Inflammatory Myopathy, Bronchiolitis Obliterans/Organizing Pneumonia, and Anti-Jo-1 Antibodies—an Interesting Association

Inflammatory myopathy, bronchiolitis obliterans/organizing pneumonia, and anti-Jo-1 antibodies--an interesting associationMar. 1997, p. 236–240 Vol. 4, No. 2
Copyright q 1997, American Society for Microbiology
Inflammatory Myopathy, Bronchiolitis Obliterans/Organizing Pneumonia, and Anti-Jo-1 Antibodies—an
Interesting Association MARK KALENIAN AND BURTON ZWEIMAN*
Allergy and Immunology Division, Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania
Received 22 July 1996/Returned for modification 29 August 1996/Accepted 18 November 1996
We report an interesting association of inflammatory myopathy, characterized pathologically as dermato- myositis, with bronchiolitis obliterans/organizing pneumonia and anti-histidyl-tRNA synthetase (Jo-1) anti- body. The relations of different types of pulmonary involvement to inflammatory myopathy and antisynthetase antibodies are discussed.
Inflammatory myopathies occur in children and adults, ei- ther as apparently primary events or associated with other systemic disorders, particularly defined connective tissue dis- eases such as systemic lupus erythematosus (SLE) (21). Studies by several groups have detected a variety of autoantibodies in the sera of patients with primary inflammatory myopathy (5, 16, 22). A patient with inflammatory myopathy seen by us illustrated a somewhat unusual complex of pathologic and im- munologic findings that was instructive in our attempts to un- derstand this very interesting group of disorders. Case report. (i) Previous history. The subject is a 53-year-
old white male engineer transferred from a community hospi- tal to the Hospital of the University of Pennsylvania (HUP) because of increasing dyspnea on exertion and muscular weak- ness of 2 months’ duration. The patient first noted these symp- toms when climbing a hill, followed by dyspnea during tennis games and brisk walking. He also noted increasing difficulty in firmly gripping golf clubs and his tennis racket, followed by generalized joint and muscle aches, particularly in the legs and shoulders. Over the next several weeks, his dyspnea and mus- cular weakness increased progressively to the point where his work-related travel was affected. The patient experienced de- creased appetite, slight weight loss, and chronic dry cough without wheezing. The patient was evaluated by a pulmonologist in his com-
munity, diagnosed as having emphysema, and treated with theophylline (Slo-bid) and inhalations of flunisolide (Aerobid) and albuterol (Proventil), which provided some relief. Several weeks later, the patient developed a scaling rash over several knuckles and near one eye. He was treated with azulfidine for a presumed flare of his psoriasis with likely joint involvement. Methotrexate therapy was not used because of existent abnor- mal liver enzyme levels. Several weeks later, while visiting family in New Jersey the subject was so weak and dyspneic, with absent appetite, fever up to 102.88F, and blood-tinged sputum, that he was hospitalized. A diagnosis of pneumonia was made, based on the presence of a patchy right lower lobe infiltrate in chest X rays. Based on findings in a ventilation- perfusion scan, the probability for pulmonary embolism was considered low. Computerized tomography (CT) of the abdomi- nal area showed only infiltrates in the lower lobes of both lungs. There was no clinical improvement despite trials of several
antibiotics, and subsequently, a patchy consolidation in the right, middle, and lower lobes appeared and bilateral pleural effusions, an enlarged heart, and possible interstitial involve- ment of the left lung were observed. Sinus X rays were normal. Laboratory studies included a complete blood count, urinaly- sis, and assays for antinuclear antibodies (ANA), anti-neutro- phil cytoplasmic antibodies, and antibodies against legionella, human immunodeficiency virus, histoplasma, and blastomyco- sis in serum, all of which were normal. The serum cryptococcal antigen test and blood culture studies were negative. Bronchos- copy showed no gross abnormalities, and smears and cultures for bacterial pathogens, fungi, and acid-fast bacilli were all negative. The past medical history of the subject included heavy smok-
ing until 20 years ago, intermittent fairly heavy alcohol intake, and psoriasis for 4 years. There was no history of similar dysp- nea or muscular symptoms in the subject’s immediate family members. The patient’s work involved residence in and travels to Singapore, but no direct exposure to suspect inhalants was reported. (ii) Evaluation in the HUP. At the time of admission, the
patient was receiving flunisolide (two puffs, thrice daily), ipra- tropium bromide (Atrovent) (two puffs, thrice daily), theo- phylline (1 200-mg tablet, four times daily), and homatropine methylbromide-hydrocone bitartrate (Hycodan) syrup every 4 h as needed for cough. His physical exam yielded the follow- ing: blood pressure, 102/64; temperature, 101.68F; pulse, 104; respiratory rate, 32; other signs, extreme dyspnea and acute respiratory distress. There were dry rales in the lower two- thirds of both lung fields. The cardiac exam was normal except for sinus tachycardia, and profound muscular weakness was seen (proximal-muscle weakness was greater than distal-mus- cle weakness). There were no fasciculations or myotonia. Deep tendon reflexes were decreased without pathologic reflexes. There was no rash or skin discoloration. (iii) Laboratory studies at admission. The results of six
laboratory studies run upon the patient’s admission to the HUP are given below. (i) Blood counts were as follows: hemoglobin/hematocrit
ratio, 10.6/31; leukocyte count, 30,900; platelet count, 527,000. (ii) Serum chemistries were as follows: Na, 129; Cl 5 87;
blood urea nitrogen/creatinine ratio, 12/0.9; glucose, 75; aspar- tate transaminase, 212; alanine transaminase, 159; albumin, 2.5; Ca21, 7.6; lactate dehydrogenase amylase, lipase, alkaline phosphatase, total bilirubin, Mg21, and PO4, normal. (iii) Serologic and culture studies yielded the following: nor-
mal ANA, rheumatoid factor, VDRL (Veneral Disease Re-
* Corresponding author. Mailing address: 512 Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104-6057. Phone: (215) 898- 6525. Fax: (215) 349-5919.
236
search Laboratory), antibody levels to hepatitis C, cytomega- lovirus, Epstein-Barr virus, legionella, and mycoplasma; sedimentation rate, 65 mm/h; complement C3 and C4 levels, normal; blood and sputum cultures, no pathogens; tuberculin (purified protein derivative) skin test, negative. (iv) Pulmonary function tests yielded the following: forced
expiratory vital capacity (FVC) 5 1.47 liters (28% of predict- ed); forced expiratory volume in 1 s (FEV1) 5 1.33 liters (32% of predicted); FEV1/FVC 5 90%; arterial blood gas analysis, pH 7.49, pO2 5 52 (93% saturation), pCO2 5 32, HCO3 5 28. (v) The electrocardiogram revealed no acute changes. (vi) High-resolution chest CT revealed moderate bilateral
pleural effusions and extensive patchy bilateral alveolar dis- ease. The differential diagnosis of the patient on admission to the
HUP included (i) pulmonary hemorrhage syndrome (despite the absence of hemoptysis), (ii) bronchiolitis obliterans/orga- nizing pneumonia (BOOP), (iii) hypersensitivity pneumonitis, (iv) bronchoalveolar carcinoma, (v) Wegener’s granulomato- sis, (vi) sarcoid, and (vii) lymphoma. Pulmonary disease associated with polymyositis (PM) was
considered in view of the patient’s progressive muscular weak- ness. However, this possibility was thought less likely because of the alveolar nature of the pulmonary infiltrates seen on X rays and by CT of the lungs. (iv) Hospital course. Because a previous bronchoscopy with
biopsy had been nonrevealing, a thorascopic lung biopsy was performed while the patient received a high dosage of inhaled
O2. The tissue removed from an involved area of the lungs showed BOOP without interstitial inflammatory changes or fibrosis (Fig. 1a). Studies for the presence of microbial patho- gens or evidence of hypersensitivity pneumonitis were nonre- vealing. Meanwhile, the patient’s muscular strength decreased pro-
gressively. A serum creatine phosphokinase (CPK) level was markedly elevated, at 4,500 units/liter (normal values are be- tween 65 and 350 ml/liter) with no increased %MB fraction. A muscle biopsy sample was obtained, and it showed collections of mononuclear inflammatory cells between muscle fibers and perifascicular atrophy (Fig. 1b). These changes were typical of dermatomyositis (DM) in the opinion of Donald Schotland, an expert in the pathology of muscle disorders, in our Department of Neurology. However, there were no gross or histologic ab- normalities in the overlying skin. Antibodies against the Jo-1 antigen were found in the patient’s serum by immunodiffusion. This finding was confirmed in the laboratory of Ira Targoff and Morris Reichlin (University of Oklahoma Health Sciences Center, Oklahoma City), where it was identified an as antibody against histidyl-tRNA synthetase. A search for malignancy was nonrevealing. Based on the findings noted above, treatment with 100 mg of
prednisone/day was initiated at a time when the patient was bedridden, because of muscular weakness and dyspnea, and requiring 6 liters of supplemental O2/min to maintain adequate oxygenation. Within 1 week, his dyspnea decreased consider- ably, and he required progressively less supplemental O2 ther-
FIG. 1. (a) Lung biopsy sample showing findings compatible with a diagnosis of BOOP. There is an extensive organizing pneumonitis, displaying a variety of inflammatory cells and marked obliteration of the bronchioles by organizing fibrous tissue. Stain, hematoxylin and eosin; magnification,3450. (b) Muscle biopsy sample, showing findings suggestive of DM with perifascicular atrophy and a sparse inflammatory cell infiltrate. Stain, hematoxylin and eosin; magnification, 3450.
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apy. There was a marked decrease in the pulmonary infiltrates seen in the chest X ray. The patient’s muscular strength also improved, and his serum CPK levels decreased. After 10 days of steroid therapy, the prednisone dosage was
tapered to 80 mg/day and the patient was transferred to the rehabilitation unit. With physical therapy and supportive train- ing, the patient’s strength improved so that the patient could walk 1,000 ft by himself, using two canes, at the time of hospital discharge 9 days later. He no longer required O2 therapy. His chest X ray was normal, and his serum CPK levels were at the upper end of the normal range, at 350 units/liter. He was transferred to outpatient care by physicians near his home in Houston, Tex., while receiving a prednisone dosage of 70 mg/ day. A follow-up report from these colleagues in Texas 1 year later indicated that the patient was working actively without evidence of relapse of pulmonary or muscle symptoms while receiving prednisone at a dosage of 10 mg/day. Discussion. This case is both unusual and instructive in two
respects. (i) The patient manifested a polymyopathy with BOOP rather than with the usual interstitial lung disease (ILD). Yet, his serum contained anti-Jo-1 antibodies. (ii) The pathologic picture in involved muscle suggested DM, although there was no gross or histologic evidence of skin involvement at the time. These aspects will be discussed in turn below. Primary inflammatory myopathies typically affect the proxi-
mal muscles more than the distal muscles, generally without atrophy or contractures (13, 21). There is involvement of esophageal muscles with dysphagia in about 25% of cases, and cardiac myositis occurs in about 30% of cases, leading to ar- rhythmia and/or congestive heart failure. Arthralgia, Raynaud’s syndrome, and occasional renal involvement are seen in some PM cases. Most of the cases of primary inflammatory myopathy fit the
criteria for a diagnosis of PM (21). DM constitutes the other one-third of all cases of idiopathic inflammatory myopathy with localized or diffuse erythema, maculogranulopapular eruptions, eczematoid, or (rarely) exfoliative or ulcerative le- sions (15). The histologic picture in the underlying muscle has certain unique features, such as perifascicular atrophy, not seen in other presentations of inflammatory myopathy (9). All types of inflammatory myopathy are generally characterized by (i) collections of inflammatory cells, mainly lymphocytes around small vessels and between muscle fibers, (ii) patchy muscle fiber necrosis with increased connective tissue deposi- tion, and (iii) some myofiber regeneration. Of particular relevance to this case report is the respiratory
involvement in inflammatory myopathy (12, 18). Prominent dyspnea occurs in a minority of cases of suspected PM or DM (PM/DM) cases due to a variety of causes, including chest cage and/or diaphragmatic muscle weakness, pulmonary hyperten- sion, pneumonitis secondary to esophageal involvement and aspiration, and adverse effects of therapy, either as a direct effect or indirectly through an increased incidence of opportu- nistic infections occurring in immunocompromised individuals. Particularly interesting is the ILD seen in 13 to 37% of PM/DM cases in different reports (1). It is conceivable that an increasing use of high-resolution CT of the lung may lead to a higher rate of detection of this complication. There is an in- creased association of polyarthritis with ILD in cases of PM/DM (17). However, there is no correlation between the extent or severity of muscle or skin involvement and the de- velopment of ILD in cases of PM/DM (2). Indeed, in about one-third of the reported cases with associated ILD the pul- monary manifestations in these patients preceded the skin and/or muscle involvement. Pulmonary involvement, if untreated, is generally steadily
progressive from mild dyspnea to pronounced restrictive lung disease and sometimes pulmonary hypertension with second- ary cardiac effects (12, 18). The median survival of PM/DM patients with ILD is reportedly reduced (18 months) from that seen in PM/DM patients with similar muscular involvement without ILD (36 months). The pulmonary pathologic picture most commonly seen in ILD associated with PM/DM is that of “usual interstitial pneumonia” (1). Diffuse alveolar damage, adult respiratory distress syndrome, and cellular interstitial pneumonia have been reported in a few cases (10, 26). A review of 14 cases of PM/DM with associated BOOP indicated that there was somewhat better survival (66%) in such cases than in cases of PM/DM with usual interstitial pneumonia (40%) (26). The limited number of reported cases of inflam- matory myopathy with BOOP were seen more commonly in patients with PM than those with DM. The profile of abnormal antibodies found in the sera of
patients with PM/DM (summarized in Table 1) has greatly interested clinical immunologists (5, 11, 16, 22). Moderate to high titers of ANA are seen in 40 to 80% of cases in different reports (11, 16). Anti-Ro and anti-RNA antibodies may be seen in cases of inflammatory myopathy, generally in those associated with other connective tissue disorders (11). Of great interest has been the group of antibodies, present almost ex- clusively in those patients with PM/DM, called myositis-spe- cific antibodies (MSA) by some investigators (11). Such MSA have been found in 35 to 40% of patients with clinically defined PM or DM (11). The most widely recognized MSA are anti- bodies directed against acyl-tRNA synthetases, cytoplasmic en- zymes which catalyze the binding of amino acids such as his- tidine, threonine, alanine, and isoleucine to tRNA (22). The MSA found most commonly is the anti-histidyl-tRNA syn- thetase, called anti-Jo-1 antibody, which is seen in about 20% of all inflammatory myopathy patients and in 30% of PM patients (14). Of particular interest is the high frequency (50 to 75%) of serum anti-Jo-1 antibodies seen in patients with in- flammatory myopathy with associated ILD (2, 20, 27). Almost all such individuals reported to have Jo-1 antibodies associated with ILD have had PM (2, 25). Therefore, our patient may be unique in that the histologic
findings in a symptomatic muscle of our patient were highly suggestive of DM in the opinion of an expert in the pathology of inflammatory myopathies. The patient had a past history of a scaling rash on the knuckles (possibly suggestive of DM). However, it should be noted that our patient had not mani- fested any gross or histologic evidence of skin involvement at the time of our evaluation. There were also no associated malignancies. Another unusual feature of our patient’s presentation was
the presence of Jo-1 antibody, confirmed to be anti-histidyl- tRNA synthetase, in inflammatory myopathy with associated BOOP. As noted above, BOOP associated with PM/DM was reported in 14 cases (26), and several scattered case reports have been published in the past several years (4, 6–8, 19). The published data does not permit estimates of the frequency of Jo-1 antibody in these cases. The association of bronchiolitis obliterans (without reported organizing pneumonia) and the presence of another anti-synthetase (anti-alanine-tRNA syn- thetase) have been reported previously (14). Therefore, fur- ther investigation will be needed to determine the frequency of the Jo-1 antibody in other patients similar to ours with the BOOP-inflammatory myopathy clinical complex. Looking at these associations from a different viewpoint
(11), patients reported to have antisynthetase antibodies gen- erally exhibit several clinical trends. (i) Almost all patients have or subsequently develop clinical manifestations of inflam-
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matory myopathy. (ii) Anti-Jo-1 antibodies are found in more PM than DM patients, whereas the other anti-synthetases (e.g., anti-PL7, anti-PL12, and anti-ET) tend to occur more com- monly in DM patients. In addition, anti-Mi-2 (another MSA) occurs in about 10% of DM patients but rarely in PM patients. (iii) Anticentromere antibodies occur very infrequently in PM/DM patients. (iv) The majority of such patients with anti- synthetase antibodies have ILD. (v) Arthritis of varying sever- ity is found in 60 to 100% of Jo-1 antibody-positive PM/DM patients. (vi) In some cases, the ILD and/or arthritis may be more of a clinical problem than the myositis at the time of initial evaluation. (vii) Fever and/or Raynaud’s syndrome is found in about 90% of cases. (viii) Hyperkeratotic lines with fissuring on the hands and sclerodactylia and telangiectasis are seen with sizable frequency. Definitive evidence of other con- nective tissue inflammatory disease has been found in only 6% of patients with antisynthetase antibodies. Although immune responses are thought to play pathogenic
roles in primary inflammatory myopathy, the exact mecha- nisms have not been clearly defined (23). Some investigators have proposed that direct cell-mediated immune reactions are pathogenic in PM, while DM may be due more to humoral responses. An associated vasculitis with local deposition of complement in children with DM has been reported. The pathogenic relevance of the antisynthetase antibodies
found in PM/DM patients is still uncertain (23). The binding of antibodies in the sera of different PM/DM patients to different epitopes in the synthetase molecules suggests to some investi- gators that antisynthetase activity is not simply a cross-reacting antibody stimulated by some environmental agent. We could find no reports of preferential deposition of such antisyn- thetase antibodies in the lung lesions associated with PM/DM. However, the association of high levels of anti-synthetases with more extensive organ involvement and disease progression in PM/DM suggests a possible prognostic role of these autoanti- bodies. The prompt, prolonged, and dramatic clinical responses of
our patient to corticosteroid therapy is gratifying. However, about 20% of patients with PM/DM do not respond to the steroids or develop unacceptable adverse effects (3). About one-third of individuals treated with immunosuppressive
agents respond in a manner allowing the reduction of the steroid dosage needed for maintenance treatment; such main- tenance treatment may be required for long periods. The fre- quency of response to such cytotoxic agents in individuals un- responsive to corticosteroids is still uncertain, with widely varying success reported (3). Therefore, much has to be learned about the mechanisms involved in this interesting group of disorders, and hopefully this will lead to more effec- tive treatment.
The cooperation of Ira Targoff and Morris Reichlin (University of Oklahoma Health Sciences Center) in performing the determinations of the antisynthetase antibody levels in the serum of our patient is greatly appreciated. This study was supported by the Immunology Research and Educa-
tion Fund of the Allergy and Immunology Division, Department of Medicine, University of Pennsylvania Medical School.
REFERENCES 1. Arsura, E. L., and A. S. Greenberg. 1988. Adverse impact of interstitial pulmonary fibrosis on prognosis in polymyositis and dermatomyositis. Semin. Arthritis Rheum. 19:29–37.
2. Bernstein, R. M., S. H. Morgan, J. Chapman, C. C. Bunn, and M. B. Mathews. 1984. Anti-Jo-1 antibody: a marker for myositis with interstitial lung disease. Br. Med. J. 289:151–152.
3. Boyd, A. S., and K. H.…