Faculty Bibliography

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

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)

OBJECTIVE: The Outcome Measures in Rheumatology (OMERACT) Vasculitis Working Group has been working toward developing a data-driven core set of outcome measures for use in clinical trials of Behcet's syndrome [Behcet disease (BD)]. This paper summarizes the group's work through OMERACT 2016, discussions during the meeting, and the future research agenda. METHODS: Qualitative patient interviews were conducted among 20 patients with BD who have different types of organ involvement. A 3-round Delphi among BD experts and patients was initiated to identify domains, subdomains, and outcomes to be assessed in clinical trials of BD. The results of these studies were discussed during OMERACT 2016 and next steps were planned. RESULTS: Patients' perspectives and priorities were identified through qualitative interviews that identified candidate domains and subdomains for inclusion in the Delphi and characterized some shortcomings of the currently used patient-reported outcomes in BD. The first round of the Delphi was completed and several domains or subdomains were endorsed by the experts and/or the patients. Because many more items were endorsed than would be feasible to assess during a clinical trial, rating and ranking of items by physicians and patients was planned as a next critical step. The challenges of assessing specific organ system involvement was also discussed. CONCLUSION: The OMERACT Behcet Syndrome Working Group research program will identify core domains for assessment in BD with the goal of developing a core set of outcome measures for use in all trials of BD with the option to incorporate additional outcomes for specific organ involvement.

OBJECTIVES/OBJECTIVE:To assess adherence to published guidelines for the treatment of Behçet's syndrome (BS) in two geographic areas. METHODS:We extracted guideline statements from the 2008 EULAR recommendations. Adherence to these statements was evaluated retrospectively in both New York (USA) and Amsterdam (The Netherlands), by reviewing records from patients fulfilling the ISG criteria. We analysed data per statement and event, and divided data according to the year in which an event occurred. We compared events prior to 2009 to those after publication of the EULAR recommendations (2009 and later). RESULTS:474 patients were evaluated, 24 of whom were from Amsterdam. Treatment adherence varied substantially across various Behçet's manifestations, ranging from 21% vs. 31% in posterior uveitis, 50% vs. 25% in arterial disease, 29% vs. 29% in arthritis and 38% vs. 55% in erythema nodosum to 65% vs. 67% in deep venous thrombosis (DVT), before and after publication of the guidelines respectively. Topical treatment of mucocutaneous disease was only 2% vs. 8%, whereas adherence in neuro-Behçet was ≥ 94% and 100% in gastrointestinal disease. CONCLUSIONS:Adherence to treatment guidelines varies substantially by Behçet's manifestation. Lack of adherence in manifestations such as eye disease and arthritis suggests that current recommendations are not sufficient or other concurrent manifestations require more aggressive treatment. The extensive use of anti-TNF agents might indicate a shift towards more aggressive treatment. Thus, our results suggest the 2008 guidelines were not in line with treatment in clinical practice over the past years and the recent revision of the recommendations was indeed needed.

BACKGROUND: Biosimilar infliximab (CT-P13) was first approved in Europe in 2013.
OBJECTIVE(S): This study compared treatment patterns of Turkish patients (pts) with a diagnosis of rheumatoid arthritis (RA) who initiated originator IFX (IFX) and either continued IFX or switched to CT-P13.
METHOD(S): Adult pts with >= 1 RA diagnosis code and IFX claim were identified in a national Turkish healthcare database. Eligible pts initiated and continued IFX (Continuer cohort; CC) or initiated IFX and switched to CT-P13 (Switch cohort; SC) during study period (Dec 1, 2010-Jun 1, 2016). The index date was defined as the CT-P13 switch date for SC or a random IFX date during the period of CT-P13 availability for CC. Cohorts were matched on age, sex, and number of IFX prescriptions during baseline. Discontinuation was defined as a switch to another biologic or no index biologic for >= 120 days without censoring. Patient demographics, discontinuation and switching were summarized with descriptive statistics.
RESULT(S): A total of 697 pts initiating IFX were studied; 87% (N = 605) continued on IFX throughout the study period; 13% (N = 92) switched to CT-P13. Mean duration of IFX therapy during the baseline period was 422 days (CC) and 438 days (SC). Average duration of postindex follow-up was 16 months (CC) and 15 months (SC). During the combined baseline and post-index periods, median time on any IFX therapy was 1,080 days (CC) and 540 days (SC). Discontinuation post-index occurred in 19% (CC) and 87% (SC); mean time from index to IFX discontinuation/censoring was 276 days (CC) while the mean time from index to CT-P13 discontinuation/censoring was 132 days. Switching from IFX to CT-P13 occurred in 13% all IFX initiators (i.e., 100% of SC) on the index date; an additional 10% of the CC cohort switched to a non-IFX anti-TNF post-index. The majority of SC (82%) switched from CT-P13 post-index and 88% of those re-initiated IFX. Regional variation in switching was noted. Switching from IFX to CT-P13 occurred most frequently in Central Anatolia (26% of 697 IFX initiators). Switching from CT-P13 occurred in > 75% of SC patients in all regions except for Aegean (44% switched from CT-P13 to another biologic, predominantly IFX).
CONCLUSION(S): In Turkey, RA patients maintained on IFX had greater treatment persistence than those who initiated IFX and switched to CT-P13. High rates of CT-P13 discontinuation favored IFX re-initiation. Reasons for discontinuation are unknown, however regional differences in practice patterns were observed

BACKGROUND: Comorbidities may contribute to disease activity and treatment response in rheumatoid arthritis (RA) patients. We defined a somatization comorbidity phenotype (SCP) and examined its influence on response to certolizumab pegol (CZP) using data from the PREDICT trial. METHODS: Patients in PREDICT were randomized to the patient-reported Routine Assessment of Patient Index Data 3 (RAPID3) or physician-based Clinical Disease Activity Index (CDAI) for treatment response assessment. Post-hoc analyses identified patients with the SCP, which included diagnosis of depression, fibromyalgia/myalgias, and/or use of medications indicated for treatment of depression, anxiety, or neuropathic pain. The effect of the SCP on RAPID3 or CDAI response at week 12 and low disease activity (LDA; Disease Activity Score in 28 joints based on erythrocyte sedimentation rate