​PAPA – Pyogenic Arthritis, Pyoderma gangrenosum and Acne

PAPA syndrome typically presents in early childhood with recurrent episodes of sterile pyogenic arthritis, but it may present in adulthood too. The distribution of joints at disease onset is typically mono- or oligoarticular (affecting a few joints) but may become polyarticular (affecting many joints) over time. Joint flares often decrease in frequency and severity in the late teens. The arthritis is intensely inflammatory, leading to joint destruction, permanent joint deformity, undersized jaw (micrognathia), and stiffening and immobility of a joint due to fusion of the bones (ankylosis). The development of cystic acne typically occurs in early puberty and continues into adulthood. Severe pyoderma gangrenosum can be one of the most challenging features of the disease, causing large, deep cutaneous ulcerations, typically located on the lower extremities. It is characterized by poor healing and rolled edges.

PAPA syndrome is an autosomal dominant autoinflammatory disorder with clear evidence of involvement of IL-1β among other inflammatory pathways.

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Diagnosis of PAPA syndrome is based on clinical findings and a family history. The ulcers may be biopsied. Biopsy shows superficial ulceration and neutrophilic inflammation. Acne biopsies show burrowing and interconnecting abscesses and scars. Laboratory studies reveal the absence of autoantibodies and rheumatoid factor; markers of systemic inflammation may be elevated or normal. There are no diagnostic laboratory tests.

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Its differential diagnosis includes idiopathic PG, as well as PG secondary to other etiologies including inflammatory bowel disease or malignancy. Other neutrophilic dermatoses should be considered, including Sweet’s syndrome (a pathologic diagnosis) and infectious causes of abscesses.

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Inflammatory markers such as ESR, CRP and SAA are elevated during flares and may remain elevated between flares. Peripheral WBC counts may be elevated with a neutrophilic predominance, and ferritin may also be increased as markers of acute inflammation. Skin and joint fluid cultures should be sterile unless a superinfection is present.

It is caused by mutations in the PSTPIP1 gene on chromosome 15q. Mutations in PSTPIP1 lead to increased pyrin binding and resultant activation of the NLRP3 inflammasome through decreased pyrin binding, leading to increased levels of IL-1β.

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Genetic testing for mutations in the PSTPIP1 gene is available. The presence of a single mutation confirms the genetic diagnosis, as this disorder is autosomally dominant. Phenotype genotype associations show that patients with cysteine substitutions have a more severe disease course with a higher risk of secondary amyloidosis. Joint radiographs may be normal or may show erosions and deformities in patients with PAPA.

Corticosteroids are useful in management of both articular and cutaneous manifestations, although high doses are often required to control the disease. The skin lesions of PAPA have responded to TNF inhibitors, i.e. etanercept, as well as IL-1 inhibitors (anakinra, canakinumab). Acne is treated with oral tetracycline or isotretinoin.

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The treatment of PG in PAPA can be very difficult, requiring multiple high dose immunosuppressants. Patients may show only a partial response to immunosuppressives. Unlike some other autoinflammatory syndromes, patients do not respond to colchicine.

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The efficacy and safety of combinations of immunosuppressives and biologics in resistant disease remains to be reported. In addition to steroids, IL-1- and TNF-targeted therapies represent so far the most successful treatment solution.