View source for Pyogenic sterile arthritis, pyoderma gangrenosum, acne

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{{SI}}
{{CMG}}; {{AE}} {{Sahar}}

{{SK}} [[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.<ref name="LindorArsenault1997">{{cite journal|last1=Lindor|first1=Noralane M.|last2=Arsenault|first2=Todd M.|last3=Solomon|first3=Herman|last4=Seidman|first4=Christine E.|last5=McEvoy|first5=Marian T.|title=A New Autosomal Dominant Disorder of Pyogenic Sterile Arthritis, Pyoderma Gangrenosum, and Acne: PAPA Syndrome|journal=Mayo Clinic Proceedings|volume=72|issue=7|year=1997|pages=611–615|issn=00256196|doi=10.4065/72.7.611}}</ref>
* The association between PSTPIP1 [[gene]] mutation and Papa syndrome was made in the year 2000.<ref name="YeonLindor2000">{{cite journal|last1=Yeon|first1=Howard B.|last2=Lindor|first2=Noralane M.|last3=Seidman|first3=J.G.|last4=Seidman|first4=Christine E.|title=Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne Syndrome Maps to Chromosome 15q|journal=The American Journal of Human Genetics|volume=66|issue=4|year=2000|pages=1443–1448|issn=00029297|doi=10.1086/302866}}</ref>
==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]].<ref name="J. SmithAllantaz2010">{{cite journal|last1=J. Smith|first1=Elisabeth|last2=Allantaz|first2=Florence|last3=Bennett|first3=Lynda|last4=Zhang|first4=Dongping|last5=Gao|first5=Xiaochong|last6=Wood|first6=Geryl|last7=L. Kastner|first7=Daniel|last8=Punaro|first8=Marilynn|last9=Aksentijevich|first9=Ivona|last10=Pascual|first10=Virginia|last11=A. Wise|first11=Carol|title=Clinical, Molecular, and Genetic Characteristics of PAPA Syndrome: A Review|journal=Current Genomics|volume=11|issue=7|year=2010|pages=519–527|issn=13892029|doi=10.2174/138920210793175921}}</ref><ref name="ShohamCentola2003">{{cite journal|last1=Shoham|first1=N. G.|last2=Centola|first2=M.|last3=Mansfield|first3=E.|last4=Hull|first4=K. M.|last5=Wood|first5=G.|last6=Wise|first6=C. A.|last7=Kastner|first7=D. L.|title=Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway|journal=Proceedings of the National Academy of Sciences|volume=100|issue=23|year=2003|pages=13501–13506|issn=0027-8424|doi=10.1073/pnas.2135380100}}</ref>
* [[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.
==Causes==
* Papa syndrome is caused by a mutation in the PSTPIP1 gene.<ref name="YeonLindor2000">{{cite journal|last1=Yeon|first1=Howard B.|last2=Lindor|first2=Noralane M.|last3=Seidman|first3=J.G.|last4=Seidman|first4=Christine E.|title=Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne Syndrome Maps to Chromosome 15q|journal=The American Journal of Human Genetics|volume=66|issue=4|year=2000|pages=1443–1448|issn=00029297|doi=10.1086/302866}}</ref>
==Differentiating Papa syndrome from Other Diseases==
* Papa syndrome must be differentiated from other [[diseases]] that cause [[arthritis]], [[skin rash]], and [[pyoderma gangreonosum]], 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 [[Familial mediterranean fever differential diagnosis|click here]].
==Epidemiology and Demographics==
* The [[prevalence]] of Papa syndrome is approximately 0.01 case per 100,000 individuals worldwide.<ref name="SchellevisStoffels2011">{{cite journal|last1=Schellevis|first1=M. A.|last2=Stoffels|first2=M.|last3=Hoppenreijs|first3=E. P. A. H.|last4=Bodar|first4=E.|last5=Simon|first5=A.|last6=van der Meer|first6=J. W. M.|title=Variable expression and treatment of PAPA syndrome|journal=Annals of the Rheumatic Diseases|volume=70|issue=6|year=2011|pages=1168–1170|issn=0003-4967|doi=10.1136/ard.2009.126185}}</ref>
* There are 53 cases of Papa syndrome in the litreture.<ref name="Martinez-RiosJariwala2018">{{cite journal|last1=Martinez-Rios|first1=Claudia|last2=Jariwala|first2=Mehul P.|last3=Highmore|first3=Kerri|last4=Duffy|first4=Karen Watanabe|last5=Spiegel|first5=Lynn|last6=Laxer|first6=Ronald M.|last7=Stimec|first7=Jennifer|title=Imaging findings of sterile pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome: differential diagnosis and review of the literature|journal=Pediatric Radiology|volume=49|issue=1|year=2018|pages=23–36|issn=0301-0449|doi=10.1007/s00247-018-4246-1}}</ref>
* 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]].<ref name="SchellevisStoffels2011">{{cite journal|last1=Schellevis|first1=M. A.|last2=Stoffels|first2=M.|last3=Hoppenreijs|first3=E. P. A. H.|last4=Bodar|first4=E.|last5=Simon|first5=A.|last6=van der Meer|first6=J. W. M.|title=Variable expression and treatment of PAPA syndrome|journal=Annals of the Rheumatic Diseases|volume=70|issue=6|year=2011|pages=1168–1170|issn=0003-4967|doi=10.1136/ard.2009.126185}}</ref><ref name="Dierselhuis2005">{{cite journal|last1=Dierselhuis|first1=M. P.|title=Anakinra for flares of pyogenic arthritis in PAPA syndrome|journal=Rheumatology|volume=44|issue=3|year=2005|pages=406–408|issn=1460-2172|doi=10.1093/rheumatology/keh479}}</ref>
* 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.<ref name="Dierselhuis2005">{{cite journal|last1=Dierselhuis|first1=M. P.|title=Anakinra for flares of pyogenic arthritis in PAPA syndrome|journal=Rheumatology|volume=44|issue=3|year=2005|pages=406–408|issn=1460-2172|doi=10.1093/rheumatology/keh479}}</ref><ref name="HoriuchiFukatsu2016">{{cite journal|last1=Horiuchi|first1=Isao|last2=Fukatsu|first2=Yuko|last3=Ushijima|first3=Junko|last4=Nakamura|first4=Eishin|last5=Samajima|first5=Koki|last6=Kadowaki|first6=Kanako|last7=Takagi|first7=Kenjiro|title=A pregnancy-associated nonfamilial case of PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, acne) syndrome|journal=Clinical Case Reports|volume=4|issue=10|year=2016|pages=989–991|issn=20500904|doi=10.1002/ccr3.662}}</ref><ref name="HongSu2009">{{cite journal|last1=Hong|first1=Jin-Bon|last2=Su|first2=Yi-Ning|last3=Chiu|first3=Hsien-Ching|title=Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA syndrome): Report of a sporadic case without an identifiable mutation in the CD2BP1 gene|journal=Journal of the American Academy of Dermatology|volume=61|issue=3|year=2009|pages=533–535|issn=01909622|doi=10.1016/j.jaad.2008.11.017}}</ref>
* [[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.<ref name="SchellevisStoffels2011">{{cite journal|last1=Schellevis|first1=M. A.|last2=Stoffels|first2=M.|last3=Hoppenreijs|first3=E. P. A. H.|last4=Bodar|first4=E.|last5=Simon|first5=A.|last6=van der Meer|first6=J. W. M.|title=Variable expression and treatment of PAPA syndrome|journal=Annals of the Rheumatic Diseases|volume=70|issue=6|year=2011|pages=1168–1170|issn=0003-4967|doi=10.1136/ard.2009.126185}}</ref>
* 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]].<ref name="Martinez-RiosJariwala2018">{{cite journal|last1=Martinez-Rios|first1=Claudia|last2=Jariwala|first2=Mehul P.|last3=Highmore|first3=Kerri|last4=Duffy|first4=Karen Watanabe|last5=Spiegel|first5=Lynn|last6=Laxer|first6=Ronald M.|last7=Stimec|first7=Jennifer|title=Imaging findings of sterile pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome: differential diagnosis and review of the literature|journal=Pediatric Radiology|volume=49|issue=1|year=2018|pages=23–36|issn=0301-0449|doi=10.1007/s00247-018-4246-1}}</ref>
* [[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]].<ref name="Dierselhuis2005">{{cite journal|last1=Dierselhuis|first1=M. P.|title=Anakinra for flares of pyogenic arthritis in PAPA syndrome|journal=Rheumatology|volume=44|issue=3|year=2005|pages=406–408|issn=1460-2172|doi=10.1093/rheumatology/keh479}}</ref>
* [[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.<ref name="CortisDe Benedetti2004">{{cite journal|last1=Cortis|first1=Elisabetta|last2=De Benedetti|first2=Fabrizio|last3=Insalaco|first3=Antonella|last4=Cioschi|first4=Stefania|last5=Muratori|first5=Flaminia|last6=D'Urbano|first6=Leila E.|last7=Ugazio|first7=Alberto G.|title=Abnormal production of the tumor necrosis factor inhibitor etanercept and clinical efficacy of tumor in a patient with PAPA syndrome|journal=The Journal of Pediatrics|volume=145|issue=6|year=2004|pages=851–855|issn=00223476|doi=10.1016/j.jpeds.2004.08.001}}</ref>
===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.<ref name="Martinez-RiosJariwala2018">{{cite journal|last1=Martinez-Rios|first1=Claudia|last2=Jariwala|first2=Mehul P.|last3=Highmore|first3=Kerri|last4=Duffy|first4=Karen Watanabe|last5=Spiegel|first5=Lynn|last6=Laxer|first6=Ronald M.|last7=Stimec|first7=Jennifer|title=Imaging findings of sterile pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome: differential diagnosis and review of the literature|journal=Pediatric Radiology|volume=49|issue=1|year=2018|pages=23–36|issn=0301-0449|doi=10.1007/s00247-018-4246-1}}</ref><ref name="TallonCorkill2006">{{cite journal|last1=Tallon|first1=B.|last2=Corkill|first2=M.|title=Peculiarities of PAPA syndrome|journal=Rheumatology|volume=45|issue=9|year=2006|pages=1140–1143|issn=1462-0332|doi=10.1093/rheumatology/kei178}}</ref>
* Other possible radiographic features include:
**Pauciarticular, erosive arthritis
**Osteophyte formation
**Diffuse joint narrowing
**Subchondral sclerosis and cyst formation
**Reactive new bone formation
**Joint deformity or destruction with ankyloses
===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 softtissue edema.<ref name="Martinez-RiosJariwala2018">{{cite journal|last1=Martinez-Rios|first1=Claudia|last2=Jariwala|first2=Mehul P.|last3=Highmore|first3=Kerri|last4=Duffy|first4=Karen Watanabe|last5=Spiegel|first5=Lynn|last6=Laxer|first6=Ronald M.|last7=Stimec|first7=Jennifer|title=Imaging findings of sterile pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome: differential diagnosis and review of the literature|journal=Pediatric Radiology|volume=49|issue=1|year=2018|pages=23–36|issn=0301-0449|doi=10.1007/s00247-018-4246-1}}</ref>
===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.<ref name="Dierselhuis2005">{{cite journal|last1=Dierselhuis|first1=M. P.|title=Anakinra for flares of pyogenic arthritis in PAPA syndrome|journal=Rheumatology|volume=44|issue=3|year=2005|pages=406–408|issn=1460-2172|doi=10.1093/rheumatology/keh479}}</ref><ref name="DemidowichFreeman2012">{{cite journal|last1=Demidowich|first1=Andrew P.|last2=Freeman|first2=Alexandra F.|last3=Kuhns|first3=Douglas B.|last4=Aksentijevich|first4=Ivona|last5=Gallin|first5=John I.|last6=Turner|first6=Maria L.|last7=Kastner|first7=Daniel L.|last8=Holland|first8=Steven M.|title=Brief Report: Genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne)|journal=Arthritis & Rheumatism|volume=64|issue=6|year=2012|pages=2022–2027|issn=00043591|doi=10.1002/art.34332}}</ref>
* Treatment options for arthritis include [[intraarticular]] [[corticosteroid]] injections. 
* Oral [[corticosteroid]] may be useful for pyoderma gangreonosum.
* 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.
==References==
{{reflist|2}}

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