AUTREV-01685; No of Pages 7

Autoimmunity Reviews xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Autoimmunity Reviews
journal homepage: www.elsevier.com/locate/autrev

1 Review

2Q4 IgA vasculitis (Henoch–Shönlein purpura) in adults: Diagnostic and

3 therapeutic aspects

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4Q5 Alexandra Audemard-Verger a,⁎, Evangeline Pillebout b, Loïc Guillevin a, Eric Thervet c, Benjamin Terrier a

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5Q6 a
Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Descartes,
6 Paris, France
7 b
Department of Nephrology, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France

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8 c
Department of Nephrology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Descartes, Paris, France

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9 a r t i c l e i n f o a b s t r a c t

10 20

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Article history: Immunoglobulin A (IgA) vasculitis, formerly called Henoch–Schönlein purpura, is an immune complex vasculitis
11 Received 1 February 2015 affecting small vessels with dominant IgA deposits. Clinical manifestations mainly involve cutaneous purpura, ar- 21
12 Accepted 5 February 2015 thralgias and/or arthritis, acute enteritis and glomerulonephritis. IgA vasculitis is more common among children 22
13 Available online xxxx
than adults, with more severe disease in adults. Gastrointestinal and renal involvements represent the principal
D 23
causes of morbidity and mortality in adults. Factors associated with long-term end-stage renal disease (ESRD) 24
14 Keywords:
15 IgA vasculitis
include baseline renal function impairment and baseline proteinuria N1 or 1.5 g/day, and on renal biopsy degree 25
16 of interstitial fibrosis, sclerotic glomeruli and fibrinoid necrosis. Management of IgA vasculitis in adults is ren- 26
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Henoch–Shönlein purpura
17 Characteristics dered difficult for clinicians because of the absence of correlation between initial presentation and long-term 27
18 Prognosis renal outcome, and the possible occurrence of spontaneous remission in patients with severe presentation or, 28
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19 Treatment in contrast, possible evolution to ESRD in patients with mild symptoms. 29

Treatment is often symptomatic because disease course is usually benign. Treatment of severe involvement, 30
including severe gastrointestinal complications or proliferative glomerulonephritis, remains controversial, with 31
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no evidence that corticosteroids or immunosuppressive agents improved long-term outcome. Prospective, 32

randomized, controlled trials are thus needed to analyze the benefit–risk ratio of such treatments. 33
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© 2015 Published by Elsevier B.V.

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40
39 Contents
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41 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
42 2. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
43 3. Classification, definition, diagnostic criteria and their limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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44 3.1. The American College of Rheumatology classification criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

45 3.2. The 1994 Chapel Hill International Consensus Conference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
46 3.3. The 2012 revised Chapel Hill International Consensus Conference for Nomenclature of Vasculitides . . . . . . . . . . . . . . . . . . . . 0
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47 3.4. Limitations of classification criteria and nomenclatures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

48 4. Clinical manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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4.1. Cutaneous involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

50 4.2. Joint involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
51 4.3. Gastrointestinal involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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52 4.4. Renal involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

53 4.5. Others' involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
54 4.6. Baseline characteristics between childhood and adulthood
55 IgA vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
56 5. Disease course and prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
57 6. Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
58 6.1. Symptomatic measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

⁎ Corresponding author at: Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin, 27, rue du Faubourg Saint-Jacques, 75679
Paris Cedex 14, France. Tel.: +33 1 58 41 14 61; fax: +33 1 58 41 14 50.
E-mail address: alexandra.audemard@gmail.com (A. Audemard-Verger).

http://dx.doi.org/10.1016/j.autrev.2015.02.003
1568-9972/© 2015 Published by Elsevier B.V.

Please cite this article as: Audemard-Verger A, et al, IgA vasculitis (Henoch–Shönlein purpura) in adults: Diagnostic and therapeutic aspects,
Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.02.003
 2 A. Audemard-Verger et al. / Autoimmunity Reviews xxx (2015) xxx–xxx

59 6.2. Colchicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
60 6.3. Dapsone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
61 6.4. Anti-leukotriene agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
62 6.5. Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
63 6.6. Azathioprine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
64 6.7. Mycophenolate mofetil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
65 6.8. Cyclosporin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
66 6.9. Cyclophosphamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
67 6.10. Rituximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
68 6.11. Other immunomodulatory approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
69 6.12. Treatment algorithm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
70 7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
71 Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
72 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

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73

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74 1. Introduction 3.1. The American College of Rheumatology classification criteria 118

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75 Immunoglobulin A (IgA) vasculitis, formerly called Henoch– In 1990, the American College of Rheumatology proposed criteria for 119
76 Schönlein purpura, is an immune complex vasculitis predominantly distinguishing IgA vasculitis from other forms of vasculitis. Four criteria 120
77 affecting small vessels. The disease was first described in 1802 by were identified: age ≤20 years at disease onset, palpable purpura, acute 121

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78 Heberden [1], and recognized as the association of purpura and abdominal pain, and biopsy showing granulocytes in the walls of small 122
79 arthralgias by Schönlein in 1837 [2]. Latter, Henoch added to this syn- arterioles or venules. The presence of any 2 or more of these criteria dis- 123
80 drome the presence of gastrointestinal symptoms in 1874 and renal in- tinguished IgA vasculitis from other forms of vasculitis with a sensitivity 124

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81 volvement in 1899 [3]. Overall, clinical spectrum of the disease mainly of 87.1% and a specificity of 87.7% [14]. 125
82 includes cutaneous purpura, arthralgias and/or arthritis, acute enteritis
83 and glomerulonephritis, with gastrointestinal and renal involvements 3.2. The 1994 Chapel Hill International Consensus Conference
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84 representing the main causes of morbidity and mortality in adults.
85 Although the cause of the disease remains unknown, it is clear that In 1994, an International Consensus Conference was convened in 127
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86 IgA system plays a central role in the pathophysiology [4]. IgA1 levels Chapell Hill to reach consensus on names of vasculitis and to construct 128
87 are commonly elevated in the serum of patients, resulting from an specific definition for each vasculitis. In the this Consensus Conference, 129
88 increase in their production and a defect in their clearance, and recent IgA vasculitis (formerly called Henoch–Schönlein purpura) was defined 130
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89 studies have shown aberrant glycosylation of IgA1 [5]. Increased IgA syn- as a small vessel vasculitis with IgA-dominant immune deposits, typically 131
90 thesis could be related to antigen exposure processed by the mucosa- involving skin, gut, and glomeruli, and associated with arthralgia/arthritis 132
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91 associated immune system. Bacteria, virus or parasitic agents were [15]. 133
92 suspected to trigger the disease in genetically prone individuals, but caus-
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93 ative agents and factors remain to be identified [6,7]. The role of genetic 3.3. The 2012 revised Chapel Hill International Consensus Conference for 134
94 background was supported by the identification of susceptibility genes Nomenclature of Vasculitides 135
95 in the human leukocyte antigen (HLA) system, including HLA-DRB1 [8].
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96 Besides “primary” IgA vasculitis, a small subset of IgA vasculitis in adults The revised International Consensus Conference took into account 136
97 could also be related to malignancies, in particular lung cancer. advances in the understanding of vasculitis. In this Consensus Confer- 137
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98 Treatment is often symptomatic because of the frequent benign ence, IgA vasculitis was chosen to replace the eponym “Henoch– 138
99 course with spontaneous remission. However, organ and life- Schönlein purpura” based on the compelling body of literature indicat- 139
100 threatening complications may occur and require more aggressive
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ing that abnormal IgA deposits in vessel walls are the defining patho- 140
101 systemic treatments, particularly in adults. Herein, we review the physiologic feature. IgA vasculitis was thus defined as a vasculitis with 141
102 diagnostic aspects, the prognosis and the therapeutic management IgA1-dominant immune deposits, still affecting small vessels, and 142
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103 of IgA vasculitis in adults. often involving the skin, gastrointestinal tract, joints, and kidney with 143
glomerulonephritis indistinguishable from IgA nephropathy [16]. 144
104 2. Epidemiology
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3.4. Limitations of classification criteria and nomenclatures 145

105 IgA vasculitis is the most common systemic vasculitis in childhood
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106 with an annual incidence of 3 to 26 per 100,000 children, occurring The ACR classification may be very useful in pediatric population, but 146
107 most frequently between 4 and 7 years [9]. In adults, the disease re- not appropriated in adults. In particular, these criteria would be not 147
108 mains rare with an annual incidence of 0.1 to 1.8 per 100,000 individ- enough sensitive to distinguish others forms of vasculitis frequent in 148
109 uals [10,11]. Disease is more frequent in males, with a male/female adults, such as cryoglobulinemia vasculitis or microscopic polyangiitis. 149
110 ratio of 1.5. While IgA vasculitis most commonly occurred in fall and New classifications including IgA-dominant immune deposits as main 150
111 winter in children, summer and winter are the most common seasons criteria could be interesting. The European League Against Rheumatism, 151
112 of onset in adults [12]. Finally, IgA vasculitis is represented worldwide Paediatric Rheumatology International Trials Organization and Paediat- 152
113 and described in all ethnic groups, but Black children had a significantly ric Rheumatology European Society (EULAR/PRINTO/PRES) have pro- 153
114 lower annual incidence than did white or Asian children [9]. posed new classification criteria in pediatric population. Based on 154
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these criteria, a patient was classified as IgA vasculitis in the presence 155
115 3. Classification, definition, diagnostic criteria and their limitations of purpura or petechiae (mandatory) with lower limb predominance 156
plus one of four criteria: (1) abdominal pain; (2) histopathology 157
116 IgA vasculitis classifications have been exhaustively reviewed (IgA); (3) arthritis or arthralgia; (4) renal involvement. Unfortunately, 158
117 elsewhere, the main classifications are [13]: these criteria are not adapted for adults. 159

Please cite this article as: Audemard-Verger A, et al, IgA vasculitis (Henoch–Shönlein purpura) in adults: Diagnostic and therapeutic aspects,
Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.02.003
 A. Audemard-Verger et al. / Autoimmunity Reviews xxx (2015) xxx–xxx 3

160 4. Clinical manifestations 4.6. Baseline characteristics between childhood and adulthood 206
IgA vasculitis 207
161 Purpura, arthralgia, and abdominal pain are known as the “classic
162 triad” of IgA vasculitis. Previous studies showed that IgA vasculitis is generally benign and 208
self-limited in children and more severe in adults [12]. Adults had a 209
163 4.1. Cutaneous involvement lower frequency of abdominal pain and fever, and a higher frequency 210
of joint symptoms. During the clinical course, adults had more frequent 211
164 Symmetric palpable purpura is nearly constant in the patients, main- and severe renal involvement [21]. 212
165 ly in the pressure areas, especially around the ankles but can extend to
166 the entire body [17]. In adults, purpura may be necrotic or hemorrhagic
167 in one third of cases. Purpura gradually and spontaneously disappears 5. Disease course and prognosis 213
168 with resting in roughly 2 weeks, but it can reoccur and became chronic.
Management of IgA vasculitis in adults is rendered difficult for clini- 214
cians because of the absence of correlation between initial presentation 215
169 4.2. Joint involvement

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and long-term renal outcome, and the possible occurrence of spontane- 216
ous remission in patients with severe presentation or, in contrast, possi- 217
170 Arthralgias are very frequent during the course of IgA vasculitis, in

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171 approximately two third of cases. Arthralgias mainly involve knees or ble evolution to end-stage renal disease (ESRD) in patients with mild 218
symptoms [22]. There are no guidelines concerning when to perform 219
172 ankles, while arthritis is very rare [17]. Myalgia have been also reported
173 but without increase of creatine phosphokinase (CPK). renal biopsy, but it seems appropriate to discuss such biopsy in case of 220

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acute renal failure related to rapidly progressive glomerulonephritis, 221
nephrotic syndrome, diagnostic uncertainty, or in case of persistent 222
174 4.3. Gastrointestinal involvement
proteinuria (N1 g/day) at 3–6 months despite angiotensin-converting 223

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enzyme inhibitors. 224
175 Gastrointestinal involvement is frequent, occurring in about two
176 third of cases. Abdominal pain is constant and represented by typical In contrast with children in whom disease flare is usually unique, re- 225

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lapses occur in adults in roughly 20% of cases. Early and acute life- 226
177 colicky pain. In a recent Spanish series, main clinical manifestations
threatening manifestations include gastrointestinal perforation and/or 227
178 were abdominal pain (100%), nausea and vomiting (14.4%), melena
bleeding and pulmonary involvement with intraalveolar hemorrhages 228
179 and/or rectorrhagia (12.9%), and positive stool guaiac test (10.3%)
[23]. Long-term organ-threatening is in contrast related to the course 229
180 [18]. Symptoms are caused by bowel ischemia and oedema. Serious
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of renal involvement. In a large study in adults, 11% of patients reached 230
181 complications include intussusception, infarction, and perforation. De-
182 scending duodenum and the terminal ileum are frequently involved, ESRD, 13% exhibited severe renal failure (estimated glomerular filtra- 231
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183 with endoscopic features including diffuse mucosal redness, petechiae, tion rate (eGFR) b30 mL/min), and 14% moderate renal insufficiency 232
184 hemorrhagic erosions and ulcers [19]. CT scan features are commonly (eGFR b50 mL/min) [24]. 233
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Factors associated with long-term ESRD include baseline renal func- 234
185 bowel wall thickening with engorgement of mesenteric vessels.
tion impairment, baseline proteinuria N 1 or 1.5 g/day, macroscopic he- 235
maturia, hypertension, and proteinuria ≥ 1 g/day during follow-up 236
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186 4.4. Renal involvement

[24–26]. On renal biopsy, degree of interstitial fibrosis, sclerotic glomer- 237
187 Renal involvement occurs with a prevalence ranging from 45 to 85% uli and fibrinoid necrosis are also associated with a poor renal prognosis 238
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188 in the literature [17]. Microscopic hematuria is the most sensitive and [24]. 239
Finally, IgA vasculitis may recur after renal transplantation. Meulders 240
189 earliest symptom suggestive of nephropathy during IgA vasculitis, in
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190 association with urine protein excretion of variable range, sometimes et al. reported a risk of renal recurrence and graft loss due to recurrence 241
in 35 and 11% at 5 years after transplantation, respectively [27]. 242
191 nephrotic. Macroscopic hematuria is exceptional. Hypertension is
192 noted in one third of cases. In adults, renal failure at the time of diagno-
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193 sis is noted in approximately 30% while occurrence of renal failure is 6. Treatments 243
194 rare in children [17]. Conversely, among all causes of glomerulonephri-
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195 tis, IgA vasculitis is responsible for only 0.6 to 2% of adult nephropathy. Treatment is often symptomatic because the disease course is usual- 244
196 The most commonly used classification was established by Pillebout ly benign. There have been many reports dealing with the use of corti- 245
197 et al., containing 5 histologic classes, as shown in Table 1, defined by the 246
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costeroid and immunosuppressive drugs. The mechanism of action,

198 degree and extension of glomerular lesions, and demonstrated strong benefit and side effects of these drugs are described below. These specif- 247
199 clinico–pathological correlation [24]. ic treatments are still controversial and their efficacy remains to be eval- 248
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uated. Currently, most available studies were performed in pediatric 249

200
Q8 4.5. Others' involvement patients, with results often extrapolated to adults. In case of severe 250
involvement, including severe gastrointestinal complications or prolif- 251
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201 Myocarditis, orchitis, alveolar hemorrhage or episcleritis represent erative glomerulonephritis, steroids or/and immunosuppressive drugs 252
202 very rare manifestations of IgA vasculitis. Central nervous or peripheral may be required. 253
203 nervous system involvement may also occur, including altered level of
204 consciousness, convulsions, focal neurological deficiency, visual loss
205 and verbal disability [20]. 6.1. Symptomatic measures 254

Benign manifestations as nonnecrotic purpura or arthralgias are 255

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t1:1 Table 1
usually managed by appropriate symptomatic measures (resting, 256
t1:2 Class Histologic description analgesia, compression stockings). Nonsteroidal antiinflammatory 257
t1:3 Class I Mesangiopathic glomerulonephritis drugs have to be avoided in case of renal or gastrointestinal involve- 258
t1:4 Class II Focal and segmentary glomerulonephritis ment. In case of kidney involvement with mild to moderate protein- 259
t1:5 Class III Endocapillary proliferative glomerulonephritis uria, angiotensin-converting enzyme inhibitors are required. Severe 260
t1:6 Class IV Endo and extracapillary proliferative glomerulonephritis gastrointestinal complications may occasionally require surgical 261
t1:7 Class V Kidney fibrosis
interventions. 262

Please cite this article as: Audemard-Verger A, et al, IgA vasculitis (Henoch–Shönlein purpura) in adults: Diagnostic and therapeutic aspects,
Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.02.003
 4 A. Audemard-Verger et al. / Autoimmunity Reviews xxx (2015) xxx–xxx

263 6.2. Colchicine In patients presenting with purpura and mild arthralgias with no 322
clinical renal involvement, or in those with microscopic hematuria, 323
264 Colchicine is an alkaloïd drug derived from Colchicum autumnale mild proteinuria and normal renal function, corticosteroids does 324
265 used for the treatment of acute gout flares since 1763. It inhibits poly- not seem to be indicated, and these forms are usually managed 325
266 morphonuclear chemotaxis to the site of inflammation by perturbing symptomatically. In adults with severe disease, nor data on the effi- 326
267 microtubule function of polymorphonuclear cell cytoskeleton and it cacy of corticosteroids to prevent progression of nephritis neither 327
268 also blocks lysosomal fusion [28]. Side effects mainly include abdominal prospective randomized controlled trials are available in the 328
269 pain and/or diarrhea. Suppressive effect of colchicine on inflammatory literature. 329
270 pathway may explain its clinical effects in some autoinflammatory dis- In contrast in children, 3 randomized, placebo-controlled, pro- 330
271 eases such as familial Mediterranean fever or Behçet disease [29,30]. Ef- spective trials were conducted. In the study by Huber et al., the authors 331
272 ficacy of colchicine has also been reported in cutaneous leukocytoclastic included 40 children to evaluate whether early corticosteroids 332
273 vasculitis by Callen et al. In their series including 13 adults, low-dose (2 mg/kg/day during 2 weeks) could reduce the rate of renal or gas- 333
274 colchicine (1 mg daily) was effective in 80% of patients, usually within trointestinal complications [42]. At one year, there was no difference 334
275 the first 7 days [31]. Purpura reoccurred after discontinuation of colchi- in the rate of renal involvement and gastrointestinal complications. 335

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276 cine, and reinstitution of the treatment was associated with disappear- Ronkainen et al. included 171 children in a double-blinded, placebo- 336
277 ance of lesions. Limitation of this study was the absence of control group controlled trial in order to evaluate the efficacy of early prednisone 337

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278 and difficulties in the evaluation of response, because of frequent spon- therapy in preventing renal and treating extrarenal and renal symp- 338
279 taneous remission during cutaneous leukocytoclastic vasculitis. Because toms [43]. Prednisone (1 mg/kg/day for 4 weeks) was effective to re- 339
280 skin biopsies from IgA vasculitis demonstrate leukocytoclastic vasculitis duce the intensity of abdominal and joint pain. Prednisone did not 340

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281 of small vessels, colchicine has been used, with few case reports show- prevent the development of renal symptoms but was effective in 341
282 ing efficacy [32,33]. This therapeutic approach could improve symp- treating them. Finally, Jauhola et al. reported 223 newly diagnosed 342
283 toms and quality of life in patients with chronic IgA vasculitis with pediatric IgA patients [44]. There was no difference in the clinical 343

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284 purpura, with a good benefit–risk ratio, but further studies are course (abdominal or joint pain, and renal involvement) between the 344
285 warranted. prednisone-treated and non-treated patients during the 6-month 345

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follow-up. 346
286 6.3. Dapsone These studies displayed some limitations, including diagnosis of IgA 347
vasculitis not biopsy-proven, inclusion of patients with mild forms and
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287 Dapsone is a bacteriostatic antibacterial sulfonamide drug used for a patients with severe forms of vasculitis, very short duration of cortico- 349
288 variety of dermatological conditions associated with accumulation of steroids, and follow-up duration lower than 1 year. 350
289 neutrophils, including leukocytoclastic vasculitis. The exact mechanism Pulses of methyprednisolone (MP) have been evaluated in retro- 351
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290 of action of dapsone remains unknown. There is evidence that dapsone spective or open-label series in pediatric patients, often in association 352
291 has an antioxidant scavenger effect, may suppress the generation of with others' therapy [45–47]. In adults, a prospective study of 86 pa- 353
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292 toxic oxygen-derived radicals in neutrophils and inhibits chimiotactism tients with primary IgA nephropathy (IgAN) with mild involvement 354
293
Q9 of neutrophils through CD11b/CD18 interactions [34]. Dapsone may (urine protein excretion of 1 to 3.5 g/d, and serum creatinine levels 355
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294 also inhibit IgA–neutrophils interactions. Side effects include hemolysis b1.5 mg/dL), patients were randomized to receive steroids or support- 356
295 and methemoglobinemia, especially in patients with glucose-6- ive therapy alone. The patients randomized to the steroid group 357
296 phosphate dehydrogenase deficiency. No controlled trial using dapsone received 1 g of MP for 3 consecutive days before the initiation of oral 358
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297 in IgA vasculitis was done, but some cases in childhood and adulthood prednisone and additional pulses 2 and 4 months later, and received 359
298 population revealed effectiveness in chronic purpuric skin lesions low dose prednisone (0.5 mg/kg/day) for 6 months [48]. Ten-year 360
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299 [35–37]. Response to dapsone is often quick, between few days and renal survival was significantly better in the steroid group than in the 361
300 one week. However, relapses occurred after discontinuation in most control group (97% versus 53%; p = 0.0003). 362
301 cases. Original report shows that abdominal pain and arthritis could This «Locatelli» schedule, with combination of pulses of MP and low 363
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302 respond to dapsone [38]. As previously indicated with colchicine, dose prednisone, is frequently used for the treatment of IgA nephropa- 364
303 randomized controlled trials are warranted to demonstrate the efficacy thy to reduce cumulated dose of steroids. The 2012 KDIGO guidelines 365
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304 of dapsone in IgA vasculitis. recommended to treat patients with IgA nephropathy with persistent 366
proteinuria N 1 g/day despite 3–6 months of optimized supportive care 367
305 6.4. Anti-leukotriene agents (including renin–angiotensin–aldosterone system inhibition and blood 368
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pressure control), and eGFR N50 mL/min, with 6-month course of 369
306 Leukotrienes were showed to be involved in the pathogenesis of IgA such steroid therapy [49]. However, these guidelines do not concern 370
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307 vasculitis in children [39]. Montelukast, a leukotriene receptor antago- IgAV, but IgA nephropathy. 371
308 nist, inhibits the cysteinyl leukotriene receptor and exhibits potential Finally, a prospective study was performed to evaluate whether 372
309 antiinflammatory effect, modulating IL-6, TNF-_, and MCP-1 through early administration of prednisone could be useful in preventing the 373
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310 the inhibition of NF_B pathway [40]. Montelukast was evaluated in development of IgA nephropathy in a pediatric population without 374
311 children as an add-on therapy on symptomatic treatment [41]. signs of nephropathy and followed up for 24–36 months [50]. Patients 375
312 Montelukast alleviated the symptoms of IgA vasculitis including purpu- received or not prednisone 1 mg/kg/day for 2 weeks. None of the pa- 376
313 ra, abdominal pain, stool occult blood, arthritis, proteinuria and hematu- tients treated with steroids and 12% of the control patients developed 377
314 ria. Montelukast also inhibited relapses during the first three months nephropathy 2–6 weeks after the initial flare. 378
315 after treatment, but did not alter the outcome of nephritis at the end
316 of the follow-up. No data are available in adults.
6.6. Azathioprine 379
317 6.5. Corticosteroids
Azathioprine has not been evaluated in adults with IgA vasculitis. In 380
318 Corticosteroids are effective on arthralgias and abdominal pain, but pediatric population, combination of azathioprine and corticosteroids 381
319 ineffective on skin purpura, and there is a considerable controversy on could be beneficial by improving clinical course of severe IgA nephritis 382
320 the benefit of corticosteroids to treat renal involvement and prevent and histological features, but studies were of small sample sizes or 383
321 evolution to end-stage renal disease. without control groups [51,52]. 384

Please cite this article as: Audemard-Verger A, et al, IgA vasculitis (Henoch–Shönlein purpura) in adults: Diagnostic and therapeutic aspects,
Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.02.003
 A. Audemard-Verger et al. / Autoimmunity Reviews xxx (2015) xxx–xxx 5

Skin and/or joint Gastrointestinal tract Renal

involvement involvement involvement

Symptomatic Moderate
Mild form Severe form
treatment Benign form Severe form form
(isolated mild (massive
(hematuria, (acute or rapidly
proteinuria (hematuria,
(analgesia and resting, abdominal bleeding, proteinuria
progressive renal
avoid NSAID if renal or <0.5 g/day, failure, crescentic
pain) perforation) >0.5 g/day,
digestive involvement) normal GFR) lesions)
normal GFR)

Colchicine 1 mg/d symptomatic Surgical Evaluation at 3 Prednisone

ACEi 1mg/kg/d
In case of failure treatment evaluation and 6 months
± MP pulses
± CYC

F
Dapsone, Proteinuria or « Locatelli »
Prednisone schedule
colchicine or >1 g/day

O
1mg/kg/d
low-dose at 3 or 6
± MP pulses
prednisone months
± CYC
in case of Failure
± surgery

O
failure

R
Discuss
Alternative
therapies:

P
CsA, rituximab

Q1 Fig. 1.
D
385 6.7. Mycophenolate mofetil multicenter, prospective, open-label trial. Fifty-four patients with 417
biopsy-proven IgA vasculitis and severe manifestations, including pro- 418
E
386 Ren et al. compared combination of mycophenolate mofetil with liferative glomerulonephritis and/or severe visceral manifestations, 419
387 low-dose prednisone and full-dose prednisone alone as induction were included [56]. At 12 months, no difference was found between 420
T

388 therapy for IgA nephritis with large proteinuria (N 2.0 g/24 h) [53]. the 2 groups (remission rate, renal outcomes, deaths and adverse 421
389 Fifty-three adults were included and divided into two groups: patients events). This study should however be analyzed with cautions. First, 422
C

390 who received oral mycophenolate mofetil 1.0 g/day with low-dose only 54 patients out of the 200 initially planned were included, 423
391 prednisone (0.4–0.5 mg/kg/day), and patients who received full-dose explaining why the trial does not have sufficient statistical power to 424
392 prednisone (0.8–1.0 mg/kg/day). At 6 months, the remission rate was detect any difference between the arms of treatment. Second, overall 425
E

393 76.9% in the full-dose prednisone group and 55.5% in the mycopheno- survival at 12 months was 96% with corticosteroids plus CYC compared 426
394 late mofetil group (not significant difference). After a median follow- to 79% with corticosteroids alone (p = 0.08). In pediatric population, 427
R

395 up of 28 months in both groups, the overall remission rate was 80.8% the prospective and randomized study by Tarshish el al. in 27 children 428
396 in the full-dose prednisone group and 77.8% in the mycophenolate with severe IgA nephritis, comparing supportive therapy with or 429
397 mofetil group, suggesting that mycophenolate mofetil could be useful without oral CYC, did not find any difference between the 2 groups for 430
R

398 for inducing remission and as steroid-sparing agent. the rate of end stage renal disease after 14 years of follow-up [57]. 431
O

6.10. Rituximab 432

399 6.8. Cyclosporin A
Rituximab, a chimeric anti-CD20 monoclonal antibody, was success- 433
C

400 Kalliakmani et al. reported 5 adults with nephritic range proteinuria,

fully used in different forms of vasculitis associated with pathogenic an- 434
401 treated with cyclosporin A (CsA) in combination with corticosteroids
tibodies or immune complexes deposition, such as ANCA-associated 435
402 [54]. All patients showed complete or partial remission of nephrotic
N

vasculitis [58] or cryoglobulinemia vasculitis [59]. Rituximab, depleting 436

403 syndrome and preserved stable renal function over a follow-up period
B cells, may reduce immune complexes containing IgA during IgA vas- 437
404 of 5 years. Other studies concerned pediatric population. Jauhola et al.
culitis and reduce disease activity. Only 4 case series of patients treated 438
U

405 have compared CsA and MP for the treatment of severe IgA vasculitis,
with rituximab are reported in the literature. Pillebout et al. described 439
406 including 24 pediatric patients with nephrotic range proteinuria or
an adult with moderate nephritis and severe skin vasculitis treated in 440
407 crescentic nephritis in kidney biopsy [55]. All patients receiving CsA
first line with rituximab without corticosteroids, the patient achieving 441
408 achieved remission of nephrotic range proteinuria within 3 months,
complete and sustained skin and renal remission [60]. Pindi Sala et al. 442
409 while the response was slower in those receiving methylprednisolone.
reported a 49-year-old patient treated with rituximab because for 443
410 Additional immunosuppressive treatment was needed in six patients
411 treated with MP compared to none with CsA.
Table 2 t2:1

412 6.9. Cyclophosphamide Proteinuria b 1 g/d Proteinuria 1–3 g/d Proteinuria N 3 g/d t2:2

Class I ACEi ACEi Steroïds t2:3

413 By analogy with other severe autoimmune diseases, cyclophospha- Class II ACEi +/− «Locatelli» schedule Steroïds t2:4
414 mide (CYC) has been used in patients with organ- or life-threatening Class III ACEi «Locatelli» schedule Steroïds t2:5
415 manifestations. In adults, Pillebout et al. compared corticosteroids with- Class IV Steroïds Steroïds +/− CYC Steroïds + CYC t2:6
Class V Conservative Conservative Conservative Q3
t2:7
416 out or with CYC in adults with severe IgA vasculitis in a 12-months,

Please cite this article as: Audemard-Verger A, et al, IgA vasculitis (Henoch–Shönlein purpura) in adults: Diagnostic and therapeutic aspects,
Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.02.003
 6 A. Audemard-Verger et al. / Autoimmunity Reviews xxx (2015) xxx–xxx

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Please cite this article as: Audemard-Verger A, et al, IgA vasculitis (Henoch–Shönlein purpura) in adults: Diagnostic and therapeutic aspects,
Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.02.003