Validation of new medication use algorithms as proxies for worsening disease activity in patients with juvenile idiopathic arthritis.

PURPOSE: To facilitate claims-based research on populations with juvenile idiopathic arthritis (JIA), we sought to validate an algorithm of new medication use as a proxy for worsening JIA disease activity. METHODS: Using electronic health record data from three pediatric centers, we defined new JIA medication use as (re)initiation of disease-modifying antirheumatic drugs or glucocorticoids (oral or intra-articular). Data were collected from 201 randomly selected subjects with (101) or without (100) new medication use. We assessed the positive predictive value (PPV) and negative predictive value (NPV) based on a reference standard of documented worsening of JIA disease activity. The algorithm was refined to optimize test characteristics. RESULTS: Overall, the medication-based algorithm had suboptimal performance in representing worsening JIA disease activity (PPV 69.3%, NPV 77.1%). However, algorithm performance improved for definitions specifying longer times after JIA diagnosis (≥1-year post-diagnosis: PPV 82.9%, NPV 80.0%) or after initiation of prior JIA treatment (≥1-year post-treatment: PPV 89.7%, NPV 80.0%). CONCLUSION: An algorithm for new JIA medication use appears to be a reasonable proxy for worsening JIA disease activity, particularly when specifying new use ≥1 year since initiating a prior JIA medication. This algorithm will be valuable for conducting research on JIA populations within administrative claims databases.

Adalimumab Effectively Decreases Inflammation Downstream of TNFα Signaling in Synoviocytes from Extended Oligoarticular Juvenile Idiopathic Arthritis.

INTRODUCTION: Fibroblast-like synoviocytes (FLS) play a critical role in inflammation that contributes to disease progression in juvenile idiopathic arthritis (JIA). In rheumatoid arthritis (RA), FLS express tumor necrosis factor alpha (TNFα). TNFα signaling has been shown to be upstream of transforming growth factor beta (TGFß) signaling. Overexpression of TNFα and TGFß, as well as related proteins, can cause increased inflammation in RA. In this study, we examine the effects of inhibiting TNFα signaling with adalimumab on FLS isolated from synovial fluid of patients with JIA. METHODS: Synovial fluid samples were selected from 41 patients in our repository. Of these samples, 23 were diagnosed with persistent oligoarticular JIA and 18 were diagnosed with extended oligoarticular JIA. All samples were taken prior to patients extending to a polyarticular course, or what we termed extended-to-be (ETB), and were on no medications or nonsteroidal anti-inflammatory drugs (NSAIDs) only at the time of arthrocentesis. For cell studies, FLS were isolated from synovial fluid and treated with adalimumab for 24 h. Protein antibody arrays were performed by RayBiotech, Inc. according to their protocols. RESULTS: In persistent FLS, TNFα (fold change [FC] = 1.2 p = 0.001), TGFß (FC = 1.5 p = 0.001), lymphotoxin alpha (LTα) (FC = 4.3 p = 0.015), soluble tumor necrosis factor receptor 1 (sTNFRI) (FC = 5.1 p = 0.008), and soluble tumor necrosis factor receptor 2 (sTNFRII) (FC = 3.8 p = 0.025) were significantly elevated in adalimumab treated cells compared to untreated cells. In ETB FLS, TNFα was significantly elevated (FC = 1.04 p = 0.023) while TGFß (FC = 1.03 p = 0.037) was significantly decreased in adalimumab-treated cells compared to untreated cells. CONCLUSIONS: This data suggests that, after only 24 h, adalimumab is effective at decreasing inflammation that occurs downstream of initial TNFα signaling in extended-to-be fibroblast-like synoviocytes.

CCL24, CXCL9 and CXCL10 are increased in synovial fluid in patients with juvenile idiopathic arthritis requiring advanced treatment.

OBJECTIVE: Oligoarticular JIA disease progression and outcomes are variable. Our objective is to detect protein markers that would allow for earlier intervention to potentially halt disease progression. In this retrospective study of serial SF samples, elevated expression of CCL24, CXCL9 and CXCL10 was linked to the eventual need for advanced medications. METHODS: Serial SF samples were selected from patients with persistent and extended oligoarticular JIA. The samples were separated into two groups: those who did and did not receive advanced medications throughout their disease course. Protein antibody arrays and Luminex assays were performed to determine changes in protein expression. RESULTS: CCL24, CXCL9 and CXCL10 expression levels were significantly higher in patients who eventually required advanced treatment than in those who did not. The expression levels of CCL24 and CXCL9 were consistently elevated in paired samples of those who later received advanced medications. In the persistent oligoarticular JIA group, CXCL10 levels remained elevated over time in those who required advanced treatment. Conversely, CCL24 levels decreased in patients who did not require advanced treatment. In the extended samples, the levels of CCL24 and CXCL10 expression increased significantly over time in the patients who ultimately required advanced treatment. CONCLUSION: In patients with oligoarticular JIA, regardless of disease onset and progression, the consistent elevation of any or all three markers, the CCL24, CXCL9 and CXCL10 in SFs was associated with the future use of advanced therapy, which could be reflective of disease severity.