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ORIGINAL ARTICLE
Ahead of print publication  

Clinical spectrum and outcomes of patients with Anti-Jo1 positive antisynthetase syndrome seen at a single tertiary care hospital in North India


1 Department of Rheumatology and Immunology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
2 Department of Pulmonary Medicine, Dayanand Medical College and Hospital, Ludhiana, Punjab, India

Date of Submission27-Oct-2021
Date of Acceptance25-Nov-2021
Date of Web Publication10-May-2022

Correspondence Address:
Vikas Gupta,
Department of Rheumatology and Immunology, Dayanand Medical College and Hospital, Tagore Nagar, Civil Lines, Ludhiana, Punjab
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_248_21

  Abstract 


Background: Antisynthetase syndrome (ASSD) is a multisystem autoimmune disease characterized by the presence of antibodies against aminoacyl-transfer RNA synthetases, most common being anti-Jo1 antibody. It is an under-recognized entity with a significant delay in diagnosis, both due to lack of awareness of this condition and presentation as “incomplete” form more often than the complete form, characterized by the presence of triad of interstitial lung disease (ILD), myositis, and arthritis. We aimed to study the clinical spectrum and outcomes of anti-Jo1 antibody-positive ASSD at a single tertiary care referral hospital in North India.
Methods: Anti-Jo1 positive ASSD patients diagnosed according to the Connors et al. criteria were included in this observational study conducted over 3 years by the departments of Rheumatology and Pulmonary Medicine at a single tertiary care hospital in North India.
Results: The clinical spectrum and treatment outcomes of 17 patients diagnosed with anti-Jo1 positive ASSD were studied. Only 2 of the 17 patients presented with the “complete” form at the onset. While 12 patients improved with treatment with steroids and immunosuppressives (mycophenolate, azathioprine, or methotrexate), five patients died, four due to sepsis and one due to progressive lung disease.
Conclusion: ASSD is an under-recognized disease, often presenting as an incomplete form rather than the classic triad of arthritis, ILD, and myositis. Infections are the major cause of death contributing to high mortality in Indian patients with ASSD.

Keywords: Anti-Jo1 antibody, antisynthetase syndrome, arthritis, interstitial lung disease, myositis



How to cite this URL:
Gupta V, Kashyap AK, Singh A. Clinical spectrum and outcomes of patients with Anti-Jo1 positive antisynthetase syndrome seen at a single tertiary care hospital in North India. Indian J Rheumatol [Epub ahead of print] [cited 2022 Jun 26]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=345011




  Introduction Top


Antisynthetase syndrome (ASSD) is a multisystem autoimmune disease characterized by the presence of circulating autoantibodies against aminoacyl-transfer RNA (tRNA) synthetases in association with one or more of the following features: myositis, interstitial lung disease (ILD), arthritis, fever, Raynaud's phenomenon, and Mechanic's hands.[1] Aminoacyl-tRNA synthetases (ARS) are enzymes that catalyze the binding of amino acids to their corresponding tRNAs, and autoantibodies directed against these enzymes are known as anti-aminoacyl tRNA synthetase (anti-ARS) antibodies or antisynthetase antibodies.[2] Till date, autoantibodies against eight ARS, including histidyl (anti-Jo-1), threonyl (anti-PL-7), alanyl (anti-PL-12), glycyl (anti-EJ), isoleucyl (anti-OJ), asparaginyl (anti-KS), phenylalanyl (anti-ZO), and tyrosyl (anti-YRS/HA) tRNA synthetases have been reported.[3] Among these, anti-Jo1 antibodies are by far the most common, found in 15% to 30% of patients with idiopathic inflammatory myositis (IIM) and 36%–60% of patients with ASSD.[3],[4],[5],[6],[7],[8] In contrast, all other anti-ARS taken together (non-anti-Jo1 ARS) are found in 5%–15% of IIM and 40%–64% of ASSD.[5],[6],[7],[8] Anti-Jo1 was the first ARS to be described in the year 1980 by Nishikai and Rechlin.[9] However, a distinct syndrome associated with these antibodies, and predominantly characterized by inflammatory myositis and pulmonary fibrosis was first recognized by Marguerie et al. in 1990.[10]

ASSD is an under-recognized entity with a significant delay in diagnosis.[11],[12],[13] The reasons for delay in diagnosis include a lack of awareness about this condition, lack of facilities for detection of anti-ARS antibodies, and its rather common initial presentation as an “incomplete” form rather than the classic triad of arthritis, myositis, and ILD.[11],[12],[14],[15]

We aimed to study the clinical presentation, delay in diagnosis, and treatment outcomes of patients with anti-Jo1 antibody-positive ASSD seen at a single tertiary care hospital.


  Methods Top


Patients

This was a retrospective study conducted by the departments of Rheumatology and Pulmonary Medicine at a single tertiary care hospital in North India. The study was approved by the institutional ethics committee (IEC no. 2021-697). Both outpatients and inpatients with a diagnosis of anti-Jo1 positive ASSD were included in the study. The diagnosis of ASSD was made according to the Connors et al. criteria.[1] Briefly, these include the presence of an anti-tRNA synthetase autoantibody along with one or more of the following features: myositis, ILD, arthritis, unexplained and persistent fever, Raynaud's phenomenon, and mechanic's hands.[1]

Patients' clinical details including symptoms and signs at presentation, investigations (immunological, biochemical, radiological), and treatment details were noted. Clinical details that were noted included fever (not attributable to any cause other than ASSD), Raynaud's phenomenon, arthralgia/arthritis, myositis (idiopathic inflammatory myopathy, IIM), cough, shortness of breath, mechanic's hands, heliotrope, or Gottron's rash. Among the immunological investigations, antinuclear antibodies (ANAs) (by immunofluorescence [IF] or enzyme-linked immunosorbent assay [ELISA]), rheumatoid factor (RF), anti-cyclic citrullinated antibodies (anti-CCP) were noted wherever available. Anti-Jo1 antibodies were tested by immunoblot assay using AESKUBLOTS ANA17-Pro kits (AESKU Diagnostics, Wendelsheim, Germany). Other antisynthetase antibodies were not tested for as these were not available at our center.

High resolution computed tomography (HRCT) thorax and pulmonary function tests with diffusion capacity of the lungs for carbon monoxide (DLCO) were done where indicated. All patients underwent serum creatine kinase measurement. Those with clinical evidence of proximal muscle weakness and/or raised serum creatine kinase levels underwent evaluation by electromyography. The “delay in diagnosis,” defined as “the time from the first symptom onset to the diagnosis of antisynthetase syndrome,” was noted. Details of treatment given and treatment outcomes on follow-up were noted.

Clinical definitions

Raynaud's phenomenon was diagnosed according to the 2014 International consensus criteria for the diagnosis of Rayanud's phenomenon.[16] Arthritis was defined by objective evidence of swelling of one or more joints with or without tenderness. In patients with proximal muscle weakness on clinical examination, the diagnosis of PM or dermatomyositis was made according to the 2017 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) Classification Criteria for Adult and Juvenile Idiopathic Inflammatory Myopathies.[17] These patients were considered to have “classic” onset myositis.[18] Patients who had subclinical evidence of myositis (raised serum creatinine kinase and presence of electromyographic triad of short, small, polyphasic motor unit potentials; fibrillations, positive sharp waves, and insertional irritability; and bizarre, high-frequency repetitive discharges) were considered to have “hypomyopathic” onset myositis.[18] “Mechanic's hands” were defined by the presence of nonpruritic, hyperkeratotic eruptions accompanied by scaling and fissuring over the ulnar aspect of the thumbs and/or the radial aspect of the index or middle fingers, present bilaterally.[19] ILD was diagnosed if following features were seen on HRCT thorax: intra-or interlobular septal thickening, ground-glass opacities, honeycombing, or tractional bronchiectasis. The ILD pattern was classified according to the American Thoracic Society/European Respiratory Society classification of the idiopathic interstitial pneumonias.[20],[21]

The onset of ASSD was considered from the first pulmonary (cough or shortness of breath), muscular (muscle weakness), or joint (arthritis/arthralgia) symptoms. Clinical features onset was considered concurrent in cases of <3 months of delay between the various manifestations.[18] Patients with all three features-ILD, myositis, and arthritis at the onset were defined as having a “complete” ASSD, whereas patients lacking at least one of these three features were defined as having an “incomplete” form of ASSD.[18]

Statistical analysis

The risk factors associated with mortality were analyzed by comparing the variables between the two studied groups (one group comprising of the deceased patients and the other comprising of those that survived). Continuous variables were analyzed by Mann–Whitney U-test and the categorical variables by Fisher's exact test. Further, multivariate Cox regression analysis was done for the studied variables. P < 0.05 was considered significant. Data were analyzed using SPSS 28.0 (SPSS Inc., Armonk, NY, USA).


  Results Top


A total of 17 patients with a median follow-up duration of 8 months were included. [Table 1] shows the clinical characteristics of the patients included in the study.
Table 1: Clinical characteristics of the anti-Jo1 positive antisynthetase syndrome patients

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Clinical features at the disease onset

Symptomatic ILD was the predominant manifestation present in 13 out of 17 patients (76.5%). 8 out of 17 patients (47.1%) had myositis, 6 with classic onset and 2 with hypomyopathic onset. The two patients with “hypomyopathic” onset myositis could be classified as having “probable” myositis as per the 2017 EULAR/ACR criteria for IIM. 58.8% of the patients (10 out of 17) had joint involvement with 8 patients having arthritis and 2 patients having arthralgia. Mechanic's hands were present in 6 patients, and a history of Raynaud's phenomenon was present in 5 patients. Five patients (29.4%) had fever attributable to ASSD.

Only 2 out of 17 patients had the “complete” form at the initial presentation, that is, had the triad of myositis, arthritis, and ILD. 15 patients presented with incomplete form, 7 with combination of two of the three features of the “classic triad” (5-myositis and ILD, 1-arthritis and ILD, 1-myositis and ILD) and 8 with single main feature of this triad (5-isolated ILD, 3-isolated arthritis). All three patients with isolated arthritis had associated fever attributable to ASSD, and one of these three patients also had Raynaud's phenomenon. Persistent fever and/or presence of Raynaud's phenomenon prompted the testing for anti-extractable nuclear antigen antibodies, including anti-Jo 1 antibodies in these patients. During follow-up, none of our patients who presented with incomplete form initially evolved into the complete form. However one patient who presented with myositis and ILD, developed arthralgia during follow-up.

Delay in diagnosis

The delay in diagnosis of ASSD ranged from 3 weeks to 12 years, with a median delay of 4 months. The longest diagnostic delay of 12 years was seen in the patient who had isolated arthritis and was being treated as rheumatoid arthritis for 12 years. On referral to a rheumatologist 12 years later, a history of Raynaud's phenomenon and recurrent fever on tapering steroids led to the diagnosis of ASSD. Interestingly, the shortest diagnostic delay of 3 weeks also occurred in the patient who presented with isolated arthritis to a rheumatologist 2 weeks after the onset of symptoms. She also had hypomyopathic onset myositis, and on evaluation, a diagnosis of ASSD was reached.

Laboratory and imaging features

[Table 2] shows the laboratory characteristics of the patients. 12 patients were tested for RF. 4 out of these 12 had RF positivity. Anti-CCP antibodies were negative in all 8 patients who were tested for the same. ANAs were tested in 10 patients by IF. Five patients had nuclear fine speckled pattern, two had both nuclear fine speckled and cytoplasmic staining, one had only cytoplasmic staining, while two were negative for ANA by IF.
Table 2: Laboratory features of anti-Jo1 positive antisynthetase syndrome patients

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13 patients out of 15 who got HRCT thorax done had ILD on imaging. “Nonspecific interstitial pneumonia” and “possible usual interstitial pneumonia” patterns were present in 6 patients each and 1 patient had an organizing pneumonia pattern. [Table 3] shows the characteristics of the 13 patients with ILD.
Table 3: Characteristics of antisynthetase syndrome patients with interstitial lung disease

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Outcomes

Among the three patients presenting with isolated arthritis, one patient was treated with methotrexate, one with mycophenolate mofetil (MMF), and another with MMF followed by azathioprine (AZA). Persistent fever was the reason to choose MMF or AZA over MTX in two patients. One patient who was treated as rheumatoid arthritis for 12 years had developed reducible deformities over this period.

13 patients who had ILD were treated with steroids, MMF, AZA, or CYC. 7 patients improved (5-MMF, 2-AZA) while 5 patients died, four due to sepsis (all four had pneumonia, including two with VAP, 1-Acinetobacter, 1-Klebsiella) and one due to progressive lung disease (treated with MMF followed by CYC) [Table 4]. One patient had worsening despite treatment (treated with AZA followed by MMF) and underwent lung transplant.
Table 4: Characteristics of anti-Jo1 positive antisynthetase syndrome patients who died

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All 8 patients with myositis (6-classic onset, 2-hypomyopathic onset) were treated with steroids and MMF, AZA, or MTX. Seven patients showed improvement with treatment (4-MMF, 2-AZA, and 1-MTX) while one, who also had ILD, died during her hospital stay due to sepsis. This patient also had subnephrotic range proteinuria, low C3 complement, and anti-histone, anti-Ro52, and anti-Ro-60 positivity in addition to anti-Jo1 positivity.

Risk factors associated with mortality

Among the nine parameters studied as risk factors associated with mortality [Table 5], “recent (within past 3 months) intravenous CYC pulse” was the only risk factor showing significant association with mortality on univariate analysis [Table 5]. However, on multivariate analysis, none of the risk factors were found to be significantly associated with mortality (data not shown).
Table 5: Relation between various parameters and mortality

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  Discussion Top


In this small case series from a single tertiary care hospital in North India, we found that only 2 out of 17 patients (11.8%) had the complete form comprising the classic triad of ILD, myositis and arthritis at the initial presentation. Most patients presented with incomplete form having either one or two of the three features of the triad at the disease onset (within 3 months of the appearance of the first symptom). This is in concordance with the findings from the previous studies. In a large multicentric study of 225 anti-Jo1 positive ASSD patients, only 19.5% of the patients were found to have the “complete form” at the disease onset.[18] Similarly, in a series of 27 anti-Jo1 positive ASSD patients from a single tertiary care center in India, only 14.8% of patients were found to have the complete form at presentation.[13] The most common initial presentations in our cohort were isolated ILD and a combination of ILD and myositis present in 5 patients (29.4%) each. In the Spanish cohort too, the most common presentation was that of isolated ILD, present in 32.4% of the patients. [Table 6] shows the comparison of our series with the previous series of anti-Jo1 positive ASSD patients.
Table 6: Comparison of our case series with the previous published series of anti-Jo1 positive antisynthetase syndrome patients

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Delay in diagnosis of ASSD in our series ranged from 3 weeks to 12 years, with a median diagnostic delay of 4 months. Previous studies have also reported significantly longer delays of up to 20 years in the diagnosis of ASSD among the patients presenting with isolated arthritis.[13],[22]

In our cohort, the median age was 45 years. We had marked female predominance in our cohort (5:1), similar to a previous Indian study which had a female-to-male ratio of 4:1.[13] Studies from European countries and Japan have also shown a female predominance with F: M ratio ranging from 1.5:1 to 6:1.[8],[14],[18],[23]

We found anti-Ro antibodies to be concurrently positive in more than half (62.5%) of our patients, similar to the findings from a large multicentric study in which anti-Ro antibodies were found to be positive in 56.5% of anti-Jo 1 positive ASSD patients.[18] RF was positive in 25% of our patients who were checked for the same, again similar to the findings seen by the AENEAS collaborative group in their cohort where 28.7% of the patients checked for the RF were positive.[18] However, all the eight patients in whom anti-CCP antibodies were checked were negative for the same in our cohort, in contrast to previous studies which have shown anti-CCP positivity ranging from 10% to 27%.[13],[24] Among the 10 patients who were checked for ANAs by IF, eight tested positive (80% positive). Previous studies have reported ANA positivity ranging from 56% to 60% among the anti-Jo 1 positive ASSD patients.[13],[24] Higher ANA positivity rate of 80% in our study could be attributed to all samples being tested by IF (rather than ELISA) and inclusion of cytoplasmic staining as positive in our analysis. Although anti-Jo 1 antibodies give a cytoplasmic fine speckled pattern on Hep-2 IF, sometimes, these may go undetected on IF due to weak or absent staining, as was the case in 20% of our patients.[3],[25] Hence, it is important to test for anti-Jo 1 antibodies either by ELISA or by line-blot assay (both commercially available), despite a negative ANA, in patients presenting with ILD or myositis. A positive anti-Jo 1 antibody in a patient presenting with ILD alone might form the basis for offering immunosuppression while in a patient presenting with PM, it might help in avoiding a muscle biopsy.

Five out of 17 patients died in our series, giving a high mortality rate of 29.4%. Four deaths occurred due to sepsis and 1 due to progressive lung disease. 2 patients were put on mechanical ventilation for progressive lung disease, however, they developed pneumonia and died of septic shock. The high mortality rate in our study is in stark contrast to that from another single center series from North India, where only one patient had died among the 27 anti-Jo1 positive ASSD patients having a median follow-up of 34 months.[13] Previous cohorts of anti-Jo1 positive ASSD patients from Hungary and Spain and a multinational cohort from Europe and US have reported mortality rates of 10% to 25%, with a median follow-up ranging from 3 to 10 years.[14],[18],[23] We found use of intravenous CYC pulse within the past 3 months to be a risk factor for mortality on univariate analysis, however, no parameter was significantly associated with mortality on multivariate analysis. In the Hungarian cohort too, where 5 out of 49 patients died, none of the investigated parameters were found to be significantly associated with mortality whereas in the Spanish cohort, older age at diagnosis was the only parameter significantly associated with mortality.[14],[23] Infections were the leading cause of mortality in our series, accounting for 4 out of 5 deaths. Other cohorts have reported progressive lung disease, infections, and malignancies as the major causes of death in ASSD patients.[8],[14],[23] Since the number of patients in our cohort is very small, it may not be not possible to make any firm conclusions, however, ours being a tertiary care referral center in North India, it is likely that we received sicker patients and hence, a referral bias might have contributed to the higher mortality rate. Nevertheless, in the wake of our study's findings, the treating clinician should be vigilant about the risk of life-threatening infections in these patients, particularly in those on cyclophosphamide.

Limitations of our study include a small sample size and a referral bias. Furthermore, we might have missed a few patients, for example, those presenting with isolated myositis to the Neurology department or those presenting with arthritis only since they might not have been tested for anti-Jo1 antibodies.


  Conclusion Top


ASSD is an under-recognized disease, often presenting as an incomplete form rather than the classic triad of arthritis, ILD, and myositis. Awareness among the clinicians about this condition's presentation as an incomplete form and testing for anti-Jo1 antibodies despite a negative ANA on immunofluorescence might help in shortening the delay in diagnosis and hence could lead to better outcomes. Infections are the major cause of death contributing to high mortality in Indian patients with ASSD.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

 
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