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Microscopic polyangiitis presenting as a Вpulmonary-muscle syndromeIs subclinical alveolar hemorrhage the mechanism of pulmonary fibrosis.

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Vol. 56, No. 6, June 2007, pp 2065–2071
DOI 10.1002/art.22633
© 2007, American College of Rheumatology
Microscopic Polyangiitis Presenting as a
“Pulmonary-Muscle” Syndrome
Is Subclinical Alveolar Hemorrhage the Mechanism of Pulmonary Fibrosis?
Julius Birnbaum, Sonye Danoff, Frederic B. Askin, and John H. Stone
tation was characterized by a pulmonary-muscle syndrome and several remarkable features. First, to our
knowledge, no similar description of a pulmonarymuscle 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
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 presen-
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.
Julius Birnbaum, MD, Sonye Danoff, MD, PhD, Frederic B.
Askin, MD, John H. Stone, MD, MPH: Johns Hopkins University
School of Medicine, Baltimore, Maryland.
Address correspondence and reprint requests to John H.
Stone, MD, MPH, Deputy Editor for Rheumatology, UptoDate, Inc.,
95 Sawyer Road, Waltham, MA 02453-3471. E-mail: jstone@
Submitted for publication September 1, 2006; accepted in
revised form February 20, 2007.
Figure 1. A, Chest computed tomography showing bibasilar predominance of fibrosis, with evidence of bilateral pleural
effusions. B, Apical extension of pulmonary fibrosis, with extensive ground-glass changes. Upper lobe fibrosis and bilateral
pleural effusions are atypical radiographic features of usual interstitial pneumonitis.
Figure 2. A and B, Features of usual interstitial pneumonitis identified on biopsy at an outside hospital include fibroblast foci
(arrows). C, Regions of temporal heterogeneity, with normal lung architecture interspersed among fibroblast foci and zones of
acellular fibrosis. (Original magnification ⫻ 250.)
Figure 3. Histopathologic features atypical of usual interstitial pneumonitis. A, Focus of leukocytoclastic capillaritis (arrow).
B, Constrictive bronchiolitis, with an area of fibrosis (arrows) interposed between respiratory epithelium and pink fascicles of
smooth muscle. C, Hemosiderin-laden macrophages (arrow). D, Fibroblast foci juxtaposed with hemosiderin-laden macrophages (arrow). (Original magnification ⫻ 250.)
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] [7] 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, antiSSB, 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 T2weighted 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
Figure 4. Coronal T2-weighted image of the lower extremities, demonstrating diffuse edema throughout the proximal thigh musculature,
consistent with a diffuse myopathy of the thighs.
vasculitis involving perimysial vessels ⬍100 ␮m 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
Figure 5. Left quadriceps muscle biopsy specimen. Bracketed area demonstrates vasculitis of the perimysial vessel, seen on
longitudinal section, with luminal obliteration. Arrow pointing to axial section of affected vessel shows a luminal diameter ⬍100
␮m. No perifascicular atrophy is noted.
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 smallvessel 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 state-
ments 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 hemosiderinladen 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 myositisspecific 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.
Manuscript preparation. Birnbaum, Danoff, Askin, Stone.
1. Feehally J, Wheeler DC, Walls J, Jones S, Lockwood CM, Savage
CO. A case of microscopic polyarteritis associated with antineutrophil cytoplasmic antibodies. Clin Nephrol 1987;27:214–5.
2. Guillevin L, Durand-Gasselin B, Cevallos R, Gayraud M, Lhote F,
Callard P, et al. Microscopic polyangiitis: clinical and laboratory
findings in eighty-five patients. Arthritis Rheum 1999;42:421–30.
3. Nada AK, Torres VE, Ryu JH, Lie JT, Holley KE. Pulmonary
fibrosis as an unusual clinical manifestation of a pulmonary-renal
vasculitis in elderly patients. Mayo Clin Proc 1990;65:847–56.
Becker-Merok A, Nossent JC, Ritland N. Fibrosing alveolitis
predating microscopic polyangiitis. Scand J Rheumatol 1999;28:
Mansi IA, Opran A, Sondhi D, Ayinla R, Rosner F. Microscopic
polyangiitis presenting as idiopathic pulmonary fibrosis: is antineutrophilic cytoplasmic antibody testing indicated? Am J Med Sci
Eschun GM, Mink SN, Sharma S. Pulmonary interstitial fibrosis as
a presenting manifestation in perinuclear antineutrophilic cytoplasmic antibody microscopic polyangiitis. Chest 2003;123:
Dyck PJ, Boes CJ, Mulder D, Millikan C, Windebank AJ, Dyck PJ,
et al. History of standard scoring, notation, and summation of
neuromuscular signs: a current survey and recommendation. J
Peripher Nerv Syst 2005;10:158–73.
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. Am J
Respir Crit Care Med 2000;161(2 Pt 1):646–64.
Fathi M, Lundberg IE. Interstitial lung disease in polymyositis and
dermatomyositis. Curr Opin Rheumatol 2005;17:701–6.
Gallien S, Mahr A, Rety F, Kambouchner M, Lhote F, Cohen P,
et al. Magnetic resonance imaging of skeletal muscle involvement
in limb restricted vasculitis. Ann Rheum Dis 2002;61:1107–9.
American Thoracic Society. American Thoracic Society/European
Respiratory Society International Multidisciplinary Consensus
Classification of the Idiopathic Interstitial Pneumonias [published
erratum appears in Am J Respir Crit Care Med 2002;166:426].
Am J Respir Crit Care Med 2002;165:277–304.
Kim EA, Lee KS, Johkoh T, Kim TS, Suh GY, Kwon OJ, et al.
Interstitial lung diseases associated with collagen vascular diseases:
radiologic and histopathologic findings [published erratum appears in Radiographics 2003;23:1340]. Radiographics 2002;22 Spec
13. King TE Jr. Clinical advances in the diagnosis and therapy of the
interstitial lung diseases. Am J Respir Crit Care Med 2005;172:
14. Harari S, Caminati A. Idiopathic pulmonary fibrosis. Allergy
15. Magro CM, Allen J, Pope-Harman A, Waldman WJ, Moh P,
Rothrauff S, et al. The role of microvascular injury in the evolution
of idiopathic pulmonary fibrosis. Am J Clin Pathol 2003;119:
16. Al Riyami BM, Al Kaabi JK, Elagib EM, El Khatim HS, Woodhouse NJ. Subclinical pulmonary haemorrhage causing a restrictive lung defect in three siblings with a unique urticarial vasculitis
syndrome. Clin Rheumatol 2003;22:309–13.
17. Schnabel A, Reuter M, Csernok E, Richter C, Gross WL. Subclinical alveolar bleeding in pulmonary vasculitides: correlation with
indices of disease activity. Eur Respir J 1999;14:118–24.
18. Buschman DL, Ballard R. Progressive massive fibrosis associated
with idiopathic pulmonary hemosiderosis. Chest 1993;104:293–5.
19. Specks U. Diffuse alveolar hemorrhage syndromes. Curr Opin
Rheumatol 2001;13:12–7.
20. Gaudin PB, Askin FB, Falk RJ, Jennette JC. The pathologic
spectrum of pulmonary lesions in patients with anti-neutrophil
cytoplasmic autoantibodies specific for anti-proteinase 3 and antimyeloperoxidase. Am J Clin Pathol 1995;104:7–16.
21. Homma S, Matsushita H, Nakata K. Pulmonary fibrosis in myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitides. Respirology 2004;9:190–6.
22. Highland KB, Silver RM. New developments in scleroderma
interstitial lung disease. Curr Opin Rheumatol 2005;17:737–45.
23. Hsia CC, Raskin P. The diabetic lung: relevance of alveolar
microangiopathy for the use of inhaled insulin. Am J Med
24. Hengstman GJ, van Engelen BG, Vree Egberts WT, van Venrooij
WJ. Myositis-specific autoantibodies: overview and recent developments. Curr Opin Rheumatol 2001;13:476–82.
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polyangiitis, subclinical, muscle, pulmonaria, syndrome, alveolar, mechanism, microscopy, hemorrhagic, вpulmonary, presenting, fibrosis
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