Table 2 Summary of current literature of 25(OH)D status and chronic childhood arthritis

Meta-Analysis Nisar et al. 2013 [12]

JRA JCA & JIA

n = 529

0–18

61.4

Mean of 14 studies 61.4 nmol/L (Range 28.7–139.8) prevalence reported from 3 studies 82% insufficient.

Cincinnati, Ohio USA Stark et al. 2006 40°N [45]

JRA

n = 49

4–10 y

79.9 ± 25.0 (39.9–142.3)

Behaviour intervention to increase calcium intake successful.

Ioannina, Greece Siampoulou et al. 2001 39°N [40]

JIA

n = 10 (6F)

13.1 ± 2.5

53.9 ± 8.5

All patients were vitamin D replete 25(OH)D > 17.5 nmol/L, most were measured between February to May.

Missouri, USA Hillman et al. 2008 37°N [54]

Children with arthritis

n = 18

3–15

82.1 ± 38.7

Supplemental vitamin D improved status, but supplemental vitamin D or calcium did not improve bone mass.

Kansas, USA Warady et al. 1994 39°N [55]

Rheumatic disease (6 with JRA)

n = 10 (7F) 6 JRA

13.(10.9–18.0)

70.1 ± 21.2

Children with rheumatic disease would benefit from receiving calcium and vitamin D supplements.

Illinois, USA Reed et al. 1991 40°N [46]

JRA

n = 13 (12F)

5–18

70.0 ± 40

Vitamin D may help prevent bone loss in children with active disease.

Istanbul, Turkey Dagdeviren- Cakir et al. 2016 41°N [21]

JIA

Active disease: n = 64 (41) Remission: 53(35)

Active disease: 9.7 ± 4.3 Remission: 9.8 ± 4.3

Active disease: 46.5 ± 23.0 Remission: 47.3 ± 27.5

Vitamin D concentrations in children with JIA were significantly lower than healthy children. Of those who were measured while in remission there was no difference in 25(OH)D concentrations.

Healthy control n = 100 66.8 ± 26.6 nmol/L.

Mexico city, Mexico Hernandez Rosiles et al. 2015 19°N [39]

JIA

n = 37 (27)

12.5 ± 3.1

55.0 ± 13.9

No difference between children with JIA and controls.

Healthy controls n = 79 59.0 ± 7.7 nmol/L.

Fortaleza, Brazil De Sousa- Studart et al. 2015 3°S [22]

JIA

n = 51 (31 F)

13.4 ± 4

55.4 ± 25.0

25(OH)D similar for disease activity status, JIA category, and arthritis severity measure.

Age sex-matched controls 25(OH)D, 75.9 ± 14.0 nmol/L.

Hangzhou, China (article in Chinese, English Abstract) Wang et al. 2015 30°N [60]

JIA

n = 53

Not reported

Median 42.6

A significant difference between JIA and control 25(OH)D p < 0.01. No correlation between 25(OH)D and JIA subtypes, ACR pediatric 30, CRP or ESR.

Control n = 106 25(OH)D 49.9 nmol/L.

Florence, Italy Stagi et al. (2014) 43°N [23]

JIA

n = 152 (115F)

16. ± 7.4

54.4 ± 20.5

JIA had reduced 25(OH)D and higher PTH compared to controls. Active disease or frequent flare-ups resulted in lower vitamin D than non-active and no frequent flare-ups.

Control group 25(OH)D 74.4 ± 28.0 nmol/L p < 0.005.

Intake JIA 164 ± 84 IU/day control 160 ± 72 IU/day.

New Delhi, India Dey et al. 2014 28°N [31]

JIA

n = 35

3–16

22.0 ± 18.0

Decreased dietary intake of vitamin D and calcium, decreased weight bearing physical activity and sunlight exposure were the major factors for low BMD. Duration of disease 2.30 ± 1.91 yrs.

Age sex-matched controls 25(OH)D 37.9 ± 10.0 nmol/L significant difference.

Intake JIA 123 ± 53.6 (50–207) control 309 ± 62.38 (213–387) IU/day.

Lodz, Poland Szyamanska-Kaluza et al. 2013 51°N [24]

JIA

n = 50 (40)

9.4 ± 5.52

43.4 ± 21.1

Vitamin D deficiency is common in this population. No correlation between disease activity, type of JIA or metabolites of vitamin D.

Control n = 28 Age, gender matched, hospitalized children 43.4 ± 40.7 nmol/L.

Sao Paulo, Brazil Munekata et al. 2013 23°S [25]

JIA- polyarticular

n = 30 (23F)

14 (4–20)

64.1 ± 21.6

High frequency of 25(OH)D deficiency in both control and JIA groups; no difference between the two. No association of 25(OH)D with disease activity.

Control group age-sex matched (n = 30). 16 non-Caucasian; mean disease duration 5y (1–12) control 2 5(OH)D 67.2 ± 19.0 nmol/L.

Oslo, Norway Lien et al. 2005 59°N [26]

JIA

n = 108

6 to 18

49.7 ± 16.5

No difference in 25(OH)D between control and JIA groups.

Control n = 108 25(OH)D 50.4 ± 8.1 nmol/L D

Intake JIA 164 ± 84 IU control 160 ± 72 IU

London, UK Rooney et al. 2000 51°N [49]

JCA

n = 34 (23F)

9.2 (4.6–13.6)

Estimated from graph 45 (14.5–62.5)

Vitamin D status was significantly lower in JCA patients than age-matched controls before treatment, Steroid-treated children have low vitamin D. All but three children received corticosteroids.

Control group 25(OH)D estimate 75 nmol/L.

Florence, Italy Falcini et al. 1998 43°N [48]

JCA

n = 47 (34)

15 months-12 years(7.13 ± 4.1)

61.4 ± 20.5

The lower serum concentrations of osteocalcin in active disease support the hypothesis that both bone formation and resorption are reduced in JRA

Controls n = 47 25(OH)D 56.7 ± 21.5 nmol/L.

Missouri, USA Pepmueller et al. 1996 37°N [43]

JRA

n = 41

4–18.5

45.7 ± 23.5

Suggest an association between decreased bone mineralization in JRA and low bone formation that is related to disease severity.

Control n = 62 65.5 ± 23.5 nmol/L significant difference.

Vitamin D intake in JRA 464 ± 262 IU

Intake of controls not reported.

Ioannina, Greece Tzoufi et al. 1994 39°N [50]

JCA

n = 35 (14)

8.8 ± 4.1

39.8 ± 20.5

Disease activity of JCA appears to be associated with lower vitamin D.

Mean disease duration 3.4 years Control n = 15 25(OH)D 68.1 ± 15.5 nmol/L control group taking corticosteroids n = 4 25(OH)D 51.4 ± 24.5 nmol/L.

Missouri, USA Hillman et al. (1994) 37°N [47]

JRA

n = 44 (28)

11.8 ± 3.8

66.6 ± 26.7

Lower bone mineral content and bone biomarkers in JRA patients that controls but higher vitamin D in JRA.

N = 37 controls 25(OH)D 53.2 ± 18.7 nmol/L.

Milano, Italy Bianchi et al. 1990 45°N [41]

JIA

n = 36 (64%)

9.96 (5–17)

45.9 nmol/L Reported from Nissar et al. Review

Suggests severe JRA has an influence on bone mass possibly mediated by a decrease in active vitamin D metabolites.

Study duration one year, controls only measured at baseline 25(OH)D 92 ± 17.5 nmol/L

N = 20

Huddinge, Sweden Johansson et al. 1986 59°N [52]

JCA

26 (all female)

11–16

63.2 ± 36.4

Statistically lower than controls, however no evidence of deficiency.

Healthy controls n = 28 76.2 ± 28.0 nmol/L

Chongqing, China Tang & Mingyue Conference Abstract 2016 29°N [27]

JIA

n = 76 (36)

8.49 ± 3.09

52.8 ± 15.3 nmol/L

JIA patients have reduced serum 25(OH)D3, particularly those with active disease or/and using glucocorticoid.

Riyahad, Saudi Arabia Alhomaidah et al. 2016 24°N [28]

JIA

n = 22 (13)

12.4

14 > 75 nmol/L 8 < 75 nmol/L

Vitamin D insufficiency is frequent in children with JIA.

Bialystok, Poland (abstract only) Goralczyk et al. 2015 53°N [29]

JIA

n = 189 (113)

3–17.7

40.6 ± 23.5

67% 25(OH)D < 50 nmol/L. Obese children had significantly reduced 25(OH)D compared to normal weight peers. Negative relationship between MTX use and 25(OH)D.

Oporto, Portugal Peixoto et al. 2013 Conference Abstract 41°N [30]

JIA

n = 40 (31)

22.3 (4–63)

10 > 75 nmol/L, 19 between 50 and 75 nmol/L, 11 < 20 nmol/L

Prevalence of vitamin D deficiency/insufficiency among JIA patients is very high.

Antalya, Turkey Comak et al. 2014 36°N [32]

JIA

n = 47 (29)

9.3 ± 3.9

44.2 ± 29.0

Only 27.7% patients had 25(OH)D > 50 nmol/L. There was a significant negative correlation between vitamin D concentration and disease activity (p = 0.01, r = − 0,37).

Salé, Morocco Bouaddi et al. (2014) 34°N [33]

JIA

n = 40 (18)

11 ± 4.23

55.4 ± 27.2

25(OH)D < 75 nmol/L in 75% of sample. Poly arthritis and oligoarthritis 25(OH)D status negatively associated with disease activity in univariate but not multivariate analysis.

Median disease duration two years.

Helinski, Finland Miettinen et al. 2013 Letter to the Editor 60°N [34]

JIA

n = 136

1–18

M: 63.9 ± 18.0

F: 62.9 ± 20.0

Suggest that JIA subtype may be associated with 25(OH)D concentration in female patients. Seasonal difference with female patients.

CambridgeUK Nisar et al. 2013 Conference Abstract 52°N [35]

JIA

n = 37 (31)

0–10 (n = 13), 11–20 (n = 12) and > 21 years (n = 12)

49.6 nmol/L (range 13.2–112.0 nmol/L).

Half of patients with JIA have low Vitamin D levels which are inversely related to disease activity and disease duration.

Boston, USA Pelajo et al. 2012 42°N [36]

JIA

n = 154 (61%)

10.6

72.9 ± 23.0

13% deficient, 42% insufficient. Age, ethnicity, season, BMI associated with 25(OH)D but not vitamin D deficiency.No association with whole sample; small negative association for new onset JIA; mean time since onset 28 months.

Helinski, Finland Markula-Patjas et al. 2012 60°N [37]

JIA

n = 50 (41)

14.8 (7.0–18.7)

53 nmol/L (20–95 nmol/L)

62% sufficient, 24% insufficient and 14% deficient.

52% taking vitamin D supplement % of DRI median and IQR 187 (57,331).

Saskatchewan, Canada McNally et al. 2009 52°N [59]

Pediatric arthralgia

n = 730 25(OH)D n = 73

< 18

59.9

Significantly more reported fall and winter as season of onset – more referrals from northern SK 40% < 50 nmol/L 42% 50–75 nmol/L Association between psychological stress, school absenteeism vitamin D insufficiency and arthralgia.

Helinski, Finland Valta et al. 2007 60°N

JIA Glucocorticoid treated

n = 62 (43)

Median 11.8 (4.6–17.9

Median 49 nmol/L 16 (23%) ≤ 37.5 nmol/L

Osteoporosis is a concern in glucocorticoid treated children with JIA.

32% prescribed 400–800 IU vitamin D daily

Mean intake 316 IU (range 44–1204 IU).

Ohio, USA Henderson et al. 1997 40°N [44]

JRA

n = 48 (37)

8.1 ± 1.9

89.4 ± 28.7

Serum 1,25-dihydroxyvitamin D concentrations were able to accurately segregate 79.6% of the JRA subjects into either the low or normal BMD groups.

%RDA 87.6 ± 52.7.

Illinois, USA Reed et al. 1993 40°N [42]

JRA

n = 27 (23)

2.9–16

84.9 ± 11.0

No difference in vitamin D status between active and inactive groups. Children with JRA who have improvement in their disease activity have an improvement in BMD heralded by an increase in serum osteocalcin values 4–87 months from disease onset.

Harrow, UK Reeve et al. 1993 51°N [53]

JCA- treated with glucocorticoids

Prednisone n = 17 Deflazacort n = 17

Prednisone 10.6 ± 3.7 Deflazacort 10.3 ± 3.9

Prednisone 140.8Deflazacort 115.6

25(OH)D was surprisingly high, there was no difference between the two groups p = 0.8.

Chicago, Illinois Reed et al. 1990 40°N [57]

Chronic Rheumatic Disease

n = 113 (82) JRA n = 83

1.5 to 21

Range of groups 44.9 ± 15.0 to 54.9 ± 22.5

No difference between those with active and inactive disease.

London, UK Elsasser et al. 1982 51°N [51]

JCA

n = 63 serum 25(OH)D n = 29

Not reported

24.5 nmol/L (9 > 25 nmol/L, 20 < 25 nmol/L)

There was a marginally significant correlation between TBD and 25(OH)D concentrations (r = 0.37. P < 0.05). Only nine children had acceptable vitamin D status.