histopathologic features that were more characteristic of MPA than of IPF. Institution of glucocorticoid and cyclophosphamide therapy led to the induction of a complete remission. The histologic findings in this case implicate subclinical episodes of alveolar hemorrhage as the mechanism of interstitial lung disease in MPA.
Microscopic polyangiitis (MPA) is a systemic inflammatory disease often associated with antineutrophil cytoplasmic antibodies (ANCAs) and characterized by necrotizing, pauci-immune vasculitis (1). When present in MPA, ANCAs are directed most often against myeloperoxidase (MPO) and termed MPO ANCAs. The organs most commonly involved in MPA include the kidneys, skin, and lungs (2). The classic form of pulmonary involvement is alveolar hemorrhage caused by pulmonary capillaritis. Interstitial lung disease may be more common in MPA than generally appreciated (3–6), but its pathophysiology remains poorly understood.
We describe a patient with MPA whose presentation was characterized by a pulmonary-muscle syndrome and several remarkable features. First, to our knowledge, no similar description of a pulmonary-muscle syndrome associated with MPA exists in the literature. Second, the detection of vasculitis within the skeletal muscle of a patient whose clinical symptoms were more suggestive of an inflammatory myopathy was instrumental in the diagnosis of MPA. The identification of MPA rather than idiopathic pulmonary fibrosis (IPF) as the mechanism underlying our patient's interstitial lung disease altered the prognosis substantially and afforded the initiation of life-saving therapy. Finally, the histopathologic features of the patient's lung disease have potential mechanistic implications for the development of interstitial lung disease in MPA, suggesting that recurrent, subclinical alveolar hemorrhage might contribute to the development of fibrotic pulmonary changes.
The patient, a 77-year-old white woman, was admitted to an outside hospital for evaluation of a progressive myopathy occurring in the context of interstitial lung disease. The patient first experienced dyspnea on exertion ∼6 months before admission. Before that time, she had been able to ambulate 3 miles a day with no difficulty. Chest radiography revealed prominent interstitial markings and bibasilar fibrosis. Over the ensuing months, the patient experienced dry cough and worsening dyspnea. Two months before admission, the patient's dyspnea had progressed to the point that she became fatigued during transfers from bed to chair. Even limited ambulation precipitated oxygen desaturation to levels <90% on room air. The patient had a 30–pack-year history of cigarette smoking but had quit smoking more than a decade before her presentation.
One month before admission, the patient noted myalgias centering on her shoulders and thighs as well as weakness on rising from a seated position. By the time of admission to an outside hospital, she had become bedbound, because of both dyspnea at rest and the inability to flex her proximal lower extremities against gravity. At the time of admission to an outside hospital, the patient required 8 liters of supplemental oxygen via face mask to maintain an oxygen saturation >90%. Her initial physical examination revealed a normal jugular venous pressure and normal heart sounds, but there were diffuse inspiratory crackles throughout the lungs. Upon neurologic examination, the patient had severely impaired strength in her iliopsoas and gluteus maximus muscles (Medical Research Council [MRC]  power of 2/5). Her proximal upper extremities demonstrated only mild weakness (MRC power of 4+/5). Distal motor and sensory function was intact.
Pulmonary function tests (PFTs) revealed a mildly restrictive pattern on lung volumes (total lung capacity of 3.92 liters, 78% of predicted; forced vital capacity 1.64 liters, 60% of predicted) with a disproportionately decreased diffusing capacity (25% of predicted). The patient underwent a transbronchial biopsy that was nondiagnostic, followed by an open-lung biopsy. The results of this procedure were interpreted initially as being consistent with usual interstitial pneumonitis (IP), a subtype of idiopathic interstitial pneumonia (8). The patient was treated with 50 mg of methylprednisolone twice a day for 3 days, yet her respiratory status continued to decline.
At the time of transfer to our center, the patient was afebrile and using accessory muscles of respiration and required 100% oxygen by face mask. A computed tomography (CT) scan of the chest obtained at our institution revealed bibasilar fibrosis, honeycombing, and traction bronchiectasis (Figure 1). However, the apical distribution of fibrosis, extensive ground-glass changes in the apices, and bilateral pleural effusions were considered atypical of usual IP.
The patient's initial laboratory evaluation revealed a normochromic, normocytic anemia (hematocrit 26%), a serum creatinine level of 0.8 mg/dl (normal 0.8–1.3 mg/dl), and an inactive urine sediment. The serum creatine kinase (CK) and aldolase levels were normal. The antinuclear antibody assay yielded positive results (titer of 1:80, nucleolar pattern), but assays for anti–double-stranded DNA, anti–Jo-1, anti-SSA, anti-SSB, anti–glomerular basement membrane, and anti–topoisomerase III antibodies yielded negative results. The patient was strongly positive for rheumatoid factor (913 IU/ml; normal <20 IU/ml), but serum complement levels were normal. An ANCA assay by indirect immunofluorescence yielded positive results at a titer of 1:40 (normal <1:20) with a perinuclear (pANCA) pattern. An enzyme-linked immunosorbent assay (ELISA) for MPO ANCAs yielded positive results (23.5 units; normal <20 units), but an ELISA for proteinase 3 ANCAs yielded negative results.
Review of the lung biopsy specimen at our institution revealed some findings suggestive of usual IP, including foci of fibroblast proliferation, architectural remodeling with a honeycomb pattern, and a spatially and temporally heterogeneous pattern of fibrosis (Figure 2). However, 3 histopathologic features were inconsistent with usual IP (Figure 3). First, there were foci of leukocytoclastic capillaritis. Second, features consistent with a constrictive bronchiolitis were present. Finally, there was evidence of a chronic hemorrhagic component, with regions of hemosiderin-laden macrophages juxtaposed with fibroblast foci. These findings excluded usual IP and suggested instead the diagnosis of a systemic vasculitis.
A magnetic resonance imaging (MRI) study of the proximal legs revealed increased signal in the quadriceps and hamstring muscles, particularly on the T2-weighted and STIR sequences, consistent with skeletal muscle edema (Figure 4). In the setting of the patient's interstitial lung disease and muscle weakness, these findings raised the possibility of an inflammatory myopathy (9). However, findings of an electromyogram (EMG) were consistent with a nonirritable myopathy, with no spontaneous discharges at rest. Activation of skeletal muscles showed evidence of early recruitment, with only a few short-duration, low-amplitude discharges. Nerve conduction studies revealed a distal, symmetric, sensorimotor polyneuropathy in the lower extremities, consistent with the patient's history of diabetes.
A muscle biopsy of the left quadriceps was performed (Figure 5). The paraffin section showed the dominant histopathologic finding: multiple regions of vasculitis involving perimysial vessels <100 μm in diameter, with transmural inflammation and luminal obliteration. The frozen section revealed a combination of type II atrophy and denervation changes, but no evidence of perifascicular atrophy to suggest dermatomyositis. The histopathologic findings of leukocytoclastic capillaritis in the lung and vasculitis within skeletal muscle, combined with ANCA positivity by both immunofluorescence and ELISA, confirmed the diagnosis of MPA.
The patient was started on cyclophosphamide (1 mg/kg/day), and her methylprednisolone dosage was tapered to prednisone (40 mg/day) over 1 week. During that week, the patient recovered antigravity strength in her lower extremities (MRC power of 3/5), and her supplemental oxygen requirements decreased to 5 liters. After 2 weeks, the patient's supplemental oxygen requirements had decreased to 2 liters, and she had recovered sufficient proximal muscle strength to transfer herself from bed with a walker. Two months after the start of cyclophosphamide, the patient no longer required supplemental oxygen and could ambulate without a walker. Now, more than 1 year after her diagnosis, the patient does not require supplemental oxygen and has full power in all extremities. Followup studies have included repeat CT scans of the chest that show resolution of apical ground-glass changes, serial PFTs that document stable pulmonary deficits, and persistently negative results for ANCA serology by both immunofluorescence and ELISA.
We report a case of MPA presenting as a “pulmonary-muscle” syndrome. This case highlights several points about MPA and offers insights into the possible mechanism of interstitial lung disease in this condition. MPA has not been reported previously as a cause of a myopathic syndrome. In this case, the normal CK levels and the absent features of muscle irritability on EMG provided initial clues against an inflammatory myopathy. The muscle biopsy demonstrated that the myopathy was secondary to vasculitis.
Despite normal CK levels, our patient was profoundly weak and had changes consistent with edema on MRI. These findings suggest that the mechanism of muscle weakness was reversible ischemia secondary to vasculitis rather than to myonecrosis, and this also explains her rapid clinical response to glucocorticoids. In contrast to the rapidity of this patient's improvement, inflammatory myopathy normally requires weeks of therapy before muscle strength improves. Similarly, because “irritability” on electrodiagnostic studies occurs when myonecrosis of muscle fibers leads to isolation and denervation from the neuromuscular junction, the lack of myonecrosis might explain why our patient had a “nonirritable” myopathic pattern of recruitment. Although edema-like changes on MRI have previously been reported in polyarteritis nodosa (a medium-vessel vasculitis) (10), our case highlights the fact that similar radiographic changes can also occur in small-vessel vasculitis. In addition to its utility in evaluation of the inflammatory myopathies, MRI may serve as an important adjunct in the evaluation of myopathy occurring in vasculitis.
Although the ultimate diagnosis for our patient was MPA, her initial clinical presentation was consistent with subacute progression of IPF. Interstitial lung disease is an underappreciated manifestation of MPA (3–6). Two American Thoracic Society consensus statements on the diagnosis of idiopathic interstitial pneumonias have emphasized the importance of excluding “collagen vascular disease” through clinical and laboratory features (8, 11), but neither these consensus statements nor several review articles explicitly list MPA or any other form of vasculitis in the differential diagnosis of idiopathic interstitial pneumonia (12–14).
Animal models of IPF indicate that endothelial cell injury and capillary hemorrhage are linked directly to the proliferation of type II pneumocytes and the ensuing fibroplasias (15). The histopathologic features of our case raise the possibility that interstitial lung disease in MPA is caused by repeated subclinical episodes of alveolar hemorrhage. The ability of subclinical alveolar hemorrhage to cause interstitial lung disease has been suggested in other forms of small-vessel vasculitis, including a report of 3 siblings with urticarial vasculitis and restrictive changes (16). Schnabel et al (17) reported an increased incidence of hemosiderin-laden macrophages in patients with ANCA-associated vasculitis and pulmonary disease compared with that in a population of patients with interstitial lung disease associated with collagen vascular diseases. Idiopathic pulmonary hemosiderosis, a disorder of unknown pathogenesis, is characterized by diffuse alveolar hemorrhage with hemosiderin-laden macrophages and restrictive lung disease associated with interstitial fibrosis (18, 19). When Gaudin et al (20) reviewed the histologic features of lung disease in 27 patients who were positive for either classic ANCA or pANCA, they found interstitial lesions in 20 patients (74%) and fibrosis in 13 (48%). Finally, Homma et al (21), who retrospectively studied a cohort of 31 patients with diagnoses of pulmonary fibrosis who also had MPO ANCAs, identified 8 patients as having syndromes consistent with MPA. Of 15 biopsy and postmortem specimens available for histopathologic study, all had background features of usual IP. Five specimens showed vasculitis.
An alternative explanation for the development of interstitial lung disease in MPA is that interstitial fibrosis is not caused directly by alveolar hemorrhage; instead, fibrosis and alveolar hemorrhage represent distinct reparative and inflammatory responses to the underlying capillaritis. In usual IP, fibroblast foci are microscopic zones of myofibroblasts that actively proliferate in response to an unknown trigger of endothelial injury (11). In our patient, fibroblast foci may have been triggered by vasculitis, with neutrophilic degranulation resulting in chemotactic damage, rupture of the alveolar endothelial basement membrane, and alveolar hemorrhage. Damage to the pulmonary microcirculation has been associated with interstitial lung disease in other syndromes, including the inflammatory myopathies (9), scleroderma (22), and even diabetes (23). A broader mechanistic implication of our case report is that since features of leukocytoclastic vasculitis were observed in the background of usual IP, damage to the pulmonary microvasculature may have an underappreciated role in some cases of idiopathic interstitial pneumonia.
When interstitial lung disease is the principal manifestation of MPA, the phenotypic similarity of pulmonary symptoms to IPF makes the diagnosis challenging. Our case illustrates that radiographic or histopathologic features inconsistent with IPF warrant an aggressive search for associated systemic causes that may be more amenable to therapy. For example, in our patient, the apical distribution of fibrosis and the significant ground-glass changes were atypical of IPF. The biopsy findings of leukocytoclastic capillaritis, constrictive bronchiolitis, and foci of hemosiderin-laden macrophages confirmed that the patient's interstitial lung disease was secondary to a systemic process.
In conclusion, we have described a case of MPA presenting as a pulmonary-muscle syndrome. Recognition that MPA can present with interstitial lung disease that resembles IPF (but with more treatment-responsive pulmonary involvement) strengthens the resolve for treatment that may be life-saving. This description of a pulmonary-muscle syndrome associated with MPA highlights the fact that in addition to testing for myositis-specific antibodies (e.g., the anti–Jo-1 antibody) (24), testing for ANCAs should be included in the evaluation of patients who present with interstitial lung disease and muscle dysfunction. Finally, the pathologic features of our case suggest that the interstitial lung disease associated with MPA may be triggered by chronic, subclinical alveolar hemorrhage.
Dr. Stone had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study design. Birnbaum, Danoff, Askin, Stone.
Acquisition of data. Birnbaum, Danoff, Askin, Stone.
Analysis and interpretation of data. Birnbaum, Danoff, Askin, Stone.