- Email: [email protected]
Management of Henoch–Schönlein purpura
SYMPOSIUM: NEPHROLOGY
Management of Henoche €nlein purpura Scho
evidence is emerging of a link with other autoinflammatory disorders associated with dysregulated interleukin-1 (IL-1) homeostasis. The 11 members of the IL-1 family of genes include the genes encoding the pro-inflammatory interleukin-1 [beta] (IL-1B) and its regulator, the anti-inflammatory IL-1ereceptor antagonist. IL-1B is a highly active pro-inflammatory cytokine that causes not only fever, anorexia, and other constitutional symptoms but also tissue damage and remodelling. A study by Gershoni-Baruch et al. from Israel demonstrated that 10% of HSP patients were homozygous for mutations of the gene encoding MEFV (the gene defective in familial Mediterranean fever), and an additional 17% had heterozygous defects. MEFV encodes the protein pyrin which regulates caspase-1 activation and consequently IL-1B production. Turkish children with FMF were found to have a 72-fold increase in HSP compared with controls. Overall, rates of HSP range from 2 to 7% in FMF and severe HSP appears to be more common in FMF, with cerebral vasculitis and severe nephritis reported. Persistentrecurrent HSP in a child with hyperimmunoglobulin (Ig) D demonstrates that other defects in inflammatory control may also modulate HSP. Human leukocyte antigen (HLA) haplotypes may also play a role in HSP susceptibility. A study of 110 Turkish children with a diagnosis of HSP showed an increased risk for the development of HSP in children carrying HLA A2, A11 and B35 antigens and a reduced risk in those bearing HLA A1, B49 and B50 antigens. An obvious candidate for a pathogenic role in HSP is IgA and of the two subclasses, only IgA1 is involved in HSP. Abnormal glycosylation of O-linked glycans in the hinge region of the molecule has been found in adults with IgA nephropathy and children with HSP and the IgA1 concentrations are two to threetimes higher than normal. It is suggested that this change makes immune complexes containing this antibody resistant to clearance from the blood, allowing them to collect in tissues and initiate inflammation.
Graham Smith
Abstract €nlein purpura (HSP) is the commonest childhood vasculitis, HenocheScho with a peak incidence in the autumn months. This supports the supposition that it is precipitated by viral infection, which then leads to the production of abnormally glycosylated immunoglobulin A (IgA) and the formation of immune complexes containing this IgA. All organs can be affected, but the purpuric skin lesions are necessary to make the diagnosis. There is little evidence for or against any particular therapeutic strategy and management of the acute episode is mainly supportive with analgesics as necessary. Recent placebo-controlled studies do not support the routine use of early steroids. Most children make a full recovery, but severe long-term renal problems can develop in a few, ultimately leading to established renal failure. Renal involvement is common in the early phase of the disease in the form of haematuria or proteinuria, and those with a more severe nephrotic picture have the greatest risk of long-term problems. However, children with only mild renal involvement initially can still run into difficulties and therefore those children with abnormal urinalysis require follow-up.
Keywords child; glomerulonephritis; HenocheScho€nlein purpura; immunoglobulin A; vasculitis
HenocheSch€ onlein purpura (HSP) is the commonest vasculitis seen in children with an incidence of up to 13.5 per 100,000 school-age children. It involves small vessels and is characterized by the finding of immunoglobulin A (IgA) deposits in biopsy tissue. There is still much about HSP which remains a mystery, but it is postulated that children with an innate susceptibility to develop HSP come into contact with an external trigger which sets off the disease process. The exact nature of the trigger is unknown and many infectious agents have been implicated. It is likely that there is no one specific mediator. The main clinical finding is a purpuric rash involving predominantly the lower limbs and buttocks (Figure 1). Abdominal and joint symptoms are commonly seen in the acute phase of HSP along with evidence of renal involvement, manifest by the presence of haematuria and/or proteinuria. The frequency of these findings at presentation is shown in Table 1.
Diagnosis There is no specific test for HSP and it is therefore a clinical diagnosis. The rash is the main diagnostic feature and important differential diagnoses include meningococcal sepsis and idiopathic thrombocytopenia. In 2005 the vasculitis group of the Paediatric Rheumatology European Society (PRES) proposed new classification criteria for paediatric vasculitides, replacing the American College of Rheumatology (ACR) classification criteria from 1990. However, these proposed modifications were mainly based on a literature review and a consensus-based process and were not formally validated. A formal statistical validation process has now taken place and amended criteria for the diagnosis of HSP have been defined. The criteria suggested are shown in Table 2. The sensitivity and specificity values were obtained by comparing the 827 children diagnosed with HSP by either their treating physician or by the consensus panel with another 150 patients with other forms of childhood vasculitides (polyarteritis nodosa 150, Wegener’s granulomatosis 60, Takayasu arteritis 87). This is a significant improvement on the ACR 1990 criteria, which allowed HSP to be diagnosed just on the basis of palpable purpura in someone under the age of 20 years. However, concern regarding continuing over-diagnosis of HSP,
Pathophysiology Investigation of patients who develop HSP has revealed a number of abnormalities which may play a role in the disease process. The nature of the abnormalities underlying susceptibility to the development of HSP are poorly understood, but
Graham Smith MA MB BS MRCP FRCPCH is Consultant Paediatric Nephrologist at the Children’s Kidney Centre, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK. Conflict of interest: none.
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SYMPOSIUM: NEPHROLOGY
similar cutaneous manifestations to HSP as well as causing arthralgia, abdominal pain and renal involvement, but has not been reported to cause any long-term renal problems. However, I am not sure that performance of a skin biopsy to exclude HSP would change the follow-up pattern of a child with persistent haematuria or proteinuria, irrespective of the diagnosis. Investigations are carried out in an attempt to exclude other diagnoses and to identify the presence of renal involvement. These are summarized in Table 3. The full blood count allows detection of thrombocytopenia. Renal involvement is common but usually limited to haematuria and/or mild proteinuria. More severe nephritis produces greater levels of proteinuria, but it is unusual for the serum creatinine to be raised at presentation.
Acute management HSP is a multi-system disease as demonstrated by case reports which have described involvement of all organs (see Table 4). However, most children with HSP follow a relatively benign course and do not require hospital admission. Treatment is symptomatic, consisting of simple analgesia for joint or abdominal discomfort. Non-steroidal anti-inflammatory agents can be used for more severe arthralgia. In the past bed rest has been advised, but this is unnecessary and patients should be allowed to be as active as they wish. Abdominal pain can be a significant problem and intussusception is then part of the differential diagnosis. A short course of oral steroids (3 days of prednisolone 2 mg/kg) may help, although the evidence to support such treatment is weak.
HSP nephritis It is the renal manifestations of HSP which are responsible for any long-term morbidity. Inflammation in the kidneys (nephritis) is suggested by the finding of haematuria and/or proteinuria. A small number of patients will develop an aggressive nephritis during their presenting disease, but this is unusual and the progression is usually more insidious. Approximately 2% of patients develop long-term renal problems and for this reason, patients with haematuria or proteinuria need to be kept under review (see below). Understandably there has been a focus on strategies to reduce the incidence of renal involvement and this has primarily been through the administration of steroids. The results of three randomized placebo-controlled studies of prednisolone started at the onset of HSP, examining the incidence of ongoing renal problems at 6 months or a year were reviewed by the Cochrane Renal group and the conclusion was that together these studies demonstrated no significant benefit of short-term prednisone therapy in preventing renal disease. The story does not get any clearer for the treatment of patients who develop more severe renal involvement. There is limited data to guide the treatment of active HSP nephritis (HSPN) and the decision about whether to embark on a potentially toxic therapy is complicated by the fact that some patients with significant nephritis will spontaneously improve. If treatment is considered there are a range of options for which success has been reported in uncontrolled series including steroids, cyclophosphamide, plasma exchange, ciclosporin, azathioprine, immunoglobulin and mycophenolate mofetil but there is only limited information from
Figure 1 Example of HSP rash.
in particular confusing it with idiopathic cutaneous small-vessel vasculitis (CSVV), has been raised by Aalberse et al. They studied the diagnostic criteria for HSP being used by Dutch paediatricians in 2004, in order to evaluate its accuracy using the presence of IgA in the skin when biopsies were available. Unfortunately only 17 skin biopsies were carried out in the 232 patients reported as having contracted HSP, but of these only nine (53%) had IgA deposits. They felt that clinical diagnosis of HSP was not always reliable and that the exclusion of HSP would allow less active follow-up, on the basis that CSVV has very
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SYMPOSIUM: NEPHROLOGY
trial comparing ciclosporin (CyA) and methylprednisolone (MP) in the treatment of HSPN. Twenty-four children with nephroticrange proteinuria or crescentic HSPN seen in a kidney biopsy were studied. Of these, seven were randomized to receive CyA for 12 months at an initial dose of 5 mg/kg and eight to receive three MP pulses of 30 mg/kg followed by prednisone for 4 months. The other nine patients received identical treatment without randomization. Kidney biopsies were performed at inclusion and after 2 years. All 11 CyA-treated patients achieved resolution of nephrotic-range proteinuria within 3 months, while the response in the MP group was slower, and in 6/13 was not achieved with the initial treatment. Additional immunosuppressive treatment was needed in none of the CyA-treated patients but in six patients treated with MP (difference in proportion 46%, p ¼ 0.008). The 2-year control biopsies showed similar improvement in both groups. After mean 6.1 years (2.2e10.4 years), 16 patients (eight CyA, eight MP) had no renal symptoms and six (three CyA, three MP) had persistent nephropathy but normal renal function. One MP-treated patient had reduced renal function and another had developed ESRD. A number of uncontrolled studies have previously described the effectiveness of CyA in the treatment of HSPN, usually in combination with steroids. This study suggests that CyA can be used alone. A concern when using CyA is nephrotoxicity, but this was not found in this study. The authors felt that C2 monitoring in addition to the C0 levels used would be helpful.
Clinical and demographic findings at presentation of HSP in 184 patients Sex Mean age Age range Rash Joint symptoms Abdominal pain Haematuria Proteinuria
92 male: 92 female 6.4 years 0.72e13.87 years 184 (100%) 156 (85%) 89 (48%) 58 (32%) 71 (39%)
Table 1
studies including any control groups. A controlled study comparing methylprednisolone and urokinase pulse therapy, with and without cyclophosphamide, showed a benefit from the use of cyclophosphamide. This compares with a study of 56 patients with histopathologically severe HSP nephritis who were randomized to receive supportive therapy with or without cyclophosphamide (90 mg/m2/day for 42 days), in which there was no difference in outcome between the two groups. Until recently this was the only randomized study looking at HSPN. Jauhola et al. have just reported the results of a randomized
Final EULAR/PRINTO/PRES HSP criteria Criterion
Description
Purpura (mandatory criterion)
Purpura (commonly palpable and in crops) or petechiae, with lower limb predominance, not related to thrombocytopeniaa Diffuse abdominal colicky pain with acute onset assessed by history and physical examination. May include intussusception and gastrointestinal bleeding Typically leucocytoclastic vasculitis with predominant IgA deposit or proliferative glomerulonephritis with predominant IgA deposit Arthritis of acute onset defined as joint swelling or joint pain with limitation on motion. Arthralgia of acute onset defined as joint pain without joint swelling or limitation on motion Proteinuria >0.3 g/24 h or >30 mmol/mg of urine albumin/ creatinine ratio on a spot morning sample Haematuria or red blood cell casts: >5 red blood cells/high power field or red blood cells casts in the urinary sediment or 2þ on dipstick Purpura or petechiae (mandatory) with lower limb predominancea and at least one of the four following criteria: Abdominal pain Histopathology Arthritis or arthralgia Renal involvement
Abdominal pain
Histopathology
Arthritis or arthralgias
Renal involvement
HSP EULAR/PRINTO/PRES Ankara 2008 classification definition: k 0.90 (95% CI 0.84e0.96)
Sensitivity (%)
Specificity (%)
AUC (%)
89
86
87.5
61
64
62.2
93
89
91.1
78
42
59.9
33
70
51.4
100
87
93.5
€nlein purpura; PRES, Paediatric Rheumatology European Society; PRINTO, AUC, area under the curve; EULAR, European League Against Rheumatism; HSP, HenocheScho Paediatric Rheumatology International Trials Organization. a For purpura with atypical distribution a demonstration of an IgA deposit in a biopsy is required.
Table 2
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SYMPOSIUM: NEPHROLOGY
consistently normal urinalysis. The overall percentage of children who developed persistent renal impairment on long-term follow-up was 1.8%. While it occurred in 5.4% of those who had abnormal urinary findings, only 1.6% of those with isolated haematuria or proteinuria developed long-term renal impairment, while that percentage increased to 20% of those who developed nephritic or nephrotic syndrome. Nephritis was defined as haematuria associated with at least one of the following: raised serum urea and creatinine, hypertension or oliguria. The recommendations from this review were: At diagnosis and at each HSP recurrence, blood pressure measurement and urinalysis need to be carried out. If haematuria and/or proteinuria are found, serum urea and creatinine should be measured. In case of normal urinalysis or if there is isolated haematuria or proteinuria without nephrotic or nephritic syndromes, a periodic check of urinalysis is needed for up to 6 months after diagnosis. There is no need for subsequent follow-up of those whose urinalysis remains normal, but measurements of serum urea and creatinine need to continue in the presence of persistent haematuria or proteinuria. In cases with a nephritic or nephrotic picture, a paediatric nephrologist needs to be consulted, as urgent evaluation is necessary and long-term renal follow-up will be needed, even after resolution of the nephritis. This is especially important in affected girls, as they will need monitoring of renal function and blood pressure during and after future pregnancies. These recommendations are appropriate in view of the available evidence.
Suggested investigations for a child presenting with palpable purpura, suspected of having HSP Blood pressure Dipstick urinalysis Full blood count Serum creatinine Urine protein:creatinine ratio Table 3
CyA was developed as an immunosuppressive agent for use in transplantation. It inhibits calcineurin, which, under normal circumstances, is responsible for activating the transcription of interleukin 2. It also inhibits lymphokine production and interleukin release and therefore reduces the function of effector T-cells. However it is now felt that the anti-proteinuric action of CyA may not be dependent on effects on T-cell function, but rather results from stabilization of the actin cytoskeleton in the kidney podocytes.
Follow-up Concern about the possible development of renal complications is the main driver for the follow-up of children after an episode of HSP. The question of which children need follow-up has been addressed by Narchi through an analysis of papers which have studied unselected groups of patients (cohorts not selected on presence or absence of renal involvement). The studies identified included a total of 1133 children. Normal urinalysis was found in 66% of the cases, while haematuria and/or proteinuria occurred in 34%, of which only 21% were in association with nephritic or nephrotic syndrome. When haematuria or proteinuria developed, it occurred in 85% of cases within 4 weeks of the diagnosis of HSP, in 91% within 6 weeks, and in 97% within 6 months. Longterm renal impairment never developed in any child who had
Long-term management In children with established renal disease secondary to HSP there are measures which can be taken to slow down its progression,
Manifestations of HSP Skin
The majority of skin lesions heal well, but scarring can occur. Occasionally bullous lesions can develop. Some boys (22%) develop involvement of the scrotal skin with underlying epididymo-orchitis, which can be misdiagnosed as testicular torsion Joints Joint involvement usually consists of arthralgia, particularly of the lower limb joints GIT Abdominal pain is a common symptom caused by inflammation of the intestinal mucosa. It can be associated with bleeding and, rarely, with the development of intussusception Kidneys Haematuria, detected on dipstick analysis of the urine, is common and usually self-limiting. Less commonly, significant proteinuria can develop and, very rarely, an acute nephritis leading to early renal impairment. As with any nephritic process, proteinuria is associated with a risk of future renal impairment Heart Rheumatic fever with complete atrioventricular block, pericarditis Liver Cholecystitis CNS Bilateral brachial plexopathy, cerebral vasculitis, cerebral haemorrhage, ataxia, peroneal neuropathy, peripheral facial palsy, Guillaine Barre syndrome, brachial plexopathy, posterior tibial nerve neuropathy, femoral neuropathy, ulnar neuropathy and mononeuritis multiplex Lung Pulmonary haemorrhage, pleural effusion, chylothorax Eyes Episcleritis, scleritis, keratitis, anterior uveitis, central retinal vein occlusion and central retinal artery occlusion Pancreas Pancreatitis Adrenals Adrenal haematoma Table 4
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SYMPOSIUM: NEPHROLOGY
5 Ozen S, Pistorio A, Iusan SM, et al. EULAR/PRINTO/PRES criteria for € nlein purpura, childhood polyarteritis nodosa, childHenocheScho hood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis 2010; 69: 798e806. 6 Aalberse J, Dolman K, Ramnath G, Rodrigues Pereira R, Davin J-C. € nlein purpura in children: an epidemiological study HenocheScho among Dutch paediatricians on incidence and diagnostic criteria. Ann Rheum Dis 2007; 66: 1648e50. 7 Narchi H. Risk of long term renal impairment and duration of follow € nlein purpura with normal or up recommended for HenocheScho minimal urinary findings: a systematic review. Arch Dis Child 2005; 90: 916e20. 8 Ronkainen J, Koskimies O, Ala-Houhala M, et al. Early prednisone therapy in HenocheSchonlein purpura: a randomized, double-blind, placebo-controlled trial. J Pediatr 2006; 149: 241e7. 9 Chartapisak W, Opastiraku SL, Willis NS, Craig JC, Hodson EM. € nlein Prevention and treatment of renal disease in HenocheScho purpura: a systematic review. Arch Dis Child 2009; 94: 132e7. 10 Zolotnitskaya A, Weiss R. Mycophenolate mofetil as a steroid sparing agent for treatment of severe HSP nephritis. Pediatr Nephrol 2011; 26: 1646. 11 Jauhola O, Ronkainen J, Autio-Harmainen H, et al. Cyclosporine A vs. €nlein nephritis: a randomized methylprednisolone for HenocheScho trial. Pediatr Nephrol 2011; 26: 2159e66. 12 Faul C, Donnelly M, Merscher-Gomez S, et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med 2008; 14: 931e8. 13 Coppo R, Peruzzi L, Amore A, et al. IgACE: a placebo-controlled, randomized trial of angiotensin-converting enzyme inhibitors in children and young people with IgA nephropathy and moderate proteinuria. J Am Soc Nephrol 2007; 18: 1880e8. 14 Krause MW, Fonseca VA, Shah SV. Combination inhibition of the renine angiotensin system: is more better? Kidney Int 2011; 80: 245e55.
commonly used in other patients with proteinuric chronic kidney disease. Effective treatment of hypertension is a clear therapeutic goal and the aim should be to start treatment if blood pressure is greater than the 90th centile, reducing it to the 50th centile. As well as having similar abnormalities of IgA glycosylation, the renal lesions of HSPN are identical to those seen in IgA nephropathy (IgAN) and therefore parallels are drawn between IgAN and HSPN. A placebo-controlled, randomized trial of the angiotensin-converting enzyme (ACE) inhibitor benazepril in children and young people (age range 9e35 years) with IgA nephropathy and moderate proteinuria, showed a clear reduction in proteinuria and slowing down of progression of renal disease. ACE inhibitors are already widely used in children with proteinuric renal disease and in light of the findings of this study, should be used in patients with proteinuria and HSP nephritis. They should also be the first line anti-hypertensive therapy. There has also been an increase in use of dual blockade of the renin-angiotensin system with an angiotensin-receptor blocker in addition to an ACEi, but as yet there is no evidence for this producing any additional benefit from the use of one agent alone.
Summary HSP is a clinical diagnosis and investigations are carried out to exclude other pathologies and identify the presence of renal involvement. There is limited data available to guide management of children with HSP, but recent studies indicate that routine administration of steroids is not beneficial. Children with haematuria and/or proteinuria should be kept under review and those with significant proteinuria (early morning urine protein:creatinine ratio persistently greater than 50 mg/mmol), hypertension or impaired renal function should be discussed with a paediatric nephrologist, because of the risk of long-term renal problems. A
FURTHER READING 1 Dinarello C. Interleukin-1 [beta] and the autoinflammatory diseases. N Engl J Med 2009; 360: 2467e70. 2 Gershoni-Baruch R, Broza Y, Brik R. Prevalence and significance of mutations in the familial Mediterranean fever gene in Henoche Schonlein purpura. J Pediatr 2003; 143: 658e61. 3 Balbir-Gurman A, Nahir A, Braun-Moscovici Y. Vasculitis in siblings with familial Mediterranean fever: a report of three cases and review of the literature. Clin Rheumatol 2007; 26: 1183e5. 4 Lau K, Wyatt R, Moldoveanu Z, et al. Serum levels of galactose-defi€nlein cient IgA in children with IgA nephropathy and HenocheScho purpura. Pediatr Nephrol 2007; 22: 2067e72.
PAEDIATRICS AND CHILD HEALTH 22:8
Practice points C
C
C
331
HSP is a clinical diagnosis. Investigations are carried out to exclude other conditions and identify the presence of nephritis Up to 40% of patients will develop haematuria and/or proteinuria. All children need to be followed up for at least 6 months to exclude renal involvement and then until the urinalysis normalizes Patients with a nephritic or nephrotic picture should be referred to a paediatric nephrologist
Ó 2011 Elsevier Ltd. All rights reserved.
Management of Henoche €nlein purpura Scho
evidence is emerging of a link with other autoinflammatory disorders associated with dysregulated interleukin-1 (IL-1) homeostasis. The 11 members of the IL-1 family of genes include the genes encoding the pro-inflammatory interleukin-1 [beta] (IL-1B) and its regulator, the anti-inflammatory IL-1ereceptor antagonist. IL-1B is a highly active pro-inflammatory cytokine that causes not only fever, anorexia, and other constitutional symptoms but also tissue damage and remodelling. A study by Gershoni-Baruch et al. from Israel demonstrated that 10% of HSP patients were homozygous for mutations of the gene encoding MEFV (the gene defective in familial Mediterranean fever), and an additional 17% had heterozygous defects. MEFV encodes the protein pyrin which regulates caspase-1 activation and consequently IL-1B production. Turkish children with FMF were found to have a 72-fold increase in HSP compared with controls. Overall, rates of HSP range from 2 to 7% in FMF and severe HSP appears to be more common in FMF, with cerebral vasculitis and severe nephritis reported. Persistentrecurrent HSP in a child with hyperimmunoglobulin (Ig) D demonstrates that other defects in inflammatory control may also modulate HSP. Human leukocyte antigen (HLA) haplotypes may also play a role in HSP susceptibility. A study of 110 Turkish children with a diagnosis of HSP showed an increased risk for the development of HSP in children carrying HLA A2, A11 and B35 antigens and a reduced risk in those bearing HLA A1, B49 and B50 antigens. An obvious candidate for a pathogenic role in HSP is IgA and of the two subclasses, only IgA1 is involved in HSP. Abnormal glycosylation of O-linked glycans in the hinge region of the molecule has been found in adults with IgA nephropathy and children with HSP and the IgA1 concentrations are two to threetimes higher than normal. It is suggested that this change makes immune complexes containing this antibody resistant to clearance from the blood, allowing them to collect in tissues and initiate inflammation.
Graham Smith
Abstract €nlein purpura (HSP) is the commonest childhood vasculitis, HenocheScho with a peak incidence in the autumn months. This supports the supposition that it is precipitated by viral infection, which then leads to the production of abnormally glycosylated immunoglobulin A (IgA) and the formation of immune complexes containing this IgA. All organs can be affected, but the purpuric skin lesions are necessary to make the diagnosis. There is little evidence for or against any particular therapeutic strategy and management of the acute episode is mainly supportive with analgesics as necessary. Recent placebo-controlled studies do not support the routine use of early steroids. Most children make a full recovery, but severe long-term renal problems can develop in a few, ultimately leading to established renal failure. Renal involvement is common in the early phase of the disease in the form of haematuria or proteinuria, and those with a more severe nephrotic picture have the greatest risk of long-term problems. However, children with only mild renal involvement initially can still run into difficulties and therefore those children with abnormal urinalysis require follow-up.
Keywords child; glomerulonephritis; HenocheScho€nlein purpura; immunoglobulin A; vasculitis
HenocheSch€ onlein purpura (HSP) is the commonest vasculitis seen in children with an incidence of up to 13.5 per 100,000 school-age children. It involves small vessels and is characterized by the finding of immunoglobulin A (IgA) deposits in biopsy tissue. There is still much about HSP which remains a mystery, but it is postulated that children with an innate susceptibility to develop HSP come into contact with an external trigger which sets off the disease process. The exact nature of the trigger is unknown and many infectious agents have been implicated. It is likely that there is no one specific mediator. The main clinical finding is a purpuric rash involving predominantly the lower limbs and buttocks (Figure 1). Abdominal and joint symptoms are commonly seen in the acute phase of HSP along with evidence of renal involvement, manifest by the presence of haematuria and/or proteinuria. The frequency of these findings at presentation is shown in Table 1.
Diagnosis There is no specific test for HSP and it is therefore a clinical diagnosis. The rash is the main diagnostic feature and important differential diagnoses include meningococcal sepsis and idiopathic thrombocytopenia. In 2005 the vasculitis group of the Paediatric Rheumatology European Society (PRES) proposed new classification criteria for paediatric vasculitides, replacing the American College of Rheumatology (ACR) classification criteria from 1990. However, these proposed modifications were mainly based on a literature review and a consensus-based process and were not formally validated. A formal statistical validation process has now taken place and amended criteria for the diagnosis of HSP have been defined. The criteria suggested are shown in Table 2. The sensitivity and specificity values were obtained by comparing the 827 children diagnosed with HSP by either their treating physician or by the consensus panel with another 150 patients with other forms of childhood vasculitides (polyarteritis nodosa 150, Wegener’s granulomatosis 60, Takayasu arteritis 87). This is a significant improvement on the ACR 1990 criteria, which allowed HSP to be diagnosed just on the basis of palpable purpura in someone under the age of 20 years. However, concern regarding continuing over-diagnosis of HSP,
Pathophysiology Investigation of patients who develop HSP has revealed a number of abnormalities which may play a role in the disease process. The nature of the abnormalities underlying susceptibility to the development of HSP are poorly understood, but
Graham Smith MA MB BS MRCP FRCPCH is Consultant Paediatric Nephrologist at the Children’s Kidney Centre, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK. Conflict of interest: none.
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Ó 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEPHROLOGY
similar cutaneous manifestations to HSP as well as causing arthralgia, abdominal pain and renal involvement, but has not been reported to cause any long-term renal problems. However, I am not sure that performance of a skin biopsy to exclude HSP would change the follow-up pattern of a child with persistent haematuria or proteinuria, irrespective of the diagnosis. Investigations are carried out in an attempt to exclude other diagnoses and to identify the presence of renal involvement. These are summarized in Table 3. The full blood count allows detection of thrombocytopenia. Renal involvement is common but usually limited to haematuria and/or mild proteinuria. More severe nephritis produces greater levels of proteinuria, but it is unusual for the serum creatinine to be raised at presentation.
Acute management HSP is a multi-system disease as demonstrated by case reports which have described involvement of all organs (see Table 4). However, most children with HSP follow a relatively benign course and do not require hospital admission. Treatment is symptomatic, consisting of simple analgesia for joint or abdominal discomfort. Non-steroidal anti-inflammatory agents can be used for more severe arthralgia. In the past bed rest has been advised, but this is unnecessary and patients should be allowed to be as active as they wish. Abdominal pain can be a significant problem and intussusception is then part of the differential diagnosis. A short course of oral steroids (3 days of prednisolone 2 mg/kg) may help, although the evidence to support such treatment is weak.
HSP nephritis It is the renal manifestations of HSP which are responsible for any long-term morbidity. Inflammation in the kidneys (nephritis) is suggested by the finding of haematuria and/or proteinuria. A small number of patients will develop an aggressive nephritis during their presenting disease, but this is unusual and the progression is usually more insidious. Approximately 2% of patients develop long-term renal problems and for this reason, patients with haematuria or proteinuria need to be kept under review (see below). Understandably there has been a focus on strategies to reduce the incidence of renal involvement and this has primarily been through the administration of steroids. The results of three randomized placebo-controlled studies of prednisolone started at the onset of HSP, examining the incidence of ongoing renal problems at 6 months or a year were reviewed by the Cochrane Renal group and the conclusion was that together these studies demonstrated no significant benefit of short-term prednisone therapy in preventing renal disease. The story does not get any clearer for the treatment of patients who develop more severe renal involvement. There is limited data to guide the treatment of active HSP nephritis (HSPN) and the decision about whether to embark on a potentially toxic therapy is complicated by the fact that some patients with significant nephritis will spontaneously improve. If treatment is considered there are a range of options for which success has been reported in uncontrolled series including steroids, cyclophosphamide, plasma exchange, ciclosporin, azathioprine, immunoglobulin and mycophenolate mofetil but there is only limited information from
Figure 1 Example of HSP rash.
in particular confusing it with idiopathic cutaneous small-vessel vasculitis (CSVV), has been raised by Aalberse et al. They studied the diagnostic criteria for HSP being used by Dutch paediatricians in 2004, in order to evaluate its accuracy using the presence of IgA in the skin when biopsies were available. Unfortunately only 17 skin biopsies were carried out in the 232 patients reported as having contracted HSP, but of these only nine (53%) had IgA deposits. They felt that clinical diagnosis of HSP was not always reliable and that the exclusion of HSP would allow less active follow-up, on the basis that CSVV has very
PAEDIATRICS AND CHILD HEALTH 22:8
328
Ó 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEPHROLOGY
trial comparing ciclosporin (CyA) and methylprednisolone (MP) in the treatment of HSPN. Twenty-four children with nephroticrange proteinuria or crescentic HSPN seen in a kidney biopsy were studied. Of these, seven were randomized to receive CyA for 12 months at an initial dose of 5 mg/kg and eight to receive three MP pulses of 30 mg/kg followed by prednisone for 4 months. The other nine patients received identical treatment without randomization. Kidney biopsies were performed at inclusion and after 2 years. All 11 CyA-treated patients achieved resolution of nephrotic-range proteinuria within 3 months, while the response in the MP group was slower, and in 6/13 was not achieved with the initial treatment. Additional immunosuppressive treatment was needed in none of the CyA-treated patients but in six patients treated with MP (difference in proportion 46%, p ¼ 0.008). The 2-year control biopsies showed similar improvement in both groups. After mean 6.1 years (2.2e10.4 years), 16 patients (eight CyA, eight MP) had no renal symptoms and six (three CyA, three MP) had persistent nephropathy but normal renal function. One MP-treated patient had reduced renal function and another had developed ESRD. A number of uncontrolled studies have previously described the effectiveness of CyA in the treatment of HSPN, usually in combination with steroids. This study suggests that CyA can be used alone. A concern when using CyA is nephrotoxicity, but this was not found in this study. The authors felt that C2 monitoring in addition to the C0 levels used would be helpful.
Clinical and demographic findings at presentation of HSP in 184 patients Sex Mean age Age range Rash Joint symptoms Abdominal pain Haematuria Proteinuria
92 male: 92 female 6.4 years 0.72e13.87 years 184 (100%) 156 (85%) 89 (48%) 58 (32%) 71 (39%)
Table 1
studies including any control groups. A controlled study comparing methylprednisolone and urokinase pulse therapy, with and without cyclophosphamide, showed a benefit from the use of cyclophosphamide. This compares with a study of 56 patients with histopathologically severe HSP nephritis who were randomized to receive supportive therapy with or without cyclophosphamide (90 mg/m2/day for 42 days), in which there was no difference in outcome between the two groups. Until recently this was the only randomized study looking at HSPN. Jauhola et al. have just reported the results of a randomized
Final EULAR/PRINTO/PRES HSP criteria Criterion
Description
Purpura (mandatory criterion)
Purpura (commonly palpable and in crops) or petechiae, with lower limb predominance, not related to thrombocytopeniaa Diffuse abdominal colicky pain with acute onset assessed by history and physical examination. May include intussusception and gastrointestinal bleeding Typically leucocytoclastic vasculitis with predominant IgA deposit or proliferative glomerulonephritis with predominant IgA deposit Arthritis of acute onset defined as joint swelling or joint pain with limitation on motion. Arthralgia of acute onset defined as joint pain without joint swelling or limitation on motion Proteinuria >0.3 g/24 h or >30 mmol/mg of urine albumin/ creatinine ratio on a spot morning sample Haematuria or red blood cell casts: >5 red blood cells/high power field or red blood cells casts in the urinary sediment or 2þ on dipstick Purpura or petechiae (mandatory) with lower limb predominancea and at least one of the four following criteria: Abdominal pain Histopathology Arthritis or arthralgia Renal involvement
Abdominal pain
Histopathology
Arthritis or arthralgias
Renal involvement
HSP EULAR/PRINTO/PRES Ankara 2008 classification definition: k 0.90 (95% CI 0.84e0.96)
Sensitivity (%)
Specificity (%)
AUC (%)
89
86
87.5
61
64
62.2
93
89
91.1
78
42
59.9
33
70
51.4
100
87
93.5
€nlein purpura; PRES, Paediatric Rheumatology European Society; PRINTO, AUC, area under the curve; EULAR, European League Against Rheumatism; HSP, HenocheScho Paediatric Rheumatology International Trials Organization. a For purpura with atypical distribution a demonstration of an IgA deposit in a biopsy is required.
Table 2
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SYMPOSIUM: NEPHROLOGY
consistently normal urinalysis. The overall percentage of children who developed persistent renal impairment on long-term follow-up was 1.8%. While it occurred in 5.4% of those who had abnormal urinary findings, only 1.6% of those with isolated haematuria or proteinuria developed long-term renal impairment, while that percentage increased to 20% of those who developed nephritic or nephrotic syndrome. Nephritis was defined as haematuria associated with at least one of the following: raised serum urea and creatinine, hypertension or oliguria. The recommendations from this review were: At diagnosis and at each HSP recurrence, blood pressure measurement and urinalysis need to be carried out. If haematuria and/or proteinuria are found, serum urea and creatinine should be measured. In case of normal urinalysis or if there is isolated haematuria or proteinuria without nephrotic or nephritic syndromes, a periodic check of urinalysis is needed for up to 6 months after diagnosis. There is no need for subsequent follow-up of those whose urinalysis remains normal, but measurements of serum urea and creatinine need to continue in the presence of persistent haematuria or proteinuria. In cases with a nephritic or nephrotic picture, a paediatric nephrologist needs to be consulted, as urgent evaluation is necessary and long-term renal follow-up will be needed, even after resolution of the nephritis. This is especially important in affected girls, as they will need monitoring of renal function and blood pressure during and after future pregnancies. These recommendations are appropriate in view of the available evidence.
Suggested investigations for a child presenting with palpable purpura, suspected of having HSP Blood pressure Dipstick urinalysis Full blood count Serum creatinine Urine protein:creatinine ratio Table 3
CyA was developed as an immunosuppressive agent for use in transplantation. It inhibits calcineurin, which, under normal circumstances, is responsible for activating the transcription of interleukin 2. It also inhibits lymphokine production and interleukin release and therefore reduces the function of effector T-cells. However it is now felt that the anti-proteinuric action of CyA may not be dependent on effects on T-cell function, but rather results from stabilization of the actin cytoskeleton in the kidney podocytes.
Follow-up Concern about the possible development of renal complications is the main driver for the follow-up of children after an episode of HSP. The question of which children need follow-up has been addressed by Narchi through an analysis of papers which have studied unselected groups of patients (cohorts not selected on presence or absence of renal involvement). The studies identified included a total of 1133 children. Normal urinalysis was found in 66% of the cases, while haematuria and/or proteinuria occurred in 34%, of which only 21% were in association with nephritic or nephrotic syndrome. When haematuria or proteinuria developed, it occurred in 85% of cases within 4 weeks of the diagnosis of HSP, in 91% within 6 weeks, and in 97% within 6 months. Longterm renal impairment never developed in any child who had
Long-term management In children with established renal disease secondary to HSP there are measures which can be taken to slow down its progression,
Manifestations of HSP Skin
The majority of skin lesions heal well, but scarring can occur. Occasionally bullous lesions can develop. Some boys (22%) develop involvement of the scrotal skin with underlying epididymo-orchitis, which can be misdiagnosed as testicular torsion Joints Joint involvement usually consists of arthralgia, particularly of the lower limb joints GIT Abdominal pain is a common symptom caused by inflammation of the intestinal mucosa. It can be associated with bleeding and, rarely, with the development of intussusception Kidneys Haematuria, detected on dipstick analysis of the urine, is common and usually self-limiting. Less commonly, significant proteinuria can develop and, very rarely, an acute nephritis leading to early renal impairment. As with any nephritic process, proteinuria is associated with a risk of future renal impairment Heart Rheumatic fever with complete atrioventricular block, pericarditis Liver Cholecystitis CNS Bilateral brachial plexopathy, cerebral vasculitis, cerebral haemorrhage, ataxia, peroneal neuropathy, peripheral facial palsy, Guillaine Barre syndrome, brachial plexopathy, posterior tibial nerve neuropathy, femoral neuropathy, ulnar neuropathy and mononeuritis multiplex Lung Pulmonary haemorrhage, pleural effusion, chylothorax Eyes Episcleritis, scleritis, keratitis, anterior uveitis, central retinal vein occlusion and central retinal artery occlusion Pancreas Pancreatitis Adrenals Adrenal haematoma Table 4
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SYMPOSIUM: NEPHROLOGY
5 Ozen S, Pistorio A, Iusan SM, et al. EULAR/PRINTO/PRES criteria for € nlein purpura, childhood polyarteritis nodosa, childHenocheScho hood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis 2010; 69: 798e806. 6 Aalberse J, Dolman K, Ramnath G, Rodrigues Pereira R, Davin J-C. € nlein purpura in children: an epidemiological study HenocheScho among Dutch paediatricians on incidence and diagnostic criteria. Ann Rheum Dis 2007; 66: 1648e50. 7 Narchi H. Risk of long term renal impairment and duration of follow € nlein purpura with normal or up recommended for HenocheScho minimal urinary findings: a systematic review. Arch Dis Child 2005; 90: 916e20. 8 Ronkainen J, Koskimies O, Ala-Houhala M, et al. Early prednisone therapy in HenocheSchonlein purpura: a randomized, double-blind, placebo-controlled trial. J Pediatr 2006; 149: 241e7. 9 Chartapisak W, Opastiraku SL, Willis NS, Craig JC, Hodson EM. € nlein Prevention and treatment of renal disease in HenocheScho purpura: a systematic review. Arch Dis Child 2009; 94: 132e7. 10 Zolotnitskaya A, Weiss R. Mycophenolate mofetil as a steroid sparing agent for treatment of severe HSP nephritis. Pediatr Nephrol 2011; 26: 1646. 11 Jauhola O, Ronkainen J, Autio-Harmainen H, et al. Cyclosporine A vs. €nlein nephritis: a randomized methylprednisolone for HenocheScho trial. Pediatr Nephrol 2011; 26: 2159e66. 12 Faul C, Donnelly M, Merscher-Gomez S, et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med 2008; 14: 931e8. 13 Coppo R, Peruzzi L, Amore A, et al. IgACE: a placebo-controlled, randomized trial of angiotensin-converting enzyme inhibitors in children and young people with IgA nephropathy and moderate proteinuria. J Am Soc Nephrol 2007; 18: 1880e8. 14 Krause MW, Fonseca VA, Shah SV. Combination inhibition of the renine angiotensin system: is more better? Kidney Int 2011; 80: 245e55.
commonly used in other patients with proteinuric chronic kidney disease. Effective treatment of hypertension is a clear therapeutic goal and the aim should be to start treatment if blood pressure is greater than the 90th centile, reducing it to the 50th centile. As well as having similar abnormalities of IgA glycosylation, the renal lesions of HSPN are identical to those seen in IgA nephropathy (IgAN) and therefore parallels are drawn between IgAN and HSPN. A placebo-controlled, randomized trial of the angiotensin-converting enzyme (ACE) inhibitor benazepril in children and young people (age range 9e35 years) with IgA nephropathy and moderate proteinuria, showed a clear reduction in proteinuria and slowing down of progression of renal disease. ACE inhibitors are already widely used in children with proteinuric renal disease and in light of the findings of this study, should be used in patients with proteinuria and HSP nephritis. They should also be the first line anti-hypertensive therapy. There has also been an increase in use of dual blockade of the renin-angiotensin system with an angiotensin-receptor blocker in addition to an ACEi, but as yet there is no evidence for this producing any additional benefit from the use of one agent alone.
Summary HSP is a clinical diagnosis and investigations are carried out to exclude other pathologies and identify the presence of renal involvement. There is limited data available to guide management of children with HSP, but recent studies indicate that routine administration of steroids is not beneficial. Children with haematuria and/or proteinuria should be kept under review and those with significant proteinuria (early morning urine protein:creatinine ratio persistently greater than 50 mg/mmol), hypertension or impaired renal function should be discussed with a paediatric nephrologist, because of the risk of long-term renal problems. A
FURTHER READING 1 Dinarello C. Interleukin-1 [beta] and the autoinflammatory diseases. N Engl J Med 2009; 360: 2467e70. 2 Gershoni-Baruch R, Broza Y, Brik R. Prevalence and significance of mutations in the familial Mediterranean fever gene in Henoche Schonlein purpura. J Pediatr 2003; 143: 658e61. 3 Balbir-Gurman A, Nahir A, Braun-Moscovici Y. Vasculitis in siblings with familial Mediterranean fever: a report of three cases and review of the literature. Clin Rheumatol 2007; 26: 1183e5. 4 Lau K, Wyatt R, Moldoveanu Z, et al. Serum levels of galactose-defi€nlein cient IgA in children with IgA nephropathy and HenocheScho purpura. Pediatr Nephrol 2007; 22: 2067e72.
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HSP is a clinical diagnosis. Investigations are carried out to exclude other conditions and identify the presence of nephritis Up to 40% of patients will develop haematuria and/or proteinuria. All children need to be followed up for at least 6 months to exclude renal involvement and then until the urinalysis normalizes Patients with a nephritic or nephrotic picture should be referred to a paediatric nephrologist
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