PAPA Syndrome Beyond Its Inflammatory Triad

Summary: PAPA Syndrome Beyond Its Inflammatory Triad Noor Bazerbashi MD, Alsayed Osman MD, Yih Chang Lin MD. Department of Internal Medicine, Division of Rheumatology, University of South Florida. Keywords: Pyogenic arthritis, pyoderma gangrenosum, PAPA, autoinflammatory disorder Background Pyogenic arthritis, pyoderma gangrenosum (PG), and acne (PAPA) syndrome is a rare autosomal dominant autoinflammatory disorder caused by a mutation that leads to elevated Interleukin-1β production. Diagnosis and treatment of this autoinflammatory disorder has its own set of challenges, and skin disease might be exceedingly difficult to control. Case A 22-year-old male with a history of childhood-onset leukopenia and anemia was referred to Rheumatology due to nonhealing skin ulcers that had persisted for four years. Initially diagnosed with acne because the lesions looked like “pimples” or “insect bites,” his condition worsened over time. Despite treatment, the lesions became chronic ulcers requiring frequent debridement. He had positive pathergy in which incisions or even the slightest trauma transformed into new lesions. The overall presentation favored PG, and skin biopsy confirmed neutrophilic pustular dermatosis . His skin disease was preceded by anemia, leukopenia, and oligoarthritis, which had started when he was 6 years old. The patient received multiple steroid courses after infection was ruled out and had no recurrence since 12 years of age. However, anemia and leukopenia persisted. He was evaluated by multiple specialties including Rheumatology, Dermatology, and Hematology. No diagnosis was established despite undergoing genetic testing, multiple bone marrow, and skin biopsies. Erythrocyte sedimentation rate and C-reactive protein were elevated. Autoimmune workup showed positive antinuclear antibody of 1 :80-speckled in pattern but complements and extractable nuclear antigen testing were unremarkable. The overall clinical picture with hyperzincemia, elevated calprotectin, and hepatosplenomegaly raised concern for an underlying autoinflammatory disorder like PAPA. Genetic testing revealed mutation in the PSTPIP1 gene confirming the diagnosis. Anakinra, an interleukin-1 receptor antagonists, was chosen as the initial treatment given his systemic symptoms with the option to switch to tumor necrosis factor inhibitors (TNFi) if needed. Discussion Systemic autoinflammatory disorders are rare, and this case illustrates how difficult they can be to diagnose, often leading to a delay in recognition. In some instances, it can take over 10 years for a diagnosis to be made, as seen in 25% of patients with autoinflammatory disorders. Genetic testing can help confirm the diagnosis in patients with the appropriate clinical features. Like our patient, the specific variant (E250K) of the proline serine threonine phosphatase-interacting protein 1 (PSTPIP1) gene was identified in hyperzincemia/hypercalprotectinemia syndrome. This mutation is known to result in severe cutaneous inflammation, arthritis, pancytopenia, and HSM. Patients are sometimes misdiagnosed with Juvenile idiopathic arthritis early during their disease course. An alternative diagnosis is sought in adolescence after transition to skin disease is noted. Treatment consists of systemic corticosteroid and biologic therapy, like interleukin-1 receptor antagonists and TNFi. Response on the other hand remains variable, but use of TNFi tends to be favored in severe skin involvement. Conclusion The classic triad of recurrent arthritis, PG, and cystic acne is a hallmark of PAPA syndrome. Early diagnosis and prompt treatment can significantly enhance patient outcomes and quality of life.