The worldwide pandemic of 2019 novel coronavirus disease (COVID-19) has posed the most substantial and severe public health issue for several generations, and therapeutic options have not yet been optimised. Vitamin D (in its “parent” form, cholecalciferol) has been proposed in the pharmacological management of COVID-19 by various sources. We aimed to determine whether COVID-19 mortality was affected by serum 25-hydroxyvitamin D (25(OH)D) levels, vitamin D status, or cholecalciferol therapy, and to elucidate any other predictors of COVID-19 mortality. Patients hospitalised with COVID-19 were opportunistically recruited from three UK hospitals, and their data were collected retrospectively. Logistic regression was used to determine any relationships between COVID-19 mortality and potential predictors, including 25(OH)D levels and cholecalciferol booster therapy. A total of 986 participants with COVID-19 were studied, of whom 151 (16.0%) received cholecalciferol booster therapy. In the primary cohort of 444 patients, cholecalciferol booster therapy was associated with a reduced risk of COVID-19 mortality, following adjustment for potential confounders (OR_adj 0.13, 95% CI 0.05–0.35, p < 0.001). This finding was replicated in a validation cohort of 541 patients (OR_adj 0.38, 95% CI 0.17–0.84, p = 0.018). In this observational study, treatment with cholecalciferol booster therapy, regardless of baseline serum 25(OH)D levels, appears to be associated with a reduced risk of mortality in acute in-patients admitted with COVID-19. Further work with large population studies needs to be carried out to determine adequate serum 25(OH)D levels, as well as multi-dose clinical trials of cholecalciferol therapy to assess maximum efficacy.

Imaging of joint inflammation provides a standard against which to derive an updated DAS for RA. Our objectives were to develop and validate a DAS based on reweighting the DAS28 components to maximize association with US-assessed synovitis. Early RA patients from two observational cohorts (n = 434 and n = 117) and a clinical trial (n = 59) were assessed at intervals up to 104 weeks from baseline; all US scans were within 1 week of clinical exam. There were 899, 163 and 183 visits in each cohort. Associations of combined US grey scale and power Doppler scores (GSPD) with 28 tender joint count and 28 swollen joint count (SJC28), CRP, ESR and general health visual analogue scale were examined in linear mixed model regressions. Cross-validation evaluated model predictive ability. Coefficients learned from training data defined a re-weighted DAS28 that was validated against radiographic progression in independent data (3037 observations; 717 patients). Of the conventional DAS28 components only SJC28 and CRP were associated with GSPD in all three development cohorts. A two-component model including SJC28 and CRP outperformed a four-component model (R² = 0.235, 0.392, 0.380 vs 0.232, 0.380, 0.375, respectively). The re-weighted two-component DAS28CRP outperformed conventional DAS28 definitions in predicting GSPD (Δtest log-likelihood <−2.6, P < 0.01), Larsen score and presence of erosions. A score based on SJC28 and CRP alone demonstrated stronger associations with synovitis and radiographic progression than the original DAS28 and should be considered in research on pathophysiological manifestations of early RA. Implications for clinical management of RA remain to be established.

Introduction: Methotrexate (MTX) is the first-line disease-modifying drug of choice in controlling active inflammation of the synovium that characterises rheumatoid arthritis, a chronic autoimmune inflammatory condition. However, many patients do not respond to treatment with MTX or cannot tolerate the medication. Pre-treatment characteristics that predict response to MTX are, therefore, of particular interest and potential clinical utility. Areas covered: This narrative review seeks to cover various genotypic and phenotypic characteristics that have been investigated as predictors of treatment response to MTX in RA. Ovid Medline searches (1946 to January 2018) were carried out for ‘methotrexate’ and ‘rheumatoid arthritis’, in combination with relevant terms. All papers identified were English language, with abstracts. Relevant references were also reviewed. Expert commentary: Despite the introduction of biologic medication and targeted therapies, MTX is likely to remain the mainstay of RA treatment, largely due to its much cheaper cost. Development of a multifactorial predictive algorithm for response to MTX may be of clinical utility, as well as routine MTX drug level testing to improve medication adherence and persistence.

Background: The 2019 novel coronavirus disease (Covid-19) worldwide pandemic has posed the most substantial and severe public health issue for several generations, and therapeutic options for it have not yet been optimised. Vitamin D has been proposed in the pharmacological management of Covid-19 by various sources. This study aimed to determine whether Covid-19 disease outcomes were affected by vitamin D status, and to elucidate any predictors of Covid-19 outcomes. Methods: Patients hospitalised with Covid-19 were opportunistically recruited from three different UK hospitals and their data were collected. Logistic regression was used to determine any relationships between vitamin D status and various predictors, including mortality and ventilation, and to determine any relationships between mortality, ventilation, and various predictors. Findings: Vitamin D status was not associated with any outcomes of Covid-19 investigated, following adjustment for age and sex. However, treatment with vitamin D was significantly associated with a reduced risk of death, following adjustment for age and sex (OR_adj 0·48, 95% CI 0·32 – 0·70, p = 1·79x10^-4). This relationship remained significant when also adjusted for baseline vitamin D levels (OR_adj 0·47, 95% CI 0·33 – 0·70, p = 1·27x10^-4). Interpretation: Treatment with vitamin D, regardless of baseline serum vitamin D levels, appears to be associated with a reduced risk of mortality in acute in-patients admitted with Covid-19. Further work on large population studies needs to be carried out to determine adequate serum levels of vitamin D, as well as multi-dose clinical trials of vitamin D treatment to assess maximum efficacy. Trial Registration: The study was also registered on Clinicaltrials.gov (reference number NCT04386044), prior to commencement. Funding: None. Declaration of Interests: The authors have no conflicts of interest. Ethics Approval Statement: Ethical approval was granted by the Health and Care Research Wales Research Ethics Committee (IRAS number 285337).

Objective: Rheumatoid arthritis (RA) susceptibility HLA–DRB1 haplotypes based on amino acid positions 11/13, 71, and 74 predict radiographic damage. The mechanism of action is unknown, but it may be mediated by inflammation. We undertook this study to systematically investigate the effect of these amino acids on nonradiographic measures of disease activity/outcomes.Methods: We tested the association of RA susceptibility HLA–DRB1 amino acids with the C‐reactive protein (CRP) level, the tender joint count (TJC), the swollen joint count (SJC), the Disease Activity Score in 28 joints (DAS28), and the Health Assessment Questionnaire (HAQ) score in the Norfolk Arthritis Register (NOAR) and Early Rheumatoid Arthritis Study (ERAS) cohorts. Longitudinal modeling of disease activity/outcomes was performed using generalized linear latent and mixed models. Mediation analysis was performed using directed acyclic graphs to investigate the paths from genetic factors to outcome.Results: A total of 2,158 patients were available for analysis in the NOAR cohort. Valine at position 11 showed the strongest association with the CRP level (P = 2.21 × 10⁻⁶), the SJC (P = 7.51 × 10⁻⁶), and the DAS28 (P = 0.002); it was marginally associated with the HAQ score (P = 0.044) but not with the TJC. The same amino acid and haplotype risk hierarchy observed for susceptibility and radiographic severity was observed for the CRP level and nonradiographic measures of disease activity/outcome, apart from the TJC. The results were replicated in the ERAS cohort. The effect of valine at position 11 on the SJC was mainly mediated by anti–citrullinated protein antibody status, the effect of which was mainly mediated by inflammation; however, the effect of valine at position 11 was also independent of the CRP level (P = 1.6 × 10⁻⁴).Conclusion: Genetic markers of RA susceptibility located within HLA–DRB1 determine the levels of clinical and systemic inflammation independently, and also determine all objective measures of disease activity and outcome.