Dermatology Online Journal

Erythema Nodosum Associated with Infliximab Therapy
Ted Rosen MD¹, Paul Martinelli MD^1,2
Dermatology Online Journal 14 (4): 3

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

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Abstract

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.

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Introduction

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 1	Figure 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.

Discussion

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.

References

1. Scallon BJ, Moore MA, Trinh H, Knight DM, Ghrayeb J. Chimeric anti-TNF-α monoclonal antibody cA2 binds recombinant transmembrane TNF-α and activates immune effector functions. Cytokine 1995;7:251-259. PubMed

2. Kent PD, Davis JM 3rd, Davis MD, Matteson EL. Bullous skin lesions following infliximab infusion in a patient with rheumatoid arthritis. Arthritis Rheum 2002;46:2257-2258. PubMed

3. Chan AT, Cleeve V, Daymond TJ. Necrotising fasciitis in a patient receiving infliximab for rheumatoid arthritis. Postgrad Med J. 2002;78:47-48. PubMed

4. Vergara G, Silvestre JF, Betlloch I, Vela P, Albares MP, Pascual JC. Cutaneous drug eruption to infliximab: report of 4 cases with an interface dermatitis pattern. Arch Dermatol 2002;138:1258-1259. PubMed

5. Devos SA, Van Den Bossche N, De Vos M, Neeyaert JM. Adverse skin reactions to anti-TNF-alpha monoclonal antibody therapy. Dermatology 2003;206:388-390. PubMed

6. Wright RC. Atopic dermatitis-like eruption precipitated by infliximab. J Am Acad Dermatol 2003;249:160-1. PubMed

7. Verea MM, Del Pozo J, Yebra-Pimentel MT, Porta A, Fonseca E. Psoriasiform eruption induced by infliximab. Ann Pharmacother 2004;38:54-57. PubMed

8. Krishnan RS, Hsu S. Serum sickness due to infliximab in a patient with psoriasis. J Drugs Dermatol 2004;3:305-308. PubMed

9. Dumont-Berset M, Laffitte E, Gerber C, Dudler J, Panizzon RG. Eczemaotus drug eruption after infliximab. Br J Dermatol 2004;151:1272-73. PubMed

10. Vermeire S, Norman M, Van Assche G, Baert F, Van Steen K, Esters, N, et. al. Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn's disease: a prospective cohort study. Gastroenterology 2003;125:32-39. PubMed

11. De Brandt M, Sibilia J, Le Loet J, Prouzeau S, Fautrel B, Marcelli C, et al. Systemic lupus erythematosus induced by anti-tumor necrosis alpha therapy: A French national survey. Arthritis Res Ther 2005:7:545-551 PubMed

12. Hern AE, Shwayder TA. Unilateral plantar erythema nodosum. J Am Acad Dermatol 1992;26:259-260. PubMed

13. Suarez SM, Paller AS. Plantar erythema nodosum: cases in two children. Arch Dermatol 1993;129:1064-1065. PubMed

14. Sanchez-Viera M, Lecona M, Soto-Melo J. Plantar erythema nodosum of childhood. J Am Acad Dermatol 1993;29:284. PubMed

15. Ohtake N, Kawamura T, Akiyama C, Furue M, Tamaki K. Unilateral plantar erythema nodosum. J Am Acad Dermatol 1994;30:654. PubMed

16. Kugathasan S, Miranda A, Nocton J, Drolet BA, Raasch C, Binion D. Dermatologic manifestations of Crohn disease in children: response to infliximab. J Pediatr Gastroenterol Nutr 2003;37:150-154. PubMed

17. Rahier JF, Lion L, Dewit O, Lambert M. Regression of Sweet's Syndrome associated with Crohn's disease after anti-tumor necrosis factor therapy. Acta Gastroenterol Belg 2005;68:376-379 PubMed

18. Clayton TH, Walker BP, Stables, GI. Treatment of chronic erythema nodosum with infliximab. Clin Exp Dermatol 2006;31:823-824. PubMed

19. Yücel, AE, Kart-Köseoglu H, Akova YA, Demirhan B, Boyacioglu S. Failure of infliximab treatment and occurrence of erythema nodosum during therapy in two patients with Behçet's disease. Rheumatology 2004;43:394-396. PubMed

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