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Juvenile Rheumatoid Arthritis

Few 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 juvenile rheumatoid arthritis, rumatoid arthritis, rhumatoid arthritis. 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 with

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 are all things that 

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. So as we think about

Before I discuss specific medications, I feel itís 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 juvenile rheumatoid arthritis juvenile rheumatoid arthritis, rumatoid arthritis, rhumatoid arthritis. 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. It is our job to treat early and aggressively so that this

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 donít 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. For children under the age of 6,

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 1997 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. But only celecoxib and rofecoxib are

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. They were allowed to enter into the

What about other studies? Well, there is one coming up here and it will be a poster tomorrow. In this study etanercept was added to dimers in nine children with JRA. Five had polyarticular onset disease, four had systemic onset disease, and according to the abstract all responded impressively without significant side effects.

Does etanercept work best for certain types of JRA? This is only anecdotal information that I was able to glean, of reports of clinicians adding it to existing methotrexate, sulfasalazine, hydroxychloroquine or cyclosporine for systemic onset JRA, which is our hardest to treat subset of JRA. Of the information that I was able to gather, most of these patients have had a dramatic response. Thereís a study coming up which will be using etanercept in the treatment of systemic JRA. It is not yet started.

Well, etanercept looks great but there are some very special issues that we need to consider in children. The first is drug stability. In small children one hates to waste a whole vial of medication when it is so expensive. Studies have indicated that the vials can be reentered if the drug has been reconstituted with bacteriostatic water for injection, and kept at 2-8 degrees centigrade for no more than 21 days. There can be up to five entries per vial. This then makes it much more cost effective in terms of treating children. The next worry is that of infections, particularly varicella. In the Pediatric Collaborative Study their were two episodes of aseptic meningitis following chicken pox. Both resolved without sequelae. It is

Other infections, if they are mild, etanercept can be continued, but if they are deemed clinically significant or serious it would be wise to hold etanercept. Next, we have to consider the question about immunizations. Do we give routine immunizations to children who are receiving etanercept or not? Certainly live vaccine should not be given. There is no data available on the effect of etanercept on the response to vaccination, nor the

Etanercept has been used longer term in patients with rheumatoid arthritis. Presented at this ACR meeting are several abstracts of patients treated for varying lengths of time. Five hundred and twelve patients have been treated for over 12 months, 180 for over 18, 73 for 24-33 months. The patientís response has been sustained for the duration of treatment and impressively, at two years 16% of patients have zero active joints. This table is taken from an abstract that will be presented. It is of 79 patients that have been treated with etanercept and methotrexate for 16-18 months. As you can see, there is sustained clinical improvement and this is ACR 20% improvement, 50%, 70% and there is good improvement at six months, 12, 18 months at each of these. Again, itís impressive that at 12 and 18 months there are indeed patients with no active joints. This study presented, actually, this morning reported the use of etanercept in 632 patients with rheumatoid arthritis treated in the first three years of disease, where they

I will be briefly discussing other new TNF drugs as they have not been tested in children. Infliximab, or Remicade is a human/mouse chimeric anti-TNF monoclonal antibody. It is given intravenously and has a half-life of 10 days. It was approved for the use in severe Crohnís disease in August of 1998, and just four days ago received approval for treatment of rheumatoid arthritis. The early studies in rheumatoid arthritis were for a very limited number of infusions but data presented at this meeting - which will be presented on Wednesday - this is the table that Iíve taken from the abstract shows that when infliximab is added to methotrexate in patients with rheumatoid arthritis at doses of 3 mg per kilogram, or 10 mg per

D2E7 is a fully humanized anti-TNF antibody. This is a table taken from an abstract to be presented on this drug, when given for the treatment of rheumatoid arthritis subcutaneously at doses of 20 mg, 40 mg and 80 mg. Patients achieving ACR 20 response of 49%, 57% and 56%, all are significant at the P less than .0001 level compared to placebo. Similarly, improvements were seen in the tender joint count, swollen joint count

Leflunomide has been extensively studied in adults with rheumatoid arthritis but has not yet been studied in children. There are several studies at this meeting that demonstrate its ability to slow radiographic progression on rheumatoid arthritis. Its clinical improvement at 12 months is sustained at 24 months with 79% achieving ACR 20 response, 56% ACR 50 response and 26% ACR 70 response. It is comparable to methotrexate in efficacy. Dr. Emery Adel tomorrow will present an abstract comparing leflunomide to methotrexate after two years. Basically there was no difference in the ACR 20 or ACR 50 response between the two medications. Common side effects of leflunomide are familiar to those seen with methotrexate:

A very exciting area of investigation of drug therapy for rheumatologic diseases is the idea that the patientís genome could predict the response to a particular medication. In the past there was a flurry of interest with respect to toxicity from gold and penicillamine in patients with certain genotypes. Recently Uto et all in Japan have focused on the expression of P-glycoprotein in TH-1 lymphocytes in patients with rheumatoid arthritis. This particular molecule is responsible for transporting drugs out of cells and is absent in most normal cells. It is encoded by the medication disease