A Proposal of a New Tool for the Assessment of Damage in Behçet Syndrome Uveitis: Cerrahpasa Ocular Damage Grading System.

INTRODUCTION/OBJECTIVE: There is currently no tool available to assess the severity of damage in uveitis due to Behçet's syndrome (BS). In this preliminary study, we developed a new grading system to evaluate ocular damage and assessed it in a prospective cohort. METHODS: A specialist in BS uveitis (YO) developed a grading system for ocular damage with five grades based on the extent of damage in the posterior segment. YO trained a senior and general ophthalmologist with sample fundus images. BS patients who had undergone color fundus photography during their routine visits in attack-free periods were included in the study. The color fundus photos of this prospective cohort were evaluated blindly by YO and his trainees using the new grading tool. Inter and intra-observer agreement between the graders were assessed by Cohen's kappa analysis. The evaluation of YO was considered as the gold standard. RESULTS: One hundred eighty-five eyes of 108 (29 F/79 M) patients with BS uveitis were graded for damage by two investigators. Their mean age was 38,58 years and their median ocular disease duration was 13 years. The gold standard and the two investigators exhibited substantial concordance with the ocular damage grading system. The inter- and intra-observer agreement were also almost perfect. CONCLUSION: The newly developed ocular damage grading system enables the standardization of damage severity in BS uveitis. It is imperative to conduct internal and external validations across diverse cohorts. Furthermore, future studies should investigate its correlation with other multimodal imaging methods such as fluorescein angiography and optical coherence tomography.

Hearing loss in Takayasu's arteritis.

OBJECTIVES: Neurosensory hearing loss is well-documented in chronic autoimmune conditions such as systemic lupus erythematosus (SLE). However, the literature lacks data on the prevalence and characteristics of hearing impairment in Takayasu's arteritis (TAK). In this cross-sectional study, our principal objective was to systematically assess the auditory function of individuals diagnosed with TAK, against SLE patients and healthy controls (HC). METHODS: Age and gender matched TAK and SLE patients followed up in a tertiary centre along with healthy controls were included in a two-phase study. In the first phase, a questionnaire on ENT symptoms was administered to the patient (TAK: n=104 and SLE: n= 151) and HC (n=174) groups. In the second phase, patients (TAK: n=53 and SLE: n=33) and HC (n=45) underwent audiometric tests. RESULTS: The questionnaire survey revealed that both TAK and SLE patients reported hearing loss (27.9%, 25.8%, 7.4%, p<0.001), tinnitus (49%, 35.8%, 13.8%, p<0.001) and vertigo (46.2%, 33.8%, 16.7%, p<0.001) at significantly higher rates than HC. Audiometry results indicated that both TAK (30.2%) and SLE patients (18.2%) had increased hearing loss compared to HC (8.9%), however, only TAK patients were found to have significantly increased risk in age adjusted logistic regression analysis (OR= 3.915, 95%CI: 1.179-12.998, p=0.026). Hearing loss was mainly neurosensory in all groups. TAK patients were affected at both low (<6000 Hz) and high (>6000 Hz) frequencies, whereas SLE patients were affected only at high frequencies. Hearing loss was significantly associated only with older age. No association was observed with the anatomical location of vascular involvement or history of stroke. CONCLUSIONS: Our study reveals an increased prevalence of hearing loss in TAK. Further research is crucial to uncover the underlying causes.

Treatment of pulmonary arterial hypertension in patients with connective tissue diseases: a systematic review and meta-analysis.

The evidence for the treatment of connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) mostly depends on subgroup or post hoc analysis of randomized controlled trials (RCTs). Thus, we performed a meta-analysis of RCTs that reported outcomes for CTD-PAH. PubMed and EMBASE were searched for CTD-PAH treatment. The selected outcomes were functional class (FC) change, survival rates, 6-min walk distance (6-MWD), clinical worsening (CW), N-terminal prohormone BNP (NT-proBNP), pulmonary vascular resistance (PVR), mean pulmonary arterial pressure (mPAP), right atrial pressure (RAP), and cardiac index (CI). The meta-analysis was conducted according to the PRISMA guidelines and registered in PROSPERO (CRD42020153560). Twelve RCTs conducted with 1837 patients were included. The diagnoses were systemic sclerosis in 59%, SLE in 20%, and other CTDs in 21%. The pharmacological interventions were epoprostenol, treprostinil, sildenafil, tadalafil, bosentan, macitentan, ambrisentan, riociguat, and selexipag. There was a significant difference between interventions and placebo in FC, 6MWD, CW, PVR, RAP, and CI that favored intervention. Our analysis showed a 39% reduction in the CW risk with PAH treatment. The short-term survival rates and mean serum NT-proBNP changes were similar between the study and control groups. Treatment for CTD-PAH had favorable effects on clinical and hemodynamic outcomes but not on survival and NT-proBNP levels. Different from the previous meta-analyses that focused on 6-MWD, time to clinical worsening, and CW as outcomes, this meta-analysis additionally reports the pooled analysis of change in FC, hemodynamic measurements (RAP, PVR, CI), and NT-proBNP, some of which have prognostic value for PAH.

HLA-B gene methylation and expression in Behçet's syndrome: a potential role of epigenetics in the pathogenesis.

OBJECTIVES: The HLA-B51 locus has the strongest association with Behçet's syndrome (BS). The presence of a CpG island in the HLA-B gene led us to examine the role of epigenetic regulation in BS. METHODS: HLA-B51 genotyping was performed via sequence-specific PCR in 15 index familial BS cases, 17 affected relatives, 26 unaffected relatives, 46 sporadic BS cases, and 41 healthy controls. HLA-B methylation level was determined using the Zymo OneStep qMethyl kit, and HLA-B51 mRNA level was assessed by quantitative real-time PCR in 14 index familial BS cases, 15 affected relatives, 15 unaffected relatives, 11 sporadic BS cases, and 10 healthy controls. RESULTS: HLA-B51 carrier ratio was 13/15 in index familial cases, 13/17 in affected relatives, 22/26 in unaffected relatives, 8/25 in healthy controls, and 35/47 in sporadic BS cases. HLA-B51 expression level in HLA-B51+ BS cases was 2.2-fold higher than in their unaffected relatives (p=0.0149) and 1.3-fold higher than in healthy controls (p=0.0188), while sporadic BS cases had a 2.7-fold higher level than healthy controls (p=0.0487). HLA-B promoter methylation was significantly lower in HLA-B51+ familial BS cases than in unaffected relatives (0.4-fold, p=0.01), affected relatives (0.36-fold, p=0.0219), and healthy controls (0.34-fold, p=0.0371) and slightly lower in HLA-B51+ sporadic BS cases than in healthy controls (0.71-fold, p=0.2347). There was an inverse correlation between HLA-B promoter methylation and HLA-B51 expression in HLA-B51+ sporadic BS cases (p=0.0164). CONCLUSIONS: This study indicates epigenetic involvement associated with the HLA-B51 locus in BS, both in familial and sporadic cases. Further studies with larger sample sizes are needed to confirm our results.

Disease and Treatment-Specific Complications of Behçet Syndrome.

PURPOSE OF REVIEW: We aimed to highlight disease-related and treatment-related complications of Behçet syndrome (BS) based on previous and recent studies and our own experience. RECENT FINDINGS: The Behçet's Disease Overall Damage Index is a newly developed instrument to assess damage in BS. Validation studies showed that damage is already present in some patients at diagnosis and continues to progress during the follow-up, mainly related to treatment complications. Nervous system and eye involvement are important causes of long-term disability. Cyclophosphamide seems to be associated with infertility and an increased risk of malignancies among BS patients, prompting the consideration of shortening the treatment duration. Flares in mucocutaneous manifestations have been reported with tocilizumab, and de novo BS manifestations with secukinumab therapy. Earlier diagnosis and treatment are essential to prevent disease-related damage in BS. Treatment-related complications seem to be the leading cause of damage during the disease course.

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.

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.

Current pharmacological solutions for Behçet's syndrome.

INTRODUCTION: Behçet's syndrome (BS) has a heterogeneous clinical phenotype, and its clinical manifestations may respond differently to drugs commonly used to treat BS. The type, dose, and duration of immunomodulatory, immunosuppressive, and biologic agents should be tailored individually. AREAS COVERED: We reviewed the literature for articles on BS management that were published until June 2022 and summarized the management options in BS for each type of organ involvement. We aimed to cover all currently available pharmacological agents used in BS, as well as surgical and interventional options, focusing on recent evidence. EXPERT OPINION: The management aims in BS are to preserve function and quality of life and to avoid damage. The choice of treatment modalities depends on the organs that are actively involved, the severity of that involvement, and prognostic factors. A treat-to-attack strategy would help improve long-term outcomes in BS.

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.

Takayasu arteritis.

PURPOSE OF REVIEW: The purpose of this review is to summarize the recent advances in Takayasu arteritis (TAK), mainly focusing on pathogenesis, imaging modalities, and management. RECENT FINDINGS: Three novel clusters based on angiographic findings were identified in the Indian cohort and replicated in the North American cohorts. Different new imaging modalities have been tried in the assessment of arterial inflammation with promising results. There is more evidence on the long-term use of tocilizumab, but relapses are common. In light of the recent findings on the pathogenesis of TAK, Janus kinase inhibitors seem to be promising. SUMMARY: Improvement in imaging modalities and in our understanding of the disease pathogenesis will allow us to better assess the disease activity and identify effective therapeutic agents.

Comparison of demographic and clinical characteristics of hospitalized COVID-19 patients with severe/critical illness in the first wave versus the second wave.

Due to current advances and growing experience in the management of coronavirus Disease 2019 (COVID-19), the outcome of COVID-19 patients with severe/critical illness would be expected to be better in the second wave compared with the first wave. As our hospitalization criteria changed in the second wave, we aimed to investigate whether a favorable outcome occurred in hospitalized COVID-19 patients with only severe/critical illness. Among 642 laboratory-confirmed hospitalized COVID-19 patients in the first wave and 1121 in the second wave, those who met World Health Organization (WHO) definitions for severe or critical illness on admission or during follow-up were surveyed. Data on demographics, comorbidities, C-reactive protein (CRP) levels on admission, and outcomes were obtained from an electronic hospital database. Univariate analysis was performed to compare the characteristics of patients in the first and second waves. There were 228 (35.5%) patients with severe/critical illness in the first wave and 681 (60.7%) in the second wave. Both groups were similar in terms of age, gender, and comorbidities, other than chronic kidney disease. Median serum CRP levels were significantly higher in patients in the second wave compared with those in the first wave [109 mg/L (interquartile range [IQR]: 65-157) vs. 87 mg/L (IQR: 39-140); p < 0.001]. However, intensive care unit admission and mortality rates were similar among the waves. Even though a lower mortality rate in the second wave has been reported in previous studies, including all hospitalized COVID-19 patients, we found similar demographics and outcomes among hospitalized COVID-19 patients with severe/critical illness in the first and second wave.

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.

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.

COVID-19 Among Patients With Inflammatory Rheumatic Diseases.

BACKGROUND: The course of novel coronavirus disease 2019 (COVID-19) has been of special concern in patients with inflammatory rheumatic diseases (IRDs) due to the immune dysregulation that may be associated with these diseases and the medications used for IRDs, that may affect innate immune responses. OBJECTIVE: In this cohort study, we aimed to report the disease characteristics and variables associated with COVID-19 outcome among Turkish patients with IRDs. METHODS: Between April and June, 2020, 167 adult IRD patients with COVID-19 were registered from 31 centers in 14 cities in Turkey. Disease outcome was classified in 4 categories; (i) outpatient management, (ii) hospitalization without oxygen requirement, (iii) hospitalization with oxygen requirement, and (iv) intensive care unit (ICU) admission or death. Multivariable ordinal logistic regression analysis was conducted to determine variables associated with a worse outcome. RESULTS: 165 patients (mean age: 50 ± 15.6 years, 58.2% female) were included. Twenty-four patients (14.5%) recovered under outpatient management, 141 (85.5%) were hospitalized, 49 (30%) required inpatient oxygen support, 22 (13%) were treated in the ICU (17 received invasive mechanic ventilation) and 16 (10%) died. Glucocorticoid use (OR: 4.53, 95%CI 1.65-12.76), chronic kidney disease (OR: 12.8, 95%CI 2.25-103.5), pulmonary disease (OR: 2.66, 95%CI 1.08-6.61) and obesity (OR: 3.7, 95%CI 1.01-13.87) were associated with a worse outcome. Biologic disease-modifying antirheumatic drugs (DMARDs) do not seem to affect COVID-19 outcome while conventional synthetic DMARDs may have a protective effect (OR: 0.36, 95%CI 0.17-0.75). Estimates for the associations between IRD diagnoses and outcome were inconclusive. CONCLUSIONS: Among IRD patients with COVID-19, comorbidities and glucocorticoid use were associated with a worse outcome, while biologic DMARDs do not seem to be associated with a worse outcome.

Mediastinal lymphadenopathy may predict 30-day mortality in patients with COVID-19.

PURPOSE: There is scarce data on the impact of the presence of mediastinal lymphadenopathy on the prognosis of coronavirus-disease 2019 (COVID-19). We aimed to investigate whether its presence is associated with increased risk for 30-day mortality in a large group of patients with COVID-19. METHOD: In this retrospective cross-sectional study, 650 adult laboratory-confirmed hospitalized COVID-19 patients were included. Patients with comorbidities that may cause enlarged mediastinal lymphadenopathy were excluded. Demographics, clinical characteristics, vital and laboratory findings, and outcome were obtained from electronic medical records. Computed tomography scans were evaluated by two blinded radiologists. Univariate and multivariate logistic regression analyses were performed to determine independent predictive factors of 30-day mortality. RESULTS: Patients with enlarged mediastinal lymphadenopathy (n = 60, 9.2%) were older and more likely to have at least one comorbidity than patients without enlarged mediastinal lymphadenopathy (p = 0.03, p = 0.003). There were more deaths in patients with enlarged mediastinal lymphadenopathy than in those without (11/60 vs 45/590, p = 0.01). Older age (OR:3.74, 95% CI: 2.06-6.79; p < 0.001), presence of consolidation pattern (OR:1.93, 95% CI: 1.09-3.40; p = 0.02) and enlarged mediastinal lymphadenopathy (OR:2.38, 95% CI:1.13-4.98; p = 0.02) were independently associated with 30-day mortality. CONCLUSION: In this large group of hospitalized patients with COVID-19, we found that in addition to older age and consolidation pattern on CT scan, enlarged mediastinal lymphadenopathy were independently associated with increased mortality. Mediastinal evaluation should be performed in all patients with COVID-19.

Aortic involvement in relapsing polychondritis: case-based review.

Relapsing polychondritis is a systemic inflammatory disease that mainly affects ears, nose, eyes, joints, and large airway. Relapsing polychondritis may also affect cardiac valves and large vessels with the aorta being most frequently involved. We conducted a systematic literature review to delineate the clinical characteristics, treatment, and outcome of relapsing polychondritis patients with aortic involvement including thoracic and abdominal aorta, aortic valve, and coronary arteries. 113 patients reported in 85 manuscripts were retrieved through the systematic literature search and references of the selected manuscripts. With the addition of a patient from our center, a total of 114 patients were included in the analyses. Aortic vessel involvement was the predominant type of involvement that was identified in 93 (82%) patients, while aortic valve involvement was identified in 41 patients (36%). The median age at aortic involvement was 37 years [IQR: 30-53] with a delay of 5 years [IQR: 1-8] between first relapsing polychondritis symptom and aortic involvement. Nineteen percent of the patients were asymptomatic at the time of aortic involvement diagnosis. The initial treatment was immunosuppressives in 41 patients (56%) and surgery in 28 patients (38%). The mortality ratio was 27% in a 24 month follow-up [IQR: 7.5-54 months]. Aortic dissection or rupture was the most frequent causes of mortality. Concomitant coronary artery involvement suggested a worse outcome. Aortic involvement in relapsing polychondritis is a mortal complication despite medical and surgical treatments. It may be asymptomatic in 19% of the patients which warrants the importance of screening.

The prognostic value of serum levels of a proliferation-inducing ligand (APRIL) in treatment-naïve patients with chronic lymphocytic leukemia

Background/aim: A proliferation-inducing ligand (APRIL) has been investigated as a prognostic marker in chronic lymphocytic leukemia (CLL) patients. However, there is no cut-off level for serum APRIL (sAPRIL) levels that predict time to treatment in CLL patients. Materials and methods: Between May and December 2012, 94 consecutive CLL patients and 25 healthy controls were assessed. sAPRIL levels were measured by ELISA. Demographic data and prognostic markers were obtained from the patients' files. Treatment-naïve patients were followed up for 6.5 years for any treatment need. Results: Patients were divided into 3 groups: Treatment-naïve (n = 47), chemotherapy receiving (n = 25), and those who had received chemotherapy previously (n = 22). There was no difference in median sAPRIL levels of patients who were receiving chemotherapy at the sampling time and the healthy controls, which indicates that sAPRIL levels might be influenced by treatment. For treatment-naïve patients, the best cut-off in predicting time to treatment was found at the sAPRIL level of 2.04 ng/mL, with 78% sensitivity and 63% specificity. Time to treatment was significantly earlier in the APRIL high group (n = 27) than in the APRIL low group (n = 20) (P = 0.010, log-rank test). Conclusion: sAPRIL, a simple, promising blood test which can be measured by ELISA, will likely obtain a place in the wide range of prognostic markers in CLL. Prospective large-scale studies are required to validate and confirm the feasibility of the proposed cut-off level of 2.04 ng/mL as a predictor of time to treatment in treatment-naïve CLL patients.