Nick J. Besselink

Assessment of disease activity is a critical component of tight-control, treat-to-target treatment strategies of rheumatoid arthritis (RA). Recently, the HandScan has been validated as a novel method for objectively assessing RA disease activity in only 1.5 min, using optical spectral transmission (OST) in hands and wrists. We describe the protocol of a randomized controlled clinical trial (RCT) to investigate whether HandScan-guided treatment aimed at ‘HandScan remission’ (HandScan arm) is at least as effective as and more cost-effective than clinically guided treatment aimed at ACR/EULAR 2011 Boolean remission (DAS arm). The study is a multi-center, double-blind, non-inferiority RCT of 18 months duration. Patients ≥ 18 years with newly diagnosed, disease-modifying antirheumatic drug (DMARD)-naïve RA according to the ACR 2010 classification criteria, will be randomized to the DAS arm or the HandScan arm. The efficacy of the arms will be compared by evaluating Health Assessment Questionnaire (HAQ) scores (primary outcome) after 18 months of DMARD therapy, aimed at remission. The equivalence margin in HAQ scores between study arms is 0.2. Secondary outcomes are differences in cost-effectiveness and radiographic joint damage between treatment arms. The non-inferiority sample size calculation to obtain a power of 80% at a one-sided p value of 0.05, with 10% dropouts, resulted in 61 patients per arm. In both arms, DMARD strategy will be intensified monthly according to predefined steps until remission is achieved; in both arms DMARDs and treatment steps are identical. If sustained remission, defined as remission that persists consistently over three consecutive months, is achieved, DMARD therapy will be tapered. The study protocol and the specifically designed decision-making software application allow for implementation of this RCT. To test a novel method of assessing disease activity and comparing (cost-)effectiveness with the contemporary method in treat-to-target DMARD strategies in early RA patients. Dutch Trial Register, NTR6388. Registered on 6 April 2017 ( NL50026.041.14 ). Protocol version 3.0, 19-01-2017.

To determine whether optical spectral transmission (OST) can be used to assess synovitis in hand and wrist joints of patients with hand osteoarthritis (OA). Hand and wrist joints of 47 primary hand OA patients with at least one clinically inflamed hand or wrist joint were assessed for synovitis by OST and ultrasound (US). Associations between standardized OST and US synovitis were studied in linear mixed effects models, across all joint types together and individually for wrist, proximal interphalangeal (PIP), and distal interphalangeal (DIP) joints, and were adjusted for OA features that showed associations with US synovitis. Diagnostic performance was determined using receiver operator characteristic (ROC) curves analysis, with US as reference standard. Altogether, 6.7% of joints showed US synovitis. Statistically significant associations between OST scores and US synovitis were found for all joints combined (Δ0.37SD, p<0.001) and PIP joints (Δ0.81SD, p<0.001), but not for DIP (Δ0.14SD, p = 0.484) or wrist joints (Δ0.37SD, p = 0.178). All associations were independent of other OA features, i.e. osteophytes and dorsal vascularity. Analysis of diagnostic performance of OST, revealed an area under the ROC curve (AUC-ROC) of 0.74 for all joints together (p<0.001), 0.69 for PIP joints (p<0.001), 0.54 for DIP joints (p = 0.486), and 0.61 for wrist joints (p = 0.234). OST scores and US synovitis are statistically significantly associated, independent of osteophytes and dorsal vascularity. At this stage, OST performs fair in the assessment of synovitis in PIP joints of hand OA patients.

Objective: Both, knee joint distraction (KJD) and high tibial osteotomy (HTO) are joint-preserving surgeries that postpone total knee arthroplasty (TKA) in younger osteoarthritis (OA) patients. Here we evaluate the 2-year follow-up of KJD versus TKA and KJD versus HTO in 2 noninferiority studies. Design: Knee OA patients indicated for TKA were randomized to KJD ( n = 20; KJD_TKA) or TKA ( n = 40). Medial compartmental knee OA patients considered for HTO were randomized to KJD ( n = 23; KJD_HTO) or HTO ( n = 46). Patient-reported outcome measures were assessed over 2 years of follow-up. The radiographic joint space width (JSW) was measured yearly. In the KJD groups, serum-PIIANP and urinary-CTXII levels were measured as collagen type-II synthesis and breakdown markers. It was hypothesized that there was no clinically important difference in the primary outcome, the total WOMAC, when comparing KJD with HTO and with TKA. Results: Both trials were completed, with 114 patients (19 KJD_TKA; 34 TKA; 20 KJD_HTO; 41 HTO) available for 2-year analyses. At 2 years, the total WOMAC score (KJDTKA: +38.9 [95%CI 28.8-48.9] points; TKA: +42.1 [34.5-49.7]; KJDHTO: +26.8 [17.1-36.6]; HTO: +34.4 [28.0-40.7]; all: P < 0.05) and radiographic minimum JSW (KJDTKA: +0.9 [0.2-1.6] mm; KJDHTO: +0.9 [0.5-1.4]; HTO: +0.6 [0.3-0.9]; all: P < 0.05) were still increased for all groups. The net collagen type-II synthesis 2 years after KJD was increased ( P < 0.05). Half of KJD patients experienced pin tract infections, successfully treated with oral antibiotics. Conclusions: Sustained improvement of clinical benefit and (hyaline) cartilage thickness increase after KJD is demonstrated. KJD was clinically noninferior to HTO and TKA in the primary outcome.

Objective: High tibial osteotomy (HTO) and knee joint distraction (KJD) are treatments to unload the osteoarthritic (OA) joint with proven success in postponing a total knee arthroplasty (TKA). While both treatments demonstrate joint repair, there is limited information about the quality of the regenerated tissue. Therefore, the change in quality of the repaired cartilaginous tissue after KJD and HTO was studied using delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC). Design: Forty patients (20 KJD and 20 HTO), treated for medial tibiofemoral OA, were included in this study. Radiographic outcomes, clinical characteristics, and cartilage quality were evaluated at baseline, and at 1- and 2-year follow-up. Results: Two years after KJD treatment, clear clinical improvement was observed. Moreover, a statistically significant increased medial (Δ 0.99 mm), minimal (Δ 1.04 mm), and mean (Δ 0.68 mm) radiographic joint space width (JSW) was demonstrated. Likewise, medial (Δ 1.03 mm), minimal (Δ 0.72 mm), and mean (Δ 0.46 mm) JSW were statistically significantly increased on radiographs after HTO. There was on average no statistically significant change in dGEMRIC indices over two years and no difference between treatments. Yet there seemed to be a clinically relevant, positive relation between increase in cartilage quality and patients’ experienced clinical benefit. Conclusions: Treatment of knee OA by either HTO or KJD leads to clinical benefit, and an increase in cartilage thickness on weightbearing radiographs for over 2 years posttreatment. This cartilaginous tissue was on average not different from baseline, as determined by dGEMRIC, whereas changes in quality at the individual level correlated with clinical benefit.

To develop an optical spectral transmission (OST) model to measure joint inflammation, and thus disease activity, as well as to evaluate (patho-)physiological findings that could lead to misclassification of inflammation. Forty-six RA patients were included in this cross-sectional study, where US scores, duplicate OST measurements and 28-joint DAS (DAS28) were acquired. With US as a reference standard, the diagnostic performance of OST in detecting inflammation at the joint level was evaluated using receiver operating characteristic (ROC) curve analyses. At the patient level, correlations with US were analysed for DAS28 and OST, and at joint level for OST and tender and swollen joint counts (TJC and SJC, respectively). Joint pathology potentially influencing misclassification by OST [erosions, osteophytes, tendon (sheath) inflammation (ab)normal vasculature and chondrocalcinosis] was evaluated for significance in a multivariate nominal logistic regression model. Diagnostic performance of OST was good for MCP [area under the ROC curve (AUC-ROC) 0.88], PIP (AUC-ROC 0.83) and wrist (AUC-ROC 0.74) joints and for all joints together (AUC-ROC 0.85). At the patient level, DAS28 correlated very poorly (ρ = 0.06) and OST moderately (ρ = 0.54) with US. At the joint level, US correlation with OST was strong (ρ = 0.64), with SJC it was weak (ρ = 0.30) and with TJC it was very weak (ρ = -0.02). Misclassification of inflammation by OST was relatively rare (17%). Dorsal erosions [odds ratio (OR) 4.0], osteophytes (OR 2.1) and extensor tendinitis (OR 4.6) increased the risk of underestimating inflammation of MCP and PIP joints and osteophytes (OR 3.0) also increased the risk of overestimating inflammation. OST is a sensitive, specific and objective technique to assess joints inflammation of the hands and wrists of RA patients, even though bone and tendon pathology increases the risk of misclassification.

Synovium is an integrated tissue of the diarthrodial joints that interacts with all the other joint tissues and specifically is important in nourishment and lubrication of the articular cartilage, removal of waste products, and immunological surveillance. Chronic as well as recurrent low-grade synovial inflammation definitely contributes to progression and symptoms of certain patients with osteoarthritis. Low-grade inflammation may even be causative in the disease. The challenge is that osteoarthritis is a heterogeneous disorder with inflammation not only of the synovial tissue but with its mediators also present in cartilage and bone. Therefore, despite the presence of inflammatory mediators, in some cases synovitis may be seen as a bystander and not as a driving force in pathogenesis. Future research must be directed toward defining the risk-to-benefit ratio for (systemic) anti-inflammatory therapy, especially when targeting mediators of low-grade inflammation.