ObjectivesBehçet's syndrome (BS) is most active during young adulthood and may cause severe disability. We had previously observed a high frequency of work disability among our Behçet's patients in a ...cross-sectional study. This time we aimed to evaluate the sustainability of work among our patients who did have a job 5 years ago.MethodsWe had surveyed work disability among 300 consecutive Behçet's syndrome patients who attended our clinic in 2009. We had observed that after excluding students, homemakers and retired patients, among the 149 work eligible patients 29 (21%) were unemployed and 120 were employed. We now evaluated those patients who did have a job 5 years ago regarding work loss and reasons for work loss, using a standard questionnaire. We also checked their hospital charts for new types of organ involvement that developed during these 5 years, and any new medications that were started.ResultsAmong the 120 patients who did have a job in 2009 (87 men, 33 women, mean age 36±8.6, disease duration 9.7±7.1 years, 48% with major organ involvement), we were able to contact 97 patients. Sixteen patients (16%) had lost their jobs during the previous 5 years. Nine of these (11%) were related with Behçet's syndrome and the rest were due to other causes (5 had retired, 1 had a baby, 1 was doing his military service). Among the 81 patients who were still working, 10 (10%) had to change their work place during the last 5 years and were unemployed for a mean of 6.7±5.3 months between these jobs.ConclusionsWork disability is an important problem among Behçet's syndrome patients. During a 5 year follow-up, 11% of patients lost their jobs due to their disease, and a further 11% had to interrupt work and change their work places. We were only able to evaluate work disability in this study, and work productivity is another important issue that needs to be studied among patients with Behçet's syndrome.Disclosure of InterestNone declared
BackgroundA decline in the frequency of AA amyloidosis secondary to rheumatoid arthritis and infectious diseases has been reported. This is probably due to more effective treatment strategies. We had ...previously reported that although amyloidosis occurs in less than 0.5% of BS patients, it is one of the leading causes of death.1–3 We had an impression that the frequency of amyloidosis is decreasing among our patients with BS.ObjectivesWe aimed to determine the change in the frequency of AA amyloidosis over years in BS pts in addition to elaborating on clinical characteristics and outcomes.MethodsWe performed a chart review to identify all pts with amyloidosis in our BS centre since 1976. We noted demographic characteristics, BS manifestations, age at BS and amyloidosis diagnosis, treatment modalities of these pts. Our endpoints were death and end stage renal disease (ESRD) requiring renal replacement therapy. The prevalence of amyloidosis was calculated separately for two periods (pts registered between 1976–2000 and 2000–2017)ResultsAmong our 9410 BS pts, 27 (0.29%) had amyloidosis.We identified 24 pts with amyloidosis among the 3820 pts in the earlier cohort and 3 additional amyloidosis among the 5590 pts in the recent cohort. The frequency of AA amyloidosis had declined from 0.62% to 0.054% in the recent cohort. M/F ratio was 22/5 and mean age at BS diagnosis was 29.5±7.4 years. Twenty-two (82%) of the pts with amyloidosis had major organ involvement (vascular involvement in 15, eye involvement in 13 and neurologic involvement in 2). Five (18%) of 27 pts had only mucocutaneous involvement.AA amyloidosis was diagnosed after a mean duration of 9.8±6.7 years (mean age at amyloidosis: 39.3±9.3 years) and was confirmed with renal biopsy in 14 pts and rectal biopsy in 13. Eight pts had non-nephrotic range proteinuria at amyloidosis diagnosis. After amyloidosis diagnosis, 24 pts continued their previous immunosuppressives and colchicine. Two of these 24 were on anti-TNFs at AA diagnosis. Biologics were initiated in 3 pts who were most recently diagnosed to have amyloidosis, anti-TNFs in 2 and tocilizumab in 1. Fourteen (52%) pts had died after a median follow-up of 3 (IQR:1–8.75) years, 3 were lost to follow-up just after amyloidosis diagnosis and 10 (37%) are still alive after a median follow up of 16 (IQR:10–23) years. The reasons for death were infections in 5, related to ESRD in 5, subarachnoid haemorrhage, gastric adenocarcinoma, liver cirrhosis and iatrogenic bowel perforation in 1 patient each. 10 (71%) of these 14 pts had developed ESRD before their deaths. Overall, 15/27 pts developed ESRD after a median follow-up of 3.5 (IQR:1.25–6.5) years after amyloidosis diagnosis. 5 of them had renal transplantation, all but 1 are still alive after 3, 4, 6, and 12 years.ConclusionsAA amyloidosis appears to be a rare, but fatal complication of BS. Around 50% of patients died after a median follow-up of 3 years after amyloidosis. This study showed a decreasing trend of AA amyloidosis due to BS similar to that observed in other inflammatory and infectious causes. The shorter follow-up duration may be contributing for the lower prevalence of AA amyloidosis in the recent cohort.References1 Yurdakul S, Arthritis Rheum1990.2 Melikoğlu M. Rheumatology(Oxford)2001.3 Kural-Seyahi E. Medicine (Baltimore)2003.Disclosure of InterestNone declared
BackgroundCyclophosphamide (CYC) remains an important treatment option for Behçet’s syndrome (BS) patients with life-threatening conditions such as arterial aneurysms. However, several adverse events ...may occur with CYC and this has led to increased use of biologic agents such as rituximab in other vasculitides.ObjectivesThe aim of this study is to delineate the outcome and short and long-term adverse events with CYC use among BS patients.MethodsWe conducted a retrospective chart review of all BS patients treated with oral or intravenous CYC between 1976 and 2006. Patients were called and a standard form was used for collecting demographic characteristics, CYC indication, cumulative dose of CYC and short-term serious adverse events necessitating the cessation of therapy and/or requiring hospitalisation and long-term adverse events (malignancy and infertility), and outcome.ResultsWe identified 198 (M/W: 184/14) BS patients who had received CYC. After a median follow up of 17 (IQR: 9–26) years after the initiation of CYC therapy, 52 (26%) patients had died within a median duration of 41–12 years, 33 (17%) were lost after a median follow-up of 9 (3.5–14) years, and 113 (57%) were contacted. CYC was prescribed for vascular involvement in 132 (67%) patients, eye involvement in 52 (26%), central nervous system involvement in 5, both vascular and eye involvement in 7 and both vascular and central nervous system involvement in 2 patients. The median duration of CYC use was 12 (IQR:4–24) months and median cumulative dose was 13.5 (IQR:6–49) gr. Among the 52 patients who died, reasons for death were vascular involvement in 26, malignancies in 7, infections in 5 (5 bacterial infections, 1 additional tuberculosis), neurologic involvement in 2, ischaemic stroke in 1, traffic accident in 1, and secondary amyloidosis in 1, esophageal variceal bleeding in 1, and unknown in 5 patients. Sixteen (8%) patients experienced serious adverse events associated with short-term CYC use and 1 of them died due to infection. Among these adverse events, haemorrhagic cystitis occurred in 7 patients, infections in 4 (1/4 died), leukopenia, acute myocardial infarction, anaphylactic reaction, azoospermia, liver toxicity, and severe nausea in 1 patient each. Overall, 16 malignancies were observed in 14 (7%) patients after a median follow up of 25 (IQR:15–26) years. The malignancies were bladder carcinoma (n=4), lung adenocarcinoma (n=3), prostate adenocarcinoma (n=2), carcinoma of unknown primary origin, pancreas adenocarcinoma, t-MDS-AML, lymphoma, colon adenocarcinoma, squamous cell carcinoma and thyroid papillary carcinoma. Among the 113 patients, we were able to question regarding infertility, 67 patients (59%) had children, 22 (19.5%) did not wish to have a child and 24 (21.5%) tried to have a child, but was not able to.ConclusionsShort term serious adverse events occurred in 8% of the patients during CYC treatment. During long term follow-up malignancies occurred in 7% and infertility in 21.5% of the patients. These results underline the need for safer and effective alternatives to CYC for serious organ involvement in BS, similar to that in other vasculitides.Disclosure of InterestNone declared
BackgroundOral ulcers (OU) are the most common sign of Behçet’s syndrome (BS) and are observed in nearly every patient. Due to their severity and frequency of reoccurrence, OU can be disabling and ...have a substantial effect on quality of life. There is an unmet need for effective treatment for OU in BS. Apremilast (APR), an oral phosphodiesterase 4 inhibitor that modulates inflammatory pathways, demonstrated efficacy in the treatment of oral and genital ulcers of BS in a phase II study.ObjectivesPhase III study to further evaluate the efficacy and safety of APR for OU in BS pts with active OU previously treated with ≥1 medication.MethodsIn this phase III, multicenter, randomised, placebo (PBO)-controlled study, 207 eligible pts were randomised (1:1) to APR 30 mg BID (n=104) or PBO (n=103) for 12 weeks, followed by a 52 week active-treatment extension. Pts had active BS, with ≥3 OU at randomization or ≥2 OU at screening +randomization, without active major organ involvement. 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 clinical characteristic that OU repeatedly remit and recur. Secondary endpoints assessed other measures of OU, including pain, OU resolution (OU-free), maintenance of OU resolution, and time to resolution. Effects on genital ulcers were also assessed. A prespecified hierarchical testing procedure was used for multiplicity adjustment.ResultsAUC for total number of OU over 12 weeks was statistically significantly lower in the APR group compared with the PBO group (table 1). This treatment effect is supported by statistically significant benefits in the APR group compared with PBO for secondary endpoints assessing OU, including pain, OU resolution, maintenance of OU resolution, and time to resolution. A numerically greater proportion of pts achieved resolution of genital ulcers at Week 12 in the APR group compared with PBO.The incidence of treatment-emergent adverse events (AEs) was comparable between APR and PBO during the PBO-controlled period (78.8% vs 71.8%, respectively). Serious AEs were observed in 3 APR pts (migraine, oral ulcer flare, genital ulcer, arthralgia, soft tissue injury) and 4 PBO pts (diarrhoea, genital and fungal infections, oral ulcer flare, acne, acute febrile neutrophilic dermatosis, erythema multiforme).ConclusionsAPR effectively reduced the number and pain of OU, improved time to oral ulcer resolution, and maintained the resolution of OU, the most common manifestation of BS. Favourable treatment effects were also observed for genital ulcer resolution. The safety profile was consistent with the known safety profile of APR.Disclosure of InterestG. Hatemi Grant/research support from: Celgene Corporation, Speakers bureau: UCB, Abbvie, Mustafa Nevzat, A. Mahr Speakers bureau: Roche Chugai, M. Takeno Consultant for: Celgene Corporation, Speakers bureau: Esai Co, Tanabe-Mitsubishi Co, D.-Y. Kim: None declared, M. Melikoglu: None declared, S. Cheng Employee of: Celgene Corporation, S. McCue Employee of: Celgene Corporation, M. Paris Employee of: Celgene Corporation, Y. Wang Employee of: Celgene Corporation, Y. Yazici Consultant for: Celgene Corporation, Sanofi, Genentech, BMS
Background Gastrointestinal involvement can be a severe complication of Behcet’s syndrome (BS) resulting in perforation and massive bleeding. Controlled data regarding treatment is lacking and long ...term prognosis is not well known. Objectives To report the demographic and disease characteristics, type of involvement, treatment modalities and outcome of BS patients with gastrointestinal involvement (GIBS). Methods We retrospectively reviewed the charts of all BS patients evaluated by gastroenterologists in our multidisciplinary BS clinic with a suspicion of gastrointestinal involvement, and surveyed those with a diagnosis of GIBS. Patients were evalauted either in the outpatient clinic or if not possible by phone calls to assess their outcome. Results There are more than 8000 recorded BS patients in our multidisciplinary outpatient clinic. 69 of them had symptoms suggesting gastrointestinal involvement and lesions on endoscopy. Among these 18 patients had other reasons for their gastrointestinal symptomes and endoscopic lesions like non-steroidal anti-inflammatory drug use, gastrointestinal tuberculosis and antibiotic associated hemorhagic colitis. The remaining 51 patients had GIBS (Table). The presenting symptoms were acute abdomen caused by perforations in 4/51 patients, massive bleeding in 8/51 patients and abdominal pain and/or diarrhea in 39/51 patients. Surgery had to be performed in 20/51 patients. The most commonly used drugs for initial management were azathioprine 2-2.5 mg/kg/day (n=33) and 5 ASA compounds 3-4 g/day (n=13). Remission was observed and there were no relapses during a mean follow-up of 44.3±46.9 months in 22/33 (67%) patients who had initially been prescribed azathioprine (2.5 mg/kg) and during 45.0±50.1 months in 9/13 (68%) patients who had been prescribed 5 ASA compounds. Other than the 33 patients who used azathioprine as their initial treatment, remission was also obtained with azathioprine in 3/4 patients who were resistant to 5 ASA compounds. Among the 10 patients who had relatively severe symptoms and persistent large ulcers despite at least 6 months of azathioprine treatment, endoscopic and symptomatic remission could be obtained with thalidomide in 4 patients, infliximab in 4 patients and adalimumab in 2 patients. After a mean follow-up of 7.1±4.8 years (range 0.25–17 years), 42 (84%) patients were in remission and 14 (28%) of these were off treatment. Four (8%) patients were still active, 3 (6%) patients had died due to non-GI releated reasons and 2 (4%) were lost to follow-up. Patients with GI involvement of BS (n)51 Men:women27:24 Mean age ± SD (years)38.5±9.3 Mean age at diagnosis of GIBS ± SD (years)31.2±7.1 Oral ulcers51/51 Genital ulcers43/51 (86%) Positive pathergy reaction27/51 (54%) Skin lesions34/51 (68%) Arthritis17/51 (33%) Uveitis10/51 (20%) Vascular involvement6/51 (12%) Neurologic involvement5/51 (10%) Conclusions 84% of patients with GIBS were in remission after a mean of 7 years of follow-up. Surgery was required in 40% of patients with GIBS. 5 ASA compounds or azathioprine provided remission and prevented relapses in two thirds of the patients. The latter was also beneficial in some patients resistant to 5 ASA compounds. Resistant and relapsing cases could be managed with thalidomide or TNF-alpha antagonists. Disclosure of Interest None Declared
BackgroundThe efficacy of rituximab (RTX) in ANCA associated vasculitis (AAV) has been shown in controlled trials. Observational data reflecting its real life use in AAV is limited.ObjectivesHere we ...present our experience with RTX therapy in AAV patients refractory to conventional treatment.MethodsWe retrospectively reviewed the records of 25 AAV patients (11 men, 14 women; mean age 42.8±14.2 SD years; mean disease duration 45.5 ± 47.5 SD months) treated with RTX between 2011 and 2015 due to inadequate response or relapse under conventional treatment modalities. Among these 25 patiens the main types of involvement at baseline were renal involvement in 14 patients, pulmonary involvement in 16, upper respiratory system in 10, ocular in 2, peripheral nervous system in 2, CNS in 1, skin in 1 patient and ear in 2 patients. We assessed treatment response with disease activity using BVAS scores, decrease in corticosteroid dose, improvement in renal functions and other organ manifestations.ResultsRTX was given for a median of 2 courses (range 1–5, courses given at fixed intervals in 21 patients) during a mean follow-up of 17.4±13.9 SD months. The reasons for RTX treatment were active renal disease in 11 patients, pulmonary involvement in 9, upper respiratory system involvement in 4, and CNS involvement in 1 patient. In addition to RTX, corticosteroids were used in 13 patients, azathioprine + corticosteroids in 7 patients, methotrexate + corticosteriods in 2 patients, solo azathioprine in 2 patients and RTX was given solo in 1 patient. At final assessment 22 patients were under follow-up, 1 was lost to follow-up after 7 months and 2 had died, due to renal failure in one and respiratory failure in the other patient. 17/25 (68%) patients were in remission (BVAS score 0) at the final assessment. 3/25 patients (12%) had experienced relapses during follow-up. The mean BVAS score during the final assessment was 1.6 ± 4.1. Mean corticosteroid dose was reduced from 42±21.9 mg/day to 15.5±21.0 mg/day (p<0.001).The last evaluation of patients with renal involvement showed stable disease in 6 improvement in 6 and worsening in 2 patients. Mean creatinine level had slightly improved from 2.1 ± 1.2 mg/day to 1.9 ± 1.4 mg/day (p=0.36). Proteinuria had decreased from 1686±1466 mg/day to 1010±1100 mg/day (p=0.02). RTX treatment was terminated in 2 patients because of infusion reaction. Four patients were hospitalized while being on RTX. The first had pneumonia and responded to antibiotics. The second patient with diffuse lung involvement had died. The third died due to renal failure and the last patient developed end stage renal disease.ConclusionsOur retrospective study showed that RTX is an effective treatment modality that enables corticosteroids tapering and remission in majority of AAV patients refractory to conventional treatment modalities. It was generally well tolerated with few serious adverse events.Disclosure of InterestNone declared
Background:TNF alpha blockers form 2nd line treatment choice for Rheumatoid Arthritis (RA) patients. Up to 30% of RA patients do not respond to TNF alpha blockers for unknown reasons, causing a ...significant impact on patients’ outcome and healthcare industry. Therefore, there is an unmet need for a tool to predict treatment response that could help clinicians to choose an optimal treatment for RA patients.Objectives:By using Immuno-Detect, an innovative targeted gene sequencing panel of 2155 mRNA targets associated with immune-inflammatory pathways, we aimed to develop an algorithm, RABIOPRED, that predicts non-response to TNF alpha blockers.Methods:Paxgene samples obtained at baseline from 68 patients naïve to TNF alpha blockers were directly profiled without extraction with Immuno-Detect panel on HTG EdgeSeq platform, a combination of a nuclease protection assay & next generation sequencing (NGS). Patients were treated with Infliximab, Etanercept or Adalimumab and disease activity score was measured based on DAS28 score at 3 months. Response to treatment was assessed by categorizing the patients according to EULAR response criteria. Gene combinations were selected using variable importance score (VIS). Predictive modeling performance was evaluated using the area under the curve (AUC) and confusion matrix.Results:Analytical validation of Immuno-Detect panel shows a very high reproducibility on Paxgene and extracted RNA samples with correlation factor of 0.975 and 0.96 respectively. In paxgene samples, among 2155 genes, 1172 mRNAs are significantly expressed with a mean CV of 9.77% (976 mRNAs and mean CV of 11.98% for RNA). Most expressed target represent only 5% of the total reads and only 20 targets are reaching 1% of total reads showing a very well balanced panel. Performance of our predictive model shows an AUC of 0.905 with 0.88 accuracy. Our algorithm predicts non-responders to TNF alpha blockers with the sensitivity of 0.78 and positive predictive value of 0.91. This algorithm will be further validated within the ongoing RABIOPRED Proof-of-Performance study (ClinicalTrials.gov Identifier: NCT03016260) based on 720 patients treated by anti-TNF alpha drugs (5 originators & 3 biosimilars) launched in December 2016.Conclusions:We are showing that Immuno-Detect panel accurately measures mRNA expression using HTG-EdgeSeq NGS platform. This panel can be further used to build signatures to predict TNF alpha blocker’s non-response. The algorithm obtained in the current study will be later on validated in a multi-centric proof-of-performance clinical study.Disclosure of Interest:None declared
BackgroundQuality of life is commonly impaired in patients with chronic inflammatory diseases. The disease itself as well as the drugs used may be responsible for this impairment. Behçet's syndrome ...(BS) is a multisystem vasculitis with a wide variety of manifestations including oral ulcers, genital ulcers, nodular lesions, papulopustular lesions, arthritis, uveitis, venous thrombosis, arterial aneurysms, neurologic and gastrointestinal involvement. Determining the factors affecting quality of life in BS patients, would help developing effective management strategies.ObjectivesWe aimed to determine the factors that impair quality of life (QoL) in BS.MethodsShort- Form 36 (SF-36) physical component score (PCS) and mental component score (MCS) and Behçet Disease Quality of Life (BDQoL) questionnaires were filled by consecutive BS patients attending our outpatient clinic. Socioeconomic factors, each type of organ involvement during the disease course, during the last 4 weeks, disabilities caused by each, treatment modalities and overall disease activity were tested with regression analysis as possible determinants of QoL.Results453 patients (M/F: 240/213, mean age: 38.2±10.8) were included in our study. 223 patients had eye involvement, 94 patients had vascular involvement, 102 patients had joint involvement, 28 patients had neurologic involvement, 2 patients had gastrointestinal involvement and 127 patients had only mucocutaneous involvement without organ involvement. Determinants of BDQoL in the whole group were BSAS, household income, perceived sufficiency income, neurologic damage, mucocutaneous involvement (R2: 0.38, p<0.001), among women were BSAS, neurologic and mucocutaneous involvement (R2: 0.36, p<0.001), and among men were disease related working disability, BSAS, household income, joint attack during the last 4 week, vascular and neurologic damage (R2: 0.39, p<0.001) Determinants of PCS in the whole group were BSAS, household income, eye, vascular and joint involvement during the last 4 week, disease related working disability (R2: 0.31, p<0.001), among men were BSAS, disease related working disability, household income, vascular involvement, vascular and joint involvement during the last 4 week (R2: 0.32, p<0.001), among women were BSAS, mucocutaneous involvement and perceived sufficiency income (R2: 0.32, p<0.001). Determinants of MCS in the whole group were BSAS, household income, neurologic damage (R2: 0.20, p<0.001), among men were BSAS, household income, neurologic damage, disease related working disability, mucocutaneous involvement (R2: 0.26, p<0.001), among women were BSAS and mucocutaneous involvement (R2: 0.21, p<0.001).ConclusionsIn addition to overall disease activity in women mucocutaneous and neurologic involvement and in men neurologic and vascular damage and joint attack seem to impair quality of life in BS. Determining the factors predicting the quality of life are important for developing management strategies and also may help determining the items that need to be addressed while developing outcome measures.Disclosure of InterestNone declared
ObjectivesThe aim of this systematic literature review was to inform the task force for updating the European League Against Rheumatism recommendations for the management of Behçet's Syndrome (BS), ...about the evidence for treatment of skin, mucosa and joint involvement of BS.MethodsA systematic literature search, data extraction and statistical analyses according to pre-specified and protocolised eligibility criteria were performed using the GRADE approach. The protocol for the review was registered and is available at PROSPERO (CRD42015027033). The Cochrane Library, including the Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessments (HTA), MEDLINE (from 1950), EMBASE (from 1980) and International Pharmaceutical Abstracts Database (IPAD) were systematically searched. Randomised controlled trials (RCT), non-randomised controlled clinical trials and open label trials (OLT) on BS comparing an active intervention (alone or in combination) with any control or placebo were eligible. If controlled trials were not available for answering a specific research question, uncontrolled evidence from cohort studies or case series involving ≥5 patients were considered. The quality of evidence was assessed by using the GRADE approach. Risk ratios were calculated for the binary outcomes whereas for the continuous outcomes we calculated the standardized mean difference (SMD).ResultsAmong the 3927 references that we have screened, 22 studies satisfied the inclusion criteria for mucocutaneous involvement and 15 studies for joint involvement. Seventeen of these studies were RCTs assessing mucocutaneous and/or joint involvement. RCTs with colchicine, azathioprine, interferon-alpha, thalidomide, etanercept and apremilast showed different levels of beneficial results on different types of skin and mucosa lesions and arthritis. Differences in the outcome measures that were used across the included studies made it difficult to compare the results. These agents were generally well tolerated with few adverse events causing withdrawal from the study in BS patients.ConclusionsIt was gratifying to see that randomised trials formed the majority (17/22, 77%) of the sources forming the basis for the recommendations related to skin mucosa and joint involvement in the updated EULAR recommendations for the management of BS.Disclosure of InterestNone declared
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