WHAT IS ALREADY KNOWN ON THIS TOPIC

IgA vasculitis is a small vessel vasculitis and the most frequently seen subtype in children.

Chronic kidney disease is a serious consequence of IgA vasculitis and active screening is required following diagnosis.

There is variation in the management of this condition related to a lack of evidence.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

A unified approach to enable equity of care for children and young people with IgA vasculitis.

Nationally accredited guidance that can act as a framework for audit and evidence generation to improve future outcomes of this condition.

Introduction

IgA vasculitis is a rare disease, however it is the most frequently experienced subtype of vasculitis in children with an estimated annual incidence of 6.8 to 30 per 100 000 childhood population.1 2 Adult-onset disease is ultrarare with an estimated incidence of 0.8–1.8 per 100 000 adult population.3 It is classified as a small-vessel vasculitis characterised by IgA1-dominant immune deposits in the vasculature and affected tissues. The condition typically presents as a purpuric, symmetrical, non-blanching rash, predominating on the extensor surfaces of the lower limbs.4 5 It is associated mainly with skin involvement together with any of gastrointestinal, musculoskeletal and/or renal involvement (termed IgAV nephritis, IgAVN).6 Overall, the disease is self-limiting in most children, however short-term morbidity related to abdominal involvement is seen and recurrent episodes are reported.7 In the longer term chronic kidney disease (CKD) is a major consequence of this condition. The incidence of kidney failure in all children presenting with IgAV is consistently reported at 1%–2%,8 9 yet it is much higher at around 10% in adult-onset disease. In studies that capture children with biopsy-proven kidney disease, termed IgAV nephritis, the rates of CKD are much higher, especially in patients with poor prognostic features such as impaired baseline kidney function.10 Current treatment options for established nephritis rely on broad-spectrum immunosuppressive agents and randomised controlled trial data have shown that the prophylactic use of high-dose corticosteroids at disease onset in all patients does not reduce the risk of developing subsequent nephritis.11 12 A lack of a standardised approach to this disease promotes variability in patient care and is a barrier to improving outcomes. Furthermore, the rarity of the disease in the adult population means that extrapolation of evidence has not been feasible. In 2019, an international European-wide collaborative effort—called the Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative—provided a milestone in advancing this condition internationally.13

The aim of this project was to use a best available evidence, group agreement, based approach to create national recommendations for the initial management and associated complications of IgAV for children and young people in the United Kingdom.

Methods

The methodological approach used a multiprofessional working group, topic areas with priority questions, a predefined scope and evidence synthesis to develop graded recommendations for IgAV (outlined in figure 1).

Figure 1

A summary of the methodology used to generate recommendations for a rare disease using a best available evidence and group agreement-based approach.

Establishing a multiprofessional working group

A multiprofessional guideline development group (termed the IgAV GDG) was established via the Royal College of Paediatrics and Child Health (RCPCH) Research and Evidence team. Members were required to submit an expression of interest and declare any conflicts of interest. The methodology adhered to clinical guideline standards outlined by the RCPCH and the UK Kidney Association (National Institute of Clinical Excellence accredited) as a collaborative venture.

Developing the scope and key questions

The IgAV GDG defined the topic areas and key questions for the scope document (table 1). The scope included the population, setting, target audience, intended users and key clinical questions. The key questions provided a framework for the systematic literature review. The scope had a period of open consultation that included direct approach to multiple stakeholder groups (see online supplemental information). The IgAV GDG agreed to present the findings as two guidelines; one for the initial management of IgAV with the intended audience to be general practitioners and general paediatricians (termed guideline 1) and a second guideline for the management of complications associated with IgAV aimed for general paediatricians and paediatric subspecialists (termed guideline 2).

Table 1

Topic areas and key questions derived for the systematic review (taken from the UK Kidney Association99 ,100)

Evidence synthesis

A systematic literature review was performed with predefined criteria. Questions about interventions were framed in Patient, Intervention, Comparator, Outcome format. The population were children and young people (aged <18 years) with a confirmed diagnosis of IgAV. The intervention was a classification tool, monitoring or therapeuticmanagement. The comparison was any intervention compared with another. The outcome was related to the diagnosis, complications, duration or severity of symptoms. General concepts were used for the population (“pediatric”, “paediatric”, “child*”, “adolescen*”) and disease (“immunoglobulin A vasculitis”, “IgA vasculitis”, “IgAV”, “Henoch Schonlein purpura”, “HSP”). Concepts were combined using Boolean operators (AND, OR and NOT).14 Three bibliographic databases were searched; Medline (https://www.nlm.nih.gov/medline), Embase (https://www.embase.com) and Cochrane Central Register of Controlled Trials (https://www.cochranelibrary.com/central).15 The process was performed according to the Cochrane Handbook for Systematic reviews of interventions.15 The results were merged, and duplicates were removed. The articles were independently screened and for full-text review according to the eligibility criteria (table 2). Two members synthesised the literature and discussed areas of disagreement. Searching of reference lists was permitted. An evidence table and a narrative summary were produced.

Table 2

Eligibility criteria for the literature search

Generation and grading of recommendations

During the process of achieving group agreement, discussions took into account existing clinical practice and national or international guidelines were evidence was limited or lacking. The modified Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system was used to evaluate the strength of the recommendation, with grade 1 being a strong recommendation (depicted by ‘we recommend’), and grade 2 being a weaker recommendation (depicted by ‘we suggest’). The quality of evidence was graded A–D with grade A being high-quality evidence, grade B moderate-quality, grade C low-quality evidence from observational studies, or controlled trials with very serious limitations, grade D evidence was generally case studies or expert opinion. Studies were downgraded if there was evidence of bias, indirectness, imprecision or inconsistency of results and the strength of the recommendation could be adjusted taking into context of the balance of benefit or harms to patients. The final draft underwent a period of 4 weeks of open consultation prior to final endorsement.

ResultsA representative multiprofessional working group

The multiprofessional working group consisted of 28 members including two patient representatives, six general paediatric consultants, one general paediatric trainee, two paediatric surgeons, one paediatric pathologist, one radiologist, three adult nephrologists with expertise in vasculitis, one paediatric gastroenterology trainee, one paediatric emergency consultant, two general practitioners, one medical student, two paediatric rheumatologists, one paediatric gastroenterologist and four paediatric nephrologists. The IgAV GDG met monthly over a 14-month period.

Generation of the scope document and primary evidence

The scope document was distributed to stakeholders and open consultation and feedback was discussed in the monthly working group meeting on 21 January 2022. Following feedback, the GI key questions were united and placed into the complication’s guideline. The systematic literature search was completed on 11 March 2022 and 82 papers were identified. The screening process is illustrated in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram (figure 2) and studies were divided according to topic areas. The initial management guideline had 66 relevant papers of which, 55 related to classification, 16 to specialist referral, 28 to nephritis and 8 to musculoskeletal involvement. The associated complication guideline had 82 relevant papers of which 33 were relevant to established nephritis, 23 to gastrointestinal or urological involvement, 3 to skin, 8 to persisting disease, 34 to recurrent disease and 22 for long-term follow-up. There were no cases of disagreement for inclusion of the papers and 33 papers were helpful for background information however they were ultimately not used to directly inform a recommendation.16–48

Figure 2

A PRISMA diagram to illustrate the selection of literature for the IgAV recommendations. IgAV, IgA vasculitis; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Recommendations and brief rationale

This article provides a brief summary of the underpinning rationale to support the recommendations (tables 3 and 4). The guidelines are available on the UK Kidney Association website (https://ukkidney.org/renal-association/news/iga-vasculitis-guideline-rcpch-endorsed).

Table 3

The recommendations for the initial management of children and young people with IgA vasculitis (IgAV) as taken from The UK Kidney Association99

Table 4

The recommendations for the management of complications associated with IgA vasculitis (IgAV) in children and young people (taken from The UK Kidney Association100)

Initial managementDisease classification

European Alliance of Associations for Rheumatology (EULAR)/Paediatric Rheumatology INternational Trials Organisation (PRINTO)/Paediatric Rheumatology European Society (PRES) Classification criteria were agreed by the IgAV GDG to classify IgAV. This was based on a study published by Ozen et al 49 involving 860 children, demonstrating excellent sensitivity and specificity when used to distinguish it from other forms of vasculitis. It formed a strong recommendation and aligned with the SHARE consortium.13

Early specialist referral

No studies were identified that adequately addressed indications for specialist referral. Therefore, studies related to the need for hospital admission and/or treatment were used to generate discussion and create two recommendations. Severe organ involvement was felt to be so significant that if missed, there may be patient harm and assigned as a strong recommendation.

Nephritis screening

There were no studies directly comparing different clinical tests for the detection of nephritis. A total of 28 studies reported the use of clinical tests, including urinalysis (20/28 studies; 71%), a combination of urinalysis and other tests (7 studies; 25%) or renal function alone (1 study; 4%). In view of the lack of evidence, the group concluded that urinalysis was the minimal acceptable standard for nephritis screening incorporating existing clinical practice.

Treatment of musculoskeletal involvement

There were no specific studies found that robustly evaluated treatments for joint involvement. Five reports included analgesia, symptomatic support, hydration and bed rest. Prednisolone, given at a high dose over 4 weeks, was evaluated in a randomised controlled trial of 171 children where it reduced pain score and duration of pain, although the duration was not statistically significant.50 Due to the lack of long-term musculoskeletal morbidity related to this condition, the IgAV GDG agreed that the limited evidence did not justify the use of high-dose corticosteroids due to the side effect profile.

Management of complicationsIgAV nephritis

The clinical indications for conducting a kidney biopsy were adapted from the SHARE initiative as this was felt to be the strongest evidence available. The ISKDC classification criteria were used in 21 studies. Koskela et al specifically compared the ISKDC classification criteria with the modified semiquantitative score suggesting superiority in predicting renal outcomes.51 The IgAV GDG were aware that studies in this area were ongoing and agreed that the ISKDC criteria were the most widely accepted in the literature and clinical practice at the time of deriving the recommendations. This is likely to be a priority area for the future update. To determine treatment initiation, the histological classification grade alone was used by most studies (9/13; 69%). No studies made direct comparisons. A further two studies (2/13; 15%) used a combination of histological features and clinical features,52 which aligned with the European SHARE initiative recommendation.13 A combination of clinical and histological features was agreed to be most reflective of clinical practice.

Aligned with previous Cochrane reviews, no studies provided conclusive evidence of a preferred treatment option for biopsy-proven nephritis. Treatments alluding to benefit included corticosteroids,11 13 17 52–70 cyclophosphamide,11 13 52 53 55 56 59 60 62 65 68 70 71 azathioprine,11 13 53 55 56 64 68 70 ciclosporin A,11 52 58 63 72 mycophenolate mofetil,11 13 52 70 tacrolimus,52 67 intravenous immunoglobulin,54 69 urokinase,60–62 triptolide,66 low molecular-weight heparin,73 plasma exchange,62 74 warfarin,61 62 dipyridamole.61 62 65 The quality of studies was weak with heterogeneity and a short list of potential agents was developed.

The use of renin-angiotensin aldosterone system inhibition (RAASi) was reviewed in six low-quality studies.11 13 53 55–57 As RAASi is standard of care for children with proteinuria, this was a specific recommendation.

Gastrointestinal involvement

For severe GI involvement, 16 studies reported positive efficacy from corticosteroids.13 39 50 59 75–86 This included one placebo controlled randomised trial (n=171 participants) demonstrating a statistically significant reduction in the severity of abdominal pain within 2 weeks from diagnosis compared with placebo.50 A systematic review by Weiss et al found a statistically significant benefit from abdominal pain within 24 hours following the use of corticosteroids.87 Weiss et al and Zhao et al demonstrated a decreased risk of intussusception, abdominal surgery, endoscopy and imaging if corticosteroids were received within 72 hours.88 89 Due to short-term morbidity, the IgAV GDG concluded that on balance, the evidence was sufficient to consider the use of a short course of corticosteroids for severe abdominal pain and/or GI bleeding, once intussusception had been excluded. Specific investigations for GI bleeding were beyond the scope.

Intussusception management

There were 11 studies regarding intussusception management (10/23; 43%).59 76 78 79 84 87–91 Weiss et al 88 described the most common abdominal surgery, which was intra-abdominal small bowel manipulation.87 88 No studies compared interventions and the quality of the evidence was weak. Due to the high risk of complications, the IgAV GDG agreed on a strong recommendation to obtain specialist advice.

Testicular involvement

Reports on testicular involvement were limited with orchiditis, defined as painful, acute scrotal oedema associated with palpable purpuric lesions.79 Five small studies described treatment,13 75 79 81 85 including the effective use of corticosteroids (a total of 15 patients in three studies).79 81 85 The literature highlighted that surgical exploration may be required to exclude differential diagnoses.75 The group agreed that a short course of corticosteroids could be considered for this complication and this aligned with the European SHARE initiative.13

Atypical disease course

Three studies (3/83; 3.6%) included performing a skin biopsy in atypical disease and it forms part of the classification criteria, therefore it was recommended.

Persisting or recurrent disease

Eight studies (8/82; 9.8%) included a definition for persisting disease and agreed on skin lesions for >1 month and 34 provided a definition for recurrent IgAV with the majority (n=19/34; 56%) using rash reappearance after a 1-month symptom-free period.

Discussion

IgA vasculitis is a small vessel vasculitis characterised by IgA1-dominant immune deposits. Due to the recognised risk of kidney failure that is consistently reported at 1%–2% in children, and far greater at 2.9%–23.9% in the adult population, there is a major unmet need for evidence generation for this condition.6 97 The aim of this project was to use a best available evidence, group agreement, based approach to develop national recommendations for the initial management of IgAV and its associated complications in children and young people. Using accredited methodology and an inclusive, multiprofessional, representative working group, evidence was generated based on key topics. Recommendations for both the initial management, aimed at primary and secondary care colleagues, and the management of complications, aimed at secondary and tertiary care colleagues, for IgAV in children and young people have been established. These guidelines have been endorsed nationally and are available online.

The derived recommendations were developed from primary evidence, incorporating pooled expertise where evidence was lacking, and largely aligned with existing international consensus management such as that published by the SHARE initiative.13 Similarities to this previous work included the accepted classification criteria, screening for nephritis and broadly the management of gastrointestinal and musculoskeletal symptoms. Topic areas that required added detail or were new included when to consider a specialist referral, kidney biopsy indications and nephritis management, the use of RAASi and the definitions of recurrent or persisting disease.

Guidelines form an important component to guide equity of treatment for rare diseases across regions and facilitate standardisation as a pathway for clinical trials. While suitable targets for this disease may not yet be apparent as the underlying pathophysiology remains incompletely understood, the reported mechanisms leading to IgAV nephritis are strikingly similar to those described in IgA nephropathy with galactose-deficient IgA1 acting as a key antibody for immune complex formation, there therefore may be repurposing opportunities.98 These first national guidelines also include parameters for audit and highlight research priorities, including defining the rates of hypertension; the indications, timing and duration of corticosteroids for GI involvement; suitable GI outcome measures and GI biomarkers; management of persisting and/or recurrent disease; and predictors and treatments for biopsy-proven nephritis. This study does have limitations, which includes the significant lack of high-quality evidence to generate strong recommendations together with areas of actively evolving research that may be subjected to change in the near future, for example, the optimal method to score the kidney histology, and finally the national based approach when this disease has unmet need for children worldwide. However, this manuscript demonstrates a successful method to unite clinical approaches despite these recognised limitations in a disease with a severe paucity of evidence. Future updates will continue to incorporate emerging evidence and reflect changes in clinical management.

Conclusion

IgAV is a rare condition that predominates in children where there is huge unmet need in evidence-based management. These guidelines provide an important foundation to standardise management nationally, which should reduce variability in clinical care ensuring equity of access for all children. Indirectly it is also anticipated that they will be a catalyst to enhance the generation of evidence.

Data availability statement

No data are available.

Ethics statementsPatient consent for publication

Not applicable.

Ethics approval

Not applicable.

Acknowledgments

The team would like to acknowledge the support received by patient associations and parent representatives who are co-authors.