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Published on 1 September 2003

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Arthritis management in paediatric patients

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Rolando Cimaz
MD
Department of Pediatrics
Istituti Clinici di Perfezionamento
Italy
E:Rolando.Cimaz@unimi.it

Juvenile idiopathic arthritis (JIA), also previously known as juvenile chronic or juvenile rheumatoid arthritis, is the commonest rheumatic disease of childhood. It is characterised by the presence of arthritis of unknown cause with onset before age 16.(1) Traditionally, it has been classified according to the onset of disease (polyarticular, pauciarticular or systemic). More recently, this classification has been changed.(2) Medical treatment of these disorders is often difficult.

Pauciarticular arthritis (when four or fewer joints are affected) is usually treated only with nonsteroidal anti-inflammatory drugs (NSAIDs), and/or with intra-articular corticosteroid joint injections. Systemic arthritis is initially treated with NSAIDs, but can become a challenge especially if polyarthritis develops. This brief review will not deal with the treatment of the rare child with persistent systemic features, but will focus mainly on the treatment of polyarticular disease.

Polyarthritis (arthritis of five or more joints) can begin in all age groups. There are two distinct subgroups of juvenile idiopathic polyarthritis, according to the presence or absence of classic IgM rheumatoid factor (RF). Rheumatoid factor-positive polyarthritis is rare in children, and mirrors rheumatoid arthritis of adults, being usually severe and rapidly progressive with multiple joint deformity and permanent disability.
 
Medical treatment
Curative treatment for JIA is not available. The aim of drug therapy is to minimise pain and inflammation, while the aim of physical therapy is to maintain or restore joint function and prevent deformity.

Drug treatment consists of firstline drugs (NSAIDs) and secondline drugs (also called slow acting antirheumatic drugs [SAARDs] or disease-modifying antirheumatic drugs [DMARDs]). Among this latter group are included hydroxychloroquine, sulfasalazine, gold salts, azathioprine, D-penicillamine, methotrexate and ciclosporin A. TNF-alpha antagonists have recently been introduced in the therapeutic armamentarium, and seem to be very promising agents for refractory cases. Corticosteroids are used only in selected situations. Of all these drugs, evidence from placebo-controlled randomised clinical trials has been achieved only for methotrexate,(3,4) etanercept,(5) and to a lesser extent sulfasalazine.(6)

NSAIDs
NSAIDs are the basic approach to virtually all forms of JIA. In polyarthritis, however, this treatment is frequently not sufficient to induce disease remission, and other agents have to be added. Acetylsalicylic acid is used much less than in the past because of the need for monitoring blood levels and because of the possibility of Reye’s syndrome. The choice of NSAID is dependent on several factors, such as availability in liquid form, dosing interval, taste, cost, and spectrum of adverse reactions.

Propionic acid derivatives include naproxen, ibuprofen, flurbiprofen and ketoprofen; acetic acid derivatives include indomethacin, tolmetin, sulindac, and diclofenac; oxicams include piroxicam and meloxicam. Choice of initial agent is also based on considerations of cost, convenience and compliance, since there is no proof that any one drug is superior to the others.

Secondline drugs
After starting with an NSAID, one should wait sufficient time (at least six to eight weeks at full dose) in order to achieve a response. In nonresponders to NSAIDs, secondline drugs should be instituted. Methotrexate is the initial drug of choice for moderate to severe forms of disease.(7) It is usually well tolerated, except for minor gastrointestinal disturbances such as nausea and vomiting. Liver enzyme monitoring is necessary. It is not yet known when the drug can be stopped after remission has been achieved.(8) Methotrexate and etanercept (an anti-TNF-alpha agent) have been proven to be superior to placebo in double-blind, placebo-controlled studies. Until more clinical experience is gained, methotrexate is the preferred choice since there are long-term study data. Higher-dose methotrexate (up to 1mg/kg/week) and etanercept are options for the nonresponders to low-dose (10mg/m(2)/week) methotrexate.

Dosages of the most commonly used secondline drugs are shown in Table 1, while an algorithm for the treatment of polyarticular JIA is shown in Figure 1.

[[HPE10_table1_54]]

[[HPE10_fig1_53]]

Glucocorticoids are the most potent anti-inflammatory drugs in the treatment of rheumatic diseases. They have anti-inflammatory and immunosuppressive effects, but because of their severe side-effects in the paediatric age group their use in JIA is very limited. Short-term, low-dose (<5–10mg/day, according to body weight) treatment with prednisolone is justified in the presence of severe polyarticular involvement, while waiting for the effect of another secondline drug such as methotrexate.

Intra-articular steroids can be used when few joints are severely affected and effusion is present.(9) Multiple joint injection can be performed under anaesthesia (general anaesthesia in young children, conscious sedation in older children). Triamcinolone hexacetonide is the most useful compound in this setting, with doses depending on joint injected and on body weight.

The use of chlorambucil is reserved for children with amyloidosis.(10) Other treatment options that are currently under evaluation and have been used in open pilot studies are leflunomide, infliximab and adalimumab (respectively, chimeric and human monoclonal antibodies against TNF-alpha), thalidomide, combination therapy with more than one secondline drug, and autologous stem cell transplantation.(11,12) Other biologicals including inhibitors of interleukin-1 and antibodies to B-cell surface antigens (rituximab) are only in an experimental phase.
 
Treatment of secondary disorders
JIA can be accompanied by osteoporosis and impaired growth (secondary to the disease itself and to medical treatment), anaemia, and gastrointestinal damage (due to medical treatment). Patients on methotrexate can be supplemented with folic or folinic acid in order to prevent methotrexate-induced side-effects.(13) To prevent osteoporosis, calcium and vitamin D preparations can be recommended in patients on chronic steroid treatment. Treatment of secondary diseases also include growth hormone,(14) bisphosphonates,(15) erythropoietin, and gastric acid secretion inhibitors, oral prostaglandin analogues, or H(2)-antagonists. Routine use of these agents as preventive measures is, however, not recommended.

References

  1. Brewer EJ, et al. Arthritis Rheum 1977;20:195-9.
  2. Petty RE, et al. J Rheumatol 1998;251:991-4.
  3. Giannini EH, et al.  N Engl J Med 1992; 326:1043-9.
  4. Woo P, et al. Arthritis Rheum 2000;43:1849-57.
  5. Lovell DJ, et al. N Engl J Med 2000; 342:763-9.
  6. van Rossum MA, et al. Arthritis Rheum 1998;41:808-16.
  7. Ilowite NT. Pediatrics 2002;109:109-15.
  8. Gottlieb BS, et al. Pediatrics 1997;100:994-7.
  9. Dent PB, Walker N. Curr Opin Rheumatol 1998;10:475-80.
  10. Savoilanen HA. J Rheumatol 1999;26:898-903.
  11. Quartier P, et al. Lancet 1999;353:1885-6.
  12. Wulffraat N, et al. Lancet 1999;353:550-3.
  13. Ravelli A, et al. Clin Exp Rheumatol 1999;17:625-7.
  14. Simon D, et al. Acta Pediatr 1999;428:100-5.
  15. Bianchi ML,  et al. Arthritis Rheum 2000;43;1960-6.


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