Expanding the clinical spectrum of biglycan-related Meester-Loeys syndrome.

Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additional BGN variant-harboring family members (9 males and 27 females). The identified BGN variants were shown to lead to loss-of-function by cDNA and Western Blot analyses of skin fibroblasts or were strongly predicted to lead to loss-of-function based on the nature of the variant. No (likely) pathogenic missense variants without additional (predicted) splice effects were identified. Interestingly, a male proband with a deletion spanning the coding sequence of BGN and the 5' untranslated region of the downstream gene (ATP2B3) presented with a more severe skeletal phenotype. This may possibly be explained by expressional activation of the downstream ATPase ATP2B3 (normally repressed in skin fibroblasts) driven by the remnant BGN promotor. This study highlights that aneurysms and dissections in MRLS extend beyond the thoracic aorta, affecting the entire arterial tree, and cardiovascular symptoms may coincide with non-specific connective tissue features. Furthermore, the clinical presentation is more severe and penetrant in males compared to females. Extensive analysis at RNA, cDNA, and/or protein level is recommended to prove a loss-of-function effect before determining the pathogenicity of identified BGN missense and non-canonical splice variants. In conclusion, distinct mechanisms may underlie the wide phenotypic spectrum of MRLS patients carrying loss-of-function variants in BGN.

Paradoxical association of C-reactive protein with endothelial function in rheumatoid arthritis.

BACKGROUND: Within the general population, levels of C-reactive protein (CRP) are positively associated with atherosclerotic cardiovascular disease (CVD). Whether CRP is causally implicated in atherogenesis or is the results of atherosclerosis is disputed. A role of CRP to protect endothelium-derived nitric oxide (EDNO) has been suggested. We examined the association of CRP with EDNO-dependent vasomotor function and subclinical measures of atherosclerosis and arteriosclerosis in patients with raised CRP resulting from rheumatoid arthritis (RA). METHODOLOGY/PRINCIPAL FINDINGS: Patients with RA (n = 59) and healthy control subjects (n = 123), underwent measures of high sensitivity CRP, flow-mediated dilation (FMD, dependent on EDNO), intima-media thickness (IMT, a measure of subclinical atherosclerosis) and aortic pulse wave velocity (PWV, a measure of arteriosclerosis). IMT and PWV were elevated in patients with RA compared to controls but FMD was similar in the two groups. In patients with RA, IMT and PWV were not correlated with CRP but FMD was positively independently correlated with CRP (P<0.01). CONCLUSIONS/SIGNIFICANCE: These findings argue against a causal role of CRP in atherogenesis and are consistent with a protective effect of CRP on EDNO bioavailability.

Functional and work outcomes improve in patients with rheumatoid arthritis who receive targeted, comprehensive occupational therapy.

OBJECTIVE: Work disability is a serious consequence of rheumatoid arthritis (RA). We conducted a 6-month, prospective randomized controlled trial comparing assessments of function, work, coping, and disease activity in employed patients with RA receiving occupational therapy intervention versus usual care. METHODS: Employed patients with RA with increased perceived work disability risk were identified by the RA Work Instability Scale (WIS; score >or=10). Patients were stratified into medium- (score >or=10 and <17) and high-risk (>or=17) groups, then randomized into occupational therapy or usual care groups. Assessments were conducted at baseline and 6 months. The primary outcome was the Canadian Occupational Performance Measure (COPM), a standardized patient self-report of function. Other outcomes included the disability index (DI) of the Health Assessment Questionnaire (HAQ); Disease Activity Score in 28 joints (DAS28); RA WIS; EuroQol Index; visual analog scales (VAS) for pain, work satisfaction, and work performance; and days missed/month. Independent sample t-tests and Mann-Whitney U tests were used. RESULTS: We recruited 32 employed patients with RA. At baseline the groups were well matched. At 6 months the improvement in the occupational therapy group was significantly greater than that in the usual care group for all functional outcomes (COPM performance P < 0.001, COPM satisfaction P < 0.001, HAQ DI P = 0.02) and most work outcomes (RA WIS [P = 0.04], VAS work satisfaction [P < 0.001], VAS work performance [P = 0.01]). Additionally, Arthritis Helplessness Index (P = 0.02), Arthritis Impact Measurement Scales II pain subscale (P = 0.03), VAS pain (P = 0.007), EuroQol Index (P = 0.02), EuroQol global (P = 0.02), and DAS28 (P = 0.03) scores significantly improved. CONCLUSION: Targeted, comprehensive occupational therapy intervention improves functional and work-related outcomes in employed RA patients at risk of work disability.

Accuracy and reliability of arthroscopic estimates of cartilage lesion size in a plastic knee simulation model.

PURPOSE: The goal of the study was to determine the accuracy and reliability of arthroscopic percent area estimates in a plastic knee simulation model. A second goal was to determine the effect of lesion location within the knee and lesion size on accuracy and reliability. TYPE OF STUDY: Cross-sectional study of arthroscopic estimates of cartilage lesion size. METHODS: Three experienced arthroscopists performed 3 sets arthroscopic percent area estimates in 5 different plastic knees. Each knee had lesions drawn on 5 surfaces (patellar, medial and lateral femoral condyle, medial and lateral tibial plateaus). Accuracy and reliability were studied using Bland and Altman limits of agreement (LOA) and intraclass correlation coefficients. RESULTS: There was a strong tendency to overestimate lesion size by over 100% on the femoral and patellar surfaces. Intraobserver and interobserver reliabilities were generally poor. The range for the 95% LOA (+/- 1.96 standard deviation [SD] of the difference scores) between repeated measurements was almost 6 times the size of the lesion itself. Reliability of estimates was poorest for the largest lesions and worse at femoral, lateral tibial, and patellar sites. CONCLUSIONS: Assessments of arthroscopic measurements using LOA found that accuracy and reliability were generally poor, although results were better at the medial tibial plateau and for smaller lesions. In spite of these problems, arthroscopy remains a promising measurement tool because it permits physical assessment of cartilage integrity. This study sets the foundations for improvement in techniques of arthroscopic measurement of cartilage lesion size.