Pathways Case Record: Myositis Associated Interstitial Lung Disease

A 22-year-old man with no significant medical history presented with subacute progressive muscle aches, lower extremity weakness, fever, and labored breathing, ultimately complicated by acute hypoxemic respiratory failure. He experienced body aches, stiffness, soreness, and bilateral leg weakness for approximately six weeks prior to presentation and a sore throat and malaise during the initial onset. At the time of symptom onset, the patient routinely performed upwards of 500 pushups daily, which was an increase in activity level. The patient developed shortness of breath without cough, prompting him to report to urgent care and then admitted to an outside hospital.

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Initial evaluation was notable for hypoxia, fever, and high white blood cell counts, suggesting an infection. He was treated with antibiotics and supplemental oxygen. Chest CT raised concerns for interstitial lung disease (ILD). Infectious, inflammatory, and rheumatologic evaluations were unremarkable. Additional tests were notable for elevated creatine kinase and myoglobin in the urine, elevated serum creatinine, high white blood cell count (neutrophilic predominance), the presence of immature blood cells, elevated procalcitonin, presence of antinuclear antibodies (ANA) and multiple autoantibodies, and high C-reactive protein levels. There was suspicion of rapidly progressive inflammatory disease leading to ILD and myopathy leading to rhabdomyolysis. He received a pulse dose of solumedrol and was intubated due to worsening hypoxia.

Two days later, he was transferred to Massachusetts General Hospital for worsening acute respiratory distress syndrome (ARDS). Veno-venous extracorporeal membrane oxygenation (vvECMO) was initiated. In addition to the notable test results above, additional testing at Mass General revealed elevated aldolase and ferritin levels, additional positive results for autoantibodies, and a high erythrocyte sedimentation rate (ESR). The serum toxicology screen performed after intubation revealed positivity for fentanyl and benzodiazepines, otherwise negative. At Mass General, he received methylprednisolone intravenously for 10 days until initiating prednisone daily, which he remains on. The immunosuppressant mycophenolate mofetil (MMF) was started before transfer; he received two infusions of rituximab and a series of intravenous immune globulin treatments. The patient is currently being considered for lung transplant evaluation.

The Pathways Consult Service in the Department of Medicine at Mass General was consulted and focused on the inflammatory profile in this patient, driven by three questions:

1. What is the driving factor of this myositis?
2. What anti-tRNA synthetase may be involved in this case?
3. How do the treatments available for anti-synthetase syndrome work?

Background and Diagnosis

Inflammatory myopathies are a heterogeneous group of connective tissue diseases associated with muscle inflammation. Not all cases present with muscular symptoms, and many systems can be affected, including pulmonary, cardiac, dermatologic, vascular, and gastrointestinal. These myopathies are usually associated with several auto-antibodies, including anti-Jo1 and anti-MDA5. When an antibody against a synthetase enzyme is present, such as anti-Jo1 (anti-histidyl tRNA synthetase), the clinical syndrome of inflammatory myopathy is called an anti-synthetase syndrome. These clinical syndromes most commonly cause muscle breakdown, proximal weakness, pulmonary inflammation and fibrosis, skin changes including the Raynaud phenomenon and mechanic's hands, and joint disease. Anti-synthetase syndrome is not usually associated with rhabdomyolysis or severe lung disease, although both are documented in the literature (J Thorac Dis, Eur J Rheumatol). Given our patient's constellation of symptoms, including autoantibody positivity of anti-Jo-1 and anti-Ro-52, we predict he has an anti-synthetase syndrome, despite the absence of other features.

Treatment for anti-synthetase syndrome broadly includes immunosuppression or immune-modulatory therapies, including glucocorticoids, mycophenolate mofetil, cyclophosphamide, intravenous immune globulin (IVIG), and rituximab. Based on the impact of these various treatments on specific aspects of the immune system, we can begin to decipher which parts of the immune system play a role in the pathogenesis of inflammatory myopathies, including anti-synthetase syndrome. Rituximab and IVIG are often used in more severe cases or those with antibody positivity (including anti-Jo1 and anti-Ro-52). Rituximab is a monoclonal chimeric antibody to CD20 that depletes the peripheral population of CD20+ B cells. Rituximab was effective in a multicenter retrospective case review of anti-synthetase ILD and was most effective in those who had failed pulse dose steroids or other traditional immunosuppressives (J Rheumatol). The efficacy of rituximab treatment of anti-Jo1 or anti-Ro52 positive anti-synthetase syndrome has also been studied. In a cohort of 61 patients, a subgroup of 7 with highly positive anti-Ro52 antibodies demonstrated a failure to traditional immunosuppressants, but a brisk response to rituximab with regards to both myositis and ILD symptoms (J Rheumatol).

Despite the extensive associations between various auto-antibodies and idiopathic inflammatory myopathies, they are more correlative than causative. How these antibodies contribute to the progression of the disease remains unclear. Additionally, it is becoming increasingly clear that IVIG and rituximab, which were traditionally believed to act on reducing B cell response, also reduce T cell responses. More recent studies revealed an essential modulatory effect on CD4+ helper T cells, which is thought to ultimately lead to the symptom improvement observed in certain rheumatologic conditions, including rheumatoid arthritis (Arthritis Rheum). This supports the hypothesis that although antibodies produced by B cells are present in inflammatory myopathies (e.g., anti-synthetase syndrome), they may not be the only portion of the immune system involved in the pathogenesis of these diseases. T cells are likely playing a parallel and, possibly, causative role. Indeed, in primary biliary cholangitis, destruction of the bile duct is mediated by cytotoxic T cells rather than humoral response despite increased auto-antibodies to the same antigen. In inflammatory myositis, B cells undergo class switching (indicating helper T cell involvement), and clonal cytotoxic T cells are present in muscle biopsies (indicating cytotoxic T cell involvement) (J Exp Med, J Clin Invest, J Immunol).

Summary and Future Steps

We suspect our patient has anti-synthetase syndrome, but further diagnostic studies (e.g., muscle MRI, electromyography, or muscle biopsy) are needed. These tests were done since they would be unlikely to change clinical management for the presumed anti-synthetase syndrome. Further studies are needed to understand better the mechanism(s) of idiopathic inflammatory myopathy. Based on the literature, we hypothesize that idiopathic inflammatory myopathies are mediated by both B cells and T cells.

To test this hypothesis, we propose three-pronged approaches:

1. Identification of auto-antibody/antigen pair(s) through immunohistochemistry analysis of patient lung, muscle, and serum samples. This would determine which cell types are targeted by the antibodies and which subcellular compartment. We could also leverage tandem mass spectrometry, to identify protein interactors of the antibodies.
2. Utilize paired T cell receptor and RNA sequencing from patient's lung or muscle tissue samples, draining lymph nodes, or peripheral blood samples to identify targets of the T cell receptors (Nat Methods). Identification of clonal T cell population with the same T cell receptor sequence would strongly suggest T cell involvement to self-antigen in the disease. Finally, pairing the clonal information with disease progression or treatment response will help identify disease-relevant cell types.
3. Perform whole-exome sequencing to find unique mutations along the tRNA-synthetase/E3 ubiquitin ligase pathways that may have predisposed our patient to (fulminant) disease.

There are many significant clinical implications of our proposed studies. First, identifying precise mechanisms of the disease will enable us to achieve a more precise immunosuppression. Current treatments with steroids, IVIG, or rituximab have broad immunosuppression as well as side effect profiles. For example, if we identify a T cell subpopulation driving the disease, we may be able to target this population to achieve disease remission while minimizing side effects. Second, as we begin to better understand the mechanisms of anergy pathway for immune tolerance (involving PD-1 and CTLA-4), we may be able to induce selective immune tolerance to self-antigen that may be curative of autoimmune diseases (Front Immunol). Indeed, abatacept (which combines the extracellular domain of CTLA-4 with Fc region of human IgG) modulates the anergy pathway and has been approved for the treatment of rheumatoid arthritis refractory to biologics such as TNF-a antagonist. It is critical to identify the culprit self-antigen(s) for the disease.

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