Ulcerated necrobiosis lipoidica successfully treated with tofacitinib

Abstract

Necrobiosis lipoidica (NL) is a granulomatous inflammatory skin disease that mainly affects middle-aged women and usually manifests on the extensor sides of the lower legs. Diabetes mellitus is a common comorbidity. Histologically, NL is characterized by collagen degeneration, granuloma formation, and perivascular inflammatory infiltrate.1 The therapy of NL is challenging, especially in cases of extensive ulceration. A 48-year-old woman presented to our outpatient clinic with extensive ulcers on the extensor sides of her legs. Skin changes began a few years prior with minor trauma and were progressing slowly. On admission, she presented with ulcers measuring up to 5 × 15 centimeters which showed a yellow center, fibrin coating, and a livid border with teleangiectasias on both tibia regions. In addition, the patient complained of severe pain (Numerical Rating Scale 8/10) with an electricizing character. The chemistry lab report showed no abnormalities, and HbA1c was in the normal range. The skin biopsy revealed ulcerated dermatitis, granulomatous infiltrate, and degenerated collagen fibers (Fig. 1). We diagnosed an ulcerated necrobiosis lipoidica and initiated therapy with oral prednisolone (0.5 mg/kg body weight per day tapered over 2 months) and topical tacrolimus. The patient received metamizole and gabapentin for analgesia. Because of insufficient therapy response and the progression of the ulcers, we started a therapy with the TNF-alpha inhibitor adalimumab with a loading dose of 80 mg subcutaneously followed by 40 mg every 2 weeks. Again, after four doses the ulcers showed no tendency of healing but continued aggravation (Fig. 2a). Ultimately, we decided to initiate a therapy with tofacitinib (JAK1/3 inhibitor) 5 mg twice a day. Tofacitinib resulted in rapid control of inflammation and progressive healing of the ulcers. In addition, we performed a hair-containing punch graft transplantation to accelerate wound healing (five grafts on each side with a diameter of 2 mm). After 5 months, the extensive wound surface was completely epithelized (Fig. 2b). Our case highlights the impressive effect immunomodulatory anti-inflammatory therapy has on ulcerated NL by blocking JAK-STAT signaling pathway. The use of JAK inhibitors in granulomatous skin diseases, for example, cutaneous sarcoidosis or granuloma annulare (GA), has recently shown a good therapeutic response.2 Particularly in sarcoidosis, tofacitinib (JAK1/3 inhibitor) and ruxolitinib (JAK1/2 inhibitor) showed a significant reduction in disease activity in both cutaneous and organ sarcoidosis.3-6 Current clinical phase 1 studies are investigating this effect systematically (NCT03910543 and NCT03793439). In addition to the auspicious effects of systemic JAK inhibitor, topical application in the treatment of GA also shows promising results and could be considered a future treatment option with less side effects compared to systemic therapy.7, 8 In regard to NL, there are two case reports in the literature of patients who could benefit from JAK inhibitor therapies. Lee et al. showed the healing of a patient who received ruxolitinib due to polycythemia vera and also had a refractory ulcerated NL that almost completely regressed.9 Damsky et al. showed an improvement of NL by using tofacitinib in combination with intralesional glucocorticosteroids.10 In granulomatous inflammatory processes, CD4 + T helper cells represent the largest lymphocyte population that produce interferon-gamma and activate macrophages, which are also upregulated in granulomatous diseases. These, in turn, release proinflammatory interleukins, for example, IL-6, IL-12, IL-23, and interferon-gamma, which act via JAK-STAT signaling pathway and are prevented through the use of JAK inhibitors.2 JAK inhibitors, which are evaluated for the treatment of many autoimmune diseases, also show promising success in granulomatous skin diseases and could be considered an effective option in the treatment of NL in the future. Open Access funding enabled and organized by Projekt DEAL.

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