Faculty Bibliography

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

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: 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

Introduction. Behcet's syndrome (BS) is formally diagnosed using the International Study Group (ISG) criteria (1), where recurrent oral ulceration and any two other symptoms (recurrent genital ulceration, uveitis, skin lesions and pathergy positivity) are required. The allowance of various symptomology in the ISG criteria has led to the reporting of varied manifestations (1), and differences in clinical presentation can complicate BS diagnosis, especially in areas where the disease prevalence is low. Aims. To explore clinical BS symptoms present at initial patient visit that are predictive of ISG criteria diagnosis at follow-up. Methods. Data from consecutive patients monitored in outpatient clinics in New York and Amsterdam were abstracted. Patients were included if diagnosis at initial visit was "suspected" or "probable BS"; patients given a formal diagnosis by ISG criteria at initial visit or a non-BS diagnosis at initial visit were excluded. Demographic data, including ancestry/ethnicity, clinical symptoms, duration of symptoms and RAPID3 were abstracted from initial visit, with follow-up ISG status (defined as meeting criteria ISG+ vs not meeting criteria ISG-) abstracted from last visit. Ancestry/ethnicity were aggregated by endemic (Turkey, Asia, Middle and Far Eastern countries, Arabic countries and Northern Africa) versus non-endemic (Italy, Greece, Spain, Portugal as well as African-American and White NY). 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 (2). Results. 189 patients were included: 169 from NY and 20 from Amsterdam. 71 (37.6%) patients were classified as ISG+ with an average of 9.4 years (+/- 8.3 years) of symptoms. Age, gender, ethnicity, duration of symptoms at enrollment, duration of follow up as well as RAPID3 and almost all clinical manifestations at baseline were comparable between ISG+ And ISG- patients. Presence of morning stiffness, family history of BS, genital ulceration, labial ulceration, skin lesions, eye disease and retinitis were each identified in the univariable model as being possibly associated with prevalence of ISG+. The final multivariable model did not include correlated symptoms (i.e. genital and labial ulceration as well as eye disease and retinitis). 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 (Figure). Area under the curve was 0.718, indicating acceptable predictive capability of the final model (2). Conclusion. Based on our data, over a third of patients with suspected or probable Behcet's developed new manifestations over time that led to classification as ISG+ Behcet's. Despite development of these new manifestations, the presence of morning stiffness, genital ulcers, skin lesions, and eye disease at initial visit were independently associated with significantly higher odds in developing ISG+ Behcet's during follow up. (Figure Presented)

Introduction. Oral ulcers, the hallmark of Behcet's syndrome, can be painful and disabling, impairing the quality of life (QoL) in patients with Behcet's syndrome. Apremilast, an oral phosphodiesterase 4 inhibitor, demonstrated efficacy in a phase II placebo-controlled study in patients with Behcet's syndrome and active oral ulcers. Moreover, a phase III study showed improvement in number and pain of oral ulcers as well as disease activity in patients with Behcet's syndrome and active oral ulcers previously treated with >=1 medication. Aims. To assess the effects of apremilast on patient-reported outcomes, including measures of disease activity and QoL, in patients with Behcet's syndrome enrolled in a phase III randomized, placebo-controlled, doubleblind study. Methods. Eligible patients (N=207) were randomized (1:1) to apremilast 30 mg twice daily (n=104) or placebo (n=103) for 12 weeks, followed by a 52-week active-treatment extension. Patients had active Behcet's syndrome, with >=3 oral ulcers at randomization or >=2 oral ulcers at screening + randomization, without active major organ involvement. The primary endpoint was area under the curve (AUC) for total number of oral ulcers over 12 weeks. The clinical improvement of oral ulcers was evaluated by assessments of oral ulcer pain, measures of disease activity, and QoL. Disease activity was measured using validated instruments that take into account other manifestations of Behcet's syndrome involving the skin, joints, gastrointestinal tract, eyes, central nervous system, and vascular involvement. These included the Behcet's Disease Current Activity Index Form (BDCAF), which consists of 3 components, and the Behcet's Syndrome Activity Score (BSAS). QoL was assessed using the Behcet's Disease QoL (BDQoL) questionnaire. BSAS and BDQoL were completed by the patients and the BDCAF was administered to the patients by the investigator. A prespecified hierarchical testing procedure was used for multiplicity adjustment. Results. The primary endpoint of the AUC for number of oral ulcers over 12 weeks was statistically significantly lower in the apremilast group compared with the placebo group. This treatment effect is supported by the statistically significant improvements observed in oral ulcer pain, measures of disease activity using the BSAS and BDCAF (Behcet's Disease Current Activity Index [BDCAI] and Patient's Perception and Clinician's Perception, respectively) and the BDQoL at Week 12 (Table). The incidence of treatment-emergent adverse events (AEs) was comparable between the apremilast and placebo groups during the placebo-controlled period (78.8% vs. 71.8%, respectively). Serious AEs were observed in 3 apremilast patients (migraine, oral ulcer flare, genital ulcer, arthralgia, soft tissue injury) and 4 placebo patients (diarrhea, genital and fungal infections, oral ulcer flare, acne, acute febrile neutrophilic dermatosis, erythema multiforme). Conclusion. This phase III study demonstrated the efficacy of apremilast in the reduction of oral ulcers. Patients reported improvements in oral ulcer pain, disease activity measures, and QoL. These findings suggest that reduction in oral ulcer is associated with improvement in overall disease activity and QoL reported by patients. The safety profile was consistent with the known safety profile of apremilast. (Table Presented)

Introduction. Oral ulcers (OU) are the most common sign of Behcet's syndrome and are observed in nearly every patient. Due to their severity and frequency of recurrence, OU can be disabling and have a substantial effect on quality of life. There is an unmet need for effective treatment for OU in Behcet's syndrome. Apremilast (APR), an oral phosphodiesterase 4 inhibitor that modulates inflammatory pathways, demonstrated efficacy in the treatment of OU of Behcet's syndrome in a phase II study. Aims. To assess the efficacy and safety of APR for OU in patients with Behcet's syndrome who have active OU previously treated with >=1 medication. Methods. In this phase III, multicenter, randomized, double-blind, placebocontrolled study, 207 eligible patients were randomized (1:1) to APR 30 mg BID (n=104) or placebo (n=103) for 12 weeks, followed by a 52-week active-treatment extension. Patients had active Behcet's syndrome, with >=3 OU at randomization or >=2 OU at screening and at randomization, without active major organ involvement. The primary endpoint was area under the curve (AUC) for total number of OU over 12 weeks. AUC reflects the change in the number of OU over time, accounting for the recurring-remitting course of OU. Secondary endpoints included OU pain measured by the visual analog scale and the proportion of patients achieving resolution of OU (OU-free) at Week 12. Results. AUC for total number of OU over 12 weeks was statistically significantly lower with APR 30 mg BID vs. placebo (129.54 vs. 222.14; p<0.0001), indicating a 42% reduction in AUC over 12 weeks. This treatment effect is supported by greater benefits with APR 30 mg BID vs. placebo as demonstrated by a reduction in the mean number of OU and OU pain (Figure), starting at Week 1 and continuing through Week 12, with a 48% reduction in number of OU and 61% reduction in OU pain at Week 12. The treatment effect was also supported by a significantly greater proportion of patients achieving OU resolution (52.9% vs. 22.3%; p<0.0001). The proportion of patients with treatment-emergent adverse events (AEs) was comparable between APR and placebo during the placebo-controlled period (78.8% vs. 71.8%, respectively). Serious AEs were observed in 3 (2.9%) patients in the APR group (migraine, OU flare, genital ulcer, arthralgia, soft tissue injury) and 4 (3.9%) patients in the placebo group (diarrhea, genital and fungal infections, OU flare, acne, acute febrile neutrophilic dermatosis, erythema multiforme). Conclusion. In patients with Behcet's syndrome, APR effectively reduced the number of OU and resulted in a significantly greater proportion of patients who achieved OU resolution compared with placebo. The decrease in OU pain paralleled the decrease in number of OU over time. Safety findings were consistent with the known profile of APR

Background/Purpose: Racial/ethnic disparities in comorbidity(CM) in rheumatoid arthritis (RA) may confound treatment and outcomes. RheumaticDisease Comorbidity Index (RDCI) is a validated tool predicting disability and mortality in RA patients. We evaluated the association between RDCI and clinical outcomes within racial/ethnic subsets of RA patients Methods: Patients enrolled in the Ethnic Minority RA Consortium (EMRAC), with at least one follow-up (FU) visit were analysed. RDCI was compiled from enrolment data. Clinical outcomes: tender joint count (TJC), swollen joint count (SJC), RAPID 3 and DAS28; medication use (recorded and aggregated as prednisone methotrexate, other DMARD, and biologic use), were recorded. Analysis of variance or chi-square tests were used to estimate enrolment differences between racial/ethnic groups. Generalized estimating equations and mixed model regression accounting for repeated measurements were used to estimate any differences between racial/ethnic groups during FU, and explore associations of RDCI on clinical outcomes and remission (DAS28<2.6), adjusting for enrolment age, gender, education, race/ethnicity and medication use.
Result(s): 1066 subjects with 3719 FU visits over 58 weeks were evaluated. Racial/ethnic disparities were seen in formal education, RAPID3, DAS28, TJC, SJC as well as CM. Additionally, racial/ethnic disparities were seen in length of FU and medication use (Table). Increased RDCI scores were significantly associated with increased enrolment RAPID3 (P=0.022) and DAS28 (P<0.001), adjusting for age, education, gender and race/ethnicity. Enrolment DAS28 was also significantly higher in Blacks (0.49, 95% CI [0.21, 0.78], P=0.001)and Hispanics (0.70, 95% CI [0.37, 1.03], P=0.001) compared to Whites. While increased RDCI significantly reduced improvement in both RAPID3 (P<0.001) and DAS28(P<0.001), RDCI was not significantly associated with reducing odds of DAS28 remission. Blacks, however, were significantly less likely to have DAS28 remission than all other race groups (Figure). Additionally, biologic use increased odds of DAS28 remission (OR=1.53, 95% CI [1.01,2.33], P=0.45), but was less with advanced age (OR=0.80, 95% CI [0.68, 0.95],P=0.009).
Conclusion(s): CM was associated with higher disease activity regardless of race/ethnicity or medication, with black patients having more CM and less odds of remission. Early access to care for management of comorbidities and disease in Black RA patients is necessary to improve outcomes (Figure Presented)