Tocilizumab-induced erythroderma

ARTICLE

Auteur(s) : Motonobu Nakamura, Yoshiki Tokura

Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan

Tocilizumab is a humanized anti-human interleukin 6 receptor (IL-6R) antibody, engineered by grafting the complementarily determining regions of a mouse anti-human IL-6R antibody into human IgG1 to create a human antibody with a human IL-6R binding site [1, 2]. Tocilizumab binds to the IL-6 binding site of human IL-6R and competitively inhibits IL-6 signaling. A series of clinical studies have shown that inhibition of IL-6 signaling by tocilizumab is therapeutically effective in Castleman disease and rheumatoid arthritis (RA). In Japan, tocilizumab began to be widely used for patients with Castleman disease and RA refractory to other therapies in 2005 and 2008, respectively. We report a 62-year-old Japanese woman who developed erythroderma after administration of tocilizumab for her RA.

Twenty four years before our first examination, the patient was diagnosed as having RA because of multiple arthralgia. Although she took oral non-steroidal anti-inflammatory drugs (NSAID), oral corticosteroid and methotrexate, the arthralgia gradually worsened. She was referred to our hospital for further treatment of RA. The patient began to receive an intravenous injection of tocilizumab, 280 mg (8 mg/kg) once per month. Two days after the first injection, the patient noticed a slight erythematous eruption on her face, which subsided in a few days. One day after the second injection, she again developed erythema on the face to chest, although, it disappeared in a few days without any treatment. A few hours after the third injection of tocilizumab, generalized erythema developed on the whole body with severe itch (figure 1). There was no oral exanthema. A peripheral blood sample showed a normal leukocyte count of 4800/μL (Normal: 3500-9500) with 15.9% eosinophils (763/μL). The serum levels of hepatic enzymes were within normal ranges. She had neither a high fever nor lymph node swelling, suggesting that she did not suffer from viral infection. We could not obtain her informed consent for a skin biopsy. Since the eruption and eosinophilia occurred in accordance with the drug injection, we diagnosed her erythroderma as a skin eruption due to tocilizumab. Since we could not obtain her informed consent for further examinations, we did not perform skin patch testing or lymphocyte stimulation tests. The administration of tocilizumab was discontinued and the erythroderma subsided in a week with topical betamethasone butyrate propionate alone.

Tocilizumab inhibits the signaling of IL-6, an important inflammation moderator. Several kinds of serious adverse events due to tocilizumab have been reviewed by Nishimoto N et al. [3]. Infections such as pneumonia, herpes zoster, acute bronchitis and pyelonephritis are the most frequently observed side effects. However, aside from herpes zoster, only one case of cutaneous adverse effects of tocilizumab has been reported in the English literature [4]. In that report [4], an initial injection of tocilizumab induced numbness and purpura in all four extremities. The purpuric lesion on the left lower limb became necrotic and was treated with a steroid-pulse therapy, resulting in complete epithelializaion of the ulcer and improvement of numbness. The changes may have been due to the direct biological or toxic effects of tocilizumab, or to immune-complex mediated vasculitis associated with skin ulceration with RA. On the other hand, our case was characterized by erythroderma and hypereosinophilia, which was aggravated on each injection. It is suggested that an allergic reaction to tocilizumab underlies the pathogenesis.

In certain transgenic mice, the overexpression of IL-6 under a keratin 14 promoter led to a thicker stratum corneum and retarded hair growth without cutaneous leukocytic infiltration [5]. This raises the possibility of a future therapeutic use of tocilizumab for skin diseases, such as psoriasis. However, it should be kept in mind that tocilizumab might induce severe drug eruptions such as erythroderma, as seen in our patient.

Acknowledgements

References

2 Nishimoto N, Terao K, Mima T, Nakahara H, Takagi N, Kakehi T. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood 2008; 112: 3959-64.

3 Nishimoto N, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Azuma J. Long-term safety and efficacy of tocilizumab, an anti-interleukin-6 receptor monoclonal anitibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5-year extension study. Ann Rheum Dis 2008; (in press).

4 Sugiura F, Kojima T, Oguchi T, et al. A case of peripheral neuropathy and skin ulcer in a patient with rheumatoid arthritis after a single infusion of tocilizumab. Mod Rheumatol 2008; (in press).

5 Turksen K, Kupper T, Degenstein L, Williams I, Fuchs E. Interleukin 6: insights to its function in skin by overexpression in transgenic mice. Proc Natl Acad Sci USA 1992; 89: 5068-72.