Evidence based pediatrics - part 9 pdf

Sulfasalazine: sulfasalazine is widely used as a DMARD in the treatment of adult RA. There is now level I evidence (from a small RCT) that sulfasalazine is more effective than placebo in the treatment of JA. 119 About half those children taking sulfasalazine (in this study, the patients had polyarticular and oligoarticular JA) showed a response in a number of important disease features, compared with about 25 percent in the placebo group. However, sulfasalazine was associated with frequent side effects. Sulfasalazine gets a grade B recom- mendation as a DMARD for JA. Gold: intramuscular gold was once commonly used in the treatment of childhood arthritis. It is associated, however, with a high toxicity rate. Because of the availability of more effective and safer alternatives (for example, methotrexate), gold is now rarely used in chil- dren. There is level I evidence that the oral preparation of gold (auranofin) has no effect in treating JA. 120 Therefore, intramuscular gold gets a grade C recommendation, while oral gold gets a grade E recommendation. Hydroxychloroquine: there is level I evidence that suggests that the response of children with JA to hydroxychloroquine is unlikely to be clinically important. 121 Hydroxychloroquine, however, has recently been widely used in combination with other DMARDs in the therapy of adult RA. There may be an as yet undefined role for hydroxychloroquine as part of com- bination therapy for JA. Hydroxychloroquine gets a grade D recommendation as monother- apy and a grade C recommendation as part of combination therapy. Azathioprine: azathioprine is a potentially cytotoxic agent that is rarely used in JA. There is level I evidence from a small study of 32 subjects with severe JA that the toxicity of azathioprine outweighs its benefit. Therefore, azathioprine gets a grade D recommen- dation. 122 Cyclosporine: because there is still a sizeable minority of children with JA who do not respond to methotrexate, many other agents that can potentially relieve inflammation have been tried. Cyclosporine is an effective agent used in the treatment of adult RA.There is only level III evidence, however, in children, which suggests that cyclosporine may have a role in JA. 123–125 Cyclosporine, therefore gets a grade C recommendation. Corticosteroids: appropriate doses of corticoteroids result in an undoubted and obvi- ous clinical response (ie, reduction of pain, stiffness, and often signs of inflammation) in the short term. However, a high likelihood of serious side effects has prompted most rheumatologists to limit the use of corticosteroids in the treatment of JA as much as pos- sible. It remains unclear whether corticosteroids have any long-term benefit. There is level I evidence that adult patients with RA develop fewer bone erosions over a 2-year period, if treated with prednisolone (7.5 mg daily) as compared with placebo. 126 A recent meta- analysis showed that the short-to medium-term effects of prednisone were the same as, or better than, other active therapies for the control of symptoms. 127 It seems reasonable to give a grade B recommendation for the short-term use of low doses of oral corticosteroids as bridging therapy in those patients with severe arthritis who require DMARDs, most of which take several months to achieve a reasonable clinical effect. Oral corticosteroids may be used to control symptoms while waiting for a DMARD to work. Corticosteroids get a grade C recommendation for longer-term use. Oral Tolerance: oral tolerance with chicken cartilage has recently generated a lot of inter- est in the treatment of inflammatory arthritis. This is due to an exciting early report (level I) of a study in adults with RA. 128 Oral tolerance is based on the proposal that small, frequent exposures to the cartilage antigen can reduce an arthritic patient’s immune response to their own cartilage. Oral tolerance has a theoretical advantage over other antiarthritic therapies; chicken cartilage is a natural substance with no known adverse effects. A subsequent study of oral tolerance (level I), again in adult RA, failed to confirm a strong effect. 129 There is only level III evidence suggesting some effect in children with arthri- tis. 130 Therefore, oral tolerance gets a grade C recommendation. Musculoskeletal Disorders 369 Uveitis Screening Children with JA are at risk of developing potentially sight-limiting uveitis. For many children with JA, this is the most worrisome aspect of their disease. The reason for concern is that the uveitis of JA is often asymptomatic and unrecognized until permanent damage has been done. Uveitis associated with JA is often easily treated; therefore, it makes sense to screen for the devel- opment of uveitis and treat it before damage occurs. Children with the oligoarticular-onset sub- type, especially those with a positive ANA test, seem to be at the highest risk for uveitis. Children with JA can present with uveitis as late as 10 years after the onset of arthritis. 131 The American Academy of Pediatrics (AAP) has published guidelines for the frequency of ophthalmologic examinations for children with JA (level III). 132 These guidelines catego- rize children as being at high risk, medium risk, or low risk. High-risk children are to be screened every 3 to 4 months, medium risk children every 6 months, and low risk children every 12 months. The AAP guidelines define high-risk children as those with oligoarticular or polyartic- ular onset, who are ANA positive, and have disease onset before the age of 7 years. Four years after the onset of arthritis, these patients are at medium risk, and 7 years after onset they are at low risk. The guidelines define medium-risk children as those with oligoarticular- or polyartic- ular-onset disease, who are ANA negative, or have the onset of their disease after age 7 years. Four years after the onset of arthritis these children become low risk. Children with systemic-onset arthritis are all considered to be in the low-risk category. Although these guidelines have not been formally evaluated, the seriousness of the prob- lem leads to a grade A recommendation. Transition. As children with JA grow into adulthood, they face special challenges. Children with arthritis may need special preparation to be able to work and adapt to a more independent life. Many children with JA have developed a special, long-term realtionship with their medical care providers. As they approach adulthood, these patients need to move from a more paternalistic pediatric health-care system to an adult-oriented health-care system where they have to fend for themselves. Many models of transition care have been put forward, but there is little or no research to guide decisions on choosing the best model. We have only testimonial evidence (level III) to support the different programs. 133,134 While it is clear that there is a need for tran- sitional services, any particular model can get only a grade C recommendation. Approach to Treatment of Juvenile Arthritis Oligoarticular-onset JA. It is initially important, when a child presents with oligoar- ticular joint inflammation, to carefully make a positive diagnosis of JA. In those children (about half the children with oligoarticular JA) who present with a single swollen joint, it is especially important to rule out other causes of monoarthritis (such as tuberculosis, hemo- philia in a boy, septic arthritis, or cancer). Children with JA should initially receive a 6-week trial of an NSAID and usually a referral to a physiotherapist. If the signs and symptoms of inflammation continue or if contractures develop, then a referral to a pediatric rheumatol- ogist or to an adult rheumatologist experienced in dealing with children should be consid- ered for joint injections and follow-up care. These children are usually at the highest risk for uveitis and should be screened as above. The prognosis in this subtype of JA is good, and families will need educational support. Polyarticular and systemic-onset JA. Children with these more severe forms of arthri- tis should be referred to a comprehensive care clinic so that they can receive the multidisci- plinary therapies listed above. These children should have uveitis screening, as appropriate. Children with chronic arthritis affecting several joints are highly likely to need transition care when they become adolescents. 370 Evidence-Based Pediatrics low (about 2 or 3 percent) frequency of coronary lesions. A single-day infusion is more cost effective than a 4-day treatment as it is associated with a shorter hospital stay. 139 Therefore, treatment of KD in the acute phase (the first 10 days of illness) with 2 g/kg of intravenous immunoglobulin (IVIG) as a single infusion gets a grade A recommendation. The traditional treatment of KD is to combine acetylsalycylic acid (ASA) in high doses (80 to 100 mg/kg/day divided into four doses) with IVIG. When the fever has resolved for 24 to 48 hours, the dose of ASA is reduced to 3 to 5 mg/kg/day to achieve an antiplatelet effect. Low-dose ASA is continued until the subacute phase resolves, usually by 6 weeks. (The subacute stage is marked by resolution of fever, elevated acute-phase reactants, high platelet count, and peeling of the skin of the digits.) However, in a meta-analysis reviewing studies of both high- and low-dose ASA there was no difference in coronary outcomes as long as high-dose IVIG was used. 140 Therefore, high-dose ASA initially and switching to low dose after 24 to 48 hours of being afebrile, as an adjunctive therapy gets a grade B recommendation. Because of the potential morbidity of the coronary lesions, patients should be seen in the acute phase by a pediatric cardiologist or by a cardiologist experienced with children for an echocardiographic evaluation and for follow-up. Henoch-Schönlein Purpura Corticosteroids Henoch-Schönlein purpura is a self-limited disease in the vast majority of cases. Supportive therapy is all that is usually required. Corticosteroids have traditionally been considered effective for reducing the symptoms of arthritis and gastrointestinal pain in HSP, but high level evidence is lacking. There is level II-3 evidence that prednisone, 1 to 2 mg/kg/day may shorten the duration of abdominal pain to a certain extent, but by 72 hours, there is no dif- ference in pain between children treated or untreated with corticosteroids. 141 More recently, investigators have examined the effects of corticosteroids in preventing the development of delayed nephropathy (which may account for more than half the cases of HSP nephritis). Two studies have reached opposite conclusions. One American study (level II-2) found that exactly the same number of children treated with prednisone devel- oped nephritis as those who were not treated. 142 Conversely, an Italian study (level II-1), in which children who did not have nephritis at presentation were treated with 2 weeks of prednisone (1 mg/kg/day) or with nothing, found that the untreated group developed nephritis more often than those who were treated. 143 In fact, nobody in the treated group developed nephritis. The number needed to treat to prevent one case of nephritis in this second study was about 9. None of the nephritis cases had persistent disease, and none developed serious renal failure; the clinical significance of this reported treatment effect is questionable. Until better evidence is available, the use of corticosteroids in HSP gets a grade C rec- ommendation. Other Treatments Factor XIII replacement was investigated in one small Japanese study (level I) after the obser- vation was made that (1) factor XIII is decreased in the plasma of patients with active HSP, and (2) that the level of factor XIII is inversely proportional to the severity of the disease. 144 The investigators found a more rapid resolution of joint, gastrointestinal, and renal findings in the factor XIII group. This study has not been replicated; therefore, at this point, factor XIII treatment must get a grade C recommendation. Another small study (level II-1) was done recently, comparing ranitidine (5 mg/kg) with placebo in children with HSP and gastrointestinal bleeding. 145 Gastrointestinal bleeding was diagnosed by abdominal pain and occult blood in the stools. This study found that signs and 372 Evidence-Based Pediatrics Musculoskeletal Disorders 373 Table 19–1 Summary of Treatments for Musculoskeletal Disorders Condition Treatment Level of Evidence Recommendation Growing pain Conservative meaures III C Stretching I B Hypermobility Physiotherapy III C Fibromyalgia Neck Support Pillow II-1 C Cognitive behavior therapy II-3 C Antidepressants I B Aerobic exercise I B Bright light I D Biofeedback I B Hypnotherapy I B Super Malic I D Homeopathy I C Backache Rest I D Traction I D Back support I B Back school I C Supervised exercise I B TENS I D Manipulation I C Acupuncture I C Juvenile arthritis Education III B Hydrotherapy I B Comprehensive team I B Fitness exercise II-3 B (see pg. 20) Wrist splints I B Steroid joint injections II-3 B (see pg. 21) NSAIDs I A Methotrexate I A Etanercept I A Sulfasalazine I B Hydroxychloroquine I D Cyclosporine III C Uveitis screening III A SLE and JDM Sun avoidance III B Fat/salt reduced diet III B Kawasaki disease IVIG I A Henoch-Schönlein Corticosteroids II-1 C purpura SLE = systemic lupus erythematosus; JDM = juvenile dermatomyositis; TENS = transcutaneous electrical nerve stimulation; NSAIDs = nonsteroidal anti-inflammatory drugs; IVIG = intravenous immunoglobulin symptoms resolved about 2 days earlier in the treated group. 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