Infliximab treatment-induced paradoxical psoriasiform reaction in patient with psoriasis vulgaris showing positive lymphocyte transportation test reaction.

Tumor necrosis factor alfa (TNF-α) antagonists are commonly used to treat inflammatory disorders and are considered particularly effective in the treatment of moderate to severe psoriasis. Paradoxically, however, new-onset occurrence or worsening of psoriasis has been increasingly recognized among patients treated with TNF-α antagonists. We report on a 60-year-old man who developed a severe psoriatic condition with diffuse alopecia during infliximab therapy for psoriasis, resulting in the discontinuation of infliximab. Lymphocyte transportation test (LTT) results were positive. Currently, there are few reports of LTT-positive cases that are related to paradoxical reactions by TNF-α antagonists. We discuss the relationship between paradoxical reaction and the mechanisms of LTT.

Case report

Before admittance to our clinic, a 60-year-old man with a 7-year history of psoriasis vulgaris received treatment consisting of topical steroids, topical vitamin D analogs, ultraviolet therapy, and cyclosporine at 2 different hospitals. Because his psoriasis showed no signs of improvement from these treatments, in May 2013 he received 5 mg/kg of infliximab at weeks 0, 2, and 6. One and a half months after the initiation of the infliximab treatment, pruritic scaly plaques developed on his trunk. After another 2 weeks, he became erythrodermic over his entire body (Fig 1, A and B). He showed diffuse alopecia on the scalp, and thick scales were observed on the palms and soles (Fig 1, C and D). A skin biopsy specimen showed psoriasiform epidermal hyperplasia with hyperkeratosis and parakeratosis, telangiectasia, perivascular lymphocytic infiltrate, and a small number of eosinophils in the papillary dermis (Fig 2).

Fig 1

Clinical appearance on admission. A, Face. B, Body. C, Scaly erythema associated with alopecia. D, The right sole.

Fig 2

Histologic specimen. Psoriasiform epidermal hyperplasia, telangiectatic blood vessels, perivascular lymphocytic infiltrate, and a small number of eosinophils in the papillary dermis. (Hematoxylin-eosin stain; original magnification: ×40.)

Serologic analysis found eosinophilia (total white blood cells 8 × 103/μL with 15.2% eosinophils). LTT was performed twice. The stimulation index (SI) was 237% (normal range, <180%) at the second week after the rashes appeared and 183% at the fourth month. Consequently, an infliximab-induced paradoxical reaction was diagnosed.

Infliximab was discontinued, and treatment with topical steroids and maxacalcitol commenced. However, there was no response to the topical therapies, and cyclosporine was subsequently started (2.5 mg/kg/d). Marked improvement was observed immediately, and the psoriasiform eruption disappeared after 9 months. Complete hair regrowth was observed after 12 weeks. The cyclosporine dosage was tapered to 1.5 mg/kg/d, and there has been no recurrence to date (November 2014).

Discussion

If successfully used, TNF-α antagonists can lead to significant improvement of disease activity in patients with a variety of autoimmune diseases and inflammatory disorders, particularly psoriasis. However, in recent years, there have been increasing reports of induced or exacerbated psoriasis among patients receiving anti TNF-α therapy.

These adverse reactions have been noted in all TNF-α inhibitors and have occurred in patients with any disease in which these agents are used as treatment. The incidence of TNF-α inhibitor–induced psoriasis has been estimated at 1.5% to 5%.1, 2 Duration of therapy before onset or worsening of psoriasis has ranged from 2 weeks to 48 months.

Interestingly, rash prognosis varies widely according to individual cases. Collamer et al analyzed 114 cases of paradoxical psoriasis, among which most patients (61%) were able to continue TNF-α antagonist therapy. However, 25% had to discontinue treatment, and some who later resumed therapy with the same agent or another TNF-α inhibitor suffered relapses.

The mechanism of TNF-α inhibitor–induced paradoxical psoriasis remains unclear. The most widely accepted hypothesis suggests there is an interaction between TNF-α and interferon alfa (IFN-α). IFN-α is an important cytokine that controls natural immunity and is mainly produced from plasmacytoid dendritic cells through stimuli such as infection or trauma. IFN-α is also identified as a key element in the early phase of psoriatic induction.5, 6 TNF-α negatively regulates IFN-α production. Therefore, anti–TNF-α therapy could increase IFN-α expression at the tissue level and induce psoriasis. Seneschal et al found a stronger production of the human myxovirus resistance protein 1 that represented a specific marker for type I IFN signaling in psoriasiform eruptions under TNF-α treatment.

There are cases that could continue using the TNF-α antagonist or show improvement if treatment were changed to other types of biologic therapies such as anti–interleukin-12/23 antibodies or anti–interleukin-17A antibodies. This finding suggests that the increase of IFN-α may only be a manifestation trigger, and the following course may be the same as that of primary psoriasis. In addition, there is a large time lag between administration and development of psoriatic lesions. It is presumably because the balance between TNF-α and IFN-α varies among individuals. In addition, certain environmental triggers (infections, ultraviolet irradiation, trauma) may be involved in the development of psoriasis.

The main mediator of adverse drug reactions is typically lymphocytes. LTT is a test to identify antigen-specific T cells to specific drugs in vitro. The peripheral blood T cells are cultured with the incriminated drug, and their subsequent proliferation was measured by harvesting 3H-thymidine. The results were expressed as the SI (SI = counts per minute with drug/without drug.)

Although there is no consensus about when the test should be performed, Kano et al found that LTT should be performed within 1 week after the onset of Stevens-Johnson syndrome or toxic epidermal necrolysis and 5 to 8 weeks after the onset of the cutaneous eruptions in cases of drug-induced hypersensitivity syndrome or drug reaction with eosinophilia and systemic symptoms. This finding suggests that regulatory T cells that increase during the acute stage may play a role in the suppression of T-cell proliferation in patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms.

There are no reports indicating LTT shows a false-positive result in patients treated with anti-TNF agents. Therefore, in this study, LTT was performed at 2 weeks (the acute stage) and again at 4 months (at the time in which the influence of this medicine was expected to be negligible and return to the normal upper limit).

The patient's condition did not change even after infliximab was discontinued, so cyclosporine treatment commenced. Cyclosporine is an immune suppressant and has been used to treat post–organ transplantation complications and autoimmune diseases. The main role of this agent is to suppress T cells. Recently, reports indicate that cyclosporine has the capacity to affect antigen-presenting cells such as B cells and dendritic cells. Tajima et al reported that cyclosporine reduces IFN-α production from the CD11c− subset of dendritic cells infected with the Sendai virus. This study suggested that cyclosporine plays a role in suppressing both the courses of T cells and plasmacytoid dendritic cells that produce IFN-α.

There are several reports of new-onset psoriasis paradoxically following TNF-α antagonist therapy. To our knowledge, this case is a rare example of erythroderma associated with alopecia that developed during infliximab therapy and showed a positive LTT result. In cases such as these, exact diagnosis and early treatment intervention are necessary.