In addition to exploring the efficacy, dosing and possible side effects of methotrexate, the panelists also discuss the impact and potential of current and emerging biologic agents.

       Dr. Goldsmith: Methotrexate has been around for 17 to 18 years. It is a folate antagonist and, in high doses, inhibits RNA and DNA production in rapidly dividing cells. However, for JIA, methotrexate acts more as an antiinflammatory agent as a result of its effects on TNF and adenosine released at sites of inflammation.

       In addition to polyarticular and oligoarticular JIA, and in some patients with systemic onset disease, methotrexate is also effective for the rash and arthritis of psoriatic JIA. The stated percentages of children with JIA who respond to methotrexate have varied over the years. However, as assessment tools have become more sophisticated, at least 60 percent of children with significant polyarticular disease respond adequately to methotrexate. Perhaps this estimate is on the low side. Is this the percentage that you both agree with?
       Dr. Lovell: I agree. It depends on the level of response that you look for. When it comes to reaching an ACR pediatric 30 level of response, the response rate with methotrexate in a variety of trials has been about 60 to 70 percent in children with polyarticular JRA and about 50 percent in kids who have systemic JIA.³⁸
       However, we are increasingly seeing that people are not satisfied with a patient just demonstrating an ACR pediatric 30 level of response. With a pediatric 30 level of response, the patients are much better but they still have an ongoing presence of inflammation in the joints. Increasingly, our treatment goal, especially for polyarticular JRA, is complete eradication of any evidence of the disease or “inactive disease.” When it comes to inactive disease, the response rate with methotrexate is around 20 to 30 percent in patients with polyarticular JIA.³⁸

A Guide To Dosing Considerations With Methotrexate
       Dr. Goldsmith: With what dose do you usually start? Are you now starting subcutaneous methotrexate prior to using it orally? Or do you still start it via the oral route and only change to the subcutaneous administration if there is an inadequate response?
       Dr. Lovell: My approach to using methotrexate is to start at 10 mg/m² body surface area. Before I start methotrexate or choose the route of administration, I talk to the family about what we know in regard to differences in the predictability of absorption with oral treatment versus subcutaneous administration. With oral treatment, the absorption of a given dose of methotrexate can be anywhere from 50 to 70 percent but it is never 100 percent. With subcutaneous administration, there is 100 percent absorption. In an individual patient, the absorption of oral methotrexate may vary from one week to the next.
       For many families, that information is sufficient for them to become very invested in the subcutaneous administration route, especially when they understand that the method of administration is very similar to that used with insulin and allergy shots. Almost all of these people know somebody with diabetes or somebody who gets allergy shots so it demystifies the setting. Many patients select the subcutaneous route from the get-go. Other families may be intimidated by the process of subcutaneous administration or the kids are hesitant. In these cases, we start out with oral administration and the understanding that if we do not achieve a certain level of benefit, switching to subcutaneous administration may be one of the treatment options.
       I do not have a strong bias one way or the other. I just have the discussion with the family and then we come to a mutual decision about which treatment approach we are going to use.
       Dr. Goldsmith: In one clinical trial, researchers concluded that there was no further benefit when the subcutaneous dose reached 15 mg/m².³⁸
       Taylor: There was a plateau effect.
       Dr. Goldsmith: Yes, there seems to a dose limit beyond which there is no further clinical benefit. Based on clinical impressions, some pediatric rheumatologists have suggested escalating of doses for other medications used for JIA. This paper shows that after detailed analysis, at least with methotrexate, this does not lead to added clinical improvement.³⁸
       Dr. Lovell: It is important to note that switching from oral methotrexate to subcutaneous administration actually increases the response rate. Rose and colleagues did a study in which patients who had not gained adequate response on oral methotrexate were switched to a similar subcutaneous dose. They found an increase in the frequency of response by about 30 percent.³⁹ Another recent paper, the first randomized, controlled trial comparing oral methotrexate to subcutaneous methotrexate in adults with new onset rheumatoid arthritis (RA), demonstrates slightly higher response rates in patients who are given subcutaneous methotrexate.⁴⁰
       If the treatment decision is to use oral methotrexate at the beginning for whatever reason, switching these patients to subcutaneous methotrexate at a later point — either for a lack of efficacy or due to side effects — is a viable treatment option.

Side Effects And Adverse Reactions: Keys To Monitoring And Patient Education
       Taylor: It has also been reported, mostly anecdotally, in the pediatric population that patients who are on either oral or, more commonly, injectable methotrexate often experience an aversion type of reaction. They actually develop nausea prior to the injection. In our experience, this is quite common. It can happen after they have received the injectable methotrexate for some period of time. You do not always see this reaction at the beginning of treatment.
       Dr. Goldsmith: Do you have a preference for using either folic acid or folinic acid concurrently with methotrexate? Taylor: I typically use folic acid (1 mg per day). If they continue to get more and more frequent oral ulcerations, one may need to consider changing therapies from a tolerance standpoint. We always have to weigh the risk and benefits but if they are having that many side effects from their medication, we have to think about other alternatives.
       Dr. Goldsmith: In a recent clinical report, it was found that bloodwork done every three months for patients on methotrexate was as safe and equally effective as the more formally recommended ACR guidelines.⁴¹ Have either of you monitored patients using this interval?
       Dr. Lovell: The data suggests that liver function testing every three months is adequate. I am comfortable with this when patients are on a stable dose and they have tolerated it for several months. However, it can be challenging as the ACR has published guidelines for methotrexate monitoring, granted they were tested and validated exclusively in adults.^42-44 However, they are the published accepted guidelines for what one should be doing in patients on methotrexate. So doing liver function testing less frequently brings up some medicolegal aspects that we need to keep in mind.
       From a practical view, the frequency of clinically important laboratory abnormalities in the CBC or liver function test or urinalysis in kids on methotrexate is very uncommon. When an abnormality does occur, it is more likely related to an intercurrent infection or the NSAIDs than the methotrexate.
       Methotrexate is a very well tolerated medication and the frequency of lab test abnormalities in patients on a stable dose is really very uncommon. I would agree that testing every three months is adequate in a patient on a stable dose of methotrexate who has tolerated it for three to six months.
       Dr. Goldsmith: What then should we tell our patients and their families about the likelihood of long-term side effects of methotrexate? It is always their major concern. We have now had nearly 20 years of experience with methotrexate and I believe we can provide information which will help them make a positive decision and feel comfortable about this medication over the long haul.
       Dr. Lovell: I agree completely. Methotrexate has been the most studied and the longest studied treatment we have for rheumatic diseases. In pediatrics, we have over 15 years of continuous use of methotrexate in hundreds of thousands of children and the long-term safety seems to be excellent. We have not seen an evolution of late side effects, even with long-term continued use. It is the medicine in which we can give the most assurance about long-term safety.
       The one thing we have not talked about is the fact that if children or adults take methotrexate, they need to be advised that they should not get pregnant while they are on the drug due to a slightly increased risk of birth defects.⁴⁵ If they are going to be on methotrexate and be sexually active, then they either need to stop the methotrexate for a period of time before they get pregnant or practice adequate birth control. This is a discussion that you need to have with families and children at regular intervals during the time that you have a patient on methotrexate. As a practitioner, you need to bring this up recurrently during the interactions you have with the family and the patient as he or she gets older because we all know it is common for pre-teens and teenagers to be sexually active, and this can change at any one point in time.
       Taylor: Another component of the discussion is the consumption of alcohol while on methotrexate. Patients should avoid alcohol consumption while they are on methotrexate. The potential for effects on the liver are significantly increased when patients consume alcohol while they are on methotrexate. I have this discussion in my practice regardless of the age of the patient. I find it is much easier and less sensitive to bring it up earlier, and then continue to address it over time as opposed to bringing it up later on in the patient’s teenage years. We all know that teenagers and adolescents, young adults, experiment over time. This is a very important conversation that I have with patients who are going off to college in terms of how it will affect their social activities and making appropriate adjustments.

When You Should Cease Utilizing Methotrexate?
       Dr. Goldsmith: You should not stop it too early. I prefer that a child’s arthritis should be inactive (as we defined earlier) at a minimum of a year to a year and a half to two years before you consider stopping methotrexate. Are there any other caveats related to this important decision?
       Dr. Lovell: This highlights the fact that we do not have a good biomarker to tell us when patients have inactive disease from a biologic point of view as opposed to a clinical point of view. We cannot easily discern when the disease has become truly inactive and gone into remission as opposed to the disease just being very well suppressed by treatment.
       Some studies in Europe show that in regard to inactive disease for six months, 12 months and longer than 12 months, in each instance, about 50 percent of the patients have a subsequent flare of their disease when they are off methotrexate therapy.^25,46,47        Accordingly, we need to tell families that if they stop treatment after six or 12 or even more months of inactive disease, there is a 30 to 50 percent chance that the disease will reactivate at some point after that and they will need to reinitiate therapy. It would be nice if we had a very widely available biomarker to predict in which patients we can stop therapy but this is not readily available at this point in time.
       Dr. Goldsmith: If a flare occurs after stopping methotrexate, in my experience, the disease often responds favorably when the medication is restarted.
       Taylor: Another area of concern centers around the issue of Epstein-Barr virus infection. If patients develop Epstein-Barr virus infection, do you continue the methotrexate or do you hold the methotrexate during the active infection? The theoretical concern would be the development of some sort of lymphoma. Some people will tend to hold methotrexate during an active EBV phase. Some will hold the methotrexate until the EBNA (Epstein Barr virus nuclear antigen) becomes positive. However, I do not think there are any established guidelines for what is routine in this situation.
       Dr. Goldsmith: I stop methotrexate during active EBV infection and use similar EBNA guidelines.

What The Studies Reveal About Etanercept
       Dr. Goldsmith: I find it hard to believe that nine years have passed since etanercept was first approved for use in children. Since that time, a number of other biologic agents have been studied in children. However, etanercept remains the most commonly used biologic agent.
       Dr. Lovell, could you provide us with some background about the seminal etanercept study that you and others authored?
       Dr. Lovell: In the initial open-label phase of the etanercept study, in regard to patients who had a very long duration of the disease and failed treatment with methotrexate and often numerous additional medications, over 75 percent of those patients demonstrated an ACR Pedi 30 level of response.⁴⁹ In many instances, the degree of improvement was much greater than even an ACR Pedi 30. When you put these patients in a double-blind portion of the study, the primary outcome measures of the percentage of patients who flared their disease and the time to which they demonstrated that flare were significantly different between the two treatment arms. Fewer patients showed a flare with etanercept and the time to flare was much longer with patients who continued treatment with etanercept.
       This study demonstrated a statistically different outcome between the two treatment arms with a relatively small number of patients so it was a very efficient study design. The study demonstrated that etanercept is a very efficacious treatment and other longer-term, open-label safety studies with etanercept in children have demonstrated that etanercept has a very positive benefit to risk ratio for children with JIA.^49,50
       Taylor: I would echo that this certainly was a landmark study in the degree of improvement and the study included patients with significant and longstanding arthritis.⁴⁹ As Dr. Lovell mentioned, these patients had previously failed methotrexate and had longstanding JIA — I believe the average duration was 5.9 years — and we saw for the first time patients exhibiting 50 percent and 70 percent response rates. In addition, the rapidity of the improvement in many patients occurred within the first two to four weeks.
       Dr. Goldsmith: At the 2007 meeting of the American College of Rheumatology (ACR), there were several papers that examined the long-term use of etanercept out to eight years.⁵¹ These studies confirmed the longevity of etanercept as an effective and safe agent. Etanercept still is, in most instances, the first biologic agent that clinicians choose. Are there any changes regarding how you use etanercept in clinical practice now? Do you ever increase the recommended dose? Also, when do you consider stopping etanercept?
       Dr. Lovell: In the original polyarticular JIA trial, we utilized twice-weekly dosing, 0.4 mg per kg per dose with a maximum of 25 mg per dose for etanercept. Since that trial, researchers have shown that once-weekly dosing in adults with RA is as effective as twice-weekly dosing.⁵² Although head-to-head comparison studies have not been performed in kids with JIA, the pharmacokinetics and clearance of etanercept in children is similar enough to adults to suggest that once-weekly dosing in children would also be effective. In many instances, etanercept is being administered as a once-weekly dose to children at 0.8 mg per kg per dose with a maximum of 50 mg. That variation in treatment has evolved with time.
       The question about pushing the dose beyond those stated doses has been looked at in a few studies in open-label fashion.⁵³ In my opinion, there is not any compelling evidence that the increase in the dose of etanercept is necessarily associated with the higher rate of response.
       The other understanding that has kind of evolved since that original trial is that perhaps etanercept is not as efficacious in systemic JIA, especially those kids with systemic JIA who have active systemic manifestations. The response rate may be more like 40 to 50 percent in those patients as opposed to 75 to 80 percent in the kids with straight polyarticular JIA.⁵⁴
       In my own mind, the unanswered question or the question that I cannot answer for families is what information we have about the longer-term safety of etanercept, say 15 to 20 years out. What is the risk of very rare side effects with etanercept in the long term? We cannot answer these questions with adult RA let alone for JIA at this point. With any of the biologics, you need to clearly tell the family that these agents are relatively new and that nobody has experience with 15 or 20 years of post-exposure to these medications.
       The other unknown to me is when we can effectively stop this treatment. The problem is even more profound with etanercept than with methotrexate because it is more common to suppress the disease so effectively that you do not see clinical manifestations. Yet you do not know whether the child really achieved biologic remission on his or her own or whether you have just very effectively treated the child’s disease. I do not feel that we have the tools to pre- dict which people can reasonably stop the treatment and which need to continue it. Therefore, I use the same rules as I do for methotrexate. I stop the medication when there have been six to 12 months of inactive disease.

Does Infliximab Have A Possible Role In The JIA Armamentarium?
       Dr. Goldsmith: Another well-studied anti-TNF agent is infliximab, a chimeric monoclonal antibody. What is your opinion about the role of infliximab for the treatment of JIA? It is not currently approved for this indication.
       Dr. Lovell: Infliximab is an excellent example of why it is important to do studies of known efficacious agents in adults and do studies in children, and not just assume that they are going to be similar in safety and efficacy. Infliximab has been known to be an effective agent for adults with RA for many years. In fact, it was the first biologic and it has been extensively studied in adults. In adults, infliximab has been dosed on a mg per kg basis so it seemed quite straightforward how to adapt it for use in children.
       We did a prospective, blinded trial in which some children were treated with 3 mg per kg per infusion, some with 6 mg per kg per infusion and some received a placebo.⁵⁵ This trial showed that the clearance of infliximab in children is significantly faster than it is in adults.
       In the group of patients who had 3 mg per kg per infusion with the maintenance of every eight weeks — after several maintenance infusions — the majority of children did not have detectable infliximab levels before their next dose. Almost 30 percent of those kids developed an anti-infliximab antibody, perhaps as a result of re-stimulating the immune system with each infusion. The development of these antibodies increases the risk of an infusion reaction three- to fourfold. In the group receiving 6 mg per kg, about 10 percent of the patients developed anti-infliximab antibodies. This is similar to adults. Very few of those patients had nondetectable levels of infliximab before their next dose.
       If you use infliximab in children and have an every eightweek interval for your maintenance dose, this study strongly suggests that your dose should be 6 mg per kg at a minimum.
       We failed to meet our primary outcome measure in this study but I think this was more a consequence of enrolling low numbers of study patients and a higher than predicted placebo response rate. However, with continued therapy, over 75 percent of the patients on infliximab demonstrated an ACR pediatric 30 level of response.
       Infliximab is a viable treatment option for children with JIA. It needs to be given at least 6 mg per kg if you are going to keep an every eight-week maintenance schedule or perhaps give it more frequently in a maintenance schedule. Some open-label clinical experience suggests a high percentage of patients with uveitis respond to infliximab therapy.⁵⁶
       One of the advantages of infliximab therapy is the IV administration. One can more specifically and accurately monitor adherence. However, infliximab also has the risk and the hassles associated with intermittent IV therapy. This can be a big issue for families especially if they live a distance from an infusion center.
       Dr. Goldsmith: There certainly are a number of children who experience infusion reactions which limit the applicability of infliximab.

Assessing The Potential Of Adalimumab And Abatacept
       Dr. Goldsmith: Two other promising biologic agents are adalimumab and abatacept. Both preparations also were the subject of several studies at the 2007 ACR meeting.^57,58
       Adalimumab is an anti-TNF agent. It is a completely humanized monoclonal antibody which is administered subcutaneously every two weeks. We now have two- to threeyear data on adalimumab in children with very good results. Does the recent approval of the drug for polyarticular JIA change any of your current therapeutic decisions? Are there specific situations when you would choose adalimumab?
       Dr. Lovell: Actually, adalimumab has already changed the practice pattern in our Pediatric Rheumatology Division in Cincinnati. The clinicians there have demonstrated that adalimumab is being used more frequently now than infliximab. Even prior to FDA approval, adalimumab has found a home in the treatment of children with polyarticular JIA, partly because it is an every two-week subcutaneous injection — which is attractive for the patient and family — and also because it is very efficacious and well tolerated. Adalimumab is going to continue to play a large role in the treatment of kids with JIA.
       Dr. Goldsmith: Adalimumab has also been used successfully for pediatric uveitis.⁵⁹
       Another equally promising preparation is abatacept. It is the first biologic agent approved for use in adult RA patients who have not responded to anti-TNF preparations. Several studies demonstrating clinically significant benefits of abatacept for JIA were presented at the 2007 ACR meeting and an application for a JIA indication has been submitted to the FDA.⁵⁸
       Abatacept selectively modulates a complex, co-stimulatory signal which is required for full T-cell activation. In a double-blind, randomized, placebo-controlled study of 190 patients, 123 achieved an ACR Pedi 30 at four months. In the follow-up, placebo-controlled arm of the study, 20 percent of the abatacept group and 53 percent of the placebo group flared.⁵⁸
       Do you have any further comments about the potential role of abatacept for JIA? With abatacept being an intravenous preparation, do infusion reactions regularly occur? What is the frequency of administration for maintenance therapy?
       Dr. Lovell: Actually, in the trial, researchers administered the first dose, then administered it two weeks later and then patients had maintenance infusion every 28 days.⁶⁰ Abatacept is a very well tolerated medication. We saw minimal infusion reactions with abatacept. It was well tolerated both during the infusion and after the infusion. It is very gratifying to see a treatment that shows 30 percent or more of the patients showing efficacy when they had failed prior biologic therapies and, in some instances, more than one biologic therapy.
       The patients that were enrolled in this trial had, on average, a disease duration of three years. Abatacept works by a very novel and thought provoking mechanism of blocking co-stimulation. Would abatacept’s effect be even greater if it was given much earlier in the JIA disease process? Would the response rate be even higher or would it be a circumstance in which one could induce a much more long-lasting response?
       In the abatacept trial, even in the blinded portion of the study with placebo infusions, there were patients at the end of the six-month, double-blind portion of the study who still demonstrated persistence of their benefit that they showed in the early open-label portion of this study. There may be patients in whom abatacept therapy induces long periods of inactive disease.
       This trial was very promising in that it showed statistically significant differences between abatacept and placebo, but we have a lot more to learn about the use of this very interesting novel agent in kids with JIA. The capabilities of abatacept may prove to be much broader and greater than what we learned from this first clinical trial, even though it was a very positive trial.
       Taylor: Over the years, one of the exciting things has been the increased understanding of the pathogenesis of each of the JIA subtypes, whether it is systemic or polyarticular JIA, and whether interleukins or tumor necrosis factors play a major role in escalating the disease. With this knowledge, we can hopefully, over time, become more and more specific in our treatment of choice for each of these disease subtypes.

IL-1 And IL-6 Mediators: What Does The Future Hold?
       Dr. Goldsmith: Now let us turn to other biologics that are characterized as either anti-IL-1 or IL-6 agents, and explore their possible role for systemic JIA. The anti-IL-1 agent, anakinra, is approved for RA in adults. Recent reports indicate that it may be particuarly useful for systemic onset JIA. Pascual and colleagues demonstrated remarkable improvement using anakinra for systemic JIA.⁶¹
       In addition to their clinical experience with anakinra, Pascual et al., also completed several elegant studies in which incubated sera from patients with systemic JIA not only induced peripheral blood mononuclear cells to secrete IL-1b but also induced the transcription of several innate immunity genes.⁶² This further supports the concept that systemic JIA may indeed primarily be a disorder of innate immunity.
       Anakinra is limited somewhat by the need for daily subcutaneous administration. However, other anti-IL-1 preparations utilizing in-line fusion proteins allow for longer duration of activity through slower release. These are the IL-1 TRAP preparations.
       Has your experience been similar to others in that 50 to 60 percent of your patients with systemic onset disease respond to anti-IL-1 mediators? Do you still prescribe an anti-TNF agent for patients with systemic onset JIA prior to using an anti-IL-1 agent?
       Dr. Lovell: In regard to systemic JIA, especially disease with active systemic features, people increasingly go to IL-1 blockade prior to using an anti-TNF agent. Pascual and others have done elegant work to demonstrate that systemic JIA, especially with systemic features, is predominantly driven by IL-1 and/or IL-6.⁶¹ Blockade of those cytokines is much more likely to be effective. In my own experience with the systemic features of systemic JIA, the response with anakinra is very quick with 80 to 90 percent of the patients responding. This IL-1 modality is often a profoundly effective treatment for systemic JIA patients. As you noted, there are a variety of agents in development that block IL-1 and many of these agents are going to be in trials for systemic JIA. This is a very optimistic and hopeful arena of treatment for kids with systemic JIA.
       Taylor: As anakinra is not approved for JIA, the challenge we often have is negotiating with insurance companies for coverage.
       Dr. Goldsmith: For a number of years, it has been known that IL-6 is an important pro-inflammatory cytokine in sys- temic JIA. IL-6 plays a direct role in the production of fever, thrombocytosis, growth retardation, microcytic anemia and the generation of acute phase reactants. The anti-IL-6 agent tocilizumab is a fully humanized antiinterleukin- 6 receptor antibody. It is not currently approved for pediatric use nor for the treatment of RA in adults. In an earlier report by Yokota et al., 10 of the 11 children treated with tocilizumab showed dramatic benefit.⁶³
       Dr. Lovell: IL-6 blockade makes perfect sense for systemic JIA. We will see what the randomized controlled trial shows. The preliminary data we have from a few open-label studies and this one randomized trial that you talked about is all very hopeful and very positive.^63,64 The large randomized placebo controlled trial will also be used to better define the dose and safety profile that should be used with tocilizumab in kids with systemic JIA.

Key Safety Considerations With Biologic Therapies
       Dr. Goldsmith: There are specific safety precautions concerning the use of biologic agents. Prior to starting anti- TNF therapy, every patient needs a tuberculin skin test. If it is positive, further assessment is necessary to identify active tuberculosis (TB). If there is no active TB, INH is prescribed and the biologic preparation is not started until one to two months later. A yearly influenza vaccine is recommended. Live immunizations should not be administered while patients are on biologic therapy. All biologics should be stopped if the patient has a significant infection.
       Taylor: We also counsel each family regarding varicella outbreaks in school and the recognition of active cases so they can bring the matter to your attention and their primary care physician’s attention in order to facilitate closer observation and/or the start of antiviral therapy.
       Dr. Lovell: It is also important to abide by the labeled avoidance of anti-TNF therapy in patients who have chronic or recurring infections of any kind, and not to initiate the treatment when there are active infections of any kind.
       I would certainly agree with you about the importance of TB screening. Since we started doing TB screening in our randomized controlled trials, even in North America, we have been surprised that there have been individuals with JIA who have been found to be TB skin test positive when we have done the screening.
       In one of the trials, when we did repeat TB screening during the course of the trial, we found children who became TB skin test positive during the time they were on treatment who were not TB skin test positive at the beginning. Repeat TB skin tests in kids who continue on anti- TNF agents is a reasonable practice because one can get exposed at different points in time.
       I think the other precaution is if children get intercurrent infections that are associated with a fever. In these circumstances, we ask the family to call us quickly and we will hold the biologic therapy until the course of the infection is more clearly established. If it turns out to be your usual short-lived childhood illness, then we can restart the anti- TNF agent quickly. If it looks like it is going to be more complicated or more serious, we continue to hold the anti- TNF therapy until the kids have improved. The practice we use with anti-TNF agents is really very similar to the practice we use in kids who are on methotrexate or steroids in terms of concern for intercurrent infections.
       Taylor: The only other thing I would add is if any of our patients are going to have a surgical procedure. If they are on anti-TNFs or other biologics, we typically hold these agents in order to allow for wound healing and surgical site healing for a period of time after the surgical procedure. Then we would resume the use of the agents.

A Few Thoughts On Early Combination Therapy
       Dr. Goldsmith: For the management of RA in adults, many clinicians have promoted a treatment paradigm which favors initiating therapy early with a combination of medications and then withdrawing parts of the regimen when clinical control is achieved. Is there any clinical data available concerning this management model in children?
       Dr. Lovell: Well, we have seen a number of studies that have demonstrated that earlier onset of treatment is associated with better outcomes for children with JIA.²⁵ There is an ongoing study that is looking at aggressive therapy with combination treatments for early onset polyarticular JIA patients. This study is funded by the National Institutes of Health and is headed up by Carol Wallace, MD. The treatments they are looking at in this study are a combination of steroids for three months in tapering doses, etanercept and methotrexate compared to methotrexate alone.
       The primary outcome for the study is induction of inactive disease at six months. While this particular trial is for polyarticular JIA, we ought to have similar ideas about treatment for systemic JIA, which we know is a very severe disease associated with an increased mortality rate. We need to continue to try to look at induction of long-term remission in these patients as a treatment goal.

When Sulfasalazine May Be An Option

Dr. Goldsmith: Whenever we discuss the use of systemic medications with parents, they often express concerns about the lack of information concerning side effects with long-term use. Sulfasalazine is an older medication and we are unlikely to see future side effect surprises. Researchers have shown that sulfasalazine is effective for polyarticular JIA.48 Do either of you have any significant experience with sulfasalazine? Under what circumstances might you recommend the use of this medicine?

Dr. Lovell: Sulfasalazine has been formally evaluated in a randomized, controlled double-blind, placebocontrolled trial in children with polyarticular JIA, and researchers found it to be superior to placebo.48 However, the level of improvement with sulfasalazine seems to be less impressive than that of methotrexate so methotrexate is used more commonly. I would agree though that sulfasalazine is a reasonable alternative if families express a reluctance to the use of methotrexate for whatever reason. In patients with spondyloarthropathy or enthesitis-related arthritis, sulfasalazine actually may be a very effective medication. It is an effective medication of moderate strength for the treatment of JIA.

Dr. Goldsmith: Adverse effects appear to be worse in children with systemic JIA. Severe hypersensitivity and anaphylaxis may occur. Leukopenia and gastrointestinal toxicity are not uncommon. Regular laboratory tests to monitor the WBC and transaminases are necessary. However, these are all known side effects that are easily recognizable and these effects cease when one stops sulfasalazine.