Pyogenic sterile arthritis, pyoderma gangrenosum, acne
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Synonyms and Keywords: PAPA syndrome
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.
- 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.
- There is no established system for the classification of PAPA syndrome.
- 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-1β) production.
- Overproduction of IL-1β is a clear molecular feature of PAPA syndrome.
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.
- There are no established risk factors for PAPA syndrome.
- 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.
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 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 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.
- 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 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
Other Diagnostic Studies
- 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.
- There are no established measures for the primary prevention of PAPA syndrome.
- There are no established measures for the secondary prevention of PAPA syndrome.
- Lindor, Noralane M.; Arsenault, Todd M.; Solomon, Herman; Seidman, Christine E.; McEvoy, Marian T. (1997). "A New Autosomal Dominant Disorder of Pyogenic Sterile Arthritis, Pyoderma Gangrenosum, and Acne: PAPA Syndrome". Mayo Clinic Proceedings. 72 (7): 611–615. doi:10.4065/72.7.611. ISSN 0025-6196.
- Yeon, Howard B.; Lindor, Noralane M.; Seidman, J.G.; Seidman, Christine E. (2000). "Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne Syndrome Maps to Chromosome 15q". The American Journal of Human Genetics. 66 (4): 1443–1448. doi:10.1086/302866. ISSN 0002-9297.
- J. Smith, Elisabeth; Allantaz, Florence; Bennett, Lynda; Zhang, Dongping; Gao, Xiaochong; Wood, Geryl; L. Kastner, Daniel; Punaro, Marilynn; Aksentijevich, Ivona; Pascual, Virginia; A. Wise, Carol (2010). "Clinical, Molecular, and Genetic Characteristics of PAPA Syndrome: A Review". Current Genomics. 11 (7): 519–527. doi:10.2174/138920210793175921. ISSN 1389-2029.
- Shoham, N. G.; Centola, M.; Mansfield, E.; Hull, K. M.; Wood, G.; Wise, C. A.; Kastner, D. L. (2003). "Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway". Proceedings of the National Academy of Sciences. 100 (23): 13501–13506. doi:10.1073/pnas.2135380100. ISSN 0027-8424.
- Schellevis, M. A.; Stoffels, M.; Hoppenreijs, E. P. A. H.; Bodar, E.; Simon, A.; van der Meer, J. W. M. (2011). "Variable expression and treatment of PAPA syndrome". Annals of the Rheumatic Diseases. 70 (6): 1168–1170. doi:10.1136/ard.2009.126185. ISSN 0003-4967.
- Martinez-Rios, Claudia; Jariwala, Mehul P.; Highmore, Kerri; Duffy, Karen Watanabe; Spiegel, Lynn; Laxer, Ronald M.; Stimec, Jennifer (2018). "Imaging findings of sterile pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome: differential diagnosis and review of the literature". Pediatric Radiology. 49 (1): 23–36. doi:10.1007/s00247-018-4246-1. ISSN 0301-0449.
- Dierselhuis, M. P. (2005). "Anakinra for flares of pyogenic arthritis in PAPA syndrome". Rheumatology. 44 (3): 406–408. doi:10.1093/rheumatology/keh479. ISSN 1460-2172.
- Horiuchi, Isao; Fukatsu, Yuko; Ushijima, Junko; Nakamura, Eishin; Samajima, Koki; Kadowaki, Kanako; Takagi, Kenjiro (2016). "A pregnancy-associated nonfamilial case of PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, acne) syndrome". Clinical Case Reports. 4 (10): 989–991. doi:10.1002/ccr3.662. ISSN 2050-0904.
- Hong, Jin-Bon; Su, Yi-Ning; Chiu, Hsien-Ching (2009). "Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA syndrome): Report of a sporadic case without an identifiable mutation in the CD2BP1 gene". Journal of the American Academy of Dermatology. 61 (3): 533–535. doi:10.1016/j.jaad.2008.11.017. ISSN 0190-9622.
- Cortis, Elisabetta; De Benedetti, Fabrizio; Insalaco, Antonella; Cioschi, Stefania; Muratori, Flaminia; D'Urbano, Leila E.; Ugazio, Alberto G. (2004). "Abnormal production of the tumor necrosis factor inhibitor etanercept and clinical efficacy of tumor in a patient with PAPA syndrome". The Journal of Pediatrics. 145 (6): 851–855. doi:10.1016/j.jpeds.2004.08.001. ISSN 0022-3476.
- Tallon, B.; Corkill, M. (2006). "Peculiarities of PAPA syndrome". Rheumatology. 45 (9): 1140–1143. doi:10.1093/rheumatology/kei178. ISSN 1462-0332.
- Demidowich, Andrew P.; Freeman, Alexandra F.; Kuhns, Douglas B.; Aksentijevich, Ivona; Gallin, John I.; Turner, Maria L.; Kastner, Daniel L.; Holland, Steven M. (2012). "Brief Report: Genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne)". Arthritis & Rheumatism. 64 (6): 2022–2027. doi:10.1002/art.34332. ISSN 0004-3591.