Measuring persistent somatic symptom related stigmatisation: Development of the Persistent Somatic Symptom Stigma scale for Healthcare Professionals (PSSS-HCP).

OBJECTIVE: Persistent somatic symptoms (PSS) describe recurrent or continuously occurring symptoms such as fatigue, dizziness, or pain that have persisted for at least several months. These include single symptoms such as chronic pain, combinations of symptoms, or functional disorders such as fibromyalgia or irritable bowel syndrome. While stigmatisation by healthcare professionals is regularly reported, there are limited measurement instruments demonstrating content validity. This study develops a new instrument to measure stigmatisation by healthcare professionals, the Persistent Somatic Symptom Stigma scale for Healthcare Professionals (PSSS-HCP). METHODS: Development was an iterative process consisting of research team review, item generation and cognitive interviewing. We generated a longlist of 60 items from previous reviews and qualitative research. We conducted 18 cognitive interviews with healthcare professionals in the United Kingdom (UK). We analysed the relevance, comprehensibility and comprehensiveness of items, including the potential for social desirability bias. RESULTS: After research team consensus and initial feedback, we retained 40 items for cognitive interviewing. After our first round of interviews (n = 11), we removed 20 items, added three items and amended five items. After our second round of interviews (n = 7), we removed four items and amended three items. No major problems with relevance, comprehensibility, comprehensiveness or social desirability were found in remaining items. CONCLUSIONS: The provisional version of the PSSS-HCP contains 19 items across three domains (stereotypes, prejudice, discrimination), demonstrating sufficient content validity. Our next step will be to perform a validation study to finalise item selection and explore the structure of the PSSS-HCP.

Symptom profiles and their risk factors in patients with post-COVID-19 condition: a Dutch longitudinal cohort study.

BACKGROUND: To improve research and care for patients with post-COVID-19 condition more insight into different subtypes of post-COVID-19 condition and their risk factors is urgently needed. We aimed to identify risk factors of post-COVID-19 condition in general and for specific symptom profiles. METHODS: This study is based on data collected within the Lifelines Coronavirus disease 2019 (COVID-19) cohort (N = 76 503). Mean pre- and post-SARS-CoV-2 infection symptom scores were compared to classify post-COVID-19 condition. Latent Profile Analysis was used to identify symptom profiles. Logistic and multinomial regression analyses were used to examine the association between demographic, lifestyle and health-related risk factors and post-COVID-19 condition, and symptom profiles, respectively. RESULTS: Of the 3465 participants having had COVID-19, 18.5% (n = 642) classified for post-COVID-19 condition. Four symptom profiles were identified: muscle pain, fatigue, cardiorespiratory and ageusia/anosmia. Female sex was a risk factor for the muscle pain and fatigue profiles. Being overweight or obese increased risk for all profiles, except the fatigue profile. Having a chronic disease increased the risk for all profiles except the ageusia/anosmia profile, with the cardiorespiratory profile being only significant in case of multimorbidity. Being unvaccinated increased risk of the ageusia/anosmia profile. CONCLUSIONS: Findings from this study suggest that Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may trigger different pathophysiological mechanisms that may result in different subtypes of post-COVID-19 condition. These subtypes have shared and unique risk factors. Further characterization of symptom profiles and quantification of the individual and societal impact of specific symptom profiles are pressing challenges for future research.

Discordance between Adolescents and Parents in Functional Somatic Symptom Reports: Sex Differences and Future Symptom Prevalence.

Functional somatic symptoms, i.e., physical complaints that cannot be sufficiently explained by an objectifiable biomedical abnormality, become increasingly more prevalent in girls than in boys during adolescence. Both parents and adolescents report more functional somatic symptoms in girls, but their reports correspond only limitedly. It remains unknown whether parent-adolescent discordance contributes to the higher symptom prevalence in girls. This study investigated parent-adolescent discordance in reported functional somatic symptoms throughout adolescence, examined the longitudinal association of parent-adolescent discordance with symptom prevalence in early adulthood and focused on sex differences in these processes. Participants included 2229 adolescents (50.7% female) from four assessments (age 11 to 22 years) of the TRAILS population cohort. Parents and adolescents reported significantly more symptoms in girls than in boys during adolescence. Variance analyses showed that throughout adolescence, parents reported fewer symptoms than girls self-reported and more than boys self-reported. Regression analyses using standardized difference scores showed that lower parent-report than self-report was positively associated with symptom prevalence in early adulthood. Polynomial regression analyses revealed no significant interaction between parent-reported and adolescent self-reported symptoms. Associations did not differ between boys and girls. The findings show that lower parent-reported than self-reported symptoms predict future symptom prevalence in both sexes, but this discordance was more observed in girls. The higher functional somatic symptom prevalence in girls might be partly explained by parental underestimation of symptoms.

How to Ensure Inclusivity in Large-Scale General Population Cohort Studies? Lessons Learned with Regard to Including and Assessing Sex, Gender, and Sexual Orientation.

Despite recent advances in the measurement of sex, gender, and sexual orientation in large-scale cohort studies, the three concepts are still gaining relatively little attention, may be mistakenly equated, or non-informatively operationalized. The resulting imprecise or lacking information hereon in studies is problematic, as sex, gender, and sexual orientation are important health-related factors. Omission of these concepts from general population cohort studies might dismiss participants' identity and experiences and pushes research on sexual or gender minority populations toward purposive sampling, potentially introducing selection bias. It also reinforces the unintentional notion of irrelevance of these concepts to health research, ultimately disadvantaging sexual and gender minority populations. Similarly, a lack of uniform measures on sex, gender, and sexual orientation hampers multi-cohort studies in which data from multiple studies are combined, facilitating increased statistical power. This paper discusses the encountered pitfalls and lessons learned on including and assessing sex, gender, and sexual orientation in large-scale general population cohort studies, exemplified by the Dutch Lifelines Cohort Study. Additionally, we propose hands-on strategies on how to operationalize these concepts in an inclusive manner that is useful for large-scale general population cohort studies.

Sex and gender differences in primary care help-seeking for common somatic symptoms: a longitudinal study.

OBJECTIVE: Women are reported to consult general practitioners (GPs) more frequently than men. However, previous studies on sex differences in help-seeking behavior for somatic symptoms do not distinguish between sex and gender, do not account for sex differences in presented symptoms, and are frequently conducted in clinical settings, automatically excluding non-help seekers. Therefore, we aim to assess the independent associations of sex and gender with primary care help-seeking for somatic symptoms in the general population. DESIGN AND SETTING: Records from the longitudinal population-based Lifelines Cohort Study were linked to routine electronic health records from GPs. SUBJECTS: Participants reporting new-onset common somatic symptoms. MAIN OUTCOME MEASURES: Associations between sex and gender, operationalized via a novel gender-index, with primary care help-seeking for somatic symptoms and differences in the strength of the association between gender and help-seeking for somatic symptoms between women and men. RESULTS: Of 20,187 individuals with linked data, 8325 participants (67.5% female; mean age = 44.5 years [SD = 12.9]) reported at least one new-onset somatic symptom. Hereof, 255 (3.1%) consulted the GP within 6 weeks of symptom onset. Female sex was positively associated with consulting the GP (OR = 1.78; 95%CI = 1.13-2.80), whereas feminine gender was not (OR = 0.67; 95%CI = 0.39-1.16). The latter association did not differ in strength between men and women. More paid working days are negatively associated with help-seeking (OR = 0.95; 95%CI = 0.91-0.98). CONCLUSIONS: The results suggest that female sex rather than feminine gender is associated with primary care help-seeking behavior for somatic symptoms. Nevertheless, clinicians should be aware that gender-related variables, such as mean paid working days, may be associated with help-seeking behavior.

Persistent somatic symptom related stigmatisation by healthcare professionals: A systematic review of questionnaire measurement instruments.

OBJECTIVE: Patients with persistent somatic symptoms (PSS) experience stigmatising attitudes and behaviours by healthcare professionals. While previous research has focussed on individual manifestations of PSS related stigma, less is known about sound ways to measure stigmatisation by healthcare professionals towards patients with PSS. This review aims to assess the quality of questionnaire measurement instruments and make recommendations about their use. METHODS: A systematic review using six databases (PubMed, Embase, CINAHL, PsycINFO, Open Grey and EThOS). The search strategy combined three search strings related to healthcare professionals, PSS and stigma. Additional publications were identified by searching bibliographies. Three authors independently extracted the data. Data analysis and synthesis followed COSMIN methodology for reviews of outcome measurement instruments. RESULTS: We identified 90 publications that met the inclusion criteria using 62 questionnaire measurement instruments. Stereotypes were explored in 92% of instruments, prejudices in 52% of instruments, and discrimination in 19% of instruments. The development process of the instruments was not rated higher than doubtful. Construct validity, structural validity, internal consistency and reliability were the most commonly investigated measurement properties. Evidence around content validity was inconsistent or indeterminate. CONCLUSION: No instrument provided acceptable evidence on all measurement properties. Many instruments were developed for use within a single publication, with little evidence of their development or establishment of content validity. This is problematic because stigma instruments should reflect the challenges that healthcare professionals face when working with patients with PSS. They should also reflect the experiences that patients with PSS have widely reported during clinical encounters.

Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study.

BACKGROUND: Patients often report various symptoms after recovery from acute COVID-19. Previous studies on post-COVID-19 condition have not corrected for the prevalence and severity of these common symptoms before COVID-19 and in populations without SARS-CoV-2 infection. We aimed to analyse the nature, prevalence, and severity of long-term symptoms related to COVID-19, while correcting for symptoms present before SARS-CoV-2 infection and controlling for the symptom dynamics in the population without infection. METHODS: This study is based on data collected within Lifelines, a multidisciplinary, prospective, population-based, observational cohort study examining the health and health-related behaviours of people living in the north of the Netherlands. All Lifelines participants aged 18 years or older received invitations to digital COVID-19 questionnaires. Longitudinal dynamics of 23 somatic symptoms surrounding COVID-19 diagnoses (due to SARS-CoV-2 alpha [B.1.1.7] variant or previous variants) were assessed using 24 repeated measurements between March 31, 2020, and Aug 2, 2021. Participants with COVID-19 (a positive SARS-CoV-2 test or a physician's diagnosis of COVID-19) were matched by age, sex, and time to COVID-19-negative controls. We recorded symptom severity before and after COVID-19 in participants with COVID-19 and compared that with matched controls. FINDINGS: 76 422 participants (mean age 53·7 years [SD 12·9], 46 329 [60·8%] were female) completed a total of 883 973 questionnaires. Of these, 4231 (5·5%) participants had COVID-19 and were matched to 8462 controls. Persistent symptoms in COVID-19-positive participants at 90-150 days after COVID-19 compared with before COVID-19 and compared with matched controls included chest pain, difficulties with breathing, pain when breathing, painful muscles, ageusia or anosmia, tingling extremities, lump in throat, feeling hot and cold alternately, heavy arms or legs, and general tiredness. In 12·7% of patients, these symptoms could be attributed to COVID-19, as 381 (21·4%) of 1782 COVID-19-positive participants versus 361 (8·7%) of 4130 COVID-19-negative controls had at least one of these core symptoms substantially increased to at least moderate severity at 90-150 days after COVID-19 diagnosis or matched timepoint. INTERPRETATION: To our knowledge, this is the first study to report the nature and prevalence of post-COVID-19 condition, while correcting for individual symptoms present before COVID-19 and the symptom dynamics in the population without SARS-CoV-2 infection during the pandemic. Further research that distinguishes potential mechanisms driving post-COVID-19-related symptomatology is required. FUNDING: ZonMw; Dutch Ministry of Health, Welfare, and Sport; Dutch Ministry of Economic Affairs; University Medical Center Groningen, University of Groningen; Provinces of Drenthe, Friesland, and Groningen.

Differences Between Women and Men Are Present in the Rate of Diagnosed Diseases After a Diagnostic Intervention is Conducted in Primary Care.

BACKGROUND: Recently it was shown that the relative lack of diagnostic interventions conducted in women mediated the negative association between female sex and diagnosed disease. However, it remains unknown whether women and men receive disease diagnoses in an equal frequency after diagnostic interventions have been performed in general practice. METHODS: We used generalized linear mixed-effect models to assess the association between diagnostic interventions and disease diagnoses when patients presented with common somatic symptoms and studied whether the association differed between female and male patients. RESULTS: In 34,268 episodes of care (61.4% female) physical examinations and specialist referrals were associated with more disease diagnoses (OR = 2.32; 95% CI = 2.17-2.49 and OR = 1.38; 95% CI = 1.27-1.49, respectively), whereas laboratory diagnostics were associated with fewer disease diagnoses (OR = 0.50; 95% CI = 0.47-0.54). Significant interaction terms showed that women presenting with back pain, tiredness, arm and/or leg symptoms and tingling extremities were provided with fewer disease diagnoses after diagnostic interventions were performed than men. We found no significant interaction term that indicated that men were provided with fewer disease diagnoses after a diagnostic intervention than women. CONCLUSION: Especially when patients present with the mentioned symptoms, general practitioners should be aware that diagnostic interventions yield fewer disease diagnoses in female patients than in men. Yet, performing fewer diagnostic interventions in women with these symptoms will further exacerbate sex differences in disease diagnoses.

Stigma perceived by patients with functional somatic syndromes and its effect on health outcomes - A systematic review.

BACKGROUND: Patients with functional somatic syndromes (FSS) experience stigma which arguably affects their health. AIM: To determine the presence of perceived stigma and its effects on physical and mental health in patients with FSS compared to patients with comparable explained conditions. METHODS: A comprehensive search of PubMed, Embase, PsycINFO, CINAHL and Cochrane Library was performed to select studies focusing on stigma perceived by patients with irritable bowel syndrome (IBS), fibromyalgia (FM) or chronic fatigue syndrome (CFS), comparing these patients to patients with comparable but explained conditions. RESULTS: We identified 1931 studies after duplicate removal. After screening we included eight studies: one study about all three FSS, one about IBS, five about FM and one about CFS. We found that patients with IBS did not consistently experience higher levels of stigma than those with a comparable explained condition. Patients with CFS and FM experienced higher levels of stigma compared to patients with comparable explained conditions. All studies showed a correlation between stigma and negative health outcomes. DISCUSSION: Patients with FSS experience stigma and negative health outcomes. However, experiencing stigma is not restricted to patients with FSS, as many patients with explained health conditions also experience stigma. Whether stigma has more negative health consequences in patients with FSS compared to patients with explained health conditions remains unclear and should be assessed in future research.

Female sex and femininity independently associate with common somatic symptom trajectories.

BACKGROUND: Multiple predictors have been associated with persistent somatic symptoms. However, previous studies problematically defined the persistence of symptoms, conflated participants' sex and gender, and focused on patient populations. Therefore, we studied associations between predictors, especially sex and gender, and longitudinal patterns of somatic symptoms in the general adult population. We also assessed whether predictors for persisting symptoms differ between sexes. METHOD: To identify developmental trajectories of somatic symptoms, assessed by the SCL-90 SOM, we used latent class trajectory modeling in the Dutch Lifelines Cohort Study [N = 150 494; 58.6% female; median time to follow-up: 46.0 (min-max: 22.0-123.0) months]. To identify predictors of trajectories, we applied multiple logistic regression analyses. Predictors were measured by surveys at baseline and a composite gender index was previously developed. RESULTS: A five-class linear LCGA model fitted the data best: 93.7% of the population had a stable symptom trajectory, whereas 1.5% and 4.8% of the population had a consistently increasing or decreasing symptom trajectory, respectively. Female sex predicted severe, stable symptom severity (OR 1.74, 95% CI 1.36-2.22), but not increasing symptom severity (OR 1.15, 95% CI 0.99-1.40). Femininity was protective hereof (OR 0.60, 95% CI 0.44-0.82 and OR 0.66, 95% CI 0.51-0.85, respectively). Merely a few predictors of symptom severity, for instance hours of paid employment and physical functioning, differed in strength between sexes. Yet, effect sizes were small. CONCLUSION: Female sex and femininity predict symptom trajectories. No large sex differences in the strength of additional predictors were found, thus it may not be clinically useful to distinguish between predictors specific to male or female patients of persistent somatic symptoms.

Sex and Gender-Related Differences in COVID-19 Diagnoses and SARS-CoV-2 Testing Practices During the First Wave of the Pandemic: The Dutch Lifelines COVID-19 Cohort Study.

Background: Although sex differences are described in Coronavirus Disease 2019 (COVID-19) diagnoses and testing, many studies neglect possible gender-related influences. Additionally, research is often performed in clinical populations, while most COVID-19 patients are not hospitalized. Therefore, we investigated associations between sex and gender-related variables, and COVID-19 diagnoses and testing practices in a large general population cohort during the first wave of the pandemic when testing capacity was limited. Methods: We used data from the Lifelines COVID-19 Cohort (N = 74,722; 60.8% female). We applied bivariate and multiple logistic regression analyses. The outcomes were a COVID-19 diagnosis (confirmed by SARS-CoV-2 PCR testing or physician's clinical diagnosis) and PCR testing. Independent variables included among others participants' sex, age, somatic comorbidities, occupation, and smoking status. Sex-by-comorbidity and sex-by-occupation interaction terms were included to investigate sex differences in associations between the presence of comorbidities or an occupation with COVID-19 diagnoses or testing practices. Results: In bivariate analyses female sex was significantly associated with COVID-19 diagnoses and testing, but significance did not persist in multiple logistic regression analyses. However, a gender-related variable, being a health care worker, was significantly associated with COVID-19 diagnoses (OR = 1.68; 95%CI = 1.30-2.17) and testing (OR = 12.5; 95%CI = 8.55-18.3). Female health care workers were less often diagnosed and tested than male health care workers (ORinteraction = 0.54; 95%CI = 0.32-0.92, ORinteraction = 0.53; 95%CI = 0.29-0.97, respectively). Conclusions: We found no sex differences in COVID-19 diagnoses and testing in the general population. Among health care workers, a male preponderance in COVID-19 diagnoses and testing was observed. This could be explained by more pronounced COVID-19 symptoms in males or by gender inequities.

Sex differences in the trajectories to diagnosis of patients presenting with common somatic symptoms in primary care: an observational cohort study.

OBJECTIVE: Little insight exists into sex differences in diagnostic trajectories for common somatic symptoms. This study aims to quantify sex differences in the provided primary care diagnostic interventions for common somatic symptoms, as well as the consequences hereof for final diagnoses. METHODS: In this observational cohort study, we used real-world clinical data from the Dutch Family Medicine Network (N = 34,268 episodes of care related to common somatic symptoms; 61,4% female). The association between patients' sex on the one hand, and diagnostic interventions and disease diagnoses on the other hand, were assessed using multilevel multiple logistic regression analyses. Structural equation modelling was used to estimate a mediation model with multiple parallel mediators to assess whether the fewer disease diagnoses given to female patients were mediated by the fewer diagnostic interventions female patients receive, compared to male patients. RESULTS: Women received fewer physical examinations (OR = 0.84, 95%CI = 0.79-0.89), diagnostic imaging (OR = 0.92, 95%CI = 0.84-0.99) and specialist referrals (OR = 0.85, 95%CI = 0.79-0.91) than men, but more laboratory diagnostics (OR = 1.27, 95%CI = 1.19-1.35). Women received disease diagnoses less often than men for their common somatic symptoms (OR = 0.94, 95%CI = 0.89-0.98). Mediation analysis showed that the fewer disease diagnosis in female patients were mediated by the fewer diagnostic interventions conducted in women compared to men. CONCLUSION: This study shows that sex inequalities are present in primary care diagnostic trajectories of patients with common somatic symptoms and that these lead to unequal health outcomes in terms of diagnoses between women and men. FPs have to be aware of these inequalities to ensure equal high-quality care for all patients.

The association of sex, age and FKBP5 genotype with common somatic symptoms: A replication study in the lifelines cohort study.

OBJECTIVE: Our aim was to replicate a recent study that reported an association between the rs9470080 CC-genotype and common somatic symptoms in women, but not in men. Additionally, we quantified the genetic contribution to phenotypic variation in common somatic symptom levels. METHODS: We used data from the Lifelines Cohort Study, including 28,299 participants (60.0% female; 44.2% CC-genotype; mean age 42.9 (14.2) years). Common somatic symptoms were measured with the SCL-90 SOM subscale. To assess the association between the rs9470080 genotype and SCL-90 SOM scores we applied similar analyses as the original study, including independent t-tests, two-way ANOVAs and a mixed ANOVA. To estimate the proportion of phenotypic variance in SCL-90 SOM scores explained by single nucleotide polymorphisms (SNPs), we used a genomic-relatedness-based restricted maximum-likelihood method. RESULTS: We could not replicate the original study's findings. We found no association between the rs9470080 genotype and common somatic symptom levels in either female or male participants (F(1, 8775) = 1.07, p = 0.30 and F(1,13,903) = 0.01, p = 0.93, respectively). Genome-wide heritability analyses show that 12.1% (p = 2.1e-08) of the phenotypic variance in common somatic symptom levels in Lifelines can be explained by SNPs. The genetic contribution to common somatic symptom levels was higher in male participants (SNP-h2 = 20.5%; p = 9.1e-08) than in female participants (SNP-h2 = 12.0%, p = 2.8e-05). CONCLUSION: Our findings of significant SNP-h2 and the sex-specific differences herein, does warrant further sex-stratified research of individual genetic variants associated with common somatic symptoms. Preferably, further research should be performed within the analytic framework of a genome-wide association study.

Sex differences in incidence of respiratory symptoms and management by general practitioners.

BACKGROUND: Differences between women and men play an important role in lung physiology and epidemiology of respiratory diseases, but also in the health care processes. OBJECTIVE: To analyse sex differences in patients encountering their general practitioner (GP) with respiratory symptoms with regard to incidence, GP's management and final diagnoses. METHODS: Retrospective cohort study, using data of the Dutch Practice Based Research Network. All patients who encountered their GP from 01-07-2013 until 30-06-2018 with a new episode of care starting with a reason for encounter in the respiratory category (R) of the ICPC-2 classification were included (n = 16 773). Multi-level logistic regression was used to analyse influence of patients' sex on management of GPs with adjustment for possible confounders. RESULTS: We found a significant higher incidence of respiratory symptoms in women than in men: 230/1000 patient years [95% confidence interval (CI) 227-232] and 186/1000 patient years (95% CI 183-189), respectively. When presenting with cough, GPs are more likely to perform physical examination [odds ratio (OR) 1.22; 95% CI 1.11-1.35] and diagnostic radiology (OR 1.25; 95% CI 1.08-1.44), but less likely to prescribe medication (OR 0.88; 95% CI 0.82-0.95) in men. When visiting the GP with dyspnoea, men more often undergo diagnostic imaging (OR 1.32; 95% CI 1.05-1.66) and are more often referred to a specialist (OR 1.35; 95% CI 1.13-1.62). CONCLUSIONS: Women encounter their GP more frequently with respiratory symptoms than men and GPs perform more diagnostic investigations in men. We suggest more research in general practice focussing on sex differences and possible confounders.

Gender and sex independently associate with common somatic symptoms and lifetime prevalence of chronic disease.

Sex and gender influence health differently. Associations between sex and health have been extensively studied, but gender (i.e. psychosocial sex) has been largely neglected, partly due to the absence of gender measures in cohort studies. Therefore, our objective was to test the unique associations of gender and sex with common somatic symptoms and chronic diseases, using a gender index created from existing cohort data. We applied LASSO logistic regression to identify, out of 153 unique variables, psychosocial variables that were predictive of sex (i.e. gender-related) in the Dutch LifeLines Cohort Study. These psychosocial variables covered gender roles and institutionalized gender. Using the estimated coefficients, gender indexes were calculated for each adult participant in the study (n = 152,728; 58.5% female; mean age 44.6 (13.1) years). We applied multiple ordinal and logistic regression to test the unique associations of the gender index and sex, and their interactions, with common somatic symptoms assessed by the SCL-90 SOM and self-reported lifetime prevalence of chronic diseases, respectively. We found that in 10.1% of the participants the gender index was not in line with participants' sex: 12.5% of men and 8.4% of women showed a discrepancy between gender index and sex. Feminine gender characteristics are associated with increased common somatic symptoms and chronic diseases, especially in men. Female sex is associated with a higher common somatic symptom burden, but not with a higher prevalence of chronic diseases. The study shows that gender and sex uniquely impact health, and should be considered in epidemiological studies. Our methodology shows that consideration of gender measures in studies is necessary and feasible, based on data generally present in cohort studies.

New insights in the pathogenesis of immunoglobulin A vasculitis (Henoch-Schönlein purpura).

Immunoglobulin A vasculitis (IgAV), also referred to as Henoch-Schönlein purpura, is the most common form of childhood vasculitis. The pathogenesis of IgAV is still largely unknown. The disease is characterized by IgA1-immune deposits, complement factors and neutrophil infiltration, which is accompanied with vascular inflammation. Incidence of IgAV is twice as high during fall and winter, suggesting an environmental trigger associated to climate. Symptoms can resolve without intervention, but some patients develop glomerulonephritis with features similar to IgA nephropathy that include hematuria, proteinuria and IgA deposition in the glomerulus. Ultimately, this can lead to end-stage renal disease. In IgA nephropathy immune complexes containing galactose-deficient (Gd-)IgA1 are found and thought to play a role in pathogenesis. Although Gd-IgA1 complexes are also present in patients with IgAV with nephritis, their role in IgAV is disputed. Alternatively, it has been proposed that in IgAV IgA1 antibodies are generated against endothelial cells. We anticipate that such IgA complexes can activate neutrophils via the IgA Fc receptor FcαRI (CD89), thereby inducing neutrophil migration and activation, which ultimately causes tissue damage in IgAV. In this Review, we discuss the putative role of IgA, IgA receptors, neutrophils and other factors such as infections, genetics and the complement system in the pathogenesis of IgA vasculitis.