Faculty Bibliography

The presence of symptom clusters, regional differences in disease expression and similarities with, for example, Crohn's disease suggest multiple pathological pathways are involved in Behçet syndrome. These features also make formulating disease criteria difficult. Genetic studies have identified HLA-B*51 to be the important genetic risk factor. However, the low prevalence of HLA-B*51 in many patients with bone fide disease, especially in non-endemic regions, suggests other factors must also be operative in Behçet syndrome. This consideration is also true for the newly proposed 'MHC-I-opathy' concept. Despite lacking a clear aetiological mechanism and definition, management of manifestations that include major vascular disease (such as Budd-Chiari syndrome and pulmonary artery involvement), eye disease and central nervous system involvement has improved with the help of new technology. Furthermore, even with our incomplete understanding of disease mechanisms, the prognoses of patients with Behçet syndrome, including those with eye disease, continue to improve.

This corrects the article DOI: 10.1038/nrrheum.2017.208.

PURPOSE OF REVIEW: Biomarkers are considered to be helpful in diagnosing, monitoring, predicting treatment response, and prognosis in clinical practice and as outcomes in clinical trials. In this article, we review the recent literature on new biomarkers and the expanding use of older ones in vasculitic conditions. RECENT FINDINGS: In antineutrophil cytoplasmic antibody-associated vasculitis patients antineutrophil cytoplasmic antibody type may be useful as a predictor of relapse and response to rituximab. Moreover, serial measurements of proteinase-3 titer may help to predict relapse. Urinary soluble CD163 levels are promising for identifying active renal vasculitis. Imaging modalities such as positron emission tomography, computerized angiography tomography, and temporal artery ultrasound maintain their role in diagnosis and disease assessment in large vessel vasculitis. Fecal calprotectin is a useful marker of active gastrointestinal involvement in Behcet's syndrome. SUMMARY: The publications reviewed here potentially may help to move the field of biomarkers in vasculitis management. However, more work toward understanding the underlying pathophysiology and effects of an intervention on the disease process are needed before true biomarkers can be realized. Further studies with appropriate control groups, using good definitions for disease states such as activity and remission are needed to guide our use of these markers correctly in the management of our patients.

Purpose/UNASSIGNED:(infliximab [IFX]) and either continued IFX or switched to CT-P13. Materials and methods/UNASSIGNED:Adult RA patients with ≥1 IFX claim were identified from the Turkish Ministry of Health database. Eligible patients initiated and continued IFX treatment (continuers cohort [CC]) or initiated IFX and switched to CT-P13 (switchers cohort [SC]) during the study period. The initial IFX claim date was defined as the index date. The switch/reference date was defined as the CT-P13 switch date for the SC or a random IFX date during the period of CT-P13 availability for the CC. Cohorts were matched by age, sex, and number of IFX prescriptions during baseline. Patient demographics, discontinuation, and switching were summarized. The baseline period was defined as the period from the index date to the switch/reference date. The follow-up period ranged from the switch/reference date to the end of data availability. Results/UNASSIGNED:<0.001). Conclusion/UNASSIGNED:Treatment patterns differed between patients prescribed IFX and CT-P13. In Turkey, RA patients maintained on IFX had greater treatment persistence (ie, fewer and later discontinuations) than those who initiated IFX and switched to CT-P13.

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 (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

Purpose/UNASSIGNED:Biosimilar IFX (CT-P13) received marketing approval in Turkey for treatment of rheumatologic diseases, including ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. Population data on real-world treatment patterns of CT-P13 following marketing approval in European countries are largely unreported. This study examined the prescribing and medication utilization patterns of innovator infliximab (IFX) and CT-P13 in Turkey for patients with RA or IBD naïve to either IFX. Materials and methods/UNASSIGNED:Adult patients with ≥1 diagnosis claim for RA or IBD and ≥1 claim for IFX or CT-P13 were identified in the Turkish Ministry of Health database during the following identification periods: 1 Oct 2014-30 May 2015 (RA) and 1 Oct 2014-31 Dec 2015 (IBD). Continuous medical and pharmacy coverage for ≥12 months before and after the date of the first dose (index) IFX or CT-P13 was also required. Separate analyses were done for each population. Results/UNASSIGNED:Seven hundred and seventy nine adult RA and 581 IBD patients met the selection criteria. The majority of RA (74%; n=575) and IBD patients (87%; n=504) were initiated on IFX. The average study observation period was 16 months for the RA and 12 months for the IBD population. Over the observation periods, discontinuation among RA patients occurred in 42% of IFX and 63% of CT-P13 while discontinuation in the IBD cohort occurred in 38% of IFX; and 62% of CT-P13. Conclusion/UNASSIGNED:In this population-based study, more IFX-naïve RA and IBD patients were initially treated with IFX than CT-P13. Discontinuation and switching were observed more often and earlier among patients treated with CT-P13 regardless of disease state. Further studies are needed to understand the reasons for these observed differences.

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)