Click here to view next page of this article Juvenile Rheumatoid ArthritisFew of the medications that we use are thoroughly tested in children and even fewer have been FDA approved. When using medications in children we must be cautious for many reasons. First, we have to be certain that we have the correct dose: 1 mg per kilogram basis. Small, medium and large is not specific enough. Obviously those medications that come in liquid form or come in multiple pill sizes that are scored and can be broken are going to be much easier to get the correct dosage. Next we must consider clearance and metabolism. By six months to a year of age renal clearance is maximal and liver cytochrome P450 is up to adult levels. Children clear methotrexate much more rapidly that adults and frequently we need to use higher doses in children than in adults. Even at doses of 1 mg per kilogram children still clear methotrexate very rapidly and we need to be open to the possibility that this rapid clearance could occur. Next, we must consider unexpected metabolism differences between children and adults and there also could be unexpected adverse effects. We have found that children taking Naprosyn often have more skin problems than adults, specifically pseudo-porphyria and this can also occur with oxaprozin as well. Long term effects are of course our greatest worry when treating children. Possible effects on growth, reproduction and the possible development of cancer. We also need to keep in mind the consideration about the disease processes themselves. Although the synovial pathology of juvenile rheumatoid arthritis is identical to that of adult rheumatoid arthritis, the systemic form or juvenile rheumatoid arthritis is indeed unique. Intense liver involvement and the potential development of macrophage activation syndrome could make the use of non-steroidal antiinflammatory drugs quite hazardous. The use of indomethacin in a child with systemic JRA who died, most likely from macrophage activation syndrome and DIC, led to the prohibition of the use of indomethacin in children for over a decade. Before I discuss specific medications, I feel it’s important to clarify the goals for treatment of childhood arthritis, for these have changed over the past two decades as we more thoroughly understand the persistent, destructive nature of rheumatoid arthrits. We need to treat for remission of disease. It is not going to go away by puberty. We realize now that nearly one-third to two-thirds of children affected will continue their disease into adulthood. Active synovitis leads to destruction in children just as it does in adult patients. Children should have normal growth, normal development and normal function. This means that we should treat them so that they can go to school every day, get to school on time, dress themselves, participate in PE, play sports, go shopping with their friends, raise their hand in class, walk from class to class, bicycle, run, go up and down stairs, hang from the monkey bars, etc. Before discussing new medications, I feel that familiar disease modifying agents should be used to their fullest extent. Methotrexate, as you know, can be given subcutaneously or even intravenously or intramuscularly. And many patients will respond better when switched to these routes. Generally we don’t go above 40 or 50 mg per week, although there are no studies of doses above this. For those patients whose disease incompletely responds to methotrexate, often sulfasalazine is added, hydroxychloroquine, sulfasalazine and hydroxychloroquine or cyclosporine. Intraarticular cortical steroids can be very helpful in squelching the synovitis of juvenile rheumatoid arthritis. This is especially useful in a child who has maybe one or two joints involved. With this approach we might be able to avoid systemic medication altogether. The use of Elamax cream, which is the newer version of Emla cream, is quite wonderful to help numb the skin before proceeding with other parts of the injection. Elamax cream is 4% lidocaine, acts in 15-20 minutes and does not require the use of tegraderm if the child can sit relatively still. Now, finally on to new drugs. This is a simplified scheme of some of the inflammatory pathways that are involved in rheumatoid synovitis. Cyclooxygenase is a major enzyme affected by non-steroidals with the resultant inhibition of prostaglandins, thromboxane and prostacyclin. In 1992 two isoforms of cyclooxygenase were definitively demonstrated and the COX hypothesis was developed. A simplified version of the COX hypothesis is as follows: first, there are two cyclooxygenase enzymes, COX-1, which constitutive or homeostatic, and COX two which is inducible and occurs in large amounts with inflammation. The second part of the COX hypothesis is that COX-1 is responsible for the side effects of non-steroidals, especially the gastrointestinal problems. The final part of the COX hypothesis is the feeling that if a drug could be developed that inhibited COX-2. Following the discovery of the two COX isoforms there was a flurry of excitement as the familiar non-steroidals were evaluated for their potency of inhibition of COX-1 versus COX-2. This table and many others like it were developed to rank the various non-steroidals for their COX-1 versus COX-2 activity. The higher the ratio the more COX-1 activity. The lower the ratio the more COX-2 activity. Unfortunately, the therapeutic concentration of all of these non-steroidals is much higher than what was used to perform these assays. Hence, these tables are clinically meaningless. There have been extensive debates as to the best assays to determine the amount of COX-1 and COX-2 inhibition. In December of 2006 and international consensus conference on this topic was held and the Whole Human Blood Assay was chosen as the gold standard, i.e. the reference assay, for establishment of the relative amounts of COX-1 versus COX-2. Based on this assay, the traditional non-steroidals and therapeutic doses inhibit both COX-1 and COX-2 non-selectively. Emesalud and meloxicam do inhibit COX-2 more than COX-1. Now, on to the anti-TNF drugs. There are three major ones being presented at this meeting. Etanercept, infliximab and D2E7. Etanercept is starred because this is the only one that has been studied in children and it is FDA approved for the use in juvenile rheumatoid arthritis. The data on the effectiveness on the treating of etanercept in treating juvenile rheumatoid arthritis was presented a year ago and will soon be published in article form. Sixty-nine children with polyarticular course juvenile rheumatoid arthritis, ages 4-17 who were refractory or intolerant to methotrexate, were all treated with etanercept at 0.4 mg per kilogram subcutaneously twice weekly in a unique study design, the Pediatric Rheumatology Collaborative Study Group. All patients received active drug in the first three months and then at the three month time period, those who were deemed responders by a core set of criteria which was internationally validated, went on to receive either placebo or Enbrel in a randomized blinded fashion. There was no difference between etanercept or placebo in the frequency of upper respiratory infections, headache, rhinitis, vomiting or accident and injuries. Only a few patients had mild to moderate injection site reactions, but these did not require treatment or discontinuation of medication. There was no development of autoantibodies and no development of anti-etanercept antibodies either. Nor were there any laboratory abnormalities. Presented this morning by Dr. Lovell was the data from 59 children who have now gone on to receive etanercept for 12-18 months. As you can see, the response has been maintained in those that have had it. These are the patients who had been on placebo.
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