19/8/2015 Henoch­Schönlein purpura (immunoglobulin A vasculitis): Management

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Official reprint from UpToDate www.uptodate.com ©2015 UpToDate

AuthorsFatma Dedeoglu, MDSusan Kim, MD, MMSc

Section EditorRobert Sundel, MD

Deputy EditorElizabeth TePas, MD, MS

Henoch­Schönlein purpura (immunoglobulin A vasculitis): Management

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Jul 2015. | This topic last updated: Jan 30, 2015.

INTRODUCTION — Henoch­Schönlein purpura (HSP), also called immunoglobulin A vasculitis (IgAV) [1], is themost common systemic vasculitis of childhood. Ninety percent of cases occur in the pediatric age group. Incontrast to other forms of systemic vasculitis, HSP (IgAV) is usually self­limited and is characterized by a tetradof clinical manifestations that vary in their presence and order of presentation:

Management of HSP (IgAV) includes supportive care, symptomatic therapy, and targeted treatment to decreasethe risk of complications. The management and prognosis of HSP (IgAV) are presented here. The pathogenesis,clinical manifestations, diagnosis, and differential diagnosis of HSP (IgAV) are discussed separately. (See"Henoch­Schönlein purpura (immunoglobulin A vasculitis): Clinical manifestations and diagnosis".)

MANAGEMENT — The vast majority of patients with Henoch­Schönlein purpura (HSP), also calledimmunoglobulin A vasculitis (IgAV), recover spontaneously. Thus, care is primarily supportive and includesadequate hydration, rest, and symptomatic relief of pain.

Most patients may be cared for in the ambulatory setting. In these patients, therapy is directed toward adequateoral hydration and symptomatic relief. Edema of the lower extremities, buttocks, and genital area is improved withbed rest and/or elevating the affected area.

Treatment of pain — Symptomatic treatment for abdominal and joint pain in patients with HSP (IgAV) includesthe use of acetaminophen or nonsteroidal antiinflammatory drugs (NSAIDs). Clinical experience and limitedobservational data suggest that the antiinflammatory effects of glucocorticoids can relieve many of themanifestations of HSP (IgAV), including the rash, arthritis/arthralgias, scrotal pain/orchitis, and gastrointestinalpain [2]. However, glucocorticoids are not usually indicated for these manifestations, unless symptoms aresevere, given the limited data and the potential side effects of the therapy. Patients with HSP (IgAV) who havegastrointestinal involvement, including bowel wall edema, may have disrupted absorption of enteral medications.Thus, failure of NSAIDs or oral glucocorticoids to benefit certain patients may be due to poor absorption. (See"Major side effects of systemic glucocorticoids".)

Mild­to­moderate pain — There are no randomized, controlled studies of the use of NSAIDs for symptomaticpain relief in patients with HSP (IgAV). However, there is no suggestion that the risk of gastrointestinalhemorrhage in a child with bowel vasculitis is increased by the use of cyclooxygenase inhibitors. Thus, we do nothesitate to use NSAIDs to control joint and abdominal pain in patients with HSP (IgAV). However, NSAIDs maybe contraindicated in patients with active gastrointestinal bleeding or glomerulonephritis, because of their effectson platelets and renal perfusion.

For symptomatic relief of pain in patients with HSP (IgAV), we use naproxen, 10 to 20 mg/kg divided into twodoses per day, because of its ease of dosing. In adolescents and adults, a maximum total daily dose of 1500 mgmay be used for a few days. For longer­term use, a maximum dose of 1000 mg/day is suggested. Ibuprofen and

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Palpable purpura in patients with neither thrombocytopenia nor coagulopathyArthralgia and/or arthritisAbdominal painRenal disease

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other NSAIDs are equally effective and may be better tolerated in some patients, although ibuprofen requires morefrequent dosing.

Severe pain — Most studies show that glucocorticoid therapy shortens the duration of abdominal pain inpatients with HSP (IgAV) [3­7]. However, glucocorticoids do not appear to otherwise impact the clinical course[8,9]. Thus, we suggest using prednisone (1 to 2 mg/kg per day, maximum dose of 60 to 80 mg per day) only inpatients with symptoms significant enough to affect their oral intake, interfere with their ability to ambulate andperform activities of daily living, and/or require hospitalization. In patients who cannot tolerate oral medications, weadminister equivalent doses of parenteral methylprednisolone (0.8 to 1.6 mg/kg per day, maximum dose of 64 mgper day). Intravenous methylprednisolone may be more beneficial early in the disease course when patients haveactive gastrointestinal disease, due to submucosal edema and hemorrhage altering absorption of oral medications.(See 'Prevention of complications' below and 'Hospitalization' below.)

When glucocorticoids are used for treating HSP (IgAV), it is important to remember that inflammation may beameliorated, but the pathophysiology of the disease does not appear to be affected. Accordingly, the glucocorticoiddose must be lowered slowly, typically over four to eight weeks, to minimize the chance of precipitating a diseaseflare by overly aggressive medication tapering. In addition, patients who are treated with glucocorticoids for severeabdominal pain require particular vigilance, since these medications can obscure the signs and symptoms ofabdominal catastrophes associated with HSP (IgAV). (See "Henoch­Schönlein purpura (immunoglobulin Avasculitis): Clinical manifestations and diagnosis", section on 'Gastrointestinal symptoms' and 'Prevention ofcomplications' below.)

Treatment of renal disease — Treatment of active renal disease in HSP (IgAV) and renal transplantation for end­stage renal disease are discussed in detail separately. (See "Renal manifestations of Henoch­Schönlein purpura(IgA vasculitis)", section on 'Treatment'.)

Hospitalization — Hospitalization is warranted for the following indications in patients with HSP (IgAV):

Intravenous hydration is provided in the hospital setting if the patient cannot maintain adequate oral intake offluids. In addition, parenteral nutrition may be required in patients who have a severe and prolonged course ofabdominal symptoms that precludes enteral nutrition.

Hospitalized patients also are monitored for potential complications from their disease. Frequent assessment ofvital signs, urine output, and hematocrit, as well as serial abdominal examinations and stool examination for bloodare required. (See "Henoch­Schönlein purpura (immunoglobulin A vasculitis): Clinical manifestations anddiagnosis", section on 'Laboratory findings' and "Henoch­Schönlein purpura (immunoglobulin A vasculitis): Clinicalmanifestations and diagnosis", section on 'Additional evaluation'.)

Inability to maintain adequate hydration with oral intakeSevere abdominal painSignificant gastrointestinal bleedingChanges in mental statusSevere joint involvement limiting ambulation and/or self­careRenal insufficiency (elevated creatinine), hypertension, and/or nephrotic syndrome

Patients with significant anemia may require red blood cell transfusion, as indicated by tachycardia andhypotension in a patient with a low hematocrit level. Blood loss from hemorrhage into the skin,gastrointestinal tract, or urine rarely depresses red blood cell levels enough to necessitate a transfusion,although superimposed decreased production due to inflammation may result in symptomatic anemia. (See"Red blood cell transfusion in infants and children: Indications".)

Patients with an abdominal examination consistent with either signs of obstruction or peritonitis ("surgicalabdomen") require prompt evaluation, including surgical consultation and/or intervention for possibleintussusception, bowel infarction, or perforation. Bowel vasculitis often cannot be diagnosed by examination

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Prevention of complications — The use of glucocorticoids in patients with HSP (IgAV) is controversial. Althoughmany clinicians describe a rapid symptomatic improvement in patients who receive glucocorticoids, data areinsufficient to confirm such an effect, and it is questionable as to whether such treatment alters clinical outcomes.In addition, there are potential side effects of glucocorticoid therapy, including the risk of obscuring the signs ofcompromised bowel viability if treatment is started after an intussusception has occurred. As a result, we do notrecommend routine glucocorticoid therapy for patients with HSP (IgAV) to treat symptoms or prevent renal orgastrointestinal complications. (See 'Treatment of pain' above.)

Initial reported benefits of glucocorticoid therapy in preventing complications from a systematic review thatincluded 3 randomized trials and 12 retrospective studies included decreased risk of intussusception, renalinvolvement, and recurrence of disease [3]. One subsequent retrospective study found a decreased risk ofgastrointestinal procedures (endoscopy, imaging, and surgery) [13].However, a prospective study of 223 childrenin Finland published after the systematic review found no effect of prednisone on the timing of the appearance ofnephritis [14] or on the clinical course during six months of follow­up [15]. A subsequent meta­analysisincorporating the results of this trial reported no differences in the risk of persistent kidney disease at 6 months(three studies) and 12 months (three studies) in children given prednisone for 14 to 28 days at presentationcompared with those who received placebo or supportive care [16]. Failure to demonstrate benefit may be anartifact of the low prevalence rate of complications and the small number of patients studied [4,17].

Additional therapies for the treatment of recalcitrant disease are not well­defined, but there are reports and caseseries that suggest benefits from medications such as colchicine and dapsone [18,19]. There are also reports ofbenefit from additional immunosuppression in cases of aggressive, recalcitrant disease, typically with renalinvolvement [16]. Management of renal disease in HSP (IgAV) is discussed in detail separately. (See "Renalmanifestations of Henoch­Schönlein purpura (IgA vasculitis)", section on 'Treatment'.)

PROGNOSIS — The short­ and long­term outcomes of children with Henoch­Schönlein purpura (HSP), also calledimmunoglobulin A vasculitis (IgAV), are generally excellent. In the absence of significant renal disease, the initialepisode of HSP (IgAV) typically resolves within one month.

In two­thirds of children, there are no recurrent episodes [2,20]. In the remaining one­third of patients, HSP (IgAV)

alone. In such cases, diagnostic imaging is necessary. Abdominal ultrasonography is typically used becauseit can detect changes in bowel wall thickness, hematomas, peritoneal fluid, and intussusception [10­12].Contrast enema studies are not useful because they may not detect small bowel intussusceptions, which arecommonly seen in patients with HSP (IgAV) [11,12]. (See "Henoch­Schönlein purpura (immunoglobulin Avasculitis): Clinical manifestations and diagnosis", section on 'Imaging studies'.)

Patients with acute changes in behavior or mental status require evaluation for a potential intracranialcomplication, such as hemorrhage. These are rare events in HSP (IgAV). Most central nervous systemfindings are transient and do not need further intervention. (See "Henoch­Schönlein purpura (immunoglobulinA vasculitis): Clinical manifestations and diagnosis", section on 'Other organ involvement'.)

Patients with renal disease may be hypertensive and require antihypertensive therapy. Close monitoring offluid and electrolyte management is imperative in patients with decreased renal function. Patients whopresent with nephrotic syndrome, hypertension, or renal insufficiency are at increased risk for long­term renalmorbidity. (See "Prevention and management of acute kidney injury (acute renal failure) in children" and"Renal manifestations of Henoch­Schönlein purpura (IgA vasculitis)", section on 'Prognosis'.)

Patients with severe arthritis usually improve with the use of NSAIDs. The risk of gastrointestinalhemorrhage resulting from bowel vasculitis has not been shown to increase when inhibitors ofcyclooxygenase are used, and therefore these agents are not contraindicated in HSP (IgAV). When thesemedications fail, administration of glucocorticoids will generally result in a rapid resolution of the arthritis.Rarely, a brief hospitalization may be required in order to provide the medications needed to relieve thearthritis. (See 'Treatment of pain' above.)

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recurs at least once, typically within four months of the initial presentation [2,21,22]. Each subsequent episode hassimilar clinical findings, but is generally milder and/or shorter in duration than the preceding one. Recurrences aremore common in patients with nephritis, in those with evidence of acute inflammation (eg, elevated erythrocytesedimentation rate [ESR]), and in patients who received treatment with glucocorticoids [21]. These findingssuggest that patients who have a more severe course of HSP (IgAV) are at increased risk of recurrence.

One retrospective review from Israel reported a longer mean interval time of 13.5 months between the first andsecond episode of HSP (IgAV) than was reported previously [23]. In addition, there was no difference in clinicaland laboratory findings between patients with recurrent disease and those without recurrence. The reasons forthese differences between study results are unclear.

Morbidity in the initial phase of HSP (IgAV) is primarily a result of gastrointestinal complications, includingintussusception and, less commonly, bowel ischemia, bowel perforation, or pancreatitis. (See "Henoch­Schönleinpurpura (immunoglobulin A vasculitis): Clinical manifestations and diagnosis", section on 'Gastrointestinalsymptoms'.)

The long­term morbidity in patients with HSP (IgAV) is a result of renal disease. The risk of chronic renal diseaseis increased in adults [24]. The severity of renal involvement correlates with the severity of the initial renalpresentation and histologic changes seen on renal biopsy. Risk factors for a worse renal prognosis includenephrotic range proteinuria, elevated serum creatinine, hypertension, and certain histologic findings. The supportivedata are discussed elsewhere. (See "Renal manifestations of Henoch­Schönlein purpura (IgA vasculitis)", sectionon 'Prognosis'.)

FOLLOW­UP — Ninety percent of children who develop renal involvement do so within two months of onset, and97 percent within six months [25]. Accordingly, all patients with Henoch­Schönlein purpura (HSP), also calledimmunoglobulin A vasculitis (IgAV), should be followed with urinalysis and blood pressure monitoring weekly orbiweekly for the first one to two months after presentation. Results from one study suggested that home urinedipstick testing was adequate for detecting development of nephritis [14]. Once the disease appears to besubsiding, additional follow­up for urine and blood pressure monitoring should be scheduled monthly at first, thenevery other month until one year after the initial presentation. To identify patients who may develop late renaldisease, continued screening (eg, urinalysis and blood pressure measurements) should be performed by theprimary care clinician during subsequent well­child visits. (See "Henoch­Schönlein purpura (immunoglobulin Avasculitis): Clinical manifestations and diagnosis", section on 'Renal studies'.)

A serum creatinine should be obtained to assess renal function in any patient with significant or persistent urinaryabnormalities or elevated blood pressure.

Patients with persistent proteinuria, hypertension, or renal insufficiency should be referred to a pediatricnephrologist for further evaluation and treatment. In addition, pregnant women with a history of HSP (IgAV) shouldbe monitored closely, as they have a higher risk of hypertension [26].

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REFERENCES

1. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus ConferenceNomenclature of Vasculitides. Arthritis Rheum 2013; 65:1.

2. Saulsbury FT. Henoch­Schönlein purpura in children. Report of 100 patients and review of the literature.Medicine (Baltimore) 1999; 78:395.

3. Weiss PF, Feinstein JA, Luan X, et al. Effects of corticosteroid on Henoch­Schönlein purpura: a systematicreview. Pediatrics 2007; 120:1079.

4. Rosenblum ND, Winter HS. Steroid effects on the course of abdominal pain in children with Henoch­

Beyond the Basics topic (see "Patient information: Vasculitis (Beyond the Basics)")

Most patients with Henoch­Schönlein purpura (HSP), also called IgA vasculitis (IgAV), may be cared for inthe ambulatory setting with therapy directed toward adequate oral hydration, bed rest, and symptomatic reliefof joint and abdominal pain.

In patients with joint and/or abdominal pain, we suggest the use of a nonsteroidal antiinflammatory agent(Grade 2C). We typically use naproxen (10 to 20 mg/kg divided into two doses per day). A maximum dose ofnaproxen of 1500 mg per day may be used for a few days provided that adequate hydration is maintained. Ifmore than a week of nonsteroidal antiinflammatory drug (NSAID) treatment is necessary, the dose ofnaproxen should not exceed 1000 mg per day. (See 'Mild­to­moderate pain' above.)

In patients with severe abdominal pain that interferes with their oral intake and who fail to respond to anonsteroidal antiinflammatory agent, we suggest the use of systemic glucocorticoids (Grade 2C). We useoral prednisone (1 to 2 mg/kg per day) for children or adults, with a maximum dose of 60 to 80 mg per day, orequivalent doses of intravenous methylprednisolone (0.8 to 1.6 mg/kg per day, maximum dose of 64 mg perday). Patients who are treated with glucocorticoids for severe abdominal pain require particular vigilance,since these medications can obscure the signs and symptoms of abdominal catastrophes associated withHSP (IgAV). Glucocorticoids should be tapered slowly, by no more than 25 percent per week, lest symptomsrelapse. (See 'Severe pain' above.)

Hospitalization is indicated in patients who fail to maintain oral hydration and require the administration ofintravenous fluids. Inpatient management may also be necessary to manage patients who have significantgastrointestinal bleeding, severe abdominal pain, changes in mental status, severe joint involvement limitingambulation and/or self­care, or evidence of significant renal disease (elevated creatinine, hypertension, orproteinuria). (See 'Hospitalization' above.)

We do not recommend glucocorticoid administration to prevent renal or gastrointestinal complications (Grade1B). (See 'Prevention of complications' above.)

Although prognosis is excellent in children with HSP (IgAV), a small minority of patients (<1 percent)develops long­term complications, primarily renal disease. In adults, the risk of significant renal disease isincreased. At present, there is no known therapeutic regimen to forestall development of renal involvement.Therapy for optimal control of HSP (IgAV)­related nephritis or nephrosis is discussed elsewhere. (See'Prognosis' above and "Renal manifestations of Henoch­Schönlein purpura (IgA vasculitis)", section on'Treatment'.)

Patients who have developed HSP (IgAV) should be seen in follow­up with screening for urinaryabnormalities and elevated blood pressure to identify patients with significant and potentially progressiverenal involvement. (See 'Follow­up' above.)

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Disclosures: Fatma Dedeoglu, MD Nothing to disclose. Susan Kim, MD, MMSc Nothing to disclose. Robert Sundel, MD Nothing todisclose. Elizabeth TePas, MD, MS Nothing to disclose.

Schonlein purpura. Pediatrics 1987; 79:1018.5. Leung SP. Use of intravenous hydrocortisone in Henoch­Schonlein purpura. J Paediatr Child Health 2001;

37:309.6. ALLEN DM, DIAMOND LK, HOWELL DA. Anaphylactoid purpura in children (Schonlein­Henoch syndrome):

review with a follow­up of the renal complications. AMA J Dis Child 1960; 99:833.7. Szer IS. Gastrointestinal and renal involvement in vasculitis: management strategies in Henoch­Schönlein

purpura. Cleve Clin J Med 1999; 66:312.8. Dudley J, Smith G, Llewelyn­Edwards A, et al. Randomised, double­blind, placebo­controlled trial to

determine whether steroids reduce the incidence and severity of nephropathy in Henoch­Schonlein Purpura(HSP). Arch Dis Child 2013; 98:756.

9. Davin JC, Coppo R. Pitfalls in recommending evidence­based guidelines for a protean disease like Henoch­Schönlein purpura nephritis. Pediatr Nephrol 2013; 28:1897.

10. Chang WL, Yang YH, Lin YT, Chiang BL. Gastrointestinal manifestations in Henoch­Schönlein purpura: areview of 261 patients. Acta Paediatr 2004; 93:1427.

11. Choong CK, Beasley SW. Intra­abdominal manifestations of Henoch­Schönlein purpura. J Paediatr ChildHealth 1998; 34:405.

12. Schwab J, Benya E, Lin R, Majd K. Contrast enema in children with Henoch­Schönlein purpura. J PediatrSurg 2005; 40:1221.

13. Weiss PF, Klink AJ, Localio R, et al. Corticosteroids may improve clinical outcomes during hospitalizationfor Henoch­Schönlein purpura. Pediatrics 2010; 126:674.

14. Jauhola O, Ronkainen J, Koskimies O, et al. Renal manifestations of Henoch­Schonlein purpura in a 6­month prospective study of 223 children. Arch Dis Child 2010; 95:877.

15. Jauhola O, Ronkainen J, Koskimies O, et al. Clinical course of extrarenal symptoms in Henoch­Schonleinpurpura: a 6­month prospective study. Arch Dis Child 2010; 95:871.

16. Chartapisak W, Opastirakul S, Hodson EM, et al. Interventions for preventing and treating kidney disease inHenoch­Schönlein Purpura (HSP). Cochrane Database Syst Rev 2009; :CD005128.

17. Huber AM, King J, McLaine P, et al. A randomized, placebo­controlled trial of prednisone in early HenochSchönlein Purpura [ISRCTN85109383]. BMC Med 2004; 2:7.

18. Saulsbury FT. Successful treatment of prolonged Henoch­Schönlein purpura with colchicine. Clin Pediatr(Phila) 2009; 48:866.

19. Shin JI, Lee JS, Chung KS. Dapsone therapy for Henoch­Schonlein purpura. Arch Dis Child 2006; 91:714.20. Meadow SR. The prognosis of Henoch Schoenlein nephritis. Clin Nephrol 1978; 9:87.21. Trapani S, Micheli A, Grisolia F, et al. Henoch Schonlein purpura in childhood: epidemiological and clinical

analysis of 150 cases over a 5­year period and review of literature. Semin Arthritis Rheum 2005; 35:143.22. Haroon M. Should children with Henoch­Schonlein purpura and abdominal pain be treated with steroids?

Arch Dis Child 2005; 90:1196.23. Prais D, Amir J, Nussinovitch M. Recurrent Henoch­Schönlein purpura in children. J Clin Rheumatol 2007;

13:25.24. Lu S, Liu D, Xiao J, et al. Comparison between adults and children with Henoch­Schönlein purpura nephritis.

Pediatr Nephrol 2015; 30:791.25. Narchi H. Risk of long term renal impairment and duration of follow up recommended for Henoch­Schonlein

purpura with normal or minimal urinary findings: a systematic review. Arch Dis Child 2005; 90:916.26. Ronkainen J, Nuutinen M, Koskimies O. The adult kidney 24 years after childhood Henoch­Schönlein

purpura: a retrospective cohort study. Lancet 2002; 360:666.

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