Cluster analysis as a clinical and research tool in Behçet's syndrome.

PURPOSE OF REVIEW: The purpose of this review was to comprehensively summarize recent phenotype research findings in Behçet's syndrome. RECENT FINDINGS: Cluster analysis has recently been employed as a phenotype research tool in Behçet's syndrome. Studies reported different clustering patterns caused by biological variation and some degree of artificial heterogeneity. However, some clusters were more consistent than others: 1) oral ulcers, genital ulcers, and skin lesions 2) oral ulcers, genital ulcers, skin lesions, and arthritis 3) oral ulcers, genital ulcers, skin lesions, and uveitis 4) oral ulcers, genital ulcers, skin lesions, and gastrointestinal involvement. A number of loci suggestive of differential risk for individual disease manifestations were proposed. Peripheral blood gene expression profile and plasma proteome exhibited significant differences in patients with different organ involvements and were able to differentiate between disease phenotypes. However, these observations require further validation and functional studies. SUMMARY: Clustering patterns in Behçet's syndrome is highly heterogeneous. Artificial heterogeneity might obscure the true biological variation of disease expression. Preliminary genetic, transcriptomic and proteomic data suggest that different pathogenetic mechanisms may operate in different phenotypes of Behçet's syndrome.

Tuberculin skin test before biologic and targeted therapies: does the same rule apply for all?

This study aimed to compare Tuberculin Skin Test (TST) and QuantiFERON®-TB Gold In-Tube (QFT-GIT) test in rheumatoid arthritis (RA) and spondyloarthritis (SpA) patients scheduled for biological and targeted synthetic disease modifying anti-rheumatic drugs (DMARDs) in a Bacillus Calmette-Guérin-vaccinated population. Adult RA (n = 206) and SpA (n = 392) patients from the TReasure database who had both TST and QFT-GIT prior to initiation of biological and targeted synthetic DMARDs were included in the study. Demographic and disease characteristics along with pre-biologic DMARD and steroid use were recorded. The distribution of TST and performance with respect to QFT-GIT were compared between RA and SpA groups. Pre-biologic conventional DMARD and steroid use was higher in the RA group. TST positivity rates were 44.2% in RA and 69.1% in SpA for a 5 mm cutoff (p < 0.001). Only 8.9% and 15% of the patients with RA and SpA, respectively, tested positive by QFT-GIT. The two tests poorly agreed in both groups at a TST cutoff of 5 mm and increasing the TST cutoff only slightly increased the agreement. Among age, sex, education and smoking status, pre-biologic steroid and conventional DMARD use, disease group, and QFT-GIT positivity, which were associated with a 5 mm or higher TST, only disease group (SpA) and QFT-GIT positivity remained significant in multiple logistic regression. TST positivity was more pronounced in SpA compared to that in RA and this was not explainable by pre-biologic DMARD and steroid use. The agreement of TST with QFT-GIT was poor in both groups. Using a 5 mm TST cutoff for both diseases could result in overestimating LTBI in SpA.

Autoimmunity in psoriatic arthritis: pathophysiological and clinical aspects

Psoriatic arthritis (PsA) is an underdiagnosed entity with a broad impact on the quality of life. Although the pathogenesis is largely unknown, autoimmune footprints of the inflammation in PsA have increasingly been recognized. Most of the genetic variation predisposing to PsA is mapped to the class I major histocompatibility complex (MHC) region and shared by a variety of autoimmune diseases. Polymorphisms in the genes IL12B, IL23R, IL13, TNIP1, TRAF3IP2, TYK2, and many others explain the non- HLA genetic risk with little known functional consequences. Entheseal and synovial cellular infiltrate with oligoclonal CD8+ T cells and occasional germinal centers, loss of regulatory T cell function, and specific autoantibodies such as anti-PsA peptide, anti-LL-37, and anti-ADAMTSL5 are the immunopathological findings suggestive of autoimmunity. These were supported by clinical observations of autoimmune multimorbidity and treatment response to calcineurin/mTOR and co-stimulation inhibition.

Different pharmaceutical preparations of colchicine for Familial Mediterranean Fever: are they the same?

This study aimed to investigate the benefit of changing the pharmaceutical preparation of colchicine in Turkish Familial Mediterranean Fever (FMF) patients resistant to one preparation in terms of frequency of the attacks. Turkish adult FMF patients under treatment with an imported colchicine preparation-in the form of compressed tablet form-due to resistance to domestic colchicine preparations, which are film- or sugar-coated tablets, and not using anti-interleukin-1 or other biologic agents were included in the study. Baseline disease characteristics along with MEFV mutations were identified. Daily colchicine doses and attack frequencies before and after the pharmaceutical change were compared. Fifty patients resistant to coated tablet preparations of colchicine and under treatment with the compressed tablets were identified. The median duration of disease was 6 (interquartile range 2.7-14) years and duration under treatment with the imported colchicine was 21 (range 8-60) months. Eight (16%), ten (20%), and 32 (64%) patients had 0-3, 4-6, and more than 7 attacks per year, respectively, before the compressed tablets. After treatment with the compressed tablet form of colchicine, 44 (88%), 5 (10%), and 1 (2%) patients had 0-3, 4-6, and more than 7 attacks, respectively (p < 0.0001). Daily colchicine doses were similar before and after the pharmaceutical change (1.85 ± 0.47 vs 1.84 ± 0.37 mg, p = 0.9). Turkish FMF patients with ongoing attacks under domestic coated tablet preparations of colchicine may benefit from the compressed colchicine tablets. This may be explained by the difference in pharmacokinetic properties of different colchicine preparations.

MEditerranean FeVer ( MEFV ) gene mutations in glomerulonephritides: a clinicopathological study

Background/aim: The aim of this study is to determine the ME diterranean F e V er ( MEFV ) gene mutation carrier rate in patients with glomerulonephritis and to investigate the association between disease features and MEFV variants. Materials and methods: Medical records regarding clinical, laboratory, histopathological, and prognostic features of 200 adult patients with biopsy-proven glomerulonephritis were evaluated retrospectively. Exons 2 and 10 of the MEFV gene of each patient were sequenced by next-generation sequencing. Variants were detected and compared with disease features. Results: MEFV mutation carrier rate was 25%, similar among disease subgroups, and higher than the previously reported rates for normal populations. Demographic, clinical, and laboratory features at diagnosis did not differ in patients with and without mutations. Refractory disease rates were 73% and 40% in carriers and noncarriers of E148Q (P = 0.051). Percentage of global sclerotic glomeruli was higher in M694V carriers than noncarriers (medians 24% vs. 0%, P = 0.047). Tubulointerstitial fibrosis was also more severe in M694V carriers. The carrier rate of M694V was 14.3% in patients eventually needing chronic renal replacement therapy (RRT) (n = 21), whereas it was 2.8% in the group without RRT (OR = 5.8 [1.28­26.3], P = 0.040). Conclusion: MEFV mutation carrier rate was higher than expected in our sample of Turkish patients with glomerulonephritis. The E148Q mutation may be associated with refractory disease. The M694V mutation was more frequent in patients who needed chronic R RT.

Near-complete recanalization of jugular vein and multiple dural sinus thromboses with warfarin in a case of antiphospholipid syndrome.

Antiphospholipid syndrome is a cause of arterial and venous thrombosis especially in the young adult population. Although dural sinus thrombosis is a relatively rare complication of antiphospholipid syndrome, it may be a cause of morbidity and mortality. Extension of thrombosis and involvement of deep venous structures are poor prognostic factors in patients with dural sinus thrombosis, but the rate of near-complete recanalization is not known in antiphospholipid syndrome-related dural sinus thrombosis. Herein, a case of antiphospholipid syndrome with multiple dural sinus, deep cerebral vein and internal jugular vein thromboses is presented with demonstrative imaging findings and near-complete recanalization after warfarin.

Anti-angiotensin II type 1 receptor autoantibodies (AT1R-AAs) in patients with systemic sclerosis: lack of association with disease manifestations.

Angiotensin II type 1 receptor autoantibodies (AT1R-AAs) are known to be associated with malignant hypertension, preeclampsia, and vascular rejection in kidney transplantation. They were also suspected to have pathogenetic role in vasculopathic changes in systemic sclerosis (SSc). Clinical data regarding AT1R-AAs in SSc are scarce. In this work, we will examine the relationship between serum levels of AT1R-AAs and disease manifestations. Serum samples from SSc patients and healthy controls were analyzed for AT1R-AAs by using a commercial ELISA kit. We examined the association of serum levels of AT1R-AA with disease duration, systolic pulmonary artery pressure (sPAP) measurements, and disease manifestations like cutaneous, lung and esophageal involvements, and the presence of digital ulcers in a cross-sectional manner. There was no statistically significant difference in levels of AT1R-AAs between SSc (n = 93) patients and healthy controls (n = 66) (p = 0.23). Serum levels of AT1R-AAs were not correlated with disease duration, sPAP measurements, and showed no association with disease manifestations like lung involvement, esophageal involvement, digital ulcers, and cutaneous fibrosis. In our SSc cohort, AT1R-AA serum levels were not different from healthy subjects and higher levels were not associated with any disease manifestation neither.

Anti-interleukin-1 treatment in 26 patients with refractory familial mediterranean fever.

OBJECTIVE: To investigate the effect of anti-interleukin-1 (anti-IL-1) treatment on the frequency and severity of attacks and other disease-related clinical parameters and to evaluate the adverse effects associated with anti-IL-1 treatment in 26 patients with refractory familial mediterranean fever (FMF). METHODS: The study included 26 FMF patients followed up in our centre using colchicine for 4 months to 30 years. The treatment was switched to anti-IL-1 treatment for various reasons; 20 cases were resistant to colchicine, 8 were intolerant to colchicine, and 3 had prolonged arthritis under colchicine. Clinical response was monitored through the number of attacks, and laboratory inflammation was monitored through erythrocyte sedimentation rate, C-reactive protein, and serum amyloid A concentrations. Colchicine resistance was defined as at least two attacks/month together with C-reactive protein and serum amyloid A levels above the normal range between attacks. The colchicine dose was increased to 2 mg/day before they were considered colchicine-resistant. RESULTS: 24 patients used anakinra (100 mg/day), and 2 used canakinumab (150 mg/month), for -36 months. Sixteen patients with colchicine resistance had no attacks under anti-IL-1 treatment, and 4 had decreased frequency and duration of attacks. Seven of 8 patients intolerant to colchicine used anakinra, and 6 were attack-free under treatment, while 1 using canakinumab had attacks under treatment. One patient with prolonged arthritis used canakinumab but arthritis showed progression and the treatment was changed to IL-6 inhibitor. Three patients had injection site erythema and one had fatigue with anti-IL-1 treatment. Topical steroids with systemic antihistaminics were sufficient for symptom control in two cases, but canakinumab treatment was given due to severe injection site erythema in one case. CONCLUSION: Anti-IL-1 agents are rational treatment modalities in patients resistant or intolerant to colchicine. Anti-IL-1 agents can control FMF attacks quite effectively and they have a promising role in the treatment of FMF.

Clusters in Behçet's syndrome.

Clustering is an important clinical feature of Behçet's syndrome (BS) and may have pathogenetic and therapeutic implications. Recent and previous studies on BS phenotype differ substantially in terms of methodology. Correlation matrices and factor analyses were not efficient enough to uncover clusters. Clustering patterns may change according to demographic factors such as age and sex. Clustering patterns may also be profoundly influenced by the misperception of symptoms that are assumed to be secondary to BS, when, in fact, they represent manifestations of BD mimics. This can give rise to misleading conclusions and should be kept in mind when interpreting data obtained by clustering or other phenotype analyses of BS. A true geographical/racial variability in disease expression could be studied in a multinational consensus cohort. Pathogenetic studies in separate clusters of BS have still been lacking.

Serum estradiol level predicts acute kidney injury in medical intensive care unit patients.

Previous studies have shown that serum estradiol (E2) levels can predict mortality in intensive care unit patients. Our study investigated the predictive role of admission estradiol level on patient mortality and development of acute kidney injury in medical intensive care unit patients with a wide range of diagnoses. We conducted a prospective cohort study using serum samples from hospitalized patients in medical, cardiac, and pulmonary intensive care units at the Ege University Hospital within 6 months. Serum estradiol levels from 118 adult patients were collected within 48 h of hospitalization. Receiver operating curves and multiple logistic regression analyses were performed to investigate its relationship with acute kidney injury development and mortality. Serum estradiol levels were significantly higher in non-survivor patients than in survivor patients [85 (19-560) pg/mL vs. 32 (3-262) pg/mL, p < 0.001]. Admission estradiol levels were significantly higher in patients with AKI on admission than in patients with chronic kidney disease (p = 0.002) and normal renal function (p = 0.017). Serum E2 levels were higher in patients with renal deterioration during follow-up than patients with stable renal functions [62 (11-560) pg/mL vs. 38 (3-456) pg/mL, p = 0.004]. An admission estradiol level of 52.5 pg/mL predicted follow-up renal deterioration with 63% sensitivity and 74% specificity. A combined (APACHE II-E) score using APACHE II and serum estradiol level predicted overall mortality with 66% sensitivity and 82% specificity. Admission estradiol level is a good marker to predict the development of acute kidney injury and mortality in medical intensive care unit patients.

Assessment of loneliness in patients with inflammatory arthritis.

AIM: This study aimed to explore loneliness and associated factors in Turkish patients with inflammatory arthritis. METHOD: Adult patients with rheumatoid arthritis (RA) (n = 58), ankylosing spondylitis (AS) (n = 53), and psoriatic arthritis (PsA) (n = 30), respectively, were included in the study. A single-item visual analog scale (VAS) for loneliness, UCLA Loneliness Scale-8 (ULS-8), Beck depression inventory (BDI), Beck anxiety inventory (BAI), revised multidimensional scale of perceived social support, Health Assessment Questionnaire-Disability Index (HAQ-DI) were used for the psychometric and functional assessments. Multiple regression models were generated for predicting the ULS-8 and HAQ-DI scores. RESULTS: There was no difference between disease groups in terms of the ULS-8 and HAQ-DI scores. Among demographic and clinical parameters, only the education status and number of drugs used had associations with the ULS-8 score. Single-item VAS score for loneliness did not predict the ULS-8 score well. There were significant correlations between the ULS-8 and HAQ-DI, depression, anxiety, social support, and physician global VAS scores. Only the education status significantly predicted (ß = -0.208) the ULS-8 score in multiple regression analysis (adjusted R2  = 0.15, P < .001). Beck depression, anxiety, and patient global VAS scores remained significant for predicting the HAQ-DI after multiple regression with the covariates ULS-8, depression, anxiety, social support, patient and physician global VAS scores, and the number of drugs used (adjusted R2  = 0.53, P < .001). Disease activity and the ULS-8 scores were not found to be associated in any disease group. CONCLUSION: Loneliness is associated with depression, anxiety, lack of social support, disability, higher number of drugs used, and lower education but not with disease activity in Turkish patients with RA, AS, and PsA. Perception and expression of loneliness vary according to the cultural background. Single-item scales for loneliness may lack reliability compared to the more comprehensive ULS-8.

Uveitis-related Factors in Patients With Spondyloarthritis: TReasure Real-Life Results.

PURPOSE: Spondyloarthritis (SpA) is a group of diseases with overlapping skeletal and extra-articular features. Acute anterior uveitis (AAU) is the most common extra-articular manifestation of SpA. The relation between AAU and SpA is well defined in the current literature. Our study aims to analyze the frequency and factors associated with AAU in different forms of SpA in a large nationwide cohort of Turkish SpA patients. DESIGN: Retrospective cohort study. METHODS: The data were obtained from the TReasure database, which compiles data from records of the web-based Rheumatoid Arthritis (RA) and SpA patients treated with biological disease-modifying anti-rheumatismal drugs from different regions of Turkey. The clinical characteristics of SpA and uveitis are recorded. RESULTS: Data of the 4,297 SpA patients were included in the study. Overall, 475 of 4,297 patients (11.0%) had experienced 1 or more episodes of uveitis. SpA patients with older age (P < .001), a smoking history (P = .004), delayed diagnosis (P = .001), longer disease duration (P < .001), arthritis (P < .001), positive HLA-B27 (P < .001), a family history of SpA (P < .001), and radiographic damage (presence of sacroiliitis, syndesmophytes, bamboo spine, hip involvement) (P < .001 for all) more commonly had uveitis. On the other hand, uveitis was less prevalent in patients with psoriasis and psoriatic arthritis (P < .001 for both). CONCLUSION: Uveitis may be the key feature leading to SpA diagnosis. Patients with radiographic damage and long disease duration have an increased risk for uveitis in both male and female SpA patients. Patients with uveitis should be referred to a rheumatologist for a thorough evaluation of SpA.

Quantitative Assessment of Salivary Gland Parenchymal Vascularization Using Power Doppler Ultrasound and Superb Microvascular Imaging: A Potential Tool in the Diagnosis of Sjögren's Syndrome

Background: Primary Sjögren's syndrome is a chronic inflammatory autoimmune disease. Minor salivary gland biopsy is the gold standard for the diagnosis of primary Sjögren's syndrome. Superb microvascular imaging, power Doppler ultrasound, and color Doppler of the salivary glands represent non-invasive, non-irradiating modality for evaluating the vascularity of the salivary glands in the diagnosis and follow-up of primary Sjögren's syndrome. Aims: To evaluate the efficacy of superb microvascular imaging and vascularity index in salivary glands for the sonographic diagnosis of primary Sjögren's syndrome. Study Design: Prospective case-control study. Methods: Twenty participants with primary Sjögren's syndrome and 20 healthy subjects were included in the study. Both parotid glands and submandibular glands were evaluated by superb microvascular imaging, power Doppler ultrasound, and color Doppler. The diagnostic accuracy of superb microvascular imaging was compared using these techniques. Results: In the patient group, the vascularity index values of superb microvascular imaging in parotid glands and submandibular glands were 3.5±1.66, 5.06±1.94, respectively. While the same values were 1.0±0.98 and 2.44±1.34 in the control group (p≤0.001). In the patient group, the vascularity index values of power Doppler ultrasound in parotid glands and submandibular glands were 1.3±1.20 and 2.59±1.82, respectively. While the same values were 0.3±0.32 and 0.85±0.68 in the control group (p≤0.001). The superb microvascular imaging vascularity index cut-off value for the diagnosis of primary Sjögren's syndrome in parotid glands that maximizes the accuracy was 1.85 (area under the curve: 0.906; 95% confidence interval: 0.844, 0.968), and its sensitivity and specificity were 87.5% and 72.5%, respectively. While the superb microvascular imaging vascularity index cut-off value for the diagnosis of primary Sjögren's syndrome in submandibular gland that maximizes the accuracy was 3.35 (area under the curve: 0.873; 95% confidence interval: 0.800, 0.946), its sensitivity and specificity were 82.5% and 70%, respectively. Conclusion: Superb microvascular imaging with high reproducibility of the vascularity index has a higher sensitivity and specificity than the power Doppler ultrasound in the diagnosis of primary Sjögren's syndrome. It can be a noninvasive technique in the diagnosis of primary Sjögren's syndrome when used with clinical, laboratory and other imaging methods.

Association of simple hematological parameters with disease manifestations, activity, and severity in patients with systemic sclerosis.

INTRODUCTION/OBJECTIVES: Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), mean platelet volume (MPV), and red cell distribution width (RDW) may potentially reflect inflammatory status in systemic autoimmune diseases. The aim of this study is to investigate the association between these proposed markers and disease manifestations, activity, and severity in systemic sclerosis (SSc). METHOD: We conducted a cross-sectional study of 69 systemic sclerosis (SSc) patients and 50 healthy volunteers in a single center. Adult patients with SSc and healthy controls were compared in terms of NLR, MLR, MPV, RDW, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Venous blood samples were drawn after at least 8 h of fasting in the morning. Extension of skin fibrosis was evaluated by using modified Rodnan skin score (mRSS). Disease severity and activity were assessed by Medsger disease severity and European Scleroderma Trials and Research Group (EUSTAR) disease activity scores, respectively. Associations of disease manifestations, clinical, laboratory, and capillaroscopic findings, mRSS, and the disease activity and severity scores with the proposed hematological markers were evaluated. Multiple regression models were generated for significant associations. RESULTS: The neutrophil number was higher (p = 0.004) and lymphocyte number was lower (p < 0.001) in SSc group compared to controls. SSc group also had higher NLR, MLR, and RDW. In multiple logistic regression, only the NLR (regression coefficient = 3.49, p = 0.031) and CRP (regression coefficient = 0.17, p = 0.037) remained significantly different between SSc and healthy control groups (Cox and Snell R2 = 0.243, Nagelkerke R2 = 0.337, p < 0.001). NLR and MLR positively correlated with mRSS, EUSTAR score, and CRP. MLR also positively correlated with Medsger score. Higher monocyte counts independently predicted higher EUSTAR and Medsger scores in multiple linear regressions. Patients with digital ulcers had higher NLR and MLR. We did not find any difference in MPV values between SSc and healthy control groups. CONCLUSIONS: Globally available and inexpensive hematological tests, particularly the NLR and MLR, may be associated with vascular and cutaneous manifestations as well as disease activity and severity in SSc.Key Points• Monocyte count itself independently predicted higher activity and severity scores in SSc.• Globally available and inexpensive hematological markers, particularly the NLR and MLR, may have an association with vascular and cutaneous manifestations as well as disease activity and severity in patients with SSc.