Faculty Bibliography

OBJECTIVE:There is an unmet need for reliable, validated, and widely-accepted outcome measures for randomized clinical trials in Behçet syndrome (BS). The Outcome Measures in Rheumatology Clinical Trials (OMERACT) BS Working Group, a large, multi-disciplinary group of experts in BS and patients with BS, worked to develop a Core Set of data-driven outcome measures for use in all clinical trials of BS. METHODS:The Core Domain Set was developed through a comprehensive, iterative, multi-stage project which included a systematic review, a focus group meeting and qualitative patient interviews, a survey among experts in BS, a Delphi exercise involving both patients and physician-experts in BS, and utilization of the data, insight, and feedback generated by these processes to develop a final Core Domain Set. RESULTS:All steps were completed and domains were delineated across the organ systems involved in this disease. Since trials in BS often focus on specific manifestations and not the disease in its entirety, the final proposed Core Set includes 5 domains mandatory for study in all trials in BS (disease activity, new organ involvement, quality of life, adverse events, and death) with additional sub-domains mandatory for study of specific organ-systems. The final Core Set was endorsed at the 2018 OMERACT meeting. CONCLUSION/CONCLUSIONS:The Core Set of Domains in BS provides the foundation through which the international research community, including clinical investigators, patients, biopharmaceutical industry, and government regulatory bodies can harmonize the study of this complex disease, compare findings across studies, and advance development of effective therapies.

BACKGROUND/UNASSIGNED:Durable, meaningful symptom responses to intra-articular saline placebo injections are observed in knee osteoarthritis (OA) trials, but it is unclear if these are due to physiological effects. PURPOSE/UNASSIGNED:To perform a prospective comparison of patient-reported outcome responses among participants with knee OA who underwent intra-articular injection of saline-based placebo or sham (dry needle). STUDY DESIGN/UNASSIGNED:Randomized controlled trial; Level of evidence, 2. METHODS/UNASSIGNED:From a 24-week randomized double-blind trial, participants with moderate to severe knee OA received 2-mL intra-articular injections of saline-based placebo (PBO; 99.45% PBS) or sham (dry needle) to the target knee. Least squares mean differences of changes from baseline to week 24 were compared between the PBO and sham groups for the following: pain Numeric Rating Scale; Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, stiffness, and function; and patient global assessment. Bang Blinding Index was used to evaluate all-group blinding on day 1 and week 24. RESULTS/UNASSIGNED:= .68). Bang Blinding Index indicated that blinding was maintained. CONCLUSION/UNASSIGNED:PBO and sham groups demonstrated equivalent patient-reported outcomes at all time points through week 24, suggesting that responses attributed to saline were contextual (ie, to the procedure) and not physiological. REGISTRATION/UNASSIGNED:NCT03122860 (ClinicalTrials.gov identifier).

Behcet syndrome is a systemic vasculitis with an unknown aetiology affecting the small and large vessels of the venous and arterial systems. The presence of symptom clusters, regional differences in disease expression and similarities with, for example, Crohn's disease suggest that multiple pathological pathways are involved in Behcet syndrome. These disease features also make formulating disease criteria difficult. Genetic studies have identified HLA-B*51 as a genetic risk factor. However, the low prevalence of HLA-B*51 in many patients with bona fide disease, especially in non-endemic regions, suggests that other factors must also be operative in Behcet syndrome. Despite lacking a clear aetiological mechanism and definition, management of manifestations that include major vascular disease, eye disease and central nervous system involvement has improved with the help of new technology. Furthermore, even with our incomplete understanding of disease mechanisms, the prognoses of patients with Behcet syndrome, including those with eye disease, continue to improve. New treatment options and a better understanding of the underlying pathogenesis for various manifestations of this condition are required to further improve the management of the disease, which will improve patient quality of life.
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There are important problems with the data analyses, interpretation, and the cited references in the recently reported retrospective cohort study of Takayasu arteritis (TAK) (1).

Behçet syndrome is a systemic vasculitis with an unknown aetiology affecting the small and large vessels of the venous and arterial systems. The presence of symptom clusters, regional differences in disease expression and similarities with, for example, Crohn's disease suggest that multiple pathological pathways are involved in Behçet syndrome. These disease features also make formulating disease criteria difficult. Genetic studies have identified HLA-B*51 as a genetic risk factor. However, the low prevalence of HLA-B*51 in many patients with bona fide disease, especially in non-endemic regions, suggests that other factors must also be operative in Behçet syndrome. Despite lacking a clear aetiological mechanism and definition, management of manifestations that include major vascular disease, eye disease and central nervous system involvement has improved with the help of new technology. Furthermore, even with our incomplete understanding of disease mechanisms, the prognoses of patients with Behçet syndrome, including those with eye disease, continue to improve. New treatment options and a better understanding of the underlying pathogenesis for various manifestations of this condition are required to further improve the management of the disease, which will improve patient quality of life.

Background/Purpose: Painful, recurring oral ulcers (OU) associated with Behcet's syndrome negatively affect quality of life (QoL). Differences across sexes were reported in the frequency of disease manifestations, disease course, and response to colchicine. The phase 3, randomized, double-blind, placebo (PBO)-controlled RELIEF study showed overall efficacy of apremilast (APR) for OU associated with Behcet's syndrome, including improvements in OU pain, disease activity, and QoL. The objective of this subgroup analysis is to evaluate the consistency of efficacy with APR in men and women with Behcet's syndrome.
Method(s): Adults with active Behcet's syndrome and >=3 OU at randomization or >=2 OU at screening and randomization, without active major organ involvement, were randomized to APR 30 mg BID or PBO during the 12-week PBO-controlled treatment phase. Randomization was stratified by sex. The primary endpoint was area under the curve for the number of OU through Week 12 (AUCWk0-12 ) to assess continued efficacy over the time period in a symptom that waxed and waned. Key secondary endpoints included OU pain, complete response (OU-free), maintenance of complete response, and QoL at Week 12. Disease activity was also assessed using Behcet's Syndrome Activity Score (BSAS) and Behcet's Disease Current Activity Index Form (BDCAF). QoL was assessed using Behcet's Disease QoL (BDQoL). Prespecified subgroup analyses in men and women were performed to assess treatment effect in primary and secondary endpoints.
Result(s): Eighty men and 127 women were randomized and received >=1 dose of study medication. Mean age was 38.7 years (men) and 40.8 years (women). Mean (SD) OU count at baseline was 3.4 (1.4) (PBO) and 3.7 (1.5) (APR) for men and 4.3 (3.2) (PBO) and 4.5 (4.5) (APR) for women. Greater improvements in favor of APR vs PBO were observed in AUCWk0-12 in men and women (Figure). Consistency in efficacy with APR was observed between men and women, with greater reduction in pain and achievement of OU complete response (OU-free) and maintenance of response at Week 12 vs PBO (Table). In men and women, consistent treatment effects in favor of APR vs PBO were observed for disease activity and QoL measures, although moderate treatment differences were observed in BDCAI (men/women) and BDQoL (men) (Table).
Conclusion(s): Consistent treatment effects in favor of APR vs PBO in clinically relevant outcomes, including OU number and pain, OU complete response, and disease activity measures, were observed in men and women with OU associated with Behcet's syndrome

Background/Purpose: Meniscal injuries are the most common pathology of the knee and are associated with pain, stiffness, and localized swelling. Meniscal damage is a frequent finding on MRI images of knee osteoarthritis (OA).1 Efforts to repair meniscal damage have been largely unsuccessful and do not prevent the progression of degenerative changes that lead to knee OA.2 The Wnt signaling pathway has been shown to be regulated during meniscal development,3 suggesting that manipulation of this pathway may influence the regenerative capacity of the meniscus. Lorecivivint (LOR; SM04690) is an intra-articular (IA), small-molecule CLK/DYRK inhibitor that modulates the Wnt pathway.4 LOR was evaluated in preclinical studies to determine its protective and anabolic effects in ex vivo explants and in a rat model of chemically induced inflammatory meniscal degeneration.
Method(s): Effects of LOR (30 nM) on matrix metalloproteinase (MMP) expression in cultured rat menisci treated with IL-1b were measured by qRT-PCR. In vivo, LOR activity was evaluated in a rat model of monosodium iodoacetate (MIA) injection-induced inflammatory meniscal degeneration. A single IA injection of MIA was immediately followed by a single IA injection of LOR (0.3 mg) or vehicle. Knees were harvested on Days 1, 4, and 11 and menisci were isolated. Anti-inflammatory effects were evaluated by qRT-PCR for TNFA and IL6 expression. Meniscal protection was evaluated by qRT-PCR for MMPs and aggrecanase. Anabolic effects were evaluated by qRT-PCR for collagens.
Result(s): In ex vivo meniscal explants, LOR inhibited expression of MMP1, MMP3, and MMP13 compared with DMSO (P< 0.01). In vivo, LOR significantly decreased expression of MMPs and aggrecanase (P< 0.05) and reduced expression of inflammatory cytokines TNFA and IL6 compared with vehicle in the rat model of inflammatory meniscal degeneration at Day 4 after MIA injection. Additionally, LOR increased expression of collagen types I, II, and III at Day 11 after MIA injection (Figure 1).
Conclusion(s): LOR exhibited protective effects in the meniscus ex vivo and in vivo by reducing catabolic enzyme expression compared with control. Anti-inflammatory effects of LOR were demonstrated by inhibition of inflammatory cytokine expression. Compared with vehicle, LOR increased collagen expression in vivo, indicating potential meniscal anabolic effects. These data support further investigation of LOR as a potential structure-modifying treatment for meniscal injuries