C L I N I C A L A N D L A B O R A T O R Y I N V E S TI G A T I O N S

BJD

British Journal of Dermatology

Diet and physical exercise in psoriasis: a randomized controlled trial* L. Naldi,1,2 A. Conti,3 S. Cazzaniga,1 A. Patrizi,4 M. Pazzaglia,4 A. Lanzoni,5 L. Veneziano,5 G. Pellacani3 and the Psoriasis Emilia Romagna Study Group 1

Centro Studi GISED, Presidio Ospedaliero Matteo Rota, Via Garibaldi 13/15, 24122 Bergamo, Italy Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy 3 Department of Dermatology, Azienda Ospedaliero-Universitaria Policlinico, Modena, Italy 4 Dermatolologia, Dipartimento di Medicina Specialistica, Diagnostica Sperimentale (DIMES), Azienda Ospedaliero-Universitaria Policlinico Sant’Orsola-Malpighi, Bologna, Italy 5 Department of Dermatology, IRCCS Ospedale Bellaria, Bologna, Italy 2

Summary Correspondence Luigi Naldi. E-mail: [email protected]

Accepted for publication 10 November 2013 Details of the Psoriasis Emilia Romagna Study Group are given in the Appendix.

Funding sources This trial was supported by a research grant from the Emilia Romagna region (Programma di Ricerca Regione Universita 2007–2009 AREA 2 Ricerca per il governo clinico).

Conflicts of interest None declared. L.N. and A.C. contributed equally to the paper and share first authorship. *Plain language summary available online DOI 10.1111/bjd.12735

Background Increased body mass index and weight gain are risk factors for psoriasis, and the prevalence of obesity in patients with psoriasis is higher than in the general population. Limited data exist regarding the role of diet in psoriasis. Objectives To assess the impact of a dietary intervention combined with physical exercise for weight loss on improving psoriasis in overweight or obese patients. Methods This study included 303 overweight or obese patients with moderate-tosevere chronic plaque psoriasis who did not achieve clearance after 4 weeks of continuous systemic treatment. They were randomized to receive either a 20week quantitative and qualitative dietary plan associated with physical exercise for weight loss or simple informative counselling at baseline about the utility of weight loss for clinical control of psoriatic disease. The main outcome was any reduction of the Psoriasis Area and Severity Index (PASI) from baseline to week 20. Results Intention-to-treat analysis showed a median PASI reduction of 48% (95% confidence interval 33
3–58
3%) in the dietary intervention arm and 25
5% (95% confidence interval 18
2–33
3%) in the information-only arm (P = 0
02). Among secondary outcomes, PASI score reduction of ≥ 50% significantly differed between study arms (49
7% with dietary intervention vs. 34
2% with information only, P = 0
006). The weight-loss target (a ≥ 5% reduction from baseline) was reached by 29
8% of patients in the dietary intervention arm compared with 14
5% in the information-only arm (P = 0
001). Conclusions A 20-week dietetic intervention associated with increased physical exercise reduced psoriasis severity in systemically treated overweight or obese patients with active psoriasis.

What’s already known about this topic?

• • •

Obesity is a risk factor for psoriasis development in both adult and paediatric populations. Psoriasis is associated with metabolic derangements, such as type II diabetes. Obesity may reduce the response to systemic treatment.

What does this study add?

•

634

This randomized controlled trial shows that an intervention combining diet restriction and promotion of physical exercise in overweight or obese patients with active

British Journal of Dermatology (2014) 170, pp634–642

© 2013 British Association of Dermatologists

Randomized trial of dietary intervention and weight loss in psoriasis, L. Naldi et al. 635

•

psoriasis helps to reduce psoriasis severity beyond the effects of systemic treatment over a 20-week period. The effect may be related to the weight loss alone, or to some indirect influence on patient compliance or other treatment components.

Psoriasis is considered a multifactorial disease that originates from an interaction between genetic predisposition and exposure to environmental risk factors.1 Increased body mass index (BMI) and increased waist circumference are risk factors for psoriasis development in both adult and paediatric populations.2–10 More than 50% of adult patients with psoriasis are overweight or obese,11 and psoriasis is associated with metabolic derangements, such as type II diabetes.12–14 Additionally, overweight and obese patients have a higher risk of more severe psoriasis.10 Registry data restricted to moderate-to-severe psoriasis indicate that such patients also have a reduced response to systemic treatment, which may be directly related to being overweight and/or potentially involve other factors, such as adherence.11 Obesity is a metabolic and inflammatory disorder.15 Even a moderate weight loss of approximately 5% can markedly reduce the incidence of diabetes and result in other beneficial health effects.16,17 Bariatric surgery and weight loss are associated with remarkable clinical improvement of psoriasis in obese patients.18,19 A small randomized clinical trial involving 60 patients with psoriasis recently showed that, compared with a normal diet, a 16-week low-energy dietetic intervention resulted in a greater decrease in psoriasis severity score, although the difference was statistically nonsignificant (P = 0
06).20 The present study examined the hypothesis that an intervention aimed at reducing weight in overweight and obese patients with psoriasis could help reduce psoriatic disease severity. We developed a randomized controlled clinical trial combining a dietary intervention and a programme of physical exercise as means to improve psoriasis symptoms beyond the effects of systemic treatment.

randomization procedure with stratification for age and BMI. The random allocation sequence was generated by using a pseudorandom number generator algorithm.21 All the participating patients gave their written informed consent, and the protocol was approved by the medical ethics committee at each participating centre.

Patients and methods

Interventions

The study was registered at clinicaltrials.gov using the identifier NCT01714284.

The active intervention was aimed at promoting lifestyle changes and focused on dietary advice and improving physical activity.22 At baseline, each participant underwent a 20-min introductory session with a dietitian at the outpatient clinic and received individual advice and personalized written instructions on the dietetic plan and physical activities. A monthly review of the dietetic plan was scheduled, which included reinforcement of the advice and possible adjustment of the diet in case of specific complaints from the patient. It was also possible for the patient to contact the dietitian for further advice. The dietetic intervention was based on the exchange system, in which foods are divided into three main groups based on the three major nutrients: carbohydrates, proteins and fat. Within each group, the maximum food allowance is defined based on the amount of calories involved. The dietetic intervention allowed three

Study design This study was an assessor-blind, randomized controlled trial in overweight and obese patients with psoriasis who had recently started systemic therapy for their condition and did not achieve clearance after 4 weeks of continuous treatment. We compared how psoriasis severity was affected by either a 20-week quantitative and qualitative dietary plan associated with physical exercise for weight loss, or the provision of simple information at baseline about the utility of weight reduction. Enrolled patients were randomized on a 1 : 1 basis to the two intervention arms, using a centralized telephone © 2013 British Association of Dermatologists

Participants Patients were recruited from the dermatology outpatient services of nine hospitals located in the Emilia Romagna region (Italy). The study included patients aged 18–80 years with a BMI of ≥ 25 kg m 2, who were diagnosed with chronic plaque psoriasis having a Psoriasis Area and Severity Index (PASI) score of 10 or higher (on a scale of 0–72, with higher scores indicating more severe disease), and who had started a systemic therapy for psoriasis and had not achieved clearance after 4 weeks of continuous treatment. The following systemic treatments were allowed: methotrexate, ciclosporin, acitretin, psoralen combined with ultraviolet A therapy (PUVA), etanercept, infliximab, adalimumab and ustekinumab. Topical agents, including vitamin D derivatives, steroids, keratolytics and emollients, were permitted as needed on limited areas (e.g. scalp, palms and soles). Patients were excluded if they had a diagnosis of psoriasis other than chronic plaque or with psoriatic arthritis, if they were cleared at entry, and if they were already on a diet or medication to reduce weight. In addition, patients were ineligible if they were pregnant or lactating, or if they had overt diabetes, history of hyper- or hypothyroidism, history of inflammatory bowel disease or other major immune-related conditions, or major systemic liver or kidney disorders.

British Journal of Dermatology (2014) 170, pp634–642

636 Randomized trial of dietary intervention and weight loss in psoriasis, L. Naldi et al.

main meals plus a maximum of two snacks. Energy intake was set at 0
8 9 resting metabolic rate (RMR) for weeks 1–12, and 1
0 9 RMR for weeks 13–20. The number of food exchanges was adjusted to encourage a distribution of 55% carbohydrate, 30% fat and 15% protein. Subjects were instructed to perform sessions of continuous aerobic physical exercise (e.g. walking) for at least 40 min three times a week. Based on the reports that beneficial health effects can be attained even with only a modest level of weight loss, the treatment goal for weight reduction was set to 5%.23 In the control group, a simple 15-min informative session was conducted at baseline about the utility of reducing weight for improving the clinical control of psoriasis. Monitoring of concomitant systemic treatment for psoriasis Participating dermatologists were instructed to review the patients’ treatment periodically according to local guidelines.24 The dosage of weight-adjusted therapies could be modified in the event that a body weight change of > 5 kg was documented at a scheduled follow-up visit. It was also permissible to stop the systemic treatment and/or to shift patients to a different therapy, but only if a patient experienced adverse events or intolerance to the prescribed treatment. Outcome measures Outcome measures were recorded at baseline and at 8, 16 and 20 weeks. The primary outcome was any percentage reduction of the PASI score (DPASI%) from baseline to week 20. The PASI score accounts for the extent of psoriatic involvement of body surface area on the head, trunk, arms and legs, as well as the severity of scale formation, erythema and plaque induration on each region of the body. Secondary outcome measures included PASI score reduction of ≥ 50% (PASI 50), ≥ 75% (PASI 75) and = 100% (PASI 100) at week 20 compared with baseline. We also calculated any reduction of the patient’s weight and waist circumference at week 20 compared with baseline, both as percentage reduction (DWeight%, DWaist%) and as absolute difference (DWeight, DWaist). BMI was calculated as weight in kg divided by height in m2, and percentage reduction in BMI (DBMI%) was calculated. All outcome variables were also evaluated as overall changes, considering the slope of the curve constructed with data from baseline and weeks 8, 16 and 20. An independent assessor (not the treating physician) who was blind to the treatment arm allocation calculated the PASI score at the different time points. Height (to the nearest mm), body weight (to the nearest 0
1 kg) and waist circumference (in cm) were measured by trained research staff. Side-effects At each visit, the primary investigator noted any adverse event occurring during the study period. In particular, information British Journal of Dermatology (2014) 170, pp634–642

was collected about potential side-effects of the low-energy diet, – including fatigue, nausea, hunger or visual disturbance – and any change in the patient’s systemic treatment for psoriasis. Statistical analysis Continuous variables were presented as medians with interquartile ranges (IQR), while categorical variables were presented as numbers with percentages. The 95% confidence interval (CI) was calculated for each outcome measure by using Wald’s method for proportions and bootstrap resampling for medians. For descriptive purposes, continuous variables were also categorized using clinically relevant thresholds. Differences between arms were tested using the Mann– Whitney U-test for continuous variables and Pearson’s v2-test for categorical variables. Stratified analysis was also performed to identify possible effect modifiers. Overall time-dependent variations in secondary outcomes were evaluated by Friedman’s test for repeated measures with Page’s test for trend in time variations. Associations between continuous variables were assessed using Spearman’s rank correlation coefficient (q). An intention-to-treat approach was adopted in the primary analyses by using the last-observation-carried-forward method to account for patients and/or data lost to follow-up. Intention-to-treat analysis was then complemented by per-protocol analysis, which considered only those patients who completed the study period with available data at follow-up. When designing this trial, we calculated that about 150 patients per arm would be needed for the study to have an 80% statistical power to detect a difference of at least 10% in the two study arms, assuming a pooled standard deviation of no more than 30%. No interim analyses were performed. Analysis was carried out using MATLAB (MathWorks, Natick, MA, U.S.A.). Two-sided P-values of < 0
05 were considered to indicate statistical significance in all tests.

Results Between February 2011 and July 2011, 588 patients were screened, 303 of whom underwent randomization (215 men and 88 women; median age, 53 years; median BMI, 30
8 kg m 2; Fig. 1). Reasons for exclusion were BMI less than 25 kg m 2 (n = 176), diagnosis other than chronic plaque psoriasis (n = 95), ongoing treatment or diet for weight loss (n = 8) or screening completed after the end of the established study period (n = 6). Baseline characteristics of the randomized patients were homogeneous in the two compared groups (Table 1). Twenty-one enrolled patients (6
9%) withdrew before the end of the study. Effectiveness Intention-to-treat analysis showed that, compared with baseline, the median PASI score at week 20 was reduced by 48
0% (95% CI 33
3–58
3) in the dietary intervention arm and 25
5% (95% CI 18
2–33
3) in the information-only arm © 2013 British Association of Dermatologists

Randomized trial of dietary intervention and weight loss in psoriasis, L. Naldi et al. 637

Fig 1. Consort diagram of patient enrolment.

(P = 0
02; Table 2). Among secondary outcomes at week 20, PASI 50 was achieved by a significantly greater proportion of patients in the dietary intervention arm (49
7%; 95% CI 41
7–57
6) than in the information-only arm (34
2%; 95% CI 26
7–41
7; P = 0
006). Compared with the information-only arm, a slightly higher proportion of patients in the dietary intervention arm achieved PASI 75 and PASI 100, but the differences were not significant (P = 0
25 and P = 0
12, respectively). The slope of change over time of median DPASI% from baseline to weeks 8, 16 and 20 was also significantly different between study groups (P = 0
03), with a relevant increasing trend in time variations (P < 0
001; Fig. 2). Regarding weight-loss parameters at week 20, the percentage reduction of BMI from baseline was 3
0% (95% CI 2
4– 3
9) in the dietary intervention arm compared with 1
9% (95% CI 1
4–2
3) in the information-only arm (P = 0
002). The goal of ≥ 5% weight loss between baseline and week 20 was reached by 29
8% (95% CI 22
5–37
1) of patients in the dietary intervention arm compared with 14
5% (95% CI 8
9– 20
1) of the information-only arm (P = 0
001). This between-group difference was confirmed by the absolute reductions of patient weight (3
0 kg, 95% CI 2
0–3
7 vs. 1
7 kg, 95% CI 1
3–2
0; P < 0
001) and waist circumference © 2013 British Association of Dermatologists

(3
0 cm, 95% CI 2
0–4
0 vs. 2
0 cm, 95% CI 1
0–2
0; P < 0
001). Figure 3 shows the slope of change over time of median ΔWeight% from baseline to weeks 8, 16 and 20 (P < 0
001). The slope of change over time also showed a significant between-group difference for all the other secondary outcomes, together with a relevant increasing temporal trend (data not shown). The effect of a dietary intervention in terms of DPASI% was higher in men (50
0%) vs. women (33
3%), in patients over 50 years old (50
0%) vs. ≤ 50 years old (40
2%), in subjects under conventional treatment for psoriasis (52
2%) vs. patients under biologics (38
8%) and in patients with a PASI score ≥ 10 (61
6%) vs. PASI < 10 (28
6%; Table 3). Higher DPASI% was also found in patients with BMI between 25
0 and 29
9 kg m 2 (52
1%) vs. those with a BMI of ≥ 30 kg m 2 (33
3%), although the difference between study arms was statistically significant only for subjects with BMI ≥ 30 kg m 2. To explore the existence of a direct interaction between clinical improvement and changes in BMI from baseline, we also analysed the correlation between DPASI% and DBMI% at week 20. This correlation was statistically significant within the dietary intervention arm (q = 0
42, P < 0
001), and close to significant for the information-only arm (q = 0
14, British Journal of Dermatology (2014) 170, pp634–642

638 Randomized trial of dietary intervention and weight loss in psoriasis, L. Naldi et al. Table 1 Baseline characteristics of randomized patients

Sex Male Female Age (years) 18–40 41–60 > 60 Weight (kg) Height (cm) BMI (kg m 2) 25
0–29
9 30
0–34
9 ≥ 35
0 Waist circumference (cm) PASI score < 10 10–20 > 20 Treatment at entryb Acitretin Adalimumab Ciclosporin Etanercept Infliximab Methotrexate PUVA(8-MOP) Ustekinumab Otherc Conventional Biological

All patients (n = 303)

Dietary (n = 151)

No. (%)

No. (%)

Median (IQR)

215 (71
0) 88 (29
0)

Median (IQR)

114 (75
5) 37 (24
5) 53
0 (19
0)

51 (16
8) 161 (53
2) 91 (30
0)

121 (40
0) 111 (36
6) 71 (23
4)

109 (72
2) 20 (13
2) 22 (14
6) (5
3) (16
6) (8
6) (19
9) (15
9) (17
2) (10
6) (6
0) (0) (41
7) (58
3)

105 (69
1) 27 (17
7) 20 (13
2) 10 26 8 23 19 27 19 16 4 64 84

(6
6) (17
1) (5
3) (15
1) (12
5) (17
8) (12
5) (10
5) (2
6) (43
2) (56
8)

P-valuea 0
08

53
0 (21)

0
99 0
80

88
0 (20
7) 170
0 (14
0) 30
8 (6
0)

0
27 0
65 0
42 0
75

109
0 (16
0) 4
0 (11
3)

0
26 0
99 0
55

61 (40
1) 58 (38
2) 33 (21
7) 112
0 (14
7) 4
0 (8
7)

8 25 13 30 24 26 16 9 0 63 88

Median (IQR)

26 (17
1) 78 (51
3) 48 (31
6) 90
0 (20
3) 170
0 (13
0) 30
8 (6
4)

110
0 (15
0) 4
0 (10
7)

(5
9) (16
8) (6
9) (17
5) (14
2) (17
5) (11
6) (8
3) (1
3) (42
5) (57
5)

No. (%)

53
0 (16
7)

60 (39
7) 53 (35
1) 38 (25
2)

214 (70
6) 47 (15
5) 42 (13
9)

Informative intervention (n = 152)

101 (66
5) 51 (33
5)

25 (16
5) 83 (55
0) 43 (28
5) 89
6 (20
5) 170
0 (14
0) 30
8 (6
2)

18 51 21 53 43 53 35 25 4 127 172

intervention

0
33

0
79

IQR, interquartile range; BMI, body mass index; PASI, Psoriasis Area and Severity Index; PUVA(8-MOP), psoralen combined with ultraviolet A therapy (8-methoxypsoralen). a P-values were calculated using the Mann–Whitney U-test for continuous variables and Pearson’s v2-test for categorical variables. bThe category ‘Other’ was excluded from comparison between conventional and biological drugs. cThis category included the association of acitretin with narrowband ultraviolet B therapy.

P = 0
08). We detected no significant differences in the effect of the dietetic intervention when separately analysing treatments administered in the hospital or under the direct supervision of a treating physician (i.e. infliximab, ustekinumab, PUVA therapy) vs. treatments delivered at home, or treatments adjusted by body weight (i.e. infliximab, ciclosporin, acitretin) vs. fixed-dose therapies (data not shown). Results of the per-protocol analysis were comparable with those of the intention-to-treat analysis (data not shown). Concomitant systemic and topical treatment Table 1 presents the distribution of systemic treatment at entry. Eighteen patients (5
9%), including seven (4
6%) in the dietetic intervention group and 11 (7
2%) in the control group, stopped the systemic treatment for psoriasis or were British Journal of Dermatology (2014) 170, pp634–642

switched to a systemic treatment that was different from the one prescribed at entry. Dose adjustment was reported for 14 patients (9
3%) in the dietetic intervention arm and six patients (3
9%) in the informative intervention arm. A total of 28 patients (9
2%), including 12 (7
9%) in the dietetic intervention group and 16 (10
5%) in the control group, regularly used a topical agent. Side-effects Only mild adverse events were noted during the study period. Seventeen patients in the dietetic intervention group and four in the information-only group complained of sensations of hunger or reported being more tired than usual at some point during the study. Constipation was reported by seven patients in the dietetic intervention group and four in the control group. © 2013 British Association of Dermatologists

Randomized trial of dietary intervention and weight loss in psoriasis, L. Naldi et al. 639 Table 2 Primary and secondary outcomes at week 20

Outcome DPASI% PASI 50 PASI 75 PASI 100 DBMI% Dweight ≥ 5% DWeight% DWeight (kg) DWaist% DWaist (cm)

Dietary intervention (n = 151)

Informative intervention (n = 152)

No. (%)

No. (%)

Median (IQR) 48
0 (64
4)

75 (49
7) 37 (24
5) 25 (16
6)

Median (IQR)

P-valuea

25
5 (58
6)

0
02 (0
03) 0
006 0
25 0
12 0
002 (< 0
001) 0
001 0
001 (< 0
001) < 0
001 (< 0
001) < 0
001 (< 0
001) < 0
001 (< 0
001)

52 (34
2) 29 (19
1) 16 (10
5) 3
0 (5
2)

45 (29
8)

1
9 (3
6) 22 (14
5)

3
0 3
0 2
5 3
0

(5
2) (4
5) (4
6) (5
0)

1
8 1
7 1
5 2
0

(3
4) (3
0) (3
0) (3
5)

IQR, interquartile range; PASI, Psoriasis Area and Severity Index; DPASI%, percentage reduction in PASI; PASI 50, PASI 75 and PASI 100, 50%, 75% and 100% reduction, respectively, in PASI; BMI, body mass index; DBMI%, percentage reduction in BMI; DWeight, reduction in weight; DWaist, reduction in waist circumference. aP-values were calculated using the Mann–Whitney U-test for continuous variables and Pearson’s v2-test for categorical variables. P-values for overall time variations are shown in parentheses, and were obtained using Friedman’s test for repeated measures. Page’s test for increasing trend over time revealed a significant P-value for all shown variables (P < 0
001).

Fig 2. Slope of change over time of percentage reduction in Psoriasis Area and Severity Index (DPASI%) in each treatment arm of the study. Median changes of DPASI% values from baseline to weeks 8, 16 and 20, together with their bootstrap 95% confidence intervals, are shown according to the randomized arm. P-value for overall time variations was obtained by using Friedman’s test for repeated measures.

Discussion The present randomized study showed that an intervention combining diet restriction and promotion of physical exercise – with the aim of reducing weight in overweight or obese patients with active psoriasis – affected psoriasis severity beyond the effect of the systemic treatment administered over a 20-week period. Even with only a slight mean reduction in weight, the active intervention group exhibited significantly reduced disease severity. Interestingly, some sex differences were observed, with men exhibiting a greater DPASI% than women. Our study had some limitations. We did not collect data on quality of life, metabolic outcomes other than BMI and waist © 2013 British Association of Dermatologists

circumference, or biochemical parameters. In our pragmatic trial, we allowed systemic treatment to be continued or modified based on the clinical judgement of the treating physician. Some of the treatments are typically adjusted according to body weight, and we allowed such adjustments to be made. However, changes in drug dosage were rare, given the limited reduction in body weight achieved in most patients. About one-third of the patients achieved our target of a 5% reduction in body weight. This limited impact may reflect the soft approach and loose monitoring that we employed in implementing the dietetic plan. In addition, specific medications may have influenced the effects of weight loss or the ability to lose weight. For example, antitumour necrosis factor agents may be associated with some weight gain, especially during British Journal of Dermatology (2014) 170, pp634–642

640 Randomized trial of dietary intervention and weight loss in psoriasis, L. Naldi et al.

Fig 3. Slope of change over time of reduction in weight (ΔWeight) in each treatment arm of the study. Median changes of ΔWeight values from baseline to weeks 8, 16 and 20, together with their bootstrap 95% confidence intervals are shown according to the randomization arm. The P-value for overall time variations was obtained by using Friedman’s test for repeated measures.

Table 3 Analysis of primary outcome at week 20 stratified for possible effect modifiers

DPASI%

Dietary intervention Median (IQR)

Sex Male 50
0 Female 33
3 Age (years) ≤ 50 40
2 > 50 50
0 Treatment at entryb Conventional 52
2 Biological 38
8 PASI score < 10 28
6 ≥ 10 61
6 BMI (kg m 2) 25
0–29
9 52
1 ≥ 30
0 33
3

Informative intervention Median (IQR)

P-valuea

(66
7) (74
5)

27
1 (65
3) 25
0 (48
4)

0
08 (0
04) 0
12 (0
18)

(70
0) (63
3)

19
9 (68
3) 27
8 (49
8)

0
17 (0
47) 0
05 (0
01)

(68
1) (67
3)

21
8 (53
9) 31
3 (68
3)

0
02 (0
007) 0
29 (0
50)

(66
7) (33
0)

20
0 (57
3) 46
2 (53
4)

0
08 (0
18) 0
02 (0
003)

(59
8) (74
1)

31
8 (62
5) 23
7 (56
9)

0
23 (0
26) 0
04 (0
06)

IQR, interquartile range; PASI, Psoriasis Area and Severity Index; DPASI%, percentage reduction in PASI; BMI, body mass index. a P-values were calculated using the Mann–Whitney U-test for continuous variables and Pearson’s v2-test for categorical variables. P-values for overall time variations are shown in parentheses and were obtained using Friedman’s test for repeated measures. Page’s test for increasing trend over time revealed a significant P-value for all variables shown (P < 0
001). bThe category ‘Other’ was excluded from comparison between conventional and biological drugs.

the first months of treatment.25 Additionally, no blinding was attempted for the interventional manoeuvre. Although the assessment of psoriasis was made by an investigator blind to the treatment received, and the follow-up schedule was British Journal of Dermatology (2014) 170, pp634–642

identical in both groups, the possibility cannot be excluded that the effect was partly related to more close supervision of patients in the interventional arm and, possibly, to increased adherence to treatment in that arm. The study also involved a relatively short follow-up period of 20 weeks. Although achievement of significant short-term weight loss is relatively uncomplicated, long-term maintenance of weight loss is generally achieved in only a proportion of subjects.23 The body weight reduction that we achieved, though rather limited, was comparable with results from other dietetic studies.17,26 Interestingly, studies in diabetes show that even a small reduction in body weight may have a large influence on metabolic control.16,17 Increased BMI and increased waist circumference are risk factors for developing psoriasis. The association has been consistently documented in both case–control studies of incident psoriasis cases and in cohort studies,2–4 and has also been observed in infantile psoriasis5–7 and psoriatic arthritis.8,9 In the largest cohort study, the risk of psoriasis was almost doubled in people with a BMI of ≥ 35
0 compared with people with BMI of 21
0–22
9. A few studies and a systematic review have also suggested a link between increased adiposity and severity of psoriasis.10,27,28 Among 2042 patients with moderate-to-severe psoriasis from the Italian Psocare registry, overweight and obese patients were associated with a reduced response to systemic treatment after 8 and 16 weeks of continuous treatment.11 Two previous small randomized studies have assessed the use of dietetic intervention for improving psoriasis.20,29 In one study, 61 patients with stable plaque psoriasis, a PASI score of ≥ 10 and a BMI of ≥ 30 were treated with a suboptimal dose of ciclosporin 2
5 mg kg 1 per day and were randomized to receive or not receive a dietitian-administered dietary intervention with caloric restriction of 500 kcal below the calculated resting energy expenditure.29 At week © 2013 British Association of Dermatologists

Randomized trial of dietary intervention and weight loss in psoriasis, L. Naldi et al. 641

24, PASI 75 and 50 were achieved by significantly larger percentages of subjects in the diet intervention group; however, losses to follow-up were high (13% in the diet group and 45% in the control arm). In a more recent Danish trial, 60 obese patients with psoriasis were randomized either to a low-energy diet (800–1000 kcal per day) for 8 weeks to induce weight loss, followed by 8 weeks of reintroduction of food intake, reaching 1200 kcal per day, or to receive instruction to continue eating ordinary healthy foods.20 The active dietary interventional arm showed a nonsignificant trend in favour of PASI improvement and a significant reduction in Dermatology Life Quality Index.20 Interestingly a larger reduction in body weight was obtained in the Danish study than in ours. This may be related to several factors, including the manner in which the dietetic intervention was conducted and the higher average body weight in the Danish study than in ours. Obesity is a metabolic and inflammatory disorder,15,30 and adipokines (e.g. chemerin and resistin) are biomarkers of obesity-related inflammation.31–33 Patients with psoriasis reportedly have higher blood levels of chemerin and resistin, which normalize during effective therapy.34 Obesity can induce overproduction of multiple proinflammatory cytokines in adipose tissue, including tumour necrosis factor and interleukin-6 and -8, which are implicated in the pathogenesis of psoriasis.35 In addition to the improvement in psoriasis severity indicated by our current results, there are numerous other incentives for obese patients with psoriasis to lose weight. Psoriasis, especially if severe, is associated with an increased risk of cardiovascular morbidity and mortality, and weight loss improves cardiovascular risk factors (e.g. arterial hypertension, diabetes and hypercholesterolemia).36,37 The results of the present study emphasize the importance of weight loss as part of a holistic multimodal treatment approach to effectively treat both the skin condition and its associated comorbid conditions in overweight patients with psoriasis.38 The long-term impact of a dietetic intervention on psoriasis remains to be explored.

Acknowledgments We wish to thank Dr Valentina Bertarini, dietitian, of the University of Modena and Reggio Emilia, who assisted us with developing the dietetic plan.

References 1 Parisi R, Symmons DP, Griffiths CE, Ashcroft DM. Identification and Management of Psoriasis and Associated ComorbidiTy (IMPACT) project team. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol 2013; 133:377–85. 2 Naldi L, Chatenoud L, Linder D et al. Cigarette smoking, body mass index, and stressful life events as risk factors for psoriasis: results from an Italian case-control study. J Invest Dermatol 2005; 125:61–7. © 2013 British Association of Dermatologists

3 Setty AR, Curhan G, Choi HK. Obesity, waist circumference, weight change, and the risk of psoriasis in women: Nurses’ Health Study II. Arch Intern Med 2007; 167:1670–5. 4 Wolk K, Mallbris L, Larsson P et al. Excessive body weight and smoking associates with a high risk of onset of plaque psoriasis. Acta Derm Venereol 2009; 89:492–7. 5 Bryld LE, Sørensen TI, Andersen KK et al. High body mass index in adolescent girls precedes psoriasis hospitalization. Acta Derm Venereol 2010; 90:488–93. 6 Ozden MG, Tekin NS, G€ urer MA et al. Environmental risk factors in pediatric psoriasis: a multicenter case-control study. Pediatr Dermatol 2011; 28:306–12. 7 Boccardi D, Menni S, La Vecchia C et al. Overweight and childhood psoriasis. Br J Dermatol 2009; 161:484–6. 8 Soltani-Arabshahi R, Wong B, Feng BJ et al. Obesity in early adulthood as a risk factor for psoriatic arthritis. Arch Dermatol 2010; 146:721–6. 9 Love TJ, Zhu Y, Zhang Y et al. Obesity and the risk of psoriatic arthritis: a population-based study. Ann Rheum Dis 2012; 71:1273– 7. 10 Armstrong AW, Harskamp CT, Armstrong EJ. The association between psoriasis and obesity: a systematic review and meta-analysis of observational studies. Nutr Diabetes 2012; 2:e54. 11 Naldi L, Addis A, Chimenti S et al. Impact of body mass index and obesity on clinical response to systemic treatment for psoriasis. Evidence from the Psocare Project. Dermatology 2008; 217:365–73. 12 Love TJ, Qureshi AA, Karlson EW et al. Prevalence of the metabolic syndrome in psoriasis: results from the National Health and Nutrition Examination Survey, 2003–2006. Arch Dermatol 2011; 147:419–24. 13 Langan SM, Seminara NM, Shin DB et al. Prevalence of metabolic syndrome in patients with psoriasis: a population-based study in the United Kingdom. J Invest Dermatol 2012; 132:556–62. 14 Coto-Segura P, Eiris-Salvado N, Gonzalez-Lara L et al. Psoriasis, psoriatic arthritis and type 2 diabetes mellitus: a systematic review and meta-analysis. Br J Dermatol 2013; 169:783–93. 15 Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444:860–7. 16 Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001; 414:782–7. 17 Toumiletho J, Lindstr om J, Eriksson JG et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subject with impaired glucose tolerance. N Engl J Med 2001; 344:1343–50. 18 Hossler EW, Wood GC, Still CD et al. The effect of weight loss surgery on the severity of psoriasis. Br J Dermatol 2013; 168:660–1. 19 de Menezes Ettinger JE, Azaro E, de Souza CA et al. Remission of psoriasis after open gastric bypass. Obes Surg 2006; 16:94–7. 20 Jensen P, Zachariae C, Christensen R et al. Effect of weight loss on the severity of psoriasis: a randomized clinical study. JAMA Dermatol 2013; 149:795–801. 21 McLeod AI, Remark AS. R58 A remark on algorithm AS 183 an efficient and portable pseudo-random number generator. Appl Stat 1985; 34:198–200. 22 Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults – the evidence report. National Institutes of Health. Obes Res 1998; 6 (Suppl. 2):51S– 209S. [No authors listed]. 23 Goldstein DJ. Beneficial health effects of modest weight loss. Int J Obes 1992; 16:397–415. 24 Gruppo di lavoro multidisciplinare in dermatologia Regione Emilia-Romagna. Trattamento sistemico della psoriasi cronica a placche moderata-grave con particolare riferimento ai farmaci biologici. Raccomandazioni sugli usi appropriati basate sulle evidenze.

British Journal of Dermatology (2014) 170, pp634–642

642 Randomized trial of dietary intervention and weight loss in psoriasis, L. Naldi et al.

25

26

27

28

29

30 31

32 33

34

Assessorato alla SanitaI e Politiche Sociali Regione Emilia Romagna, ottobre 2009. Alcorn N, Tierney A, Wu O et al. Impact of anti-tumour necrosis factor therapy on the weight of patients with rheumatoid arthritis. Ann Rheum Dis 2010; 69:1571. Truby H, Baic S, de Looy A et al. Randomised controlled trial of four commercial weight loss programmes in the UK: initial findings from the BBC ‘diet trials’. BMJ 2006; 332:1309–14. Takahashi H, Tsuji H, Takahashi I et al. Prevalence of obesity/adiposity in Japanese psoriasis patients: adiposity is correlated with the severity of psoriasis. J Dermatol Sci 2009; 55:74–6. Murray ML, Bergstresser PR, Adams-Huet B, Cohen JB. Relationship of psoriasis severity to obesity using same-gender siblings as controls for obesity. Clin Exp Dermatol 2009; 34:140–4. Gisondi P, Del Giglio M, Di Francesco V et al. Weight loss improves the response of obese patients with moderate-to-severe chronic plaque psoriasis to low-dose cyclosporine therapy: a randomized, controlled, investigator-blinded clinical trial. Am J Clin Nutr 2008; 88:1242–7. Tchernof A, Despres JP. Pathophysiology of human visceral obesity: an update. Physiol Rev 2013; 93:359–404. Lago F, Dieguez C, Gomez-Reino J, Gualillo O. Adipokines as emerging mediators of immune response and inflammation. Nat Clin Pract Rheumatol 2007; 3:716–24. Berenbaum F, Eymard F, Houard X. Osteoarthritis, inflammation and obesity. Curr Opin Rheumatol 2013; 25:114–18. Piya MK, McTernan PG, Kumar S. Adipokine inflammation and insulin resistance: the role of glucose, lipids and endotoxin. J Endocrinol 2013; 216:T1–15. Gisondi P, Lora V, Bonauguri C et al. Serum chemerin is increased in patients with chronic plaque psoriasis and normalizes following treatment with infliximab. Br J Dermatol 2013; 168:749–55.

British Journal of Dermatology (2014) 170, pp634–642

35 Hamminga EA, van der Lely AJ, Neumann HA, Thio HB. Chronic inflammation in psoriasis and obesity: implications for therapy. Med Hypotheses 2006; 67:768–73. 36 Gelfand JM, Neimann AL, Shin DB et al. Risk of myocardial infarction in patients with psoriasis. JAMA 2006; 296:1735–41. 37 Stern RS, Nijsten T. Going beyond associative studies of psoriasis and cardiovascular disease. J Invest Dermatol 2012; 132:499–501. 38 Naldi L. The search for effective and safe disease control in psoriasis. Lancet 2008; 371:1311–12.

Appendix The members of the Psoriasis Emilia Romagna Study Group are Roberta Miglietta, Claudia Padalino and Alberto Giannetti (Department of Dermatology, Azienda Ospedaliero-Universitaria - Policlinico, Modena, Italy); Silvia Santoro and Francesca Satolli (Department of Dermatology, Azienda Ospedaliero Universitaria, Parma, Italy); Stefano Donelli (Department of Dermatology, Ospedale di Piacenza, Piacenza, Italy); Francesco Savoia (Unit of Dermatology, Ospedale di Ravenna, Azienda Unita Sanitaria Locale, Ravenna, Italy); Vito Di Lernia (Department of Dermatology, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy); Annarosa Virgili and Alessandro Borghi (Department of Dermatology, University of Ferrara, Arcispedale S. Anna, Ferrara, Italy); and Franco Alessandrini and Raffaella Di Crecchio (Unit of Dermatology, Ospedale G.B. Morgagni-L. Pieranto, Forlı, Italy).

© 2013 British Association of Dermatologists