Philip J Hashkes, MD, MSc
Head, Pediatric Rheumatology Unit
Shaare Zedek Medical Center
Jerusalem, Israel
(formerly Cleveland Clinic)
Associate Professor of Pediatrics, Hebrew University Medical School
It is well known by physicians and families that Down syndrome (DS) is associated with the development of autoimmune diseases, particularly thyroid dysfunction, diabetes mellitus and celiac disease. Children with DS regularly undergo screening for these diseases, often in specialized clinics. What is much less known is the association between DS and the development of juvenile idiopathic arthritis (JIA), the most common chronic rheumatic autoimmune disease in childhood.
Dina is a 6 – year girl with DS (name and age changed) who developed psoriasis at age 3 years. A year later she started to develop episodic pain and “locking” of the knee. Her parents described her walking as “funny” for as long as they can remember. She walks very slowly with her knees bent (almost a shuffle) and her back with an exaggerated arched posture to keep her balance. Mother also described that she is very irritable (at home and in school) and lacks concentration in school, leading to very little progress in intellectual and social development. In repeated visits with her physicians, including specialists in DS, the family was told this was a developmental issue and needed more physical therapy. Her primary physician, with whom I share several common patients with arthritis, was not satisfied and referred the patient to me about 2 years after the start of her symptoms. I found that Dina had polyarthritis (meaning arthritis in more than 4 joints) JIA, especially in the knees, hips and wrists. We started treatment with a one-time steroid injection to the knees and wrists (using sedation) and weekly injections of methotrexate, the standard initial therapy for polyarthritis JIA. She responded dramatically to therapy both in her gait (although she still needs physical therapy to improve joint range of motion and to “relearn” correct walking) and her social and school performance.
JIA is found in approximately 1:1000 children. However, the prevalence in children with DS is estimated as 20 times that – nearly 2%! There are several barriers to the correct diagnosis of JIA, with a large series showing a 19-month average time to diagnosis compared to 4 months for “regular” JIA. I believe the main reason is lack of awareness of this increased risk but objective factors such as a decreased ability of the child to verbalize symptoms, such as pain and morning stiffness, the attribution of the gait and fine motor abnormalities to delayed development of children with DS or related to hypermobility/low muscle tone common among these children. Children with DS may appear to have “swelling” of the hands due to their “general” appearance in DS and these children may have problems with drainage of the lymph fluid (“lymphedema”). Multiple medical problems in these children and important non-medical issues may also delay the correct referral.
Arthritis in children in DS may differ in some respects from “regular” JIA, although several of the differences may be due to the delay in diagnosis. There is more involvement of the hands/wrists than in other children with arthritis, and these children develop earlier damage (“erosions” seen on radiographs) to their joints. One other aspect in their arthritis that may lead to a delay in diagnosis is that their inflammatory markers are often normal, leading (incorrectly) to the assumption that the child does not have an inflammatory disease. Modern imaging techniques, such as the use of ultrasound and MRI can aid in the diagnosis of unclear cases, especially with normal inflammatory markers. There are also some children with DS who develop a form of arthritis called systemic JIA, which starts with high daily fevers and rash in addition to arthritis. Children with DS and systemic JIA, particularly younger children, are at higher risk of developing very severe lung disease as a complication of the disease or possibly the treatments used specifically for this form of arthritis.
Some studies indicate that children with DS-related arthritis respond less well to standard treatment, including methotrexate and biologic therapies. That has not been my experience. I believe the main explanation is due to the delay in diagnosis – there are many studies in JIA stating that the response to treatment is dependent on timely diagnosis. It is true that children with DS may be susceptible to more side effects related to their medications, particularly methotrexate, such as developing a low white blood cell count and infections (including COVID-19 as shown in adults with DS!), so they may need more laboratory monitoring of their medications than the usual regimen used in children with “regular” JIA.
I wish to share some pointers on when to suspect JIA in children with DS:
- Regression in gross and/or fine motor skills, especially in gait.
- Worse gait symptoms after rest or upon awakening from sleep.
- Joint swelling noticed by parents or caretakers.
- Loss of motion of the joint (e.g. inability to completely straighten or bend the knees or wrists).
- Personal history of another autoimmune disease or a first degree relative with psoriasis.
It is important that physicians who specialize in treating DS regularly screen these children during routine care for potential arthritis by history and physical examination (NOT only by laboratory tests) and refer those with suspicion to a pediatric rheumatologist. Early referral and diagnosis equal a better chance to respond to therapy, improved function with less disability and joint damage, and perhaps even a better long-term outcome.