Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study.

Takayasu arteritis is a rare inflammatory disease of large arteries. We performed a genetic study in Takayasu arteritis comprising 6,670 individuals (1,226 affected individuals) from five different populations. We discovered HLA risk factors and four non-HLA susceptibility loci in VPS8, SVEP1, CFL2, and chr13q21 and reinforced IL12B, PTK2B, and chr21q22 as robust susceptibility loci shared across ancestries. Functional analysis proposed plausible underlying disease mechanisms and pinpointed ETS2 as a potential causal gene for chr21q22 association. We also identified >60 candidate loci with suggestive association (p < 5 × 10-5) and devised a genetic risk score for Takayasu arteritis. Takayasu arteritis was compared to hundreds of other traits, revealing the closest genetic relatedness to inflammatory bowel disease. Epigenetic patterns within risk loci suggest roles for monocytes and B cells in Takayasu arteritis. This work enhances understanding of the genetic basis and pathophysiology of Takayasu arteritis and provides clues for potential new therapeutic targets.

The assessment of malnutrition and severity of gastrointestinal disease by using symptom-based questionnaires in systemic sclerosis: is it related to severe organ involvement or capillary rarefaction at microcirculation?

OBJECTIVES: Gastrointestinal (GI) system is commonly affected in sytemic sclerosis (SSc) patients who are also known to be at risk for malnutrition. We aimed to investigate the relationship between severity of GI disease, malnutrition and severity of organ involvement including microvasculopathy. METHODS: A hundred and thirty-four SSc patients were included into the study; disease activity and severity, the University of California, Los Angeles, Scleroderma Clinical Trials Consortium Scleroderma Gastrointestinal scale 2.0 (UCLA SCTC GIT 2.0) and malnutrition universal screening tool (MUST) were cross-sectionally assessed. Nailfold video-capillaroscopy(NVC) was performed to evaluate microvasculopathy. RESULTS: SSc patients who are at medium to high risk for malnutrition (n=20); had more frequently limited pulmonary function, lung involvement, pulmonary hypertension, capillary rarefaction and NVC late pattern than those at low risk for malnutrition. Capillary rarefaction (≤6/mm) was shown to be independently associated with medium to high risk for malnutrition defined by using MUST. Capillary rarefaction and severe skin involvement were found to be independently related to 'severe' or 'very severe' GI disease defined by using UCLA SCTC GIT 2.0. UCLA SCTC GIT 2.0 scores were not found to be good discriminative in patients at risk for malnutrition allowing for a ROC curve of area under the curve (AUC)<0.8). CONCLUSIONS: Assessment of gastrointestinal complaints and nutritional status by using symptom based questionnaires reflected the severity of GI disease and malnutrition including some limitations. Capillary rarefaction and severe skin involvement might be determining factors for malnutrition risk and severe GI disease.

Certolizumab pegol in the treatment of Takayasu arteritis.

Objectives: Certolizumab pegol (CZP) is a PEGylated antigen-binding fragment-fragment of a humanized mAb neutralizing TNF. It lacks Fc-fragment and has a very low potential to cross the placenta. We aimed to report the efficacy and safety of CZP in a case series of patients with refractory Takayasu arteritis (TA). Methods: Ten females of reproductive age (18-35 years) with TA were treated with CZP (at a dose of 400 mg at weeks 0, 2 and 4 and at 200 mg every 2 weeks thereafter) for a median of 10 months (range 3-28). Prior to CZP administration all patients received glucocorticoids and ± MTX, CYC, AZA, HCQ, LEF or MMF. Six patients were previously treated with other biological anti-cytokine drugs. The National Institutes of Health criteria and the Indian Takayasu Clinical Activity Score 2010 were used to define disease activity. Results: All patients rapidly responded to treatment with CZP and were able to taper prednisone and MTX doses. Treatment with CZP resulted in a significant decrease in median serum CRP levels and normalization of Indian Takayasu Clinical Activity Score 2010 score in 9 of 10 patients. Remission of systemic vasculitis was achieved in all patients. Seven patients maintained remission for at least 4 months, while one patient developed relapse after 2 years of CZP treatment. Side effects included mild infections (n = 5). Conclusion: Our case series suggests that CZP may be an effective and steroid-sparing treatment option in patients with active TA even if they did not previously respond to other TNF inhibitors or tocilizumab.

Methodology of a new inflammatory arthritis registry: TReasure

Background/aim: The TReasure registry, created in 2017, is an observational multicenter cohort that includes inflammatory arthritis patients. This article reviews the methodology and objectives of the TReasure registry established to collect data from rheumatoid arthritis (RA) and spondyloarthritis (SpA) patients. Methodology: Fifteen rheumatology centers in Turkey will contribute data to the TReasure database. The actual proprietor of the database is the Hacettepe Rheumatology Association (HRD) and Hacettepe Financial Enterprises. Pharmaceutical companies that operate in Turkey (in alphabetical or er), Abbvie, Amgen, BMS, Celltrion Healthcare, Novartis, Pfizer, Roche, and UCB, support the TReasure registry. TReasure is a web-based database to which users connect through a URL (https://www.trials-network.org/treasure) with their unique identifier and passwords provided for data entry and access. TReasure records demographic and clinical features, comorbidities, radiology and laboratory results, measures of disease activity, and treatment data. Discussion: TReasure will provide us with various types of data, such as a cross-sectional view of the current nationwide status of the patients currently receiving these treatments, and retrospective data as much as allowed by the participating centers' records. Finally, a high-quality prospective dataset will be built over the ensuing years from patients with a new diagnosis of RA or SpA.

Development of the Takayasu Arteritis Integrated Disease Activity Index.

OBJECTIVE: Accurate clinical assessment of disease activity in Takayasu arteritis (TAK) can be challenging. 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) can directly measure vascular inflammation. This study details the development of a new type of disease activity index called the Takayasu's Arteritis Integrated Disease Activity Index (TAIDAI). METHODS: Clinical symptoms for TAIDAI were identified from a literature review. Each symptom was paired with FDG-PET findings in corresponding arterial territories. Constitutional symptoms were paired with acute phase reactant levels. One point was given for each clinical symptom paired with supporting FDG-PET or laboratory abnormalities and summed into the TAIDAI score. A TAIDAI of ≥1 defined active disease. To assess performance of TAIDAI, face validity, content validity, and sensitivity to change were evaluated within a prospective observational cohort study of patients with TAK. RESULTS: Seventeen clinical symptoms were paired with imaging or laboratory abnormalities. In a cohort of 96 patients contributing 204 study visits, TAIDAI showed excellent sensitivity (96.3%) and good specificity (79.2%) compared to physician's clinical assessment. TAIDAI significantly correlated with physician global assessment, PET Vascular Activity Score, patient global assessment, and acute phase reactant levels. In patients treated with either tumor necrosis factor inhibitors or tocilizumab, a TAIDAI of 0 was achieved in 21 (91%) of 23 patients who met a predefined definition of clinical response. CONCLUSION: TAIDAI is new type of disease activity index in TAK in which clinical symptoms are integrated with specific laboratory and imaging findings. TAIDAI should be validated in future randomized controlled trials in TAK.

Comparison of methotrexate and azathioprine as the first-line steroid-sparing immunosuppressive agents in patients with Takayasu's arteritis.

BACKGROUND: Immunosuppressive (IS) agents are recommended for the first-line treatment of patients with active Takayasu's arteritis (TAK) together with glucocorticoids (GCs). However, there is limited data comparing the efficacy and outcomes of different IS agents for this purpose. OBJECTIVES: In this study, we aimed to compare the outcomes of two most frequently used first-line IS agents, namely methotrexate (MTX) and azathioprine (AZA) in TAK patients. METHODS: TAK patients who received any IS agent in addition to GCs as the initial therapy were included in this multicentre, retrospective cohort study. Clinical, laboratory and imaging data of the patients were assessed. In addition, a matched analysis (cc match) using variables 'age', 'gender' and 'diffuse aortic involvement' was performed between patients who received MTX or AZA as the first-line IS treatment. RESULTS: We recruited 301 patients (F/M: 260/41, mean age: 42.2 ± 13.3 years) from 10 tertiary centres. As the first-line IS agent, 204 (67.8 %) patients received MTX, and 77 (25.6 %) received AZA. Less frequently used IS agents included cyclophosphamide in 17 (5.6 %), leflunomide in 2 (0.5 %) and mycophenolate mofetil in one patient. The remission, relapse, radiographic progression and adverse effect rates were similar between patients who received MTX and AZA as the first-line IS agent. Vascular surgery rate was significantly higher in the AZA group (23% vs. 9 %, p = 0.001), whereas the frequency of patients receiving ≤5 mg/day GCs at the end of the follow-up was significantly higher in the MTX group (76% vs 62 %, p = 0.034). Similarly, the rate of vascular surgery was higher in AZA group in matched analysis. Drug survival was similar between MTX and AZA groups (median 48 months, MTX vs AZA: 32% vs 42 %, p = 0.34). IS therapy was discontinued in 18 (12 MTX, 6 AZA) patients during the follow-up period due to remission. Among those patients, two patients had a relapse at 2 and 6 months, while 16 patients were still on remission at the end of a mean 69.4 (±50.9) months of follow-up. CONCLUSIONS: Remission, relapse, radiographic progression and drug survival rates of AZA and MTX were similar for patients with TAK receiving an IS agent as the first-line f therapy. The rate of vascular surgery was higher and the rate of GC dose reduction was lower with AZA compared to MTX at the end of the follow-up.

Frequency and the effects of spondyloarthritis-spectrum disorders on the clinical course and management of Takayasu arteritis: an observational retrospective study.

OBJECTIVES: Extravascular findings of Takayasu arteritis (TAK) often share features with the spondyloarthritis (SpA) spectrum of disorders. However, the characteristics of this overlap and its effect on the vascular manifestations of TAK are not fully known. Therefore, we aimed to investigate the frequency of SpA-related features in TAK patients. MATERIAL AND METHODS: In this observational retrospective study, 350 patients with TAK classified according to ACR 1990 criteria, from 12 tertiary rheumatology clinics, were included and evaluated for the presence of axSpA, IBD, or psoriasis. Demographic, clinical features, angiographic involvement patterns, disease activity, and treatments of TAK patients with or without SpA were analyzed. RESULTS: Mean age was 45.5 ± 13.6 years and mean follow-up period was 76.1 ± 65.9 months. Among 350 patients, 31 (8.8%) had at least one additional disease from the SpA spectrum, 8 had IBD, 8 had psoriasis, and 20 had features of axSpA. In the TAK-SpA group, TAK had significantly earlier disease onset, compared to TAK-without-SpA (p = 0.041). SpA-related symptoms generally preceded TAK symptoms. Biological treatments, mostly for active vasculitis, were higher in the TAK-SpA group (70.9%) compared to TAK-without-SpA (27.9%) (p < 0.001). Vascular involvements were similar in both. CONCLUSION: Our study confirmed that diseases in the SpA spectrum are not rare in TAK. Vascular symptoms appeared earlier in such patients, and more aggressive therapy with biological agents was required in the TAK-SpA group, suggesting an association between TAK and SpA spectrum. Key Points • The pathogenesis of Takayasu arteritis is mediated by an MHC class I alelle (HLA-B*52), similar to spondyloarthritis-disorders. • Extravascular findings of Takayasu arteritis are in the spectrum of spondyloarthritis disease. • This frequent coexistence between Takayasu arteritis and spondyloarthritic disorders suggests a relationship rather than a coincidence.

Metabolic syndrome is associated with increased cardiovascular risk and disease damage in patients with Takayasu arteritis.

OBJECTIVE: Metabolic syndrome (MetS) is one of the preventable risk factors for cardiovascular disease (CVD). The aim of this study was to investigate the effect of MetS on CVD and cumulative organ damage in a multi-center, large cohort of patients with Takayasu arteritis (TAK). METHODS: This is a cross-sectional study involving 192 consecutive TAK patients from seven tertiary rheumatology centers in Turkey. Clinical data of TAK patients fulfilling the 1990 American College of Rheumatology classification criteria were collected from medical records. They were evaluated for risk factors of CVD, disease activity, damage, and MetS at their last visits. RESULTS: A total of 192 consecutive TAK patients were included in this study. One hundred and fifty-eight (82%) were female, the mean age was 43.3 ± 13 years, and mean disease duration was 13.5 ± 9.3 years. MetS was detected in 50 (26%) of the patients and CVD was detected in 28 (14.6%). The presence of MetS was detected as an independent risk factor for CVD (P < 0.001). In addition, the mean vasculitis damage index of the group with MetS was significantly higher than in the other patients (4.5 ± 3.3 vs 3.2 ± 2.2, respectively, P = 0.004). CONCLUSION: The presence of MetS in TAK is associated with increased CVD and disease damage. Awareness and management of MetS can improve disease prognosis in patients with TAK.

Pregnancy in Takayasu's arteritis has a high risk of hypertension-related fetomaternal complications: A retrospective study of a Turkish cohort.

BACKGROUND: This study aimed to examine fetomaternal outcomes in pregnant women in a large Turkish Takayasu arteritis (TAK) cohort and to evaluate the effects of pregnancy on the disease in those patients. METHODS: This is a cohort study involving 296 pregnancies of 112 TAK patients from 8 tertiary rheumatology centers in Turkey. Pregnancies were divided into 2 groups as pre-d (before disease onset) and post-d (after disease onset). In addition, post-d pregnancies were further divided into 2 subgroups according to fetomaternal complications (FMC) development status. Finally, patients were grouped into those with and without a history of pregnancy after disease onset. RESULTS: In post-d pregnancies, rates of worsening hypertension, new-onset hypertension, and preeclampsia were higher than in pre-d pregnancies (0.9% vs 16%, P < .001, 0.5% vs 5.3%, P = .012, and 0% vs 4%, P = .013, respectively). Patients with FMC were more likely to have renal artery involvement (65% vs 21%, P = .003). The patients who had post-d were younger, had longer disease duration, and had more relapses number than other patients (P < .001, P = .028, P = .016, respectively). Vasculitis Damage Index (VDI) results were similar in patients with or without post-d pregnancies. CONCLUSION: Pregnancies after disease onset were found to be associated with HT and preeclampsia/eclampsia. HT-related FMCs are increased in TAK, and patients with renal artery involvement are at higher risk. The number of relapses increases in patients who become pregnant after disease onset, but pregnancy was not an independent risk factor for relapse. Pregnancy after the onset of disease had no negative effect on VDI.

Childhood-onset versus adult-onset Takayasu arteritis: A study of 141 patients from Turkey.

AIM: To compare childhood-onset (c-TAK) versus adult-onset Takayasu arteritis (a-TAK) patients for vascular involvement, disease activity, damage, and treatment. METHODS: Patient charts from two tertiary-care centers of a pediatric and adult rheumatology clinic were reviewed. Adult patients diagnosed before the age of 18 years were included in the childhood-onset group. The activity was assessed with the physician's global assessment (PGA) and Indian Takayasu Clinical Activity Score (ITAS). The damage was evaluated with Takayasu Arteritis Damage Score (TADS) and Vasculitis Damage Index (VDI). RESULTS: Twenty-four c-TAK (follow-up duration: 53 months) and 117 a-TAK patients (follow-up duration: 68 months) were analyzed. Aorta involvement was more prevalent (79% vs. 33%), and the median PGA score was higher in the c-TAK group (9 vs. 7), whereas the mean Indian Takayasu Arteritis Score was similar (14 vs. 13) among both groups. Median VDI score was lower for c-TAK patients (4 vs. 5), whereas TADS was similar for children and adults (8 vs. 8). Higher incidence of glucocorticoid related side-effects, a longer time to diagnosis and upper extremity claudication seemed to account for higher VDI scores in adults. CONCLUSION: Aorta involvement was more common among children with TAK, whereas upper extremities were relatively spared. Biologic agents were used more commonly among children which may be explained by higher rates of aortic involvement. However, c-TAK patients did not have greater cumulative damage.

HADS-depression score is a mediator for illness perception and daily life impairment in Takayasu's arteritis.

INTRODUCTION/OBJECTIVES: The aim of this study was to evaluate the relationships among the disease activity, illness perception, daily life performance, anxiety and depression status as potential mediators in Takayasu's arteritis (TAK) patients. METHOD: In this cross-sectional study, 77 TAK patients were included. Data were collected by a clinical examination and a structured questionnaire regarding patient reported outcome measures (PROMs). Indian Takayasu's Arteritis Activity Score2010 (ITAS2010) was used to assess the disease activity (0: inactive vs ≥ 1: active). Illness Perception Questionnaire-Revise (IPQ-R), Work Productivity and Activity Impairment (WPAI) and Hospital Anxiety and Depression Scale (HADS) as PROMs were used to understand for the patient' perspective. After preliminary analysis, complex relationships among these variables were evaluated by mediation analyses in the study. RESULTS: WPAI-Daily impairment score, HADS-A and HADS-D scores as well as IPQ-R Consequence score were found be high in active TAK patients (p = 0.008; p = 0.001; p = 0.031; p = 0.001). HADS-D score was also correlated with WPAI-Daily impairment score and IPQ-R Consequence score (p < 0.05). In mediation analysis, IPQ-R Consequence score was directly mediated by disease activity (ITAS2010) (p = 0.0173) and indirectly mediated through HADS-D score (p = 0.0003). Similarly, HADS-D score was associated with poor WPAI-Daily impairment score in the mediation analysis in the indirect path (p = 0.0069). Disease activity (ITAS2010) also increased WPAI-Daily impairment score in direct path (p = 0.043). CONCLUSIONS: Active TAK patients perceived their illness more seriously and experienced more impairment in their daily life. Depression status as the mediator influenced them poorly. These interactions could give clues to improve PROMs in the clinical practice. Key Points •IIness perception, disease activity, mental status and daily life performance, assessed as patient-reported outcome measures, have a complex relationship in Takayasu's arteritis. •IPQ-R Consequence score, WPAI-Daily impairment score, HADS-Depression and HADS-Anxiety scores were found be high in active TAK patients. •In mediation analysis, IPQ-R Consequence score was directly mediated by disease activity and indirectly mediated through HADS-D score. Similarly, disease activity increased WPAI-Daily impairment score in direct and HADS-D in indirect paths.

Biologic treatments in Takayasu's Arteritis: A comparative study of tumor necrosis factor inhibitors and tocilizumab.

OBJECTIVE: To compare the treatment outcomes of TNF inhibitors and tocilizumab (TCZ) in patients with Takayasu arteritis. METHODS: Takayasu arteritis patients who were refractory to conventional immunosuppressive (IS) drugs and received biologic treatment were included in this multicenter retrospective cohort study. Clinical, laboratory and imaging data during follow-up were recorded. Remission, glucocorticoid (GC) sparing effect, drug survival was compared between TNF inhibitor and TCZ treatments. Also, a subgroup matched comparison was performed between groups. RESULTS: One hundred and eleven (F/M: 98/13) patients were enrolled. A total of 173 biologic treatment courses (77 infliximab, 49 TCZ, 33 adalimumab, 9 certolizumab, 3 rituximab, 1 ustekinumab and 1 anakinra) were given. Tocilizumab was chosen in 23 patients and TNF inhibitors were chosen in 88 patients as first-line biologic agent. Complete/partial remission rates between TCZ and TNF inhibitors were similar at 3rd month and at the end of the follow-up. GC dose decrease (≤4 mg) or discontinuation of GCs was achieved in a similar rate in both groups (TNF inhibitors vs TCZ: 78% vs 59%, p = 0.125). Drug survival rate was 56% in TNF inhibitors and 57% in TCZ group (p = 0.22). The use of concomitant conventional ISs did not affect the drug survival (HR =0.78, 95% CI =0.42-1.43, p = 0.42). The match analysis showed similar results between groups in terms of relapse, decrease in GC dose, surgery need and mortality. CONCLUSION: The efficacy and safety outcomes and drug survival rates seem to be similar for TNF inhibitors and tocilizumab in patients with Takayasu arteritis.

Assessment of damage in Takayasu's arteritis.

OBJECTIVE: To assess the progression and the factors associated with damage in Takayasu's arteritis (TAK) patients during routine follow-up. METHODS: Patients diagnosed with TAK and had >6 months follow-up were enrolled in this study retrospectively. Takayasu's arteritis damage score (TADS) and vasculitis damage index (VDI) were determined at diagnosis and at the end of the follow-up and variables associated with damage scores were assessed. RESULTS: One-hundred fourteen patients (F/M: 101/13) were included in the study. The mean age at diagnosis, median symptom duration at baseline visit and mean follow-up duration were 35.3±13.3 years, 12 (0-360) months and 76.9±51.4 months, respectively. Median VDI score was 4.0 (1-8) and median TADS score was 7.0 (1-15) at baseline assessment. At the end of the follow-up, median VDI score increased to 5.0 (1-17) and TADS score to 8.0 (1-19). The median number of disease-related items were higher in TADS (8 items vs 4 items). At least one new corticosteroid (CS)-related damage item occurred in 35 patients (31%). Age at symptom-onset and cumulative CS doses were predictor factors for higher VDI score (≥5), whereas age at symptom-onset and disease duration were associated with increase in TADS (≥8). Gender and number of relapses were not associated with damage scores. CONCLUSION: Damage assessment with VDI seems to capture treatment-related damage better, whereas TADS provides some additional information on disease-related damage in Takayasu's arteritis. Older age at symptom onset, disease duration and cumulative CS dose were associated with higher damage scores. The relapse frequency did not influence the damage level in our routine-follow-up of TAK patients.