Faculty Bibliography

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.

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.

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

OBJECTIVES/OBJECTIVE:To explore patterns of real-world early RA (ERA) care across countries. METHODS:An online survey was disseminated to practising rheumatologists across Europe and the US, also made accessible on social media between April and May 2015. Survey questions (n=38) assessed the structure and setting of ERA clinics, times to diagnosis and treatment, patient monitoring, guideline use and data recording. RESULTS:A total of 212 rheumatologists from 39 countries (76% European) completed the survey. 62% had an ERA clinic based at a university hospital. Patient referral to rheumatology was mainly (78%) via primary care; 44% had an agreed ERA local referral pathway, 15% a national pathway. Only 16% had dedicated ERA clinics, the majority being practitioners in Northern Europe with access to a local or national referral pathway. Data for research were collected by 42%. Treatment guidelines were followed by the majority, especially rheumatologists practising in Europe. Variations existed in the use of initial DMARDs with treatment decisions reported to be influenced by international/national guidelines in 71%/61%. No significant relationship between country gross national income and the availability of ERA clinics was seen. CONCLUSIONS:This study provides comparative benchmark information regarding the global provision of ERA care. Substantial variations exist in referral and early assessment pathways with guidelines having a most apparent impact in Northern Europe. Provision of an ERA service does not appear to be constrained by cost, with conceptual factors, e.g. clinician engagement, perhaps playing a role. These initial insights could potentially help harmonise ERA management across countries.

BACKGROUND:The effect of IL-1 blocking therapy on mucocutaneous manifestations of Behçet's disease is incompletely understood. METHODS:Six patients with Behçet's disease and ongoing oral/genital ulcers for ≥1 month were enrolled into an adaptive, two-phase clinical trial and included in the analysis. Study duration was 6 months with extension up to 16 months. All were treated non-blinded with anakinra 100 mg subcutaneous daily with the option to escalate the dose to 200 mg in partial responders after 1 month and 300 mg after 6 months. Patients recorded the number and severity of ulcers in daily diaries. The primary outcome was remission defined as no ulcers on physical exam for two consecutive monthly visits between months 3 and 6. Secondary outcomes included the number and severity of patient-reported ulcers, patient/physician global scores, and standardized disease activity scores. RESULTS:Two of six patients achieved the primary outcome. Five of six patients had improvement in the number and severity of ulcers. Non-statistically significant improvements were seen in secondary outcomes. Over the entire study, patients reported ≥1 oral and ≥1 genital ulcer on 665 (66%) and 139 (14%) days, respectively. On anakinra 200 mg vs 100 mg, patients reported fewer days with oral ulcers (65% vs 74% of days, p = 0.01) and genital ulcers (10% vs 22% of days, p < 0.001) and milder oral ulcer severity (p < 0.001). Increase of anakinra to 300 mg did not result in further improvements. Adverse events were notable for mild infections. CONCLUSION/CONCLUSIONS:Anakinra at an optimal dose of 200 mg daily had an acceptable safety profile and was partially effective in the treatment of resistant oral and genital ulcers in Behçet's disease. TRIAL REGISTRATION/BACKGROUND:Clinicaltrials.gov. NCT01441076 . Registered on 24 September 2011.

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.

Objectives: An unmet need for reliable, validated and widely accepted outcome measures for trials in Behcets syndrome (BS) was identified through: a systematic review; a survey among Behcets experts; and an outcome measures interest group meeting during the 16th International Conference on BS The OMERACT BS Working Group has been working to advance outcome measures in BS with the goal of creating a core set of data-driven measures for use in clinical trials for BS starting with a Delphi. This abstract describes the results for round one of the Delphi. Methods: A list of possible domains and outcomes was prepared using the results of a systematic literature review on outcomes assessed in previous Behcets studies, qualitative patient interviews, and expert opinion. A three round Delphi has begun among physicians from different specialties experienced in BS and among patients with BS. The patient survey was the same as the physician survey with medical terms explained. The web based survey was formatted in both English and Turkish and emailed to 123 physicians and 130 patients. Agreement by more than seventy percent of either physicians or patients resulted in an item accepted. Results: 74 physicians and 35 patients participated in Round 1. The physicians were experts in BS from 21 countries and from within a wide range of specialties, including Rheumatology, Ophthalmology, Internal Medicine, Dermatology, Gastroenterology, and Neurology. Among the participating patients there was good representation of each type of organ involvement please see Table 1 for results. In addition to these domains, more than seventy percent of patients endorsed the assessment of pain, fatigue, sleep, sexual functioning, psychological functioning, and acute phase reactants in all trials of BS. Conclusions: Multiple disease related domains in BS have been identified by physicians and patients as important to address in clinical trials, suggesting that a core set for all trials will be needed and subdomains for subsets of disease will also be useful. Rating and ranking of these domains and subdomains in the next two rounds will enable the development of a core set of domains to be assessed in trials of BS