henoCh-sChönlein purpura – a review INTRODUCTION

henoCh-sChönlein purpura – a review INTRODUCTION

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  116 Current Allergy & Clinical Immunology, August 2010 Vol 23, No. 3 H ENOCH - SCHÖNLEIN   PURPURA  – A   REVIEW Paul Sinclair,   MB ChB, DCH, FCP(Paed)SAConsultant paediatric nephrologist, Vincent Palotti and Red Cross War Memorial Children’s Hospitals, Cape Town, South Africa  INTRODUCTION Henoch-Schönlein purpura (HSP) is the commonest acute vasculitis of childhood. It is typified by a classic palpable cutaneous purpura, associated with abdominal and joint symptoms. The long-term prognosis is vari-able, though generally good, but depends on the degree of renal involvement. The treatment remains somewhat controversial, with few established protocols.The first description was probably made by Heberden (the same person who gave his name to Heberden’s nodes) in 1801, of a young boy with ‘blood points’ over the shins and abdominal pain, who also had blood in the stools and painful oedema. The title however was given to Johan Schönlein who in 1837 described an as-sociation between purpura and joint pain as ‘peliosis rheumatica’, and one of his pupils Eduard Henoch who linked all four symptoms of purpura, abdominal pain, joint pain and kidney involvement in 1868.This article tries to highlight some of the diagnostic is-sues and shed some light on the evolving knowledge of whom and when and how to treat. DEFINITION HSP is an acute leucocytoclastic vasculitis, typified by IgA deposits affecting small vessels of the skin, joints, gastrointestinal tract (GIT) and kidneys. According to the 1990 classification, 1  the diagnosis can be made if at least two of the following criteria are present:1. Palpable purpura (without thrombocytopenia)2. Age <20 years at time of diagnosis3. Bowel angina4. Vessel-wall granulocytes on biopsy. CLINICAL FEATURES Table I lists the major clinical features. Cutaneous   manifestations are the first sign in the ma-jority of cases (70%) and most often involve the lower extremities and buttocks (Fig. 1). The vasculitis /purpura are often accompanied by oedema. Joints   (Fig. 2) are involved in the majority of cases, involving lower limbs (ankles and knees) more com-monly. Gastrointestinal   pain is often the most debilitating of the HSP symptoms, and can be further complicated by GIT haemorrhage (14-38%), intussusception, obstruc-tion or perforation. Renal   symptoms have a wide range of severity, from asymptomatic microscopic haematuria, to full-blown nephrotic syndrome or nephritis. Most renal involve-ment occurs early, 85% within the first month, although it can develop later; follow-up to 6 months is recom-mended.Other symptoms are rare and usually involve the central nervous system or lungs, from pulmonary haemorrhage through to convulsions.Age does play a role in the symptomatology, with chil-dren younger than 2 years showing predominantly cu-taneous symptoms and signs, as well as a much lower incidence of renal and gastrointestinal involvement. The peak incidence is in the 4-6-year-old age group with fig-ures around 70/100 000 population, with a very slight male predominance.Recurrence is relatively common and 30% of patients will have one or more recurrences of acute vasculitis. The average duration of disease is 4 weeks and while steroids will shorten this period, current data suggest there is no correlation between steroid use and in-creased frequency of relapse. 3,4   DIFFERENTIAL DIAGNOSIS Vasculitis is not a com-mon childhood condi-tion and HSP is difficult to confuse with other small-vessel vascu-litides, but a relatively short list of alternative possibilities are shown in Table II. Most of these conditions can Correspondence: Dr P Sinclair, e-mail: paeds@jaywalk.co.za ABSTRACT Henoch-Schönlein purpura (HSP), the commonest childhood vasculitis, is typified by skin, joint, gastro-intestinal tract and renal involvement. It shows peak incidence between the ages of 4 and 6 years and has a recurrence rate of 30%. Investigations are useful in differentiating HSP from other vasculitides but the diagnosis is clinical. Renal damage via an immune complex glomerulonephritis is the most serious long-term complication and warrants the greatest attention from clinicians: to establish who requires long-term follow-up, renal biopsy and immunosup-pressive therapy. Immunosuppressive regimens are varied, and local experience with corticosteroids and azathioprine, as well as reported studies, is dis-cussed in more detail. Table I. Major clinical manifestations of HSP in children based on four studies  .2    Clinical feature   Blanco et al.  Calvino et al  . Allen et al  .  Fisher et al  .  All  N  =116 N  =78 N  =131 N  =119 N  =444 Purpura (%) 100 100 100 100 100Joint pain (%) 80 78 68 76 75Gastrointestinal (%) 64 73 53 76 65Renal involvement (%) 25 54 41 54 43  Current Allergy & Clinical Immunology, August 2010 Vol 23, No. 3 117 be excluded or diagnosed clinically, but immune-sero-logical markers and a full blood count will distinguish doubtful cases. PATHOGENESIS  IgA1 has been implicated as the most important inflam-matory role player. This has been suggested by an in-crease in serum IgA levels and IgA-containing immune complexes in the majority of patients, and dense IgA deposits shown in the vessel walls of affected organs.An abnormal glycosylation of the O-linked oligosaccha-rides unique to the hinge region of IgA1 has been pos-tulated as a pathogenic factor by reducing the clearance of IgA1. Alternatively there may be dysregulation of B and T lymphocytes allowing overproduction of IgA1, fol-lowing an appropriate immune stimulant. A number of potential triggers including infective agents, vaccines and drugs, have been identified (Table III).The IgA immune complexes deposit in the vascular walls of affected organs, triggering a typical inflam-matory response via both complement pathways and direct cell activation, leading to endothelial destruction and invasion by leucocytes.There is no evidence of a direct or simple inheritance pattern for HSP. Although sibling, twin and familial oc-currences have been reported and although the C4 null allele has been shown to be a more frequent finding in HSP sufferers, there is no gene or single locus identi-fied. It is thought rather to be a multifactorial disease involving many genes and environmental factors. DIAGNOSIS HSP is a clinically obvious condition in the majority of cases, but laboratory investigation would include: Full blood count,  to exclude thrombocytopenia; most often thrombocytosis is found in HSP. Anaemia may be present but is usually an indicator of GIT haemorrhage or severe haematuria. Renal function  is obviously very important and assists in identifying some with a rapidly progressive glomerular disease. Erythrocyte sedimentation rate   (ESR) is elevated in approximately 60%, but is a nonspecific inflammatory marker. IgA levels   are elevated in 25-50% of patients. C3 and C4   are not often decreased in circulation (only in around 5-20%). Albumen levels   are diminished in cases of nephrotic syndrome and/or protein-losing enteropathy which may occur. Antineutrophil cytoplasmic autoantibodies (ANCAs) of the IgA   subtype   have along with antistreptolysin o titres (ASOT) been shown to be elevated in some studies but are of little prognostic or diagnostic assistance. Occult faecal blood   is seen in 25%. Factor XIII   plasma levels can be measured in atypical cases and are decreased in the majority, even prior to purpura formation. Skin biopsy   is a useful diagnostic tool in atypical cases, and reveals a typical leucocytoclastic vasculitis with ne-crosis of the vascular wall and inflammatory cell infil-trate, accompanying IgA dermal deposition. Fig. 1. Typical distribution of palpable purpura in He- noch-Schönlein purpura. Fig. 2. Henoch-Schönlein purpura in the upper limb, showing swelling of the elbow joint. Table II. Differential diagnosis  Common Henoch-Schönlein purpura Kawasaki diseaseOther vasculitides Wegener’s granulomatosis Polyarteritis nodosa Systemic lupus erythematosus Urticarial purpura/vasculitis hypersensitivity Vasculitis Vasculitis associated with: Behçet’s syndrome Familial mediterranean fever Cogan’s syndrome Hypocomplementaemic urticarial vasculitisOther Acute poststreptococcal glomerulonephritis Leukaemia Idiopathic thrombocytopenic purpura Table III. Potential triggers  Bacteria Streptococcus pyogenes, Staphylococcus aureus, Mycoplasma, Shigella, Yersinia, Legionella, Salmonella, Helicobacter pylori, Campylobacter  Viruses Adeno, parvo, hepatitis B, Varicella zoster  , Epstein-Barr, coxsackie, herpes, HIVDrugs Thiazides, ACE inhibitors, NSAIDs, antibioticsOther Insect bites, food allergies, Toxocara canis  HIV – human immunodeficiency virus, ACE – angiotensin- converting enzyme, NSAID – nonsteroidal anti-inflammatory drug  118 Current Allergy & Clinical Immunology, August 2010 Vol 23, No. 3 Gastric mucosal biopsies   show a similar pattern to the skin and the appearance can be very similar to the bi-opsy findings in hypersensitivity vasculitis. Renal biopsy   is indicated where the risk of long-term renal damage is suspected and more aggressive thera-py may be required. However the timing of the biopsy and the usefulness of the ISKDC (International Study of Kidney Disease in Children) classification, as shown in Table IV, have been questioned. 5,6  This controversy sur-rounds the presence of crescents determining stage or grade and fails to accommodate the maturity of these crescents, leading to under- or overtreatment. A semi-quantitative scoring system taking into account the acute or chronic nature of the findings has also been used. 6 The typical findings are of diffuse IgA deposits, often accompanied by IgG or C3 in the mesangium with cel-lular infiltrates. Renal involvement  It is worthwhile discussing this clinical entity in a little more depth, as it is the site of long-term sequelae and disease following this typically self-limiting disease.It is safe to say that a negative urinalysis guarantees the HSP patient a clean bill of renal health, although this must be qualified: urine should be clear, on follow up, until 6 months post primary diagnosis. Proteinuria and haematuria will occur in about 30-40% of patients with HSP, but only 85% of these will be picked up at the time of initial diagnosis: 95% by 6 weeks and 97% by 6 months post diagnosis. 7  However an active urinary sediment or mild proteinuria (<1g/24 hours) are not commonly associated with permanent renal impair-ment, around 1-2%. Patients with nephritic or nephrotic syndromes, however, have a 20% risk of permanent renal impairment.HSP patients should therefore be followed up for 6 months to ensure there is no renal involvement, and those with nephritis or nephrotic syndrome investigated further, treated aggressively and followed up closely. RED CROSS CHILDREN’S HOSPITAL REVIEW 2005-2010 This review, summarised in Table V, is potentially skewed, as it represents only the biopsied HSP patients coming through Red Cross Children’s Hospital Renal Unit, which is a tertiary referral centre. It does indicate overall good outcomes with aggressive, though not standardised immunosuppressive therapy. Two inter-esting observations can be made: • Of the 7 patients biopsied 4 were referrals from private doctors, raising concerns that in the public sector patients are being missed, not referred or not followed up adequately, and then present later in chronic renal failure. • Only 7 biopsies in 5 years at a major renal centre (all patients had significant glomerulonephritis) indicates that we are not seeing the full spectrum of renal HSP in the community. TREATMENT OF HENOCH-SCHÖNLEIN PURPURA From the publication of Huber  et al. ’s 3  small (but con-sidered significant) study in 2004 the use of prednisone in the treatment of uncomplicated HSP has been a little confused. This group concluded that early use of ste-roids did not prevent the progression to or of Henoch-Schönlein nephritis (HSN) and questioned whether ste-roids with all their potential side-effects should be used at all. There is significant evidence that prednisone re-duces the severity and length of extrarenal symptoms, most notably abdominal pain and joint pain and swell-ing, and in some studies a reduction in gastrointestinal complications (invaginations, haemorrhage). Though most treatment provides symptomatic relief, there ap-pear to be no long-term benefits in using steroids, in terms of shortening the overall length of the illness, re-ducing recurrences or progression of HSN.This statement needs to be qualified; in treating HSN, high-dose pulsed steroids in combination with other immunosuppressive drugs (cyclophosphamide, cy-closporin, azathioprine) have shown reduction in pro-gression to end-stage kidney disease (ESKD)/renal im-pairment.Table VI summarises some of the different reports on treatment strategies and outcomes in children with HSN. 5  Many immunosuppressive regimens have been used in combination with steroids, both in severely symp-tomatic or recurrent HSP and (most commonly) in HSN. Pulsed cyclophosphamide with methylprednisolone is well accepted therapy in crescentic or rapidly progres-sive nephritis, though in HSN results appear to be just as good with the use of cyclosporin or azathioprine therapy. As is indicated in the above table, there are no established evidence-based protocols that have been studied in a randomised controlled method. Other methods of treatment  ACE inhibitors   are successfully used in reducing protei-nuria as well as controlling blood pressure in HSN. NSAIDs   are useful adjunctive therapy to alleviate pain, but must be used with caution if GIT haemorrhage or renal impairment is present. Immunoglobulin  has been used in small uncontrolled groups, mainly adults. But there is no evidence to sup-port its use or safety in HSP or HSN. Plasmapheresis.  Hattori et al  . 7  suggest that plasma-pheresis, used as sole therapy early in the disease course, may be associated with good outcome, but this study reports a small number of patients and has no control group. Late plasmapheresis does not appear to alter outcome. Anticoagulants, fibrinolytics and factor XIII therapy   have all been used in combination with immunosuppression and their individual benefits are difficult to extrapolate. Rituximab   has been used more recently in small series with good individual response. 8   Table IV. International Study of Kidney Disease in Children (ISKDC) classification ISKDC Grade Pathoanatomical findings  I Minimal alterationII Mesangial proliferationIII A Focal proliferation or sclerosis with <50% crescentsIII B Diffuse proliferation or sclerosis with <50% crescentsIV A Focal proliferation or sclerosis with 50-75% crescentsIV B Diffuse proliferation or sclerosis with 50-75% crescentsV A Focal proliferation or sclerosis with >75% crescentsV B Diffuse proliferation or sclerosis with >75% crescentsVI Membranoproliferation  Current Allergy & Clinical Immunology, August 2010 Vol 23, No. 3 119 Leucocytopheresis   has been described in case reports as treatment for severe/chronic forms of HSP. 9   SO WHO NEEDS TREATMENT? In HSP without renal involvement, steroid therapy is a useful adjunct to supportive therapy, improving symp-toms and alleviating pain and discomfort, and should be used cautiously and sparingly according to patient needs.Gastrointestinal haemorrhage and pulmonary complica-tions are fortunately uncommon and will need specific surgical intervention as indicated. Intravenous steroids may be considered for supportive therapy, for short pe-riods, though the use of steroids only reduces GIT pain and not the risk of GIT haemorrhage.Predicting the group with renal involvement who will show progressive, destructive disease is more difficult, but clear risk factors include: • Acute glomerulonephritis • Nephrotic syndrome• Older children, >7 years of age, and all adults• Severe bloody stools CONCLUSION Henoch-Schönlein purpura, the commonest acute vas-culitis of childhood, is a well recognised clinical disease, typified by the purpuric rash involving the buttocks and extremities and accompanied by joint and abdominal pain. It is most often a self-limiting, single-episode event requiring analgesia during its 4-6-week process. It is important, in every case, to perform a urine dipstick analysis to identify at-risk individuals. These patients need to be followed up for 6 months to avoid missing any potential HSN complications. Within this group of patients with a positive urinalysis (proteinuria and haematuria), more aggressive follow-up and investigation is essential, to further identify the patients with nephritis or nephritic syndrome or rapidly progressive glomerular nephritis, as early intervention has been clearly shown to prevent renal failure in the majority. Table V. Summary of HSP patients who underwent biopsy at Red Cross Children’s Hospital Renal Unit 2005-2010  Patient / Age at Symptoms Time of biopsy Biopsy grade Treatment Outcome Year of diagnosis post diagnosis and immunology birth (years) TS 1997 10 Left orbital 3 weeks Grade II IgA 3 + IVI dexamethazone Lost to follow-up cellulitis then hydrocortisone Rash pre biopsy Proteinuria 3 months oral Haematuria prednisone post Oedema LB 1990 13 Abdominal pain 2 years (on Grade II – III A 12 weeks po Currently on ACE Rash prednisone and IgA neg cyclophosphamide inhibitor Arthralgia azathioprine) and prednisone for Creat 92 (2009) Haematuria 6 months (slow wean) with 2 years azathioprine CP 2002 6 Rash 6 weeks Grade II IgA 3+ Prednisone for Off all treatment Oedema 2 years and Creat 43 (2010) Arthritis azathioprine Haematuria for 1 year ACE inhibitor ZA 1996 6 Rash 6 months Grade IIIA Prednisone Lost to follow-up Abdominal pain (on prednisone) 2 cellular 6 months and vomiting crescents (slow wean) Proteinuria IgA 2+ 6 months Haematuria azathioprine Hypertension ACE inhibitor and diureticsFJ 1997 11 Rash 6 months Grade II 12 weeks po Persistent Proteinuria IgA + cyclophosphamide haematuria (nephrotic range) and 6 months (repeat biopsy Haematuria prednisone with mesangiocapillary) Renal failure 1 year azathioprine JZ 1996 9 Abdominal pain 5 weeks Grade IV A 3 x doses IV Well off all Rash Cellular cyclophosphamide therapy Arthralgia crescents then 6 months Formal GFR 115 Haematuria IgA + azathioprine and ml/min/1.73m 2  Proteinuria plus ATN weaning prednisone Hypertension Seizure AW 1998 6 Recurrent rash 6 months (on Grade I-II 3 months Urine clear Abdominal pain azathioprine) IgA neg prednisone and Creat 62 Haematuria 18 months Off all treatment (macro) azathioprine ATN – acute tubular necrosis; GFR – glomerular filtration rate  120 Current Allergy & Clinical Immunology, August 2010 Vol 23, No. 3 So although there is no consensus, HSP with nephri-tis (HSN) is a significant risk factor for permanent renal impairment, and there is building evidence that early and aggressive therapy with pulsed steroids and con-tinuation immunosuppressive therapy should be used, preferably after a renal biopsy to identify the presence of crescents. This will prevent a significant number of patients progressing to end stage renal failure.Steroid use in uncomplicated HSP remains an area for more research, but at the present time is a safe option for severely symptomatic disease, with no evidence to suggest an increase risk of early relapse, recurrence or GIT haemorrhage. Occasionally intravenous steroid therapy may be required in severe gastrointestinal dis-ease, though the majority of patients will benefit from a short course of oral corticosteroids. Acknowledgement Photographs courtesy of Dr Ralph Diedericks, consul-tant paediatric ambulatory care, Red Cross War Memo-rial Children’s Hospital. Declaration of conflict of interest The author declares no conflict of interest. REFERENCES 1. Mills JA, Michel BA, Bloch DA, et al  . The American College of Rheu-matology 1990 Criteria for Classification of Henoch-Schonlein pur-pura. Arthritis Rheum  1990; 33: 1114-1121. 2. Elefthiou D, Dillon MJ, Brogan PA. Advances in childhood vasculti-tis, Henoch Schonlein purpura. Medscape Pediatrics    Curr Opin Rheumatol 2009; 21: 411-418. 3. Huber AM, King J, McLaine P, Klassen T, Pothos M. A randomised, placebo-controlled trial of prednisone in early Henoch Schonlein pur-pura (ISRCTN85109383). BMC Medicine   2004; 2: 7. 4. McCarthy HJ, Tizard EJ. Clinical practice; diagnosis and manage-ment of Henoch Schonlein purpura. Eur J Pediatr 2010; 169: 643-650. 5. Ronkaineu J. Henoch Schonlein purpura in children: a long term outcome and treatment. Academic dissertation, University of Oulu, 25 November 2005. 6. Foster BJ, Bernard C, Drummond KN, Sharma AK. Effective therapy for severe Henoch-Schonlein purpura nephritis with prednisone and azathioprine: a clinical and histopathologic study. J Pediatr   2000; 136: 370-375. 7. Narchi H. Risk of long term renal impairment and duration of follow up recommended for Henoch Schonlein purpura with a normal or minimal urinary findings: a systematic review. Arch Dis Child 2005; 90: 916-920. 8. Hattori M, Ito K, Konomoto T, Kawaguchi, Yoshioka T, Khono M. Plasmapheresis as the sole therapy for rapidly progressive Henoch-Schonlein purpura nephritis in children. Am J Kidney Dis   1999; 33: 427-433. 9. Donnithoren K, Atkinson J, Hinze C, et al  . Rituximab therapy for severe refractory chronic Henoch Schonlein purpura. J Pediatrics 2009; 155: 136-139.10. Nkakhato T, Tanaka H, Suzuki K, Ito E. Successful treatment with leucytapheresis in refractory Henoch Schonlein purpura: case re-port. Clin Rheumatol   2003; 22: 248-250. Table VI. Reports of treatment strategies and outcomes in children with HSN  5  First Year No. Therapy Mean Patients in Minor CRD ESRD author follow up remission urinary (years) abnormality Niaudet 1998 38 MP, P 8 27 3 4 4Kawasaki 2004 6 PP, MP, U, P, D 4.6 2 3 1 0Öner 1995 12 MP, P, CP, D 0.5 7 3 1 1Kawasaki 2003 56 MP, U, P, D 9.7 39 10 5 1Singh 2002 11 MP, P, Az 4.7 9 1 1 0Tanaka 2003 9 P, CP 6.5 7 2 0 0Iijima 1998 14 P, CP, H, D 7.5 9 4 1 0Hattori 1999 9 PP 5.4 4 2 1 2Tarshish 2004 28 CP 3.7 13 8 4 3Tarshish 2004 28 Only supportive 3.7 14 6 4 4Shin 2005 10 Az, P >1 6 4 0 0Shin 2005 10 P >1 4 2 1 3Shin 2005 7 CyA, P 5.5 6 0 1 0Foster 2000 19 P, Az 5.3 10 6 2 1 CRD – chronic renal disease, ESRD - end stage renal disease, MP – methylprednisolone pulses, P – oral prednisone/prednisolone, CP – cyclo-phosphamide, D – dipyridamole, U – urokinase, Az – azathioprine, H – heparin/warfarin, PP – plasmapheresis, CyA – cyclosporine A.
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