PAPA syndrome

Overview

PAPA syndrome, short for Pyogenic Arthritis, Pyoderma gangrenosum, and Acne syndrome, is an extremely rare autoinflammatory disorder characterized by recurrent sterile joint inflammation, severe skin ulcers, and cystic acne. It belongs to a group of diseases known as autoinflammatory syndromes, which are caused by dysfunctions in the innate immune system rather than infections or autoimmune mechanisms. PAPA syndrome typically begins in early childhood, often presenting initially with episodes of painful joint swelling. As the individual grows older, skin manifestations such as severe nodulocystic acne and ulcers caused by pyoderma gangrenosum become more prominent. The disease is chronic and relapsing, requiring long-term medical management.

Causes

PAPA syndrome is caused by mutations in the PSTPIP1 gene (proline-serine-threonine phosphatase-interacting protein 1), which plays a key role in regulating inflammatory responses. The mutated gene leads to dysregulation of the inflammasome, a multi-protein complex responsible for producing pro-inflammatory cytokines such as interleukin-1β (IL-1β). This overactivation of inflammatory pathways results in recurrent sterile inflammation of joints and skin tissues. PAPA syndrome follows an autosomal dominant inheritance pattern, meaning a child only needs to inherit one mutated copy of the gene from an affected parent to develop the disorder. However, some cases may also result from new (de novo) mutations.

Symptoms

The symptoms of PAPA syndrome typically develop in stages, with joint symptoms often appearing first in early childhood, followed by skin manifestations during adolescence or adulthood. Key clinical features include:

• Pyogenic arthritis: Recurrent episodes of sterile arthritis, particularly in the knees, ankles, and wrists. These episodes cause painful, swollen joints filled with inflammatory fluid but no detectable infection.

• Pyoderma gangrenosum: Painful, rapidly expanding skin ulcers with a necrotic base, usually appearing on the legs. These lesions are prone to secondary infections and poor healing.

• Severe acne: Nodulocystic acne and abscesses affecting the face, back, and chest. Lesions can be deep, scarring, and resistant to conventional acne treatments.

• Chronic inflammation: Elevated inflammatory markers (e.g., CRP, ESR) are common during flares, along with systemic symptoms such as fatigue and malaise.

Diagnosis

Diagnosing PAPA syndrome can be challenging due to its rarity and symptom overlap with other autoimmune or infectious conditions. Diagnosis is based on clinical findings, family history, and genetic testing. Common steps include:

• Clinical evaluation: A detailed history of recurrent arthritis, skin ulcers, and acne, especially in the absence of infection, raises suspicion.

• Laboratory tests: Elevated white blood cell counts and inflammatory markers (ESR, CRP) may be seen during flares. Cultures from joints and skin lesions are sterile (no bacterial growth).

• Imaging: X-rays or MRI of affected joints may show joint effusions but no infectious destruction.

• Skin biopsy: May help confirm pyoderma gangrenosum and rule out other ulcerative skin conditions.

• Genetic testing: Definitive diagnosis is made by identifying mutations in the PSTPIP1 gene.

Treatment

Treatment for PAPA syndrome focuses on controlling inflammation and preventing joint damage and skin complications. Since it is an autoinflammatory condition, immunosuppressive and biologic therapies are often required. Key treatment options include:

• NSAIDs and corticosteroids: Used to reduce inflammation and pain during acute flares of arthritis or skin lesions.

• Immunosuppressants: Medications such as methotrexate or cyclosporine may be prescribed to control systemic inflammation.

• Biologic therapies: Targeted biologics, particularly IL-1 inhibitors like anakinra or canakinumab, have shown significant effectiveness in controlling symptoms and reducing flares.

• TNF inhibitors: Such as infliximab or etanercept, may be beneficial for some patients with severe skin manifestations.

• Topical treatments: Antibiotics or corticosteroid creams may be used as adjuncts for acne or minor skin lesions.

• Wound care: For pyoderma gangrenosum ulcers, proper wound management and infection prevention are essential.

Prognosis

The prognosis of PAPA syndrome varies depending on the severity of symptoms and how early treatment is initiated. With appropriate use of anti-inflammatory and biologic therapies, many patients experience reduced frequency and intensity of flares and can lead relatively normal lives. However, untreated or poorly controlled disease may lead to permanent joint damage, chronic skin ulcers, and significant scarring from acne. Regular follow-up with rheumatology and dermatology specialists is essential for optimal management. While the condition is lifelong, advances in targeted immunotherapy have significantly improved long-term outcomes and quality of life for affected individuals.