Association between the functional PTPN22 G788A (R263Q) polymorphism and susceptibility to autoimmune diseases: A meta-analysis.

This study explored whether the functional protein tyrosine phosphatase nonreceptor 22 (PTPN22) G788A (R263Q) polymorphism is associated with susceptibility to autoimmune diseases. A meta-analysis was conducted using 23 comparative studies with a total of 16,719 patients and 17,783 controls. The meta-analysis showed an association between the A allele of the PTPN22 G788A polymorphism and decreased risk of autoimmune diseases in all subjects (p < 0.001). Analysis after stratification by ethnicity indicated that the PTPN22 788A allele was significantly associated with autoimmune diseases in Europeans (p < 0.001) but not in Latin Americans. Meta-analysis by autoimmune disease type showed a significant negative association between the PTPN22 788A allele and systemic lupus erythematous (SLE) (p = 001), rheumatoid arthritis (RA) (p = 0.008), ulcerative colitis (UC) (p = 0.016), but not Crohn's disease (CD). A single study for each showed no association between the PTPN22 788A allele and systemic sclerosis, giant cell arteritis, Henoch-schonlein purpura, uveitis, and Grave's disease. This meta-analysis demonstrates that the PTPN22 G788A polymorphism confers protection against SLE, RA, and UC, supporting evidence of association of the PTPN22 gene with a subgroup of autoimmune diseases.

Inducible nitric oxide synthase gene polymorphisms are associated with a risk of nephritis in Henoch-Schönlein purpura children.

Henoch-Schönlein purpura (HSP) is the most common form of systemic small-vessel vasculitis in children, and HSP nephritis (HSPN) is a major complication of HSP and is the primary cause of morbidity and mortality. Previous studies have suggested that inducible nitric oxide synthase (iNOS) may play an important role in the pathogenesis of HSP. In this study, we performed a detailed analysis to investigate the potential association between iNOS polymorphisms and the risk of HSP and the tendency for children with HSP to develop HSPN in a Chinese Han population. A promoter pentanucleotide repeat (CCTTT)n and 10 functional single-nucleotide polymorphisms (SNPs) from 532 healthy controls and 513 children with HSP were genotyped using the MassARRAY system and GeneScan. The results suggested that the allelic and genotypic frequencies of the rs3729508 polymorphism were nominally associated with susceptibility to HSP. In addition, there was a significant difference in the allelic distribution of the (CCTTT)12 repeats and rs2297518 between the HSP children with and without nephritis; the HSP children with nephritis exhibited a significantly higher frequency of the (CCTTT)12 repeats and A allele of rs2297518 than the HSP children without nephritis (P FDR = 0.033, OR = 1.624, 95% CI = 1.177-2.241 and P FDR = 0.030, OR = 1.660, 95% CI = 1.187-2.321, respectively). CONCLUSION: Our results support that iNOS polymorphisms are associated with the risk of HSP and may strongly contribute to the genetic basis of individual differences in the progression to nephritis among children with HSP in the Chinese Han population. What is Known: • The etiology of HSP is unknown, but the genetic factors may play an important role in the pathogenesis of HSP. • iNOS could contribute to the development and clinical manifestations of HSP, and this has not been studied extensively so far. What is New: • Our results support that iNOS polymorphisms not only are associated with HSP risk but also strongly contribute to the genetic basis of individual differences in the progression of HSP to nephritis among Chinese Han children.

Association between IL17A and IL17F polymorphisms and risk of Henoch-Schonlein purpura in Chinese children.

Previous studies suggested that interleukin-17 and Th17 cell play an important role in the pathogenesis of childhood Henoch-Schonlein purpura (HSP). The purpose of our study is to elucidate whether the IL17A and IL17F gene polymorphisms are susceptibility genes for the development of HSP in Chinese children. A total of 148 HSP patients and 202 controls were enrolled for analyzing the single nucleotide polymorphisms (SNP) of IL17A (rs2275913, rs8193037 and rs3819025) and IL17F (rs763780 and rs9463772). TaqMan Real-Time polymerase chain reaction method was used in SNP genotyping. Compared to the healthy controls, the IL17A rs2275913 variant allele A showed a significant association with HSP [odds ratio (OR) 0.70; 95 % CI 0.51-0.94, P = 0.018]. Genotyping analysis demonstrated rs2275913 was associated with a decreased HSP risk (G/A vs. G/G: OR 0.56; 95 % CI 0.33-0.95; A/A vs. G/G: OR 0.46; 95 % CI 0.24-0.86; P = 0.032). Also, our findings showed that the A allele of IL17A rs3819025 was associated with a higher risk of HSP nephritis (OR 1.61; 95 % CI 1.00-2.58; P = 0.047). In addition, a risk haplotype of IL17A (GGA) was found (OR 1.84; 95 % CI 1.17-2.88; P = 0.008). However, no significant differences between HSP patients and healthy controls were observed when comparing genotype, allele or haplotype frequencies of the IL17F rs763780 and rs9463772 polymorphisms. In this study, we confirmed that the rs2275913 polymorphism of the IL17A gene was associated with susceptibility to HSP in Chinese children. However, there was no relationship between IL17F rs763780 and rs9463772 polymorphisms and HSP susceptibility.

Severe erosive lesions in the digestive tract of patients with Henoch-Schönlein Purpura (HSP) and its impact on prognosis - presentation of two cases and statistical review of adult-onset Japanese HSP.

INTRODUCTION: Although many pediatric patients with Henoch-Schönlein Purpura (HSP) recover spontaneously, disease activity in adult patients often cannot be controlled by treatment. PURPOSE: To assess the specific signs not formerly considered to be those of uncontrollable adult HSP patients. PATIENTS AND METHODS: Clinical records of 2 adult patients who died during HSP were reviewed and previous reports on HSP were consulted. RESULTS: Both patients had lesions in the digestive tract diagnosed as hemorrhagic erosion in the small intestine and colon. They were elderly and showed renal dysfunction. They died from severe infection after potent immunosuppressive treatment. A univariate analysis showed that age of over 60 years, severe renal symptoms (nephrotic syndrome and/or end-stage renal failure), Birmingham Vasculitis Activity Score (BVAS) of more than 18 points, massive immunosuppression and melena had significantly higher prevalence among patients who died. Multivariate statistical analysis with theoretical quantification analysis II revealed that age of over 60 and severe renal symptoms (nephrotic syndrome and/or end-stage renal failure) contributed to poor prognosis. The presence of melena did not contribute to poor prognosis despite results of the univariate analysis and our clinical impressions. DISCUSSION: In multivariate statistical analysis, melena was selected as a sign of severe erosive lesions in the digestive tract because some of the patients were not examined by fiberscopy. Melena is caused by various lesions in the digestive tract and each of them has different effects on prognosis. CONCLUSION: Elderly HSP patients with severe renal impairment should be carefully treated. Examination of the digestive tract by fiberscopy is recommended when melena is observed in these patients.

The change of Th17/Treg cells and IL-10/IL-17 in Chinese children with Henoch-Schonlein purpura: A PRISMA-compliant meta-analysis.

BACKGROUND: To date, the relationship of Th17 and Treg cells to Henoch-Schonlein purpura (HSP) in children remains controversial. Therefore, a systematic review and meta-analysis was conducted to reveal the potential role of the Th17 and Treg cells in children in acute stage of HSP. METHODS: PubMed, Embase, Web of Science and China National Knowledge Internet (CNKI) were systematically searched for eligible studies up to November 03, 2017. Quality assessment was carried out according to the modification of the Newcastle-Ottawa Scale (NOS). The data were analyzed by Stata SE12.0 (StataCorp, College Station, TX). Standard mean difference (SMD) with 95% confidence intervals (CI) was calculated continuous data. RESULTS: A total of 25 eligible studies were identified after a thorough literature search. The pooled results of the meta-analysis showed that values of Th17 frequency (SMD = 2.60; 95% CI: 1.98 to 3.23; P < .0001; I = 90.3%, P < .0001) and IL-17 level (SMD = 3.53; 95% CI: 2.71 to 4.35; P < .0001; I = 95.6%, P < .001) were significantly higher in children with HSP as compared to healthy children. In contrast, our analysis showed significant lower values of Treg frequency (SMD = -2.86; 95% CI: -3.53 to -2.19; P < .001; I = 92.4%, P < .001). However, no significance of IL-10 level was observed between children with HSP and healthy children (SMD = -1.22; 95% CI: -2.78 to 0.33; P < .01; I = 95.9%, P < .001). CONCLUSION: In conclusion, our meta-analysis indicated that increased frequency of Th17 cells and level of IL-17, but lower frequency of Treg cells are associated with HSP in childhood. Considering the limitations of this meta-analysis, large-scaled studies need to be conducted to validate the current results.

Lack of association between NPHS2 gene polymorphisms and Henoch-Schönlein purpura nephritis.

Henoch-Schönlein purpura (HSP) is one of the most common forms of small-vessel vasculitis in childhood, and renal involvement (HSP nephritis, HSPN) is the main determinant of morbidity after acute phase. Considering the racial diversity and clinical heterogeneity in the prevalence, genetic factors might play a role in pathogenesis of HSP and HSPN. Direct sequencing was performed after PCR amplification of all 8 exons of the NPHS2 gene in 20 Chinese children with HSPN and 30 controls in present study. The genetic analyses revealed 3 polymorphisms (954T > C heterozygous, 1038A > G heterozygous and homozygous, all in exon 8) in 7 out of 20 patients studied, but there was no significant difference in the genotypic and allelic frequencies of these polymorphisms between the patients and controls. The result did not support the possible role of the NPHS2 gene in susceptibility to HSPN in the population studied. Studies in a larger sample population with different genetic backgrounds will be necessary in the future.

Antiphospholipid antibodies in Turkish children with thrombosis.

Antiphospholipid syndrome is a systemic disorder characterized by arterial and/or venous thrombosis, thrombocytopenia, recurrent fetal loss, and presence of antiphospholipid antibodies (APA). The importance of APA in Turkish children with thrombosis is unknown. This study aimed to evaluate the frequency of APA positivity, associated risk factors other than APA, and outcome in children with APA and thrombosis. The presence of APA was investigated in 138 children presenting for evaluation of thrombosis; other prothrombotic risk factors were also studied. The frequency of APA positivity among 138 children was 11.6% (16/138). The mean age of these 16 children (10 female, 62.5%) was 9.57 +/- 4.59 years (range, 2.5-18.0 years). The mean follow-up period was 31.7 +/- 21.7 months (range, 5-60 months). Recurrence was observed during follow-up in two patients (12.5%). Ten patients (62.5%) had arterial thrombosis, five patients (31.3%) venous thrombosis, and one patient (6.3%) purpura fulminans. Among the thrombotic children with APA, 11 (68.8%) had more than one prothrombotic risk factor other than circulating APA [five patients (31.3%) had two risk factors, two patients (12.5%) had three, and four patients (25.0%) had four]. Five patients (31.3%) had no additional risk factors. APA should be tested in all children with thrombosis, especially those with arterial thrombosis.

A Case of Henoch-Schonlein Purpura Associated with Rotavirus Infection in an Elderly Asian Male and Review of the Literature.

BACKGROUND Henoch-Schönlein purpura (HSP), a small vessel vasculitis mediated by deposition of immune-complexes containing IgA in the skin, gut, and glomeruli, often presents with abdominal pain, purpuric rash in the lower extremities and buttocks, joint pain, and hematuria. The disease most commonly targets children but can affect adults who tend to have a worse prognosis. CASE REPORT We discuss a case of HSP in an elderly Chinese male who presented with severe proximal bowel inflammation, vasculitic rash, and proteinuria; he was found to have positive stool rotavirus and giardia. He improved significantly with high dose steroids. We believe rotavirus may have been a triggering event in this patient. A brief review of the literature is also presented. CONCLUSIONS This is the first case report describing a classic presentation of HSP in an adult following a rotavirus infection. HSP can cause significant morbidity and mortality in adult patients predominantly from progressive renal failure; therefore careful management and monitoring is important. GI infections seem to be a common trigger for HSP and this case report suggests that rotavirus may be part of the spectrum.

Lack of Association between Interleukin-8 Gene +781 C/T Polymorphism and Henoch-Schönlein Purpura in Childhood.

Henoch-Schönlein purpura (HSP), a common allergic hemorrhagic disease, occurs frequently in children affecting kidney, joint and skin. While interleukin-8 (IL-8) plays an important role in inflammation, the association between IL-8 gene +781 C/T polymorphism and HSP remains unclear. Interleukin-8, an important chemokine related to the initiation and amplification of acute inflammatory responses, has been reported to be involved in the pathogenesis of some autoimmune and inflammatory diseases. In this study, we aimed to investigate whether IL-8 gene +781 C/T (rs2227306) polymorphism has an influence on susceptibility and clinical manifestations of patients to HSP. This hospital-based case-control study comprised 192 patients with HSP and 202 healthy controls. The genotypes of IL-8 gene +781 C/T polymorphism were identified using PCR-TaqMan method. All genotype frequencies of both groups (patients and controls) conformed to the Hardy-Weinberg equilibrium. No significant differences in allele or genotype frequencies of IL-8 gene +781 C/T polymorphism were observed between patients with HSP and controls (p=0.98, χ2=0.000 and p=0.49, χ2=1.432, respectively). When patients were stratified for the presence of joint, gastrointestinal and renal manifestations, genotype frequencies of IL-8 gene polymorphism were found no statistically significant differences (p>0.05). Our findings do not support that IL-8 gene +781 C/T polymorphism has an effect on the susceptibility to HSP in Chinese children.

Chemokine MCP1/CCL2 gene polymorphism influences Henoch-Schönlein purpura susceptibility in Iranian Azeri-Turkish patients.

BACKGROUND: Henoch-Schönlein purpura (HSP) is the most common small-vessel vasculitis and mainly affects children. Although its pathophysiology is unknown, several studies have indicated the possible involvement of infections and genetic factors in the development of HSP. The human leukocyte antigen (HLA) gene family and several other genes involved in the inflammatory system have been studied. The CCL2 gene, encoding chemokine monocyte chemo-attractant protein 1 (MCP-1/CCL2), is one of several cytokine genes clustered on chromosome 17. The encoded protein displays chemotactic activity for monocytes. METHODS: This is a case-control study comparing 36 children diagnosed with HSP within the Iranian Azeri-Turkish ethnic population and 50 healthy adults from the same ethnic group. CCL2, C-2518T polymorphism genotypes were determined by polymerase chain reaction and by PVUII restriction enzyme analysis and subsequent agarose gel electrophoresis. RESULTS: Our results showed a significant association between the allelic and genotypic frequency of this gene and HSP disease in this cohort. The results of this study indicate that frequencies of the T allele of CCL2 (P = 0.015) and the TT genotype (P = 0.004) are significantly higher in HSP patients. A comparison of clinical symptoms and laboratory data with CCL2 C-2518T polymorphism showed that patients with the TT genotype presented a higher clinical score and more severe clinical features. CONCLUSIONS: MCP1/CCL2 C-2518T gene polymorphism is associated with susceptibility to HSP. This is the first study to report a significant association between MCP1/CCL2 C-2518T and a susceptibility to HSP in this population.

The profile of adult onset Henoch-Schönlein purpura in an Asian population.

BACKGROUND: Henoch-Schönlein purpura (HSP) is less common in adults and has been linked with a more severe clinical syndrome as well as a higher frequency of renal disease and internal malignancy. Renal involvement in adult HSP has been significantly associated with antecedent infections, pyrexia at time of first presentation, and purpura above the waist. We aim to evaluate the frequency of cutaneous and extra-cutaneous features and identify the predictive factors for renal involvement in Asian adults with HSP. METHODS: We performed a retrospective study of 48 adult Asian patients diagnosed with HSP based on the European League Against Rheumatism (EULAR) criteria at a tertiary hospital in Singapore between January 2000 and December 2011. RESULTS: The most common cutaneous manifestations were palpable purpura (73%), papules (31%), and petechiae (27%). Forty-percent had cutaneous lesions extending above the waist. Fifteen patients (31%) had gastrointestinal symptoms, 21 (44%) had joint involvement, and 27 (56%) had renal disease. Seventy-percent of patients with pyrexia at presentation experienced renal disease, whereas only 30% without pyrexia had renal involvement (P = 0.018). Sixty-six percent of patients with purpura had renal involvement as compared to 31% in those without purpura (P = 0.049). The frequency of renal involvement in patients with purpura above the waist (52%) was similar to those with purpura below the waist (55%). CONCLUSIONS: Our study confirms that HSP in adults tends to be more severe with a high incidence of extracutaneous manifestations, especially renal disease. Pyrexia at presentation and the presence of purpura were significant predictive factors for renal involvement.

MEFV gene mutations in Egyptian children with Henoch-Schonlein purpura.

BACKGROUND: Due to an increased frequency of vasculitis in FMF patients, many investigators have studied MEFV mutations in patients with HSP. The aim of the study is to investigate the frequency and clinical significance of MEFV mutations in Egyptian children with Henoch-Schonlein purpura (HSP). Investigating MEFV mutations in controls may help in estimating the prevalence of MEFV mutation carrier rate in Egyptian children. METHODS: The study enrolled 90 individuals, sixty children with Henoch-Schonlein purpura (HSP), together with 30 sex-and age-matched apparently healthy controls. The entire study group was screened for 12 common MEFV mutations using a reverse hybridization assay of biotinylated PCR products. RESULTS: Patients with HSP had a significantly higher frequency of MEFV mutations (61.7%), when compared to the apparently healthy control population (36.7%). V726A was the most frequent mutation with an allelic frequency of 10.8%. Ninety- one percent of patients with MEFV mutations were heterozygous for one mutation, while 8.1% had a compound heterozygous MEFV gene mutations. The mutation V726A, followed by E148Q, were the leading mutations, present in 16.6% and in 13.3% of controls. CONCLUSIONS: MEFV mutations may be related to HSP susceptibility in children. The mutations were not associated with any clinical and laboratory manifestations. Screening for MEFV mutations in larger number of HSP children may be beneficial to evaluate any possible relationship between certain types of MEFV mutations and HSP, and compare the HSP MEFV mutations to the types of MEFV mutations associated with FMF.

MEFV gene mutations (M694V, V726A, M680I, and A744S) in Iranian children with Henoch-Schönlein purpura.

INTRODUCTION: Henoch-Schönlein purpura (HSP) is the most common systemic vasculitis in children. Several risk factors play important role in pathogenesis of HSP. We aimed to study the MEFV gene mutations (M694V, V726A, M680I, and A744S) in Iranian children with HSP. MATERIAL AND METHODS: 50 unrelated pediatric cases were studied regarding M694V, V726A, M680I, and A744S mutations using ASO-PCR method. RESULTS: 24% of cases had a mutation. 22% of cases had M694V mutations. One out of 50 (2%) patients had V726A mutation. In 76% of cases no mutation was determined. In other hand, 13 out of 100 alleles (13%) were carrier for one mutation. 12 out of 100 alleles had M694V mutations (% 12) and I out of 100 alleles had V726A mutation (%1). In 87 out of 100 alleles no mutation was detected. M680I and A744S mutations were not found in tested group. Mutation study and analysis demonstrated that the most frequent mutation was M694V (22%). Frequency of alleles were 0.12, 0.01,0,0,0.13, and 0.87 regarding M694V, V726A, M680I, A744S, total mutation, and wild type alleles, respectively. Our findings imply that M694V was dominant mutation. CONCLUSIONS: This report as the first investigation of its kind in Iranian Azeri Turkish patients implying that M694V mutations are more frequent in tested group in comparison with general population. So it is suggested that investigation of M694V mutations should be considered as genetic test for diagnosis of HSP among Iranian Azeri Turkish patients.

[Histocompatibility antigens and acute vascular purpura]. / Antígenos de histocompatibilidad y púrpura vascular aguda.

INTRODUCTION: Some kidney diseases are associated to HLA antigens. Nyulassy found an increase in HLA-B35 in patients with Henoch-Schönlein's purpura suffering nephritis (HSP-N). Our study searched for associations of HLA antigens and anaphylactoid purpura nephritis in Mexican mestizo patients. MATERIAL AND METHODS: HLA-A,B, and C antigens were detected by two-step microcytotoxicity in 22 patients with HSP-N and compared to those of 665 healthy subjects of the same ethnic background. RESULTS: A significant association was found between HSP-N and HLA-Aw19 single (pc less than 0.05) or in haplotype form (Aw19-B35) (pc less than 0.005). HLA B35 alone was associated to HSP-N but only at non corrected level (pc less than 0.05). DISCUSSION: The significant association between HLA-Aw19 and Aw19-B35 and HSP-N may indicate a risk factor in Mexican mestizo patients to develop this case.

Incidence of Henoch-Schönlein purpura, Kawasaki disease, and rare vasculitides in children of different ethnic origins.

BACKGROUND: The frequency and ethnic variation of Henoch-Schönlein purpura, Kawasaki disease, and rarer vasculitides during childhood are not well characterised. Our aim was to ascertain the incidence and ethnic distribution of these conditions in children resident in a region of the UK with a diverse ethnic mix. METHODS: 1.1 million children younger than age 17 years live in the West Midlands. Between Sept 1, 1996, and Aug 31, 1999, we surveyed this population with monthly questionnaires sent to 321 consultants, a single questionnaire sent to 2860 family doctors, and review of 406 case notes with diagnostic codes for vasculitis. We included in the analyses children who fulfilled established criteria for vasculitis with disease onset during the study, and calculated incidence rates from population rates derived from the census of 1991. FINDINGS: We identified 586 new instances of vasculitis and connective tissue disease. The estimated annual incidence of Henoch-Schönlein purpura was 20.4 per 100000, and was highest between the ages of 4 years and 6 years (70.3 per 100000). The estimated annual incidence of Kawasaki disease was 5.5 per 100000 in children younger than 5 years, and was highest in Indian subcontinent Asian children (14.6 per 100000). Indian subcontinent Asian and black children had the highest incidence of systemic lupus erythematosus, juvenile dermatomyositis, and other primary systemic vasculitides. INTERPRETATION: Childhood Henoch-Schönlein purpura is more frequent in the West Midlands than previously reported, and Kawasaki disease has a higher incidence than previously indicated in the UK, with the highest incidence in Indian subcontinental Asian children. Other vasculitis is rare in childhood.