Onset of pyoderma gangrenosum after tocilizumab therapy for Takayasu arteritis: A new undescribed paradoxical reaction

Takayasu arteritis (TA) is a rare primary granulomatous large vessel vasculitis mainly involving the aorta and its major branches. Skin involvement has been observed in 2.8–28% of patients, including Raynaud phenomenon, erythema nodosum-like lesions, necrotic or ulcerated nodules, livedo reticularis, and purpura.1 Only a few cases of pyoderma gangrenosum (PG) have been described in English-language literature.2 On this topic, we would like to report a case of PG which occurred during therapy with tocilizumab in a patient with refractory TA. A 19-year-old woman with a 6-year history of TA was referred to our outpatients' service for abrupt onset of ulcerative lesions on the lower legs. For many years, she underwent several treatments including systemic steroids, cyclophosphamide and mycophenolate mofetil, with no significant improvement. For 1 year, she was under treatment with Methotrexate (MTX) 20 mg/week s.c. and Prednisone 25 mg/day, with suboptimal control of the disease. Therefore, off-label therapy with Tocilizumab (TCZ) 162 mg/week s.c was started. Ten days after the first administration, indurated plaques appeared on the extensor surface of both legs, with multiple undermined painful ulcers (Figure 1A). No history of recent trauma was reported. Multiple bacterial cultures from the ulcer showed no evidence of infection. A pathergy test was not performed. A biopsy specimen including the margin and the floor of the ulcer, performed 3 weeks after its development, showed a large number of neutrophils, plasma cells, lymphocytes and multinucleated giant cells infiltrating the dermis and subcutaneous tissue. Special histochemical stains (PAS, Ziehl-Neelsen) for fungi and mycobacteria were negative. The diagnosis of PG was made. TCZ and MTX were prudently stopped. Treatment with prednisone 50 mg/day induced progressive improvement of skin lesions within 1 month. We decided, with the patient, to continue TCZ administration, with reappearance of PG lesions after the second injection (Figure 1B). TCZ was therefore discontinued indefinitely. Therapy with prednisone 50 mg/day and adalimumab 40 mg/every 2 weeks resulted in progressive healing of skin ulcers within 3 months (Figure 1C). We decided to start the patient on adalimumab because it can be used in both diseases. Since relapses are quite common with PG, there was a possibility that the occurrence of relapses could be attributed to the common course of the disease, instead of the use of TCZ. As time elapsed since our patient's treatment with TCZ and the onset of PG, as well as its recurrence after TCZ suspension and re-administration supported the diagnosis of paradoxical drug-induced reaction, further reinforced by score 7 in the Naranjio algorithm for the assessment of likelihood of adverse drug reactions.3 Paradoxical reactions can be defined as the appearance or exacerbation during treatment with a biologic agent of a pathological condition that usually responds to this class of drugs.4 The skin is one of the main organs affected by these reactions, presenting a wide spectrum of clinical aspects, that reflects complex interactions between host-specific factors, immune-mediated comorbidities, immune-regulatory mechanisms, and targeted immune-modulation. PG can occur at any stage of the disease process of TA, with a marked preponderance in Asian females and a peak onset between the first and the third decades of life.2 In both diseases, elevated serum levels of interleukin (IL)-6 have been detected.4-6 IL-6 is a multifunctional cytokine with a wide range of biological activities in various target cells, regulating immune responses and acute phase reactions.7 As for the pathogenesis of PG, IL-6 is involved in the activation and accumulation of neutrophils in affected tissue, and its level decreases after successful PG treatment.4 High serum IL-6 levels and high levels of IL-6 expression in the aortic wall have been also reported in TA patients.5 For this reason, the humanized anti-interleukin 6 receptor antibody TCZ has been recently used in both diseases as therapeutic alternative in case of treatment failure or steroid dependence.8, 9 The possibility of new-onset PG should be considered after the start of TCZ in TA patients. Our case could be included in the ever-growing list of the paradoxical reactions to biologic therapies. There are no competing interests to declare. F.B., MD and PhD, is responsible for the approval of the final version of the manuscript; conception and planning of the study; participation in design of the study; elaboration and writing of the manuscript; critical review of the literature; and critical review of the manuscript. D.S., MD, is responsible for the approval of the final version of the manuscript; participation in design of the study; and critical review of the manuscript. A.S., MD, is responsible for the approval of the final version of the manuscript; participation in design of the study; and critical review of the literature. F.M., MD, is responsible for the approval of the final version of the manuscript; participation in design of the study; and critical review of the literature. L.B., MD, is responsible for the approval of the final version of the manuscript; elaboration and writing of the manuscript; critical review of the literature; and critical review of the manuscript. S.P.C., MD, is responsible for the approval of the final version of the manuscript and critical review of the manuscript. R.G., MD, is responsible for the approval of the final version of the manuscript; conception and planning of the study; participation in design of the study; and critical review of the manuscript.