Failure of infliximab treatment and occurrence of erythema nodosum during therapy in two patients with Behçet's disease

A. E. Yücel, H. Kart-Köseoglu, Y. A. Akova1, B. Demirhan2 and S. Boyacioglu3

Departments of Rheumatology, 1Ophthalmology, 2Pathology and 3Gastroenterology, Baskent University, Ankara, Turkey

Correspondence to: A. E. Yücel. E-mail: eftal{at}dr.com

SIR, Here we describe two Behçet's disease (BD) cases in which treatment with infliximab failed and erythema nodosum (EN) developed during therapy.

Case 1 is a 56-yr-old man who had been investigated for recurrent oral and genital ulcers and erythema nodosum and diagnosed with BD. The patient presented to our gastroenterology out-patient clinic with bloody rectal discharge and generalized musculoskeletal pain. A perianal fistula was detected during rectoscopy. Subsequent endoscopic examination revealed diffuse mucosal oedema and aphthous ulcers in the caecum, and a few aphthous ulcers and normal mucosa in the ascending colon. Intestinal biopsies showed chronic colitis and ileitis.

The patient's signs and findings were interpreted as gastrointestinal involvement of BD, and he was prescribed a regimen of 5 mg/kg intravenous infliximab. After the first infusion of infliximab, the patient's arthralgia and myalgia improved and his erythrocyte sedimentation rate and C-reactive protein level had both decreased. However, the rectal discharge continued. Thirty days after the fourth dose of infliximab, the patient developed multiple erythema nodosum lesions on both legs. Infliximab therapy was stopped.

Case 2 is a 20-yr-old woman who had had acneiform skin lesions, eye involvement, recurrent oral and genital ulcers, and was diagnosed with BD. In September 2000, the patient exhibited bilateral red eyes, significant loss of vision and acneiform skin lesions. Physical examination was unremarkable apart from multiple acneiform lesions. Eye examination revealed scleritis and ocular myositis. Laboratory testing including antinuclear antibodies and antineutrophil cytoplasmic antibodies was normal.

In November 2000, she developed painful nodular skin lesions on her left leg that were compatible with panniculitis while taking methylprednisolone. Pathological examination revealed septal inflammation and venulitis in the fat tissue that was compatible with erythema nodosum. In the following months, similar suppurative erythema nodosum lesions occurred while being treated with azathioprine, methotrexate and methotrexate plus cyclosporin along with methylprednisolone.

In June 2001, she experienced significant loss of vision in both eyes. A regimen of infliximab infusions at 5 mg/kg was added to the regular treatments of methylprednisolone, methotrexate and colchicine. The first dose of infliximab therapy improved the patient's vision and overall well-being. However, 3 days after the third infusion at week 6, the vision in both eyes deteriorated significantly and the patient developed multiple erythema nodosum lesions similar to previous ones. Eye examination revealed scleritis. Infliximab was then discontinued.

After the infliximab was stopped, subcutaneous interferon therapy was attempted, but she could not tolerate this. Consequently, intermittent intravenous cyclophosphamide was added to the methylprednisolone, methotrexate and colchicine regime. At the time of writing, the patient had been on this regimen for approximately 2 yr. She had had four attacks of erythema nodosum panniculitis during this time, and her vision had deteriorated.

Case reports suggest that infliximab is very effective for treating patients with BD [1]. To date, there are four published case reports of five BD patients with gastrointestinal involvement that were treated with infliximab [25]. One of the reported patients had a perianal fistula that closed immediately after the first infusion [2], and the condition of all five of the reported patients improved after infliximab therapy. Infliximab had no effect on the perianal fistula in our case.

Our second patient had scleritis, which has rarely been reported in BD [6]. Infliximab therapy has yielded marked improvement in patients with uveitis due to this disease [1]. In our case, visual acuity improved dramatically at the start of infliximab therapy; however, the patient's vision suddenly deteriorated 3 days after the third dose.

The inflammation in patients with BD is believed to be mediated by T-helper (Th)-1 type cytokines, a group that includes tumour necrosis factor (TNF)-{alpha} [7]. This may explain why infliximab is often effective in BD patients. To our knowledge, failure of infliximab in BD and development or exacerbation of erythema nodosum lesions during infliximab treatment in this patient group have not been reported previously.

We did not test for infliximab antibodies. However, we believe that antibodies are unlikely to be the cause of the erythema nodosum and treatment failure: these events occurred soon after starting therapy in both patients and despite additional immunosuppression in the case of patient 2.

Thalidomide is another agent that is used to treat BD. This drug reduces the level of TNF-{alpha} in cells by accelerating the degradation of its messenger RNA [8]. In one controlled study of patients with BD, Hamuryudan et al. [9] reported that thalidomide treatment was associated with increased numbers of erythema nodosum lesions. There is no explanation for exacerbation of erythema nodosum during infliximab or thalidomide therapy. However, it seems that failure of infliximab treatment and development of erythema nodosum lesions in some patients with BD may be related to Th-2 cytokines, which are also reported to be important in the pathogenesis of BD [10].

We suggest that this agent may not be the magic solution for all patients with this disease, and that it may aggravate erythema nodosum lesions in some cases.

The authors have declared no conflicts of interest.

References

  1. Sfikakis PP. Behçet's disease: a new target for anti-tumour necrosis factor treatment. Ann Rheum Dis 2002;61(Suppl 2):ii51–3.[Medline]
  2. Travis SP, Czajkowski M, McGovern DP, Watson RG, Bell AL. Treatment of intestinal Behçet's syndrome with chimeric tumour necrosis factor alpha antibody. Gut 2001;49:725–8.[Abstract/Free Full Text]
  3. Hassard PV, Binder SW, Nelson V, Vasiliauskas EA. Anti-tumor necrosis factor monoclonal antibody therapy for gastrointestinal Behçet's disease: a case report. Gastroenterology 2001;120:995–9.[ISI][Medline]
  4. Mussack T, Landauer N, Ladurner R et al. Successful treatment of cervical esophageal perforation in Behçet's disease with drainage operation and infliximab. Am J Gastroenterol 2003;98:703–4.[CrossRef][ISI][Medline]
  5. Kram MT, May LD, Goodman S, Molinas S. Behçet's ileocolitis: successful treatment with tumor necrosis factor-{alpha} antibody (infliximab) therapy: report of a case. Dis Colon Rectum 2003;46:118–21.[ISI][Medline]
  6. Chang HK, Cho EH. A case of nodular scleritis in association with Behçet's disease. Korean J Intern Med 2001;16:47–9.[Medline]
  7. Sayinalp N, Ozcebe OI, Ozdemir O, Haznedaroglu IC, Dundar S, Kirazli S. Cytokines in Behçet's disease. J Rheumatol 1996;23:321–2.[ISI][Medline]
  8. Calabrese L, Fleischer AB. Thalidomide: current and potential clinical applications. Am J Med 2000;108:487–95.[CrossRef][ISI][Medline]
  9. Hamuryudan V, Mat C, Saip S et al. Thalidomide in the treatment of the mucocutaneous lesions of the Behçet syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998;128:443–50.[Abstract/Free Full Text]
  10. Raziuddin S, al-Dalaan A, Bahabri S, Siraj AK, al-Sedairy S. Divergent cytokine production profile in Behçet's disease. Altered Th1/Th2 cell cytokine pattern. J Rheumatol 1998;25:329–33.[ISI][Medline]
Accepted 24 September 2003