Targeting inflammation, fibrosis, and vascular dysfunction in systemic sclerosis: the role of diet and complementary and alternative medicine

Abstract

Purpose of review

Patients with systemic sclerosis (SSc) often seek advice regarding diet including functional foods, and complementary and alternative medicine (CAM) as adjunctive therapies. This review summarizes existing literature regarding these approaches.

Recent findings

Study results of low Fermentable Oligosaccharides, Disaccharides, Monosaccharides, And Polyols (FODMAP), Mediterranean and ketogenic diets suggest symptom reduction and beneficial microbiota modulation in SSc, though sample sizes are small. Nitrate-rich and antioxidant supplements such as omega-3 fatty acids show promise in lowering inflammation and oxidative stress in the circulation. Herbal remedies like curcumin have demonstrated antifibrotic properties in preclinical models. Topical agents (e.g., rosemary oil, vitamin E gel) and nutritional vitamins (e.g., C, D, E) are also frequently used, though robust clinical trials are lacking.

Summary

CAM, dietary interventions, and functional foods may aid in SSc management, but more rigorous research is needed to provide definitive evidence.

INTRODUCTION

The exposome – including disordered sleep, gut dysbiosis, environmental exposures, diet, and stress – has garnered interest as a factor in systemic sclerosis (SSc) pathogenesis. Complementary and alternative medicine (CAM), rooted in Eastern practices, have gained popularity among physicians and patients as a potential SSc treatment [1,2^▪]. SSc typically manifests in adulthood, prompting questions about its triggers and treatment [3]. This review highlights literature on functional foods, diets, vitamins, and supplements for managing SSc (see Table 1). 

Table 1.

Key terms definitions related to dietary and complementary interventions in systemic sclerosis

Term	Definition	Examples from this review
Diet	A structured pattern of food intake tailored for therapeutic or preventive purposes, often aimed at modulating symptoms or disease activity.	Low-FODMAP, Ketogenic, Mediterranean
Functional foods	Foods or food components providing health benefits beyond basic nutrition, frequently by modulating physiological functions or reducing disease risk.	Beetroot, Rosemary, Curcumin
Vitamins	Organic compounds essential for normal metabolism, often supplemented to support cell function, immune response, and antioxidant activity.	Vitamin C, Vitamin D, Vitamin E
Dietary supplements	Orally consumed products containing one or more dietary ingredients (e.g., minerals, amino acids, herbs) intended to supplement the diet.	L-arginine, Omega-3 Fatty Acids, Para-Aminobenzoic Acid, Zinc

Box 1.

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We searched OVID (1/2010–4/2024) using terms [scleroderm* or systemic scleros*], [alternative medicine], [alternative or complementary], [therap* or medicine* or drug*], [diet* or food or herbal], [supplement*] and [nutraceutical* or nutriceutical* or neutraceutical*]. We prioritized evidence-based clinical trials, systematic reviews, and observational studies.

DIET

Diet refers to structured food intake tailored for therapeutic or preventive purposes [4^▪]. In SSc, impaired peristalsis and dysbiosis may intensify gastrointestinal symptoms. Diet influences gut flora impacting symptoms from inflammation (e.g., fatigue, pain) and smooth muscle dysfunction (e.g., diarrhea) [5]. For instance, an observational study of 42 SSc patients found significant associations between increased dietary sodium, suboptimal caloric intake, malnutrition, and weight loss with pulmonary hypertension, heart failure, elevated transaminases, and skin fibrosis in SSc [6]. Specifically, Mediterranean, ketogenic, and low Fermentable Oligosaccharides, Disaccharides, Monosaccharides, And Polyols (FODMAP) diets have been studied in SSc.

LOW FODMAP

The low-FODMAP diet restricts ingestion of short-chain carbohydrates that are poorly absorbed in the small intestine. This reduces fermentation by gut bacteria that increases osmotic load and promotes pathobiont overgrowth, bacteria with inflammatory potential. In a cross-sectional study, 66 SSc patients with moderate-to-severe gastrointestinal symptoms underwent stool microbiota 16S rRNA sequencing and completed the UCLA SCTC GIT 2.0, a questionnaire measuring reflux, bloating, and bowel-related symptom severity, and 35 completed dietary surveys. Among 19 low-FODMAP followers, abundance of Streptococcus, Enterococcus, Klebsiella, and Enterobacter (the later three correlated with bloating and reflux) were reduced compared to 16 non low-FODMAP followers. Although total GIT 2.0 scores were not different between groups (P = 0.349), low FODMAP diet adherence may positively influence pathobiont composition in SSc patient stool [7].

KETOGENIC

The ketogenic diet, high in unsaturated fat and low in carbohydrates, induces ketosis where β-hydroxybutyrate (BHB) becomes the primary energy source. BHB exerts anti-inflammatory effects by inhibiting the NLR family pyrin domain containing 3 (NLRP3) inflammasome, an innate immune sensor. BHB prevents potassium efflux and reduces apoptosis-associated speck-like protein with a caspase-recruitment domain (ASC) oligomerization, thereby attenuating caspase-1 activation and downstream interleukin (IL) secretion in murine and human monocytes, IL-1β and IL-18 [8].

Unlike ketone bodies or short-chain fatty acids, BHB inhibits NLRP3 activation triggered by adenosine triphosphate, palmitate, and ceramides, independent of adenosine monophosphate-activated protein kinase (AMPK), reactive oxygen species (ROS), autophagy, or G protein-coupled receptor-109a [9^▪]. These mechanisms support ketogenic diet's potential as an anti-inflammatory strategy.

MEDITERRANEAN

The Mediterranean diet, rich in olive oil, whole grains, legumes, fruits, nuts, vegetables, dairy, and fish, provides antioxidants and anti-inflammatory nutrients including carotenoids, vitamins A, C, and E, flavonoids, zinc, and selenium⁹. Anti-inflammatory mechanisms include lowering lipids, reducing oxidative damage, decreasing platelet aggregation and inflammatory markers [C-reactive protein (CRP), IL-6, and tumor necrosis factor-α (TNF-α)]. Mediterranean diets support a probiotic gut microbiome—an ecosystem characterized by beneficial gut metabolite production and greater abundance of bacteria associated with lower inflammation and improved gut function [10^▪,11].

A prospective cohort of 2,023 general population adults assessed Mediterranean diet adherence via the Mediterranean Diet Score (numeric scale: 0–9) and found that score increases of 2–6 points over twelve years significantly reduced inflammation [β= -0.372, 96% confidence interval (96% CI) -0.720 to –0.025] based on a composite score of CRP, white blood cell and platelet counts, and granulocyte:lymphocyte ratio [12]. A cross-sectional survey of 387 SSc patients using the 14-item Mediterranean Diet Adherence Screener found 15% had optimal (score > 10), 71% moderate (6–9), and 14% low (0–5) adherence. Low adherence was linked to worse quality-of-life [e.g., work absenteeism (P = 0.05), depression (P = 0.048), Raynaud phenomenon (P = 0.03), digital ulcers (P = 0.001), and reflux (inverse correlation, P = 0.05)] [13].

FUNCTIONAL FOODS

Functional foods, herbal substances and foods for improved health and symptom reduction, remain understudied [14]; however, beetroot, rosemary, and curcumin may be beneficial SSc treatments.

BEETROOT

Beetroot is a nitrate-rich food containing vitamins, betalains, and phytonutrients, consumed as a supplement for its vasodilatory, anti-inflammatory, and thermoregulatory properties [15]. For Raynaud phenomenon sufferers in whom nitric oxide is low, beetroot may improve vascular function by boosting nitric oxide availability.

A double-blind, randomized crossover study of 23 patients with primary and secondary Raynaud phenomenon (17% with SSc) compared beetroot juice (12.4 mmol nitrate) to nitrate-depleted beetroot juice (NDBJ; 0.1 mmol of inorganic nitrate) and found that acute (140 ml consumed on testing days) and chronic (70 ml/day for 13 days + 140 ml consumed on testing days) supplementation improved thumb blood flow postcold challenge. Regardless of treatment duration, both beetroot juice and NDBJ significantly reduced systolic BP (acute NDBJ, P = 0.02; acute beetroot juice, P < 0.001; chronic NDBJ, P < 0.001; chronic beetroot juice, P < 0.001) and diastolic BP (acute NDBJ, P = 0.02; acute beetroot juice, P < 0.001; chronic NDBJ, P < 0.001; chronic beetroot juice, P < 0.001). IL-10 levels, an anti-inflammatory cytokine, increased significantly with acute NDBJ and beetroot juice (both P < 0.001), chronic NDBJ (P = 0.001), and chronic beetroot juice (P = 0.002). Plasma nitrate and nitrite were significantly elevated after both acute and chronic beetroot juice compared to NDBJ (P < 0.001 for all comparisons), with no differences between acute and chronic supplementation (P > 0.05). Serum pan-endothelin, a vasoconstrictor elevated in Raynaud phenomenon, decreased significantly with beetroot juice (P = 0.03). Thus, direct and indirect nitric oxide supplementation may improve Raynaud phenomenon [16].

ROSEMARY

Rosemary officinalis L, a medicinal herb from the Lamiaceae family, has antioxidant, anti-inflammatory, antimicrobial, vasodilatory, and wound-healing effects. A cross-over study design case report described an SSc patient whose hands were treated with rosemary oil 10% mixed with olive oil 90% daily, followed by olive oil 100% daily, each for three days. Daily infrared thermography following oil application showed increased right index finger mean temperature for the oil mixture (28.5°C–30.6°C) but not oil olive (25.13°C–24.03°C), while the left index finger showed minimal changes that were attributed to carpal tunnel syndrome [17]. In an open-label pilot study of twelve SSc-RP patients, a one-time hand application of olive oil 100% followed by rosemary oil 10% three hours later resulted in subjective increased hand warmth, although infrared thermography failed to show significant changes [18]. Thus, rosemary oil may improve Raynaud phenomenon symptoms and index finger skin temperature though sample sizes were small.

CURCUMIN

Curcumin, the active polyphenol in turmeric (Curcuma longa), exhibits anti-inflammatory and antifibrotic effects. It inhibits transforming growth factor-beta (TGF-β) signaling, a central fibrosis driver in SSc. In a bleomycin-induced mouse model, the curcumin analog LG283 significantly reduced dermal thickening/collagen deposition (P < 0.01). These antifibrotic effects were attributed to inhibition of TGF-β–induced Smad3 phosphorylation (a key mediator of profibrotic gene expression), and SNAIL1 and SNAIL2 expression (profibrotic transcription factors) [19]. In cultured SSc, but not healthy, lung fibroblasts, 6 h of 10 μM curcumin exposure selectively induced apoptosis. This effect involved altered protein kinase C epsilon signaling and reduced detoxification enzyme expression, including glutathione S-transferase P1 and heme oxygenase-1 [20]. Furthermore, a meta-analysis of 66 randomized clinical trials (RCTs) found that turmeric/curcumin supplementation significantly reduced levels of systemic inflammatory markers [CRP, TNF-α, and IL-6] and improved antioxidant markers [total antioxidant capacity, superoxide dismutase (SOD) activity, and malondialdehyde] in individuals with various health conditions. These findings support curcumin's potential role for modulating inflammation and oxidative stress in SSc patients [21].

VITAMINS

Vitamins – organic substances that are classified either as fat soluble (e.g., vitamin D and E) or water soluble (e.g., vitamin B and C) – support cell function and growth [22].

VITAMIN C, D, AND E

Vitamin C (ascorbic acid) is both an enzymatic and nonenzymatic antioxidant with anti-inflammatory properties. In a 6-month study of 13 diffuse cutaneous (dc) SSc patients, those receiving cyclophosphamide (500 mg/m² monthly) plus vitamin C (1000 mg/day) and vitamin E (400 IU/day) had significantly lower skin thickening progression rates compared to six patients only receiving cyclophosphamide (P < 0.04) [23].

Vitamin D is a steroid hormone with immunomodulatory and antifibrotic properties. Reduced Vitamin D receptor (VDR) expression in dermal fibroblasts from SSc patients and fibrosis mouse models is partly driven by TGF-β signaling. VDR activation by the selective agonist paricalcitol blocks Smad3 phosphorylation thereby reducing collagen production and fibroblast activation. In bleomycin-induced and constitutively active TGF-β receptor I mouse models, paricalcitol significantly reduced skin fibrosis via TGF-β/Smad pathway inhibition [24]. Thus, vitamin C and D supplementation may be beneficial for SSc skin fibrosis.

A systematic review of 40 studies confirmed the high prevalence of vitamin D deficiency in SSc and its correlation with severity (e.g., pulmonary hypertension, digital ulcers). Standard supplementation (800 IU/day) is often insufficient due to malabsorption or impaired vitamin D activation in fibrotic skin [25]. Vitamin D also supports reduction/oxidation (redox) homeostasis. A prospective study of 50 female SSc patients found significantly elevated urinary oxidative DNA damage markers, especially 8-oxo-2′-deoxyguanosine (8-oxo-dG), as well as reduced serum vitamin D and lower VDR gene expression measured by RT-PCR compared to controls. After intramuscular 150 000 IU (baseline and 3 months) and oral vitamin D 800 IU (six months daily), 8-oxo-dG levels declined, and whole blood mRNA VDR expression increased, particularly among patients with lung, joint, and gastrointestinal involvement [26]. These findings advance our understanding of vitamin D's role in modulating inflammation, oxidative stress, and fibrosis.

Vitamin E, a lipid-soluble antioxidant, regulates immune and fibrotic responses. A cross-sectional study of 14 women with SSc who took vitamin E (400 mg/day) for the prior six months showed persistent abnormalities of erythrocyte oxidation-balance measures compared to 23 untreated healthy controls. Specifically, they found increased levels of lipid peroxidation products in SSc overall (P < 0.01), and reduced catalase and SOD activity (P < 0.05) in four dcSSc patients, and increased glutathione peroxidase activity (P < 0.01) in ten limited cutaneous SSc patients, versus controls. Thus, SSc patients may have oxidative stress defense mechanism imbalances with reduced ability to degrade hydrogen peroxide even with vitamin E supplementation [27].

A 24-week open-label study assessed twelve SSc patients receiving pentoxifylline (800 mg/day) plus vitamin E (800 IU/day) and compared them to a group of nine dcSSc patients treated with 6 months of cyclophosphamide (0.5–1 g/m²). The pentoxifylline/vitamin E versus cyclophosphamide group showed a significant modified Rodnan Skin Score reduction from 25.7 to 18.7 (P = 0.03) versus 37.7 to 32.8 (P = 0.06) at week 16, respectively [28]. An open-label study of 27 SSc patients with 86 digital ulcers among them found 15 patients treated with topical vitamin E gel twice-weekly healed significantly faster (13.22 ± 2.72 weeks) compared to 12 receiving standard ulcer care (20.94 ± 3.65 weeks); P < 0.0001 [29]. However, a double-blind RCT of 36 SSc patients (assigned to receive vitamin E 500 mg/day or vitamin E 1000 mg/day or placebo) found no improvement in lipid peroxidation levels [urinary F(2)-isoprostanes] or microvascular perfusion (laser doppler perfusion imager) after 3 weeks of treatment [30]. These results suggest vitamin E may exert antioxidant and wound-healing effects in SSc, with greater benefits from prolonged supplementation and, possibly, higher dosage.

DIETARY SUPPLEMENTS

Dietary supplements are orally consumed products containing nutrients like trace elements or minerals to support health [31]. Supplements with some evidence in SSc include L-arginine, omega-3 fatty acids, potassium para-aminobenzoic acid, and zinc.

L-ARGININE SUPPLEMENTATION

L-arginine is an amino acid and NO precursor. Nitric oxide deficiency leads to endothelial derangements that may contribute to vascular fibrosis in SSc (e.g., Raynaud phenomenon and pulmonary arterial hypertension) [32]. Elevated asymmetric dimethylarginine (ADMA) levels act as a competitive antagonist of nitric oxide synthesis. L-arginine supplementation may help counteract nitric oxide deficiency by promoting nitric oxide production and competing with ADMA [32].

Nitric oxide modulates the transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), specificity protein-1, and activating protein-1 through multiple pathways, leading to reduced collagen gene expression [33,34]. Pathologically elevated ADMA blood levels can be seen in dcSSc patients [35]. Nitrate therapy and L-arginine supplementation to enhance the nitric oxide pathway are proposed as SSc-RP and digital ulcer treatments [36,37]. In a case series of four patients with SSc-RP, oral L-arginine supplementation depending on Raynaud phenomenon symptoms and severity (ranging from 2 to 6 g per day) reversed digital necrosis in two and improved Raynaud phenomenon symptoms in two [38]. Thus, arginine supplementation may be useful for SSc-RP patients.

OMEGA 3 FATTY ACIDS

Omega-3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid and docosahexaenoic acid, exhibit anti-inflammatory and immunomodulatory properties. Derived from cold-water fish, flaxseeds, and walnuts, PUFAs transform into resolvins and protectins, mediators which terminate inflammation by enhancing macrophage efferocytosis (apoptotic cell clearance to curb inflammation) and downregulating pro-inflammatory NF-kB and mitogen-activated protein kinase pathways [39]. They promote alternatively activated macrophages (M2) polarization, suppress IL-2, TNF-α, and interferon gamma production by CD8⁺ T cells, and shift CD4⁺ T cell differentiation away from T helper 1/Th1 cell and T helper 17/Th17 cell phenotypes while enhancing regulatory T cell activity, key mechanisms in SSc fibrosis and autoimmunity [40].

In preclinical models, PUFAs attenuate TGF-β–driven skin and lung fibrotic signaling [40]. Though not studied in SSc, a meta-analysis of 23 RCTs in rheumatoid arthritis patients found nonsignificant overall reduction in CRP (SMD: −0.11; 95%CI: −0.28–0.06; P = 0.1928). However, meta-regression found higher doses of omega-3 fatty acids significantly reduced CRP (b-coefficient: 0.11; 95% CI: 0.02–0.20; P = 0.0243) [41^▪]. Since elevated CRP levels are a hallmark of inflammation in SSc, particularly in those with interstitial lung disease, and anti-inflammatory agents like tocilizumab have shown clinical benefits, omega-3 intake may similarly help reduce systemic inflammation [42].

POTASSIUM PARA-AMINOBENZOIC ACID

Para-aminobenzoic acid (PABA), a naturally occurring compound and intermediate in bacterial folate biosynthesis, supports nucleic acid synthesis and DNA assembly. While nonessential in humans, it is present in liver, whole grains, mushrooms, and brewer's yeast. PABA has been used as adjuvant therapy to treat fibrotic diseases such as Peyronie's disease and Dupuytren's contracture [43]. Additionally, PABAs potassium salt form, potassium para-aminobenzoate (KPAB), has been used in SSc. In a retrospective study of 390 SSc patients that assessed the effect of KPAB treatment on forced vital capacity (FVC), overall, those adequately treated (KPAB 12 or 12.5 g daily for a duration of 3 months–20.6 years) showed significantly less decline versus untreated (no KPAB) or inadequately treated patients (those with less KPAB exposure for any reason) (P = 0.003). Specifically, lung fibrosis (on chest X-ray) patients treated (n = 15) versus untreated (n = 10) with KPAB demonstrated less decline in FVC (mean ± SD -0.047 ± 0.052 versus -0.191 ± 0.240) over a mean ± range follow-up 5.8 (1.1–13.0) and 2.1 (0.3–6.9) years, respectively [44]. Thus, KPAB treatment may be a useful adjunctive therapy in SSc-interstitial lung disease, but additional prospective studies need to be conducted before broad treatment is recommended.

ZINC

Zinc – an essential micronutrient and the body's second most abundant trace element – supports DNA synthesis, gene transcription, cell proliferation, collagen formation, and immune functions like antibody production and inflammatory signaling [45^▪▪]. SSc patients often face malnutrition from avoidant and restrictive food intake disorder, impaired gastrointestinal function with malabsorption, anorexia, microstomia, dysmotility, SIBO, and early satiety resulting in iron, selenium, copper, and zinc deficiencies. In fact, zinc deficiencies were present in 48% of 82 patients in a retrospective cross-sectional cohort study and 15% of 176 patients in another prospective study [46,47].

Zinc serves as a cofactor for matrix metalloproteinases (MMPs), enzymes crucial for regulating collagen deposition and breakdown in the extracellular matrix. Zinc deficiency increases ROS production and dysregulated MMP activity, promoting skin fibrosis [48]. Additionally, lung fibrosis models demonstrated zinc restoration through SLC39A8 transporter facilitates alveolar cell regeneration, suggesting a protective role in pulmonary tissue [48,49]. Supporting the beneficial effects of zinc, a small pilot study with 17 SSc patients reported that high-dose zinc gluconate (83.3 mg/day) resulted in partially or completely remitted morphea based on clinical evaluation [50]. These findings support zinc supplementation as a potential adjunct therapy in SSc and morphea for its antioxidant and wound-healing properties.

CONCLUSION

Complementary and alternative medicine including functional foods, diets, vitamins, and supplements are a topic of interest among physicians and patients. Although many of these interventions, such as vitamin D, omega-3 fatty acids, and curcumin, show mechanistic plausibility and favorable safety profiles, data remain largely preclinical or observational. Likewise, while dietary patterns like the Mediterranean, low FODMAP, and ketogenic diets may support gut health, inflammation reduction, or vascular function, randomized controlled trials in SSc populations are lacking (see Table 2). Future prospective studies and RCTs of these promising therapies are needed to clarify efficacy, standardize protocols, and guide clinical recommendations.

Table 2.

Summary of discussed interventions including proposed mechanisms of action, pathophysiology, and supporting references

Intervention	Proposed mechanism(s)	Relevance to SSc	Reference (Author, Year), Study design
Low-FODMAP diet	↓ fermentable carbs → ↓ osmotic load ↓ pathobionts like Klebsiella, Enterococcus	Alters gut microbiota; may reduce bloating, reflux, and SIBO-related GI symptoms	Nguyen et al., 2023 [7], cross-sectional SSc cohort
Ketogenic diet	↑ BHB → inhibits NLRP3 inflammasome → ↓ IL-1β, IL-18	Theoretically anti-inflammatory; no SSc trials yet	Youm et al., 2015 [8], mechanistic
Mediterranean diet	↓ CRP, IL-6, TNF-α; improves microbiome & antioxidant status	Low adherence linked to worse RP, digital ulcers, depression, reflux	• Dobroslavska et al., 2024 [9▪], narrative review • Abrignani et al., 2024 [10▪], narrative review • Bonaccio et al., 2023 [12], prospective cross-sectional cohort • Natalello et al., 2023 [13], cross-sectional
Beetroot	↑ NO bioavailability, ↓ BP, ↑ IL-10, ↓ endothelin	May improve RP-related vasculopathy and digital perfusion	Shepherd et al., 2019 [16], randomized crossover RP cohort (some SSc)
Rosemary oil	Antioxidant and vasodilatory properties → ↑ warmth perception	Modest improvements in self-reported RP symptoms and temperature	• Von Schoen-Angerer et al., 2018 [17], case report • Vagedes et al., 2022 [18], open-label pilot
Curcumin	Inhibits TGF-β/Smad3, ↓ collagen, ↑ fibroblast apoptosis	Anti-fibrotic effects in mouse models and SSc lung fibroblasts	• Utsunomiya et al., 2022 [19], preclinical • Tourkina et al., 2004 [20], cell-based
Vitamin C	Antioxidant with anti-inflammatory properties	May lower skin thickening progression rates in SSc	Ostojic et al., 2011 [23], RCT SSc cohort
Vitamin D	VDR activation → ↓ Smad3 → ↓ collagen; antioxidant effects	Deficiency is common; supplementation reduces oxidative stress markers and increased VDR in SSc patients	• Schneider et al., 2021 [25], systematic review • Dal-Bekar et al., 2023 [26], prospective
Vitamin E	Impaired erythrocyte redox balance in SSc, patients based on SOD, glutathione peroxidase, and catalase activity. Patients may benefit from vitamin E antioxidant properties to help optimize enzyme activities. Oral formulation may reduce skin thickening rates in SSc and topical form may promote wound healing in SSc digital ulcers	Reduced MRSS scores and improved digital ulcer healing in small studies	• Dworniak K, Duchnowicz P et al., 2013 [27], experimental • Souza et al., 2009 [28], open-label trial • Fiori et al., 2009 [29], RCT
L-Arginine	Precursor to NO; counteracts ADMA inhibition ↑ Vasodilatory properties	May improve PAH, RP, and digital ulcers via vascular NO pathway	• Dooley et al., 2006 [35], observational • Rembold et al., 2003 [38], case series
Omega-3 fatty acids	↑ Resolvins/protectins → ↓ NF-κB, MAPK, ↑ Treg, ↓ Th17	May reduce ILD inflammation and vascular dysfunction; not yet SSc-specific trials	Gkiouras et al., 2024 [41▪], meta-analysis study (rheumatoid arthritis, not SSc, patients)
PABA/KPAB	Inhibits collagen cross-linking	May slow FVC decline in patients with SSc-associated interstial lung disease	Zarafonetis et al., 1989 [44], retrospective SSc cohort
Zinc	Cofactor for matrix metalloproteinases (MMP), enzymes crucial for regulating collagen deposition and breakdown in the extracellular matrix Zinc affects collagen via specific transporters in lung tissue	High deficiency prevalence in SSc; possible anti-fibrotic and epithelial repair roles in the skin	• Dupont et al., 2018 [46], retrospective cross-sectional SSc cohort • Läubli et al., 2020 [47], prospective SSc cohort • Lin et al., 2017 [48], mechanistic

ADMA, asymmetric dimethylarginine; BHB, β-hydroxybutyrate; BP, blood pressure; CRP, C-reactive protein; FODMAP, Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols; FVC, forced vital capacity; GI, gastrointestinal; IL-1β, interleukin 1 beta; IL-10, interleukin 10; IL-18, interleukin 18; IL-6, interleukin 6; ILD, interstitial lung disease; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinases; MRSS, Modified Rodnan Skin Score; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, NOD-like receptor family pyrin domain-containing 3; NO, nitric oxide; PAH, pulmonary arterial hypertension; RCT, randomized controlled trial; RP, Raynaud phenomenon; SIBO, small intestinal bacterial overgrowth; Smad, Suppressor of Mothers Against Decapentaplegic; SSc, systemic sclerosis; TGF-β, transforming growth factor-beta; Th17, T helper 17 cell; TNF-α, tumor necrosis factor-alpha; Treg, regulatory T cell; VDR, vitamin D receptor.

Acknowledgements

The authors would like to thank Lorena Vasquez, MS, RDN, for her expert guidance in evaluating dietary strategies relevant to systemic sclerosis, and Alyssa Grimshaw, MBA, MSLIS, MPH, for valuable assistance with literature retrieval and reference management. The authors gratefully acknowledge Agrani Dixit, BA, for her contributions to data synthesis and critical review of early manuscript drafts.

Financial support and sponsorship

There was no funding for the publishment of this manuscript.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

• ▪ of special interest

• ▪▪ of outstanding interest