Acute presentation of rheumatoid arthritis following cancer chemotherapy using the topoisomerase I inhibitor irinotecan

A 57 year old man presented with abdominal pain and low-grade fever for one month. Computerised tomography/positron emission tomography (CT-PET) scanning suggested a tumour in the ascending colon. Laparoscopic right hemicolectomy was performed, and revealed a moderately-differentiated adenocarcinoma associated with serosal penetration, lymphovascular invasion, and multiple peritoneal tumour deposits. Postoperatively he received twelve cycles of palliative chemotherapy consisting of 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) with relief of abdominal discomfort. Immediately following cessation of chemotherapy, however, he developed generalized arthralgia with pain and swelling affecting the small joints of both hands, as well as both shoulders, associated with mild fever and no deformity. Repeat CT-PET scan confirmed static stable disease. Laboratory results revealed a mild anemia, normal liver and renal function, and normal serum alkaline phosphatase and calcium levels. A bone scan showed no evidence of metastases, whereas skeletal survey confirmed arthritic changes in the small joints of hands with no erosion. Inflammatory markers were elevated, with an erythrocyte sedimentation rate of 109 mm/hr and C-reactive protein level of 4.25 (mg/dl). Antinuclear antibody (ANA), C3 and C4 levels were normal, but rheumatoid factor (RF) was markedly elevated (849 IU/ml). A diagnosis of acute rheumatoid arthritis was made, and symptom relief was rapid following initiation of oral steroids.

Since colonic cancer and rheumatoid arthritis are both common diseases, isolated anecdotes of their simultaneous occurrence may well reflect the play of chance [1], [2]. In fact, the incidence of colonic cancer is significantly reduced in patients with well-established rheumatoid arthritis [3], [4], presumably due to the chemopreventive effects of chronic non-steroidal anti-inflammatory drug ingestion [5–7]. Recently, however, rheumatoid-like polyarthritis has been reported as a presenting symptom of colon cancer [8], in which disorder rheumatoid factor seropositivity correlates with stage [9]. A further well-recognized association is that of rheumatoid arthritis exacerbation following termination of cancer chemotherapy [10–12].

Of particular relevance to the present case is the use of the topoisomerase I enzyme inhibitor irinotecan, which has recently become a popular component of colon cancer chemotherapy [13]. Antibodies to topoisomerase I have long been recognized as a diagnostic marker of autoimmune rheumatic disease [14]; since such antibodies functionally inhibit topoisomerase I activity [15], a direct role in the pathogenesis of rheumatic disease is plausible [16]. Moreover, antibodies to topoisomerase I appear to identify rheumatic disease patients with underlying malignancies [17].

To our knowledge, the present report is the first to document an acute onset of florid rheumatoid factor-positive polyarthritis in association with chemotherapy for metastatic colon cancer using topoisomerase I inhibitors. Clinicians treating such patients are advised to be aware of this potential iatrogenic association, and to undertake appropriate serological investigation in the event of symptoms. It is intriguing to speculate that catalytic topoisomerase I inhibition may either have contributed directly to this presentation, or else triggered a compensatory upregulation of topoisomerase enzyme expression, creating testable hypotheses for future research into the pathogenesis and/or therapy of autoimmune rheumatic disorders.