Search

Objective: Despite the strong association between gout and pre-diabetes, the role of metformin in gout among individuals with pre-diabetes remains uncertain. We compared the incidence rates of gout in adults with pre-diabetes starting metformin with those not using antidiabetic treatments., Methods: We conducted a new-user, propensity score-matched cohort study using electronic health records from an academic health system (2007-2022). Pre-diabetes was defined based on haemoglobin A1c levels. Metformin users were identified and followed from the first metformin prescription date. Non-users of antidiabetic medications were matched to metformin users based on propensity score and the start of follow-up. The primary outcome was incident gout. Cox proportional hazards models estimated the HR for metformin. Linear regression analyses assessed the association between metformin use and changes in serum urate (SU) or C-reactive protein (CRP)., Results: We identified 25 064 individuals with pre-diabetes and propensity score-matched 1154 metformin initiators to 13 877 non-users. Baseline characteristics were well balanced (all standardised mean differences <0.1). The median follow-up was 3.9 years. The incidence rate of gout per 1000 person-years was lower in metformin users 7.1 (95% CI 5.1 to 10) compared with non-users 9.5 (95% CI 8.8 to 10.2). Metformin initiation was associated with a reduced relative risk of gout (HR 0.68, 95% CI 0.48 to 0.96). No relationship was found between metformin and changes in SU or CRP., Conclusions: Metformin use was associated with a reduced risk of gout among adults with pre-diabetes, suggesting that metformin may be important in lowering gout risk in individuals with pre-diabetes., Competing Interests: Competing interests: Disclosure of interests: DHS receives salary support from unrelated research contracts to Brigham and Women’s Hospital from CorEvitas, Janssen and Novartis. AT receives salary support from unrelated research contracts to Brigham and Women’s Hospital from Eli Lilly. AT serves as a consultant in areas unrelated to this research to Novo Nordisk and Proteomics International. SKT reports consulting fees from Novartis. JM: None declared. SF: None declared. MLP: None declared. LMS: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Introduction: Chronic kidney disease (CKD) is a common comorbidity of rheumatoid arthritis (RA). The association of longitudinal RA disease activity with long-term kidney function has remained uncertain., Method: We analysed a multicentre prospective RA registry in the USA from 2001 to 2022. The exposure was updated time-averaged Clinical Disease Activity Index (TA-CDAI) categories from study enrolment. The primary outcome was a longitudinal estimated glomerular filtration rate (eGFR) change. Secondary outcomes included developments of CKD stage G3a (eGFR<60 mL/min/1.73 m 2 ) and stage G3b (eGFR<45 mL/min/1.73 m 2 ). Results were adjusted for relevant time-fixed and time-varying covariates., Results: 31 129 patients (median age: 58.0 years, female: 76.3%, median eGFR: 90.7 mL/min/1.73 m 2 ) contributed 234 973 visits and 146 778 person-years of follow-up. Multivariable mixed-effect linear model showed an average annual eGFR decline during follow-up in the TA-CDAI-remission group of -0.83 mL/min/1.73 m 2 and estimated additional annual declines (95% CI) of -0.09 (-0.15 to -0.03) in low, -0.17 (-0.23 to -0.10) in moderate and -0.18 (-0.27 to -0.08) mL/min/1.73 m 2 in high disease activity patients. Compared with TA-CDAI remission, adjusted HRs (95% CI) for CKD stage G3a during follow-up were 1.15 (1.01 to 1.30) in low, 1.22 (1.06 to 1.40) in moderate and 1.27 (1.05 to 1.52) in high disease activity; for CKD stage G3b, 1.22 (0.84 to 1.76) in low, 1.66 (1.12 to 2.45) in moderate and 1.93 (1.16 to 3.20) in high disease activity., Conclusions: Higher RA disease activity was associated with accelerated eGFR decline and increased risk of clinically relevant kidney dysfunction. Future intervention studies should attempt to replicate the association between RA disease activity and eGFR., Competing Interests: Competing interests: WCW reports having served as a scientific advisor or consultant to Actos, Akebia, Ardelyx, AstraZeneca, Bayer, Cadrenal, GlaxoSmithKline, Lilly, Merck, Natera, Pharmacosmos, Unicycive, Vera and Zydus. SKT reports consulting fees from Novartis. LH reports employment of CorEvitas, consultant to AbbVie, Bristol Myers Squibb, Pfizer, Roche and speakers bureau for Bristol Myers Squibb. DHS reports salary support through research contracts to his institution from CorEvitas, Janssen and Novartis., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objective: Recent large-scale randomised trials demonstrate that immunomodulators reduce cardiovascular (CV) events among the general population. However, it is uncertain whether these effects apply to rheumatoid arthritis (RA) and if certain treatment strategies in RA reduce CV risk to a greater extent., Methods: Patients with active RA despite use of methotrexate were randomly assigned to addition of a tumour necrosis factor (TNF) inhibitor (TNFi) or addition of sulfasalazine and hydroxychloroquine (triple therapy) for 24 weeks. Baseline and follow-up 18 F-fluorodeoxyglucose-positron emission tomography/CT scans were assessed for change in arterial inflammation, an index of CV risk, measured as an arterial target-to-background ratio (TBR) in the carotid arteries and aorta., Results: 115 patients completed the protocol. The two treatment groups were well balanced with a median age of 58 years, 71% women, 57% seropositive and a baseline disease activity score in 28 joints of 4.8 (IQR 4.0, 5.6). Baseline TBR was similar across the two groups. Significant TBR reductions were observed in both groups-ΔTNFi: -0.24 (SD=0.51), Δtriple therapy: -0.19 (SD=0.51)-without difference between groups (difference in Δs: -0.02, 95% CI -0.19 to 0.15, p=0.79). While disease activity was significantly reduced across both treatment groups, there was no association with change in TBR (β=0.04, 95% CI -0.03 to 0.10)., Conclusion: We found that addition of either a TNFi or triple therapy resulted in clinically important improvements in vascular inflammation. However, the addition of a TNFi did not reduce arterial inflammation more than triple therapy., Trial Registration Number: NCT02374021., Competing Interests: Competing interests: DHS receives research support through his institution from Abbvie, Amgen, CorEvitas and Moderna. He receives royalties from UpToDate on unrelated chapters. JTG has been a consultant for AbbVie, Pfizer, Eli Lilly and Company, Bristol Meyers Squibb, Gilead, Novartis in the last 3 years and received an unrestricted grant from Pfizer. Over the past 36 months, PMR received investigator-initiated research grant support from Novartis, Kowa, Amarin, Pfizer, Esperion, NHLBI, NCI and Operation Warp Speed; served as a consultant to Corvidia, Novartis, Flame, Agepha, Alynlam, IQVIA, R-Pharma, Horizon Therapeutics, Inflazome, AstraZeneca, Jannsen, Civi Biopharm, SOCAR, Novo Nordisk, Health Outlook, Omeicos, the Baim Institute, Boehringer-Ingelheim, Montai Health, Cardiol Therapeutics, the Peter Munk Institute (University of Toronto); and the Foundation Leducq (Paris, FR); and received non-monetary research support from the Pfizer Bristol Myers Squibb Alliance and from Quidel, Inc to conduct federally funded COVID-19 research. PMRo is also listed as a co-inventor on patents held by his institution, the Brigham and Women’s Hospital. None of these conflicts relate to the current manuscript. JMB has nothing to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Colchicine may have beneficial effects on cardiovascular (CV) disease, but there are sparse data on its CV effect among patients with gout. We examined the potential association between colchicine and CV risk and all-cause mortality in gout., Methods: The analyses used data from an electronic medical record (EMR) database linked with Medicare claims (2006-2011). To be eligible for the study cohort, subjects must have had a diagnosis of gout in the EMR and Medicare claims. New users of colchicine were identified and followed up from the first colchicine dispensing date. Non-users had no evidence of colchicine prescriptions during the study period and were matched to users on the start of follow-up, age and gender. Both groups were followed for the primary outcome, a composite of myocardial infarction, stroke or transient ischaemic attack. We calculated HRs in Cox regression, adjusting for potential confounders., Results: We matched 501 users with an equal number of non-users with a median follow-up of 16.5 months. During follow-up, 28 primary CV events were observed among users and 82 among non-users. Incidence rates per 1000 person-years were 35.6 for users and 81.8 for non-users. After full adjustment, colchicine use was associated with a 49% lower risk (HR 0.51, 95% CI 0.30 to 0.88) in the primary CV outcome as well as a 73% reduction in all-cause mortality (HR 0.55, 95% CI 0.35 to 0.85, p=0.007)., Conclusions: Colchicine use was associated with a reduced risk of a CV event among patients with gout., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: Atrial fibrillation (AF) is the most common arrhythmia associated with cardiovascular disease and mortality. Recent studies suggest an association between inflammation, hyperuricaemia and AF, but little is known whether gout is associated with AF risk., Methods: Using data from a US commercial insurance plan (2004-2013), we conducted a cohort study to evaluate the risk of incident AF in patients with gout versus osteoarthritis. Patients with gout or osteoarthritis were identified with ≥2 diagnoses and ≥1 dispensing for gout or osteoarthritis medications. Incident AF was defined as a new AF diagnosis and a new dispensing for anticoagulants or antiarrhythmics. The risk of incident AF in gout was also compared with the non-gout group., Results: We identified 70 015 patients with gout and 210 045 with osteoarthritis, matched on age, sex and index date. The mean age was 57 years, and 81% were men. Over the mean 2-year follow-up, the incidence rate of AF per 1000 person-years was 7.19 in gout and 5.87 in osteoarthritis. The age, sex and index date-matched HR of AF was 1.23 (95% CI 1.14 to 1.32) in gout versus osteoarthritis. In a multivariable Cox regression, adjusting for age, sex, comorbidities, medications and healthcare usage, the HR of AF in gout was 1.13 (95% CI 1.04 to 1.23). When compared with non-gout, the multivariable HR of AF in gout was also increased (HR 1.21, 95% CI 1.11 to 1.33)., Conclusions: In this large population-based cohort study, gout was associated with a modestly increased risk of incident AF compared with osteoarthritis and non-gout after adjusting for other risk factors., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: Dipeptidyl peptidase-4 (DPP4), also known as CD26, is a transmembrane glycoprotein that has a costimulatory function in the immune response. DPP4 inhibitors (DPP4i) are oral glucose-lowering drugs for type 2 diabetes mellitus (T2DM). This study evaluated the risk of incident rheumatoid arthritis (RA) and other autoimmune diseases (AD) such as systemic lupus erythematosus, psoriasis, multiple sclerosis and inflammatory bowel disease, associated with DPP4i in patients with T2DM., Methods: Using US insurance claims data (2005-2012), we conducted a population-based cohort study that included initiators of combination therapy with DPP4i (DPP4i plus metformin) and non-DPP4i (non-DPP4i plus metformin). RA and other AD were identified with ≥2 diagnoses and ≥1 dispensing for AD-specific immunomodulating drugs or steroids. Composite AD includes RA or other AD. Propensity score (PS)-stratified Cox proportional hazards models compared the risk of AD in DPP4i initiators versus non-DPP4i, controlling for potential confounders., Results: After asymmetric trimming on the PS, 73 928 patients with T2DM starting DPP4i combination therapy and 163 062 starting non-DPP4i combination therapy were selected. Risks of incident RA and composite AD were lower in the DPP4i group versus non-DPP4i with the PS-stratified HR of 0.66 (95% CI 0.44 to 0.99) for RA, 0.73 (0.51 to 1.03) for other AD and 0.68 (95% CI 0.52 to 0.89) for composite AD., Conclusions: In this large cohort of diabetic patients, those initiating DPP4i combination therapy appear to have a decreased risk of incident AD including RA compared with those initiating non-DPP4i combination therapy. These results may suggest possible pharmacological pathways for prevention or treatment of AD., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Previous studies have suggested a potential risk of cervical cancer in patients with systemic inflammatory diseases (SID) such as inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE)., Objectives: To assess the risk of high-grade cervical dysplasia, a surrogate endpoint for cervical cancer and cervical cancer, in women with SID, including IBD, psoriasis, rheumatoid arthritis (RA) or SLE, compared with the risk in women without SID., Methods: Using US insurance data (2001-2012), we conducted a cohort study of 133,333 women with SID, based on two or more diagnoses and one or more dispensed prescription for disease-specific treatment, and 533,332 women without SID. High-grade cervical dysplasia and cervical cancer was defined by a validated algorithm with a positive predictive value of ≥81%., Results: Over the mean follow-up of 2.1 years, the crude incidence rate of high-grade cervical dysplasia and cervical cancer per 100,000 person-years was the highest at 141.1 in SLE and the lowest at 82.2 in psoriasis among women with SID, and 73.4 in women without SID. The multivariable HR adjusted for potential confounders was 1.07 (95% CI 0.79 to 1.45) in IBD, 0.96 (95% CI 0.73 to 1.27) in psoriasis, 1.49 (95% CI 1.11 to 2.00) in RA and 1.53 (95% CI 1.07 to 2.19) in SLE. Multivariable HRs were increased, but not statistically significant, in IBD, RA and SLE with baseline use of systemic immunosuppressive drugs or steroids., Conclusions: The risk of high-grade cervical dysplasia and cervical cancer was 1.5 times higher in women with RA and SLE than in those without SID. The risk may be increased in IBD with use of systemic immunosuppressive drugs or steroids., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: There is increasing interest in discontinuing biological therapies for patients with rheumatoid arthritis (RA) achieving good clinical responses, provided patients maintain clinical benefit., Methods: We assessed patients with RA from the Corrona registry who discontinued treatment with their first tumour necrosis factor inhibitor (TNFi) while in low-disease activity (LDA) or lower levels of disease activity. Patients were followed until they lost clinical benefit, defined as increased disease activity or change in RA medications. Duration of maintenance of clinical benefit was estimated using the Kaplan-Meier method. Cox proportional hazard models were assessed to identify factors related to maintenance of benefit., Results: We identified 717 eligible patients with RA from 35,656 in the Corrona registry. At discontinuation, patients had a median RA duration of 8 years, mean clinical disease activity score of 4.3±0.11; 41.8% were using TNFi as monotherapy. 73.4% of patients maintained benefit for >12 months after discontinuing therapy and 42.2% did so through 24 months. Factors predictive of maintaining clinical benefit in multivariate analysis included lower disease activity, less pain and better functional status at the time of TNFi discontinuation. Among 301 patients initiating their first TNFi within the registry, faster responders (ie, those who achieved LDA in 4 months or less) did better than slower responders (HR 1.54 (95% CI 1.17 to 2.04)). RA disease duration did not affect maintenance of clinical benefit., Conclusions: Discontinuation of a first course of TNFi may be associated with persistent clinical benefit. Half of patients maintained response through 20 months. Several patient characteristics may help predict persistent benefit., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: We compared the effectiveness of abatacept (ABA) versus a subsequent anti-tumour necrosis factor inhibitor (anti-TNF) in rheumatoid arthritis (RA) patients with prior anti-TNF use., Methods: We identified RA patients from a large observational US cohort (2/1/2000-8/7/2011) who had discontinued at least one anti-TNF and initiated either ABA or a subsequent anti-TNF. Using propensity score (PS) matching (n:1 match), effectiveness was measured at 6 and 12 months after initiation based on mean change in Clinical Disease Activity Index (CDAI), modified American College of Rheumatology (mACR) 20, 50 and 70 responses, modified Health Assessment Questionnaire (mHAQ) and CDAI remission in adjusted regression models., Results: The PS-matched groups included 431 ABA and 746 anti-TNF users at 6 months and 311 ABA and 493 anti-TNF users at 12 months. In adjusted analyses comparing response following treatment with ABA and anti-TNF, the difference in weighted mean change in CDAI (range 6-8) at 6 months (0.46, 95% CI -0.82 to 1.73) and 12 months was similar (-1.64, 95% CI -3.47 to 0.19). The mACR20 responses were similar at 6 (28-32%, p=0.73) and 12 months (35-37%, p=0.48) as were the mACR50 and mACR70 (12 months: 20-22%, p=0.25 and 10-12%, p=0.49, respectively). Meaningful change in mHAQ was similar at 6 and 12 months (30-33%, p=0.41 and 29-30%, p=0.39, respectively) as was CDAI remission rates (9-10%, p=0.42 and 12-13%, p=0.91, respectively)., Conclusions: RA patients with prior anti-TNF exposures had similar outcomes if they switched to a new anti-TNF as compared with initiation of ABA., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objectives: To determine among patients with autoimmune diseases in the USA whether the risk of non-viral opportunistic infections (OI) was increased among new users of tumour necrosis factor α inhibitors (TNFI), when compared to users of non-biological agents used for active disease., Methods: We identified new users of TNFI among cohorts of rheumatoid arthritis (RA), inflammatory bowel disease and psoriasis-psoriatic arthritis-ankylosing spondylitis patients during 1998-2007 using combined data from Kaiser Permanente Northern California, two pharmaceutical assistance programmes for the elderly, Tennessee Medicaid and US Medicaid/Medicare programmes. We compared incidence of non-viral OI among new TNFI users and patients initiating non-biological disease-modifying antirheumatic drugs (DMARD) overall and within each disease cohort. Cox regression models were used to compare propensity-score and steroid- adjusted OI incidence between new TNFI and non-biological DMARD users., Results: Within a cohort of 33 324 new TNFI users we identified 80 non-viral OI, the most common of which was pneumocystosis (n=16). In the combined cohort, crude rates of non-viral OI among new users of TNFI compared to those initiating non-biological DMARD was 2.7 versus 1.7 per 1000-person-years (aHR 1.6, 95% CI 1.0 to 2.6). Baseline corticosteroid use was associated with non-viral OI (aHR 2.5, 95% CI 1.5 to 4.0). In the RA cohort, rates of non-viral OI among new users of infliximab were higher when compared to patients newly starting non-biological DMARD (aHR 2.6, 95% CI 1.2 to 5.6) or new etanercept users (aHR 2.9, 95% CI 1.5 to 5.4)., Conclusions: In the USA, the rate of non-viral OI was higher among new users of TNFI with autoimmune diseases compared to non-biological DMARD users., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Prior research suggests an important role of systemic inflammation in pathogenesis of atrial fibrillation (AF). It is well known that rheumatoid arthritis (RA), a chronic, systemic inflammatory disorder, increases the risk of cardiovascular disease (CVD), but little evidence exists whether the risk of AF is increased in RA., Methods: Using data from a large US commercial insurance plan, we examined the incidence rate (IR) of hospitalisation for AF in patients with RA compared with non-RA. RA patients were identified with ≥2 separate visits coded for RA and ≥1 disease-modifying antirheumatic drug dispensing. The IR of AF in RA patients was also compared with those with osteoarthritis, a chronic non-inflammatory condition., Results: There were 20 852 RA and 104 260 non-RA patients, matched on age, sex and index date. The mean follow-up was 2 years. The IR per 1000 person-years of AF was 4.0 (95% CI 3.4 to 4.7) in RA and 2.8 (95% CI 2.6 to 3.0) in non-RA patients. The IR ratio for AF was 1.4 (95% CI 1.2 to 1.7) in RA compared with non-RA patients. In a multivariable Cox model adjusting for a number of risk factors such as diabetes, CVD, medications and healthcare utilisation, the risk of AF was no longer increased in RA (HR 1.1, 95% CI 0.9 to 1.4) compared with non-RA patients. There was also no difference in the AF risk between RA and osteoarthritis patients., Conclusions: Our results show no increased risk of AF associated with RA, after adjusting for various comorbidities, medications and healthcare use.

Objectives: We conducted a systematic review to assess the design and 'failure definition' in studies of biologic discontinuation in rheumatoid arthritis (RA)., Methods: We found 403 studies on PubMed, and included nine published papers and five abstracts from scientific meetings. We used a structured extraction form to collect information regarding study design and outcome (failure) definition., Results: Three types of studies were found: randomised controlled trials, long-term extension studies of clinical trials and prospective discontinuation studies. The largest study had 196 subjects in the discontinuation arm. Most studies allowed concomitant use of non-biologic drugs at biologic discontinuation. Heterogeneity was also found in the failure definition. Although all studies used measures of disease activity, the threshold for failure and the time point of assessment differed among studies. Few studies incorporated changing use of non-biologic drugs or glucocorticoids into the failure definition., Conclusions: Although many studies have examined the outcome of biologic discontinuation, they have all been relatively small. Typical practice studies from registries may add important information but will likely need to rely on a broader failure definition.

Background: While heart failure (HF) is associated with elevations in tumor necrosis factor (TNF)α, several trials of TNF antagonists showed no benefit and possibly worsening of disease in those with known severe HF. We studied the risk of new or recurrent HF among a group of patients receiving these agents to treat rheumatoid arthritis (RA)., Methods: We used data from four different US healthcare programmes. Subjects with RA receiving methotrexate were eligible to enter the study cohort if they added or switched to a TNF antagonist or another non-biological disease modifying antirheumatic drug (nbDMARD). These groups were compared in Cox regression models stratified by propensity score decile and adjusted for oral glucocorticoid dosage, prior HF hospitalisations, and the use of loop diuretics., Results: We compared 8656 new users of a nbDMARD with 11 587 new users of a TNF antagonist with similar baseline covariates. The HR for the TNF antagonists compared with nbDMARD was 0.85 (95% CI 0.63 to 1.14). The HR was also not elevated in subjects with a history of HF. But, it was elevated prior to 2002 (HR 2.17, 95% CI 0.45 to 10.50, test for interaction p=0.036). Oral glucocorticoids were associated with a dose-related gradient of HF risk: compared with no use, 1≤5 mg HR 1.30 (95% CI 0.91 to 1.85), ≥5 mg HR 1.54 (95% CI 1.09 to 2.19)., Conclusions: TNF antagonists were not associated with a risk of HF hospital admissions compared with nbDMARDs in this RA population.

Objectives: Secondary fibromyalgia (FM) is common among patients with inflammatory arthritis, but little is known about its incidence and the factors leading to its development. The authors examined the incidence of secondary FM in an early inflammatory arthritis cohort, and assessed the association between pain, inflammation, psychosocial variables and the clinical diagnosis of FM., Methods: Data from 1487 patients in the Canadian Early Arthritis Cohort, a prospective, observational Canadian cohort of early inflammatory arthritis patients were analysed. Diagnoses of FM were determined by rheumatologists. Incidence rates were calculated, and Cox regression models were used to determine HRs for FM risk., Results: The cumulative incidence rate was 6.77 (95% CI 5.19 to 8.64) per 100 person-years during the first 12 months after inflammatory arthritis diagnosis, and decreased to 3.58 (95% CI 1.86 to 6.17) per 100 person-years 12-24 months after arthritis diagnosis. Pain severity (HR 2.01, 95% CI 1.17 to 3.46) and poor mental health (HR 1.99, 95% CI 1.09 to 3.62) predicted FM risk. Citrullinated peptide positivity (HR 0.48, 95% CI 0.26 to 0.88) was associated with decreased FM risk. Serum inflammatory markers and swollen joint count were not significantly associated with FM risk., Conclusions: The incidence of FM was from 3.58 to 6.77 cases per 100 person-years, and was highest during the first 12 months after diagnosis of inflammatory arthritis. Although inflammation was not associated with the clinical diagnosis of FM, pain severity and poor mental health were associated with the clinical diagnosis of FM. Seropositivity was inversely associated with the clinical diagnosis of FM.