Faculty Bibliography

OBJECTIVE:Matching-adjusted indirect comparison was used to assess the comparative effectiveness of secukinumab 150 mg and adalimumab 40 mg in biologic-naïve patients with ankylosing spondylitis (AS) for up to 1 year. METHODS:Pooled individual patient data from the secukinumab arms of MEASURE 1 (NCT01358175) and MEASURE 2 (NCT01649375) trials (n=197) were matched against the AT-LAS (NCT00085644) adalimumab population (n=208). Logistic regression analysis was used to determined weights to match for age, sex, Bath AS Functional Index, C-reactive protein levels, and previous tumor necrosis factor inhibitor therapy. Recalculated Assessment of SpondyloArthritis International Society (ASAS) 20 and 40 responses at weeks 8, 12, 16, 24, and 52 from MEASURE 1/2 (effective sample size=120) were compared with those of ATLAS. Anchored (placebo-adjusted) comparisons were possible until week 12, and unanchored (non-placebo-adjusted) comparisons were necessary thereafter. RESULTS:For placebo-anchored ASAS 20 and 40 comparisons up to week 12, there were no differences between secukinumab and adalimumab. For unanchored comparisons at week 16, ASAS 20 was higher for secukinumab [odds ratio 1.60 (95% confidence interval, 1.01-2.54); p=0.047]; at week 24, ASAS 20 and 40 were higher for secukinumab [1.76 (1.11-2.79); p=0.017 and 1.79 (1.14-2.82); p=0.012, respectively]; and at week 52, ASAS 40 was higher for secukinumab [1.54 (1.06-2.23); p=0.023] than for adalimumab. CONCLUSION/CONCLUSIONS:There were no differences observed in placebo-adjusted ASAS 20 and 40 responses up to 12 weeks between secukinumab- and adalimumab-treated patients with ankylosing spondylitis. After week 12, secukinumab demonstrated signs of greater improvement in non-placebo-adjusted ASAS 20 and 40 responses than adalimumab.

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)

Background/Purpose: Behcet's syndrome is a chronic, multi-systeminflammatory disorder characterized by recurrent oral ulcers (OU) that can bedisabling and negatively affect quality of life. Apremilast (APR), an oralphosphodiesterase 4 inhibitor that modulates inflammatory pathways, has demonstratedefficacy in the treatment of OU of Behcet's syndrome in a phase III, multicenter, randomized, double-blind, placebo (PBO)-controlled study (RELIEF).
Method(s): In this phase III, multicenter study, adult patients with active Behcet's syndrome (with >=3 OU at randomizationor >=2 OU at screening + randomization, without active major organinvolvement) were randomized (1:1) to receive APR 30 mg BID or PBO BID for 12weeks followed by a 52-week active-treatment phase. The primary endpoint was area under the curvefor total number of OU over 12 weeks (OU AUCWk0-12). AUC reflectsthe change in the number of OU over time, accounting for the clinicalcharacteristic that OU repeatedly remit and recur. In a planned analysis, OUAUCWk0-12 was examined among subgroups of patients defined by BLdemographics and disease characteristics.
Result(s): A total of 207 patients were randomized and received >=1 dose of study medication (APR:n=104; PBO: n=103). At BL, mean numbers of OU were 4.2 for APR and 3.9 for PBO. At Week 12, least-squares mean OU AUCWk0-12 (LSmean +/-SE) was significantly lower in patients receiving APR vs. PBO (129.5 +/- 15.9 vs. 222.1 +/-15.9; P<0.0001). A treatment effect in favor of the APR treatment group vs. PBO was observed for AUCWk0-12 for OU counts in each of the prespecified subgroups examined. A favorable treatment effect was observed for each demographic subgroup, BL disease characteristic(including duration of disease and BL OU count), geographic region, and prior use of colchicine and corticosteroids (Figure). The incidence of adverse events (AEs) was comparable between APR and PBO (78.8% and 71.8%, respectively). The most common AEs were diarrhea, nausea, headache, and upper respiratory tract infection; most AEs were mild or moderate in severity.
Conclusion(s): Subgroup analyses of the AUC for the number of OU from BL through Week 12 demonstrated the consistent efficacy of apremilast in all of the subgroups analyzed. The safety profile was consistent with the known safety profile of APR. (Figure Presented)

Background/Purpose: There is an unmet need for reliable, validated, and widely-accepted outcome measures for clinical trials in Behcet's syndrome (BS). 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 sub-domains 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 subdomains), 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/Purpose: Behcet's syndrome is a chronic, relapsing, multi-system inflammatory disorder characterized by recurrent oral ulcers (OU), which can be disabling and substantially impact quality of life. In a phase III study (RELIEF), apremilast (APR) reduced the number and pain of OU in patients with active Behcet's syndrome over 12 weeks.
Method(s): In this phase III, multicenter, placebo (PBO)-controlled study, adult patients 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 PBO or APR 30 mg BID for 12 weeks. All patients then received APR treatment through Week 64. The primary endpoint was area under the curve (AUCWk0-12) for total number of OU over 12 weeks, which reflects the number of OU over time and accounts for the recurring-remitting course of OU. The current analysis assessed APR efficacy in the treatment of OU for up to 28 weeks.
Result(s): A total of 207 patients were randomized and received >=1 dose of study medication (PBO: n=103; APR: n=104). At baseline (BL), mean OU counts were 4.2 (APR) and 3.9 (PBO) and mean visual analog scale pain scores were 61.2 (APR) and 60.8 (PBO). The primary endpoint of AUCWk0-12 was achieved; a statistically significantly lower AUCWk0-12 was observed for APR vs. PBO (129.54 vs. 222.14; P<0.0001, multiple imputation). APR treatment resulted in a significantly lower number of OU (P<=0.0015, multiple imputation) and reduction in OU pain (P<=0.0035, mixed-effects model for repeated measures) compared with PBO at every visit from Week 1 through Week 12. APR efficacy was sustained with continued treatment through 28 weeks. At Week 28, 62% of patients achieved complete response of OU, with a 70% relative reduction in OU pain from BL. Patients initially randomized to PBO and switched to APR at Week 12 showed comparable benefits (Figures). At Week 28, 59.0% of patients achieved complete remission of OU, with a 68% relative reduction in OU pain from BL. The incidence of any adverse event (AE) was comparable between APR and PBO during the PBO-controlled period (78.8% and 71.8%, respectively). The most common AEs were diarrhea, nausea, headache, and upper respiratory tract infection; most AEs were mild or moderate in severity. No new safety concerns were identified with up to 28 weeks of APR treatment.
Conclusion(s): APR demonstrated efficacy in the treatment of OU in patients with active Behcet's syndrome. Benefits were sustained for up to 28 weeks with continued treatment. APR was generally well tolerated and safety was consistent with the known safety profile of apremilast. (Figure Presented)

Background/Purpose: Behcet's syndrome (BS) is formally diagnosed using the International Study Group (ISG) criteria, 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, and differences in clinical presentation can complicate BS diagnosis, especially in areas where the disease prevalence is low. The purpose of this study was to explore clinical BS symptoms present at initial patient visit that are predictive of ISG criteria diagnosis at follow-up.
Method(s): 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. 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 model2.
Result(s): 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.
Conclusion(s): 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 followup. (Figure Presented)