Hypovitaminosis D is Associated with Greater Body Mass Index and Disease Activity in Pediatric Systemic Lupus Erythematosus

doi:10.1016/j.jpeds.2009.02.033

The Journal of Pediatrics

Volume 155, Issue 2, August 2009, Pages 260-265

https://doi.org/10.1016/j.jpeds.2009.02.033 Get rights and content

Objectives

To determine whether pediatric systemic lupus erythematosus (SLE) is associated with alterations in the vitamin D-parathyroid hormone (PTH) axis and to assess the relation between vitamin D deficiency and SLE activity.

Study Design

25-hydroxy vitamin D [25(OH)D], 1,25-dihydroxy vitamin D [1,25(OH)₂D], and intact PTH were measured in subjects with SLE (n = 38) and healthy controls (n = 207), ages 5 to 21 years. Vitamin D status and its relation with disease activity were assessed using multivariable logistic and linear regression.

Results

Severe vitamin D deficiency (25(OH)D <10 ng/ml) was observed in a significantly higher proportion of subjects with SLE (36.8% vs 9.2%, P < .001). In SLE, the odds ratio (OR) for severe deficiency was 2.37 (P = .09), adjusting for age, sex, race, and season. However, for each 1 SD greater body mass index (BMI) z-score, 25(OH)D levels were 4.2 ng/mL lower (P = .01) in SLE, compared with controls. Adjusting for 25(OH)D levels, SLE was associated with significantly lower 1,25(OH)₂D (P < .001) and intact PTH levels (P = .03). Greater SLE disease activity index scores were observed in those with 25(OH)D <20 ng/mL (P = .01).

Conclusions

SLE was associated with vitamin D deficiency, particularly among those subjects with SLE who were overweight. Future studies should assess the effect of vitamin D supplementation on skeletal and nonskeletal outcomes in SLE.

Section snippets

Methods

Children and adolescents with SLE between 5 and 21 years of age with at least 3 months' diagnosis were eligible for enrollment. Subjects were recruited from the approximately 70 children with SLE actively followed at The Children's Hospital of Philadelphia. The diagnosis of SLE was confirmed using the American College of Rheumatology criteria.¹³ Healthy control subjects between 5 and 21 years of age were recruited from pediatric practices and through local advertisements as part of a study of

Results

Demographic and anthropometric characteristics of SLE and control subjects are provided in Table I. The frequency of arthritis, rash, and hematologic, renal, and neuropsychiatric disease were similar to another North American pediatric SLE cohort (Table II).⁹ The majority of subjects with SLE received immunosuppressive medications (97%), and at the time of the study visit, hydroxychloroquine (89%), and corticosteroid therapy (84%). The median prednisone dose was 10 mg (range, 0 to 60 mg).

Discussion

Vitamin D deficiency is common among adults with SLE.28, 29, 30, 31, 32 One study reported that 25(OH)D status was not associated with SLEDAI scores,³¹ but the majority of participants were Caucasian (98%) with SLEDAI scores <3 (81%). The racial diversity and range of disease severity in our study may have allowed us to detect a relation between vitamin D status, disease characteristics, and severity.

The determinants of vitamin D deficiency in SLE are likely multifactorial. Melanin, which is

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Vitamin D is a conditionally required nutrient that is biologically inactive but can be converted to a steroid hormone, 1,25(OH)₂D₃. This hormone regulates gene expression by interacting with the vitamin D receptor. The classical biological action of vitamin D is part of an endocrine hormone system that regulates calcium homeostasis. This system coordinates the renal metabolism of the vitamin D₃ prohormone 25(OH)D₃ into 1,25(OH)₂D₃, which is then released to act as an endocrine hormone on classical target tissues such as the intestine, kidney, and bone. However, it is now known that 1,25(OH)₂D₃ can regulate gene expression in other tissues where it influences a broad array of non-calcium metabolism–related processes, for example, development of cancer, regulation of the immune system, and brain and neural cells, as well as modifying risk of development of metabolic diseases. The expanded roles for vitamin D have led to considerable controversy regarding the level of vitamin D status that is optimal for human health.
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Systemic lupus erythematosus (SLE) is a systemic autoimmune disease where chronic inflammation and tissue or organ damage is observed. Due to various suspected causes, inadequate levels of vitamin D (a steroid hormone with immunomodulatory effects) has been reported in patients with SLE, however, contradictory.
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PubMed, SCOPUS, ScienceDirect and Google Scholar electronic databases were searched systematically without restricting the languages and year (up to March 2, 2019) and studies were selected based on the inclusion criteria. Mean difference (MD) along with 95% confidence intervals (CI) were used and the analyses were carried out by using a random-effects model. Different subgroup and sensitivity analyses were conducted. Study quality was assessed by the modified Newcastle-Ottawa Scale (NOS) and publication bias was evaluated by a contour-enhanced funnel plot, Begg's and Egger's tests.
We included 34 case-control studies (2265 SLE patients and 1846 healthy controls) based on the inclusion criteria. Serum levels of vitamin D was detected significantly lower in the SLE patients than that in the healthy controls (MD: −10.44, 95% CI: −13.85 to −7.03; p < .00001). SLE patients from Asia (MD: −13.75, 95% CI: −21.45 to −6.05; p = .0005), South America (MD: -3.16, 95% CI: −4.62 to −1.70; p < .0001) and Africa (MD: −16.15, 95% CI: −23.73 to −8.56; p < .0001); patients residing below 37° latitude (MD: −11.75, 95% CI: −15.79 to −7.70; p < .00001); serum vitamin D during summer season (MD: -7.89, 95% CI: −11.70 to −4.09; p < .0001), patients without vitamin D supplementation (MD: -15.57, 95% CI: −19.99 to −11.14; p < .00001) or on medications like hydroxychloroquine, corticosteroids or immunosuppressants without vitamin D supplementation (MD: -16.46, 95% CI: −23.86 to −9.05; p < .0001) are in higher risk in presenting inadequate serum levels of vitamin D. The results remained statistically significant from different sensitivity analyses which represented the robustness of this meta-analysis. According to the NOS, 91.2% of the studies were considered as of high methodological quality (low risk of bias). No significant publication bias was detected from contour-enhanced and trim and fill funnel plots or Begg's test.
Inadequate levels of serum vitamin D is significantly high in patients with SLE compared to healthy subjects, therefore, vitamin D supplementation with regular monitoring should be considered as part of their health management plans.
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Systemic lupus erythematosus (SLE) and juvenile SLE (jSLE) are autoimmune disorders naturally associated with several genetic, environmental, hormonal, and immunological contributing factors. It has been assumed that vitamin D deficiency may have a role in the immune activation of patients with SLE and play an active part in many comorbidities and even complications. A host of clinical studies suggested that vitamin D exerts inhibitory effects on many immunological abnormalities associated with SLE, also in children and adolescents, while different reports have hypothesized that vitamin D may be associated with accelerated cardiovascular disease in SLE. This review updates and summarizes the information related to the immunoregulatory effects of vitamin D and its importance in jSLE, discusses the innumerable correlations between vitamin D and disease activity, including clinical expression and gene polymorphisms of vitamin D receptor as well as the recommendations for vitamin D supplementation in these patients. Despite the excitement raised by many data obtained about vitamin D and its influence on several aspects of the disease, further well-designed perspective trials are required to define the exact role that vitamin D may have in the management of both SLE and jSLE.
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Citation Excerpt :
Such hypothesis is also corroborated by the finding that VitD intake was not associated with the risk of SLE development in a prospective study [269]. Contradictory results have been obtained when the association between high disease activity in SLE with low VitD serum concentrations has been investigated [270,271], although in children with juvenile SLE an inverse correlation between 25OHD serum levels and disease activity has been described [272]. Although one study found that low VitD levels correlate with flare-up in SLE [273], another study could not confirm these data [274].
Vitamin D (VitD) is a prohormone most noted for the regulation of calcium and phosphate levels in circulation, and thus of bone metabolism. Inflammatory and immune cells not only convert inactive VitD metabolites into calcitriol, the active form of VitD, but also express the nuclear receptor of VitD that modulates differentiation, activation and proliferation of these cells. In vitro, calcitriol upregulates different anti-inflammatory pathways and downregulates molecules that activate immune and inflammatory cells. Administration of VitD has beneficial effects in a number of experimental models of autoimmune disease. Epidemiologic studies have indicated that VitD insufficiency is frequently associated with immune disorders and infectious diseases, exacerbated by increasing evidence of suboptimal VitD status in populations worldwide. To date, however, most interventional studies in human inflammatory and immune diseases with VitD supplementation have proven to be inconclusive. One of the reasons could be that the main VitD metabolite measured in these studies was the 25-hydroxyVitD (25OHD) rather than its active form calcitriol. Although our knowledge of calcitriol as modulator of immune and inflammatory reactions has dramatically increased in the past decades, further in vivo and clinical studies are needed to confirm the potential benefits of VitD in the control of immune and inflammatory conditions.

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: Funding for this project was provided by the American College of Rheumatology Research and Education Foundation's Physician Scientist Development Award (TBW), NIH (P60-MD000209 and K23 RR021969), and the Clinical and Translational Research Center (UL1-RR024134). The authors declare no conflicts of interest, real or perceived.

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Original ArticleHypovitaminosis D is Associated with Greater Body Mass Index and Disease Activity in Pediatric Systemic Lupus Erythematosus

Objectives

Study Design

Results

Conclusions

Section snippets

Methods

Results

Discussion

J Nutr

Am J Clin Nutr

Am J Clin Nutr

J Pediatr

J Am Diet Assoc

Am J Clin Nutr

Semin Nephrol

Am J Clin Nutr

Am J Clin Nutr

Metabolism

Am J Med Sci

Autoimmun Rev

Am J Clin Nutr

Am J Clin Nutr

Am J Clin Nutr

Vitamin D deficiency

N Engl J Med

Strengths and limitations of current epidemiologic studies: vitamin D as a modifier of colon and prostate cancer risk

Nutr Rev

Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis

JAMA

Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis

Int J Epidemiol

Vitamin D deficiency and risk of cardiovascular disease

Circulation

Prevalence and etiology of low bone mineral density in juvenile systemic lupus erythematosus

Arthritis Rheum

High insulin levels and increased low-density lipoprotein oxidizability in pediatric patients with systemic lupus erythematosus

Arthritis Rheum

Suppressive effect of 1alpha,25-dihydroxyvitamin D3 on type I IFN-mediated monocyte differentiation into dendritic cells: impairment of functional activities and chemotaxis

J Immunol

Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus

Arthritis Rheum

Original Article
Hypovitaminosis D is Associated with Greater Body Mass Index and Disease Activity in Pediatric Systemic Lupus Erythematosus