Pyogenic sterile arthritis, pyoderma gangrenosum, acne
Synonyms and keywords: PAPA syndrome

# Overview
Pyogenic sterile arthritis, pyoderma gangrenosum, acne syndrome, PAPA syndrome, is one of the inherited autoinflammatory disorders. PAPA syndrome presents with the triad of aseptic arthritis, pyoderma gangrenosum, and acne. However, not all the features may be present in all the patients.

# Historical Perspective
- PAPA syndrome was first discovered by Dr. Noralane M. Lindor, in 1997 following visiting several patients from three generations of a family with similar presentations.
- The association between PSTPIP1 gene mutation and PAPA syndrome was made in the year 2000.

# Classification
- There is no established system for the classification of PAPA syndrome.

# Pathophysiology
- The exact pathogenesis of PAPA syndrome is not fully understood. However, it develops as a result of a mutation in the PSTPIP1 gene.
- Mutation is inherited in an autosomal dominant mode.
- The mutation leads to a hyper-phosphorylated PSTPIP1 protein which changes its action in the inflammasome involved in interleukin-1 (IL-1) production.
- Overproduction of IL-1 is a clear molecular feature of PAPA syndrome.

# Causes
- PAPA syndrome is caused by a mutation in the PSTPIP1 gene.

# Differentiating PAPA syndrome from Other Diseases
- PAPA syndrome must be differentiated from other diseases that cause arthritis, skin rash, and pyoderma gangrenosum, such as Blau syndrome, familial cold autoinflammatory syndrome, chronic recurrent multifocal osteomyelitis (CRMO) , and juvenile idiopathic arthritis (JIA).
- For more information on the differential diagnosis of PAPA syndrome please click here.

# Epidemiology and Demographics
- The prevalence of PAPA syndrome is approximately 0.01 case per 100,000 individuals worldwide.
- There are 53 cases of PAPA syndrome in the literature.
- PAPA syndrome commonly affects children. However, it may develop later in some individuals.
- There is no racial predilection to PAPA syndrome.
- PAPA syndrome affects men and women equally.
- The majority of PAPA syndrome cases are reported in  Europe, New Zealand, and the USA.

# Risk Factors
- There are no established risk factors for PAPA syndrome.

# Screening
- There is insufficient evidence to recommend routine screening for PAPA syndrome.

# Natural History, Complications, and Prognosis
- PAPA syndrome first manifests with signs and symptoms of arthritis by 1 to 10 years of age. Skin lesions usually develop later in adolescence and they tend to affect the skin of limbs.
- The disease shows variable expressivity and incomplete penetrance.
- Common complications of PAPA syndrome include erosive arthritis.
- The disease severity usually decreases by the age. However, there is no data available on the prognosis of PAPA syndrome.
- The disease may lead to serious joint destruction.

# Diagnosis

## Diagnostic Study of Choice
- There are no established criteria for the diagnosis of PAPA syndrome. The diagnosis may be made clinically.
- Genetic analysis and location of a mutation in the PSTPIP1 gene may be done for the confirmation of the diagnosis. However, there are reported cases of PAPA syndrome with negative genetic results.

## History and Symptoms
- A positive history of recurrent arthritis,  skin ulceration, and acne is suggestive of PAPA syndrome.
- The presenting symptom of PAPA syndrome is usually culture-negative arthritis.

## Physical Examination
- Physical examination of patients with PAPA syndrome is usually remarkable for arthritis, cystic acne, pathergy, and pyoderma gangreonosum.
- Fever may also accompany each flare of the disease.

## Laboratory Findings
- Laboratory findings consistent with the diagnosis of PAPA syndrome include elevated serum levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and WBC.
- Skin lesions and joint fluid are sterile. However, synovial fluid shows neutrophilic infiltrate.
- Tumor necrosis factor-a and interleukin-1 levels has been observed to be elevated in the blood of PAPA syndrome cases.

## Electrocardiogram
- There are no ECG findings associated with PAPA syndrome.

## X-ray
- There are no specific x-ray findings associated with PAPA syndrome. However, an x-ray may be helpful in the diagnosis of complications of arthritis, which include soft tissue swelling, and large joint effusion.
- Other possible radiographic features include pauciarticular, erosive arthritis, Osteophyte formation, diffuse joint narrowing, subchondral sclerosis and cyst formation, reactive new bone formation, and joint deformity or destruction with ankylosis.

## Echocardiography or Ultrasound
- There are no echocardiography/ultrasound  findings associated with PAPA syndrome.

## CT scan
- There are no CT scan findings associated with PAPA syndrome.

## MRI
- There are no specific  MRI findings associated with PAPA syndrome. However, a MRI may be helpful in the diagnosis of complications of arthritis, which include synovitis, synovial hypertrophy, increased enhancement, bone marrow edema/enhancement and surrounding soft tissue edema.

## Other Imaging Findings
- There are no other imaging findings associated with PAPA syndrome.

## Other Diagnostic Studies
- There are no other diagnostic studies associated with PAPA syndrome.

# Treatment

## Medical Therapy
- There is no treatment for PAPA syndrome; the mainstay of therapy is supportive care.
- Treatment options for arthritis include intraarticular corticosteroid injections.
- Oral corticosteroid may be useful for pyoderma gangrenosum.
- Anakinra (interleukin-1 antagonist) has also been observed to be effective in the management of disease flares especially arthicular symptoms.
- Adalimumab (tumor necrosis factor  antagonist) may be effective against cutaneous manifestations of this disorder.

## Surgery
- Surgical intervention is not recommended for the management of PAPA syndrome.

## Primary Prevention
- There are no established measures for the primary prevention of PAPA syndrome.

## Secondary Prevention
- There are no established measures for the secondary prevention of PAPA syndrome.