Faculty Bibliography

Dual-specificity tyrosine phosphorylation-regulated kinase-1A (DYRK1A) is known to phosphorylate the microtubule-associated tau protein. Overexpression is correlated with tau hyperphosphorylation and neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD). This study assessed the potential of SM07883, an oral DYRK1A inhibitor, to inhibit tau hyperphosphorylation, aggregation, NFT formation, and associated phenotypes in mouse models. Exploratory neuroinflammatory effects were also studied. SM07883 specificity was tested in a kinase panel screen and showed potent inhibition of DYRK1A (IC₅₀  = 1.6 nM) and GSK-3β (IC₅₀  = 10.8 nM) kinase activity. Tau phosphorylation measured in cell-based assays showed a reduction in phosphorylation of multiple tau epitopes, especially the threonine 212 site (EC₅₀  = 16 nM). SM07883 showed good oral bioavailability in multiple species and demonstrated a dose-dependent reduction of transient hypothermia-induced phosphorylated tau in the brains of wild-type mice compared to vehicle (47%, p < 0.001). Long-term efficacy assessed in aged JNPL3 mice overexpressing the P301L human tau mutation (3 mg/kg, QD, for 3 months) exhibited significant reductions in tau hyperphosphorylation, oligomeric and aggregated tau, and tau-positive inclusions compared to vehicle in brainstem and spinal cord samples. Reduced gliosis compared to vehicle was further confirmed by ELISA. SM07883 was well tolerated with improved general health, weight gain, and functional improvement in a wire-hang test compared to vehicle-treated mice (p = 0.048). SM07883, a potent, orally bioavailable, brain-penetrant DYRK1A inhibitor, significantly reduced effects of pathological tau overexpression and neuroinflammation, while functional endpoints were improved compared to vehicle in animal models. This small molecule has potential as a treatment for AD.

Background/Purpose : Behcet's syndrome is a chronic, multi-system inflammatory disorder characterized by painful, recurrent oral ulcers (OU) that can impair quality of life (QoL). Apremilast (APR), an oral phosphodiesterase 4 inhibitor, demonstrated efficacy in the treatment of OU of Behcet's syndrome in a phase III, multicenter, randomized, double-blind, placebo (PBO)-controlled study (RELIEF). We report short-and long-term results from RELIEF for the efficacy of APR treatment on QoL and physical function for up to 64 weeks. Methods : A total of 207 patients were randomized (1:1) to APR 30 mg twice daily (APR 30 BID) or PBO twice daily for a 12-week PBO-controlled phase, followed by a 52-week active treatment extension. Eligible patients were >=18 years old, had active Behcet's syndrome, with >=3 OU at randomization or >=2 OU at screening and randomization ry endpoint and change from baseline in BDQoL score and SF-36v2 PCS, MCS and PF scores at Week 12. Data at Week 64 are as observed. Results : The primary efficacy endpoint of AUCWk0-12 for the number of OU was significantly lower in APR 30 BID vs PBO patients ( P < 0.0001); improvement in the number of OU and OU pain was sustained in patients continuing APR 30 BID treatment for up to 64 weeks and emerged in patients switched from PBO to APR 30 BID for Weeks 12 to 64. Significant improvements were observed with APR 30 BID vs PBO in mean change from baseline at Week 12 in BSAS ( P < 0.0001), BDCAF components ( P <=0.0335), and BDQoL score ( P =0.0003). The improvements in BSAS, BDCAF, and BDQoL outcomes were maintained in patients continuing APR 30 BID treatment for up to 64 weeks, and comparable effects were observed at Week 64 among patients who switched from PBO to APR 30 BID. Significant improvements were also observed in mean change from baseline at Week 12 in SF-36v2 PCS ( P =0.0204), MCS ( P < 0.0001), and PF ( P =0.0060) scores in APR 30 BID vs PBO patients. These effects in SF-36v2 scores were also maintained at Week 64 among patients initially randomized to APR 30 BID, and the improvements were generally similar among patients who switched from PBO to APR 30 BID (Table). Conclusion : Patients with active Behcet's syndrome treated with APR 30 BID vs PBO experienced significant reductions in OU and clinically meaningful improvements at Week 12 in disease activity and QoL. Improvements were sustained at Week 64 in patients continuing APR treatment

Osteoarthritis (OA) may be associated with substantial work disability, morbidity, costs, and increased mortality rates, often similar to rheumatoid arthritis (RA), documented in many published reports over the last 4 decades. However, OA generally has been viewed as less severe than RA. This discrepancy may be explained in part by:a) RA may have been considerably more severe in the past, prior to effective therapies.b) most older individuals have radiographic joint damage, which often is not associated with clinical symptoms.c) RA is associated with abnormal laboratory tests, which are regarded as conveying greater significance than symptoms of pain and disability according to a "biomedical model," the dominant paradigm of modern medicine.d) Most reports of OA and RA have emphasised differences between the 2 diseases even beyond laboratory abnormalities in pathogenesis, physical findings, and imaging.e) Even pain and functional disability seen in both diseases are assessed using different patient self-report questionnaires, a WOMAC (Western Ontario McMaster Universities osteoarthritis index) in OA, and HAQ (health assessment questionnaire) in RA.An identical measure is required for optimal direct comparisons, which has been used in 8 studies performed between 1979 and 2019 at 8 sites in North America, Europe, and Australia. These studies were primarily based on retrospective analyses at sites which collected a patient questionnaire in routine clinical care by all patients at all visits to inform clinical decisions. A pain visual analogue scale (VAS) was higher in OA compared to RA in 11/12 patient groups, while physical function on a HAQ (health assessment questionnaire) or derivative MDHAQ (multidimensional HAQ) and RAPID3 (routine assessment of patient index data) were slightly higher in RA before 2013 and higher in OA in later reports. Furthermore, a study of population-based data from the 1978 US Health Interview Survey indicated similar levels of disability and earnings losses according to surrogate variables for OA and RA. Therefore, at least over the last 40 years, pain and functional disability in OA have appeared to be severe and similar to RA. These observations also-illustrate the potential value of using an identical patient questionnaire in all patients at all visits in routine care settings, analogous to using the same laboratory tests such as erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) in all rheumatic diseases, and maintaining a database of the results for later analyses.

The RELIEF study assessed apremilast (APR) efficacy and safety for oral ulcers (OU) associated with Behcet's syndrome, a chronic disorder characterized by recurrent OU that can impact quality of life (QoL). Adult patients (pts) with active Behcet's syndrome (>=3 OU at randomization or >=2 OU at screening and randomization without active major organ involvement) were randomized (1:1) to placebo (PBO) or APR 30 mg twice daily for 12 wks and then continued APR (APR/APR) or switched from PBO to APR (PBO/APR) through Wk 64. Pts then entered a 4-wk posttreatment observational follow-up. The primary endpoint, area under the curve for the number of OU over 12 wks (AUCWk0-12), reflects the number of OU over time and accounts for the recurring-remitting course of OU. Change from baseline in OU pain visual analogue scale, complete response (% of pts with no OU), partial response (% of pts with >=50% reduction in OU count), disease activity (Behcet's Disease Current Activity Form, comprising the Behcet's Disease Current Activity Index [BDCAI], Pt's and Clinician's Perception of Disease Activity and Behcet's Syndrome Activity Score [BSAS]) and QoL (Behcet's Disease QoL [BDQoL]) were assessed. Of 207 pts randomized and receiving >=1 dose of study medication (PBO: n = 103; APR: n = 104), 178 entered the active treatment phase (PBO/APR: n = 83; APR/APR: n = 95); 143 pts (PBO/APR: n = 68; APR/APR: n = 75) completed Wk 64. AUCWk0-12 was significantly lower with APR vs PBO (LS mean difference [95% CI]: -92.6 [-130.6, -54.6]; P<0.0001). Significantly lower OU counts (P<=0.0015) and greater improvement from baseline in OU pain (P<=0.0035) were observed with APR vs PBO each wk from Wks 1- 12, and the efficacy of APR was sustained up to 64 wks. Significantly more pts achieved complete and partial response of OU at Wk 12 with APR vs PBO (P<0.0001); effects were maintained through Wk 64 in APR/APR pts who remained in the study (complete response: 53.3%; partial response: 76.0%). Improvements in BDCAI (P = 0.0335), BSAS (P<0.0001) and BDQoL (P = 0.0003) were significant with APR vs PBO at Wk 12 and maintained at Wk 64. Improvements decreased within 4 wks of APR discontinuation. The most common adverse events with APR were diarrhoea, nausea, headache and upper respiratory tract infection; no new safety concerns emerged. APR demonstrated efficacy in OU in pts with active Behcet's syndrome that was sustained up to 64 wks with continued treatment. Safety was consistent with APR's known profile

Background: The Routine Assessment of Patient Index Data 3 (RAPID3) is an outcome measure of disease activity widely used in the USA as part of routine care1 and is entirely derived from patient self-reported measures (Health Assessment Questionnaire-Disability Index [HAQ-DI] or multidimensional HAQ [MDHAQ], Pain visual analog scale [VAS] and Patient's Assessment of Disease Activity [PtGA] VAS). However, the lack of more objective, traditional physician assessments, such as joint counts, may lead to residual active disease that will be missed.
Objective(s): To examine trajectories for improvement in RAPID3 score over time and PsA manifestations not measured specifically by RAPID3 in subjects achieving RAPID3 near remission (REM) or low disease severity at Week 52.
Method(s): Pooled analyses of the phase III PALACE 1, 2 and 3 studies were performed for subjects assigned to receive APR 30 mg twice daily (BID) at baseline (BL). Subjects with available scores on RAPID3 components (HAQ-DI, Pain VAS and PtGA VAS) at Week 52 were included and grouped according to RAPID3 categories at Week 52 (near REM: <=3; low: >3 to <=6; moderate: >6 to <=12; and high: >12 to 30). Mean RAPID3 scores were assessed from BL through Week 52. Other measures of PsA disease activity were reported longitudinally by RAPID3 category at Week 52.
Result(s): The analysis included 376 APR subjects, with 42 with near REM and 42 with low severity at Week 52. Overall, mean RAPID3 trajectories improved overtime with greater mean improvements observed for those achieving RAPID3 near REM and low disease severity by Week 52. At a mean level, subjects in moderate RAPID3 at baseline were associated with achievement of RAPID3 near REM or low disease severity by Week 52 with APR (Figure). Many subjects who achieved RAPID3 near REM or low disease severity at Week 52 showed improvements in articular and extra-articular disease activity, although not all manifestations were controlled at Week 52 (Table); mean TJC was higher than expected in subjects achieving RAPID3 targets at Week 52 and there was no association between low mean RAPID3 and mean Psoriasis Area and Severity Index (PASI) scores.
Conclusion(s): At a mean level, subjects in moderate RAPID3 at baseline were associated with achievement of RAPID3 near REM or low disease severity targets with APR by Week 52. Achievement of RAPID3 targets was associated with improvement, but not necessarily control, of all articular and extra-articular manifestations. Complementing the RAPID3 measure with joint and skin assessments may help to evaluate achievement of treatment goals in clinical practice

Background: Behcet's syndrome is a chronic, relapsing, multi-system inflammatory disorder characterized by recurrent oral ulcers (OU) that can impact quality of life (QoL).
Objective(s): To assess apremilast (APR) efficacy and safety for the treatment of OU associated with Behcet's syndrome in the phase III RELIEF study for up to 64 wks and at 4-wk follow-up (after APR discontinuation).
Method(s): Adult patients (pts) with active Behcet's syndrome (defined by 3 OU at randomization or 2 OU at screening and at randomization without active major organ involvement) were randomized (1:1) to placebo (PBO) or APR 30 mg twice daily for 12 wks. All pts then received APR through Wk 64. Pts who completed the Wk 64 visit or discontinued treatment at any time and for any reason in the study entered a 4-wk posttreatment observational follow-up. The primary endpoint was area under the curve for the number of OU over 12 wks (AUCWk0-12), which reflects the number of OU over time and accounts for the recurring-remitting course of OU. Other outcomes included change from baseline in OU pain VAS, complete response (% of pts with no OU) or partial response (% of pts with 50% reduction in number of OU), disease activity (Behcet's Disease Current Activity Form [BDCAF], composed of the Behcet's Disease Current Activity Index [BDCAI], Pt's and Clinician's Perception of Disease Activity and Behcet's Syndrome Activity Score [BSAS]), and QoL (Behcet's Disease QoL [BDQoL]).
Result(s): A total of 207 pts were randomized and received 1 dose of study medication (PBO: N=103; APR: N=104); 178 pts entered the active treatment phase (PBO/APR: N=83; APR: N=95) and 143 pts (PBO/APR: N=68; APR: N=75) completed Wk 64. The primary endpoint of AUCWk0-12 was achieved; significantly lower AUCWk0-12 was observed for APR vs PBO (P<0.0001). Significantly lower OU counts (P0.0015) and OU pain (P0.0035) were observed with APR vs PBO from Wks 1 through 12; APR efficacy was sustained up to 64 wks (Figure). Significantly greater improvements with APR were observed in complete and partial response of OU at Wk 12 (P<0.0001); effects were maintained through Wk 64 (53.3% and 76.0%, respectively). Pts initially randomized to PBO and switched to APR at Wk 12 showed comparable benefits through Wk 64 (Figure). Improvements in disease activity (BDCAI: P=0.0335; BSAS: P<0.0001) and QoL (BDQoL: P=0.0003) were significant in pts receiving APR vs PBO at Wk 12 and maintained at Wk 64. Comparable effects in pts who switched from PBO to APR were observed at Wk 64. After APR was discontinued before or at Wk 64, the improvements in OU assessments decreased within 4 wks. Disease activity measures and BDQoL similarly indicated recurrence of symptoms at the 4-wk follow-up. Incidence of any adverse event (AE) was comparable for pts initially randomized to APR vs PBO during the PBO-controlled period (78.8% vs 71.8%) and through Wk 64 for pts who continued APR vs pts who switched from PBO to APR (84.3% vs 86.5%). The most common AEs with APR were diarrhea, nausea, headache and upper respiratory tract infection; most AEs were mild/moderate in severity, and no new safety concerns were identified.
Conclusion(s): APR demonstrated efficacy in the treatment of OU in pts with active Behcet's syndrome. Benefits were sustained for up to 64 wks with continued treatment. APR was well tolerated, and safety was consistent with the known safety profile of APR

Background: There is an unmet need for reliable, validated, and widelyaccepted outcome measures for clinical trials in Behcet's syndrome (BS).
Objective(s): The Outcome Measures in Rheumatology Clinical Trials (OMERACT) Behcet's Syndrome Working Group has worked to advance the creation of a data-driven Core Domain Set for use in all clinical trials.
Method(s): The Core Domain Set was developed through a comprehensive, iterative, multi-stage, multi-year project that followed the methodologically rigorous processes and standards set forth by OMERACT: I) a systematic review; ii) a survey among experts in BS; iii) an outcome measures interest group meeting during the International Conference on Behcet's Disease; iv) qualitative patient interviews; v) a three-round modified Delphi exercise involving both patients with BS and a multidisciplinary set of physicians expert in BS, focused on obtaining consensus on the domains of illness necessary in the study of BS; and vi) utilization of the data, insight, and feedback generated by the outlined processes to develop a final Core Domain Set. The final Core Set was presented and put up for a vote of endorsement at the 2018 OMERACT meeting.
Result(s): All steps in the processes outlined were completed. The systematic review clearly demonstrated the substantial variability in the domains studied in clinical trials of BS and a lack availability of validated outcome measures in BS. The survey of physicians, the in-person meeting of experts, and the qualitative research with patients all helped generate an extensive list of candidate domains and sub-domains to consider for use in clinical trials. It also become clear that there was a need and strong interest in delineating domains across the several major organ systems involved in this disease and in recognizing that clinical trials in BS often focus on specific manifestations and not the disease in its entirety. The Delphi involved 74 physicians expert in BS from 21 countries and from a wide range of specialties, and 64 patients from 10 countries. The Delphi utilized both ratings and rankings to prioritize the 56 domains and subdomains originally under consideration. The final proposed Core Set included 5 sub-domains mandatory for study in all trials in BS, with additional sub-domains mandatory for study of specific organ-systems when that system is the focus of a trial: Mucocutaneous (2 additional sub-domains), ocular (4), central nervous system (3), musculoskeletal (2), vascular (4), and gastrointestinal (2). The final Core Set was strongly endorsed at the 2018 OMERACT meeting.
Conclusion(s): Multiple disease-related domains in BS have been identified by physicians and patients as important to address in clinical trials, leading to the development and endorsement of a final Core Set of Domains for use in clinical trials in BS. The Core Set provides the foundation through which the international research community, including clinical investigators, patients, the biopharmaceutical industry, and government regulatory bodies can harmonize the study of this complex disease, compare findings across studies, and advance development of effective agents

Objectives/UNASSIGNED:Rheumatoid arthritis (RA) is an autoimmune disease accompanied by pain, joint stiffness, and swelling, impacting quality of life. RA is also an articular disorder affecting multiple organ systems. Oxidative stress and antioxidants may play a role in the disease process. The oxidative balance score (OBS) is a composite estimate of exogenous dietary, lifestyle, and medication factors associated with antioxidant and pro-oxidant properties. This study examined the relationship between OBS and disease activity in RA. Methods/UNASSIGNED:-defined pro-oxidant (polyunsaturated fatty acid and iron) and antioxidant (selenium, vitamin C, vitamin E, α-carotene, β-carotene, lutein + zeaxanthin, lycopene, cryptoxanthine; use of aspirin and non-steroidal anti-inflammatory drugs, and alcohol) exposure factors. A higher OBS scored indicated more antioxidant and less pro-oxidant exposure. Partial correlations examined the relationship between OBS and disease activity, while controlling for age, using IBM SPSS Statistics. Results/UNASSIGNED: = 0.103); as OBS increased, physical function, pain, and disease activity improved. No statistically significant relationships were seen between OBS and the other measures of disease activity. Conclusions/UNASSIGNED:In this study, a higher OBS score was associated with lower disease activity. More research is needed to understand the relationship of these lifestyle exposures to RA. Funding Sources/UNASSIGNED:NYU Steinhardt Research Challenge Grant.