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Juvenile Rheumatoid Arthritis

Juvenile rheumatoid arthritis was first described by Dr. Stills in the late 1800’s. Still’s disease is still used sometimes to describe systemic onset juvenile rheumatoid arthritis.  The etiology isn’t known. Infection continues to be an area of interest.

Some people have tried to link Rubella virus to juvenile rheumatoid arthritis, and there was even one paper - I think it was the New England Journal of Medicine, like 12 years ago - where one of the investigators would get the synovial tissue and the blood from a group of patients with juvenile rheumatoid arthritis and try and culture Rubella. In some of the patients they actually found the virus. But they were not able to prove a cause and effect link. Obviously, genetic predisposition is important. Different genetics than in adult rheumatoid arthritis. HLA-DR5, 6 and 8 are the most commonly cited ones and it does vary with the different subtypes. The HLA-DR4 is linked with the adult type rheumatoid arthritis.

There are three distinct subtypes that usually are fairly obvious within a few weeks or a couple of months of presentation. Occasionally patients with systemic onset may graduate into polyarticular, or oligoarticular may turn into polyarticular. That can happen. But in general we divide it into three subtypes; systemic onset.

The patients generally feel pretty well, even with tremendous synovitis of the knee. It’s not going to be hot like you would think it would be when you examine it. A little bit warm, non-tender. You move it around, the patient - even a little baby - won’t complain. They are running around, very active. It’s quite a bit different from a patient with polyarticular disease or certainly systemic onset where they are quite ill. These patients may limp a little bit in the morning, and as the day goes on they sort of feel a little better and run around. Otherwise they feel pretty good, their appetite is good. One of the only important extraarticular manifestations.

Systemic onset is the most severe form, accounting for about 20%. Not only is it the most severe form, it is also the most difficult to diagnose, especially if you don’t see one of the two characteristic features. If the child just has fever you certainly have to worry about infection, malignancies, and other things that would be associated with fever. This disease does occur at any age, including adults. I have seen patients diagnosed with systemic onset as old as in their 60’s. It’s a fairly even distribution up into young adults. Boys and girls are involved about equally, and the articular manifestations are often absent early on.

This is just a picture of the fever curve. In my hospital the temperatures are charted differently on different floors, which … I don’t understand that. I think they should use the same forms throughout the hospital, but they don’t. I like to see the graph, especially on a pediatric floor, I think that’s probably a good idea. I think most infectious disease people would also like to see a graph. The classic temperature pattern is that of an intermittent fever. And what you see is this temperature drops down pretty regularly to normal. It’s usually in the early morning hours and then the fever spikes in the late afternoon, evening, and some patients can have two spikes in a day and that’s what you are seeing here. In the late morning and then in the evening again. That’s what you are looking for.

The extraarticular manifestations of JRA do vary with the subtype. As I mentioned, the skin rash is associated with systemic onset. The eye involvement, chronic uveitis, is pretty much found in the oligoarticular patients. Occasionally it is found in polyarticular. I don’t think there are many reports in the systemic onset. The heart, basically with severe polyarthritis or systemic onset, you can get pericarditis or effusion, rarely a myocarditis. The lungs, again pleuritis, rarely fibrosis. The liver involvement; patients with systemic onset or very active polyarticular disease may have a mild hepatitis. The patient with systemic onset may even have hepatomegaly and therefore the patient’s often worked up for various malignancies. But also if you are going to use salicylates, children, like adults.

This is just showing you a picture of what happens to a patient with chronic uveitis. What an ophthalmologist sees, if they use a slit lamp, you look in the bottom of the anterior chamber and you see just a collection of inflammatory cells and that’s what they are looking for. Very very subtle. There is going to be no pain in the eye, no redness and again it occurs chronically. By the time the child notices symptoms they usually have lost quite a bit of vision. What’s happened in this child is that they’ve developed what they call synechiae, which is tenting of the iris due to chronic inflammation and scarring. Most of these patients, because of adequate screening, do pretty well if they get it with topical steroids. There are still some patients who don’t respond well and topical steroids can cause cataract formation, which can be treated surgically but it’s still a complication. This is a picture of a young child. I remember this child. He was not very steroid responsive.

Erythema marginatum. This is a boy with rheumatic fever and the rash generally occurs on the trunk. What you see is these kind of scalloped continuous lesions that never completely form a circle. They go about three-quarters of a circle, or whatever, and it’s not painful, not itchy, generally occurring after the initial infection. Usually after the carditis. If you see this rash, like the rash of Lyme disease, nothing else …it’s pretty distinctive and it makes your diagnosis. Rheumatologists almost have to be closet dermatologists because our diseases, some of the diseases that have skin manifestations, that’s more helpful than anything else, any of the lab tests.

Another thing is the hypermobility syndrome. This is one of the most common things that pediatric rheumatologists see. Because of the hypermobility, the patients often have articular symptoms, pain. May even have small effusions in their knees on exam. These patients may be like the Ehlers-Danlos or Marfan’s where they don’t have the complete expression of the disease but they do have lax connective tissue disease.

The management of a patient with arthritis; this is sort of my four pillars, if you will. It’s patient and family education. The patient has to know about the disease. If you have a young child then it’s much more important to educate the family to understand what to expect, when they should be concerned, when they should call you. Otherwise you’ll have a patient or family that has never called you when it’s important, or else they are calling you for every little thing.

The drugs are very similar to adults. There are some differences. Salicylates: how many of you have more than two patients in your practice on high dose aspirin for antiinflammatory treatment? That’s what I expected. I have one patient. And it’s someone that I tried a bunch of other medications on, like Naprosyn and Indocin and he developed edema, hypertension and finally on his own he just started taking a lot of aspirin and it worked. So he’s the only one I’ve kept on them. I think salicylates are great. In children, compliance is going to be a problem, even though aspirin does come as a liquid, and also the concern of Reye’s syndrome even though it’s very rare and it can be prevented with certain precautions. Parents just aren’t going to go for it.

The patient that doesn’t respond, you can use slow-acting antirheumatic drugs or sometimes called disease-modifying drugs. I think certainly even NSAID’s can be included in that for oligoarticular patients. These medications, some of them, do really modify the disease, although in children it is not nearly as well documented. Gold salts, almost similar to adult rheumatoid arthritis. I don’t think there is a child in the Philadelphia area that is getting gold salts.

Immunosuppressive agents: I think methotrexate has really made a big difference in these patients. It helps a lot. It helps keep kids off steroids or reduce the dose, I think it prevents damage, and if a child responds and can tolerate it, it’s a good drug. Actually, children seem to require higher doses. It’s not unusual to see a child on 20 or 30 mg of methotrexate. I’m not exactly sure why. Maybe it’s the way the liver affects the drug, I don’t know. But it’s not unusual to see a small child on higher doses than you certainly would expect. Azathioprine can be used in a patient who otherwise can’t take or does not respond to methotrexate. I think it’s something that pediatricians would feel a little uncomfortable using because of it’s long term toxicity. Cyclophosphamide is an option. I would certainly not use it regularly. Cyclosporine is something that has been used and I think that with methotrexate or even alone it’s a good steroid-sparing agent.