Faculty Bibliography

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)

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. We evaluated the relationship between disease activity, according to Routine Assessment of Patient Index Data 3 (RAPID3) after 6-month treatment with tofacitinib, and long-term outcomes at 24 months. This was a post hoc analysis of two 24-month, phase 3, randomized controlled trials in methotrexate (MTX)-naïve (ORAL Start [NCT01039688]) or MTX-inadequate responder patients (ORAL Scan [NCT00847613]) receiving tofacitinib 5 or 10 mg twice daily (BID) as monotherapy or with background MTX. RAPID3 scores were calculated at baseline, month (M)6, and M24, and defined as remission (≤ 3), low (LDA; > 3-≤ 6), moderate (MDA; > 6-≤ 12), or high disease activity (HDA; > 12). Clinical Disease Activity Index (CDAI), Health Assessment Questionnaire-Disability Index (HAQ-DI) scores, and radiographic non-progression (modified Total Sharp Scores ≤ 0) at M24 were evaluated by M6 RAPID3 response. Among patients receiving tofacitinib 5 or 10 mg BID, respectively, 42.2 and 51.5% (ORAL Start) and 29.8 and 39.0% (ORAL Scan) achieved RAPID3 remission/LDA at M6. Most patients maintained/improved RAPID3 responses at M24. A higher proportion of patients in RAPID3 remission/LDA versus MDA/HDA at M6 achieved CDAI remission, reported normative HAQ-DI scores (< 0.5), and achieved both normative HAQ-DI scores and radiographic non-progression at M24. Patients achieving RAPID3 remission/LDA after 6-month treatment with tofacitinib 5 or 10 mg BID have improved long-term outcomes versus patients with MDA/HDA. These findings support the use of RAPID3 to monitor longer-term disease activity in conjunction with physician-assessed measures.

Background: Behcet's syndrome (BS) is an auto-inflammatory vasculitis, most common in countries along the ancient Silk Road. Classification of BS most often is done with the International Study Group criteria (ISG criteria)1. ISG criteria positivity for BS is reached when a patient has recurrent oral ulceration and any two of the following symptoms: recurrent genital ulceration, uveitis, skin lesions and pathergy positivity. However, many other manifestations are reported1. Differences in clinical presentation can complicate classification of the diagnosis, especially in areas where the disease is low in prevalence. Thus, some patients are classified as "probable BS". In some of these cases patients developed additional symptoms over time and met the ISG criteria in a later stage. Objectives: To describe characteristics of patients presenting with a probable diagnosis of BS in Amsterdam and New York and to study if patients who eventually met the ISG criteria differ from those who did not. Methods: We included consecutive patients classified as possible BS to our outpatient clinics in New York and Amsterdam. Patients fulfilling ISG criteria at enrollment were excluded, as well as patients in whom an alternative diagnosis was made at enrollment. Baseline data were evaluated retrospectively and patients were divided into two groups: those developing ISG positive (ISG +or "true") BS during follow up and those who did not meet ISG criteria after follow-up (ISG-). Turkey, Asia, Middle and Far Eastern countries, Arabic countries and Northern Africa were considered endemic areas; Italian, Greek, Hispanic, Portugese, African- American and Caucasian patients were considered not from endemic areas. Statistical analysis was performed using SPSS, with Chi-square tests or Fisher's exact tests for categorical data and independent sample t-tests for numerical data. Results: 189 patients were included, of whom 20 were from Amsterdam. During follow up, 71 patients (37.6%) could be classified as "true" Behcet's syndrome after a mean period of 9.4 years (+/-8.3 years) after onset 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 for both groups. Labial ulcers and skin manifestations at enrollment were more frequently reported. Genital ulcers as a group was not significantly associated with developing "true" Behcets, nor were specific skin manifestations such as erythema nodosum. We also considered HLA-B*51, pathergy, erythrocyte sedimentation rate and C-reactive protein, but due to a large amount of missing data, we were unable to draw any significant conclusions for these variables. Figure 1 Baseline data from all patients who were classified as probable Behcet's syndrome at enrollment Conclusions: About a third of patients classified as probable Behcet's syndrome at enrollment develop new manifestations over time. Thus, they can be reclassified as ISG positive ("true") BS. Based on our data, presence of skin manifestations and labial ulcers at enrollment was significantly higher in the group eventually developing a ISG criteria positive BS

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.

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