{'fraction_non_alphanumeric': 0.03640886476707372, 'fraction_numerical': 0.011533242876526458, 'mean_word_length': 5.19467787114846, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Non-melanoma skin cancer as a possible adverse event due to anti-interleukin-6 treatment

We report the first case of tocilizumab (TCZ)-attributable skin squamous cell carcinoma (SCC) in a 53-yearold male with rheumatoid arthritis (RA). Organ transplant recipients have a particularly increased risk of skin cancer, especially SCC, owing to the need for long-term immunosuppression. A doseand drug-dependent relationship has been established for well-known immunosuppressive drugs such as ciclosporin and tacrolimus (1). Some anti-tumour necrosis factor-α (anti-TNF-α) drugs may also increase the risk of skin cancer (2). Recently, malignant melanoma was reported as a possible adverse event associated with TCZ treatment in a patient with RA (3). A 53-year-old Caucasian man was referred to the Department of Dermatology with a histologically proven actinic keratosis on his right nasal ala that had been refractory to standard treatment. The lesion was recalcitrant to removal by punch biopsy and repetitive cryotherapy. Total skin examination showed no further suspicious lesions or signs of regional lymphadenitis. His prior medical history included seropositive, anti-cyclic citrullinated peptide antibody-positive erosive RA (diagnosed 3 years earlier). He reported no prior skin disease or allergies. Current medications included subcutaneous injections of methotrexate (MTX), TCZ (RoACTEMRA®), folic acid, ibuprofen, paracetamol, and supplements of calcium and vitamin D. Earlier treatments in previous years included sulphasalazine for 6 weeks, hydroxychloroquine for 4 months, and certolizumab pegol for 2 months. Planned daylight photodynamic therapy was delayed for 5 weeks because of bad weather. An incomplete treatment response was noted and topical treatment with ingenol mebutate 150 μg/g daily for 3 days was prescribed. After 4 weeks, treatment failure was observed again and malignancy was suspected. The lesion had progressed substantially in that time, with two additional punch biopsies again showing only actinic keratosis. Based on a clinical suspicion of SCC, a wide excision and reconstruction was performed. Radical surgery was confirmed by frozen sections. Excision included removal of the right lateral wall, tip segment including the upper lateral cartilage and mucosa, the soft triangle, and lower dorsal and tip segment (Figure 1). Reconstruction was performed with a right nasolabial flap as the lining and a three-stage forehead flap as the outer lining. A free composite helical ear graft was used to reconstruct the soft triangle in the three-stage operation. The initial pathology report showed perineural invasion close to the resection margins; however, additional biopsies during the second stage surgery 4 weeks later showed no residual tumour. Unfortunately, partial necrosis of the forehead flap developed, which necessitated a fourth stage operation. Immunosuppression is associated with an increased risk of various neoplasms. In organ transplant recipients, the risk of non-melanoma skin cancer, primarily SCC, is increased over 50 times (1). Not only the degree of immunosuppression but also the specific target affects the risk. For example, mammalian target of rapamycin (mTOR) inhibitors exert a lower risk of skin malignancy compared with calcineurin inhibitors (4). More recently, TNF-α inhibitors were reported to increase the risk of skin cancer (2), but a clear relationship was not confirmed in a metaanalysis (5). The analysis was, however, limited by only 1 year of follow-up, whereas skin cancer does not usually appear in the first 5 years (6). TCZ is an anti-interleukin-6 (anti-IL-6) drug reserved for severe RA. Invasive tumour growth only months after the initiation of TCZ therapy suggests a possible causal relationship, with a Naranjo score of 2 [i.e. an adverse event occurred after drug initiation (+2), possible alternative causes (−1), supporting evidence that the drug was to blame (+1)] (7). We hypothesize that TCZ-induced up-regulation of epidermal growth factor (EGF) and its receptors could play a pivotal role in SCC development (8). EGF-receptor upregulation during TCZ therapy, was recently shown in a paper on treatment of ovarian cancer cell lines (9). Furthermore, we speculate that TCZ may have disrupted the inhibitory impact of IL-6 on a pre-existing indolent actinic keratosis, triggering perineural 82 Scand J Rheumatol 2019;48:82–84