Antisynthetase Syndrome-A Associated With Anti-PL-12 A Less Recognized Entity

Diffuse parenchymal lung/pulmonary diseases (DPLD) and interstitial lung disease, (ILD) are the umbrella terms collectively used to refer to the aetiologically varying or heterogeneous group of diseases that share clinical, physiologic, and radiographic similarities. The choices and prognosis of treatment substantially vary among different causes of ILD. Hence, determining the right etiology is of critical importance. 

Connective tissue diseases are the common causes of DPLDs while ILD is one of the important factors responsible for causing morbidity and mortality in patients with antisynthetase syndrome. The involvement of the interstitial tissues in this recognized entity, especially with the anti-PL-12 antibody positivity, is often progressive and severe with poor response to treatments including steroids. 

We have described a case of a young woman with the antisynthetase syndrome with diffuse glucocorticoid-resistant interstitial pneumonia, who was stabilized with a combination therapies using of mycophenolate and cyclophosphamide.

Introduction 

The diffuse parenchymal lung diseases, collectively referred to as ILDs (interstitial lung diseases), include the group of diseases having variable etiologies that have certain common similarities in radiographic, physiologic, clinical, and pathologic manifestations. 

The term "interstitial" suggests that the primary and the most dominant site of involvement in these cases is the pulmonary interstitium. However, the term could be misleading, as most of these disease states are sometimes associated with an extensive involvement of the pulmonary vasculature and alveoli. 

DPLDs may also be divided into idiopathic or those with known causes. The common identifiable causes of ILD include the exposure to environmental and occupational agents, drug-induced toxicity in the pulmonary tissues, and radiation-induced injury to the lungs. 

ILD may also complicate the pathogenesis of some connective tissue diseases such as rheumatoid arthritis, scleroderma, systemic lupus erythematosus, mixed connective tissue disease, dermatomyositis, and polymyositis. 

Interstitial lung disease (ILD) might complicate the development of idiopathic inflammatory myopathies. It can also be a major cause of mortality and morbidity. 

The specific pattern of the interstitial involvement tends to vary from non-specific interstitial pneumonia, organizing pneumonia, usual interstitial pneumonia, to acute interstitial pneumonia. ASS (Antisynthetase syndrome) refers to a systemic autoimmune myopathy of inflammatory nature that usually presents with arthritis, arthralgia, fever, Raynaud's phenomenon, interstitial lung disease, and mechanic's hands. 

This syndrome is marked by the detection of the ASA (aminoacyl-transfer RNA synthetase autoantibodies). ILD in patients with ASS could be of a rapidly progressive nature with a very poor response to glucocorticoids. 

Case Study:

A 35-year-old lady, with no comorbidities, presented with three months of symptoms of progressive dyspnoea and dry cough. She complained of weight loss of 3 kg over about 3 months and skin lesions with itching on the legs. She had no fever, alteration of the bowel and bladder habits, allergic background, or any thyroid disease. 

She complained of muscle pain and generalized weakness. Physical evaluation of the patient revealed pigmented papules on the hands and legs. The features of mechanics’ hands were also noted. The auscultation of the chest revealed fine crackles in both the lung bases. CT scan of the chest revealed bilateral ground-glass opacities in the lower lobes with subpleural sparing and septal thickening that was consistent with the pattern of non-specific interstitial pneumonia. 

Blood counts, renal functions, urinalysis, and thyroid tests of the patient were normal. CRP and ESR levels were higher. 2-D Echocardiogram showed normal left ventricular functions without any evidence of PAH. Atypical pneumonia was considered one of the differential diagnoses based on which bronchoscopy and BAL evaluation of the woman was performed for infective agents, all of which showed negative results. 

The consultation for rheumatology was requested for the arthralgia and skin lesions. The testing for ANA by myositis and immunoblot profile was done. ANA blot revealed a strong positivity for the Ro 52 while the myositis profile showed a strong positivity for Ro 52 and PL-12. 

The diagnosis of PL-12-linked antisynthetase syndrome was made and the woman was counseled for the potential course and prognosis of the disease. 

The patient did not have specific clinical characteristics of myositis, and her muscle enzymes including LDH, SGOT, CPK, and SGPT were within the normal limits. Hence, electroneuromyography (ENMG) was not recommended in this case. 

The spirometry and DLCO of the patient showed moderate restriction and limitation. The 6 MWT showed exercise-associated desaturation following a 6 MWD for 280 meters.

A pulse dose of methylprednisolone was administered to her (1 gram a day for three days). This was followed by the administration of prednisolone in a daily dose of 60 mg in tapering doses. 

At about three weeks of treatment, she still remained symptomatic without any significant clinical response. The CT scan of the chest was repeated that revealed persisting ILD and worsening of the septal thickening. 

The spirometry showed worsening of the FVC and a 6 MWD for 240 meters indicating a fall of 40 meters from the initial reading. 

In view of the severe nature of the disease and the lack of response to these therapies, she was started on a monthly treatment with cyclophosphamide (1000 mg/m2) for six months following which she showed symptomatic improvement. Her lung functions and radiological abnormalities stabilized. 

Later, Mycophenolate was added to the treatment plan after 6 months in a dose of 2 grams per day, and steroidal drugs were tapered. She remained on radiological, clinical, and functional follow-up with regular monitoring for drug toxicity.

Discussion

IIMs (Idiopathic inflammatory myopathies) refer to a group of acquired autoimmune diseases. An exhaustive review of patients based on their histopathological and clinical features has suggested that IIMs could be classified as dermatomyositis (DM), polymyositis (PM), immune-mediated necrotizing myopathies, or inclusion body myositis. 

Myositis is sometimes associated with malignancies and may present as an overlap syndrome with any other connective tissue disease. Antisynthetase syndrome is marked by varying permutations of arthritis/arthralgia, inflammatory myopathies, ILD, Raynaud's phenomenon, fever, and mechanic's hands. It could be viewed upon as a pathological entity that can overlap with PM or DM and is marked by the presence of autoantibodies, including myositis-specific autoantibodies, to aminoacyl-t RNA synthetase. 

The autoantibodies are directed against the cytoplasmic enzymes, which catalyze the binding of certain amino acids to matching tRNA during the translation phase of the synthesis of proteins. 

Patients with ASS also have features, which can overlap with other CTDs, like severe gastroesophageal reflux disease, Raynaud's phenomenon, and non-erosive arthritis. The symptoms of ILD often predominate as presenting features. 

The prevalence of ILD in patients with the antisynthetase syndrome is high. In one research study that included 203 patients with the antisynthetase syndrome, the incidence of ILD was found to be 86%, which was much higher than the prevalence of arthralgia/arthritis (60%) and myositis (73%). 

Also, it was found that the patients with antisynthetase syndrome may not have the symptoms of classic myopathy at the initial stages. Myositis may present at the later stages as the disease progresses. The prevalence of autoantibodies in individuals with IIM tends to vary widely. 

The current knowledge has classified antisynthetase syndrome as a highly distinct entity within a group of inflammatory myopathies. 

Conclusion 

Immunosuppression is considered a cornerstone for the treatment of antisynthetase syndrome. Lung and muscle diseases may not always track together and hence, require separate monitoring by the interdisciplinary team of pulmonologists and rheumatologists. 

Corticosteroids have been the first line of treatment for IIMs. However, there is a frequent recurrence of lung diseases following corticosteroid tapering. Hence, additional immunosuppressive agents may be added for the management of refractory muscle and lung diseases and also as corticosteroid-sparing agents. 

The commonly used adjunctive agents in these cases are azathioprine, tacrolimus, rituximab, mycophenolate mofetil, and cyclophosphamide. 

Different combinations of immunosuppressive drugs have been tried for the management of refractory ILD caused due to PM or DM. Glucocorticoids, calcineurin inhibitors, and monthly cyclophosphamide might be used as a combined treatment plan. Based on the limited data available in support of this approach, alternate choices could be the well-established options, like rituximab, basiliximab, and intravenous immunoglobulin.

Summary

This report has summarised the successful story of a young woman with antisynthetase syndrome and ILD that was resistant to the standard immunosuppressive therapies. She was treated with the addition of cyclophosphamide and later, mycophenolate. 

This case is noteworthy on several accounts. The antisynthetase syndrome is a common cause of rapidly progressive ILD. Most case series reported so far have the anti-Jo-1 related ASS, in contrast to the anti-PL-12 antibodies, indicating the need for testing for the extended myositis antibody panel in the suspected cases of ILD linked to ASS. 

The importance of continued radiological, clinical, and functional monitoring for ensuring prompt response needs to be stressed and therapy with multiple agents is needed, especially in the non-responders.