To determine classification criteria for juvenile idiopathic arthritis (JIA)-associated chronic anterior uveitis (CAU).
Machine learning of cases with JIA CAU and 8 other anterior uveitides.
Cases of anterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the anterior uveitides. The resulting criteria were evaluated on the validation set.
One thousand eighty-three cases of anterior uveitides, including 202 cases of JIA CAU, were evaluated by machine learning. The overall accuracy for anterior uveitides was 97.5% in the training set and 96.7% in the validation set (95% confidence interval 92.4, 98.6). Key criteria for JIA CAU included (1) chronic anterior uveitis (or, if newly diagnosed, insidious onset) and (2) JIA, except for the systemic, rheumatoid factor–positive polyarthritis, and enthesitis-related arthritis variants. The misclassification rates for JIA CAU were 2.4% in the training set and 0% in the validation set.
The criteria for JIA CAU had a low misclassification rate and seemed to perform well enough for use in clinical and translational research.
J uvenile idiopathic arthritis (JIA) is a collection of inflammatory arthritic diseases characterized by onset before the 16th birthday and arthritis persisting for at least 6 weeks and includes the diseases previously known as juvenile rheumatoid arthritis and juvenile chronic arthritis. , Juvenile idiopathic arthritis encompasses at least 7 distinct diseases: (1) systemic arthritis; (2) oligoarthritis; (3) rheumatoid factor–negative polyarthritis; (4) rheumatoid factor–positive polyarthritis; (5) psoriatic arthritis; (6) enthesitis-related arthritis (ERA); and (7) undifferentiated arthritis. In addition, oligoarthritis is divided into persistent oligoarthritis and extended oligoarthritis. , The International League of Associations for Rheumatology (ILAR) criteria for JIA are outlined in Table 1 . The most common type of JIA is oligoarthritis, accounting for 40%-60% of cases, followed by rheumatoid factor–positive polyarthritis (20%-25%), systemic arthritis (10%-20%), rheumatoid factor–negative polyarthritis (5%-10%), ERA (5%-10%), undifferentiated arthritis (5%-10%), and psoriatic arthritis (5%).
|Systemic arthritis||Arthritis in ≥1 joint with daily fever of ≥2 weeks duration plus ≥1 of:|
|1. Evanescent, erythematous rash|
|2. Generalized lymph node enlargement|
|3. Hepatomegaly and/or splenomegaly|
|Exclusions : a, b, c, d (see footnote)|
|Oligoarthritis||Arthritis affecting 1-4 joints during the first 6 months of disease|
|Persistent||Affecting ≤4 joints throughout the disease course|
|Extended||Affecting a total of >4 joints after the first 6 months of disease|
|Exclusions : a, b, c, d, e|
|Rheumatoid factor–negative polyarthritis||Arthritis affecting ≥5 joints during the 1 st 6 months of disease; a test for rheumatoid factor is negative.|
|Exclusions : a, b, c, d, e|
|Rheumatoid factor–positive polyarthritis||Arthritis affecting ≥5 joints during the first 6 months of disease; ≥2 tests for rheumatoid factor ≥3 months apart are positive in the first 6 months of disease|
|Exclusions : a, b, c, e|
|Psoriatic arthritis||Arthritis and psoriasis OR arthritis plus ≥2 of:|
|2. Nail pitting or onycholysis|
|3. Psoriasis in a first-degree relative|
|Exclusions : b, c, d, e|
|Enthesitis-related arthritis||Arthritis and enthesitis OR arthritis OR enthesitis plus ≥2 of:|
|1. Sacroiliac joint tenderness and/or inflammatory lumbosacral pain|
|2. Presence of HLA-B27 antigen|
|3. Acute anterior uveitis|
|4. History of spondyloarthritis or acute anterior uveitis in a first-degree relative|
|Exclusions : a, d, e|
|Undifferentiated arthritis||Arthritis fulfilling criteria in no category or in ≥2 categories|
Chronic anterior uveitis is a well-recognized manifestation of JIA. It typically presents in children within 4 years of the onset of the arthritis, with the highest risk in the first year. The median age of onset of the uveitis is 5-6 years. , Approximately 90% of children with uveitis will present within 8 years of the diagnosis of the arthritis, but occasionally the interval may be longer. It typically presents as an asymptomatic anterior uveitis in a “white” eye, diagnosed on ophthalmologic screening. In a small percentage (<10%) the uveitis will present before the arthritis. , , The presence of antinuclear antibodies (ANA) in the blood is a risk factor for JIA-associated chronic anterior uveitis, and the majority of cases of JIA-associated chronic anterior uveitis are ANA-positive, but JIA-associated chronic anterior uveitis can occur in the absence of a positive test for ANA. Among children with JIA and a positive ANA, the estimated lifetime risk of chronic anterior uveitis is ∼30%-40%. , Patients with systemic JIA or rheumatoid factor–positive polyarthritis are at low risk for uveitis. Among children with oligoarthritis and rheumatoid factor–negative polyarthritis, it seems that the type of arthritis is less important than the ANA; ANA-positive oligoarthritis persistent, oligoarthritis extended, and rheumatoid factor–negative polyarthritis all have an estimated risk of ∼30%. Conversely, ERA is an HLA-B27-associated disease, and the uveitis seen in children with ERA is an acute anterior uveitis, as in adult HLA-B27-associated diseases. , Juvenile psoriatic arthritis in younger children is a small-joint arthritis, and the uveitis phenotype typically is chronic. Conversely, older children with juvenile psoriatic arthritis may develop a psoriatic spondylitis picture, which can be associated with HLA-B27 and an acute anterior uveitis.
The Standardization of Uveitis Nomenclature (SUN) Working Group is an international collaboration that has developed classification criteria for 25 of the most common uveitides using a formal approach to development and classification. Among the anterior uveitides studied was JIA-associated chronic anterior uveitis.
The SUN Developing Classification Criteria for the Uveitides project proceeded in 4 phases, as previously described: (1) informatics, (2) case collection, (3) case selection, and (4) machine learning. ,
As previously described, the consensus-based informatics phase permitted the development of a standardized vocabulary and the development of a standardized, menu-driven hierarchical case collection instrument.
Case Collection and Case Selection
De-identified information was entered into the SUN preliminary database by the 76 contributing investigators for each disease, as previously described. , , Cases in the preliminary database were reviewed by committees of 9 investigators for selection into the final database, using formal consensus techniques described in the accompanying article. , Because the goal was to develop classification criteria, only cases with a supermajority agreement (>75%) that the case was the disease were retained in the final database (ie, were “selected”).
The final database then was randomly separated into a training set (∼85% of cases) and a validation set (∼15% of cases) for each disease, as described in the accompanying article. Machine learning was used on the training set to determine criteria that minimized misclassification. The criteria then were tested on the validation set; for both the training set and the validation set, the misclassification rate was calculated for each disease. The misclassification rate was the proportion of cases classified incorrectly by the machine learning algorithm when compared to the consensus diagnosis. For JIA-associated chronic anterior uveitis, the diseases against which it was evaluated were cytomegalovirus anterior uveitis, herpes simplex virus anterior uveitis, varicella zoster virus anterior uveitis, spondylitis/HLA-B27-associated anterior uveitis, tubulointerstitial nephritis with uveitis, Fuchs uveitis syndrome, sarcoidosis-associated anterior uveitis, and syphilitic anterior uveitis.
Two hundred fifty-one cases of JIA-associated chronic anterior uveitis were collected, and 202 (80%) achieved supermajority agreement on the diagnosis during the “selection” phase and were used in the machine learning phase. These cases of JIA-associated chronic anterior uveitis were compared to 881 cases of other anterior uveitides, including 89 cases of cytomegalovirus anterior uveitis, 123 cases of varicella zoster virus anterior uveitis, 146 cases of Fuchs uveitis syndrome, 101 cases of herpes simplex virus anterior uveitis, 184 cases of spondylitis/HLA-B27-associated anterior uveitis, 94 cases of tubulointerstitial nephritis with uveitis, 112 cases of sarcoidosis-associated anterior uveitis, and 32 cases of syphilitic anterior uveitis. The characteristics at presentation to a SUN Working Group investigator of the cases with JIA-associated chronic anterior uveitis are listed in Table 2 . The criteria developed after machine learning are listed in Table 3 . The overall accuracy for anterior uveitides was 97.5% in the training set and 96.7% in the validation set (95% confidence interval 92.4, 98.6). The misclassification rate for JIA-associated chronic anterior uveitis in the training set was 2.4% and in the validation set was 0%.
|Number of cases||202|
|Age, median, years (25th, 75th percentile)||5 (3, 7)|
|Age category, years (%)|
|Asian, Pacific Islander||1|
|Uveitis course (%)|
|Keratic precipitates (%)|
|Anterior chamber cells, grade (%)|
|Anterior chamber flare, grade (%)|
|Sectoral iris atrophy||0|
|Patch iris atrophy||0|
|Diffuse iris atrophy||0|
|IOP, involved eyes|
|Median, mm Hg (25th, 75th percentile)||14 (12, 18)|
|Proportion patients with IOP > 24 mm Hg either eye (%)||6|
|Vitreous cells, grade (%)|
|Positive antinuclear antibody (% entire population)||64|
|Positive antinuclear antibody (% of those tested) a||81|