A Chronic Ulcer in a Patient Under Biologic Treatment: A Quiz

A 64-year-old Italian man living in Tuscany, who had received adalimumab for five years due to long-standing psoriatic arthritis, presented with a 12-month history of painful ulcers on the right thigh (Figure 1a,b). The lesions had gradually enlarged and become increasingly painful. His medical history included only mild chronic kidney disease but was otherwise unremarkable. On physical examination, four ulcers were noted. They were deep, with purulent bases and erythematous-violaceous undermined borders. He reported no systemic symptoms. There was no lymphadenopathy or mucosal involvement. The differential diagnosis included paradoxical pyoderma gangrenosum, cutaneous leishmaniasis, mycobacterial skin infection, and deep fungal infection. Past treatments included topical antibiotics and systemic corticosteroids (prednisone 0.75 mg/kg/day), which were both ineffective. Complete blood count, liver and C-reactive protein were within normal ranges. Ulcer swabs for bacteria and fungi were negative. Histopathological examination of an incisional biopsy taken from the ulcer edge showed a dense granulomatous infiltrate consisting of histiocytes, lymphocytes, and plasma cells in the superficial and mid-dermis (Figure 2a). Giemsa staining revealed abundant intra- and extracellular oval basophilic bodies, each showing a distinct nucleus (Figure 2b). Your diagnosis?… Diagnosis: Cutaneous leishmaniasis Molecular analysis confirmed the diagnosis of cutaneous leishmaniasis (CL) caused by Leishmania infantum. The patient was successfully treated with oral miltefosine at the dose of 50 mg three times a day for two months, leading to complete resolution of the lesions (Figure 3). Systemic therapy with an extended treatment duration was selected because of the patient's immunocompromised status and the presence of multiple, deep, chronic lesions consistent with complex cutaneous leishmaniasis; while miltefosine was preferred over amphotericin B or pentavalent antimonials due to underlying renal impairment and the patient's preference for an oral outpatient treatment strategy.1, 2 The patient was educated to adhere to clinical follow-up and to promptly report the appearance of any new cutaneous or mucosal lesions. Cutaneous leishmaniasis is a protozoal infection transmitted by the bite of sandflies and remains endemic in Mediterranean countries, including southern Italy, where L. infantum is prevalent.3 Typical lesions include indolent papules, nodules, or ulcers. However, in immunocompromised patients, particularly those receiving tumor necrosis factor (TNF)-α inhibitors such as adalimumab, clinical presentations may be atypical, more severe, and sometimes painful.4 This case was initially misdiagnosed as pyoderma gangrenosum (PG), a sterile neutrophilic dermatosis that is often a diagnosis of exclusion and that may occur paradoxically under anti-TNF agents, among others. Indeed, PG is commonly treated with systemic immunosuppression, including corticosteroids and biologics. Such therapies can be deleterious in the setting of unrecognized infections such as leishmaniasis.5 In our patient, systemic corticosteroids likely exacerbated parasitic proliferation and lesion progression. Few cases of ulcerative, PG-like CL have been reported in literature.6-10 Often located on the lower limbs, they present with violaceous, undermined borders and fail to respond to corticosteroids or biologics. Histological examination revealed granulomatous inflammation with amastigotes, and the diagnosis was confirmed via Giemsa staining, culture, or PCR. Reported Leishmania species included L. major, L. tropica, L. panamensis, and L. infantum.6-10 In immunosuppressed patients, atypical and aggressive forms of CL are more likely due to impaired granulomatous containment of the parasite.1 In these patients, PG-like ulcers should prompt clinicians to consider infectious mimickers. A travel history or residence in endemic areas should raise suspicion for CL. Early histopathologic analysis, combined with Leishmania-specific stains or molecular testing, is critical in all refractory or atypical ulcers prior to starting or escalating immunosuppression.1 First-line topical treatments for CL include cryotherapy, thermotherapy, intralesional antimonials, and topical paromomycin, whereas first-line systemic therapies include liposomal amphotericin B, miltefosine, and pentavalent antimonials. Miltefosine has shown favorable efficacy and tolerability for L. infantum and other species, also in immunosuppressed individuals.2 This case underscores the need for heightened clinical suspicion and thorough diagnostic evaluation in patients with chronic ulcers under biologic treatment. In particular, CL must be excluded in endemic regions before labeling a lesion as idiopathic or paradoxical PG, as misdiagnosis can lead to inappropriate immunosuppression, worsening infection, and delayed recovery. Angelo Valerio Marzano reports consultancy/advisory boards disease-relevant honoraria from AbbVie, Amgen, Boehringer-Ingelheim, Bristol Myers Squibb, Incyte, Leopharma, Novartis, Pfizer, Sanofi, and UCB.