Most people are aware of arthritis in adults, but few are aware that children may be affected as well. Juvenile idiopathic arthritis (JIA) is the most common type of arthritis in young people and affects ~1 in every 1,000 children worldwide. Left undiagnosed and untreated, the condition can deteriorate joints in the body and lead to debilitating pain. Over the last two decades, there has been a push to better understand and educate the public about JIA. Novel treatment options are starting to take hold with more research, including pediatric clinical trials. This research has led to exciting new treatment methodologies and medicines for the management of JIA.
In light of JIA Awareness Month, its treatments, its stigma, and more, we spoke with Dr. Johnny Peppers, Executive Director of Drug Development for the Center of Global Drug Development and Center for Pediatric Clinical Development at PRA. Dr. Peppers has a PhD in genetics and background in immunology, with over 20 years of experience developing adult and pediatric drugs for autoimmune diseases such as JIA. Read his insights on JIA below.
Does JIA differ from adult arthritis at all? Does it present different symptoms?
First and foremost, the word “idiopathic” is the “I” in “JIA.” That’s a fancy way of saying that the condition is from an unknown origin and the pathogenesis of the disease is still unclear. With that, I’d like to distinguish the differences between juvenile idiopathic arthritis (JIA) and adult arthritis.
When we're talking about adult arthritis, there are several types (osteoarthritis, psoriatic and rheumatoid).
Osteoarthritis in adults involves “wear and tear” that occurs due to overuse. It’s usually age-related and uncommon in children. Injury and obesity may lead to earlier diagnoses due to the added joint stress. I'll keep the ongoing focus on rheumatoid arthritis (RA) and psoriatic arthritis (PsA) from an adult standpoint, as they are more directly relatable to JIA.
Rheumatoid/psoriatic arthritis in adults and JIA in kids are all autoimmune diseases. In other words, in each of these individuals, the immune system breaches tolerance and attacks the tissue within the joints, leading to inflammation and joint destruction. However, RA and PsA are distinct conditions, each with their own specific causalities. As such, treatment paradigms only occur in adults.
In children and adolescents, the most common type of arthritis in children is JIA. It's an umbrella term that actually includes several arthritic conditions combined in a single indication, all of which are simply thrown into a single amalgam.
The first subtype is systemic arthritis. It consists of about 10-20% of all JIA cases. The presence of arthritis and intermittent fever for at least two weeks, plus one of the following, defines the disease: typical rash, generalized lymphadenopathy, hepatosplenomegaly, or serositis. In general, systemic symptoms of fever and rash resolve after the emergence of polyarthritis, which makes distinguishing it from regular polyarticular JIA challenging.
The next subtype is oligoarthritis. This subset is the most common form of JIA in the developed world. In this case, generally patients have a small number of joints (<4 at 6 months post-diagnosis) that are affected, usually the larger joints such as knees, ankles, and elbows. While joint damage/erosions are possible, the most-common issue with these subjects is the potential development of uveitis (inflammation of the eye’s middle layer).
Next, polyarthritis, also known as poly-articular JIA, differentiates from oligoarthritis by the necessity of inflammation of a large number of joints. About 25% of all cases of JIA fall into this category. Polyarthritis is generally symmetrically focused in the hands, but there may be some weight-bearing joints affected.
Polyarthritis can be broken down into two components according to rheumatoid factor (RF) positivity. Rheumatoid factors are proteins produced by the immune system. They can attack healthy tissue in your body. In both subgroups, girls are more likely to be diagnosed than boys. The first subgroup occurs in younger children more frequently (4-12 years of age). The RF-negative subgroup may have greater involvement of the hip joints and generally has a more severe prognosis. The onset of disease occurs in older teens and has a potential, if not treated effectively, for significant long-term joint damage.
Juvenile psoriatic arthritis (jPSA) is still an important topic of discussion in pediatric rheumatology. According to the criteria, the disease is defined by arthritis coupled with either a psoriatic rash or two of the following: dactylitis (sausage fingers), onycholysis (nail pitting), or psoriasis in a first-degree relative. Since the joint involvement generally occurs a few years before the development of skin manifestations, the diagnosis can be challenging.
The last subtype is enthesitis-related arthritis (ERA). ERA has been one of the most controversial topics in pediatric rheumatology for the last 25 years. These patients show characteristics of both JIA and juvenile joint disease of the vertebral column (spondyloarthropathy). The disease is typically seen among males after the age of six. It can affect some joints such as the hips and lower back. Sometimes it occurs in the knees and the Achilles tendons. Ineffective treatment leads to disease progression and the development of ankylosing spondylitis seen among adults.
There’s continued research and discussions to try and differentiate between these conditions more effectively. The reality is that when a child presents to a pediatric rheumatologist with one of these arthritic conditions, it's extremely difficult upfront to try and diagnose without extensive testing. This may take a substantial amount of time to understand and modify treatment algorithms to determine what pathway is most effective.
The reality is that when a child presents to a pediatric rheumatologist with one of these arthritic conditions, it's extremely difficult upfront to try and diagnose without extensive testing.
Dr. Johnny Peppers, Executive Director of Drug Development for the Center of Global Drug Development and Center for Pediatric Clinical Development
This heterogeneity in manifestations of disease is one of the key differentiations between adult and pediatric patients. Rheumatologists have developed step-by-step treatment paradigms to diagnose RA specifically, and they have treatment specifically for RA.
To recap, JIA is several different types of arthritis that are thrown into one group. It generally requires extensive testing and diagnoses. As such, they try and treat it with an umbrella approach initially and refine that umbrella approach as time goes on. The primary difference is that pediatric JIA is an amalgam of multiple sub-types of arthritis conditions, whereas RA is a single condition.
Is JIA treated differently than adult arthritis?
Once the indication is firmly established, rheumatologists try to treat the disease before it has a chance to progress. Part of the nature of these arthritic conditions is the deterioration of the joint over time. This deterioration can manifest in the cartilage and supporting tissues, eroding to the point where there’s bone-on-bone contact. At that point, there are erosions within the bone itself—areas where the immune system is actively going in and removing portions of bone. With bone-on-bone contact comes excruciating, constant pain and discomfort. That’s why rheumatologists move as quickly as possible into biological response modifiers.
Initial treatment algorithms for each of the JIA subtypes are similar. Pediatric rheumatologists are able to distinguish which subtypes the patient may have. This focus may impact the direction of the patient’s future examinations and concerns that the pediatric rheumatologist has with the patient.
The first step in all of these treatment paradigms is to reduce the impact of inflammation within the affected joints. This is initially done by exploring combinations of non-steroidal anti-inflammatory drugs (NSAID)s. NSAIDs include aspirins or naproxen. This helps reduce inflammation. Rheumatologists will usually initiate exercises and approaches to try and stretch the joints.
They then move forward to utilizing corticosteroids as a secondary approach. Steroids help greatly reduce inflammation. However, long-term use of steroids, especially in children, can cause a host of additional side effects. As such, long-term steroid use is something rheumatologists try to avoid.
Disease Modifying Anti-Rheumatic Drugs (DMARDs) are the next stage of treatment options. They are generally agents that have an immunosuppressive mechanism of action and are used in conjunction with NSAIDs and Steroids. The most commonly used DMARD in patients with JIA is methotrexate.
Lastly, biologics have been a major breakthrough in the treatment of JIA. These drugs counteract specific pathways within the immune system and have shown substantial improvement in treatment of all subtypes of JIA. The types of biologics approved for JIA include inhibitors for anti-TNF, T-cell co-stimulation via CTLA4 pathways, and JAK inhibition.
There are new drugs coming to the market for adults and pediatric populations. One of the greatest things I've seen in my pediatric experience is that health authorities have finally realized that children are not little adults. Right now, approximately 70% of medications that are used in pediatrics have never been tested in children. They've only been tested or approved and adults and applied to children under the assumption that if it works in adults, it must work in a child.
Now, health authorities are mandating that any new clinical program in adults must also involve a pediatric development plan. This plan has to be approved by the FDA and EMA, and if companies don’t do this, they don't get approval for their adult indications.
How can we properly address the misconception that only adults get arthritis?
Patient advocacy and supporting patient advocacy is the first and foremost way of spreading awareness to the public.
The reality is people often think of arthritis as an “old person’s disease” because the typical onset for an individual with RA is in their mid to late 30s. However, children under the age of 5 years can and do develop forms of JIA.
Educating the public that there are arthritic conditions that occur in children is a significant issue. Fortunately, there are a number of advocacy groups for both patients and health care professionals that include the Juvenile Idiopathic Arthritis Foundation, the American College of Rheumatology, and the European League Against Rheumatism. These organizations do extensive amounts of research and patient outreach to help patients and their caregivers. In addition, they are the ones that are responsible for a great deal of the educational information that you see on the Internet regarding these specific conditions.
How can we properly educate children on the risk of JIA and who might be at risk?
These autoimmune diseases generally have a genetic component. Although the patient may be the first in their family to be diagnosed, we should pay more attention to a child’s sibling, parent, or close relative with an autoimmune disease. Individuals with familial involvement have a greater propensity of developing one of these indications. The unfortunate reality is that you can't always predict that a particular child will get JIA, which means that treatment is not initiated until the condition becomes manifest.
It’s also important to continue developing materials specifically for children. We’re starting to do a better job with pediatric clinical trial participation. We now think about pediatric informed consent and pediatric assent and developing better educational tools for patients and caregivers. It’s becoming more necessary to develop these materials, such as comic books, that cover these topics in a way that children can read and understand.
Recently, I was at a meeting at the American College of Rheumatology. A presentation that I found to be informative was from a pediatric rheumatologist. Her focus was developing these materials for children. In this case, she developed a story book. Once a child was diagnosed with pediatric JIA, they could sit down by themselves, read the book, and get an age-appropriate baseline understanding of their disease—including treatment information and additional facts. We can't expect children to understand adult-related concepts—we have to ensure that everything is available to them. We have to let children take control of their conditions and actively learn to manage their treatments.
Children must have some level of control. They feel unsure, they’re nervous, they're scared, and they feel like they've lost control because they don't understand what's happening and why things are being done to them. Any type of pediatric educational material is incredibly important. These materials also allow them to have informed conversations with their parents.
What is currently being done to raise awareness for JIA? Is there any stigma involved that we have to watch out for?
It all comes back to patient advocacy. The organizations for JIA are outstanding—I've had a great opportunity to work with a number of them and attend functions that they put together. They have yearly statewide and national functions to promote research and clinical trials. They also educate patients about what's being done, whom to contact, and physicians to see for treatments. Any support for patient advocacy is important.
JIA is a lifelong condition. The associated stigma treats children like they’re in a fragile state—that we should be treating them differently than other kids. We have to realize that kids need to be treated as kids. If they do have a particular indication of JIA, there are things we need to watch out for, like certain levels of activity or side effects of the medicines. But we need to realize that they're still children and deserve to have as normal development and growing up as possible.
We also must make sure that we keep focused and help reduce the worry these indications create. For example, you can't catch JIA from someone, so there's no reason why these children should be isolated, excluded, or limited in any way, assuming that their physicians and their parents are on board.