Complementary therapies for patients with systemic sclerosis

Abstract

Patients with systemic sclerosis often seek information regarding complementary and nutrition-based therapy. Some study results have shown that vitamins D and E, probiotics, turmeric, l-arginine, essential fatty acids, broccoli, biofeedback, and acupuncture may be beneficial in systemic sclerosis care. However, large randomized clinical trials have not been conducted. This review summarizes current data regarding various complementary therapies in systemic sclerosis and concludes with recommendations.

Introduction

Patients with autoimmune diseases including systemic sclerosis (SSc) inquire about dietary modifications and supplements. Twenty-five percent of early SSc patients enrolled in the Genetics versus Environment in Scleroderma Outcomes Study (GENISOS) reported complementary and alternative therapy use. ¹ The Trination Study Group reported alternative medicine use in ~50% of patients with systemic lupus erythematosus (SLE) in the United States, Britain, and Canada. ² Patients seeking versus uninterested in alternative medical therapies were younger, better educated, and less satisfied with medical care, independent of disease severity (assessed by the revised Systemic Lupus Activity Measure instrument). ² Thus, clinicians seeking strong therapeutic alliances should initiate nutrition and complementary treatment discussions. Herein, we summarize evidence and current recommendations regarding nutrition-based and complementary therapies relevant to SSc treatment.

Methods

A comprehensive Ovid Medline literature was performed to identify SSc complementary and nutrition-based therapies with significant available literature. Subject headings and key words included systemic scleroderma/sclerosis, dietary supplements, vitamins, and complementary therapies. Through consensus, we included additional therapies that patients frequently ask about in our experience. Herein, we review the following: vitamins D and E, probiotics, turmeric, l-arginine, essential fatty acids (EFAs), broccoli, biofeedback, and acupuncture.

Vitamin D

Metabolism and vitamin D mechanism of action

In addition to its calcium homeostasis and bone health roles, vitamin D modulates innate and adaptive immunity.^3,4 Skin, exposed to ultraviolet B radiation, converts 7-dehydrocholesterol to pre-vitamin D3 then with heat to cholecalciferol that is first hydroxylated in the liver to 25-hydroxyvitamin D3 (calcidiol), then again in the kidneys to 1,25-hydroxyvitamin D3 (calcitriol/active vitamin D). Calcitriol binds to small intestinal and bone cell receptors to increase calcium and phosphorus gut absorption and bone matrix mineralization, respectively (Figure 1). Calcitriol also binds innate (macrophages and dendritic) and adaptive (B- and T-) immune cell surface receptors to enhance immune tolerance, a mechanism that may confer benefit in autoimmune diseases ⁵ (Table 1 and Figure 1).

Figure 1.

Vitamin D regulation of calcium homeostasis, bone health, and immune system. Vitamin D is acquired from two sources: the skin and the gastrointestinal tract. In skin, ultraviolet light and heat converts 7-dehydrocholesterol to cholecalciferol. In the gastrointestinal tract, inactive vitamin D is absorbed from dietary sources such as milk, cheese, and legumes. Inactive vitamin D is converted to the active form, calcitriol, via hydroxylation in the liver and kidneys resulting in increased intestinal calcium and phosphorus absorption, increased bone resorption and bone matrix mineralization, and immune response regulation.

Table 1.

Immune response to 1,25-dihydroxyvitamin D.^4,6,7

Innate immunity
Dendritic cells	Increase T cell apoptosis induced by dendritic cells Inhibit monocyte to dendritic cell maturation Increase dendritic cell IL-10 production
Macrophages	Decrease antigen presentation by macrophages
Adaptive immunity
B cells	Inhibit proliferation, differentiation to plasma cells, and production of antibodies
T cells	Inhibit Th1 cells: decreases IL-2 and IFN-γ production Stimulate Th2 cells: increases IL-4, IL-5, and IL-10 production Decrease IL-17 production by T helper cells Activate regulatory and natural killer T cells

Vitamin D and SSc disease activity

Hypovitaminosis D, defined as <30 ng/mL level, ³ is prevalent in SSc. In a Vacca et al. ⁸ study, 131 out of 156 (84%) SSc patients in northern France and southern Italy were vitamin D deficient (calcidiol < 30 ng/mL), and 44 out of 156 (28%) had levels <10 ng/mL, independent of disease subtype (limited/lcSSc vs diffuse cutaneous/dcSSc), although unadjusted for sun exposure. In Israel, 1029 patients with autoimmune diseases had lower mean (SD) calcidiol levels compared to controls (11.0 ng/mL (± 5.8) in 229 SSc patients; 11.9 ng/mL (± 11.1) in 138 SLE patients; 9.3 ng/mL (± 4.4) in 56 rheumatoid arthritis (RA) patients vs European control value of 21.6 ng/mL). ⁹ A 2-year study of 161 patients with early undifferentiated connective tissue disease (UCTD) showed significantly lower baseline vitamin D levels in the 21% of patients who developed RA, SLE, mixed connective tissue disease (MCTD), or Sjogren’s syndrome compared to those with persistent UCTD. ¹⁰ The authors conclude that hypovitaminosis D may be one factor associated with UCTD progression to specific connective tissue diseases.

Studies examining the correlation between calcidiol and SSc demonstrate conflicting results. Vacca et al. ⁸ showed that lower vitamin D levels correlated with higher European Disease Activity Scores (r = −0.17, p = 0.04), a score that includes points for skin, vascular, pulmonary, joint, and laboratory values (low complement and elevated erythrocyte sedimentation rate (ESR)); higher acute phase reactants (ESR: r = −0.23, p = 0.004; C-reactive protein (CRP): r = −0.22, p = 0.01); increased pulmonary arterial systolic pressure on echocardiography (p = 0.004), and pulmonary fibrosis on computed tomography (CT) scans (p = 0.04). ⁸ Montabone et al. ¹¹ demonstrated an association between hypovitaminosis D and worse physical component scores measured on the Medical Outcomes Study Short-Form (SF)-36 questionnaire (p = 0.04) in 101 patients with SSc. Similarly, Sampaio-Barros et al. ¹² reported positive correlations between serum vitamin D levels and vitality (r = 0.385, p = 0.017), social function (r = 0.320, p = 0.050), emotional role (r = 0.321, p = 0.049), and mental health (r = 0.531, p = 0.0006) on the SF-36 in 38 women with dcSSc. No significant associations between vitamin D level and SSc disease duration (r = −0.280, p = 0.088) or modified Rodnan skin score (mRSS) (r = 0.028, p = 0.866) were identified. Moreover, investigators found significant negative associations between vitamin D level and avascular area on nailfold capillaroscopy as assessed using a bifocal stereomicroscope (r = −0.347, p = 0.033), diffuse devascularization, defined by number of capillary loops in a linear 1-mm-wide area where normal is ⩾7 loops (r = −0.355, p = 0.029), and hand grip strength (r = −0.331, p = 0.042). ¹² Trombetta et al. ¹³ studied 154 SSc patients and found lower vitamin D levels in those with versus without lung fibrosis (16.1 ± 8 ng/mL vs 20 ± 10 ng/mL; p = 0.04), peripheral vascular disease (p = 0.03), kidney disease (p = 0.02), and gastrointestinal (GI) disease (p = 0.05), but no significant difference in digital ulcers (DUs) between groups. Alternatively, Calzolari et al. ¹⁴ found no association between vitamin D deficiency and SSc subtype, GI involvement, or cutaneous ulcers in 60 SSc patients. Thus, hypovitaminosis D may be associated with increased inflammatory markers, worse patient-reported measures of SSc disease activity, abnormal nailfold capillaroscopy, and lung, GI, vascular, and kidney diseases, but a causal relationship has not been established.

Vitamin D supplementation in SSc

In 2015, the US Preventive Service Task Force (USPSTF) determined there was insufficient evidence to support laboratory screening for vitamin D deficiency in asymptomatic, non-pregnant adults, and insufficient evidence to recommend daily vitamin D supplementation (cholecalciferol dose > 400 IU) for primary fracture prevention in premenopausal women or men. ¹⁵ However, recommendations excluded patients with medical conditions including bone, endocrine, and autoimmune diseases where determining serum vitamin D level could be considered disease assessment rather than routine screening. ¹⁵

Although no large prospective trials have determined the effect of vitamin D supplementation on clinical outcomes, SSc patients may demonstrate low vitamin D levels despite standard vitamin D supplemental dosages. In 48 SSc patients, Rios Fernandez et al. ¹⁶ found calcidiol levels <30 ng/mL in 81% and <10 ng/mL in 9.5% of patients, despite 60% of the cohort taking 800 IU/day of cholecalciferol. Similarly, Trombetta et al. ¹³ studied 154 SSc patients and found that those taking oral cholecalciferol 1000 IU daily for ⩾6 months had similar serum calcidiol levels as untreated patients (18.8 ± 10 ng/mL vs 18.7 ± 9 ng/mL, respectively; p = 0.81). The high vitamin D deficiency prevalence in SSc patients on standard doses of vitamin D may be related to poor absorption of fat-soluble vitamins due to SSc GI tract involvement, ⁸ avoidance of vitamin D–rich foods (i.e. sardines, salmon and tuna) due to symptomatic gastroesophageal reflux disease or small intestine bacterial overgrowth (SIBO), or decreased vitamin D activation in thick skin. However, Trombetta et al. ¹³ demonstrated higher mean serum calcidiol concentrations (ng/mL) during summer months compared to autumn, spring, and winter (14.6 ± 7.8 (winter), 17.2 ± 7.9 (spring), 21.43 ± 10 (summer), 20.2 ± 10 (autumn); p = 0.03) in 154 European SSc patients. Although no formal recommendation exists regarding vitamin D supplementation in SSc, the general recommendation for patients with malabsorption is cholecalciferol 50,000 IU daily, every other day, or weekly to achieve target calcidiol levels (30–60 ng/mL) for up to 5 months followed by 50,000 IU weekly for maintenance. ³ In SSc patients without malabsorption, cholecalciferol (600–800 IU daily) may be adequate as initial supplementation and maintenance if baseline calcidiol level is mildly reduced. ¹⁷

Vitamin E

DUs occur in up to 50% of SSc patients and result in higher levels of disability compared to those without DUs.^18,19 Topical vitamin E may improve DUs by promoting vasodilation via enhanced prostanoid release. ²⁰ DUs result from SSc vasculopathy-related damage to endothelial cells that increases vasoconstrictor production (i.e. endothelin) and decreases vasodilator production (i.e. prostacyclin and nitric oxide (NO)). ¹⁸ Tissue ischemia leads to oxygen free-radical injury and ulceration. ¹⁸ In vitro, vitamin E exposure causes human aortic endothelial cells to release prostanoids (prostaglandin I₂/PGI₂ and PGE) that promote vasodilation and inhibit platelet aggregation. ²¹

Vitamin E in SSc

In an open-labeled, randomized SSc pilot study, the use of topical vitamin E gel (n = 15) led to faster DU healing compared to placebo (n = 12) (13.22 ± 2.72 vs 20.94 ± 3.65 weeks; p < 0.01). ²⁰ There were no significant differences between groups in SSc subtype, autoantibodies, sex, and age. Both groups received a standard DU care protocol twice per week: (1) cleansing, irrigation by physiological solution; (2) disinfection by sodium hypochlorite 5%, followed by rinsing with physiological solution; (3) curettage of eschar (if present) with scalpel; (4) application of vitamin E gel on the lesion in experimental group; and (5) application of hydrogel and/or gauze and covering lesion with paraffin gauze. Participants applying the vitamin E gel self-reported less analgesic medication use (17.82 ± 4.59 vs 26.26 ± 19.16 doses; p = 0.0022). ²⁰ Although limited by small sample size and self-reported use of pain medication with potential for recall bias, these data suggest that vitamin E gel may be a useful DU therapy. These results underscore the importance of proper DU care, ²² as both groups improved.

Prospective studies using oral vitamin E have not illustrated a similar treatment effect. One case report demonstrated echocardiographic normalization of SSc-associated cardiomyopathy in a 60-year-old patient after vitamin E (600 mg daily) was added to her treatment regimen, 6 months after failing standard care. ²³ However, a randomized, blinded trial investigated oral vitamin E (500 or 1000 mg) versus placebo for 3 weeks in 33 SSc patients and found no difference in cutaneous blood flow variation in response to cooling before versus after treatment in any group. ²⁴ In addition, urinary F2-isoprostane levels (a biomarker for lipid peroxidation that is increased in SSc) were similar between groups. Authors concluded that these data did not support phase III clinical trials investigating oral vitamin E in SSc. ²⁴

Probiotics

Gut microbiota and immune function

An estimated 10¹⁴ bacterial cells compose the healthy human gut microbiota. ²⁵ Intestinal epithelial cells and gut-associated lymphoid tissue (GALT) are involved in antigenic ignorance and active tolerance toward gut commensals. In antigenic ignorance, GI tract cells maintain separation between microbe antigens and immunoreactive cells. In active tolerance, specific antigens induce an anti-inflammatory response and reactive immune cell deletion. Dendritic and regulatory T cells produce IL-12 and IL-10 that dictate whether the immune response is inflammation or tolerance, respectively. ²⁶

The importance of gut microbiota in regulating immunity is evident from studies of gut microbiota-deficient mice raised within germ-free incubators. These mice demonstrate a skewed cytokine profile with a decreased T helper cell (TH1/TH2) ratio and lower tumor necrosis factor (TNF)-α, IgA-producing B cells, and lymphoid follicle levels that can lead to type II and III hypersensitivity reactions and autoimmune disease. ²⁷ Microbiota reintroduction by selectively adding certain bacteria into the diet, including Bacteroides fragilis, lactobacillus, and the peptidoglycan of gram-negative bacteria, promotes lymphoid organogenesis, induces CD4 + T cell activation, and restores TH1/TH2 cytokine balance, possibly leading to a more balanced immune system response.^28,29

The complex interplay between gut microbiota and immune response has led researchers to manipulate the gut microbiota for disease management (Table 2). For example, in patients with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD), probiotics such as Lactobacillus casei and Lactobacillus rhamnosus GG are associated with health-related quality of life improvement and disease flare reduction.^37,38 Although the precise mechanism is unknown, probiotics have been shown to induce intestinal epithelial cell production of alkaline phosphatase that dephosphorylates and inactivates endotoxins produced by pathogenic bacteria (i.e. Bacteroides species). ³⁹ Mouse model colitis experiments have shown that exposure to Lactobacillus rhamnosus decreases epithelial cell permeability, ⁴⁰ suggesting that probiotics help maintain a tight gut epithelial barrier that reduces antigen translocation and promotes healthy gut immunity.

Table 2.

Probiotics.

Probiotic	Human disease in which benefit is shown
Yeast
Saccharomyces boulardii	Clostridium difficile infection 30
Gram-positive organism
Bifadobacteria infantis	Irritable bowel disease 31
Lactococcus lactis (engineered to produce IL-10 or trefoil factors)	Crohn’s disease 32
Lactobacillus plantarum 299v	Antibiotic-associated diarrhea 33
Bifidobacterium infantis or lactobacillus GG	Systemic sclerosis 34
Combination regimens
Lactobacillus rhamnosus GG combined with Bifidobacterium lactis	Bacterial infections 35
VSL#3 (Lactobacillus casei, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus bulgaricus, Bifidobacterium longum, Bifidobacterium breve, Bifidocacterium infantis, and Streptococcus thermophilus)	Ulcerative Colitis 36

Probiotics and SSc

Gut microbiota perturbations may be a pathologic SSc feature. ⁴¹ Patients with SSc demonstrate differences in fecal microflora compared to healthy individuals. Volkmann et al. ⁴² compared colonic microbial composition in 17 SSc patients (six dcSSc, median disease duration 6.6 years) with age- and sex-matched healthy controls from a microbiome repository. Fewer sigmoidal and cecal Faecalibacterium, Clostridium, and Rikinella commensal species and greater pathobiont species, such as Fusobacterium and Proteobacteria, were observed in SSc patients versus controls. ⁴² Study limitations include cross-sectional design, small sample size, and potential batch effect because placebo and SSc samples were analyzed by high-throughput sequencing separately.

Probiotics may benefit SSc patients by restoring microbiota balance. A 2011 pilot study by Frech et al. ³⁴ studied eight lc- and two dcSSc patients with moderate to severe abdominal distention attributed to SSc GI involvement. Baseline and 2-month scores for bloating on the University of California at Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0), a validated 34-item scoring system, were compared in patients taking either probiotics Bifidobacterium infantis or lactobacillus. ⁴³ There was significant improvement in total GIT 2.0 score (effect size (ES) = 0.82), bloating/distension (ES = 1.76), reflux (ES=0.33), and emotional scales (ES = 0.18) in the probiotics group. ³⁴ Study limitations include lack of placebo arm and blinding, small sample size, short therapy duration, limited follow-up, and lack of controlling for SIBO. A placebo-controlled, double-blinded trial in 2016 randomized 37 SSc patients (median disease duration 6 years; SSc subtype unspecified) to lactobacillus or placebo and measured UCLA SCTC GIT 2.0 score differences between baseline and 2-month follow-up. A significant difference between treatment and control groups was observed in esophageal reflux (0.91 vs 1.89; p = 0.001), abdominal distention (0.7 vs 1.89; p = 0.001), and social functioning (0.33 vs 0.78; p = 0.001) mean scores; however, the total GIT score was not different (0.68 vs 1.29; p > 0.05). ⁴⁴ Study limitations include small sample size and failure to exclude other causes of bloating/distention, such as gastroparesis.

Despite favorable side-effect profile, no US regulations presently ensure probiotic purity. Probiotics are classified as “foods” and regulated by the Center for Food Safety and Applied Nutrition. The US Food and Drug Administration (FDA) has not yet approved probiotics for the treatment of disease. ⁴⁵ In 2012, the European Food Safety Authority Union (EFSA) rejected probiotic health claims, classifying them as supplements. ⁴⁶ Table 2 summarizes selected organisms used as probiotic agents in diseases including SSc; however, no consensus exists regarding probiotic strains or concentrations that support immune homeostasis.

Turmeric

Immune function and turmeric

Curcumin is the yellow component of the root of turmeric, a plant frequently used in South Asian and Middle Eastern cuisine, and has been shown to have antioxidant, anti-inflammatory, and anti-fibrotic properties in vitro and in vivo. ⁴⁷ Curcumin is thought to exert its anti-inflammatory effect through inhibition of NF-κB, AP-1, STAT, and MAP kinases with a net decrease in inflammatory cytokines including IL-1 and IL-6.^47–49 NF-κB is a pro-inflammatory transcription factor activated by inflammatory cytokines and most potently by TNF-α. ⁴⁹ Curcumin is hypothesized to block NF-κB activation by inhibiting IκBα kinase (IKK) and AKT (Figure 2) ⁴⁹ and decreasing anti-apoptotic signals (promoting apoptosis) in human myeloid leukemia cells by preventing the activation of NF-κB.^49,50 In cultured synovial fibroblasts from RA patients, curcumin induced apoptosis through downregulation of anti-apoptotic signals (Bcl-2) which led investigators to hypothesize that curcumin may be used to limit synovial hyperplasia. ⁵¹

Figure 2.

Curcumin inhibition of IkBα phosphorylation. Lipopolysaccharide (LPS) binds Toll-like receptor 4 (TLR-4) and activates IκBα kinase (IKK). Activated IKK phosphorylates IκBα, activating nuclear factor (NF)-κB that then travels to the nucleus and inhibits apoptosis and increases cell proliferation and angiogenesis of tumor cells (Panel A). Curcumin suppresses IKK activation, thus preventing phosphorylated IκBα activation of NF-κB and blocking its pro-inflammatory effects (Panel B).

Curcumin and SSc

In vitro results support a role for curcumin as an anti-fibrotic therapy for SSc patients via transforming growth factor-beta (TGF-β) signaling modulation.^52,53 Cultured dermal fibroblasts from SSc patients secrete increased extracellular matrix and type 1 collagen (Col 1) in response to TGF-β (pro-fibrotic signaling molecule) stimulation compared to healthy controls. ⁵⁴ However, exposure to curcumin may help normalize TGF-β signaling in SSc fibroblasts based upon experiments in cultured renal fibroblasts. Gaedeke et al. ⁵² studied curcumin’s effect on downstream TGF-β targets (Col 1, plasminogen activator inhibitor-1 (PAI-1), and fibronectin (FN)) in cultured TGF-β stimulated renal fibroblasts and found that 30 min of pre-treatment with curcumin (0–20 μmol/L) prior to addition of TGF-β (5 ng/mL) resulted in a dose-dependent decrease in Col I, PAI-1, FN, and TGF-β1 mRNA production. Likewise, Song et al. ⁴⁸ treated cultured SSc dermal fibroblasts from skin biopsies of five immunosuppressant naïve women with curcumin (2, 5, or 10 μM) prior to incubation with TGF-β (5 ng/mL) and quantified expression of multiple pro-fibrotic genes and transforming growth interacting factor (TGIF), a potential inhibitor of TGF-β. Pro-fibrotic gene expression (i.e. Col 1, FN, and PAI-1) was reduced, and TGIF levels were increased in curcumin-treated versus untreated fibroblasts. Thus, curcumin may exert an anti-fibrotic effect by increasing TGIF levels and modulating TGF-β signaling (Figure 3). ⁴⁸

Figure 3.

Effect of curcumin on transforming growth factor beta. Transforming growth factor beta (TGF-β) acts on dermal fibroblasts to promote cell growth and proliferation. Addition of curcumin leads to increased transforming growth interacting factor (TGIF) expression which dampens TGF-β effects.

Despite potent anti-fibrotic in vitro effects, curcumin bioavailability in vivo is low (51.2 ng/mL in serum), even at high doses (12 g/day). ⁵⁵ Cancer patients taking curcumin doses (4000, 6000, and 8000 mg) lacked treatment-related adverse events, but had low average peak serum concentrations (0.51 ± 0.11, 0.63 ± 0.06, and 1.77 ± 1.87 μM, respectively). ⁵⁶ Oral curcumin doses necessary to generate bioactive serum concentrations may be prohibitive, as doses above 8000 mg were bulky and intolerable. Co-administering curcumin (2000 mg) with piperine (5 mg), an inhibitor of hepatic glucuronidation involved in curcumin metabolism, doubled curcumin bioavailability in healthy volunteers, providing a foundation for future trials co-administering these agents. ⁵⁵ Additionally, Kim et al. demonstrated that curcumin may have an anticoagulant effect that may be important to consider in some SSc patients. ⁵⁷

L-arginine

L-arginine and the NO pathway

L-arginine may treat Raynaud’s phenomenon (RP) by increasing endothelial cell production of NO to promote vasodilation. Arginine is substrate for nitric oxide synthase (NOS) that produces tissue NO. ⁵⁸ Two NOS isoforms are relevant to SSc: inducible NOS (iNOS) and endothelium NOS (eNOS). iNOS expression is low in healthy tissue and upregulated when exposed to pro-inflammatory cytokines (e.g. IL-1, TNF-α, IFN-γ), and lipopolysaccharide (LPS). Elevated iNOS expression is observed in lesional SSc versus normal skin and may play a role skin fibrosis and free-radical-induced endothelial cell injury.^59,60 Conversely, low eNOS expression by SSc endothelial cells impairs vascular relaxation and promotes vasculopathy (i.e. RP and pulmonary arterial hypertension (PAH)). ⁵⁸ Thirty-three SSc patients (13 dcSSc, 20 lcSSc) with skin disease that was clinically scored (0 = normal; 1 = indurated phase; 2 = fibrotic phase; and 3 = end-stage (tethering and atrophy)) underwent skin biopsies that were histologically scored (0 = normal or minimal perivascular edema; 1 = normal dermal matrix with marked perivascular edema; 2 = abnormal matrix protein deposition with fibrosis, elastosis or loss of reticular-papillary dermal definition; and 3 = dense fibrosis, epidermal atrophy, and adenexal loss). ⁵⁹ Increased iNOS and decreased eNOS gene expression correlated with worsening clinical-histopathological SSc grade. ⁵⁹ Thus, a metabolic switch may occur in SSc dermal endothelial cells during skin disease progression that alters NOS isoform balance that may result in NO-induced free-radical endothelial cell injury. ⁵⁹

Endogenously produced asymmetric dimethylarginine (ADMA) in tissue inhibits NOS. ADMA levels are increased in patients with secondary RP, DU, and SSc-PAH and correlate with PAH severity indices including the 6-min walk test.^61,62 Supplementation with l-arginine may overcome the competitive inhibition by ADMA and increase NO production to promote vasodilation and improve SSc vasculopathy. ⁶³ However, controversy exists regarding whether ADMA is elevated in SSc tissue. Two studies measuring ADMA levels in SSc-RP demonstrated opposite results. Specifically, one study (n = 187) found no increase in serum ADMA from controls, ⁶⁴ while another study (n = 89) found significantly increased serum ADMA levels in dcSSc patients. ⁶⁵ Furthermore, because iNOS is elevated in late-stage SSc skin, increasing NO to promote vasodilation could paradoxically result in NO-related free-radical endothelial cell injury. ⁵⁹

L-arginine and SSc

Studies evaluating l-arginine supplementation in SSc-RP demonstrate conflicting results. A case series of four SSc patients with DUs, refractory to calcium channel blockade, reported DU improvement with oral l-arginine (up to 6 g daily) that worsened upon discontinuation. ⁶⁶ In another series, four pregnant SSc patients (three lcSSc, one dcSSc) treated with oral or intravenous l-arginine experienced improvement in frequency and severity of RP without adverse effects. ⁶⁷ Khan and Belch ⁶⁸ studied eight SSc patients in a double-blind crossover study comparing l-arginine (8 g daily for 28 days) to placebo and found no improvement in vascular response, measured by laser Doppler flowmetry after endothelial-dependent vasodilator exposure (acetylcholine). Currently, no formal recommendations exist regarding l-arginine use in SSc.

Essential Fatty Acids (EFAs)

EFAs and vascular reactivity

EFAs are precursors for prostaglandin synthesis ⁶⁹ and may benefit SSc-RP by improving vascular reactivity. In rats with cannulated carotid arteries and dissected aorta, exposure to EFAs versus placebo decreased vascular reactivity in response to renin and angiotensin II and decreased platelet aggregation in supernatant from dissected aorta, measured by ADP-induced aggregation assay. ⁶⁹ EFAs may improve vascular response to ischemia by shifting to a balance between thromboxane A₃ and prostacyclin I₃ that favors vasodilatation and decreased platelet aggregation. ⁷⁰

Fatty Acids in SSc

Fish oil and evening primrose contain EFAs (i.e. omega-3 fatty acids, gamma linolenic acid (GLA)) ⁷¹ and have been studied as supplements for RP. DiGiacomo et al. ⁷² conducted a randomized trial administering 12 omega-3 fatty acid tablets daily (3.96 g eicosapentaenoic acid, 2.64 g docosahexaenoic acid) versus olive oil placebo tablet to patients with primary (n = 20) or secondary (n = 12) RP. Outcomes included baseline to 17-week follow-up difference in digital arterial flow (DAF), digital systolic pressure (DSP), and time to RP onset in 40°C–10°C water bath. Each outcome was analyzed in primary RP, and DAF was analyzed in secondary RP patients. In the total cohort, baseline to 6-week mean DAF in 40°C water bath increased in the treatment group (9.1 ± 4.6 to 11 ± 2.9 percent/min) and decreased in placebo group (10.8 ± 3.6 to 8.0 ± 2.1 percent/min) (p = 0.004). Likewise, among primary RP patients only, baseline to 6-week mean DAF increased in the treatment group (9.94 ± 4.2 to 11.0 ± 2.8 percent/min) and decreased in the placebo group (9.6 ± 4.2 to 7.8 ± 2 percent/min) (p = 0.008). However, among secondary RP drug- versus placebo-treated patients, mean DAF was not different from baseline to 6 weeks. This differential treatment response may be due to fixed, anatomic SSc-related vascular changes. Authors conclude that fish oil may improve primary but not secondary RP.

Other EFA studies in SSc yield conflicting results. Belch et al. ⁷³ studied 21 primary or secondary RP patients who received evening primrose oil (efamol) versus placebo for 8 weeks. ⁷⁴ Fewer (weighted mean difference of 20 fewer attacks, p < 0.01) and shorter (1633.80 fewer minutes over a 2-week period after 6 weeks of therapy, p < 0.001) RP attacks were observed in the treatment versus placebo group, but there was no difference between groups in RP severity by visual analog scale (VAS) (p = 0.21). Conversely, Stainforth et al. ⁷¹ randomized 25 SSc patients to 6 months of EFA (GLA) versus placebo and found no difference in DAF measurements in response to cold challenge (~17°C) between groups. These studies were limited by small sample size.^71,73,74 Thus, future EFA clinical studies in SSc should be prospective and include adequate patient numbers.

Broccoli/Nrf2 Pathway

Immune function, broccoli, and the Nrf2 pathway

Cruciferous vegetables (i.e. broccoli, cauliflower, cabbage, etc.) contain glucosinolates that are hydrolyzed by endogenous plant enzymes (myrosinases) into antioxidant compounds called isothiocyanates, including sulforaphane. ⁷⁵ Sulforaphane activates nuclear factor-erythroid 2-related factor 2 (Nrf2), a transcription factor that increases transcription of antioxidant genes such as NAD(P)H quinone oxidoreductase-1 (NQO1) and glutathione S-transferase^76,77 and decreases transcription of pro-inflammatory genes. Specifically, inactive Nrf2 is sequestered in the cytoplasm by Kelch-like ECH-associated protein 1 (Keap1). Sulforaphane prevents binding of Keap1 to Nrf2, allowing Nrf2 to translocate to the nucleus where it disrupts the recruitment of RNA polymerase II to LPS-induced pro-inflammatory genes, such as IL-6 and IL-1β (Figure 4).^78,79 LPSs on the outer membrane of gram-negative bacteria typically elicit a strong immune response. ⁸⁰ Sulforaphane also decreases NF-κB nuclear translocation by inhibiting phosphorylation of IkBα, thus dampening NF-κB inflammatory effects (Figure 4). ⁸¹

Figure 4.

Mechanism of action of sulforaphane. Lipopolysaccharides in gram-negative bacteria activate Toll-like receptor 4 and induce production of pro-inflammatory cytokines (e.g. tumor necrosis factor-α (TNF-α), interleukin-1-β (IL-1β)). The transcription factor, Nrf2, is bound by Keap-1 in the cytoplasm, but cruciferous vegetable-derived sulforaphane liberates and activates Nrf2 permitting its nuclear translocation. In the nucleus, Nrf2 disrupts recruitment of RNA polymerase II to LPS-induced pro-inflammatory genes, such as IL-6 and IL-1β. Nrf2 is hypothesized to also inhibit the activation of NF-κB, a pro-inflammatory transcription factor.

To investigate broccoli supplements as antioxidants, Hwang and Lim ⁸⁰ isolated and injected sulforaphane from broccoli into murine LPS-activated macrophages. Sulforaphane-treated macrophages demonstrated lower active NF-κB levels, evidenced by decreased iNOS activation, suggesting that sulforaphane has antioxidant activity and prevents NF-κB activation. Townsend et al. tested the effect of a freeze-dried broccoli-enriched diet in healthy aged (18 months old) and adult (4 months old) male and female mice that received daily intraperitoneal LPS injections for 28 days. Mice (n = 5–7/group) were randomized to regular chow with or without 10% broccoli (~0.5 µmol of sulforaphane per gram). IL-1β level and Nrf2 antioxidant enzyme activity in liver and brain tissue were measured at 4 weeks. ⁸² Broccoli consumption resulted in a modest reduction in oxidative stress markers (cytochrome b-245 β), but did not mitigate LPS-induced IL-1β elevation. These data suggest that higher supplemental doses of sulforaphane may be needed to produce an anti-inflammatory effect.

Broccoli/Nrf2 in SSc

The anti-inflammatory potential of the Nrf2 pathway has prompted research examining the effect of Nrf2 activation in SSc animal models and skin biopsies from SSc patients. ⁷⁶ Wei et al. ⁷⁶ reported reduced Nrf2 activity and expression in SSc skin biopsies versus healthy controls. In cultured SSc fibroblasts, Nrf2 overexpression led to an attenuated TGF-β-induced inflammatory response. In addition, Nrf2 knockout versus wild-type mice showed greater bleomycin-induced skin fibrosis. These data suggest that Nrf2 has both anti-fibrotic and anti-inflammatory properties; however, there are no in-human data to support increased cruciferous vegetable ingestion as an SSc therapy. VEDA-1209, a compound that emulates sulforaphane, has been shown to reduce inflammation and skin fibrosis in two distinct scleroderma animal models. ⁸³ However, cruciferous vegetables may increase bloating symptoms in SSc patients with GI involvement, an important consideration for future clinical work.

Biofeedback

Temperature biofeedback has been studied as RP treatment and teaches patients to increase hand temperature using relaxation techniques, mental imagery, and spoken phrases while receiving continuous digital temperature change feedback. ⁸⁴ Electromyographic (EMG) biofeedback has been used as a biofeedback control in RP studies whereby patients receive feedback on frontalis muscle EMG changes, a surrogate for overall tension, during general relaxation training. ⁸⁵ The Raynaud’s Treatment Study Investigators conducted a prospective clinical trial that randomized 313 patients with primary RP to nifedipine (30–60 mg daily) (n = 77), pill placebo (n = 81), temperature biofeedback (intensive baseline course with refresher instruction and assigned “homework” throughout the year) (n = 81), or control (EMG) biofeedback (same biofeedback teaching frequency) (n = 74). Investigators measured RP attacks during one winter month approximately 12 months after treatment initiation. Temperature biofeedback did not reduce RP attacks compared to control biofeedback or nifedipine. ⁸⁶ Conversely, Sporbeck et al. ⁸⁷ conducted a prospective, randomized trial evaluating temperature biofeedback or deep oscillation thrice weekly for 12 weeks versus no treatment for RP in 28 SSc patients (nine dcSSc, 19 lcSSc) and measured RP severity by VAS. Deep oscillation applies a low intensity electrostatic field to a target area to improve lymphatic drainage.^87,88 Compared to no treatment, temperature biofeedback improved (p < 0.02), while deep oscillation did not significantly improve (p = 0.055) RP severity. Digital temperature during cold stress challenge was not different between groups. Study limitations include small sample size and subjective primary outcome.

A meta-analysis of data from 111 primary or secondary RP patients from four clinical trials showed that sham versus temperature biofeedback was superior, weighted mean difference of −1.21 (fewer) RP attacks; 95% confidence interval (CI) −1.68 to −0.73 (p < 0.01). ⁷⁴ Of note, there was significant heterogeneity among the trials included in the analysis (I² = 93.7%), and the more recent, positive study by Sporbeck et al. was not included. Together, these results suggest that weekly temperature biofeedback sessions followed by at-home practice may not be sufficient training for patients with RP and that daily or three times weekly temperature biofeedback sessions may be required. Another possibility is that a combination of temperature biofeedback and oral medications are better than either alone.

Acupuncture

Acupuncture involves small needle insertion (0.12−0.35 mm diameter, 7–125 mm length) to specific acupoints mapped by meridian theory that are believed to impart physiologic change.^89,90 Meridians map the location of acupoints used in China for centuries. ⁹⁰ Acupressure provides non-puncturing pressure to acupuncture sites. ⁹¹ In SSc, acupuncture targeting GI acupoints (PC6 and/or ST36) has been investigated to treat GI dysmotility. ⁹² Wollaston et al. ⁹¹ applied acupressure to Neiguan point PC6 (GI, antiemetic point) versus sham acupressure to 16 SSc patients (mean disease duration 7.1 years), and 17 healthy controls while monitoring gastric myoelectric activity using surface electrogastrogram electrodes to detect GI gastric rhythm modulation from baseline. Investigators found significant alterations in gastric myoelectric activity in the treatment versus control group and postulated that further studies may determine if acupuncture improves GI symptoms over time. A case report describes two SSc patients with disease duration 7 and 30 years, refractory to immunosuppressive therapy, who experienced subjective improvement in joint pain, heart burn severity, and fatigue as well as mRSS reduction and widening of maximal oral aperture after the addition of acupuncture. ⁹³ Maeda et al. ⁹⁴ studied 11 SSc patients (four dcSSc, seven lcSSc), six scleroderma spectrum disorder patients, and seven healthy controls and found electrical acupuncture-stimulation therapy led to increased skin surface temperature (typically 1−1.5°C) in 14 of 17 patients with SSc or scleroderma spectrum disorder and none of the healthy controls. However, no other clinical outcomes were reported, including RP frequency. Acupuncture in SSc study results suggest that acupuncture could be considered, though evidence is limited, in SSc patients with symptomatic GI disease or RP.

Conclusion

In the current age of information and evidence-based medicine, patients and clinicians seek sound evidence regarding dietary and supplemental therapies for autoimmune disease treatment. Vitamins D and E, probiotics, curcumin, l-arginine, EFAs, broccoli, biofeedback, and acupuncture have been studied in SSc, yet, well-designed, prospective studies that account for important patient factors, such as SSc and/or RP disease duration and GI involvement, are needed to draw firm conclusions. Hypovitaminosis D is prevalent in SSc, but prospective studies are needed to determine if a causal relationship exists between low vitamin D and associated increased inflammatory markers, worse patient-reported measures of SSc disease activity, abnormal nailfold capillaroscopy, and lung, GI, vascular, and kidney diseases. Vitamin E may be an effective topical addition to DU standard care for digital ulcer healing and pain. Carefully selected probiotics may lead to improved total UCLA GIT 2.0 score, and improvement in reflux, abdominal distention, and social functioning domains. Curcumin, with demonstrable in vitro anti-inflammatory effects and favorable safety profiles, may be reasonable, but high doses are needed for adequate bioavailability and concern exists regarding potential increased bleeding risk. L-arginine and EFAs in SSc requires further study. Broccoli’s activation of Nrf2 anti-inflammatory mechanisms may reduce inflammation in vitro and in animal models, but evidence in patients is lacking. Finally, insufficient data exist to recommend for or against the use of biofeedback or acupuncture in SSc, though no adverse events have been reported. Important lessons have been learned from the study of complementary therapies in SSc and some data are promising. Future studies will determine the precise role, if any, for complementary therapies in the care of patients with SSc.