Pathways Case Record: Investigating Paraneoplastic Autoimmunity: A Case of Dermatomyositis in a Patient With Rectal Adenocarcinoma

A 55-year-old woman with a history of resected rectal adenocarcinoma was admitted for progressive proximal muscle weakness and rash. Following a previous diagnosis of rectal adenocarcinoma, she underwent neoadjuvant chemotherapy with FOLFOX followed by chemoradiation with capecitabine. The tumor was completely resected eight months after diagnosis.

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After completing her cancer treatment, the patient felt well overall for approximately a year until she had surgery for hip osteoarthritis. As she recovered from surgery, she noticed prominent weakness in her hips and shoulders, which she attributed to deconditioning. The weakness progressed for two months when she presented to her primary care physician. Her symptoms continued to progress and thus, she was admitted one month later with diffuse rash and muscle weakness.

Upon admission, she was noted to have elevated creatine kinase (CK) and transaminases. Her skin biopsy was inconclusive. Femur MRI revealed myositis, with the most prominence observed in the anterior compartments. A muscle biopsy of the left thigh revealed inflammation consistent with dermatomyositis but with some atypical signs leading to the diagnosis of inflammatory myositis overlap syndrome. Serologic antibody testing showed high titers of antinuclear antibodies (ANA) and anti-dsDNA. A comprehensive myositis antibody panel was negative for anti-Jo1, anti-TIF1-γ, anti-NXP2, and anti-MDA-5 but positive for anti-PM/SCl100.

The Pathways Consult Service in the Department of Medicine at Massachusetts General Hospital was consulted and focused on the potential association between autoimmune diseases and malignancies, which was driven by two questions:

1. Does the patient have dermatomyositis?
2. Does she have a paraneoplastic autoimmune disease?

Background and Diagnosis

Dermatomyositis is a rare inflammatory disease marked by skin rash and muscle weakness. Criteria for classification of various idiopathic inflammatory myopathies (such as dermatomyositis) include clinical manifestation (e.g., muscle weakness and cutaneous findings), involvement of other organ systems, biochemical markers, and muscle biopsy features (Ann Rheum Dis). Our patient met multiple criteria for dermatomyositis, including biochemical markers (elevated CK and transaminases) and some pathological features on the muscle biopsy. However, overlap in serologic and histologic with other myopathies and connective tissue disorders complicates proper diagnosis.

Known myositis-specific antibody profiles may shed insight into additional aspects of the clinical phenotype presented in the patient (Clin Rev Allergy Immunol). For example, patients with antibodies against Jo-1, EJ, and PL-7 often present with anti-synthetase syndrome. Interestingly, the TIF1-γ antibody is strongly associated with malignancy (Curr Opin Rheumatol). This led us to wonder whether this antibody may represent the link between her prior malignancy and current presentation; however, TIF1-γ autoantibody was not present in our patient. Although our patient had elevated ANA, suggesting the presence of numerous autoantibodies, the only positive antibody with the myositis-associated anti-PM-Scl100, which is not specific for dermatomyositis. Since the antibody panel did not provide significant insights, the Pathways Consult Service team was interested in what antibodies were measured during the ANA assay.

Current dermatomyositis literature does not demonstrate strong evidence of genetic inheritance or viral etiology. Still, it does provide some evidence for connections between environmental exposures (UV radiation, hydroxyurea) (Arthritis Rheum, Australas J Dermatol) and malignancy (Arthritis Rheumatol). Malignancy may trigger dermatomyositis through autoimmune processes. Indeed, a link between cancer and autoimmunity was recently described in a study showing anti-RNApol3 in scleroderma (Arthritis Rheumatol). In this case, a missense mutation in the tumor genome led to the development of a neoantigen and subsequent autoantibody production. These findings, coupled with a history of rectal adenocarcinoma, led us to hypothesize that the malignancy was driving the autoimmune condition in our patient.

Based on our current understanding of dermatomyositis and our patient's medical history, we propose two potential mechanisms for her condition:

1. Her immune system is reacting to tumor-produced neoantigens (from either occult recurrence of rectal cancer or development of a second malignancy), leading to autoimmunity
2. She has unidentified circulating autoantibodies that bind to antigens typically present in skin and muscle tissue

Investigating the neoantigens through whole-exome sequencing of the tumor and observing antigen-T cell interactions may provide a critical window into our patient's disease presentation. Additionally, isolating autoantibodies in circulating plasmablasts (immature plasma B cells) and subsequent sequencing for heavy and light chains would enable us to map clonally dominant sequences. We could then reverse engineer the monoclonal antibody and introduce these to the patient sample to isolate the antigen(s) contributing to disease in our patient.

Summary and Future Steps

The term "dermatomyositis" represents a diagnostic box defined by clinical and histologic observations that do not reflect the true complexity and heterogeneity of the underlying disease pathophysiology of the disease. Previous studies have established a connection between malignancy and the formation of autoantibodies in scleroderma, leading our team to hypothesize a similar phenomenon in our patient. Following consultation with our panel of experts, we designed a series of experiments to establish whether this was truly a driving factor in the disease. Although these complex experiments would require years of work, our exploration into the connection between malignancy and autoimmune disease culminates in two clinical recommendations:

1. Our patient should be thoroughly screened for other malignancies, including a transvaginal ultrasound for ovarian cancer
2. Shorter intervals should be implemented for age-appropriate cancer screenings in a patient with dermatomyositis

Learn more about the Pathways Consult Service at Mass General

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