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

OBJECTIVES: To study the molecular pathogenesis of PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome, a debilitating hereditary autoinflammatory disease caused by dominant mutation in PSTPIP1. METHODS: Gene knock-out and knock-in mice were generated to develop an animal model. THP1 and retrovirally transduced U937 human myeloid leukaemia cell lines, peripheral blood mononuclear cells, small interfering RNA (siRNA) knock-down, site-directed mutagenesis, cytokine immunoassays, coimmunoprecipitation and immunoblotting were used to study inflammasome activation. Cytokine levels in the skin were evaluated by immunohistochemistry. Responsiveness to Janus kinase (JAK) inhibitors was evaluated ex vivo with peripheral blood mononuclear cells and in vivo in five treatment-refractory PAPA patients. RESULTS: The knock-in mouse model of PAPA did not recapitulate the human disease. In a human myeloid cell line model, PAPA-associated PSTPIP1 mutations activated the pyrin inflammasome, but not the NLRP3, NLRC4 or AIM2 inflammasomes. Pyrin inflammasome activation was independent of the canonical pathway of pyrin serine dephosphorylation and was blocked by the p.W232A PSTPIP1 mutation, which disrupts pyrin-PSTPIP1 interaction. IFN-γ priming of monocytes from PAPA patients led to IL-18 release in a pyrin-dependent manner. IFN-γ was abundant in the inflamed dermis of PAPA patients, but not patients with idiopathic pyoderma gangrenosum. Ex vivo JAK inhibitor treatment attenuated IFN-γ-mediated pyrin induction and IL-18 release. In 5/5 PAPA patients, the addition of JAK inhibitor therapy to IL-1 inhibition was associated with clinical improvement. CONCLUSION: PAPA-associated PSTPIP1 mutations trigger a pyrin-IL-18-IFN-γ positive feedback loop that drives PAPA disease activity and is a target for JAK inhibition.

What can inherited immunodeficiencies reveal about pyoderma gangrenosum?

Pyoderma gangrenosum (PG) is a rare ulcerative neutrophilic dermatosis that is occasionally associated with primary immunodeficiency. Though contributions from dysregulation of the innate immune system, neutrophil dysfunction and genetic predisposition have been postulated, the precise pathogenesis of PG has not yet been elucidated. This article reviews reported cases of coexisting PG and primary immunodeficiency in order to gain insight into the complex pathophysiology of PG. Our findings suggest that variations in genes such as RAG1, ITGB2, IRF2BP2 and NFκB1 might play a role in genetically predisposing patients to develop PG. These studies support the feasibility of the role of somatic gene variation in the pathogenesis of PG which warrants further exploration to guide targeted therapeutics.

PAPA-like syndrome with heterozygous mutation in the MEFV gene.

A patient presented with a history of recurrent pyoderma gangrenosum, arthritis and extensive acne, prompting a genetic workup for PAPA syndrome. An MEFV mutation was identified and a change in therapeutic strategy from anakinra to colchicine was successful. Click https://www.wileyhealthlearning.com/#/online-courses/b52447c0-1d37-472d-b0c0-7817352d6f68 for the corresponding questions to this CME article.

[Neutrophilic and pustular dermatoses : New autoinflammatory diseases and syndromes]. / Neutrophilenreiche und pustulöse Dermatitiden : Neue autoinflammatorische Erkrankungen und Syndrome.

This article reviews noninfectious inflammatory dermatoses with mainly neutrophilic infiltrates and the formation of pustules. The infiltrate containing neutrophils may either be mild as in urticaria or very dense, even with leukocytoclasia, as in Sweet syndrome or pyoderma gangrenosum. Neutrophilic infiltrates and pustular eruptions are caused by different noninfectious immunomechanisms. For some of them, mutations have been found (e.g. NLRC4 mutation in cryopyrin-associated periodic syndromes (CAPS) leading to activation of the inflammasome; IL36RN mutation in pustular psoriasis resulting in uncontrolled IL36 signaling). Neutrophilic dermatoses are of high interest, as they may be the cause of underlying benign or malignant conditions. In recent years, efficient targeted therapies have been developed.

Imaging findings of sterile pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome: differential diagnosis and review of the literature.

Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is a rare autosomal-dominant autoinflammatory disease of incomplete penetrance and variable expression. PAPA syndrome is the result of a mutation in the proline serine threonine phosphatase-interacting protein 1 (PSTPIP1/CD2BP1) gene located on chromosome 15, which results in an abnormal overproduction of the pro-inflammatory cytokine interleukin-1ß (IL-1). This syndrome clinically manifests as early onset of recurrent episodes of acute aseptic inflammation of the joints, generally occurring in the first two decades of life, followed by manifestation of characteristic skin lesions in the third decade, after an obvious decline in the joint symptoms. Although uncommon, the potential clinical implications of PAPA syndrome warrant an appropriate diagnosis in a timely fashion.

Autoinflammation in pyoderma gangrenosum and its syndromic form (pyoderma gangrenosum, acne and suppurative hidradenitis).

BACKGROUND: Pyoderma gangrenosum (PG) is a rare skin disease characterized clinically by ulcers with undermined borders, and histologically by neutrophil-rich infiltrates. PG may occur alone, in syndromic forms or associated with systemic diseases, such as inflammatory bowel disease and haematological or rheumatological disorders. OBJECTIVES: To determine a specific genetic background related to autoinflammation for PG. METHODS: We assessed autoinflammation by evaluating the cytokine profile and genes involved in classic autoinflammatory diseases in 13 patients with PG and in seven patients with the syndromic form, known as PASH (pyoderma gangrenosum, acne and suppurative hidradenitis). RESULTS: In skin samples, the expression of interleukin (IL)-1ß and its receptors, IL-17 and its receptor, and tumour necrosis factor-α and its receptors were significantly higher in both PG (P = 0·001) and in PASH (P < 0·001) than in controls. The chemokines IL-8; chemokine (C-X-C motif) ligand 1/2/3; chemokine (C-X-C motif) ligand 16; and RANTES (regulated on activation, normal T-cell-expressed and secreted) were also overexpressed. Cases of PG and PASH showed mutations in the autoinflammatory genes MEFV, NLRP3, NLRP12, NOD2, LPIN2 and PSTPIP1. CONCLUSIONS: Overexpression of cytokines/chemokines, along with genetic changes, supports the hypothesis that PG and its syndromic form, PASH, are a spectrum of polygenic autoinflammatory conditions.

Haematological involvement associated with a mild autoinflammatory phenotype, in two patients carrying the E250K mutation of PSTPIP1.

OBJECTIVES: Hyperzincaemia/hypercalprotectinemia (Hz/Hc) syndrome is a recently described condition caused by a specific de novo mutation (E250K) affecting PSTPIP1 gene. It has a phenotype distinct from classical pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome that includes severe systemic and cutaneous inflammation, hepatosplenomegaly, arthritis without sequelae, pancytopenia and failure to thrive. METHODS: We describe an 8-year-old boy who presented recurrent right knee swelling mimicking septic arthritis and persistent bone marrow involvement, without cutaneous involvement. RESULTS: Molecular analysis of the PSTPIP1 gene revealed the presence of a heterozygous E250K mutation. No growth failure was detected nor in the patient neither in his mother, carrying the same variant. Blood zinc and calprotectin MRP8/14 concentrations of the patient were found to be markedly increased. Therapy with anakinra was started with rapid disappearance of clinical symptoms and normalization of CRP levels in 24 hours, but persistence of bone marrow involvement. CONCLUSIONS: The patient described has a milder phenotype, with no skin features, minor episodes of arthritis with no sequelae and normal growth. Compared to the patients with de novo mutations described in the literature, familial cases seem to have a milder phenotype. Our case further confirms the lack of efficacy of anakinra on bone marrow involvement.

Alarming consequences - autoinflammatory disease spectrum due to mutations in proline-serine-threonine phosphatase-interacting protein 1.

PURPOSE OF REVIEW: To give an overview about the expanding spectrum of autoinflammatory diseases due to mutations in proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) and new insights into their pathogenesis. RECENT FINDINGS: In addition to classical pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome, PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome has been described as a distinct clinical phenotype of PSTPIP1-associated inflammatory diseases (PAID) and other entities are emerging. In addition to dysregulation of IL-1ß release from activated PAPA monocytes that requires NLR family, pyrin domain containing 3 (NLRP3), PSTPIP1 mutations have an general impact on cellular dynamics of cells of the innate immune system. In addition, overwhelming expression and release of the alarmins myeloid-related protein (MRP) 8 and 14 by activated phagocytes and keratinocytes, which promote innate immune mechanisms in a Toll like receptor (TLR) 4-dependent manner, are a characteristic feature of these diseases and form a positive feed-back mechanism with IL-1ß. SUMMARY: Autoinflammatory diseases due to PSTPIP1 mutations are not restricted to the classical PAPA phenotype but might present with other distinct clinical features. MRP8/14 serum levels are a hallmark of PAPA and PAMI and can be used as screening tool to initiate targeted genetic testing in suspected cases. The feedback mechanism of IL-1ß and MRP-alarmin release may offer novel targets for future therapeutic approaches.

Gene Therapy for Pyoderma Gangrenosum: Optimal Transfection Conditions and Effect of Drugs on Gene Delivery in the HaCaT Cell Line Using Cationic Liposomes.

BACKGROUND/AIMS: Pyoderma gangrenosum (PG) is a rare ulcerative skin disease, currently treated empirically with immunosuppression. PG is a good target for gene therapy since the skin is easily accessible. This study used the FDA-approved vector Lipofectamine® 2000 to investigate in vitro transfection of skin keratinocytes. The aim was to determine an optimum transfection protocol, including the effect of drugs currently used to treat PG on the efficiency of gene transfer, since gene therapy is unlikely to be used as monotherapy. METHODS: Cells of the HaCaT line were transfected with the lacZ reporter gene, and transgene expression was measured after a given time period. Conditions tested were: relative concentrations of DNA and Lipofectamine®, time from transfection to measurement of expression, pH, and exposure to clinically relevant drugs (hydrocortisone, methotrexate, infliximab). RESULTS: The greatest levels of ß-galactosidase expression were observed using a DNA:Lipofectamine® ratio of 1:5 (µg/µl) on day 3 after transfection, using culture medium at pH 7, and in the presence of hydrocortisone. Transfection efficiency was reduced by the presence of methotrexate and not significantly affected by infliximab. CONCLUSION: Gene therapy is a potential future strategy for the management of PG; this study is a step towards the development of a topical gene-based agent.

The genetics of pyoderma gangrenosum and implications for treatment: a systematic review.

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by painful skin ulcerations for which treatment can be challenging. The genetic basis of PG may provide a better understanding of the disease and new targets for treatment. We systematically reviewed the published literature regarding the syndromes and genetic mutations associated with PG. A literature search was performed through the clinical queries PubMed (National Library of Medicine) database and the Cochrane database. The studies were assessed and then categorized as relating to syndromes or specific gene mutations. Two hundred and eight articles were identified, describing 823 cases of PG. A total of 537 (65·2%) cases were associated with inflammatory bowel disease, 133 (16·1%) with polyarthritis and 103 (12·5%) with haematological disorders. Thirty-one cases of pyogenic arthritis, pyoderma gangrenosum and acne, and its variants, were identified. Two patients had mutations in MTHFR and two had mutations in JAK2. Fourteen (1·7%) cases were familial. PG responded to different treatments depending on the setting. For example, treatment with B vitamins improved PG in cases of mutations in MTHFR, whereas patients with myelodysplastic syndrome improved with thalidomide treatment. PG can occur in isolation, associated with systemic disease or as part of various syndromes. Different genetic causes may be best treated with particular treatments. Understanding its genetic basis can help elucidate new potential targets for drug development.

Pathophysiology of pyoderma gangrenosum (PG): an updated review.

Pyoderma gangrenosum is a challenging skin condition to identify and treat because of its multifactorial pathogenesis. It is a rare cutaneous manifestation diagnosed clinically by exclusion of infection, neoplasia, thrombophilia, and other inflammatory conditions. Pathogenetic and treatment studies are scarce. Abnormalities in the function of inflammatory cytokines, the immune system, and neutrophils combined with specific genetic mutations predispose patients to develop this complex disease process. Early recognition of patients at risk for pyoderma gangrenosum, the necessity to improve its early diagnosis, and the future outlook of targeted and personalized therapies relies on the improved comprehension of the complex pathogenesis of pyoderma gangrenosum.

Pyoderma gangrenosum, acne and ulcerative colitis in a patient with a novel mutation in the PSTPIP1 gene.

BACKGROUND: Pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is a rare hereditary, autosomal dominant, auto-inflammatory disease caused by mutations in the PSTPIP1 gene, which encodes proline-serine-threonine phosphatase interacting protein 1. The fact that PSTPIP1 is involved in immune regulation provides a rationale for treatment of this rare disease with interleukin (IL)-1 signalling blocking agents. AIM: We investigated a 33-year-old man with a long-standing history of ulcerative colitis, severe acne and recurrent skin ulcerations, and a 3-year history of a recalcitrant pustular rash. METHODS: We used direct sequencing to search for mutations in the PSTPIP1 gene. RESULTS: Examination of biopsies obtained from pustules and skin ulcers revealed folliculitis and ulceration with a diffuse neutrophilic dermal infiltrate, consistent with a diagnosis of pyoderma gangrenosum. Because of the known association of acne and pyoderma gangrenosum in PAPA syndrome, we determined the entire coding sequence of the PSTPIP1 gene, and identified a hitherto unreported heterozygous mutation predicted to alter a highly conserved residue (p.G403R) and to be damaging to the protein function. Based on this finding, we initiated treatment with a human IL-1 receptor antagonist, anakinra, which led to a dramatic improvement in the patient's condition. CONCLUSIONS: We describe a novel mutation in PSTPIP1 resulting in pyoderma gangrenosum, acne and ulcerative colitis. This novel constellation of clinical manifestations, which we term 'PAC syndrome', suggests the need to regroup all PSTPIP1-associated phenotypes under one aetiological group.

Inflammation in mice ectopically expressing human Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne (PAPA) Syndrome-associated PSTPIP1 A230T mutant proteins.

Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne Syndrome (PAPA syndrome) is an autoinflammatory disease caused by aberrant production of the proinflammatory cytokine interleukin-1. Mutations in the gene encoding proline serine threonine phosphatase-interacting protein-1 (PSTPIP1) have been linked to PAPA syndrome. PSTPIP1 is an adaptor protein that interacts with PYRIN, the protein encoded by the Mediterranean Fever (MEFV) gene whose mutations cause Familial Mediterranean Fever (FMF). However, the pathophysiological function of PSTPIP1 remains to be elucidated. We have generated mouse strains that either are PSTPIP1 deficient or ectopically express mutant PSTPIP1. Results from analyzing these mice suggested that PSTPIP1 is not an essential regulator of the Nlrp3, Aim2, or Nlrc4 inflammasomes. Although common features of human PAPA syndrome such as pyogenic arthritis and skin inflammation were not recapitulated in the mouse model, ectopic expression of the mutant but not the wild type PSTPIP1 in mice lead to partial embryonic lethality, growth retardation, and elevated level of circulating proinflammatory cytokines.

Atypical severe combined immunodeficiency caused by a novel homozygous mutation in Rag1 gene in a girl who presented with pyoderma gangrenosum: a case report and literature review.

Severe combined immunodeficiency (SCID) is a heterogeneous group of inherited defects involving the development of T- and/or B-lymphocytes. We report a female with atypical severe combined immunodeficiency caused by a novel homozygous mutation at cDNA position 2290 (c.2290C > T) in exon 2 of the RAG1 gene. The patient presented with bronchopneumonia, pyoderma gangrenosum (PG), pancytopenia and splenomegaly. She presented to us with pancytopenia and splenomegaly at the age of 11. Her condition was complicated by PG on left lower ankle at the age of 12. She experienced bronchopneumonia at the age of 15. She was diagnosed with RAG1 deficiency at the age of 16. Her immunological presentation included leucopenia and diminished number of B cells.

A novel de novo PSTPIP1 mutation in a boy with pyogenic arthritis, pyoderma gangrenosum, acne (PAPA) syndrome.

Autoinflammatory disorders are a group of Mendelian disorders characterized by seemingly unprovoked inflammatory bouts without high-titer autoantibodies or antigen-specific T-cells and are probably due to defects in the innate immunity. We here report on a 4-year-old Arabic boy with the clinical presentation of an autoinflammatory disorder, namely Pyogenic Arthritis, Pyoderma Gangrenosum and Acne (PAPA) syndrome. The presentation includes abscess formation after immunization and recurrent mono-articular acute arthritis in various joints that responded favourably to systemic glucocorticosteroids, albeit without acne or pyoderma gangrenosum. The mutation analysis of the boy identified a novel de novo mutation in PSTPIP1, the gene responsible for PAPA syndrome. We recommend that the diagnosis of PAPA syndrome should be entertained in the differential diagnosis of patients with recurrent sterile pyogenic arthritis prior to the development of pyoderma gangrenosum or acne in order to initiate a timely management of the disorder.