The panelists discuss the prevalence of juvenile idiopathic arthritis (JIA) and review key clinical characteristics of the JIA subtypes.

       Donald Goldsmith, MD: Juvenile idiopathic arthritis (JIA) is a group of heterogeneous disorders characterized by arthritis that lasts for six weeks or longer with onset before the age of 16 years.

       Over the years, several different classification criteria have been used. The International League of Associations for Rheumatology (ILAR) has provided the most recent classification system.¹ Their aim was to bridge the nomenclature heterogeneity and the differences between the European and North American criteria. In doing this, more homogeneous groups of children are identified and this will advance research on the cause, pathogenesis, and epidemiology of the disease. This will also help with the interpretation of outcome studies.
       The term juvenile idiopathic arthritis is now the preferred terminology, replacing juvenile rheumatoid arthritis or juvenile chronic arthritis. The new ILAR classification includes seven categories based on features that present during the first six months of illness.
       This classification still needs validation and clearly has restrictions that are intrinsic to any system that is founded primarily on clinical criteria. Therefore, it is likely that continued modifications will be needed as new information about the pathogenesis of JIA emerges.
       Study results are varied but the current estimate is that JIA occurs in 115 to 130 per 100,000 children in the United States. However, many feel that this estimate is an under-representation of the number of patients with JIA in the U.S.
       Janalee Taylor, MSN, RN, CNP: The general mortality rate for JIA is higher than that of the general population. However, most of the mortality related to JIA is within the systemic disease subtype.
       Dr. Goldsmith: In the early 90s, a seminal discussion by Wallace and Levinson alerted the pediatric rheumatology community that the prognosis of JIA was not as good as previously thought and that a large number of children continued to have active disease into adulthood.² This was a sea change concerning our concepts of JIA and gradually changed the approach to therapy over the next several years.
       Studies show that approximately 50 percent of children with JIA — and this is greatly dependent upon the variety of JIA that a child has — will continue to have active arthritis into adulthood. Those are older numbers, however, and we believe these percentages will decrease with the increased use of newer therapeutic agents.
       Daniel Lovell, MD: Juvenile idiopathic arthritis is really one of the more common chronic diseases in children. It rates up there in frequency close to cystic fibrosis. It is far more common than muscular dystrophy. There is a common public misperception that arthritis does not exist in children. In point of fact, it is the most common rheumatic disease in children.³
       Taylor: You alluded to it, Dr. Goldsmith. After having been in the field for so many years, we have seen different generations of treatment. Now, probably for the first time, we are entering an era of treatment when the potential to change the true outcome of the disease lies before us. There were eras of aspirin and nonsteroidal antinflammtory drugs (NSAIDs). Then we entered the era of gold and corticocosteroids, and then methotrexate. Now we have the era of biologics.
       The potential ahead of us is much different as we carry on this conversation in 2008 than it would have been even 10 years ago.

Recognizing The Clinical Signs Of Oligoarticular JIA And Polyarticular JIA
       Dr. Goldsmith: The current ILAR classification system for JIA includes seven categories. The first category is oligoarticular JIA. This is a group of children who clinically present with four or fewer affected joints. It is a younger age group, with the most common age of presentation being from ages 2 to 4. Oligoarticular JIA most often affects females. These children have very few systemic symptoms and usually function quite well aside from their articular disease. However, this group has the highest prevalence of one of the most common and worrisome extraarticular manifestations, the development of uveitis.
       The most commonly involved joints are the knee and the ankle, with the knee being the most affected joint at presentation. Patients may have a persistent oligoarticular course or some may have an extended oligoarticular course in which children develop arthritis in more than four joints six months after the initial onset. This group represents about 40 to 50 percent of the initial oligoarticular group.
       With regard to children who will develop the extended oligoarticular variety of JIA, predictors include: the development of earlier changes in upper extremity joints such as the wrist or small joints of the hand; an elevated ESR rate and/or C-reactive protein (CRP); and the presence of three or four affected joints at onset. Within 18 months to two years, there is reasonable predictability as to which patients will develop extended disease.
       Dr. Lovell: This highlights the fact that children can start out apparently having one subtype of JIA and then can evolve over time to having a different subtype. You need to keep an open mind as to how a child’s symptoms and signs evolve over time so you can more accurately assess the need for treatment.
       Dr. Goldsmith: The second and third groups, as defined by ILAR, include the polyarticular JIA subtypes, which are divided into rheumatoid factor negative and rheumatoid factor positive polyarthritis. By definition, five or more joints are involved within the first six months of disease.
       The rheumatoid factor negative subgroup is predominantly female. These patients most often present at two age peaks, 2-4 years and 6-12 years of age. However, there may be some heterogeneity within this group with some children having asymmetrical polyarthritis and a higher frequency of a positive ANA test. At presentation, symmetrical large and small joints are most often affected. It is not uncommon for cervical spine changes to occur and temporomandibular joint (TMJ) involvement may also develop. These children also have a 30 to 40 percent chance of having a positive antinuclear antibody (ANA), and the ESR is usually moderately elevated (40 to 60 mm/h).
       Taylor: Dr. Goldsmith, you talked about possible cervical spine involvement in patients with polyarticular JIA. (It can also occur in patients with systemic onset JIA.) These patients may need surgeries for JIArelated issues or, more commonly, issues unrelated to JIA (e.g. appendicitis, ovarian cyst). In these cases, we find it helpful to obtain cervical spine films to look for atlantoaxial instability or cervical fusion prior to intubation and anesthesia. In addition, limitation of the TMJs may make intubation more difficult.
       Dr. Goldsmith: Rheumatoid factor positive polyarticular JIA closely resembles adult rheumatoid factor positive rheumatoid arthritis and usually affects adolescent females. In addition to the development of symmetric arthritis in small and large joints, these children may develop typical rheumatoid nodules. The ESR is most often quite elevated. Rheumatoid factor positive polyarticular JIA is more likely to require early aggressive medical therapy so anticipatory discussions with the patient and his or her family are needed.
       Both rheumatoid factor positive and negative polyarticular JIA subgroups may also develop uveitis but do so at a lower frequency than those with oligoarticular JIA. We will revisit the topic of uveitis later in the discussion. Are there any other thoughts on the polyarticular groups?
       Dr. Lovell: One of the characteristics that very obvi- ously distinguishes JIA from RA in adults is that this group of rheumatoid factor positive polyarticular patients represents about 10 percent of the overall JIA population. Accordingly, anywhere from 90 to 95 percent of JIA patients are going to be rheumatoid factor negative. This is in contrast to adults as the vast majority of adults with RA, at least 80 percent, are rheumatoid factor positive. A negative rheumatoid factor in a child with arthritis certainly does not eliminate JIA as a consideration.

A Closer Look At Systemic Onset JIA
       Dr. Goldsmith: The fourth group is systemic onset JIA. This subtype stands out as a unique clinical and pathologic entity. Recent findings indicate that systemic onset JIA is likely to be a disorder of the innate immune system rather than the adaptive immune system.⁴ It is one of the few rheumatic disorders with a relatively equal sex prevalence although there is a very slight male predilection. This subtype is characterized by significant high spiking fevers, a characteristic rash, serositis, hepatosplenomegaly and lymphadenopathy. There is a prominent leukocytosis, thrombocytosis and the rather rapid development of significant anemia. The ESR and CRP are markedly elevated. Both rheumatoid factor and ANA tests are classically negative.
       The articular pattern which emerges — and this sometimes occurs several months after the onset of systemic symptoms — is most often polyarticular and symmetrical with both large joints (such as knees, elbows or wrists) as well as small joints of the hands and feet being involved. However, there is also a small group of patients who demonstrate an oligoarticular pattern. This pattern may be a positive prognostic sign forthese particular children with fewer developing progressive arthritis or prolonged systemic symptoms.        Children with systemic-onset JIA may also be predisposed to develop macrophage activation syndrome (MAS), a potentially life-threatening disorder that is seemingly mediated by a “cytokine storm,” which is preceded by NK and cytotoxic T-cells that are most often responding to a viral infection. This cytokine excess leads to rapid macrophage ingestion of many blood elements and a DIC-like picture. When a child with systemic JIA suddenly becomes persistently febrile, increasingly irritable or lethargic, and shows a profound drop in white blood cells (WBCs) or platelets, and ESR, MAS should be considered as the likely diagnosis. Early recognition of MAS is critical so medical intervention may be successful. When MAS occurs as a result of other disorders such as malignancy, it is most often referred to as HLH (hemophagocytic lymphohistiocytosis).
       Dr. Lovell: I completely agree with your comments about the seriousness of systemic JIA. Even though these patients represent only about 10 to 15 percent of the overall cases of JIA, they do represent about 80 percent of the patients who die as a result of complications of their systemic JIA.⁵ The vast majority of the time, it is due to MAS.
       When it comes to patients with systemic JIA, part of the treatment is maintaining a high index of suspicion and emphasizing open communication with the family so if a child gets symptoms suggestive of MAS, the child can be seen and treated very early in the disease process. That is the key to having better outcomes for those patients who unfortunately often do develop MAS.
       Taylor: I would also echo the high index of suspicion for the MAS in patients with systemic onset JIA. We should also note that the diagnostic criteria for MAS and HLH are not the same. We do not have welldefined diagnostic criteria as of yet for MAS. Often when patients present with symptoms — especially when they are seen by other subspecialties — and they do not meet the classification criteria for HLH, then MAS is often not diagnosed or suspected.
       Dr. Lovell: Another unique aspect of JIA is the presence of chronic inflammatory eye disease. This is known by a variety of names but is most commonly called uveitis. This is inflammation in the front part of the eye. It is much more common, as Dr. Goldsmith said, in children with oligoarticular subtypes of disease but it can be seen in other JIA subtypes. The vast majority of the time, in well over 80 percent of the cases, there are no associated symptoms so it is routine in the care of these children to have ophthalmologists do eye exams on a regular basis to provide for early detection of the uveitis that may be present.
       The American Academy of Pediatrics (AAP) has developed guidelines for the frequency of slit lamp exams.⁶ The exams are most frequent in the children who have oligoarticular disease and least frequent in the patients with systemic JIA. However, it is a critical part of their treatment. If you wait until there are changes on the ophthalmology exam or until the child complains of symptoms related to uveitis, that is often very late in the disease course and those symptoms are a consequence of serious eye complication. Eye screening with a slit lamp exam by an ophthalmologist or a trained, capable optometrist is critical as part of the treatment for these children.

A Guide To Enthesitis-Related JIA
       Dr. Goldsmith: The next subtype is enthesitis-related JIA. The ILAR inclusion of this group is a major addition to the previous classification systems. This subtype also encompasses arthritis associated with inflammatory bowel disease, ankylosing spondylitis and undifferentiated spondyloarthropathy. It is most common in males older than 8 years of age and there is usually a history of a related illness in family members.
       As the subtype name infers, the patient not only has arthritis but enthesitis as well. Enthesitis is inflammation located at insertion sites of tendons, ligaments or fascia to bone. Enthesitis primarily occurs at the insertion of the Achilles tendon, insertions of the plantar fascia and also at the 2, 6 and 10 o’clock positions around the patella.
       Involved joints are primarily lower extremity joints, most often the knee and the ankle. The first metatarsophalangeal (MPJ) and midtarsal joints may also be affected. It often takes years for sacroiliac and lumbosacral spine changes to develop. This group of patients is most often HLA-B27 positive and they are ANA and rheumatoid factor negative.
       Uveitis also occurs in enthesitis-related arthritis. However, in this group, uveitis is acute in onset. These patients present with photophobia (red eye) and most often have unilateral and ocular discomfort whereas the uveitis associated with oligoarticular JIA is customarily asymptomatic.
       This group often responds to non-steroidal antiinflammatory drugs (NSAIDs) and we will talk about this treatment later in the discussion.

A Pertinent Overview Of Psoriatic JIA And Undifferentiated JIA
       Dr. Goldsmith: The sixth subtype, psoriatic JIA, was also added to the ILAR classification system. This can be particularly difficult to identify in children without clinically recognized psoriasis when active arthritis is first identified. Accordingly, the clinician needs to have a high index of suspicion based on certain historical points and physical findings.
       This subgroup usually presents in mid-childhood. Most often, clinicians will see asymmetric polyarthritis involving the small joints of the hands, knees and ankles. There is often a subacute presentation. A characteristic finding is a sausage digit with swelling over the entire digit, spreading beyond the joint margins and likely involving the surrounding tendon sheath.
       Another clue for this diagnosis, prior to any noticeable psoriasis, is the presence of nail pits. More than two pits on any individual is suspicious. These are best identified at the bedside with an ophthalmoscope using a positive lens to identify the affected nail changes.
       There is often a positive family history of psoriasis. Additionally, these children may futher mimic the oligoarticular JIA group in that chronic and relatively asymptomatic uveitis may develop. The ANA is also frequently positive.
       Dr. Lovell: One of the challenges with psoriatic arthritis is that the arthritis can develop and be present for months or years before the psoriasis manifests itself in the child. Alternatively, the psoriasis can be so mild that if it occurs prior to the arthritis presentation, it could be completely resolved by the time you see the child with arthritis. Family history becomes key in the continued observation of the child.
       Dr. Goldsmith: The remaining subtype is undifferentiated arthritis. Children with chronic arthritis who do not fulfill criteria for any of the other subgroups or fulfill criteria for more than one of the other subgroups are considered to have undifferentiated arthritis. Hopefully, the number of children in this category will grow smaller and vanish. Based on the pace of progress over the last several years, this seems not just possible but quite likely.