The Revolution and Evolution of Biologics for Juvenile Idiopathic Arthritis

In the last 20 years, therapeutic advances for the treatment of juvenile idiopathic arthritis have been rapid and significant. The advances have largely come in the form of biologic therapies, including injectable anti-tumor necrosis factor agents, interleukin-1 and interleukin-6 blockers and agents to block T-cell signaling. A class of oral janus kinase inhibitors are also being tested in children with juvenile idiopathic arthritis and may be poised to add another component to the armamentarium of physicians.

Most experts, including Daniel J. Lovell, MD, MPH, Joseph E. Levinson Endowed-chair of pediatric rheumatology, professor of pediatrics at the University of Cincinnati Medical Center, associate director of the Division of Rheumatology and chairman of the Pediatric Rheumatology Collaborative Study Group at Cincinnati Children’s Hospital, are encouraged by these developments.

“I have been taking care of these patients for 35 years, and I have far more options than I have ever had,” he told Healio Rheumatology. “In the last 5 [years] or 7 years, it has been a revolution in the treatment of this disease.”

For all of the success, these drugs come with some cost. Adverse event profiles in patients with juvenile idiopathic arthritis (JIA) point to risks of serious infection, increased incidence of blood or central nervous system disorders, and psoriasis. While long-term data exist for mainstays such as etanercept (Enbrel, Amgen), whether new players like canakinumab (Ilaris, Novartis), which gained FDA approval for systemic JIA in 2013, and tocilizumab (Actemera, Genetech), which gained FDA appproval for polyarticular forms of JIA in 2013 and systemic JIA in 2011, can demonstrate similar safety with longer follow-up remains to be seen.

For Timothy Beukelman, MD, MSCE, associate professor of pediatrics in the Division of Pediatric Rheumatology at the University of Alabama at Birmingham, there is another complication.

“It is important to understand that JIA is not one disease,” he said. “It is comprised of many diseases we lump into one group.”

That group is comprised of systematic JIA, oligoarthritis, polyarticular arthritis that can be rheumatoid factor negative or positive, psoriatic arthritis, enthesitis-related arthritis and undifferentiated arthritis.

Beukelman suggested there is more specified understanding of the differences between rheumatoid arthritis (RA) and various spondyloarthropathies in adults than there is in children.

“We are hoping to use the discoveries made in adults with arthritis to further understand the specific diseases in children,” Beukelman said. “The problem is that pharma does not develop drugs for JIA, so if we find a drug that works in RA or spondyloarthritis in adults, we use it to treat children. What we are trying to do is figure out which drugs are most effective in these different types of JIA.”

Treatments

Drugs in the anti-tumor necrosis factor (TNF) agent class that have been studied or approved in JIA include etanercept and adalimumab (Humira, AbbVie). Anakinra (Kineret, Swedish Orphan Biovitrum) is the primary interleukin (IL)-1 receptor agonist and canakinumab targets IL-1 beta. Tocilizumab (Actemra, Hoffmann-LaRoche) targets the IL-6 receptor. Abatacept (Orencia, Bristol-Myers Squibb) has a unique mechanism of action as a fusion protein composed of the Fc region of IgG1 and interrupts T-cell signaling rather than blocking a single cytokine.

Then there are JAK kinase inhibitors, the most recent players on the scene. Tofacitinib (Xeljanz, Pfizer) leads this particular charge due to its approval for RA in adults, several are planned to be studied in JIA and likely will eventually make their way toward approval for JIA. These will be the first new oral therapies for JIA.

In the 2013 FDA recommendations, Ringold and colleagues wrote that a number of biologic therapies can be used in JIA. Anakinra and tocilizumab may be considered as first-line therapy for certain populations, while abatacept and canakinumab are more frequently recommended for use after suboptimal outcomes with glucocorticoid, NSAIDs, leflunomide or methotrexate therapy.

Matthew Stoll, MD, associate professor in pediatric rheumatology at the University of Alabama at Birmingham, and colleagues, conducted a review which indicated anti-TNF inhibitors had not only “shown tremendous benefit” in polyarticular JIA, but may be useful in enthesitis-related arthritis and psoriatic JIA. They added a combination of methotrexate with an anti-TNF agent may be an effective approach in JIA. Other findings indicated abatacept and tocilizumab also have demonstrated efficacy in polyarticular JIA. Regarding systemic JIA, while TNF therapies may be less effective, IL-1 and IL-6 blockade may be more effective, according to Stoll and colleagues. They noted IL-1 and IL-6 inhibitors provide the additional benefit of dealing with macrophage activation syndrome, while anakinra with cyclosporine and corticosteroids may reduce the necessity of cytotoxic drugs. A monoclonal antibody TNF inhibitor, such as infliximab or adalimumb, either as monotherapy or in combination with methotrexate has demonstrated the capacity to manage JIA-associated uveitis. That said, biologics are not without complications, according to the findings.

“Overall, the biologics have demonstrated an impressive safety record in children with JIA, although children do need to be monitored for rare but potentially dangerous adverse events, such as tuberculosis and other infections; paradoxical development of additional autoimmune diseases; and possibly an increased risk of malignancy,” they wrote. They also suggested clinical decision-making is imperative. “Finally, there may be a window of opportunity during which children with JIA will demonstrate most optimal responses to aggressive therapy, underscoring the need for rapid diagnosis and initiation of treatment,” the investigators wrote.

Stoll discussed the findings in an interview with Healio Rheumatology. “In treatment of polyarticular JIA, combination therapy with a TNF inhibitor and methotrexate appears to be of greater effectiveness than monotherapy with a TNF inhibitor alone,” he said. “This has been demonstrated in prospective studies of adults with rheumatoid arthritis. The data in JIA comes from the German etanercept registry, in which combination therapy resulted in slightly higher rates of ACR30 and ACR70 responses as compared to etanercept therapy alone.”

He noted, however, there is insufficient evidence to make a recommendation about methotrexate or other conventional disease-modified antirheumatic drugs (DMARDs) in juvenile spondyloarthritis.

“The data in adults with ankylosing spondylitis would suggest a limited role for traditional DMARDs in the management of axial spondyloarthritis in children,” he said. “For systemic JIA, the role of methotrexate is also uncertain. The systemic features often respond well to anakinra or tocilizumab; however, methotrexate may also help with the arthritis.”

Prescription Patterns

In short, there is some ambiguity about which drugs to use for which diseases. The recommendations are a work in progress, and while studies like the one conducted by Stoll and colleagues help clinicians navigate the complicated territory, more data are needed. With this in mind, researchers have found it necessary to look back at prescribing patterns to see what drugs physicians are using and how they are using them.

In the Childhood Arthritis Prospective Study (CAPS), Davies and colleagues aimed to describe prescriptions during the first 3 years after presentation and determine whether patterns of therapy have changed with the advent of biologics. Results indicated 58% of 1,051 children were treated with synthetic DMARDs, while 20% were treated with biologics. Children with more serious conditions, such as polyarthritis and systemic arthritis, were more likely to receive both DMARDs and biologics. Among children with oligoarthritis, 35% were treated with DMARDs and 10% received biologics. After 2006, the number of children who received DMARDs increased. Biologic prescribing patterns were similar before and after 2006, according to the results.

“A high proportion of children presenting with JIA received DMARDs plus/minus biologics during 3 years of follow-up,” the researchers concluded. “This was most common for patients with severe JIA but was also prescribed for patients with oligoarticular disease, despite the lack of evidence for effectiveness in this category.”

Kimme Hyrich, MD, PhD, FRCPC, professor of epidemiology and honorary consultant in rheumatology at the Arthritis Research UK Centre for Epidemiology, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences and Faculty of Biology Medicine and Health at the University of Manchester, was a researcher on this study. “The CAPS cohort is significant because we have been capturing data about children presenting to a rheumatologist at seven hospitals in the [United Kingdom] U.K. since 2001,” she said. “They are followed until they are discharged, either because they are well, they move or they go to an adult hospital.”

Hyrich said traditionally, long-term outcomes in JIA have been poorly described in the literature.

“There are many cross-sectional or retrospective studies that are dated,” she said. “But in the last 10 years with the emergence of studies like CAPS, we are looking at all facets of the disease.”

The researchers were not surprised to see that around 60% of the children were treated with DMARDs and around 20% received biologics in the first 3 years of treatment. “However, we were surprised to see a high proportion of children with oligoarthritis receiving both methotrexate and biologics,” she said. “This was not explained.”

One possible reason is most data for JIA includes children with polyarticular disease, according to Hyrich. “Children with oligoarthritis are excluded from many trials,” she said. “It is only in recent years, with disease registries like ours, that we see children with other forms of JIA included in data sets. This will lead to robust experimental studies.”

There is one certainty, though, according to Hyrich. “Children were receiving methotrexate and biologics because steroids alone were not controlling disease,” she said.

Anti-TNF Inhibitors

Another data set from Davies and colleagues investigated etanercept in terms of safety. The aim was to compare the rates of medically significant infections in children with JIA treated with etanercept and those found in children treated with methotrexate. They also aimed to compare the rates between combination therapy with the two drugs and monotherapy with etanercept, according to the findings. The analysis included 852 children treated with etanercept and 260 treated with methotrexate. There were 109 medically significant infections reported in the etanercept group and 24 reported with methotrexate. Medically significant infection rates were higher with etanercept than with controls (propensity score decile adjusted hazard ratio = 2.13). The risk was elevated in patients treated with combination therapy or etanercept monotherapy.

“[Etanercept] therapy is associated with an increased risk of [medically significant infections],” the researchers concluded. “However, this increased risk disappears when considering only [serious infections], which suggests that either there were differences in the severity of infections and/or there was a possible reporting bias.”

Despite the infection risk, the outlook for anti-TNF inhibitors is positive, according to Beukelman. “The introduction of TNF inhibitors for the treatment of JIA has completely revolutionized the field,” he said. “Children who would have been previously confined to wheelchairs are now participating in sports. As far as risks, the possible risk of malignancy associated with anti-TNF inhibitors is still of concern, but it is difficult to get any fully conclusive answer in children because cancer is rare.”

Among adults with RA who receive TNF inhibitors, the most likely association is an increased risk of non-melanoma skin cancer, but not any other type of cancer, according to Beukelman. “As for the increased risk of infection in children, it appears to be small,” he said.

For Lovell, the breakthrough with etanercept is not to be understated.

“It was an eye-opening experience for all involved, including parents, patients and physicians,” Lovell said. “We saw kids get better so quickly and so dramatically, beyond our wildest fantasies. We had to come up with more stringent outcome measures to show improvement and make higher levels of response to measure what they were experiencing.”

Lovell acknowledged the possible increased risk of malignancy, including lymphoma. But added that studies in JIA patients without biologic exposure demonstrate an increased frequency of malignancies compared to healthy pediatric populations. In addition, to date several studies have shown the malignancy risks in JIA patients with and without biologic treatment were similar. However, additional studies are needed with longer duration of biologic treatment. There may be an increased incidence of psoriasis and uveitis.

“All of this is worth it, because we are seeing kids who are 15 [years] or 20 years into this disease with no joint damage,” he said. “That was unheard of before anti-TNF inhibitors.”

The newest such drug on the market is adalimumab. “We do not have 20 years of safety experience with it in adults or children, but it is similar to the rest of the agents in that class,” Lovell said. “The short-term safety profile is similar to etanercept, so I would expect the long-term profile to be, as well.”

Hyrich stressed studying the risks associated with all of these drugs is crucial. “In the U.K. and increasingly in the United States, Germany and other places, there are studies established to look at the safety of these drugs in children,” she said. “The challenge is you need large patient numbers, which we do not have in JIA.”

“We should be concerned about the safety,” she said. “We need to enter every child prescribed these drugs into a registry.”

Targeted IL-1, IL-6 Receptors

Ruperto and colleagues conducted two clinical trials that involved canakinumab in children aged 2 [years] to 19 years with systemic JIA and active systemic features. The primary endpoint was an adapted JIA ACR 30 response (ie, JIA ACR30 plus control of SJIA-associated fever). For the second trial, children were treated with 32 weeks of the study drug in an open-label design. The patients who demonstrated a response underwent glucocorticoid tapering and assigned to continued therapy with the study drug or placebo. Time to flare of systemic JIA served as the primary outcome in the second study.

Results of the first study indicated at day 15, the adapted JIA ACR30 response rate was 84% among 43 children who received the study drug and 10% among 41 children who received placebo. For the second trial, 100 patients were randomly assigned canakinumab or placebo. Results of this study showed a significant difference of 74% of patients treated with canakinumab did not experience a flare, while 25% of those in the placebo group did not flare. Glucocorticoids were ultimately discontinued in 33% of this cohort.

“These two phase 3 studies show the efficacy of canakinumab in systemic JIA with active systemic features,” the researchers concluded.

Another critical study was conducted by DiBenedetti and colleagues who randomly assigned 112 children aged 2 years to 17 years with active systemic JIA to tocilizumab or placebo. Twelve-week results indicated the primary endpoint of an adapted JIA ACR30 response was met by 85% of 75 children in the study drug group and in 24% of 37 children in the placebo group. By week 52, tocilizumab yielded at least a 70% improvement in children with no fever. At that time point, a 90% improvement was reported in 59% of children in the tocilizumab arm. About half of patients who received tocilizumab had no joints with active arthritis and discontinued oral glucocorticoids. Although infection, neutropenia and increased aminotransferase levels were common among children who received tocilizumab, the researchers concluded the drug was effective in severe, persistent JIA.

“The IL-1 and IL-6 blockades have revolutionized our system of JIA outcomes,” Lovell said. “Systemic JIA has, historically, had the highest mortality rate. We did not have good treatment options until people started using IL-1 and IL-6 blockades. So in the studies, we can see a dramatic improvement within a couple days. In some of these studies, within 2 hours, the inflammatory markers dropped precipitously.”

One concern, at the moment, is the drugs have not been available long enough for safety data to mature, according to Lovell.

“It is difficult to speculate on the long-term outcomes,” he said. “One of the things we have learned is these blockades do not decrease risk of macrophage activation syndrome, so that is something we will need to watch.”

The main adverse event to counsel patients about is the increased risk of infection with these agents, according to Susan Shenoi, MD, MS, clinical director of rheumatology at Seattle Children’s Hospital. “In addition, they can cause cytopenias, transaminitis, elevated lipid profiles, local injection site reactions or infusion reactions and the development of antibodies,” she said. “As they are relatively newer medications, the long-term risk profile is unknown.”

For Stoll, it is important to pursue options. “Inhibition of IL-1 and IL-6 are the best options for the systemic phase, but optimal management of the chronic articular phase is unclear,” he said.

Abatacept and JAK Kinase Inhibitors

Shenoi described how abatacept stands apart from the other agents. “Abatacept results in decreased T-cell function by blocking costimuation through binding to CD80/86 on the antigen presenting cells and preventing further interaction with CD28,” she said. “It is given as an infusion every 4 weeks and is used in polyarticular course JIA. The main adverse events include infusion reactions and increased infection risk. Its advantage lies in a different mechanism of action and hence, this is sometimes used when other therapies have failed.”

Hyrich added that activation of T cells requires two signals, one of which involves CTLA4. “Abatacept blocks CTLA4,” she said. “This is a relatively new drug. Because we have had such success with other agents, there is little evidence about it yet. We still do not know exactly how to use it to obtain optimal results.”

While abatacept is often used in patients who have failed another therapy, Beukelman noted this does not mean it is necessarily better or more effective. “It is not superior or inferior to the cytokine therapies,” he said. “In a head-to-head trial with adalimumab in adults with rheumatoid arthritis, the results were almost identical.”

The main issue, as is often the case with JIA, is that there are simply too few patients to study it effectively, according to Beukelman. “Hopefully, as more studies in adults emerge, we get a better sense of how to use this in JIA,” he said.

Lovell said that when abatacept was studied in a double-blind placebo-controlled trial in children with polyarticular forms of JIA, it did not demonstrate statistically significant better control of JIA than placebo.

The main advantage of the JAK kinase inhibitors is that these treatments are oral, according to Shenoi. “The JAK kinase inhibitor is currently being studied in the pediatric population,” she said. “They are exciting because these small molecules are an oral alternative to the biologic medications, which are injections or infusions. This, as you can imagine, is particularly appealing to parents who struggle to give little children weekly shots or regular infusions.”

Beukelman, however, qualified this opinion. “We may have to think about adherence,” he said. “While no one enjoys an injection, sometimes it is easier to administer a quick and relatively painless injection once a week or every 2 weeks than to remember to take an oral medication twice a day. I am sure if we were to talk to some parents of children who are defiant, they might agree.”

Hyrich added pills, such as methotrexate, can also commonly induce nausea.

Tofacitinib, the first JAK kinase drug to be approved in rheumatoid arthritis, is in phase 3 trials in JIA patients. “We hope it will be effective, but we do not know yet,” Lovell said.

Genetics

Rachelle Donn, MB, ChB, PhD, reader in complex disease genetics in the Centre for Musculoskeletal Research at the University of Manchester, and colleagues investigated genetic associations with phenotypic traits in JIA. They suggested there are shortcomings in understanding the relevance of genetic associations with phenotypic traits which limits the development of drugs to treat the disease. However, genome-wide association studies, combined with fine-mapping studies in children with JIA, have shown the clinical community which SNPs may be present in these children.

Donn and Adam Stevens MSc, PhD, a research fellow at the Institute of Human Development at the University of Manchester, addressed these findings with Healio Rheumatology. They suggested precision medicine can be enhanced with the use of information on responder and non-responder status. Genome-wide SNP variant information may improve this, as may gene expression or proteomic studies.

“SNP variant analyses can be severely limited within this arena by the small numbers of the patients included within the studies undertaken,” they said. “However, utilizing networks for comparison analysis of several gene expression data sets can be powerful. This allows for the prioritization of key pathways of importance for further validation.”

The study highlights the relevance of utilizing network analysis in the way described in the data set, according to Donn and Stevens. “We have also strengthened the observation that there are different pathological processes which underlie the age of disease onset and the type of JIA subgroup that manifests,” they said. “There is much current interest around redefining JIA classification, and age may be a key defining feature that is important in this phenotypic expression. Similarly, the therapeutic response of a biologic agent may be affected by the age of the treated child. These are important points that we plan to go on to investigate.”

The take-home message is biologic therapies may be most optimally used as a tailored regimen to a child with JIA, Donn and Stevens added. “While the selection of biologics has improved, based largely on the enhanced understanding of the underlying pathology of the JIA subtype being treated, individualization of the treatment has yet to be achieved,” they wrote. “As such, up to a third of patients will still fail to respond adequately.”

Look Ahead

Shenoi noted there are other JAK kinase inhibitors apart from tofacitinib being studied in adult RA.

“New therapies are also being approved for adults with psoriatic arthritis, such as an oral phosphodiesterase inhibitor (aprelimast) and ustekinumab, which is an Il-12/23 blocker,” she said. “I am hopeful these will be studied in the pediatric population soon.”

Biosimilars also may be available for use soon, according to Shenoi. “Two current large North American pediatric rheumatology groups are systematically studying and conducting research in pediatric rheumatic diseases,” she said. “The Childhood Arthritis and Rheumatology Research Alliance maintains a disease registry, collecting data on several diseases, and recently published a consensus treatment document in JIA that identified best strategies for treatment of these diseases.”

Lovell added many of these studies are based in large part on the pediatric rule passed by Congress in 2002. “This has made all the difference in the world for a variety of drugs,” he said. “There are far more trials being done in pediatric diseases, such as JIA, than ever before.”

Many groups are looking at innovative ways of controlling inflammation, according to Lovell. “They are looking more closely at specific diseases and fitting the biologics to what we know of the mechanism,” he said. “Accordingly, effectiveness has dramatically improved.”

For Stoll, there is no getting around the long process of the scientific method. “At this point, there is no way to know in advance which child will respond to which medication,” he said. “In practice, it often becomes a matter of trial and error, trying different biologics if the child has a poor response or adverse events to the initial selection.”

The issue may not be a matter of new drugs or more drugs, according to Beukelman. “The biologics currently available for JIA have led to unbelievable advances in expected outcomes,” he said. “We are starting to recognize that giving them earlier in the disease course leads to better response rates. To me, that is the need: understanding how to use the current drugs, and not necessarily more new drugs.”

The task then becomes one of improving clinical decision-making, Beukelman added. “There needs to be more studies of the risks and benefits of stopping biologic therapy when children appear to have inactive disease,” he said. “We do not know much about this. Clinicians will stop therapy because children do not appear to need them. Sometimes this is successful, sometimes not. What are the implications of that? Are we making this disease harder to treat in the future by stopping? Are we causing long-term damage when these children have disease flare? These are questions that need answers.”

A final point made by Beukelman is overall understanding of juvenile arthritic disease should be more at the forefront in the minds of clinicians and researchers. “We have 21st-century therapies, but we still talk about the disease in 19th-century descriptive terms,” he said.

• References:
• Barnes et al. Arthritis Rheumatol. 2009;doi:10.1002/art.24601.
• Davies R. Arthritis Rheumatol. 2015;doi:10.1002/art.39197.
• Davies R, et al. Semin Arthritis Rheum. 2016;doi:10.1016/j.semarthrit.2016.06.001.
• DeBenedetti F, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1112802.
• Donn R, et al. Pediatr Rheumatol Online J. 2016;doi:10.1186/s12969-016-0078-4.
• Habibi S, et al. Int J Clin Rheum. 2012;doi:10.2217/ijr.11.75.
• Pascual et al. J Exp Med. 2005;doi:10.1084/jem.20050473.
• Ringold S. Arthritis Care & Research. 2013;doi:10.1002/acr.22087.
• Ruperto N, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1205099.
• Stoll ML, et al. Pediatric Rheumatology. 2014;doi:10.1186/1546-0096-12-13.

• For more information:
• Timothy Beukelman, MD, MSCE, can be reached at 1600 7th Ave. South, CPP 210, Birmingham, AL 35233; email: tbeukelman@peds.uab.edu.
• Rachelle Donn, MB, ChB, PhD; and Adam Stevens, MSc, PhD, can be reached at The Centre for Musculoskeletal Research, 2nd Floor, Stopford Building, Oxford Rd., Manchester, England M13 9PT; email: Rachelle.Donn@manchester.ac.uk.
• Kimme Hyrich, MD, PhD FRCPC, can be reached at The University of Manchester, Room 2.800, Stopford Building, Oxford Rd., Manchester, England M13 9PT; email: kimme.hyrich@manchester.ac.uk.
• Daniel J. Lovell, MD, MPH, can be reached at Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., ML 4010Cincinnati, OH 45229; email: daniel.lovell@cchmc.org.
• Matthew Stoll, MD, can be reached at 1600 7th Ave. South, CPP 210, Birmingham, AL 35233; email: mstoll@peds.uab.edu.

Disclosures: Donn, Shenoi, Stevens and Stoll report no relevant financial disclosures. Beukelman reports he receives consulting fees from Genentech-Roche, Novartis and UCB Pharma. Hyrich reports she receives honoraria from AbbVie and Pfizer. Lovell reports he receives research grants or funding from AbbVie, Bristol-Myers Squibb, Pfizer and Roche and consulting fees from Boehringer Ingelheim, Celgene, GlazoSmitKline, Janssen, Takeda and UCB Pharma.