18-Year Study Shows Inconsistencies in Treating, Classifying JIA

Jeff Craven

February 15, 2022

"Children are not little adults" is a common refrain in pediatric medicine, but when it comes to a condition like juvenile idiopathic arthritis (JIA), rheumatologists might be better off treating pediatric and adult rheumatic disease more similarly.

Dr Dawn Wahezi

A recent study published in Arthritis Care & Research followed children diagnosed with JIA for 18 years. Although not the first long-term study to examine children with JIA, it is unique in that it took place "during a time where biologic DMARDs [disease-modifying antirheumatic drugs] were emerging as a fundamental therapy in the management of children with JIA," said Dawn M. Wahezi, MD, chief of the division of pediatric rheumatology at the Children's Hospital at Montefiore in New York City, who was not involved with the study.

Additionally, the study highlights the International League of Associations for Rheumatology (ILAR) consensus-based classification criteria as an imperfect method to categorize patients with JIA.

Mia Glerup, MD, PhD, of the department of pediatrics at Aarhus University Hospital in Aarhus, Denmark, and colleagues prospectively analyzed 373 patients from Denmark, Norway, Sweden, and Finland with new-onset JIA between 1997 and 2000 and evaluated them at baseline, 8 years, and 18 years. At each visit, the researchers collected data on demographics, disease activity, ILAR category, treatment, and blood samples.

Patients in the cohort were mostly girls (66.7%) with a median age of 5.9 years at onset. Approximately one third (34.8%) of patients were antinuclear antibody (ANA) positive and 21.6% were HLA-B27 positive. The most common JIA categories at baseline were persistent oligoarthritis (53.9%), polyarticular rheumatoid factor (RF) negative (21.1%), and undifferentiated arthritis (10.2%).

Glerup and colleagues found that the proportion of patients not receiving DMARDs declined from 73.2% at baseline to 59.7% at 8 years, and then rose again to 70% at 18 years (risk ratio, 1.3; P = .003). The group of 103 patients who used conventional DMARDs (cDMARDs) either as monotherapy or in combination with a biologic DMARD (bDMARD) at 8 years dwindled to 44 (42.7%) at 18 years (RR, 0.4; P < .001), whereas 32 of 52 patients (61.5%) using bDMARDs at 8 years were still taking them at 18 years (RR, 0.6; P = .02). Across the whole study, 14.7% of patients never received any JIA treatment, and 33 of 85 patients (38.8%) on continuous DMARDs developed uveitis during the study period.

Overall, 62.7% of patients received DMARDs at least once, including 89.7% with polyarticular RF negative, 77.3% with oligoarticular extended, 76.9% with systemic, 75.7% with juvenile enthesitis-related arthritis (ERA), 66.7% with polyarticular RF-positive, 65.2% with juvenile psoriatic arthritis (JPsA), 58.9% with undifferentiated JIA, and 27.6% of patients with persistent oligoarticular disease.

The median number of active joints dropped from 3 (range, 1-30) at baseline to 0 at 8 years (range, 0-13), whereas the median cumulative number of affected joints was rose from 3 at baseline (range, 1-30) to 6 at 8 years (range, 1-41). At last follow-up, the median number of active joints was 0 (range, 0-5) and median cumulative number of affected joints was 7 (range, 1-47). The percentage of patients in remission barely changed from 52% at 8 years to 51% at 18.

Some patients also changed ILAR categories during the study period, with 7% shifting between baseline and 8 years, and 11% shifting between 8-year and 18-year follow-up. Compared with baseline, by the 18-year follow-up time point there was a significant decrease in the number of patients categorized as oligoarticular (230 vs 197 patients; P = .02), a significant increase in patients in the psoriatic ILAR category (8 vs 28 patients; P < .001), and a nonsignificant increase in the number of patients in the undifferentiated category (45 vs 63 patients; P = .06).

"Almost half of the changes in the distribution between the ILAR categories were caused by updated information on heredity in a first-degree relative obtained at the follow-up visits," Glerup and colleagues write.

The results of the long-term study show that patients are "likely to remain in remission — with the converse also evident, as patients still with evidence of disease activity at 8 years after disease onset were more likely to have refractory disease," Wahezi said.

Dr Lisa Imundo

Commenting on the study's findings, Lisa F. Imundo, MD, director of adolescent rheumatology at Columbia University Medical Center in New York City, said they are "great news to be able to give parents of young kids with arthritis." However, she questioned whether the results are generalizable to populations of patients "who are in the worst prognostic group."

For example, a substantial proportion of patients were classified under the oligoarticular category. "That's already a group that we know from experience tends to have a better outcome than some of the other groups of JIA," she said.

"That kind of weaves its way through the whole study, because then they show a lot of patients have come off their medication. Patients who had more severe disease in more joints would be less likely, I think, to just stop their medication and stop going to doctors," Imundo explained.

Although the study is valuable for its long-term follow-up, there is also a question of generalizability across a more diverse ethnic and racial group. The authors do not elaborate on the racial breakdown of their patients, Imundo said, "so we're going to have to assume that the vast majority are going to [have] Caucasian Nordic ethnic background, and that goes along with them having this high percentage of HLA-B27 positivity, which is a gene that's more prevalent in northern European populations."

Dr Jonathan Hausmann

Jonathan Hausmann, MD, a pediatric and adult rheumatologist at Boston Children's Hospital, Boston, Massachusetts, told Medscape Medical News that he believes the overall conclusions from the study — that JIA persists over time and that ILAR classification is a somewhat imprecise measure of assessing JIA types in children — would be generalizable to other groups.

However, long-term registries evaluating JIA in more diverse populations, such as the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry, could confirm these results, said Hausmann, who is a registry informatics associate with CARRA and was not associated with the research.

Long-Term Management of JIA

In an accompanying editorial, Jaime Guzman, MD, MSc, and Ross E. Petty, MD, PhD, of British Columbia Children's Hospital and the University of British Columbia, Vancouver, Canada, said a rheumatologist's interpretation of the study would be tied to what they learned about children with arthritis in medical school. They would see the glass as "half full" if children who achieved remission stayed in remission if they learned that a child might end up outgrowing JIA but potentially develop lifelong disability, whereas others may focus on the outcome of approximately half of patients not achieving remission.

"When I was going through medical school, I remember learning that JIA is a disease of children, and typically, they outgrow it as they become adults," Hausmann said. "I think this study and many other studies have shown that that's actually not the case — that in fact, it may be a majority of kids continue having active disease even through adulthood."

If a rheumatologist knows JIA is likely to continue into adulthood, "that's huge," Hausmann said. "That means when we first diagnose patients with JIA as kids, we need to set expectations with the families that this may not just go away; this may be something that could be more lifelong."

Education on the part of the patient, their parents, and their clinician on the expected trajectory of the disease is critical so that children can continue their own care as they transition to adulthood, Hausmann explained. "The earlier the kids develop the skills to discuss their medicines, their side effects, the better they'll be able to transition to adult medicine," he said.

For the patients who go into remission and stay in remission, the message is also important. "To have the reassurance that a lot of those kids won't be having active joint symptoms or need to be on medication, that's a huge positive message that can get out there, so I think that's great," Imundo said.

Time to Move on From ILAR Classification?

Another big takeaway from the study was how patients' ILAR classification changed across the 18-year follow-up. First proposed in 1995, the JIA ILAR classification has been revised several times for clarification purposes. In its current form, the ILAR classification considers a patient's history when categorizing JIA types but also includes factors such as immediate family history. This system of assessing JIA has been criticized and there are initiatives to create a new JIA classification system to replace it.

"The ILAR criteria were designed to classify patients 6 months after disease onset in an attempt to find some commonality in clinical phenotypes, prognosis, and suggested management," Wahezi said. "While there continues to be debate as to whether we can improve our classification of JIA patients, it is not surprising that phenotypes may evolve over time as new clinical features develop. As pediatric rheumatologists, we are well accustomed to having to modify management plans as children manifest with new clinical features over time."

Although the percentage of patients who switched ILAR classifications over the study period was "much higher" than she thought, Imundo said it was the reasons provided in the study that seemed odd to her. "The classification scheme relies on your family history, like someone else in your family now has psoriasis, so your arthritis classification changes," she explained.

"We want to head toward a much more unified classification scheme, a simpler one. We now understand that some of the diseases that we see in pediatrics are really the equivalent or same disease in adults," she said.

"Most of the pediatric categories of JIA have distinct adult correlates," Hausmann agreed. RF-positive polyarthritis in children and rheumatoid arthritis in adults are correlated, as are systemic JIA and adult-onset Still's disease, he explained. "That has been borne out also by genetic susceptibility studies that the genetic predispositions to systemic arthritis in children is the same as the genetic predisposition to adult-onset Still's disease in adults. By and large, there are a lot of similarities between the two.

"I think we need to incorporate some of that knowledge in better classifying kids with JIA so that we can find the best treatments and the best outcomes, and we can provide information to families about the expected course of the disease over time so that can inform our discussions."

Some pediatric rheumatologists accept the classification system is flawed, but not all concur with the degree to which these problems impact patient care. "While the ILAR classification criteria may be subject to criticism, it does provide general context and prognostic implications for patients and families," Wahezi said.

"The medicines certainly are very similar across the JIA categories, so the implications are not as broad" when classification changes," Hausmann said. "But it certainly shows that there are things that we still don't know. I think classification is actually pretty important because it might give you a sense of how persistent the disease will be."

Imundo said the ILAR classification's "time is limited," and rheumatologists may soon need to adopt a new way of classifying children with rheumatic disease — "a more data-driven, genetics-driven scheme."

"These categories are so imperfect, and the patients are changing. I feel like that says to me, let's find something that's more predictive that really helps us a little better than what we have now," she said.

The study had no specific funding. The authors of the study and the editorial have disclosed no relevant financial relationships. Hausmann reports receiving salary support from CARRA. Imundo and Wahezi have disclosed no relevant financial relationships.

Arthritis Care Res. Published online January 10, 2022. Abstract, Editorial

Jeff Craven is an independent journalist living in Wilmington, Delaware.

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