Table 2.

Summary of the clinical study selected. Abbreviations: SSc, systemic sclerosis; vit D, vitamin D; DLCO, diffusing lung capacity of the lung for carbon monoxide; ANA, antinuclear antibodies; BMD, bone mineral density; BMI, body mass index; dcSSc, diffuse cutaneous SSc; lcSSc, limited cutaneous SSc; VDR, vitamin D receptors; CT, computed tomography; DUs, digital ulcers; ET-1, endothelin 1; FGF-23, Fibroblast growth factor 23.

Authors	Journal and Year	Design of the Trial	Patients	Endpoints	Main Findings
Rios-Fernandez et al. [36]	Clin. Exp. Rheumatol., 2012	Case-control	100 SSc vs. 100 control	Prevalence of osteopenia/osteoporosis among SSc patients and controls; association of vit D levels with clinical manifestations of SSc	SSc patients had a higher prevalence of osteopenia and osteoporosis; vit D levels are associated with calcinosis, heart involvement, DLCO, and ANA positivity
Ibn Yacoub et al. [37]	Rheumatol. Int., 2012	Case-control	60 SSc patients vs. 60 age and gender-matched controls	Comparison of the BMD in women with SSc and controls; the relationship between vit D status and disease parameters and BMD	BMD was significantly lower in SSc patients than in controls; in multiple regression models, there were significant correlations between BMD and longer duration of SSc, severe joint involvement, malabsorption syndrome, and the positivity of anti-DNA topoisomerase I antibodies; Vitamin D levels were correlated with the severity of joint pain, with anti-DNA topoisomerase I positivity and with BMD in the lumbar spine and femoral neck
Atteritano et al. [38]	PloS ONE, 2013	Case-control	54 postmenopausal women with SSc and 54 postmenopausal controls	Comparison of BMD in SS patients and healthy controls; the prevalence of vertebral fractures	BMD at the lumbar spine, femoral neck, and total femur and ultrasound parameters at calcaneus were significantly lower in SSc patients, with a higher prevalence of vertebral fractures; SSc patients had a lower vit D plasma concentration, which was inversely related to BMD
Corrado et al. [39]	PloS ONE, 2015	Case-control	64 SSc vs. 35 healthy controls	Evaluations of BMD, BMI, and vit D levels in two skin subsets (limited or diffuse) of SSc patients	BMD is significantly lower in dcSSc than in lcSSc and healthy controls; Vit D serum levels are higher in healthy controls than in SSc patients; among them, those affected by dcSSc showed lower levels than those with lcSSc in dcSSc (p < 0.001); vit D levels are not associated with internal organ involvement
Sampaio-Barros et al. [40]	Rev. Bras. Reumatol., 2016	Cross-sectional	38 diffuse SSc patients	Correlation of vit D levels with organ involvement, antibody profile, BMD, results of questionnaires assessing the quality of life, nailfold capillaroscopy findings	Vit D levels were not correlated with organ involvement; vit d was lower in Scl-70+ subjects (p = 0.039); vit D levels were negatively correlated with quality of life, BMD and capillaroscopy findings
Kamal et al. [41]	Immunol. Inves., 2016	Case-control	30 SSc patients and 60 healthy subjects	Evaluation of the potential association of VDR gene polymorphisms ApaI, and TaqI with SSc susceptibility in the Egyptian population.	No significant association of VDR ApaI and TaqI polymorphisms with SSc susceptibility
Atteritano et al. [42]	Int. J. Mol. Sci., 2016	Case-control	40 SSc patients vs. 40 healthy control	Assess the prevalence of vitamin D insufficiency and correlation with clinical parameters in SSc	Lower vitamin D levels were found in SSc patients vs healthy control. Skin involvement and pulmonary hypertension were associated with vitamin D deficiency
Groseanu et al. [43]	Eur. J. Rheumatol.	Cross-sectional	51 SSc patients	Evaluation of vitamin D concentration in SSc patients and its possible association with clinical manifestations	High prevalence of hypovitaminosis D (only 9.8% of subjects reached satisfactory levels); no correlation between vitamin D concentration and autoantibody profile, the extent of skin involvement; direct correlation of vitamin D with the DLCO, diastolic dysfunction, digital contractures, and muscle weakness
Trombetta et al. [44]	PloS ONE, 2017	Retrospective cohort	154 SSc patients	Evaluation of possible correlations between vit D concentration and clinical manifestations	Vit D plasma levels were similar among patients with different clinical phenotypes and autoantibody positivity; vit. D concentrations were lower in those with bibasal fibrotic changes at lung CT scan
Giuggioli et al. [45]	Clin. Rheumatol., 2017	Cross sectional	140 SSc patients, 49 supplemented and 91 not supplemented	Evaluation of possible correlations between vit D supplementation and clinical manifestations	SSc patients undergoing vit D supplementation showed higher vit D plasma levels, a lower prevalence of autoimmune thyroiditis, and a higher frequency of anticentromere antibodies
Park et al. [46]	Clin. Rheumatol., 2017	Case-control	40 SSc women vs. 80 healthy controls	Investigate the association of vit D deficiency with digital ulcers (DUs), carotid intima-media thickness and brachial-ankle pulse wave velocity	Vit D deficiency was an independent risk factor for DUs development, while it was not associated with atherosclerosis or arterial stiffness
Zhang et al. [47]	Int. J. Rheum. Dis., 2017	Case-control	60 SSc vs. 60 healthy controls	Evaluation of vit D serum levels in SSc patients and healthy controls; evaluation of the potential association between vit. D and clinical features	Serum vit D levels were significantly lower in SSc patients, with no associations with clinical features of the disease
Ahmadi et al. [48]	Iran. J. Public Health, 2017	Case-control	60 SSc patients vs. 30 healthy controls	Comparison of serum Klotho, FGF-23, and 25-hydroxy vit D levels in the SSc patients and healthy controls.	Serum Klotho and vit D concentrations are significantly lower in SSc patients than in the control group; no significant difference in FGF-23 levels between groups
Hajialilo et al. [49]	Rheumatol. Int., 2017	Case-control	60 SSc patients vs. 60 healthy controls	Comparison of serum ET-1, α-Klotho, and vit D levels in patients with lcSSc and dcSSc scleroderma compared to healthy subjects	ET-1 was higher in SSc patients, while α-Klotho and 25(OH)D3 were lower in patients; Vit D levels were not associated with a specific autoantibody pattern
Kotyla et al. [50]	J. Clin. Med., 2018	Case-control	48 SSc patients vs. 23 healthy controls	Assessment of the levels of vit D, α-Klotho, and FGF23 in SSc patients; association with clinical features	Vit D levels are lower in SSc patients. Vit D was not associated with the extent of skin involvement or disease severity
Gupta et al. [51]	Indian Dermatol. Online J., 2018	Case-control	38 SSc patients vs. 38 health controls	Evaluation of vit D levels in SSc, in comparison to healthy controls and association with the extent of skin involvement	Vit D levels were lower in SSc patients and inversely associated with skin involvement assessed by the modified Rodnan skin score
Li et al. [52]	Arch. Med. Res., 2019	Case-control	100 SSc patients and 100 healthy controls	Evaluation of the potential association of eight VDR gene polymorphisms ApaI, and TaqI with SSc susceptibility	ApaI and BglI polymorphism genotypes were significantly associated with the risk of SSc.
Caimmi et al. [53]	Int. J. Rheum. Dis., 2019	Retrospective cohort	65 SSc patients	Evaluation of the association between vit D levels variation over time and development of DUs	The reduction of vit D level was correlated with an increased risk of developing DUs
Horvath et al. [54]	Arthritis Res. Ther., 2019	Case-control	44 SSc patients vs. 33 healthy controls	Evaluation of bone alterations in SSc	BMD measured at the femoral neck and lumbar spine was lower in SSc patients than in controls; hypovitaminosis D was more frequent in SSc patients (60%) than in controls (39.3%; p = 0.003)
Hax et al. [55]	J. Clin. Rheumatol., 2020	Case-control	50 SSc patients vs. 35 healthy controls	Evaluation of the correlation between serum levels of vit D and cytokines concentrations in SSc	Despite a more frequent vit D supplementation, SSc patients showed lower vit D levels; vit D plasma concentration was not correlated with cytokine profile
Runowska et al. [56]	Reumatologia, 2021	Retrospective cohort	112 patients with connective tissue disease; 44 with SSc	Evaluation of hypovitaminosis D prevalence among rheumatic diseases patients	Hypovitaminosis D is highly prevalent in SSc patients, despite vitamin D supplementation