Skin melanoma in a rheumatoid arthritis patient treated with infliximab

Tumour necrosis factor a (TNF-α) plays an important role in the pathogenesis of rheumatoid arthritis (RA). Anti-TNF-α agents reduce disease activity of disease-modifying antirheumatic drug (DMARD) refractory RA patients, as monotherapy or in combination with methotrexate. There is evidence of an increased risk of serious infections in RA patients treated with anti-TNF blockers [1, 2]. However, it is not clear whether this kind of therapy increases the risk of malignancy [3-5].

A case report
We report the development of malignant melanoma in a patient treated with infliximab for methotrexate resistant severe RA. A 53-year-old woman with 15-year history of seropositive RA was admitted to our department in July 2005 due to exacerbation of the RA process. In the past she was treated with Salazopyrin at 2 g/day (for 6 years). Three years before admission, therapy with methotrexate (15 mg/week) was started. Due to the lack of improvement, cyclosporine A (3 mg/kg/day) was added to the treatment for three months. That treatment was also ineffective. The therapy with cyclosporine was stopped and the patient was admitted to our department. The patient was qualified for infliximab therapy (3 mg/kg in weeks 0, 2, 6, and every 8 weeks). A rapid and satisfactory improvement in her general clinical condition was observed. After two weeks of therapy, morning stiffness disappeared, ESR and CRP normalized, the number of tender and swollen joints decreased – ACR70 was obtained (treatment with infliximab in combination with methotrexate was effective) (Table I).
In July 2006, during a routine examination before infusion of infliximab, an enlargement of the pigmented naevus on the skin of the right arm was observed. However, the skin around the naevus and its surface was in normal condition. The patient was referred to a dermatologist. Macroscopic features did not suggest malignant character of the skin lesion. The decision of prophylactic excision of the naevus was taken due to immunosuppressive treatment in the immunocompromised patient. On 31 August 2006 the 0.8 cm naevus was resected with a small (0.1–0.3 mm) margin of skin in the oncology outpatient clinic. Histopathological diagnosis was as follows: malignant melanoma epithelioides type SSMM of the skin. Clark III, Breslow 0.4 mm. Immunohistochemical typing revealed HMB45 (+); S100 (+); melanin (+) and confirmed the diagnosis of skin cancer. The immunosuppressive treatment was immediately discontinued. The patient was qualified only for radicalization of excision. The surgery was performed on 6 October 2006. A fragment of the skin and adipose tissue (3 × 2.5 × 1.7 cm) without malignant melanoma was removed. According to the oncologist’s decision, the patient does not require either radio- or chemotherapy. Ultrasonography of the lymph nodes is to be performed every 4 months and self monitoring of the naevus is necessary. In March 2007, ultrasonography of lymph nodes and skin examination did not reveal any pathology (Fig. 1).

Discussion
Many of the medications used in the treatment of RA may be associated with an increased risk of the development of malignancy [1, 4, 6]. There is some evidence of a dose-dependent increased risk of malignancies in patients with RA treated with anti-TNF antibody therapy [5, 7, 8]. Literature data confirm the fact that among patients with RA, the use of TNF inhibitors and prednisone were associated with an increased risk of non-melanoma skin cancers [5, 9, 10].
This case history is the first description of the development of melanoma during infliximab therapy in an RA patient. Systematic control of the pigmented naevus in our patient resulted in early diagnosis of melanoma. Despite the benign clinical features of the lesion, an excision was performed, because of the increased risk of malignancy in RA during DMARD treatment. Histopathological evaluation and immunohistochemistry led to the diagnosis of skin melanoma. The skin cancer was diagnosed before the neoplastic process became generalized [3, 6, 10, 11].
The long-term immunosuppressive effects of TNF-α blockers are unknown. Treatment with biological agents is still too recent for a full knowledge of its long-term safety. Appropriate follow-up is required to define its long-term effect on malignancies and other side effects [12].
The skin changes in our patient appeared 12 months after the onset of therapy. We have no evidence that the described malignancy is directly connected to the applied therapy. However, it seems to us that systematic control of the pigmented naevus during anti-TNF therapy should be strongly recommended. The prophylactic excision of suspected skin lesions can save the lives of our patients.

References
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