Sinem Nihal Esatoglu

Bone marrow transplantation for Behçet’s disease: a case report and systematic review of the literature

OBJECTIVES Behçets disease (BD) can be life threatening and may be refractory to corticosteroids and immunosuppressives. There has been some experience with haematopoietic stem cell transplantation (HSCT) in BD either for severe, refractory disease or for a haematological condition. The objectives of this study were to describe a BD patient undergoing HSCT and to evaluate the outcomes of BD patients who underwent HSCT. METHODS We report a BD patient with refractory gastrointestinal (GI) involvement who had HSCT for concomitant myelodysplastic syndrome (MDS). We also performed a systematic literature search regarding HSCT for either refractory disease or concomitant haematological conditions in BD patients. RESULTS A 30-year-old woman with refractory GI BD involvement with trisomy 8 MDS underwent a successful myeloablative allogeneic HSCT resulting in complete resolution of both BD and MDS. Additionally we identified 14 manuscripts providing data on 19 patients with BD who had HSCT. Among these 20 patients, including ours, refractory disease was the indication of transplantation in 9, while 11 patients were transplanted because of accompanying haematological conditions. Transplant indications for the nine patients (four male, five female) with refractory BD were neurological involvement in five, pulmonary artery aneurysm in two, GI disease in one and not reported in one patient. Three patients with neurological disease, both patients with pulmonary artery aneurysm and the patient with intestinal involvement achieved complete remission of their disease. Six patients transplanted for haematological conditions, including the presented case, also had GI involvement of BD. All of these patients achieved complete remission of GI findings after HSCT. CONCLUSION When considering HSCT, the potential adverse events and complications, which can be fatal, need to be kept in mind.

Characteristics, Treatment, and Long-Term Outcome of Gastrointestinal Involvement in Behcet's Syndrome: A Strobe-Compliant Observational Study From a Dedicated Multidisciplinary Center

AbstractGastrointestinal involvement is rare in Behçets syndrome (BS) patients from the Mediterranean basin. We report the demographic and disease characteristics, treatment modalities, and outcome of patients with gastrointestinal involvement in BS (GIBS).We retrospectively reviewed the charts of all BS patients in our BS clinic with a diagnosis of GIBS. Patients were invited to the clinic to assess their outcome.Among 8763 BS patients, we identified 60 with GIBS (M/F: 32/28, mean age at diagnosis: 34 ± 10, mean follow-up: 7.5 ± 4 years), after excluding 22 patients with mimicking symptoms. Six (10%) had juvenile-onset BS. The most common intestinal localization was ileocecal region (36/59, 61%) mainly as big oval ulcer/s. Initial treatment was azathioprine for moderate to severe (n = 37) and 5-ASA for mild cases (n = 16). Anti-TNFs and/or thalidomide provided remission in 12 of 18 (67%) refractory patients. Emergency surgery was required in 22 patients. Nine patients did not receive postoperative immunomodulators and 8 relapsed. Overall, 48 of 60 (80%) patients were in remission (29/48 without treatment) at the time of survey. Three recently treated and 2 refractory patients were still active, 3 had died due to non-GI-related reasons, and 4 were lost to follow-up.Careful evaluation for excluding mimickers is important during the diagnosis of GIBS. Azathioprine seems to be a good choice as first-line treatment with high remission rates and few adverse events. Thalidomide and/or TNF-alpha antagonists may be preferred in resistant cases. Surgery may be required for perforations or massive bleeding, and postoperative immunosuppressive treatment is necessary for preventing postoperative recurrences.

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.

Long-term follow-up of secondary amyloidosis patients treated with tumor necrosis factor inhibitor therapy: A STROBE-compliant observational study

Abstract There are no treatment modalities, which were proven to prevent the deposition of amyloid, proteinuria, and loss of renal function due to amyloidosis. Anti-tumor necrosis factor agents (anti-TNFs) were shown to decrease the production of serum amyloid A protein. We aimed to evaluate the long-term efficacy and safety of anti-TNFs in secondary (AA) amyloidosis patients treated in a single center. Thirty-seven patients with AA amyloidosis were started an anti-TNF for AA amyloidosis between March 2001 and June 2008 and followed until May 2016 unless deceased. They were surveyed for the endpoints of death, development of end-stage renal disease (ESRD), switch to another agent due to worsening of amyloidosis and adverse events. Among the 37 patients, 12 (32%) had died, 9 (24%) had ESRD, and 8 (22%) had started another group of biologic due to worsening of amyloidosis indicated by an increase in proteinuria, 5 (14%) patients are still doing well with anti-TNFs, and 3 (8%) are off treatment at the end of a median follow-up of 10 (interquartile range [IQR]: 5.5–10.5) years since the start of anti-TNFs and 10 (IQR: 8–13) years since the diagnosis of AA amyloidosis. Most common serious adverse events were sepsis and thrombotic events observed in 8 and 4 patients, respectively. Treatment with anti-TNFs may be associated with a higher survival rate compared with historic cohorts of AA amyloidosis, especially when started early with a lower serum creatinine level at baseline. Caution is needed regarding serious adverse events, especially infections.

Behçet’s syndrome: providing integrated care

Behçet’s syndrome (BS) is a multisystem vasculitis that presents with a variety of mucocutaneous manifestations such as oral and genital ulcers, papulopustular lesions and erythema nodosum as well as ocular, vascular, gastrointestinal and nervous system involvement. Although it occurs worldwide, it is especially prevalent in the Far East and around the Mediterranean Sea. Male gender and younger age at disease onset are associated with a more severe disease course. The management of BS depends on the severity of symptoms. If untreated, morbidity and mortality are considerably high in patients with major organ involvement. Multidisciplinary patient care is essential for the management of BS, as it is for other multisystem diseases. Rheumatologists, dermatologists, ophthalmologists, neurologists, cardiovascular surgeons and gastroenterologists are members of the multidisciplinary team. In this study, we reviewed the epidemiology, etiology, diagnostic criteria sets, clinical findings and treatment of BS and highlighted the importance of the multidisciplinary team in the management of BS.

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

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.

Biomarkers in vasculitis.

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 Behçets 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.