Search

A subset of Takayasu arteritis (TAK) has onset in the pediatric age group (≤18 years). The differences in mortality between pediatric-onset and adult-onset TAK are unclear. Therefore, we undertook a systematic review with meta-analysis to compare mortality risk in pediatric-onset with adult-onset TAK. Scopus, Pubmed (MEDLINE and Pubmed Central), recent conference abstracts, clinicaltrials.gov, and the Cochrane database were searched up to August 2023 for relevant studies. Five studies (all of moderate or high quality on the Newcastle Ottawa scale) were identified which had compared mortality between 151 pediatric-onset and 499 adult-onset TAK. Pediatric-onset TAK was associated with a significantly higher risk of death than adult-onset TAK (pooled risk ratio 2.27, 95% confidence interval 1.05 - 4.85, I 2 =0%). Cardiovascular disease and infections were the major causes of death in both pediatric-onset and adult-onset TAK. Sub-group analyses identified a greater mortality risk with pediatric-onset TAK in retrospective (but not prospective) studies and in studies of high quality (but not in those of moderate quality). Meta-regression did not reveal a significant influence of differences in sex distribution or age or the proportions of patients with pediatric-onset or adult-onset TAK on the pooled mortality risk. An increased mortality risk with pediatric-onset TAK on meta-analysis is consistent with more frequent severe organ manifestations of pediatric-onset TAK (heart failure, renal failure) when compared with adult-onset TAK. Future studies should systematically evaluate differences in the pathogenesis between pediatric-onset and adult-onset to understand the reasons for such observed differences in the mortality risk., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: A subset of Takayasu's arteritis (TAK) begins in the paediatric age group (≤18 years). Differences in prognosis between paediatric-onset and adult-onset TAK are unclear. We compared the differences in the presentation and survival between paediatric-onset and adult-onset TAK in our cohort of TAK., Methods: From a retrospective cohort of TAK, clinical presentation, angiographic features, treatments received, disease activity, and survival were compared between paediatric-onset and adult-onset TAK. Multivariable-adjusted logistic regression models were used to compute adjusted odds ratio (aOR) with 95% confidence intervals (95%CI) for paediatric-onset vs. adult-onset TAK. Hazard ratios (HR, with 95%CI) for mortality with paediatric-onset vs adult-onset TAK (crude, adjusted for prognostic covariates or differences in presentation) and propensity score-matched survival analyses were estimated., Results: Among 56 paediatric-onset and 135 adult-onset TAK, chest pain (aOR 3.21, 95%CI 1.06-9.74), heart failure (aOR 3.16, 95%CI 1.05-9.53), headache (aOR 2.60, 95%CI 1.01-6.74), ascending aorta (aOR 3.02, 95%CI 1.04-8.80) and left renal artery involvement (aOR 2.45, 95%CI 1.04-5.80) were more frequent in paediatric-onset TAK. Despite similar longitudinal patterns of disease activity and glucocorticoid or disease-modifying antirheumatic drug (DMARD) use, mortality was higher for paediatric-onset TAK (HR, unadjusted 6.13, 95%CI 1.51-24.91; adjusted for prognostic covariates gender, diagnostic delay, baseline disease activity, number of conventional and biologic/targeted synthetic DMARDs used, 4.97, 95%CI 1.20-20.58; adjusted for differences between groups 5.54, 95%CI 1.22-25.09; after propensity-score matching for prognostic covariates, 54 pairs, log-rank p-value 0.026)., Conclusions: Considering the greater mortality risk, greater vigilance is required while managing paediatric-onset TAK.

Background: We analyzed differences in presentation and survival of Takayasu arteritis (TAK) with or without renal artery involvement (RAI) from a large monocentric cohort of patients with TAK., Methods: Clinical and angiographic features were compared between TAK with versus without RAI, with bilateral versus unilateral RAI, and with bilateral RAI versus without RAI using multivariable-adjusted logistic regression. Inter-group differences in survival were analyzed [hazard ratios (HR) with 95% confidence intervals (95%CI)] adjusted for gender, age at disease onset, diagnostic delay, baseline disease activity, and significant clinical/angiographic inter-group differences after multivariable-adjustment/propensity score matching (PSM)., Results: Of 215 TAK, 117(54.42%) had RAI [66(56.41%) bilateral]. TAK with RAI or with bilateral RAI had earlier disease onset than without RAI (p < 0.001). Chronic renal failure (CRF) was exclusively seen in TAK with RAI. TAK with RAI (vs without RAI) had more frequent hypertension (p = 0.001), heart failure (p = 0.047), abdominal aorta (p = 0.001) or superior mesenteric artery involvement (p = 0.018). TAK with bilateral RAI (vs unilateral RAI) more often had hypertension (p = 0.011) and blurring of vision (p = 0.049). TAK with bilateral RAI (vs without RAI) more frequently had hypertension (p = 0.002), heart failure (p = 0.036), abdominal aorta (p < 0.001), superior mesenteric artery (p = 0.002), or left subclavian artery involvement (p = 0.041). Despite higher morbidity (hypertension, CRF), mortality risk was not increased with RAI vs without RAI (HR 2.32, 95%CI 0.61-8.78), with bilateral RAI vs unilateral RAI (HR 2.65, 95%CI 0.52-13.42) or without RAI (HR 3.16, 95%CI 0.79-12.70) even after multivariable adjustment or PSM., Conclusion: RAI is associated with increased morbidity (CRF, hypertension, heart failure) but does not adversely affect survival in TAK. Key Points •Renal artery involvement in TAK is associated with chronic renal failure. •TAK with renal artery involvement more often have heart failure and hypertension. •Bilateral renal artery involvement (compared with unilateral) is more often associated with hypertension and visual symptoms. •Renal artery involvement is not associated with an increased risk of mortality in TAK., (© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Objectives: The present study validates the 2022 ACR/European Alliance of Associations for Rheumatology (EULAR) classification criteria for Takayasu's arteritis (TAK), compared with the 1990 ACR TAK classification criteria., Methods: The fulfilment of 2022 ACR/EULAR and 1990 ACR TAK criteria from four referral centres was assessed for TAK compared with extracranial giant cell arteritis (EC-GCA) and other controls. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), likelihood ratio of a positive test (LR+) or negative test (LR-), and area under receiver operating characteristics curve (AUC) were calculated., Results: Among 504 patients with TAK (404 females) and 222 controls (151 females, 144 patients with EC-GCA), the 2022 ACR/EULAR criteria had better sensitivity (95.83% vs 82.94%) and NPV, but poorer specificity (63.51% vs 90.54%), PPV, LR+, LR- and AUC at the pre-determined cut-offs than the 1990 ACR criteria. The 2022 ACR/EULAR criteria had greater specificity (76.06% vs 57.62%) and AUC (0.845 vs 0.771), with similar sensitivity (93% vs 96.53%) in males as in females. The 2022 ACR/EULAR criteria performed similarly with only EC-GCA as controls (sensitivity 95.83%, specificity 60.42%, AUC 0.781). Sensitivity remained similar, whereas specificity was higher for 40-60 years vs <40 years. Cut-offs of ≥6 (sensitivity 91.87%, specificity 82.88%) and ≥7 (sensitivity 86.71%, specificity 86.49%), or removing the point for female sex (sensitivity 92.64%, specificity 81.08%) greatly improved the balance between sensitivity and specificity., Conclusion: The poor specificity of the 2022 ACR/EULAR TAK criteria in real-life settings was improved by increasing the cut-off to 6 or 7, or removing the point for female sex., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To evaluate diagnostic accuracy for active Takayasu arteritis (TAK) for two novel 18 F-fluorodeoxyglucose PET-CT parameters, the inflammatory volume (MIV) and total inflammatory glycolysis (TIG), to quantitate volume of metabolically-active arterial tissue., Methods: From a cohort of TAK (n = 36, 35 immunosuppressive-naïve), images of PET-CTs were reviewed for mean and maximum standardized uptake value (SUV mean and SUV max ), target-to-blood pool ratio (TBR), target-to-liver ratio (TLR), and PET Vasculitis Activity Score (PETVAS). Regions of interest were drawn to semiautomatically calculate MIV in areas of 18 F-fluorodeoxyglucose uptake ≥ 1.5 SUV mean after excluding physiological tracer uptake. TIG was calculated by multiplying MIV with SUV mean . PET-CT parameters, ESR, CRP, and clinical disease activity scores were compared against the gold standard of physician global assessment of disease activity (PGA, active/inactive)., Results: Using dichotomized cut-offs for active TAK at SUV max (≥ 2.21), SUV mean (≥ 1.58), TBR (≥ 2.31), TLR (≥ 1.22), PETVAS (various cut-offs), ESR (≥ 40 mm/hour), and CRP (≥ 6 mg/L), the novel indices MIV (≥ 1.8) and TIG (≥ 2.7) performed similar [area under the receiver operating characteristics curve (AUC) 0.873 for both] to SUV max (AUC 0.841) and SUV mean (AUC 0.851), and better than TBR (AUC 0.773), TLR (AUC 0.773), PETVAS [≥ 5.5 (AUC 0.750), ≥ 10 (AUC 0.636), ≥ 15 (AUC 0.546)], ESR (AUC 0.748), or CRP (AUC 0.731). MIV and TIG had similar agreement with PGA or CRP as with SUV max or SUV mean , and better agreement than TBR, TLR, or PETVAS cut-offs., Conclusions: MIV and TIG performed similarly, therefore, are viable alternatives to existing PET-CT parameters to assess TAK disease activity in this preliminary report. Key Points • MIV and TIG performed similar to SUV max and SUV max for disease activity assessment in TAK. • MIV and TIG distinguished active TAK better than TBR, TLR, PETVAS cut-offs, ESR, or CRP. • MIV and TIG had better agreement with PGA or CRP than TBR, TLR, or PETVAS cut-offs., (© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Arterial wall damage in Takayasu arteritis (TAK) can progress despite immunosuppressive therapy. Vascular fibrosis is more prominent in TAK than in giant cell arteritis (GCA). The inflamed arterial wall in TAK is infiltrated by M1 macrophages [which secrete interleukin-6 (IL-6)], which transition to M2 macrophages once the inflammation settles. M2 macrophages secrete transforming growth factor beta (TGF-β) and glycoprotein non-metastatic melanoma protein B (GPNMB), both of which can activate fibroblasts in the arterial wall adventitia. Mast cells in the arterial wall of TAK also activate resting adventitial fibroblasts. Th17 lymphocytes play a role in both TAK and GCA. Sub-populations of Th17 lymphocytes, Th17.1 lymphocytes [which secrete interferon gamma (IFN-γ) in addition to interleukin-17 (IL-17)] and programmed cell death 1 (PD1)-expressing Th17 (which secrete TGF-β), have been described in TAK but not in GCA. IL-6 and IL-17 also drive fibroblast activation in the arterial wall. The Th17 and Th1 lymphocytes in TAK demonstrate an activation of mammalian target organ of rapamycin 1 (mTORC1) driven by Notch-1 upregulation. A recent study reported that the enhanced liver fibrosis score (derived from serum hyaluronic acid, tissue inhibitor of metalloproteinase 1, and pro-collagen III amino-terminal pro-peptide) had a moderate-to-strong correlation with clinically assessed and angiographically assessed vascular damage. In vitro experiments suggest the potential to target arterial wall fibrosis in TAK with leflunomide, tofacitinib, baricitinib, or mTORC1 inhibitors. Since arterial wall inflammation is followed by fibrosis, a strategy of combining immunosuppressive agents with drugs that have an antifibrotic effect merits exploration in future clinical trials of TAK., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Misra, Singh, Sharma and Agarwal.)

This review overviews the challenges in the assessment of disease activity, damage, and therapy of Takayasu arteritis (TAK). Recently developed disease activity scores for TAK are more useful for follow-up visits and require validation of cut-offs for active disease. A validated damage score for TAK is lacking. Computed tomography angiography (CTA), magnetic resonance angiography (MRA), and ultrasound enable the evaluation of vascular anatomy and arterial wall characteristics of TAK. 18-fluorodeoxyglucose (18-FDG) positron emission tomography (PET) visualizes arterial wall metabolic activity and complements the information provided by circulating C-reactive protein (CRP) levels. ESR and CRP alone moderately reflect TAK disease activity. TAK is corticosteroid-responsive but relapses upon tapering corticosteroids. Conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) are the first-line maintenance agents, and tumor necrosis factor-alpha inhibitors, tocilizumab, or tofacitinib are second-line agents for TAK. Revascularization procedures for TAK should be used judiciously during periods of inactive disease., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Takayasu arteritis (TAK) refractory to conventional disease-modifying anti-rheumatic drugs (DMARDs) is commonly treated with biologic DMARDs such as tocilizumab or tumor necrosis factor-alpha inhibitors (TNFi). The 2021 American College of Rheumatology (ACR) recommendations preferred TNFi to tocilizumab. Therefore, we conducted a systematic review with meta-analysis to assess the evidence base for tocilizumab in TAK by updating a previous systematic review on DMARDs in TAK through searches on MEDLINE, Pubmed Central, Scopus, major international Rheumatology conference abstracts, and clinical trial databases from January 2021 to November 2022. Thirty-five studies involving 1082 TAK [one randomized controlled trial (RCT), eleven controlled and twenty-one uncontrolled studies, most of moderate to high quality] had evaluated tocilizumab in TAK. The RCT of tocilizumab versus placebo failed to meet its primary end-point of superiority of tocilizumab on an intention-to-treat analysis (hazard ratio 0.41, 95%CI 0.15-1.10) but successfully met the secondary end-point of superiority on per-protocol analysis (hazard ratio 0.34, 95%CI 0.11-1.00). A meta-analysis of six studies identified similar rates of clinical remission [risk ratio (RR) tocilizumab vs TNFi 1.03, 95%CI 0.91-1.17)], angiographic stabilization (RR 1.00, 95%CI 0.72-1.40) or adverse events (RR 0.84, 95%CI 0.54-1.31) with tocilizumab or TNFi. A meta-analysis of three studies identified superior clinical response (RR 1.55, 95%CI 1.15-2.10) and adverse effect profile (RR 0.45, 95%CI 0.25-0.80) with tocilizumab than cyclophosphamide. Pooled data from uncontrolled studies identified clinical response in 85%(95%CI 79-91%) and angiographic stabilization in 82% (95%CI 68-94%). Our study suggests similar evidence for treating TAK with tocilizumab or TNFi, contrary to the ACR 2021 recommendations., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Takayasu arteritis (TAK) is a less common large-vessel vasculitis which can occur in either children or adults. However, differences between pediatric-onset and adult-onset TAK have not been systematically analyzed. We undertook a systematic review (pre-registered on PROSPERO, identifier CRD42022300238) to analyze differences in clinical presentation, angiographic involvement, treatments, and outcomes between pediatric-onset and adult-onset TAK. We searched PubMed (MEDLINE and PubMed Central), Scopus, major recent international rheumatology conference abstracts, Cochrane database, and clinicaltrials.gov, and identified seven studies of moderate to high quality comparing pediatric-onset and adult-onset TAK. Meta-analysis of 263 pediatric-onset and 981 adult-onset TAK suggested that constitutional features (fever, and in subgroup analyses, weight loss), hypertension, headache, and sinister features of cardiomyopathy, elevated serum creatinine, and abdominal pain were more frequent in pediatric-onset TAK, whereas pulse loss/pulse deficit and claudication (particularly upper limb claudication) were more frequent in adult-onset TAK. Hata's type IV TAK was more common in pediatric-onset TAK, and Hata's type I TAK in adult-onset TAK. Children with TAK also appeared to require more intense immunosuppression with more frequent use of cyclophosphamide, biologic DMARDs, tumor necrosis factor alpha inhibitors, and, in subgroup analyses, tocilizumab in pediatric-onset TAK than in adult-onset TAK. Surgical or endovascular procedures, remission, and risk of mortality were similar in both children and adults with TAK. No studies had compared patient-reported outcome measures between pediatric-onset and adult-onset TAK. Distinct clinical features and angiographic extent prevail between pediatric-onset and adult-onset TAK. Clinical outcomes in these subgroups require further study in multicentric cohorts., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

It is now well established that Th17 lymphocytes associate with myriad immune-mediated inflammatory diseases. Over the past one and a half decades, a subset of Th17 lymphocytes viz. Th17.1 lymphocytes has been identified in pre-clinical and clinical models of inflammatory rheumatic diseases. These lymphocytes secrete IL-17A (signature cytokine of Th17 lymphocytes) as well as IFN-γ (the signature cytokine of Th1 lymphocytes). They express the chemokine markers for Th1 (CXCR3) as well as Th17 (CCR6) lymphocytes. Th17.1 lymphocytes also express the drug efflux protein p-glycoprotein, which associates with resistance to corticosteroids and other immunosuppressive drugs. This narrative review overviews the evidence regarding Th17.1 lymphocytes in different inflammatory rheumatic diseases. It is now recognized that Th17.1 lymphocytes are increased in the synovial fluid of affected joints in rheumatoid arthritis (RA) and associate with poor treatment response to abatacept. Th17.1 lymphocytes from synovial fluid of RA are less responsive to immunosuppression than those from the peripheral blood. In sarcoidosis, Th17.1 lymphocytes are concentrated in mediastinal lymph nodes and alveolar lining. Such Th17.1 lymphocytes in sarcoidosis are the predominant source of IFN-γ in the sarcoid lung. Th17.1 lymphocytes are elevated in lupus and Takayasu arteritis and associate with disease activity. Future studies should evaluate isolated Th17.1 lymphocytes from peripheral blood or sites of pathology such as synovial fluid and assess their modulation with immunosuppressive therapy in vitro. The analysis of gene expression signature of isolated Th17.1 lymphocytes might enable the identification of newer therapeutic strategies specifically targeting these cell populations in inflammatory rheumatic diseases. Key Points • Th17.1 lymphocytes are a subset of Th17 lymphocytes secreting both IFN-γ and IL-17 • Th17.1 lymphocytes drive neutrophilic inflammation, granuloma formation, and corticosteroid resistance • Th17.1 lymphocytes are elevated in rheumatoid arthritis and sarcoidosis at sites of inflammation • Increased circulating Th17.1 lymphocytes have been identified in lupus and Takayasu arteritis and associate with active disease., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Corticosteroid-sparing disease-modifying anti-rheumatic drugs are an area of active exploration in large vessel vasculitis (LVV), i.e., Takayasu arteritis (TAK) and Giant Cell Arteritis (GCA). The role of Janus kinase (JAK) inhibitors has been recently identified in different inflammatory rheumatic diseases. We conducted a systematic review of the use of JAK inhibitors in LVV across MEDLINE, Scopus, Web of Science, EMBASE, PubMed Central, Cochrane database of controlled trials, clinicaltrials.gov, and major recent international conferences. We identified four cohort studies and ten case reports. The JAK inhibitors used in these studies were tofacitinib, baricitinib, and ruxolitinib. A cohort study in TAK compared 27 patients treated with tofacitinib with 26 others treated with methotrexate, with better clinical outcomes with tofacitinib but similar angiographic stabilization, relapses, corticosteroid-sparing effect, and adverse events in both groups. Most of the other studies favored clinical responses with JAK inhibitors in LVV but with a paucity of data on other outcomes. Most of the included studies were of moderate quality. Evidence from pre-clinical models of LVV as well as limited in vivo data in patients with TAK appears to suggest that JAK inhibition reduces adventitial fibrosis, intimal proliferation, and inflammatory T lymphocyte infiltration in the media as well as reduces resident memory T cells in the vascular wall (which are otherwise resistant to corticosteroids). Ongoing clinical trials of tofacitinib, baricitinib, and upadacitinib in LVV shall help to further clarify the potential promise of JAK inhibitors for LVV (PROSPERO registration number CRD42021273359). KEY POINTS : •Tofacitinib appeared to associate with better clinical outcomes than methotrexate in TAK. •JAKinibs reduce adventitial fibrosis, intimal proliferation, and inflammatory vascular infiltrate in pre-clinical models of LVV. •Tofacitinib downregulates resident memory vascular T lymphocytes in pre-clinical models of LVV., (© 2021. International League of Associations for Rheumatology (ILAR).)

Background: Takayasu arteritis (TAK) is a large vessel vasculitis affecting relatively younger population. Since literature on bibliometric analysis of TAK is scarce, we analyzed top-cited articles in TAK to address this knowledge gap., Methods: We analyzed the top hundred cited articles in TAK on Web of Science and Scopus for time of publication, article type, country of origin, source journal, and authors. Furthermore, we conducted univariable- and multivariable-adjusted linear regression analyses to explore associations of rank of cited articles, mean number of annual citations, and total citations with traditional (journal impact factor, CiteScore) and alternative (PlumX) metrics., Results: Concordance between databases was 76%. Most top-cited articles were from the USA, Japan, or the UK, and published in Annals of the Rheumatic Diseases, Arthritis and Rheumatism, and Circulation and Rheumatology (Oxford). Original articles comprised a majority of these top-cited articles. Articles describing criteria or disease management recommendations received the highest mean number of citations. Performing multivariable-adjusted linear regression analyses, years of publication associated with mean annual citations on Web of Science as well as total citations across databases (p < 0.01). The 2-year JIF significantly associated with mean annual citations on Web of Science (p = 0.047). On Scopus, the number of captures denoted under PlumX metrics consistently associated with citations (p < 0.001)., Conclusion: Both traditional and alternative metrics associate with higher citations in TAK. Development of disease assessment and clinical practice guidelines and conduct and reporting of randomized controlled trials to guide TAK management are important research areas. The key points themselves are all right. Key Points • A majority of top-cited papers in TAK are original articles. • Both traditional and alternative metrics associate with number of citations for these papers. • Recommendations for disease assessment or clinical practice and clinical trials are important research agenda in TAK., (© 2021. International League of Associations for Rheumatology (ILAR).)

The pharmacotherapy of Takayasu arteritis (TAK) with disease-modifying anti-rheumatic drugs (DMARDs) is an evolving area. A systematic review of Scopus, Web of Science, Pubmed Central, clinical trial databases and recent international rheumatology conferences for interventional and observational studies reporting the effectiveness of DMARDs in TAK identified four randomized controlled trials (RCTs, with another longer-term follow-up of one RCT) and 63 observational studies. The identified trials had some concern or high risk of bias. Most observational studies were downgraded on the Newcastle-Ottawa scale due to lack of appropriate comparator groups. Studies used heterogenous outcomes of clinical responses, angiographic stabilization, normalization of inflammatory markers, reduction in vascular uptake on positron emission tomography, reduction in prednisolone doses and relapses. Tocilizumab showed benefit in a RCT compared to placebo in a secondary per-protocol analysis but not the primary intention-to-treat analysis. Abatacept failed to demonstrate benefit compared to placebo for preventing relapses in another RCT. Pooled data from uncontrolled observational studies demonstrated beneficial clinical responses and angiographic stabilization in nearly 80% patients treated with tumour necrosis factor alpha inhibitors, tocilizumab or leflunomide. Certainty of evidence for outcomes from RCTs ranged from moderate to very low and was low to very low for all observational studies. There is a paucity of high-quality evidence to guide the pharmacotherapy of TAK. Future observational studies should attempt to include appropriate comparator arms. Multicentric, adequately powered RCTs assessing both clinical and angiographic responses are necessary in TAK., (© 2021. International League of Associations for Rheumatology (ILAR).)

We evaluated clinical response, normalization of inflammatory markers, angiographic stabilization (primary outcomes), relapses and adverse events (secondary outcomes) in Takayasu arteritis (TAK) patients following corticosteroid monotherapy. MEDLINE, EMBASE, Web of Science, Scopus, Pubmed Central, Cochrane library, clinical trial databases and major international Rheumatology conferences were searched for studies reporting outcomes in TAK following corticosteroid monotherapy (without language/date restrictions). Risk ratios were calculated for controlled studies. Proportions were pooled for uncontrolled studies. Heterogeneity was assessed using I 2 statistic. Quality assessment of individual studies utilized the Newcastle-Ottawa scale. GRADE methodology ascertained certainty of individual outcomes across studies. Twenty-eight observational studies (1098 TAK) were identified. Twenty-three uncontrolled studies (580 TAK) were synthesized in meta-analysis. Clinical response was observed in 60% (95% CI 45-74%, 19 studies), normalization of inflammatory markers in 84% (95% CI 54-100%, 4 studies) and angiographic stabilization in 28% (95% CI 6-57%, 4 studies). Relapses occurred in 66% (95% CI 18-99%, 4 studies). Adverse events were reported in 51% (95% CI 2-99%, 4 studies). All pooled estimates had considerable heterogeneity, unexplained by subgroup analyses (time period, geographic location or number of patients). Two studies reported lesser restenosis following vascular surgery and fewer relapses when corticosteroids were combined with immunosuppressants compared with corticosteroid monotherapy. All outcomes had very low certainty. While corticosteroid monotherapy induces clinical response in most TAK patients, angiographic stabilization is observed in fewer than one-third. Most patients relapse following corticosteroid withdrawal. Preliminary evidence supports up-front addition of immunosuppressants to retard angiographic progression and reduce relapses (PROSPERO identifier CRD42021242910)., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Takayasu's arteritis (TA) affects young women in the childbearing age group. We studied obstetric outcomes in these patients before and after disease onset., Methods: Women aged more than 18 years with Takayasu's arteritis (ACR 1990 criteria) were included. Demographic data, clinical features, disease activity using Indian Takayasu Arteritis clinical score (ITAS), Disease Extent Index for TA (DEI.TaK) and damage assessment using TA Damage score (TA), history of conception and maternal and fetal outcomes were recorded from hospital records and telephonic interview. Results are in median and IQR., Results: Of the 64 women interviewed, aged 29 (24-38) years and disease duration 5 (4-10) years, 74 and 38 pregnancies had occurred before and after disease diagnosis in 29 and 20 women respectively. In eight, the diagnosis was made during pregnancy. Age at disease onset was 22 (18-30) years. Type 5 disease was the most common (n = 32, 59.3%), and an equal number of patients had Ishikawa's class I and II disease (n = 26, 40.6%). Median ITAS (n = 44) was 13 (7-16), DEI.Tak 12.5 (9-16.75) and TADS 8 (6.5-10). Twenty-five patients wanted to get pregnant, of which 8 (32%) did not do so because of their disease. Fifteen were unmarried of whom 6 did not marry due to disease. Obstetric outcomes were poorer in pregnancies that occurred after the onset of disease as compared with those before it (RR = 1.5, p = 0.01). Pregnancies after the onset of TA carried a very high risk of maternal [RR3.9 (1.8-8.5), P < 0.001] as well as fetal complications [RR = 2.0 (1.2-3.4), p = 0.001]. Hypertension was the most common maternal complication and occurred most often in the last trimester. The baby weight at birth was lower in pregnancies after disease (2.3 vs. 3.0, p = 0.01). Wong's score greater than or equal to 4 predicted lower birth weight (p = 0.04). ITAS, ITAS-A, DEI. Tak and TADS could not predict obstetric outcomes, and ITAS score exhibited moderate correlation with DEI. Tak (r = 0.78) and TADS (r = 0.58)., Conclusion: Women with TA suffer from extremely high risk of poor maternal and foetal outcomes. Wong's scoring can be useful to predict birth weight.

Quantitative assessment of disease activity is important for effective care of patients with Takayasu arteritis (TA). Activated glutaminolysis and reduced glycolytic flux is the hallmark of active inflammation. Based on this, we hypothesize that the circulatory Glutamine/Glucose ratio (QGR) can serve as an indicant of active inflammation in TA. To probe this hypothesis, the serum samples were collected from 45 active and 53 inactive TA patients fulfilling American College of Rheumatology (ACR) criteria and assessed for disease activity according to Indian Takayasu Clinical Activity Score (ITAS) using acute phase reactant-erythrocyte sedimentation rate [ITAS-A (ESR)]. The quantitative profiles of circulatory metabolites implicated in glutaminolysis (Glutamine and Glutamate) and those which estimate glycolytic flux (i.e. glucose and lactate) were measured using high field (800 MHz) NMR spectroscopy. The recorded spectra were analyzed using CHENOMX NMR Suite and the estimated concentration profiles were compared and evaluated for their diagnostic potential using Metaboanalyst. Compared to inactive-TA patients, the sera of active-TA patients were characterized by significantly decreased serum levels of glutamine and lactate suggesting that these patients exhibit activated glutaminolysis and reduced glycolytic activity. This is further supported by significantly decreased QGR and lactate to glucose ratio (LGR) levels in active compared to inactive TA patients. The receiver operating characteristic (ROC) curve analysis revealed satisfactory accuracy, sensitivity and specificity for QGR [with area under ROC curve (AUROC) = 0.76 and 95% confidence interval (CI) = 0.66-0.84) compared to that for LGR (with AUROC = 0.67 and CI = 0.561-0.77). Therefore, we believe that the circulatory QGR has the potential to serve as surrogate marker for the assessment of disease activity in TA patients. However, the use of this ratio in clinical settings will require future studies on large patient cohorts and procedural optimization as well to improve accuracy., Competing Interests: Declaration of Competing Interest On behalf of all authors, the corresponding authors state that there is no conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Takayasu arteritis (TA) is a challenging large vessel vasculitis to treat. Distinguishing disease activity from vascular damage is difficult, often relying on clinician judgement aided by composite clinical disease activity indices with angiographic evidence of vessel wall thickening or vessel wall hypermetabolism demonstrable on positron emission tomography computerized tomography (PET CT). Glucocorticoids form the mainstay of remission induction. While other conventional disease modifying anti-rheumatic drugs (cDMARDs) or biologic DMARDs (bDMARDs) are commonly used, evidence supporting their usefulness is sparse and generally of low quality. The only two randomized controlled trials (RCT) of a DMARD in TA failed to show efficacy of abatacept in reducing relapses of TA, however, tocilizumab showed a trend towards reduction in time to relapses. Of the cDMARDs, methotrexate, azathioprine, mycophenolate mofetil (MMF), leflunomide and cyclophosphamide have shown clinical efficacy in case series, with some evidence that methotrexate, azathioprine and MMF might retard angiographic progression. Among bDMARDs, anti-tumor necrosis factor alpha agents and tocilizumab may be useful in patients refractory to cDMARDs with retardation of angiographic progression, based on evidence derived from mostly retrospective case series, whereas the role of rituximab and ustekinumab needs further elucidation. Revascularization, either surgical or endovascular, is the treatment of choice to relieve critical, symptomatic stenoses and are best undertaken during inactive disease. Emerging evidence suggests that patients with TA also have increased cardiovascular risk and this requires appropriate management. Large studies involving multiple centers are the need of the hour to appropriately evaluate utility of currently available immunosuppressive therapy in TA., (© 2019 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

We discuss recent and prospective research in small and large vessel vasculitis. Large cohorts of Takayasu arteritis (TA) have been recently published from across the world, clarifying our understanding of this uncommon disease. Novel open-ended approaches like large-scale genotyping, proteomics and metabolomics have helped gain novel insights into TA, giant cell arteritis (GCA) and anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). Recent advances in the imaging of TA and GCA offer promise for earlier diagnosis and better monitoring of response to therapy. Although two randomized controlled trials of abatacept and tocilizumab failed to meet their primary end-points, successful large-scale studies of abatacept and tocilizumab in GCA hold promise for better disease control. While cyclophosphamide has revolutionized the management of AAV, increasing use of rituximab as an alternative induction regimen, as well as use of novel approaches involving reduced or no corticosteroid use for AAV and alternative agents such as avacopan (a complement 5a receptor antagonist) hold promise for lesser toxic induction regimens in the future. Increasingly, the risk of cardiovascular events and comorbidities such as osteoporosis are being recognized as factors affecting long-term prospects of patients with vasculitis. There is a shift in emphasis to utilize patient-reported outcomes to more accurately gauge the impact of vasculitides and their treatment., (© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Despite many studies focused on involvement of T cell in pathogenesis of Takayasu arteritis (TaK), very few have explored the role of B cells. Hence, we sought evidence of B cell involvement in a large cohort of TaK by measuring serum levels of B cell survival factors activation factor (BAFF) and A proliferation inducing ligand (APRIL). Serum BAFF and APRIL levels were measured by ELISA in 50 patients and 48 healthy individuals, and further assessed for correlation with outcome measures, such as Indian Takayasu Clinical Activity Score-ESR (ITAS-ESR) and Takayasu arteritis Damage score (TADS). Forty women and ten men of median age 26 (11-52) and disease duration of 3 years (0.1-22) were studied. Type V disease was the most common subset (n = 31), while type I, II, III, and IV was seen in ten, four, three, and two patients respectively. Serum APRIL levels were raised in patients as compared to healthy controls [2087.5 pg/ml (1480.0-2279.0) vs. 1288.64 pg/ml, (844.2-1632.9) p = 0.01]. Median serum APRIL level was also raised in patients with active disease (n = 24) as compared to inactive disease (n = 26) 2098.79 pg/ml, (1930.75-2768.75) vs. 1802.5 pg/ml, (1066.75-2098); p = 0.03). Serum BAFF levels were not raised in patients with TaK when compared to healthy Individuals. Neither BAFF, nor APRIL levels correlated with disease activity (ITAS-ESR) or TADS. Elevated APRIL levels in active TaK suggest probable role of B cells in pathogenesis.

Takayasu arteritis (TA) is a large vessel vasculitis of unknown pathogenesis. Assessment of disease activity is a challenge, and there is an unmet need for relevant biomarker(s). In our previous study, NMR based serum metabolomics had revealed distinctive metabolic signatures in TA patients compared with age/sex matched healthy controls and systemic lupus erythematosus (SLE). In this study we investigate whether the metabolites correlate with disease activity. Patients with TA fulfilling American College of Rheumatology (ACR) criteria were enrolled, and disease activity was assessed using Indian Takayasu Clinical Activity Score using acute phase reactant-erythrocyte sedimentation rate [ITAS-A (ESR)]. Sera were analyzed using 800 MHz NMR spectrometer to identify metabolites [based on partial least squares discriminant analysis (PLS-DA) VIP (variable importance in projection) score > 1.0 and permutation test, p-value <0.01]. 45 active and 53 inactive TA patients with median age 27 [(IQR) 22-35 years] and 27 [(IQR) 23-37 years], female to male ratio 3.5:1 and 4.9:1, and median duration of illness 5 [(IQR) 2-9 years] and 3 [(IQR) 1-6 years], respectively, were enrolled. The key metabolites with highest discriminatory potential in active TA (ITAS-A ≥ 4) were glutamate and N-acetyl glycoprotein (NAG), both elevated, with area under the curve 0.775 and 0.769 ( p-value <0.001). On follow up assessment, metabolic spectra started to differ with change in disease activity. This large cohort of patients revealed metabolic profiles discriminating between clinically active and inactive TA patients. It suggests glutamate and NAG have strong potential as biomarkers for disease activity in TA and may serve as a guide to therapy. We are now working to further validate these results in longitudinal studies.

Takayasu's arteritis (TA) and Giant cell arteritis (GCA) comprise the large vessel vasculitides (LVV). Patients with LVV are treated with disease-modifying anti-rheumatic drugs (DMARDs), both conventional (cDMARDs) and biologic (bDMARDs). We undertook a scoping review to assess the effectiveness of cDMARDs in TA and GCA. We could identify 11 studies in TA and 18 studies in GCA. There were only 3 randomized controlled trials on methotrexate, one on hydroxychloroquine and two on cyclosporine in GCA, the others being case series (including all studies on TA). Most of these studies had small patient numbers (median 15 in TA and 27 in GCA). Outcome measures reported in different studies were heterogenous. Overall, methotrexate, leflunomide, azathioprine, mycophenolate mofetil and cyclophosphamide were effective in TA (low quality of evidence). Methotrexate (high quality of evidence), hydroxychloroquine and cyclosporine (moderate quality of evidence) appeared to be ineffective in GCA. Azathioprine (moderate quality of evidence), leflunomide, mycophenolate mofetil, cyclophosphamide and dapsone (low quality of evidence) were effective in GCA. There exists a paucity of high quality evidence to guide use of cDMARDs in TA and GCA. There is an unmet need to conduct large multi-centric randomized placebo-controlled trials to accurately assess the utility on cDMARDs in LVV., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Takayasu arteritis (TA) is a large vessel vasculitis involving the aorta and its major branches. Insidious inflammation usually results in gradual arterial narrowing; however, critical organ ischemia is rare. We describe a young male with TA who presented with acute mesenteric ischemia requiring intestinal resection, followed by critical limb ischemia. In our literature review, we identified intestinal gangrene as a rare manifestation of TA. However, intestinal ischemia as the first manifestation of TA has been scarcely reported in the literature. Also, ischemia of the intestine occurring together with critical limb ischemia is extremely unusual. Rheumatologists should be aware of TA as a rare cause of gastrointestinal vasculitis in young adults, which can be easily suspected by routinely examining all the peripheral pulses.

Takayasu's arteritis (TA) is a granulomatous large vessel vasculitis more commonly seen in India. The vascular inflammation in TA results in stenoses of affected vessels. Usually this is a slow process with good collateral circulation; only rarely does critical limb ischemia result. We present two patients of TA who presented with gangrene of extremities, and review eight prior such patients reported in the literature. With appropriate diagnosis and treatment with oral corticosteroids and low-dose aspirin, none of our patients had recurrence at a mean follow-up of 3.8 ± 2.8 years. Although rare, TA can present with gangrene and rheumatologists need to be aware of this unusual but limb-threatening manifestation of TA to institute appropriate therapy in a timely manner.

The aim of this was to assess clinical features and outcome in pediatric-onset Takayasu's arteritis (TA). Retrospective data analysis of patients diagnosed with TA over last 13 years with onset before 18 years of age was done. Their presenting features, activity (by NIH criteria, ITAS2010, ITAS-A), disease extent (by DEI.Tak) and angiographic findings were retrieved from clinic files. Treatment received and follow-up data on disease activity and damage by TA damage score (TADS) were also analyzed. Wherever repeated angiography data were available, the same was analyzed. Values are expressed as median with interquartile range in brackets. There were 29 patients (19 females) with median age at diagnosis of 14 (13-16) years and delay to diagnosis of 1 (0.4-2) year. Common presenting symptoms were pulse loss (23/29) and hypertension (22/29). Patients had extensive disease at presentation with median DEI.Tak of 12 (9.5-15); 23/29 had elevated acute-phase reactants, and 28/29 were active at presentation [median ITAS2010 13 (8-15.5), ITAS-A 14 (10-17)]. Numano's type V was the commonest angiographic type (22/29). At a median follow-up of 2.4 (1.5-5.1) years, 2/20 were active whereas all had sustained damage despite a majority (17/20) being on immunosuppression. The median TADS was 8 (6.3-9.8) with pulse loss, claudication and hypertension being the commonest damage item. Two needed renal artery stenting to control hypertension. Angiographic assessment at least 2 years apart demonstrated disease progression in 5 of 6 patients despite immunosuppression. Significant damage accrued on follow-up despite immunosuppression and control of disease activity. Hypertension remains the major long-term morbidity.

Takayasu arteritis (TA) is a debilitating, systemic disease that involves the aorta and large arteries in a chronic inflammatory process that leads to vessel stenosis. Initially, the disease remains clinically silent (or remains undetected) until the patients present with vascular occlusion. Therefore, new methods for appropriate and timely diagnosis of TA cases are needed to start proper therapy on time and also to monitor the patient's response to the given treatment. In this context, NMR-based serum metabolomic profiling has been explored in this proof-of-principle study for the first time to determine characteristic metabolites that could be potentially helpful for diagnosis and prognosis of TA. Serum metabolic profiling of TA patients (n = 29) and healthy controls (n = 30) was performed using 1D (1)H NMR spectroscopy, and possible biomarker metabolites were identified. Using projection to least-squares discriminant analysis, we could distinguish TA patients from healthy controls. Compared to healthy controls, TA patients had (a) increased serum levels of choline metabolites, LDL cholesterol, N-acetyl glycoproteins (NAGs), and glucose and (b) decreased serum levels of lactate, lipids, HDL cholesterol, and glucogenic amino acids. The results of this study are preliminary and need to be confirmed in a prospective study.

Darpan Radheshyam Thakare,1,2,&ast; Kritika Singh,1,&ast; Tooba Qamar,1 Deeksha Singh,1 Sandeep Balakrishnan,1 Upendra Rathore,1 Neeraj Jain,3 Manish Ora,4 Durga Prasanna Misra1 1Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, Uttar Pradesh, India; 2Department of Clinical Immunology and Rheumatology, King George Medical University (KGMU), Lucknow, Uttar Pradesh, India; 3Department of Radiodiagnosis, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, Uttar Pradesh, India; 4Department of Nuclear Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, Uttar Pradesh, India&ast;These authors contributed equally to this workCorrespondence: Durga Prasanna Misra, Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, 226014, Uttar Pradesh, India, Email durgapmisra@gmail.com; dpmisra@sgpgi.ac.inPurpose: Existing biomarkers including C-reactive protein (CRP) do not adequately distinguish active and inactive TAK. We compared serum p-glycoprotein (p-gp)/Multidrug Resistance Protein 1 (MDR1), monomeric CRP (mCRP), CRP, and mCRP:CRP ratio in Takayasu arteritis (TAK) and healthy controls and their relationship with disease activity.Patients and Methods: Serum p-gp mCRP (ELISA) and CRP (nephelometry) were compared between consecutive adults with TAK (> 18 years) enrolled from a prospective cohort (n = 92) and healthy controls (n = 29), and between active vs inactive TAK (n = 46 each). In a subset of active immunosuppressive-naïve TAK (n = 29), correlation was assessed between serum p-gp and p-gp expression on circulating T helper lymphocyte populations: overall (CD4+), Th17 (CD4+IL-17+), Th17.1 (CD4+IL-17+IFN-γ+) lymphocytes [normalized to Tregs (CD4+CD25+FoxP3+)]. Changes in serum p-gp, mCRP, CRP, and mCRP:CRP were compared before and after immunosuppression (n = 29). Data was represented using median (Q1-Q3). Receiver operating characteristics (ROC) curves were generated for TAK vs controls, and active vs inactive TAK with serum p-gp, mCRP, CRP, and mCRP:CRP. Multivariable-adjusted linear regression was used to predict active disease with serum p-gp, mCRP, CRP, or mCRP:CRP.Results: Serum p-gp (11.19 vs 8.05 ng/mL), mCRP (1.61 vs 1.25 μg/L), and CRP (5.40 vs 2.1 mg/L) were elevated in TAK vs controls (p < 0.05 for all). CRP was higher and mCRP:CRP ratio was lower in active vs inactive TAK (p < 0.001). ROC curves identified moderate prediction for active disease with CRP and inactive disease with serum p-gp (area under ROC curve 0.705 and 0.392, respectively). Multivariable-adjusted linear regression confirmed association of CRP with active disease (p = 0.009) and serum p-gp with inactive disease (p = 0.041). In treatment-naïve TAK, serum p-gp negatively correlated with p-gp+Th17.1 lymphocytes (Spearman’s rho=− 0.39, p = 0.046). CRP and serum p-gp were significantly lowered following immunosuppressive therapy in treatment-naïve TAK (p < 0.05).Conclusion: Serum p-gp and mCRP are elevated in TAK. Serum p-gp is associated with inactive disease.Keywords: Takayasu arteritis, MDR1 protein, C-reactive protein, large vessel vasculitis, aortoarteritis, disease activity