Abstract
Objective. To investigate the uncommon co-occurrence of antisynthetase syndrome (AS) and sarcoidosis.
Methods. From 2000 to 2015, patients with sarcoidosis were extracted from a retrospective multicentric cohort of 352 patients with AS.
Results. Ten patients (2.8%; 6 men, 8 whites, 5 smokers, median age 50 yrs) had both AS and sarcoidosis. Most of the time, sarcoidosis and AS occurred simultaneously (n = 7). Antibody testing revealed anti-Jo1 (n = 5), anti-PL12 (n = 4), or anti-PL7 (n = 1). Finally, no patient had a worsening of muscular condition, 5 patients presented respiratory deterioration, 3 remained stable, and 2 showed improvement.
Conclusion. Sarcoidosis may be underdiagnosed in patients with AS.
Antisynthetase syndrome (AS) is an inflammatory myopathy associated with interstitial lung disease (ILD) and autoantibodies to aminoacyl-tRNA synthetase. Other symptoms may occur such as polyarthritis, Raynaud phenomenon (RP), or mechanic hands1. AS may constitute an overlap syndrome with other connective tissue diseases (CTD)2.
Sarcoidosis is an immune disorder with granulomatous reaction to an unknown antigen, with pulmonary involvement in 90% of the cases and extrapulmonary localizations in half of the cases3. Co-occurrence of autoimmune diseases and sarcoidosis is uncommon4,5. For instance, association of sarcoidosis with systemic lupus erythematosus, systemic sclerosis, primary biliary cirrhosis, autoimmune cytopenia, or Sjögren syndrome has been described6,7. However, the combination of AS and sarcoidosis is particularly rare, reported in only 2 cases8,9. We conducted a retrospective multicentric study to investigate the presentation and outcome of this co-occurrence of diseases.
MATERIALS AND METHODS
Our study received institutional review board approval and the requirement for signed informed consent was waived according to French legislation (CLEA-2016-028).
From 2000 to 2015, a cohort of 352 patients with AS was assembled from 10 French university hospitals (women/men ratio = 2/8; median age at diagnosis 50 yrs). The diagnosis of AS was based on the presence of compatible ILD and/or inflammatory myopathy with anti-tRNA-synthetase autoantibodies2,10. To exclude false-positive patients, we included patients only if they had at least 2 positive tests for myositis-specific antibodies (Luminex and Linear dot for anti-Jo1 or 2 consecutive intense immunodot for anti-PL7/PL12). Fourteen patients with noncaseous granulomas on biopsy were selected from the whole cohort. Four patients did not fulfill sarcoidosis diagnosis according to the American Thoracic Society/European Respiratory Society (ATS/ERS) statement11. Thus, 10 patients with sarcoidosis associated with AS were included. Demographic, clinical, and paraclinical data and outcomes were collected from medical records (PC).
For each patient, 2 lung computed tomography (CT) scans were reviewed and analyzed: at diagnosis and at the last medical followup. Finally, the CT pattern of ILD was consensually defined (PYB, PC, and YU) in agreement with international ATS/ERS CT criteria for idiopathic interstitial pneumonia12.
For outcome analysis, we defined pulmonary progression or improvement according to New York Heart Association stage of dyspnea, pulmonary function tests (> 10% of predicted value of forced vital capacity or in carbon monoxide transfer factor 6 months after the inclusion and/or at the end of the study), and/or the occurrence of symptomatic pulmonary hypertension (PH) confirmed by right heart catheterization. Muscular deterioration was defined as increasing muscle weakness according to Muscular Disability Rating Scale, or a rise of creatine kinase (CK) > twice the normal range2.
RESULTS
Patients’ characteristics at diagnosis are reported in Table 1. There were 10 patients, including 4 men, 8 whites, 5 smokers. Thus, 2.8% of patients with AS also had a confirmed sarcoidosis. The onset of clinical manifestations occurred at the median age of 50 years (range: 35–69). None had history of neoplasia. Median followup was 47 months (from 18 to 165 mos). Patients’ characteristics during followup are reported in Table 2. In most cases, sarcoidosis and AS occurred at the same time (n = 7). Sarcoidosis started first in 2 patients (10 and 24 mos) while AS occurred first in the last case (24 mos).
At sarcoidosis diagnosis, 7 patients complained of fatigue, 4 reported a significant weight loss (from 2 to 9 kg), and 1 had fever. Most patients (n = 8) disclosed an inflammatory syndrome with a median CRP level at 17 mg/l (from 3 to 77).
Initial lung CT scans (Figure 1) showed commonly nonspecific interstitial pneumonia (NSIP; n = 6), NSIP with organizing pneumonia (NSIP-OP; n = 2), and unclassifiable ILD (n = 1). Most patients had mediastinal-hilar lymphadenopathies (n = 7) that were noncompressive (n = 7) and/or noncalcified (n = 5; Table 1).
The bronchoalveolar lavage lymphocyte count was increased in only 1 case. However, noncaseating granulomas were discovered in biopsies: bronchial (n = 5), mediastinal (n = 1), pleural (n = 1), skin (n = 2), or salivary glands (n = 1).
Extrapulmonary features related to AS were as follows: inflammatory polyarthralgia (n = 6), mechanic hands (n = 2), RP (n = 5), and myositis (n = 4). In relation to sarcoidosis, 3 patients had biopsy-proven cutaneous nodules and 3 others had peripheral lymphadenopathies.
Biological findings showed slightly elevated CK and lactate dehydrogenase levels, with median values 1.3 and 2 times the normal range, respectively. Antinuclear antibodies were positive for 6 patients. Antibody testing revealed anti-Jo1 (n = 5), anti-PL12 (n = 4), and anti-PL7 (n = 1), whereas anti-RNP, anti-DNA, anticitrullinated protein antibodies, and rheumatoid factor were negative. The distribution of the AS autoantibody subtypes was not different in AS patients with or without sarcoidosis2.
At diagnosis, angiotensin-converting enzyme level was increased only twice (median level 33 IU/l; range: 5–150 IU/l).
Inflammatory myopathy was confirmed on muscular biopsies (n = 4/6) and muscle histology never revealed granuloma. All the patients with muscular symptoms fulfilled the European Neuromuscular Centre classification criteria for inflammatory myopathy (n = 5), and 1 additional patient was classified as having dermatomyositis according to a biopsy-proven heliotrope rash13. The remaining 4 patients, who were hypomyopathic or amyopathic, fulfilled the additional criteria for overlap myositis from Troyanov, et al14.
When 18F-fluorodeoxyglucose positron emission tomography was performed (n = 4), hypermetabolic activity was always found in place of mediastinal-hilar lymphadenopathies and pulmonary parenchyma.
All patients were treated with steroids. Nine patients needed immunosuppressive therapy, including methotrexate (n = 7), azathioprine (n = 3), IV cyclophosphamide (CYC; n = 2), and mycophenolate mofetil (n = 1; Table 2).
At the end of the study, the median dose of prednisone was 12.5 mg/d (0–30).
No patient experienced a worsening of muscular condition. Deterioration in respiratory status occurred in 5 patients, while 3 remained stable and only 2 improved (Table 2). In 4 cases, lung fibrosis appeared (n = 2) and/or worsened (n = 2) during the followup. Accordingly, 9 patients had fibrosis at the end of the followup. One patient underwent lung transplantation. Further, signs of pulmonary hypertension were found on cardiac ultrasonography in 4 patients: 1 case at diagnosis and the others during the followup. By right heart catheterization (n = 4), PH was confirmed in 2 patients: 1 with group 3 precapillary PH and the other with postcapillary PH (Table 2). This last patient died from cardiac failure: although initial heart investigations were normal, the patient developed at Year 1 right bundle branch block concomitantly with lung function worsening. Echocardiography found a severely dilated cardiomyopathy, with 40% of left ventricular ejection fraction. Steroid pulses and IV CYC failed to improve the patient’s condition.
DISCUSSION
Our study showed several important findings: (1) sarcoidosis is probably underdiagnosed in patients with AS; (2) lung manifestations were those usually seen in AS rather than those found in sarcoidosis; (3) intrathoracic lymphadenopathies were often typical of sarcoidosis; and (4) pulmonary severity resulted from AS rather than from sarcoidosis.
The evaluated prevalence of sarcoidosis in patients with AS may be underlined in this series because 2.8% is far higher than common findings. Some biases are to be considered, however. First, having a systemic disease necessitates multiple investigations allowing the recognition of asymptomatic diseases, which might have been overlooked in other contexts. Then, the age tended to be higher than is usually seen in sarcoidosis. This finding must be all the more underscored considering that both diseases were often concomitant.
We can hypothesize that the 2 diseases may share some similar immunological background. Sarcoidosis involves adaptive Th1 response and production of interleukin 2 + interferon (IFN)-γ. Likewise, AS involves a Th1 response with activation of the type I IFN pathway3. Further, sarcoidosis-like granulomatosis as well as AS have been described in patients treated with exogenous IFN-α15,16.
Concerning the presentation, all cases were typical for both diseases. Sarcoidosis was typical according to thoracic lymphadenopathy, perilymphatic micronodules, cutaneous nodules, and peripheral lymphadenopathy, and all cases had evidence of noncaseating granulomatous lesions, mostly from the thoracic sphere. On the other hand, extrapulmonary features and the biologic profile were typical of AS. Because the lungs may often be involved in both diseases, it was interesting to search for signs to indicate one disease or the other. The phenotype of our patients was complex and taught us to be careful with unusual presentations.
When a diagnosis of sarcoidosis is made, we must pay attention to untypical extrapulmonary features. NSIP pattern during sarcoidosis should lead the physician to search also for CTD, including AS. Obviously, concomitant AS diagnosis has to be taken into account for the specific treatment management. Finally, as is often observed in these “overlapping patients,” pulmonary evolution may be severe, requiring screening for PH17.
In case of atypical signs for AS such as cutaneous nodules or lymphadenopathy (which may suggest cancer in the context of myositis), sarcoidosis should be considered. Physicians might thus look for suggestive clinical findings and histological evidence of granulomas.
The diagnosis of sarcoidosis should lead to a systematic evaluation of all specific organ damage3, leading to a dedicated therapeutic management. Because rituximab could be promising both in AS and in sarcoidosis separately, its use could theoretically be effective in refractory patients who have both AS and sarcoidosis18,19,20. However, further studies are required to assess this point.
This series showed that clinicians should be aware of possible associations between sarcoidosis and AS. Atypical clinical imaging and biology features may indicate such an association. Both diagnoses are important to establish as they imply particular diagnostic investigation, monitoring, and management.
- Accepted for publication April 13, 2018.