Nonvitamin, Nonmineral Dietary Supplement Use in Individuals with Rheumatoid Arthritis

Introduction

Natural product–derived, nonvitamin, nonmineral (NVNM) dietary supplements (DS), such as glucosamine or fish oil, are the most common complementary and alternative medicine modality used by the general population in the United States, with treatment of musculoskeletal complaints being the most common reason for their use (1). Although the prevalence of NVNM DS use by adults in the general population has remained constant at 18–19% over the past decade, the specific products used have not, as reflected both by sales data and reported patterns of use in national health surveys (2–5). For example, use of fish oil and probiotics by the general population has increased, whereas use of glucosamine and/or chondroitin sulfate (G&CS) has decreased (1).

National surveys have documented higher DS use in women, those taking prescription medicines, and those with chronic diseases (6, 7). Therefore, as summarized in a scoping review of the literature recently published by our research group, it is not surprising that NVNM DS use is even more common in adults with rheumatoid arthritis (RA) (31–60% prevalence), a chronic systemic autoimmune disorder disproportionately affecting women (77% of patients in RA registries) that is managed with intensive pharmacologic regimens (8–10). Although pharmacologic management of RA has advanced rapidly in recent years (11), studies indicate that incentives remain for patients with RA to incorporate DS into their treatment regimen, including dissatisfaction with current treatments and perceived benefits of the added treatment (4). Averse pharmacodynamic or pharmacokinetic interactions between NVNM DS and drugs are well documented (12–14); however, interactions between NVNM DS and RA pharmaceuticals have not specifically been studied. However, individuals with RA have a higher theoretical risk for adverse effects associated with NVNM DS due to their frequent use of multiple pharmaceuticals with known side effects (10), as well as associated systemic manifestations of the disease itself. Critically, because only a minority of patients with RA report NVNM DS use to their providers (9), any such untoward effects could be attributed to other causes and thus go unnoticed.

Given this apparently widespread but individually underreported use of NVNM DS in RA, data from population-based surveys identifying current patterns of specific NVNM DS use are of great relevance for clinical RA management. However, previously published studies, as summarized in our recent review of the literature (9), are limited in scope in terms of design and size (median, n = 153), with almost half having been published more than a decade ago. Thus, data reflecting current NVNM DS usage in RA are limited. For example, since 2010, only 3 of 7 reports are full publications (compared with abstracts) (9): a study detailing usage by African Americans in the southern United States (15) and 2 non-US studies (16, 17), only 1 of which included data on specific products used. Even in studies collecting information on specific products, inclusion of open-ended questions to capture products beyond those prespecified is uncommon; of 8 US studies reported since 1983 (9), only 1 published in 2004 (n = 95) appears to have incorporated this element of study design (18). In addition, although overall prevalence of NVNM DS use in RA appears similar across time (1980–2015) and geographical locations, averaging 47% (9), no study has directly compared specific product use between culturally and/or geographically distinct populations (e.g., between countries), and multiregional data from the United States are only available in abstract form (19). In addition, no studies have examined associations between use of NVNM DS and cohort characteristics, including concurrent use of specific RA pharmaceuticals (9).

Therefore, a comprehensive assessment to identify a full range of specific types of NVNVM DS used by individuals with RA was undertaken to include simultaneous assessment of usage patterns across the United States, including the western United States, an understudied region for which the most recent data, published over a decade ago (2004), were limited to 95 subjects (18). An additional primary aim of this study, given the potential for DS-drug interactions in a population with high polypharmacy use, was to examine associations between use of NVNM DS and prescribed RA pharmaceuticals, as well as over-the-counter vitamin or mineral DS (VM DS) recommended for use in RA by health care providers, for example, vitamin D to mitigate bone loss or folate to counter toxic effects of methotrexate (20, 21), a common first-line RA pharmaceutical (10). Associations between other cohort characteristics and patterns of DS use were also assessed.

Methods

Results

Discussion

In studies published over the past 4 decades, NVNM DS use in RA exceeded that of the general adult population more than 2-fold, with marine oils and G&CS being the most commonly used products worldwide and in the United States (9). In the current study, although prevalence remained high and use of marine oils and G&CS was still common, there were also notable differences. Most striking was the identification of turmeric as the most common NVNM DS currently used worldwide and in the United States (30% prevalence) and the increasingly prevalent use of ginger (13%), a plant botanically related to turmeric (27, 28). In contrast, neither turmeric nor ginger appeared in prior RA studies (9), with the exception of 2 US studies published more than a decade ago documenting infrequent (<5%) use (18, 29). This increased prevalence mirrors temporal shifts in US sales, as turmeric and ginger currently hold third and sixth place among top-selling botanical DS sales in the United States, after a decade of exponential or doubling of sales, respectively (2, 3, 5).

However, compelling scientific evidence of efficacy does not appear to be driving these changes in NVNM DS use in RA. Only 4 small clinical studies (n = 86 total subjects treated) using products of variable (and undocumented) composition and doses for short-term treatment have been published and provide some evidence for turmeric DS tolerability and efficacy in ameliorating joint symptoms in RA, only 2 of which were randomized, double blinded, and placebo controlled (30–33). For ginger, we are aware of only a single short-term clinical trial (n = 35 treated) testing a ginger product of uncharacterized composition, demonstrating benefits in reducing RA joint symptoms (34). Because botanical products, unlike drugs, are chemically complex, a lack of characterization of product content in these botanical clinical trials is a particular concern, a limitation compounded by the relative lack of US federal oversight of the content of botanical DS sold (35–37). Of the other 2 top NVNM DS documented here, more data are available for fish oil/ω-3 PUFU in RA, with evidence of moderate quality demonstrating efficacy in reducing RA joint symptoms and improving risk factors for cardiovascular disease, a systemic manifestation of RA (38–40). In contrast, a placebo-controlled study investigating glucosamine in RA did not demonstrate efficacy (41).

Certain unique elements of our study design could have also contributed to differences in specific NVNM DS identified and their prevalence compared with previous studies (9). Two such elements and particular strengths of this study were its large size, relative to prior studies, and the inclusion of open-ended queries to ensure capture of a complete range of DS products used. Additionally, recruitment of participants outside of the setting of rheumatology specialty clinics, uncommon in prior studies (9), may also have captured a wider population with variable access to care. An additional strength of this study was its simultaneous assessment of NVNM usage patterns across geographic areas in the United States, including the western United States, which had not been surveyed in almost 2 decades, and Arizona, a population never previously assessed (9). It was not clear when systematically reviewing prior published studies whether geographic differences in product usage between studies were due to cultural, temporal, or other factors (9); however, in the current study, patterns of NVNM DS use were similar across US regions and when compared with other countries, with the notable exception of ginger DS use, which was more prevalent in non US-countries. These findings suggest that prior unique patterns of NVNM DS use in noncontemporaneous studies could have been more reflective of temporal rather than geographic or cultural trends. At the same time, it must be noted that the current study, whose recruitment methods were focused on US populations, was underpowered to assess US compared with non-US NVNM DS use. The fact that ginger DS use was still found to be significantly higher in non-US countries suggests that global differences still exist.

A limitation of this study is its reliance on a self-selected cohort, which could have overrepresented individuals with a particular interest in NVNM DS. However, the similar prevalence of NVNM DS usage reported here across geographic regions compared with prior RA studies, including those assessing RA registry data (9), suggests that self-selection was likely not a major limiting factor. A second limitation of the study design was its reliance on a self-report of RA not verified through medical records or direct assessment of RA criteria in study participants (23). However, elimination of individuals with likely juvenile idiopathic arthritis (previously known as juvenile RA) (23) and those lacking a detailed history of treatment with specific RA pharmaceuticals (DMARDs and/or biologics), as recommended for RA treatment by the American College of Rheumatology (10), likely limited inclusion to those diagnosed with RA by health care providers. A lack of validation of the DS survey method by physical inspection of actual NVNM DS products used, analogous to methodology used for NHANES (42), is a limitation of this study, as was the lack of inclusion of queries related to dosing, duration of use, or information about the source of recommendations influencing NVNM DS product use.

A unique strength of this study, compared with earlier reports (9), was its analysis of associations between use of NVNM DS and cohort characteristics. Although not queried here, because of prior evidence that individuals with RA infrequently report NVNM DS use to providers (9), such population-based data may provide insights relevant to patient safety. The preponderance of middle-aged women in this study is reflective of RA patient populations in general (e.g., 64–86% women in RA patient registries, with average age 50–68 y) (8); however, underrepresentation of men (7%) was a study limitation, such that lower reported ever use of NVNM DS by men was not statistically significant. Hispanics were also underrepresented (25, 26); however, ever NVNM DS use by Hispanics was still found to be significantly lower than in non-Hispanics.

Because biologics are recommended in RA when first-line DMARD treatments are insufficient to meet treatment goals (10, 24), biologic use (ever, never, or current) was a key variable in analyses assessing associations between cohort characteristics and NVNM DS use. It was thus notable that subjects reporting ever or current use of biologics were less likely to report ever or concurrent use of NVNM DS. Because patients with RA, on or off biologics, often do not reach target treatment goals (10, 24), it is possible that individuals on first-line DMARDs turn to NVNM DS more frequently in lieu of biologics. In this regard, a limitation of this study was the lack of information gathered related to systemic manifestations of RA or other comorbidities that could have influenced NVNM DS choices.

From a safety standpoint, it is notable that concurrent use of NVNM DS with RA pharmaceuticals was reported by almost half of the participants, including concurrent use of 3 or more NVNM DS by more than one-third. Because adverse pharmacodynamics or pharmacokinetic interactions between DS and pharmaceuticals are not uncommon (12–14) and NVNM DS content is variable and minimally regulated (35–37), frequent use of any NVNM DS, including turmeric, the most common, should provide a cautionary note for health care providers when assessing clinical responses in RA populations. Focusing on turmeric as an example, as is true for many NVNM DS frequently used for RA (9), although preclinical evidence supports RA treatment efficacy (43, 44), clinical evidence of both efficacy and safety is scant for RA (30–33). Notably, although published turmeric clinical trials in non-RA populations suggest a 5% risk of liver injury that is likely idiosyncratic (45), a recent report of turmeric DS-induced autoimmune hepatitis (45) and emerging international reports of turmeric DS-related liver damage (46) suggest that caution should be exercised when monitoring turmeric DS use in those at higher risk for autoimmune diseases and/or possible hepatotoxic drug-DS interactions. Indeed, because methotrexate induces liver enzyme elevations in one-third of users (47) and one-third of methotrexate users in this current study reported concurrent turmeric DS use, it is readily apparent that a potential role for turmeric in contributing to hepatocellular damage in RA methotrexate users could be obscured if turmeric use was not disclosed by the patient and/or considered by the physician.

Ever use of NVNM DS was more common in those also reporting ever use of VM DS, with use of 3 or more VM DS reported by the majority of current VM DS users. Vitamin D, postulated to play a role in RA pathogenesis when deficient and known to mitigate musculoskeletal side effects associated with RA and/or its treatment (48–50), was the most commonly used VM DS product. However, given reports of a higher prevalence of vitamin D deficiency in RA populations (49), it is notable that only 63% of respondents reported current vitamin D use. Similarly, concurrent use of methotrexate with folate (including leucovorin), the second most commonly used VM DS, although common and consistent with current guidelines aimed at mitigating methotrexate gastrointestinal side effects and liver toxicity (21, 47), was reported by only 83% of methotrexate users, possibly reflecting noncompliance.

As with all treatment plans, open communication between patients and providers about multimodal approaches to RA management is likely to enhance clinical outcomes related to safety and efficacy, even when high-quality data are lacking. Because NVNM DS use is frequently not reported by individual patients with RA to health care professionals (9), the population-based data presented here may help direct these conversations while also potentially identifying relevant NVNM DS for further study to address both safety and efficacy in RA populations.

Supplementary Material

Notes

Source of support: This research was supported by the National Center for Complementary and Integrative Health (NCCIH) at the NIH (R34AT007837). Views expressed here are solely the responsibility of the authors and do not necessarily represent those of the NIH or NCCIH.

Author disclosures: The authors report no conflicts of interest.

Supplemental Table 1 and survey tool (Supplemental Figure 1) are available from the “Supplementary data” link in the online posting of the article and from the same link in the online table of contents at http://jn.nutrition.org.

Abbreviations used: DMARDs, disease-modifying antirheumatic drugs; DS, dietary supplement; G&CS, glucosamine and/or chondroitin sulfate; NVNM, nonvitamin, nonmineral; RA, rheumatoid arthritis; VM, vitamin or mineral.