IgA vasculitis in children

Immunoglobulin A (IgA) vasculitis (IgAV), classically known as Henoch-Schönlein purpura, is a type of non-thrombocytopenic small-vessel vasculitis and is the most frequent form of childhood systemic vasculitis (annual incidence: 3-26.7 per 100,000, depending on the country)^1-3. IgAV is more frequent in childhood with a peak incidence around 4-6 years of age^2,4. The disease usually presents with a palpable purpuric rash, gastrointestinal pain and bleeding, kidney involvement, arthralgia and/or arthritis^1-4.Testicular inflammation (orchitis: 14% of male patients) is also seen, manifested by pain and swelling⁵.

IgAV has a seasonal variation, suggesting a role for environmental triggers and geographic distribution, and has a slight male predominance⁵. It occurs more frequently in certain parts of the world, such as Korea and Japan, but has equal distribution in all ethnicity grups⁵. The presentation in adults differs from that in children; adults rarely have abdominal pain and frequently have joint involvement⁵.

In 2013, the Revised Chapel Hill Consensus Conference defined IgAV at any age as a vasculitis with IgA-dominant immune deposits that affects small vessels, involving the skin, gut, and glomeruli, being associated with arthralgia or arthritis⁶. Kidney involvement is characterized by an IgA-dominant immune deposit indistinguishable from the pattern found in primary IgA nephropathy (IgAN). Criteria include a diagnosis of non-thrombocytopenic skin purpura with lower limb predominance as the main symptom and 1 of 4 additional criteria: 1) abdominal pain, 2) arthritis or joint pain, 3) kidney involvement (proteinuria >0.3 g/24h or a urine protein/creatinine ratio >30 mg/mmol on a spot morning sample or hematuria of >5 erythrocytes/high-power field), and 4) a leukocytoclastic vasculitis with predominant IgA deposits or kidney biopsy with predominant IgA deposits. Purpura with atypical distribution requires the presence of IgA deposits in the biopsy specimen⁷.

IgAV is considered a benign disease in children (around 94% of affected children achieve full and spontaneous recovery within two years), but its prognosis depends on the extent and the progression of kidney involvement¹. Overall, 40-50% of affected children have kidney involvement ranging from microscopic hematuria to rapidly progressive glomerulonephritis, contributing to 1-2% of all chronic kidney disease (CKD) stage 5.² In adults, the disease frequently occurs with atypical clinical features, severe kidney involvement, and with unfavorable outcome³. Recurrence (around 1/3 of patients) is more frequent in patients with kidney involvement and its duration is usually milder or shorter than the original episode⁴.

Genetics plays a role in determining the appearance of the disease and its severity, although there is no clear genetic correlation with primary IgAN^3,5. It is very likely that the complement system is involved in addition to the coagulation and fibrinolytic systems⁸. Activation of the complement system in an environment of endothelial cell damage could lead to thrombotic microangiopathy³.

Currently, the hypothesis of an abnormal immune response to various antigens in genetically susceptible individuals is accepted⁴. It has been suggested that the first hit in the development of vasculitis lesions may be due to the formation of antibodies directed against the endothelial cells. These antibodies might be elicited by mimicry between microorganisms and endothelial cells with cross reactive production of IgA anti-endothelial cells³. Non-infectious agents such as medications, vaccines, and malignancies are also reported as triggering agents⁴.

The study by Kara et al., published in the current issue of Braz. J. Nephrol., used stringent criteria to select participants⁹. The diagnosis of IgAV was defined according to criteria accepted by the European Rheumatism Association (EULAR)⁷. Renal biopsies were classified according to the International Study of Kidney Disease in Children (ISKDC). Clinical outcome was graded according to modified Meadow's criteria¹⁰. Blood samples were assessed for hemoglobin, leukocytes and lymphocytes, neutrophil/lymphocyte ratio (NLR), platelets, mean-platelet volume, immunoglobulin A levels, and C-reactive protein. The frequency of gastrointestinal, scrotal, and kidney manifestations was documented. Steroids were used as first-line treatment and cyclophosphamide or cyclosporin-A were used in refractory cases.

Most patients were under 10 years of age, predominantly male, with skin and gastrointestinal involvement, and had hematuria and proteinuria at onset. Kidney biopsies were classified mostly as grade II and III according to ISKDC. Most patients were grade B (minor urinary abnormalities) and grade A (normal), respectively, on short- and long-term outcomes. The authors divided the patients in two groups (group I: grade I - II and group II: grade III - IV) according to ISKDC criteria and age group (≤10yr and >10yr). There was no difference between the groups (p=0.744).

The authors found significant correlation between scrotal involvement and unfavorable outcome in seven patients (14.8%). Only neutrophil/lymphocyte ratio was found significantly higher in those with scrotal involvement, which may be attributed to disease severity and inflammation¹⁰. According to Buscatti et al., the scrotal involvement occurred in almost one fifth of IgAV patients, mostly as acute subtype¹¹.

Kidney dysfunction, proteinuria, hypertension, and crescentic nephritis at onset were significantly associated to unfavorable outcome³. Shi et al. in a meta analysis showed that older age at onset, lower glomerular filtration rate, initial renal features of nephrotic syndrome and nephritic-nephrotic syndrome, and renal biopsy with crescentic nephritis were predictive of poor prognosis in children with IgAV¹². Dyga and Szczepańska emphasize that most organ manifestations of IgAV are benign and self-limiting⁴. The study by Kara et al. report a significant correlation between hypertension and kidney impairment with unfavorable outcome⁹.

The recent European consensus (SHARE initiative) on diagnosis and treatment of IgAV provides a severity definition for IgAVN and recommends the prompt start of oral steroids (first-line) and IV pulses or immunosupression as second line treatment¹³. Mild IgAVN requires a more aggressive treatment with steroid pulses as first line treatment. ACE inhibitors are indicated as a supportive long-term therapy^3,13. Akbalik Kara et al. treated all patients with steroids⁹. Fifteen were treated with oral cyclophosphamide for 8-12 weeks and complete remission was achieved within 3 to 6 months after beginning cyclophosphamide or cyclosporine-A. No significant difference was found in the effects of the two drugs on short- and long-term results.

The study by Akbalik Kara et al. contributes to the knowledge of IgAV and may change clinical practice. The three main messages are: (a) scrotal involvement in pediatric patients with IgAV can be associated with unfavorable outcome, (b) Cy-A and cyclophosphamide may be effective in steroid unresponsive IgAV pediatric patients, and (c) the disease has a good prognosis in children. However, other studies found that some children can progress to end-stage kidney disease. It seems reasonable that all IgAV pediatric patients, with no exception, should be periodically screened for urinalysis, blood pressure, and kidney function. Identifying children at greatest risk for progressive loss of kidney function is key to reducing the incidence of irreversible CKD. Hopefully, future studies will address these important questions.

REFERENCES

• ¹
  Davin JC, Coppo R. Henoch-Schönlein purpura nephritis in children. Nat Rev Nephrol. 2014 Jul;10:563-73. DOI: https://doi.org/10.1038/nrneph.2014.126
  » https://doi.org/10.1038/nrneph.2014.126
• ²
  Williams CEC, Toner A, Wright RD, Oni L. A systematic review of urine biomarkers in children with IgA vasculitis nephritis. Pediatr Nephrol. 2021 May;36:3033-44. DOI: https://doi.org/10.1007/s00467-021-05107-7
  » https://doi.org/10.1007/s00467-021-05107-7
• ³
  Peruzzi L, Coppo R. IgA vasculitis nephritis in children and adults: one or different entities?. Pediatr Nephrol. 2021 Nov;36:2615-25. DOI: https://doi.org/10.1007/s00467-020-04818-7
  » https://doi.org/10.1007/s00467-020-04818-7
• ⁴
  Dyga K, Szczepańska M. IgA vasculitis with nephritis in children. Adv Clin Exp Med. 2020;29(4):513-9. DOI: https://doi.org/10.17219/acem/112566
  » https://doi.org/10.17219/acem/112566
• ⁵
  Oni L, Sampath S. Childhood IgA vasculitis (Henoch-Schonlein purpura) - advances and knowledge gaps. Front Pediatr. 2019 Jun;7:257. DOI: https://doi.org/10.3389/fped.2019.00257
  » https://doi.org/10.3389/fped.2019.00257
• ⁶
  Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012 Revised International Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum. 2013;65(1):1-1. DOI: https://doi.org/10.1002/art.37715
  » https://doi.org/10.1002/art.37715
• ⁷
  Ozen S, Pistorio A, Iusan SM, Bakkaloglu A, Herlin T, Brik R, et al. EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: final classification criteria. Ann Rheum Dis. 2010 May;69(5):798-806.
• ⁸
  Chua JS, Zandbergen M, Wolterbeek R, Baelde HJ, Van Es LA, Fijter JW, et al. Complement-mediated microangiopathy in IgA nephropathy and IgA vasculitis with nephritis. Mod Pathol. 2019 Apr;32:1147-57. DOI: https://doi.org/10.1038/s41379-019-0259-z
  » https://doi.org/10.1038/s41379-019-0259-z
• ⁹
  Akbalık KM, Demircioğlu KB, Büyükçelik M, Balat A. Renal biopsy in children with IgA vasculitis. Braz J Nephrol. 2021 Jul 28; [Epub ahead of print]. DOI: https://doi.org/10.1590/2175-8239-JBN-2021-0035
  » https://doi.org/10.1590/2175-8239-JBN-2021-0035
• ¹⁰
  Meadow SR, Glasgow EF, White RH, Moncrieff MW, Cameron JS, Ogg CS. Schönlein-Henoch nephritis. Q J Med. 1972 Jul;41(163):241-58.
• ¹¹
  Buscatti IM, Abrão HM, Kozu K, Marques VLS, Gomes RC, Sallum AME, et al. Characterization of scrotal involvement in children and adolescents with IgA vasculitis. Adv Rheumatol. 2018 Nov;58:38. DOI: https://doi.org/10.1186/s42358-018-0039-3
  » https://doi.org/10.1186/s42358-018-0039-3
• ¹²
  Shi D, Chan H, Yang X, Zhang G, Yang H, Wang M, et al. Risk factors associated with IgA vasculitis with nephritis (Henoch-Schönlein purpura nephritis) progressing to unfavorable outcomes: a meta-analysis. PLoS One. 2019 Oct;14(10):e0223218. DOI: https://doi.org/10.1371/journal.pone.0223218
  » https://doi.org/10.1371/journal.pone.0223218
• ¹³
  Ozen S, Marks SD, Brogan P, Groot N, Graeff N, Avcin T, et al. European consensus-based recommendations for diagnosis and treatment of immunoglobulin A vasculitis - the SHARE initiative. Rheumatology. 2019 Mar;58(9):1607-16. DOI: https://doi.org/10.1093/rheumatology/kez041
  » https://doi.org/10.1093/rheumatology/kez041

Publication Dates

• Publication in this collection
  11 Feb 2022
• Date of issue
  Jan-Mar 2022

History

• Received
  29 Nov 2021
• Accepted
  01 Dec 2021