Recurrent immunoglobulin A vasculitis in children and adolescents: prevalence and associated risk factors
Article information
Abstract
Background
Immunoglobulin A vasculitis (IgAV) is a systemic vasculitis characterized by potential recurrence.
Purpose
This study aimed to explore the prevalence of and factors associated with IgAV recurrence. The clinical phenotypes of childhood- and adolescent-onset IgAV were described and compared.
Methods
This retrospective cohort analysis included patients aged ≤18 years and diagnosed with IgAV treated in a tertiary academic center between January 2010 and December 2022. Recurrence was classified by the reappearance of purpuric/petechiae or other features that reappeared after at least 1 asymptomatic month.
Results
The 361 patients with IgAV had a mean age of 7.7±3.9 years; 53.2% of them were female. All patients with IgAV exhibited skin manifestations. Gastrointestinal (GI) and musculoskeletal (MSK) features were observed in 214 (59.3%) and 219 patients (60.7%), respectively. Renal involvement was observed in 82 patients (22.7%). The prevalence of childhood- and adolescent-onset IgAV was 269 (74.5%) and 92 (25.5%), respectively. Patients with childhood-onset IgAV had significant GI manifestations (P=0.01), had MSK features (P=0.002), and required hospitalization (P=0.004). In contrast, patients with adolescent-onset IgAV had significant renal involvement (P<0.001) and required a longer duration of corticosteroids treatment (P<0.001). Of the study population, 119 patients (35.6%) experienced recurrence. During the 12-month follow-up period, 98 patients (27.1%) had recurrent IgAV at a median 1.9 months (interquartile range, 1.2–4.8 months). On the multivariable Cox proportional hazards regression analysis, corticosteroids treatment was significantly associated with IgAV recurrence (hazard ratio, 1.99; 95% confidence interval, 1.266–3.157; P=0.003).
Conclusion
Renal involvement was more prevalent in adolescent-onset IgAV, whereas MSK and GI involvement were more common in childhood-onset IgAV. Recurrence was noted in 35.6% of the population. Therefore, vigilant monitoring for recurrence is necessary.
Key message
Question: What can predict immunoglobulin A vasculitis (IgAV) recurrence, and when does it occur? How do childhood- and adolescent-onset IgAV compare?
Finding: The IgAV recurrence rate was 35.6%. It usually occurred within 12 months and was associated with corticosteroids treatment.
Meaning: Childhood-onset IgAV more commonly featured gastrointestinal and musculoskeletal manifestations and required hospitalization. Adolescent-onset IgAV more commonly featured renal involvement. Vigilant monitoring for recurrence is necessary, particularly with corticosteroids treatment.
Graphical abstract. IgAV, immunoglobulin A vasculitis.
Introduction
Immunoglobulin A vasculitis (IgAV), formerly known as Henoch-Schönlein purpura, is a predominantly small vessel vasculitis characterized by IgA1-dominant deposition. Clinical phenotypes consist of purpuric/petechial or nonblanchable rash with musculoskeletal (MSK) involvement, gastrointestinal (GI) or renal involvement [1,2]. Other features include scrotal involvement, subcutaneous edema, pulmonary hemorrhage, or central nervous system involvement. IgAV is the most common systemic vasculitis in children with an estimated incidence of 29.9 per 100,000 children [3] and usually occurs between 4 to 6 years of age [4,5]. The prevalence of IgAV in adults is lower, with phenotypes and outcomes different from those of children [6,7].
The outcome of IgAV in children is generally benign. In most patients, IgAV resolve in a month. In the short term, massive GI bleeding/perforation and intussusception are major hazardous complications of IgAV [4,8,9]. Chronic kidney disease (CKD) is the main long-term consequence secondary to IgAV with nephritis [4,10]. Therefore, periodic following clinical features, blood pressure, and urinalysis are essential for early diagnosis and prompt treatment of the recurrence of IgAV [11,12].
Recurrence of IgAV has been reported to vary from 4.6% to 35% [4,5,9,13-18]. Predictors of recurrent IgAV comprised of older age, persistent purpura, bowel ischemia, renal involvement, coexisting allergic rhinitis, the combination of rash, MSK, GI and renal involvements, leukocytosis and prolonged corticosteroids treatment [13,16,17,19,20]. Importantly, recurrent episodes of IgAV may lead to a prolonged course of disease treatment, and an increased risk of complications. More understanding of the prevalence of recurrent IgAV and associated factors can assist clinicians predict the course and plan the treatment. Proactive monitoring in patients at risk of recurrence can also lead to early treatment and may reduce complications. Our primary objectives were to explore the prevalence and factors associated with recurrent IgAV. The time to develop recurrent IgAV was also analyzed. Secondary objectives were to describe clinical phenotypes and compare them between childhood-onset IgAV and adolescent-onset IgAV.
Methods
1. Study design and setting
This was a retrospective cohort study conducted at the Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, in Bangkok, Thailand. Our center is the largest tertiary academic referral center in the region. All data from diagnosis to follow up were retrieved from January 2010 to December 2022 via an electronic medical record using the International Classification of Diseases, Tenth Revision code D69.0. The research protocol for this study obtained ethical approval from the Siriraj Institutional Review Board (COA) number Si 537/2023, in accordance with the Declaration of Helsinki. Because this study was retrospective, the requirement for informed consent and assent was waived.
2. Participants
Participants in this study were patients ≤18 years of age diagnosed with IgAV according to EULAR/PRINTO/PReS classification criteria [21]; the presence of purpura and at least one of the following 4 symptoms: abdominal pain, arthritis or arthralgia, leukocytoclastic vasculitis with predominant IgA deposits/proliferative glomerulonephritis with predominant IgA deposits in histopathology, or renal involvement. The age cut-point for childhood-onset at <10 years and adolescent-onset at 10–19 years was defined in accordance with the definition for adolescence by the World Health Organization [22].
3. Data collection
Demographic and clinical phenotypes included sex, age at diagnosis, family history of IgAV, preceding infection within 1 month, weight, height, duration of the disease. Clinical features; skin, MSK, GI, renal, scrotal, pulmonary, and central nervous system were collected. Laboratory results included complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), urinalysis, antinuclear antibody, complement and stool occult blood were recorded. Imaging studies were obtained comprising abdominal ultrasound and computed tomography if performed. Histopathological results were obtained if performed. Renal biopsy was performed in patients with glomerular filtration rate (GFR) <90 mL/min/1.73m2, nephrotic-range proteinuria (UPCR >2 mg/mg), or persistent subnephrotic-range proteinuria >2–4 weeks [23,24]. Treatment of nonsteroidal anti-inflammatory drugs, acetaminophen, corticosteroids, intravenous immunoglobulin, colchicine, dapsone, azathioprine, cyclophosphamide, mycophenolate mofetil, biologics, and enalapril were gathered. Corticosteroids are indicated for patients with severe abdominal pain, GI bleeding, orchitis, hemorrhagic bullae, severe organ- or life-threatening vasculitis, and moderate to severe IgAV nephritis. Prednisolone is administered at 1–2 mg/kg/day for 1–2 weeks, followed by tapering over 4–6 weeks based on clinical response. Other disease-modifying antirheumatic drugs, including mycophenolate mofetil, azathioprine, calcineurin inhibitor or cyclophosphamide, may be used for refractory disease or inability to wean from corticosteroids. The pediatric vasculitis activity score (PVAS) was evaluated to determine disease severity [25].
Our protocol for the follow-up patient with IgAV encompassed clinical features, weight, height, vital signs including blood pressure measurement and urinalysis as follows; every 2 weeks during the first month of the disease, then monthly for 5 months, then every 2 months thereafter for 6 months, then every 3 months twice, every 6 months once and then yearly. Our protocol is comparable to the recommendations endorsed by international associations [11,12,23].
4. Outcome measurement
The recurrence of IgAV was classified by the reappearance of purpuric/petechiae rash [11,26] or other features that reappeared after a period of at least one month without symptoms. Proteinuria was defined as spot UPCR >0.2 mg/mg. Hematuria was classified as red blood cell >5/high-power field. Hypertension was defined if blood pressure >95th percentile according to age and sex. The GFR was calculated using a modified Schwartz formula [27]. CKD was defined as GFR<60 m L/min/1.73 m2 for >3 months [28]. IgAV with nephritis was classified according to the international study of kidney disease in children [29].
5. Statistical analysis
All statistical analyzes were performed with IBM SPSS Statistics ver. 20.0 (IBM Co., USA). Descriptive statistics were used for analysis. Categorical data were reported as frequencies with percentages. Continuous data were presented as either mean±standard deviations for normally distributed data or median with interquartile range (IQR) for nonnormally distributed data. Comparison of differences in clinical characteristics and investigation findings between childhood-onset IgAV and adolescent-onset IgAV were analyzed using an independent samples t test (for normally distributed data) and Mann-Whitney U test (for nonnormally distributed data) for continuous variables, while categorical variables underwent via the chi-square test and Fisher exact test. The time from diagnosis to recurrent IgAV was analyzed using Kaplan-Meier survival analysis. The data was censored if there was no recurrence or if the subject was lost to follow-up. Factors associated with recurrent IgAV were assessed using Cox proportional hazards regression analysis. Variables with P value <0.2 from the univariable analysis were entered into the multivariable Cox proportional hazards regression analysis. The PVAS was also entered into the multivariable Cox proportional hazards regression analysis to adjust for potential confounder of disease severity. Predictors were reported as the hazard ratio (HR) and the 95% confidence interval (CI). Variables with a P value less than 0.05 were considered statistically significant.
Results
1. Clinical phenotypes
There were 361 patients with IgAV included in this study; 192 females (53.2%) and 169 males (46.8%) with a mean age of 7.7±3.9 years. The median duration of follow-up (IQR) from diagnosis was 16.5 (2.4–58.3) months. Ninety-five patients (26.3%) had preceding infection prior to IgAV diagnosis.
All IgAV patients had skin manifestation; 277 patients (76.7%) developed palpable purpura, 27 patients (7.5%) developed petechiae, and 152 patients (42.1%) had nonblanchable rash. Subcutaneous edema and hemorrhagic bullae were found in 9 (2.5%) and 7 patients (1.9%), respectively. GI involvement was found in 214 patients (59.3%) with abdominal pain being the most common manifestation at 189 (52.4%). GI bleeding occurred in 62 (17.2%). No intussusception or bowel perforation was detected in our cohort. MSK features were reported in 219 patients (60.7%). Arthritis and arthralgia were observed in 103 (28.5%) and 116 patients (32.1%), respectively. Oligoarticular involvement of the lower extremities was the most common joint distribution. Orchitis was observed in 12 patients (3.3%). Renal involvement was observed in 82 patients (22.7%). Fifty-five patients (15.2%) underwent a renal biopsy. Half of patients required hospitalization at the time of IgAV diagnosis (184 patients, 51%). Corticosteroids was prescribed in 228 patients (63.2%) and 11 patients also received pulsed intravenous methylprednisolone. The median duration of corticosteroids was 51 days (25.5–120 days).
2. Childhood-onset IgAV and adolescent-onset IgAV
The prevalence of childhood-onset (<10 years) IgAV and adolescent-onset IgAV (10–19 years) was 269 (74.5%) and 92 (25.5%), respectively. Childhood-onset IgAV had significant GI manifestation (P=0.010), MSK features (P=0.002), and required hospitalization (P=0.004). In contrast, those with adolescent-onset IgAV had significantly renal involvement (P<0.001) and required longer duration of corticosteroids treatment (P<0.001). The clinical features of all patients and the clinical features compared between childhood-onset IgAV and adolescent-onset IgAV are shown in Table 1.
Comparative analysis of patients with childhood- versus adolescent-onset IgA vasculitis (N=361)
3. Recurrence of IgAV and outcomes
Twenty-seven patients were lost to follow-up after the initial visit and 334 patients were analyzed for the recurrence of IgAV. There were 119 patients (35.6%) with recurrent IgAV. The clinical features compared between patients with recurrent IgAV and nonrecurrent IgAV are demonstrated in Table 2. Univariable Cox proportional hazards regression analysis found that preceding infection, ESR >20 mm/hr and corticosteroids treatment were associated with the recurrence of IgAV (all P<0.2). However, based on the multivariable Cox proportional hazards regression analysis, the significant factor associated with the recurrence of IgAV was corticosteroids treatment (HR, 1.99; 95% CI, 1.266–3.157; P=0.003). The factors associated with the recurrence of IgAV are shown in Table 3. Subgroup analysis of factors associated with the recurrence of IgAV in patients with GI involvement or renal involvement are shown in the Supplementary Table 1. The overall time from IgAV diagnosis to the time of recurrence of IgAV is shown in Fig. 1. The time of recurrence of IgAV between patients with renal and without renal involvement was not statistically different (Fig. 2). There were significant differences in the time of recurrence of IgAV between those with and without corticosteroids treatment (P<0.001) (Fig. 3). There were 98 patients (27.1%) with recurrent IgAV during 12-month follow-up at a median time of 1.9 months (IQR, 1.2–4.8 months). The outcomes and complications of patients with IgAV are described in Table 4. The majority (345, 95.6%) went into complete remission. CKD >stage 2 was observed in 8 patients (2.2%). There were 4 patients who received dialysis; 2 with hemodialysis and 2 with continuous ambulatory peritoneal dialysis. None received kidney transplantation. There were no significantly different outcomes between childhood-onset IgAV and adolescent-onset IgAV (P>0.05). Two patients were subsequently diagnosed with systemic lupus erythematosus. One patient with IgAV with end-stage renal disease died of intracranial hemorrhage secondary to a hypertensive crisis.
Comparative analysis of patients with recurrent versus nonrecurrent immunoglobulin A vasculitis (N=334)
Factors associated with IgAV recurrence
Kaplan-Meier curve demonstrating time to recurrence of immunoglobulin A vasculitis.
Kaplan-Meier analysis of time to recurrence in patients with and without renal involvement in immunoglobulin A vasculitis.
Kaplan-Meier analysis of time to recurrence in patients treated with corticosteroids versus those not treated with corticosteroids in immunoglobulin A vasculitis.
Outcomes of immunoglobulin A vasculitis (N=361)
Discussion
Recurrence of IgAV was observed in 35.6% of our cohort. Treatment with corticosteroids was associated with the recurrence of IgAV. Disparity in phenotypes was found between childhood-onset IgAV and adolescent-onset IgAV in that renal involvement is more prevalent in adolescents, while MSK and GI involvement with hospitalization were more common in younger children. CKD occurred in 2.2%.
Recurrence of IgAV is a significant concern, as this can increase the risk of complications and require a longer treatment time. Our study observed a 35.6% recurrence of IgAV. Marro et al. [18] described a recurrence rate of approximately 30% in a small series of pediatric patients with IgAV; all of them returned with purpuric rash and MSK complaints. Calvo-Rio et al. [30] similarly reported a recurrence rate of IgAV at 32% at the median time of 1 month following diagnosis. Recurrent IgAV was lower at 16.4% in one study [20]; however, a recurrent episode in that study was defined by a 3-month symptom-free interval, which may have resulted in a lower prevalence. Only 9.5% of the study by Liao et al. [15] had recurrent IgAV in which they defined the recurrence as a disease flare-up following complete remission without medications for at least 3 months. The varying prevalence of recurrence of IgAV was shown to be secondary to different definitions of recurrence used in each study. Therefore, standardized definitions of recurrence must consistently be used for homogeneity classification [11,26]. In our study, the recurrent IgAV was classified by the reappearance of the rash or other clinical features of IgAV that reappeared following a period of at least one month free symptoms. This could reflect not only true disease flare-ups but also relapsing symptoms during corticosteroids tapering.
Several clinical phenotypes have been reported as a predictor of the recurrence of IgAV. The combination of all 4 systems that involve rash, MSK, GI, and renal involvement may serve as a predictor of recurrent IgAV [13]. GI and MSK involvement were predictors of IgAV recurrence [30]. Recurrent IgAV was associated with severe renal involvement in another study [5]. Nephritis was reported to be up to 46% in one study with an increased risk of nephritis in those with recurrent IgAV [31]. In addition, older age at the time of disease onset was related to recurrent IgAV [4,15]. Delayed diagnosis and treatment were reported in a series of recurrent and persistent IgAV [18]. Our results did not find specific clinical phenotypes as predictors of recurrent IgAV. We hypothesize that the recurrent IgAV may be mediated by immune dysfunction or genetic factors rather than initial clinical phenotypes. However, corticosteroids treatment was associated with recurrent IgAV. Our finding was in line with the previous study by Lei et al. [20], which found that long-term corticosteroids treatment was associated with recurrent IgAV regardless of the time of initiation. This could be possibly explained by that patients requiring corticosteroids treatment had the tendency of harboring more severe features and could potentially have disease occurrence during the clinical course. Thus, for clinical implications, careful follow-up of recurring symptoms of IgAV in patients receiving corticosteroids treatment is necessary.
Interestingly, the disparity of clinical features between childhood-onset IgAV and adolescent-onset IgAV was illustrated in our study. We found that childhood-onset IgAV had more GI manifestation, MSK involvement, and required hospitalization, while adolescent-onset IgAV had more renal involvement which required longer duration of corticosteroids treatment. Specifically, our study documented an overall renal involvement of 22.7%; childhood-onset IgAV with nephritis (18.2%), and adolescent-onset IgAV (35.9%). Renal involvement was documented in about 30% in other series [4,5,15]. Female aged >10 years old with elevated CRP were risk factors for renal involvement in IgAV [32]. IgAV with nephritis was identified in 32.4% in the study by Chatpaitoon et al. [33] and age >10 years was one of the risk factors for renal involvement. Similar findings of increased renal involvement with increased age were also demonstrated in another study [15]. Renal involvement was less apparent in IgAV patients with GI according to the study by Aziz et al. [34] Possible explanations for this age-dependent disparity include differences in immune maturation and pubertal immunoendocrine changes. Serum IgA levels increase with age, reaching adult levels during adolescence [35], potentially contributing to more pronounced IgA deposition in the kidneys. Additionally, hormonal changes during puberty may enhance immune and inflammatory responses [36], contributing to greater renal involvement in adolescents with IgAV. In contrast, severe GI involvement was higher in patients with biopsy-proven IgAV with nephritis [4]. In general, these findings reflect different phenotypes across ages in IgAV, which may result in a different prognosis and monitoring.
Our study has limitations and results should be interpreted with caution. Data were retrospectively retrieved from electronic medical records from a single academic tertiary center. Referral bias should be addressed as our center is the largest academic referral center and results may not be generalized to the general population. As we only analyzed the time of first recurrence, the outcomes of the following recurrent episodes were not taken into account. To our knowledge, our study illustrated the prevalence of recurrent IgAV using the standard follow-up protocol and provided details of differences in clinical features and outcomes between childhood-onset IgAV and adolescent-onset IgAV.
To summarize, we observed a discrepancy of clinical features across ages. The prevalence of renal involvement increased with age. The recurrence rate of IgAV illustrated was 35.6% and occurred mostly within 12 months. Corticosteroids treatment was associated with recurrent IgAV. Therefore, vigilant monitoring for recurrent disease is necessary, in particular for those receiving corticosteroids treatment. More studies regarding the outcome of multiple recurrences should be explored. Prospective study with long-term follow-up in multiple centers is justified. Our study provides insight into the recurrence of IgAV and the disparity of phenotypes in childhood-onset and adolescent-onset IgAV.
Supplementary Materials
Supplementary Table 1-2 are available at https://doi.org/10.3345/cep.2025.01158.
Factors associated with recurrence of IgAV in patients with gastrointestinal involvement (n=214)
Factors associated with recurrence of IgAV in patients with renal involvement (n=82)
Notes
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Funding
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Acknowledgments
The authors extend their sincere appreciation to Ms. Julaporn Pooliam, MSc (Statistics), for her invaluable support with the statistical analyses and Ms. Nara Amie Indrambarya for her assistance with the graphics. The authors gratefully acknowledge the professional English editing by Mr. James Mark Simmerman.
Author Contributions
Conceptualization: NA, MS, TC, SC; Formal Analysis: NA, MS, TC, SC; Investigation: NA, MS, TC, SC; Methodology: NA, MS, TC, SC; Project Administration: SC; Writing – Original Draft: NA, SC; Writing – Review & Editing: NA, MS, TC, SC