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 [[Periodic fever syndrome|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 (statistics)|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-1|IL-1β]]) production.
*Overproduction of [[IL-1|IL-1β]] is a clear [[molecular]] feature of PAPA syndrome.

==Causes==

*PAPA syndrome is [[Causes|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 [[Differential diagnosis|differentiated]] from other [[diseases]] that cause [[arthritis]], [[skin rash]], and [[pyoderma gangrenosum]], such as [[Blau syndrome]], [[familial cold autoinflammatory syndrome]], [[chronic recurrent multifocal osteomyelitis]] ([[Chronic recurrent multifocal osteomyelitis|CRMO]]) , and [[juvenile idiopathic arthritis]] ([[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 literature.<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 [[Neutrophil|neutrophilic]] infiltrate.
*[[Tumor necrosis factor-alpha|Tumor necrosis factor-a]] and [[Interleukin 1|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 [[Association (statistics)|associated]] with PAPA syndrome.

===X-ray===

*There are no specific [[x-ray]] findings [[Association (statistics)|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 (pattern recognition)|features]] include pauciarticular, erosive arthritis, [[osteophytes|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 [[Association (statistics)|associated]] with PAPA syndrome.

===CT scan===

*There are no [[CT scan]] findings [[Association (statistics)|associated]] with PAPA syndrome.

===MRI===

*There are no specific  [[MRI]] findings [[Association (statistics)|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]].<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 [[Association (statistics)|associated]] with PAPA syndrome.

===Other Diagnostic Studies===

*There are no other [[diagnostic]] studies [[Association (statistics)|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 gangrenosum]].
*[[Anakinra]] ([[Interleukin 1|interleukin-1]] [[antagonist]]) has also been observed to be effective in the management of [[disease]] flares especially [[Joint|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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