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Table 1 Characteristics and results of the selected studies

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

Study Study design 25(OH) D (ng/ml) levels * SSc patients with low vitamin D levels Main results
SSc patients
(n)
Controls
(n)
< 10 ng/ml
n (%)
< 30 ng/ml
n (%)
Ahmadi et al., 2017 [15] 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 [16] 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 [14] 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 [17] 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 [18] 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 [19] Cross-sectional -
(60)
-
-
26a
(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 [20] 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 [21] Cross-sectional 23(3–92)b
(18)(60)
39(14–138)b
(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 [22] 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 [23] 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 [12] 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 [24] 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 [25] 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 [26] Cross-sectional 13.1(4–48)b
(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 [27] Cross-sectional 9.8 ± 4.1d
(140)
-
-
40/91d
(44)
91/91d
(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 [8] 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 [28] Cross-sectional 19.5 ± 77.8c
(38)
100 ± 31.3c
(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 [29] 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 [30] 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 [13] 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 on lumbar spine (p = 0.002) and femoral neck (p = 0.032).
Kamal et al., 2016 [31] Cross-sectional -
(30)
-
(60)
-
-
-
-
No association between VDR polymorphisms (ApaI and TaqI) and SSc susceptibility. Significant association between ApaI and diffuse cutaneous SSc.
Matsuoka et al., 1991 [32] 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 [33] Cross-sectional 18.5(7.5–37)b
(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 [34] 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 [35] Cross-sectional 43.7(25–68)b
(40)
57.5(40–81)b
(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 [36] 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 [37] 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 [10] 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 [38] 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 [39] 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 [40] Cross-sectional 8.7(4.5–18)b
(46)
16.5(9–21)b
(30)
   Lower serum vitamin D levels in SSc patients (p = 0.02). No correlation with mRSS.
Trombetta et al., 2017 [41] 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 [42] Cohort 15.4(8–25)b
(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 [9] 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 [43] 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.
  1. Abbreviations: ANA antinuclear antibodies, APS antiphospholipid syndrome, BMD bone mineral density, BMI body mass index, CRP C-reactive protein, DLCO diffusion capacity of carbon monoxide, DM dermatomyositis, DU digital ulcers, EDAS European Disease Activity Score, ESR erythrocyte sedimentation rate, ET-1 Endotelina 1, GERD gastroesophageal reflux disease, HAQ Health Assessment Questionnaire, mRSS modified Rodnan skin score, OA osteoarthritis, PASP pulmonary arterial systolic pressure on Doppler echocardiography, PM polymyositis, RA rheumatoid arthritis, RF rheumatoid factor, SF-36 Short-Form-36 Questionnaire, SLE systemic lupus erythematosus, SSc systemic sclerosis, TGF-β transforming growth factor β, VDR vitamin D receptor
  2. * Data are presented as mean ± standard deviation, except when indicated otherwise
  3. aThese author presented only the proportion of patients with 25(0H) D < 12 ng/ml
  4. bMedian (25–75th percentile)
  5. cMedian ± IQR
  6. dVitamin D levels only in non-supplemented patients (91/140)