Association of Vitamin D Deficiency with Psoriasis and Metabolic Syndrome: A Case-Control Study in Indian Patients.

Background: Substantial evidence suggests a higher risk of metabolic syndrome as a result of persistent inflammation in patients with psoriasis. Psoriasis may also be associated with vitamin D deficiency. Aim: To correlate vitamin D deficiency with psoriasis and metabolic syndrome. Materials and
Methods: Serum vitamin D levels were quantified, and metabolic syndrome was assessed in 42 cases whose psoriasis severity had been measured by PASI and in an equal number of age/gender-matched controls. The resultant data were analyzed statistically. The odds ratio was calculated wherever applicable and a two-tailed P < 0.05 was considered statistically significant.
Results: Vitamin D deficiency (<20 ng/ml) occurred in 43 subjects [(51.19%); 26 (62%), patients and 17 (40.4%), controls] and was statistically significant in patients (OR: 2.39, P = 0.044) though lacking correlation with disease severity. Metabolic syndrome seen in 25 (30%) subjects-15 (36%) patients and 10 (24%) controls-emerged to be significant (OR: 3.71, P = 0.047) in cases with vitamin D deficiency. Hypertension-observed in 31 (37%) subjects; 18 (43%) cases, 9 each (21.4%) with/without metabolic syndrome and 13 (31%) controls, 7 (16.6%) with and 6 (14.3%) without metabolic syndrome (P = 0.25)-correlated independently with vitamin D deficiency in patients (P = 0.009). Conclusions: Despite limitations of small sample size and observational nature, our study-probably the first such hereto from India-showed statistically significant associations between vitamin D deficiency, metabolic syndrome, and hypertension in patients with psoriasis. Future larger studies are needed for strengthening this evidence prior to the recommendation of its clinical application in the optimum management of patients. Copyright:

Introduction

Substantial evidence suggests an association of serum 25-hydroxyvitamin D [25(OH)] deficiency with the pathogenesis of psoriasis by mediating activation of dendritic cells and T lymphocytes.[123] In addition, inflammation underlying the chronic immune dysregulation of psoriasis predisposes its patients to metabolic syndrome (MS)—a constellation of abdominal obesity, impaired glucose tolerance, dyslipidemia, and hypertension[4] —as also low serum vitamin D levels, whose supplementation has been reported to ameliorate psoriatic skin lesions as well as cardiovascular manifestations consequent to MS.[5]

Vitamin D deficiency/insufficiency occurs among 50%–90% of the general population of India.[6] Thus, this case-control study was conducted in a semi-urban area of Maharashtra.

Materials and Methods

After obtaining institutional ethical clearance, we enrolled 42 patients of psoriasis presenting to the dermatology department of our tertiary-care hospital with effect from September 2018 to June 2020 and an equal number of age and sex-matched controls without any dermatoses.

Exclusion criteria for participants in the study were age <18 years, pregnancy, lactation and postpartum (up to 1 year), concomitant (other) chronic inflammatory or autoimmune disorders, and for cases with psoriasis, therapies with radiation and oral/topical vitamin D during the last 3 months.

After obtaining informed consent, data recorded in a proforma included the age of onset, type of psoriasis and severity as per PASI, sun exposure, skin type, BMI, serum 25(OH)D levels, family history, joint/nail involvement, and history of smoking/consumption of alcohol. Grades of the severity of psoriasis, based on PASI, were mild (<5), moderate (5–10), and severe (>10). Fasting blood samples were tested for glucose, lipid profile, and serum 25(OH)D, the last by chemiluminescence microparticle immunoassay. Vitamin D levels were graded as per the definition by the Endocrine Society (USA): Optimal, ≥30; deficient, <20; and insufficient, 20–29 ng/ml.[7] MS was diagnosed as per the International Diabetes Federation (IDF), 2006 criteria: Waist circumference, (≥90 cm for men and ≥80 cm for women for Indians); blood pressure, ≥130 systolic or ≥85 mm Hg diastolic or on hypertension therapy; serum triglycerides (TG), >150 mg/dL or on TG therapy; high-density lipoprotein-cholesterol (HDL-C), <50 mg/dL (women) or <40 mg/dL (men) or on HDL-C therapy; and fasting plasma glucose, ≥100 mg/dL or on anti-diabetic therapy.[8]

Statistical analysis was done using SPSS software, Version 23 (SPSS Inc., Chicago, IL, USA). Odds ratio (OR) was calculated as applicable and a two-tailed P < 0.05, was considered statistically significant.

Results

The demographic and biochemical characteristics of the study population are summarized in Table 1. Male:female ratio was 1.62:1. Serum vitamin D levels were significantly lower (P = 0.021) in cases than controls. Prevalence of metabolic syndrome among psoriasis patients and controls did not differ significantly (P = 0.23), with 15 (36%) cases and 10 (24%) controls fulfilling its IDF definition criteria. Hypertension was observed in 31 (37%) subjects—18 (43%) cases; 9 each (21.4%) with/without metabolic syndrome and 13 (31%) controls; 7 (16.6%) with and 6 (14.3%) without metabolic syndrome (P = 0.25). Twenty-nine (69%) cases had early-onset (<40 years) type I psoriasis and 13 (31%) had type II. Chronic plaque psoriasis, the predominant morphological presentation, was seen in 35 (83.3%); duration of disease ranged from 3 months to 15 years (mean: 5 (±4.33) years). PASI scores ranged from 2 to 15 (mean: 6.42 ± 4.16). Family history of psoriasis was positive in three (7%) patients, two having type 1 psoriasis; three (7%), had psoriatic arthritis. Twenty-nine (69%) cases showed nail changes; the most common being pits, 27 (65%), and the specific, salmon patch, 4 (10%).

Table 1

Baseline characteristics of cases and controls

Parameters	Cases (n=42)	Controls (n=42)	P
Mean age (years)	39.67±12.36	39.71±12.32	0.99
Male/female	26/16	26/16	1
Sun exposure >30 min/day	22	26	0.38
Smoking	6	8	0.56
Alcohol consumption	10	12	0.62
Metabolic syndrome	15	10	0.23
Mean vitamin D levels (ng/ml)	18.67±7.84	22.66±7.74	0.021
Hypertension	18 (42.86%)	13 (30.95%)	0.25
Diabetes mellitus	14 (33.33%)	10 (23.81%)	0.33
Dyslipidemia	21 (50%)	15 (35.71%)	0.18
Low HDL cholesterol	11 (26.19%)	9 (21.43%)	0.61
Central obesity	28 (66.67%)	29 (69.05%)	0.82

HDL: High-density lipoprotein

Mean 25(OH)D levels (ng/ml) were: cases, 18.66 ± 7.84 and controls, 22.66 ± 7.73; insufficient (20–29) levels: 26 (30.9%) subjects (cases as well as controls) and deficient (<20) levels: 43 (51.19%) subjects, more (P = 0.049) in patients (26, 62%) than controls (17, 40.4%).

While there were no significant differences regarding age, gender, BMI, disease duration, sun exposure, smoking, and diabetes mellitus between those with normal or deficient vitamin D levels, hypertension was more prevalent in the vitamin D-deficient patients (P = 0.009). In particular, there was no linear correlation between the severity of psoriasis and vitamin D levels (P = 0.81) [Table 2].

Table 2

Distribution of variables according to serum vitamin D in patients

Parameters	25(OH)D (<20 ng/dl) (n=26)	25(OH)D (>20 ng/dl) (n=16)	P
Ean age (years)	39.27±13.23	40.41±11.19	0.76
Mean BMI	26.96±5.67	26.06±5.98	0.69
Mean duration (Y)	5.06±4.74	4.92±3.71	0.92
Mean PASI	6.27±4.01	6.69±4.53	0.76
Gender (%, male)	16 (61.54)	10 (62.5)	0.95
Sun exposure <30 min/day	12 (46.15%)	8 (50%)	0.81
Smoking	4 (15.38%)	2 (12.5%)	0.79
Hypertension	12 (46.15%)	2 (12.5%)	0.009
Diabetes mellitus	12 (46.15%)	7 (43.75%)	0.88

PASI: Psoriasis area severity index, BMI: Body mass index

Statistically significant association [OR: 2.39, 95% CI: 0.99–5.74, P = 0.044] emerged between the presence of psoriasis and vitamin D deficiency (<20 ng/mL) even after adjustment for confounding factors, namely BMI, age, gender, sun exposure, metabolic syndrome, occupation, and Fitzpatrick skin type [Table 3].

Table 3

Independent predictors of 25(OH)D deficiency

Variables	Odds ratio	95% CI	P
Psoriasis with 25(OH)D <20 ng/ml	2.39	0.99-5.74	0.044
Age (years)	1	0.42-2.37	0.99
Gender (male/females)	1	0.41-2.41	1
BMI	1.47	0.62-3.47	0.38
Metabolic syndrome	1.78	0.69-4.60	0.23
Sun exposure <30 min/day	1.48	0.62-3.52	0.38

CI: Confidence interval, BMI: Body mass index

Binary logistic regression model for vitamin D (<20 ng/ml) showed significantly more prevalence of metabolic syndrome in vitamin D-deficient patients [OR: 3.71, 95% CI: 0.85–16.21, P = 0.047] [Table 4].

Table 4

Binary logistic regression model for 25(OH)D (<20 ng/ml) in cases

Variables	Odds ratio	95% CI	P
Age (years)	0.70	0.19-2.49	0.76
Gender	0.96	0.27-3.47	0.69
BMI	2.43	0.68-8.70	0.16
Metabolic syndrome	3.71	0.85-16.21	0.047
PASI	1.17	0.34-4.06	0.81
Sun exposure <30 min/day	0.86	0.25-2.98	0.81
Duration (years)	0.75	0.18-3.06	0.68

CI: Confidence interval, PASI: Psoriasis area severity index, BMI: Body mass index

Discussion

Vitamin D deficiency is associated with many autoimmune inflammatory conditions, including psoriasis. Among the patients with psoriasis, there is a higher prevalence of cardiovascular comorbidities.[46] In the present study, significantly lower serum vitamin D levels and a 2.4 times higher risk (P = 0.044) of 25(OH)D deficiency emerged in cases with psoriasis independent of age, gender, occupation, skin type, sun exposure, BMI, and MS. Similar were the observations of several studies:[39101112] 2.89 times (P = 0.03) increased risk of vitamin D deficiency in the study by Orgaz-Molina et al.[10] and 2.5 times (P = 0.01) by Gisondi et al.[3] Wilson et al.[13] observed no different mean 25(OH)D levels in those with and without psoriasis. The association of vitamin D deficiency and psoriasis could be relevant for several reasons; first, known regulatory action of vitamin D3 via vitamin D receptor (VDR) on keratinocytic proliferation and differentiation; second, modulation of the altered expression of K1 and K10 in the psoriatic skin[11] and lastly, mediation of enhanced VDR expression and activity influencing the immunomodulatory actions of dendritic cells and T lymphocytes.[12] Topical vitamin D is believed to treat psoriatic skin lesions by elevating 1, 25(OH)D3 receptor expression in epidermal basal keratinocytes leading to reduced keratinocyte proliferation, increased differentiation, and immunomodulation.[1415] Vitamin D also mediates suppression of IL-17, a key cytokine in the pathogenesis of psoriasis.[16] Moreover, the well-established treatment modality of phototherapy for psoriasis has been found to significantly raise serum vitamin D levels and the beneficial effect of narrowband ultraviolet (UV) B radiation is now hypothesized to be mediated via this increase.[1718]

The overall prevalence of vitamin D deficiency (<20 ng/ml) seen in 43 (51.19%) of our study participants was slightly lower than that in an Italian study by Gisondi et al.[3] (41.46%) and much lower (9.8% and 17. 4%) than in two Spanish studies by Orgaz-Molina et al.[1011] The higher prevalence in India of this deficiency may be attributed to high fiber and low dietary intake of vitamin D, negligible sun exposure possibly related also to impaired quality of life, religious practices such as wearing burkha or purdah, genetic factors such as increased 25(OH)D-24 hydroxylase causing degradation of 25(OH)D to inactive metabolites, and increased pollution interfering with UV mediated synthesis of vitamin D in the skin.[6]

Lack of correlation of vitamin D level with age, sex, sun exposure, smoking, glucose levels, duration of psoriasis, and PASI score (P > 0.05) in our study was also reported by Orgaz -Molina et al.[9] and Gisondi et al.[3] Chandrashekar et al.[12] observed a significant negative correlation between severity of psoriasis and 25(OH)D, which could have been influenced by the exclusion of those on systemic therapy, resulting in the majority of participants having mild disease (PASI <5). Our study had three (7%) cases with psoriatic arthritis and found—as was the case in studies by Gisondi et al.[3] and Orgaz-Molina et al.[10] —no association between psoriatic arthritis and vitamin D deficiency.

The higher prevalence of metabolic syndrome in our study patients (36%) than controls (10%) was not statistically significant (P = 0.23). Orgaz-Molina et al.[9] noted metabolic syndrome in 30% cases and 17% controls (P = 0.143), which too was not significant. The inflammatory process of psoriasis predisposes its patients to a combination of cardiovascular risk factors, including increased BMI and central obesity, which get translated to increased fat deposits.[5] Inflammatory and anti-inflammatory markers (CRP, adiponectin, leptin, resistin, and Lp-PLA2) play a role in these conditions.[19]

We observed lower serum vitamin D levels (14.75 ± 6.69 ng/ml) in psoriatic patients with metabolic syndrome than those without (20.84 ± 7.70 ng/ml) (P = 0.047). Orgaz-Molina et al.[9] also reported significantly lower levels of vitamin D (24.1 ± 7.5 ng/ml) in patients with metabolic syndrome (32.8 ± 8.9 ng/ml).

Another important finding in our patients was the significant likelihood [OR: 3.71, P = 0.047] of developing metabolic syndrome in cases with vitamin D deficiency. Orgaz-Molina et al.[9] observed a significant negative correlation (P = 0.007) between metabolic syndrome in psoriatic patients with vitamin D insufficiency. Being fat-soluble, vitamin D tends to accumulate in fat, reducing its levels in circulation. Low serum levels of adiponectin, an anti-inflammatory adipokine highly expressed by adipocytes, are associated with harmful metabolic states such as diabetes, metabolic syndrome, atherosclerotic cardiovascular disease, and psoriasis. Leptin is a pro-inflammatory adipokine that activates macrophages and monocytes to produce IL-6 and TNF-α. It also augments the production of proinflammatory Th1 cytokines and simultaneously suppresses the production of anti-inflammatory Th2 cytokines.[19] It has been observed that calcitriol 125(OH)2D]) has the potential to suppress the production of macrophage-derived pro-inflammatory cytokines such as IL-6 that accumulate in the fat deposits. The serum levels of adiponectin are related negatively to obesity and positively to 25(OH)D levels. Calcitriol has also been reported to stimulate adiponectin secretion.[20]

Psoriatic patients with hypertension in our study showed vitamin D deficiency (P = 0.009). Vitamin D could probably interfere in the downregulation of the renin-angiotensin-aldosterone system, leading to lower levels of angiotensin II and reduced vasoconstriction. The enzyme, 1α-hydroxylase which converts 25(OH)D to 1,25-dihydroxy vitamin D2 125(OH)2D]), is expressed in various tissues, including human endothelial cells, human vascular smooth muscle cells (VSMCs), macrophages, and throughout the kidney system. 1,25(OH)2 D suppresses the expression of renin, enhances insulin secretion and sensitivity, and blocks the proliferation of VSMCs.[21] Moreover, it has been proposed that adiponectin may play a protective role against the development of hypertension.[19] Al-Daghri et al. from Saudi Arabia who conducted a 1-year prospective study to determine whether correction in vitamin D status could reverse the already established manifestations of metabolic syndrome observed a decline in the prevalence of metabolic syndrome from 25.2% to 13.0%. This suggests that correction of vitamin D levels through increased intake of a vitamin D-rich diet and greater sun exposure can lead to an improved cardio-metabolic profile.[22]

Limitations of the study

Our study had a small sample size. Its observational nature did not enable the determination of the direction of the association, that is, whether vitamin D deficiency is a risk factor for MS in psoriasis or vice versa. Cases and controls were recruited over 2 years; thus, seasonal variations could not be taken into consideration. Furthermore, we did not consider dietary vitamin D intake, though patients on oral vitamin D supplementation or drugs that interfere with calcium metabolism were excluded.

Conclusion

Our study—probably the first such hereto among Indian subjects—confirmed statistically significant associations between vitamin D deficiency, metabolic syndrome, and hypertension in patients with psoriasis. These findings, if strengthened by future larger studies, may justify the mandatory screening of patients with psoriasis for vitamin D deficiency and counseling regarding metabolic syndrome and its potential comorbidities.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.