Addition of Cyclosporine to Adalimumab Improved Psoriasis And Adalimumab-Induced Injection Site Reaction

Sir,

Adalimumab, the first fully human therapeutic monoclonal antibody that blocks tumor necrosis factor-α (TNF-α), is used for the treatment of psoriasis.[1] One adverse event known to occur after injection of adalimumab is injection-site reaction (ISR), the mechanism of which remains unclear. In this report we present an effective treatment of adalimumab-induced delayed-type ISRs in a psoriasis patient through the addition of cyclosporine A (CsA) to the patient's regimen.

A 46-year-old man had suffered from widespread chronic plaque psoriasis for 35 years [Figure 1a] and failed to respond to a variety of treatments, including CsA and narrow-band ultraviolet B. He was therefore prescribed subcutaneous injections of adalimumab (40 mg) at fortnightly intervals. He initially experienced notable improvement of psoriasis but, starting with the tenth injection, gradually developed edematous erythema at the injection site [Figure 1b]. It appeared 12–18 h after each injection and lasted 4–5 days, thus assuming a pattern consistent with ISR. Starting with the tenth injection, the ISR appeared three times in a row following adalimumab injection, each time developing more rapidly and involving a greater area than previously. Topical steroid applications did not provide relief, and the patient noticed that the efficacy of adalimumab against psoriasis had decreased. We added methotrexate, but its effect was insufficient. Combined therapy consisting of adalimumab and CsA (150 mg per day) was therefore initiated. With this regimen there was dramatic improvement of ISR, followed by improvement of the psoriasis.

Figure 1.

Clinical manifestations. (a) Sharply demarcated erythematous scaly papules and plaques over the entire body. (b) After the tenth subcutaneous injection of adalimumab, erythematous indurated annular plaques appeared at the injection site on the abdomen

It has been reported that ISR occurs in 29.3% of patients taking etanercept and 15.3% of patients taking adalimumab. Both immediate and delayed adverse reactions can be observed in ISR, suggesting that both type I and type IV hypersensitivity mechanisms can be involved; however, the detailed mechanisms underlying ISR remains unclear.[2] In our case, the development of adalimumab-induced ISR 12–18 hours after injection and the fact that it lasted for 4–5 days suggests that this ISR is a delayed-type hypersensitivity mediated through a type IV hypersensitivity mechanism. Intriguingly, the typical histological findings in delayed-type ISR consist of mild dermal edema with a superficial perivascular infiltrate of lymphocytes and eosinophils. Most of the dermal infiltrate is composed of mature CD4⁻ CD8⁺ cytotoxic T-lymphocytes.[3]

In our patient, the ISR was attenuated by addition of CsA to the therapy. CsA is an immunosuppressive agent used to treat immune disorders, including psoriasis. CsA can inhibit delayed hypersensitivity reactions and bring about a marked decrease in mononuclear cell infiltration[4] by inhibiting the primary T-helper lymphocyte activation and decreasing its cytokine release. Given this, the response to CsA seen in our case suggests that CsA attenuated T-cell activation, leading to the resolution of ISR and that the suppression of ISR restored the efficacy of adalimumab, resulting in excellent control of psoriasis.

This paper, although limited to our experience with a single case, sheds light on the mechanism of delayed-type ISR and presents a treatment option for patients with refractory psoriasis and with ISR following adalimumab.