Current and Future Treatment of Childhood and Adolescent Arthritis

 Video Presentation

1. Introduction
2. Oligoarthritis
3. Extended oligoarthritis
4. Polyarthritis - rheumatoid factor negative
5. Polyarthritis - rheumatoid factor positive
6. Systemic onset arthritis
7. Arthritis associated with psoriasis
8. Arthritis associated with enthesitis
9. Arthritis associated with infection, or reactive arthritis

 

Introduction

Hi. I am Dr. Thomas Lehman, Chief of the Division of Pediatric Rheumatology at the Hospital for Special Surgery and Professor of Pediatrics at Cornell University Medical Center. What we are going to talk about today is the state-of-the-art in the treatment of children with juvenile onset arthritis.

I would like to start by showing you this picture of a 32-year-old white female who came to me a long time ago, while I was practicing in the Navy, to tell me that pediatric rheumatologists were unnecessary. She developed arthritis as a small child and was told that she needed to take aspirin. She had an upset stomach after the first few aspirin and rejected all further therapy. More than 20 years later, she wanted to show me how well she looked. I think you would agree she doesn't look like a 32-year-old.

And in fact, when you look at her hands, you see that those shouldn't be the hands of a 32-year-old young lady either. We have got to be able to do better with it than this and, with treatment and proper care, we certainly can.

This picture shows me standing next to one of my patients who started out with JRA when he was 9. He had severe active disease. He has been under my care almost the entire time. As you can see, he is taller than I am. He is able to go about all his normal things and, in fact, he now works as a news reporter for one of the local television stations.

When you look at his x-rays, and this is his wrist, you see that despite the fact that we have been able to keep him a fully functional individual, he has had bony progression over time. We have changed the functional outcome of the disease, but not bony progression.

So when you are confronted with a group of young children such as this in our clinic, you have to ask yourself "What are we going to do to get them the best possible outcome in the future?" We need to make sure they have a good functional outcome, but for long term well-being, we want to make sure they have a good bony outcome as well.

In the 21st century, we are having a revolution in pediatric rheumatology. There is no longer a disease "juvenile rheumatoid arthritis." Instead, we are calling it "childhood onset arthritis." and "juvenile idiopathic arthritis." We have new names. We have new criteria for the diagnosis, and we have a new approach. Is this important? What does it really mean?

New names: juvenile inflammatory or juvenile idiopathic arthritis have at least eight subtypes, not the three that they traditionally teach in the textbooks for juvenile arthritis. There is oligoarthritis, extended oligoarthritis, polyarthritis rheumatoid factor negative polyarthritis, rheumatoid factor positive polyarthritis, systemic onset arthritis, arthritis associated with psoriasis, arthritis associated with enthesitis, and arthritis associated with infection, or reactive arthritis. Probably there are going to be more subtypes as well.

In addition, it's important to realize that not all childhood arthritis is in fact juvenile idiopathic arthritis. Some forms, such as reactive arthritis, are independent of this. Is this just naming or is it important? Why should you care what you call it? The answer is to understand that these are, in fact, different diseases with a different prognosis and a different best therapy. We have to be talking about the same thing in order to understand what we are doing.

Imagine that you are a physician when penicillin first came on the market. We have an objective definition of meningitis. It is any child with more than 10 white cells in his cerebral spinal fluid, and we are determined to test whether or not penicillin works in the treatment of meningitis.

One physician in this study has an epidemic of aseptic meningitis and the penicillin makes no difference and everybody does well. Another physician is treating a number of children with tubercular meningitis. They meet the same criteria but penicillin makes no difference and everybody does poorly. The third physician is treating a group of children who have influenza meningitis, which is sensitive to penicillin. For this group, the group that gets penicillin does extremely well, while the group that does not get penicillin does poorly. And it makes a very big difference; but because we only have a single definition of meningitis, they will have to pool their data as to whether or not penicillin works, and you have nonsense.

There are different causes, different etiologies, and different best treatments for the different sub-groups of children with arthritis. Unless we properly classify these children, we are not going to get meaningful information. Almost every paper you read today about juvenile rheumatoid arthritis groups all the patients together, and the data are unreliable.

Oligoarthritis

I would like to start by talking about the different sub-groups. The first group to talk about is typical oligoarthritis seen in a young child with fewer than four joints involved during the first six months of disease. Characteristically, it is large joints, knees, and ankles almost exclusively,rarely wrists, rarely elbows. These children never start with finger involvement; they never start with hip involvement. If it is the hips or the fingers, this is not going to turn out to be typical oligoarticular arthritis.

Usually these children are one to five years of age. It is far more frequent in girls than boys. They are often ANA positive, they often have eye disease, and they need to be screened frequently for uveitis. One important thing: do not accept this diagnosis in somebody over the age of 9. There is oligoarthritis over the age of 9, but it is not oligo JIA. It is most often associated arthritis or another type of arthritis.

True oligoarthritis is the type of arthritis that children do usually grow out of. The normal side effects of this arthritis are either eye disease, which can have permanent residua and even lead to blindness if not properly detected and treated, and leg length discrepancy. Aggressive therapy is not usually indicated for these children.

A few personal rules in evaluating children with oligoarthritis: these are my own personal rules, they are not without possible exception, and they are not the rules in the textbook, but they are important to understand. First of all, children with typical oligoarthritis never have a hemoglobin of less than 11. They never have a sed rate greater than 40. The white count is never significantly elevated, the sed rate is never significantly elevated, and there is no fever and no rash. It is important to understand that this group is different. If any of these rules are violated, this is a child who is likely to go on to have extended disease and is likely to go on to have polyarthritis.

Why is this important? Imagine that you are the parent of the child and you go to the physician and he says your child has typical pauciarticular JRA or JIA and he is going to grow out of it. Time goes by, your child is getting worse, and the physician now says we have to use more aggressive therapy. Any natural parent says "Wait a minute, you told me my child was going to outgrow this. Why should I accept a therapy that has potentially severe side effects for a disease my child is going to grow out of?" The answer is that the physician mis-labeled this. If the physicians are careful, they don't get themselves into this trap to begin with, and then parent/physician understanding will do much better and they will have a much better relationship with parents and parents will advance the therapy as necessary.

Treatment for oligoarthritis is usually very simple. The normal nonsteroidal antiinflammatory drugs are almost invariably effective for these children. Intra-articular steroids may be helpful, and there is some reason to believe the more aggressive use of intra-articular steroids will prevent a significance incidence of leg length discrepancy. Of course, it won't be effective in every child. These children shouldn't need methotrexate. They should never need steroids except for intra-articular injections. They don't need other immunosuppressors. They never need the biologic meds. With almost no exceptions, they don't need steroids.

Extended oligoarthritis

The next group I would like to talk about is the children who do violate that rule. These are the ones that have extended oligoarthritis. Although they may have had four or fewer joints involved during the first six months of disease, over time they develop more joints. These children are at high risk to go on to having long lasting, permanent arthritis. They are not going to grow out of it. They need more aggressive therapy.

The most important thing here again -- start with the NSAIDs while you are evaluating these children. But as soon as you see that they are going to be a more difficult group, you want to start giving them aggressive therapy to modify the outcome of their disease. Plaquenil is helpful in this group; sulfasalazine is helpful in this group, but of course there is a very high incidence of allergic reactions. This needs to be done by a physician who is familiar with sulfasalazine. Methotrexate is also very effective for this group. 80 to 90% of this group will respond to one of these drugs and not need anything further. Those children who don't respond may need etanercept or other immunosuppressors, such as cyclosporin or azathioprine, or they may need one of the newer biologics that have become available, such as etanercept, if necessary. Oral steroids are virtually never necessary in this age group.

Polyarthritis - rheumatoid factor negative

This is a much more aggressive disease, again, -- more than four joints involved during the first six months of disease. The disease can occur any age group, it is not typically found in young children, but it may involve young children. Again, girls more often than boys. Typically, it is a subacute onset. It comes on over weeks. When somebody tells you they have polyarticular JRA with explosive onset, they are usually describing a child who had infection associated arthritis or one of the other arthritides, not true polyarticular JRA.

This group, again, should not have rash. They may have high sed rates. The white count and hemoglobin are highly variable. This is a chronic condition, and it needs to be aggressively treated. In contrast, the infection associated arthritis that it is often confused with may go away relatively quickly with only mild therapy. So make sure you know what you are talking about.

Rheumatoid factor negative polyarthritis is an area that is under construction as far as the nomenclature group is concerned. This is because we know many of these children have psoriasis-associated arthritis. However, because so many people think they might have psoriasis and are confused between the definitions of psoriasis and seborrhea, to be included as psoriasis-associated arthritis appropriately the nomenclature committee wants you to have doctor-diagnosed psoriasis.

On the other hand, if the patient or the family thinks there is a family history of psoriasis, you cannot be included as polyarthritis rheumatoid factor negative. You have to be put in the "under construction category". This needs to be worked out, but it doesn't matter from the physician's point of view. Caring for children with psoriatic arthritis and children with psoriasis associated arthritis, and children with rheumatoid factor negative polyarthritis all involve the same set of medications.

Treatment for this group emphasizes the nonsteroidal anti-inflammatory drugs and rapid movement forward to using hydroxychloroquine, methotrexate, sulfasalazine, etanercept and other immunosuppressives, as necessary.

Polyarthritis - rheumatoid factor positive

The rheumatoid factor positive polyarthritis group simply represents the early onset of adult type rheumatoid arthritis. It typically occurs in teenage girls, occasionally in boys. If you see a young child who is rheumatoid factor positive, this does not confirm the diagnosis of juvenile rheumatoid arthritis or childhood onset adult type rheumatoid arthritis.

Rheumatoid factor positivity under the age of 10 is more often associated with mixed connective tissue disease, hepatitis, bacterial endocarditis and other rheumatic, but not rheumatoid arthritis related, conditions. Again, watch out for these children that are rheumatoid factor positive, they tend to do poorly. They may be ANA positive. You have to watch out because they may have a low white count. This is not lupus. More often, this is Felty's syndrome.

The ANA in this rheumatoid factor positive group is not typically associated with the occurrence of eye disease or uveitis. Do also be aware there are definite reports of children who had typical JIA as a child who later on in life developed absolutely typical lupus. We think there is a shared genetic predisposition, but, in effect, two separate diseases are occurring in the same patient. It's rare but it is well described.

The rheumatoid factor positive patients need NSAIDs, sulfasalazine, and Plaquenil, methotrexate, etanercept and other biologics, relatively early. This is a bad disease that is going to cause progressive joint destruction over time. Everything you can do to alter the outcome is important and should be done at the beginning, before a lot of damage has accumulated. We have good medication preventing bony progression of disease. We cannot undo the bony progression except with surgical replacement.

Systemic onset arthritis

Systemic onset arthritis is a wholly separate entity. It has nothing to do with the other diseases that are called juvenile idiopathic arthritis or in the past were called juvenile rheumatoid arthritis. Instead of girls more often than boys, the division here is equal. It can occur at any age, but should include fever and the fever has to fall back to normal at least once each day.

The arthritis may not be obvious. Initially, there can be marked elevation of the white count and platelet count. I have seen white counts as high as 95,000 and platelet counts over a million in children who had definite systemic onset JIA. Here, unlike all the other forms, the arthritis may first appear in the hips. Watch out for children who have systemic onset JRA who have a low white count or a low platelet count or are in too much pain. The child with too much pain needs to be carefully evaluated for infection and carefully evaluated for leukemia, lymphoma or other neoplastic disease including neuroblastoma. Malignancies do sneak into every clinic every year. The big hints are either the white count is too low or the platelet count is too low or the patient is in too much pain.

Children with simple JIA are not crying on the table without being touched. Children with malignancies often are. The outcome of JIA with systemic onset is highly variable. Some of these children recover completely. Others, especially teenage boys, seem to be left with some mild wrist involvement and occasional rash with exertion, while other children have a very severe chronic destructive course and do poorly.

Treatment for systemic onset JIA has to be aggressive. You have to get these children under control and prevent progression and bony destruction of this disease. Nonsteroidal anti-inflammatory drugs are a first place to start. Plaquenil may be helpful. Sulfasalazine has been helpful for some groups. Many patients respond to methotrexate if none of the earlier drugs has worked.

Other immunosuppressives such as cyclosporin and azathioprine have been used. It is important to remember that none of these drugs work consistently. This is one of these situations in which the good news is that none of these drugs work more than a third of a time. We have five of them, so we ought to be able to find one that works. Etanercept works very well. Infliximab (Remicade) has been tried in some children, and we recently reported from the Hospital for Special Surgery in the Journal of Pediatrics good results with thalidomide therapy.

In the old days, there was talk about using combinations of the biologics, and this will need to be explored to see what we can to do get these children better. And there have been experiments with autologous bone marrow transplant. This worked very well when the first four children were done, and they had four miraculous successes. But when they went from 4 to 24 children, they had four deaths and they had backed off, but they are now restarting this very carefully. This should be done only in an experienced center and only as a last resort, but it is there as a last resort for these children who are doing poorly.

There are a number of new drugs that are coming on the market. The selective COX -2 inhibitors, such as Vioxx, Celebrex and now Bextra, have decreased GI irritation, but are not any more effective than the other nonsteroidal anti-inflammatory drugs in controlling the disease. If you have a child who is well controlled on a regular anti-inflammatory drug, there is no reason to switch over to a COX-2.

There is increasing experienced with leflunomide, increasing experiences with CellCept or methyl-thalamic acid, and there is some experience with doxycycline in the older children. It can't be used in children under the age of 10, because it will permanently stain their teeth. However, in the older children it has been repeatedly shown to be a good agent for the long term. If you put half of the group on doxycycline and half of the group on placebo and continue their other therapy the same, the group getting doxycycline will do better.

However, teenagers don't tolerated doxycycline well, although many take it for acne. When you add it to children for arthritis, you get complaints about stomach upset and photosensitivity. Only about a quarter of the children to whom I give doxycycline in the teenage years will stay on it, despite its benefit for acne, etc.

Other new drugs: Etanercept has been an extremely powerful agent in blocking tumor necrosis factor alpha by blocking the receptor, and we have had some extraordinarily dramatic outcomes in children receiving this. It doesn't work for every child every time, but it looks to be a very good drug for children who have failed first line therapy.

There is a risk of reduced efficacy over time. There is some thought about whether methotrexate needs to be used concurrently with etanercept to prevent the development of antibodies against etanercept, but this has not been a major problem. There are clearly studies showing that methotrexate plus etanercept is better than methotrexate alone. The use of etanercept versus etanercept plus methotrexate has not been clearly studied.

You do have to worry about the risk of increased infection, particularly with combinations of drugs, and we monitor these children carefully. We avoid the drugs if there is any sense that the children have or have recently been exposed to a serious infection. Be very concerned about chicken pox in the younger child here.

Other risks associated with etanercept include drug-induced lupus and possibly some clotting abnormalities. None of these has occurred with any significant frequency in children or adults, but they have certainly been noted. Runny nose or rhinorrhea, pain at the injection site, mild bruising, and occasional headache have all been reported for a child who is doing dramatically better on the drug. These are not significant side effects.

Other new drugs, include anakinra (Kineret), the IL-1 receptor agonist, has been used. DQE-7, which is going to be called adaluminab, has been used in some children in preliminary studies and appears to be a very effective drug. Adaluminab blocks tumor necrosis factor, while the IL-1 receptor agonist blocks IL-1. There have been some preliminary reports of an anecdotal nature out of Japan using IL-6 blockers to treat systemic onset JRA. Although these preliminary reports are favorable, they are based on extremely small numbers. Hard data other than conversational remarks has not been available to date.

Remicade is a direct antibody of the tumor necrosis factor alpha that has been used extensively in Crohn's disease. It has also been used extensively in adult rheumatoid arthritis. It requires repeated IV infusions. It has been used in children. Especially in the higher doses that have been tried in some children with systemic onset disease, it seems to be associated with a greatly increased risk of infection.

Why is it that we as doctors can't come up with good drugs to treat these children with arthritis and get rid of this problem? It is important to remember that arthritis is a chronic inflammatory response. If you looked at the body's response to an infection of any chronic nature and you look at the body's response to arthritis, they are the same. We can wipe out your arthritis, but when we do so, inadvertently we have wiped out your ability to fight infection as well. You can't wipe out the immune system, stop the arthritis, and leave the child vulnerable to infection. Because the responses are so coarsely linked, we haven't found a way to eliminate severe arthritis without risk for infection. It is a "Catch-22".

There are a number of new drugs you will hear about, such as glucosamine and chondroitin sulfate, that are being reported in the press. It is important to remember that glucosamine has been shown to have a mild beneficial effect in adults with osteoarthritis. However, no beneficial effect in rheumatoid arthritis or in children has ever been established. We don't have an accepted dose in childhood. Parents may ask you about it, and if they wish to give it we can't give them any real advice, except to say that in adults with osteoarthritis it appears safe but only minimally effective.

Chondroitin sulfate has been shown to increase the instance of stomach upset. There is probably no benefit in letting the parents give this to the children. Magnets have been shown not to work. You can give people black plastic discs that are not magnetized and you get the same response rate. Copper bracelets don't work. Fish oils, the Omega-3 fatty acids, have been extensively studied in the past. You have to take a tremendous number of these to get any significant benefit. It has been shown that you can fool the body for about three months, but by six months, the body is readjusted and you are right back to the same inflammatory state you were in before. There is no long-term benefit.

You hear about diets. It is quite true. No member of George Washington's army who ate a tomato is alive today. Nonetheless, all the diets have been studied. If you tell them that on a special diet they are going to get better, 30% of the patients getting no nightshades get better, but so did 30% of the people eating extra tomatoes, potatoes, mushrooms. It doesn't make a difference.

There are a number of other things that people hear about on the Internet that they are going to ask you about. None of these is being manufactured in facilities that are under any kind of supervision. There is no proof that any of these is safely made, contain the part they claim they contain, or are safe to give to children. Often when they analyze these things they are found to be contaminated with heavy metals and other things that none of us would want our children to have. They are best avoided.

Arthritis associated with psoriasis

Arthritis associated with psoriasis is an important thing to understand. Children do not need to have psoriasis to have the arthritis associated with psoriasis. This confuses everybody. What we are really trying to say is that this is the arthritis that follows the same pattern that is seen in people who have arthritis with clear-cut psoriasis. Furthermore, when these children are followed for 10 to 20 years, many of them, although they did not have psoriasis at the onset of their arthritis, do develop psoriasis later in life. That is how we know these two conditions are associated with each other. Look out for these cases; they often have a family history of psoriasis in a first degree relative. They may have dactylitis, which is a swollen finger or sausage digit. It can be an index finger, a little finger, a thumb. Often if you examine them carefully, the family comes in saying the child has jammed the finger or she stubbed her toe, but it has been three months and the child hasn't gotten better. "We don't know what to do, we think it's a tumor, we thought it was an injury." But when you evaluate these children carefully, you often find on the same side they have a toe that matches the finger, or a finger that matches the toe, where they are tender and swollen.

Look for nail pitting or other evidence of psoriasis in the child. Look carefully through that family history of psoriasis. Often these children are ANA positive and it is very important to recognize this; so that they do get eye disease. I have children seen sent to me after six or more months of hand surgeons worrying about what kind of tumor they have in the finger. Because they were worried about a tumor, they never thought to screen the child for ANA or to screen the child for the presence of eye disease. By the time they reach my care, they have significant eye disease.

Whenever you see a child with a sausage digit, make sure they are screened for eye disease. There is a high probability that they are going to go on to have psoriasis associated arthritis. The other thing that is important to understand is that often the original joint will respond very nicely to therapy and go away. But this disease comes back again. You need to keep monitoring these children. It may be six months, it may be six years before you see them back in your office, but they have a high probability of recurrence and needing to be treated again. Any number of joints may be involved in this group but often it is just a finger or toe at the beginning.

Why should we care about psoriasis-associated arthritis? It has a different etiology; it has different genetics; it has different best therapy; it has different prognosis. If you lump it in as just another type of JRA or JIA, you are going to confuse all of your data about what the long-term outcome is likely to be. This occurs is girls more often than boys. It can occur in any age group; although the dactylitis is most often small children, I have seen teenagers who thought it was recurrent athletic injury. Well, again, chronic and recurrent.

Treatment - nonsteroidal anti-inflammatory drugs may get you through the initial stages, but because we know this is progressively recurrent disease, often these children need sulfasalazine. If they are allergic to sulfa drugs, you may want to use hydroxychloroquine (Plaquenil). Many require methotrexate. Occasionally, cyclosporin is very good for this group a well. Etanercept has been very effective in this group. We will have to wait and see what the other biologics are able to do for them but, aggressively treated, this group does well. If you turn your back on this group, they often have recurrences and come back in with bad disease over a period of years.

Arthritis associated with enthesitis

The arthritis associated with enthesitis is another important group. The hallmark of enthesitis is tendon insertion inflammation. Therefore, the key thing when you are evaluating these children is not so much swollen joints, though they may have them, but periarticular pain, i.e., pain around the joint where the tendons insert. This is often mis-diagnosed as somebody who is clumsy, with recurrent sport injuries, frequent strains or sprains. Look for heel pain, Achilles tendon pain, for the child who has had recurrent things. Often these children have additional findings, like back stiffness and hip stiffness, but they don't think that is why they are in your office. They are complaining to you about their ankle. You have to ask them specifically about their back pain. Often, they will excuse it away and they actually even get angry when you ask them about other joints, because to them, this is just an injury that they want to get over and get on with their lives.

You need to show them the other findings and help them understand that they have a chronic disease. This typically occurs in teenagers, boys more often than girls, but there are plenty of girls. About half are HLA B-27 positive. That is greater than the normal population, which is 8%, but more than half are not B-27 positive. You do not need this marker to make the diagnosis.

Look for the other manifestations of the disease -- the heel pain, the wrist pain. They often deny they are there, but it is obvious on examination. This makes it easy to make the right diagnosis.

When you are evaluating these children, ask the parents if there is a family history of back pain. Often the fathers have back pain because they say "Oh it was an old athletic injury" or "Oh I was working on a car" or "I lifted something up." But frequently they have the same disease. You should question them carefully.

There is a mixed prognosis for this group. Watch out for the HLA B-27 positive boys. Some of them go on to get ankylosing spondylitis. This is a good example of some of the uncertainties we have in this field. When HLA B-27 was first discovered and we realized we had HLA B-27 positive teenage boys, we thought "Uh-oh you are all going to go on to get ankylosing spondylitis." Ten years later, many of these same boys were doing well. Over ten years, only about 25% of these children go on to get ankylosing spondylitis. Most of them seem to do well.

But, many of the people who look well ten years after diagnosis are now in their early 30s and 40s and are starting to have serious problems and change towards ankylosing spondylitis again. We don't know what the right number is, but now it looks like a significant number of the B-27 positive boys will go on to develop ankylosing spondylitis.

If there is just joint involvement on X-ray, be careful. This is a group that is going to need significant disease modifying therapy. Especially the group with an elevated sedimentation rate. The group with normal labs and normal sedimentation rate tends to do well. There are some chronic problems. But the group with a high sedimentation rate that is B-27 positive, chronic disease, may be recurrent, and it is probably early ankylosing spondylitis.

Treatment for this group: the nonsteroidal anti-inflammatory drugs are a good place to start. Sulfasalazine is extremely effective in this age group. Plaquenil may be effective. Methotrexate works well here. Etanercept works well here. We don't have much experience with the other biologics. Most of the patients get well with the drugs I mentioned already.

Of course, there are many other causes of childhood arthritis. I strongly criticized the definition of JIA and pointed out that we have many different diseases here. Imagine if we were to reverse things and I was to define adult onset rheumatoid arthritis as anybody with arthritis in one joint for more than three months or two or more joints for more than six weeks over sixteen years of age. Every adult rheumatologist would say "You're crazy; I have all these different diseases that cause arthritis in adults." Well, we have all the same diseases in childhood. Gout doesn't occur in childhood; I have never seen a convincing temporal arteritis in childhood. All of the other diseases that the adult rheumatologists take care of we can see in childhood. So, calling them all the same thing is just as silly as calling all of the adult diseases the same.

Arthritis associated with infection, or reactive arthritis

Arthritis associated with infection, or reactive arthritis is probably the most common cause of arthritis in childhood. It usually follows a viral infection. It can follow strep. It can also be associated with gonococcus and gonorrhea. It can also be associated with meningitis, not pneumococcal meningitis, but meningococcal meningitis. Children can also walk into your office with arthritis and turn out to have one of the vascular diseases. They can have lupus, scleroderma, dermatomyositis, systemic onset vasculitis, even Kawasaki's -- all of these diseases occur frequently in childhood.

Thank you.

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posted 7/14/2002