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Malignancy and autoimmunity: causally or casually related?

Coexistent malignancy and autoimmune rheumatic disease requires the physician to explore a causal link. Rheumatic manifestations mimicking autoimmune diseases can precede, accompany or follow the onset of neoplastic disease. Identified links include shared environmental factors such as smoking with rheumatoid arthritis and lung cancer, and a common disease such as inflammatory bowel disease with spondyloarthritis and colon cancer. Long-term and often severe immune stimulus of autoimmune disease has been linked to malignancy of the immune system, and paradoxically, long-term suppression of the immune response as exemplified in organ transplantation, is also linked to risk of subsequent malignancy. Cytokine, hormone and immune-mediated physiology has been implicated in both the causation of malignancy and as a basis of paraneoplastic autoimmune disorders. Within rheumatology, the therapeutic targeting of tumor necrosis factor (TNF) has been a milestone of modern therapeutics. Pro-inflammatory TNF was originally discovered as a factor derived from endotoxin-stimulated macrophages that induced necrosis in tumors, and its inhibition theoretically raised the potential to increase malignancy. Confounding this linear view has been the implication of pro-inflammatory cytokines in the causation of neoplasia, with TNF promoting the growth and spread of several tumors by TNF receptor 1. Occasionally paraneoplastic rheumatism is the basis for symptoms of systemic autoimmune diseases. The medical literature abounds with case-reports and series of patients initially diagnosed with rheumatic disease in whom subsequently a malignancy is identified. The case series by Kisacik et al. in this issue is a reminder of this phenomenon, whereby the paraneoplastic syndrome presents no more than 2 years before the diagnosis of cancer. The authors compared paraneoplastic arthritis (PA) with early rheumatoid arthritis (ERA), two clinically challenging conditions with masquerading common features. Their PA case definition requirement of age over 45 years and predominantly affecting lower limbs and sparing of the small joints of the hands may have influenced their findings of older age in PA compared to the comparator patients derived from an early arthritis trial. Symmetry is often a function of the number of joints involved, with polyarthritis and hence symmetry noted more in the ERA cohort. The measured inflammatory markers were higher in PA despite the lower joint count, perhaps indicative of a greater interleukin (IL)-6 contribution in this illness, although individual cytokine profiles were not studied. No diagnostic factors were identified that categorically differentiate PA from ERA, but PA had a 2 : 1 male : female ratio, whereas ERA was 0.35 : 1. Importantly they confirmed that the presence of rheumatoid factor (RF) or cyclic citrullinated peptide (CCP) antibodies does not exclude PA, and as these tests are part of the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) diagnostic criteria, not surprisingly they were found more commonly in the ERA group. Kisacek et al. found lung and breast cancer were the most common solid tumors, with lymphoma and leukemia the most common hematologic malignancy. Rugiene et al. found PA is a relatively rare syndrome occurring in < 3% of solid tumors and more often in the elderly. In infants presenting with musculoskeletal symptoms, the rate of malignancies is < 0.25%. Identification of discriminating factors for PA remains difficult. Symmetrical small joint polyarthritis occurring after the age of 45 years, with high inflammatory markers in the absence of RF and CCP antibodies has been proposed as a red flag for PA, but the differential is broad for this scenario, and rarely is it malignancy based. Elevated lactic dehydrogenase (LDH) levels warrant investigation as a clue to hematological malignancy in adults and children. Hematological malignancies, including monoclonal gammopathies are another “chicken and egg – malignancy and autoimmunity” scenario. In a small series of four patients by Cho et al. in this issue, the authors highlight the range of autoimmune disorders in which a monoclonal gammopathy (MG) may subsequently be found. In two cases the autoimmune disease and MG were diagnosed at the same time, and emphasises that