PRSYM—At the virtual 2021 Pediatric Rheumatology Symposium (PRSYM), three speakers discussed JIA-associated uveitis, systemic JIA (sJIA) and pulmonary involvement in sJIA.
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Mindy Lo, MD, PhD, assistant professor of pediatrics at Harvard Medical School and director of the pediatric rheumatology fellowship training program at Boston Children’s Hospital, began the session by discussing guidelines for screening for JIA-associated uveitis.
The ACR guideline published in 2019 notes that patients who were identified as high risk for uveitis include those with anti-nuclear antibodies (ANAs), who had JIA onset prior to age 7 and a disease duration of less than or equal to four years.1 European guidelines from the Single Hub and Access Point for Pediatric Rheumatology in Europe (SHARE) indicate that, although several screening protocols have been published, no evidence exists that any one protocol is superior to another.2 Thus, the exact method for screening for uveitis may not be of utmost importance. What is essential is thinking to screen for this condition in a systematic manner.
Dr. Lo said disease activity in patients with JIA can be a relevant marker of potential ophthalmologic involvement. In a study of 98 patients with JIA-associated uveitis followed over the course of six years, researchers found a 73% concordance between active uveitis and arthritis. This finding indicates that arthritis activity in patients with JIA should prompt evaluation of uveitis activity.3
Regarding treatment, Dr. Lo stated a three-month benchmark is important in several respects. First, if steroid treatment alone does not result in uveitis inactivity within three months or if there is reactivation of inflammation with steroid tapering during this interval, systemic immunosuppression, such as with a tumor necrosis factor (TNF) α inhibitor, is warranted. Second, in cases in which cataract surgery is indicated, it’s important to achieve at least three months of uveitis inactivity prior to surgery.
With respect to treatment options, a number of mostly retrospective studies indicate that adalimumab may lead to higher rates of remission and lower rates of relapse of JIA-associated uveitis than infliximab. With regard to treatments beyond TNF inhibitors, options may include tocilizumab and abatacept. Janus kinase inhibitors, such as baricitinib, are currently under investigation as possible treatments for JIA-associated uveitis.
When to stop treatment is a question many rheumatologists face when caring for patients with JIA-associated uveitis. In a study of 98 patients with JIA-associated uveitis, factors associated with achieving uveitis inactivity included JIA onset at older than 4 years, uveitis onset at older than 5 years and adalimumab use. Although no specific laboratory parameters were predictive of achieving uveitis inactivity, decreasing arthritis activity was associated with uveitis inactivity.4
In the next portion of the session, Michael Ombrello, MD, tenure-track investigator, Translational Genetics and Genomics Unit, Pediatric Translational Research Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Bethesda, Md., discussed systemic JIA (sJIA). This condition manifests with a chronic inflammatory arthritis and fever, plus at least one of the following: salmon pink rash, generalized lymphadenopathy, organomegaly or serositis.
Dr. Ombrello noted that sJIA is phenotypically heterogeneous, genetically complex and appears to involve hyperactivation of the innate immune system. Severe complications of disease can include pericardial effusions, macrophage activation syndrome and interstitial lung disease. Although familial inheritance of the disease is not typical, the strongest genetic locus risk association is with HLA-DRB1.
Treatment of sJIA may include the use of non-steroidal anti-inflammatory drugs (NSAIDs); glucocorticoids; disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate; and biologics that—in particular—inhibit interleukin (IL) 1, such as anakinra, canakinumab and rilonacept, or IL-6, such as tocilizumab.
An intriguing question Dr. Ombrello posed was: Is there a therapeutic window of opportunity in sJIA? In 2020, Henderson et al. characterized T cells from patients with acute and chronic sJIA using flow cytometry, mass cytometry and RNA sequencing. Using these data, the researchers found evidence of an evolution of Th17 polarization in sJIA. This process, which begins in regulatory T cells and progresses to effector T cells, is consistent with a biphasic model of disease pathogenesis and indicates T cells may be a potential treatment target in sJIA.5
Dr. Ombrello noted that studies such as this one may provide clues to the best time to initiate treatment. The nature of that treatment may evolve as we better understand the pathogenesis of disease.
The final portion of the session was led by Grant Schulert, MD, PhD, assistant professor of pediatrics, Division of Rheumatology, Cincinnati Children’s Hospital, and focused on lung disease in sJIA. Dr. Schulert noted that most children with sJIA-associated lung disease do not have pulmonary involvement at presentation, but develop signs of disease in the first two years after diagnosis. Signs may include shortness of breath, chronic cough, concern for recurrent pneumonia and even clubbing of the fingers.
Of the 39 patients with suspected, probable or definite sJIA-associated lung disease at the Cincinnati Children’s Hospital, the majority of patients were female and 85% had a history of macrophage activation syndrome. Also, their total serum IL-18 was significantly higher than in patients with sJIA and no evidence of lung disease. Frequent radiographic findings on computed tomography (CT) chest scans included pleural, bronchial wall or peribronchovascular thickening and septal widening.6
Regarding disease management, Dr. Schulert described three core tenets of treatment:
- Controlling underlying sJIA disease activity;
- Targeting pulmonary inflammation; and
- Preventing lung infections.
To treat the underlying sJIA, it’s important to stop any ineffective biologic therapies and ensure no drug reactions occur that may include pulmonary side effects.
For the treatment of sJIA-associated lung disease that manifests as interstitial lung disease, such medications as cyclosporine, mycophenolate mofetil and abatacept may be options. But more data are needed to support these therapies.
Finally, prophylaxis against Pneumocystis jirovecii and aggressive treatment of any active lung infections are both necessary elements of management.
Jason Liebowitz, MD, completed his fellowship in rheumatology at Johns Hopkins University, Baltimore, where he also earned his medical degree. He is currently in practice with Skylands Medical Group, N.J.
- Angeles-Han ST, Ringold S, Beukelman T, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the screening, monitoring and treatment of juvenile idiopathic arthritis-associated uveitis. Arthritis Care Res (Hoboken). 2019 Jun;71(6):703–716. Epub 2019 Apr 25.
- Constantin T, Foeldvari I, Anton J, et al. Consensus-based recommendations for the management of uveitis associated with juvenile idiopathic arthritis: The SHARE initiative. Ann Rheum Dis. 2018 Aug;77(8):1107–1117. Epub 2018 Mar 28.
- Liebling EJ, Faig W, Chang JC, et al. The temporal relationship between juvenile idiopathic arthritis disease activity and uveitis activity. Arthritis Care Res (Hoboken). 2020 Oct 12. Epub ahead of print.
- Heiligenhaus A, Klotsche J, Tappeiner C, et al. Predictive factors and biomarkers for the 2-year outcome of uveitis in juvenile idiopathic arthritis: Data from the inception cohort of newly diagnosed patients with juvenile idiopathic arthritis (ICON-JIA) study. Rheumatology (Oxford). 2019 Jun 1;58(6):975–986.
- Henderson LA, Hoyt KJ, Lee PY, et al. Th17 reprogramming of T cells in systemic juvenile idiopathic arthritis. JCI Insight. 2020 Mar 26;5(6):e132508.
- Schulert GS, Yasin S, Carey B, et al. Systemic juvenile idiopathic arthritis-associated lung disease: Characterization and risk factors. Arthritis Rheumatol. 2019 Nov;71(11):1943–1954. Epub 2019 Oct 1.