Atopic dermatitis has been characterized as an autoimmune or auto-allergic phenomenon in which environmental allergens resembling human proteins activate auto-reactive T-cells to release pro-inflammatory cytokines of the T-helper 2 (Th2) cytokine profile (IL-4, IL-5, IL-10, and IL-13) (1-3). Infliximab is a chimeric IgG1 monoclonal antibody that blocks the effects of the inflammatory cytokine tumor necrosis factor (TNF)-[alpha]. Infliximab has been shown to benefit greatly patients suffering from diseases associated with a Th1 profile (IL-1, TNF-[alpha], and IFN-[mu]), such as psoriasis, Crohn's disease and rheumatoid arthritis (4-8). Some researchers have suggested that disrupting the Th1-Th2 balance by downregulating Th1 cytokines may result in manifestations of Th2 disease. Consistent with this hypothesis, we present the cases of three patients who exhibited vivid manifestations of atopic dermatitis after the inception of infliximab induction therapy.
In May 2002, a 45-year-old Asian man off all other medications began infliximab induction therapy for his 16-year history of moderate to severe plaque-type psoriasis. The patient received 3 mg/kg of infliximab, which was administered at weeks 0, 2, and 6. Initially, the patient was assessed to have a Psoriasis Area Severity Index (PASI) score of 13.9 with 24.1% total body surface area (TBSA) involvement. Dramatic improvements were noted in the extent of the patient's psoriasis, and his PASI score declined to 3.9 by week 10 of the treatment.
Three weeks after the second infusion, the patient noted a pruritic and eczematous eruption on the neck, antecubital regions, and popliteal fossa (Figure 1). During week 5, his eczema worsened, with increasing pruritis at week 8, which was temporarily relieved with an emollient. By week 14, two months after his last treatment, these symptoms of atopic dermatitis improved with emollients, but his PASI increased to 5.6. Flare of the subject's atopic dermatitis was noted, consisting of new outbreaks on the anterior torso, lateral arms, and medial legs. Likely due to the waning effects of the infliximab treatment, several psoriatic plaques continued to worsen slightly in both severity and increased area of involvement (PASI 11.7). The subject started triamcinolone 0.1% topical therapy after week 26, and his eczema resolved 4 weeks later (PASI 12.2).
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An obese, white 62-year-old woman commenced infliximab to treat her long history of rheumatoid arthritis. Previous to this therapy, the patient reported a constellation of symptoms consistent with atopy, including asthma, allergic rhinitis, and dermatitis. Therapy was initiated in June 2000, with infusions occurring at 6 to 8 week intervals (5 mg/ng IV).
The patient returned in November 2001 complaining of an eruption of 2-3 weeks duration with pruritis lasting three days. On exam, the patient had faintly reticulated and hyperemic macules on the upper arm from a pruritic eruption, horizontal abdominal excoriations, and follicular erythematous papules adjacent to small petechiae with scale on the lower extremities. These physical findings were felt to be consistent with either a drug reaction, or an atopic flare of the upper extremities, and stasis dermatitis on the lower extremities. The patient was prescribed 0.1% triamcinolone cream and instructed to moisturize her extremities.
In July 2003, the patient experienced a pruritic eruption consisting of erythematous coin-shaped lesions with scale on the shins and calves, with a pompholyx-like blisters present on both the palms and dorsal aspect of the hands (Figures 2-3), consistent with nummular eczema. The patient responded well to cephalexin and triamcinolone 0.1% cream, and she was started on clobetasol propionate 0.05% cream.
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A 15-year-old white adolescent male with a history of atopic dermatitis, which had largely resolved by late childhood and early adolescence, was treated for Crohn's disease with infliximab therapy in November 2002, receiving an infusion of 5 mg/kg. Two weeks later, the second dose was administered, followed by a third and fourth dose separated by one month intervals. All subsequent infusions occurred at intervals of 8 weeks (5 mg/kg). In mid-January 2003, the patient presented to his dermatologist with a large dermatitic eruption measuring 11 cm by 10 cm in the left antecubital fossa. This initial area was associated with molluscum contagiosum, which predated the infliximab treatment. Two weeks later, additional lesions of faint erythema and scale were present over the back, trunk, dorsum of hands, and popliteal fossa. After a three week course of treatment with triamcinolone and tacrolimus, the patient improved markedly by late February. Areas of impetiginization on the lip and arms were treated successfully with mupirocin and cephalexin. The lichenified regions on the arm were treated with fluticasone propionate, and the patient continued tacrolimus therapy for other areas of dermatitis.
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In May, the patient experienced a recurrent flare of nummular eczema, including a quarter-sized lesion with scale on the left parietal scalp, a thick, half-dollar-sized lesion on the left extensor arm (Figure 4). Additional dime-sized lesions on the left extensor leg (Figure 5), and a bright erythema extending from the dorsum of the feet into the interdigital spaces. All three of these areas were assessed using a KOH stain, but none showed evidence of hyphae. Clobetasol propionate was prescribed, and the patient responded very well to this therapy for most areas. One month later, a centimeter-sized area of inflammation and excoriation persisted on the left aspect of the scalp, and a smaller area was present on the anterior scalp. Fungal cultures were negative, and the scalp biopsy stain was periodic acid-Schiff (PAS)-negative, confirming the lack of fungal etiology. Intralesional triamcinolone was given using less than 0.5 cc of a 10 mg/cc concentration injected directly into the troublesome area. The patient continued to treat the scalp using a clobetasol propionate solution for the scalp. The dermatitic areas required maximal therapy of tacrolimus ointment and topical corticosteroids to prevent the lesions from flaring. These medications were used until the infliximab infusions were stopped, at which time the areas resolved completely.
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All three of these patients underwent infliximab infusion therapy for the treatment of classic Th1 disease processes. The experience of the patient from Case 1 presented a quintessential example of the antagonism between the Th1 and Th2 response, in this case characterized by psoriasis and atopic dermatitis, respectively. Although the course of his psoriasis improved significantly by blocking TNF-[alpha] and depressing the Th1 profile, the infliximab treatment appears to have upregulated the Th2 cytokine expression due to the counter-regulatory relationship between the Th1 and Th2 response. Clinically, the resulting syndrome of atopy manifested as eczematous and allergic symptoms. To our knowledge, this is the first reported case of a patient whose infliximab therapy for the treatment of psoriasis resulted occurred with a concomitant outbreak of atopic dermatitis, likely due to the complex relationship between Th1 and Th2 cells and their associated cytokine profiles.
The second and third cases demonstrate clinical manifestations of nummular dermatitis in the context of the opposing Th1 and Th2 mediated responses. The nummular eruptions seen in the woman being treated for rheumatoid arthritis was most likely attributable to the depressed Th1 action of infliximab, and this patient may have been predisposed to such a reaction due to her history of atopy. A similar response was observed in the adolescent suffering from Crohn's disease, a Th1-mediated inflammatory bowel disease. In this pediatric case, the patient's pre-existing condition was both exacerbated and more refractory to treatment during administration of concomitant infliximab therapy. Although nummular eczema generally occurs in the middle-aged and elderly due to undetermined causes, these coin-shaped plaques may not necessarily be associated with dry skin or atopy (9). Nummular eczema eruptions have not been previously reported in association with infliximab therapy.
Various biologics that target Th1 cytokine production for the treatment of psoriasis provide promising results for patients suffering from chronic, refractory plaque psoriasis. These biologic agents provide important opportunities for continual elucidation of the basic immunological mechanism's underlying psoriasis. Cutaneous drug eruptions to infliximab have been described as erythema multiforme, leukocytoclastic vasculitis, perniosis-like eruption, superficial granuloma annulare, acute folliculitis, lichenoid drug eruption, and atopic dermatitis-like eruptions (10-12). All of these reported cases refer to patients who were receiving infliximab therapy for a rheumatologic condition or Crohn's disease, although one of these patients also had a history of both psoriasis and asthma (12). It has been suggested that psoriasis and atopic dermatitis are subject to a counter-regulatory balance between the Th1 and Th2 response. In this case series, we presented three vivid clinical manifestations of this theoretical antagonism.
The authors have no conflict of interest to disclose.
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JOANNA L CHAN AB (1), LINDA DAVIS-REED MD (2), ALEXA BOER KIMBALL MD MPH (3)
1 MEDICAL STUDENT, DEPARTMENT OF DERMATOLOGY, STANFORD UNIVERSITY MEDICAL CENTER, STANFORD, CALIFORNIA
2 PRIMARY PRACTICE, CHICO, CALIFORNIA
3 ASSISTANT PROFESSOR, DEPARTMENT OF DERMATOLOGY, STANFORD UNIVERSITY MEDICAL CENTER, STANFORD, CALIFORNIA
ADDRESS FOR CORRESPONDENCE:
Alexa Boer Kimball MD MPH
Stanford University School of Medicine
Department of Dermatology
900 Blake Wilbur Dr., RoomW0024
Stanford, CA 94305-5334
Phone: (650) 724-7054
Fax: (650) 618-1681
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