Introduction: IgA vasculitis (IgAV) is the most common systemic vasculitis in childhood. Purpuric rash is a mandatory criterion for diagnosing IgAV, it is mostly localized on the lower extremities and gluteal region, although it can also appear atypically affecting the face, trunk and upper extremities. In the most severe cases, ulcerations, necrosis and bullae can be present. Objectives: To evaluate the characteristics of cutaneous manifestations in patients with IgAV and to examine its association with clinical features. Subjects and methods: Retrospective analysis of data from patients with IgAV diagnosed and treated at the Referral Centre for Paediatric and Adolescent Rheumatology of the Ministry of Health of the Republic of Croatia, in the period from January 2009 to December 2021. Results: IgAV was diagnosed in 234 patients, 124 boys and 110 girls with the median (range) age at the time of diagnosis of 6.5 (4.5–8.2) years. All patients had a purpuric rash, and in 127 of them (54.3%) IgAV began with a rash. Cutaneous manifestations were most often presented in the form of palpable purpura and/or petechiae (87.2%) and in all patients were localized on the lower extremities. In 103 patients (44%) purpuric rash spread further to the upper extremities, trunk and/or face. At least one skin relapse occurred in 47 patients (20.1%). The most severe cutaneous manifestations which included ulcerations and necrosis developed in 11 patients (4.7%). Patients with cutaneous manifestations spread above the waist had a more statistically significant gastrointestinal involvement compared to patients with cutaneous manifestations affecting the lower extremities and gluteal region (50.5% vs. 36.6%, p=0.033), higher incidence of IgA vasculitis nephritis (IgAVN) (31.1% vs. 19.8%, p=0.048) and were more frequently treated with systemic glucocorticoids (68% vs. 52.7%, p=0.018) and angiotensin-converting enzyme inhibitors (14.5% vs. 5.3%, p=0.016). Almost all patients with ulcerations and necrosis required treatment with systemic glucocorticoids compared to the rest (90.9% vs. 57.8%,p=0.031). Conclusion: We observed that patients with purpuric rash spread above the waist have more frequently affected gastrointestinal system and a higher incidence of IgAVN. The prevalence of ulcerations and necrosis in IgAV is less common than the standard purpuric rash and this group of patients required systemic glucocorticoid therapy.
Key words: IgA vasculitis, cutaneous manifestations, children
Sažetak
Uvod: IgA vaskulitis (IgAV) najčešći je sistemski vaskulitis dječje dobi. Purpurični osip ključan je kriterij za dijagnozu IgAV-a, a najčešće je rasprostranjen po donjim udovima i gluteusima, iako može biti proširen i na atipičnim mjestima poput lica, trupa i gornjih udova. U najtežim slučajevima mogu biti prisutne ulceracije, nekroze i bule. Cilj: Utvrditi osobitosti kožnih promjena u bolesnika s IgAV-om te ispitati njihovu povezanost s kliničkim značajkama. Ispitanici i metode: Retrospektivna analiza podataka bolesnika s IgAV-om dijagnosticiranih i liječenih u Referentnom centru za pedijatrijsku i adolescentnu reumatologiju Ministarstva zdravstva RH, u razdoblju od siječnja 2009. do prosinca 2021. godine. Rezultati: IgAV je dijagnosticiran u 234 bolesnika, 124 dječaka i 110 djevojčica s medijanom (rasponom) dobi u trenutku dijagnoze 6,5 (4,5 – 8,2) godina. Svi su bolesnici imali kožni osip, a u njih 127 (54,3%) IgAV je i započeo osipom. Kožne promjene najčešće su bile zastupljene u obliku palpabilne purpure i/ili petehija (87,2%) i u svih bolesnika bile su lokalizirane po donjim udovima. U 103 bolesnika (44%) kožni osip se dalje proširio na ruke, trup i/ili lice. U 47 bolesnika (20,1%) došlo je do barem jednog recidiva kožnih promjena. Najteže kožne promjene u vidu ulceracija i nekroza razvilo je 11 bolesnika (4,7%). Bolesnici s kožnim promjenama proširenim iznad donjih udova imali su statistički značajno češće zahvaćen gastrointestinalni sustav u odnosu na bolesnike s kožnim osipom ograničenim na donje udove i glutealno (50,5% u odnosu na 36,6%, p=0,033), veću pojavnost nefritisa (IgAVN) (31,1% u odnosu na 19,8%, p=0,048) te su češće liječeni sistemskim glukokortikoidima (68% u odnosu na 52,7%, p=0,018) i inhibitorima angiotenzin konvertaze (14,5% u odnosu na 5,3%, p=0,016). Gotovi svi bolesnici s ulceracijama i nekrozama zahtjevali su liječenje sistemskim glukokortikoidima u odnosu na sve preostale bolesnike (90,9% u odnosu na 57,8%, p=0,031). Zaključak: Uočili smo da bolesnici s kožnim osipom proširenim iznad donjih udova imaju češće zahvaćen gastrointestinalni sustav i češću pojavu IgAVN-a. Učestalost ulceracija i nekroza u IgAV-u rjeđa je od klasične slike kožnog osipa i takvi bolesnici zahtijevali su liječenje sistemskim glukokortikoidima.
Ključne riječi: IgA vaskulitis, kožne manifestacije, djeca
Introduction
IgA vasculitis (IgAV), formerly known as Henoch-Schönlein purpura (HSP), is the most common form of childhood vasculitis with an estimated worldwide annual incidence of 3–55.9 cases per 100,000 children (1–3). In the Republic of Croatia, the average annual incidence of IgAV is 6.79 per 100,000 children (4). Palpable purpura and/or petechiae without thrombocytopenia and other underlying coagulation disorders are a recognizable feature of the disease and at the same time a necessary criterion in making a diagnosis (5). The purpuric rash is most often spread on the extensor sides of the lower extremities and the gluteal region, although it can also be spread to the upper extremities, abdomen, face and ears. In the beginning, the skin lesions appear as clusters of erythema, urticaria and maculopapular rash, and then they turn into petechiae, ecchymoses and purple induration up to 1 cm in diameter, which are distributed on the previously changed skin. The skin lesions then change colour from red and purple to brownish and fade after ten days, leaving some patients with areas of gradual hyperpigmentation (6). Less than 5% of children may develop necrosis, ulceration and bullae on the skin, while the appearance of such skin forms has been described in as many as 60% of adult patients (7). In such cases, as well as with skin lesions that are diffusely distributed, it is recommended to perform a skin biopsy to rule out other forms of vasculitis, especially ANCA-associated vasculitis (8). A skin biopsy in patients with IgAV shows leukocytoclastic vasculitis characterized by fibrinoid necrosis of the small blood vessels of the papillary dermis (capillaries, venules and arterioles), perivascular oedema and neutrophil infiltration with neutrophil nucleus fragmentation, while direct immunofluorescence of the skin shows predominant IgA deposits and complement component C3 in the dermis. (5). And while the purpuric rash usually passes spontaneously, that is, with the application of short-term symptomatic treatment, the most severe cutaneous forms require special therapy. In addition to that, some previous studies have already shown that the prevalence of purpuric rash as well as recurrences of purpura can significantly contribute to the increased risk for the occurrence of more severe gastrointestinal forms of the disease as well as the development of IgA vasculitis nephritis (IgAVN), the most significant chronic complication of the disease (9–12). The aim of this paper is to show the cutaneous manifestations in IgAV and to determine the association of their characteristics with the clinical and laboratory features of the disease and the selection of therapy.
SUBJECTS and methods
In the period from January 2009 to December 2021, a retrospective study was conducted at the Division of Clinical Immunology, Allergology and Rheumatology at the Department of Paediatrics, University Hospital Centre Zagreb, the Referral Centre for Paediatric and Adolescent Rheumatology of the Ministry of Health of the Republic of Croatia, which included patients younger than 18 years of age who are diagnosed with IgAV according to the EULAR/PRINTO/PRES criteria (5). The research was approved by the Ethics Committee of the University Hospital Centre Zagreb and the School of Medicine, University of Zagreb. Demographic, clinical and laboratory data on patients were collected from a database based on medical records. Demographic data included the patient’s gender and age at the time of IgAV diagnosis, while clinical data included the duration of hospitalization expressed in days, the leading initial symptom of the disease, the presence and type of prodromal infection, isolated microbiological agents, the prevalence of purpuric rash, joint involvement, gastrointestinal, renal and urogenital system, the presence of severe cutaneous changes (ulcerations, necrosis, bullae), time from the onset of the disease to the onset of nephritis (in days), systolic blood pressure values, skin biopsy, kidney biopsy, type of medication and number of relapses. Purpuric rash is categorized into one of two groups according to its prevalence: 1. purpuric rash localized on the lower extremities and the gluteal region; 2. purpuric rash spread above the lower extremities to the upper extremities, trunk and face (generalized purpura). Disease relapse was defined as the recurrence of symptoms and signs characteristic of IgAV after an asymptomatic period of at least one month. Laboratory findings included inflammatory indicators: erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and ferritin; red blood cell count, haemoglobin, haematocrit, white blood cell count, platelet count; biochemical blood tests: creatinine, urea, estimated glomerular filtration rate (eGFR), total proteins, serum albumins; coagulation factor tests: prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, D-dimers; urine tests: presence of erythrocyturia (defined as >5 erythrocytes in urine sediment) and/or proteinuria (defined as ≥2+ proteins in urine sediment), albumin/creatinine ratio in urine (values >3 mg/mmol were considered pathological); 24-hour urine analysis for quantification of proteinuria (defined as >0.15 g/day of total excreted proteins); immunological tests: immunoglobulin classes (IgA, IgG, IgM, total IgE), antinuclear antibodies (ANA), complement components C3 and C4, total complement activity (CH50), antistreptolysin O titer (ASTO) and faecal occult blood test (FOBT). Microbiological tests performed on patients with a history of infection included a nasopharyngeal swab.
Statistical processing of the data was performed using the MedCalc program for the Windows operating system, and the data were presented in tables and graphics. The normality of data distribution was tested using the Shapiro–Wilk test. Continuous variables for values that do not have a normal distribution are shown as the median and interquartile range (25 to 75 percentiles), and categorical variables are shown as percentages. Differences in categorical variables between two groups of patients were examined using the χ2 test and Fisher’s exact test, and in quantitative variables using the Mann-Whitney U test. All p-values lower than 0.05 were considered as statistically significant.
Results
In the period from 1st January 2009 to 31st December 2021, 234 patients were diagnosed with IgAV, among whom there were 124 boys and 110 girls, in a ratio of 1.13:1 with a median age of 6.5 (4,5–8,2) years of age at the time of the diagnosis. Table 1 shows the demographic and clinical characteristics of patients with IgAV.
The most common skin efflorescences in the mentioned cohort of patients were papules in combination with purpuric changes, which were present in 122 patients (52.2%). The next most frequent occurrences were isolated petechiae, which were present in 82 patients (35%), while the rarest was a combination of purpuric and macular changes (in 15 patients, or 6.4%). Purpuric changes with hematomas were present in 4 patients (1.7%). 11 patients (4.7%) had severe cutaneous manifestations, ulcerations and necrosis. In 47 patients (20.1%), cutaneous manifestations had at least one recurrence. 131 patients (56%) had a skin rash localized on the legs and gluteal area, in 50 patients the rash affected not only the lower extremities but also the hands (21.4%), while in 53 patients the skin on the legs, arms, trunk and face was affected (22, 6%). A skin biopsy was performed on only one patient who had a dense purpuric rash on the skin of the arms and legs with efflorescences 1 cm in diameter and central necrosis and papules on the skin of the face. The skin biopsy indicated leukocytoclastic vasculitis with neutrophil infiltration, especially in the small blood vessels of the dermis and deposits of IgA and C3, and thus the histopathological finding with the clinical features of the patient was included in the diagnosis of IgAV.
A statistically significantly higher proportion of patients with skin rash spread over the lower extremities suffered from gastrointestinal system involvement (50.5% compared to 36.6%, p=0.033), they developed IgAVN (31.1% compared to 19.8%, p=0.048), they had a large amount of protein in urine (24.3% versus 12.2%, p=0.016) and underwent a kidney biopsy (15.5% versus 6.8%, p=0.033) compared to patients with a skin rash affecting the lower extremities. Patients with skin rashes spread over the lower extremities were more often treated with glucocorticoids (68% versus 52.7%, p=0.018) and antihypertensives from the group of angiotensin-converting enzyme inhibitors (14.5% versus 5.3%, p=0.016) with a longer duration of hospitalization (p=0.006), and the time to onset of IgAVN was also longer (p=0.007). No statistically significant differences between the groups were observed in laboratory findings (Table 2). Also, no statistically significant difference was observed in the involvement of the gastrointestinal system (45.5% versus 42.6%, p=0.852) and the incidence of IgAVN (45.5% versus 23.8%, p=0.146) in patients with severe cutaneous manifestations compared to the rest of the patients. Among 11 patients with severe cutaneous manifestations, 10 of them (90.9%) were treated with systemic glucocorticoids, while only one patient was treated with local glucocorticoid therapy for ulcerations. Patients with ulcerations and necrosis were statistically more significantly treated with systemic glucocorticoids compared to all other patients (90.9% vs. 57.8%, p=0.031). In 1 patient (9.1%) scars remained after ulcerations, and in 3 patients (27.3%) hyperpigmentation remained. The follow-up of all patients was performed for at least 6 months, during which time recurrences of skin rash occurred in 47 patients (20.1%). In 224 patients (95.8%) with IgAV complete recovery was achieved, while 10 of these patients (4.3%) had IgAVN with proteinuria <1 g/dU and their clinical follow-up was continued.
Discussion
The purpose of this retrospective study conducted at the Referral Centre for Paediatric and Adolescent Rheumatology of the Ministry of Health of the Republic of Croatia was to analyse the cutaneous manifestations, the key clinical criterion for the diagnosis of this most common childhood vasculitis, and to point out the possible connection between the characteristics of the cutaneous manifestations and other clinical and laboratory features of the disease. In the majority of children with IgAV, cutaneous manifestations are typical in the form of palpable non-thrombocytopenic purpura localized on the lower extremities and the gluteal region (5,6). In our cohort of 234 patients, all had a case of skin rash in the area of the lower extremities, most often on the lower extremities and feet, and a typical palpable skin rash was present in 204 patients (87.2%), which in practical terms allows the clinician to diagnose the disease with great certainty. However, the appearance of slightly less common cutaneous manifestations such as papules, macules or haematomas in combination with a typical rash is also possible. The most severe cutaneous manifestations in the form of ulcerations and necrosis were developed by 11 patients (4.7%), which is in accordance with the literature data (6,7). The exact cause and mechanism of such skin changes in IgAV are not clear, and include trauma, pressure, skin fragility, immune dysregulation, local action of leukocyte esterase and matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) leading to proteolysis of collagen in the skin (13). Studying the possible connection between more severe cutaneous manifestations and the clinical features of the disease, we noticed that literature data is scarce and contradictory (9,14–16). In this cohort of 234 patients with IgAV, in which 11 (4.7%) developed the most severe cutaneous manifestations, no significant association was observed with other clinical manifestations of the disease, primarily gastrointestinal manifestations and IgAVN.
Several studies have investigated whether there is an association between the prevalence of skin rash and systemic manifestations in IgAV (9–12,17,18). Some studies have shown that cutaneous manifestations spread above the waist level significantly increase the risk of gastrointestinal system involvement (9,11,12) and the development of IgAVN (9,10,17), while studies conducted on a group of adult patients with IgAV showed significant association with the development of arthritis (17). On the other hand, Poterucha et al did not find a connection between the prevalence of skin rash and systemic manifestations in IgAV (18). We observed that patients with purpuric rash spread above the waist have more frequently affected gastrointestinal system and a higher incidence of IgAVN. Another association between cutaneous manifestations spread over the lower extremities and IgAVN is manifested in the higher frequency of proteinuria and the longer time required for the onset of IgAVN. These patients were more likely to undergo invasive procedures such as kidney biopsy. Since the skin rash that has spread from the lower extremities and the gluteal region to the arms, trunk and face indicates that the inflammatory process in small blood vessels is developing with the continuous release of inflammatory mediators, it seems logical to conclude that such patients develop gastrointestinal manifestations and IgAVN with greater frequency, have significantly longer hospitalization time, and require treatment with systemic glucocorticoids and antihypertensive drugs. According to the recommendations of the Single Hub and Access Point for Pediatric Rheumatology in Europe (SHARE), oral prednisolone is indicated in the treatment of mild and moderate IgAVN, while antihypertensives from the group of angiotensin-converting enzyme inhibitors should preferably be included in the treatment of all patients in whom proteinuria has appeared as part of IgAVN for the sake of achieving a favourable effect on the prevention or limitation of secondary glomerulonephritis (8). Although the SHARE recommendations do not specify any guidelines for the treatment of spread cutaneous manifestations as well as the most severe ones, most of our patients received systemic glucocorticoids in such cases, especially patients with ulcerations and necrosis. Since in a large number of patients the diagnosis of IgAV is already clear on the basis of the clinical features, a skin biopsy is rarely indicated. This is also indicated by the SHARE recommendations, according to which a skin biopsy is required in the case of an atypical rash to exclude other diagnoses, especially ANCA-associated vasculitis, which in older children may present with symptoms and signs compatible with IgAV at the onset of the disease. In case there is an indication for a skin biopsy, it should be done at the site of the newly appeared cutaneous manifestations (8). In our study, a skin biopsy was performed in only one patient with severe cutaneous manifestations and an atypical appearance of a purpuric rash. Therefore, it can be said that skin biopsy in children with IgAV is an exception rather than the rule. The follow-up of all patients was performed for at least 6 months and all of them recovered from the cutaneous manifestations, except for one patient with ulcerations who developed scars. Ten patients are still under clinical follow-up and treated for IgAVN.
The main limitation of this paper is the retrospective nature of the research, as well as the small number of patients with the most severe cutaneous manifestations in the form of ulcerations and necrosis, on the basis of which recommendations related to therapy and follow-up of such patients could be made, which certainly remains one of the future challenges. Nevertheless, we gave an overview of the cutaneous manifestations of the most common childhood vasculitis in the Republic of Croatia, in which we observed that the frequency of severe cutaneous manifestations in IgAV is less frequent than the standard clinical features of purpuric rash and/or petechiae. We also observed that patients with a skin rash that spread from the lower extremities to the hands, trunk and face had more frequent systemic manifestations of the disease, i.e. more often the gastrointestinal system was involved along with a higher incidence of IgAVN, which certainly requires a closer clinical follow-up of such patients in order for the possible complications of IgAV to be recognized and treated in time.
Financial support: Croatian Science Foundation (Hrvatska zaklada za znanost) IP-2019-04-8822.
Conflict of interest statement: The authors declare no conflict of interest.
REFERENCES / Literatura
18. Poterucha TJ, Wetter DA, Gibson LE, Camilleri MJ, Lohse CM. Correlates of systemic disease in adult Henoch-Schönlein purpura: a retrospective study of direct immunofluorescence and skin lesion distribution in 87 patients at Mayo Clinic. J Am Acad Dermatol. 2012;67(4):612-6.
Table 1 Demographic and clinical features in IgAV patients, N=234
Tablica 1. Demografska i klinička obilježja bolesnika s IgAV-om, N = 234
Legend / Legenda: IgAV: IgA vasculitis / IgA vaskulitis; F/Ž: female gender / ženski spol; M: male gender / muški spol; GI: gastrointestinal / gastrointestinalni; IgAVN: IgA vasculitis nephritis / IgA vaskulitis nefritis; IQR/IR: interquartile range / interkvartilni raspon; NSAID: non-steroidal anti-inflammatory drugs / nesteroidni protuupalni lijekovi. Data are presented as percentages, statistical significance set at *P<0.05 / Podatci su prikazani u postotcima, statistička značajnost postavljena na *P<0,05. aX 2 test / X 2 test; bFisher’s exact test / Fisherov egzaktni test; cMann-Whitney U-test / Mann-Whitneyjev U-test
Table 2 Laboratory findings in IgAV patients, (N=234)
Tablica 2. Laboratorijski nalazi bolesnika s IgAV-om, (N=234)
Legend / Legenda: ESR/SE: erythrocyte sedimentation rate / sedimentacija eritrocita; CRP: C-reactive protein / C-reaktivni protein; eGFR: estimated glomerular filtration rate / procijenjena glomerularna filtracija; PT/PV: prothrombin time / protrombinsko vrijeme; APTT/APTV: activated partial thromboplastin time / aktivirano parcijalno tromboplastinsko vrijeme; IgA: immunoglobulin A / imunoglobulin A; IgG: immunoglobulin G / imunoglobulin G; IgM: immunoglobulin M / imunoglobulin M; total IgE / uIgE: total immunoglobulin E / ukupni imunoglobulin E; ANA: antinuclear antibodies / antinuklearna antitijela; C 3: complement component C 3 / C 3 komponenta komplementa; C 4: complement component C 4 / C 4 komponenta komplementa; CH 50: total complement activity / ukupni komplement; ASTO: antistreptolysin O titer / antistreptolizinski titar; IQR/IR: interquartile range / interkvartilni raspon. Data are presented as a median (interquartile range) as well as percentages, statistical significance set at *P<0.05 / Podatci su prikazani kao medijan (interkvartilni raspon) i u postotcima, statistička značajnost postavljena na *P<0,05. aX 2 test / X 2 test bFisher’s exact test / Fisherov egzaktni test cMann-Whitney U-test / Mann-Whitneyjev U-test