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Interstitial lung disease with autoantibodies againstaminoacyl-tRNA synthetases in the absence of clinically apparent myositis
Interstitial Lung Disease With Autoantibodies Against Aminoacyl-tRNA Synthetases in the Absence of Clinically Apparent Myositis Alan W. Friedman, Ira N. Targoff, and Frank C. Arnett Autoantibodies against aminoacyl-tRNA synthetases (antisynthetases) have been found to be highly specific for polymyositis and dermatomyositis and to correlate strongly with complicating interstitial lung disease (ILD). We describe the clinical presentations and course of 10 patients with ILD and anti-synthetase antibodies in whom underlying myositis was not clinically evident. Anti-PL-12 antibodies (antialanyl-tRNA synthetase) were most common (60%), followed by anti-Jo-1 (antihistidyl-tRNA synthetase) and anti-OJ (anti-isoleucyl-tRNA synthetase) (20% each). All 10 patients had anticytoplasmic antibodies by indirect immunofluorescence on HEp-2 cells. Five of 10 presented with features of connective tissue disease, whereas two presented with acute respiratory failure, two with insidious onset of diminished exercise tolerance, and one with persistent cough. All but one patient received corticosteroids, four were given oral cyclophosphamide, and two azathioprine. ILD resolved or stabilized in five patients (50%), and progressed in four (40%). The "'antisynthetase syndrome" may occur in the absence of clinical myositis, and the ILD in these patients is usually responsive to therapy. Antisynthetase testing should be considered in patients with ILD who have a cytoplasmic pattern by antinuclear antibody (ANA) testing on HEp-2 cells, because early recognition and treatment of such patients affects their clinical course. Semin Arthritis Rheum 26:459-467. Copyright © 1996 by W.B, Saunders Company INDEX WORDS: Interstitial lung disease; myositis; autoantibodies.
UTOANTIBODIES reacting with aminoacyl-tRNA synthetases occur in the sera of 25% to 40% of adult patients with the idiopathic inflammatory myopathies, polymyositis and dermatomyositis, a-3 Anti-Jo-1 (antihistidyltRNA synthetase) was the first of these "antisynthetases" to be discovered 4-6 and is detectable in approximately 15% to 30% of myositis patients overall, more commonly in polymyositis than in dermatomyositis. 2,7-9Additional but less common antisynthetases were subsequently discovered more often in patients with dermatomyositis, and include: anti-PL-7 (antithreonyl-tRNA synthetase), anti-PL-12 (antialanyl-tRNA synthetase), anti-OJ (anti-isoleucyl-tRNA synthetase), and anti-EJ (antiglycyl-tRNA synthetase).I°-12 Individual patients usually produce only one of these autoantibodies, but, when present, they are usually considered highly specific for an inflammatory myopa-
A
thy.l-3,9-12
From the Division of Rheumatology and Clinical lmmunogenetics, Department of Internal Medicine, University of TexasHouston Health Science Center, Houston, TX, and the Department of Medicine, University of Oklahoma Health Sciences Center, Veterans Affairs Medical Center, and Oklahoma Medical Research Foundation, Oklahoma City, OK. Alan W. Friedman, MD: Assistant Professor of Medicine, Division of Rheumatology and Clinical Immunogenetics, Department of Internal Medicine, University of Texas-Houston Health Science Center, Houston, TX; Ira N. Targoff, MD: Associate Professor of Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Veterans Affairs Medical Center, and Oklahoma Medical Research Foundation, Oklahoma City, OK; Frank C. Arnett, MD: Professor of Medicine, Division of Rheumatology and Clinical Immunogenetics, Department of Internal Medicine, University of Texas-Houston Health Science Center, Houston, TX. Supported by a grant from the Muscular Dystrophy Association, and the George S. Bruce, Jr., Professorship in Arthritis and Other Rheumatic Diseases (Dr. Arnett); and NIH grants no. AR32214 and no. AI27181 and Department of Veterans Affairs Medical Research Funds (Dr. Targoff). Address reprint requests to Alan W. Friedman, MD, University of Texas-Houston Health Science Center, 6431 Fannin, MSB 5.270, Houston, TX77030. Copyright © 1996 by W.B. Saunders Company 0049-0172/96/2601-000355.00/0
Seminars in Arthritis and Rheumatism, Vo126, No 1 (August), 1996: pp 459-467
459
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FRIEDMAN, TARGOFF, AND ARNETT
Myositis patients with any of the antisynthetases also have a high frequency of interstitial lung disease (ILD), 2,8,13-17 and 68% to 89% of patients with both myositis and ILD have anti-synthetases. 2,14The prognosis for survival in patients with antisynthetases is poorer than that of other myositis patients, in part because of the lung disease, which may be severe, including a fulminant picture resembling the adult respiratory distress syndrome. 2'16'18 Several other clinical features besides lung involvement are more common among myositis patients with antisynthetases compared with their counterparts without antisynthetases, including inflammatory arthritis (usually nonerosive), Raynaud's phenomenon, fever, and a hyperkeratotic lesion of the fingers ("mechanic's hands"). 2,19 This clinical picture has been referred to as the "anti-synthetase syndrome. ''a,2,2°,21 Because individual patients may not demonstrate all of these clinical features, it can be difficult to recognize the syndrome before obtaining a positive test for one of the defining antisynthetase autoantibodies. Occasionally, patients with ILD and antisynthetase antibodies but without overt myositis have been noted. 14,17,22,23 It seems likely that such patients have been underrecognized, because these antibodies are usually not sought in the absence of obvious myositis. We now describe 10 patients with antisynthetase antibodies whose clinical picture was dominated by ILD in the absence of clinically evident myositis, despite follow-up for as long as 13.5 years. The pulmonary abnormalities associated with antisynthetase antibodies appear, in many instances, to be responsive to corticosteroid or immunosuppressive therapy. 2,17,24Most patients with ILD in this study responded well to therapy, thus underscoring the importance of recognizing this autoimmune syndrome promptly even when myositis is absent. PATIENTS AND METHODS
Patients Sera from all 170 patients referred to the Rheumatology Service of the University of Texas-Houston Health Science Center between 1985 and 1994 who had or were given a clinical diagnosis of polymyositis or dermatomyositis, all of whom satisfied the criteria of Bohan and
Peter, 25were tested for myositis-specific autoantibodies, including testing for all five known antisynthetases. In addition, sera from all 26 patients with interstitial lung disease and a positive indirect immunoftuorescence test for antinuclear (ANA) or anticytoplasmic antibodies who could not be satisfactorily classified as having a connective tissue disease (rheumatoid arthritis, 26 scleroderma, 27 or systemic lupus erythematosus 28) were similarly studied. Patients with chest radiographs interpreted clinically as showing bilateral interstitial infiltrates with no identifiable infectious or occupational cause were considered to have pulmonary involvement. In those who could be tested, a carbon monoxide diffusing capacity or forced vital capacity less than 70% of predicted were considered to have pulmonary function evidence of restrictive lung disease. Myositis was considered clinically absent if there was no significant proximal muscle weakness by history and physical examination, and the serum creatine kinase (CK) was less than twice normal (normal range, 20 to 191 U/L).
Myositis Autoantibody Testing Sera were tested for antisynthetase autoantibodies by immunoprecipitation as previously described. 12,2z,23 Briefly, for nucleic acid analysis, 3 to 5 mg protein A-Sepharose was coated with 20 txL patient serum, washed, and incubated with extract of 106 HeLa cells. Immunoprecipitates were recovered by phenol extraction and analyzed by 8 mol/L urea 10% polyacrylamide gel electrophoresis (PAGE), developed with silver stain. For protein analysis, similarly coated beads were incubated with extract of 105 HeLa cells that had been labeled with 35S-methionine. Immunoprecipitates were recovered by heating in sample buffer and analyzed by 10% sodium dodecyl sulfate PAGE. Each serum was also tested by Ouchterlony immunodiffusion against calf thymus extract, which was helpful for confirmation of anti-Jo-1 and anti-PL-7 (other anti-synthetases are not reliably detected by immunodiffusion). In addition, sera were tested by indirect immunofluorescence on HEp-2 cells using commercial slides (Antibodies Inc., Davis, CA) for autoantibody screening, by countercurrent immunoelectrophoresis for autoantibodies directed against
ILD AND ANTISYNTHE'I'ASES
Ro/SSA, La/SSB, U1RNP, and Sm,29 by passive immunodiffusion and immunoprecipitation for anti-topoisomerase I (Scl-70) and anti-PMScl antibodies and by indirect immunofluorescence using Crithidia luciliae as antigen substrate for anti-double-stranded DNA antibodies. 30 RESULTS
Among the 170 myositis patients studied over the interval 1985 to 1994, 45 (26%) had antisynthetase antibodies, of whom 35 (78%) also had interstitial lung disease. A total of 35 of the 51 patients (69%) with both myositis and ILD had an antisynthetase antibody. Further analyses of all of these myositis patients will be reported separately. Among the 26 patients with ILD and a positive ANA or anticytoplasmic antibodies but without clinical myositis, 10 (38%) had one of the antisynthetase antibodies (Table 1). Seven were women, and ethnic backgrounds were diverse. Eight of these had no sign of muscle abnormality. Two (patients 2 and 8) had lowlevel elevations of serum creatine kinase before initiation of corticosteroid therapy. None had proximal muscle weakness. Electromyography, performed in patients 4 and 5, was normal. Antibodies reacting with PL-12 were most common (6 of 10, 60%), followed by anti-Jo-1 and anti-OJ (2 of 10 each, 20%). All 10 patients had anticytoplasmic antibodies by indirect immunofluorescence on HEp-2 cells (example in Fig 1), and seven (70%) also had antinuclear reactivity, all at relatively low titer. No patient displayed anticentromere reactivity. Five (50%) had positive rheumatoid factor activity, three (30%) had anti-Ro/SSA antibodies, and one (10%) had anti-UIRNP. No patient had elevated levels of anti-double-stranded DNA, Sm, topoisomerase 1 (Scl-70), or PM-Scl antibodies. Five of the 10 patients presented with features of connective tissue disease, including arthritis, Raynaud's phenomenon, or vasculitis, prompting referral to the Rheumatology Service (Table 1). In contrast, the remaining five patients presented with problems related to interstitial lung disease, without clinical features of connective tissue disease, and came to the attention of the Rheumatology service only because of a positive test for ANA or rheuma-
461
toid factor. Two of these patients (numbers 4 and 8) presented with acute, rapidly progressive respiratory failure, two (numbers 2 and 5) with insidious onset of diminished exercise tolerance, and one (number 10) with a persistent nonproductive cough. Open lung biopsies were performed in five patients, and transbronchial biopsies were performed in two others (numbers 7 and 9). The biopsy specimen from patient 2 showed interstitial infiltrates with numerous lymphocytes and plasma cells. Patient 4 had pathological features consistent with bronchiolitis obliterans and organizing pneumonia in some areas, and diffuse interstitial pneumonitis in other areas. Patient 5 was given a pathological diagnosis of fibrosing alveolitis in Great Britain. Tissue specimens from patient 8 showed acute and chronic interstitial inflammation, and specimens from patient 10 showed diffuse interstitial infiltrates with abundant lymphocytes and plasma cells, multifocal lymphoid aggregates, and mild-tomoderate interstitial fibrosis. Transbronchial biopsy specimens from patients 7 and 9 showed focal interstitial fibrosis and isolated bronchial inflammation, respectively. In none of these lung biopsy specimens were granulomata seen, and all were negative by stains and culture for bacterial and fungal pathogens. The most frequent clinical manifestations in these patients, other than lung disease, were fever (5 of 10, 50%), leukocytoclastic vasculitis and other cutaneous lesions (4 of 10, 40%), Raynaud's phenomenon (3 of 10, 30%) and arthritis (2 of 10, 20%). The clinical courses of these patients were variable (Table 2). All but one received corticosteroids, four patients were also given oral cyclophosphamide; and two, azathioprine. The mean duration of follow-up was 3.7 years (range, 0.04 to 13.5 years). The pulmonary disease resolved or stabilized in four patients (40%), whereas in one (10%), it initially improved dramatically, but then progressively worsened despite treatment. Patients 2 and 7 improved dramatically with corticosteroid therapy, and have remained in complete remission for 3 and 9 years, respectively. Patient 5 had fibrosing alveolitis documented by open lung biopsy 13 years earlier, and had a complete remission after 2 years of therapy with prednisolone and azathioprine. He
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FRIEDMAN, TARGOFF, AND ARNE'FI-
Table 1: D e m o g r a p h i c , Clinical and Serologic Features of Patients W i t h A n t i s y n t h e t a s e A n t i b o d i e s and Interstitial Lung Disease Patient number Age (yr) Gender Ethnic group Mode of presentation
Reason for referral Interstitial lung disease Restrictive pattern ILD on open lung biopsy ILD on transbronchial biopsy Muscle disease Elevated CK (U/L) Abnormal EMG Other manifestations Arthritis Raynaud's phenomenon Other rash Fever Autoantibodies (reciprocal titers) RF ANA Cytoplasmic staining Anti-tRNA synthetase Ab Other auto-Ab
1 46 F Mexican Cutaneous vasculitis, Raynaud's, dyspnea, sclerodactyly, fever CTD
2 36 M White DOE, cough
3 60 F White Cutaneous vasculitis, Raynaud's, LR
4 30 F Black RFRMV
5 29 M White DOE
ILD, + A N A
CTD
ILD, + A N A
ILD, +ANA, +RF
4NA
+ +
4-
4-
+
NA
+
+
NA
NA
NA
318 NA
+
-
m
NA m
m
4-
V -
-
V, DL, LR -
+
80 +
320 +
+
80 160 +
640 40 +
PL-12
OJ
PL-12
Jo-1
Jo-1
Ro/SSA
Ro/SSA
Ro/SSA
-
m
Abbreviations: F, female; M, male; DOE, dyspnea on exertion; RFRMV, respiratory failure requiring mechanical ventilation; LR, livedo reticularis; GN, glomerulonephritis; CTD, connective tissue disease; ILD, interstitial lung disease; ANA, antinuclear antibody; RF, rheumatoid factor; NA, information not available; CK, creatine kinase level (normal range, 20 to 191 U/L); EMG, electromyogram; V, cutaneous leukocytoclastic vasculitis; DL, discoid lupus; LE, photosensitive rash attributed to lupus; MH, mechanic's hands; Ab, antibody.
remained in remission for another 10 years before he noticed a decline in exercise tolerance and sought medical attention. He improved dramatically with reinstitution of prednisolone and azathioprine, and has continued to do well for the past year. Patient 4 was ventilator dependent and had failed to respond to highdose corticosteroids (including 1,000 mg methylprednisolone "pulses") over a 3-week period. Oral cyclophosphamide was added, and within 2 weeks, she was able to be weaned off mechani-
cal ventilatory support and eventually resumed a relatively normal activity level at home. She relapsed after 6 months of combination therapy, coincident with an aggressive taper of the corticosteroid component. Patient 3 stabilized with corticosteroid therapy, and patient number 10 has not yet received any immunomodulatory therapy. In contrast, lung disease progressed steadily in three patients (30%) despite corticosteroid or cytotoxic therapy, eventually resulting in the
ILD AND ANTISYNTHETASES
463
Table 1 : Demographic, Clinical and Serologic Features of Patients With Antisynthetase Antibodies and Interstitial Lung Disease (Cont'd) 6
7
8
9
10
47
50
26
38
47
F
F
F
F
M
Black
Black
Black
Mexican
Black
Fever, myalgias,
Arthritis, sicca, GN,
RFRMV
Fever, oral ulcers,
Cough
arthritis
CTD
DOE
c u t a n e o u s vasculitis
CTD
ILD,+ANA
CTD
ILD,+RF
+
+
NA
+
-
NA
NA
+
NA
+
NA
+
+
-
-
204
-
-
NA
NA
NA
NA
NA
+
+
-
_
_
_
_
+
LE
-
-
V
MH
+
-
+
+
-
-
640
-
-
320
40
-
40
80
320
+
+
+
+
+
PL-12
OJ
PL-]2
PL-]2
PL-12
U1RNP
.
.
death of two (numbers 6 and 8). Patient number 8 was ventilator dependent and progressed to death within 2 weeks of diagnosis, whereas patients 6 and 9 progressed slowly despite immunosuppressive therapy. One patient was lost to follow-up after initial evaluation in the hospital. DISCUSSION
Antisynthetase autoantibodies have generally been found in patients with polymyositis and dermatomyositis, particularly in those patients with associated ILD. This large series of 170 myositis patients confirms the association of antisynthetase antibodies with complicating
.
.
ILD. In addition, it documents that some patients with ILD but without clinical myositis have these "myositis-specific" autoantibodies. A few patients with antisynthetase antibodies and interstitial lung disease in the absence of clinical myositis have been reported previously, 14'17'22'23 including 3 of the 10 patients in the current series (patients 2, 6, and 7). The frequency of antisynthetase antibodies among patients considered to have idiopathic interstitial lung disease is unclear. In one previous study, sera from 15 such patients were negative for anti-Jo-1 activity by passive immunodiffusion and countercurrent immunoelectrophoresis. 31 Although that study did not find any
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FRIEDMAN, TARGOFF, AND ARNETT
Fig 1. Indirect immunofluorescence of serum from patient number 10 on HEp-2 cells, HEp-2 cells demonstrate intense cytoplasmic staining (arrow). The nuclei (left of arrow) are also positively stained in this preparation (positive ANA). The dark intranuclear structures represent nucleoli. (Original magnification 4O0x.)
these earlierStudies had anti-synthetase antibodies other than anti-Jo-1. A prospective evaluation of patients with idiopathic interstitial lung disease is therefore necessary to establish the true frequency of the antisynthetase syndrome as a cause of "idiopathic" interstitial pulmonary disease. In our study, we were referred only a comparatively small group of patients with ILD alone, which was probably highly selected. Despite follow-up for a mean duration of 3.7 years (including eight patients with at least 1
precipitin lines, the non-Jo-1 antisynthetases, which were most common in our series, were not specifically sought, and may go undetected using those techniques. Another study examined 62 patients with cryptogenic pulmonary fibrosis and found two with anti-Jo-1, using countercurrent immunoelectrophoresis and confirmation by immunoprecipitation. 14Anti-EJ and anti-OJ are usually not detected by immunoelectrophoresis, and anti-PL-12 also may be missed. It is possible, then, that some of the patients in
Table 2: Clinical Course of Patients With Antisynthetase Antibodies and Interstitial Lung Disease Patient no. 1 Duration of 0.04 followup (yr) Treatment(s) Pred, Ctx Outcome Current Unknown status ILD Unknown
Abbreviations:
2 3.5
3 3.5
4 1.25
5 13.5
6 1.5
7 9.5
8 0.04
9 3
10 1
Pred
Pred
Pred, Ctx
Pred, Aza
Pred
Pred, Aza
Pred
Pred, Ctx
None
Living
Living
Living
Living
Deceased Living
Deceased Living
Living
Resolv- Stabiliz- Improved Improved Progresed ed x 6 x 11 sed months, years, then prothen progressed gressed. Improved after restarting Pred & Aza
Resolv- Progresed sed
Pred, predisone; Ctx, oral cyclophosphamide; Aza, azathioprine; ILD, interstitial tung disease.
Progres- Stable sed
ILD AND ANTISYNTHETASES
year of follow-up), none of our patients with ILD and antisynthetase antibodies developed evidence of inflammatory muscle disease. Because this was a retrospective study, the patients were not systematically evaluated for chemical, electromyographic, or histologic evidence of myositis. In the absence of muscle weakness or an elevated serum CK, invasive testing would be difficult to justify. Even if all 10 patients had positive electromyographic and histologic studies, only patients 2 and 8 would meet the criteria of Bohan and Peter. 25 Three patients had been treated with corticosteroids before evaluation for myositis, and 9 of 10 patients were treated with corticosteroids after the diagnosis of autoimmune lung disease was established. As such, it is possible that myositis was prevented, or sufficiently pharmacologically suppressed so as to escape detection. Thus, the aim of this study was to confirm the association of antisynthetase antibodies and ILD in the absence of clinically apparent myositis, not to determine whether muscle iinflammation always occurs in association with antisynthetases. If even subtle muscle inflammation could be confidently excluded by all available means, it would suggest that these autoantibodies do not specifically participate in muscle injury, nor are they produced as a reaction to muscle injury. A generalized reaction to muscle injury seems unlikely, because only 25% to 40% of patients with known inflammatory myopathies make anti-synthetase autoantibodies. With the notable exception of myositis, the other clinical features of our patients with ILD are generally comparable to those in patients with antisynthetase antibodies in most series described previously. Marguerie et a117 found Raynaud's phenomenon in 27 of 29 patients with antJisynthetases, as well as high frequencies of sclerodactyly (21 of 29) and calcinosis (7 of 29). Only one of our patients (patient 1) had this scleroderma-like picture, including Raynaud's phenomenon, sclerodactyly, and lung disease. Other U.S. series have also failed to find a high frequency of scleroderma overlap in patients with antisynthetases. 2,23,3z The initial disease presentation in our patients included five with obvious systemic connective tissue disease, two with rapidly progressive respiratory failure, two with only mild
465
dyspnea on exertion, and one with a persistent nonproductive cough. Most (3 of 5) of the patients with apparent connective tissue disease had not noticed any pulmonary symptoms initially, and the diagnosis of interstitial lung disease was made after auscultation showed crackles over the lung fields. This wide variation in severity of antisynthetase-associated lung involvement also has been observed in patients with antisynthetase-associated myositis with pulmonary disease. 16Thus, the lung involvement in the antisynthetase syndrome should be viewed as a clinical spectrum ranging from an acute, life-threatening pulmonary presentation to a slowly progressive lung disease with or without other features of a connective tissue disease. The resolution or stabilization of pulmonary disease seen in four of our patients is noteworthy, particularly when compared with the prognosis of most cases of idiopathic 1LD. A potential favorable response to corticosteroid or other immunosuppressive therapy can be expected in many patients with ILD and an antisynthetase antibody, but early diagnosis is critical, presumably because of a reversible inflammatory component. Marguerie et a117 noticed a similar trend of clinical improvement in lung disease in four of seven patients treated with corticosteroids and cyclophosphamide. We are unable, however, to determine in this small series whether specific antisynthetase antibodies, such as anti-PL-12, are associated with a more severe clinical course or worse prognosis. It may be of note that anti-Jo-1 was found in only 2 of 10 patients in this series, but is by far the most common antisynthetase antibody among myositis patients. Because of the small number of patients with non-Jo-1 antisynthetases thus far reported, the significance of differences observed between the clinical pictures associated with different antisynthetases is difficult to evaluate. However, previous studies, which included some of the patients in this series, have suggested that anti-PL-12 and anti-OJ are more commonly found in the absence of myositis than is anti-Jo-1. 22,23 The current study supports those observations and suggests that anti-PL-12 may be less specific for myositis than anti-Jo-1. However, the specificity of all anti-synthetases for a condition, especially
466
FRIEDMAN, TARGOFF, AND ARNETT
lung disease, within this spectrum of inflammatory myopathies appears to be extremely high. An additional factor in the high frequency of anti-PL-12 among this group of patients may be an increased frequency of anti-PL-12 among myositis patients in the geographic area of this study. Even when only patients satisfying criteria for myositis are considered, anti-PL-12 appears to be more common in the southwest than in the northern and eastern regions of the United States. 33 The high frequency of antiPL-12 is particularly striking when compared with anti-PL-7, an antisynthetase that is very rare in the Houston myositis population, but comparable in frequency to anti-PL-12 in other studies.2,3j7,23 Some laboratories do not routinely report cytoplasmic fluorescence on ANA testing and,
occasionally, anti-Jo-l-positive sera are truly negative for cytoplasmic fluorescence. However, it seems prudent to screen patients with ILD, either as an isolated problem or in conjunction with other signs or symptoms of connective tissue disease, with an indirect immunofluorescence test for antinuclear antibodies (ANA), using HEp-2 cells as tissue substrate. If immunofluorescence shows a cytoplasmic pattern (with or without nuclear fluorescence), a search for antiaminoacyl-tRNA synthetase antibodies is suggested. ACKNOWLEDGMENTS The authors thank Margaret Dougherty, Grace L. Griffin, and Leigh Anne Mason for technical assistance in preparing the manuscript and tables.
REFERENCES 1. Targoff IN: Immune manifestations of inflammatory muscle disease. Rheum Dis Clin North Am 20:857-880, 1994 2. Love LA, Left RL, Fraser DD, et al: A new approach to the classification of idiopathic inflammatory myopathy: Myositis-specific autoantibodies define useful homogeneous patient groups. Medicine 70:360-374, 1991 3. Bernstein RM, Bunn CC, Hughes GRV, et al: Cellular protein and RNA antigens in autoimmune disease. Mol Biol Med 2:105-120, 1984 4. Nishikai M, Reichlin M: Heterogeneity of precipitating antibodies in polymyositis and dermatomyositis: Characterization of the Jo-1 antibody system. Arthritis Rheum 23:881-888, 1980 5. Mathews MB, Bernstein RM: Myositis autoantibody inhibits histidyl-tRNA synthetase: A model for autoimmunity. Nature 304:177-179, 1983 6. Yang DCH, Dang CV, Arnett FC: Rat liver histidyltRNA synthetase: Purification and inhibition by the myositisspecific anti-Jo-1 autoantibody. Biochem Biophys Res Commun 120:15-21, 1984 7. Arnett FC, Hirsch TJ, Bias WB, et al: The Jo-1 antibody system in myositis: Relationships to clinical features and HLA. J Rheumatol 8:925-930, 1981 8. Hochberg MC, Feldman D, Stevens MB, et al: Antibody to Jo-1 in polymyositis/dermatomyositis: Association with interstitial pulmonary disease. J Rheumatol 11:663665, 1984 9. Targoff IN, Reichlin M: Measurement of antibody to Jo-1 by ELISA and comparison to enzyme inhibitory activity. J Immunol 138:2874-2882, 1987 10. Mathews MB, Reichlin M, Hughes GR, et al: Antithreonyl tRNA synthetase: A second myositis-related autoantibody. J Exp Med 160:420-434, 1984 11. Bunn CC, Bernstein RM, Mathews MB: Autoantibodies against alanyl-tRNA synthetase and tRNA (ALA)
coexist and are associated with myositis. J Exp Med 163:12811291, 1986 12. Targoff IN: Autoantibodies to aminoacyl-transfer RNA synthesases for isoleucine and glycine: Two additional synthetases are antigenic in myositis. J Immunol 144:17371743, 1990 13. Yoshida S, Akizuki M, Mimori T, et al: The precipitating antibody to an acidic nuclear protein antigen, the Jo-1, in connective tissue diseases: A marker for a subset of polymyositis with interstitial pulmonary fibrosis. Arthritis Rheum 26:604-611, 1983 14. Bernstein RM, Morgan SH, Chapman J, et al: AntiJo-1 antibody: A marker for myositis with interstitial lung disease. Br Med J 289:151-152, 1984 15. Hirakata M, Mimori T, Azizuki M, et al: Autoantibodies to small nuclear and cytoplasmic ribonucleoproteins in Japanese patients with inflammatory muscle disease. Arthritis Rheum 35:449-456, 1992 16. Targoff IN: The inflammatory muscle diseases, in Cannon GW, Zimmerman GA (eds): The Lung in Rheumatic Diseases. New York, Marcel Dekker, 1990, pp 303328 17. Marguerie C, Bunn CC, Beynon HLC, et al: Polymyositis, pulmonary fibrosis and autoantibodies to aminoacyltRNA synthetase enzymes. Q J Med 77:1019-1038, 1990 18. Clawson K, Oddis CV: Adult respiratory distress syndrome (ARDS) in myositis patients with anti-Jo-1 antibody. Arthritis Rheum 36:$256, 1993 19. Stahl NI, Klippel JH, Decker JL: A cutaneous lesion associated with myositis. Ann Intern Med 91:577-579, 1979 20. Targoff IN, Trieu EP, Plotz PH, et al: Antibodies to glycyl-transfer RNA synthetase in patients with myositis and interstitial lung disease. Arthritis Rheum 35:821-830, 1992 21. Miller FW: Myositis-specific autoantibodies: Touchstones for understanding the inflammatory myopathies. JAMA 270:1846-1849, 1994
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22. TargoffIN, Trieu EP, Miller FW: Reaction of anti-OJ autoantibodies with components of the multi-enzyme complex of anainoacyl-tRNA synthetases in addition to isoleucyltRNA synthetase. J Clin Invest 91:2556-2564, 1993 23. Targoff IN, Arnett FC: Clinical manifestations in patients with antibody to PL-12 antigen (alanyl-tRNA synthetase). Am J Med 88:241-251, 1990 24. AI-Janadi M, Smith CD, Karsh J: Cyclophosphamide treatment of interstitial pulmonary fibrosis in polymyositis/ dermatomyositis. J Rheumatol 16:1592-1596, 1989 25. Bohan A, Peter JB: Polymyositis and dermatomyositis (parts 1 and 2). N Engl J Med 292:344-347, 403-407, 1975 26. Arnett FC, Edworthy SM, Bloch DA, et al: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315-324, 1988 27. Masi AT, Rodnan GP, Medsger TA Jr, et al: Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 23:581-590, 1980 28. Tan EM, Cohen AS, Fries JF, et al: The 1982 revised
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criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271, 1982 29. Johnson CD, Edmonds JP, Holborow E J: Precipitating antibody to DNA detected by two-stage electroimmunodiffusion. Lancet II:883-886, 1973 30. Aarden LA, De Groot ER, Feltkamp TEW: Immunology of DNA. III. Crithidia luciliae, a simple substrate for the determination of anti-dsDNA with the immunofluorescence technique. Ann NY Acad Sci 254:505-515, 1975 31. Wasicek CA, Reichlin M, Montes M, et al: Polymyositis and interstitial lung disease in a patient with anti-Jo-1 prototype. Am J Med 76:538-544, 1984 32. Oddis CV, Medsger TA Jr, Cooperstein LA: A subluxing arthropathy associated with the anti-Jo-1 antibody in polymyositis/dermatomyositis. Arthritis Rheum 33:1640-1645, 1990 33. Love LA, Burgess SH, Hill PC, et al: Geographical and seasonal clustering in the onset of idiopathic inflammatory myopathy (IIM) in groups defined by myositis-specific autoantibodies (MSA). Arthritis Rheum 35:$40, 1992
UTOANTIBODIES reacting with aminoacyl-tRNA synthetases occur in the sera of 25% to 40% of adult patients with the idiopathic inflammatory myopathies, polymyositis and dermatomyositis, a-3 Anti-Jo-1 (antihistidyltRNA synthetase) was the first of these "antisynthetases" to be discovered 4-6 and is detectable in approximately 15% to 30% of myositis patients overall, more commonly in polymyositis than in dermatomyositis. 2,7-9Additional but less common antisynthetases were subsequently discovered more often in patients with dermatomyositis, and include: anti-PL-7 (antithreonyl-tRNA synthetase), anti-PL-12 (antialanyl-tRNA synthetase), anti-OJ (anti-isoleucyl-tRNA synthetase), and anti-EJ (antiglycyl-tRNA synthetase).I°-12 Individual patients usually produce only one of these autoantibodies, but, when present, they are usually considered highly specific for an inflammatory myopa-
A
thy.l-3,9-12
From the Division of Rheumatology and Clinical lmmunogenetics, Department of Internal Medicine, University of TexasHouston Health Science Center, Houston, TX, and the Department of Medicine, University of Oklahoma Health Sciences Center, Veterans Affairs Medical Center, and Oklahoma Medical Research Foundation, Oklahoma City, OK. Alan W. Friedman, MD: Assistant Professor of Medicine, Division of Rheumatology and Clinical Immunogenetics, Department of Internal Medicine, University of Texas-Houston Health Science Center, Houston, TX; Ira N. Targoff, MD: Associate Professor of Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Veterans Affairs Medical Center, and Oklahoma Medical Research Foundation, Oklahoma City, OK; Frank C. Arnett, MD: Professor of Medicine, Division of Rheumatology and Clinical Immunogenetics, Department of Internal Medicine, University of Texas-Houston Health Science Center, Houston, TX. Supported by a grant from the Muscular Dystrophy Association, and the George S. Bruce, Jr., Professorship in Arthritis and Other Rheumatic Diseases (Dr. Arnett); and NIH grants no. AR32214 and no. AI27181 and Department of Veterans Affairs Medical Research Funds (Dr. Targoff). Address reprint requests to Alan W. Friedman, MD, University of Texas-Houston Health Science Center, 6431 Fannin, MSB 5.270, Houston, TX77030. Copyright © 1996 by W.B. Saunders Company 0049-0172/96/2601-000355.00/0
Seminars in Arthritis and Rheumatism, Vo126, No 1 (August), 1996: pp 459-467
459
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FRIEDMAN, TARGOFF, AND ARNETT
Myositis patients with any of the antisynthetases also have a high frequency of interstitial lung disease (ILD), 2,8,13-17 and 68% to 89% of patients with both myositis and ILD have anti-synthetases. 2,14The prognosis for survival in patients with antisynthetases is poorer than that of other myositis patients, in part because of the lung disease, which may be severe, including a fulminant picture resembling the adult respiratory distress syndrome. 2'16'18 Several other clinical features besides lung involvement are more common among myositis patients with antisynthetases compared with their counterparts without antisynthetases, including inflammatory arthritis (usually nonerosive), Raynaud's phenomenon, fever, and a hyperkeratotic lesion of the fingers ("mechanic's hands"). 2,19 This clinical picture has been referred to as the "anti-synthetase syndrome. ''a,2,2°,21 Because individual patients may not demonstrate all of these clinical features, it can be difficult to recognize the syndrome before obtaining a positive test for one of the defining antisynthetase autoantibodies. Occasionally, patients with ILD and antisynthetase antibodies but without overt myositis have been noted. 14,17,22,23 It seems likely that such patients have been underrecognized, because these antibodies are usually not sought in the absence of obvious myositis. We now describe 10 patients with antisynthetase antibodies whose clinical picture was dominated by ILD in the absence of clinically evident myositis, despite follow-up for as long as 13.5 years. The pulmonary abnormalities associated with antisynthetase antibodies appear, in many instances, to be responsive to corticosteroid or immunosuppressive therapy. 2,17,24Most patients with ILD in this study responded well to therapy, thus underscoring the importance of recognizing this autoimmune syndrome promptly even when myositis is absent. PATIENTS AND METHODS
Patients Sera from all 170 patients referred to the Rheumatology Service of the University of Texas-Houston Health Science Center between 1985 and 1994 who had or were given a clinical diagnosis of polymyositis or dermatomyositis, all of whom satisfied the criteria of Bohan and
Peter, 25were tested for myositis-specific autoantibodies, including testing for all five known antisynthetases. In addition, sera from all 26 patients with interstitial lung disease and a positive indirect immunoftuorescence test for antinuclear (ANA) or anticytoplasmic antibodies who could not be satisfactorily classified as having a connective tissue disease (rheumatoid arthritis, 26 scleroderma, 27 or systemic lupus erythematosus 28) were similarly studied. Patients with chest radiographs interpreted clinically as showing bilateral interstitial infiltrates with no identifiable infectious or occupational cause were considered to have pulmonary involvement. In those who could be tested, a carbon monoxide diffusing capacity or forced vital capacity less than 70% of predicted were considered to have pulmonary function evidence of restrictive lung disease. Myositis was considered clinically absent if there was no significant proximal muscle weakness by history and physical examination, and the serum creatine kinase (CK) was less than twice normal (normal range, 20 to 191 U/L).
Myositis Autoantibody Testing Sera were tested for antisynthetase autoantibodies by immunoprecipitation as previously described. 12,2z,23 Briefly, for nucleic acid analysis, 3 to 5 mg protein A-Sepharose was coated with 20 txL patient serum, washed, and incubated with extract of 106 HeLa cells. Immunoprecipitates were recovered by phenol extraction and analyzed by 8 mol/L urea 10% polyacrylamide gel electrophoresis (PAGE), developed with silver stain. For protein analysis, similarly coated beads were incubated with extract of 105 HeLa cells that had been labeled with 35S-methionine. Immunoprecipitates were recovered by heating in sample buffer and analyzed by 10% sodium dodecyl sulfate PAGE. Each serum was also tested by Ouchterlony immunodiffusion against calf thymus extract, which was helpful for confirmation of anti-Jo-1 and anti-PL-7 (other anti-synthetases are not reliably detected by immunodiffusion). In addition, sera were tested by indirect immunofluorescence on HEp-2 cells using commercial slides (Antibodies Inc., Davis, CA) for autoantibody screening, by countercurrent immunoelectrophoresis for autoantibodies directed against
ILD AND ANTISYNTHE'I'ASES
Ro/SSA, La/SSB, U1RNP, and Sm,29 by passive immunodiffusion and immunoprecipitation for anti-topoisomerase I (Scl-70) and anti-PMScl antibodies and by indirect immunofluorescence using Crithidia luciliae as antigen substrate for anti-double-stranded DNA antibodies. 30 RESULTS
Among the 170 myositis patients studied over the interval 1985 to 1994, 45 (26%) had antisynthetase antibodies, of whom 35 (78%) also had interstitial lung disease. A total of 35 of the 51 patients (69%) with both myositis and ILD had an antisynthetase antibody. Further analyses of all of these myositis patients will be reported separately. Among the 26 patients with ILD and a positive ANA or anticytoplasmic antibodies but without clinical myositis, 10 (38%) had one of the antisynthetase antibodies (Table 1). Seven were women, and ethnic backgrounds were diverse. Eight of these had no sign of muscle abnormality. Two (patients 2 and 8) had lowlevel elevations of serum creatine kinase before initiation of corticosteroid therapy. None had proximal muscle weakness. Electromyography, performed in patients 4 and 5, was normal. Antibodies reacting with PL-12 were most common (6 of 10, 60%), followed by anti-Jo-1 and anti-OJ (2 of 10 each, 20%). All 10 patients had anticytoplasmic antibodies by indirect immunofluorescence on HEp-2 cells (example in Fig 1), and seven (70%) also had antinuclear reactivity, all at relatively low titer. No patient displayed anticentromere reactivity. Five (50%) had positive rheumatoid factor activity, three (30%) had anti-Ro/SSA antibodies, and one (10%) had anti-UIRNP. No patient had elevated levels of anti-double-stranded DNA, Sm, topoisomerase 1 (Scl-70), or PM-Scl antibodies. Five of the 10 patients presented with features of connective tissue disease, including arthritis, Raynaud's phenomenon, or vasculitis, prompting referral to the Rheumatology Service (Table 1). In contrast, the remaining five patients presented with problems related to interstitial lung disease, without clinical features of connective tissue disease, and came to the attention of the Rheumatology service only because of a positive test for ANA or rheuma-
461
toid factor. Two of these patients (numbers 4 and 8) presented with acute, rapidly progressive respiratory failure, two (numbers 2 and 5) with insidious onset of diminished exercise tolerance, and one (number 10) with a persistent nonproductive cough. Open lung biopsies were performed in five patients, and transbronchial biopsies were performed in two others (numbers 7 and 9). The biopsy specimen from patient 2 showed interstitial infiltrates with numerous lymphocytes and plasma cells. Patient 4 had pathological features consistent with bronchiolitis obliterans and organizing pneumonia in some areas, and diffuse interstitial pneumonitis in other areas. Patient 5 was given a pathological diagnosis of fibrosing alveolitis in Great Britain. Tissue specimens from patient 8 showed acute and chronic interstitial inflammation, and specimens from patient 10 showed diffuse interstitial infiltrates with abundant lymphocytes and plasma cells, multifocal lymphoid aggregates, and mild-tomoderate interstitial fibrosis. Transbronchial biopsy specimens from patients 7 and 9 showed focal interstitial fibrosis and isolated bronchial inflammation, respectively. In none of these lung biopsy specimens were granulomata seen, and all were negative by stains and culture for bacterial and fungal pathogens. The most frequent clinical manifestations in these patients, other than lung disease, were fever (5 of 10, 50%), leukocytoclastic vasculitis and other cutaneous lesions (4 of 10, 40%), Raynaud's phenomenon (3 of 10, 30%) and arthritis (2 of 10, 20%). The clinical courses of these patients were variable (Table 2). All but one received corticosteroids, four patients were also given oral cyclophosphamide; and two, azathioprine. The mean duration of follow-up was 3.7 years (range, 0.04 to 13.5 years). The pulmonary disease resolved or stabilized in four patients (40%), whereas in one (10%), it initially improved dramatically, but then progressively worsened despite treatment. Patients 2 and 7 improved dramatically with corticosteroid therapy, and have remained in complete remission for 3 and 9 years, respectively. Patient 5 had fibrosing alveolitis documented by open lung biopsy 13 years earlier, and had a complete remission after 2 years of therapy with prednisolone and azathioprine. He
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FRIEDMAN, TARGOFF, AND ARNE'FI-
Table 1: D e m o g r a p h i c , Clinical and Serologic Features of Patients W i t h A n t i s y n t h e t a s e A n t i b o d i e s and Interstitial Lung Disease Patient number Age (yr) Gender Ethnic group Mode of presentation
Reason for referral Interstitial lung disease Restrictive pattern ILD on open lung biopsy ILD on transbronchial biopsy Muscle disease Elevated CK (U/L) Abnormal EMG Other manifestations Arthritis Raynaud's phenomenon Other rash Fever Autoantibodies (reciprocal titers) RF ANA Cytoplasmic staining Anti-tRNA synthetase Ab Other auto-Ab
1 46 F Mexican Cutaneous vasculitis, Raynaud's, dyspnea, sclerodactyly, fever CTD
2 36 M White DOE, cough
3 60 F White Cutaneous vasculitis, Raynaud's, LR
4 30 F Black RFRMV
5 29 M White DOE
ILD, + A N A
CTD
ILD, + A N A
ILD, +ANA, +RF
4NA
+ +
4-
4-
+
NA
+
+
NA
NA
NA
318 NA
+
-
m
NA m
m
4-
V -
-
V, DL, LR -
+
80 +
320 +
+
80 160 +
640 40 +
PL-12
OJ
PL-12
Jo-1
Jo-1
Ro/SSA
Ro/SSA
Ro/SSA
-
m
Abbreviations: F, female; M, male; DOE, dyspnea on exertion; RFRMV, respiratory failure requiring mechanical ventilation; LR, livedo reticularis; GN, glomerulonephritis; CTD, connective tissue disease; ILD, interstitial lung disease; ANA, antinuclear antibody; RF, rheumatoid factor; NA, information not available; CK, creatine kinase level (normal range, 20 to 191 U/L); EMG, electromyogram; V, cutaneous leukocytoclastic vasculitis; DL, discoid lupus; LE, photosensitive rash attributed to lupus; MH, mechanic's hands; Ab, antibody.
remained in remission for another 10 years before he noticed a decline in exercise tolerance and sought medical attention. He improved dramatically with reinstitution of prednisolone and azathioprine, and has continued to do well for the past year. Patient 4 was ventilator dependent and had failed to respond to highdose corticosteroids (including 1,000 mg methylprednisolone "pulses") over a 3-week period. Oral cyclophosphamide was added, and within 2 weeks, she was able to be weaned off mechani-
cal ventilatory support and eventually resumed a relatively normal activity level at home. She relapsed after 6 months of combination therapy, coincident with an aggressive taper of the corticosteroid component. Patient 3 stabilized with corticosteroid therapy, and patient number 10 has not yet received any immunomodulatory therapy. In contrast, lung disease progressed steadily in three patients (30%) despite corticosteroid or cytotoxic therapy, eventually resulting in the
ILD AND ANTISYNTHETASES
463
Table 1 : Demographic, Clinical and Serologic Features of Patients With Antisynthetase Antibodies and Interstitial Lung Disease (Cont'd) 6
7
8
9
10
47
50
26
38
47
F
F
F
F
M
Black
Black
Black
Mexican
Black
Fever, myalgias,
Arthritis, sicca, GN,
RFRMV
Fever, oral ulcers,
Cough
arthritis
CTD
DOE
c u t a n e o u s vasculitis
CTD
ILD,+ANA
CTD
ILD,+RF
+
+
NA
+
-
NA
NA
+
NA
+
NA
+
+
-
-
204
-
-
NA
NA
NA
NA
NA
+
+
-
_
_
_
_
+
LE
-
-
V
MH
+
-
+
+
-
-
640
-
-
320
40
-
40
80
320
+
+
+
+
+
PL-12
OJ
PL-]2
PL-]2
PL-12
U1RNP
.
.
death of two (numbers 6 and 8). Patient number 8 was ventilator dependent and progressed to death within 2 weeks of diagnosis, whereas patients 6 and 9 progressed slowly despite immunosuppressive therapy. One patient was lost to follow-up after initial evaluation in the hospital. DISCUSSION
Antisynthetase autoantibodies have generally been found in patients with polymyositis and dermatomyositis, particularly in those patients with associated ILD. This large series of 170 myositis patients confirms the association of antisynthetase antibodies with complicating
.
.
ILD. In addition, it documents that some patients with ILD but without clinical myositis have these "myositis-specific" autoantibodies. A few patients with antisynthetase antibodies and interstitial lung disease in the absence of clinical myositis have been reported previously, 14'17'22'23 including 3 of the 10 patients in the current series (patients 2, 6, and 7). The frequency of antisynthetase antibodies among patients considered to have idiopathic interstitial lung disease is unclear. In one previous study, sera from 15 such patients were negative for anti-Jo-1 activity by passive immunodiffusion and countercurrent immunoelectrophoresis. 31 Although that study did not find any
464
FRIEDMAN, TARGOFF, AND ARNETT
Fig 1. Indirect immunofluorescence of serum from patient number 10 on HEp-2 cells, HEp-2 cells demonstrate intense cytoplasmic staining (arrow). The nuclei (left of arrow) are also positively stained in this preparation (positive ANA). The dark intranuclear structures represent nucleoli. (Original magnification 4O0x.)
these earlierStudies had anti-synthetase antibodies other than anti-Jo-1. A prospective evaluation of patients with idiopathic interstitial lung disease is therefore necessary to establish the true frequency of the antisynthetase syndrome as a cause of "idiopathic" interstitial pulmonary disease. In our study, we were referred only a comparatively small group of patients with ILD alone, which was probably highly selected. Despite follow-up for a mean duration of 3.7 years (including eight patients with at least 1
precipitin lines, the non-Jo-1 antisynthetases, which were most common in our series, were not specifically sought, and may go undetected using those techniques. Another study examined 62 patients with cryptogenic pulmonary fibrosis and found two with anti-Jo-1, using countercurrent immunoelectrophoresis and confirmation by immunoprecipitation. 14Anti-EJ and anti-OJ are usually not detected by immunoelectrophoresis, and anti-PL-12 also may be missed. It is possible, then, that some of the patients in
Table 2: Clinical Course of Patients With Antisynthetase Antibodies and Interstitial Lung Disease Patient no. 1 Duration of 0.04 followup (yr) Treatment(s) Pred, Ctx Outcome Current Unknown status ILD Unknown
Abbreviations:
2 3.5
3 3.5
4 1.25
5 13.5
6 1.5
7 9.5
8 0.04
9 3
10 1
Pred
Pred
Pred, Ctx
Pred, Aza
Pred
Pred, Aza
Pred
Pred, Ctx
None
Living
Living
Living
Living
Deceased Living
Deceased Living
Living
Resolv- Stabiliz- Improved Improved Progresed ed x 6 x 11 sed months, years, then prothen progressed gressed. Improved after restarting Pred & Aza
Resolv- Progresed sed
Pred, predisone; Ctx, oral cyclophosphamide; Aza, azathioprine; ILD, interstitial tung disease.
Progres- Stable sed
ILD AND ANTISYNTHETASES
year of follow-up), none of our patients with ILD and antisynthetase antibodies developed evidence of inflammatory muscle disease. Because this was a retrospective study, the patients were not systematically evaluated for chemical, electromyographic, or histologic evidence of myositis. In the absence of muscle weakness or an elevated serum CK, invasive testing would be difficult to justify. Even if all 10 patients had positive electromyographic and histologic studies, only patients 2 and 8 would meet the criteria of Bohan and Peter. 25 Three patients had been treated with corticosteroids before evaluation for myositis, and 9 of 10 patients were treated with corticosteroids after the diagnosis of autoimmune lung disease was established. As such, it is possible that myositis was prevented, or sufficiently pharmacologically suppressed so as to escape detection. Thus, the aim of this study was to confirm the association of antisynthetase antibodies and ILD in the absence of clinically apparent myositis, not to determine whether muscle iinflammation always occurs in association with antisynthetases. If even subtle muscle inflammation could be confidently excluded by all available means, it would suggest that these autoantibodies do not specifically participate in muscle injury, nor are they produced as a reaction to muscle injury. A generalized reaction to muscle injury seems unlikely, because only 25% to 40% of patients with known inflammatory myopathies make anti-synthetase autoantibodies. With the notable exception of myositis, the other clinical features of our patients with ILD are generally comparable to those in patients with antisynthetase antibodies in most series described previously. Marguerie et a117 found Raynaud's phenomenon in 27 of 29 patients with antJisynthetases, as well as high frequencies of sclerodactyly (21 of 29) and calcinosis (7 of 29). Only one of our patients (patient 1) had this scleroderma-like picture, including Raynaud's phenomenon, sclerodactyly, and lung disease. Other U.S. series have also failed to find a high frequency of scleroderma overlap in patients with antisynthetases. 2,23,3z The initial disease presentation in our patients included five with obvious systemic connective tissue disease, two with rapidly progressive respiratory failure, two with only mild
465
dyspnea on exertion, and one with a persistent nonproductive cough. Most (3 of 5) of the patients with apparent connective tissue disease had not noticed any pulmonary symptoms initially, and the diagnosis of interstitial lung disease was made after auscultation showed crackles over the lung fields. This wide variation in severity of antisynthetase-associated lung involvement also has been observed in patients with antisynthetase-associated myositis with pulmonary disease. 16Thus, the lung involvement in the antisynthetase syndrome should be viewed as a clinical spectrum ranging from an acute, life-threatening pulmonary presentation to a slowly progressive lung disease with or without other features of a connective tissue disease. The resolution or stabilization of pulmonary disease seen in four of our patients is noteworthy, particularly when compared with the prognosis of most cases of idiopathic 1LD. A potential favorable response to corticosteroid or other immunosuppressive therapy can be expected in many patients with ILD and an antisynthetase antibody, but early diagnosis is critical, presumably because of a reversible inflammatory component. Marguerie et a117 noticed a similar trend of clinical improvement in lung disease in four of seven patients treated with corticosteroids and cyclophosphamide. We are unable, however, to determine in this small series whether specific antisynthetase antibodies, such as anti-PL-12, are associated with a more severe clinical course or worse prognosis. It may be of note that anti-Jo-1 was found in only 2 of 10 patients in this series, but is by far the most common antisynthetase antibody among myositis patients. Because of the small number of patients with non-Jo-1 antisynthetases thus far reported, the significance of differences observed between the clinical pictures associated with different antisynthetases is difficult to evaluate. However, previous studies, which included some of the patients in this series, have suggested that anti-PL-12 and anti-OJ are more commonly found in the absence of myositis than is anti-Jo-1. 22,23 The current study supports those observations and suggests that anti-PL-12 may be less specific for myositis than anti-Jo-1. However, the specificity of all anti-synthetases for a condition, especially
466
FRIEDMAN, TARGOFF, AND ARNETT
lung disease, within this spectrum of inflammatory myopathies appears to be extremely high. An additional factor in the high frequency of anti-PL-12 among this group of patients may be an increased frequency of anti-PL-12 among myositis patients in the geographic area of this study. Even when only patients satisfying criteria for myositis are considered, anti-PL-12 appears to be more common in the southwest than in the northern and eastern regions of the United States. 33 The high frequency of antiPL-12 is particularly striking when compared with anti-PL-7, an antisynthetase that is very rare in the Houston myositis population, but comparable in frequency to anti-PL-12 in other studies.2,3j7,23 Some laboratories do not routinely report cytoplasmic fluorescence on ANA testing and,
occasionally, anti-Jo-l-positive sera are truly negative for cytoplasmic fluorescence. However, it seems prudent to screen patients with ILD, either as an isolated problem or in conjunction with other signs or symptoms of connective tissue disease, with an indirect immunofluorescence test for antinuclear antibodies (ANA), using HEp-2 cells as tissue substrate. If immunofluorescence shows a cytoplasmic pattern (with or without nuclear fluorescence), a search for antiaminoacyl-tRNA synthetase antibodies is suggested. ACKNOWLEDGMENTS The authors thank Margaret Dougherty, Grace L. Griffin, and Leigh Anne Mason for technical assistance in preparing the manuscript and tables.
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coexist and are associated with myositis. J Exp Med 163:12811291, 1986 12. Targoff IN: Autoantibodies to aminoacyl-transfer RNA synthesases for isoleucine and glycine: Two additional synthetases are antigenic in myositis. J Immunol 144:17371743, 1990 13. Yoshida S, Akizuki M, Mimori T, et al: The precipitating antibody to an acidic nuclear protein antigen, the Jo-1, in connective tissue diseases: A marker for a subset of polymyositis with interstitial pulmonary fibrosis. Arthritis Rheum 26:604-611, 1983 14. Bernstein RM, Morgan SH, Chapman J, et al: AntiJo-1 antibody: A marker for myositis with interstitial lung disease. Br Med J 289:151-152, 1984 15. Hirakata M, Mimori T, Azizuki M, et al: Autoantibodies to small nuclear and cytoplasmic ribonucleoproteins in Japanese patients with inflammatory muscle disease. Arthritis Rheum 35:449-456, 1992 16. Targoff IN: The inflammatory muscle diseases, in Cannon GW, Zimmerman GA (eds): The Lung in Rheumatic Diseases. New York, Marcel Dekker, 1990, pp 303328 17. Marguerie C, Bunn CC, Beynon HLC, et al: Polymyositis, pulmonary fibrosis and autoantibodies to aminoacyltRNA synthetase enzymes. Q J Med 77:1019-1038, 1990 18. Clawson K, Oddis CV: Adult respiratory distress syndrome (ARDS) in myositis patients with anti-Jo-1 antibody. Arthritis Rheum 36:$256, 1993 19. Stahl NI, Klippel JH, Decker JL: A cutaneous lesion associated with myositis. Ann Intern Med 91:577-579, 1979 20. Targoff IN, Trieu EP, Plotz PH, et al: Antibodies to glycyl-transfer RNA synthetase in patients with myositis and interstitial lung disease. Arthritis Rheum 35:821-830, 1992 21. Miller FW: Myositis-specific autoantibodies: Touchstones for understanding the inflammatory myopathies. JAMA 270:1846-1849, 1994
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22. TargoffIN, Trieu EP, Miller FW: Reaction of anti-OJ autoantibodies with components of the multi-enzyme complex of anainoacyl-tRNA synthetases in addition to isoleucyltRNA synthetase. J Clin Invest 91:2556-2564, 1993 23. Targoff IN, Arnett FC: Clinical manifestations in patients with antibody to PL-12 antigen (alanyl-tRNA synthetase). Am J Med 88:241-251, 1990 24. AI-Janadi M, Smith CD, Karsh J: Cyclophosphamide treatment of interstitial pulmonary fibrosis in polymyositis/ dermatomyositis. J Rheumatol 16:1592-1596, 1989 25. Bohan A, Peter JB: Polymyositis and dermatomyositis (parts 1 and 2). N Engl J Med 292:344-347, 403-407, 1975 26. Arnett FC, Edworthy SM, Bloch DA, et al: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315-324, 1988 27. Masi AT, Rodnan GP, Medsger TA Jr, et al: Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 23:581-590, 1980 28. Tan EM, Cohen AS, Fries JF, et al: The 1982 revised
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criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271, 1982 29. Johnson CD, Edmonds JP, Holborow E J: Precipitating antibody to DNA detected by two-stage electroimmunodiffusion. Lancet II:883-886, 1973 30. Aarden LA, De Groot ER, Feltkamp TEW: Immunology of DNA. III. Crithidia luciliae, a simple substrate for the determination of anti-dsDNA with the immunofluorescence technique. Ann NY Acad Sci 254:505-515, 1975 31. Wasicek CA, Reichlin M, Montes M, et al: Polymyositis and interstitial lung disease in a patient with anti-Jo-1 prototype. Am J Med 76:538-544, 1984 32. Oddis CV, Medsger TA Jr, Cooperstein LA: A subluxing arthropathy associated with the anti-Jo-1 antibody in polymyositis/dermatomyositis. Arthritis Rheum 33:1640-1645, 1990 33. Love LA, Burgess SH, Hill PC, et al: Geographical and seasonal clustering in the onset of idiopathic inflammatory myopathy (IIM) in groups defined by myositis-specific autoantibodies (MSA). Arthritis Rheum 35:$40, 1992