Faculty Bibliography

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.

The Wnt pathway is upregulated in tendinopathy, affecting inflammation and tenocyte differentiation. Given its potential role in tendinopathy, this signaling pathway may be a relevant target for treatment. The current study examined the therapeutic potential of SM04755, a topical, small-molecule Wnt pathway inhibitor, for the treatment of tendinopathy using in vitro assays and animal models. In vitro, SM04755 decreased Wnt pathway activity, induced tenocyte differentiation, and inhibited catabolic enzymes and pro-inflammatory cytokines in human mesenchymal stem cells, rat tendon-derived stem cells, and human peripheral blood mononuclear cells. Evaluation of the mechanism of action of SM04755 by biochemical profiling and computational modeling identified CDC-like kinase 2 (CLK2) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) as molecular targets. CLK and DYRK1A inhibition by siRNA knockdown or pharmacological inhibition induced tenocyte differentiation and reduced tenocyte catabolism. In vivo, topically applied SM04755 showed therapeutically relevant exposure in tendons with low systemic exposure and no detectable toxicity in rats. Moreover, SM04755 reduced tendon inflammation and showed evidence of tendon regeneration, decreased pain, and improved weight-bearing function in rat collagenase-induced tendinopathy models compared with vehicle control. Together, these data demonstrate that CLK2 and DYRK1A inhibition by SM04755 resulted in Wnt pathway inhibition, enhanced tenocyte differentiation and protection, and reduced inflammation. SM04755 has potential to benefit symptoms and modify disease processes in tendinopathy. This article is protected by copyright. All rights reserved.

Background/Purpose: Lorecivivint (LOR), a novel intra-articular (IA) CLK/DYRK inhibitor that modulates Wnt and inflammatory pathways, is in development as a knee osteoarthritis (OA) treatment. To further evaluate the safety and exploratory efficacy of a single LOR injection that was administered into the target knee joint of subjects with moderate to severe knee OA from two consecutive Phase 2 trials, an extension study was performed with the primary objective of evaluating serious adverse events (SAEs), as well as analyzing safety data for all doses and efficacy data for the (pivotal) 0.07 mg LOR dose.
Method(s): This was a 5-year, Phase 3, multicenter, observational, extension study of completer subjects (NCT02951026) from a 12-month Phase 2a (Yazici, Y. et al. Arthritis Rheumatol. 72, 1694-1706 (2020)) and a 6-month Phase 2b (Yazici, Y. et al. Osteoarthr. Cartil. In Press, (2021)) trial of LOR. The study was terminated in Year 3 as relevant long-term safety information became limited in the absence of repeated LOR administration. Subjects received a single LOR or vehicle placebo (PBO) injection at their Phase 2 parent-trial baseline visit (Month 0). Pooled data from clinic visits at 6, 12, 24, and 36 months were used to analyze safety outcomes (serious AEs, knee-related AEs, and AEs of newly diagnosed conditions needing treatment). A post hoc baseline-adjusted ANCOVA on 0, 3, 6, 12, and 18-month data points (across current and parent trials) was used to compare changes from baseline in a subject subgroup (unilateral symptoms, no widespread pain, 18-month post-injection radiograph at study termination) in WOMAC Pain and Function subscores and medial joint space width (mJSW) between 0.07 mg LOR and PBO groups.
Result(s): Of 703 subjects, 119 (17%) subjects discontinued prior to study termination. Subject characteristics are shown in Table 1. The safety analysis set included 495 LOR-treated subjects and 208 control subjects (Table 2). Four AEs in 3 (0.6%) subjects across LOR groups were considered related to the study drug; no subjects withdrew from the study due to a treatment-related AE. Incidence was similar between LOR and PBO groups. Sixty-eight SAEs in 38 (5.4%) subjects were reported with none considered related to treatment by investigators. One death occurred in the control group. Post hoc efficacy analyses demonstrated that subjects in the 0.07 mg LOR group (n=59) showed greater mean improvements from baseline in both WOMAC Pain and Function at 6 (Pain: -8.16, 95% CI [-15.60, -0.71], P=0.032; Function: -9.47 [-17.09, -1.84], P=0.015) and 12 (Pain: -8.51 [-15.17, -1.85], P=0.013; Function: -9.62 [-16.83, -2.42], P=0.009) months vs. subjects in the control group (n=70) (Figure 1). No mJSW progression was observed in any group over 18 months. Limitations included using subjects (completers) more likely to be responders and not controlling for other treatments in the extension study period.
Conclusion(s): LOR appeared safe and well tolerated. Efficacy analyses on the described subset of completer subjects demonstrated durable symptom improvements in WOMAC Pain and Function for up to at least 12 months vs. contr ols

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: Knee osteoarthritis (OA) is a painful condition leading to joint damage and impaired function. Intra-articular (IA) corticosteroid injections are frequently prescribed to treat pain. Lorecivivint (LOR), a novel IA CLK/ DYRK inhibitor that modulates Wnt and inflammatory pathways, appeared safe and demonstrated patient-reported outcome pain and function improvements compared with placebo in a Phase 2b knee OA trial (Yazici, Y. et al. Osteoarthr. Cartil., 2021). While lorecivivint is proposed for stand-alone use, in clinical practice, providers might administer lorecivivint in close time proximity to IA corticosteroid. This open-label, parallel-arm, healthy volunteer study was conducted to assess potential safety and tolerability (primary objectives), and pharmacokinetic (PK) interactions (secondary objective), between lorecivivint and triamcinolone acetonide (TCA) when the two medications were administered 7 days apart.
Method(s): Healthy volunteers were randomized to Treatment Arm 1 (IA 40 mg TCA on Day 1 followed by IA 0.07 mg lorecivivint on Day 8) or Treatment Arm 2 (IA 0.07 mg lorecivivint on Day 1 followed by IA 40 mg TCA on Day 8). All injections were performed on the right knee. For each treatment arm, treatment-emergent adverse events (TEAEs) were categorized by epoch, with Epoch 1 spanning from first until second injection, and Epoch 2 spanning from second injection until end of study. In Treatment Arm 1, plasma TCA levels were assessed on Days 1 (before TCA dosing and up to 12 h after), 2 (24 h after), 3, 5, 8 (before lorecivivint dosing and up to 8 h after), 11, and 15. Plasma lorecivivint concentrations were assessed on Day 8 (before lorecivivint dosing and up to 8 h after). In Treatment Arm 2, plasma lorecivivint levels were assessed on Days 1 (before lorecivivint dosing and up to 8 h after), 8 (up to 8 h after TCA dosing), 9 (24 h after), 10, and 12. Plasma TCA levels were assessed on Days 8 (before TCA dosing and up to 12 h after), 9 (24 h after), 10, 12, 15, 18, and 22.
Result(s): Forty subjects (n=20/arm; age 41.3+/-7.2 years; BMI 27.8+/-2.98 kg/m²; female 40.0%) were evaluated. A total of 18 TEAEs were reported by 11 (27.5%) subjects (Table 1). TEAEs were similar between arms and there were no serious adverse events. In all subjects and at all time points, plasma lorecivivint concentrations were below the limit of quantification (0.1 ng/mL). Geometric mean concentrations (Figure 1) and PK parameters for TCA were similar between treatment arms.
Conclusion(s): There were no quantifiable plasma concentrations of lorecivivint in either treatment arm, and the PK of TCA was unaffected by previous lorecivivint injection. No safety signals were observed. These results suggest that IA administration of lorecivivint and triamcinolone in close proximity (7 days apart) should not pose a safety concern

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

OBJECTIVES/OBJECTIVE:Behçet's syndrome (BS) is a systemic vasculitis with heterogeneous clinical presentation and a relapsing disease course. The International Study Group (ISG) criteria are most often used for classification. A significant proportion of patients is classified as probable BS because they do not fulfil the criteria at initial presentation. The aim of this study is to explore clinical BS symptoms present at initial patient visit predictive of ISG criteria diagnosis during follow-up. METHODS:Patients classified as probable BS at initial visit were included. Follow-up ISG status (defined as meeting criteria ISG+ vs. not meeting criteria ISG-) was abstracted from last visit. Univariable logistic regression was used to screen initial visit clinical features and symptoms with follow-up ISG status. All variables that passed screening at p<0.10 were included in the final multivariable model, which was then used to create a probability risk score. RESULTS:189 patients were included (169 from New York and 20 from Amsterdam). 71 (37.6%) patients were classified as ISG+ during follow-up. In the final model, presence of morning stiffness, genital ulcers, skin lesions, and eye disease were associated with increased odds of ISG+, adjusting for age, symptom duration and family history. This was used to create a probability risk score. CONCLUSIONS:Over a third of patients with suspected or probable BS developed new manifestations over time that led to classification as ISG+ BS. The presence of morning stiffness, genital ulcers, skin lesions and eye disease at initial visit were independently associated with significantly higher odds for developing ISG+ Behçet's during follow-up.

OBJECTIVES/OBJECTIVE:This study assessed the efficacy and safety of apremilast for the oral ulcers associated with Behçet's syndrome (BS) up to 64 weeks. METHODS:The phase 3, double-blind, placebo-controlled RELIEF study randomised adult patients with active BS to placebo or apremilast 30 mg twice daily for 12 weeks, followed by an extension phase with all patients receiving apremilast through Week 64 and 4-week post-treatment follow-up (upon treatment discontinuation). The primary endpoint was area under the curve for the number of oral ulcers over 12 weeks (AUCWk0-12), reflecting the number of oral ulcers over time and accounting for their recurring-remitting course. Oral ulcer number, complete and partial responses, pain and disease activity and quality of life (QoL) were also assessed throughout the study. RESULTS:A total of 207 participants were randomised and received at least one dose of study medication; 178 entered the extension phase and 143 completed Week 64. AUCWk0-12 was significantly lower with apremilast versus placebo (p<0.0001), and oral ulcers number, pain, complete/partial responses, disease activity and QoL with apremilast versus placebo showed improvements at Week 12, which were maintained through Week 64. The most common adverse events were diarrhoea, nausea, headache and upper respiratory tract infection; no new safety concerns were observed with longer-term apremilast exposure. CONCLUSIONS:In patients with oral ulcers associated with BS, apremilast was efficacious and benefits were sustained up to 64 weeks with continued treatment. Apremilast was well tolerated, and safety was consistent with its known safety profile.

INTRODUCTION/BACKGROUND:Established thresholds for patient-reported outcomes (PROs) provide clinically relevant responder data from trials. Lorecivivint (LOR) is an intra-articular (IA) therapy in development for knee osteoarthritis (OA). A post hoc analysis from a phase 2b trial (NCT03122860) determined proportions of LOR responders. METHODS:A 24-week, randomized trial of 0.07 mg LOR demonstrated PRO improvements compared with PBO in moderate-to-severe knee OA participants. Participants treated with LOR and PBO achieving 30%/50%/70% improvements at weeks 12 and 24 in Pain Numeric Rating Scale (NRS), WOMAC Pain/Function subscales, Patient Global Assessment (PtGA), and OMERACT-OARSI responder criteria were determined. Odds ratios (ORs) and 95% confidence intervals [CIs] were compared with PBO. RESULTS:There were 115 and 116 participants in the LOR and PBO groups, respectively. For Pain NRS, LOR increased ORs of achieving 30% [week 12, OR = 2.47 (1.45, 4.19), P < 0.001; week 24, OR = 2.37 (1.40, 4.02), P < 0.01] and 50% [week 24, OR = 1.89 (1.11, 3.23), P < 0.05] improvements over baseline. For WOMAC Pain, LOR increased ORs of achieving 30% [week 24, OR = 1.79 (1.06, 3.01), P < 0.05] and 50% [week 12, OR = 1.79 (1.06, 3.03), P < 0.05; week 24, OR = 1.73 (1.02, 2.93), P < 0.05] improvements. For WOMAC Function, LOR increased ORs of achieving 30% [week 12, OR = 1.85 (1.10, 3.12), P < 0.05; week 24, OR = 1.93 (1.14, 3.26), P < 0.05] improvements. For PtGA, LOR increased ORs of achieving 50% [week 12, OR = 2.28 (1.25, 4.16), P < 0.01] improvements. LOR produced numerical increases at the 70% threshold. LOR increased ORs of achieving OMERACT-OARSI responses [week 12, OR = 2.21 (1.29, 3.78); P < 0.01; week 24, OR = 2.57 (1.49, 4.43), P < 0.001] and strict responses [week 12, OR = 2.13 (1.26, 3.61), P < 0.01; week 24, OR = 2.05 (1.21, 3.47), P < 0.01]. CONCLUSIONS:LOR (0.07 mg) demonstrated improved PRO threshold responses across single and composite measures of pain, function, and patient global assessment compared with PBO, with benefits sustained to 24 weeks.

Background: Behcet's syndrome, a chronic, multi-system variable vessel vasculitis, is often characterized by painful oral ulcers (OU) affecting quality of life (QoL). Apremilast (APR), an oral PDE4 inhibitor, demonstrated efficacy in OU treatment in the phase 3 multinational RELIEF study.
Objective(s): To evaluate APR efficacy in OU treatment in patients with active Behcet's syndrome in a prespecified subgroup of patients enrolled in 13 European RELIEF sites (France, Germany, Greece, and Italy).
Method(s): patients were adults with active Behcet's syndrome and >=3 OU at randomization or >=2 OU at screening and randomization, without active major organ involvement. Patients were randomized (1:1) to APR 30 mg BID or PBO during a 12-week double-blind phase. The primary endpoint was area under the curve for the number of OU through Week 12 (AUCWk0-12). Other outcomes were OU pain visual analog scale (VAS); achievement of OU complete response (ie, OU-free) and maintenance of OU complete response (ie, complete response at Week 6 and remaining OU-free for >=6 additional weeks); OU partial response (ie, OU reduction >=50%); disease activity (Behcet's Syndrome Activity Score [BSAS]; Behcet's Disease Current Activity Form [BDCAF], including Behcet's Disease Current Activity Index [BDCAI], and Patient's and Clinician's Perception of Disease Activity); and QoL (BDQoL; Short Form Health Survey version 2 [SF-36v2], including Physical Functioning [PF] scale and Physical and Mental Component Summary [PCS, MCS]).
Result(s): Of 207 patients randomized and treated in RELIEF, 52 were in the European subgroup. Mean (+/-SD) age in the subgroup was 39 (+/-12) years; 54% were women. Baseline disease characteristics were similar between treatment groups (Table 1). Patients receiving APR achieved lower AUCWk0-12 for OU vs PBO (Figure 1) and greater reduction in pain. A greater proportion of patients receiving APR achieved complete, maintained, or partial OU responses at Week 12 vs those receiving PBO (Table 1). Consistent treatment effects favoring APR vs PBO were observed in disease activity, as shown by BSAS and BDCAF component scores at Week 12 (Table 1). Greater improvement in SF-36v2 MCS was observed favoring APR vs PBO at Week 12, and moderate treatment differences were seen for other QoL measures (BDQoL, SF-36v2 PF, and SF-36v2 PCS).
Conclusion(s): In the European subgroup of patients with Behcet's syndrome and OU in RELIEF, APR resulted in greater reduction in OU count, OU pain, and disease activity as well as favorable treatment effect on QoL measures than PBO. These results are consistent with the efficacy of APR treatment in the overall RELIEF population