Successful treatment of pyoderma gangrenosum complicated by JAK2V617F mutation-positive myelofibrosis with adalimumab and systemic steroid

SK has no conflict of interest. KH has received honoraria for speaker and consultancy from AbbVie, Eisai and Novartis.KM has received honoraria for speaker and consultancy from AbbVie, Eisai and Novartis.HF has received honoraria for speaker and consultancy from AbbVie, Eisai and Novartis.Hideki Fujita is an Editorial Board member of The Journal of Dermatology and a coauthor of this article. To minimize bias, they were excluded from all editorial decision-making related to the acceptance of this article for publication.Dear Editor, Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by painful, rapidly progressing ulcers, and often associated with systemic diseases such as inflammatory bowel disease, rheumatoid arthritis, and hematologic malignancies.However, cases of PG concomitant with myelofibrosis are particularly uncommon. Here, we present a case of PG complicated by myelofibrosis that was successfully treated with systemic corticosteroid, adalimumab, and ruxolitinib.A 57-year-old man was referred to our department with a fever and a painful ulcer of the right upper back that occurred one month previously. His medical history included JAK2V617F mutation-positive myelofibrosis, glaucoma, and hyperuricemia. Upon examination, a round-shaped, 7x8 cm-sized yellowish ulcer with mound-like edges and surrounding erythema was observed on the upper right back. (Fig. 1a). Laboratory examination revealed elevated white blood cell count (19,800/µL), platelet count (576,000/µL), and C-reactive protein (145 mg/L). Myeloblasts and erythroblasts were also identified in the peripheral blood. Computed tomography showed splenomegaly.Histopathology of the lesion revealed neutrophil infiltration in the dermis (Fig. 1b,c).Based on these findings, the patient was diagnosed with pyoderma gangrenosum (PG) associated with myelofibrosis. Three-week treatment with 30 mg/day of oral prednisolone failed to reduce the size of the ulcer (Fig. 1d). Therefore, anti-tumor necrosis factor (TNF)-α antibody adalimumab therapy (40 mg/week) was combined. Then, the ulcer began to epithelialize, with epithelialization rates of 50% at seven weeks, 90% at 12 weeks, and 100% at 16 weeks after the initiation of adalimumab therapy (Fig. 1e).However, because thrombocytosis caused by myelofibrosis deteriorated, 10 mg/day of oral ruxolitinib, a Janus kinase (JAK) 2 inhibitor, was started while adalimumab was reduced to 40 mg biweekly. Ruxolitinib was gradually increased to 40 mg/day due to myelofibrosis progression, and adalimumab was reduced to 40 mg every 3-4 weeks and eventually discontinued. He died 22 months after his first visit due to myelofibrosis progression, with no recurrence of skin ulcers during this period (Fig. 1f).PG is a relatively rare inflammatory skin disease characterized by hyperplastic and gangrenous ulcers in which neutrophils play a major role. 1) In Japanese patients, underlying systemic diseases are present in 50.3% of the patients. These include ulcerative colitis (23.5%), Crohn's disease (7.2%), arthritis (9.7%), hematologic malignancies (8.7%), and Takayasu's arteritis (1.2%). 1) Most of the associated hematologic malignancies are myelodysplastic syndromes, but myelofibrosis is observed in rare cases. 2,3) Treatment of PG is challenging, especially when it is associated with hematologic diseases, due to its complex pathophysiology involving neutrophilic inflammation and cytokine dysregulation. Standard treatments, such as oral corticosteroids and immunosuppressants, often provide limited effectiveness, particularly in refractory cases.In recent years, TNF inhibitors have been used in severe PG cases, and adalimumab is approved for PG in Japan. Although there was a case of PG with JAK2V617F mutationpositive myelofibrosis showing good response to systemic steroids, our patient did not show improvement by systemic steroid monotherapy. 4) Currently, there are no established treatment strategies for myelofibrosis-associated PG. This is the first reported case of PG complicated by myelofibrosis successfully treated with a TNF inhibitor in combination with systemic steroid. However, the influence of TNF inhibitors on the course of myelofibrosis remains unknown.An activating somatic mutation JAK2V617F identified in our patient confers a proliferative and survival advantage to hematopoietic progenitor cells. 4) This mutation is found in 50-60% of patients with myelofibrosis. 4) Ruxolitinib, a JAK inhibitor, targets JAK1 and JAK2 pathways, which play essential roles in hematopoiesis and immune regulation. 5) By inhibiting these pathways, ruxolitinib is able to reduce cellular proliferation in myelofibrosis. The JAK/STAT pathway is also known to be activated in neutrophilic dermatoses, including PG, suggesting that JAK inhibition might help control excessive neutrophil activity at inflammatory sites. 1) Interestingly, JAK2V617F mutation has been associated with constitutive and enhanced activation of neutrophils. 4) Because no recurrences were observed even after the dose reduction of adalimumab, ruxolitinib may have helped maintain PG remission in our patient. Indeed, PG with polycythaemia vera having JAK2V617F mutation has been successfully treated with ruxolitinib monotherapy. 5) This case showed successful treatment of PG complicated by myelofibrosis using a combination of systemic corticosteroid, adalimumab, and ruxolitinib. The effectiveness observed in this case suggests that targeting multiple inflammatory pathways using JAK and TNF inhibitors may be promising in managing PG associated with myelofibrosis positive for JAK2 mutation. Further research is needed to confirm this idea and evaluate the long-term safety and efficacy of combined JAK and TNF inhibition in similar cases.(726/1000)