Key Points
Question
Does vitamin D supplementation reduce psoriasis severity through the winter?
Findings
In this randomized clinical trial that included 122 participants with plaque psoriasis (average Psoriasis Area and Severity Index score, 3.1), 120 participants completed the study, and there was no measurable effect on psoriasis severity in the group that received vitamin D of 20 000 IU per week for 4 months during winter (intervention group). Levels of 25-hydroxyvitamin D in the intervention group increased to a less-than-expected degree based on previous experimental data in the same source population.
Meaning
The trial results suggest that vitamin D supplementation did not affect psoriasis severity; however, low baseline severity scores and a lower than expected increase in 25-hydroxyvitamin D levels in the intervention group may have affected the results.
Abstract
Importance
Topical vitamin D analogues are routine treatment for psoriasis, but the effect of oral supplementation has not been established.
Objective
To examine the effect of vitamin D supplementation on psoriasis severity throughout the winter.
Design, Setting, and Participants
This randomized, double-blind placebo-controlled clinical trial with 2 parallel groups was performed through 2 winter seasons (2017 to 2018 and 2018 to 2019). Randomization was computer generated. All participants, health care clinicians, and outcome assessors were masked to group assignment. Each participant was followed for 4 months. The presented analyses were conducted in May 2022. The trial was conducted at the clinical research unit of the University Hospital of North Norway (Tromsø; Norway). Adults from the general population in Tromsø with active plaque psoriasis and 25-hydroxyvitamin D (25[OH]D) levels of less than 24 ng/mL (to convert to nmol/L, multiply by 2.496) were included.
Intervention
Vitamin D (cholecalciferol, 100 000 IU, loading dose, followed by 20 000 IU/week) or placebo for 4 months.
Main outcomes and Measures
Psoriasis Area Severity Index (PASI) (primary outcome), Physician Global Assessment, self-administered PASI, and Dermatology Life Quality Index scores (secondary outcomes).
Results
A total of 122 participants (46 women [37.7%]; mean [SD] age, 53.6 [10.0] years; mean [SD] PASI score, 3.1 [2.0]; mean [SD] serum 25(OH)D, 14.9 [3.9] ng/mL) were included. Of these, 60 (49.2%) were randomized to the vitamin D group and 62 (50.8%) to the placebo group. A total of 120 participants (59 vitamin D [49.2%]/61 placebo [51.8%]) completed the study. By completion, mean (SD) 25(OH)D levels were 29.7 (5.2) ng/mL (vitamin D) and 12.0 (3.8) ng/mL (placebo). There was no significant difference in change in PASI score between the groups (adjusted difference, 0.11; 95% CI, −0.23 to 0.45). There was no significant difference in change in Physician Global Assessment score (adjusted odds ratio, 0.66; 95% CI, 0.27-1.63), self-administered PASI (adjusted difference, −0.60; 95% CI, −1.76 to 0.55) or Dermatology Life Quality Index (adjusted difference, −0.86; 95% CI, −1.9 to 0.19) between the groups. No adverse effects of the intervention were registered.
Conclusion and Relevance
The results of this randomized clinical trial showed that vitamin D supplementation did not affect psoriasis severity. Low baseline severity scores may explain the lack of measurable effect. Levels of 25(OH)D in the intervention group increased to a less-than-expected degree based on previous experimental data from the same source population, and this may have affected the results.
Trial Registration
ClinicalTrials.gov Identifier: NCT03334136
This randomized clinical trial examines the effect of vitamin D supplementation on psoriasis severity throughout the winter.
Introduction
Vitamin D (vitD) has several effects that are relevant to psoriasis.1,2 Most important is the regulatory effects on the immune system and keratinocyte proliferation and maturation,3 which are both disturbed in psoriasis.1,2,3 These vitD effects are used in daily clinical management of psoriasis through the application of topical vitD analogues.4 As ultraviolet B (UV-B) increases vitD production in the skin, it has been questioned whether vitD effects partially account for the treatment effect of UV-B on psoriasis.5,6
Studies that establish a treatment effect of oral vitD on psoriasis are lacking. Favorable outcomes following vitD supplementation have been described in open trials and case reports,7,8,9,10 but the results from the 3 previous randomized clinical trials (RCTs) were inconsistent.11,12,13,14,15 These RCTs did not consider possible effect modification by season,13,14,15 and only 1 included participants with lower serum 25-hydroxyvitamin D (25[OH]D) levels15 (the preferred marker of an individual’s vitD status16).
The present study was conducted during winter in North Norway; thus, we were able to separate the effects of vitD from those of UV exposure. Moreover, we included participants with lower 25(OH)D levels, who are most likely to benefit from supplementation.
We hypothesized that elevating 25(OH)D to recommended levels in patients with psoriasis with lower 25(OH)D levels would reduce psoriasis severity during winter. We examined the effect of vitD supplementation on psoriasis severity as measured by Psoriasis Area Severity Index (PASI), Physician Global Assessment (PGA), self-administered PASI (SAPASI), and Dermatology Life Quality Index (DLQI) scores.
Methods
Trial Design, Location, and Setting
This RCT with 2 parallel groups was performed at the clinical research unit of the University Hospital of North Norway (UNN) (Tromsø, Norway). The trial was conducted during winter, when UV exposure was insufficient for pre-vitD production in the skin.17
Ethics, Trial Registration, Monitoring, and Reporting
The regional ethics committee of North Norway and the Norwegian Medicines Agency approved the study (Supplement 1). It was performed according to the Helsinki Declaration and International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines E6 for good clinical practice and preregistered in ClinicalTrials.gov (NCT03334136). All participants provided written informed consent. Data were collected in a study-specific electronic database (RedCAP). An independent monitor from the clinical research department of UNN monitored the study. We followed the Consolidated Standards of Reporting Trials (CONSORT) guideline when reporting the trial findings.
Eligibility Criteria and Recruitment
We included adults from the general population in Tromsø aged 18 to 79 years with active plaque psoriasis (PASI score >0) and baseline 25(OH)D levels less than 24 ng/mL (to convert to nmol/L, multiply by 2.496). We primarily recruited participants from the Tromsø Study cohort. The Tromsø Study is a population-based multipurpose health survey performed for the seventh time during 2015 and 2016 (Tromsø7).18 Everyone aged 40 to 99 years living in the municipality of Tromsø was invited (n = 32 591), and 21 083 (64.7%) attended.18 The survey included serum 25(OH)D measurement and self-reported psoriasis.18,19
From October 2016 to April 2017, we conducted a pilot study as a part of another vitD intervention trial (the D-COR study), which invited participants in Tromsø7 with 25(OH)D levels less than 16.8 ng/mL.20 We included 7 participants through the pilot study (eMethods in Supplement 2).
The primary study was performed through 2 winter seasons: 2017 to 2018 (season 1) and 2018 to 2019 (season 2). We sent invitations to the participants in Tromsø7 with 25(OH)D levels less than 24 ng/mL who reported active psoriasis during the previous 12 months. As recruitment was slower than anticipated and the enrollment window limited by season, we decided to expand recruitment during season 2. In November 2018, we invited participants from the general population aged 18 to 79 years who did not participate in Tromsø7. By response to advertisement, we sent a formal invitation.
A study nurse performed a phone prescreening of participants who replied to assess eligibility. A dermatologist (M.J.) screened eligible participants to confirm active plaque psoriasis. Blood samples were drawn to confirm 25(OH)D levels of less than 24 ng/mL and assess for exclusion criteria (Box20). The flow of participants through the trial is presented in the Figure.
Box. Inclusion and Exclusion Criteria.
Inclusion Criteria
Adults from the general population in Tromsø aged 18 to 79 years.
Active plaque psoriasis (PASI >0).
Measured serum 25(OH)D levels less than 24 ng/mL at baseline.
Exclusion Criteria
Nut allergy (the study capsules contain peanut oil).
Primary hyperparathyroidism.
Granulomatous diseases.
Measured blood pressure greater than 174 mmHg systolic and greater than 104 mmHg diastolic.
Measured creatinine levels greater than 130 μmol/L (male individuals) and greater than 120 μmol/L (female individuals).
Measured HbA1c levels greater than 9.0 %.
Pregnancy.
Kidney stones during the previous 5 years.
Clinical signs of proximal myopathy.
Participants received a diagnosis of or treatment for organ cancer or malignant melanoma during the previous 12 months.
Participants deemed seriously physically or mentally ill and unfit for participation.
Participants who used solarium more than twice a month.
Participants planning travel in tropical areas for more than 2 weeks during the study period.
Participants who received phototherapy or heliotherapy during the previous month.
Participants who used vitD supplementation of more than 800 IU per day.
Participants who initiated or increased a dose of systemic treatment for psoriasis/psoriatic arthritis during the previous 2 months.
During season 1, we excluded those who participated in the D-COR study.20
Participants could not use solarium, phototherapy or heliotherapy, vitD supplementation (other than the study medication); initiate new systemic treatment that influenced psoriasis severity; or use topical vitD analogues during the study.
Figure. CONSORT Flow Diagram.
Data Collected at Study Visit 1
Enrollment ranged from mid-October to mid-January. Study visit 1 included blood samples; medical history (covering general health, psoriasis, systemic and topical medication, physical activity, smoking habits, vitD intake, and solar exposure); measurement of height, weight, hip, and waist circumference; and conventional blood pressure. The participants brought their topical medication for weighing.
The dermatologist (M.J.) assessed psoriasis severity using the PASI and PGA 6-point scale. The participants completed the questionnaires for the SAPASI and DLQI. A description of the scoring instruments is available in the eMethods in Supplement 2.
The dermatologist used the Psoriasis Epidemiology Screening Tool and examined joints to screen for psoriatic arthritis. Participants reported severity of current joint symptoms using a visual analog scale from 0 to 10 (recorded in millimeters).
Randomization, Allocation Concealment, and Masking
Randomization was computer generated using block randomization stratified by vitD status (< or ≥10 ng/mL), PASI score (< or ≥5), and body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) (< or ≥27), and an allocation ratio of 1:1. The study drug was cholecalciferol, 20 000 IU (Dekristol; Mibe), or an identical-looking placebo (Hasco-Lek; Siechnice). Independent personnel at the hospital pharmacy of UNN prepacked the drugs in numbered identical containers. At visit 1, a study nurse dispensed the drugs according to the assigned randomization number. All participants, health care clinicians, and outcome assessors were masked to group assignment. The study staff could not access the randomization key until monitoring was completed and the database locked. Postintervention 25(OH)D levels were analyzed after study completion.
Intervention
The intervention was either cholecalciferol (100 000 IU loading dose, then 20 000 IU per week) or placebo for 4 months. The vitD dose was chosen based on experience from previous vitD intervention trials,20,21,22 aiming to raise 25(OH)D levels to more than 32 ng/mL in the vitD group. The participants took 5 capsules while at the clinical research unit and 1 capsule weekly afterwards (registered on a diary card).
8-Week Follow-up
A study nurse performed a phone follow-up after 8 weeks to register any adverse events. The participants returned an 8-week questionnaire (including details on medications used, visual analog scale for joint pain, and DLQI and SAPASI score).
4-Month Follow-up, Visit 2
At study visit 2, after 4 months we repeated the data collection performed at visit 1 and registered any adverse events. The same dermatologist (M.J.) conducted the assessments. We reweighed any tube(s) of topical medication and calculated the amount used.
The participants returned their diary card and remaining study capsules. We calculated compliance (used capsules [dispensed capsules − remaining capsules] divided by number of Mondays since inclusion).
We advised participants to take vitD, 800 IU, daily after study completion and ask their general practitioner to remeasure their 25(OH)D levels the following winter. The participants received a gift card ($19.29 USD) to cover travel expenses.
Outcome Variables
The primary end point was the group difference in change in psoriasis severity as measured by PASI score at baseline and 4 months. The secondary end points were the difference in change in PGA, SAPASI, and DLQI scores and difference in use of topical treatment for psoriasis.
Measurements
The Department of Laboratory Medicine at UNN measured serum 25(OH)D levels using an in-house liquid chromatography–tandem mass spectrometry method that detected 25(OH)D3 and 25(OH)D2. The sum of these is presented as 25(OH)D in the Results. To confirm the unexpected low rise in 25(OH)D levels and minimize variance, we reanalyzed frozen serum for all 25(OH)D measurements in 1 batch. The reanalyzed values are reported. For details regarding biochemical analyses, see the eMethods in Supplement 2.
Power Calculation and Statistical Analysis
To have 80% power to detect a 0.5 SD change in PASI scores using a .05 significance level, we needed 64 participants in each group (intervention or placebo). We aimed to include 130 participants, with a maximum of 160.
Statistical analysis was performed using SPSS, version 27 (IBM). All analyses were 2-sided, and the presented results were analyzed per protocol. Intention-to-treat analyses (last observation carried forward) were performed but did not alter the result.
We assessed difference in change in all continuous outcome variables using linear regression (analysis of covariance), with the respective change variable as the outcome, treatment group as the fixed factor, and the respective baseline value as the covariate. We evaluated the fit of the models, including normality, outliers, and homogeneity of variance, by assessing the standardized residuals (histograms, scatterplots of residuals against predicted values). All were deemed a reasonably good fit without transformation of the data. We used Cook distances and leverage values to identify influential cases and ran sensitivity analyses to explore the effects of these. We evaluated the homogeneity of the regression slopes assumption by inspecting scatterplots of the outcome variable against the covariate and assessing baseline-by-treatment interaction terms in the regression models. If violated, we performed sensitivity analyses, including the interaction term, and reevaluated the fit of the model. The difference in change in PGA scores was assessed using ordinal logistic regression, with baseline PGA score as the covariate. Change in PGA scores had 3 levels (−1, 0, and 1). The assumption of proportional odds was met. The placebo group was the reference group in all regression models.
We performed sensitivity analyses by adjusting the main models for smoking, baseline 25(OH)D levels, BMI, and joint symptoms. We applied linear regression to assess the contribution of known predictors of 25(OH)D response to supplementation (baseline BMI, age, sex, and baseline 25[OH]D levels)23 and travel to tropical locations.
Results
Baseline characteristics of the 122 included participants are shown in Table 1. Detailed psoriasis-related anamnestic information is available in eTable 1 in Supplement 2. Only 53 participants (43.3%) had an affected body surface area (BSA) of more than 10% in any area at baseline (Table 1).
Table 1. Characteristics of the Participants in the Vitamin D and Placebo Groups at Baseline and After 4 Months.
| Characteristic | Vitamin D | Placebo | ||
|---|---|---|---|---|
| Baseline | After 4 mo | Baseline | After 4 mo | |
| Total, No. | 60 | 59 | 62 | 61 |
| Main study, No. (%) | 57 (95.0) | 56 (94.9) | 58 (93.5) | 58 (95.1) |
| Pilot study, No. (%) | 3 (5.0) | 3 (5.1) | 4 (6.3) | 3 (4.9) |
| Age, mean (SD), y | 53.3 (10.9) | NA | 54.0 (9.1) | NA |
| Sex, No. % | ||||
| Male | 37 (61.7) | 37 (62.7) | 39 (62.9) | 39 (63.9) |
| Female | 23 (38.3) | 22 (37.3) | 23 (37.1) | 22 (36.1) |
| Weight, mean (SD), kg | 86.5 (17.0) | 86.9 (17.8) | 83.4 (16.3) | 84.3 (16.4) |
| BMI, mean (SD) | 28.9 (5.4) | 29.0 (5.7) | 28.0 (4.3) | 28.4 (4.2) |
| Daily smoking, No. (%) | 7 (11.7) | 6 (10.2) | 15 (24.2) | 13 (21.3) |
| Daily snuff consumption, No. (%) | 10 (16.7) | 9 (15.3) | 7 (11.3) | 6 (9.8) |
| Previously confirmed PsA at baseline, No. (%) | 7 (11.7) | NA | 6 (9.7) | NA |
| Possible PsA diagnosed at study visit, No. | 0 | 0 | 1 | 0 |
| PASI score, mean (SD) | 3.2 (2.1) | 2.9 (2.2) | 2.9 (1.9) | 2.6 (1.7) |
| SAPASI score, mean (SD) | 4.0 (3.2) | 3.6 (3.2) | 3.5 (2.9) | 3.7 (4.5) |
| DLQI score, mean (SD) | 4.4 (4.0) | 3.8 (3.4) | 4.8 (3.9) | 4.9 (3.9) |
| PGA score, No. (%) | ||||
| Minimal | 10 (16.7) | 12 (20.3) | 10 (16.1) | 9 (14.8) |
| Mild | 36 (60.0) | 33 (55.9) | 40 (64.5) | 38 (62.3) |
| Moderate | 14 (23.3) | 14 (23.7) | 12 (19.4) | 14 (23.0) |
| Marked/severe | 0 | 0 | 0 | 0 |
| BSA any area >10%, No. (%) | 29 (48.3) | 25 (41.7) | 24 (38.7) | 18 (29.0) |
| 25(OH)D total, mean (SD), ng/mL | 15.1 (3.4) | 29.7 (5.2) | 14.8 (4.6) | 12.0 (3.8) |
| Calcium, mean (SD), mg/dL | 9.40 (0.33) | 9.28 (0.39) | 9.44 (0.34) | 9.36 (0.32) |
| Phosphate, mean (SD), mg/dL | 3.04 (0.56) | 3.00 (0.52) | 3.20 (0.50) | 3.02 (0.55) |
| PTH, mean (SD), pg/mL | 51.6 (17.5) | 54.9 (15.0) | 45.0 (14.0) | 52.7 (15.9) |
Abbreviations: 25(OH)D, 25-hydroxyvitamin D; BSA, body surface area; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); DLQI, Dermatology Life Quality Index; NA, not applicable; PASI, Psoriasis Area Severity Index; PGA, Physician Global Assessment; PsA, psoriatic arthritis; PTH, parathyroid hormone; SAPASI, self-administered Psoriasis Area Severity Index.
SI conversion factors: To convert 25(OH)D to nmol/L, multiply by 2.496; for calcium to mmol/L, multiply by 0.25; for PTH to ng/L, multiply by 1.
A total of 120 participants completed the study (Figure). Compliance with the intervention was 98.6%.
The use of systemic and topical treatment was balanced between the groups. No participant used systemic medication for psoriasis. Three participants used disease-modifying drugs for psoriatic arthritis in stable dose through the study.
Postintervention 25(OH)D levels are shown in Table 1. Only 24 participants (41.1%) in the vitD group reached 25(OH)D levels of 30 ng/mL or greater postintervention. No treatment-specific adverse effects were registered during the study.
Primary and Secondary Outcomes
There was no significant difference in change in PASI scores between the groups (adjusted difference, 0.11; 95% CI, −0.23 to 0.45; P = .52) (Table 2). Participants in the vitD group had 34% decreased odds of being in the higher PGA change categories (0 or 1) compared with the placebo group. However, the result was not significant (adjusted odds ratio, 0.66; 95% CI, 0.27-1.63; P = .37) (Table 2). There was no significant difference in change in SAPASI (adjusted difference, −0.60; 95% CI, −1.76 to 0.55; P = .30) or DLQI scores overall (adjusted difference, −0.86; 95% CI, −1.9 to 0.19; P = .11) between the groups (Table 2).
Table 2. Difference in Change in PASI, SAPASI, and DLQI Scores and ORs of Difference in PGA Scores Between Treatment and Placebo Groups After 4 Months.
| Outcome | Vitamin D (n = 59) | Placebo (n = 61) | Difference in change (unadjusted) (95% CI)a | Difference in change (adjusted) (95% CI)a,b | P value (adjusted)a,b |
|---|---|---|---|---|---|
| Change in PASI score, mean (SD) | −0.34 (0.98) | −0.41 (0.97) | 0.07 (−0.28 to 0.42) | 0.11 (−0.23 to 0.45) | .52 |
| Change in SAPASI score, mean (SD) | −0.50 (2.26) | 0.25 (3.96) | −0.75 (−1.9 to 0.43) | −0.60 (−1.76 to 0.55) | .30 |
| Change in DLQI score, mean (SD) | −0.59 (3.54) | 0.10 (3.17) | −0.69 (−1.9 to 0.52) | −0.86 (−1.9 to 0.19) | .11 |
| Change in PGA score, No. (%) | OR (unadjusted)a | OR (adjusted) a , b | |||
| −1 | 8 (13.6) | 5 (8.2) | NA | NA | NA |
| 0 | 46 (78.0) | 49 (80.3) | NA | NA | NA |
| 1 | 5 (8.5) | 7 (11.5) | 0.64 (0.26 to 1.55) | 0.66 (0.27 to 1.63) | .37 |
Abbreviations: DLQI, Dermatology Life Quality Index; NA, not applicable; OR, odds ratio; PASI, Psoriasis Area Severity Index; PGA, Physician Global Assessment; SAPASI, self-administered Psoriasis Area Severity Index.
Linear regression model for continuous outcomes and ordinal logistic regression with OR estimates for PGA score.
Adjusted for baseline value.
The used amount of topical medication (measured in grams) was not significantly different between the groups. Details regarding the topical therapies used are available in the eResults in Supplement 2.
Sensitivity analyses did not change the results (eResults in Supplement 2). Correlations between the outcome measures are shown in eTable 4 in Supplement 2.
Explorative Analyses
To assess a potential change in severity for those with more disease activity, we performed explorative analyses in subgroups defined by the respective median baseline value for the continuous outcomes (Table 3). These analyses revealed no new findings for PASI or SAPASI scores, or DLQI scores less than the median. However, in those with DLQI scores greater than the median (DLQI ≥4), the difference in DLQI change was significant in favor of the vitD group (adjusted difference, −2.07; 95% CI, −3.67 to −0.46; P = .01). The difference was seen mainly on the DLQI subscales of symptoms and feelings, personal relationships, and treatment (eTable 5 in Supplement 2). An explorative analysis of subgroups with moderate or higher PGA scores (n = 26) led to a substantial loss of power and did not reveal new findings.
Table 3. Difference in Change in PASI, SAPASI, and DLQI Scores Between Treatment and Placebo Groups After 4 Months in Subgroups Defined by the Median of the Baseline Value.
| Outcome | Subgroup | Vitamin D | Placebo | Difference in change | Difference in change | P value | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Baseline | 4 Mo | Baseline | 4 Mo | |||||||||
| No. | Mean (SD) score | No. | Mean (SD) score | No. | Mean (SD) score | No. | Mean (SD) score | (unadjusted) (95% CI)a | (adjusted) (95% CI)a | (adjusted)a | ||
| PASI score | <2.70 | 28 | 1.6 (0.6) | 27 | 1.5 (0.9) | 32 | 1.5 (0.8) | 31 | 1.4 (0.8) | −0.07 (−0.40 to 0.26) | −0.04 (−0.37 to 0.29) | .80 |
| ≥2.70 | 32 | 4.6 (1.9) | 32 | 4.1 (2.3) | 30 | 4.5 (1.4) | 30 | 3.7 (1.5) | 0.26 (−0.33 to 0.84) | 0.26 (−0.32 to 0.85) | .38 | |
| SAPASI score | <3.12 | 26 | 1.4 (0.9) | 24 | 1.9 (1.8) | 35 | 1.6 (0.9) | 35 | 2.5 (1.8) | −0.58 (−1.41 to 0.25) | −0.59 (−1.43 to 0.25) | .17 |
| ≥3.12 | 34 | 6.0 (2.9) | 34 | 4.8 (3.4) | 27 | 5.9 (2.8) | 26 | 5.3 (6.3) | −0.44 (−2.63 to 1.75) | −0.45 (−2.65 to 1.75) | .69 | |
| DLQI score | <4.00 | 28 | 1.5 (1.0) | 27 | 3.0 (2.9) | 28 | 1.9 (1.0) | 28 | 2.6 (2.0) | 0.69 (−0.53 to 1.92) | 0.73 (−0.52 to 1.99) | .25 |
| ≥4.00 | 32 | 6.9 (3.9) | 32 | 4.6 (3.6) | 34 | 7.2 (3.8) | 33 | 6.9 (4.0) | −1.86 (−3.66 to −0.05) | −2.07 (−3.67 to −0.46) | .01 | |
Abbreviations: DLQI, Dermatology Life Quality Index; PASI, Psoriasis Area Severity Index; SAPASI, self-administered Psoriasis Area Severity Index.
Linear regression model. The adjusted model includes baseline value.
Exploratory analysis restricted to participants with an affected BSA of more than 10% in any area (n = 53) had only minor effects on the adjusted difference in change values and odds ratios. The same was found when excluding participants who traveled to tropical locations during the study (n = 10). A linear model that included baseline BMI, age, sex, baseline 25(OH)D levels,23 and travel to tropical locations explained 15% of the variation in postintervention 25(OH)D levels in the vitD group (eTable 3 in Supplement 2).
Discussion
This RCT did not show an effect of weekly vitD supplementation on psoriasis severity as measured by PASI, PGA, and SAPASI scores or use of topical treatment. We also did not find an effect on psoriasis-related quality of life as measured by DLQI scores.
This study’s general population approach resulted in very low average baseline psoriasis severity, and the anticipated worsening of severity in winter did not materialize. The PASI has limited responsiveness in mild disease, particularly when psoriasis affects less than 10% of BSA in any area.24 Change in PASI scores then depends on change in plaque severity scores and may be underestimated.24 Only 53 participants (43.3%) in the sample had a baseline BSA of greater than 10% in any area, making it almost impossible to detect change. Therefore, improvement and deterioration may have been missed. The SAPASI has the same limitations as PASI when BSA is less than 10% in any area. Change in PGA scores showed a favorable response to vitD supplementation, but the results were not statistically significant. Difference in the use of topical treatment could have been a surrogate marker for the difference in treatment effects. However, the study participants used on average small amounts (if any) of topical medications, making the measure less valuable.
Psoriasis can have substantial effects on quality of life that do not always correlate with disease severity measurements.25 On average, the study participants had low DLQI scores, and these were only weakly correlated with SAPASI, PGA, and PASI scores postintervention. The DLQI captures other symptoms of disease than solely visible ones (eg, pruritus and pain)25 and could indicate changes not captured by the severity measures. However, an effect of vitD supplementation on DLQI was not apparent in this trial.
Considering the low baseline severity scores, lack of (or possibly undetected) winter deterioration, and weak PASI/SAPASI responsiveness in mild disease, we found it warranted to explore the effects in subgroups based on the median split. For PASI and SAPASI, this revealed no new insight. Those with a BSA less than 10% were close to evenly distributed among the median split groups, which left us with the same limitations as in the primary analysis. In those with baseline DLQI scores greater than the median (≥4), we found a significant difference in DLQI score change in favor of vitD. A DLQI change of −2 points is considered small.26 However, in the study subsample, this represented a 29% improvement. This finding may suggest a small favorable response to vitD on psoriasis-related symptoms that we were not able to detect using the chosen severity scoring instruments.
This trial’s findings regarding PASI and PGA scores align with 2 previous RCTs from New Zealand.13,14 Low baseline severity scores make them have the same limitations in effect assessment as in this study. Moreover, the participants in those studies had sufficient average baseline 25(OH)D levels, making them less likely to benefit from supplementation. Their results may also have been affected by increases in 25(OH)D levels in the placebo groups.13,14 In contrast to the present study’s findings, an RCT from Thailand that included patients with mild psoriasis and low baseline 25(OH)D levels found a small significant effect on PASI score in favor of vitD after 3 months but borderline significant effects after 6 months.15 The study was small, did not consider the effect of concomitant topical therapy, and reported small differences in 25(OH)D levels postintervention between the intervention and placebo group. A recent meta-analysis that included the 3 mentioned RCTs was inconclusive.11
Immunomodulatory effect of vitD is believed to depend on maintaining 25(OH)D levels greater than 30 ng/mL.12 The vitD dose given in the present trial exceeded the 1500 to 2000 IU per day or greater that is recommended by the Endocrine Society to maintain 25(OH)D levels greater than 30 ng/mL.16 Based on the response to an equal vitD supplementation regimen given in previous RCTs performed in the same population, we expected the vitD group to reach average 25(OH)D level of greater than 32 ng/mL.20,21,22 One of these previous trials (D-COR) also had an equal intervention length and similar inclusion and exclusion criteria as the present study.20 In the D-COR subsample that enrolled from mid-October to mid-January, the mean 25(OH)D level in the vitD group was 34.4 ng/mL postintervention, and 75% reached 25(OH)D levels of 30 ng/mL or greater (personal communication, R. J.; October 14, 2021). In contrast, only 41.1% reached 25(OH)D levels of 30 ng/mL or greater in the vitD group of the present study, although compliance was strong. This was surprising and may have influenced the results. A higher average BMI in this study compared with D-COR20 may explain some of the observed differences in 25(OH)D response. However, when exploring this, much of the variation in postintervention 25(OH)D levels was unexplained by known predictors of responses to vitD supplementation (BMI, baseline 25(OH)D levels, age, and sex)23 or travel to tropical areas during the study. We hypothesize that there may be genetic differences in uptake, distribution, and enzymatic processing of cholecalciferol in persons with psoriasis compared with the general population. Vitamin D nonresponsiveness, possibly caused by genetic differences, has been suggested in relation to psoriasis7 and autoimmune diseases generally.12,27 Favorable outcomes of high vitD doses on psoriasis severity have been reported,7,8 but to our knowledge not evaluated in RCTs. A recent US study suggested a preventive effect of vitD supplements on autoimmune disease risk.28 Moreover, a recent mendelian randomization study found evidence of a causal relationship between genetically predicted lower 25(OH)D levels and incident psoriasis.29 Therefore, vitD may contribute to prevention and treatment of psoriasis.
Strengths and Limitations
This trial’s major limitations were the low baseline severity scores and the lower-than-expected rise in 25(OH)D levels, which were described previously. This study had several strengths. Foremost, there was a thorough randomized controlled design and elimination of sunshine as a source of vitD, as well as the creation of a true placebo group. We also had detailed information on possible confounders, few dropouts, and high compliance. Furthermore, the same dermatologist did all assessments, minimizing differences in severity scoring.
Conclusions
Based the findings of this randomized clinical trial, any large effect of vitD supplementation on psoriasis severity seems unlikely in those with mild disease (PASI <5). We cannot make conclusions on whether vitD supplementation has a small to moderate effect based on the study data, considering the discussed limitations. Future trials should include cases with more extensive psoriasis and/or use severity measurements, which are more sensitive in the lower spectrum. Also, future trials should ensure the achievement of the targeted 25(OH)D level, possibly aiming at the 25(OH)D level that is achieved through UV-B treatment (>40 ng/mL).30 Further biological analysis investigating the vitD metabolism in persons with psoriasis are warranted.
Trial protocol
eMethods.
eResults.
eTable 1. Psoriasis description anamnestic at baseline
eTable 2. Body surface area (BSA) affected at baseline
eTable 3. Linear regression assessing predictors of 25(OH)D levels post-intervention in the vitamin D group
eTable 4. Correlations between the psoriasis severity measures and DLQI scores at baseline and after 4 months
eTable 5. Results of linear regression analysis assessing difference in change in DLQI subscales between treatment and placebo groups after 4 months, in the participants with DLQI≥4 at baseline
Data sharing statement
Footnotes
Abbreviations: 25(OH)D, 25-hydroxyvitamin D; BP, measured blood pressure; HbA1c, hemoglobin A1c; IU, international units; PASI, Psoriasis Area and Severity Index; vitD, vitamin D.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial protocol
eMethods.
eResults.
eTable 1. Psoriasis description anamnestic at baseline
eTable 2. Body surface area (BSA) affected at baseline
eTable 3. Linear regression assessing predictors of 25(OH)D levels post-intervention in the vitamin D group
eTable 4. Correlations between the psoriasis severity measures and DLQI scores at baseline and after 4 months
eTable 5. Results of linear regression analysis assessing difference in change in DLQI subscales between treatment and placebo groups after 4 months, in the participants with DLQI≥4 at baseline
Data sharing statement