Pyogenic Arthritis, Pyoderma Gangrenosum And Acne Syndrome Research Articles

Interrupting an IFN-γ-dependent feedback loop in the syndrome of pyogenic arthritis with pyoderma gangrenosum and acne

ObjectivesTo study the molecular pathogenesis of PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome, a debilitating hereditary autoinflammatory disease caused by dominant mutation in PSTPIP1.MethodsGene knock-out and knock-in mice were...

Pyogenic Arthritis, Pyoderma Gangrenosum and Acne (PAPA) and PAPA-Like Syndromes: Systematic Review of the Literature

Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is a rare autosomal dominant autoinflammatory disorder caused by mutations in the PSTPIP1/CD2BP1 gene. We systematically reviewed 93 patients with PAPA and PAPA-like syndrome. Most patients were male (65.9%) mainly born to non-consanguineous parents. The median (IQR) age at the onset of symptoms and diagnosis was 6.0 (2.0- 8.0) and 25.0 (7.0-32.0) years, respectively. 62.5% of patients were presented with arthropathies and septic arthritis was the most common (54.2%) initial diagnosis. Joint disorders were the most common findings (n=71, 78.9%) starting at the median (IQR) age of 4.0 (2.0-8.0) years, mainly in the knee (56.5%), ankle (36.9%), and elbow (47.8%). Skin involvement (62 (66.7%)) initially presented at a median (IQR) age of 12.0 (20.-10.0) years and included pyoderma gangrenosum (n=41, 44.1%), acne (n=43, 46.2%), and nodulocystic acne (n=19, 20.4%). There was a stronger association between skin manifestations and the development of the classic triad (P<0.001) compared to joint disorders (P=0.05) and patients with lower age of onset were more prone to the progression of the complete triad (P=0.18). Corticosteroids (n=45, 50.0%) with or without anakinra (33.3%) were the treatments applied in the majority of patients. PAPA/PAPA-like syndromes involve mainly non-axial joints in early childhood and later skin in the second decade of life. Only 26.4% of the patients manifested the classical triad of PAPA syndrome. There is no clear genotype-phenotype association in these disorders. More studies are required to investigate the therapeutic options in PAPA/PAPA-like syndromes.

Rare missense variants in the SH3 domain of PSTPIP1 are associated with hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic, debilitating skin disease for which few treatment options are available. While most HS is sporadic, some rare kindred show a high-penetrance, autosomal-dominant inheritance. We wanted to identify rare variants that could contribute to HS risk in sporadic cases using candidate gene sequencing. We ultimately identified 21 genes for our capture panel. We included genes of the γ-secretase complex (n= 6) because rare variants in these genes sometimes cause familial HS. We added Notch receptor and ligand genes (n= 13) because γ-secretase is critical for processing Notch receptor signaling. Clinically, some people with PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome, a rare inflammatory disease, have concurrent HS. Rare variants in PSTPIP1 are known to cause PAPA syndrome, so we included PSTPIP1 and PSTPIP2 in the capture panel. We screened 117 individuals with HS for rare variations and calculated the expected burden using Genome Aggregation Database (gnomAD) allele frequencies. We discovered two pathogenic loss-of-function variants in NCSTN. This class of NCSTN variant can cause familial HS. There was no increased burden of rare variations in any γ-secretase complex gene. We did find that individuals with HS had a significantly increased number of rare missense variants in the SH3 domain of PSTPIP1. This finding, therefore, implicates PSTPIP1 variation in sporadic HS and further supports dysregulated immunity in HS. Our data also suggests that population-scale HS genetic research will yield valuable insights into disease pathology.

Pioderma gangrenoso

.Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis, characterized by unknown aetiology and sterile neutrophilic infiltrate on histological examination, clinically showing recurrent skin ulcers and mostly affecting lower limbs areas. In 2/3 of the cases, PG is secondary to another disorder such as inflammatory bowel and lymphoproliferative diseases, infections, rheumatic diseases and auto-inflammatory syndromes. The paper describes the cases of three paediatric patients showing the association of PG with rheumatic conditions such as Behçet’s disease, chronic recurrent multifocal osteomyelitis (CRMO) and PAPA (Pyogenic Arthritis, Pyoderma gangrenosum and Acne) syndrome and proposes a diagnostic flow-chart to help paediatricians recognize PG and associated conditions.

O19 A case of pyogenic arthritis, pyoderma gangrenosum and acne syndrome

Case report - IntroductionConsidering an auto-inflammatory disorder is important where recurrent fevers are a presenting feature. Performing a genetic panel is essential in these cases; however, it can be negative even in the presence of an underlying auto-inflammatory disorder. Our case highlights the importance of this with a reminder that a negative gene panel does not completely exclude an underlying auto-inflammatory disorder in the presence of suggestive history and clinical examination findings.Case report - Case descriptionA 5-year-old girl presented with recurrent episodes of fever (>38 °C), abdominal pain and joint pains (back, wrist, hip, knee & ankle). Past medical history included episodes of self-resolving neutropenia. Initial clinical examination revealed mouth ulcers, a significant number of dental caries, a petechial rash and genital erythema. There was no active joint disease. A pustular like itchy rash developed on/off over time affecting the buttocks, genital area, knees and elbows. Episodes increased in frequency becoming once per month, lasting for 5 days on average, resulting in a significant amount of time off school. Initial differential diagnosis included periodic fever and cyclical neutropenia. White blood cells ranged from 4.3 to 20.1 (10^9/l), Neutrophils ranged from 1.1 to 11.4 (10^9/l), CRP 0.7 to 149.5 (mg/L), ESR 2 to 15 (mm/hr). Serum Amyloid A ranged from 8.0 to 370 (mg/L). Immunology and haematology consults were sought with cyclical neutropenia deemed unlikely. A primary immunodeficiency screen was negative. Initial genetic analysis for periodic fever was negative; however, this was later reanalysed and revealed a pathogenic mutation in the PSTPIP1 gene and a mutation in the TMEM173 gene. A mutation in the PSTPIP1 gene, on chromosome 15q24 is associated with Pyogenic Arthritis, Pyoderma gangrenosum and Acne (PAPA) Syndrome.A trial of colchicine was commenced, with eventual titration of the dose, achieving a good response. Occasional episodes now occur 1—2-times monthly with a reduced temperature rise, minimal arthralgia and are of a shorter duration. Dental extraction was also performed due to 9 periodontal abscesses. Skin care advice included use of emollient-barrier creams, antihistamines and oral antibiotics when indicated.Case report - DiscussionPAPA – Pyogenic Arthritis, Pyoderma Gangrenosum and Acne are a triad of symptoms that together combine to form this rare auto-inflammatory disorder. It is an autosomal dominant condition. It is the result of a mutation of the (PSTPIP1/CD2BP1) gene located on chromosome 15. Studies of families affected have revealed a variable penetrance, including some asymptomatic carriers. Clinicians should be mindful when ascertaining what conditions and symptoms other family members have, as PAPA could be the underlying causative condition. The recurrent aseptic inflammation of the joints normally manifests within the first two decades of life. The skin symptoms manifest within the third decade. All three symptoms rarely appear instantaneously. The diagnosis is clinical with confirmation by genetic testing. Reported treatments includes the use of corticosteroids, arthrocentesis – for relieving pain, and biologics – namely anti IL1 and anti TNF therapy. We felt this case was interesting as the patient described demonstrated a good response to colchicine and highlighted the difficulties that can present in making the diagnosis. With a confirmed diagnosis the clinician can then appropriately follow up the patient, giving them and potential family members the best care available.Case report - Key learning pointsOur case highlights the importance of multi-specialty input particularly when faced with a rare or complex case in order to exclude other potential causes. Although genetic testing has significantly improved in helping with the diagnosis of auto-inflammatory disorders, it must be highlighted the importance of good clinical assessment and interpretation of more standard investigations. This is particularly relevant where genetic panelling is returned as negative and concerns persist of an underlying auto-inflammatory disorder. We hope to raise awareness of the varied presentation of PAPA syndrome particularly in the younger age groups where skin presentations may not be a predominant presenting feature. It is also important to emphasise that the main features of PAPA syndrome rarely present simultaneously. Current clear treatment pathways do not exist due to the rarity of this condition within the paediatric population – a number of agents are suggested in the literature with colchicine achieving good control in our patient described.

Pyoderma gangrenosum and its syndromic forms: evidence for a link with autoinflammation.

Pyoderma gangrenosum is a rare inflammatory neutrophilic dermatosis manifesting as painful ulcers with violaceous, undermined borders on the lower extremities. It may occur in the context of classic syndromes like PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) and SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis), as well as in a recently described entity named PASH (pyoderma gangrenosum, acne and suppurative hidradenitis). Pyoderma gangrenosum has recently been included within the spectrum of autoinflammatory diseases, which are characterized by recurrent episodes of sterile inflammation, without circulating autoantibodies and autoreactive T cells. In PAPA syndrome, different mutations involving the PSTPIP1 gene, via an increased binding affinity to pyrin, induce the assembly of inflammasomes. These are molecular platforms involved in the activation of caspase 1, a protease that cleaves inactive prointerleukin (pro-IL)-1β to its active isoform IL-1β. The overproduction of IL-1β triggers the release of a number of proinflammatory cytokines and chemokines, which are responsible for the recruitment and activation of neutrophils, leading to neutrophil-mediated inflammation. In SAPHO syndrome, the activation of the PSTPIP2 inflammasome has been suggested to play a role in inducing the dysfunction of the innate immune system. Patients with PASH have recently been reported to present alterations of genes involved in well-known autoinflammatory diseases, such as PSTPIP1, MEFV, NOD2 and NLRP3. Pyoderma gangrenosum and its syndromic forms can be regarded as a single clinicopathological spectrum in the context of autoinflammation.

Whole-Exome Analysis of Autoimmune Lymphoproliferative Syndrome-like Diseases

ALPS is characterized by chronic lymphoproliferation in combination with autoimmunity; mutations of molecules involved in FAS-dependent pathways play causative roles in this syndrome. The hallmarks of ALPS are an elevated CD4/CD8 double-negative T (DNT) cell count and attenuated induction of apoptosis by FAS stimulation. Autoimmune thrombocytopenia and/or hemolytic anemia are common in cases of ALPS; the combination of autoimmune thrombocytopenia and hemolytic anemia is referred to as Evans syndrome. ALPS is diagnosed in 47% of patients who present with Evans syndrome. Some patients with ALPS-like syndromes harbor mutations in RAS or PRKCD.In this study, we performed whole-exome analysis of undiagnosed patients exhibiting autoimmunity in combination with lymphoproliferation. Fifteen pediatric patients presenting with autoimmunity were enrolled in this study. Although not all of them fulfilled the diagnostic criteria of ALPS, most of them exhibited an ALPS-like phenotype, an autoimmune hematological disorder such as Evans syndrome, or immune thrombocytopenia with hepatosplenomegaly. Elevated counts of DNT cells among TCRαβ-positive cells were observed in some cases. All of the subjects screened negative for mutations in FAS, FASL, KRAS, and NRAS. These patients were subjected to whole-exome analysis, which revealed several mutations with known disease associations. One patient carried a mutation in CASP10, a causative gene for ALPS-CSAP (ALPS 2). This patient exhibited a typical ALPS phenotype with an elevated DNT cell count. In addition, we identified CTLA4 mutations in two patients, one of whom was described as ALPS type V (ALPS 5) and the other as CTLA4 haploinsufficiency with autoimmune infiltration (CHAI). A mutation in STAT3 was present in one patient. Dominant-negative mutations in the STAT3 gene result in hyper-IgE syndrome. Recently, an activating mutation of STAT3 was reported in infantile-onset multisystem autoimmune disease (ADMIO). It should be noted that an activating mutation of STAT3 results in a phenotype very similar to that of ALPS. Intriguingly, two autoinflammatory associated genes, PSTPIP1 and RNASEH2B were identified. Mutations in RNASEH2B causes Aicardi-Goutière syndrome (AGS), which phenotypically overlaps with SLE. Typical AGS develops as a results of biallelic mutations in causative genes. In this case, a heterozygous frame shift mutation was identified. Further evaluation is required to confirm whether this heterozygous frame shift mutation RNASEH2B really causes SLE or ALPS like symptoms. PSTPIP1 mutation causes pyogenic Arthritis, pyoderma gangrenosum and acne (PAPA) syndrome. The identified E250K mutation was one of the typical mutation in this disease. This patient exhibited SLE like symptom with hepatosplenomegaly without typical PAPA syndrome like symptoms, such as acne or pyoderma of the skin. Sequencing of the remaining patients yielded inconclusive results.The classical ALPS diagnostic procedure is well designed and suitable for identification of FAS-dependent apoptotic dysregulation. However, the measurement of FAS-dependent apoptosis requires technical skill, and the data quality is therefore dependent on the investigator. Moreover, RAS-associated ALPS-like disease (RALD, ALPS 3) and ALPS 5 (CHAI) cannot be identified by conventional ALPS diagnostic procedures. Therefore, the methods for diagnostic classification of these diseases need to be updated. It is interesting that mutations of autoinflammatory associated genes are involved in ALPS or SLE like patients. Our results reveal that a comprehensive genomic approach is a powerful tool for the characterization of ALPS or ALPS-like diseases. Together with recent progress in genome analysis in the PID field, our analyses provide an updated list of genes for use in differential diagnosis of ALPS-like diseases. This update will facilitate convenient genomic approaches such as comprehensive targeted sequencing focusing on genes involved in ALPS or ALPS-like diseases. This approach can be directly applied in the clinic to yield diagnostic benefits. DisclosuresNo relevant conflicts of interest to declare.

Clinical and genetic analyses in a patient with PAPA syndrome complicated with inflammatory bowel disease

PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome is an autoinflammatory disease linked to mutations in the PSTPIP1 gene. These mutations produce a hyper-phosphorylated PSTPIP1 protein and alter its participation in the activation of the “inflammasome”.

Cerebral vascular findings in PAPA syndrome: cerebral arterial vasculopathy or vasculitis and a posterior cerebral artery dissecting aneurysm

A young patient with PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome developed an unusual cerebral arterial vasculopathy/vasculitis (CAV) that resulted in subarachnoid hemorrhage from a ruptured dissecting posterior cerebral...

Novel PSTPIP1 gene mutation in a patient with pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome

IntroductionPyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is a rare autosomal dominant disease that usually presents in childhood with recurrent sterile arthritis. As the child ages into puberty, cutaneous features develop and arthritis subsides. We report the case of a now 25-year-old male patient with PAPA syndrome with the E250K mutation in PSTPIP1. We also present a systematic literature review of other PAPA cases. MethodWe conducted a literature search of PubMed using the following search terms: E250K mutation, PSTPIP1, and PAPA. ResultsPAPA syndrome is caused by mutations on chromosome 15q affecting the proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene, also known as CD2-binding protein 1 (CD2BP1). The reported cases of PAPA syndrome currently in the literature involve mutations in A230T and E250Q. One case of a novel E250K mutation has been reported, which presented with a different phenotype to previously described cases of PAPA syndrome. ConclusionWith variation present between disease presentations from case to case, it is possible that the spectrum of PAPA syndrome is wider than currently thought. Further research is needed which may uncover an as-yet undiscovered genetic abnormality linking these interrelated diseases together.

PReS-FINAL-2238: PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome: results from the Eurofever registry

PAPA syndrome is a very rare autoinflammatory condition. Few data are nowadays available about the clinical characteristic, the response to treatment and the outcome of this disease.

FRI0026 Evidence for interleukin (IL)-1β pathway activation in monocytes from patients with familial mediterranean fever (fmf) and pyogenic sterile arthritis, pyoderma gangrenosum and acne (papa) syndrome

BackgroundFamilial Mediterranean fever (FMF) and Pyogenic Arthritis, Pyoderma gangrenosum and Acne (PAPA) syndrome are autoinflammatory disorders that are thought to share similar pathoetiology. While FMF is due to mutations of...

Pyoderma Gangrenosum, Acne Conglobata, Suppurative Hidradenitis, and Axial Spondyloarthritis

We report the case of a patient with a simultaneous presence of pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and axial spondyloarthritis. This condition differs from both the PASH (pyoderma gangrenosum, acne, and suppurative hidradenitis) syndrome, in which arthritis is absent, and the PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome, in which suppurative hidradenitis is lacking. Our patient failed to respond to etanercept therapy, whereas all dermatologic and rheumatic manifestations completely regressed following infliximab infusion. We therefore propose that simultaneous presence of pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and seronegative spondyloarthritis might represent a distinct syndrome that could be termed the PASS syndrome. Tumor necrosis factor α therapies seem to play selective roles.

Rare hereditary autoinflammatory disorders: Towards an understanding of critical in vivo inflammatory pathways

Hereditary autoinflammatory syndromes are monogenic disorders with an inborn error of innate immunity, and include periodic fever syndromes such as familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome and cryopyrin-associated periodic syndromes (CAPS), pyogenic diseases such as pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPAS), and granulomatous diseases such as Blau syndrome. By identifying the genetic abnormalities and subsequent analyses of the molecular mechanisms underlying these disorders, several critical in vivo pathways for inflammatory processes have been discovered. In this review, three categories of autoinflammatory disorders are discussed: inflammasomopathies, receptor antagonist deficiencies and proteasome disability syndromes. Inflammasomopathies are diseases with dysregulated NLRP3 inflammasome activation, and include CAPS with NLRP3, FMF with MEFV, and PAPAS with PSTPIP1 mutations. Analyses of these diseases have clarified some critical pathways regulating NLRP3 inflammasome signaling. Receptor antagonist deficiencies include the newly defined deficiency for interleukin-1 receptor antagonist resulting in sterile multifocal osteomyelitis with periostosis and pustulosis, and deficiency for interleukin-36 receptor antagonist resulting in generalized pustular psoriasis. The identification of these genetic abnormalities has revealed a critical role for receptor antagonists of IL-1 family cytokines in regulating neutrophil activation/recruitment. Finally, proteasome disability syndromes with PSMB8 mutations include Nakajo-Nishimura syndrome and related disorders distributed globally. Analyses of these diseases have unexpectedly shown a critical role of the ubiquitin-proteasome system in the regulation or homeostasis of inflammation/metabolism. Since there still remain a number of predicted but undefined hereditary autoinflammatory syndromes, further clinical and genetic approaches are required to discover novel in vivo critical inflammatory pathways.

Targeted treatment of pyoderma gangrenosum in PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome with the recombinant human interleukin-1 receptor antagonist anakinra

The triad of sterile pyogenic arthritis, pyoderma gangrenosum and acne is known by the acronym of PAPA syndrome. It is a rare autosomal dominant disease of early onset. The treatment of pyoderma gangrenosum is challenging as there is often only partial response to systemic glucocorticosteroids and immunosuppressive therapies. We report the rapid and lasting response of pyoderma gangrenosum to the targeted treatment with the recombinant human interleukin-1 receptor antagonist (rHuIL-1Ra) anakinra in a patient with PAPA syndrome.

Peculiarities of PAPA syndrome

To describe a family from New Zealand with the pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, an autoinflammatory, variably expressed, erosive destructive form of arthritis. Information was gained through medical records and interviews of the affected patients and wider family. DNA sequencing was performed at Seay Center for Musculoskeletal Research Texas Scottish Rite Hospital for Children. Five patients were affected over three generations with an E250Q mutation found on the CD2BP1 gene on chromosome 15. Common features included a severe, pauciarticular-onset, destructive peripheral arthritis, beginning at ages 5, 5, 2, 3 and 1(1/2) years. This combination marked cervical ankylosis (in two members), micrognathia and a more severe phenotype is unique. A third-generation family member treated early with DMARDs is following a less severe course. The skin involvement was variable, all with degrees of acne from puberty, though only one patient displayed pyoderma gangrenosum. A clear pattern of the arthritis switching off in adolescence and the triggering of skin disease was observed. Differing degrees of joint destruction, and cervical ankylosis in this family with the E250Q mutation demonstrate PAPA syndrome's variable expression. Further understanding of this rare condition and its pathway may allow better targeting of treatments, not just for families with this specific syndrome but also for other, more common, forms of arthritis.