When are supplements warranted-and which ones are best supported by the evidence?
References1. Shea B, Swinden MV, Tanjong Ghogomu E, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2013 May 31;(5):CD000951.2. Kostoglou-Athanassiou I, Athanassiou P, Lyraki A, et al. Vitamin D and rheumatoid arthritis. Ther Adv Endocrinol Metab. 2012;3:181-187.3. Haque UJ, Bathon JM, Giles JT. Association of vitamin D with cardiometabolic risk factors in rheumatoid arthritis. Arthritis Care Res. 2012;64:1497-1504.4. Johns Hopkins Arthritis Center. https://www.hopkinsarthritis.org/patient-corner/disease-management/rheumatoid-arthrtis-nutrition/5. Suzuki Y, Wakabayashi T. Management of osteoporosis associated with rheumatoid arthritis and glucocorticoid-induced osteoporosis. Clin Calcium. 2015;25:1825-1834.6. Simopoulos AP. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed Pharmacother. 2002;56:365-379.7. Lourdudoss C, Di Giuseppe D, Wolk A, et al. Dietary intake of polyunsaturated fatty acids and pain in spite of inflammatory control among methotrexate-treated early rheumatoid arthritis patients. Arthritis Care Res. 2018;70:205-212.8. Pattison DJ, Silman AJ, Goodson NJ, et al. Vitamin C and the risk of developing inflammatory polyarthritis: prospective nested case-control study. Ann Rheum Dis. 2004;63:843-847.
The most commonly observed vitamin and mineral deficiencies in patients with rheumatoid arthritis (RA) are folic acid; vitamins C, D, B6, B12, and E; calcium; magnesium; zinc; and selenium. Studies have shown that some-but not all-supplements may improve disease activity and reduce pain associated with RA.
Methotrexate interferes with the metabolism of folate, a water-soluble B vitamin (vitamin B9). A study by Shea and colleagues1 showed that these effects are substantially modified by the addition of supplemental folic acid or folinic acid therapy. Folic acid or folinic acid supplementation produced a 26% relative risk reduction (9% absolute risk reduction) in the incidence of GI adverse effects (nausea, vomiting, abdominal pain). Supplementation was associated with protective effects against methotrexate-induced abnormal serum transaminase elevation: 76.9% relative (16% absolute) risk reduction (relative risk [RR], 0.23; 95% CI, 0.15 to 0.34; P < .00001). Fewer patients with RA withdrew from methotrexate therapy for any reason: 60.8% relative (15.2% absolute) risk reduction (RR, 0.39; 95% CI, 0.28 to 0.53; P < .00001).
Vitamin D deficiency is at least as common in patients with RA as in the general population, where the prevalence may be as high as 50%. It contributes to bone loss and bone pain in both RA and osteoarthritis and has been implicated in the mechanisms of RA disease activity. Vitamin D deficiency also increases risks of RA-associated cardiovascular disease (CVD) and metabolic disease. A contributing factor is that many of the treatments for RA, such as hydroxychloroquine and corticosteroids, are known to deplete vitamin D reserves.
Vitamin D is readily available from natural sources, including sunlight and food sources such as eggs, oily fish, and mushrooms. Despite this, some estimates show that half of the world’s population may have vitamin D deficiency.
Supplementation is the single most effective solution to correcting vitamin D deficiency. Vitamin D is added to many cereals and milk products in the US. In addition, supplemental tablets are recommended, particularly for people at risk for RA- or osteoarthritis-related bone loss. Although studies are limited, they suggest that vitamin D supplementation may be useful for the prevention of RA and for the reduction of musculoskeletal pain. The optimal dose is not established for RA.
Calcium levels are often reduced in patients with RA, particularly as a result of RA treatments. Calcium supplementation is effective in reducing the risks of RA-induced osteoporosis.
Omega-3 and omega-6 fatty acids are essential acids that are necessary to multiple body functions. Inflammation, a primary mechanism in RA, is influenced by both omega-3 and omega-6 fatty acids. Omega-3 fatty acids inhibit inflammatory responses, while omega-6 fatty acids exacerbate them. A 2016 article in Rheumatology Network also pointed to the potential protective effects of omega-3 fatty acids against the development of RA.
A dietary imbalance in the consumption of greater amounts of omega-6 fatty acids than omega-3s in Western countries has contributed to inflammatory-mediated diseases such as RA and CVD. In a recent Swedish study, omega-3 fatty acid intake was also inversely associated with unacceptable pain in patients with RA.7 Specifically, the ratio of omega-6 to omega-3 fatty acids (but not high omega-6 alone) correlated directly with refractory and unacceptable pain and was not associated with inflammation.
Antioxidants such as vitamin C, vitamin E, and selenium have long been linked to the development of inflammation.
Claims have been made that increased intake of natural substances containing vitamin E (eg, green tea, peanut oil and peanut butter, canola oil, spinach) can reduce joint pain and damage in RA. However, the benefits of antioxidants such as vitamin E in RA remain unproven.
The reported benefits of the antioxidant vitamin C are somewhat better supported, as vitamin C deficiency has been linked to up to a 2 to 3 times greater risk of inflammatory RA.8 This study looked at direct sources from fruits and vegetables, however, and improvements as a result of vitamin C supplementation have not been quantified.
