Vitamin A supplementation in rheumatological diseases: A systematic review of the available clinical evidence

INTRODUCTION

Vitamin A (Vit. A) is an essential micronutrient required for various physiological functions in the human body. It plays a critical role in vision, maintenance of epithelial tissue integrity, growth and development, as well as in immune and reproductive processes. Since it cannot be synthesized endogenously, an adequate daily intake is necessary to prevent deficiency.^[1]

Vit. A is also involved in immune regulation through complex interactions with multiple immune components. Its signaling pathways influence cell differentiation and the activity of effector immune cells under different physiological and pathological conditions. The effects of Vit. A on autoimmune responses appear to be context-dependent, varying according to factors such as the tissue microenvironment and the stage of disease. For instance, experimental studies have demonstrated that supplementation can improve renal damage in murine lupus nephritis, while in other models, it may worsen inflammatory lesions in organs such as the lungs and skin.^[2]

Beyond its immunomodulatory effects, Vit. A is essential for maintaining epithelial barrier integrity and mucosal immunity, playing a central role in host defense against infections. Vit. A deficiency (VAD) has been associated with impaired barrier function, reduced immunoglobulin A (IgA) production, and increased susceptibility to respiratory and gastrointestinal infections. This aspect is particularly relevant in patients with rheumatic diseases, who frequently receive immunosuppressive therapies and are at increased risk of infectious complications. Therefore, understanding the potential impact of Vit. A on infection susceptibility may have important clinical implications in rheumatology.

Given its well-recognized dose-dependent toxicity, particularly with chronic exposure, the use of Vit. As a therapeutic strategy, autoimmune diseases must be approached with caution. Targeted interventions considering the distinct signaling pathways involved are needed to reduce the risk of adverse outcomes, especially with long-term use. Previous research has investigated the role of Vit. A in several autoimmune conditions, including type 1 diabetes (T1D), multiple sclerosis (MS), and inflammatory bowel disease.^[3]

Considering these findings, exploring the role of Vit. A in autoimmune and rheumatic diseases is of particular interest. However, studies in this area remain scarce, with only a few reports focusing on systemic lupus erythematosus (SLE)^[4,5] and other rheumatic diseases.

The objective of this article is to review the current clinical and immunological evidence regarding the role of Vit. A in rheumatic diseases, including its potential implications for host defense.

MATERIALS AND METHODS

RESULTS

Table 1 summarizes the studies evaluating Vit. A supplementation in rheumatic diseases. A limited number of human studies were identified, including a total of 72 patients from the two studies specifically evaluating Vit. A supplementation in SLE, in addition to small studies assessing Vit. A–based interventions in other rheumatologic contexts, such as Sjögren’s syndrome and osteoarthritis. The studies focusing on SLE primarily evaluated immunological outcomes rather than validated clinical disease activity indices. These studies were conducted in Indonesia and Japan. The mean age of participants was approximately 31.2 years, and all were female. Disease duration was not reported in either study. Only one trial specified the Vit. A dosage was 100,000 IU/day for 2 weeks.

Regarding outcomes, the first study reported no significant changes in clinical or laboratory parameters related to SLE. However, Vit. A supplementation was associated with enhanced antibody-dependent cell-mediated cytotoxicity, increased natural killer cell activity, and a greater blastogenic response to mitogen and interleukin 2 (IL-2) stimulation. The second study demonstrated a significant increase in regulatory T cells (Treg) differentiation (33.9 ± 1.6 vs. 21.8 ± 1.1%, P = 0.000) along with a decrease in Th17 differentiation (27.2 ± 2.5 vs. 37.4 ± 1.3%, P = 0.000).

In Sjögren’s syndrome, an open observational study demonstrated that short-term high-dose Vit. A supplementation (100,000 IU/day for 2 weeks) was associated with increased antibody-dependent cell-mediated cytotoxicity and enhanced natural killer cell activity, indicating immunological modulation, although no standardized clinical disease activity outcomes were reported.^[6]

In osteoarthritis, a double-blind controlled trial evaluating a Vit. A–containing antioxidant formulation selenium plus vitamins A, C and E (Selenium-ACE) did not demonstrate significant clinical benefit compared with placebo.^[7]

No adverse effects related to Vit. A supplementation was reported in either of the included studies.

Despite an extensive search strategy covering multiple databases and more than five decades of publications, no additional or more recent human clinical studies evaluating Vit. A supplementation in rheumatic diseases was identified.

DISCUSSION

Studies evaluating serum levels of Vit. A in rheumatic diseases have consistently shown reduced concentrations compared with healthy controls. For example, in juvenile idiopathic arthritis, significantly lower serum levels of beta-carotene (0.57 ± 0.41 vs. 0.71 ± 0.26 mmol/L, P < 0.05) and retinol (918 ± 246 vs. 1176 ± 300 IE/L, P < 0.01) have been reported.^[8] Similarly, in rheumatoid arthritis, serum retinol levels were significantly decreased compared with both matched healthy controls (P < 0.001) and patients with osteoarthritis.^[9] These findings suggest that hypovitaminosis A may be a common feature across different rheumatic diseases; however, whether this represents a causal factor, a consequence of chronic inflammation, or a nutritional epiphenomenon remains unclear.

Several mechanisms have been proposed to explain how Vit. A may exert beneficial effects in autoimmune and rheumatic diseases. One key pathway involves the regulation of intestinal barrier integrity and microbiome composition. VAD has been associated with alterations in gut microbial communities similar to those found in autoimmune conditions. For instance, an increased abundance of Bacteroides species, such as Bacteroides vulgatus, has been linked to T1D^[9] and MS,^[10] and similar changes are observed in VAD states.^[11] A potential protective mechanism is that Vit. A promotes the expression and assembly of tight junction proteins in intestinal epithelial cells, thereby enhancing gut barrier function and reducing intestinal permeability.^[12] This “anti-leaky gut” effect may help prevent abnormal immune activation in genetically susceptible individuals.

Experimental findings by Vien et al.^[4] further support the immunomodulatory role of Vit. A. Their study demonstrated that supplementation enhanced antibody-dependent cell-mediated cytotoxicity, increased natural killer cell activity, and improved the blastogenic response to mitogen and IL-2. These changes could potentially correct or mitigate specific immune dysfunctions observed in SLE. However, these findings are preliminary, and additional studies are required to determine whether these immunological improvements result in sustained clinical benefits. Similar immunological effects have also been reported in a small study involving patients with Sjögren’s syndrome, reinforcing that Vit. A-related immune modulation is not exclusively restricted to SLE.

In addition to immunomodulation, Vit. A plays a central role in host defense and infection prevention, which is particularly relevant in rheumatology. Patients with autoimmune rheumatic diseases are frequently exposed to immunosuppressive therapies, increasing their susceptibility to infections. Vit. A is known to support mucosal immunity, epithelial barrier integrity, and IgA-mediated immune responses, all of which are critical for protection against respiratory and gastrointestinal infections. Although none of the included studies directly evaluated infectious outcomes, the biological plausibility suggests that adequate Vit. A status may influence infection risk in this population. This aspect deserves specific investigation in future clinical studies.

Despite these promising observations, the current evidence is limited by several important gaps. None of the available studies compared Vit. A supplementation directly with standard-of-care therapies makes it difficult to determine whether it has an additive or synergistic effect. Furthermore, sample sizes were small, and although SLE represents the most extensively studied condition, human data in other rheumatic diseases, such as Sjögren’s syndrome and osteoarthritis, remain extremely limited and heterogeneous. Future research with larger cohorts, extended follow-up, and inclusion of other rheumatic conditions is necessary to generate more robust data regarding efficacy, safety, and optimal dosing regimens.

Another major limitation is the lack of detailed reporting on adverse effects. Vit. A is known to have dose-dependent toxicity, especially with chronic use, and excessive intake has been associated with hepatic, skeletal, and neurological complications. The absence of systematic safety data in the existing studies raises concerns about the long-term feasibility of supplementation as a therapeutic strategy. Future trials must include rigorous safety monitoring, including biochemical and clinical assessments, to allow a balanced evaluation of both benefits and risks.

Moreover, mechanistic studies in humans remain scarce. While animal models suggest that Vit. A may promote a shift toward a more regulatory immune phenotype; these effects likely vary depending on disease subtype, genetic predisposition, and environmental factors. Translational studies integrating immunophenotyping, microbiome profiling, and metabolomic analyses are needed to clarify the context-dependent effects of Vit. A. Such approaches may help identify subgroups of patients most likely to benefit from supplementation, paving the way for personalized therapeutic strategies.

CONCLUSION

The current literature on Vit. A supplementation in rheumatic diseases remains very limited, with SLE representing the most extensively and systematically investigated condition to date, despite the existence of limited human data in other rheumatic contexts such as Sjögren’s syndrome and osteoarthritis. Reported findings indicate potential immunological benefits, such as increased frequencies of Treg and reduced differentiation of Th17 cells. However, the clinical implications of these immunological changes are still unclear. Further research is needed to determine whether these effects translate into meaningful improvements in disease activity and patient outcomes. Beyond immunological effects, the potential impact of Vit. A on infection susceptibility represents an additional and clinically relevant dimension, particularly in immunosuppressed patients with rheumatic diseases. Future studies should include larger and more diverse patient populations, as well as well-defined clinical and laboratory endpoints, to clarify the therapeutic potential of Vit. A across a broader spectrum of rheumatic diseases.