Author Affiliations: Department of Dermatology and Skin Science (Drs de Gannes, Ghoreishi, and Dutz) and Division of Rheumatology (Drs Shojania and Dutz), Department of Medicine, University of British Columbia, Vancouver; Division of Rheumatology, Department of Medicine, University of Western Ontario, London (Drs Pope and Bell); Division of Rheumatology, Department of Medicine, University of Alberta, Edmonton (Dr Russell); Division of Dermatology, Department of Medicine, University of Calgary, Calgary, Alberta (Dr Adams); and Department of Pathology, Vancouver General Hospital, Vancouver (Dr Martinka).
New onset or worsening of psoriasis has been reported in patients treated with tumor necrosis factor α (TNF-α) inhibitors for a variety of rheumatologic conditions. There is mounting evidence that a key innate immune pathway for triggering common human autoimmune disease, including psoriasis, involves plasmacytoid dendritic cell precursors (PDCs) and type 1 interferon (IFN) production. We present herein a case series with clinical and histopathologic evidence of psoriasis in patients with rheumatologic disease treated with TNF-α inhibitors. We propose that the cross regulation between TNF-α and IFN may have a role in the pathogenesis of this reaction.
We observed new-onset psoriasis (n = 13) or severe exacerbation of psoriasis (n = 2) in 15 patients with a variety of rheumatologic conditions—rheumatoid arthritis (n = 13), psoriatic arthritis (n = 1), and seronegative arthritis (n = 1)—during treatment with etanercept (n = 6), infliximab (n = 5), and adalimumab (n = 4). Immunohistochemical staining of skin biopsy specimens for myxovirus-resistance protein A (MxA, a surrogate marker for lesional type 1 IFN activity) showed increased staining in TNF-α inhibitor–induced psoriasis compared with psoriasis vulgaris.
New onset or severe exacerbation of psoriasis is a rare complication of TNF-α inhibitor therapy. The finding of increased production of IFN-α in TNF-α inhibitor–induced psoriasis is a possible pathophysiologic explanation for this reaction.
The therapeutic approach to rheumatologic conditions has changed dramatically in recent years with the introduction of biological therapies such as tumor necrosis factor α (TNF-α) inhibitors. Targeted therapy with biological agents has also provided new therapeutic options for patients with moderate to severe psoriasis. Paradoxically, there have been several reports in the medical literature of new-onset psoriasis or worsening of preexisting skin disease in patients treated with TNF-α inhibitors for psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease.1- 14 This reaction has been reported in patients taking each of the 3 TNF-α inhibitors and seems to be a class effect. In a recent online survey of rheumatologists, 63% of respondents answered “yes” when asked “Have you seen psoriasis or other skin reactions in patients on TNF-α inhibitors?”15
The mechanisms underlying this undesirable effect have yet to be elucidated. However, there is mounting evidence that a key innate immune pathway for triggering common human autoimmune disease involves plasmacytoid dendritic cell precursors (PDCs) and type 1 interferon (IFN) production. It has been shown that PDC-derived IFN is essential in stimulating the local activation and expansion of pathogenic T cells leading to the development of psoriatic skin lesions.16
Herein, we present a case series with clinical and histopathologic evidence of psoriasis in 15 patients treated with TNF-α inhibitors for a variety of rheumatologic conditions. We introduce the hypothesis that the cross-regulation between TNF-α and IFN may have a role in the pathogenesis of this reaction.
The clinical histories of patients who developed psoriasis during TNF-α inhibitor therapy are summarized in Table 1. Detailed case reports of 2 patients, including clinical and histopathologic images, are presented herein.
A 41-year-old woman with rheumatoid arthritis and no personal or family history of psoriasis was treated with rofecoxib, leflunomide, and etanercept. Twenty-six months after the initiation of TNF-α inhibitor therapy, and 1 month after beginning treatment with leflunomide, she developed an erythematous pustular eruption on her palms and soles (palmoplantar pustulosis) that evolved into psoriasiform changes (Figure 1A and B). A skin biopsy specimen showed psoriasiform epidermal hyperplasia with hyperkeratosis and confluent parakeratosis. There were a few telangiectatic blood vessels in the papillary dermis associated with a perivascular lymphocytic infiltrate and occasional neutrophils. The findings were consistent with psoriasis (Figure 1C).
Patient 1, a 41-year-old woman with rheumatoid arthritis, developed new-onset palmoplantar pustulosis after 26 months of etanercept therapy. Erythematous scaly plaques arose on her left heel (A) and left palm (B). C, Skin biopsy specimen showed psoriasiform epidermal hyperplasia with hyperkeratosis and confluent parakeratosis. There were a few telangiectatic blood vessels in the papillary dermis associated with perivascular lymphocytic infiltrate and occasional neutrophils. The findings were consistent with psoriasis (hematoxylin-eosin, original magnification ×100).
The etanercept and leflunomide regimens were discontinued, and treatment with topical steroids in combination with calcipotriol was started. Her skin eruptions improved, but her joint disease flared. She resumed etanercept treatment and continued undergoing topical therapy for her skin disease. She has not had a relapse of her psoriasis despite continuation of etanercept therapy. Her joint disease remains under good control.
A 59-year-old woman with a 50-year history of juvenile-onset psoriatic arthritis and psoriasis (treatment-resistant skin disease beginning in her 30s, with minimal skin disease for the past 15 years) was treated with etidronate, prednisone (long-term low dose [5 mg/d for >10 years] with no change in dose prior to exacerbation of psoriasis), methotrexate, acyclovir (prophylaxis for recurrent herpes simplex hepatitis), and infliximab. Twelve months after initiation of TNF-α inhibitor therapy, she developed guttate papules and scaly plaques over the trunk and extremities, with clustering over the lower back (Figure 2A). There was thick scale over the dorsal aspect of both feet, with diffuse scale involving the soles (Figure 2B). A skin biopsy specimen showed psoriasiform epidermal hyperplasia associated with parakeratosis, telangiectatic blood vessels, perivascular lymphocytic infiltrate, and occasional neutrophils in the papillary dermis and lower epidermis. The findings were consistent with psoriasis (Figure 2C).
Patient 2, a 59-year-old woman with juvenile-onset psoriatic arthritis, developed worsening of her preexisting psoriasis after 12 months of infliximab therapy. A, Guttate psoriasis involved the trunk, especially the lower back. B, Plaque psoriasis on the dorsal and plantar aspects of the feet. C, Skin biopsy specimen showed psoriasiform epidermal hyperplasia associated with parakeratosis, telangiectatic blood vessels, perivascular lymphocytic infiltrate, and occasional neutrophils in the papillary dermis and lower epidermis. The findings were consistent with psoriasis (hematoxylin-eosin, original magnification ×100).
Serologic analysis revealed a positive antinuclear antibody (ANA) titer of 1:160 homogeneous pattern and 1:80 speckled pattern. Anti-DNA findings were negative. A pre–TNF-α inhibitor therapy ANA titer was not available. Infliximab treatment was discontinued, and etanercept therapy was started to treat her joint and skin disease. In addition, corticosteroids in combination with salicylic acid were used as topical therapy. Unfortunately, despite dual therapy, her skin disease has continued to progress over her trunk and lower legs. Her joint disease remains well controlled with etanercept.
Cases were collected from dermatology and rheumatology offices across Canada. Clinical histories and images, skin biopsy specimen pathology reports, hematoxylin-eosin–stained slides, and paraffin-embedded specimens were collected for each case when available.
Literature was reviewed using a variety of MEDLINE (1966 to present) and PubMed (1950 to December 2005) searches, using the terms tumor necrosis factor alpha inhibitor, TNF-α inhibitor, infliximab, etanercept, and adalimumab combined with the words skin reactions, rash, psoriasis, palmoplantar pustulosis, and palmoplantar psoriasis. Twelve peer-reviewed publications and 2 poster abstract presentations were identified.
Paraffin-embedded skin specimens were available from 4 patients undergoing TNF-α inhibitor therapy and 2 patients with untreated psoriasis vulgaris. Informed consent was obtained from all patients prior to routine skin biopsy procedures. In all patients, the diagnosis of psoriasis was confirmed histologically by a dermatopathologist (M.M.).
Paraffin-embedded sections were deparaffinized and stained with standard hematoxylin-eosin. Immunohistochemical staining was performed using an avidin-biotin peroxidase system (Vector Laboratories, Burlington, Ontario) after antigen retrieval by microwave pretreatment. The human-specific primary antibody used was anti–myxovirus-resistance protein A (MxA) monoclonal antibody (clone M143). Counterstaining was with hematoxylin-eosin. Images were captured with a SPOT RT color camera (Diagnostic Instruments, Sterling Heights, Mich) using an Olympus BX 61 microscope (Olympus America Inc, Center Valley, Pa).
Eleven women and 4 men between ages 19 and 78 years were included in this study. Of the 15 patients described in our study, 13 developed new-onset psoriasis following TNF-α inhibitor therapy. Psoriasis developed in 6 patients taking etanercept, 5 taking infliximab, and 4 taking adalimumab. Duration of therapy prior to onset of skin disease ranged from 2 to 62 months. None of the patients who were undergoing long-term prednisone therapy for their rheumatologic disease had their prednisone dose adjusted prior to the onset of psoriasis. Nine of the 15 patients had pustular lesions on their palms and soles. Other clinical presentations included guttate and plaque psoriasis on the trunk and extremities and scalp psoriasis. When a skin biopsy specimen was available for review (n = 5), histologic findings were consistent with psoriasis. Thirteen of the 15 patients continued to undergo TNF-α inhibitor therapy for their primary rheumatologic disease. Four patients treated their skin disease successfully with topical corticosteroids, while 9 patients continued to have persistent skin disease despite topical therapy. Two patients discontinued their TNF-α inhibitor therapy with the new onset of psoriasis. In 1 patient, the cutaneous lesions resolved completely under treatment with topical corticosteroids and calcipotriol, whereas the other patient had persistent skin disease despite topical therapy. Tumor necrosis factor α inhibitor therapy was effective in controlling the underlying rheumatologic disease in all patients. Interestingly, patient 7 developed skin disease under treatment with all 3 TNF-α inhibitors (Table 1) as well as a lupuslike reaction (pericarditis and positive ANA) under infliximab therapy. Summative statistics for our case series are listed in Table 2.
A literature search revealed 43 cases (31 in peer-reviewed publications, 12 in poster abstract presentations) of new onset or severe exacerbation of psoriasis in patients with autoimmune diseases treated with TNF-α inhibitor therapy. Details of these cases are summarized in Table 3. Data were available for 21 women and 11 men, ranging in age from 19 to 69 years (data unavailable for the other 11 patients). The TNF-α inhibitor therapy induced cutaneous psoriasiform eruptions in patients with ankylosing spondylitis (n = 9), plaque psoriasis (n = 2), rheumatoid arthritis (n = 26), ulcerative colitis (n = 2), Crohn disease (n = 2), and Behçet disease (n = 2). Skin disease developed in 11 patients undergoing treatment with etanercept, 24 taking infliximab, and 8 taking adalimumab. Duration of therapy prior to the onset or worsening of psoriasis ranged from 2 weeks to 48 months. New-onset psoriasis developed in 24 cases (10 patients had exacerbation of preexisting disease, and there were 9 patients with unknown clinical histories). Twenty-eight of the 43 patients presented with palmoplantar pustulosis. Other clinical presentations included guttate or plaque psoriasis on the trunk and extremities, flexural psoriasis, scalp psoriasis, and nail disease. Histologic findings, available in 20 of 43 cases, were consistent with psoriasis. Cutaneous eruptions were controlled with topical corticosteroid treatment alone or in combination with salicylic acid or calcipotriol in 18 patients (data unavailable for 25 patients). One patient required psoralen UV-A therapy to control her psoriasis, and another used acitretin in combination with topical therapy. Sixteen patients continued treatment with TNF-α inhibitor therapy for their primary autoimmune disease and controlled their skin disease with topical therapy alone (9 patients stopped therapy; data were unavailable in 18 patients). Three patients were rechallenged with TNF-α inhibitor therapy without any recurrence of their skin disease. Summative statistics for patients identified in the literature review are listed in Table 2.
Psoriasis is a chronic condition of still uncertain cause. Tumor necrosis factor α is a well-documented contributor to the psoriatic skin lesion. An essential role for TNF-α in the genesis of psoriatic plaques has been demonstrated experimentally.17 Inhibition of TNF-α effectively treats psoriasis in most patients.18- 19 Yet in the patients described herein, psoriasis developed de novo or worsened under treatment with TNF-α inhibitor therapy.
Recently, IFN-α production by dermal plasmacytoid dendritic cells has been identified as a key element in the early phase of psoriatic skin lesion induction.20 Tumor necrosis factor α regulates IFN-α production, and neutralization of endogenous TNF-α sustains IFN-α production by plasmacytoid dendritic cells.21 Inhibition of TNF-α has been shown to induce the overexpression of IFN-α–regulated genes in patients with systemic-onset juvenile arthritis. We therefore proposed that TNF-α inhibition might induce locally sustained IFN-α production in patients developing psoriasis while undergoing this therapy.
The MxA is an adenosine triphosphatase that is selectively induced in response to type 1 IFNs (IFN-α and IFN-β) and that may be used as a surrogate marker for lesional type 1 IFN activity.22- 23 We therefore stained and compared lesional samples from patients with TNF-α inhibitor–induced psoriasis (n = 4; data presented for patient 1 and patient 2 only) and psoriasis vulgaris (n = 2) with antibodies to MxA (Figure 3). While both patients with TNF-α inhibitor–induced psoriasis and psoriasis vulgaris demonstrated epidermal MxA staining, epidermal staining for MxA was significantly more intense in patients treated with TNF-α inhibitors. Cytoplasmic MxA staining was noted in dermal vascular endothelial cells and inflammatory mononuclear cells only in psoriatic lesions from patients receiving TNF-α inhibitor therapy and not in psoriatic lesions from patients with psoriasis vulgaris.
Patients with tumor necrosis factor α (TNF-α) inhibitor–induced psoriasis (A and B) (original magnification ×100) and psoriasis vulgaris (C and D) (original magnification ×100) demonstrated epidermal myxovirus-resistance protein A (MxA) staining. However, epidermal staining for MxA was significantly more intense in patients treated with TNF-α inhibitors. Cytoplasmic MxA staining was noted in lesional dermal vasculature and in the perivascular lymphocytic infiltrate only in psoriatic lesions from patients who underwent TNF-α inhibitor therapy (inset A and B) (original magnification ×400) and not in psoriatic lesions from patients with psoriasis vulgaris (inset C and D) (original magnification ×400). For all panels, the avidin-biotin peroxidase staining system was used for MxA along with hematoxylin-eosin counterstain, as described in the “Methods” section.
Psoriasis is a chronic inflammatory skin disease in which T-cell–mediated cytokine production drives keratinocyte proliferation and angiogenesis.24 Although TNF-α is a crucial cytokine in the inflammatory cascade leading to psoriasis,17 paradoxical induction of psoriasis has recently been noted in patients with nonpsoriatic autoimmune diseases treated with TNF-α inhibition.12 We observed new onset or severe exacerbation of psoriasis in 15 patients with a variety of rheumatologic conditions, including rheumatoid arthritis, psoriatic arthritis, and seronegative arthritis during treatment with etanercept, infliximab, and adalimumab. More than half of the patients presented with palmoplantar pustulosis. Most of the cases of TNF-α–induced psoriasis reported in the literature also showed a palmoplantar distribution and a pustular pattern. In both of our patient series and in the literature, most of the cutaneous eruptions were controlled with topical therapy, and patients were able to continue treatment with TNF-α inhibitor therapy for their primary rheumatologic disease.
The development of psoriasis of the skin in a patient with a rheumatologic disease does not necessarily mean that a misdiagnosis of the rheumatologic condition has been made. The cooccurence of rheumatoid arthritis and psoriasis of the skin in the same patient is rare. In the German national data bank for rheumatologic diseases, 0.2% of patients with definite rheumatoid arthritis and 0.3% of patients with seropositive rheumatoid arthritis simultaneously had psoriasis of the skin.15 In 3 of the trials that we reviewed (2 prospective and 1 retrospective), the incidence of TNF-α inhibitor–induced psoriasis was estimated at 3% in patients with spondyloarthropathy2 and 2.3% to 5% in patients with rheumatoid arthritis.4,12 Although the prevalence of psoriasis might be higher among patients with chronic inflammatory arthritic conditions, the occurrence in up to 5% of patients treated with TNF-α inhibitors clearly exceeds the prevalence that might be expected by chance, especially given the short periods of observation.12 The mechanism underlying this paradoxical reaction has not been determined.
Interferon α has recently been implicated in the induction of psoriatic skin lesions.25 Clinical evidence in favor of a link between psoriasis and IFN-α includes the induction and the worsening of psoriasis after injection of recombinant IFN-α.26 Cutaneous application of imiquimod cream, a potent inducer of IFN-α, has been described to induce exacerbation of cutaneous psoriasis.16 Plasmacytoid dendritic cells, the natural IFN-α–producing cells, have recently been shown to infiltrate the skin of patients with psoriasis and to produce IFN-α.20 Using a xenograft model of human psoriasis, it was demonstrated that IFN-α expression is a key event in the early stages of psoriasis development.20 Furthermore, the IFN-α signaling pathway is activated in psoriatic skin,27 and psoriatic T cells demonstrate an increased sensitivity to IFN-α.28 Finally, IFN-α induces the expression of CXCR3 on T cells, facilitating homing to the skin.29 Injury and infection have been 2 triggers proposed to induce pathogenic IFN-α production by plasmacytoid dendritic cells in individuals genetically predisposed to psoriasis.25
Tumor necrosis factor α has recently been shown to regulate INF-α production.21 This regulation has been shown to occur at 2 levels. Tumor necrosis factor α can inhibit the maturation of plasmacytoid dendritic cells from hematopoietic progenitors and can also inhibit IFN-α release by plasmacytoid dendritic cells activated by viral infection. Neutralization of TNF-α increases the production of IFN-α by plasmacytoid dendritic cells in vitro and results in the overexpression of IFN-α–regulated genes in the blood leukocytes of patients with systemic-onset juvenile arthritis.21 Intriguingly, TNF-α inhibition has also been shown to result in increased expression of CXCR3 in the circulating T cells of patients with rheumatoid arthritis, possibly promoting skin homing of these cells.30 Finally, type 1 interferons play a major role in the pathogenesis of systemic lupus erythematosus.31 Based on these results, it has been proposed that dysregulation of IFN-α may underlie the development of ANAs and lupuslike syndromes in patients undergoing anti-TNF therapy.21
We demonstrate that patients undergoing anti-TNF therapy who develop psoriasis have increased IFN-α expression in the lesional dermal vasculature and in the perivascular lymphocytic infiltrate as indicated by persistent MxA expression. We suggest that TNF-α inhibitor therapy may produce aberrant IFN-α expression at the tissue level in predisposed individuals and thus promote psoriasis lesion induction similar to infection or injury. The significant delay between initiation of TNF-α inhibitor therapy and psoriasis onset suggests that aberrant IFN-α expression is only 1 of a number of factors leading to lesion formation.
Interestingly, other cutaneous eruptions associated with TNF-α inhibitor therapy include lupuslike eruptions, dermatomyositislike eruptions, and cutaneous vasculitis.4 Both cutaneous lupus erythematosus32 and dermatomyositis33 have been associated with dysregulation of IFN-α. In this regard, 1 of our patients (patient 7) had both a psoriasiform eruption and evidence of lupuslike autoimmunity.
Patients with connective tissue diseases have an increased incidence of ANAs. Development of ANAs in patients treated with TNF-α inhibitors is not uncommon34 and is generally thought to be clinically irrelevant because few patients develop clinical lupus syndromes.35 The presence of ANAs prior to TNF-α inhibitor therapy may indicate a predisposition to aberrant INF-α regulation. Whether the presence of ANAs in patients prior to anti–TNF-α therapy is a risk factor for IFN-α–related autoimmune adverse effects is currently unknown. The risks of prolonged anti–TNF-α therapy in terms of the promotion of systemic and local autoimmunity are likewise still unknown. It is clear, however, from our case series that most patients with TNF-α inhibitor–associated psoriasis do not require cessation of TNF-α inhibitor therapy, and the psoriasis may be treated with success using current topical treatments.
Correspondence: Jan P. Dutz, MD, FRCPC, Department of Dermatology and Skin Science, The Skin Care Centre, 835 West 10th Ave, Vancouver, British Columbia, Canada V5Z 4E8 (email@example.com).
Financial Disclosure: Dr Shojania has received research funding and speaking honoraria from Abbott, Amgen, Schering, and Centocor.
Accepted for Publication: May 18, 2006.
Author Contributions: Dr Dutz had full access to the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: de Gannes and Dutz. Acquisition of data: de Gannes, Ghoreishi, Pope, Russell, Bell, Adams, Shojania, Martinka, and Dutz. Drafting of the manuscript: de Gannes and Dutz. Administrative, technical and material support: Ghoreishi, Martinka, and Dutz. Study supervision: Dutz.
Funding/Support: This study was supported in part by the Infectious and Inflammatory Diseases Program of the Child and Family Research Institute (Children's and Women's Health Centre of British Columbia), Vancouver.
Acknowledgment: We thank Ken Blocka, MD, FRCPC, for contributing details of the clinical history of patient 2 and Kevin Peter, MD, FRCPC, for contributing details of the clinical history of patients 14 and 15. We also thank Otto Haller, MD, for providing us with anti-MxA monoclonal antibody clone M143.
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