T. Mulder (1), R.L.N. Huijsmans (1), B. de Klerk (2), J.S. Kamphuis (3), P.E. Spronk (1,4)
Departments of 1 Intensive Care, 2 Rheumatology, and 3 Clinical Chemistry and Hematology, Gelre Hospitals, the Netherlands 4 Expertise Center for Intensive care Rehabilitation (ExpIRA), Apeldoorn, the Netherlands
T. Mulder - email@example.com
Antisynthetase syndrome, a rare cause of respiratory failure
A 72-year-old patient was admitted to the intensive care unit with respiratory failure due to rapidly progressive interstitial lung disease (ILD). All cultures and PCRs focused on ILD were negative and a paraneoplastic phenomenon was deemed unlikely after screening for malignancy. Inflammatory myositis was suspected as the patient also presented fever, progressive pitting oedema and arthritis in both hands and feet. A myositis blot revealed high titres of anti-Jo-1 antibodies: the patient was diagnosed with antisynthetase syndrome and was treated with high-dose corticosteroids, cyclophosphamide and intravenous immunoglobulins with a gradual full recovery. Antisynthetase syndrome should be considered in patients with idiopathic or rapidly progressive ILD.
A 72-year-old man without relevant medical history presented to the emergency department with dyspnoea, cough and fever. He reported pain in both wrists and ankles and progressive pitting oedema around these joints in the last few weeks. His medical history did not reveal any relevant comorbidities, no recent travel, no exposure to potential sources of infectious diseases, no allergies and no use of any medication. On physical examination, a fever of 39.2°C, fine crackles upon pulmonary auscultation and extensive pitting oedema in hands and feet were found. Laboratory analysis showed CRP 142 mg/l, leukocytes 12.3/nl but no other abnormalities. Urine analysis was normal. On the chest X-ray, several consolidations were seen (figure 1A). SARS-CoV-2 PCR was negative. An atypical pneumonia was suspected and the patient was admitted after blood cultures were drawn and a throat swab for PCR of the most common respiratory pathogens was taken, and empirical antibiotic treatment with ceftriaxone and doxycycline was initiated awaiting these results. To investigate the cause of the pitting oedema, a cardiac ultrasound was done which excluded cardiac failure. Nephrotic syndrome and thyroid dysfunction were also ruled out.
The respiratory symptoms and fever did not resolve in the following days and a CT scan was performed which showed extensive ground glass opacities (COVID-19 Reporting and Data System class 5) and subpleural nodular infiltrates that could match interstitial lung disease (ILD) (figure 1B). A second negative PCR ruled out SARS-CoV-2. Subsequently, bronchoalveolar lavage was performed with minor signs of inflammation, and absence of pneumocystis, fungi or signs of viral pneumonitis. As all microbial cultures and PCR on
common respiratory pathogens were negative, a daily dose of 40 mg prednisolone was started. Three days after starting prednisolone, the respiratory symptoms progressed to respiratory failure and the patient was admitted to the intensive care unit (ICU) where he was intubated and supported with invasive mechanical ventilation. We started 1 mg/kg intravenous prednisolone and continued the diagnostic work up. To look further for the cause of this respiratory failure, rheumatoid factor, ANA, ANCA serology and screening for connective tissue diseases were tested but all were negative. We performed age and sex appropriate screening for a malignancy to assess the presence of a paraneoplastic phenomenon, but all tests were negative. Because of generalised pitting oedema and arthritis, inflammatory myositis was suspected and analysis for autoimmune disease was further extended with myositis blot screening for associated autoantibodies. This revealed an anti-Jo-1 titre of 1147 cubic units (ref. <20). Combined with a creatine kinase (CK) concentration of 2021 U/L and the ILD, the diagnosis antisynthetase syndrome (ASS) was confirmed.
The patient was supported by mechanical ventilation for five weeks. Initially, high PEEP and inspiratory pressure was needed due to low pulmonary compliance. After approximately two weeks, pulmonary function improved significantly with decreasing PEEP and inspiratory pressure levels.
After antisynthetase syndrome was established, we started methylprednisolone pulse treatment for three days, as well as cyclophosphamide once every month combined with a three-day course of intravenous immunoglobulins. The course of the anti-Jo-1 titres, CK levels and the administered treatment is shown in figure 2. Loop diuretics were initiated in an attempt to reduce generalised oedema and to improve oxygenation. This was ceased after a few days as we found a hypovolaemic state with ultrasound and urine analysis. Due to progressive renal failure, we started continuous venovenous haemodialysis. Due to high CK concentrations, an EMIC filter was used during the first days. Once the oedema had slowly resolved, hyperkeratosis around the fingertips of both hands (mechanic’s hands) was seen, a sign typical for antisynthetase syndrome. Despite discontinuation of sedation, severe muscle weakness was noted as the patient was able to move only his facial muscles. After 70 days in the ICU, the patient was discharged to the general ward where intensive rehabilitation was continued.
We describe a typical case of antisynthetase syndrome (ASS), a rare disorder with an estimated incidence of 0.56 new patients per 100,000 persons per year. ASS is associated with autoantibodies directed against the aminoacyl-RNAt-complex (anti-ARS). This is a cytoplasmic enzyme that attaches amino acids to the corresponding tRNA. To date, eleven anti-ARS antibodies have been found in association with ASS (table 1).
Anti Jo-1 is most commonly found and accounts for 75% of ASS patients.[4,5] In order to establish the diagnosis of ASS, patients must have positive serological testing for an anti-ARS autoantibody, combined with at least one of the following clinical manifestations: inflammatory myopathy, ILD, fever, Raynaud’s phenomenon, arthritis or cutaneous hyperkeratosis also known as mechanic’s hands. In our patient, the myositis blot demonstrated high anti-Jo-1 antibody titres. All other autoantibodies associated with inflammatory myositis were negative. Other classifying signs in our case were ILD, arthritis, fever, and cutaneous hyperkeratosis.
Several observational studies investigated the clinical profiles of the different autoantibodies. ILD is a common extra-muscular manifestation of autoimmune myositis in general, but has a higher prevalence in ASS. ILD is associated with all subtypes of ASS, with reported prevalences between 80 and 95%.[7,8] Common findings on high-resolution computed tomography scans (HRCT) are non-specific interstitial pneumonia or diffuse ground glass opacities, micronodules, airtrapping or subpleural consolidations.[5,9] ILD can be the first or only manifestation of ASS, especially in patients with anti-PL7, anti-PL12, anti-KS or anti-OJ antibodies. Myositis and severe muscle weakness is more common in anti-Jo-1 and anti-EJ subgroups,[10,11] as well as with anti-OJ antibodies. This is often associated with increased serum CK levels. Most patients with muscle involvement suffer from weakness in the proximal limbs, but also the oesophagus, neck muscles and less frequently the respiratory and cardiac muscles can be affected. The distal muscles are often spared. The diagnosis is typically made by combining HRCT, anti-ARS serology, physical examination and symptoms. Therefore, histological analysis of muscle of lung tissue has no added value.
In the absence of high-level evidence due to small cohorts and case series, there are no international guidelines on the management of ASS.[9,12] Immunosuppressive therapy with corticosteroids is the cornerstone of the treatment. In patients with rapidly progressive ILD induction therapy with methylprednisolone pulse treatment combined with cyclophosphamide or rituximab are advised. Intravenous immunoglobulins might be added as well. Treatment should be tapered gradually in approximately six months, reducing the dose of corticosteroids with 20-25% every month until a daily dose of 5 to 10 mg prednisolone is reached. Maintenance therapy includes low-dose prednisolone, combined with methotrexate, azathioprine or mycophenolate mofetil.
ILD is considered to be the most life-threatening complication of ASS and therefore a good indicator of the prognosis.[13,14] The risk of ILD is also associated with the specific autoantibody present, which explains the differences in prognosis between the autoantibody subgroups. Anti-PL12 and anti-PL7 are associated with a rapidly progressive and severe ILD. In the anti-Jo-1 subgroup, ILD is less prevalent and this subgroup therefore has a better prognosis than non-anti-Jo-1 patients.[7,11,15] In a retrospective cohort of 103 patients with anti-Jo-1 ASS with ILD, the presence of anti-Jo-1 antibodies was associated with a five-year survival of 86%. This is comparable with another study that compared five-year survival between patients with anti-Jo-1 antibodies and those with other antibodies, which showed 90% and 75% five-year survival, respectively. Apart from the type of autoantibodies, other factors that could predict progressive pulmonary disease are male sex, age >55 years, low diffusion capacity, decreased pulmonary forced vital capacity, muscle weakness and high fibrosis score on HRCT. One severe complication associated with ILD is pulmonary hypertension. A study by Hervier et al. found pulmonary hypertension in 7.9% of their study cohort. All of these patients had ILD. The survival in these patients was significantly lower than in those without pulmonary hypertension and with a three-year survival of 58%. A retrospective study in 86 patients with anti-Jo-1 ASS demonstrated that the disease negatively affects quality of life. In this cohort, 15.1% of patients reached remission, 63.9% improved and 20.9% deteriorated. Of those in complete remission, 31% were not able to return to previous normal activities due to fatigue and persistent moderate to severe muscle weakness. Other complications due to immunosuppressive therapy such as opportunistic infections or osteoporosis were also reported. Immunosuppressive therapy could be discontinued in only 4.7% of the cases. This study also found that deterioration of ASS was associated with a higher antibody titre at the time of diagnosis. The correlation between disease activity, measured by serum creatine kinase levels, and anti-Jo-1 titres has been described before. Whereas dermatomyositis is known to be associated with an increased risk of malignancy, this association has not been established for ASS.
ASS should be considered in patients with idiopathic ILD found on HRCT and/or acute respiratory distress syndrome of unknown origin, especially in the presence of other symptoms such as inflammatory myositis, Raynaud’s phenomenon, mechanic’s hands or fever, combined with ASS specific antibodies. ILD, however, can be the first or only manifestation of ASS. Induction therapy with high dose corticosteroids combined with cyclophosphamide, rituximab or immunoglobulins is recommended.
All authors declare no conflict of interest. No funding or financial support was received. Written informed consent was obtained from the patient for the publication of this case report (and the accompanying images).
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