Comparative Benefits and Harms of Basal Insulin Analogues for Type 2 Diabetes: A Systematic Review and Network Meta-analysis.

Background: Basal insulin analogues aim for protracted glycemic control with minimal adverse effects. Purpose: To assess the comparative efficacy and safety of basal insulin analogues for adults with type 2 diabetes mellitus (T2DM). Data Sources: Several databases from inception to April 2018 without language restrictions, ClinicalTrials.gov to April 2018, references of reviews, and meeting abstract books. Study Selection: Randomized trials lasting at least 12 weeks that compared efficacy (change in hemoglobin A1c [HbA1c] level from baseline [primary outcome]; percentage of patients with HbA1c level <7% at end of study and change in body weight [secondary outcomes]) and safety (hypoglycemia) of basal insulin analogues. Data Extraction: Two authors independently extracted data and assessed risk of bias for each outcome. All authors evaluated overall confidence in the evidence. Data Synthesis: Thirty-nine trials (26 195 patients) assessed 10 basal insulin analogues. Low- to very-low-quality evidence indicated that thrice-weekly degludec (Deg-3TW) was inferior to most other regimens for reducing HbA1c level, with mean differences ranging from 0.21% (vs. degludec, 100 U/mL [Deg-100]) to 0.32% (vs. glargine, 300 U/mL [Glar-300]). High- to moderate-quality evidence suggested that detemir had a favorable weight profile versus all comparators, and Glar-300 was associated with less weight gain than glargine, 100 U/mL (Glar-100); Deg-100; degludec, 200 U/mL (Deg-200); Deg-3TW; and LY2963016. Low- and very-low-quality evidence suggested that Deg-100, Deg-200, and Glar-300 were associated with lower incidence of nocturnal hypoglycemia than detemir, Glar-100, LY2963016, and neutral protamine lispro (NPL). Incidence of severe hypoglycemia did not differ among regimens, except NPL, which was associated with increased risk versus Deg-100, detemir, Glar-100, and Glar-300. Limitations: Results are based mostly on indirect comparisons. Confidence in summary estimates is low or very low due to individual-study limitations, imprecision, or inconsistency. Conclusion: Low-quality evidence suggests that basal insulin analogues for T2DM do not substantially differ in their glucose-lowering effect. Low- and very-low-quality evidence suggests some regimens may be associated with lower risk for nocturnal hypoglycemia (Deg-100, Deg-200, and Glar-300) or less weight gain (detemir and Glar-300). Primary Funding Source: None. (PROSPERO: CRD42016037055).

Association between response rates and survival outcomes in patients with newly diagnosed multiple myeloma. A systematic review and meta-regression analysis.

OBJECTIVES: We performed a systematic review and meta-regression analysis of randomized control trials to investigate the association between response to initial treatment and survival outcomes in patients with newly diagnosed multiple myeloma (MM). METHODS: Response outcomes included complete response (CR) and the combined outcome of CR or very good partial response (VGPR), while survival outcomes were overall survival (OS) and progression-free survival (PFS). We used random-effect meta-regression models and conducted sensitivity analyses based on definition of CR and study quality. RESULTS: Seventy-two trials were included in the systematic review, 63 of which contributed data in meta-regression analyses. There was no association between OS and CR in patients without autologous stem cell transplant (ASCT) (regression coefficient: .02, 95% confidence interval [CI] -0.06, 0.10), in patients undergoing ASCT (-.11, 95% CI -0.44, 0.22) and in trials comparing ASCT with non-ASCT patients (.04, 95% CI -0.29, 0.38). Similarly, OS did not correlate with the combined metric of CR or VGPR, and no association was evident between response outcomes and PFS. Sensitivity analyses yielded similar results. CONCLUSIONS: This meta-regression analysis suggests that there is no association between conventional response outcomes and survival in patients with newly diagnosed MM.

Clinical trial eligibility of a real-world connective tissue disease cohort: Results from the LEAP cohort.

INTRODUCTION: Classification criteria aim to identify a homogenous population of patients for research. We aimed to quantify how well phase-III trials in connective tissue diseases (CTDs) represent a real-world cohort. METHODS: A comprehensive review of all major published phase-III trials in CTDs was performed (clinicaltrials.gov). Classification criteria utilised most commonly in clinical trials were applied to a multicentre unselected CTD cohort. RESULTS: There were 42 CTD trials identified, with no trials in mixed (MCTD) or undifferentiated CTD (UCTD). The majority of trials (N = 38, 90 %) required patients to meet classification criteria for their respective disease. Eight (19.0 %) excluded patients with overlapping CTDs and a further two (4.8 %) excluded specific overlapping features, such as pulmonary arterial hypertension. One study explicitly allowed overlap syndromes. Our real-world CTD cohort included 391 patients. Patients with UCTD or MCTD (91/391, 23.3 %) would be excluded from participation in clinical trials for not having an eligible diagnosis. Of patients with primary Sjögren's syndrome (pSS), SLE, systemic sclerosis (SSc) or idiopathic inflammatory myopathy (IIM), 211/300 (70.3 %) met the classification criteria for their respective diagnosis and 24/211 (11.4 %) met criteria for >1 CTD. In total, 187/391 (47.8 %) would be eligible for recruitment, based upon their physician diagnosis, and most stringent trial eligibility criteria. CONCLUSION: In an unselected, real-world CTD cohort, up to half of patients are ineligible for clinical trials due to not meeting classification criteria, overlapping features or a lack of trials within their primary disease. To address this inequality in access to novel therapies, clinical trial design should evolve eligibility criteria in CTDs.

Cardiovascular Disease and Cardiac Imaging in Inflammatory Arthritis.

Cardiovascular morbidity and mortality are more prevalent in inflammatory arthritis (IA) compared to the general population. Recognizing the importance of addressing this issue, the European League Against Rheumatism (EULAR) published guidelines on cardiovascular disease (CVD) risk management in IA in 2016, with plans to update going forward based on the latest emerging evidence. Herein we review the latest evidence on cardiovascular disease in IA, taking a focus on rheumatoid arthritis, psoriatic arthritis, and axial spondylarthritis, reflecting on the scale of the problem and imaging modalities to identify disease. Evidence demonstrates that both traditional CVD factors and inflammation contribute to the higher CVD burden. Whereas CVD has decreased with the newer anti-rheumatic treatments currently available, CVD continues to remain an important comorbidity in IA patients calling for prompt screening and management of CVD and related risk factors. Non-invasive cardiovascular imaging has been attracting much attention in view of the possibility of detecting cardiovascular lesions in IA accurately and promptly, even at the pre-clinical stage. We reflect on imaging modalities to screen for CVD in IA and on the important role of rheumatologists and cardiologists working closely together.

The role of whole-body MRI in musculoskeletal inflammation detection and treatment response evaluation in inflammatory arthritis across age: A systematic review.

OBJECTIVE: To evaluate the relation between whole-body MRI (WBMRI) outcomes and disease activity measures, including clinical examination, composite scores, and other imaging outcomes, and the ability of WBMRI to detect treatment response in patients with inflammatory arthritis (IA) across age. METHODS: Human studies published as full text or abstract in the PubMed and MEDLINE and Cochrane databases from inception to 11th April 2021 were systematically and independently searched by two reviewers. Studies including patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), spondyloarthritis (SpA), juvenile idiopathic arthritis (JIA) or unclassified inflammatory arthritis (UA) who underwent WBMRI and which reported on disease outcomes were included. RESULTS: Nineteen full-text studies were eligible for inclusion: 2 interventional, 7 retrospective and 10 prospective observational studies, comprising 540 participants (SpA 38.7%, RA 24.8%, JIA 17.8%, PsA 11.5%, healthy controls 5.9%, UA 1.3%). Abstracts of 6 conference papers were reported separately. Five studies in PsA and SpA and 4 in RA measured the frequency of WBMRI-detected and clinically-detected synovitis, and all found the former to be more frequent. Less enthesitis was detected by WBMRI than clinical examination in 5/8 studies. After biologic treatment, the WBMRI inflammation scores declined in 3 studies in SpA and 2 in RA, whilst in 3 studies the results were equivocal. CONCLUSION: The ability of WBMRI to assess disease activity and treatment response in IA was adequate overall. Further studies are needed to corroborate WBMRI findings with IA outcomes and investigate the clinical value of subclinical inflammation.

Adalimumab or etanercept as first line biologic therapy in enthesitis related arthritis (ERA) - a drug-survival single centre study spanning 10 years.

OBJECTIVES: To analyse and compare drug-survival of adalimumab and etanercept (and their biosimilars) in biologic-naïve patients with ERA (Enthesitis-Related Arthritis). METHODS: In this retrospective observational study, conventional statistics and machine-learning were applied to compare drug-survival (adalimumab, etanercept and their biosimilars initiated: 2009-2019) in ERA and identify determinants. The primary outcome was discontinuation of treatment due to primary- or secondary-failure and adverse drug-reactions. RESULTS: During the observation period, 99 of 188 patients with ERA on first-line TNF inhibitors (etanercept-n=108, adalimumab-n=80) discontinued their treatment (median survival-time 3.9years, 95%CI 2.6-4.9years). Adalimumab was associated with longer drug-survival compared to etanercept especially after an initial positive response, with the median time to treatment discontinuation 4.9years (95% CI 3.9-5.7) for adalimumab, compared to 2years (95%CI 1.4-4.0) for etanercept (HR of treatment-discontinuation-0.49, 95%CI 0.32--0.75, p=0.001). Adjusted by propensity-score, adalimumab-methotrexate combination was associated with longer drug survival, compared to adalimumab-monotherapy (HR-0.41, 95%CI 0.20-0.85), etanercept-monotherapy (HR-0.28, 95%CI 0.15-0.53), and etanercept-methotrexate combination (HR-0.39, 95%CI 0.21-0.73). The presence of HLA-B27 was associated with longer drug-survival (HR-0.50, 95%CI 0.29-0.87) following an initial positive response. Higher-CRP at baseline was associated with higher rate of primary-failure (HR-1.68, 95%CI 1.08-2.62). Axial-ERA (sacroiliitis±spinal-involvement) was associated with poorer drug-survival for both primary- and secondary-failure (overall HR-2.03, 95%CI 1.22-3.40). Adjusted by propensity-score, shorter drug-survival was observed in patients with baseline-CRP≥12.15 mg/L, but only in the context of axial-ERA, not in peripheral-ERA (no sacroiliitis/spinal-involvement) (HR-2.28, 95%CI 1.13--3.64). CONCLUSION: Following an initial positive primary response, continuing methotrexate with adalimumab was associated with the longest drug-survival compared to adalimumab-monotherapy or etanercept-based regimens. Axial-ERA was associated with a poorer drug-survival. A CRP >12.15 in patients with axial-ERA was associated with a higher rate of primary-failure. Further prospective studies are required to confirm these findings.

Cardiovascular Disease in the Systemic Vasculitides.

The vasculitides are a heterogeneous group of disorders, characterized by inflammatory cell infiltration and necrosis of blood vessels that cause vascular obstruction or aneurysm formation, affecting various organs such as lungs, kidneys, skin and joints. Cardiac involvement is commonly encountered in primary systemic vasculitis and it is associated with increased morbidity and mortality. Depending on the dominant pathophysiological mechanism, heart complications may manifest in different ways, including myocardial ischemia due to impaired micro- or macrovascular circulation, progressive heart failure following valvular heart disease and myocardial dysfunction, (sub) clinical myocarditis, pericarditis, pulmonary hypertension as well as arteritis of coronary vessels. Beyond cardioprotective regimens, aggressive immunosuppression reduces the inflammatory burden and modulates the progression of cardiovascular complications. Perioperative management of inflammation, when surgical treatment is indicated, improves surgical success rates and postoperative long-term prognosis. We aim to provide an overview of the pathogenetic, diagnostic and therapeutic principles of cardiovascular involvement disease in the various forms of systemic vasculitis.

Switching patients with inflammatory arthritis from Etanercept (Enbrel®) to the biosimilar drug, SB4 (Benepali®): A single-centre retrospective observational study in the UK and a review of the literature.

OBJECTIVE/AIM: SB4 (Benepali®), the Etanercept biosimilar, is licenced in the UK for the same indications as the reference product, Enbrel®. In 2016, the Rheumatology Department at Blackpool Teaching Hospitals switched the Etanercept patients, who gave consent, to SB4. A proportion of these patients switched back to Etanercept and therefore we aimed to investigate the reasons of SB4 withdrawal and compare our results with the current evidence. METHODS: We included all the patients switched to SB4 until April 2018, identified from the departmental biologics database. We also searched the published and grey literature through November 2018 for similar articles. RESULTS: 72 Etanercept patients switched to SB4, of which 19 (26.4%) switched back to Etanercept within 6 months on the biosimilar product. All the 19 patients remained on Etanercept until the time of data analysis. The main reason of withdrawal was loss of effect (LOE, 58%). In RA, the duration on Etanercept was associated with SB4 withdrawal (OR 1.43 [95% CI 1.02, 2.00]) and LOE was reflected in the DAS- 28, PGS and CRP increase and in the number of tender joints (all p <0.05). We found ten observational studies reporting 3184 patients, who switched from Etanercept to SB4 and 432 of them (14%) stopped SB4. CONCLUSION: The majority (73.6%) stayed on SB4, which is consistent with the current evidence. Taking also into consideration the results of the other studies, it is unclear if this withdrawal is a true failure on SB4, nocebo effect or spontaneous disease flare.