Role of Vitamin D in Systemic Sclerosis: A Systematic Literature Review

Table 1

Characteristics of selected studies on serum vitamin D in systemic sclerosis.

Reference	Study design	Patients	Outcome
Lo Gullo et al., 2021 [10]	Case-control study	36 SSc patients and 36 healthy controls	Correlation between serum vitamin D and CD34+ cell ().; No correlation between serum vitamin D levels and CRP ().; No difference in vitamin D levels in dcSSc patients compared to lcSSc patients.; No association between vitamin D, body mass index, and endothelial markers in SSc.
Isola et al., 2021 [11]	Clinical trial	35 SSc patients, 36 with periodontitis (PD), 36 with both SSc and periodontitis, and 37 controls	Lower vitamin D values in subjects with PD and SSc plus PD than to SSc and healthy subjects ().; Negative association between vitamin D levels and PD in SSc ().; Association between lower vitamin D and CRP ().
Hax et al., 2020 [12]	Case-control study	50 SSc patients and 35 healthy nonmatched controls	Lower vitamin D levels in SSc patients ().; 25-Hydroxyvitamin D [25(OH)D] levels inversely correlated with parathyroid hormone (PTH) levels ().; No significant associations between vitamin D and serum cytokines.; No association between vitamin D serum levels and the duration and frequency of sun exposure ( and , respectively) or with the sun block use ().
Paolino et al., 2020 [13]	Retrospective study	36 consecutive postmenopausal SSc female patients	Significant differences in malnourished SSc patients in the median values of PTH () and vitamin D levels ().
González-Martín et al., 2020 [14]	Cross-sectional study	70 patients diagnosed with SSc (diffuse or limited forms)	Lower levels of vitamin D in 59% of the SSc patients.; Inverse association between serum vitamin D levels and carotid intima-media thickness ().
Horváth et al., 2019 [15]	Case-control study	44 SSc patients and 33 healthy controls	Vitamin D deficiency in SSc patients ().
Caimmi et al., 2019 [16]	Retrospective longitudinal study	65 SSc patients	Negative association between vitamin D levels and the risk of digital ulcers developing ().; No significant differences in vitamin D between SS with or without vitamin D supplementation ().; No significant differences in vitamin D variations for disease subset (), disease activity (), previous digital ulcers (), incident pulmonary arterial hypertension (), delta of body mass index (), delta of forced vital capacity () or diffusion capacity of carbon monoxide (DLCO) (), smoking habit (), modified Rodnan skin score (mRSS) ().
Di Liberto et al., 2019 [17]	Prospective case-control study	45 SSc patients and 35 controls	The treatment with 1,25(OH)(2)D of regulatory T cells increased the production of IL-10, a cytokine able to modulate immune response ().
Corallo et al., 2019 [18]	Prospective study	62 SSc Caucasian patients	No association between serum vitamin D levels and sarcopenia ().
Gupta et al., 2018 [19]	Pilot study	38 SSc patients, 38 controls	Significantly lower serum vitamin D levels in SSc patients compared with healthy controls ().; No correlation between serum vitamin D levels and age, gender, disease duration or its variants, type of autoantibodies, presence of digital ulceration, or systemic involvement.; Inverse correlation between serum vitamin D levels and mRSS ().
Taylan et al., 2018 [20]	Cross-sectional study	46 SSc patients and 30 healthy controls	Significantly lower vitamin D levels in SSc patients ().
Kotyla et al., 2018 [21]	Case-control study	48 patients with diffuse systemic sclerosis and 23 controls	A weak correlation between vitamin D levels and iFGF23 ().; No association between vitamin D levels and the extent of skin involvement or disease activity ().
Trombetta et al., 2017 [22]	Retrospective study	154 SSc patients	A significant correlation of vitamin D levels with lung involvement (), peripheral vascular (), kidney (), and gastrointestinal damage () and with seasonality () in SSc patients.; Correlation between 25(OH)D and calcium serum concentrations ().; No statistically significant correlation between 25(OH)D and gender (), age (), Raynaud’s phenomenon duration (), disease duration (), dcSSc, lcSSc ().; No significant correlations between digital ulcer incidence and 25(OH)D serum concentrations ().
Ahmadi et al., 2017 [23]	Case-control study	60 SSc patients (30 diffuse scleroderma and 30 limited scleroderma), 30 age- and sex-matched healthy controls	Lower serum levels of vitamin D in the SSc patients compared with healthy controls ().; No significant differences in serum vitamin D levels between dcSSc and lcSSc ().
An et al., 2017 [24]	Meta-analysis	554 SSc patients and 321 controls	Lower serum vitamin D levels in SSc compared with healthy controls, in dcSSc compared to lcSSc.; No correlation between vitamin D deficiency and mRSS (), systolic pulmonary pressure (), gastrointestinal ulcer (), and pulmonary involvement ().
Hajialilo et al., 2017 [25]	Cross-sectional study	60 SSc patients and 60 healthy controls	Significantly lower vitamin D levels in SSc patients ().; No significant correlation between 25(OH)D levels and the presence of calcinosis and positive results for autoantibodies.
Zhang et al., 2017 [26]	Case-control study	60 SSc patients and 60 healthy controls	Lower vitamin D levels () in SSc patients compared with healthy controls.; High ratio of pulmonary involvement in patients with vitamin D insufficiency.
Giuggioli et al., 2017 [27]	Case-control study	140 patients	Hypovitaminosis D associated with autoimmune thyroiditis () and calcinosis ().; Decreased 25(OH)D levels correlated with increased PTH ().
Park et al., 2017 [28]	Pilot study	40 female SSc patients and 80 healthy controls	Vitamin D deficiency associated with digital ulcer (), but not with atherosclerosis or arterial stiffness ().
Cruz-Domínguez et al., 2017 [29]	Cohort study	220 SSc patients	Lower vitamin D levels in SSc with and without calcinosis.; No association between vitamin D levels and calcinosis ().
Groseanu et al., 2016 [30]	Cross-sectional study	51 SSc patients	Positive correlation between decreased vitamin D levels and pulmonary fibrosis () and low DLCO ().; Negative correlation between vitamin D status and diastolic dysfunction (), digital contractures (), and muscle weakness ().; Negative association between vitamin D supplementation and development of digital ulcers ().
Atteritano et al., 2016 [31]	Case-control study	40 patients with scleroderma and 40 healthy controls	Significantly lower serum vitamin D in SSc patients ().; Inverse correlation between vitamin D serum concentrations in SSc and systolic pulmonary artery pressure ().; Significant correlation between vitamin D and PTH serum levels in SSc ().; Significant association between vitamin D insufficiency and mRSS ().
Sampaio-Barros et al., 2016 [32]	Cross-sectional study	38 female patients with diffuse SSc	Lower levels of vitamin D in anti-Scl-70-positive compared to anti-Scl-70-negative SSc ().; Positive correlation of vitamin D levels with weight (), BMI (), total femur BMD (), femoral neck BMD (), SF-36-Vitality (), SF-36-Social Function (), SF-36-Emotional Role (), and SF-36-Mental Health ().; Negative correlation between 25(OH)D and quality of life in dcSSc: HAQ-Reach () and HAQ-Grip Strength ().; Negative correlation between vitamin D levels and severe nailfold capillaroscopy alterations: diffuse devascularization () and avascular areas ().
Carmel et al., 2015 [33]	Case-control study	54 SSc patients and 41 healthy controls	Positive correlation between IgM 25(OH)D antibodies and scleroderma ().; No correlation between vitamin D antibodies and other autoantibodies, disease severity, or target organ damage.
Corrado et al., 2015 [34]	Case-control study	64 postmenopausal SSc patients and 35 healthy control postmenopausal women	Significantly lower 25(OH)D levels in dcSSc compared to the lcSSc ().; A significant association between degree skin fibrosis and circulating levels of 25(OH)D ().; No correlation between 25(OH)D levels and presence of anti-centromere or anti-topoisomerase I autoantibodies and the disease duration. No correlation between malabsorption and 25(OH)D levels.
Atteritano et al., 2013 [35]	Case-control study	54 SSc women and 54 postmenopausal controls	Significantly lower vitamin D levels in SSc patients ().; Significant correlation between vitamin D and PTH levels in SSc ().
Rios Fernández et al., 2012 [36]	Case-control study	100 SSc patients and 100 controls	Lower levels of vitamin D in SSc from the north of Spain in comparison with those in south of Spain ().; Low bone mineral density (BMD) in 86% SSc with low levels of vitamin D (<30 ng/ml) compared with 66.7% of those with normal levels ().; Significant association between vitamin D level heart involvement (), positive antinuclear antibody (ANA) (), and low DLCO ().
ibn Yacoub et al., 2012 [37]	Case-control study	60 SSc patients and 60 controls	Very low levels of vitamin D () in SSc patients compared with controls.; Significant correlation between vitamin D levels and joint pain severity, immunological status, and BMD in lumbar spine and femoral neck.
Avouac et al., 2012 [38]	Cross-sectional study	71 women with SSc, 139 women with RA, and 227 healthy women	Low levels of vitamin D is a risk factor for fractures ().
Shinjo et al., 2011 [39]	Case-control study	10 patients with JoSSc and 10 healthy controls	High prevalence of 25(OH)D insufficiency in JoSSc () and correlation with hip BMD (femoral neck and total femur: and , respectively).
Arnson et al., 2011 [40]	Retrospective cohort study	327 European patients with SSc and 141 healthy controls	Lower serum vitamin D concentrations () and inverse relationship with cutaneous tissue fibrosis ().; A negative correlation between vitamin D concentration and patient age ().
Gambichler et al., 2011 [41]	Observational study	137 SSc patients	Lower vitamin D levels ().; No significant relationship between serum 25(OH)D levels and SSc subtypes, lung fibrosis, renal involvement, gastroesophageal reflux disease, digital ulcers, mRSS, ANA, age, sex, BMD, and therapy.
Seriolo et al., 2011 [42]	Case-control study	53 SSc female patients with SSc and 35 sex-, age-, and season-matched control	During winter: vitamin D insufficiency in 60% SSc compared with 38% matched controls (); lower average serum 25(OH)D levels among SSc compared with controls ().; During summer: 64% SSc patients and 36% controls with vitamin D insufficiency (); 24% SSc vs. 12% control with vitamin D deficiency (); lower average serum 25(OH)D levels among SSc compared with controls ().
Caramaschi et al., 2010 [43]	Prospective study	65 SSc patients	Association between patients with vitamin D deficiency and longer disease duration (), lower DLCO (0.014), higher estimated PAP (), higher values of erytrocyte sedimentation rate (ESR) (), and C-reactive protein (CRP) () and with nailfold videocapillaroscopic pattern () in comparison with patients with vitamin D insufficiency.
Rios Fernández et al., 2010 [44]	Cohort study	63 SSc patients	Lower vitamin D levels.; No significant correlation between vitamin D levels and sPAP and the presence or absence of lung fibrosis ().
Calzolari et al., 2009 [45]	Case-control study	60 SSc patients and 60 matched controls	Lower levels of vitamin D in SSc patients compared with controls ().; No significant association between vitamin D concentrations and disease features (lcSSc or dcSSc, gastrointestinal involvement, cutaneous ulcers, and joint involvement) and no correlation with mRSS.; Vitamin D and serum C-telopeptide of type I collagen negatively correlated in SSc ().; Vitamin D correlates with physical performance score assessed by the Medical Outcomes Study SF-36 (Short Form-36 questionnaire) ().
Vacca et al., 2009 [6]	Prospective study	156 consecutive SSc patients (90 from Northern France and 66 from Southern Italy)	Slight association between vitamin D and anti-centromere antibodies ().; Significant negative correlation between low serum vitamin D levels and European Disease Activity Score ().; No correlation with CRP ().; Vitamin D deficiency associated with sPAP estimated by echocardiography () and pulmonary fibrosis ().; No associations between vitamin D deficiency and acroosteolysis, calcinosis, HAQ, or Medsger disease severity scores.
Braun-Moscovici et al., 2008 [46]	Retrospective study	134 Mediterranean SSc patients	Hypovitaminosis D significantly correlated with ethnicity (Arab origin) ().; Statistically significant relationship between vitamin D and PTH (), but not between vitamin D and acroosteolysis ().
Hulshof et al., 2000 [47]	Double-blind, placebo-controlled trial	27 patients: 20 with morphea and 7 with SSc	No significant difference in SSc between the placebo and 1,25(OH)(2)D groups after 9 months of treatment in the skin score, esophageal body motility, and oral aperture.; No significant change in S-PIIINP in serum samples of SSc patients after 1,25(OH)(2)D treatment.
Humbert el al., 1993 [48]	Open prospective, uncontrolled study	11 SSc patients	Vitamin D treatment improved significantly oral aperture and flexion index distance () and skin extensibility ().