Sharing insights from the literature and their clinical experience, the panelists discuss key aspects of NSAID management and the use of intraarticular corticosteroids.

       Dr. Goldsmith: When we make a diagnosis of JIA, I think most of us start the therapeutic regimen with a NSAID. Ms. Taylor, how do you use NSAIDs for the treatment of children with JIA?
       Taylor: Certainly we do start with NSAIDs and probably the primary NSAID that we use would be naproxen since we have longstanding experience with this agent. It is FDAapproved for use in JIA. Naproxen is available in both suspension form and tablet form, and can be given twice a day versus some of the older NSAIDs that patients have to take several times a day.
       Dr. Goldsmith: Would you comment on any problems with naproxen that may occur?
       Taylor: The main side effects that we see are gastrointestinal side effects and these have been reported in the literature.²³ We recommend that patients take this medication with food. Another caveat, which has been reported in the literature, is the development of pseudoporphyria. This seems to be much more common in children with fair skin and blond hair. It often looks like little scratches on the skin but it causes skin fragility and may lead to flat, hypopigmented scarring. If we see this, we often switch to a different NSAID to see if we can avoid the complication of pseudoporphyria.
       Dr. Goldsmith: In your experience, does pseudoporphyria also occur with other NSAIDs?
       Taylor: It does but not with the same frequency as it does with naproxen. The potential is certainly there but we often try and switch, depending upon the age of the child, to the NSAID that seems to be the best.
       Dr. Lovell: Pseudoporphyria has been reported with all the NSAIDs but it is far more common with naproxen. For some reason, this side effect also seems to be far more common in children than in adults.
       Dr. Goldsmith: As an additional point, skin fragility related to pseudoporphyria may continue for several months after you have stopped the medication, and it often takes up to one to two years to heal. Accordingly, it is important to remind the family about this. One theme that we face regularly now is that an increasing number of families are reluctant to use medications, even NSAIDs. What is your experience with naproxen and other NSAID-related side effects?
       Dr. Lovell: In my own experience, about 80 percent of the patients who take naproxen tolerate it fine. The assuring thing is that the frequency of medically important side effects or severe adverse events is really very low with all the NSAIDs in these children.
       There is a great deal of controversy in the literature about the involvement of NSAIDs and selective Cox-2 NSAIDs with thrombotic events and GI ulceration, etc. While that is a very important discussion for adult patients, GI ulceration and bleeding in children related to NSAID therapy is extraordinarily uncommon. In a recent survey of all the pediatric rheumatologists in North America, no one reported seeing any significant thrombotic events such as stroke or heart attack associated with NSAID therapy in the patients with JIA that they had treated.²⁴
       There are side effects but they are more like nuisance side effects such as abdominal discomfort or nausea. In a certain percentage of children, the use of NSAIDs will be associated with mood changes or headaches or sleepiness. These side effects often start soon after patients begin using the NSAID.²⁵ If you forewarn the family about these effects, they can stop the NSAID if these effects occur. These effects cease very quickly and then you can try another NSAID. I let the parents know about these things beforehand so they are prepared.
       The pseudoporphyria with naproxen is an unusual skin manifestation. It is often totally asymptomatic. However, you still want to advise families about it so they can look for it. If one gets those skin lesions, they often heal with small atrophic scars. As Dr. Goldsmith said, it can take a couple of years for those to heal to the point where they are not apparent on the skin.
       Taylor: I think the other caveat that families need to be aware of is that it can take several weeks before they see a benefit to the NSAIDs. They are often looking for improvement in the swelling and symptoms in just a few weeks. We try and educate them about the length of time. Some of the studies that have been done indicate that it may take up to 12 weeks until you see a maximal benefit from the NSAID.^26-28
       Dr. Goldsmith: So 12 weeks is your initial trial with naproxen?
       Taylor: Typically that is the case. We might switch to another one then but often families will come in and they will say: “Well, it has been four weeks and we have not seen any improvement yet.” So we try and give them more time on that NSAID before switching agents. Just because they may not respond to one NSAID does not mean they may not respond to another.
       Dr. Lovell: There is a lot of public confusion about NSAIDs. That is in part because they are used for a wide variety of indications. There are some that are over-thecounter agents and some that are prescription agents. The view of NSAIDs being analgesic-only agents or symptom- relieving agents is selling them short. If they are given on a consistent basis in therapeutic doses, they can be very effective antiinflammatory agents and really change the manifestations of the disease, both symptomwise and on the physical exam. The trials of all the NSAIDs have demonstrated that there are statistically significant changes in objective measures of the disease that are associated with NSAID therapy.
       One should advise the family that the NSAID is being used as an antiinflammatory agent but in order for the agent to achieve that effect, it needs to be given in therapeutic dosages and taken on a regular basis. As Ms. Taylor said, the NSAID may take more than just a few weeks to achieve the therapeutic benefit.
       In regard to the duration of NSAID therapy, this depends a great deal on the type of JIA that one is talking about. For many children with persistent oligoarticular JIA, NSAID therapy, with or without intraarticular injections of steroids, is the mainstay of therapy. For many of these children, one can adequately treat them with NSAIDs alone. However, when it comes to more extensive forms of JIA such as polyarticular JIA, the move to treatments in addition to NSAIDs can occur very early. The majority of pediatric rheumatologists sees NSAID therapy as just part of the therapy program and are adding second-line agents very quickly for patients who have obvious polyarticular involvement.

When You Should Consider Other NSAID Options
       Dr. Goldsmith: What would be your choice of NSAID after naproxen if there were significant gastrointestinal side effects? Would you be likely to change to another classical NSAID or move to celecoxib, which was recently approved for use in JIA?
       Dr. Lovell: In my own practice, the pseudoporphyria issue occurs frequently enough in certain groups. I am talking about young fair-haired, fair-skinned females. There is enough frequency to the point where I have reservations about using naproxen as the initial NSAID in these little girls who seem to have the highest risk for developing pseudoporphyria. For these patients, I think about using NSAIDs other than naproxen from the beginning. If naproxen is not effective, then my subsequent NSAIDs of choice are either meloxicam or celecoxib. Both are FDA-approved for use in children with JIA.
       It is important to keep in mind that it is very difficult to administer medications at school now so three-timesa- day dosing and certainly four-times-a-day dosing medications are very difficult burdens to put on patients and families. Accordingly, as much as possible, I try to stay with medications that have once or twice daily b.i.d. dosing, which can be done entirely at home. Naproxen and celecoxib fit this criteria.
       Taylor: I would just add that in some patients, especially teen-agers, in whom adherence can be an issue, nabumetone may also be an option for treatment because they can take it once a day.
       Dr. Goldsmith: Another advantage of nabumetone is that it will regularly dissolve and form a slurry if placed in about two to three teaspoons of water.
       Taylor: One of the challenges we often face is that third-party payors require a trial of several generic NSAIDs before you can try one of the Cox-2 inhibitors or other agents.
       Dr. Goldsmith: Also, with regard to insurance companies, it is advantageous that the medications we choose are formally approved for use in patients with JIA. This also helps to reassure families as they do their research about medications on the Internet.
       The most worrisome side effects of real severity associated with NSAIDs occur when a child continues to take these medications while experiencing a significant gastrointestinal illness. In these situations, the child is at significant risk for serious dehydration related kidney complications. Under these circumstances, it is important to have informed patients quickly stop any NSAID.

NSAIDs And Methotrexate: What You Should Know
       Dr. Goldsmith: Various papers in the pharmacologic literature touch upon concerns about concomitant use of NSAIDs and methotrexate.²⁹ Do you have any reservations about using NSAIDs along with methotrexate?
       Dr. Lovell: All the trials of methotrexate that have been done in JIA involved patients who were taking concurrent NSAIDs.^30-32 The potential is that one medication may affect the clearance of the other so the levels are slightly higher if the patient is on two medications at the same time. However, when it comes to both NSAIDs and methotrexate, there is a very broad therapeutic window of tolerance. A change of 10 to 15 percent in the serum level of methotrexate related to concurrent NSAID use is really of minimal clinical importance. It has been routine since the beginning of methotrexate use for JIA that clinicians use it in combination with NSAID therapy.
       We have been using this combination for over 20 years with JIA and even longer in adults. I believe it is a very effective combination. In fact, JIA is a disease in which the mechanisms of the pathophysiology of the disease are multifactorial. Juvenile idiopathic arthritis does not just affect joints in one way. It affects the body in many different ways by many different mechanisms. Studies have shown that combination therapy that works by different mechanisms is probably the preferred way to treat these patients.²⁵

Other Considerations With NSAID Management
       Taylor: In regard to NSAIDs, with so many of them available over-the-counter now, I do try and counsel patients that as we prescribe NSAIDs for antiinflammatory effect, they should avoid using concomitant NSAIDs for headache or pain relief. There is more of a potential for having increased GI disturbances so we try to avoid that. I would rather they use acetaminophen for headache or pain relief.
       Dr. Lovell: I think another thing to keep in mind with the use of NSAIDs is that they do affect platelet adhesion. If patients are going to be undergoing surgery of any kind, there needs to be a discussion between the physician and the family to determine the appropriate period of time the child would need to be off the NSAID therapy before and after the surgery to minimize the risk of bleeding. This is especially true for surgeries that have to do with the mouth and the throat such as removal of tonsils or adenoids.
       Dr. Goldsmith: What is your recommendation as to when NSAIDs should be discontinued prior to surgery?
       Taylor: This is often dependent on the surgeon who is performing the procedure because they each have their various protocols that they like to follow. Most commonly, it is usually about one to two weeks prior to surgery, depending on the surgeon’s protocol.
       In addition, it is important to remember that the newer Cox-2 inhibitors do not inhibit platelet aggregation. This is a consideration if a patient must stay on a NSAID during that time.

A Closer Look At Intraarticular Corticosteroids
       Dr. Goldsmith: In the last 10 to 15 years, the use of intraarticular corticosteroids has revolutionized the care of children with JIA, particularly those with oligoarticular JIA. Initially, there was some reluctance to introduce corticosteroids into the joints of a growing child for fear of injuring the growth plates. However, these concerns no longer exist and intraarticular corticosteroids are now an integral part of management for several JIA subgroups. Which corticosteroid preparation do you use and how often do you perform these injections?
       Taylor: We tend to use triamcinolone hexacetonide. Researchers from Germany looked at triamcinolone hexacetonide in comparison to triamcinolone acetamide alone and found that triamcinolone hexacetonide resulted in longer benefit.³⁴ They found that triamcinolone hexacetonide was much more effective and was given at a lower dose than triamcinolone acetamide.
       In regard to the number of intraarticular corticosteroid injections, I have not seen any trials that say how often you can do this. I believe the general practice is to not inject joints much more often than every six months.
       Dr. Lovell: My rule of thumb is not to inject a joint more often than every four to six months. However, I have had patients in which I have had to do it more frequently than that. We have injected a joint in some patients and it gets better for a month but the inflammation reoccurs or does not completely resolve. You inject it a second time and you get a significant result. It is not always the case that a single injection satisfies the goals for what you are hoping to achieve.
       However, when it comes to a patient who continues to have recurrence of active disease in a joint or patients who have several joints with active disease, and you have to do repeat steroid injections, you need to question the effectiveness of your overall treatment program. There may be other options to more adequately control the disease systemically so patients do not have recurrent episodes of swollen, painful joints that need injections.
       On the other hand, there are patients with oligoarticular disease who have arthritis in only one or two joints. For these patients, joint injections are fully adequate to control their disease. You can do joint injections to maintain an inactive state in that joint or induce an inactive state. Then as soon as some findings come back, treatment with NSAIDs maintains disease control and can do an excellent job of treating the disease.
       Researchers have shown that intraarticular steroid injections truly impact not only the symptoms and the presence of effusion, but also positively impact the amount of inflammatory disease you see on the joint on MRI.^35-37 Intraarticular steroids provide more than just symptomatic relief. They really get at the disease process in a very significant and profound way.
       Dr. Goldsmith: Do you use intraarticular injections without comcomitant use of NSAIDs?
       Dr. Lovell: Intraarticular steroids are probably the treatment of choice for a patient with monoarticular disease. When there is localized disease, it makes perfect sense to use an intraarticular steroid and put the treatment where the pathology is located. If you can avoid exposing the child to systemic medications, even though they are well tolerated, it is a good way to go.
       Dr. Goldsmith: On a practical point, when it comes to children 10 or younger, we perform the injections using conscious sedation. For children 11 and older, we try to avoid sedation and perform injections in the outpatient area. Do you also have that policy?
       Dr. Lovell: Yes. Our guidelines are very similar to yours. We have also utilized the OR induction room and have the anesthesiologist give light anesthesia in the induction room and do the joint injection there. We probably have used light anesthesia more often recently than conscious sedation.
       Taylor: We have used oral midazolam in the clinic if we felt that we could accomplish the procedure in that manner and the child was old enough. The other avenue that we have utilized is interventional radiology, depending on the joints that are being injected. For example, we may use an imaging-guided procedure for smaller joints of the wrist and the subtalar joint in order to attain proper and precise injection.
       Dr. Goldsmith: What are your specific recommendations for post-injection care?
       Taylor: Our protocol is to have the patients be at rest. They do not have to be totally non-ambulatory but they should avoid exercising and be limited to minimal ambulation around the house for at least 48 hours in order to allow for better absorption of the medication. As Dr. Lovell mentioned, many patients get a profound effect and feel much better after the injection. We want to avoid any overuse or potential injury to the joint, and feel like it works better if they rest for about 48 hours prior to resuming normal activities.
       Dr. Goldsmith: We all agree that intraarticular corticosteroid therapy is a valuable tool in the treatment of some of our children with JIA and, in some instances, these injections may be all that are needed.

Dr. Lovell: When it comes to patients with JIA, we usually try to avoid the use of systemic corticosteroids as a prominent part of the long-term treatment approach due to the known short-term and longterm side effects of oral corticosteroids. Having said that, whenever you look at populations of patients with JIA, we see that steroids are part of the treatment regimen in 20 to 30 percent of the patients.

The reality is that current treatment approaches in the last couple of years have not been able to avoid steroids in all patients as part of the treatment program. Our hope is that the emergence of more effective therapies will allow us to rely on steroids much less than we have in the past. Certainly, steroids do have a role to play in life-threatening complications of systemic JIA such as MAS and myocarditis and, in some cases, pericarditis.

Dr. Goldsmith: Systemic corticosteroids are associated with multiple serious adverse effects that absolutely limit their use in JIA, aside from the aforementioned significant complications associated with systemic JIA.33 I also consider the use of corticosteroids as bridge therapy in extremely compromised patients with early polyarticular disease while introducing remissive medications. Corticosteroids are also particularly burdensome in children because of their effects on linear growth.