Pantothenic acid (PA), traditionally referred to as vitamin B5, is an essential water-soluble micronutrient required for the biosynthesis of coenzyme A (CoA), a central cofactor involved in mitochondrial energy production, fatty-acid β-oxidation, acetylation reactions, lipid metabolism, steroidogenesis and neurotransmitter synthesis. Its metabolic relevance extends to immune regulation, epithelial repair and redox balance, processes that are critically involved in the pathophysiology of rheumatologic diseases (1,2). Historically, PA has been used in dermatology and wound healing; however, its therapeutic implications for systemic inflammation and autoimmunity have received limited attention (1).

Given its influence on mitochondrial bioenergetics, fatty-acid metabolism, acetyl-CoA generation and redox pathways, PA may exert anti-inflammatory and immunomodulatory effects relevant to fatigue, pain, immune dysfunction and epithelial integrity, features commonly observed in rheumatic diseases. Clinical symptoms associated with PA insufficiency or suboptimal levels, such as fatigue, musculoskeletal discomfort, mood disturbances, sensory symptoms and impaired immune responses, overlap with several rheumatologic conditions (1).

A growing body of research has focused on vanin-family pantetheinases, particularly vanin-1, an enzyme regulating PA homeostasis through pantetheine cleavage and cysteamine generation. Vanin-1 activity affects oxidative stress responses, leukocyte migration and inflammatory cascades, and its expression is increased in tissues relevant to rheumatologic pathophysiology, such as cartilage and renal epithelium (3). Notably, urinary vanin-1 has emerged as a potential biomarker of active lupus nephritis, reinforcing the biological plausibility of interventions affecting PA metabolism (4).

Early clinical studies from the mid-20th century documented substantial improvement in cutaneous lupus with high-dose PA or panthenol, often combined with vitamin E, demonstrating reductions in erythema, scaling and lesion size (5-7). Later investigations have explored PA supplementation in osteoarthritis (OA), fibromyalgia (FM) and systemic lupus erythematosus (SLE), reporting benefits in pain, stiffness, fatigue, depression and cutaneous manifestations, although findings remain limited by small sample sizes, heterogeneous dosing, and confounding by co-supplementation (8-11).

A key historical point concerns the discrepancy in the nomenclature of B-complex vitamins, particularly between North American and continental European scientific traditions. PA was originally designated as vitamin B3 in the 1930s to 1940s, as the third nitrogen-containing B vitamin to be identified, while nicotinic acid/nicotinamide (‘niacin’) was designated as vitamin B5, based on chronological discovery (1,2). Although American literature gradually shifted after the 1990s, promoting the widespread use of the designations of niacin = B3 and pantothenic acid = B5, no formal IUPAC ruling has ever altered the classical nomenclature. Consequently, numerous textbooks and academic sources from continental Europe (e.g., Russia, Germany and France) continue to use PA = B3 and niacin = B5, occasionally causing confusion among international readers (12). This historical discrepancy is directly relevant to early dermatologic and rheumatologic studies on PA, which were authored during the period in which PA was universally referred to as vitamin B3, not B5 (5-7).

Recognizing this nomenclature divergence is essential, as it prevents misinterpretation of older literature and ensures accurate comparison of clinical interventions across historical and contemporary studies. The present systematic review aimed to synthesize the available human evidence on PA supplementation in rheumatic diseases, contextualize mechanistic pathways linking PA to inflammation and immune regulation, and identify gaps requiring rigorous modern investigation.

The present systematic review highlights both foundational and contemporary evidence on PA supplementation in rheumatic diseases, reframing these findings within the evolving field of immunometabolism. As the essential precursor to CoA, PA supports multiple biochemical processes relevant to inflammation and tissue repair, including mitochondrial bioenergetics, fatty-acid oxidation, acetyl-CoA homeostasis and steroidogenesis. Clinically, insufficient PA may manifest as fatigue, musculoskeletal discomfort and impaired barrier integrity, features commonly observed in chronic inflammatory disorders and are thus supportive of supplementation strategies (1). In addition to these established mechanisms, PA also contributes to sphingolipid and phospholipid biosynthesis, epigenetic acetylation processes and antioxidant regulation, providing broader biochemical plausibility for its contribution to immune and tissue homeostasis. In comparison, although other B vitamins (such as B3 and B6) exert anti-inflammatory effects, PA is unique due to its obligatory incorporation into CoA-dependent metabolic pathways.

A key mechanistic connection lies in the vanin-1 pantetheinase pathway. Vanin-1 activity generates cysteamine, a modulator of oxidative stress responses and inflammatory signaling. Its expression in both leukocytes and renal tubular cells has prompted interest in its urinary secretion as a biomarker of lupus nephritis activity (3,4). A previous preclinical study also suggested that altered vanin-1 signaling may contribute to chondrogenesis dynamics and aberrant mineralization, linking this axis to degenerative joint conditions and soft-tissue calcification (3). Although a direct causal chain from PA supplementation to vanin-1 modulation remains hypothetical, this axis provides a compelling biological rationale for biomarker-driven interventional trials. Notably, the role of PA in regulating oxidative stress and immune activation may intersect with vanin-1-mediated redox pathways, strengthening the mechanistic framework for testing PA in SLE.

Among the available clinical data, cutaneous lupus exhibits the most consistent therapeutic signal. Small series and uncontrolled interventions report rapid and sustained improvements in dermatologic lesions with PA-based regimens (5-7). Despite considerable variability in dosing, administration route and co-supplementation, the recurrence of response patterns, alongside reductions in fatigue and flare frequency, suggests potential adjunctive utility in selected SLE phenotypes (5-7,11). Further research is required to incorporate validated dermatologic scoring systems, blinded outcome assessment and stratification according to cutaneous subtype (acute, subacute and discoid) to refine treatment expectations. The historical use of high-dose PA in these studies, without significant toxicity, further supports its safety profile and justifies renewed evaluation under controlled contemporary designs.

In FM, preliminary benefit was observed with intravenous multi-micronutrient therapy (10). Although attribution to PA alone is not possible, mechanistic plausibility is supported by its contributions to CoA-dependent cellular energy and acetylcholine biosynthesis, aligning with FM models of mitochondrial inefficiency and autonomic dysfunction. Comparative studies isolating PA or manipulating PA content within IV formulations, while incorporating objective endpoints, such as actigraphy, pressure pain thresholds and validated fatigue metrics, would clarify PA-specific effects. Additionally, classical descriptions of pantothenic acid deficiency leading to ‘burning feet syndrome’, a neuropathic condition responsive to PA supplementation, support the hypothesis that PA may influence sensory pathways relevant to FM and autoimmune neuropathies.

Evidence in OA remains inconclusive. A previous open-label study reported improvements in stiffness and pain with low-dose oral PA combined with B-complex vitamins (9), whereas another randomized controlled trial revealed no advantage of PA plus L-cysteine over the placebo (8). Differences in OA phenotype, baseline severity, intervention design and outcome measurement likely contributed to divergent results. Given the global burden of OA and the scarcity of disease-modifying options, larger rigorously designed trials incorporating standardized pain/function endpoints, imaging modalities and biomarkers of cartilage turnover are warranted. Potential mechanistic links between CoA-dependent metabolism, chondrocyte bioenergetics and osteoarthritic cartilage degeneration warrant further exploration.

Safety findings across available studies appear reassuring, with predominantly mild and transient adverse events. Notably, lupus trials utilized supra-nutritional PA doses without major toxicity signals (5-7,11). Nonetheless, limited sample sizes, short follow-up intervals, and insufficient systematic reporting of laboratory trends and drug interactions restrict firm conclusions. As PA participates in acetylation reactions required for the metabolism of several pharmaceutical agents, its potential influence on drug pharmacokinetics, particularly in patients receiving corticosteroids, antimalarials, NSAIDs, or immunosuppressants, warrants further investigation in future studies.

The present systematic review provides a comprehensive appraisal of all human clinical studies in rheumatic settings to date, integrating mechanistic insight with clinical phenotype and immunometabolic context. However, the interpretability of available data is constrained by small cohorts, heterogeneous interventions, variable dosing, the absence of blinding in the majority of studies and reliance on historical controls in cutaneous lupus research. Additionally, the only OA randomized controlled trial and a pilot FM randomized controlled trial evaluated multi-ingredient preparations, obscuring the individual contribution of PA (8,10). Concomitant vitamin use (e.g., B-complex and vitamin E) and differing administration routes (oral vs. intravenous) further complicate the attribution of the effects. Furthermore, additional evidence from Eastern European literature, including a patented panthenol-containing formulation used to accelerate tendon healing in systemic sclerosis and a study demonstrating improved xerophthalmia with a panthenol-containing ophthalmic solution (Stillavit) in rheumatoid arthritis, suggests broader reparative and epithelial-trophic roles for PA that merit investigation.

Several priorities thus emerge for subsequent research: i) Clinical trials: Well-powered randomized studies of oral PA monotherapy in lupus and OA, including dose-ranging phases to determine minimal effective and maximal tolerated doses are warranted. ii) Mechanistic exploration: The quantification of CoA-related metabolites, acetyl-CoA and vanin-1 activity/expression is required to investigate PA-responsive biological pathways and evaluate vanin-1 as a predictive or pharmacodynamic biomarker in SLE (3,4,13). iii) Pragmatic FM trials: The assessment of PA as an adjunct to standard care using patient-centered outcomes (pain interference, sleep quality and fatigue) and metabolic profiling is warranted to identify responder subgroups with impaired CoA flux. iv) Expansion to other rheumatic diseases: Systematic evaluation in rheumatoid arthritis, spondyloarthritis, Sjögren's syndrome, myositis, systemic sclerosis and vasculitis is required, given shared inflammatory and oxidative mechanisms (14-16).

In conclusion, across multiple decades of research, PA supplementation has exhibited potential therapeutic value in specific rheumatologic contexts, most notably in cutaneous forms of lupus, while producing preliminary yet promising findings in FM and more inconsistent outcomes in OA. Safety profiles reported to date are generally acceptable, with mostly mild and transient adverse effects. However, the evidence base remains limited by small sample sizes, heterogeneous dosing regimens, frequent co-supplementation and the absence of modern randomized designs, which collectively restrict firm conclusions regarding efficacy and optimal treatment strategies.

Given these limitations, PA should be considered an investigational adjunct rather than an established therapy, pending confirmation from contemporary randomized controlled trials. Future studies are required to incorporate standardized dosing protocols, validated dermatologic and musculoskeletal outcome measures, biomarker integration (particularly CoA-related metabolites and vanin-1), and systematic pharmacovigilance to evaluate potential interactions with immunomodulatory agents.

In the interim, PA supplementation may be cautiously explored as an adjunctive strategy in selected patient populations, provided that dosing, concomitant therapies and safety parameters are carefully monitored. Robust, well-designed clinical trials are urgently required to clarify its therapeutic potential and define its role within modern rheumatologic practice.