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Erythema nodosum associated with infliximab therapy

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Erythema Nodosum Associated with Infliximab Therapy
Ted Rosen MD1, Paul Martinelli MD1,2
Dermatology Online Journal 14 (4): 3

1. Department of Dermatology, Baylor College of Medicine, Houston, TX.
2. Michael E DeBakey VA Medical Center, Houston, TX


A number of unrelated cutaneous adverse events have been rarely associated with administration of infliximab. This drug has been used to control erythema nodosum when the latter was associated with Crohn disease. We herein report the paradoxical occurrence of erythema nodosum, verified by repeated challenges, following infliximab infusion given for ankylosing spondylitis. Despite this side effect, the patient elected to continue therapy due to a high degree of efficacy.


Although a small number of disparate cutaneous adverse reactions have been reported in association with tumor necrosis factor-alpha (TNF-α) inhibition therapy, such occurrences appear to be relatively rare. We report herein a fairly obvious association of erythema nodosum in conjunction with and complicating periodic infliximab infusions for the management of ankylosing spondylitis.

Case Report

A 38-year-old man presented with a chief complaint of "sores" on his feet that had been intermittently present for approximately 1 year, but that had worsened dramatically in the last 24 hours. He denied fevers, chills, malaise, and upper respiratory or gastrointestinal symptoms. The patient had a 4-year history of ankylosing spondylitis treated with infliximab infusions in a dose of 4 mg/kg administered every 8 weeks for the last 2 years. His most recent infusion was the day prior to presentation. He took no other medications except for ibuprofen as needed for back pain.

Figure 1Figure 2
Figure 1. Multiple tender plantar nodules
Figure 2. Near view of one nodular lesion

Physical examination revealed an afebrile man in no apparent distress. Tender, erythematous to violaceous, multinodular plaques were noted on the medial aspects of bilateral plantar feet, with more pronounced involvement of the left foot (Figs. 1 & 2). No purulent material, fluctuance, or crepitus were noted.

Figure 3
Figure 3. Septal panniculitis on biopsy (H&E, 40x)

A punch biopsy was performed and demonstrated a predominantly septal panniculitis without evidence of vasculitis, compatible with erythema nodosum (Fig. 3). Gram, GMS and AFB tissue stains were negative for bacteria, fungi, and mycobacteria, respectively. A tissue culture was also performed and was negative for all organisms. Additional laboratory tests, including antinuclear antibodies, complete blood count, urinalysis, serum chemistries, and hepatic function panel, were all within normal limits.

A diagnosis of plantar erythema nodosum was made. Given the worsening of disease activity soon after infliximab was infused, it was postulated that infliximab may be the etiology of erythema nodosum in this patient. Discontinuation of the medication was recommended to confirm the theory, but the patient elected to remain on infliximab because it was very effective in controlling the symptoms associated with ankylosing spondylitis. In the 6 months since his initial visit, the patient continues to have intermittent painful flares of the disease temporally associated with ongoing infliximab treatments.


Infliximab is a chimeric monoclonal antibody composed of human constant and murine variable regions that binds to and blocks circulating and tissue-bound TNF-α [1]. Infliximab is used to treat chronic inflammatory disorders mediated by TNF-α, and is approved in the United States for the treatment of adult and pediatric Crohn disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, and psoriatic arthritis.

Several adverse cutaneous reactions have been associated with infliximab treatment, including leukocytoclastic vasculitis, lichenoid drug reactions, perniosis-like eruptions, superficial granuloma annulare, non-specific bullous lesions, psoriasiform dermatitis, serum sickness reactions, eruptions with an interface dermatitis, eczematous (atopy-like) eruptions and cutaneous and soft-tissue infections [2-9]. In addition, infliximab is also associated with the development of autoimmunity, including drug-induced lupus erythematosus [10, 11].

The lesions of erythema nodosum typically occur symmetrically on bilateral extensor extremities. There are numerous etiologies of erythema nodosum, including infection, sarcoidosis, inflammatory bowel disease, and drug allergy. The occurrence of plantar erythema nodosum is an uncommon but well-described presentation of the disease, documented primarily in isolated case reports of children and usually associated with a known preceding infection [12-15].

To our knowledge, there are no reports in the English literature of erythema nodosum induced by infliximab. In fact, infliximab has been successfully used to treat erythema nodosum, as well as other cutaneous manifestations of Crohn disease [16-18]. However, there are also cases in which infliximab failed to control erythema nodosum (in patients with Behçet disease), suggesting that the medication may not be uniformly effective in treating erythema nodosum [19].

The patient presented in this report represents, to our knowledge, the first case of erythema nodosum occurring initially during treatment with infliximab. Because the patient declined to discontinue infliximab infusions, it is impossible to state with absolute certainty that the medication, rather than his underlying disease state, is the cause of erythema nodosum. This is unlikely, as the articular manifestation of the patient's illness was entirely controlled by infliximab. Additionally, the temporal association of erythema nodosum flares with therapeutic infusions and the lack of any other identifiable etiology support a direct relationship between the anti-TNF-α therapy and an uncommon adverse cutaneous reaction. In any event, even if infliximab did not "cause" erythema nodosum in this patient, it has been unable to control the disease.


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