Impact of MEFV Mutations on Inflammatory Activity and Long-Term Relapse in Pediatric IgA Vasculitis

Impact of MEFV Mutations on Inflammatory Activity and Long-Term Relapse in Pediatric IgA Vasculitis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of MEFV Mutations on Inflammatory Activity and Long-Term Relapse in Pediatric IgA Vasculitis Göktuğ Özdemir, Esma Kaya Özdemir, Asım Gültekin This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8599952/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Feb, 2026 Read the published version in BMC Pediatrics → Version 1 posted 17 You are reading this latest preprint version Abstract Background IgA vasculitis (IgAV), formerly Henoch–Schönlein purpura, is the most common systemic vasculitis of childhood. MEFV mutations have been linked to enhanced inflammatory responses and vasculitis, although their impact on long-term outcomes remains unclear. Objectives To determine the prevalence of MEFV mutations in children with IgAV and to evaluate their associations with clinical features, inflammatory markers, and long-term outcomes, including relapse. Methods In this retrospective cohort, 62 children diagnosed with IgAV were screened for eight common MEFV mutations and classified according to mutation status. Demographic, clinical, laboratory, and outcome variables were compared between groups. Long-term follow-up data were used to assess relapse and renal outcomes. Results MEFV mutations were detected in 24/62 patients (38.7%). Mutation-positive patients had higher ESR and CRP levels and lower serum albumin levels (p < 0.05 for all). Long-term follow-up data were available in 57/62 patients. Relapse occurred more frequently in mutation-positive than mutation-negative patients (27.3% vs. 5.7%; p = 0.028). In multivariate analysis, MEFV mutation positivity and elevated ESR were independent predictors of relapse. Conclusions MEFV mutations were common in children with IgAV and were associated with higher inflammatory activity and increased relapse risk, despite similar systemic involvement at presentation. In settings with a high prevalence of MEFV variants, mutation status may contribute to clinical risk stratification. Larger studies are needed to clarify its prognostic value. IgA vasculitis Henoch–Schönlein purpura MEFV Familial Mediterranean Fever pediatric vasculitis relapse inflammation INTRODUCTION IgA vasculitis (IgAV), formerly known as Henoch–Schönlein purpura (HSP), is the most common systemic small-vessel vasculitis in childhood. It is characterized by IgA-mediated immune complex deposition in small vessels, leading to non-thrombocytopenic palpable purpura, arthritis/arthralgia, abdominal pain, gastrointestinal bleeding, and renal involvement ( 1 , 2 ). Although the clinical course is often self-limited, disease severity varies, and renal involvement or relapse may contribute to prolonged corticosteroid exposure, repeated healthcare utilization, and long-term morbidity. Reported relapse rates differ substantially across pediatric IgAV cohorts, and predictors of recurrent or persistent disease activity remain insufficiently defined. The MEFV (Mediterranean Fever) gene, located on chromosome 16p13.3, encodes pyrin, a cytosolic protein that regulates innate immunity by modulating inflammasome assembly and interleukin-1β (IL-1β) secretion ( 3 , 4 ). Variants in MEFV may disrupt pyrin function, resulting in dysregulated inflammasome activity and amplified inflammatory responses. Beyond Familial Mediterranean Fever (FMF), increased frequencies of MEFV variants have been described in several inflammatory and vasculitic disorders, including IgAV, inflammatory bowel disease, polyarteritis nodosa, and juvenile idiopathic arthritis ( 5 , 6 ). These observations have raised the hypothesis that MEFV mutations may act as genetic modifiers, influencing inflammatory pathways and clinical expression in immune-mediated diseases ( 7 , 8 ). In pediatric IgAV, MEFV mutations have been linked to heightened inflammation, but their impact on disease phenotype and long-term outcomes remains insufficiently understood ( 9 – 11 ). Despite accumulating evidence on prevalence and acute clinical features, data regarding long-term outcomes such as relapse or persistent renal involvement remain limited. Determining whether MEFV variants influence chronic disease behavior is clinically relevant, particularly in populations with a high frequency of MEFV variants. Based on this rationale, we hypothesized that MEFV variants may contribute to inflammatory burden and disease trajectory in pediatric IgAV. The present study aimed to determine the frequency of MEFV mutations in children with IgAV and to evaluate their association with inflammatory markers, clinical features, and long-term outcomes, including relapse. MATERIALS AND METHODS Study Design and Patients This retrospective observational study included 62 pediatric patients diagnosed with IgA vasculitis (IgAV, formerly Henoch–Schönlein purpura) who were evaluated and followed at a tertiary care university hospital in Turkey between January 2005 and April 2012. The diagnosis of IgAV was established according to the American College of Rheumatology (ACR) classification criteria. Inclusion criteria were: (i) age < 18 years at diagnosis, (ii) fulfillment of ACR criteria for IgAV, and (iii) availability of complete clinical and laboratory data at presentation. Exclusion criteria were: (i) prior diagnosis of Familial Mediterranean Fever (FMF) or other chronic autoinflammatory or rheumatologic diseases, (ii) chronic kidney disease, and (iii) insufficient medical records. Data Collection Demographic characteristics (age and sex), presenting symptoms, and systemic involvement were obtained from institutional medical records. Clinical manifestations and laboratory findings were extracted from admission and follow-up documentation. Laboratory evaluations included white blood cell count, hemoglobin concentration, platelet count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), total protein, serum albumin, renal function tests, urinalysis, and fecal occult blood testing. Clinical symptoms, complications, and treatment modalities (nonsteroidal anti-inflammatory drugs, corticosteroids, colchicine, intravenous fluids, and hospitalization) during follow-up were additionally recorded. Definition of Relapse and Follow-Up Strategy Relapse was defined as the reappearance of palpable purpura and/or systemic manifestations (gastrointestinal or joint involvement) after at least four weeks of complete clinical remission. Long-term follow-up data were obtained through outpatient visits and telephone interviews when necessary. All patients were followed for a minimum of six months, and long-term outcome analyses included those with at least 12 months of available follow-up data. Renal outcomes assessed during follow-up included persistent hematuria, persistent proteinuria, hypertension, and progression to chronic kidney disease. MEFV Gene Analysis MEFV genetic analysis was performed after written informed consent was obtained from legal guardians. Peripheral blood samples were collected for genomic DNA extraction. The most frequently reported pathogenic and likely pathogenic MEFV variants were analyzed using multiplex polymerase chain reaction (PCR) followed by reverse hybridization targeting E148Q, P369S, F479L, M680I (G/C), M694V, V726A, K695R, and K761H. Agarose gel electrophoresis (2%) was performed to verify amplification, followed by hybridization on nitrocellulose membranes for mutation detection according to the manufacturer’s guidelines. This panel detects the most common MEFV hotspot variants but does not cover rare variants outside these regions. Patients were categorized into two groups based on the presence or absence of MEFV mutations, and comparative analyses were performed accordingly. Statistical Analysis Statistical analyses were performed using SPSS for Windows (version 21.0; SPSS Inc., Chicago, IL, USA). The Kolmogorov–Smirnov test was used to assess the normality of data distribution. Continuous variables were expressed as mean ± standard deviation (SD) for normally distributed data or median with interquartile range (IQR) for non-normally distributed data. Normally distributed variables were compared using the independent samples t-test, while non-normally distributed variables were compared using the Mann–Whitney U test. Categorical variables were analyzed using Pearson’s Chi-square test or Fisher’s exact test, as appropriate. Variables with a p-value < 0.10 in univariable analyses were included in a multivariable logistic regression model to identify independent predictors of relapse, with results reported as odds ratios (ORs) and 95% confidence intervals (CIs). A two-tailed p-value < 0.05 was considered statistically significant. Given the limited number of relapse events (n = 8), a parsimonious multivariable logistic regression model was constructed including only two variables—MEFV mutation status (positive vs. negative) and ESR (per 1 mm/h increase)—to minimize the risk of overfitting. RESULTS I. Study Population A total of 62 pediatric patients diagnosed with IgA vasculitis (IgAV) were enrolled. The cohort included 39 males (62.9%) and 23 females (37.1%), with a mean age of 8.56 ± 3.21 years (range: 1–15). All patients presented with palpable purpura. No central nervous system, pulmonary, or cardiac involvement was observed. Articular, gastrointestinal, renal, urogenital, and subcutaneous edema involvement occurred in 48 (77.4%), 33 (53.2%), 14 (22.6%), 7 (11.3%), and 8 (12.9%) patients, respectively. Occult blood in stool was identified in 13 patients (21%), all of whom displayed gastrointestinal symptoms. Renal involvement based on laboratory findings was present in 14 patients (22.6%). Proteinuria was detected in 9 (14.5%) and hematuria in 13 (21%). Of these 14 patients, isolated hematuria was observed in 8 (57.1%), hematuria with proteinuria in 4 (28.6%), and nephrotic-range proteinuria in 2 (14.3%). Serum creatinine remained within normal limits in all cases. II. MEFV Mutation Status MEFV gene mutations were identified in 24 patients (38.7%), while 38 (61.3%) carried no detectable mutation. The most common variant was p.Met694Val (M694V), observed in 11 patients (17.7%), including 7 heterozygous, 1 homozygous, and 3 compound heterozygous carriers. The distribution of MEFV variants is presented in Table 1 . Table 1 Distribution of MEFV Gene Variants in 62 Children with IgAV Mutation Type n % Heterozygous p.Glu148Gln (E148Q) 3 4.8 Heterozygous p.Met694Val (M694V) 7 11.3 Heterozygous p.Val726Ala (V726A) 4 6.5 Heterozygous p.Met680Ile (M680I) 3 4.8 Heterozygous p.Glu148Gln + p.Met694Val 2 3.2 Heterozygous p.Glu148Gln + p.Val726Ala 1 1.6 Heterozygous p.Met680Ile + p.Met694Val 1 1.6 Heterozygous p.Val726Ala + p.Met680Ile 2 3.2 Homozygous p.Met694Val (M694V) 1 1.6 No mutation detected 38 61.3 Total 62 100 II. Laboratory Findings The mean serum CRP level was 23.7 ± 18.4 mg/L and the mean ESR was 38.2 ± 21.6 mm/h. Leukocytosis and thrombocytosis were observed in 18 (29.0%) and 14 (22.6%) patients, respectively. The median leukocyte count was 11,800/mm³ (IQR: 9,300–14,500). Serum creatinine levels were within normal limits in all patients. When stratified according to MEFV mutation status, patients carrying MEFV variants demonstrated significantly higher ESR (p = 0.003) and CRP (p = 0.004) levels and significantly lower serum albumin levels (p = 0.009) compared to mutation-negative patients. No statistically significant differences were observed in leukocyte count, platelet count, hemoglobin, or total protein levels between groups. Laboratory parameters according to mutation status are summarized in Table 2 and Table 3 . Table 2 Laboratory Parameters According to MEFV Mutation Status Parameter Mutation Absent (n = 38) Mean ± SD Mutation Present (n = 24) Mean ± SD p-value WBC (×10³/mm³) (NR: 4.5–13.5) 11.67 ± 4.64 12.34 ± 3.93 0.56 Hemoglobin (g/dL) (NR: 11.5–15.5) 13.03 ± 0.97 12.86 ± 1.29 0.58 Platelets (×10³/mm³) (NR: 150–450) 385.23 ± 117.27 380.12 ± 81.46 0.85 ESR (mm/h) 19.97 ± 11.62 37.95 ± 25.94 0.003 Total Protein (g/dL) (NR: 6.4–8.3) 7.22 ± 0.64 7.14 ± 0.77 0.67 Albumin (g/dL) (NR: 3.5–5.2) 4.04 ± 0.58 3.62 ± 0.58 0.009 NR : Normal reference range Test : Independent samples t-test Table 3 CRP Levels According to MEFV Mutation Status Mutation Status n Min (mg/L) Max (mg/L) Median (mg/L) p-value Absent 38 1.0 78.4 8.2 0.004 Present 24 1.0 246.0 20.2 Test : Mann–Whitney U test IV. Clinical Outcomes and Follow-up A total of 27 patients (43.5%) required hospitalization, with a median hospital stay of 5 days (IQR: 3–7). The most frequent reasons for admission were gastrointestinal involvement (n = 18), renal involvement (n = 6), and pain management (n = 3). Systemic corticosteroids were administered to 19 patients (30.6%), NSAIDs to 41 (66.1%), colchicine to 2 (3.2%), and intravenous fluids to 7 (11.3%). Comparison of clinical manifestations revealed no significant differences between mutation-positive and mutation-negative groups. Table 4 Systemic Involvement According to MEFV Mutation Status Systemic Involvement Mutation Absent n (%) Mutation Present n (%) Total n (%) p-value Joint 29 (76.3%) 19 (79.2%) 48 (77.4%) 0.78 Renal 7 (18.4%) 7 (29.2%) 14 (22.6%) 0.31 Gastrointestinal 19 (50.0%) 14 (58.3%) 33 (53.2%) 0.53 Subcutaneous Edema 5 (13.2%) 3 (12.5%) 8 (12.9%) 0.94 Urogenital 4 (10.5%) 3 (12.5%) 7 (11.3%) 0.81 During long-term follow-up (67.4 ± 18.2 months), complete outcome data were available for 57 of 62 patients (91.9%). Severe complications occurred exclusively in MEFV mutation–positive patients. One heterozygous M694V carrier developed hemolytic uremic syndrome, and two patients (including one homozygous M694V carrier) required colchicine therapy. These findings suggest that certain MEFV variants may predispose to more severe disease manifestations. Relapse was documented in 6 of 22 mutation-positive patients (27.3%) and in 2 of 35 mutation-negative patients (5.7%), representing a significant difference between groups (Fisher’s exact, p = 0.028), as shown in Table 5 . Relapses were predominantly observed among patients carrying M694V-containing genotypes, as summarized in Table 6 , supporting the hypothesis that MEFV variants may modify the chronicity of IgAV. In a parsimonious multivariable logistic regression model including MEFV mutation status and ESR, both variables remained independently associated with relapse (MEFV mutation positivity: OR 3.12, 95% CI 1.08–9.04, p = 0.036; ESR: OR 1.04 per 1 mm/h increase, 95% CI 1.01–1.07, p = 0.020), suggesting that genetic predisposition and inflammatory burden jointly modify long-term disease behavior. Table 5 Relapse According to MEFV Mutation Status (Long-Term Follow-up) Variable Mutation (+) Mutation (−) Total Followed patients (n) 22 35 57 Relapse (n, %) 6 (27.3%) 2 (5.7%) 8 (14.0%) No relapse (n, %) 16 (72.7%) 33 (94.3%) 49 (86.0%) Statistical test Fisher’s exact p = 0.028 Table 6 Genotype-Specific Relapse Patterns Genotype n Relapse n (%) Heterozygous M694V 7 2 (28.6%) Homozygous M694V 1 1 (100%) E148Q + M694V 1 1 (100%) M680I + M694V 1 1 (100%) Other genotypes* 3 0 (0%) Mutation-negative 35 2 (5.7%) Notes: “Other genotypes” include E148Q, V726A, M680I without M694V involvement. Values based on patients with available long-term follow-up data (n = 57). DISCUSSION In this pediatric cohort of immunoglobulin A vasculitis (IgAV; formerly Henoch–Schönlein purpura), we examined the prevalence of MEFV gene mutations and their potential associations with inflammatory parameters and long-term clinical outcomes. IgAV represents the most common systemic small-vessel vasculitis of childhood, typically characterized by palpable purpura, arthralgia/arthritis, abdominal pain, and renal involvement ( 12 – 15 ). Although many patients follow a self-limited course, a subset experience recurrent or prolonged disease activity, and predictors of long-term outcomes remain insufficiently defined ( 14 – 16 ). To date, studies specifically addressing long-term disease trajectories in MEFV-associated IgAV are limited, leaving an important knowledge gap that the present work sought to address ( 17 , 18 ). MEFV mutations were identified in 38.7% of patients in our cohort. This frequency is higher than those reported in some published reference populations and aligns with previous pediatric IgAV studies describing an overrepresentation of MEFV variants ( 19 – 21 ). Pyrin, the protein encoded by MEFV, regulates innate immune signaling and inflammasome assembly through IL-1β-mediated pathways ( 22 , 23 ). Functionally relevant MEFV variants can enhance inflammasome activation and cytokine release, providing a biologically plausible basis for modified inflammatory responses ( 23 , 24 ). Consistent with this mechanistic framework, MEFV-positive patients demonstrated significantly higher ESR and CRP levels and significantly lower serum albumin levels compared with mutation-negative patients. These findings align with prior studies reporting elevated acute-phase reactants and a more pronounced inflammatory milieu among MEFV mutation carriers ( 25 – 26 ). Collectively, this supports the hypothesis that MEFV variation may augment systemic inflammatory burden in IgAV. Beyond inflammatory markers, clinically significant complications were observed exclusively among MEFV-positive patients. These included hemolytic uremic syndrome and colchicine-responsive gastrointestinal symptoms, reflecting atypical or refractory disease patterns not typically associated with classical IgAV ( 17 , 18 ). Although anecdotal, such findings are consistent with emerging reports describing modified disease trajectories in patients carrying MEFV mutations (36). Given that pyrin-inflammasome activation and IL-1β signaling represent targetable pathways, these observations may hold implications for individualized monitoring or early therapeutic consideration in selected cases ( 27 ). Relapse represented another clinically relevant outcome in our cohort. Relapse occurred significantly more frequently in MEFV-positive patients than in those without mutations, and in multivariable modeling both MEFV positivity and elevated ESR were independently associated with recurrent disease. These findings suggest that genetic predisposition and inflammatory burden jointly influence long-term disease behavior. Relapse contributes to cumulative morbidity, prolonged corticosteroid exposure, and increased healthcare utilization, and several cohort studies have emphasized its clinical impact in childhood IgAV ( 28 – 30 ).In line with our observations, prior reports have linked higher inflammatory and immunologic markers with more severe systemic and renal involvement and, in some studies, with an increased risk of relapse or persistent disease activity. Recent pediatric cohorts and systematic reviews have highlighted the prognostic value of inflammatory indices (such as neutrophil-to-lymphocyte ratio, D-dimer, serum albumin, and immunoglobulin levels) for nephritis and adverse outcomes in IgAV (31,32). Taken together, our data extend this literature by suggesting that MEFV variation may interact with systemic inflammation to shape the chronicity of IgAV. This study has limitations that warrant consideration. The retrospective design and single-center nature may affect generalizability, and the MEFV testing panel did not encompass all rare variants or other autoinflammatory genes. Additionally, the number of relapse events was modest, and the lack of environmental and genetic co-factor assessment limits mechanistic interpretation. These findings should therefore be viewed as hypothesis-generating and supportive of the need for larger, prospective, and genomically integrated studies to better delineate gene–inflammation interactions in pediatric IgAV. CONCLUSION In conclusion, MEFV mutations were common in this pediatric IgAV cohort and were associated with a heightened inflammatory profile, clinically significant complications, and increased relapse risk, despite comparable systemic involvement at presentation. These findings suggest that MEFV mutation status may carry prognostic relevance and could support risk stratification in pediatric IgAV. Larger studies are needed to validate these observations and to determine whether genetically informed monitoring or targeted anti-inflammatory approaches may improve long-term outcomes in affected children. Declarations Author Contributions GO and AG designed the study; GO and EKO collected the data; GO performed the statistical analyses; GO, EKO and AG interpreted the data; GO and AG drafted the manuscript; and GO, EKO, and AG critically revised the manuscript for important intellectual content. All authors have read and approved the final version of the manuscript. Funding This study was supported by the Scientific Research Projects Coordination Unit of Cumhuriyet University (CÜBAP) under project number T-526. Ethics Approval and Consent to Participate All procedures involving human participants were conducted in accordance with institutional and national research committee standards and with the 1975 Helsinki Declaration and its later amendments. The study protocol was approved by the Clinical Research Ethics Board of Cumhuriyet University (Approval date/number: 17.01.2012/39). Written informed consent for participation was obtained from all participants or their legal guardians, in accordance with national regulations and institutional requirements. Consent to Publication Not applicable. Data Availability Statement The data supporting the findings of this study are available from the corresponding author upon reasonable request. Conflict of Interest The authors declare no conflicts of interest. Acknowledgment Not applicable. Clinical Trial Number Not applicable. References Leung AKC, Barankin B, Leong KF. Henoch-Schönlein purpura in children: an updated review. Curr Pediatr Rev. 2020;16(4):265–76. https://doi.org/10.2174/1573396316666200508104708 . Parums DV. A review of IgA vasculitis (Henoch-Schönlein purpura) past, present, and future. Med Sci Monit. 2024;30:e943912. https://doi.org/10.12659/MSM.943912 . Heilig R, Broz P. Function and mechanism of the pyrin inflammasome. Eur J Immunol. 2018;48(2):230–8. https://doi.org/10.1002/eji.201746947 . 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Cite Share Download PDF Status: Published Journal Publication published 27 Feb, 2026 Read the published version in BMC Pediatrics → Version 1 posted Editorial decision: Revision requested 09 Feb, 2026 Reviews received at journal 09 Feb, 2026 Reviews received at journal 07 Feb, 2026 Reviewers agreed at journal 04 Feb, 2026 Reviewers agreed at journal 04 Feb, 2026 Reviewers agreed at journal 04 Feb, 2026 Reviewers agreed at journal 04 Feb, 2026 Reviewers agreed at journal 04 Feb, 2026 Reviewers agreed at journal 03 Feb, 2026 Reviewers agreed at journal 02 Feb, 2026 Reviewers agreed at journal 02 Feb, 2026 Reviewers agreed at journal 02 Feb, 2026 Reviewers invited by journal 02 Feb, 2026 Editor invited by journal 19 Jan, 2026 Editor assigned by journal 16 Jan, 2026 Submission checks completed at journal 16 Jan, 2026 First submitted to journal 14 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8599952","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":584863548,"identity":"aef83d77-26ed-451f-a0e7-983e693e6019","order_by":0,"name":"Göktuğ Özdemir","email":"","orcid":"","institution":"Sivas Cumhuriyet University","correspondingAuthor":false,"prefix":"","firstName":"Göktuğ","middleName":"","lastName":"Özdemir","suffix":""},{"id":584863549,"identity":"877ab555-a7fa-492b-8109-3340131ee2ae","order_by":1,"name":"Esma Kaya Özdemir","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA40lEQVRIiWNgGAWjYBACCTiLvQFIGFiQooXnAEiLBE6VWLRIJKDycQLJ9jOGHz782SYvH/n86oYfBRIM/O3dCXi1SPPkGEvObLttuPF2TtnNHqDDJM6c3YBXixxDjoE0b8Ntxo2zc9Ju8AC1GEjkEtDC/8b4958/t+03zjyTdvMPMVqkJXLMpBnYbifOl2A/dpsoWyRnPCuz7G27nbyBJ4fttoyBBA9Bv0icT95848ef27bz248/u/nmj40cf3svfi0MDBwGYMrgAA+YwUNAOQiwPwBT8g1QxigYBaNgFIwCdAAAN8NLEwwslUMAAAAASUVORK5CYII=","orcid":"","institution":"Sivas Cumhuriyet University","correspondingAuthor":true,"prefix":"","firstName":"Esma","middleName":"Kaya","lastName":"Özdemir","suffix":""},{"id":584863550,"identity":"23293d94-6bda-49d0-a8ac-ffcfe1825fcd","order_by":2,"name":"Asım Gültekin","email":"","orcid":"","institution":"Sivas Cumhuriyet University","correspondingAuthor":false,"prefix":"","firstName":"Asım","middleName":"","lastName":"Gültekin","suffix":""}],"badges":[],"createdAt":"2026-01-14 09:23:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8599952/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8599952/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12887-026-06664-2","type":"published","date":"2026-02-27T15:58:29+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":103765951,"identity":"8c5ae522-94a9-4a01-abef-d36882cc7179","added_by":"auto","created_at":"2026-03-02 16:11:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":667928,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8599952/v1/12f0676d-3dea-4e98-aaf4-276eb627fdfb.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of MEFV Mutations on Inflammatory Activity and Long-Term Relapse in Pediatric IgA Vasculitis","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eIgA vasculitis (IgAV), formerly known as Henoch\u0026ndash;Sch\u0026ouml;nlein purpura (HSP), is the most common systemic small-vessel vasculitis in childhood. It is characterized by IgA-mediated immune complex deposition in small vessels, leading to non-thrombocytopenic palpable purpura, arthritis/arthralgia, abdominal pain, gastrointestinal bleeding, and renal involvement (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Although the clinical course is often self-limited, disease severity varies, and renal involvement or relapse may contribute to prolonged corticosteroid exposure, repeated healthcare utilization, and long-term morbidity. Reported relapse rates differ substantially across pediatric IgAV cohorts, and predictors of recurrent or persistent disease activity remain insufficiently defined.\u003c/p\u003e \u003cp\u003eThe MEFV (Mediterranean Fever) gene, located on chromosome 16p13.3, encodes pyrin, a cytosolic protein that regulates innate immunity by modulating inflammasome assembly and interleukin-1β (IL-1β) secretion (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Variants in MEFV may disrupt pyrin function, resulting in dysregulated inflammasome activity and amplified inflammatory responses.\u003c/p\u003e \u003cp\u003eBeyond Familial Mediterranean Fever (FMF), increased frequencies of MEFV variants have been described in several inflammatory and vasculitic disorders, including IgAV, inflammatory bowel disease, polyarteritis nodosa, and juvenile idiopathic arthritis (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). These observations have raised the hypothesis that MEFV mutations may act as genetic modifiers, influencing inflammatory pathways and clinical expression in immune-mediated diseases (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). In pediatric IgAV, MEFV mutations have been linked to heightened inflammation, but their impact on disease phenotype and long-term outcomes remains insufficiently understood (\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite accumulating evidence on prevalence and acute clinical features, data regarding long-term outcomes such as relapse or persistent renal involvement remain limited. Determining whether MEFV variants influence chronic disease behavior is clinically relevant, particularly in populations with a high frequency of MEFV variants. Based on this rationale, we hypothesized that MEFV variants may contribute to inflammatory burden and disease trajectory in pediatric IgAV. The present study aimed to determine the frequency of MEFV mutations in children with IgAV and to evaluate their association with inflammatory markers, clinical features, and long-term outcomes, including relapse.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Patients\u003c/h2\u003e \u003cp\u003e This retrospective observational study included 62 pediatric patients diagnosed with IgA vasculitis (IgAV, formerly Henoch\u0026ndash;Sch\u0026ouml;nlein purpura) who were evaluated and followed at a tertiary care university hospital in Turkey between January 2005 and April 2012. The diagnosis of IgAV was established according to the American College of Rheumatology (ACR) classification criteria. Inclusion criteria were: (i) age\u0026thinsp;\u0026lt;\u0026thinsp;18 years at diagnosis, (ii) fulfillment of ACR criteria for IgAV, and (iii) availability of complete clinical and laboratory data at presentation. Exclusion criteria were: (i) prior diagnosis of Familial Mediterranean Fever (FMF) or other chronic autoinflammatory or rheumatologic diseases, (ii) chronic kidney disease, and (iii) insufficient medical records.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData Collection\u003c/h3\u003e\n\u003cp\u003eDemographic characteristics (age and sex), presenting symptoms, and systemic involvement were obtained from institutional medical records. Clinical manifestations and laboratory findings were extracted from admission and follow-up documentation. Laboratory evaluations included white blood cell count, hemoglobin concentration, platelet count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), total protein, serum albumin, renal function tests, urinalysis, and fecal occult blood testing. Clinical symptoms, complications, and treatment modalities (nonsteroidal anti-inflammatory drugs, corticosteroids, colchicine, intravenous fluids, and hospitalization) during follow-up were additionally recorded.\u003c/p\u003e\n\u003ch3\u003eDefinition of Relapse and Follow-Up Strategy\u003c/h3\u003e\n\u003cp\u003eRelapse was defined as the reappearance of palpable purpura and/or systemic manifestations (gastrointestinal or joint involvement) after at least four weeks of complete clinical remission. Long-term follow-up data were obtained through outpatient visits and telephone interviews when necessary. All patients were followed for a minimum of six months, and long-term outcome analyses included those with at least 12 months of available follow-up data. Renal outcomes assessed during follow-up included persistent hematuria, persistent proteinuria, hypertension, and progression to chronic kidney disease.\u003c/p\u003e\n\u003ch3\u003eMEFV Gene Analysis\u003c/h3\u003e\n\u003cp\u003eMEFV genetic analysis was performed after written informed consent was obtained from legal guardians. Peripheral blood samples were collected for genomic DNA extraction. The most frequently reported pathogenic and likely pathogenic MEFV variants were analyzed using multiplex polymerase chain reaction (PCR) followed by reverse hybridization targeting E148Q, P369S, F479L, M680I (G/C), M694V, V726A, K695R, and K761H. Agarose gel electrophoresis (2%) was performed to verify amplification, followed by hybridization on nitrocellulose membranes for mutation detection according to the manufacturer\u0026rsquo;s guidelines. This panel detects the most common MEFV hotspot variants but does not cover rare variants outside these regions. Patients were categorized into two groups based on the presence or absence of MEFV mutations, and comparative analyses were performed accordingly.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using SPSS for Windows (version 21.0; SPSS Inc., Chicago, IL, USA). The Kolmogorov\u0026ndash;Smirnov test was used to assess the normality of data distribution. Continuous variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) for normally distributed data or median with interquartile range (IQR) for non-normally distributed data. Normally distributed variables were compared using the independent samples t-test, while non-normally distributed variables were compared using the Mann\u0026ndash;Whitney U test. Categorical variables were analyzed using Pearson\u0026rsquo;s Chi-square test or Fisher\u0026rsquo;s exact test, as appropriate. Variables with a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.10 in univariable analyses were included in a multivariable logistic regression model to identify independent predictors of relapse, with results reported as odds ratios (ORs) and 95% confidence intervals (CIs). A two-tailed p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Given the limited number of relapse events (n\u0026thinsp;=\u0026thinsp;8), a parsimonious multivariable logistic regression model was constructed including only two variables\u0026mdash;MEFV mutation status (positive vs. negative) and ESR (per 1 mm/h increase)\u0026mdash;to minimize the risk of overfitting.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003e \u003cb\u003eI. Study Population\u003c/b\u003e \u003c/p\u003e \u003cp\u003eA total of 62 pediatric patients diagnosed with IgA vasculitis (IgAV) were enrolled. The cohort included 39 males (62.9%) and 23 females (37.1%), with a mean age of 8.56\u0026thinsp;\u0026plusmn;\u0026thinsp;3.21 years (range: 1\u0026ndash;15). All patients presented with palpable purpura. No central nervous system, pulmonary, or cardiac involvement was observed.\u003c/p\u003e \u003cp\u003eArticular, gastrointestinal, renal, urogenital, and subcutaneous edema involvement occurred in 48 (77.4%), 33 (53.2%), 14 (22.6%), 7 (11.3%), and 8 (12.9%) patients, respectively. Occult blood in stool was identified in 13 patients (21%), all of whom displayed gastrointestinal symptoms.\u003c/p\u003e \u003cp\u003eRenal involvement based on laboratory findings was present in 14 patients (22.6%). Proteinuria was detected in 9 (14.5%) and hematuria in 13 (21%). Of these 14 patients, isolated hematuria was observed in 8 (57.1%), hematuria with proteinuria in 4 (28.6%), and nephrotic-range proteinuria in 2 (14.3%). Serum creatinine remained within normal limits in all cases.\u003c/p\u003e \u003cp\u003e \u003cb\u003eII. MEFV Mutation Status\u003c/b\u003e \u003c/p\u003e \u003cp\u003eMEFV gene mutations were identified in 24 patients (38.7%), while 38 (61.3%) carried no detectable mutation. The most common variant was p.Met694Val (M694V), observed in 11 patients (17.7%), including 7 heterozygous, 1 homozygous, and 3 compound heterozygous carriers. The distribution of MEFV variants is presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDistribution of MEFV Gene Variants in 62 Children with IgAV\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMutation Type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeterozygous p.Glu148Gln (E148Q)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeterozygous p.Met694Val (M694V)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeterozygous p.Val726Ala (V726A)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeterozygous p.Met680Ile (M680I)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeterozygous p.Glu148Gln\u0026thinsp;+\u0026thinsp;p.Met694Val\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeterozygous p.Glu148Gln\u0026thinsp;+\u0026thinsp;p.Val726Ala\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeterozygous p.Met680Ile\u0026thinsp;+\u0026thinsp;p.Met694Val\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeterozygous p.Val726Ala\u0026thinsp;+\u0026thinsp;p.Met680Ile\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHomozygous p.Met694Val (M694V)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo mutation detected\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \n\u003cp\u003e\u003cb\u003eII. Laboratory Findings\u003c/b\u003e\u003c/p\u003e\n\u003cp\u003eThe mean serum CRP level was 23.7\u0026thinsp;\u0026plusmn;\u0026thinsp;18.4 mg/L and the mean ESR was 38.2\u0026thinsp;\u0026plusmn;\u0026thinsp;21.6 mm/h. Leukocytosis and thrombocytosis were observed in 18 (29.0%) and 14 (22.6%) patients, respectively. The median leukocyte count was 11,800/mm\u0026sup3; (IQR: 9,300\u0026ndash;14,500). Serum creatinine levels were within normal limits in all patients.\u003c/p\u003e \u003cp\u003eWhen stratified according to MEFV mutation status, patients carrying MEFV variants demonstrated significantly higher ESR (p\u0026thinsp;=\u0026thinsp;0.003) and CRP (p\u0026thinsp;=\u0026thinsp;0.004) levels and significantly lower serum albumin levels (p\u0026thinsp;=\u0026thinsp;0.009) compared to mutation-negative patients. No statistically significant differences were observed in leukocyte count, platelet count, hemoglobin, or total protein levels between groups. Laboratory parameters according to mutation status are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLaboratory Parameters According to MEFV Mutation Status\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMutation Absent (n\u0026thinsp;=\u0026thinsp;38) Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMutation Present (n\u0026thinsp;=\u0026thinsp;24) Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC (\u0026times;10\u0026sup3;/mm\u0026sup3;) \u003cem\u003e(NR: 4.5\u0026ndash;13.5)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e11.67\u0026thinsp;\u0026plusmn;\u0026thinsp;4.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.34\u0026thinsp;\u0026plusmn;\u0026thinsp;3.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin (g/dL) \u003cem\u003e(NR: 11.5\u0026ndash;15.5)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e13.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.86\u0026thinsp;\u0026plusmn;\u0026thinsp;1.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelets (\u0026times;10\u0026sup3;/mm\u0026sup3;) \u003cem\u003e(NR: 150\u0026ndash;450)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e385.23\u0026thinsp;\u0026plusmn;\u0026thinsp;117.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e380.12\u0026thinsp;\u0026plusmn;\u0026thinsp;81.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESR (mm/h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e19.97\u0026thinsp;\u0026plusmn;\u0026thinsp;11.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e37.95\u0026thinsp;\u0026plusmn;\u0026thinsp;25.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal Protein (g/dL) \u003cem\u003e(NR: 6.4\u0026ndash;8.3)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e7.22\u0026thinsp;\u0026plusmn;\u0026thinsp;0.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e7.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumin (g/dL) \u003cem\u003e(NR: 3.5\u0026ndash;5.2)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e4.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e3.62\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.009\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cb\u003eNR\u003c/b\u003e: Normal reference range\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cb\u003eTest\u003c/b\u003e: Independent samples t-test\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCRP Levels According to MEFV Mutation Status\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMutation Status\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMin (mg/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMax (mg/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMedian (mg/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbsent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e78.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.004\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e246.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e20.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cb\u003eTest\u003c/b\u003e: Mann\u0026ndash;Whitney U test\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e\u003cb\u003eIV. Clinical Outcomes and Follow-up\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA total of 27 patients (43.5%) required hospitalization, with a median hospital stay of 5 days (IQR: 3\u0026ndash;7). The most frequent reasons for admission were gastrointestinal involvement (n\u0026thinsp;=\u0026thinsp;18), renal involvement (n\u0026thinsp;=\u0026thinsp;6), and pain management (n\u0026thinsp;=\u0026thinsp;3).\u003c/p\u003e \u003cp\u003eSystemic corticosteroids were administered to 19 patients (30.6%), NSAIDs to 41 (66.1%), colchicine to 2 (3.2%), and intravenous fluids to 7 (11.3%).\u003c/p\u003e \u003cp\u003eComparison of clinical manifestations revealed no significant differences between mutation-positive and mutation-negative groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSystemic Involvement According to MEFV Mutation Status\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystemic Involvement\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMutation Absent n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMutation Present n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTotal n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJoint\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29 (76.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19 (79.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e48 (77.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7 (18.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (29.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14 (22.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastrointestinal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14 (58.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e33 (53.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubcutaneous Edema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5 (13.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8 (12.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrogenital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4 (10.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7 (11.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eDuring long-term follow-up (67.4\u0026thinsp;\u0026plusmn;\u0026thinsp;18.2 months), complete outcome data were available for 57 of 62 patients (91.9%).\u003c/p\u003e \u003cp\u003eSevere complications occurred exclusively in MEFV mutation\u0026ndash;positive patients. One heterozygous M694V carrier developed hemolytic uremic syndrome, and two patients (including one homozygous M694V carrier) required colchicine therapy. These findings suggest that certain MEFV variants may predispose to more severe disease manifestations.\u003c/p\u003e \u003cp\u003eRelapse was documented in 6 of 22 mutation-positive patients (27.3%) and in 2 of 35 mutation-negative patients (5.7%), representing a significant difference between groups (Fisher\u0026rsquo;s exact, p\u0026thinsp;=\u0026thinsp;0.028), as shown in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. Relapses were predominantly observed among patients carrying M694V-containing genotypes, as summarized in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e, supporting the hypothesis that MEFV variants may modify the chronicity of IgAV.\u003c/p\u003e \u003cp\u003eIn a parsimonious multivariable logistic regression model including MEFV mutation status and ESR, both variables remained independently associated with relapse (MEFV mutation positivity: OR 3.12, 95% CI 1.08\u0026ndash;9.04, p\u0026thinsp;=\u0026thinsp;0.036; ESR: OR 1.04 per 1 mm/h increase, 95% CI 1.01\u0026ndash;1.07, p\u0026thinsp;=\u0026thinsp;0.020), suggesting that genetic predisposition and inflammatory burden jointly modify long-term disease behavior.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRelapse According to MEFV Mutation Status (Long-Term Follow-up)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMutation (+)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMutation (\u0026minus;)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFollowed patients (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelapse (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (27.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (5.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (14.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo relapse (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (72.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (94.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e49 (86.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStatistical test\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFisher\u0026rsquo;s exact\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003ep\u0026thinsp;=\u0026thinsp;0.028\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGenotype-Specific Relapse Patterns\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGenotype\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRelapse n (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeterozygous M694V\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (28.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHomozygous M694V\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eE148Q\u0026thinsp;+\u0026thinsp;M694V\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eM680I\u0026thinsp;+\u0026thinsp;M694V\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther genotypes*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMutation-negative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (5.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eNotes:\u003c/h3\u003e\n\u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e\u0026ldquo;Other genotypes\u0026rdquo; include E148Q, V726A, M680I without M694V involvement.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eValues based on patients with available long-term follow-up data (n\u0026thinsp;=\u0026thinsp;57).\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this pediatric cohort of immunoglobulin A vasculitis (IgAV; formerly Henoch\u0026ndash;Sch\u0026ouml;nlein purpura), we examined the prevalence of MEFV gene mutations and their potential associations with inflammatory parameters and long-term clinical outcomes. IgAV represents the most common systemic small-vessel vasculitis of childhood, typically characterized by palpable purpura, arthralgia/arthritis, abdominal pain, and renal involvement (\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Although many patients follow a self-limited course, a subset experience recurrent or prolonged disease activity, and predictors of long-term outcomes remain insufficiently defined (\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). To date, studies specifically addressing long-term disease trajectories in MEFV-associated IgAV are limited, leaving an important knowledge gap that the present work sought to address (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMEFV mutations were identified in 38.7% of patients in our cohort. This frequency is higher than those reported in some published reference populations and aligns with previous pediatric IgAV studies describing an overrepresentation of MEFV variants (\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Pyrin, the protein encoded by MEFV, regulates innate immune signaling and inflammasome assembly through IL-1β-mediated pathways (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Functionally relevant MEFV variants can enhance inflammasome activation and cytokine release, providing a biologically plausible basis for modified inflammatory responses (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eConsistent with this mechanistic framework, MEFV-positive patients demonstrated significantly higher ESR and CRP levels and significantly lower serum albumin levels compared with mutation-negative patients. These findings align with prior studies reporting elevated acute-phase reactants and a more pronounced inflammatory milieu among MEFV mutation carriers (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Collectively, this supports the hypothesis that MEFV variation may augment systemic inflammatory burden in IgAV.\u003c/p\u003e \u003cp\u003eBeyond inflammatory markers, clinically significant complications were observed exclusively among MEFV-positive patients. These included hemolytic uremic syndrome and colchicine-responsive gastrointestinal symptoms, reflecting atypical or refractory disease patterns not typically associated with classical IgAV (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Although anecdotal, such findings are consistent with emerging reports describing modified disease trajectories in patients carrying MEFV mutations (36). Given that pyrin-inflammasome activation and IL-1β signaling represent targetable pathways, these observations may hold implications for individualized monitoring or early therapeutic consideration in selected cases (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRelapse represented another clinically relevant outcome in our cohort. Relapse occurred significantly more frequently in MEFV-positive patients than in those without mutations, and in multivariable modeling both MEFV positivity and elevated ESR were independently associated with recurrent disease. These findings suggest that genetic predisposition and inflammatory burden jointly influence long-term disease behavior. Relapse contributes to cumulative morbidity, prolonged corticosteroid exposure, and increased healthcare utilization, and several cohort studies have emphasized its clinical impact in childhood IgAV (\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e).In line with our observations, prior reports have linked higher inflammatory and immunologic markers with more severe systemic and renal involvement and, in some studies, with an increased risk of relapse or persistent disease activity. Recent pediatric cohorts and systematic reviews have highlighted the prognostic value of inflammatory indices (such as neutrophil-to-lymphocyte ratio, D-dimer, serum albumin, and immunoglobulin levels) for nephritis and adverse outcomes in IgAV (31,32).\u003c/p\u003e \u003cp\u003eTaken together, our data extend this literature by suggesting that MEFV variation may interact with systemic inflammation to shape the chronicity of IgAV.\u003c/p\u003e \u003cp\u003eThis study has limitations that warrant consideration. The retrospective design and single-center nature may affect generalizability, and the MEFV testing panel did not encompass all rare variants or other autoinflammatory genes. Additionally, the number of relapse events was modest, and the lack of environmental and genetic co-factor assessment limits mechanistic interpretation. These findings should therefore be viewed as hypothesis-generating and supportive of the need for larger, prospective, and genomically integrated studies to better delineate gene\u0026ndash;inflammation interactions in pediatric IgAV.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn conclusion, MEFV mutations were common in this pediatric IgAV cohort and were associated with a heightened inflammatory profile, clinically significant complications, and increased relapse risk, despite comparable systemic involvement at presentation. These findings suggest that MEFV mutation status may carry prognostic relevance and could support risk stratification in pediatric IgAV. Larger studies are needed to validate these observations and to determine whether genetically informed monitoring or targeted anti-inflammatory approaches may improve long-term outcomes in affected children.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthor Contributions\u003c/p\u003e\n\u003cp\u003eGO and AG designed the study; GO and EKO collected the data; GO performed the statistical analyses; GO, EKO and AG interpreted the data; GO and AG drafted the manuscript; and GO, EKO, and AG critically revised the manuscript for important intellectual content. All authors have read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Scientific Research Projects Coordination Unit of Cumhuriyet University (C\u0026Uuml;BAP) under project number T-526.\u003c/p\u003e\n\u003cp\u003eEthics Approval and Consent to Participate\u003c/p\u003e\n\u003cp\u003eAll procedures involving human participants were conducted in accordance with institutional and national research committee standards and with the 1975 Helsinki Declaration and its later amendments. The study protocol was approved by the Clinical Research Ethics Board of Cumhuriyet University (Approval date/number: 17.01.2012/39). Written informed consent for participation was obtained from all participants or their legal guardians, in accordance with national regulations and institutional requirements.\u003c/p\u003e\n\u003cp\u003eConsent to Publication\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eData Availability Statement\u003c/p\u003e\n\u003cp\u003eThe data supporting the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003eConflict of Interest\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003eAcknowledgment\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eClinical Trial Number\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLeung AKC, Barankin B, Leong KF. Henoch-Sch\u0026ouml;nlein purpura in children: an updated review. 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Front Pediatr. 2023;11:1164099. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fped.2023.1164099\u003c/span\u003e\u003cspan address=\"10.3389/fped.2023.1164099\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"IgA vasculitis, Henoch–Schönlein purpura, MEFV, Familial Mediterranean Fever, pediatric vasculitis, relapse, inflammation","lastPublishedDoi":"10.21203/rs.3.rs-8599952/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8599952/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eIgA vasculitis (IgAV), formerly Henoch\u0026ndash;Sch\u0026ouml;nlein purpura, is the most common systemic vasculitis of childhood. MEFV mutations have been linked to enhanced inflammatory responses and vasculitis, although their impact on long-term outcomes remains unclear.\u003c/p\u003e\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eTo determine the prevalence of MEFV mutations in children with IgAV and to evaluate their associations with clinical features, inflammatory markers, and long-term outcomes, including relapse.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this retrospective cohort, 62 children diagnosed with IgAV were screened for eight common MEFV mutations and classified according to mutation status. Demographic, clinical, laboratory, and outcome variables were compared between groups. Long-term follow-up data were used to assess relapse and renal outcomes.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eMEFV mutations were detected in 24/62 patients (38.7%). Mutation-positive patients had higher ESR and CRP levels and lower serum albumin levels (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 for all). Long-term follow-up data were available in 57/62 patients. Relapse occurred more frequently in mutation-positive than mutation-negative patients (27.3% vs. 5.7%; p\u0026thinsp;=\u0026thinsp;0.028). In multivariate analysis, MEFV mutation positivity and elevated ESR were independent predictors of relapse.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eMEFV mutations were common in children with IgAV and were associated with higher inflammatory activity and increased relapse risk, despite similar systemic involvement at presentation. In settings with a high prevalence of MEFV variants, mutation status may contribute to clinical risk stratification. Larger studies are needed to clarify its prognostic value.\u003c/p\u003e","manuscriptTitle":"Impact of MEFV Mutations on Inflammatory Activity and Long-Term Relapse in Pediatric IgA Vasculitis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-03 15:06:37","doi":"10.21203/rs.3.rs-8599952/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-10T04:54:18+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-09T11:36:17+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-07T12:51:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"39851920420857201400075037816547490243","date":"2026-02-04T23:47:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"247692959350372815639965114107169210314","date":"2026-02-04T17:57:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"218511031567620221413215316439713588485","date":"2026-02-04T15:15:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"234526912263257800540687432246359410282","date":"2026-02-04T13:09:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"39780417366208970712639248441829227992","date":"2026-02-04T09:23:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"245107857307658076934484781668965929301","date":"2026-02-03T08:05:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"219250687650828177570246101099189786300","date":"2026-02-02T14:42:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"163371880070539824454840478715745010003","date":"2026-02-02T09:35:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"269681130610967538935971666290948732614","date":"2026-02-02T09:23:39+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-02T08:50:41+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-19T06:24:26+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-16T11:32:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-16T11:27:12+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2026-01-14T09:12:41+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ecf0b917-c189-4128-9ac0-4f642c41cbc4","owner":[],"postedDate":"February 3rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-02T16:08:04+00:00","versionOfRecord":{"articleIdentity":"rs-8599952","link":"https://doi.org/10.1186/s12887-026-06664-2","journal":{"identity":"bmc-pediatrics","isVorOnly":false,"title":"BMC Pediatrics"},"publishedOn":"2026-02-27 15:58:29","publishedOnDateReadable":"February 27th, 2026"},"versionCreatedAt":"2026-02-03 15:06:37","video":"","vorDoi":"10.1186/s12887-026-06664-2","vorDoiUrl":"https://doi.org/10.1186/s12887-026-06664-2","workflowStages":[]},"version":"v1","identity":"rs-8599952","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8599952","identity":"rs-8599952","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}