Successful Treatment of PAPA Syndrome with Dual Adalimumab and Tacrolimus Therapy.

Abstract

Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is a rare autosomal dominant disorder with variable expressivity [1] and results from mutations in the PSTPIP1 gene. The PSTPIP1 protein is a cytoskeletal protein within hematopoietic cells that serves as a scaffold for the binding of other cellular proteins, such as pyrin, protein tyrosine phosphatases, c-Abl, CD2, and WASP. Through these interactions, PSTPIP1 regulates several cellular functions including IL-lβ release, cytoskeleton organization, cell migration, and T-cell activation [2, 3]. Depending on the mutation location within the PSTPIP1 gene and consequent alterations in protein-protein interactions, a spectrum of autoinflammatory disorders may result and are collectively referred to as PSTPIP1-associated inflammatory diseases (PAID). While the underlying pathogenesis is not completely understood, the PAID spectrum is characterized by dysregulated IL-lβ release and neutrophil responses [4] and clinically manifests as recurrent bouts of untriggered inflammation involving various organ systems [5]. PAPA syndrome is only one entity within the PAID spectrum and classically presents with sterile pyogenic arthritis, pyoderma gangrenosum (PG), and cystic acne. Due to heterogeneous presentations, delays in diagnosis and misdiagnoses as autoimmune or immunodeficiency conditions are common. Given the rarity of PAPA syndrome and other disorders in the PAID spectrum, no guideline-based treatment approaches exist and previous reports highlight the significant variability in responses to monotherapy with two of the most common long-term therapies utilized: IL-1β antagonists and TNF-α inhibitors [2, 6]. Other anti-inflammatory agents are reserved for treatment failures, and dual therapy, except in combination with steroids, is rarely reported for treatment of PAPA syndrome [3, 6]. Early diagnosis and initiation of effective treatment to induce remission, however, are vital to decreasing the morbidity and mortality associated with these autoinflammatory disorders. We present here a case of an adolescent female referred to our immunology clinic for suspected immunodeficiency, but who was subsequently diagnosed with and treated for PAPA syndrome with combination adalimumab and tacrolimus therapy. To our knowledge, this is the first report of the effective and safe use of tacrolimus in combination with adalimumab for PAPA syndrome. Case Presentation A 12-year-old female was referred to our immunology clinic for evaluation of a possible immunodeficiency given her history of recurrent infections since 1 year of age. Her pertinent clinical history is summarized in Figure 1a. She initially developed recurrent purulent otitis media (OM), requiring multiple sets of tympanostomy tubes. At 5-years-old, she developed erythema, bruising, swelling, and pain of her left ankle that was initially attributed to trauma. Over several months, her symptoms extended to involve her bilateral ankles, knees, wrists, and hands. Following a rheumatology evaluation, she was diagnosed with seronegative polyarticular juvenile idiopathic arthritis (JIA). After failing therapy with naproxen, methotrexate was attempted but discontinued after four months due to an increase in OM. Her arthritis interestingly resolved spontaneously over the next several months without further treatment. Open in a separate window Figure 1: a) Our patient’s clinical history was significant for recurrent episodes of purulent otitis media, polyarticular juvenile idiopathic arthritis (JIA), two episodes of pyogenic sterile arthritis and osteomyelitis of the right elbow, and various cutaneous manifestations including recurrent episodes of cellulitis and abscesses, pyoderma gangrenosum (PG), and nodulocystic acne. Arrows indicate initiation of adalimumab and addition of tacrolimus. * represents PG flare during lapse of adalimumab therapy for 6–8 weeks. b) Dermatopathology from biopsy of left breast lesion revealed a mixed lobular panniculitis with interstitial neutrophils and lymphocytes and features consistent with a neutrophilic dermatosis. c) Erythematous, violaceous ulcerated plaque that represents PG lesion prior to treatment. d) PG lesion following treatment with adalimumab with reduction in erythema, ulceration, and size. e) PG lesion following addition of tacrolimus to adalimumab has healed into a hypertrophic scar.