Subject(s)
Cesarean Section , Cytokines , Pyoderma Gangrenosum , Humans , Pyoderma Gangrenosum/diagnosis , Pyoderma Gangrenosum/blood , Pyoderma Gangrenosum/pathology , Female , Cytokines/blood , Adult , Pregnancy , Postoperative Complications/blood , Postoperative Complications/diagnosis , Postoperative Complications/etiology , Postoperative Complications/immunologyABSTRACT
OBJECTIVE: Dominantly inherited PSTPIP1 mutations cause a spectrum of autoinflammatory manifestations epitomized by PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome.). The connections between PSTPIP1 and PAPA syndrome are poorly understood, although evidence suggests involvement of pyrin inflammasome activation. Interleukin-18 (IL-18) is an inflammasome-activated cytokine associated with susceptibility to macrophage activation syndrome (MAS). This study was undertaken to investigate an association of IL-18 with PAPA syndrome. METHODS: Clinical and genetic data and serum samples were obtained from patients referred to institutions due to symptoms indicative of PAPA syndrome. Serum IL-18, IL-18 binding protein (IL-18BP), and CXCL9 levels were assessed by bead-based assay, and free IL-18 levels were assessed by enzyme-linked immunosorbent assay. RESULTS: The symptoms of PSTPIP1-positive patients with PAPA syndrome overlapped with those of mutation-negative patients with PAPA-like conditions, but mutation-positive patients had earlier onset and a greater proportion had a history of arthritis. We found uniform elevation of total serum IL-18 in treated PAPA syndrome patients at levels nearly as high as those seen in NLRC4-associated autoinflammation with infantile enterocolitis patients, and well above levels found in most familial Mediterranean fever patients. Serum IL-18 elevation in PAPA syndrome patients persisted despite fluctuations in disease activity. Levels of the soluble IL-18 antagonist IL-18BP were modestly elevated, and PAPA syndrome patients had detectable free IL-18. PAPA syndrome was rarely associated with elevation of CXCL9, an indicator of interferon-γ activity, but no PAPA syndrome patients had a history of MAS. CONCLUSION: PAPA syndrome is a refractory and often disabling monogenic autoinflammatory disease associated with chronic and unopposed elevation of serum IL-18 levels but not with risk of MAS. These findings affect our understanding of the diseases in which IL-18 is overproduced and suggest a link between pyrin inflammasome activation, IL-18, and autoinflammation, without susceptibility to MAS.
Subject(s)
Acne Vulgaris/blood , Acne Vulgaris/genetics , Adaptor Proteins, Signal Transducing/genetics , Arthritis, Infectious/blood , Arthritis, Infectious/genetics , Cytoskeletal Proteins/genetics , Interleukin-18/blood , Mutation , Pyoderma Gangrenosum/blood , Pyoderma Gangrenosum/genetics , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Infant , Male , Middle Aged , Retrospective Studies , Young AdultSubject(s)
Acquired Hyperostosis Syndrome/complications , Pyoderma Gangrenosum/pathology , Skin Diseases/pathology , Sweet Syndrome/pathology , Administration, Oral , Aged , Cephalosporins/administration & dosage , Cephalosporins/therapeutic use , Drug Therapy, Combination , Glucocorticoids/therapeutic use , Humans , Male , Neutrophils/pathology , Prednisolone/administration & dosage , Prednisolone/therapeutic use , Pyoderma Gangrenosum/blood , Pyoderma Gangrenosum/diagnosis , Pyoderma Gangrenosum/drug therapy , Skin Diseases/blood , Skin Diseases/complications , Sweet Syndrome/blood , Sweet Syndrome/diagnosis , Sweet Syndrome/drug therapy , Treatment OutcomeSubject(s)
Ileostomy/adverse effects , Interleukin-8/blood , Postoperative Complications/blood , Pyoderma Gangrenosum/blood , Administration, Cutaneous , Aged , Diverticulitis, Colonic/surgery , Female , Humans , Ointment Bases/administration & dosage , Postoperative Complications/diagnosis , Postoperative Complications/drug therapy , Postoperative Complications/etiology , Pyoderma Gangrenosum/diagnosis , Pyoderma Gangrenosum/drug therapy , Pyoderma Gangrenosum/etiology , Skin/pathology , Tacrolimus/administration & dosage , Treatment OutcomeSubject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Etoposide/therapeutic use , Myelodysplastic Syndromes/complications , Pyoderma Gangrenosum/complications , Trisomy , C-Reactive Protein/analysis , Chromosomes, Human, Pair 8 , Female , Granulocyte Colony-Stimulating Factor/blood , Humans , Interleukin-8/blood , Middle Aged , Myelodysplastic Syndromes/blood , Myelodysplastic Syndromes/drug therapy , Prothrombin Time , Pyoderma Gangrenosum/blood , Pyoderma Gangrenosum/drug therapyABSTRACT
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.
Subject(s)
Acne Vulgaris/genetics , Adaptor Proteins, Signal Transducing/genetics , Arthritis, Infectious/genetics , Cytoskeletal Proteins/genetics , Metal Metabolism, Inborn Errors/genetics , Mutation/genetics , Pyoderma Gangrenosum/genetics , ATP-Binding Cassette Transporters/blood , Acne Vulgaris/blood , Acne Vulgaris/diagnosis , Acne Vulgaris/drug therapy , Antirheumatic Agents/therapeutic use , Arthritis, Infectious/blood , Arthritis, Infectious/diagnosis , Arthritis, Infectious/drug therapy , Biomarkers/blood , C-Reactive Protein/metabolism , Calgranulin B/blood , Child , DNA Mutational Analysis , Genetic Predisposition to Disease , Heterozygote , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Male , Metal Metabolism, Inborn Errors/blood , Metal Metabolism, Inborn Errors/diagnosis , Metal Metabolism, Inborn Errors/drug therapy , Phenotype , Predictive Value of Tests , Pyoderma Gangrenosum/blood , Pyoderma Gangrenosum/diagnosis , Pyoderma Gangrenosum/drug therapy , Risk Factors , Treatment Outcome , Zinc/bloodSubject(s)
Acne Vulgaris/blood , Arthritis, Infectious/blood , Interleukin-18/blood , Pyoderma Gangrenosum/blood , Adult , Humans , MaleABSTRACT
OBJECTIVE: To provide a rationale for anti-IL-1 treatment in pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) by defining whether IL-1ß secretion is enhanced; requires NLRP3; and correlates with proline-serine-threonine phosphatase-interacting protein 1 mutations, disease activity and/or the clinical picture in PAPA. METHODS: Monocytes were isolated from 13 patients and 35 healthy donors and studied at baseline and following activation. Secretion pattern of IL-1ß, IL-1α, IL-1Ra, IL-6, IL-18 and TNF-α was assessed in supernatants by ELISA. The NLRP3 requirement for IL-1ß secretion was investigated by silencing technique in PAPA and healthy donor monocytes. Long-term follow-up (mean 26 months, range 4-38) was performed in five patients enrolled in an anti-IL-1 regimen. RESULTS: IL-1ß secretion in PAPA is increased, requires NLRP3 and correlates with disease activity. Patients with a history of osteoarticular flares release more IL-1ß, IL-6 and TNF-α compared with those with predominant cutaneous recurrences. Monocytes from patients in anti-IL-1 treatment dramatically reduced IL-1ß secretion after ex vivo activation, and long-term follow-up demonstrated decreased frequency of flares and normalization of acute phase reactants in all the patients. A straightforward correlation between genotype and IL-1ß signalling was not observed suggesting that factors other than mutation itself may play a role in regulating IL-1ß secretion and response to treatment in PAPA. CONCLUSION: PAPA patients with active lesions display increased NLRP3-mediated IL-1ß secretion, and long-term efficacy of IL-1 blockade was demonstrated. Even if other mechanisms related to the complex proline-serine-threonine phosphatase-interacting protein 1 protein networking might play additional roles, this study further supports the potential of IL-1 blockade as an effective therapeutic strategy in PAPA syndrome.
Subject(s)
Acne Vulgaris/drug therapy , Arthritis, Infectious/drug therapy , Immunologic Factors/antagonists & inhibitors , Interleukin-1/antagonists & inhibitors , Monocytes/drug effects , Pyoderma Gangrenosum/drug therapy , Acne Vulgaris/blood , Acne Vulgaris/pathology , Adolescent , Adult , Arthritis, Infectious/blood , Arthritis, Infectious/pathology , Case-Control Studies , Child , Child, Preschool , Disease Progression , Female , Follow-Up Studies , Humans , Immunologic Factors/pharmacology , Interleukin-1/pharmacology , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Male , Middle Aged , Monocytes/physiology , NLR Family, Pyrin Domain-Containing 3 Protein/physiology , Pyoderma Gangrenosum/blood , Pyoderma Gangrenosum/pathology , Signal Transduction/drug effects , Treatment Outcome , Tumor Necrosis Factor-alpha/metabolism , Young AdultABSTRACT
BACKGROUND: No data are available as to the phenotype of circulating lymphocyte subsets in pyoderma gangrenosum (PG). AIM: To analyse the expression of different chemokine receptors associated to T-helper (Th)1 (CCR5), Th2 (CCR4) and Th17 (CCR6), as well as the regulatory T-cell subset (Treg) and dendritic cell polarization in the blood of newly diagnosed untreated PG patients. MATERIALS AND METHODS: Multi-parameter flow cytometry was performed on blood samples from 10 PG patients collected at first diagnosis among centres belonging to the Italian Immuno-pathology Group. Blood samples from 10 age- and sex-matched healthy controls (HC) were used as controls. RESULTS: PG patients are characterized by an over-expression in the blood of the CD4+CCR5+ and CD4+CCR6+ and a down-regulation of CD4+CCR4+ counts with respect to healthy subjects. Moreover, they show increased levels of myeloid derived dendritic cells type1 and reduced levels of the Treg CD4+CD25highFOXP3+ subset. CONCLUSIONS: The pattern of chemokine expression argues in favour of a Th1 (CCR5+) and Th17 (CCR6+) polarization with a down-regulation of Th2 (CCR4+).
Subject(s)
Pyoderma Gangrenosum/immunology , T-Lymphocyte Subsets , Adolescent , Adult , Aged , Female , Flow Cytometry , Humans , Italy , Male , Middle Aged , Pyoderma Gangrenosum/blood , Pyoderma Gangrenosum/pathology , Young AdultABSTRACT
A 66-year-old woman presented after an episode of accidental trauma with a painful ulcer on her scalp which rapidly enlarged in size, accompanied by central necrosis and undermining ulceration. The patient's past history was negative for underlying systemic disease, although she had had a similar post-traumatic intractable leg ulcer 3 years prior, which was unresponsive to surgical management but successfully treated with systemic steroids. A biopsied specimen from the scalp showed marked neutrophilic infiltrates in the dermis, compatible with a diagnosis of pyoderma gangrenosum (PG). The large ulcerative lesion responded very well to oral steroid therapy, showing rapid epithelialization. Serum levels of granulocyte colony-stimulating factor and interleukin-6 were significantly elevated prior to treatment, with decrease to normal levels after treatment. Serum tumor necrosis factor (TNF)-α and granulocyte macrophage colony-stimulating factor levels were within normal limits. The significance and pathogenic role of cytokine burst in PG is reviewed and discussed.
Subject(s)
Cytokines/blood , Pyoderma Gangrenosum/blood , Aged , Female , Granulocyte Colony-Stimulating Factor/blood , Humans , Interleukin-6/blood , Prednisolone/therapeutic use , Pyoderma Gangrenosum/drug therapy , Pyoderma Gangrenosum/pathologyABSTRACT
The association of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) has recently been described and suggested to be a new entity within the spectrum of autoinflammatory syndromes, which are characterized by recurrent episodes of sterile inflammation, without circulating autoantibodies and autoreactive T-cells. We conducted an observational study on 5 patients with PASH syndrome, analyzing their clinical features, genetic profile of 10 genes already known to be involved in autoinflammatory diseases (AIDs), and cytokine expression pattern both in lesional skin and serum. In tissue skin samples, the expressions of interleukin (IL)-1ß and its receptors I and II were significantly higher in PASH (P = 0.028, 0.047, and 0.050, respectively) than in controls. In PASH patients, chemokines such as IL-8 (P = 0.004), C-X-C motif ligand (CXCL) 1/2/3 (P = 0.028), CXCL 16 (P = 0.008), and regulated on activation, normal T cell expressed and secreted (RANTES) (P = 0.005) were overexpressed. Fas/Fas ligand and cluster of differentiation (CD)40/CD40 ligand systems were also overexpressed (P = 0.016 for Fas, P = 0.006 for Fas ligand, P = 0.005 for CD40, and P = 0.004 for CD40 ligand), contributing to tissue damage and inflammation. In peripheral blood, serum levels of the main proinflammatory cytokines, that is, IL-1ß, tumor necrosis factor-α, and IL-17, were within the normal range, suggesting that in PASH syndrome, the inflammatory process is mainly localized into the skin. Four out of our 5 PASH patients presented genetic alterations typical of well-known AIDs, including inflammatory bowel diseases, and the only patient lacking genetic changes had clinically evident Crohn disease. In conclusion, overexpression of cytokines/chemokines and molecules amplifying the inflammatory network, along with the genetic changes, supports the view that PASH syndrome is autoinflammatory in origin.
Subject(s)
Acne Vulgaris/complications , Autoimmune Diseases/genetics , Cytokines/blood , Hidradenitis Suppurativa/complications , Pyoderma Gangrenosum/complications , Acne Vulgaris/blood , Acne Vulgaris/genetics , Adolescent , Adult , Autoimmune Diseases/blood , CD40 Antigens/metabolism , E-Selectin/metabolism , Female , Hidradenitis Suppurativa/blood , Hidradenitis Suppurativa/genetics , Humans , L-Selectin/metabolism , Male , Matrix Metalloproteinases/metabolism , Middle Aged , Pyoderma Gangrenosum/blood , Pyoderma Gangrenosum/genetics , Sialic Acid Binding Immunoglobulin-like Lectins/metabolism , Skin/metabolism , Tissue Inhibitor of Metalloproteinases/metabolism , Young Adult , fas Receptor/metabolismABSTRACT
BACKGROUND: Pyoderma gangrenosum (PG) and erythema nodosum (EN) are the most common cutaneous manifestations of inflammatory bowel disease (IBD) but little is known regarding their etiopathogenesis. METHODS: We performed a case-control study comparing characteristics between IBD patients with a documented episode of PG (PG+) and/or EN (EN+) with those without PG (PG-) and EN (EN-). Data on clinical features were obtained by chart review. IBD-related serology was determined using enzyme-linked immunosorbent assay and genome-wide data generated using Illumina technology. Standard statistical tests for association were used. RESULTS: We identified a total of 92 cases of PG and 103 cases of EN with genetic and clinical characteristics, of which 64 PG and 55 EN cases were available for serological analyses. Fewer male subjects were identified in the PG(+) (odds ratio 0.6, P = 0.009) and EN(+) groups (odds ratio 0.31, P = 0 < 0.0001). Colonic disease, previous IBD-related surgery, and noncutaneous extra-intestinal manifestations were more common among both PG(+) and EN(+) patients compared with controls. PG(+) was associated with anti-nuclear cytoplasmic antibody seropositivity (P = 0.03) and higher anti-nuclear cytoplasmic antibody level (P = 0.02) in Crohn's disease. Genetic associations with PG included known IBD loci (IL8RA [P = 0.00003] and PRDM1 [0.03]) as well as with USP15 (4.8 × 10) and TIMP3 (5.6 ×10). Genetic associations with EN included known IBD susceptibility genes (PTGER4 [P = 8.8 × 10], ITGAL [0.03]) as well as SOCS5 (9.64 × 10), CD207 (3.14 × 10), ITGB3 (7.56 × 10), and rs6828740 (4q26) (P < 5.0 × 10). Multivariable models using clinical, serologic, and genetic parameters predicted PG (area under the curve = 0.8) and EN (area under the curve = 0.97). CONCLUSION: Cutaneous manifestations in IBD are associated with distinctive genetic characteristics and with the similar clinical characteristics, including the development of other extra-intestinal manifestations suggesting shared and distinct etiologies.
Subject(s)
Antibodies, Antinuclear/blood , Biomarkers/analysis , DNA/genetics , Erythema Nodosum/etiology , Inflammatory Bowel Diseases/complications , Pyoderma Gangrenosum/etiology , Adult , Case-Control Studies , Enzyme-Linked Immunosorbent Assay , Erythema Nodosum/blood , Erythema Nodosum/pathology , Female , Follow-Up Studies , Genotype , Humans , Inflammatory Bowel Diseases/blood , Inflammatory Bowel Diseases/genetics , Male , Odds Ratio , Polymerase Chain Reaction , Prognosis , Pyoderma Gangrenosum/blood , Pyoderma Gangrenosum/pathologyABSTRACT
Here, we present a young male patient who was admitted with alveolar hemorrhage, arthritis and cutaneous lesions, who later developed bilateral orbital involvement and pyoderma gangrenosum (PG). He also had pathergy test positivity. The patient was refractory to conventional immunosuppressive therapy. Therefore, multiple devastating PG lesions and disease activity in granulomatosis with polyangiitis (GPA) were controlled with infliximab. Later, rituximab was used with success to prevent recurrence of symptoms. The relationship of PG with various autoimmune diseases is known; however, PG in GPA has been only rarely reported. Biologic agents might prove to be effective in GPA and PG patients who are refractory to standard immunosuppressive therapy.
Subject(s)
Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antibodies, Monoclonal/therapeutic use , Granulomatosis with Polyangiitis/drug therapy , Immunosuppressive Agents/therapeutic use , Pyoderma Gangrenosum/drug therapy , Adult , Drug Therapy, Combination , Granulomatosis with Polyangiitis/blood , Granulomatosis with Polyangiitis/diagnosis , Granulomatosis with Polyangiitis/immunology , Humans , Infliximab , Male , Pyoderma Gangrenosum/blood , Pyoderma Gangrenosum/diagnosis , Pyoderma Gangrenosum/immunology , Rituximab , Treatment OutcomeSubject(s)
Antibodies, Monoclonal/therapeutic use , Cytokines/blood , Dermatologic Agents/therapeutic use , Inflammation Mediators/blood , Pyoderma Gangrenosum/drug therapy , Skin/drug effects , Antitubercular Agents/therapeutic use , Biopsy , Drug Therapy, Combination , Glucocorticoids/therapeutic use , Humans , Infliximab , Latent Tuberculosis/diagnosis , Latent Tuberculosis/drug therapy , Male , Middle Aged , Prednisone/therapeutic use , Pyoderma Gangrenosum/blood , Pyoderma Gangrenosum/diagnosis , Pyoderma Gangrenosum/immunology , Skin/pathology , Treatment Outcome , Wound Healing/drug effectsABSTRACT
Pyoderma gangrenosum is an uncommon ulcerative cutaneous neutrophilic dermatosis. In about 50 percent of cases, it is associated with systemic diseases like inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythromatosus, hematological diseases and various malignancies. There is no specific laboratory finding or histological features pathognomonic of pyoderma gangrenosum and it is often a diagnosis of exclusion. Here, we report an elderly female without history of any systemic disorders, presenting to us with extensive, bilaterally symmetrical, deep leg ulcers along with multiple superficial ulcers involving the right groin which was diagnosed as pyoderma gangrenosum. The only positive rheumatologic marker was serum anti-cyclic cittrulinated peptide2 antibody, which was found to be strongly positive. Dramatic response to systemic corticosteroid followed by successful split skin grafting was observed in our patient.
Subject(s)
Antibodies/blood , Pyoderma Gangrenosum/blood , Anti-Inflammatory Agents/therapeutic use , Biomarkers/blood , Female , Humans , Middle Aged , Prednisolone/therapeutic use , Pyoderma Gangrenosum/drug therapy , Pyoderma Gangrenosum/surgery , Skin TransplantationABSTRACT
Acute myeloid leukemia (AML) is malignant tumor of haemopoietic precursor cells of non-lymphoid lineage. AML can atypically present with non-spesific cutaneous lesions or wounds. There are rare acute leukemia cases which present with genital ulcerations or pyoderma gangrenosum in the literature. The effect of acute leukemia on wound healing is not known, but it is thought that cytopenias and chemotherapy can impair wound healing in patients with leukemia. The effects of chemotherapeutic agents on wound healing are arguable. Here we present wound care strategies and simultaneously applied chemotherapy in an AML patient.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Acute/complications , Leukemia, Myeloid, Acute/drug therapy , Pyoderma Gangrenosum/complications , Adult , Cytarabine/administration & dosage , Humans , Idarubicin/administration & dosage , Leukemia, Myeloid, Acute/blood , Male , Pancytopenia/diagnosis , Pyoderma Gangrenosum/blood , Pyoderma Gangrenosum/drug therapy , Wound Healing/drug effectsSubject(s)
Blood Component Removal/methods , Colitis, Ulcerative/therapy , Interleukin-6/blood , Interleukin-8/blood , Phosphatidylserines/blood , Prothrombin/analysis , Pyoderma Gangrenosum/therapy , Adsorption , Antibodies/blood , Colitis, Ulcerative/blood , Colitis, Ulcerative/complications , Colitis, Ulcerative/immunology , Granulocytes , Head , Humans , Male , Monocytes , Pyoderma Gangrenosum/blood , Pyoderma Gangrenosum/etiology , Pyoderma Gangrenosum/immunology , Young AdultSubject(s)
Immunoglobulin G/therapeutic use , Pyoderma Gangrenosum/drug therapy , Receptors, Tumor Necrosis Factor/therapeutic use , Adult , Arthritis, Rheumatoid/epidemiology , Comorbidity , Etanercept , Female , Humans , Immunoglobulin G/administration & dosage , Lupus Erythematosus, Cutaneous , Male , Middle Aged , Pyoderma Gangrenosum/blood , Pyoderma Gangrenosum/epidemiology , Pyoderma Gangrenosum/physiopathology , Receptors, Tumor Necrosis Factor/administration & dosage , Receptors, Tumor Necrosis Factor/antagonists & inhibitors , RecurrenceABSTRACT
Pyoderma gangrenosum is a chronic, painful, ulcerative skin disease of unknown etiology. In 50 % of the cases, it is associated with systemic disease, primarily with inflammatory bowel disease. It can develop over areas of trauma or surgical wounds, possibly because of local immunoreactant deposits. We describe the case of a cANCA-positive patient with colonic diverticulitis who developed pyoderma gangrenosum over a saphenectomy scar.