Corticosteroid monotherapy for the management of Takayasu arteritis-a systematic review and meta-analysis.

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 I2 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).

Evaluation of Metabolic Parameters on Use of Newer Antiepileptics Versus Conventional Antiepileptics in Patients of Generalised Tonic-Clonic Seizure: An Observational Study.

Background and objective Epilepsy is the commonest serious neurological condition and around 50 million people live with epilepsy (PWE). Primary and secondary generalised tonic-clonic seizures (GTCS) together constitute up to 50% of adult and adolescent epilepsy. GTCS respond well to broad-spectrum AEDs like valproate, phenytoin, levetiracetam, lamotrigine, and topiramate. Carbamazepine and oxcarbazepine are considered alternatives. Metabolic derangements with the conventional AEDs (phenytoin causes loss of bone mass in women, phenytoin and carbamazepine produce increases in serum lipid and C-reactive protein, weight gain with valproate) are well documented. But, there is limited data regarding the effect of the newer AEDs on metabolic parameters. Thus, this study was undertaken to assess the effects of the newer AEDs on the metabolic profile of patients with epilepsy. Material and methods A prospective observational study was conducted in the Department of Pharmacology, in collaboration with the Department of Neurology at S.C.B. Medical College and Hospital, Cuttack. 100 diagnosed patients with GTCS receiving monotherapy of either conventional or newer anti-epileptics were included in the study. Their metabolic parameters like total cholesterol, serum sodium, serum TSH and fasting blood glucose were collected at baseline, three months, and six months. ADRs were collected during the entire study period and causality assessment was done using WHO-UMC Causality Assessment Scale. All the data were analysed using SPSS 20.0 after applying appropriate statistical tests. Results There was a significant increase in total cholesterol in all four groups (p=0.002) but a pathological increase in the phenytoin and oxcarbazepine groups. There was a significant rise in the serum TSH levels in all groups except levetiracetam, but a pathological increase was seen with phenytoin and valproate, i.e., the conventional ones. Statistically significant hyponatremia was seen with valproate and oxcarbazepine. A rise in the FBS was seen with both phenytoin and valproate (p=0.002) but a pathological rise was seen with phenytoin. Out of the total reported ADRs, 53.5% were seen with conventional AEDs, and the rest 46.5% were seen with newer ones. Conclusion The advent of newer anti-epileptic drugs has unfolded wider horizons to the treatment of epilepsy. Each of these drugs has a unique mechanism of action, making it less prone to resistance. Metabolic derangements are a key determinant in the compliance of these drugs as they can predispose to other co-morbidities. Periodic monitoring of the various metabolic parameters is useful and together with patient counselling can improve the effectiveness of the anti-epileptic drugs.

The effectiveness of tocilizumab and its comparison with tumor necrosis factor alpha inhibitors for Takayasu Arteritis: A systematic review and meta-analysis.

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.

A systematic review of clinical and preclinical evidences for Janus kinase inhibitors in large vessel vasculitis.

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.

Presentation and clinical course of pediatric-onset versus adult-onset Takayasu arteritis-a systematic review and meta-analysis.

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.

Patient-Reported Outcome Measures in Takayasu Arteritis: A Systematic Review and Meta-Analysis.

INTRODUCTION: We conducted a systematic review of patient-reported outcome measures (PROMs) regarding quality of life, disability, mood abnormalities (anxiety, depression), fatigue, illness perceptions and fibromyalgia in Takayasu arteritis (TAK). Wherever available, comparisons with healthy controls, disease controls or longitudinal changes in PROMs were noted. METHODS: MEDLINE, EMBASE, Scopus, Web of Science and Pubmed Central databases, major recent international rheumatology conference abstracts, clinical trial databases and the Cochrane library were searched for relevant articles. Wherever possible, outcome measures across studies were pooled using the restricted maximum likelihood model. Inter-group differences were pooled and compared using standardized mean differences (SMD) with 95% confidence intervals (95% CI). Heterogeneity was assessed using the I2 statistic. Quality of randomized controlled trials was assessed using the Cochrane risk of bias tool. For cross-sectional and cohort studies, the Joana Briggs Institute checklist and Newcastle-Ottawa scale were used, respectively. GRADE methodology was used to determine the certainty of evidence for outcomes. RESULTS: Twenty-one studies (all but one observational) involving 1311 patients with TAK and 308 healthy controls were identified. Ten studies (559 TAK patients, 182 healthy controls were synthesized in a meta-analysis. Patients with TAK had worse quality of life (pooled SMD - 6.66, 95% CI - 10.08 to - 3.23 for individual domains; - 0.64, 95% CI - 1.19 to - 0.09 for pooled physical and mental component scores of 36-item Short Form Survey), depression (SMD 0.26, 95% 0.05-0.47) and anxiety (SMD 0.34, 95% CI - 0.06 to 0.75) scores and higher disability (SMD 0.64, 95% CI 0.43-0.84) than healthy controls. Patients with active TAK had worse quality of life, depression and work impairment when compared with those with inactive disease. Included studies were of moderate to high quality. Certainty of evidence for individual outcomes was low to very low. CONCLUSION: Literature on PROMs in TAK, albeit sparse, appears to indicate worse scores in patients with TAK compared to healthy individuals. These results, however, require cautious interpretation. Development of a TAK-specific PROM is an important focus of the research agenda.

Disease-modifying anti-rheumatic drugs for the management of Takayasu arteritis-a systematic review and meta-analysis.

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.

Enthesitis-related arthritis: current perspectives.

In this narrative review, we overview the recent literature on enthesitis-related arthritis (ERA). For the purpose of our review, we searched Scopus for recent articles on this subject from 2013 onward, including some classic older articles for perspective. ERA is a juvenile idiopathic arthritis (JIA) subtype more common in males, associated in a majority with human leucocyte antigen B27. Such children generally present with asymmetric oligoarthritis or polyarthritis, predominantly of lower limb joints, associated with enthesitis or sacroiliitis. While diagnosis remains clinical, ultrasound is being increasingly used to detect subclinical enthesitis and for guiding entheseal site injections. Spine MRI can help detect sacroiliitis, inflammatory spinal changes, and pelvic sites of enthesitis in such patients. The recent juvenile spondyloarthropathy disease activity index recognizes the key clinical features of ERA, viz enthesitis and inflammatory back pain, which other disease activity indices used in JIA did not include. Management includes NSAIDs with physical therapy. Conventional disease-modifying agents like sulfasalazine and methotrexate may be used to minimize duration of NSAID use and in those with high inflammatory burden. In patients refractory to these drugs, biologics such as antitumor necrosis factor alpha agents have proven useful, based on evidences from randomized controlled trials and retrospective registry analyses. Factors predicting a poorer outcome in such children include hip or ankle involvement or restricted spinal mobility. Considering that children with ERA have overall poorer long-term outcomes than other subtypes of JIA, there is a need to further optimize therapeutic strategies for such patients.