Faculty Bibliography

Background/Purpose : The Routine Assessment of Patient Index Data 3 (RAPID3) is an outcome measure of disease activity 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). The Clinical Disease Activity in Psoriatic Arthritis (cDAPSA; 0-154) includes objective and subjective physician assessments (i.e., a composite of swollen and tender joints counts [SJC and TJC]), along with Patient's Assessment of Pain (PAP) and PtGA. In subjects receiving apremilast (APR), we examined trajectories for improvement in RAPID3 scores among subjects achieving RAPID3 near remission (REM) or low severity, cDAPSA among subjects achieving cDAPSA REM or low disease activity (LDA), and psoriatic arthritis (PsA) manifestations not measured by either outcome measure by Week 52. Methods : Pooled analyses of the phase III PALACE 1, 2, and 3 studies were performed for subjects assigned to receive APR 30 mg BID at baseline (BL). Subjects with available scores on RAPID3 and cDAPSA components at Week 52 were included and grouped according to RAPID3 categories at Week 52 (near REM: <3; low severity: >3 to <6; moderate severity: >6 to <12; and high severity: >12 to 30) and cDAPSA categories at Week 52 (REM: <4; LDA: >4 to <13; moderate disease activity: >13 to <27; high disease activity: >27). Mean RAPID3 and cDAPSA scores were assessed from BL through Week 52. Other measures of PsA disease activity were reported longitudinally by RAPID3 and cDAPSA categories at Week 52. Results : The RAPID3 and cDAPSA analysis included 376 and 375 APR subjects, respectively. Achievement of near REM or low severity (RAPID3) or REM or LDA (cDAPSA) by Week 52 with APR were associated with improvements over time in mean RAPID3 ( Figure 1 ) and cDAPSA ( Figure 2 ) trajectories. Subjects who achieved cDAPSA treatment targets were associated with no or mild articular and extra-articular manifestations at Week 52. Achieving RAPID3 treatment targets at Week 52 was associated with improvements in articular and extra-articular disease activity, although not all manifestations were controlled at Week 52 ( Table ). In both RAPID3 and cDAPSA analyses, similar improvements in SJC and TJC were observed for patients with REM or low severity (RAPID3) or REM or LDA (cDAPSA) at Week 52. In the RAPID3 analysis, mean TJC was higher than expected at Week 52, and achieving near REM RAPID3 scores was not associated with lower mean Psoriasis Area and Severity Index scores. Conclusion : Subjects who achieved RAPID3 and cDAPSA targets showed early improvements in disease activity by Week 16 and sustained improvements to Week 52 with continued treatment. Achievement of treatment targets was also associated with improvements in other domains not captured directly by RAPID3 or cDAPSA. Given that some patients may exhibit different disease outcomes from the population, a more comprehensive assessment may help better evaluate treatment targets.

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

Background/Purpose : Oral ulcers, the hallmark lesion of Behcet's syndrome (BS) can be disabling and impair eating, drinking and speaking. Despite recent advances in systemic medications for the treatment of oral ulcers, some patients do not achieve complete remission. Topical agents may help such patients by decreasing the pain and duration of oral ulcers. Pentoxifylline (PTX) is a methylxanthine derivative that inhibits phosphodiesterase and is thought to have immunomodulatory effects in addition to improving blood flow which is its main reason for use in peripheral vascular disorders. The aim of this study is to assess the efficacy and safety of PTX gel for oral ulcers in patients with BS. We also aimed to explore the best tools for the assessment of treatment response to topical agents in randomized controlled trials (Clinicaltrial.gov ID: NCT 03888846). Methods : This was an open-label, randomized, parallel group study comparing PTX gel in addition to colchicine (PTX-COL) with colchicine alone (COL). Patients with BS who were treated with colchicine and not using any other systemic medications for BS, having at least one oral ulcer that appeared during the last 48 hours were included. PTX 5% gel with a dose of 1000 mg/day was applied in 4 divided doses per day for 14 days. Patients were contacted daily for 14 consecutive days. Photographs were taken every 24 -48 hours and graphical processing software was used to calculate the area of the index ulcer. Duration of the index ulcer, time to start of index ulcer shrinkage, time to 50% reduction in oral ulcer pain on a 10 mm visual analog scale (VAS), change from baseline in the area of the index ulcer over time, total number of oral ulcers and adverse events were evaluated. A total of 60 patients are planned to be recruited. We present here results of the interim analysis of the first 21 patients. Results : A total of 21 patients (ratio M:F 1:1.1, mean age:39.9 years), 11 in the PTX-COL group and 10 in the COL group have completed the study at the time of this analysis. One patient in the PTX-COL group withdrew from the study after day 1 and was not included in the current analysis. Mean duration of index ulcer, time to start of index ulcer shrinkage, time to 50% reduction in oral ulcer pain, and total number of oral ulcers during 14 days in each group were lower in the PTX-COL group as presented in the Table. Change from baseline in the area of index ulcer over time is shown in the Figure. There were no serious adverse events. Seven patients in the PTX-COL group reported transient discomfort and nausea while they kept the gel in their mouth, 1 patient withdrew from the study for this reason. Conclusion : The preliminary analysis of the first 21 patients of this open label, randomized trial showed that PTX gel may be a promising agent for decreasing the duration and pain of oral ulcers in patients with BS: However, caution is required when interpreting these results in a yet small number of patients. Duration of oral ulcers, time to start of ulcer shrinkage and 50% reduction in pain score seem to be relevant outcomes for studying topical agents in RCTs for oral ulcerations of BS. (Figure Presented)

Background: Behcet syndrome is a chronic, multisystem 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).
Method(s): A total of 207 patients were randomized (1:1) to APR 30 mg BID or PBO BID for a 12-week PBO-controlled phase, followed by a 52-week active treatment extension. Eligible patients were >=18 years old, had active Behcet syndrome, with >=3 OU at randomization or >=2 OU at screening and randomization, and without active major organ involvement. The primary efficacy endpoint was area under the curve for the number of OU from baseline through 12 weeks (AUCWk0-12). Clinical improvement of OU was evaluated by assessments of OU pain (100 mm VAS) and measures of disease activity and QoL. Disease activity measures included the Behcet Disease Current Activity Index Form (BDCAF) and Behcet Syndrome Activity Score (BSAS). QoL assessments included the Behcet Disease QoL (BDQoL) and the 36-item Short-Form Health Survey version 2 (SF-36v2), consisting of Physical and Mental Component Summary (PCS and MCS) scores and Physical Functioning domain (PF) score. An ANCOVA model was used to analyze the primary endpoint and change from baseline in BDQoL score and SF-36v2 PCS, MCS, and PF scores.
Result(s): The primary efficacy endpoint of AUCWk0-12 for the number of OU was significantly lower in APR vs PBO patients (P <.0001). Significant improvements were observed with APR versus PBO in the mean change from baseline to Week 12 in BDQoL score (P =.0003), which was supported by significant improvements in the mean change from baseline to Week 12 in SF-36v2 PCS (P =.0204), MCS (P <.0001), and PF (P =.0060) scores in APR versus PBO patients. In all of the SF-36v2 subscale scores, a 10% to 25% greater proportion of patients receiving APR versus PBO experienced an improvement of at least 2.5 points (minimal clinically important difference) at Week 12.
Conclusion(s): APR demonstrated significant reductions in OU through Week 12 and clinically meaningful improvements in Behcet syndrome-related and overall health-related QoL, including physical and mental function.
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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.

BACKGROUND:The small-molecule phosphodiesterase 4 inhibitor apremilast modulates cytokines that are up-regulated in Behçet's syndrome. In a phase 2 trial involving patients with Behçet's syndrome, apremilast reduced the incidence and severity of oral ulcers. Data on the efficacy and safety of apremilast in patients with Behçet's syndrome who had active oral ulcers and had not previously received biologic agents are limited. METHODS:In a phase 3 trial, we randomly assigned, in a 1:1 ratio, patients who had Behçet's syndrome with active oral ulcers but no major organ involvement to receive either apremilast at a dose of 30 mg or placebo, administered orally, twice daily for 12 weeks, followed by a 52-week extension phase. The primary end point was the area under the curve (AUC) for the total number of oral ulcers during the 12-week placebo-controlled period (with lower values indicating fewer ulcers). There were 13 secondary end points, including complete response of oral ulcers, change from baseline in pain associated with oral ulcers, disease activity, and change from baseline in the Behçet's Disease Quality of Life score (range, 0 to 30, with higher scores indicating greater impairment in quality of life). Safety was also assessed. RESULTS:A total of 207 patients underwent randomization (104 patients to the apremilast group and 103 to the placebo group). The AUC for the number of oral ulcers was 129.5 for apremilast, as compared with 222.1 for placebo (least-squares mean difference, -92.6; 95% confidence interval [CI], -130.6 to -54.6; P<0.001). The change from baseline in the Behçet's Disease Quality of Life score was -4.3 points in the apremilast group, as compared with -1.2 points in the placebo group (least-squares mean difference, -3.1 points; 95% CI, -4.9 to -1.3). Adverse events with apremilast included diarrhea, nausea, and headache. CONCLUSIONS:In patients with oral ulcers associated with Behçet's syndrome, apremilast resulted in a greater reduction in the number of oral ulcers than placebo but was associated with adverse events, including diarrhea, nausea, and headache. (Funded by Celgene; ClinicalTrials.gov number, NCT02307513.).

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

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.