Pulmonary artery involvement due to Behçet's syndrome and Hughes Stovin syndrome: a comparative study.

OBJECTIVES: Hughes-Stovin syndrome (HSS) is a rare inflammatory condition defined as pulmonary artery aneurysms (PAA) associated with deep vein thrombosis. It is similar to vascular involvement of Behçet's syndrome (BS), but differs in the absence of typical skin-mucosal findings. Whether HSS is a distinct entity or a form fruste of BS is debated. We formally compared HSS cases retrieved from the literature to BS patients with PAI followed by a tertiary centre. METHODS: A systemic literature search using 'Hughes Stovin syndrome' as the key word covering the period between 2000 and 2023 revealed 58 (43 M/15 F) case reports (PROSPERO: CRD42023413537). We identified 74 (62M/12 F) BS patients with PAI followed up in a tertiary centre in Turkey from 2000 until 2020. We evaluated two cohorts head-to-head in terms of demographic and clinical features. RESULTS: BS and HSS patients were found to be comparable with regard to several demographic, clinical and histopathological features. However, PAA were significantly more frequent and isolated pulmonary artery thrombosis (PAT) less common in HSS than that found in BS. Moreover, patients with HSS were more likely to be treated with anti-coagulants and vascular or surgical interventions, whereas less likely to receive immunosuppressive treatment. CONCLUSIONS: Our study indicates that HSS is indeed an 'incomplete form of BS'. It can be considered as evidence supporting the notion that the vascular phenotype develops independently from skin-mucosa lesions and uveitis in BS. However, HSS has been described mainly focusing on aneurysms, overlooking the aspect of in-situ thrombosis.

Tocilizumab may not be a good option for vascular involvement due to Behçet's syndrome.

OBJECTIVES: Tocilizumab has been increasingly reported as an alternative therapeutic agent in the management of Behçet's syndrome (BS) and it has been mostly tried in BS patients with neurological and eye involvement. As therapeutic responses to each drug may vary across different types of BS involvement, we aimed to report seven patients with large vessel involvement treated with tocilizumab. METHODS: We enrolled seven BS patients with vascular involvement who were given tocilizumab at the Behçet's Disease Research Centre in Istanbul University-Cerrahpasa between 2000 and 2022. Demographic information, BS features, types of vascular involvement, previous and concomitant medications, C-reactive protein (CRP) levels, imaging modality results, and outcomes were documented from the patients' medical records. RESULTS: Within a median of 6 months after the initiation of tocilizumab, 5 patients experienced vascular relapses. These relapses included the emergence of new bilateral pulmonary artery aneurysms, a new pulmonary artery thrombus, parenchymal lung involvement, deep vein thrombosis in the lower extremity, and pseudotumor cerebri in one patient each. CRP levels were normal in 4 of the 5 patients at the time of vascular relapse. One of these 5 patients and another patient with aortitis had an exacerbation of mucocutaneous symptoms. In the last patient, venous ulcers did not respond to tocilizumab and were complicated with infection. CONCLUSIONS: Tocilizumab could potentially exacerbate vascular manifestations, similar to what is observed with mucocutaneous lesions in BS patients. Furthermore, CRP levels appear to be ineffective in monitoring these patients.

Carotid artery ultrasonography and shear wave elastography in Takayasu's arteritis: a comparative analysis with diabetes mellitus.

OBJECTIVES: Takayasu's arteritis (TAK) is a chronic inflammatory large vessel vasculitis with a grim prognosis due to the excessive risk for cardiovascular (CV) diseases. Its diagnosis relies on radiographic imaging and its differentiation particularly from atherosclerosis could be challenging. Hypothesising that vascular morphology observed in TAK would be comparable to that found in type 2 diabetes mellitus (T2DM), a prototype for advanced atherosclerosis, we compared two disease groups using carotid artery B mode US and shear wave elastography (SWE). METHODS: A total of 72 patients with TAK (63F/9M; mean age: 42.7± 10.0 years) and 74 patients with T2DM (65F/9M; mean age: 50.2± 7.1 years) were studied. Intima-media thickness (IMT), outer diameter and arterial stiffness as assessed by SWE values were measured on the common carotid artery (CCA) and atherosclerotic plaques were recorded. Clinical characteristics, CV risk factors and previous history of CV diseases were determined. Framingham risk score was calculated. RESUULTS: Patients with TAK exhibited significantly lower atherosclerotic risk but higher systolic blood pressure (BP) levels compared to those with T2DM. The mean values of CCA IMT, outer diameter, and stiffness were significantly elevated among patients with TAK compared to those with T2DM. Carotid artery plaques were evenly distributed between the study groups, but their anatomical localisation and composition differed significantly. While coronary artery disease (CAD) was more prevalent among T2DM patients, cerebrovascular diseases were more frequent among TAK patients. CONCLUSIONS: Our study revealed distinctive vascular alterations and atherosclerotic changes when compared to advanced atherosclerosis associated with T2DM. Apart from these, higher levels of systolic BP and significantly different distribution of CV diseases between TAK and T2DM also suggest that TAK should be handled with distinct assessment strategies than that employed in conventional atherosclerotic conditions.

Anakinra in idiopathic recurrent pericarditis: a comprehensive case series and literature review.

OBJECTIVE: Idiopathic recurrent pericarditis (IRP) is defined by recurring episodes of pericardial inflammation without a known cause. This study investigates the safety and efficacy of anakinra, an interleukin­1 inhibitor, as a successful therapy for IRP in cases resistant to conventional treatment. METHODS: A retrospective evaluation of patients treated at our autoinflammatory center between 2011 and 2023 was conducted. Patient files were examined for demographic, clinical, and treatment response data, including nonsteroid anti-inflammatory drugs (NSAIDs), corticosteroids, and colchicine. Monogenic autoinflammatory disease screening was performed for Mediterranean Fever (MEFV), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase (MVK), nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3), and nucleotide-binding oligomerization domain-containing protein 2 (NOD2). Patients who experienced multiple episodes of pericarditis were diagnosed with recurrent pericarditis. The study evaluated anakinra treatment in IRP patients unresponsive to conventional therapy. RESULTS: The study included 21 participants, 9 (42.9%) female and 12 (57.1%) male. The average age of the participants was 43.1 ± 16.5 years. The MEFV mutation analysis revealed that 2 (9.5%) had a mutation in exon 10 and 4 (19.0%) had one in exon 2. Out of the 16 cases, 15 successfully discontinued steroid treatment. Four patients (19.0%) experienced injection site reactions. C­reactive protein (CRP) levels were measured at an average of 196 ± 67.8 mg/l before and 2.6 ± 3.15 mg/l after anakinra treatment. CONCLUSION: In conclusion, the study adds to the growing evidence for the efficacy of interleukin-1 inhibitors, such as anakinra, as a promising treatment modality for IRP in cases resistant to conventional treatment.

Infliximab for vascular involvement in Behçet's syndrome.

OBJECTIVE: Vascular involvement is an important cause of morbidity and mortality in patients with Behçet's syndrome (BS). We aimed to survey the efficacy and safety of infliximab (IFX) in BS patients with vascular involvement followed in a dedicated tertiary center. METHODS: Charts of all BS patients who used IFX for vascular involvement between 2004 and 2022 were reviewed. Primary endpoint was remission at Month 6, defined as lack of new clinical symptoms and findings associated with vascular lesion, lack of worsening of the primary vascular lesion and a new vascular lesion on imaging, and CRP < 10 mg/L. Relapse was defined as development of a new vascular lesion or recurrence of the preexisting vascular lesion. RESULTS: Among the 127 patients (102 men, mean age at IFX initiation: 35.8 ± 9.0 years) treated with IFX, 110 (87%) had received IFX for remission induction and 87 of these (79%) were already on immunosuppressives when the vascular lesion requiring IFX developed. The remission rate was 73% (93/127) at Month 6 and 63% (80/127) at Month 12. Seventeen patients experienced relapses. Remission rates were better among patients with pulmonary artery involvement and venous thrombosis compared to patients with non-pulmonary artery involvement and venous ulcers. Fourteen patients had adverse events leading to IFX discontinuation and 4 had died due to lung adenocarcinoma, sepsis, and pulmonary hypertension-related right heart failure due to pulmonary artery thrombosis (n = 2). CONCLUSION: Infliximab seems to be effective in majority of BS patients with vascular involvement, even in those who are refractory to immunosuppressives and glucocorticoids.

Mycophenolate mofetil may be an alternative for maintenance therapy of Behçet syndrome uveitis: a single-center retrospective analysis.

Experience with mycophenolate in uveitis due to Behçet syndrome (BS) is limited. Twelve patients with panuveitis or posterior uveitis who were started mycophenolate were included. Data on demographic characteristics, therapies, ocular attacks, and adverse events were extracted from patient charts. Seven patients with BS uveitis were prescribed mycophenolate for remission induction, of which 6 were refractory/intolerant to conventional immunosuppressives. Mycophenolate was combined with anti-TNFs in 3 patients, resulting in no further ocular attacks. Mycophenolate had to be stopped in the fourth patient due to adverse events. The remaining 3 patients continued to have ocular attacks and were switched to other agents without any drop in visual acuity. Among the 5 patients who were prescribed mycophenolate for maintenance, 2 were relapse free, but 3 experienced ocular attacks. One patient had an exacerbation of mucocutaneous lesions, and 2 experienced adverse events. Mycophenolate monotherapy may not be adequate for remission induction of refractory BS uveitis, but it can be a safe and effective alternative when combined with a biologic agent. It may also be an option for maintenance therapy.

Trial of Apremilast for Oral Ulcers in Behçet's Syndrome.

BACKGROUND: The small-molecule phosphodiesterase 4 inhibitor apremilast modulates cytokines that are up-regulated in Behçet's syndrome. In a phase 2 trial involving patients with Behçet's syndrome, apremilast reduced the incidence and severity of oral ulcers. Data on the efficacy and safety of apremilast in patients with Behçet's syndrome who had active oral ulcers and had not previously received biologic agents are limited. METHODS: In a phase 3 trial, we randomly assigned, in a 1:1 ratio, patients who had Behçet's syndrome with active oral ulcers but no major organ involvement to receive either apremilast at a dose of 30 mg or placebo, administered orally, twice daily for 12 weeks, followed by a 52-week extension phase. The primary end point was the area under the curve (AUC) for the total number of oral ulcers during the 12-week placebo-controlled period (with lower values indicating fewer ulcers). There were 13 secondary end points, including complete response of oral ulcers, change from baseline in pain associated with oral ulcers, disease activity, and change from baseline in the Behçet's Disease Quality of Life score (range, 0 to 30, with higher scores indicating greater impairment in quality of life). Safety was also assessed. RESULTS: A total of 207 patients underwent randomization (104 patients to the apremilast group and 103 to the placebo group). The AUC for the number of oral ulcers was 129.5 for apremilast, as compared with 222.1 for placebo (least-squares mean difference, -92.6; 95% confidence interval [CI], -130.6 to -54.6; P<0.001). The change from baseline in the Behçet's Disease Quality of Life score was -4.3 points in the apremilast group, as compared with -1.2 points in the placebo group (least-squares mean difference, -3.1 points; 95% CI, -4.9 to -1.3). Adverse events with apremilast included diarrhea, nausea, and headache. CONCLUSIONS: In patients with oral ulcers associated with Behçet's syndrome, apremilast resulted in a greater reduction in the number of oral ulcers than placebo but was associated with adverse events, including diarrhea, nausea, and headache. (Funded by Celgene; ClinicalTrials.gov number, NCT02307513.).

Frequency of AA amyloidosis has decreased in Behçet's syndrome: a retrospective study with long-term follow-up and a systematic review.

OBJECTIVE: A decline in the frequency of AA amyloidosis secondary to RA and infectious diseases has been reported. We aimed to determine the change in the frequency of AA amyloidosis in our Behçet's syndrome (BS) patients and to summarize the clinical characteristics of and outcomes for our patients, and also those identified by a systematic review. METHODS: We identified patients with amyloidosis in our BS cohort (as well as their clinical and laboratory features, treatment, and outcome) through a chart review. The primary end points were end-stage renal disease and death. The prevalence of AA amyloidosis was estimated separately for patients registered during 1976-2000 and those registered during 2001-2017, in order to determine whether there was any change in the frequency. We searched PubMed and EMBASE for reports on BS patients with AA amyloidosis. Risk of bias was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool. RESULTS: The prevalence of AA amyloidosis was 0.62% (24/3820) in the earlier cohort and declined to 0.054% (3/5590) in the recent cohort. The systematic review revealed 82 cases in 42 publications. The main features of patients were male predominance and a high frequency of vascular involvement. One-third of patients died within 6 months after diagnosis of amyloidosis. CONCLUSION: The frequency of AA amyloidosis has decreased in patients with BS, which is similar to the decrease observed for AA amyloidosis due to other inflammatory and infectious causes. However, AA amyloidosis is a rare, but potentially fatal complication of BS.

Emergence of new manifestations during infliximab treatment in Behçet's syndrome.

OBJECTIVES: Infliximab (IFX) is increasingly being used for the treatment of severe manifestations of Behçet's syndrome (BS). However, emergence of new manifestations has also been occasionally reported during IFX treatment. We aimed to assess the frequency of new manifestations in our BS patients treated with IFX. METHODS: A chart review was conducted to identify all BS patients treated with IFX in our clinic between 2004 and 2020. Demographic data, indications for IFX initiation, concomitant treatments and outcomes were recorded. A new manifestation was defined as the emergence of a new organ involvement or mucocutaneous manifestation developing for the first time during IFX treatment or within 12 weeks after the last infusion of IFX. RESULTS: Among our 282 patients who used IFX, 19 (7%) patients had developed a total of 23 new manifestations during a mean follow-up of 20.0 (15.3) months. Patients with vascular involvement were more likely to develop a new manifestation (12/19, 63%). Initial manifestations that required IFX were in remission at the time of new manifestation in 14/19 patients. IFX treatment was intensified (n = 6) and/or glucocorticoids, immunosuppressives or colchicine was added to IFX (n = 21). IFX was switched to another agent for the remaining manifestations (n = 8). These treatment modifications led to remission in 17/19 patients. CONCLUSION: New manifestations developed during IFX treatment in 7% of our patients with BS. They could be managed by intensifying IFX treatment or adding other agents in the majority of these manifestations.

Screening for latent tuberculosis before starting TNF-alpha inhibitors in a population with high BCG vaccination rates.

It is assumed that in candidates for TNF-alpha inhibitor (TNFi) treatment, tuberculin skin test (TST) may be unreliable, since BCG vaccination causes false positive and drugs cause false negative results, favoring the use of Quantiferon or T-spot assays. However, these tests may not be readily available in all parts of the world. We aimed to determine the reliability of TST with respect to BCG vaccination and drugs in candidates for TNFi treatment, and how isoniazid is tolerated, assuming that the use of TST would result in increased isoniazid use. We included 1031 adult patients who were prescribed a TNFi for the first time. We analysed the association of BCG and drugs with TST and Quantiferon results, the determinants of a positive TST, and evaluated the tolerability of isoniazid. BCG vaccination and male sex were associated with positive TST (OR 3.56, 95% CI 1.98-6.41 and OR 2.54, 95% CI 1.75-3.68, respectively), while prednisolone and azathioprine were associated with negative TST (OR 0.63, 95% CI 0.43-0.91 and OR 0.40, 95% CI 0.11-0.76). Isoniazid was prescribed to 684 (66.3%) patients and had to be discontinued in 12.2% of these before 9 months, most commonly due to hepatotoxicity (44%). One patient developed tuberculosis despite isoniazid use. BCG vaccination may be associated with false positive TST, despite a long time since vaccination in candidates for TNFi treatment. Prednisolone and azathioprine use were associated with negative TST. Despite the high frequency of isoniazid use associated with using TST instead of QTF, isoniazid was generally well tolerated.

The incidence, clinical characteristics, and outcome of COVID-19 in a prospectively followed cohort of patients with Behçet's syndrome.

Initial case series of small number of patients at the beginning of the pandemic reported a rather guarded prognosis for Behçet's syndrome (BS) patients infected with SARS-CoV-2. In this prospective study, we describe the incidence, clinical characteristics, disease course, management, and outcome in a large cohort of BS patients with laboratory-confirmed infection of SARS-CoV-2. We defined a cohort of 1047 registered BS patients who were aged between 16 and 60 years and seen routinely before the pandemic at the multidisciplinary outpatient clinic. We followed prospectively this cohort from beginning of April 2020 until the end of April 2021. During 13 months of follow-up, of the 1047 (599 M/448 F) patients, 592 (56.5%) were tested for SARS-CoV-2 PCR at least once and 215 (20.5%; 95% CI 0.18-0.23) were tested positive. We observed 2 peaks which took place in December 2020 and April 2021. Of the 215 PCR positive patients, complete information was available in 214. Of these 214, 14 (6.5%) were asymptomatic for COVID-19. In the remaining, the most common symptoms were anosmia, fatigue, fever, arthralgia, and headache. A total of 40 (18.7%) had lung involvement, 25 (11.7%) were hospitalized, 1 was admitted to the intensive care unit while none died. Favipiravir was the most prescribed drug (74.3%), followed by colchicine (40.2%), and hydroxychloroquine (20.1%) in the treatment of COVID-19. After COVID-19, 5 patients (2.3%) were given supplemental O2 and 31 (14.5%) antiaggregant or anticoagulants. During COVID-19, of the 214 PCR positive patients, 116 (54.2%) decreased the dose of their immunosuppressives or stopped taking completely; 36 (16.8%) experienced a BS flare which was mostly oral ulcers (10.3%). None of the patients reported a thrombotic event. A total of 93 (43.5%) patients reported BS flares after a median 45 days of COVID-19 infection and this was found to be significantly associated with immunosuppressive drug discontinuation. Multiple regression analysis adjusted for age and gender indicated that smoking and using interferon-alpha decreased the likelihood of getting COVID-19. The incidence and severity of COVID-19 did not differ between those who were using colchicine or not. The cumulative incidence of COVID-19 in this prospectively followed cohort of BS patients was almost two folds of that estimated for the general population living in Istanbul, Turkey, however, the clinical outcome of COVID-19 was not severe and there was no mortality. The protective effect of smoking and interferon deserves further investigation. On the other hand, colchicine did not have any positive or negative effect against COVID-19. Significant number of patients flared after COVID-19, however, this was significantly associated with immunosuppressive discontinuation during the infection. Contrary to our previous observations, COVID-19 did not seem to exacerbate thrombotic events during or after the infection.

Apremilast for oral ulcers associated with active Behçet's syndrome over 68 weeks: long-term results from a phase 3 randomised clinical trial.

OBJECTIVES: This study assessed the efficacy and safety of apremilast for the oral ulcers associated with Behçet's syndrome (BS) up to 64 weeks. METHODS: The phase 3, double-blind, placebo-controlled RELIEF study randomised adult patients with active BS to placebo or apremilast 30 mg twice daily for 12 weeks, followed by an extension phase with all patients receiving apremilast through Week 64 and 4-week post-treatment follow-up (upon treatment discontinuation). The primary endpoint was area under the curve for the number of oral ulcers over 12 weeks (AUCWk0-12), reflecting the number of oral ulcers over time and accounting for their recurring-remitting course. Oral ulcer number, complete and partial responses, pain and disease activity and quality of life (QoL) were also assessed throughout the study. RESULTS: A total of 207 participants were randomised and received at least one dose of study medication; 178 entered the extension phase and 143 completed Week 64. AUCWk0-12 was significantly lower with apremilast versus placebo (p<0.0001), and oral ulcers number, pain, complete/partial responses, disease activity and QoL with apremilast versus placebo showed improvements at Week 12, which were maintained through Week 64. The most common adverse events were diarrhoea, nausea, headache and upper respiratory tract infection; no new safety concerns were observed with longer-term apremilast exposure. CONCLUSIONS: In patients with oral ulcers associated with BS, apremilast was efficacious and benefits were sustained up to 64 weeks with continued treatment. Apremilast was well tolerated, and safety was consistent with its known safety profile.

Clinical course of acute deep vein thrombosis of the legs in Behçet's syndrome.

OBJECTIVES: Lower extremity deep vein thrombosis (LEDVT) is a serious complication of Behçet's syndrome. Management constitutes mainly of administration of immunosuppressives, but the predictors of relapse and the optimal choice of immunosuppressives remain unclear. In this prospective study, we aimed to detect the risk and predictors of relapse and treatment response to different modalities. METHODS: All Behçet's syndrome patients who presented with a first episode of acute LEDVT between 2010 and 2014 were prospectively followed with a standard protocol. Acute LEDVT was confirmed by Doppler ultrasonography. Serial planned Doppler ultrasonography assessments were performed during follow-up and additionally repeated in case of clinical suspicion. Recanalization rate was assessed at each visit. Our first-line treatment strategy consisted of AZA and CSs. IFN-alpha was used in patients who were refractory to or could not tolerate AZA or had concomitant eye involvement requiring further treatment. RESULTS: Thirty-three patients with LEDVT (26 M/7 F) were prospectively followed for 40.7 ± 13.4 months. Among the 33 patients, 23 relapses were observed in 15 patients. Relapse rates were 29%, 37% and 45% at 6, 12 and 24 months, respectively. Among the possible predictors of relapse, poor recanalization was the only significant factor [hazard ratio 4.34 (95% CI 1.96, 10.0)]. Overall 29 patients were treated with AZA and 17 with IFN-alpha. The relapse rate was lower and recanalization rate was higher with IFN-alpha compared with AZA (12% vs 45% and 86% vs 45%). CONCLUSION: The relapse rate for LEDVT in Behçet's syndrome is high despite AZA treatment. IFN-alpha seems to be a promising agent for preventing LEDVT relapses and achieving good recanalization.

Long term follow-up of Behçet's syndrome patients treated with cyclophosphamide.

OBJECTIVES: CYC remains an important treatment option for Behçet's syndrome (BS) patients with life-threatening manifestations. However, adverse events may occur with CYC and this has led to increased use of biologic agents in other vasculitides. We investigated short and long term adverse events associated with CYC use in BS patients. METHODS: We conducted a retrospective chart review of all BS patients treated with CYC between 1972 and 2006. Patients were called in and a standard form was used for collecting demographic characteristics, indication for CYC, its cumulative dose and short term adverse events, defined as those causing discontinuation of CYC, hospitalization and/or death, long term adverse events, including infertility and malignancy, and outcome. RESULTS: Of 5790 BS patients, 198 (3.4%) had used at least one dose of CYC. Main indications were vascular or neurological involvement. After a median follow-up of 17 years, 52 (26%) patients had died, 113 (57%) could be contacted, and 33 (17%) were lost to follow-up. Vascular involvement was the leading cause of death (n = 27). Seventeen (9%) patients experienced short term adverse events with haemorrhagic cystitis being the most common. After a median follow-up of 25 years (interquartile range: 15-26 years), 17 malignancies occurred in 15 (8%) patients. Infertility was experienced by 26 (30%) patients. CONCLUSION: Long term adverse events such as malignancy and infertility were major problems in our BS patients treated with CYC. These results underline the need for safer treatment modalities that are at least as effective as CYC.

Outcome of invasive procedures for venous thrombosis in Behçet's syndrome: case series and systematic literature review.

OBJECTIVES: Systemic therapy aimed at suppressing the diffuse inflammation in the vessel wall is the major treatment modality for venous thrombosis in Behçet's syndrome (BS). Endovascular and/or surgical interventions are also used. We here report five patients who were referred to our clinic after having such interventions and also present a literature review to assess the outcome of invasive procedures for venous thrombosis in BS. METHODS: Our patients were presented and a literature search for endovascular and/or surgical interventions in Pub-Med was performed. Recanalisation, reocclusion or other complications were assessed as outcomes. RESULTS: Five BS patients with lower extremity thrombosis were referred to our clinic with post thrombotic syndrome due to incomplete recanalisation or infectious complication after endovascular interventions. Twenty-one articles reporting on 36 patients were found suitable for review. There were totally 21 lower extremity venous intervention cases, 14 of which had failure such as complication, reocclusion or incomplete recanalisation. Reocclusions occurred in 10 patients and reinterventions to 8 of them could restore flow only in 4 cases. Ileal infarct and vena cava wall-duodenal perforation were major complications. Invasive procedures of 8 abdominal thrombosis cases resulted with death due to ileus in one patient, and reocclusion in another. Seven of the 12 upper extremity/superior vena cava thrombosis cases resulted with reocclusions. CONCLUSIONS: Endovascular and surgical interventions seemed to be unsuccessful because of recurrent infectious and vascular complications in 22 (53.6%) of 41 patients with venous thrombosis. The indication of these procedures is controversial. Their economic burden on the healthcare system must be considered.

Biosimilar infliximab for Behçet's syndrome: a case series.

OBJECTIVES: The efficacy and safety of biosimilar infliximab (bio-IFX) was shown in randomised controlled trials and it was approved for all indications of the reference product in several countries. However, a previous case series of 3 patients with Behçet's syndrome (BS) reported disappointing results. We aimed to share our experience with bio-IFX treatment in different types of organ involvement in patients with BS. METHODS: We reviewed the charts of all BS patients who were prescribed reference infliximab (ref-IFX) or bio-IFX in our BS clinic. Among the 181 BS patients who were prescribed IFX since 2003, 6 (3%) were prescribed bio-IFX due to refractory disease despite conventional immunosuppressives. RESULTS: A total of 6 patients (mean age: 32.1±6.2, mean disease duration: 5.3±1.8 years, 5 men and 1 woman) received bio-IFX for uveitis, nervous system, vascular and joint involvement. Four of the 6 patients obtained remission and stayed in remission during the 16±6.5 months they used bio-IFX. Among the 4 patients who obtained remission, 2 were switched to ref-IFX due to unavailability of bio-IFX infusion set and did not experience adverse events or loss of efficacy. However, relapses occurred during tapering. The other 2 patients are still in remission with bio- IFX. Among the remaining 2 patients, one had to be switched to ref-IFX after the first infusion, due to a change in the reimbursement policy and the other was non-responsive. CONCLUSIONS: Our limited experience showed that bio-IFX may be a safe and effective alternative for patients with BS, refractory to conventional immunosuppressives.

Apremilast for Behçet's syndrome--a phase 2, placebo-controlled study.

BACKGROUND: Oral ulcers, the hallmark of Behçet's syndrome, can be resistant to conventional treatment; therefore, alternative agents are needed. Apremilast is an oral phosphodiesterase-4 inhibitor that modulates several inflammatory pathways. METHODS: We conducted a phase 2, multicenter, placebo-controlled study in which 111 patients with Behçet's syndrome who had two or more oral ulcers were randomly assigned to receive 30 mg of apremilast twice daily or placebo for 12 weeks. This regimen was followed by a 12-week extension phase in which the placebo group was switched to apremilast and a 28-day post-treatment observational follow-up phase. The patients and clinicians were unaware of the study assignments throughout the trial. The primary end point was the number of oral ulcers at week 12. Secondary outcomes included pain from these ulcers (measured on a 100-mm visual-analogue scale, with higher scores indicating worse pain), the number of genital ulcers, overall disease activity, and quality of life. RESULTS: The mean (±SD) number of oral ulcers per patient at week 12 was significantly lower in the apremilast group than in the placebo group (0.5±1.0 vs. 2.1±2.6) (P<0.001). The mean decline in pain from oral ulcers from baseline to week 12 was greater with apremilast than with placebo (-44.7±24.3 mm vs. -16.0±32.5 mm) (P<0.001). Nausea, vomiting, and diarrhea were more common in the apremilast group (with 22, 9, and 12 incidents, respectively, among 55 patients) than in the placebo group (with 10, 1, and 2 incidents, respectively, among 56 patients), findings that were similar to those in previous studies of apremilast. There were two serious adverse events in patients receiving apremilast. CONCLUSIONS: Apremilast was effective in treating oral ulcers, which are the cardinal manifestation of Behçet's syndrome. This preliminary study was neither large enough nor long enough to assess long-term efficacy, the effect on other manifestations of Behçet's syndrome, or the risk of uncommon serious adverse events. (Funded by Celgene; ClinicalTrials.gov number, NCT00866359.).

Rituximab for anti-neutrophil cytoplasmic antibodies-associated vasculitis: experience of a single center and systematic review of non-randomized studies.

Rituximab (RTX) is becoming a standard treatment for patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) but heterogeneity exists regarding its use. We present our uncontrolled experience with RTX in patients with refractory AAV and also the results of a systematic review of non-randomized studies on RTX in AAV patients. We retrospectively reviewed the records of AAV patients treated with RTX following an inadequate response to immunosuppressives between 2011 and 2015. The systematic review covered all English articles listed in PubMed until June 2017. There were 25 AAV patients (21 GPA, four unclassified) treated with RTX (median 2, IQR 1-3 courses; median follow-up 24, IQR 17-50 months). The kidney and the lung were the most commonly affected organs, observed in 14 and 16 patients, respectively. Complete remission rate was 72% at month 6 and 88% at month 12. Two patients had died and three serious adverse events occurred. The systematic review included 56 studies on 1422 patients with the majority being on refractory or relapsing disease. There was wide variability regarding disease characteristics, endpoints, concomitant immunosuppressives and RTX schedule. Most studies reported > 80% complete or partial remission rates with the lowest response (37.5%) for granulomatous lesions. The relapse rate was 30%. Infections and infusion reactions were the main adverse events. Our experience with RTX in refractory AAV is in line with the literature in terms of efficacy and safety. The systematic review underlines many uncertainties on its optimal use.