Yesim Ozguler

Pulmonary artery involvement in Behçet׳s syndrome: Effects of anti-Tnf treatment

OBJECTIVES Anti-TNF agents are being increasingly used in patients with Behçet׳s syndrome (BS) when conventional immunosuppressives fail. However, experience with anti-TNF treatment on pulmonary artery involvement (PAI) of BS is limited. METHODS A chart review revealed 13 patients with PAI (all men) treated with anti-TNF agents (12 infliximab and 1 adalimumab) following an inadequate response to immunosuppressives for 12.2 ± 9.5 SD months and 2 male patients who developed PAI while receiving infliximab for large vein thrombosis for 10 months and for parenchymal central nervous system involvement for 2 years, respectively. RESULTS The first patient developing PAI while receiving infliximab responded to cyclophosphamide and prednisolone but the second died with hemoptysis within 1 month. At the end of the survey, 6 of the 13 patients with PAI were continuing these agents for 25.5 ± 16.2 SD months with good response, 4 stopped anti-TNF treatment after a mean of 23 ± 9.8 SD months after achieving clinical and radiologic response and 1 patient with good response went to another center after receiving infliximab for 10 months and the remaining 2 experienced serious infections (lung tuberculosis and aspergillosis) necessitating early withdrawal. Two patients relapsed within 3 years after stopping anti-TNF agents and concomitant azathioprine. One developed mesenteric vein thrombosis necessitating bowel resection and the second developed new PAI that was controlled with cyclophosphamide and prednisolone after short courses of infliximab, adalimumab, and canakinumab. CONCLUSION Anti-TNF treatment seems to be effective for refractory PAI of BS but may not prevent its development. Relapses can be seen after withdrawal. Caution is required for their serious adverse effects.

Factors Affecting the Tuberculosis Risk in Patients Receiving Anti-Tumor Necrosis Factor-α Treatment

Background: Tumor necrosis factor (TNF)-α inhibitors are known to increase the risk of tuberculosis (TB). Objectives: To examine the factors associated with an increased risk of TB in patients receiving anti-TNF-α treatment (aTNF-α-T). Method: Of 3,094 patients who received aTNF-α-T between 2003 and 2013, a total of 1,964 subjects with a follow-up time longer than 6 months were identified and included in this retrospective analysis. Potential risk factors for the development of TB in patients receiving aTNF-α-T were evaluated. Results: Of the 1,964 patients, 1,009 (51%) were male and 955 (49%) were female, with a mean age of 39.7 ± 13.9 years. The primary conditions requiring aTNF-α-T included ankylosing spondylitis (n = 875), rheumatoid arthritis (n = 711), Behçets disease (n = 83), and others (n = 295). Sixteen patients [8 (50%) males and 8 (50%) females; 5 (31.2%) with pulmonary TB and 11 (68.8%) with extrapulmonary TB] developed TB, with a corresponding TB incidence of 466/100,000. No significant associations were found between age, gender, smoking history, pack-years of smoking, isoniazid (INH) chemoprophylaxis, type of anti-TNF-α agent, use of other immunosuppressive drugs, and the risk of TB (p > 0.05). Multivariate logistic regression analysis showed a significantly higher risk of TB in patients diagnosed with Behçets disease, and a significantly lower risk of TB in patients with a tuberculin skin test wheal ≥10 mm in diameter (p < 0.05). Conclusion: aTNF-α-T is associated with an increased risk of pulmonary or extrapulmonary TB, even when follow-up protocols and INH chemoprophylaxis are implemented, and TB often develops in the later stages of treatment. The risk of TB was higher in patients with Behçets disease and lower in patients who had a strong tuberculin skin test reaction.

2018 update of the EULAR recommendations for the management of Behçet’s syndrome

Several new treatment modalities with different mechanisms of action have been studied in patients with Behçet’s syndrome (BS). The aim of the current effort was to update the recommendations in the light of these new data under the auspices of the European League Against Rheumatism (EULAR) Standing Committee for Clinical Affairs. A task force was formed that included BS experts from different specialties including internal medicine, rheumatology, ophthalmology, dermatology, neurology, gastroenterology, oral health medicine and vascular surgery, along with a methodologist, a health professional, two patients and two fellows in charge of the systematic literature search. Research questions were determined using a Delphi approach. EULAR standardised operating procedures was used as the framework. Results of the systematic literature review were presented to the task force during a meeting. The former recommendations were modified or new recommendations were formed after thorough discussions followed by voting. The recommendations on the medical management of mucocutaneous, joint, eye, vascular, neurological and gastrointestinal involvement of BS were modified; five overarching principles and a new recommendation about the surgical management of vascular involvement were added. These updated, evidence-based recommendations are intended to help physicians caring for patients with BS. They also attempt to highlight the shortcomings of the available clinical research with the aim of proposing an agenda for further research priorities.

SAT0368 A Systematic Literature Review on The Treatment of Major Organ Involvement of Behçet's Syndrome Informing The Eular Recommendations for The Management of Behçet's Syndrome

Background The first EULAR recommendation for the management of Behçets syndrome (BS) was published in 2008 and since then new data including biologic agents have appeared. Objectives To review the evidence for efficacy and safety of management strategies in BS patients with eye, vascular, gastrointestinal (GI) and neurologic involvement. Methods We used the GRADE methodology as framework for guidelines development. For the systematic literature review, we searched The Cochrane Library, Database of Abstracts of Reviews of Effects, Health Technology Assessments, MEDLINE, EMBASE and International Pharmaceutical Abstracts Database. Randomized controlled trials (RCT), controlled clinical trials, or open label trials comparing an active drug in patients with BS with other agents or placebo were included. If controlled trials were not available for answering a specific research question, uncontrolled evidence from prospective or retrospective studies or case series about a minimum of 5 patients were also included. Results We reviewed the titles and abstracts of 3927 references, followed by the full texts of 397. A total of 166 studies related with major organ involvement met our inclusion criteria. Three RCTs with cyclosporine-A (CycA) and 1 with azathioprine (AZA) showed beneficial results in BS patients with eye involvement. There were several observational studies with interferon-α and TNF-α antagonists in patients with eye involvement, including those among patients refractory to conventional treatment modalities. Decreases in the frequency of ocular attacks, remission and improvement in visual acuity were observed in the majority of patients treated with these agents. As for vascular involvement, retrospective studies showed that immunosuppressives (IS) significantly decreased the frequency of recurrences in BS patients with deep vein thrombosis (RR 95%CI: 5.8, 2.8–11.8). A similar effect was not observed with anticoagulants+IS compared with IS alone (RR 95%CI: 1.5, 0.8–2.6). Observational studies showed that cyclophosphamide and high dose glucocorticoids (GC) decreased mortality in patients with arterial aneurysms. Treatment with IS and GC decreased postoperative complications in patients who had surgery for arterial aneurysms. Observational studies showed beneficial results with 5-ASA derivatives and AZA in the initial management of BS patients with GI involvement. Remission could be obtained with thalidomide and/or TNF- α antagonists in the majority of patients with refractory GI involvement. Retrospective studies also showed IS decreased postoperative recurrences in patients operated for intestinal perforations or major bleeding (RR 95%CI: 0.56, 0.33–0.95). Observational studies in BS patients with neurologic involvement showed IS and GC improved the outcome. CycA should be avoided in such patients since retrospective studies showed that CycA had increased the risk of development of neurologic involvement (RR 95%CI: 12.6, 4.7–33.7). Conclusions It is sobering to note that the majority of the studies forming the basis for the recommendations related to major organ involvement in the updated EULAR recommendations for the management of BS come from observational studies. Disclosure of Interest None declared

Developing a Core Set of Outcome Measures for Behçet Disease: Report from OMERACT 2016

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 Behçet’s syndrome [Behçet 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 Behçet 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.

Recommendations in the American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis Related to the Use of Biologic Agents in Patients With a History of Cancer Need Reconsideration: Comment on the Article by Singh et al.

they used to develop these guidelines. The section on management of high-risk comorbidities includes strong recommendations for managing hepatitis B virus (HBV) and HCV infection and endorses the use of immunosuppressive therapy when prophylactic antiviral therapy is administered. Although we wholeheartedly agree with those recommendations, we were disappointed that no changes from the 2008 ACR recommendations (2) were put forth regarding screening for HBV (and accordingly HCV). We suggest that because the standards of screening and preventing HBV reactivation have changed dramatically, the ACR guidelines are accordingly overdue for changes. The 2008 ACR guidelines (2) suggested screening for HBV when administering methotrexate and leflunomide and in patients at high risk of acquiring HBV infection (e.g., engaging in parenteral drug use or high-risk sexual activity). In 2010, we proposed that it was time to change these guidelines to include a more liberal policy that, at the minimum, would include screening prior to initiation of biologic therapy (3). Since that time, a Boxed Warning regarding HBV reactivation has been added to the prescribing information for the biologic agent rituximab (4). Screening for HBV infection prior to initiating treatment with rituximab is now mandatory, which serves as evidence of the veracity of screening before beginning treatment with a biologic agent. It also should be noted that the ACR guidelines have been out of step with the 2008 Centers for Disease Control and Prevention Guidelines (5), which recommended screening of all patients scheduled to receive immunosuppressive medications. Finally, we draw attention to a key meeting in early 2014 that was sponsored by the American Association for the Study of Liver Diseases (AASLD) with support from the American Academy of Dermatology, the American Society of Clinical Oncology, and the ACR at which one of the authors (LHC) presented the concerns of the rheumatology community. An article synthesizing the recommendations from this workshop, enhanced by a systematic review of the literature and crafted by an expert panel of world-renowned hepatologists, was published online in January 2015 and in print in February 2015 (6). In this article, the authors again assert that there is “good evidence to support routine screening of all patients prior to undergoing chemotherapy or immunosuppressive therapy.” Gone are caveats regarding highrisk behavior, the geographic origin of patients (e.g., areas with a high prevalence of infection), and the precise immunosuppressive agent. The authors simply state that when immunosuppressive therapy is being contemplated, screening should be performed. In an elegant editorial published in 2012, Lok and colleagues summarized the challenges posed and solutions needed in the title, “Reactivation of hepatitis B during immunosuppressive therapy: potentially fatal yet preventable” (7). The opinion piece was a call to arms to increase screening and prevention, and we strongly believe it is time for the ACR to align itself with these changes. Although we understand the rigor of the process that has gone into developing the ACR guidelines, we must also question whether such a process is adequate to keep pace with important treatment issues especially in terms of safety, where the publishing of even a few instances of a rare complication (e.g., progressive multifocal leukoencephalopathy) can generate letters from regulatory agencies to health care providers. Perhaps we should take note of other organizations similarly generating guidelines in fast-changing fields. We would like to draw attention in particular to the HCV treatment guidelines published by the AASLD and the Infectious Disease Society of America (8). These organizations now use a web-based process for the rapid formulation and dissemination of evidence-based, expert-developed recommendations and in fact explicitly state that “static versions” (i.e., printouts, slides, etc.) may be outdated and urge practitioners to review the evidence provided on the web site. Guidelines are being increasingly scrutinized and need to be assessed for their efficacy and cost effectiveness (9). It has been suggested that increased efficiency in guideline utilization (e.g., HBV/HCV screening) may be enhanced by attempts to construct common themes across guidelines. This could be achieved if all organizations involved in the treatment of patients with immunosuppression or receiving immunosuppressive therapy could actually agree on and disseminate a cohesive front.

Management of skin, mucosa and joint involvement of Behçet’s syndrome: A systematic review for update of the EULAR recommendations for the management of Behçet’s syndrome

OBJECTIVES The aim of this systematic review was to inform the update of European League Against Rheumatism (EULAR) Recommendations for the management of Behçets syndrome (BS), on the evidence for the treatment of skin, mucosa and joint involvement of BS. METHODS A systematic literature search, data extraction, statistical analyses and assessment of the quality of evidence were performed according to a pre-specified protocol using the PRISMA guidelines. Studies that assessed the efficacy of an intervention in comparison to an active comparator or placebo for oral ulcers, genital ulcers, papulopustular lesions, nodular lesions or arthritis were included. Where possible, risk ratios were calculated for binary outcomes and mean difference for continuous outcomes. RESULTS Among the 3927 references that were screened, 37 were included in the analyses. Twenty-seven of these assessed mucocutaneous and 17 assessed joint involvement. Twenty-one of these studies were randomised controlled trials (RCTs). RCTs with colchicine, azathioprine, interferon-alpha, thalidomide, etanercept and apremilast showed beneficial results with some differences according to lesion type and gender. These agents were generally well tolerated with few adverse events causing withdrawal from the study. CONCLUSIONS RCTs comprised more than a half (21/37, 57%) of the sources included in the evidence synthesis related to skin, mucosa and joint involvement applicable for the EULAR Recommendations for the management of BS. Differences in the outcome measures that were used across the included studies often made it difficult to combine and compare the results.

AB0574 Fecal Calprotectin Level Looks Promising in Identifying Active Disease in behÇet's Syndrome Patients with Gastrointestinal Involvement: A Controlled and Pilot Study

Background The fecal calprotectin (FC) level is widely used as a non-invasive method for identifying patients with active Crohns disease (CD) and ulcerative colitis. Gastrointestinal involvement of Behçets syndrome (GIBS) shows clinical and endoscopic similarities to CD. A previous study in a small number of Behçets syndrome (BS) patients with mainly mucocutaneous lesions showed that serum calprotectin levels did not differ between active and inactive patients (1). Another study suggested that FC may help to diagnose GIBS patients (2). We are not aware of studies addressing whether FC levels help to distinguish active GIBS patients from those in remission. Objectives To determine whether FC levels help predict active disease in GIBS patients. Methods We collected fecal specimens from 23 GIBS (11 M, 12 F and mean age 44±9 years) patients before colonoscopy. The reasons for colonoscopy were assessing active disease in patients presenting with abdominal pain (with or without diarrhea) (n=9) or confirmation of a remission in asymptomatic patients (n=16). Four symptomatic and 3 asymptomatic patients had active ulcers by endoscopy. On the other hand, 5 symptomatic and 13 asymptomatic patients did not have ulcers by endoscopy. We also included 22 active and 25 inactive CD patients as controls. We used 150 μg/g as the cut-off for a positive FC level. We also looked at the correlation between FC and serum CRP levels, Crohns disease activity index (CDAI) and disease activity index for intestinal Behçets disease (DAIBD) scores. Results FC was >150 μg/g in all of the 7 GIBS patients with ulcers compared to 4/16 of GIBS patients without ulcers (OR, 95%CI: 42 to 888). The mean FC was 1125±800 μg/g (95%CI: 341 to 1908) among symptomatic patients with ulcers (n=4) and 209±213 μg/g (95%CI: 22 to 396) among symptomatic patients without ulcers (n=5). On the other hand, the mean FC was 243±73 μg/g (95%CI: 158 to 328) among asymptomatic patients with ulcers (n=3) and 95±160 μg/g (95%CI: 0.4 to 189) among asymptomatic patients without ulcers (n=11). Among CD patients, 16/25 active patients and 3/22 patients in remission had FC level >150 μg/g (OR, 95%CI: 11 to 49). There was a low correlation between FC and serum CRP levels (r=0.3, p=0.1), a moderate correlation between FC levels and CDAI scores (r=0.5, p=0.02) and very low correlation between FC and DAIBD scores (r=0.01, p=0.9). Among the 4 GIBS patients who had high FC levels despite being in remission for gastrointestinal involvement, 1 had active mucocutaneous lesions, 1 had concomitant macrophage activation syndrome, and 1 had polycythemia vera with trisomy 8. None of the patients were receiving NSAIDs that could increase FC levels. Conclusions Pending the study of more number of patients, FC may turn out to be a useful non-invasive tool for ruling out active gastrointestinal lesions in asymptomatic GIBS patients. A high FC level demands caution for the presence of active ulcers especially in symptomatic patients, but whether the presence of other BS manifestations can cause false positive results remains to be studied. References Oktayoglu P et al. Scand J Clin Lab Invest. 2015 Kim DH et al. ECCO.2014 Disclosure of Interest None declared

FRI0240 The clinical course of the acute deep vein thrombosis of the legs in behCet's syndrome

Background 15-50% of patients with Behçet’s syndrome have vascular involvement (BS). Lower extremity deep vein thrombosis (LEDVT) makes up 70% of all vascular involvement (1,2). Objectives The aim of this study was to determine the clinical course of LEDVT about which there has been little data. Methods Consecutive BS patients attending our BS outpatient clinic were included after an acute or subacute first episode of LEDVT in one leg. They might have had previous contralateral LEDVT. The same radiologist performed a structured and detailed lower extremity Doppler ultrasonography (US). All deep veins, VCI and major superficial veins were examined at 1,3,6,18 and 24 months after the index event. Nodular lesions that evolved during follow-up were also examined for their US structure to differentiate between superficial vein thrombosis and erythema nodosum. Results Within 20 months 31 patients (4F, 27M) with LEDVT in a previously uninvolved leg were studied. 10 patients had had a previous episode of LEDVT in the opposite leg. Mean age was 29.5±7, mean disease duration since disease onset was 49.5±34.6, and the mean follow-up duration during the study was 13.4±6.2 months. Veins involved in order of frequency were popliteal vein (42%), superficial femoral vein (31%), crural veins (29%) and common femoral vein (27%). VCI was involved in 3 (5%) patients. 14 patients (45%) relapsed during follow-up. 11 patients relapsed with a superficial thrombophlebitis and 5 patients relapsed with a new deep vein thrombosis. Mean time to relapse was 2.83±1.99 months when the relapse was a superficial thrombophlebitis and 6.0±2.3 months when the relapse was a LEDVT (P=0.001). Only 3 out of 19 patients who had a recanalization (≥50%) at month 3 follow-up had a relapse whereas a relapse was observed in 11 of the 12 patients with poor recanalization (<50%) (P=0.001). All 3 patients with VCI involvement had venous skin ulcers in the lower extremity and these 3 patients were also the only patients with skin ulcers in the whole group. 17/31 (55%) patients developed nodular lesions during the study. 13/17 had had previous episodes of nodular lesions while in 4 patients these appeared for the first time. Doppler ultrasonographic examination of these nodules revealed superficial thrombophlebitis in 12 (70%). Conclusions The more common vascular relapse after an episode of LEDVT is superficial thrombophlebitis. Relapses of a superficial thrombophlebitis occur earlier than relapses with a LEDVT. Poor recanalization of the index LEDVT at 3 months is associated with relapses. The presence of skin ulcers seems to go along with inferior vena caval thrombosis. As expected, LEDVT in BS is associated more with superficial thrombophlebitis than with erythema nodosum-type lesions (3). References Melikoglu M, Ugurlu S, Tascilar K, et al. Large vessel involvement in Behçet’s syndrome: a retrospective survey. Ann Rheum Dis. 2008; 67 (Suppl II): 67. Sarica-Kucukoglu R, Akdag-Kose A, Kayabali M, et al; Vascular involvement in Behçet’s disease: a retrospective analysis of 2319 cases. Int J Dermatol. 2006; 45: 919 – 921 Tunc R, Keyman E, Melikoglu M, Fresko I, Yazici H. Target organ associations in Turkish patients with Behçet’s disease: a cross sectional study by exploratory factor analysis. J Rheumatol. 2002; 29:2393-6 Disclosure of Interest None Declared

Management of major organ involvement of Behçet's syndrome: a systematic review for update of the EULAR recommendations

Objective To assess the efficacy and safety of treatment modalities for major organ involvement of Behçets syndrome (BS), in order to inform the update of the EULAR recommendations for the management of BS. Methods A systematic literature review of all randomized controlled trials, controlled clinical trials, or open label trials assessing eye, vascular, nervous system or gastrointestinal system involvement of BS was performed. If controlled trials were not available for answering a specific research question, uncontrolled studies or case series were also included. Results We reviewed the titles and abstracts of 3927 references and 161 studies met our inclusion criteria. There were only nine randomized controlled trials. Observational studies with IFN-α and monoclonal anti-TNF antibodies showed beneficial results for refractory uveitis. Meta-analysis of case-control studies showed that immunosuppressives decreased the recurrence rate of deep vein thrombosis significantly whereas anticoagulants did not. CYC and high dose glucocorticoids decreased mortality in pulmonary arterial aneurysms and postoperative complications in peripheral artery aneurysms. Beneficial results for gastrointestinal involvement were obtained with 5-ASA derivatives and AZA as first line treatment and with thalidomide and/or monoclonal anti-TNF antibodies in refractory cases. Observational studies for nervous system involvement showed improved outcome with immunosuppressives and glucocorticoids. Meta-analysis of case-control studies showed an increased risk of developing nervous system involvement with ciclosporin-A. Conclusion The majority of studies related to major organ involvement that informed the updated EULAR recommendations for the management of BS were observational studies.