Late onset leflunomide-induced cutaneous ulcers in a seronegative arthritis patient: A case report

Abstract

The differential diagnosis for chronic cutaneous ulcers is wide. Once the common causes have been excluded, infrequent ones, including drugs, should be considered. We report the case of a 67 year old woman with multiple ulcers not responding to conventional treatment. Multiple investigations including laboratory testing, skin biopsies and tissue cultures were negative. A few cases of leflunomide-induced cutaneous ulcers are reported in the literature. Our patient was on this drug for 12 years. Discontinuation of leflunomide led to ulcers resolution. This is the longest reported time interval between leflunomide initiation and ulceration onset.

Introduction

Leflunomide is a disease-modifying antirheumatic drug used for the treatment of inflammatory arthritis. It inhibits the dihydroorotate-dehydrogenase enzyme which plays an important role in pyrimidine synthesis. ¹ Cutaneous reactions to this drug are rare (approximately 2%); they include pruritus, telogen effluvium, vasculitis and more serious cutaneous adverse events such as Stevens-Johnson syndrome/toxic epidermal necrolysis.^1,2 Approximately 10 cases of leflunomide-induced skin ulcers have been reported in the literature which mostly involved the upper and lower extremities. ² Herein we describe the case of a seronegative arthritis patient who developed leflunomide-induced cutaneous ulcers after 12 years on this therapy.

Case report

A 67-year-old woman was referred to the Dermatology clinic in November 2021 with a 1-month history of three progressing painful ulcers on the abdomen. Past medical history was significant for seronegative arthritis, hypertension, hypothyroidism, bipolar disorder, cerebrovascular accident as well as celiac disease associated with dermatitis herpetiformis that was in remission. The patient was taking leflunomide, levothyroxine, valsartan, amlodipine, hydromorphone, lorazepam, quetiapine and vitamin D.

The patient reported that the ulcerations first developed after a mild trauma. Skin examination showed three round fibrinous ulcers (0.5–0.8 cm) involving the right lower abdomen. She was started on clobetasol 0.05% cream daily. Skin biopsies for pathology and tissue cultures were obtained. The histopathology was nonspecific and showed no signs of vasculitis, neoplasm, viral inclusions or any findings suggestive of pyoderma gangrenosum. Tissue cultures were negative for atypical mycobacteria and subcutaneous mycosis. Bacterial tissue culture showed Staphylococcus epidermidis that was treated with a 10-day course of oral cefadroxil 500 mg with minimal improvement. Topical steroid was discontinued and switched to fusidic acid ointment with foam dressings.

By March 2022, the three initial ulcers had healed. However the patient developed approximately 10 new round ulcerations (0.5–1 cm) involving the inframammary folds and abdomen. Subsequently, new ulcerations appeared in the left groin and some abdominal ulcers increased in size despite the use of fusidic acid ointment and hydrocolloid dressings (Figure 1). Given that the histopathology was nonspecific and that the ulcerations showed a geometrical configuration, a factitious etiology was considered.

Figure 1.

Ulcers of the left inguinal area in July 2022.

In August 2022, new ulcers developed on the buttocks whereas some ulcerations on the abdomen healed. An extensive workup was performed which included a complete blood count, complements C3 and C4, immunoglobulins (IgG, IgM, IgA), antineutrophil cytoplasmic antibodies, antiphospholipid antibodies, serum protein electrophoresis as well as lymphocyte count that were all within normal limits. Erythrocyte sedimentation rate was slightly elevated (29) in the setting of seronegative arthritis. C-reactive protein value was normal (6,9). A second biopsy was performed on the edge of an abdominal ulceration which showed lymphohistiocytic inflammation with few neutrophils, spongiosis of the epidermis, acanthosis and Gram-positive cocci in the corneal layer.

The patient was referred to the ulcer clinic for a second opinion in September 2022. The ulcers on the left abdomen, left thigh and buttocks were still present (Figure 2). At this point in time, leflunomide was suspected as a potential culprit which was taken by the patient since 2008. It was stopped in April 2019 given that the arthritis was in remission and was subsequently resumed at a dose of 20 mg per os daily in August 2019 for arthritis reactivation. Leflunomide was stopped in September 2022 with the treating rheumatologist and local wound care was continued. At follow-up in December 2022, the ulcers on the abdomen and the buttocks were almost healed (Figure 3) and the ones on the left thigh were completely reepithelialized. We concluded that the patient’s ulcerations were induced by leflunomide.

Figure 2.

Ulcers of the left inguinal area and abdomen in September 2022.

Figure 3.

Ulcers of the left inguinal area and abdomen in December 2022.

Discussion

To the best of our knowledge, we report the case of leflunomide-induced ulcers with the longest time interval between leflunomide initiation and ulceration onset (12 years). The cases in the literature reported the development of ulcers ranging from 4 weeks to 13 months after leflunomide initiation.^1–5 Vittori et al. ⁶ described a case of cutaneous ulcers occurring 10 years after leflunomide initiation. The authors suggested that prior drug tolerance may not play a protective role in the development of leflunomide-induced ulcers. Our patient was initially on leflunomide for 11 years. The medication was resumed after 4 months of discontinuation due to arthritis reactivation. She developed the cutaneous ulcerations 2 years after resuming leflunomide. The impact of this therapeutic pause is difficult to assess. Although the half-life of leflunomide is typically known to be 2 weeks, its active metabolite (A77 1726) has been found in some patients’ blood serum 2 years after the last intake. ² Therefore, tolerance to the drug in our patient has possibly been maintained despite discontinuation of treatment. In our patient, the Naranjo Adverse Drug Reaction Probability Scale demonstrated a probable link (score of 7) between the development of ulcers and leflunomide. ⁷

Regarding pathogenesis, the active metabolite A77 1726 of leflunomide prevents the rapid proliferation of lymphocytes and other rapidly proliferating cell lines, including the epidermal growth factor. ⁴ Leflunomide’s toxic effect on epidermal cell lines prevents ulcers from healing. ⁴ Clinically, leflunomide-induced ulcers have been described primarily on the upper and lower extremities with no distinctive morphology.^1–6

The only effective therapeutic intervention is discontinuation of leflunomide which is also reflected in our patient.^1–6 Other adjuvant therapies, such as cholestyramine washout, corticosteroids,^1,5,6 cyclophosphamide, ⁶ skin grafts^5,6 and azathioprine ¹ have been added after leflunomide discontinuation with varying results.

This case demonstrates the importance of considering drug-induced ulcerations in patients with lesions not responding to conventional treatment. It also shows that leflunomide-induced ulcers can occur more than a decade after initiation of the drug.