Dualities of the vitamin D in systemic sclerosis: a systematic literature review

Schneider, Laiana; Hax, Vanessa; Monticielo, Odirlei; Macedo, Tamires Ferri; Barreto, Roberta Kern Menna; Marcondes, Natália Aydos; Chakr, Rafael

doi:10.1186/s42358-021-00192-6

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Research • Adv. rheumatol. 61 • 2021 • https://doi.org/10.1186/s42358-021-00192-6 copy

Dualities of the vitamin D in systemic sclerosis: a systematic literature review

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Background:

Systemic sclerosis (SSc) is a chronic disease characterized by autoimmunity, vasculopathy, and visceral and cutaneous fibrosis. Vitamin D has several functions in the immunological system, and different studies have suggested a potential role in triggering autoimmune diseases. Patients with SSc may present with low serum levels of vitamin D, but the association between hypovitaminosis D and disease onset or any clinical manifestation is still obscure. Our goal was to verify the causal relationship between hypovitaminosis D and SSc onset or any particular clinical manifestation in the literature.

Methods:

A systematic literature review was performed through February 24th, 2021 on Pubmed, Lilacs/BIREME, and Cochrane databases. The eligible studies were read in full text, and, in the absence of exclusion criteria, were included in this review after consensus between two reviewers.

Results:

Forty articles met the eligibility criteria and the main results of each study are described. In most studies, SSc patients showed a higher prevalence of vitamin D deficiency and insufficiency compared to controls. Additionally, in some reports serum levels of vitamin D were inversely correlated with the severity of SSc. Oral supplementation did not seem to affect serum levels of vitamin D. Four of the included studies were with experimental models.

Conclusion:

In conclusion, vitamin D deficiency seems to have a role in susceptibility to SSc, as well as in the clinical manifestations of the disease.

Keywords:
Vitamin D; Systemic sclerosis; 25-hydroxyvitamin D; Deficiency

Study	Study design	25(OH) D (ng/ml) levels ^* * Data are presented as mean ± standard deviation, except when indicated otherwise		SSc patients with low vitamin D levels		Main results
Study	Study design	SSc patients (n)	Controls (n)	< 10 ng/ml n (%)	< 30 ng/ml n (%)	Main results
Ahmadi et al., 2017 [¹⁵15. Ahmadi R, Hajialilo M, Ghorbanihaghjo A, Mota A, Raeisi S, Bargahi N, et al. FGF-23, Klotho and vitamin D levels in scleroderma. Iran J Public Health. 2017;46(4):530–6.]	Cross-sectional	15 ± 4.7 (60)	27.2 ± 8.7 (30)			Serum Klotho and vitamin D lower in SSc patients (p < 0.001). Higher intact PTH in SSc patients (p < 0.001).
Arnson et al., 2011 [¹⁶16. Arnson Y, Amital H, Agmon-Levin N, Alon D, Sanchez-Castanon M, Lopez-Hoyos M, et al. Serum 25-OH vitamin D concentrations are linked with various clinical aspects in patients with systemic sclerosis: a retrospective cohort study and review of the literature. Autoimmun Rev. 2011;10(8):490–4. https://doi.org/10.1016/j.autrev.2011.02.002. https://doi.org/10.1016/j.autrev.2011.02... ]	Cross-sectional	13.5±9 (327)	21.6 ± 9.7 (141)			Lower vitamin D levels in SSc patients (p< 0.001). Association with lower DLCO (p < 0.02). Inverse association with skin extent (mRSS> 10; p = 0.02) and RF expression (p < 0.001).
Atteritano et al., 2013 [¹⁴14. Atteritano M, Lasco A, Mazzaferro S, Macri I, Catalano A, Santangelo A, et al. Bone mineral density, quantitative ultrasound parameters and bone metabolism in postmenopausal women with depression. Intern Emerg Med. 2013;8(6):485–91. https://doi.org/10.1007/s11739-011-0628-1. https://doi.org/10.1007/s11739-011-0628-... ]	Cross-sectional	18.3 ± 4.1 (54)	39.6 ± 7.5 (54)			Lower vitamin D levels in SSc patients (p< 0.001). Association with PTH (p= 0.001), osteocalcin (p< 0.05), deoxypyridinoline (p < 0.05) and BMD on lumbar spine and femur (p < 0.05).
Atteritano et al., 2016 [¹⁷17. Atteritano M, Santoro D, Corallo G, Visalli E, Buemi M, Catalano A, et al. Skin involvement and pulmonary hypertension are associated with vitamin D insufficiency in scleroderma. Int J Mol Sci. 2016;17(12).]	Cross-sectional	25.8 ± 12.8 (40)	35.1 ± 9.1 (40)	0 (0)	20 (50)	Lower vitamin D levels in SSc patients (p = 0.0003). Association with skin extent (mRSS> 10; p = 0.02) and PASP> 35 mmHg (p = 0.02). No association with subtype and autoantibodies.
Belloli et al., 2011 [¹⁸18. Belloli L, Ughi N, Marasini B. Vitamin D in systemic sclerosis. Clin Rheumatol. 2011;30(1):145–6. https://doi.org/10.1007/s10067-010-1564-6. https://doi.org/10.1007/s10067-010-1564-... ]	Cross-sectional	18.1 ± 15.2 (43)	17.3 ± 12 (99 - OA)	15 (34.8)	37 (86)	No significantly difference in insufficiency or deficiency between groups, regardless of disease duration, subtype and autoantibodies.
Braun-Moscovici et al., 2008 [¹⁹19. Braun-Moscovici Y, Furst DE, Markovits D, Rozin A, Clements PJ, Nahir AM, et al. Vitamin D, parathyroid hormone, and acroosteolysis in systemic sclerosis. J Rheumatol. 2008;35(11):2201–5. https://doi.org/10.3899/jrheum.071171. https://doi.org/10.3899/jrheum.071171... ]	Cross-sectional	(60)		26^a a These author presented only the proportion of patients with 25(0H) D < 12 ng/ml (46)		High PTH associated with vitamin D deficiency (p = 0.01), calcinosis (p = 0.009), and acrosteolysis (p = 0.015). No significant correlation between supplementation and vitamin D levels.
Caimmi et al., 2019 [²⁰20. Caimmi C, Bertoldo E, Pozza A, Caramaschi P, Orsolini G, Gatti D, et al. Vitamin D serum levels and the risk of digital ulcers in systemic sclerosis: a longitudinal study. Int J Rheum Dis. 2019;22(6):1041–5. https://doi.org/10.1111/1756-185X.13554. https://doi.org/10.1111/1756-185X.13554... ]	Cohort	(65)				Lower vitamin D levels in patients with incident DU in relation to patients with no incident DU over 5 years (- 17.4 vs 13.0, p=0,018).
Calzolari et al., 2009 [²¹21. Calzolari G, Data V, Carignola R, Angeli A. Hypovitaminosis D in systemic sclerosis. J Rheumatol. 2009;36(12):2844 author reply 5.]	Cross-sectional	23(3–92)^b b Median (25–75th percentile) (18)(60)	39(14–138)^b b Median (25–75th percentile) (60)	4 (6.7)	38 (63.4)	Lower vitamin D levels in SSc patients (p<0.001). No association with disease subtype, cutaneous ulcers, skin extent, gastrointestinal and joint involvement.
Caramaschi et al., 2010 [²²22. Caramaschi P, Dalla Gassa A, Ruzzenente O, Volpe A, Ravagnani V, Tinazzi I, et al. Very low levels of vitamin D in systemic sclerosis patients. Clin Rheumatol. 2010;29(12):1419–25. https://doi.org/10.1007/s10067-010-1478-3. https://doi.org/10.1007/s10067-010-1478-... ]	Cross-sectional	15.8 ± 9.1 (65)		19 (29.2)	62 (95.4)	Association with lung disease (p = 0.009),longer disease duration (p = 0.026), lower DLCO (p= 0.014), and higher PASP (p = 0.037), ESR (p = 0.001) and CRP (p = 0.004).
Carmel et al., 2015 [²³23. Carmel NN, Rotman-Pikielny P, Lavrov A, Levy Y. Vitamin D antibodies in systemic sclerosis patients: findings and clinical correlations. Isr Med Assoc J. 2015;17(2):80–4.]	Cross-sectional	(54)	(41)		39 (82.1)	Anti-25(OH) D IgM antibodies more frequent in SSc patients and in a higher level (p=0.002). No correlation with severity, other autoantibodies and target organ damage.
Corrado et al., 2015 [¹²12. Corrado A, Colia R, Mele A, Di Bello V, Trotta A, Neve A, et al. Relationship between body mass composition, bone mineral density, skin fibrosis and 25(OH) vitamin D serum levels in systemic sclerosis. PLoS One. 2015;10(9): e0137912. https://doi.org/10.1371/journal.pone.0137912. https://doi.org/10.1371/journal.pone.013... ]	Cross-sectional	15.7 ± 10.2 (64)	22.9 ± 9.1 (35)			Lower vitamin D levels in patients, especially in diffuse cutaneous SSc (p<0.001). Negative correlation with mRSS (p<0.05). No association with any internal organ involvement.
Cruz-Domínguez et al., 2017 [²⁴24. Cruz-Dominguez MP, Garcia-Collinot G, Saavedra MA, Medina G, Carranza- Muleiro RA, Vera-Lastra OL, et al. Clinical, biochemical, and radiological characterization of the calcinosis in a cohort of Mexican patients with systemic sclerosis. Clin Rheumatol. 2017;36(1):111–7. https://doi.org/10.1007/s10067-016-3412-9. https://doi.org/10.1007/s10067-016-3412-... ]	Cohort	(109)				Lower vitamin D levels in SSc patients with and without calcinosis (19.1 vs. 13.1; p = 0.56).
Di Liberto et al., 2019 [²⁵25. Di Liberto D, Scazzone C, La Rocca G, Cipriani P, Lo Pizzo M, Ruscitti P, et al. Vitamin D increases the production of IL-10 by regulatory T cells in patients with systemic sclerosis. Clin Exp Rheumatol. 2019;37(Suppl 119(4)):76–81.]	Cross-sectional	22.1 ± 9.7 (45)				Low vitamin D levels in SSc patients. Similar percentage of regulatory T-cells (Tregs) in SSc patients and control group, with higher percentage in SSc patients taking cholecalciferol. Impaired Tregs capability to suppress T cell proliferation in SSc patients. Increase in IL-10 in vitro production of patients Tregs after treatment with (1,25(OH)2D3).
Gambichler et al., 2011 [²⁶26. Gambichler T, Chrobok I, Hoxtermann S, Kreuter A. Significantly decreased serum 25-hydroxyvitamin d levels in a large german systemic sclerosis cohort. J Rheumatol. 2011;38(11):2492–3 author reply 4.]	Cross-sectional	13.1(4–48)^b b Median (25–75th percentile) (133)		49 (35.8)	123 (89.8)	No association with disease subtype, BMI, lung fibrosis, renal involvement, GERD, digital ulcers, mRSS, autoantibodies and therapy.
Giuggioli et al., 2017 [²⁷27. Giuggioli D, Colaci M, Cassone G, Fallahi P, Lumetti F, Spinella A, et al. Serum 25-OH vitamin D levels in systemic sclerosis: analysis of 140 patients and review of the literature. Clin Rheumatol. 2017;36(3):583–90. https://doi.org/10.1007/s10067-016-3535-z. https://doi.org/10.1007/s10067-016-3535-... ]	Cross-sectional	9.8 ± 4.1^d d Vitamin D levels only in non-supplemented patients (91/140) (140)		40/91^d d Vitamin D levels only in non-supplemented patients (91/140) (44)	91/91^d d Vitamin D levels only in non-supplemented patients (91/140) (100)	Lower vitamin D levels in not supplemented patients (9.8 ± 4.1 vs. 26 ± 8.1; p < 0.0001), but only 15/49 (31%) supplemented patients reached the normal range of vitamin D.
Groseanu et al., 2016 [⁸8. Groseanu L, Bojinca V, Gudu T, Saulescu I, Predeteanu D, Balanescu A, et al. Low vitamin D status in systemic sclerosis and the impact on disease phenotype. Eur J Rheumatol. 2016;3(2):50–5. https://doi.org/10.5152/eurjrheum.2015.0065. https://doi.org/10.5152/eurjrheum.2015.0... ]	Cross-sectional	17.1 ± 9.1 (51)		12 (23.5)	46 (90.2)	Positive correlation with DLCO (p = 0.019). Negative correlation of vitamin D with diastolic dysfunction, digital contractures and muscle weakness. No correlation with autoantibodies or skin extent. Higher vitamin D levels in patients with usual supplementation (25.5%), but the difference between groups failed to reach statistical significance (p = 0.488).
Gupta et al., 2018 [²⁸28. Gupta S, Mahajan VK, Yadav RS, Mehta KS, Bhushan S, Chauhan PS, et al. Evaluation of serum vitamin D levels in patients with systemic sclerosis and healthy controls: results of a pilot study. Indian Dermatol Online J. 2018;9(4): 250–5. https://doi.org/10.4103/idoj.IDOJ_328_17. https://doi.org/10.4103/idoj.IDOJ_328_17... ]	Cross-sectional	19.5 ± 77.8^c c Median ± IQR (38)	100± 31.3^c c Median ± IQR (38)	13 (34.2)	23 (60.5)	Lower vitamin D levels in SSc patients (p = 0.001). Inverse correlationwith mRSS. No correlation with age, disease duration, autoantibodies, digital ulcers, or systemic involvement.
Hajialilo et al., 2017 [²⁹29. Hajialilo M, Noorabadi P, Tahsini Tekantapeh S, Malek MA. Endothelin-1, alphaKlotho, 25(OH) Vit D levels and severity of disease in scleroderma patients. Rheumatol Int. 2017;37(10):1651–7. https://doi.org/10.1007/s00296-017-3797-z. https://doi.org/10.1007/s00296-017-3797-... ]	Cross-sectional	14.9 ± 4.6 (60)	30.4 ± 7.9 (60)			Serum ET-1 higher in SSc patients (p=0.001). Serum α-Klotho and vitamin D lower in SSc patients (p=0.001). Association of vitamin D with gastrointestinal involvement on Medsger severity scale (p = 0.003).
Hax et al., 2020 [³⁰30. Hax V, Gasparin AA, Schneider L, Monticielo OA, Soares HMF, Streit MDA, et al. Vitamin D and cytokine profiles in patients with systemic sclerosis. J Clin Rheumatol. 2020;26(7):289–94. https://doi.org/10.1097/RHU.0000000000001112. https://doi.org/10.1097/RHU.000000000000... ]	Cross-sectional	23.9 ± 8.5 (50)	30.2 ± 6.2 (35)	2 (4%)	36 (72%)	Lower vitamin D levels in SSc patients compared to control group and lower vitamin D levels in SSc patients not taking vitamin D supplementation. No associations between vitamin D and cytokine levels or between vitamind D levels and disease duration.
Ibn-Yacoub et al., 2012 [¹³13. Ibn Yacoub Y, Amine B, Laatiris A, Wafki F, Znat F, Hajjaj-Hassouni N. Bone density in Moroccan women with systemic scleroderma and its relationships with disease-related parameters and vitamin D status. Rheumatol Int. 2012; 32(10):3143–8. https://doi.org/10.1007/s00296-011-2150-1. https://doi.org/10.1007/s00296-011-2150-... ]	Cross-sectional	10.9 ± 2.7 (30)	57.4 ± 4.2 (30)	8 (26.7)	30 (100)	Lower vitamin D levels in SSc patients (p=0.001). Association with number of painful (p = 0.006) and swollen joints (p = 0.013) and anti-Scl70 (p = 0.027). Association of vitamin D with BMD
Kamal et al., 2016 [³¹31. Kamal A, Gamal SM, Elgengehy FT, Alkemary AK, Siam I. Association of VDR ApaI and TaqI gene polymorphisms with the risk of scleroderma and Behcet's disease. Immunol Investig. 2016;45(6):531–42. https://doi.org/10.1080/08820139.2016.1180302. https://doi.org/10.1080/08820139.2016.11... ]	Cross-sectional	(30)	(60)			on lumbar spine (p = 0.002) and femoral neck (p = 0.032). No association between VDR polymorphisms (ApaI and TaqI) and SSc susceptibility. Significant association between ApaI and diffuse cutaneous SSc.
Matsuoka et al., 1991 [³²32. Matsuoka LY, Dannenberg MJ, Wortsman J, Hollis BW, Jimenez SA, Varga J. Cutaneous vitamin D3 formation in progressive systemic sclerosis. J Rheumatol. 1991;18(8):1196–8.]	Cross-sectional	28 ± 3 (19)	29±3 (19)			Hypovitaminosis D common in SSc patients and healthy controls. No correlation with skin extent.
Montabone et al., 2016 [³³33. Montabone E, Data V, Carignola R. Vitamin D status and quality of life in systemic sclerosis patients. J Clin Rheumatol. 2016;22(4):229–30. https://doi.org/10.1097/RHU.0000000000000406. https://doi.org/10.1097/RHU.000000000000... ]	Cross-sectional	18.5(7.5–37)^b b Median (25–75th percentile) (35)		4 (11)	30 (85)	Association with a worse physical component on SF-36 and physical function (p < 0.04). No association with gastrointestinal, kidney and cardiopulmonary involvement.
Orbach et al., 2007 [³⁴34. Orbach H, Zandman-Goddard G, Amital H, Barak V, Szekanecz Z, Szucs G, et al. Novel biomarkers in autoimmune diseases: prolactin, ferritin, vitamin D, and TPA levels in autoimmune diseases. Ann N Y Acad Sci. 2007;1109(1): 385–400. https://doi.org/10.1196/annals.1398.044. https://doi.org/10.1196/annals.1398.044... ]	Cross-sectional	11 ± 5.8 (229)				Lower vitamin D levels in different autoimmune diseases (SSc, SLE, PM, DM, APS, and RA).
Park et al., 2017 [³⁵35. Park EK, Park JH, Kweon SM, Kim GT, Lee SG. Vitamin D deficiency is associated with digital ulcer but not with atherosclerosis or arterial stiffness in patients with systemic sclerosis: a pilot study. Clin Rheumatol. 2017;36(6): 1325–33. https://doi.org/10.1007/s10067-017-3622-9. https://doi.org/10.1007/s10067-017-3622-... ]	Cross-sectional	43.7(25–68)^b b Median (25–75th percentile) (40)	57.5(40–81)^b b Median (25–75th percentile) (80)	2 (5)	12 (30)	Association with digital ulcers (p = 0.012). No association with arterial stiffness, atherosclerosis, autoantibodies, mRSS, lung disease, PASP, ESR and CRP.
Rios Fernández et al., 2010 [³⁶36. Rios Fernandez R, Fernandez Roldan C, Callejas Rubio JL, Ortego CN. Vitamin D deficiency in a cohort of patients with systemic scleroderma from the south of Spain. J Rheumatol. 2010;37(6):1355; author reply 6. https://doi.org/10.3899/jrheum.091143. https://doi.org/10.3899/jrheum.091143... ]	Cross-sectional	(48)		5 (9.5)	39 (81)	No significant vitamin D correlation with PASP or lung fibrosis. Hypovitaminosis D was common, despite 60.4% of patients were taking usual supplementation.
Rios Fernández et al., 2012 [³⁷37. Rios-Fernandez R, Callejas-Rubio JL, Fernandez-Roldan C, Simeon-Aznar CP, Garcia-Hernandez F, Castillo-Garcia MJ, et al. Bone mass and vitamin D in patients with systemic sclerosis from two Spanish regions. Clin Exp Rheumatol. 2012;30(6):905–11.]	Cross-sectional	(90)		10 (11)	69 (76.7)	Association of vitamin D with calcinosis (p<0.034), heart involvement (p < 0.012), DLCO (p < 0.006) and positive ANA (p < 0.017). Hypovitaminosis D was common, despite 58.9% of patients were taking usual supplementation. Vitamin D deficiency was not different between groups (52% vs. 66.7%).
Sampaio-Barros et al., 2016 [¹⁰10. Sampaio-Barros MM, Takayama L, Sampaio-Barros PD, Bonfa E, Pereira RM. Low vitamin D serum levels in diffuse systemic sclerosis: a correlation with worst quality of life and severe capillaroscopic findings. Rev Bras Reumatol Engl Ed. 2016;56(4):337–44. https://doi.org/10.1016/j.rbre.2016.05.006. https://doi.org/10.1016/j.rbre.2016.05.0... ]	Cross-sectional	20.7 ± 8.2 (38)		4 (11)	33 (87)	Vitamin D positive correlation with anti-Scl70 (p = 0.039) and some SF-36 domains (vitality, social function, emotional role and mental health). Negative correlation with HAQ-reach and HAQ-grip strength. Positive correlation of vitamin D with BMI (p = 0.038) and femur BMD (p = 0.037).
Seriolo et al., 2011 [³⁸38. Seriolo B, Molfetta L, Cutolo M. Seasonal variations in serum levels of 25- hydroxyvitamin D in patients with systemic sclerosis. Clin Rheumatol. 2011; 30(3):445–6. https://doi.org/10.1007/s10067-011-1684-7. https://doi.org/10.1007/s10067-011-1684-... ]	Cross-sectional	21.7 ± 13.4 (53)	39.4 ± 15.4 (35)	13 (24)	47 (88)	Seasonal variation in patients and controls (highest values in summer, p<0.01). Significantly lower levels in SSc patients in all seasons.
Shinjo et al., 2011 [³⁹39. Shinjo SK, Bonfa E, de Falco CV, Pereira RM. Low bone mass in juvenile onset sclerosis systemic: the possible role for 25-hydroxyvitamin D insufficiency. Rheumatol Int. 2011;31(8):1075–80. https://doi.org/10.1007/s00296-010-1421-6. https://doi.org/10.1007/s00296-010-1421-... ]	Cross-sectional	18.1 ± 6.4 (10)	25.1 ± 6.6 (10)			Lower vitamin D levels in juvenile SSc patients (p = 0.04). Positive correlation with femur BMD (p = 0.02).
Taylan et al., 2019 [⁴⁰40. Taylan A, Birlik M, Kenar G, Toprak B, Gundogdu B, Gurler O, et al. Osteoprotegrin interacts with biomarkers and cytokines that have roles in osteoporosis, skin fibrosis, and vasculopathy in systemic sclerosis: a potential multifaceted relationship between OPG/RANKL/TRAIL and Wnt inhibitors. Mod Rheumatol. 2019;29(4):619–24. https://doi.org/10.1080/14397595.2018.1500736. https://doi.org/10.1080/14397595.2018.15... ]	Cross-sectional	8.7(4.5–18)^b b Median (25–75th percentile) (46)	16.5(9–21)^b b Median (25–75th percentile) (30)			Lower serum vitamin D levels in SSc patients (p=0.02). No correlation with mRSS.
Trombetta et al., 2017 [⁴¹41. Trombetta AC, Smith V, Gotelli E, Ghio M, Paolino S, Pizzorni C, et al. Vitamin D deficiency and clinical correlations in systemic sclerosis patients: a retrospective analysis for possible future developments. PLoS One. 2017; 12(6):e0179062. https://doi.org/10.1371/journal.pone.0179062. https://doi.org/10.1371/journal.pone.017... ]	Cross-sectional	18.7±9 (154)			124 (80.5)	Association of vitamin D with pulmonary fibrotic changes (p = 0.04). Correlation with some domains of Medsger severity scale (peripheral vascular, renal and gastrointestinal involvement). Vitamin D levels not influenced by usual supplementation (p = 0.81).
Ursini et al., 2017 [⁴²42. Ursini F, D’Angelo S, Padula A, Leccese P, Abignano G, Mennillo GA, et al. Vitamin D deficiency in systemic sclerosis: a possible role of subclinical liver fibrosis? Retrospective analysis from an Italian cohort. Clin Rheumatol. 2017; 36(12):2871–2. https://doi.org/10.1007/s10067-017-3709-3. https://doi.org/10.1007/s10067-017-3709-... ]	Cohort	15.4(8–25)^b b Median (25–75th percentile) (124)			13 (89.5)	Inverse correlation with mRSS (p = 0.03) and subclinical liver fibrosis (evaluated using the aspartate aminotransferase-to-platelet ratio index; p = 0.02). No correlation with age and disease duration.
Vacca et al., 2009 [⁹9. Vacca A, Cormier C, Piras M, Mathieu A, Kahan A, Allanore Y. Vitamin D deficiency and insufficiency in 2 independent cohorts of patients with systemic sclerosis. J Rheumatol. 2009;36(9):1924–9. https://doi.org/10.3899/jrheum.081287. https://doi.org/10.3899/jrheum.081287... ]	Cross-sectional	19 ± 11 (156)		44 (28)	131 (84)	Association of vitamin D with higher PASP (p = 0.004), lung fibrosis (p=0.04), anticentromere (p=0.04) and ESR (p = 0.008). No association with calcinosis, HAQ, or Medsger severity score. Negative correlation with EDAS (p=0.04). Vitamin D levels not influenced by usual supplementation (p = 0.1).
Zhang et al., 2017 [⁴³43. Zhang L, Duan Y, Zhang TP, Huang XL, Li BZ, Ye DQ, et al. Association between the serum level of vitamin D and systemic sclerosis in a Chinese population: a case control study. Int J Rheum Dis. 2017;20(8):1002–8. https://doi.org/10.1111/1756-185X.12794. https://doi.org/10.1111/1756-185X.12794... ]	Cross-sectional	26.5 ± 6.3 (60)	36.3 ± 14.2 (60)		45 (75)	Lower vitamin D levels in SSc patients (p<0.001). More frequent lung involvement, but without significance (p = 0.08). No difference in joint involvement, autoantibodies, ESR and CRP.

Author	Year	Research Design	Main results
Slominski et al. [⁴⁴44. Slominski A, Janjetovic Z, Tuckey RC, Nguyen MN, Bhattacharya KG, Wang J, et al. 20S-hydroxyvitamin D3, noncalcemic product of CYP11A1 action on vitamin D3, exhibits potent antifibrogenic activity in vivo. J Clin Endocrinol Metab. 2013;98(2):E298–303. https://doi.org/10.1210/jc.2012-3074. https://doi.org/10.1210/jc.2012-3074... ]	2013	Culture of skin fibroblasts from patients and controls	Efficacy of vitamin D in inhibiting TGF-induced collagen synthesis and inhibiting cell proliferation in fibroblasts from patients and controls; vitamin D suppressed fibrogenesis in a bleomycin-induced sclerosis model.
Terao et al. [⁴⁵45. Terao M, Yang L, Matsumura S, Yutani M, Murota H, Katayama I. A vitamin D analog inhibits Th2 cytokine- and TGFbeta -induced periostin production in fibroblasts: a potential role for vitamin D in skin sclerosis. Dermatoendocrinol. 2015;7(1):e1010983. https://doi.org/10.1080/19381980.2015.1010983. https://doi.org/10.1080/19381980.2015.10... ]	2015	Experimental model	Effect of vitamin D analogue on periostin expression in fibroblasts and bleomycin-induced sclerosis model; maxacalcitol reduces the expression of periostin and TGF-β and suppresses the Th2 response.
Usategui et al. [⁴⁶46. Usategui A, Criado G, Del Rey MJ, Fare R, Pablos JL. Topical vitamin D analogue calcipotriol reduces skin fibrosis in experimental scleroderma. Arch Dermatol Res. 2014 Oct;306(8):757–61. https://doi.org/10.1007/s00403-014-1466-6. https://doi.org/10.1007/s00403-014-1466-... ]	2014	Cutaneous fibrosis in animal model	Effect of the topical analogue of vitamin D (calcipotriol) on cytokines and the development of fibrosis in rats with bleomycin-induced sclerosis; calcipotriol overexpressed Th2 axis expression, with antifibrotic effect.
Zerr et al. [⁴⁷47. Zerr P, Vollath S, Palumbo-Zerr K, Tomcik M, Huang J, Distler A, et al. Vitamin D receptor regulates TGF-beta signalling in systemic sclerosis. Ann Rheum Dis. 2015;74(3):e20. https://doi.org/10.1136/annrheumdis-2013-204378. https://doi.org/10.1136/annrheumdis-2013... ]	2014	Culture of skin fibroblasts from patients and controls	Expression of VDR in experimental model and fibroblasts; effect of paricalcitol on bleomycin- induced fibrosis model and overexpression of TGF-β receptor (TBRICA); VDR characterization as a negative regulator of TGF-β / Smad pathway signaling.

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[1] * Correspondence: laia_schneider@hotmail.com