Management of Juvenile Idiopathic Arthritis

Transcription

1 Symposium on Rheumatology Management of Juvenile Idiopathic Arthritis Sujata Sawhney Sir Ganga Ram Hospital, New Delhi, India. Abstract. Juvenile idiopathic arthritis (JIA) is a relatively uncommon disorder in childhood. Expertise however should be the corner stone of care of children with JIA, as early appropriate treatment is mandatory to ensure best possible short and longterm outcome for children with JIA. Therefore comprehensive treatment centers (with multi disciplinary teams) should be based in tertiary level academic centers. This article deals with both specific and generic issues encountered in managing children with JIA. [Indian J Pediatr 2002; 69 (10): ] Key words: Juvenile; Arthritis; Treatment Introduction and General Principles of Management Juvenile idiopathic arthritis (JIA) is the umbrella term that encompasses a heterogeneous group of chronic childhood arthritides of unknown cause. The clinical spectrum of diseases in this group is variable: the child may have one or two swollen joints, or be ravaged by persistent fevers and aggressive polyarthritis. It is a chronic disease with an unpredictable course, marked by exacerbations and remissions. The incidence of JIA ranges from 10 to 50 per , making it relatively uncommon in childhood. Expertise however should be the corner stone of care of children with JIA. Therefore comprehensive treatment centers should be based in tertiary level academic centers The treatment team should consist of the following members: A pediatric rheumatologist, a nurse specialist, physical and occupational therapist, a child psychologist and a social worker all working with the child's primary care pediatrician. Consultations with an orthopedic surgeon, dietician, and dentist should be available when required. The central focus of the team should be the child and family. This care is well described by the term "shared care" which is extensively practiced in the western world. The tertiary team guides specific therapy based on expertise and experience, while the local primary pediatrician offers routine care, growth monitoring, vaccination, drug monitoring and liaises closely both with the tertiary level team and community resources such as the school. This approach is well suited to deliver comprehensive care to the child with a chronic disease. 1 Goals of Treatment The aims of treatment of JIA are conveniently divided into immediate and long-term. The immediate aims are to control inflammation, preserve vision, relieve pain and Reprint requests: Dr. Sujata Sawhney, B-602, Som Vihar, R.K. Puram, New Delhi , India. sujatasawhney@vsnl.net discomfort, prevent deformities and preserve function. The long- term goals are to minimize side effects of the disease and drugs, promote normal growth and development of the child, minimize impact of the chronic disease on the family, educate the child and family and finally rehabilitate the child." Treatment Modalities Treatment will be divided into two parts: First- specific modalities for each of the subtypes of JIA, and secondly generic issues such as newer drugs, the role of therapists, growth issues, osteoporosis, compliance, transition, when to stop therapy, and outcome measures for the whole group of diseases. Specific Treatment Modalities for Each Subtype of JIA Oligoarticular JIA Intraarticular (LA) injections and appropriate use of Non Steroidal Anti-inflammatory Drugs (NSAIDs) are the mainstay of treatment for this subtype of JIA. A skilled individual should give the joint injection with age appropriate sedation, or preferably a general anesthetic. Triamcinalone hexacetonide is the preferred steroid preparation due to the long-term and predominantly local effects, with a reported median duration of improvement for a period of 74 weeks. This particular formulation is currently not available in India, though triamcinalone acetonideisis. Accelerated linear growth of the involved leg is typical in this disease as the knee and ankle joints are the most commonly involved and the arthritis is frequently asymmetric. Early and continued use of IA steroid has been recently shown to be associated with less leg length discrepancy in young children with oligoarticular JIA. 4-5 The choice of NSAIDs is empiric, though in the USA only three are licensed for use in children (Naprosyn, ibuprofen and tolmetin). Clinical trails of NSAIDs by the PRCSG (Pediatric Rheumatology collaborative study

2 Sujata Sawhney group) in the U.S.A concluded that 65% of the children who were going to respond would do so in the first 4 weeks. If a child does not respond it is logical to use an NSIAD from a chemical class different to the one used earlier. Cox 2 inhibitors have been shown to be effective in adults with significant reduction of gastrointestinal side effects. Studies are still forth coming in children. 2 ' Details of commonly used NSAIDs are detailed in Table 1. Disease modifying anti rheumatic drugs (DMARD's) are generally not recommended for this group, although occasionally methotrexate may be useful for difficult to control uveitis or when damage to a critical joint ^reatens function (wrist/hip). In the persistent oligoarticular group this is all that is required. If the disease extends, methotrexate should be considered for the treatment. Polyarthritis The aim here is two fold: early introduction of DMARD'susually methotrexate and rapid disease control with intravenous methyl prednisolone boluses, or oral steroids. There is evidence for the safety and efficacy of once weekly methotrexate in JIA. Methotrexate is started at a dose of 15mg/m2/week and built up as needed. Children require and tolerate larger doses than adults, at lmg/kg/ week or up to 30mg/m2/week. Doses of 20 to 25 mg are therefore commonly used in children under six years. Thereafter children's requirement and tolerance both fall such that doses above mg are unusual. Oral methotrexate is not well absorbed in doses above 10mg/ m2, and there is data to support the subcutaneous route as a routine. Most clinicians would switch to the subcutaneous route at doses greater than 0.5mg/kg/ week. Folk acid at a dose of Img/day is often given to children receiving methotrexate and appears to lessen the toxicity and increase the tolerability of the drug. Precautions to be exercised while the patient is on methotrexate are as follows: no live vaccination, avoidance of alcohol, and no pregnancy while on the drug. Regular monitoring of hemoglobin, white cell count, platelets and liver function tests every 4-6 weeks is mandatory. Data also supports the use of sulphasalazine in the treatment of polyarticular JIA, though tolerability is poor in one third of patients. 8 " 11 Systemic Onset JIA Drug management of systemic onset JIA aims to alleviate both the systemic features and the arthritis. For the more severe cases management is challenging, and may need DMARD combination and/or repeated pulsing with I.V. Methylprednisolone. Some mild cases clear up spontaneously. The fever may be treated with Ibuprofen 40-50mg/kg/day, or naprosyn at a dose of 20mg/kg/ day. In the more severe case steroids may be needed at a dose of 1 to 2 mg/kg/day. I.V. Methylprednisolone is also used to induce remission at a dose of 30mg/kg/day (maximum 500 mg) for three consecutive days, and may be repeated after one week. Methotrexate remains the DMARD of choice for the children who have arthritis. Untreated, systemic onset JIA can be complicated by macrophage activation syndrome (also known as hemophagocytic syndrome) which presents with persistent fevers, drop in the platelet count, lowering of the ESR, and livei: function abnormalities with coagulopathy. This condition has a high mortality and is best treated with IV methylprednisolone and cyclosporin Enthesitis Related Arthritis This group is believed to represent the adult equivalent of ankylosing spondylitis and reactive arthritis. The difference is that peripheral arthritis and not sacroilitis is the main clinical feature. The treatment of choice for the peripheral arthritis in this group is sulphasalazine at mg/kg/day, using doses as high as 2 gm/day. The NSAID of choice in this group is indomethacin. With significant systemic manifestations of the disease methotrexate is often added Psoriatic Arthritis Asymmetric involvement of small joints especially the" DIP joint, and dactylitis is characteristic of psoriatic arthritis. Significant nail pitting often precedes arthritis. The skin and joint disease may not always follow the same course. In addition to local skin treatment NSAIDS/ LA. steroids are used for localized disease involving a few joints, and methotrexate is used for aggressive disease involving multiple joints Uveitis Standard treatment of uveitis is the use of topical methyl prednisolone and mydriatics to prevent synechiae. Methotrexate and other DMARD have been tried, but there is no clear evidence that they are especially useful in uveitis resistant to steroid treatment. The benefit seen TABLE 1. NSAIDs NSAID Total daily dose Maximum daily dose No. of doses/day Side effects Naproxen mg/kg/day 1000 mg 2 Cutaneous pseudoporphyria Ibuprofen mg/kg/day 3200 mg 3 or 4 Well tolerated Diclofenac. 2.5 mg/kg/day 125 mg 2 Gastritis Indomethacin mg/kg/day 200 mg 2 Headache Piroxicam mg/kg/day 20 mg 4 Gastritis

3 Management of Juvenile Idiopathic Arthritis with methotrexate is evident at higher doses, when used subcutaneously or intravenously. Uveitis in JIA is silent and painless except in children with enthesitis related arthritis that have acute painful anterior uveitis. Thus, it is mandatory that patients with JIA be electively screened for uveitis at regular intervals, as untreated uveitis is known to cause visual loss and morbidity u - GENERIC ISSUES IN THE MANAGEMENT OF JIA When Should Methotrexate be Stopped? There is paucity of published data to support evidencebased decisions in this area. Most authors suggest that discontinuation of methotrexate when treatment induced' remission has persisted for less than 1 year frequently results in return of arthritis within 6 months of drug discontinuation NSAIDS and other medications are discontinued prior to attempting withdrawal of methotrexate. Combination DMARD Therapy Combination therapy is the rule rather than the exception in treating adult rheumatoid arthritis (RA), where use of weekly methotrexate along with daily hydroxychloroquine and sulphasalazine appears to give good results without any increase in toxicity. 18 This approach is reserved for the difficult to control JIA patient who does not respond adequately to subcutaneous methotrexate at a dose of up to 30 mg/m 2. Failure to respond adequately or poor tolerability can occur in approximately a quarter of" these children. In addition to the combination suggested above Cyclosporin may be combined with methotrexate. Pulsed I.V. Methylprednisolone may be used at regular intervals. Cyclophosphamide may be tried. Etanercept and /or leflunamide may be used Newer Drugs Recently approved agents for rheumatoid arthritis (RA), including infliximab, etanercept leflunamide, celecoxib, and rofecoxib, have notvbeen; adequately studied in pediatric patients, and therole of these agents, (except for etanercept) in children with JIA remains to be determined Cox-2 Inhibitors Is the new group of non-steroidals amongst which are celecoxib and rofecoxib. This group of drugs has a better tolerability and safety in adults. They are not yet licensed fur use in children. 21 Leflunamide: It is a new DMARD licensed for the treatment of adults with active RA. It is converted to an active metabolite that inhibits de novo synthesis of pyrimidine and prevents activation of T lymphocytes that are involved in the pathogenesis of RA. Blinded trails in adult patients have well proven the efficacy of this drug. At the doses used, some clinical benefit of methotrexate over leflunamide was observed in the first year of treatment. 22 Etanercept Tumor necrosis factor (TNF), a pro inflammatory cytokine produced by macrophages and T cells contributes to synovitis and joint destruction. Soluble TNF receptors such as Etanercept serve as physiologic regulators of the inflammatory response by inhibiting TNF pctivity. Etanercept is a recombinant human tumor necrosis factor (TNF) receptor Fc fusion protein. Double blind, randomized controlled studies have shown etanercept to be effective therapy in patients with RA who have had inadequate response to DMARDs, in combination with methotrexate, and as early monotherapy. Similar results were seen in juvenile and psoriatic arthritis in DMARD nonresponders Safety issues are a concern because of the ubiquitous role of TNF. To date the only consistent adverse event seen with etanercept has been injection site reactions. There should be caution, however, with usinj~ etanercept in patients with a serious infection, or recurrent infections or patients with untreated or latent tuberculosis. As of yet there has not been seen an increase of malignancies. Rare neurological and hematological events have been noted. Etanercept has been a significant addition to the armamentarium of medications for the treatment of RA,. juvenile and psoriatic arthritis. Infliximab This is an antibody to rumour necrosis factor (TNF)-alpha. Up until October 2001 approximately patients had received infliximab through out the world. Of these 70 were reported to have tuberculosis. Active tuberculosis may develop soon after the initiation of treatment with infliximab. Thus before prescribing the drug, physicians should screen patients for latent tuberculosis infection or disease Stem Cell Transplantation in JIA Autologpus haemopoietic stem-cell transplantation (AHSCT) has been described as a possible treatment for severe autoimmune disease refractory to conventional treatment. The first four children with severe forms of juvenile jdiopathic arthritis, to?eceiye AHSCT were reported in 1999, 28 and collaborative European trails with strict entry criteria and pre transplant conditioning are on going. Care of the Adolescence, Transition Issues and Compliance JIA is a chronic disease, with a third of patients carrying the disease into their adult years. Delayed adolescence both physically and emotionally is being recognized more widely and adolescent centered services to aid transition

4 Sujata Sawhney to adulthood have a major role to play in the long term care of the patient with JIA. Transition to adult care is a process that begins in the adolescent age. Attention to vocational skills, independent living skills, arid selfadvocacy warrant careful care and planning. Compliance with the treatment regime including medication, blood monitoring, exercises, splint usage and regular'-visits to health professionals are demanding on the child and family. Muladisdplinaiy teams under one roof are ideally suited to deliver this care. Patient and parent education and incorporation of the needs of the child and family members in planning care are essential to ensure that the patient adheres to the plan Physiotherapy and Occupational Therapy The therapists are the key personnel to restore function and strength of affected joints and musculature. Together they plan a treatment program that incorporates a range o'f exercises, stretches for the joints, and activities of daily living. The occupational therapist has two important roles: to provide custom made splints to maintain joint position especially for the wrist and the knee joint, and assist children whose disability requires modification of the environment. Children and adolescents both can improve aerobic endurance through participation in weight bearing physical conditioning programs without any disease exacerbation or increased pain. They can also achieve decreased joint signs and symptoms through increased physical activity. Lastly the therapist is usually the key person to educate the parents, and school personnel to ensure integration of therapy goals into the child's daily routine. 27 Osteoporosis and Growth Retardation Thereare many factors that adversely affect bone mass in children with JIA. Active arthritis has a well-known osteopenic effect around joints (periarticular osteopenia) and often systemically. Medications used in arthritis, especially steroids also have a known osteopenic effect. Decreased physical fitness and participation in organized sport, in addition to poor vitamin D and calcium intake contribute to the low bone mineral density (BMD). Interventional studies are lacking, and until sound evidence is available the following strategies are generally employed to optimize bone mass in children with JIA:. aggressive control of disease activity, avoidance of corticosteroid use, and optimizing physical activity and calcium intake. Bisphosphonates -alendronate has been recently shown to be effective in treating secondary osteoporosis in juvenile idiopathic arthritis. This drug crosses the placenta and is highly teratogenic. It is thus mandatory for patients to avoid pregnancy during the period of treatment and for up to six months after discontinuation. Finally, growth hormone also improves the growth retardation and osteoporosis, particularly where the disease is stable but not in remission. 896 The best strategy to maximize growth is aggressive disease control, nutritional support and judicious yet minimal use of steroids Outcome Measures These are critical objective parameters both for therapeutic trials and for day-to-day office practice to judge whether or not the patient has improved. An international consensus conference proposed "The definition of improvement" to assess disease response. Variables in this core set to assess outcome consist of 1) physician global assessment of disease activity; 2) parent/ patient assessment of overall well-being; 3) functional ability by a validated test; 4) number of joints with active arthritis; 5) number of joints with limited range of motion; and 6) erythrocyte sedimentation rate. The definition of improvement in JIA is as follows: at least 30% improvement from baseline in 3 of any 6 variables in the core set, with no more than 1 of the remaining variables worsening by >30%. The outcome criteria are not yet used in Indian studies as work on the "Indian version" of the CHAQ (Childhood health assessment questionnaire), a "functional ability" tool in children is still ongoing. 31 Prognosis * The prognostic factors can be classified as per the different categories of JIA. A poor outcome in the systemic form correlates with markers of disease activity, such as fever and polyarticular involvement, within the first 6 months. The risk of joint destruction in oligoarthritis is proportional to the severity of arthritis within the first 2 years. Polyarthritis with a positive rheumatoid factor is associated with marked disability in adulthood. In a group of psoriatic patients, the risk of developing sacroilitis is higher in male and HLA-B27- positive patients. Patients with enthesitis-related arthritis with lower limb, knee, and tarsal involvement also are at greater risk of developing sacroilitis. Chronic uveitis is a complication of JIA observed mainly in patients with oligoarthritis associated with positive antinuclear antibodies in serum. Finally, secondary amyloidosis is observed mainly in children with systemic JIA. 32 Can We Do Better? One third of children with JIA will have significant active disease well into their adult years and 50-60% have some form of disability or deformity in adulthood. Major disabilities occur in 10% of patients. This is data from the western world where a referral system is very well established, and where intervention is directed by multidisciplinary teams in tertiary level academic centers. There are no long-term outcome studies available in India where we do not have a good referral system, and have only a few dedicated teams to look after these children. Two strategies are likely to help children with JIA in our country: Increased awareness amongst general pediatricians and orthopedic surgeons about the urgency 277-

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