Anti-synthetase syndrome masquerading as recurrent pneumonia
- Ka U Lio and
- Si Li
- Medicine, Temple University Hospital, Philadelphia, Pennsylvania, USA
- Correspondence to Dr Ka U Lio; kau.lio@tuhs.temple.edu
Abstract
Anti-synthetase syndrome (ASS) is a rare inflammatory myopathy with a wide variety of clinical presentations. ASS-related interstitial lung disease (ASS-ILD) presents with rapid onset and progression, which could often be confused with other more common acute processes such as pneumonia, especially when ILD can be the sole manifestation. A woman in her 50s presented with recurrent dyspnoea for 2 months requiring multiple hospital admissions, and each time, she was diagnosed with multifocal pneumonia and treated with antibiotics. On admission, the evaluation revealed a markedly elevated creatine kinase level at 3258 U/L and a CT scan of the chest revealed worsening scattered ground-glass opacities. Given the concern for ILD as the cause of antibiotic failure, she underwent bronchoscopy with bronchoalveolar lavage which revealed non-specific interstitial pneumonia. A subsequent myositis panel revealed a positive anti-Jo-1 antibody, and she was diagnosed with ASS-ILD. She completed a course of intravenous immunoglobulin and methylprednisolone and experienced significant clinical improvement with the resolution of hypoxaemia and improved polyarthralgia.
ASS could often be misdiagnosed as other more common acute lung processes, as a clinically subtle course can escape detection given its rarity, as well as its non-specific and highly variable presentations. This case highlights the importance of early suspicion and consideration of performing specific autoantibody testing when evaluating patients with a suspicion of undifferentiated autoimmune condition.
Background
Anti-synthetase syndrome (ASS) is a rare inflammatory myopathy defined by the presence of an antibody directed against one of several aminoacyl-transfer RNA (tRNA) synthetases. The initial clinical presentation and plain chest radiographs are usually non-specific and may mimic infection,1–5 especially in the COVID-19 era. We hereby present a case of a woman in her 50s with ASS who had previous misdiagnoses. Greater awareness of this syndrome is needed for earlier diagnosis and treatment.
Case presentation
A woman in her 50s with a medical history of morbid obesity, migraine, hypothyroidism, essential hypertension, depression and tobacco dependence presented with recurrent dyspnoea on exertion, cough and polyarthralgia.
Prior to her presentation at our institution, she had multiple visits and was hospitalised twice. In the first hospitalisation, she presented with cough, dyspnoea, fever and scattered bilateral ground-glass opacities on imaging (figure 1A,B). She was diagnosed with sepsis and treated with antibiotics (intravenous ceftriaxone 1 g daily and oral azithromycin 500 mg daily for 5 days) for multifocal pneumonia, as well as intravenous methylprednisolone 0.5 mg/kg for 5 days for possible COVID-19 infection given a compatible clinical presentation and radiographic findings. Her symptoms were later attributable to smoking-related pneumonitis after a negative infectious workup (including COVID-19) and steroids were continued as her symptoms improved with steroids. A month later, she was hospitalised for the second time due to persistent dyspnoea and new onset of joint pain. Workup at that time was notable for elevated creatine kinase (CK) at 646 U/L, C reactive protein at 6.79 mg/dL and sedimentation rate at 71 mm/hour. Rheumatoid factor, cyclic citrullinated peptide and antinuclear antibody were negative. She was treated again with antibiotics (intravenous vancomycin 15 mg/kg every 12 hours and piperacillin–tazobactam 4.5 g every 8 hours for 7 days) and steroids (prednisone 40 mg daily) for joint pain, and eventually discharged home with a prolonged 2-week steroid taper and instructed to follow up with rheumatology for further workup.
(A,B) Chest CT scan at initial presentation: diffuse bilateral ground-glass opacities in bilateral lungs, consistent with multifocal pneumonia including atypical/viral pneumonia. (C,D) Chest CT scan after antibiotic treatment: worsening scattered ground-glass opacities, some of which are peripheral and some of which are peribronchovascular. (E,F) Chest CT scan after treatment with immunosuppressive therapy: scattered ground-glass in the bilateral lungs, overall decreased in size. (G,H) Chest CT scan at follow-up: redemonstrated peripheral-based interstitial reticulation with patchy parenchymal ground-glass opacities predominantly in the lower lobes.
She re-presented at our institution as her symptoms worsened again at the end of the steroid taper. A review of system was notable for severe pain and swelling in the small joints of her hands, diffuse myalgias, generalised weakness and intermittent fevers. She denied erythema, rashes or photosensitivity. She further denied any recent sick contacts, international travel history, or a family history of cancer or rheumatic diseases.
On presentation, vital signs were as follows: temperature of 98.8°F, heart rate of 107 beats/min, blood pressure of 152/88 mm Hg, respiration of 18 breaths/min and oxygen saturation of mid-80% on room air which improved to 96% on 3 L of oxygen. On examination, the patient was unable to speak in full sentences and noted to have bibasilar rales, scattered rhonchi and wheezing on lung auscultation. The musculoskeletal examination was notable for swelling and tenderness in multiple metacarpophalangeal, distal and proximal interphalangeal joints associated with a limited range of motion. Neurological examination was normal except for reduced muscle strength as follows: 3/5 in bilateral deltoids and iliopsoas, 4/5 in bilateral biceps, triceps, knee flexors and extension. The rest of the examination was notable for thickened, fissured and scaly skin on the digits of both hands.
Investigations
Laboratory evaluation revealed chronic leucocytosis at 21.9 x109/L without bandemia, normal lactate and an elevated CK at 3258 U/L. Extensive infectious workup was negative, including blood culture, sputum culture, COVID-19 nasopharyngeal swab and serum IgG, urine streptococcal antigen and urine Legionella antigen. A CT pulmonary angiogram was performed, which showed no pulmonary embolism but revealed worsening scattered ground-glass opacities, some of which were peripheral and some peribronchovascular (figure 1C,D). Given the concern for interstitial lung disease (ILD) as a cause for antibiotic failure from prior hospitalisation, further autoimmune workup was sent, and she underwent bronchoscopy with bronchoalveolar lavage. The results of the bronchoscopy revealed benign lung tissue, focal mild fibrosis and chronic inflammation with intra-alveolar pigmented macrophages, mild anthracosis and reactive pneumocytes, consistent with non-specific interstitial pneumonia.
Intravenous antibiotics were initially started for sepsis with a presumed pulmonary source and discontinued after a negative infectious workup. Intravenous steroids were also started for possible ILD which later transitioned to a steroid taper while waiting for the results of most autoimmune workup. The subsequent myositis panel returned with a positive anti-Jo-1 antibody and negative melanoma differentiation-associated gene-5 antibody. Results of other workups, including hypersensitivity pneumonitis panel, antineutrophil cytoplasmic antibody, anti-scleroderma-70 antibody, RNA polymerase antibody, anti-dsDNA antibody, anti-smith antibody, anti-SSA antibody and anti-SSB antibody, were negative.
Treatment
After multidisciplinary discussions with pulmonology and rheumatology, she was diagnosed with ASS, and the decision was made to initiate inpatient immunosuppressive therapy. She received a 5-day course of intravenous immunoglobulin (IVIG) at 2 g/kg and intravenous methylprednisolone 1 g for 3 days followed by a taper. The patient showed significant clinical improvement with the resolution of hypoxaemia and polyarthralgia. A repeat CT revealed a decrease in the size of scattered ground-glass opacities (figure 1E,F). She was eventually discharged with mycophenolate mofetil 1000 mg two times per day and prednisone taper (40 mg for 7 days, 35 mg for 7 days, 30 mg for 7 days, 25 mg for 7 days and 20 mg for 7 days).
Outcome and follow-up
A follow-up CT scan after 3 months revealed stable peripheral-based interstitial reticulation and ground-glass opacities (figure 1G,H). Unfortunately, the patient developed headaches, fatigue, nausea and vomiting following the second round of IVIG infusion. Subsequent workup revealed a thrombus formation in the aortic arch (figure 2). A hypercoagulable workup was performed, but no significant findings were identified except for an indeterminate level of anticardiolipin IgM. The formation of aortic thrombus was believed to be related to IVIG therapy or underlying ASS, and the decision was made to discontinue IVIG. The patient was started on rituximab and had close follow-ups with rheumatology, pulmonary, physical therapy and rehabilitation. A subsequent repeat hypercoagulable workup yielded negative results, and the anticardiolipin IgM level was normal. After a shared risk-and-benefit discussion with the patient, anticoagulation was discontinued.
(A) Coronal view and (B) transverse view. A filling defect adherent to the anterior wall of the distal aortic arch consistent with intraluminal thrombus.
Discussion
ASS is a rare autoimmune disorder with an incidence ranging from 1.2 to 2.5 cases per million.6 7 ASS is a subtype of idiopathic inflammatory myositis, a heterogeneous group of systemic autoimmune disorders of unclear aetiology.8 The development of ASS is believed to occur in individuals who are genetically susceptible and exposed to chronic immune system activation and environmental factors.9 The correlation between tobacco use and the development of ASS has been previously reported,10 11 which may be relevant in our case given the patient’s history of smoking.
ASS is characterised by the presence of autoantibodies against aminoacyl-tRNA and thus far eight tRNA synthetases have been described.12 Among these, the most common antibody is anti-Jo-1 (anti-histidyl-tRNA synthase antibody), which accounts for 60% of all tRNA antibodies in one cohort study.13 ASS has a wide variety of clinical presentations which include myositis, arthritis, ILD, Raynaud’s phenomenon, fever and mechanic’s hands.14 15 Patients with a positive Jo-1 antibody most often present with the classic triad of myositis, ILD and arthritis, although only a minority of patients (19% in one study) exhibit the full triad at disease onset.14 Arthritis tends to be symmetrical and involves the wrist, metacarpophalangeal and proximal interphalangeal joints.14 In our case, the recurrence of joint pain, along with persistent dyspnoea with evolving ground-glass opacities despite completion of antibiotics, raises suspicion for undifferentiated autoimmune conditions involving the lungs, muscles and joints. This prompts the need for further autoimmune workup, including myositis antibody screening.
Compared with other inflammatory myopathies such as dermatomyositis or polymyositis, ASS has a higher prevalence of ILD with a rapid and progressive course, which can be easily mistaken for other more common, acute lung processes such as pneumonia. Several case reports have documented instances where ASS was initially misdiagnosed as pneumonia, as summarised in table 1. In our case, the patient experienced subtle and non-specific symptoms, leading to a misdiagnosis of multifocal pneumonia on multiple occasions before the correct diagnosis was made. The time from symptom onset to diagnosis was 4 months.
Summary of published cases of anti-synthetase syndrome being misdiagnosed as pneumonia
Summary of published cases of anti-synthetase syndrome being misdiagnosed as pneumonia
A multitude of non-infectious diseases can mimic infection and fail to respond to antibiotic regimens until the correct diagnosis is established. Common non-infectious mimickers of pneumonia include pulmonary oedema, thromboembolic disease, lung cancer, immunological causes such as Wegener’s granuloma, cryptogenic organising pneumonia, pulmonary alveolar proteinosis and sarcoidosis. The first step of investigation should always involve a thorough review of the patient’s history and initial microbiological results. Important epidemiological clues may indicate the presence of unusual microorganisms, warranting a more aggressive approach when the aetiology remains unknown. A multidisciplinary evaluation involving rheumatology and pulmonary, along with specific serological and radiographic assessments, is critical for an accurate diagnosis. In our case, bronchoscopy played a significant role in confirming the diagnosis through tissue sampling and direct visualisation of the airways.
ASS remains a diagnostic challenge as clinically subtle disease can escape detection given its rarity as well as its non-specific and highly variable clinical presentations. In addition, tests for myositis-specific antibodies are often not ordered in the initial evaluation of patients with polyarticular pain, as in our case, and the diagnosis of ASS is often delayed leading to increased morbidity. Paradoxically, the patient experienced partial improvement of symptoms after being treated for non-specific airway inflammation by steroids which was falsely interpreted as a response to antibiotics on previous admissions. There are two proposed classification criteria for ASS, and both of which require the presence of an anti-tRNA synthetase antibody along with specific clinical features.16 17 Table 2 demonstrates the two classification criteria for ASS.
The two classification criteria for anti-synthetase syndrome
| Connors et al16 | Solomon et al17 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| ILD, interstitial lung disease. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Anti-synthetase antibody plus one or more of the following:
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Anti-synthetase antibody plus two major criteria or one major and two minor criteria:
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Ethics statements
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Footnotes
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Contributors The following author was responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content—KUL. The following authors gave final approval of the manuscript—KUL and SL.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.
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