The role of synovial inflammation in osteoarthritis

Osteoarthritis (OA) is a multifactorial joint disease and one of the leading causes of pain and disability in older adults. It has long been hypothesised that synovium plays an important role in the initiation and progression of OA. This thesis aims to investigate the associations between synovial inflammation in the knee and important disease outcomes of OA, and the therapeutic effects of vitamin D supplementation on synovial inflammation. This thesis utilises data from two clinical studies. The first one is a cohort study with a total number of 977 participants randomly selected from the local community (51% female; aged 62 ± 7 years) at baseline. 404 participants were followed up approximately 2.7 ± 0.4 years later. Synovial inflammation (assessed as effusion-synovitis), cartilage volume, cartilage defects, tibial bone area, and bone marrow lesions (BMLs) were assessed using magnetic resonance imaging (MRI). X-ray was used to assess radiographic changes including joint space narrowing (JSN) and osteophytes. Questionnaires were used to assess knee pain, knee function, knee stiffness, physical activity, and other disease status. Another study is a multi-centre, parallel, randomised, placebo-controlled trial which was conducted in symptomatic knee OA patients aged 63 ± 7 years (208 females). 413 patients were allocated to either a 50,000 IU monthly vitamin D3 capsule (n=209) or placebo (n=204) for 24 months. Knee effusion-synovitis, cartilage defects, cartilage volume and BMLs were assessed using MRI. Knee symptoms were assessed at baseline and months 3, 6, 12, 24 using Western Ontario and McMaster University Index of OA (WOMAC) questionnaire. Serum 25-hydroxylvitamin D (25-(OH)D) was assayed by Liaison method utilising a direct competitive chemiluminescent immunoassay. In Chapter 4 the cross-sectional and longitudinal associations between site-specific effusion-synovitis and knee pain were examined in older adults. We found that effusionsynovitis in the suprapatellar pouch was consistently associated with weight-bearing and nonweight-bearing pain while those in central and posterior sites were only associated with nonweight-bearing (inflammatory) knee pain. These associations were independent of age, sex, body mass index (BMI), cartilage defects, BMLs and ROA. In Chapter 5, we examined if effusion-synovitis was associated with knee structural changes cross-sectionally and longitudinally in older adults. Suprapatellar pouch effusionsynovitis at baseline predicted the development/progression of cartilage defects and BMLs as well as cartilage volume loss. Effusion-synovitis was independently associated with cartilage defects after adjustments for other structural abnormalities. The associations between effusion-synovitis and BMLs and cartilage volume were largely dependent on cartilage defects, suggesting potential causal pathways. In Chapter 6, natural history and clinical significance of quantitatively measured effusion-synovitis were described in older adults. The mean (±SD) size of effusion-synovitis in participants was 1.64 cm\\(^2\\) (±1.34 cm\\(^2\\)) at baseline with 29% improving and 22% worsening in size over 2.7 years. Males had larger effusion-synovitis size than females. Baseline effusion-synovitis also positively associated with changes in cartilage defects and BMLs, while it is negatively associated with change in cartilage volume. No associations were found between baseline structural alterations and change in effusion-synovitis size. In Chapter 7, we further examined clinical relevance of effusion-synovitis using effusion-synovitis volume measurement in patients with knee OA. Baseline BML, cartilage defect, JSN and osteophyte scores were significantly associated with the change in effusionsynovitis volume. However, neither baseline effusion-synovitis volume nor score was significantly associated with changes in BMLs, cartilage defects or cartilage volume. There were no significant associations between knee effusion-synovitis volume and measures at patellofemoral joint. In Chapter 8, the effects of vitamin D supplementation on effusion-synovitis were determined in patients with knee OA. Baseline effusion-synovitis volume was 8.0 ml with a prevalence of 52%. After a 24-month intervention, the vitamin D group had a less increase in total effusion-synovitis volume than the control group (between group difference: -1.94 ml, p=0.02). The between-group differences were particularly significant in suprapatellar pouch region, and in patients who had effusion-synovitis at baseline. In conclusion, the series of relevant studies indicate that synovial inflammation plays a pivotal role in the pathogenesis of knee OA. Synovial inflammation contributed to knee pain and predicted the development or progression of disease outcomes such as cartilage defects and BMLs in older adults, most of them being in early stages of osteoarthritic changes; in contrast, cartilage defects and bone abnormalities accelerated progression of effusion-synovitis only in those with established OA. Vitamin D as an attractive therapeutic intervention has shown a beneficial effect on halting the worsening of effusion-synovitis in knee OA patients. Our work suggests that effusion-synovitis can be used as a disease diagnostic feature and an outcome measure in OA trials. Targeting on the effusion-synovitis can be implicated for future development of disease-modifying OA drugs (DMOADs). Future work is required to confirm the relationship between effusion-synovitis and joint structural changes in patients with early and/or late stages of OA in longer-term cohort studies. Clinical trials are also needed to examine whether treatments such as vitamin D supplementation can reduce progression of effusion-synovitis (as the primary outcome) in knee OA patients with inflammatory phenotype.

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