Higher Vitamin D Levels Pre-Methotrexate Linked to Lower Mortality in RA

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After adjusting for risk factors, patients in the > 50 nmol/L pre-methotrexate initiation group exhibited a 28% reduced risk of mortality when compared with those in the ≤ 50 nmol/L group

A national cohort of patients with rheumatoid arthritis (RA) revealed higher vitamin D levels (> 50 nmol/L) prior to methotrexate initiation exhibited lower subsequent mortality, according to a study published in Nutrients.1

Previous research has indicated Vitamin D can help to regulate immune function patients with autoimmune disease, including RA, is associated with the 28-joint Disease Activity Score (DAS28) and Health Assessment Questionnaire Disability Index (HAQ-DI) in patients with early RA, and with serum C-reactive protein (CRP) levels in both patients and the general population.2,3

“From a patient perspective, there is increasing interest in ‘natural’ or adjunct treatment options for autoimmune disease including RA,” wrote investigator Shahdi K Malakooti, MD, assistant professor at Case Western Reserve University School of Medicine, and colleagues. “However, clinicians face a paucity of clinical guidelines regarding target Vitamin D levels in immune health.”

In the retrospective study, investigators evaluated the link between 25-hydroxyvitamin D (25[OH]D) prior to the initiation of methotrexate treatment in adult patients with RA as well as all-cause mortality among a national Veterans Affairs (VA) cohort. They reviewed the charts of a local RA cohort at the Cleveland VA, which included information on the first Vitamin D level in the VA system (n = 197) and the level within 1 year prior to methotrexate initiation (n = 105). The diagnoses, medications, and Vitamin D supplementation was confirmed at multiple time points.

Survival rates of patients with 25(OH)D levels > 50 nmol/L and ≤50 nmol/L were assessed using the Cox Proportional Hazard Model and adjusted for risk factors.

Overall, 15,109 patients with clinically diagnosed RA were included in the nationwide cohort. The median age was 63 years and most (n = 12,344, 82%) were male. In the year leading up to initiating treatment with methotrexate, 25(OH)D levels > 50 nmol/L were present in 81% (n = 12,286) of patients and ≤ 50 nmol/L was reported in 19% (n = 2823). Patients with levels > 50 nmol/L were older, less frequently obese, less frequently smokers, and less frequently Black, Hispanic, or Latino.

The mortality hazard increased for each additional year of age (1.08 per year, 1.07–1.08, P <.001), an underweight BMI (2.05, 1.55–2.72, P <.001), and if patients ever smoked (1.33, 1.17–1.50, P <.001).

After adjusting for risk factors, patients in the > 50 nmol/L pre-methotrexate initiation group exhibited a 28% reduced risk of mortality when compared with those in the ≤ 50 nmol/L group (hazard ratio [HR]: .72, confidence interval [CI]: .64—.80, P <.001). Proportions of patients with clinical measurements of 25(OH)D levels > 50 nmol/L at baseline and pre-methotrexate (n = 48) were comparable to the national cohort (76.8% vs 82.1%, respectively).

Investigators cited the observational, retrospective nature of the study as a limitation. Additionally, subjects with low Vitamin D levels at the first check may have been overrepresented in patients with regular 25(OH)D testing in the longitudinal analysis. However, longitudinal Vitamin D levels were not required in the mortality analysis. The variation in clinical lab data reporting did not allow investigators to assess 25(OH)D values as > 20 ng/mL or < 20 ng/L. Finally, the influence of social drivers of health on Vitamin D levels and survival outcomes were not assessed.

Although the study demonstrated the correlation between Vitamin D and mortality in this patient population, investigators mentioned it has yet to be determined whether increasing the levels of Vitamin D in deficient patients could impact all-cause mortality.

“Our overall observation of lower Vitamin D levels at the time of first-line therapy (methotrexate) initiation for RA associating with greater mortality indicates another link between Vitamin D homeostasis and bio-immune health,” investigators concluded. “Mechanisms underlying this relationship are yet to be determined, and future trials on Vitamin D supplementation are needed to understand how Vitamin D status affects immune health and mortality risk in autoimmune diseases.”


  1. Malakooti SK, Siddiqui H, Wilson B, et al. Higher Vitamin D Levels before Methotrexate Therapy Initiation Are Associated with Lower Subsequent Mortality in Patients with Rheumatoid Arthritis. Nutrients. 2024;16(3):401. Published 2024 Jan 30. doi:10.3390/nu16030401
  2. Wimalawansa, S.J. Infections and Autoimmunity-The Immune System and Vitamin D: A Systematic Review. Nutrients 202315, 3842
  3. Mouterde, G.; Gamon, E.; Rincheval, N.; Lukas, C.; Seror, R.; Berenbaum, F.; Dupuy, A.M.; Daien, C.; Daures, J.P.; Combe, B. Association Between Vitamin D Deficiency and Disease Activity, Disability, and Radiographic Progression in Early Rheumatoid Arthritis: The ESPOIR Cohort. J. Rheumatol. 202047, 1624–1628.