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Clinical Characteristics of Biopsy-Proven IgA Vasculitis in Children and Adults: A Retrospective Cohort Study
ORIGINAL ARTICLE
Clinical Characteristics of Biopsy-Proven IgA Vasculitis in Children and Adults: A Retrospective Cohort Study Michel Villatoro-Villar, MD, MS; Cynthia S. Crowson, PhD; Kenneth J. Warrington, MD; Ashima Makol, MBBS; Steven R. Ytterberg, MD; and Matthew J. Koster, MD Abstract Objective: To describe the differences in clinical characteristics and outcome between adult- and childhood-onset biopsy-proven IgA vasculitis (IgAV) in North America. Patients and Methods: Patients with IgAV diagnosed from January 1, 1997, through December 31, 2016, were retrospectively identified. Data were abstracted from direct medical record review. KaplanMeier methods were used to estimate survival rates. Results: A total of 243 patients with IgAV were included (227 [93.4%] white, 141 [58.0%] male); 174 patients were adults (21 years), and 69 were younger than 21 years. Compared with patients younger than 21 years, adults at baseline more frequently had ulcerative skin lesions (19 [10.9%] vs 1 [1.4%]; P¼.02) and nephrotic-range proteinuria (21 of 96 [21.9%] vs 1 of 38 [2.6%]; P¼.007) but less commonly had abdominal pain (59 [33.9%] vs 42 [60.9%]; P<.001), ischemic gastrointestinal tract involvement (18 [10.3%] vs 14 [20.3%]; P¼.04), and arthralgias (66 [37.9%] vs 42 [60.8%]; P<.001). During 389 person-years of follow-up, 29 deaths were observed. Five-year survival rates for patients aged younger than 21, 21 to 50, and 51 years or older were 100%, 94%, and 40%, respectively. In comparison to data from the United States life tables for whites, patients 51 years or older at diagnosis had a greater than 7-fold increased risk of mortality (standardized mortality, 7.60 [95% CI, 5.0111.06]; P<.001). Conclusion: IgA vasculitis in adults is associated with more severe skin/kidney involvement and poorer renal outcome. Among adults with IgAV, patients aged 51 years or older at diagnosis have significantly higher mortality (P<.001). ª 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) n Mayo Clin Proc. 2019;94(9):1769-1780
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gA vasculitis (IgAV), formerly known as Henoch-Schönlein purpura, is an immune-mediated small-vessel vasculitis in which deposition of IgA1-dominant immune complexes leads to pathologic involvement of the skin, kidneys, gastrointestinal (GI) tract, and joints.1,2 Palpable purpura is usually the first and most characteristic sign.3,4 IgA vasculitis is the most common form of childhood vasculitis and is 2 to 15 times more common in children than in adults. The estimated annual incidence of IgAV in children varies from 6.1 to 20.4 per
100,000 children, with the highest proportion occurring within the first 10 years of life.5-9 However, in adults the annual incidence is lower and has been estimated at 1.4 to 5.1 per 100,000 adults, with an increased frequency in the fifth and sixth decades of life and a slight male predominance.10-13 Differences in both the presentation and outcome have been described in adults compared with children, with most studies reporting a higher frequency of severe renal manifestations and poorer renal outcome among the adult population.14-25 Although
From the Division of Rheumatology (M.V.-V., C.S.C., K.J.W., A.M., S.R.Y., M.J.K.) and Department of Health Sciences Research (C.S.C.), Mayo Clinic, Rochester, MN.
Mayo Clin Proc. n September 2019;94(9):1769-1780 n https://doi.org/10.1016/j.mayocp.2019.04.034 www.mayoclinicproceedings.org n ª 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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multiple European and Asian studies have been reported, cohorts evaluating the differences between patients with adult- and childhood-onset IgAV in North America are limited. The aim of this study was to describe the differences between baseline clinical characteristics and outcomes of childhood- and adult-onset biopsy-proven IgAV from a large, North American, singleinstitution cohort. PATIENTS AND METHODS Study Population This study was performed in accordance with the ethical standards of the Helsinki Declaration and was approved by Mayo Clinic, Rochester, Minnesota, Institutional Review Board (IRB #17-004520). Patients diagnosed as having IgAV at the Mayo Clinic in Rochester, Minnesota, from January 1, 1997, through December 31, 2016, were retrospectively identified. An institutional clinical database was used to search for all patients with at least one International Classification of Diseases, Ninth Revision, Clinical Modification or International Classification of Diseases, Tenth Revision, Clinical Modification code for HenochSchönlein purpura or cutaneous vasculitis (Supplemental Table 1, available online at http://www.mayoclinicproceedings.org) during an inpatient or outpatient encounter. Identified patients were then further evaluated through direct medical record review. Inclusion criteria for this study were the presence of all of the following: cutaneous findings of IgAV, biopsy (skin and/or kidney) with histologic evidence of small-vessel vasculitis on light microscopy, and the presence of predominant IgA deposition on direct immunofluorescence. All patients were required to fulfill classification criteria for IgAV by either the 1990 American College of Rheumatology criteria and/or the European League Against Rheumatism/Paediatric Rheumatology International Trials Organization/ Paediatric Rheumatology European Society (EULAR/PRINTO/PRES) criteria for HenochSchönlein purpura.1,26 Patients with a clinical diagnosis of IgAV but an inconclusive initial 1770
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biopsy were included provided one or more subsequent skin or kidney biopsy confirmed classic features of IgAV. In a small subset of patients, baseline biopsy was deferred but performed later in the course of follow-up. These patients were included if the subsequently obtained biopsy yielded evidence consistent with IgAV. In such circumstances, the date of diagnosis was the initial onset of clinical symptoms consistent with IgAV. Patients with isolated renal involvement, even if IgA deposition was identified on renal biopsy, were excluded in order to avoid confusion with IgA nephropathy. Further exclusions included the presence of any of the following conditions: IgA monoclonal gammopathy of uncertain significance, multiple myeloma, cryoglobulinemia, hepatitis B, hepatitis C, or other documented primary systemic small-vessel vasculitis. Patients were divided into 2 groups based on the first age at onset of clinical symptoms attributable to IgAV, with 21 years or older considered as adult onset.
Clinical and Laboratory Data Clinical and laboratory data obtained at baseline and at each follow-up visit were confirmed through direct medical record review. Risk factors associated with IgAV were considered to be potential precipitant events if they occurred within 1 month before the onset of symptoms attributable to IgAV. For this study, events of interest included previous infection, antibiotic exposure, immunizations, and use of nonsteroidal anti-inflammatory drugs. The type of skin lesions (eg, purpura, ulcers, nodules) and their distribution were abstracted from records of the the initial and subsequent visits. Joint symptoms and GI tract abnormalities were also recorded. Renal involvement included microscopic hematuria, gross hematuria, nonnephrotic proteinuria (NNP), nephrotic proteinuria (NP), and renal insufficiency. Definitions used for assessment of renal, joint, and GI tract involvement are outlined in Supplemental Table 2 (available online at http://www. mayoclinicproceedings.org).
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The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation in patients aged 18 years or older and the Bedside Schwartz equation for those younger than 18 years. Chronic kidney disease stages were considered according to the National Kidney Foundation Kidney Diseases Outcomes Quality Initiative recommendation.27 Disease Status Disease status at each visit was classified according to definitions adapted from Audemard-Verger et al.28 Complete response was considered as improvement in all baseline clinical manifestations including (if present) reduction of proteinuria to urinary protein levels of less than 0.5 g/d, disappearance of hematuria or reduction to less than 10 red blood cells per high-power field (RBCs/hpf), and less than 20% decrease of eGFR from baseline. Partial response was considered as improvement in at least one-half of baseline clinical manifestations and in the case of renal involvement, an improvement of proteinuria to less than 50% of the baseline value, disappearance of hematuria or reduction to less than 10 RBCs/hpf, and less than 20% decrease of eGFR from baseline. Nonresponse was considered as lack of improvement in any organ system or improvement in less than half of the manifestations present at baseline. Relapse was defined as reappearance of clinical signs of vasculitis, attributable to IgAV, occurring after a symptom-free period of at least 1 month. Outcome The status at the last documented follow-up was used for overall outcome. Renal outcomes included resolution of hematuria and proteinuria, renal impairment (eGFR <50 mL/min per 1.73 m2), and development of end-stage renal disease (ESRD), defined as an eGFR of less than 15 mL/min per 1.73 m2, uremia, and requirement of dialysis or renal transplant. Severe bowel involvement was defined as necessity of bowel surgery, bowel hemorrhage (requiring blood transfusion), or objective evidence of ischemia or infarct. Mayo Clin Proc. n September 2019;94(9):1769-1780 www.mayoclinicproceedings.org
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Mortality for any cause following IgAV diagnosis was recorded and cause of death was noted, when available. Deaths were attributable to IgAV if the cause of death was development of organ failure leading to death during a time that IgAV was active and no other explanation of organ failure was present (eg, sepsis, cancer, heart failure). Statistical Analyses Descriptive statistics (percentage, mean) were used to summarize patient characteristics. Comparisons between age groups were performed using c2 and rank sum tests. Survival rates were estimated using the Kaplan-Meier method and were compared with expected survival rates for persons of the same age, sex, and calendar year estimated using US population life tables for whites. The standardized mortality ratio (SMR) was estimated as the ratio of the observed and expected number of deaths. The 95% CIs for the SMR were calculated assuming that the expected rates are fixed and the observed rates follow a Poisson distribution. The cumulative incidence of each outcome (eg, hematuria, proteinuria) adjusted for the competing risk of death was estimated.29 These methods are similar to the Kaplan-Meier method with censoring of patients who are still alive at last follow-up. However, patients who die before experiencing the outcome are appropriately accounted for to avoid overestimation of the rate of occurrence of the outcome, which can occur if such individuals are simply censored at death. For the progression through disease states (eg, relapse, partial or complete response), Aalen-Johansen methods (a multistate generalization of cumulative incidence) were used to estimate the prevalence of each disease state over time.30 Univariable Cox models were used to examine prognostic factors of relapse, partial response, complete response, and resolution of renal involvement. Analyses were performed using SAS statistical software, version 9.4 (SAS Institute) and R 3.4.2 (R Foundation for Statistical Computing). RESULTS The clinical database search identified 745 potential patients based on diagnostic
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TABLE 1. Clinical Characteristics of Patients With IgA Vasculitis at Diagnosis, Stratified by Age Groupa,b,c Age at diagnosis (y) Variable Demographic characteristics Age (y) Male White BMI (kg/m2) Comorbidities Diabetes mellitus Hypertension ESRD or dialysis
<21 (n¼69)
21 (n¼174)
Total (N¼243)
P value
12.75.7 39 (56.5) 64 (92.8) 22.87.7
50.917.4 102 (58.6) 163 (93.7) 32.28.8
40.122.9 141 (58.0) 227 (93.4) 29.69.5
<.001 .77 .83 <.001
39 (22.4) 65 (37.4) 8 (4.6)
39 (16.0) 65 (26.7) 8 (3.3)
<.001 <.001 .07
0 (0) 0 (0) 0 (0)
Baseline characteristics Previous infection Recent URId Antibiotic exposure NSAIDs exposure Fever Weight loss
27 13 11 1 10 3
(39.1) (48) (15.9) (1.4) (14.5) (4.3)
73 22 47 17 24 10
(42.0) (31) (27.0) (9.8) (13.8) (5.7)
100 35 58 18 34 13
(41.2) (35) (23.9) (7.4) (14.0) (5.3)
.10 .01 .08 .03 .88 .68
Abdominal involvement Nonischemic Abdominal pain Nausea/vomiting Diarrhea Ischemic Hematochezia/melena Hematemesis
43 43 42 15 5 14 13 2
(62.3) (62.3) (60.9) (21.7) (7.2) (20.3) (18.8) (2.9)
75 74 59 34 26 18 17 1
(43.1) (42.5) (33.9) (19.5) (14.9) (10.3) (9.8) (0.8)
118 117 101 49 31 32 30 3
(48.6) (48.1) (41.6) (20.2) (12.8) (13.2) (12.3) (1.2)
.007 .005 <.001 .70 .11 .04 .05 .14
Skin involvement Palpable purpura Lower extremity Upper extremity Abdomen/back Chest/trunk Ulceration
69 69 68 35 19 8 1
(100) (100) (98.6) (50.7) (27.5) (11.6) (1.4)
174 173 169 95 65 32 19
(100) (99.4) (97.1) (54.6) (37.4) (18.4) (10.9)
243 242 237 130 84 40 20
(100) (99.6) (97.5) (53.5) (34.6) (16.5) (8.2)
.53 .53 .52 .59 .15 .20 .02
Arthralgia Lower extremity Upper extremity
42 (60.8) 39 (56.5) 17 (24.6)
Neuropathy
0 (0)
Renal involvement Microscopic hematuria Gross hematuria Proteinuria Nonnephrotic rangee Nephrotic rangef Creatinine (mg/dL) eGFR (mL/min/1.73 m2) Renal insufficiencyg
47 (68.1) 33 (47.8) 3 (4.3) 38 (55.1) 37/38 (97.4) 1/38 (2.6) 0.70.3 113.629.7 1 (1.4)
Laboratory studies C-reactive protein (mg/L) ESR (mm/h)
26.829.9 17.615.4
66 (37.9) 60 (34.5) 29 (16.7)
108 (44.4) 99 (40.7) 46 (18.9)
.001 .002 .15
13 (7.5)
13 (5.3)
.02
115 (66.1) 162 (66.7) .76 81 (46.6) 114 (46.9) .86 6 (3.4) 9 (3.7) .74 96 (55.2) 134 (55.1) .99 75/96 (78.1) 112/134 (83.6) .007 21/96 (21.9) 22/134 (16.4) .007 1.41.4 1.21.3 <.001 78.935.6 88.937.4 <.001 12 (6.9) 13 (5.3) .09 40.742.6 30.327.9
37.440.3 27.226.0
.14 .04
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coding. Following direct medical record review, 502 patients were excluded for the following reasons: symptoms suggestive of IgAV but without biopsy ever performed (n¼153), isolated cutaneous vasculitis without clinical features of IgAV or IgA deposition on biopsy (n¼147), cutaneous vasculitis due to other primary systemic vasculitis (n¼91), cutaneous vasculitis secondary to identified precipitant (autoimmune disease [n¼15], drug reaction [n¼12], hepatitis [n¼2]), nonvasculitic purpura (n¼73), and IgA nephropathy (n¼9). Baseline Characteristics A total of 243 patients (227 [93.4%] white, 141 [58.0%] male) met inclusion criteria for biopsy-proven IgAV. Sixty-nine patients were younger than 21 years (children), and 174 were 21 years or older (adults). Among the adult cases, 90 were 51 years of age or older at diagnosis. Baseline characteristics are further outlined in Table 1. The mean SD age for patients younger than 21 years at diagnosis was 12.75.7 years compared with 50.917.4 years for those 21 years or older at diagnosis. American College of Rheumatology criteria for IgAV were met in 69 patients younger than 21 years (100%) and in 171 adults (98.3%). The EULAR/PRINTO/PRES criteria were met in 68 patients younger than 21 years (99.6%) and in all 174 adults (100%). The distribution of skin lesions was similar between children and adults, with lower extremity involvement predominantly noted (68 [98.6%] and 169 [97.1%]), followed by upper extremities (95 [54.6%] and 29 [16.7%]), abdomen/lower back (19 [27.5%] and 65 [37.4%]), and chest/upper back (8 [11.6%] and 32 [18.4%]), respectively. Diffuse distribution with involvement of the upper and lower extremities and torso was seen in 17 of 52 children (24.6%) and 50 adults (28.7%). Skin ulceration occurred more frequently in adults than children (19 [10.9%] vs 1 [1.4%]; P¼.02). Patients younger than 21 years had more abdominal symptoms compared with adults (43 [62.3%] vs 45 [43.1%]; P¼.007). Abdominal pain was the most common GI tract
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IGA VASCULITIS IN CHILDREN AND ADULTS
symptom in both groups and was more frequent in children (42 [60.9%] vs 59 [33.9%]; P<.001). Ischemic GI tract symptoms, in general, were also seen more often in children than in adults (14 [20.3%] vs 18 [10.3%]; P¼.04). Hematochezia/melena occurred in 13 children (19.8%) and 17 adults (9.8%) but did not reach statistical significance (P¼.05). Hematemesis was rare (2 children, 1 adult). No bowel perforations or intussusceptions were present at diagnosis. Abdominal imaging (computed tomogrpahy [CT], magnetic resonance imaging [MRI], ultrasonography [US]) was performed in 55.6% of patients at baseline (102 adults and 33 children). The leading abdominal findings among those who underwent CT or MRI abdominal imaging were bowel wall thickening (22 of 71 adults [31.0%] and 5 of 17 children [29.4%]), followed by bowel edema (11 of 71 adults [155%] and 4 of 17 children [23.5%]). Among patients with at least one abdominal US, CT, or MRI, intestinal infarcts were seen in 1 child (3.0%) and 3 adults (2.9%). At baseline, renal involvement was documented in 66.7% of the entire cohort (162 patients) and did not differ between groups. Proteinuria was the most frequent finding, present in 38 children (55.1%) and 96 adults (55.2%). Among the 134 patients with proteinuria, NNP was seen in 112 (83.6%) and NP in 22 (16.4%). Nonnephrotic proteinuria was more frequently found in patients younger than 21 years than in adults (37 of 38 patients [97.4%] vs 75 of 96 [78.1%]; P¼.007), whereas NP was more often noted in adults (21 of 96 [21.9%] vs 1 of 38 [2.6%]; P¼.007). At diagnosis, hematuria was present in 123 patients (50.6%); microscopic hematuria was documented in 114 (46.9%) and gross hematuria in 9 (3.7%), similar in both groups. Among children (n¼36) and adults (n¼87) with hematuria, less than 10 RBCs/hpf were observed in 16 (44.4%) and 32 (36.8%), 10 to 49 RBCs/hpf in 14 (38.9%) and 32 (36.8%), and 50 or more RBCs/hpf in 6 (16.7%) and 23 (26.4%), respectively. Given that the study period covered 20 years of IgAV diagnosis, patients were further evaluated to determine if there were any Mayo Clin Proc. n September 2019;94(9):1769-1780 www.mayoclinicproceedings.org
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TABLE 1. Continued Age at diagnosis (y) Variable
<21 (n¼69)
21 (n¼174)
Total (N¼243)
198.0100.3
375.8315.9
323.1280.4
P value
Laboratory studies, continued Serum IgA (mg/dL) Initial treatment Oral CS Topical CS ACEI/ARB NSAID CIS
52 39/52 8/52 9/52 12/52 7/52
(75.4) 130 (74.7) 182 (74.9) (75.0) 106/130 (81.5) 145/182 (79.7) (15.4) 33/130 (25.4) 41/182 (22.5) (17.3) 31/130 (23.8) 40/182 (22.0) (23.1) 21/130 (16.2) 33/182 (18.1) (13.5) 15/130 (11.5) 22/182 (12.1)
.06 .92 .32 .15 .34 .27 .72
ACEI/ARB ¼ angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; BMI ¼ body mass index; CIS ¼ conventional immunosuppressive drugs; CS ¼ corticosteroids; eGFR ¼ estimated glomerular filtration rate; ESR ¼ erythrocyte sedimentation rate; ESRD ¼ end-stage renal disease; NSAIDs ¼ nonsteroidal anti-inflammatory drugs; URI ¼ upper respiratory tract infection. b Data are presented as mean SD or No. (percentage) of patients. c SI conversion factors: To convert creatinine values to mmol/L, multiply by 88.4; to convert C-reactive protein values to nmol/L, multiply by 9.524; to convert IgA values to mg/L, multiply by 10. d Percentages based on number of patients with documented presence of infection OR. e 0.2 g/d, <3.5 g/d. f 3.5 g/d. g eGFR <15 mL/min or dialysis requirement. a
differences in baseline characteristics per study decade. Patients (adult- and childhood-onset) who were diagnosed as having IgAV between 1997 and 2006 were compared with those diagnosed between 2007 and 2016. No significant differences in baseline characteristics were observed between these 2 time periods (P>.05, respectively). Histopathology Baseline skin biopsy was performed in 164 patients (67.5%), renal biopsy in 42 (17.3%), and skin-kidney biopsies (combined) in 16 patients (6.6%). Skin biopsy was performed more frequently in adults than in patients younger than 21 years (137 [78.7%] vs 28 [40.6%]; P<.001). Among patients with a clinical diagnosis of IgAV in whom biopsy was not performed at the onset of symptoms (n¼3) or was performed and results were inconclusive (n¼18), all had a confirmatory biopsy within 2 years of their initial IgAV symptoms. The mean SD time from diagnosis to kidney biopsy was 24.834.2 days and did not differ significantly between groups (P¼.47).
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100
Prevalence (%)
80
60
40
20
0
1
2 3 Months
6
1
2
3 Years
4
5
39
29
23
Time since diagnosis No: 205
184
Active
168 Death
135
94 Relapse
59
Partial
Complete
FIGURE 1. Prevalence of IgA vasculitis disease state at each study time point during follow-up. At 1 year after diagnosis 42% (95% CI, 30%-51%) had complete response, 32% (95% CI, 24%-39%) had a partial response, 10% (95% CI, 6%-13%) had no response, 5% (95% CI, 0%-10%) had relapse, and 12% (95% CU, 5%-19%) were deceased.
Mesangial IgA deposits were identified through direct immunofluorescence in all cases. Proliferative glomerulonephritis was noted in 34 patients (14.0%), crescentic glomerulonephritis in 19 (7.8%), focal sclerosis in 4.9%, and necrotizing glomerulonephritis in 8 (3.3%). Treatment At diagnosis, 182 patients (74.9%) received treatment. The mean SD time from diagnosis to initial treatment was 2.28.7 days, similar in both groups. Corticosteroids (CSs), systemic and topical, were the primary treatments used (in 145 of 182 patients [79.7%] and 41 of 182 [22.5%], respectively). The initial systemic CS dose (or prednisone equivalent) was higher in adults than in children (mean, 2.65.5 vs 1.52.7 mg/kg; P¼.04), with a median of 60 mg/d (0.9 mg/kg) in adults and 40 mg/d (0.6 mg/kg) in children. A CS bolus (>80 mg prednisone or equivalent for one or more consecutive doses) at baseline was employed in 16 patients (14 adults). 1774
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Angiotensin-converting enzyme inhibitors/ angiotensin II receptor blockers were initiated in 40 of 182 patients (22.0%), nonsteroidal anti-inflammatory drugs in 33 of 182 (18.1%), and conventional immunosuppressive drugs (CIS) in 22 of 182 (12.1%). Among patients started on CIS at baseline, azathioprine and mycophenolate mofetil were most frequently used (n¼8 for each), followed by methotrexate (n¼7) and cyclophosphamide (n¼4). Dapsone was used in 5% of patients and colchicine in 3%. Plasma exchange (n¼2), antileukotriene agents (n¼3), and rituximab (n¼1) were uncommonly employed at the time of diagnosis in this cohort, which dates to 1997. Outcome Disease Status During Follow-up. The mean SD length of follow-up was similar between groups; 1.82.2 years in children and 1.52.3 years in adults, with a total of 389 person-years of follow-up. The prevalence of disease states over time is presented in Figure 1. At 1 year after diagnosis 42% (95% CI, 30%-51%) had complete response, 32% (95% CI, 24%-39%) had a partial response, 10% (95% CI, 6%-13%) had no response, 5% (95% CI, 0%-10%) had relapse, and 12% (95% CU, 5%-19%) were deceased. A total of 151 patients achieved complete response. During the first 5 years of disease, patients were in complete response only 40% of the time. Twenty-six patients (17 adults, 9 children) experienced at least one first relapse; 18 patients had a single relapse, 6 patients had 2 relapses, and 2 patients had 4 relapses. Active skin lesions were the most frequently observed finding during relapse (in 21 patients [80.8%]), predominantly in adults (16 [94.1%] vs 5 [55.6%]; P¼.02). Nonischemic abdominal symptoms (2 [22.2%] vs none [0%]; P¼.04) were more common in children at relapse. Renal involvement with worsening or recurrence of hematuria (4 [44.4%] children, 7 [41.2%] adults) and/or proteinuria (5 [55.6%] children, 9 [52.9%] adults) was similar between groups. Risk factor analysis of baseline parameters and their association with time to complete response, partial response, and first
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relapse revealed that baseline hematuria (>10 RBC/hpf or gross; hazard ratio [HR], 0.48 [95% CI, 0.27-0.84]; P¼.01) and proteinuria (HR, 0.68 [95% CI, 0.50-0.93]; P¼.02) resulted in a longer time to complete response. Sex, baseline creatinine level, eGFR, distribution of cutaneous vasculitis, arthritis, abdominal involvement, and the presence of crescentic or proliferative glomerulonephritis were not associated with a difference in time to complete response or first relapse. Given the lack of a standardized approach to treatment, patients who received only a single medication during their treatment course were analyzed for risk association with disease status outcome. Patients who received only CSs (P¼.50), dapsone (P¼.22), or colchicine (P¼.13) did not have a significantly different length of time to complete response (P¼.50); however, patients who received only CIS (vs no CSs, colchicine, or dapsone) took longer to achieve complete response (HR, 0.64; 95% CI, 0.42-0.99; P¼.04) (Table 2). Patients who received only CSs, CIS, or dapsone did not differ in the time to first relapse, but patients who received only colchicine experienced relapse sooner (HR, 13.02; 95% CI, 2.94-57.67; P<.001). Patients who received angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, whether taking at the time of diagnosis (HR, 0.66; 95% CI, 0.46-0.94; P¼.02) or starting after diagnosis (HR, 0.66; 95%
CI, 0.46-0.93; P¼.02) took longer to achieve complete response. Renal Outcome. During the study period, a total of 179 patients had hematuria (123 baseline and 56 more at follow-up), with the cumulative incidence of hematuria increasing from 50.6% at baseline to 78% (95% CI, 72%-84%) by 1 year and 179 had proteinuria (134 at baseline and 45 more at follow-up), with the cumulative incidence of proteinuria increasing from 55.1% at baseline to 77% (95% CI, 72%-84%) by 1 year (Supplemental Figure 1, available online at http://www. mayoclinicproceedings.org). Among the 179 patients with hematuria at baseline or during follow-up, 104 patients experienced resolution of hematuria, with 52% (95% CI, 44%61%) experiencing resolution by 1 year and 84% (95% CI, 77%-92%) by 5 years after the development of hematuria. Of the 179 patients with proteinuria, 97 had resolution of proteinuria during follow-up, with 50%; (95% CI, 42%-58%) experiencing resolution by 1 year and 72%; (95% CI, 64%-89%) by 5 years after development of proteinuria (Supplemental Figure 2, available online at http://www. mayoclinicproceedings.org). A risk factor analysis evaluating age, sex, baseline renal function, type of baseline renal involvement, and characteristics of renal histopathology found no specific factors associated with increased likelihood of resolution of renal involvement.
TABLE 2. Risk Factor Analysis for Time to Complete Response, Partial Response, or Relapsea,b Complete response HR (95% CI)
P value
Partial response HR (95% CI)
P value
ACEI/ARB Present at diagnosis (vs none) Started after diagnosis (vs none)
0.66 (0.46-0.94) 0.66 (0.46-0.93)
.02 .02
0.98 (0.70-1.37) 1.05 (0.76-1.44)
.89 .78
CS only (vs no CS, CIS, colchicine, or dapsone)
0.87 (0.59-1.29)
.50
1.21 (0.87-1.70)
.26
CIS only (vs no CS, CIS, colchicine, or dapsone)
0.64 (0.42-0.99)
.04
1.09 (0.73-1.64)
.66
Colchicine (vs no CS, CIS, colchicine, or dapsone)
0.55 (0.25-1.20)
.13
1.03 (0.56-1.92)
.92
Dapsone (vs no CS, CIS, colchicine, or dapsone)
1.36 (0.83-2.22)
.22
0.73 (0.42-1.25)
.25
Risk factor
ACEI/ARB ¼ angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker; HR ¼ hazard ratio; CIS ¼ conventional immunosuppressive drugs; CS ¼ corticosteroids. b Relapse was assessed in the subset of patients who achieved complete response. Multiple responses or relapses per person are included and appropriately accounted for in the models. a
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100
100
80
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D
FIGURE 2. Survival of the study population (solid line) compared with expected rates from the United States life tables for whites (dashed line) for patients younger than 21 years (A), 21 to 50 years (B; standardized mortality ratio [SMR], 5.62; 95% CI, 0.68-20.29), 51 years or older (C; SMR, 7.60; 95% CI, 5.01-11.06), and overall (D; SMR, 7.34; 95% CI, 4.91-10.54).
A reduction in eGFR by 30 mL/min per 1.73 m2 or more was reported in 38 patients by last follow-up; 10% (95% CI, 7%-16%) at 3 months, 21% (95% CI, 15%-30%) at 1 year, and 39% (95% CI, 28%-54%) at 5 years after IgAV diagnosis. Overall, 26 patients had development of ESRD after diagnosis, with a cumulative incidence of 10% (95% CI, 6%14%) at 1 year and 15% (95% CI, 8%-22%) at 5 years. Following the diagnosis of IgAV, dialysis was initiated in 13 patients: 3 younger than 21 years, 2 aged 21 to 50 years, and 8 who were 51 years or older. Renal transplant was performed in 4 patients (3 children, 1 adult). Analysis of patients diagnosed between 1997 and 2006 and those diagnosed between 2007 and 2016 revealed no difference in outcome based on study decade. Mortality. In total, 29 deaths were observed over 389 patient-years of follow-up
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(27 among patients aged 51 years, 2 in patients aged 21-50 years, and none in patients <21 years at diagnosis). Causes of death included malignancy (n¼9), cardiopulmonary disease (n¼6), infection/sepsis (n¼6), complication of IgAV (n¼3), ESRD (n¼3), and other causes (n¼2). Five-year survival rates in patients with IgAV for those younger than 21 years, 21 to 50 years, and 51 years or older at diagnosis were 100% (95% CI, 100%-100%), 94% (95% CI, 87%-100%), and 40% (95% CI, 9%-26%), respectively. In comparison to United States life tables for whites (Figure 2), patients with IgAV had similar survival rates for patients younger than 21 years and 21 to 50 years; however, patients 51 years or older at diagnosis had a greater than 7-fold increased risk of mortality compared with the US white population (SMR, 7.60; 95% CI, 5.01-11.06; P<.001).
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DISCUSSION Most studies evaluating patients with IgAV have been performed in Asia and Europe, with few studies describing this condition in North America. This report represents the largest, single-institution, North American cohort comparing adult- and childhoodonset biopsy-proven IgAV and provides additional information regarding the differences in presentation and long-term outcomes. Cutaneous involvement in IgAV with palpable purpura is a prominent feature and commonly the earliest manifestation observed. Patients in the current study had distributions of cutaneous involvement similar to that reported by other investigators.14,18,21,22,31 Although the distribution of palpable purpura was similar between adult- and childhood-onset IgAV in the current series, adults had more severe lesions, with ulcerative or hemorrhagic skin findings detected in 10.9% compared with only 1.4% of children. Although few studies have reported the presence of such skin lesions among patients with IgAV, Hitomi et al31 identified ulcers or hemorrhagic bullae in 14.1% of their adult population compared with 5.4% of children. The presence of ulcerative lesions has been reported by other groups evaluating only adult-onset IgAV, with frequencies between 13% and 35%.28,32,33 These findings highlight that clinicians must consider IgAV in patients with ulcerative skin lesions, particularly if present in adults, and underscore the benefit of direct immunofluorescence, which would assist in the diagnosis of IgAV in such cases. Renal involvement was present in over two-thirds of both adults and children in the present series. Although rates of hematuria and proteinuria at baseline were similar between adults and children, the presence of severe proteinuria was significantly higher among adults (P¼.007), a feature that has been similarly observed in other comparative cohort studies.14-16,18,20 It has been suggested by some authors that renal involvement in IgAV occurs early in the disease, with few patients having development of renal pathology beyond 4 weeks from Mayo Clin Proc. n September 2019;94(9):1769-1780 www.mayoclinicproceedings.org
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IgAV diagnosis.21,34 In the current series, hematuria was present in 50.6% and proteinuria in 55.1% at presentation but increased to 78% and 71% at one year, respectively. Shrestha et al35 observed a similar increasing incidence of hematuria after diagnosis in their cohort of 37 adult-onset IgAV patients with hematuria from 46% of patients at baseline and to more than 66% at last visit. In a study of 322 children and adolescents with IgAV, Buscatti et al36 reported that among those without nephritis in the first 3 months, 28% had development of renal involvement during follow-up. These findings of lateronset renal involvement suggest that active surveillance is necessary to identify patients with delayed renal pathology from IgAV. The long-term renal outcome for patients with IgAV has been suggested to be favorable compared with other small-vessel vasculitides associated with nephritis.37,38 The findings of the current series support this hypothesis because 84.X% of patients with hematuria and 72.X% with proteinuria had resolution by 5 years. Despite a notable portion of patients with persistence of hematuria or proteinuria in the current series, reduction of eGFR by 30 mL/min per 1.73 m2 or more occurred in only 38, ESRD in 26, and requirement of dialysis in 13 patients. In their IgAV nephritis cohort (83 children, 136 adults), Coppo et al19 observed similar persistence of mild to moderate renal abnormalities with normal renal function in 55%, while only 8% of the cohort had development of severe renal impairment and 11% required dialysis. A higher rate of ESRD and dialysis requirement in adults compared with children was not observed in the current series but has been noted in other reports.18,22,25 However, compared with the current cohort, the studies reporting worse renal outcomes had significantly higher rates of baseline renal involvement and renal insufficiency in adults compared with children, whereas in our study, the rates at baseline were similar. IgA vasculitis has been considered a selflimited disease, but our study found that the
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disease course can be dynamic. During the first 5 years of the disease in the current study, patients were in complete response only 40% of the time, and relapses occurred in 26 patients. Although the rates of remission14,18,20,22,23,25 and frequency of relapses14,16,18,19,22 are lower in our study population than in other cohorts, this difference is likely due in part to the strict definitions of disease status used in the current study. This variance is further supported by similar frequencies of disease status in our study compared with the report by Audemard-Verger et al,28 from which our disease status definitions were adapted. Our study noted a significant increase in mortality among patients with IgAV aged 51 years or older at diagnosis, with a greater than 7-fold increased risk of death compared with the US white population life tables (P<.001). Limited information is available regarding the risk of death among adults with IgAV. Beyond the current study, only Pillebout et al32 have reported this feature with sufficient detail for comparison. Among the 250 adults in their study, 64 patients (26%) died. The most common causes were cancer (27%), infection (16%), evolution of IgAV (11%), and cardiovascular disease (9%). Although it is expected based on age that patients with adult-onset IgAV would have a higher likelihood of development of cancer than those with childhood-onset IgAV, the high frequency of cancerassociated deaths seen by Pillebout et al32 and also in the current cohort appear out of proportion to deaths from cardiopulmonary disease, renal disease, and infection. An association between malignancy and the development of IgAV has also been proposed by others22,39; however, additional research is needed to understand whether a pathophysiologic connection is present. The findings of this study must be interpreted in the context of its limitations. First, because of its retrospective nature, information obtained is reliant on the presence of data available for medical record review. Second, although ethnic variations have not been noted among patients with IgAV, our patient cohort was 93.4% white, and 1778
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therefore the features may not be fully generalizable to other populations. Third, although all patients in this cohort had biopsy-proven IgAV, it is generally less common for pediatric patients to have biopsy for confirmation of disease. As such, a requirement for biopsy-proven IgAV may bias toward selecting pediatric patients with atypical or more severe presentations of disease. Fourth, medication regimens were not standardized and were at the discretion of the treating physician. Because of the heterogeneity of treatments used, comparisons of outcome based on medications received were not feasible. Fifth, the adult population in this cohort had a higher frequency of baseline comorbid conditions compared with the childhood-onset patients. Although this is expected because of the increased age at diagnosis in the adult cohort, it is possible that the presence of such conditions may hinder the evaluation of renal outcomes and determination of clinical response. Despite the limitations present, this study has important strengths, including that all cases were biopsy proven and seen at the same institution. In addition, the size of this report is notable for being the largest North American cohort comparing adultand childhood-onset IgAV. CONCLUSION This study provides further evidence that there are differences in the presentation and outcome between patients with adultand childhood-onset IgAV. In this cohort, adult patients with IgAV had more frequent skin ulcers and greater frequency of severe proteinuria. Patients aged 51 years or older at diagnosis had a significantly higher risk of death compared with the general population (P<.001), most commonly due to malignancy. Further research is needed to understand potential pathophysiologic implications of cancer and adult-onset IgAV. SUPPLEMENTAL ONLINE MATERIAL Supplemental material can be found online at http://www.mayoclinicproceedings.org. Supplemental material attached to journal
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articles has not been edited, and the authors take responsibility for the accuracy of all data. Abbreviations and Acronyms: CS = corticosteroid; CIS = conventional immunosuppressive drugs; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; GI = gastrointestinal; HR = hazard ratio; IgAV = IgA vasculitis; NNP = nonnephrotic proteinuria; NP = nephrotic proteinuria; RBCs/hpf = red blood cells per high-power field; SMR = standardized mortality ratio
Potential Competing Interests: Dr Warrington has received grants from GlaxoSmithKline plc and Eli Lilly and Company for clinical trial support (funds paid to his institution). The other authors report no competing interests. Data Previously Presented: These data were presented in part at the 2018 American College of Rheumatology/Association of Rheumatology Health Professionals annual meeting in Chicago, IL. Correspondence: Address to Matthew J. Koster, MD, Division of Rheumatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 ([email protected]).
REFERENCES 1. Mills JA, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of HenochSchönlein purpura. Arthritis Rheum. 1990;33(8):1114-1121. 2. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11. 3. Piram M, Mahr A. Epidemiology of immunoglobulin A vasculitis (Henoch-Schönlein): current state of knowledge. Curr Opin Rheumatol. 2013;25(2):171-178. 4. Heineke MH, Ballering AV, Jamin A, Ben Mkaddem S, Monteiro RC, Van Egmond M. New insights in the pathogenesis of immunoglobulin A vasculitis (Henoch-Schönlein purpura). Autoimmun Rev. 2017;16(12):1246-1253. 5. Piram M, Maldini C, Biscardi S, et al. Incidence of IgA vasculitis in children estimated by four-source capture-recapture analysis: a population-based study. Rheumatology (Oxford). 2017;56(8): 1358-1366. 6. Mossberg M, Segelmark M, Kahn R, Englund M, Mohammad AJ. Epidemiology of primary systemic vasculitis in children: a population-based study from southern Sweden [published correction appears in Scand J Rheumatol. 2018 Jul;47(4):344]. Scand J Rheumatol. 2018;47(4):295-302. 7. Gardner-Medwin JM, Dolezalova P, Cummins C, Southwood TR. Incidence of Henoch-Schönlein purpura, Kawasaki disease, and rare vasculitides in children of different ethnic origins. Lancet. 2002;360(9341):1197-1202. 8. Aalberse J, Dolman K, Ramnath G, Pereira RR, Davin JC. Henoch Schönlein purpura in children: an epidemiological study among Dutch paediatricians on incidence and diagnostic criteria. Ann Rheum Dis. 2007;66(12):1648-1650. 9. Okubo Y, Nochioka K, Sakakibara H, et al. Nationwide epidemiological survey of childhood IgA vasculitis associated hospitalization in the USA. Clin Rheumatol. 2016;35(11): 2749-2756. 10. Hocevar A, Rotar Z, Ostrovrsnik J, et al. Incidence of IgA vasculitis in the adult Slovenian population. Br J Dermatol. 2014; 171(3):524-527.
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11. García-Porrúa C, González-Gay MA. Comparative clinical and epidemiological study of hypersensitivity vasculitis versus Henoch-Schönlein purpura in adults. Semin Arthritis Rheum. 1999;28(6):404-412. 12. González-Gay MA, García-Porrúa C. Systemic vasculitis in adults in northwestern Spain, 1988-1997: clinical and epidemiologic aspects. Medicine (Baltimore). 1999;78(5):292-308. 13. Romero-Gómez C, Aguilar-García JA, García-de-Lucas MD, et al. Epidemiological study of primary systemic vasculitides among adults in southern Spain and review of the main epidemiological studies. Clin Exp Rheumatol. 2015;33(2, suppl 89): S-11-S-18. 14. Blanco R, Martínez-Taboada VM, Rodríguez-Valverde V, García-Fuentes M, González-Gay MA. Henoch-Schönlein purpura in adulthood and childhood: two different expressions of the same syndrome. Arthritis Rheum. 1997;40(5):859-864. 15. Uthman I, Kassak K, Nasr FW. Henoch-Schönlein purpura in adulthood and childhood: comment on the article by Blanco et al [letter]. Arthritis Rheum. 1998;41(8):1518-1520. 16. Lin SJ, Huang JL. Henoch-Schönlein purpura in Chinese children and adults. Asian Pac J Allergy Immunol. 1998;16(1):21-25. 17. Coppo R, Amore A, Gianoglio B; Italian Group of Renal Immunopathology. Clinical features of Henoch-Schönlein purpura. Ann Med Interne (Paris). 1999;150(2):143-150. 18. García-Porrúa C, Calviño MC, Llorca J, Couselo JM, GonzálezGay MA. Henoch-Schönlein purpura in children and adults: clinical differences in a defined population. Semin Arthritis Rheum. 2002;32(3):149-156. 19. Coppo R, Andrulli S, Amore A, et al. Predictors of outcome in Henoch-Schönlein nephritis in children and adults. Am J Kidney Dis. 2006;47(6):993-1003. 20. Uppal SS, Hussain MA, Al-Raqum HA, et al. Henoch-Schönlein’s purpura in adults versus children/adolescents: a comparative study. Clin Exp Rheumatol. 2006;24(2, Suppl 41):S26-S30. 21. Hung SP, Yang YH, Lin YT, Wang LC, Lee JH, Chiang BL. Clinical manifestations and outcomes of Henoch-Schönlein purpura: comparison between adults and children. Pediatr Neonatol. 2009;50(4):162-168. 22. Kang Y, Park JS, Ha YJ, et al. Differences in clinical manifestations and outcomes between adult and child patients with HenochSchönlein purpura. J Korean Med Sci. 2014;29(2):198-203. 23. Gupta V, Aggarwal A, Gupta R, et al. Differences between adult and pediatric onset Henoch-Schönlein purpura from North India. Int J Rheum Dis. 2018;21(1):292-298. 24. Lu S, Liu D, Xiao J, et al. Comparison between adults and children with Henoch-Schönlein purpura nephritis. Pediatr Nephrol. 2015;30(5):791-796. 25. Batu ED, Sari A, Erden A, et al. Comparing immunoglobulin A vasculitis (Henoch-Schönlein purpura) in children and adults: a single-centre study from Turkey. Scand J Rheumatol. 2018; 47(6):481-486. 26. Ozen S, Pistorio A, Iusan SM, et al; Paediatric Rheumatology International Trials Organisation (PRINTO). 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;69(5):798-806. 27. Inker LA, Astor BC, Fox CH, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis. 2014; 63(5):713-735. 28. Audemard-Verger A, Terrier B, Dechartres A, et al; French Vasculitis Study Group. Characteristics and management of IgA vasculitis (Henoch-Schönlein) in adults: data from 260 patients included in a French multicenter retrospective survey. Arthritis Rheumatol. 2017;69(9):1862-1870. 29. Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999; 18(6):695-706.
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30. Putter H, Fiocco M, Geskus RB. Tutorial in biostatistics: competing risks and multi-state models. Stat Med. 2007; 26(11):2389-2430. 31. Hitomi K, Izaki S, Teraki Y, et al. Characterization of adult-type IgA vasculitis (Henoch-Schönlein purpura): a retrospective study of 122 cases. Open Dermatol J. 2014;8:51-59. 32. Pillebout E, Thervet E, Hill G, Alberti C, Vanhille P, Nochy D. Henoch-Schönlein purpura in adults: outcome and prognostic factors. J Am Soc Nephrol. 2002;13(5):1271-1278. 33. Yong AM, Lee SX, Tay YK. The profile of adult onset HenochSchönlein purpura in an Asian population. Int J Dermatol. 2015; 54(11):1236-1241. 34. Chang WL, Yang YH, Wang LC, Lin YT, Chiang BL. Renal manifestations in Henoch-Schönlein purpura: a 10-year clinical study. Pediatr Nephrol. 2005;20(9):1269-1272.
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35. Shrestha S, Sumingan N, Tan J, Alhous H, McWilliam L, Ballardie F. Henoch Schönlein purpura with nephritis in adults: adverse prognostic indicators in a UK population. QJM. 2006; 99(4):253-265. 36. Buscatti IM, Casella BB, Aikawa NE, et al. Henoch-Schönlein purpura nephritis: initial risk factors and outcomes in a Latin American tertiary center. Clin Rheumatol. 2018;37(5):1319-1324. 37. Brogan P, Eleftheriou D, Dillon M. Small vessel vasculitis. Pediatr Nephrol. 2010;25(6):1025-1035. 38. Westman K, Flossmann O, Gregorini G. The long-term outcomes of systemic vasculitis. Nephrol Dial Transplant. 2015; 30(suppl 1):i60-i66. 39. Mitsui H, Shibagaki N, Kawamura T, Matsue H, Shimada S. A clinical study of Henoch-Schönlein purpura associated with malignancy. J Eur Acad Dermatol Venereol. 2009;23(4):394-401.
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Clinical Characteristics of Biopsy-Proven IgA Vasculitis in Children and Adults: A Retrospective Cohort Study Michel Villatoro-Villar, MD, MS; Cynthia S. Crowson, PhD; Kenneth J. Warrington, MD; Ashima Makol, MBBS; Steven R. Ytterberg, MD; and Matthew J. Koster, MD Abstract Objective: To describe the differences in clinical characteristics and outcome between adult- and childhood-onset biopsy-proven IgA vasculitis (IgAV) in North America. Patients and Methods: Patients with IgAV diagnosed from January 1, 1997, through December 31, 2016, were retrospectively identified. Data were abstracted from direct medical record review. KaplanMeier methods were used to estimate survival rates. Results: A total of 243 patients with IgAV were included (227 [93.4%] white, 141 [58.0%] male); 174 patients were adults (21 years), and 69 were younger than 21 years. Compared with patients younger than 21 years, adults at baseline more frequently had ulcerative skin lesions (19 [10.9%] vs 1 [1.4%]; P¼.02) and nephrotic-range proteinuria (21 of 96 [21.9%] vs 1 of 38 [2.6%]; P¼.007) but less commonly had abdominal pain (59 [33.9%] vs 42 [60.9%]; P<.001), ischemic gastrointestinal tract involvement (18 [10.3%] vs 14 [20.3%]; P¼.04), and arthralgias (66 [37.9%] vs 42 [60.8%]; P<.001). During 389 person-years of follow-up, 29 deaths were observed. Five-year survival rates for patients aged younger than 21, 21 to 50, and 51 years or older were 100%, 94%, and 40%, respectively. In comparison to data from the United States life tables for whites, patients 51 years or older at diagnosis had a greater than 7-fold increased risk of mortality (standardized mortality, 7.60 [95% CI, 5.0111.06]; P<.001). Conclusion: IgA vasculitis in adults is associated with more severe skin/kidney involvement and poorer renal outcome. Among adults with IgAV, patients aged 51 years or older at diagnosis have significantly higher mortality (P<.001). ª 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) n Mayo Clin Proc. 2019;94(9):1769-1780
I
gA vasculitis (IgAV), formerly known as Henoch-Schönlein purpura, is an immune-mediated small-vessel vasculitis in which deposition of IgA1-dominant immune complexes leads to pathologic involvement of the skin, kidneys, gastrointestinal (GI) tract, and joints.1,2 Palpable purpura is usually the first and most characteristic sign.3,4 IgA vasculitis is the most common form of childhood vasculitis and is 2 to 15 times more common in children than in adults. The estimated annual incidence of IgAV in children varies from 6.1 to 20.4 per
100,000 children, with the highest proportion occurring within the first 10 years of life.5-9 However, in adults the annual incidence is lower and has been estimated at 1.4 to 5.1 per 100,000 adults, with an increased frequency in the fifth and sixth decades of life and a slight male predominance.10-13 Differences in both the presentation and outcome have been described in adults compared with children, with most studies reporting a higher frequency of severe renal manifestations and poorer renal outcome among the adult population.14-25 Although
From the Division of Rheumatology (M.V.-V., C.S.C., K.J.W., A.M., S.R.Y., M.J.K.) and Department of Health Sciences Research (C.S.C.), Mayo Clinic, Rochester, MN.
Mayo Clin Proc. n September 2019;94(9):1769-1780 n https://doi.org/10.1016/j.mayocp.2019.04.034 www.mayoclinicproceedings.org n ª 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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multiple European and Asian studies have been reported, cohorts evaluating the differences between patients with adult- and childhood-onset IgAV in North America are limited. The aim of this study was to describe the differences between baseline clinical characteristics and outcomes of childhood- and adult-onset biopsy-proven IgAV from a large, North American, singleinstitution cohort. PATIENTS AND METHODS Study Population This study was performed in accordance with the ethical standards of the Helsinki Declaration and was approved by Mayo Clinic, Rochester, Minnesota, Institutional Review Board (IRB #17-004520). Patients diagnosed as having IgAV at the Mayo Clinic in Rochester, Minnesota, from January 1, 1997, through December 31, 2016, were retrospectively identified. An institutional clinical database was used to search for all patients with at least one International Classification of Diseases, Ninth Revision, Clinical Modification or International Classification of Diseases, Tenth Revision, Clinical Modification code for HenochSchönlein purpura or cutaneous vasculitis (Supplemental Table 1, available online at http://www.mayoclinicproceedings.org) during an inpatient or outpatient encounter. Identified patients were then further evaluated through direct medical record review. Inclusion criteria for this study were the presence of all of the following: cutaneous findings of IgAV, biopsy (skin and/or kidney) with histologic evidence of small-vessel vasculitis on light microscopy, and the presence of predominant IgA deposition on direct immunofluorescence. All patients were required to fulfill classification criteria for IgAV by either the 1990 American College of Rheumatology criteria and/or the European League Against Rheumatism/Paediatric Rheumatology International Trials Organization/ Paediatric Rheumatology European Society (EULAR/PRINTO/PRES) criteria for HenochSchönlein purpura.1,26 Patients with a clinical diagnosis of IgAV but an inconclusive initial 1770
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biopsy were included provided one or more subsequent skin or kidney biopsy confirmed classic features of IgAV. In a small subset of patients, baseline biopsy was deferred but performed later in the course of follow-up. These patients were included if the subsequently obtained biopsy yielded evidence consistent with IgAV. In such circumstances, the date of diagnosis was the initial onset of clinical symptoms consistent with IgAV. Patients with isolated renal involvement, even if IgA deposition was identified on renal biopsy, were excluded in order to avoid confusion with IgA nephropathy. Further exclusions included the presence of any of the following conditions: IgA monoclonal gammopathy of uncertain significance, multiple myeloma, cryoglobulinemia, hepatitis B, hepatitis C, or other documented primary systemic small-vessel vasculitis. Patients were divided into 2 groups based on the first age at onset of clinical symptoms attributable to IgAV, with 21 years or older considered as adult onset.
Clinical and Laboratory Data Clinical and laboratory data obtained at baseline and at each follow-up visit were confirmed through direct medical record review. Risk factors associated with IgAV were considered to be potential precipitant events if they occurred within 1 month before the onset of symptoms attributable to IgAV. For this study, events of interest included previous infection, antibiotic exposure, immunizations, and use of nonsteroidal anti-inflammatory drugs. The type of skin lesions (eg, purpura, ulcers, nodules) and their distribution were abstracted from records of the the initial and subsequent visits. Joint symptoms and GI tract abnormalities were also recorded. Renal involvement included microscopic hematuria, gross hematuria, nonnephrotic proteinuria (NNP), nephrotic proteinuria (NP), and renal insufficiency. Definitions used for assessment of renal, joint, and GI tract involvement are outlined in Supplemental Table 2 (available online at http://www. mayoclinicproceedings.org).
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The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation in patients aged 18 years or older and the Bedside Schwartz equation for those younger than 18 years. Chronic kidney disease stages were considered according to the National Kidney Foundation Kidney Diseases Outcomes Quality Initiative recommendation.27 Disease Status Disease status at each visit was classified according to definitions adapted from Audemard-Verger et al.28 Complete response was considered as improvement in all baseline clinical manifestations including (if present) reduction of proteinuria to urinary protein levels of less than 0.5 g/d, disappearance of hematuria or reduction to less than 10 red blood cells per high-power field (RBCs/hpf), and less than 20% decrease of eGFR from baseline. Partial response was considered as improvement in at least one-half of baseline clinical manifestations and in the case of renal involvement, an improvement of proteinuria to less than 50% of the baseline value, disappearance of hematuria or reduction to less than 10 RBCs/hpf, and less than 20% decrease of eGFR from baseline. Nonresponse was considered as lack of improvement in any organ system or improvement in less than half of the manifestations present at baseline. Relapse was defined as reappearance of clinical signs of vasculitis, attributable to IgAV, occurring after a symptom-free period of at least 1 month. Outcome The status at the last documented follow-up was used for overall outcome. Renal outcomes included resolution of hematuria and proteinuria, renal impairment (eGFR <50 mL/min per 1.73 m2), and development of end-stage renal disease (ESRD), defined as an eGFR of less than 15 mL/min per 1.73 m2, uremia, and requirement of dialysis or renal transplant. Severe bowel involvement was defined as necessity of bowel surgery, bowel hemorrhage (requiring blood transfusion), or objective evidence of ischemia or infarct. Mayo Clin Proc. n September 2019;94(9):1769-1780 www.mayoclinicproceedings.org
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Mortality for any cause following IgAV diagnosis was recorded and cause of death was noted, when available. Deaths were attributable to IgAV if the cause of death was development of organ failure leading to death during a time that IgAV was active and no other explanation of organ failure was present (eg, sepsis, cancer, heart failure). Statistical Analyses Descriptive statistics (percentage, mean) were used to summarize patient characteristics. Comparisons between age groups were performed using c2 and rank sum tests. Survival rates were estimated using the Kaplan-Meier method and were compared with expected survival rates for persons of the same age, sex, and calendar year estimated using US population life tables for whites. The standardized mortality ratio (SMR) was estimated as the ratio of the observed and expected number of deaths. The 95% CIs for the SMR were calculated assuming that the expected rates are fixed and the observed rates follow a Poisson distribution. The cumulative incidence of each outcome (eg, hematuria, proteinuria) adjusted for the competing risk of death was estimated.29 These methods are similar to the Kaplan-Meier method with censoring of patients who are still alive at last follow-up. However, patients who die before experiencing the outcome are appropriately accounted for to avoid overestimation of the rate of occurrence of the outcome, which can occur if such individuals are simply censored at death. For the progression through disease states (eg, relapse, partial or complete response), Aalen-Johansen methods (a multistate generalization of cumulative incidence) were used to estimate the prevalence of each disease state over time.30 Univariable Cox models were used to examine prognostic factors of relapse, partial response, complete response, and resolution of renal involvement. Analyses were performed using SAS statistical software, version 9.4 (SAS Institute) and R 3.4.2 (R Foundation for Statistical Computing). RESULTS The clinical database search identified 745 potential patients based on diagnostic
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TABLE 1. Clinical Characteristics of Patients With IgA Vasculitis at Diagnosis, Stratified by Age Groupa,b,c Age at diagnosis (y) Variable Demographic characteristics Age (y) Male White BMI (kg/m2) Comorbidities Diabetes mellitus Hypertension ESRD or dialysis
<21 (n¼69)
21 (n¼174)
Total (N¼243)
P value
12.75.7 39 (56.5) 64 (92.8) 22.87.7
50.917.4 102 (58.6) 163 (93.7) 32.28.8
40.122.9 141 (58.0) 227 (93.4) 29.69.5
<.001 .77 .83 <.001
39 (22.4) 65 (37.4) 8 (4.6)
39 (16.0) 65 (26.7) 8 (3.3)
<.001 <.001 .07
0 (0) 0 (0) 0 (0)
Baseline characteristics Previous infection Recent URId Antibiotic exposure NSAIDs exposure Fever Weight loss
27 13 11 1 10 3
(39.1) (48) (15.9) (1.4) (14.5) (4.3)
73 22 47 17 24 10
(42.0) (31) (27.0) (9.8) (13.8) (5.7)
100 35 58 18 34 13
(41.2) (35) (23.9) (7.4) (14.0) (5.3)
.10 .01 .08 .03 .88 .68
Abdominal involvement Nonischemic Abdominal pain Nausea/vomiting Diarrhea Ischemic Hematochezia/melena Hematemesis
43 43 42 15 5 14 13 2
(62.3) (62.3) (60.9) (21.7) (7.2) (20.3) (18.8) (2.9)
75 74 59 34 26 18 17 1
(43.1) (42.5) (33.9) (19.5) (14.9) (10.3) (9.8) (0.8)
118 117 101 49 31 32 30 3
(48.6) (48.1) (41.6) (20.2) (12.8) (13.2) (12.3) (1.2)
.007 .005 <.001 .70 .11 .04 .05 .14
Skin involvement Palpable purpura Lower extremity Upper extremity Abdomen/back Chest/trunk Ulceration
69 69 68 35 19 8 1
(100) (100) (98.6) (50.7) (27.5) (11.6) (1.4)
174 173 169 95 65 32 19
(100) (99.4) (97.1) (54.6) (37.4) (18.4) (10.9)
243 242 237 130 84 40 20
(100) (99.6) (97.5) (53.5) (34.6) (16.5) (8.2)
.53 .53 .52 .59 .15 .20 .02
Arthralgia Lower extremity Upper extremity
42 (60.8) 39 (56.5) 17 (24.6)
Neuropathy
0 (0)
Renal involvement Microscopic hematuria Gross hematuria Proteinuria Nonnephrotic rangee Nephrotic rangef Creatinine (mg/dL) eGFR (mL/min/1.73 m2) Renal insufficiencyg
47 (68.1) 33 (47.8) 3 (4.3) 38 (55.1) 37/38 (97.4) 1/38 (2.6) 0.70.3 113.629.7 1 (1.4)
Laboratory studies C-reactive protein (mg/L) ESR (mm/h)
26.829.9 17.615.4
66 (37.9) 60 (34.5) 29 (16.7)
108 (44.4) 99 (40.7) 46 (18.9)
.001 .002 .15
13 (7.5)
13 (5.3)
.02
115 (66.1) 162 (66.7) .76 81 (46.6) 114 (46.9) .86 6 (3.4) 9 (3.7) .74 96 (55.2) 134 (55.1) .99 75/96 (78.1) 112/134 (83.6) .007 21/96 (21.9) 22/134 (16.4) .007 1.41.4 1.21.3 <.001 78.935.6 88.937.4 <.001 12 (6.9) 13 (5.3) .09 40.742.6 30.327.9
37.440.3 27.226.0
.14 .04
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coding. Following direct medical record review, 502 patients were excluded for the following reasons: symptoms suggestive of IgAV but without biopsy ever performed (n¼153), isolated cutaneous vasculitis without clinical features of IgAV or IgA deposition on biopsy (n¼147), cutaneous vasculitis due to other primary systemic vasculitis (n¼91), cutaneous vasculitis secondary to identified precipitant (autoimmune disease [n¼15], drug reaction [n¼12], hepatitis [n¼2]), nonvasculitic purpura (n¼73), and IgA nephropathy (n¼9). Baseline Characteristics A total of 243 patients (227 [93.4%] white, 141 [58.0%] male) met inclusion criteria for biopsy-proven IgAV. Sixty-nine patients were younger than 21 years (children), and 174 were 21 years or older (adults). Among the adult cases, 90 were 51 years of age or older at diagnosis. Baseline characteristics are further outlined in Table 1. The mean SD age for patients younger than 21 years at diagnosis was 12.75.7 years compared with 50.917.4 years for those 21 years or older at diagnosis. American College of Rheumatology criteria for IgAV were met in 69 patients younger than 21 years (100%) and in 171 adults (98.3%). The EULAR/PRINTO/PRES criteria were met in 68 patients younger than 21 years (99.6%) and in all 174 adults (100%). The distribution of skin lesions was similar between children and adults, with lower extremity involvement predominantly noted (68 [98.6%] and 169 [97.1%]), followed by upper extremities (95 [54.6%] and 29 [16.7%]), abdomen/lower back (19 [27.5%] and 65 [37.4%]), and chest/upper back (8 [11.6%] and 32 [18.4%]), respectively. Diffuse distribution with involvement of the upper and lower extremities and torso was seen in 17 of 52 children (24.6%) and 50 adults (28.7%). Skin ulceration occurred more frequently in adults than children (19 [10.9%] vs 1 [1.4%]; P¼.02). Patients younger than 21 years had more abdominal symptoms compared with adults (43 [62.3%] vs 45 [43.1%]; P¼.007). Abdominal pain was the most common GI tract
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symptom in both groups and was more frequent in children (42 [60.9%] vs 59 [33.9%]; P<.001). Ischemic GI tract symptoms, in general, were also seen more often in children than in adults (14 [20.3%] vs 18 [10.3%]; P¼.04). Hematochezia/melena occurred in 13 children (19.8%) and 17 adults (9.8%) but did not reach statistical significance (P¼.05). Hematemesis was rare (2 children, 1 adult). No bowel perforations or intussusceptions were present at diagnosis. Abdominal imaging (computed tomogrpahy [CT], magnetic resonance imaging [MRI], ultrasonography [US]) was performed in 55.6% of patients at baseline (102 adults and 33 children). The leading abdominal findings among those who underwent CT or MRI abdominal imaging were bowel wall thickening (22 of 71 adults [31.0%] and 5 of 17 children [29.4%]), followed by bowel edema (11 of 71 adults [155%] and 4 of 17 children [23.5%]). Among patients with at least one abdominal US, CT, or MRI, intestinal infarcts were seen in 1 child (3.0%) and 3 adults (2.9%). At baseline, renal involvement was documented in 66.7% of the entire cohort (162 patients) and did not differ between groups. Proteinuria was the most frequent finding, present in 38 children (55.1%) and 96 adults (55.2%). Among the 134 patients with proteinuria, NNP was seen in 112 (83.6%) and NP in 22 (16.4%). Nonnephrotic proteinuria was more frequently found in patients younger than 21 years than in adults (37 of 38 patients [97.4%] vs 75 of 96 [78.1%]; P¼.007), whereas NP was more often noted in adults (21 of 96 [21.9%] vs 1 of 38 [2.6%]; P¼.007). At diagnosis, hematuria was present in 123 patients (50.6%); microscopic hematuria was documented in 114 (46.9%) and gross hematuria in 9 (3.7%), similar in both groups. Among children (n¼36) and adults (n¼87) with hematuria, less than 10 RBCs/hpf were observed in 16 (44.4%) and 32 (36.8%), 10 to 49 RBCs/hpf in 14 (38.9%) and 32 (36.8%), and 50 or more RBCs/hpf in 6 (16.7%) and 23 (26.4%), respectively. Given that the study period covered 20 years of IgAV diagnosis, patients were further evaluated to determine if there were any Mayo Clin Proc. n September 2019;94(9):1769-1780 www.mayoclinicproceedings.org
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TABLE 1. Continued Age at diagnosis (y) Variable
<21 (n¼69)
21 (n¼174)
Total (N¼243)
198.0100.3
375.8315.9
323.1280.4
P value
Laboratory studies, continued Serum IgA (mg/dL) Initial treatment Oral CS Topical CS ACEI/ARB NSAID CIS
52 39/52 8/52 9/52 12/52 7/52
(75.4) 130 (74.7) 182 (74.9) (75.0) 106/130 (81.5) 145/182 (79.7) (15.4) 33/130 (25.4) 41/182 (22.5) (17.3) 31/130 (23.8) 40/182 (22.0) (23.1) 21/130 (16.2) 33/182 (18.1) (13.5) 15/130 (11.5) 22/182 (12.1)
.06 .92 .32 .15 .34 .27 .72
ACEI/ARB ¼ angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; BMI ¼ body mass index; CIS ¼ conventional immunosuppressive drugs; CS ¼ corticosteroids; eGFR ¼ estimated glomerular filtration rate; ESR ¼ erythrocyte sedimentation rate; ESRD ¼ end-stage renal disease; NSAIDs ¼ nonsteroidal anti-inflammatory drugs; URI ¼ upper respiratory tract infection. b Data are presented as mean SD or No. (percentage) of patients. c SI conversion factors: To convert creatinine values to mmol/L, multiply by 88.4; to convert C-reactive protein values to nmol/L, multiply by 9.524; to convert IgA values to mg/L, multiply by 10. d Percentages based on number of patients with documented presence of infection OR. e 0.2 g/d, <3.5 g/d. f 3.5 g/d. g eGFR <15 mL/min or dialysis requirement. a
differences in baseline characteristics per study decade. Patients (adult- and childhood-onset) who were diagnosed as having IgAV between 1997 and 2006 were compared with those diagnosed between 2007 and 2016. No significant differences in baseline characteristics were observed between these 2 time periods (P>.05, respectively). Histopathology Baseline skin biopsy was performed in 164 patients (67.5%), renal biopsy in 42 (17.3%), and skin-kidney biopsies (combined) in 16 patients (6.6%). Skin biopsy was performed more frequently in adults than in patients younger than 21 years (137 [78.7%] vs 28 [40.6%]; P<.001). Among patients with a clinical diagnosis of IgAV in whom biopsy was not performed at the onset of symptoms (n¼3) or was performed and results were inconclusive (n¼18), all had a confirmatory biopsy within 2 years of their initial IgAV symptoms. The mean SD time from diagnosis to kidney biopsy was 24.834.2 days and did not differ significantly between groups (P¼.47).
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100
Prevalence (%)
80
60
40
20
0
1
2 3 Months
6
1
2
3 Years
4
5
39
29
23
Time since diagnosis No: 205
184
Active
168 Death
135
94 Relapse
59
Partial
Complete
FIGURE 1. Prevalence of IgA vasculitis disease state at each study time point during follow-up. At 1 year after diagnosis 42% (95% CI, 30%-51%) had complete response, 32% (95% CI, 24%-39%) had a partial response, 10% (95% CI, 6%-13%) had no response, 5% (95% CI, 0%-10%) had relapse, and 12% (95% CU, 5%-19%) were deceased.
Mesangial IgA deposits were identified through direct immunofluorescence in all cases. Proliferative glomerulonephritis was noted in 34 patients (14.0%), crescentic glomerulonephritis in 19 (7.8%), focal sclerosis in 4.9%, and necrotizing glomerulonephritis in 8 (3.3%). Treatment At diagnosis, 182 patients (74.9%) received treatment. The mean SD time from diagnosis to initial treatment was 2.28.7 days, similar in both groups. Corticosteroids (CSs), systemic and topical, were the primary treatments used (in 145 of 182 patients [79.7%] and 41 of 182 [22.5%], respectively). The initial systemic CS dose (or prednisone equivalent) was higher in adults than in children (mean, 2.65.5 vs 1.52.7 mg/kg; P¼.04), with a median of 60 mg/d (0.9 mg/kg) in adults and 40 mg/d (0.6 mg/kg) in children. A CS bolus (>80 mg prednisone or equivalent for one or more consecutive doses) at baseline was employed in 16 patients (14 adults). 1774
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Angiotensin-converting enzyme inhibitors/ angiotensin II receptor blockers were initiated in 40 of 182 patients (22.0%), nonsteroidal anti-inflammatory drugs in 33 of 182 (18.1%), and conventional immunosuppressive drugs (CIS) in 22 of 182 (12.1%). Among patients started on CIS at baseline, azathioprine and mycophenolate mofetil were most frequently used (n¼8 for each), followed by methotrexate (n¼7) and cyclophosphamide (n¼4). Dapsone was used in 5% of patients and colchicine in 3%. Plasma exchange (n¼2), antileukotriene agents (n¼3), and rituximab (n¼1) were uncommonly employed at the time of diagnosis in this cohort, which dates to 1997. Outcome Disease Status During Follow-up. The mean SD length of follow-up was similar between groups; 1.82.2 years in children and 1.52.3 years in adults, with a total of 389 person-years of follow-up. The prevalence of disease states over time is presented in Figure 1. At 1 year after diagnosis 42% (95% CI, 30%-51%) had complete response, 32% (95% CI, 24%-39%) had a partial response, 10% (95% CI, 6%-13%) had no response, 5% (95% CI, 0%-10%) had relapse, and 12% (95% CU, 5%-19%) were deceased. A total of 151 patients achieved complete response. During the first 5 years of disease, patients were in complete response only 40% of the time. Twenty-six patients (17 adults, 9 children) experienced at least one first relapse; 18 patients had a single relapse, 6 patients had 2 relapses, and 2 patients had 4 relapses. Active skin lesions were the most frequently observed finding during relapse (in 21 patients [80.8%]), predominantly in adults (16 [94.1%] vs 5 [55.6%]; P¼.02). Nonischemic abdominal symptoms (2 [22.2%] vs none [0%]; P¼.04) were more common in children at relapse. Renal involvement with worsening or recurrence of hematuria (4 [44.4%] children, 7 [41.2%] adults) and/or proteinuria (5 [55.6%] children, 9 [52.9%] adults) was similar between groups. Risk factor analysis of baseline parameters and their association with time to complete response, partial response, and first
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relapse revealed that baseline hematuria (>10 RBC/hpf or gross; hazard ratio [HR], 0.48 [95% CI, 0.27-0.84]; P¼.01) and proteinuria (HR, 0.68 [95% CI, 0.50-0.93]; P¼.02) resulted in a longer time to complete response. Sex, baseline creatinine level, eGFR, distribution of cutaneous vasculitis, arthritis, abdominal involvement, and the presence of crescentic or proliferative glomerulonephritis were not associated with a difference in time to complete response or first relapse. Given the lack of a standardized approach to treatment, patients who received only a single medication during their treatment course were analyzed for risk association with disease status outcome. Patients who received only CSs (P¼.50), dapsone (P¼.22), or colchicine (P¼.13) did not have a significantly different length of time to complete response (P¼.50); however, patients who received only CIS (vs no CSs, colchicine, or dapsone) took longer to achieve complete response (HR, 0.64; 95% CI, 0.42-0.99; P¼.04) (Table 2). Patients who received only CSs, CIS, or dapsone did not differ in the time to first relapse, but patients who received only colchicine experienced relapse sooner (HR, 13.02; 95% CI, 2.94-57.67; P<.001). Patients who received angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, whether taking at the time of diagnosis (HR, 0.66; 95% CI, 0.46-0.94; P¼.02) or starting after diagnosis (HR, 0.66; 95%
CI, 0.46-0.93; P¼.02) took longer to achieve complete response. Renal Outcome. During the study period, a total of 179 patients had hematuria (123 baseline and 56 more at follow-up), with the cumulative incidence of hematuria increasing from 50.6% at baseline to 78% (95% CI, 72%-84%) by 1 year and 179 had proteinuria (134 at baseline and 45 more at follow-up), with the cumulative incidence of proteinuria increasing from 55.1% at baseline to 77% (95% CI, 72%-84%) by 1 year (Supplemental Figure 1, available online at http://www. mayoclinicproceedings.org). Among the 179 patients with hematuria at baseline or during follow-up, 104 patients experienced resolution of hematuria, with 52% (95% CI, 44%61%) experiencing resolution by 1 year and 84% (95% CI, 77%-92%) by 5 years after the development of hematuria. Of the 179 patients with proteinuria, 97 had resolution of proteinuria during follow-up, with 50%; (95% CI, 42%-58%) experiencing resolution by 1 year and 72%; (95% CI, 64%-89%) by 5 years after development of proteinuria (Supplemental Figure 2, available online at http://www. mayoclinicproceedings.org). A risk factor analysis evaluating age, sex, baseline renal function, type of baseline renal involvement, and characteristics of renal histopathology found no specific factors associated with increased likelihood of resolution of renal involvement.
TABLE 2. Risk Factor Analysis for Time to Complete Response, Partial Response, or Relapsea,b Complete response HR (95% CI)
P value
Partial response HR (95% CI)
P value
ACEI/ARB Present at diagnosis (vs none) Started after diagnosis (vs none)
0.66 (0.46-0.94) 0.66 (0.46-0.93)
.02 .02
0.98 (0.70-1.37) 1.05 (0.76-1.44)
.89 .78
CS only (vs no CS, CIS, colchicine, or dapsone)
0.87 (0.59-1.29)
.50
1.21 (0.87-1.70)
.26
CIS only (vs no CS, CIS, colchicine, or dapsone)
0.64 (0.42-0.99)
.04
1.09 (0.73-1.64)
.66
Colchicine (vs no CS, CIS, colchicine, or dapsone)
0.55 (0.25-1.20)
.13
1.03 (0.56-1.92)
.92
Dapsone (vs no CS, CIS, colchicine, or dapsone)
1.36 (0.83-2.22)
.22
0.73 (0.42-1.25)
.25
Risk factor
ACEI/ARB ¼ angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker; HR ¼ hazard ratio; CIS ¼ conventional immunosuppressive drugs; CS ¼ corticosteroids. b Relapse was assessed in the subset of patients who achieved complete response. Multiple responses or relapses per person are included and appropriately accounted for in the models. a
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100
100
80
80 Survival (%)
Survival (%)
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60 40 20
0 0
2
A
4 6 8 Years after diagnosis
10
100
100
80
80
60 40
0
0 4 6 8 Years after diagnosis
4 6 8 Years after diagnosis
10
0
2
4 6 8 Years after diagnosis
10
40 20
2
2
60
20
0
0
B
Survival (%)
Survival (%)
40 20
0
C
60
10
D
FIGURE 2. Survival of the study population (solid line) compared with expected rates from the United States life tables for whites (dashed line) for patients younger than 21 years (A), 21 to 50 years (B; standardized mortality ratio [SMR], 5.62; 95% CI, 0.68-20.29), 51 years or older (C; SMR, 7.60; 95% CI, 5.01-11.06), and overall (D; SMR, 7.34; 95% CI, 4.91-10.54).
A reduction in eGFR by 30 mL/min per 1.73 m2 or more was reported in 38 patients by last follow-up; 10% (95% CI, 7%-16%) at 3 months, 21% (95% CI, 15%-30%) at 1 year, and 39% (95% CI, 28%-54%) at 5 years after IgAV diagnosis. Overall, 26 patients had development of ESRD after diagnosis, with a cumulative incidence of 10% (95% CI, 6%14%) at 1 year and 15% (95% CI, 8%-22%) at 5 years. Following the diagnosis of IgAV, dialysis was initiated in 13 patients: 3 younger than 21 years, 2 aged 21 to 50 years, and 8 who were 51 years or older. Renal transplant was performed in 4 patients (3 children, 1 adult). Analysis of patients diagnosed between 1997 and 2006 and those diagnosed between 2007 and 2016 revealed no difference in outcome based on study decade. Mortality. In total, 29 deaths were observed over 389 patient-years of follow-up
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(27 among patients aged 51 years, 2 in patients aged 21-50 years, and none in patients <21 years at diagnosis). Causes of death included malignancy (n¼9), cardiopulmonary disease (n¼6), infection/sepsis (n¼6), complication of IgAV (n¼3), ESRD (n¼3), and other causes (n¼2). Five-year survival rates in patients with IgAV for those younger than 21 years, 21 to 50 years, and 51 years or older at diagnosis were 100% (95% CI, 100%-100%), 94% (95% CI, 87%-100%), and 40% (95% CI, 9%-26%), respectively. In comparison to United States life tables for whites (Figure 2), patients with IgAV had similar survival rates for patients younger than 21 years and 21 to 50 years; however, patients 51 years or older at diagnosis had a greater than 7-fold increased risk of mortality compared with the US white population (SMR, 7.60; 95% CI, 5.01-11.06; P<.001).
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DISCUSSION Most studies evaluating patients with IgAV have been performed in Asia and Europe, with few studies describing this condition in North America. This report represents the largest, single-institution, North American cohort comparing adult- and childhoodonset biopsy-proven IgAV and provides additional information regarding the differences in presentation and long-term outcomes. Cutaneous involvement in IgAV with palpable purpura is a prominent feature and commonly the earliest manifestation observed. Patients in the current study had distributions of cutaneous involvement similar to that reported by other investigators.14,18,21,22,31 Although the distribution of palpable purpura was similar between adult- and childhood-onset IgAV in the current series, adults had more severe lesions, with ulcerative or hemorrhagic skin findings detected in 10.9% compared with only 1.4% of children. Although few studies have reported the presence of such skin lesions among patients with IgAV, Hitomi et al31 identified ulcers or hemorrhagic bullae in 14.1% of their adult population compared with 5.4% of children. The presence of ulcerative lesions has been reported by other groups evaluating only adult-onset IgAV, with frequencies between 13% and 35%.28,32,33 These findings highlight that clinicians must consider IgAV in patients with ulcerative skin lesions, particularly if present in adults, and underscore the benefit of direct immunofluorescence, which would assist in the diagnosis of IgAV in such cases. Renal involvement was present in over two-thirds of both adults and children in the present series. Although rates of hematuria and proteinuria at baseline were similar between adults and children, the presence of severe proteinuria was significantly higher among adults (P¼.007), a feature that has been similarly observed in other comparative cohort studies.14-16,18,20 It has been suggested by some authors that renal involvement in IgAV occurs early in the disease, with few patients having development of renal pathology beyond 4 weeks from Mayo Clin Proc. n September 2019;94(9):1769-1780 www.mayoclinicproceedings.org
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IgAV diagnosis.21,34 In the current series, hematuria was present in 50.6% and proteinuria in 55.1% at presentation but increased to 78% and 71% at one year, respectively. Shrestha et al35 observed a similar increasing incidence of hematuria after diagnosis in their cohort of 37 adult-onset IgAV patients with hematuria from 46% of patients at baseline and to more than 66% at last visit. In a study of 322 children and adolescents with IgAV, Buscatti et al36 reported that among those without nephritis in the first 3 months, 28% had development of renal involvement during follow-up. These findings of lateronset renal involvement suggest that active surveillance is necessary to identify patients with delayed renal pathology from IgAV. The long-term renal outcome for patients with IgAV has been suggested to be favorable compared with other small-vessel vasculitides associated with nephritis.37,38 The findings of the current series support this hypothesis because 84.X% of patients with hematuria and 72.X% with proteinuria had resolution by 5 years. Despite a notable portion of patients with persistence of hematuria or proteinuria in the current series, reduction of eGFR by 30 mL/min per 1.73 m2 or more occurred in only 38, ESRD in 26, and requirement of dialysis in 13 patients. In their IgAV nephritis cohort (83 children, 136 adults), Coppo et al19 observed similar persistence of mild to moderate renal abnormalities with normal renal function in 55%, while only 8% of the cohort had development of severe renal impairment and 11% required dialysis. A higher rate of ESRD and dialysis requirement in adults compared with children was not observed in the current series but has been noted in other reports.18,22,25 However, compared with the current cohort, the studies reporting worse renal outcomes had significantly higher rates of baseline renal involvement and renal insufficiency in adults compared with children, whereas in our study, the rates at baseline were similar. IgA vasculitis has been considered a selflimited disease, but our study found that the
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disease course can be dynamic. During the first 5 years of the disease in the current study, patients were in complete response only 40% of the time, and relapses occurred in 26 patients. Although the rates of remission14,18,20,22,23,25 and frequency of relapses14,16,18,19,22 are lower in our study population than in other cohorts, this difference is likely due in part to the strict definitions of disease status used in the current study. This variance is further supported by similar frequencies of disease status in our study compared with the report by Audemard-Verger et al,28 from which our disease status definitions were adapted. Our study noted a significant increase in mortality among patients with IgAV aged 51 years or older at diagnosis, with a greater than 7-fold increased risk of death compared with the US white population life tables (P<.001). Limited information is available regarding the risk of death among adults with IgAV. Beyond the current study, only Pillebout et al32 have reported this feature with sufficient detail for comparison. Among the 250 adults in their study, 64 patients (26%) died. The most common causes were cancer (27%), infection (16%), evolution of IgAV (11%), and cardiovascular disease (9%). Although it is expected based on age that patients with adult-onset IgAV would have a higher likelihood of development of cancer than those with childhood-onset IgAV, the high frequency of cancerassociated deaths seen by Pillebout et al32 and also in the current cohort appear out of proportion to deaths from cardiopulmonary disease, renal disease, and infection. An association between malignancy and the development of IgAV has also been proposed by others22,39; however, additional research is needed to understand whether a pathophysiologic connection is present. The findings of this study must be interpreted in the context of its limitations. First, because of its retrospective nature, information obtained is reliant on the presence of data available for medical record review. Second, although ethnic variations have not been noted among patients with IgAV, our patient cohort was 93.4% white, and 1778
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therefore the features may not be fully generalizable to other populations. Third, although all patients in this cohort had biopsy-proven IgAV, it is generally less common for pediatric patients to have biopsy for confirmation of disease. As such, a requirement for biopsy-proven IgAV may bias toward selecting pediatric patients with atypical or more severe presentations of disease. Fourth, medication regimens were not standardized and were at the discretion of the treating physician. Because of the heterogeneity of treatments used, comparisons of outcome based on medications received were not feasible. Fifth, the adult population in this cohort had a higher frequency of baseline comorbid conditions compared with the childhood-onset patients. Although this is expected because of the increased age at diagnosis in the adult cohort, it is possible that the presence of such conditions may hinder the evaluation of renal outcomes and determination of clinical response. Despite the limitations present, this study has important strengths, including that all cases were biopsy proven and seen at the same institution. In addition, the size of this report is notable for being the largest North American cohort comparing adultand childhood-onset IgAV. CONCLUSION This study provides further evidence that there are differences in the presentation and outcome between patients with adultand childhood-onset IgAV. In this cohort, adult patients with IgAV had more frequent skin ulcers and greater frequency of severe proteinuria. Patients aged 51 years or older at diagnosis had a significantly higher risk of death compared with the general population (P<.001), most commonly due to malignancy. Further research is needed to understand potential pathophysiologic implications of cancer and adult-onset IgAV. SUPPLEMENTAL ONLINE MATERIAL Supplemental material can be found online at http://www.mayoclinicproceedings.org. Supplemental material attached to journal
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articles has not been edited, and the authors take responsibility for the accuracy of all data. Abbreviations and Acronyms: CS = corticosteroid; CIS = conventional immunosuppressive drugs; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; GI = gastrointestinal; HR = hazard ratio; IgAV = IgA vasculitis; NNP = nonnephrotic proteinuria; NP = nephrotic proteinuria; RBCs/hpf = red blood cells per high-power field; SMR = standardized mortality ratio
Potential Competing Interests: Dr Warrington has received grants from GlaxoSmithKline plc and Eli Lilly and Company for clinical trial support (funds paid to his institution). The other authors report no competing interests. Data Previously Presented: These data were presented in part at the 2018 American College of Rheumatology/Association of Rheumatology Health Professionals annual meeting in Chicago, IL. Correspondence: Address to Matthew J. Koster, MD, Division of Rheumatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 ([email protected]).
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