AUTREV-01516; No of Pages 4

Autoimmunity Reviews xxx (2014) xxx–xxx

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

1 Review

2 The diagnosis and classification of Henoch–Schönlein purpura: An

3 updated review☆

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4Q1 Yao-Hsu Yang a, Hsin-Hui Yu a, Bor-Luen Chiang b,⁎

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5 a
Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
6 b
Department of Medical Research, National Taiwan University Hospital, Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
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a r t i c l e i n f o a b s t r a c t

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9 Article history: Henoch–Schönlein purpura (HSP) is a common childhood systemic vasculitis with clinical characteristics of cu- 20
10 Accepted 13 November 2013 taneous palpable purpura, arthralgia/arthritis, bowel angina, and hematuria/proteinuria. HSP is identified mainly 21

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11 Available online xxxx based on the above presentations. Combined with pathohistological findings of leukocytoclastic vasculitis (LCV) 22
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14 and IgA-immune deposits in vessel walls and/or glomeruli increase the diagnostic sensitivity and specificity. 23
15 Keywords:
However, considering the accessibility of biopsy and some patients with atypical presentations, there are still 24
16 Henoch–Schönlein purpura
17 Diagnostic criteria
medical unmet needs in HSP diagnosis. This article reviews the diagnosis of HSP including the aspects of classi-
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18 Differential diagnosis fication criteria, differential diagnosis, and some laboratory findings as the biomarkers with diagnostic potential. 26
19 Biomarker © 2014 Published by Elsevier B.V. 27
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32 Contents
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34 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
35 2. Diagnostic criteria of HSP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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36 2.1. The American College of Rheumatology (ACR) criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

37 2.2. Michel's criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
38 2.3. Chapel Hill Consensus Conference (CHCC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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39 2.4. Helander's criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

40 2.5. European League Against Rheumatism/Paediatric Rheumatology International Trials Organization/Paediatric Rheumatology European
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41 Society (EULAR/PRINTO/PRES) criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

42 3. Differential diagnosis of HSP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
43 4. Biomarkers for HSP diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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44 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
45 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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47 1. Introduction bowel angina, and hematuria/proteinuria. Treatment is supportive 53

because the disease course is usually benign and self-limited [3]. 54
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48 Henoch–Schönlein purpura (HSP) is a systemic small vessel vasculi- Progressive impairment of renal function, bowel perforation, and 55
49 tis that occurs commonly in children. The annual incidence is 13–20 per central nerve system involvement is rare but major morbidity of HSP 56
50 100,000 children under 17 years old [1,2]. It is characterized by [4–6]. Aggressive therapies with steroid and/or immunosuppressants 57
51 non-thrombocytopenic palpable purpura that mostly located on the de- are then indicated under such conditions. 58
52 pendent parts like lower extremities and buttocks, arthralgia/arthritis, Although this disease is not uncommon in children, the etiology and 59
pathogenesis are still yet to be determined. Previous epidemiological 60
studies have found striking seasonal variations in HSP, with most 61
☆ Financial support: This work was partly supported by a grant from the National cases occurring in the autumn and winter. HSP has also been associated 62
Science Council, Taiwan (grant number: NSC 100-2314-B-002-095-MY3). with a history of preceding infections, especially upper respiratory tract 63
⁎ Corresponding author at: Department of Medical Research, National Taiwan
infection [1,3,7]. In addition, other characteristics of HSP include the 64
University Hospital, No. 7 Chung-Shan South Road, Taipei, Taiwan. Tel.: +886 2 2312
3456x67302; fax: +886 2 2311 9087. deposition of IgA and C3 in small vessel walls, polymorphonuclear 65
E-mail address: gicmbor@ntu.edu.tw (B.-L. Chiang). neutrophil infiltration around the vessel and in vessel walls, and 66

1568-9972/$ – see front matter © 2014 Published by Elsevier B.V.

http://dx.doi.org/10.1016/j.autrev.2014.01.031

Please cite this article as: Yang Y-H, et al, The diagnosis and classification of Henoch–Schönlein purpura: An updated review, Autoimmun Rev
(2014), http://dx.doi.org/10.1016/j.autrev.2014.01.031
 2 Y.-H. Yang et al. / Autoimmunity Reviews xxx (2014) xxx–xxx

67 increased serum levels of IgA and proinflammatory cytokines at the acute adults [3]. To distinguish between HV and HSP, Michel and co-workers 99
68 stage [3,8]. Combined, HSP is regarded as a specific immune-mediated conducted a study comparing 93 patients with HV and 85 patients 100
69 entity induced by environmental factors, particularly infections. with HSP and identified 6 criteria: palpable purpura not related to 101
70 Clinically, since there are no disease-specific laboratory abnormali- thrombocytopenia, bowel angina, gastrointestinal bleeding, hematuria, 102
71 ties, HSP is currently diagnosed based on symptoms and signs and histo- age ≤20 years at disease onset, and no history of medication intake at 103
72 pathological findings [3,9]. In this article, we reviewed and compared disease onset (Table 1). They found 3 or more criteria from the above 104
73 various diagnostic criteria of HSP. In addition, differential diagnosis of list of 6 yielded 87.1% of correctly classified HSP cases; and 2 or fewer 105
74 HSP and some potential biomarker that may assist in diagnosing HSP criteria from the same list of 6 correctly classified 74.2% of HV cases [12]. 106
75 were also reviewed.
2.3. Chapel Hill Consensus Conference (CHCC) 107
76 2. Diagnostic criteria of HSP
Although ACR has proposed classification criteria for HSP that would 108
77 Schönlein first described HSP as triad of purpuric rash, arthritis, and provide a standard way to evaluate patients with similar presentations, 109
78 abnormalities of the urinary sediment in 1837 [10]. In 1874, Henoch there is no strict uniform definition of this disease. In an attempt to 110

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79 described the association of purpuric rash, abdominal pain with bloody address this problem, a consensus conference on nomenclature of 111
80 diarrhea, and proteinuria [11]. Up to date, several sets of diagnostic systemic vasculitis was held in Chapel Hill in 1994 [13]. They finally 112

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81 criteria for HSP have been proposed; the detail and comparison of provided a consensus for HSP definition: it is a small vessel vasculitis 113
82 these different classification criteria were further reviewed and with IgA-dominant immune deposits, typically involves skin, gut, and 114
83 discussed as follows. glomeruli, and is associated with arthralgia/arthritis (Table 1). This 115

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definition was according to the opinion of an expert panel, but was not 116
84 2.1. The American College of Rheumatology (ACR) criteria validated with patient data and was not intended to function as a set of 117
classification criteria [14]. Moreover, IgA-immune vascular deposits are 118

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85 In 1990, ACR first proposed criteria for identifying HSP by comparing not specific for HSP because they are found in other vasculitis syndromes 119
86 85 patients who had HSP with other 722 patients with other vasculitis. such as erythema nodosum, cryoglobulinemia, coagulopathic vasculopa- 120

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87 Four criteria were finally identified including palpable purpura not thies and livedoid vasculitis [15,16]. 121
88 related to thrombocytopenia, age ≤ 20 years at disease onset, acute
89 abdominal pain, and granulocytes in the walls of small arterioles and 2.4. Helander's criteria
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90 venules on biopsy (Table 1). A patient shall be diagnosed with HSP if
91 at least 2 of these criteria are present. The presence of any two or Many vasculitis like urticarial vasculitis, microscopic polyarteritis 123
92 more criteria yielded a sensitivity of 87.1% and specificity of 87.7% [9]. nodosa, and collagen vascular disease could be confused as HSP if 124
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one uses solely ACR criteria that do not include IgA-immune deposits 125
93 2.2. Michel's criteria within small vessels [14]. In 1995, Helander, DeCastro, and Gibson 126
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proposed their revised criteria for HSP including cutaneous IgA vas- 127
94 By ACR criteria, however, a patient with other vasculitis presents cular deposits, age 20 years or younger, gastrointestinal involve- 128
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95 with non-thrombocytopenic palpable purpura and granulocytes in ment, upper respiratory tract infection prodrome, and renal biopsy 129
96 small vessel walls or around vessels on biopsy could be classified as hav- showing mesangioproliferative glomerulonephritis with or without 130
97 ing HSP without other findings. For example, hypersensitivity vasculitis IgA deposition (Table 1). The presence of 3 or more of above 5 criteria 131
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98 (HV), a kind of leukocytoclastic vasculitis (HCV) that commonly affects in patients with palpable purpura and histopathological LCV yielded 132
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t1:1 Table 1
t1:2 Summary of classification criteria for Henoch–Schönlein purpura (HSP) diagnosis.
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t1:3 Classification Diagnostic criteria

t1:4 ACR 1990 [9] ≥2 of the following:

t1:5 1. Palpable purpura, not thrombocytopenic
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t1:6 2. Bowel angina

t1:7 3. Wall granulocytes on biopsy
t1:8 4. Age ≤20 years at disease onset
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t1:9 Michel et al. 1992 [12] ≥3 of the following: HSP; ≤2 of the following: HV
t1:10 1. Palpable purpura, not thrombocytopenic
t1:11 2. Bowel angina
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t1:12 3. Gastrointestinal bleeding

t1:13 4. Hematuria
t1:14 5. Age ≤20 years at disease onset
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t1:15 6. No history of medication intake at disease onset

t1:16 CHCC 1994 [13] Vasculitis, with IgA-dominant immune deposits, affecting small vessels (ie, capillaries, venules, or arterioles); typically involves skin,
gut, and glomeruli and is associated with arthralgias or arthritis
t1:17 Helander et al. 1995 [17] Palpable purpura, not thrombocytopenic with LCV + ≥3 of the following:
t1:18 1. Vascular IgA deposition
t1:19 2. Age ≤20 years at disease onset
t1:20 3. Gastrointestinal involvement
t1:21 4. Upper respiratory tract infection prodrome
t1:22 5. Mesangioproliferative glomerulonephritis with or without IgA deposition
t1:23 EULAR/PRINTO/PRES 2010 [20] Palpable purpura, not thrombocytopenic/petechiae (mandatory) + ≥ one of the following
t1:24 1. Diffuse abdominal pain
t1:25 2. Histopathology: typical LCV with predominant IgA deposits or proliferative glomerulonephritis with predominant IgA deposits
t1:26 3. Arthritis or arthralgias
t1:27 4. Renal involvement (proteinuria: N0.3 g/24 h or N30 mmol/mg of urine albumin to creatinine ratio on a spot morning sample; and/or
hematuria, red blood cell casts: N5 red cells per high power field or ≥2+ on dipstick or red blood cell casts in the urinary sediment)

t1:28 ACR, The American College of Rheumatology; HV, hypersensitivity vasculitis; CHCC, Chapel Hill Consensus Criteria; LCV, leukocytoclastic vasculitis; EULAR/PRINTO/PRES, European League
t1:29 Against Rheumatism/Paediatric Rheumatology International Trials Organization/Paediatric Rheumatology European Society.

Please cite this article as: Yang Y-H, et al, The diagnosis and classification of Henoch–Schönlein purpura: An updated review, Autoimmun Rev
(2014), http://dx.doi.org/10.1016/j.autrev.2014.01.031
 Y.-H. Yang et al. / Autoimmunity Reviews xxx (2014) xxx–xxx 3

133 sensitivity and specificity greater than 90% [17]. However, the skin and count. If it is difficult to decide the cause of cutaneous purpuric lesions 168
134 kidney biopsies and direct immunofluorescence staining for IgA limit that may be presented in other types of vasculitis such as urticarial vas- 169
135 their usage in clinical practice, especially for pediatric patients. culitis, cryoglobulinemia, and HV, a skin biopsy and immunofluores- 170
cence study may assist in the diagnosis [3,16,17,20]. Some rheumatic 171
136 2.5. European League Against Rheumatism/Paediatric Rheumatology diseases might have presentation of cutaneous vasculitis [3,16,21–25]. 172
137 International Trials Organization/Paediatric Rheumatology European Clinical characteristics combined with laboratory abnormalities usually 173
138 Society (EULAR/PRINTO/PRES) criteria provide assistance to determine the underlying diseases. Furthermore, 174
since abdominal pain is commonly presented in HSP, the more common 175
139 Since the above criteria have some limitations [9,12–14,17,18], in causes of acute surgical abdomen must be considered [3]. 176
140 2005 the vasculitis working group of the PRES proposed new classifica-
141 tion criteria for pediatric vasculitis including HSP, endorsed by the 4. Biomarkers for HSP diagnosis 177
142 EULAR. However, these proposed modifications were mainly based on
143 a literature review and a consensus-based process and were not validat- In HSP, the platelet count is normal or increased. A moderate leuko- 178
144 ed. Therefore, EULAR, PRINTO and PRES conducted a statistical valida- cytosis with a left shift is noted in some patients. Antinuclear antibody is 179

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145 tion process in 2008, with a large-scale, web-based data collection mostly undetectable, and serum levels of C3 and C4 are usually within 180
146 [19]. In 2010, the EULAR/PRINTO/PRES criteria for HSP were formally normal limit [3]. Although some proinflammatory cytokines and 181

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147 published. The criteria include palpable purpura as a mandatory criteri- chemokines are elevated at acute stage [8,26], these laboratory abnor- 182
148 on, together with at least one of the following findings: diffuse abdom- malities are not specific for HSP but can be seen in a variety of inflamma- 183
149 inal pain, LCV with predominant IgA deposits on skin biopsy, acute

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tory conditions. The presence of LCV and IgA-immune deposits on skin 184
150 arthritis or arthralgias in any joint, and renal involvement as evidenced and/or kidney biopsies significantly increases the diagnostic accuracy 185
151 by proteinuria and/or hematuria (Table 1). The sensitivity and specific- for HSP [14,17,20]. However, many vasculitis and glomerulonephritis 186

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152 ity of these classification criteria were 100% and 87% respectively [20]. show similar histopathological findings [14–16,27]. 187
153 Comparing with ACR criteria, EULAR/PRINTO/PRES criteria chose The immune deposits in HSP are principally composed of IgA1 that 188
154 histopathology showing typically LCV with predominant IgA deposits predominates in serum. IgA1 is structurally different from IgA2 in the 189

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155 or proliferative glomerulonephritis with predominant IgA deposits for hinge region of the heavy chain, where it is rich of proline and com- 190
156 all doubtful cases with atypical purpura distribution. Other differences posed of 5–6 O-linked glycosylation sites. An abnormal glycosylation 191
157 were related to the inclusion of joint and renal involvement [20]. of the IgA1 hinge region would occur in the context of a deficiency of ga-
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158 When either set of criteria as applied to their pediatric population, lactose and/or sialic acid; such a molecule is prone to cause IgA aggre- 193
159 EULAR/PRINTO/PRES criteria showed a better sensitivity and specificity gation and thus macromolecular complexes [8]. Like IgA1 in IgA 194
160 than ACR criteria [14,20]. However, EULAR/PRINTO/PRES criteria were
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nephropathy, recent studies have shown aberrant glycosylation of 195
161 originally derived from data of 823 children with HSP and 356 children IgA1 in HSP patients with nephritis [28,29]. In addition to the structure 196
162 with other vasculitis, such criteria have not been validated in adults of IgA1 in HSP, the search for antigenic epitopes that IgA1 binds to is 197
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163 [19,20]. another important and interesting issue to be addressed. A variety of 198
IgA autoantibodies have been found associated with HSP including IgA 199
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164 3. Differential diagnosis of HSP rheumatoid factor [30], IgA anticardiolipin antibodies [31,32], and IgA 200
antiendothelial cell antibodies [33,34]. Recently, we found IgA1 of HSP 201
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165 HSP must be distinguished from other diseases with similar presen- patients bound well to β2 glycoprotein I (β2GPI) and some β2GPI- 202
166 tations (Table 2). Thrombocytopenic purpura like immune thrombocy- derived linear peptides. These IgA anti-β2GPI antibodies were cross- 203
167 topenic purpura can be easily identified by the detection of low platelet reactive to endothelial cells and induced complement-dependent cell 204
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lysis [35]. Although aberrant glycosylated IgA1 and some of above IgA 205
autoantibodies are likely to play a pathogenic role in HSP, whether 206
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t2:1 Table 2 they are diagnostic biomarkers for HSP needs more studies to validate. 207
t2:2 Differential diagnosis of Henoch–Schönlein Purpura (HSP).
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t2:3 Diseases 5. Conclusion 208

t2:4 Thrombocytopenic purpura
t2:5 Immune thrombocytopenic purpura The current diagnostic criteria have high sensitivity and specificity; 209
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t2:6 Thrombotic thrombocytopenic purpura

most HSP patients are accurately diagnosed based on them. However, 210
t2:7 Other types of vasculitis
t2:8 Hypersensitivity vasculitis some patients have atypical presentations and biopsies are sometimes 211
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t2:9 Urticarial vasculitis not easily obtained. Therefore, the development of less invasive labora- 212
t2:10 Mixed cryoglobulinemia tory tests that are of diagnostic value is needed. Clearly, the elucidation 213
t2:11 Cutaneous polyarteritis of HSP pathogenesis becomes important that may identify some 214
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t2:12 ANCA-associated small vessel vasculitis

disease-specific biomarkers assisting in HSP diagnosis. 215
t2:13 Rheumatic diseasesa
t2:14 Systemic lupus erythematosus
t2:15 Rheumatoid arthritis
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t2:16 Sjögren syndrome
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(2014), http://dx.doi.org/10.1016/j.autrev.2014.01.031
 4 Y.-H. Yang et al. / Autoimmunity Reviews xxx (2014) xxx–xxx

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Please cite this article as: Yang Y-H, et al, The diagnosis and classification of Henoch–Schönlein purpura: An updated review, Autoimmun Rev
(2014), http://dx.doi.org/10.1016/j.autrev.2014.01.031