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HENOcH-ScHNLEIN

Paul Sinclair, MB ChB, DCH, FCP(Paed)SA


Consultant paediatric nephrologist, Vincent Palotti and Red Cross War Memorial Childrens Hospitals, Cape Town, South Africa

PURPURA
DEFINITION

A REVIEW

ABSTRACT Henoch-Schnlein purpura (HSP), the commonest childhood vasculitis, is typied by skin, joint, gastrointestinal 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 immunosuppressive therapy. Immunosuppressive regimens are varied, and local experience with corticosteroids and azathioprine, as well as reported studies, is discussed in more detail.

HSP is an acute leucocytoclastic vasculitis, typied by IgA deposits affecting small vessels of the skin, joints, gastrointestinal tract (GIT) and kidneys. According to the 1990 classication,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 diagnosis 3. Bowel angina 4. Vessel-wall granulocytes on biopsy.

CLINICAL FEATURES
Table I lists the major clinical features. Cutaneous manifestations are the rst sign in the majority 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 commonly. Gastrointestinal pain is often the most debilitating of the HSP symptoms, and can be further complicated by GIT haemorrhage (14-38%), intussusception, obstruction or perforation. Renal symptoms have a wide range of severity, from asymptomatic microscopic haematuria, to full-blown nephrotic syndrome or nephritis. Most renal involvement occurs early, 85% within the rst month, although it can develop later; follow-up to 6 months is recommended. 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 children younger than 2 years showing predominantly cutaneous 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 gures 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 increased frequency of relapse.3,4

INTRODUCTION
Henoch-Schnlein purpura (HSP) is the commonest acute vasculitis of childhood. It is typied by a classic palpable cutaneous purpura, associated with abdominal and joint symptoms. The long-term prognosis is variable, though generally good, but depends on the degree of renal involvement. The treatment remains somewhat controversial, with few established protocols. The rst description was probably made by Heberden (the same person who gave his name to Heberdens 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 Schnlein who in 1837 described an association 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 issues and shed some light on the evolving knowledge of whom and when and how to treat.

Table I. Major clinical manifestations of HSP in children based on four studies.2 Clinical feature Purpura (%) Joint pain (%) Gastrointestinal (%) Blanco et al. N=116 100 80 64 Calvino et al. Allen et al. N=78 100 78 73 54 N=131 100 68 53 41 Fisher et al. All N=119 100 76 76 54 N=444 100 75 65 43

DIFFERENTIAL DIAGNOSIS
Vasculitis is not a common childhood condition and HSP is difcult to confuse with other small-vessel vasculitides, but a relatively short list of alternative possibilities are shown in Table II. Most of these conditions can

Renal involvement (%) 25

Correspondence: Dr P Sinclair, e-mail: paeds@jaywalk.co.za

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Table II. Differential diagnosis Common Henoch-Schnlein purpura Kawasaki disease

Other vasculitides Wegeners granulomatosis Polyarteritis nodosa Systemic lupus erythematosus  Urticarial purpura/vasculitis hypersensitivity Vasculitis Vasculitis associated with: Behets syndrome Familial mediterranean fever Cogans syndrome Hypocomplementaemic urticarial vasculitis

Fig. 1. Typical distribution of palpable purpura in Henoch-Schnlein purpura. be excluded or diagnosed clinically, but immune-serological markers and a full blood count will distinguish doubtful cases.

Other Acute poststreptococcal glomerulonephritis Leukaemia  Idiopathic thrombocytopenic purpura

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 nonspecic inammatory 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 necrosis of the vascular wall and inammatory cell inltrate, accompanying IgA dermal deposition.

PATHOGENESIS
IgA1 has been implicated as the most important inammatory role player. This has been suggested by an increase 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 oligosaccharides unique to the hinge region of IgA1 has been postulated as a pathogenic factor by reducing the clearance of IgA1. Alternatively there may be dysregulation of B and T lymphocytes allowing overproduction of IgA1, following an appropriate immune stimulant. A number of potential triggers including infective agents, vaccines and drugs, have been identied (Table III). The IgA immune complexes deposit in the vascular walls of affected organs, triggering a typical inammatory 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 occurrences have been reported and although the C4 null allele has been shown to be a more frequent nding in HSP sufferers, there is no gene or single locus identied. It is thought rather to be a multifactorial disease involving many genes and environmental factors.

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, HIV Drugs  Thiazides, ACE inhibitors, NSAIDs, antibiotics Other Insect bites, food allergies,Toxocara canis

Fig. 2. Henoch-Schnlein purpura in the upper limb, showing swelling of the elbow joint.

HIV human immunodeciency virus, ACE angiotensinconverting enzyme, NSAID nonsteroidal anti-inammatory drug

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Table IV. International Study of Kidney Disease in Children (ISKDC) classication ISKDC Grade I II Pathoanatomical ndings Minimal alteration Mesangial proliferation

III A  Focal proliferation or sclerosis with <50% crescents III B  Diffuse proliferation or sclerosis with <50% crescents IV A  Focal proliferation or sclerosis with 50-75% crescents IV B  Diffuse proliferation or sclerosis with 50-75% crescents V A  Focal proliferation or sclerosis with >75% crescents V B  Diffuse proliferation or sclerosis with >75% crescents VI Membranoproliferation

standardised immunosuppressive therapy. Two interesting 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 signicant glomerulonephritis) indicates that we are not seeing the full spectrum of renal HSP in the community.

TREATMENT PURPURA

OF

HENOCH-SCHNLEIN

Gastric mucosal biopsies show a similar pattern to the skin and the appearance can be very similar to the biopsy ndings in hypersensitivity vasculitis. Renal biopsy is indicated where the risk of long-term renal damage is suspected and more aggressive therapy may be required. However the timing of the biopsy and the usefulness of the ISKDC (International Study of Kidney Disease in Children) classication, as shown in Table IV, have been questioned.5,6 This controversy surrounds the presence of crescents determining stage or grade and fails to accommodate the maturity of these crescents, leading to under- or overtreatment. A semiquantitative scoring system taking into account the acute or chronic nature of the ndings has also been used.6 The typical ndings are of diffuse IgA deposits, often accompanied by IgG or C3 in the mesangium with cellular inltrates.

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 qualied: 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 impairment, 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.

From the publication of Huber et al.s3 small (but considered signicant) 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 steroids did not prevent the progression to or of HenochSchnlein nephritis (HSN) and questioned whether steroids with all their potential side-effects should be used at all. There is signicant evidence that prednisone reduces the severity and length of extrarenal symptoms, most notably abdominal pain and joint pain and swelling, and in some studies a reduction in gastrointestinal complications (invaginations, haemorrhage). Though most treatment provides symptomatic relief, there appear to be no long-term benets in using steroids, in terms of shortening the overall length of the illness, reducing recurrences or progression of HSN. This statement needs to be qualied; in treating HSN, high-dose pulsed steroids in combination with other immunosuppressive drugs (cyclophosphamide, cyclosporin, azathioprine) have shown reduction in progression to end-stage kidney disease (ESKD)/renal impairment. 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 symptomatic or recurrent HSP and (most commonly) in HSN. Pulsed cyclophosphamide with methylprednisolone is well accepted therapy in crescentic or rapidly progressive 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 proteinuria 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 support its use or safety in HSP or HSN. Plasmapheresis. Hattori et al.7 suggest that plasmapheresis, 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, brinolytics and factor XIII therapy have all been used in combination with immunosuppression and their individual benets are difcult to extrapolate. Rituximab has been used more recently in small series with good individual response.8

RED CROSS CHILDRENS REVIEW 2005-2010

HOSPITAL

This review, summarised in Table V, is potentially skewed, as it represents only the biopsied HSP patients coming through Red Cross Childrens Hospital Renal Unit, which is a tertiary referral centre. It does indicate overall good outcomes with aggressive, though not 118

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Table V. Summary of HSP patients who underwent biopsy at Red Cross Childrens Hospital Renal Unit 2005-2010 Patient / Age at Symptoms Year of diagnosis birth (years) TS 1997 10 Time of biopsy post diagnosis Biopsy grade Treatment and immunology IVI dexamethazone then hydrocortisone pre biopsy 3 months oral prednisone post Outcome

Left orbital 3 weeks Grade II IgA 3 + cellulitis Rash Proteinuria Haematuria Oedema

Lost to follow-up

LB 1990 13 Abdominal pain 2 years (on Grade II III A Rash prednisone and IgA neg Arthralgia azathioprine) Haematuria CP 2002 6 Rash 6 weeks Grade II IgA 3+ Oedema Arthritis Haematuria ZA 1996 6 Rash 6 months Grade IIIA Abdominal pain (on prednisone) 2 cellular and vomiting crescents Proteinuria IgA 2+ Haematuria Hypertension FJ 1997 11 JZ 1996 9 AW 1998 6 Rash 6 months Grade II Proteinuria IgA + (nephrotic range) Haematuria Renal failure Abdominal pain 5 weeks Rash Arthralgia Haematuria Proteinuria Hypertension Seizure Grade IV A Cellular crescents IgA + plus ATN

12 weeks po Currently on ACE cyclophosphamide inhibitor and prednisone for Creat 92 (2009) 6 months (slow wean) with 2 years azathioprine Prednisone for 2 years and azathioprine for 1 year ACE inhibitor Prednisone 6 months (slow wean) 6 months azathioprine ACE inhibitor and diuretics 12 weeks po cyclophosphamide and 6 months prednisone with 1 year azathioprine 3 x doses IV cyclophosphamide then 6 months azathioprine and weaning prednisone Off all treatment Creat 43 (2010)

Lost to follow-up

Persistent haematuria (repeat biopsy mesangiocapillary) Well off all therapy Formal GFR 115 ml/min/1.73m2

Recurrent rash 6 months (on Grade I-II Abdominal pain azathioprine) IgA neg Haematuria (macro)

3 months prednisone and 18 months azathioprine

Urine clear Creat 62 Off all treatment

ATN acute tubular necrosis; GFR glomerular ltration rate

Leucocytopheresis has been described in case reports as treatment for severe/chronic forms of HSP.9

Older children, >7 years of age, and all adults Severe bloody stools

SO WHO NEEDS TREATMENT?


In HSP without renal involvement, steroid therapy is a useful adjunct to supportive therapy, improving symptoms and alleviating pain and discomfort, and should be used cautiously and sparingly according to patient needs. Gastrointestinal haemorrhage and pulmonary complications are fortunately uncommon and will need specic surgical intervention as indicated. Intravenous steroids may be considered for supportive therapy, for short periods, 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 difcult, but clear risk factors include: Acute glomerulonephritis Nephrotic syndrome

CONCLUSION
Henoch-Schnlein purpura, the commonest acute vasculitis of childhood, is a well recognised clinical disease, typied 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 followup 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.

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Table VI. Reports of treatment strategies and outcomes in children with HSN5 First Year No. Therapy author Niaudet Kawasaki ner Kawasaki Singh Tanaka Iijima Hattori Tarshish Tarshish Shin Shin Shin Foster 1998 2004 1995 2003 2002 2003 1998 1999 2004 2004 2005 2005 2005 2000 38 6 12 56 11 9 14 9 28 28 10 10 7 19 MP, P PP, MP, U, P, D MP, P, CP, D MP, U, P, D MP, P, Az P, CP P, CP, H, D PP CP Only supportive Az, P P CyA, P P, Az Mean follow up (years) 8 4.6 0.5 9.7 4.7 6.5 7.5 5.4 3.7 3.7 >1 >1 5.5 5.3 Patients in remission 27 2 7 39 9 7 9 4 13 14 6 4 6 10 Minor CRD urinary abnormality 3 3 3 10 1 2 4 2 8 6 4 2 0 6 4 1 1 5 1 0 1 1 4 4 0 1 1 2 ESRD

4 0 1 1 0 0 0 2 3 4 0 3 0 1

CRD chronic renal disease, ESRD - end stage renal disease, MP methylprednisolone pulses, P oral prednisone/prednisolone, CP cyclophosphamide, D dipyridamole, U urokinase, Az azathioprine, H heparin/warfarin, PP plasmapheresis, CyA cyclosporine A.

So although there is no consensus, HSP with nephritis (HSN) is a signicant risk factor for permanent renal impairment, and there is building evidence that early and aggressive therapy with pulsed steroids and continuation immunosuppressive therapy should be used, preferably after a renal biopsy to identify the presence of crescents. This will prevent a signicant 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 disease, though the majority of patients will benet from a short course of oral corticosteroids.

2.  Elefthiou D, Dillon MJ, Brogan PA. Advances in childhood vascultitis, 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 purpura (ISRCTN85109383). BMC Medicine 2004; 2: 7. 4.  McCarthy HJ, Tizard EJ. Clinical practice; diagnosis and management of Henoch Schonlein purpura. Eur J Pediatr 2010; 169: 643650. 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 ndings: 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 HenochSchonlein 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 report. Clin Rheumatol 2003; 22: 248-250.

Acknowledgement
Photographs courtesy of Dr Ralph Diedericks, consultant paediatric ambulatory care, Red Cross War Memorial Childrens Hospital. Declaration of conict of interest
The author declares no conict of interest.

REFERENCES
1.  Mills JA, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 Criteria for Classication of Henoch-Schonlein purpura. Arthritis Rheum 1990; 33: 1114-1121.

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