Background
Psoriasis affects 2–3% of the population in Sweden and 20–30% of individuals with psoriasis develop psoriatic arthritis (PsA), a chronic rheumatic disease leading to synovitis, enthesitis and sometimes also axial involvement [
1]. Both psoriasis and PsA are strongly associated with obesity and the metabolic syndrome (MetS) [
2]. International observational studies have reported prevalence of obesity (body mass index (BMI) ≥ 30 kg/m
2) in 45% of PsA patients and of MetS in 30–45% [
3‐
5]. Previous studies have shown that obesity increases the risk of developing both psoriasis and PsA and that obesity is associated with higher disease activity, poorer treatment response and lower chance of achieving minimal disease activity (MDA) [
3,
6‐
10]. Patients with PsA also have an increased risk of cardiovascular disease (CVD) [
11‐
13]. Chronic inflammation, which accelerates the atherosclerotic process, in combination with higher prevalence of cardiovascular (CV) risk factors among PsA patients is believed to contribute to this increased risk [
14‐
16].
Although the associations between PsA and obesity, BMI and disease activity are well known, there is to the best of our knowledge only one prior interventional study which has prospectively assessed the effects of weight loss treatment in PsA [
17].
The aim of this study was to determine the effects of weight loss treatment with very low energy diet (VLED) on the disease activity in joints, entheses and skin in patients with PsA and obesity. The primary endpoint of the study was the percentage of patients reaching minimal disease activity (MDA) after 6 months weight loss treatment. Secondary endpoints were the percentage of patients reaching American College of Rheumatology (ACR) and Psoriatic Arthritis Response Criteria (PsARC).
Discussion
This study aimed to prospectively investigate the association between VLED weight loss treatment and disease activity in patients with PsA and obesity. We found significant improvement of the disease activity in joints, entheses and skin, reduction of CRP, PLT and parameters assessing function at the 6 months follow-up. The primary endpoint, patients with MDA, increased from 29.3% at baseline to 53.7% at 6 months (
p = 0.002). PSARC was reached by 46% of the patients, and the ACR 20, 50 and 70 responses were 51%, 34% and 7% respectively. As a comparison, randomized controlled trials of TNF inhibitors on PsA have typically reported ACR 20 and 50 responses of 50–60% and 30–40% respectively, whereas the reported ACR 20 and 50 responses to placebo have been 15–25% and 0–5% [
31,
32]. Reduction in weight correlated in a dose-response manner with higher ACR 20 response rate and greater reductions in DAS28CRP and HAQ. The treatment which resulted in a substantial weight loss of in median 18.6% of the baseline weight was well tolerated with only few and mild side effects and was perceived as feasible by a majority of the patients. Further, we found that a higher BMI at baseline was associated with increased disease activity and poorer self-reported function. The present study thus supports the hypothesis that obesity is a promotor of disease activity in PsA.
The mechanisms linking PsA occurrence and disease activity with obesity has not been fully clarified. Both immunological, biomechanical and behavioural mechanisms are likely to be involved in the interplay between PsA and obesity. PsA, obesity and atherosclerosis are conditions characterized by chronic inflammation, mediated via partly common immunologic pathways. Tumour necrosis factor α (TNFα), interleukin (IL)23, IL17, IL6 and IL1β are all key cytokines in the pathogenesis of PsA. The white adipose tissue (WAT) can produce the same cytokines (TNFα, IL-23, IL-17, IL-6, IL-1β) in addition to both pro-inflammatory adipokines (resistin, fetuin-A, chemerin, leptin) and adipokines viewed as primarily anti-inflammatory (adiponektin, omentin) [
33]. In obese individuals, WAT is infiltrated by immune cells, such as M1-type macrophages, dendritic cells, IL17 producing T-lymphocytes (Th17) and B-lymphocytes [
34]. Moreover, in obesity, there is a persistent over-production of the pro-inflammatory cytokines and adipokines, which may fuel the autoimmune inflammation in PsA [
34,
35]. Interestingly, there is also evidence that localized inflammation in fat pads inside joints, juxta-posed to entheses and underneath psoriatic skin lesions may play a local pathophysiological role in PsA and psoriasis [
36]. Elevated levels of leptin and resistin and lower levels of adiponectin in serum adjusted for BMI have been shown in patients with PsA and psoriasis in comparison with healthy controls. Elevated serum leptin and resistin have also been associated with an increased burden of skin and joint inflammation [
37,
38].
Biomechanical stress may be another factor linking obesity with PsA. PsA is characterized by enthesitis, which is a chronic inflammation at attachment sites of tendons and ligaments, anatomical locations often subject to mechanical stress [
39]. The weight load of obesity leads to both increased mechanical stress and risk of local microdamage. In the general population, obesity is also associated with pathology of entheses and tendons, in both upper and lower extremities [
40]. In PsA, repeated occupational lifting of heavy loads and exposure to injury or bone fracture has been associated with onset of inflammatory arthritis in subjects with psoriasis [
41,
42]. Psoriasis is also known to develop at sites of trauma, the so-called Köbner response [
43]. Studies on animal models for spondyloarthritis (TNF
ΔARE and DBA/1 mice) have provided further proof for the importance of mechanical stress, by showing that unloading of the hind limb or tail suspension prohibited enthesitis and new bone formation in these mice [
44].
Behavioural factors can also be a link between PsA and obesity. Pain and skin disease can induce a vicious cycle of lowered physical activity and over-eating, leading to obesity and further reduction of the mobility and physical activity [
8,
45]. Efficient weight loss treatment could help reverse this process. Patients with PsA are at increased risk of developing CV and thromboembolic disease [
12,
13]. In addition, obesity has been shown to be associated with poorer response and adherence to TNF inhibitor therapy [
17,
46]. We recommend that weight loss treatment should be considered as complementary to pharmacological treatment in patients with PsA and obesity, since weight loss may improve both disease activity, effect of drug treatment and CV risk profile.
The reduced disease activity seen in the PsA patients after the VLED treatment in the present study could be due to a combination of mechanisms: metabolic effects associated with dietary energy restriction, reduction of pro-inflammatory mediators produced by the WAT, reduced loading of joints and entheses, especially in the back and lower limbs and reduced pain sensitivity. In situations of negative energy balance cells switch to utilize non-hepatic glucose, ketone bodies and free fatty acids as energy source [
47]. This has a dampening and pro-apoptotic effect on activated T lymphocytes, which primarily depend on aerobic glycolysis [
48]. Energy restriction and weight loss is also associated with increased levels of glucocorticoids and adiponectin and reduced levels of IL-6, TNFα and leptin in serum [
49,
50]. In the current study, a negative energy balance was mainly present during the 12–16 weeks of strict VLED treatment. After this time point, only six patients (15%) had a further weight loss, whereas the rest of the patients had an increase in weight between the 3 and 6 months visits, indicative of a positive energy balance. The patients will be followed for 2 years to determine the relation between BMI and disease activity when the patients are no longer in a hypocaloric condition.
Obesity is associated with increased pain sensitivity in inflammatory rheumatic diseases, osteoarthritis and fibromyalgia [
45]. In the current study, the change in composite scores for disease activity after weight loss was mainly driven by a reduction in the number of tender joints and entheses and by lowered patients’ VAS for pain and global disease activity, although there was also a reduction in parameters reflecting inflammation, such as CRP, PLT, swollen joints count and BSA.
There is one prior study which has prospectively studied the effects of weight loss in patients with PsA and obesity or overweight starting treatment with a TNF-inhibitor. After 6 months treatment, the patients with a successful weight loss (≥ 5%) had a higher rate of achieving MDA than those without a successful weight loss (MDA 50% vs 23%;
p < 0.001) [
17]. The patients had higher disease activity at baseline than in the present study, but the weight loss, which was achieved by a hypocaloric diet, was lower. One earlier randomized trial studied the effects of low-energy diet (LED) treatment (800–1000 kcal/day) compared with an ordinary healthy all-round diet in patients with psoriasis and obesity (30 vs. 30) and reported improvement of DLQI and cardiovascular risk profile in the LED arm, but only a trend towards improvement of Psoriasis Area and Severity Index (PASI) after 16 weeks. The weight loss was however correlated with the reduction of PASI. The beneficial effects were sustained at 64 weeks follow-up [
51,
52]. Positive effects on psoriasis have also been reported retrospectively by patients after bariatric surgery in earlier studies [
53,
54].
There are some limitations of the study. First, the present study lacks a control group. The success of the weight loss treatment is reliant on the patients’ determination to follow the given instructions and refrain from intake of energy-containing foods and beverages other than the VLED and non-caloric beverages during the initial strict period of 12–16 weeks. To be effective, VLED treatment must be based on the patients’ active decision and randomization between VLED and care-as-usual was therefore considered unsuitable. Second, no blinding of the assessors was made. Third, a high disease activity was not an inclusion criterion of the study, which may have affected the results. In fact, 29% of the patients had already MDA at baseline. Nevertheless, the study was able to show significant association between weight loss and reduced disease activity. Fourth, no documentation of the side effects (obstipation, freezing, loss of hair and hypotension) was done; hence, no exact data on the occurrence can be presented. No serious adverse event occurred however during the study. Fifth, the study was relatively short in duration, and it is indeed a great challenge to achieve long-term weight loss. The patients will however be followed during 24 months.
Strengths of the present study are the prospective design and the powerful intervention that resulted in a substantial weight loss due to excellent adherence to the dietary regime. The study demonstrates that adding a weight loss treatment to the conventional pharmacologic treatment in patients with PsA and obesity may lead to benefits including lowering of several measures of disease activity along with the weight reduction.