Nutritional Strategies for Psoriasis: Current Scientific Evidence in Clinical Trials

European Review for Medical and Pharmacological Sciences 2018; 22: 8537-8551 Nutritional strategies for psoriasis: current scientific evidence in clinical trials

E. ZUCCOTTI1, M. OLIVERI1, C. GIROMETTA2, D. RATTO1, C. DI IORIO1, A. OCCHINEGRO1, P. ROSSI1

1Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy 2Department of Earth and Environmental Science, University of Pavia, Pavia, Italy

Abstract. – OBJECTIVE: Several nutritional Key Words strategies for the management of psoriasis are Psoriasis, Nutrition, Vitamin D, Obesity, Omega-3, promising. Even if recent data support that nu- Selenium, Zinc, Botanicals. trition may play a pivotal role in prevention and co-treatment and despite patient’s concerns regarding the best nutritional habits, the consen- sus regarding the nutritional strategies to be Introduction adopted lacks in clinical settings. In this man- uscript, the effects of several nutritional strat- Psoriasis is an inflammatory, chronic skin dis- egies for psoriasis patients such as hypocalor- ease that significantly affects the patient’s quality ic diet, vitamin D, fish oil, selenium, and zinc supplementation were systematically reviewed. of life. Psoriasis is a T-cell-mediated autoimmune Randomized controlled trials (RCTs) on bene- dermatological disorder and has to be consid- ficial botanical oral supplements were also in- ered a multifactorial disabling condition caused cluded in the analysis. by the interaction between genetic and environ- MATERIALS AND METHODS: For each topic, a mental triggers. Psoriasis affects 0.09-11.43% of search was conducted in MEDLINE electronic da- the population worldwide, according to the WHO tabases for articles published in English between Global Report on Psoriasis1. The incidence of pso- January 1, 1990 and September 2018. Two inde- riasis differs based on geography and ethnicity; a pendent reviewers assessed and extracted the higher prevalence is observed in Caucasians than data. Only controlled clinical trials were selected. in Asians and African Americans; in EU, Nordic RESULTS: The evidence regarding the current nutritional strategies for psoriasis patients populations are more affected than Mediterra- were summarized and translated into a global, nean. The skin inflammatory process follows a re- comprehensible recommendation. lapsing and remitting course. The pathology may CONCLUSIONS: Weight loss combined with occur at any age, including childhood; however, a a healthy lifestyle was shown to be very bene- peak in psoriasis development occurs at two age ficial for patients with moderate to severe dis- ranges (16-22 and 57-60 years)2,3. Males and fe- ease with a significant reduction of the Psoria- males are equally affected4. A mild form of the sis Area and Severity Index (PASI) score. Cur- disease with less than 3% of the skin surface im- rently, oral vitamin D supplementation for pre- pacted affects two-thirds of patients. The quality vention or treatment of psoriasis in adults with of life can be decreased due to psoriasis causing normal vitamin D levels is not recommended; reduced work productivity, increased physical however, psoriasis patients with a deficit in plas- 5 ma vitamin D levels are advised to complement disability, and impaired social relations . Psoriasis with oral supplements to prevent psoriasis-re- is a multifactorial disease caused by the interac- lated comorbidities. Instead of zinc, selenium, tion between genetic and environmental triggers6. and omega 3 supplements have been proven Recently, due to genome-wide association stud- beneficial for psoriasis patients. Among botan- ies, more than 60 disease susceptibility regions ical species, Dunaliella bardawil (D. bardawil), related to Th17 cell activation have been identi- Tripterygium wilfordii (T. wilfordii), Azadirach- fied6. Both adaptive and innate immune systems ta indica (A. indica), Curcuma longa (C. longa), are thought to be responsible for psoriasis patho- and HESA-A are the most beneficial. In conclusion, a close cooperation between nutritionists genesis. Environmental factors such as emotional and dermatologists may be useful for the man- stress and smoking can negatively influence the agement of psoriasis. onset of symptoms and the severity of the dis-

Corresponding Author: Paola Rossi, MD; e-mail: [email protected] 8537 E. Zuccotti, M. Oliveri, C. Girometta, D. Ratto, C. Di Iorio, A. Occhinegro, P. Rossi ease7. An environmental factor of high interest to patients is the influence of diet8; improper nutrition, inadequate body weight, and metabolic diseases may increase the clinical symptoms or even trigger the disease. The immunological response is primarily driven by activated T helper 1 cells, and the consequent release of cytokines results in proliferation of keratinocytes. Interleuk- ins such as IL1β, IL17, IL22 IL23, and TNF-α are involved9 in the immunological response. During inflammation, regulatory T (Treg) cells play an important role, due to their ability to inhibit the immunological response and maintain the cutaneous immune homeostasis10 (Figure 1). Studies on animal models of autoimmunity have demonstrat- ed that defects in Treg cell number or function can contribute to autoimmune diseases. This knowl- edge is now being applied to human autoimmune diseases such as psoriasis. In psoriatic lesions, the epidermal keratinocytes are identified by ab- normal proliferation, incomplete differentiation, and decreased apoptosis. Consequently, inflam- Figure 1. Bidirectional link between psoriasis and obesity matory cellular infiltrate is found in both dermis and the effect of hypocaloric diet. and epidermis11, and the epidermal barrier at the skin lesion sites is impaired. These lesions induce the typical erythro-squamous psoriatic skin dam- nutritional strategies that can successfully prevent ages, which are preferentially identified on the future major comorbidities are urgently needed. scalp, elbows, knees, and lower back12. Clinical Recently, it has been reported that keratinocytes features, especially size and distribution of the of psoriasis patients have a faster turnover com- psoriatic lesions, allow classification of psoriasis pared to normal skin cells and differential glucose into plaque, guttate, pustular, and erythrodermic requirement. In particular, in skin keratinocytes, types13. Currently, the Psoriasis Area and Severity Glut1 facilitative glucose transporter is selective- Index (PASI) score is the preferred method to es- ly required for keratinocytes proliferation induced timate the disease severity and its extent14. Skin is by injury and/or inflammation. Indeed, in mouse the target organ in which psoriasis appears, even models of psoriasis-like disease Glut1 inactiva- if inflammatory responses occur in other areas13; tion decreased hyperplasia. This scientific evi- evidence indicates that psoriasis is a systemic dence suggests that a new therapeutic target can inflammatory process with comorbidities such be searched in Glut1 inhibition treatment but fur- as metabolic syndrome15, adult cardiac disease16 ther studies need to elucidate the involved mech- (CVD), type 2 diabetes mellitus, hypertension, he- anisms21. To better understand the pathogenesis patic steatosis (HS), depression17, and inflamma- of psoriasis, Koebner phenomenon was initially tory bowel disease18. These conditions and their reported as the formation of psoriasiform lesions related comorbidities can cause relevant physical after cutaneous trauma in the uninvolved skin of and psychological burdens in patients affected; psoriasis patients22. Subsequently, the definition thus, several authors consider psoriasis a system- has been extended to lesions developed after trau- ic pathology. Psoriasis and type 2 diabetes share ma in people with no pre-existing dermatosis23. several genetic and immunological abnormali- Koebner phenomenon is estimated to occur in ties. It has been reported19,20 a positive correlation approximately 25% of psoriasis patients after var- between the severity of psoriasis and the risk of ious traumatic injuries; however, these episodes developing diabetes. Glycemic control and its may be unrecognized. Among the “skin stressor regular monitoring can help to otpimize the qual- causal factor”, there is also tattoos and the number ity of life in psoriatic patients and education and of people that develop this disease after a tattoo is diabetes prevention efforts are indicated for pso- increasing. The introduction of pigments into the riasis patients. All strategies, with the inclusion of skin disturbs the epidermal balance and initiates

8538 Nutritional strategies for psoriasis: current scientific evidence in clinical trials a local inflammatory reaction, which may be the Obese patients have a two-fold increased risk of first step towards the development of psoriasis in psoriasis and in epidemiological studies, obesity subjects who have never experienced symptoms was shown to lead to a poorer clinical outcome previously. In these cases, the tattoo can become for psoriasis patients28. Behavioural actions may the triggering element via skin inflammation, play an important role in the correlation between causing activation of the autoimmune system and obesity and psoriasis. In fact, a sedentary lifestyle leading to the disease23. is closely related to psoriasis29; psoriasis patients avoid physical activities because the skin pa- Obesity and Psoriatic Condition thology may be evident to other people. Obesity, The bidirectional link between obesity and in particular abdominal obesity, is considered a psoriasis is well established with obesity pre- chronic low-grade inflammatory condition where disposing to psoriasis and psoriasis favouring adipocytes secrete proinflammatory signals such obesity24,25 (Figure 2). In a systematic review as adipokines and cytokines (e.g., TNFα and IL- based on nine studies (a sample size of 134,823 6)30,31. Adipose tissue inflammation is induced psoriasis patients), Fleming et al26 suggested that by macrophages, resident immune cells that con- psoriasis patients are more likely to be over- stitute the second largest cellular component af- weight or obese and a statistically significant ter adipocytes in adipose tissue. Obesity causes association exists between increased psoriasis changes in the number and functional activity of severity and higher body mass index (BMI). In a macrophages resulting in the activation of local systematic review and meta-analysis study pub- and later systemic inflammatory responses, trig- lished by Upala et al24 in 2015 that included 7 gering the transition from simple adiposity to randomised controlled trials (RCTs; 878 partici- diseases such as type 2 diabetes, ischemic heart pants) a greater reduction in the severity of pso- disease, and arterial hypertension. The overall riasis score (measured with PASI) was observed prevalence of pediatric psoriasis is estimated at in patients achieving weight loss reduction due approximately 2%, with 20,000 children young- to non-pharmacological interventions compared er than 10 years of age diagnosed yearly32. In an with controls. Every increase in BMI results international cross-sectional study15, the odds ra- in a 9% higher risk of psoriasis onset and a 7% tio (OD) of obesity (BMI ≥ 85th percentile) in higher risk of increased PASI score27 (Figure 2). children with psoriasis was 3.60 and 4.92 for

Figure 2. Immunological response in non-psoriatic skin and in psroatic skin. IL = interleukin, TNF-α = tumor necrosis factor-alpha, IFN-γ = interferon-gamma; Treg = regulatory T cells; DC = dendritic cells.

8539 E. Zuccotti, M. Oliveri, C. Girometta, D. Ratto, C. Di Iorio, A. Occhinegro, P. Rossi mild and severe disease, respectively, compared and observed decreased psoriasis severity, derma- with controls. Similar findings were observed in tologically better quality of life, and lower body a case-control study of children 5-15 years of weight compared with controls. The effects of di- age with moderate to severe plaque psoriasis, etary intervention combined with physical exer- where the odds of having a BMI ≥ 85th percentile cise on weight loss were investigated in 303 over- for psoriatic children was more than 4-fold com- weight or obese patients with moderate-to-severe pared with controls33 (OR = 4.4). In a prospec- chronic plaque psoriasis. Patients included in the tive trial34 comparing 20 children 9-17 years of study did not achieve remission after 4 weeks of age with psoriasis (≥ 5% of body surface area) or continuous systemic treatment. The patients were psoriatic arthritis, 30% of children met the crite- divided into two groups: one group followed a 20- ria for metabolic syndrome, compared with 5% week dietary plan associated with physical exer- in the control group. Psoriasis is associated with cise for weight loss and another group received metabolic syndrome35 and a higher cardiovascu- only simple informative counselling regarding lar risk36. In a cross-sectional study37, psoriasis the benefits of weight loss for psoriatic disease. was shown to be associated with metabolic syn- Sessions of physical exercise included aerobic drome and worsen with increasing disease sever- physical exercise for at least 40 minutes 3 times a ity. These findings were later substantiated in a week. PASI score reduction was statistically sig- 2013 meta-analysis38, where the pooled OR for nificantly different in approximately 48% of sub- metabolic syndrome was 2.26. These data indi- jects in the dietary intervention group compared cate that clinically, psoriasis patients should be with 25% of subjects in the information-only considered as a pivotal step for patient assess- group. In conclusion, 20 weeks of dietetic inter- ment. Current clinical data39,40 show that nutri- vention with increased physical exercise reduced tional consultation may help psoriasis patients psoriasis severity in overweight or obese psoriasis in either the treatment of the disease severity or patients44. In a prospective study by Jensen et al45 decrease the obesity-related comorbidities. patients with obesity and psoriasis were observed for 16 weeks, a significant improvement in pso- Hypocaloric Diet as a Nutritional riasis severity, dermatologically better quality of Strategy for Psoriasis life, greater weight loss, and clinically improved As previously shown, a well-established bidi- important PASI scores in patients who received rectional link exists between psoriasis and obesi- a hypocaloric diet compared with controls. The ty. Obesity is associated with increased psoriasis intervention group received a low-calorie diet incidence, higher psoriasis severity, and reduced (800-1,000 kcal/day) for 8 weeks followed by response to conventional psoriasis treatment. 8 weeks of reintroduction (1,200 kcal/day). The Weight reduction, as a result of intervention with beneficial effects of weight reduction on the se- a tailored hypocaloric diet, it can be helpful to verity of psoriasis and amounts of plasma glucose patients with psoriasis who are overweight or and glycated haemoglobin were maintained at 1 obese, leading to significant improvement in pso- year45. In a clinical RCT46, 42 obese patients after riasis severity41-44. An investigator-blinded clin- discontinuing methotrexate therapy, began a hy- ical RCT was conducted with 61 patients. Diet pocaloric diet regimen or a free diet for 24 weeks and subsequent body weight reduction increased and were followed-up for an additional 12 weeks. the therapeutic response to cyclosporine in obese Maintenance of psoriasis remission was not sig- patients with moderate-to-severe chronic plaque nificantly different between patients following a psoriasis41. Compared with controls, the patients hypocaloric or free diet, and relapse was already in the hypocaloric diet group had significantly observed at week 12; however, the remission greater improvement in psoriasis severity. The tended to be better in the intervention group. In same result was obtained in a prospective RCT another study47, 138 overweight/obese patients testing the effects of a 24-week low-calorie diet with psoriatic arthritis starting treatment with (≤1000 kcal/day) on 262 overweight/obese pso- TNF-α blockers were divided into two groups: riasis patients receiving biologic therapy. Com- 69 patients received a hypocaloric diet and 69 a pared with the controls, patients in the hypocalor- freely managed diet. TNF-α may contribute to ic diet group had a significantly greater reduction the extent of psoriatic lesions in obese patients. in psoriasis severity and body weight42. Guida et Blocking TNF-α production helps interrupt the al43 conducted a prospective study on the effects inflammatory cycle of psoriatic disease, but does of a 6-month hypocaloric diet in 44 obese patients not improve insulin sensitivity in obese patients

8540 Nutritional strategies for psoriasis: current scientific evidence in clinical trials with type 2 diabetes47. Changes in metabolic vari- inflammatory diseases. Recent data provided ables were measured, and a complete clinical by Barrea et al53,54 demonstrates that there is a rheumatologic evaluation was performed in all significant correlation between adherence to the patients at baseline and after a 6-month follow-up MD, assessed using the PREDIMED trial55, and to determine whether Minimal Disease Activ- the PASI score which describes the severity of ity (MDA) criteria was achieved. Regardless of psoriasis. In particular, the results showed that the type of diet, a successful weight loss of more the less the MD was adhered to, the higher the ≥5% from baseline values during treatment with percentage of psoriatic patients was if compared TNF-α blockers was associated with a higher rate to the control group. PREDIMED questionnaire of MDA criteria achieved in overweight/obese shows that EVOO and fish consumption have an patients with psoriatic arthritis47. Bariatric surgery autonomous predictive rate for PASI score and may be considered an extreme approach for the C-reactive protein (CRP) levels, which is the treatment of psoriasis; however, for obese patients main protein of the acute phase of inflamma- with many comorbidities, the Roux-en-Y gastric tion. Psoriatic patients evidenced a statistically bypass has been the most effective48,49. Rome- significant decrease in the use of MD dietary ro-Talamás et al50 reported that among 33 high- components (EVOO, fruits, fish, and nuts) and a ly obese patients under active medical treatment statistically significant increase in the use of red for psoriasis and subjected to a bariatric surgery, processed meats compared to healthy controls. nearly 40% experienced a relevant improvement Furthermore, a higher consumption of EVOO is in clinical severity of psoriasis positively associ- associated to a lower psoriasis severity, support- ated with the rate of postoperative weight loss. No ing, even more, the possible positive effects of RCT studies are available in which the effect of MD in psoriasis patients53. In addition, Barrea a low-calorie diet or weight reduction surgery in et al54 have proved that psoriatic patients have a children was evaluated. A recent review51 showed higher intake of simple carbohydrates, total fat that hypocaloric diet improves weight and der- and ω-6/ω-3 PUFA ratio together with a lower matological state as an adjuvant intervention to consumption of proteins, complex carbohy- standard medical treatments such as cyclosporine, drates, MUFA, ω-3 PUFA, and fibers. The PUFA methotrexate, biologic therapy, and photothera- metabolism is most active in the skin. Therefore, py. Diet alone may not be sufficient to maintain essential fatty acid (EFA) cutaneous deficiency a low psoriatic score achieved by therapeutic re- can be related to epidermal hyperproliferation mission in patients that discontinue their medical and increased the permeability of the epidermal treatment17,46. Education regarding diet, nutrition, barrier. Linoleic acid (LA) is an epidermal com- weight, and physical activity are important in the ponent of ceramides, which are useful to avoid prevention and treatment of psoriasis and should epidermal water loss and to maintain its perme- be a first line intervention aimed at improving pa- ability. LA dietary deficiency may consequently tient prognosis52. cause scaly disorder. High levels of arachidonic acid and of its derivatives with pro-inflammatory Mediterranean Diet (MD) and Psoriatic activity are present in cutaneous lesions of pso- Condition: What is Known riatic patients. The following two conditions can The Mediterranean Diet (MD) distinguishes occur simultaneously, contributing to disease: itself amongst others by a prevalent intake of • High levels of arachidonic acid due to the ac- fruit, green and yellow vegetables, whole cere- tion of phospholipase A2 on phospholipids of als, potatoes, beans, nuts, seeds and other kinds the cellular membrane; of food, which are very rich in antioxidants and • Low Omega 3/Omega 6 ratio due to dietary polyphenols. The source of fats is represented deficiency56,57. by Extra Virgin Olive Oil (EVOO), whereas an- An anti-inflammatory condition is therefore imal fats such as butter, cream, and lard are not achievable by a reduction of arachidonic acid and included. Dairy products (mainly light cheese an incremental intake of eicosapentaenoic acid and yogurt), fish and poultry are consumed in (EPA)58. low-to-moderate percentages whereas wine, red A tailored MD with high intake of MUFA and meat, and eggs are limited. Many epidemiolog- ω-3 PUFA, vegetables, fruit, and fibers, together ical studies have suggested that the MD offers with a restricted intake of saturated fats, simple beneficial health effects, especially upon- car carbohydrates, and sugars, should be suggested as diovascular, metabolic, neoplastic and chronic a nutritional approach in psoriatic patients.

8541 E. Zuccotti, M. Oliveri, C. Girometta, D. Ratto, C. Di Iorio, A. Occhinegro, P. Rossi

Vitamin D and Psoriasis from 19-101 psoriasis patients. In 3 of the 4 stud- Although topical treatment with vitamin D is ies, no statistically significant effect of vitamin D well established and represents an effective and supplementation on psoriasis severity was report- safe treatment option in combination with topical ed65,68,69; however, a correlation between serum vi- corticosteroids59,60, the beneficial effects of vitamin tamin D level and psoriasis severity was observed D oral supplementation remain uncertain. Mam- in one study69. An improvement of immunological mals acquire vitamin D in two ways, via synthe- parameters was reported by Gaal et al66 in patients sis in the skin by the sun (or other UVB sources) with psoriatic arthropathy. In conclusion, oral vi- or from the diet. The biologically active form of tamin D supplementation for prevention or treat- vitamin D is 1,25-dihydroxyvitamin D3. The ment of psoriasis in adults with normal vitamin D main source of vitamin D3 is also from exposure levels is currently not recommended51. However, to sunlight, accounting for more than 90% of the individuals deficient in plasma vitamin D should body’s vitamin D requirement. The active form of complement with oral supplements to prevent vitamin D and its receptor regulates the differentia- psoriasis-related comorbidities. tion and proliferation of keratinocytes, the balance Reference for the right assessment of vitamin of the cutaneous immune system, and the process D intake can be found in Dietary Reference Values of apoptosis. Recent data69 have shown that serum (DRVs) for nutrients Summary Report recently vitamin D levels are lower in psoriasis patients. approved by European Food and Safety Authority Furthermore, an inverse correlation between low (EFSA) panel on Dietetic Product 2017. Concern- vitamin D status and psoriasis has consistent- ing vitamin D, EFSA defined the adequate intake ly shown a deficiency of serum concentration of (AI) in adults, pregnant, breastfeeding women, 25-hydroxyvitamin D correlates with severity of children (> 12 months), and teenager equivalent disease in chronic plaque psoriasis62. Hypothetical- to 15 µg/day under conditions of assumed mini- ly, low vitamin D status is associated with obesity mal cutaneous vitamin D synthesis. and psoriasis. Based on this hypothesis, vitamin This AI level should guarantee a normal plas- D supplementation might aid in the prevention of ma level in healthy subjects and should not be- psoriasis-related comorbidities. A study by Merola lieve as therapeutic level for psoriatic treatment: et al63 on 70,437 female nurses in the United States improving psoriasis has not to be considered as an using self-administrated semi-quantitative food outcome in DRVs-EFSA evaluation. frequency questionnaires in 1994, 1998, 2002, and 2006 showed that vitamin D intake had no impact Psoriasis and Microbiota on the development of psoriasis. Recent evidence has highlighted the pivot- Vitamin D might represent a key modulator al role of microbiota in the pathophysiology of of immune and inflammatory mechanisms64. The chronic inflammatory diseases and of its impact immune regulatory properties of vitamin D are on the efficacy of therapeutic agents. Besides local mediated, at least partially, through regulatory T symbiotic interactions between gut and microbio- cells (Treg) induction. Following presentation by ta, more complex systemic effects, including the tolerogenic dendritic cells, Treg can be induced in skin, act on the rest of the body70. The dominant the peripheral tissues from naive cells64. An inter- types of bacteria in healthy skin assure a stable ruption of the immunological homeostasis and a microbiota. This is constituted by four bacterial reduction of the inflammation process in psoria- phyla: Actinobacteria, Firmicutes, Proteobacte- sis patients might be due to low vitamin D levels ria, and Bacteroidetes. Among Bacteroidetes, the which decrease the number of circulatory Treg64. genera Corynebacterium, Propionibacterium, To analyze the impact of vitamin D on psoriasis and Staphylococcus are the most abundant71-73. patients, electronic databases in MEDLINE were Host-dependent factors such as lifestyle, medical searched for clinical trials published up to 1990. treatment, immune system, and external environ- The systematic search strategy using the com- ment, have a direct influence on the composition bined terms “psoriasis” and “Vitamin D” identi- of skin microbiota71. Skin microbiota composi- fied 1,510 papers. After full-text screening and el- tion is related to different dermatological dis- igibility criteria analysis, four papers were finally eases including psoriasis, atopic dermatitis, and selected and are reported in Table I65-68. Only RCTs acne vulgaris74,75. Microbiota colonizing psoriatic were selected. In all studies, the effects of oral plaques have been investigated, and a decreased supplementation with 1,25-dihydroxyvitamin D3 relative abundance of Propionibacterium was for 3-12 months was reported. Sample size varied described70,76,77. In a larger study that enrolled 75

8542 Nutritional strategies for psoriasis: current scientific evidence in clinical trials

Table I. Selected studies regarding the effects of vitamin D supplementation in psoriasis patients. RCT: randomized clinical trial; DBPCT: double blind placebo controlled trials. Tools used to measure the severity and the extent of psoriasis: Psoriasis Area Severity Index (PASI), Physicians Global Assessment (PGA), Dermatology Life Quality Index (DLQI), and Psoriasis Disability Index (PDI). Author Number Study Supplement Supple- Study Conclusions of patients design 1aoh mentation endpoints (dropout Vitamin D3 duration excluded) (months)

Siddiqui et al65 50 DBPCT 1 μg/day 3 PASI No significant difference between treated and placebo group.in moderate to severe psoriasis Gaal et al66 19 RCT 0.5 μg/day 3 Immuno- Significant immunomodulatory modulatory effect in patients with effect polyarticular psoriasis. Jarrett et al67 65 RPCT 100,000 IU 6 PASI, PGA, No significant difference monthly DLQI, PDI between treated and placebo group Ingram et al68 101 RPCT 100,000 IU 12 PASI and No direct benefit of vitamin D3 monthly serum 25(OH)D supplementation. In some concentrations subgroups relationship assessed at between 25(OH)D and 3-monthly psoriasis severity intervals patients with psoriasis (and 124 healthy controls), when compared to control mice83 and had lower two distinct clusters, called cutaneotypes, were levels of pro-inflammatory cytokines84 (TNF-a, identified: a Proteobacteria-associated microbio- IL-6, IL-23, IL-17, IL-17F, and IL-22). The role ta, and a Firmicutes and Actinobacteria-associat- of Lactobacillus pentosus in psoriasis patients ed microbiota. This last cutaneotype was enriched still needs to be investigated. The development in lesion specimens when compared to controls78 of microbiota-targeted therapy and its potential (odds ratio 3.52). The trigger that causes the shift use for novel diagnostic approaches to cutaneous from a host-symbiosis to a host-dysbiosis mi- diseases is still in progress75. crobiota interaction in the skin is not yet fully investigated. Longitudinal studies addressed to Nutritional Supplements Used investigate the dynamics of microbiota composi- by Psoriasis Patients Other tion during plaque resolution, and relapsing could Than Conventional Medicine provide new insight into the role of microbiota Complementary medicine, which uses uncon- during triggering, propagation, and maintenance ventional substances/treatments, has always been of plaques79. common among eastern populations and is cur- The gut and the skin are intricately relat- rently gaining popularity in the western world. ed through what is referred to as the “gut-skin According to the National Center for Comple- axis”80. In psoriatic patients, gut microbiota mentary and Integrative Health (USA), comple- seems to be considerably modified, with a sig- mentary medicine includes a wide range of prod- nificantly reduced abundance of Akkermansia ucts such as herbs, medicinal mushrooms, muciniphilia when compared to healthy con- vitamins, minerals and probiotics, and several trols81. A randomized double-blind placebo-con- practices such as magnetotherapy, or acupuncture. trolled trial82 evidences that patients treated When a non-mainstream treatment is used in place with a daily oral dose of Lactobacillus parca- of conventional medicine, it is considered ‘alter- sei NCC2461 exhibit decreased skin sensitivity, native’ (definition of Complementary and Alter- have a hastened barrier function recovery and native Medicine, CAM, according to the National preserve skin more efficiently after treatment Center for Complementary and Integrative with agents such as sodium lactate and urea. Health). When a non-mainstream treatment is Mice fed with Lactobacillus pentosus developed used together with conventional medicine, it is a milder form of imiquimod-induced psoriasis considered ‘complementary’ (Complementary

8543 E. Zuccotti, M. Oliveri, C. Girometta, D. Ratto, C. Di Iorio, A. Occhinegro, P. Rossi and Integrative Alternative Medicine, CIM). Der- coenzyme Q10 (50 mg daily), vitamin E (50 mg matology has experienced a trend toward CAM; daily), and selenium (48 µg daily) with positive one review evaluating seven dermatological sur- effects. Furthermore, in a study93 consisting of 34 veys showed a 35-69% of prevalence in CAM use patients, oral supplementation with a combination by patients69. Because the simultaneous conven- of micronutrients (folic acid, magnesium, iron, tional and CAM practices could potentially cause zinc, copper, manganese, selenium, chromium, both side effects and benefits, investigating any iodine, and vitamins A, D, E, K, C, B1, B2, B3, alternative or integrative therapies used as substi- B6, and B12) for 3 months in conjunction with tutes or supplemental medicine to the convention- low-dose methotrexate significantly improved al therapy is useful for dermatologists. If self-ad- psoriasis severity. Concomitant treatment with ministered, complementary medicine is to be methotrexate and micronutrients in a randomized avoided for any reason, the beneficial effects of double-blind trial94 showed an improvement in macro- and micronutrient supplementation for PASI score and a significant decrease in IL-1β and improving psoriasis condition should be consid- TNF-α levels with a significant correlation be- ered. The most common oral dietary supplements tween changes in both IL-1β and TNF-α levels used by psoriasis patients are fish oil, selenium, and PASI score. Due to limited data regarding the and zinc85,86. Fish oil and omega 3 supplements effectiveness of selenium supplementation, no are the most commonly used CAM supplements recommendation is available to date for the use of not only by psoriasis patients87 but also patients selenium as a supplement for the treatment of pso- with other dermatological diseases. Millsop et al40 riasis. Based on the extensive use of CAM agents reviewed the study on the efficacy of fish oil sup- in the treatment of psoriasis, the most common plementation in psoriasis patients; 12 of 15 trials and effective oral botanicals have been recently selected as controlled studies showed a benefit. reviewed85,95,96. The green microalga Dunaliella The dosage varies; however, the average dose of bardawil (D. bardawil; Ben-Amotz and Avron), is eicosapentaenoic acid (EPA) was 4 g/day and of referred as the richest known source of β-caro- docosahexaenoic acid (DHA) was 2.6 g/day. tene. Found in natural salt lakes, salt ponds, and These supplements should be taken for longer pe- hypersaline coastal pools, Dunaliella salina (D. riods (from 1-6 months) to obtain an effective im- salina) is halophilic and distributed worldwide97. provement in psoriasis. In one study, eating just 6 Apart from beta-carotene, at least nine categories ounces (170 g) of fatty fish daily was shown to of secondary metabolites from D. salina have improve psoriasis when compared with white fish been reviewed because they show antioxidant, an- consumption40. Among oral supplements used by ti-cancerous, anti-inflammatory, eye-sight im- psoriasis patients, data regarding oral supplemen- proving, and antimicrobial properties98. Green- tation with zinc is controversial88. Despite the berger et al99 tested the oral assumption of D. general use of zinc oral supplementation in psori- bardawil in 34, mild, chronic plaque psoriasis pa- asis patients, RCTs were conducted in only two tients. Due to the significant increase of all-trans old studies. In a double-blind crossover trial by beta-carotene plasma levels, PASI score decreased Clemmensen et al89 with 24 patients suffering in 61.3% of patients, almost double than in con- from psoriatic arthritis, oral zinc sulphate was trols (6 weeks). Although statistical significance found effective without any severe side-effects. was not reached, the Dermatology Life Quality In- Conversely, Burrows et al90 reported no statisti- dex (DLQI) confirmed a positive trend at 12 weeks cally significant differences in psoriasis and se- compared with controls (Table II). Tripterygium verity index scores associated with zinc sulphate wilfordii Hook F (TwHF; Celastraceae) is native to supplementation in 24 chronic psoriasis patients South Central China and is an important herb used over a 12-week period. Selenium is an essential in traditional Chinese medicine (TCM) against sev- element with antiproliferative and immune regu- eral autoimmune and inflammatory diseases. TwHF latory properties. Decreased serum selenium lev- is reported to contain bioactive triptolides and ter- els were associated with increased psoriasis se- penoids100-102 particularly effective in the treatment verity. A study by Wacewicz et al91 showed that, of rheumatoid arthritis103. Regarding the applica- when alterations in the serum levels of selenium, tion of TwHF in the treatment of psoriasis vulgar- zinc, copper, total antioxidants, and C-reactive is, Lv et al104 reviewed numerous RCTs in the lit- protein (CRP) occur, supplementation with sele- erature focusing on internal use and considering nium is advised. In a relevant study92, psoriasis the PASI score as the main outcome. Significant diseases were treated with an oral combination of reductions of PASI score at least up to PASI 70

8544 Table II. Selected studies regarding the effects of oral botanicsls for psoriasis. RCT: randomized clinical trial; DBPCT: double blind placebo controlled trials; DB: double blind. Tools used to measure the severity and extent of psoriasis: Psoriasis Area Severity Index (PASI), Physicians Global Assessment (PGA), Dermatology Life Quality Index (DLQI).

Author Treatment Number and Study Dose and Methods Efficacy Adverse type of psoriasis design duration effects

Greenberger Dunaniella 34, mild, chronic Prospective, 1 capsule/day, PASI score, PASI score improvement in None et al99 bardawil DB 6 weeks DLQI treatment compared to control; not significance in DLQI between two groups LV et al104 Tripterigium 1872 Systematic Tripterygium PASI score PASI score improvement in Several mild side wilfordii review, glycosides treatment compared to control effects 20 RCT 10-30 mg/day, 1-3 months Pandey et al108 Azadirachta 50 RCT 3 capsules/day, PASI score PASI score improvement in None indica 12 weeks treatment compared to control (neem tree) Strong et al115 Oenothera 51 DBPCT 12 × 500 mg No significant difference None biennis capsules combined was noted in the rate with fish oil, of deterioration 7 months Oliwiecki Oenothera 37 DB, parallel 12 × 500 mg Assesment of No significant improvement None et al116 biennis trial capsules, combined erythema, in clinical severity of psoriasis with marine oil, scaling and or change in transepidermal 6 months overall severty water loss Antiga et al119 Curcuma 63, mild to DBPCT 2 g/day PASI score PASI score improvement One patient had longa moderate combined with in treatment compared diarrhea topical steroid to control Carrion- Curcuma 21, moderate RCT Double 6 Tablets x12 mg PASI score Therapeutic response present None Gutierrez longa to severe blind curcumin/day if coupled with visible light et al120 and visible light phototherapy phototherapy Kurd et al121 Curcuma 12, moderate Prospetive, 4.5g/day, PASI score, Only two patients achieved GI upset or heat longa to severe controlled, 12 weeks PGA PASI 75 or a PGA of excellent intolerance/ open label hot flashes Ahmadi HESA-A 28, chronic RCT 2X25mg/Kg Clinical 64,2% clearance of psoriatic None et al130 tablet for 6 months determination of plaques and 35.8% psoriasis severity had mild disease Barikbin HESA-A 19, chronic RCT 30 mg/Kg, PASI score PASI score reduced in 73,7% None et al131 4-30 weeks and increased in 6.3%. Statistically significant correlation between the duration of treatment and PASI improvement

8545 E. Zuccotti, M. Oliveri, C. Girometta, D. Ratto, C. Di Iorio, A. Occhinegro, P. Rossi were reported in all the reviewed publications. rion-Gutierrez et al120 showed oral curcumin is a Based on a meta-analysis of the same literature, photosensitiser and thus an adjuvant in photo- Lv et al104 refuted the previously suggested unfa- therapy. Conversely, Kurd et al121 reported a low vourable cost-to-benefit ratio of several mild ad- response rate when oral curcumin was the only verse effects105 from TwHF such as gastrointesti- supplement administered as treatment (Table II). nal reactions, skin dryness, and increased urea Patented under Iranian authority, HESA-A is nitrogen (Table II). Azadirachta indica A. Juss manufactured according to the traditional Per- (A. indica; Meliaceae), the neem tree, is native sian medicine and composed of mineral, herbal, to regions from Assam to Indochina and has been and animal (marine shrimp) fractions122-124. Be- used for thousands of years in traditional Indian cause HESA-A is mainly a herbal compound, all medicine against a plethora of diseases. In nu- the components belong to the Apiaceae family; merous studies, bioactive metabolites isolated Kelussia odoratissima (K. odoratissima) Mo- from A. indica and the wide range of their ac- zaff. (wild celery) is coupled with Cuminum tions have been investigated, even for the treat- cyminum (C. cyminum) L. (cumin), alternatively, ment of dermatological diseases106,107. However, Apium graveolens (A. graveolens) L. (cultivated the only evidence for its efficacy in the treatment celery) is coupled with Carum carvi (C. carvi) L. of psoriasis was reported by Pandey et al108, (wild cumin). Only K. odoratissima is endemic where a significant decrease in PASI score was to Iran, whereas the other mentioned species observed after 12 weeks of consuming A. indica share a wider native range in eastern Asia, Eu- in a RCT of 50 patients. According to the au- rope, and North Africa. Each species in HESA-A thors, this may be due to the inhibition of prosta- has been reported to have medicinal properties; glandin synthetase by nimbidin, a secondary me- K. odoratissima is effective against food-borne tabolite present in A. indica essential oil109 (Table pathogenic bacteria125. Antibacterial, antifungal, II). Oenothera biennis L., the evening primrose, and anti-inflammatory properties have also been is native to Mexico and Eastern USA. The eve- reviewed for A. graveolens as well as C. cymi- ning primrose seed oil (EPSO) has been reported num and C. carvi126-128. Among the numerous ef- effective against several diseases including der- fects associated with C. cyminum, the reduction matitis and psoriasis, mainly due to its unsaturat- of skin disorders has been attributed to the high ed fatty acid component and phytosterols110-114. content of vitamin E, whereas vitamins A and C In two reports115,116, a supplement made by a are higher in A. graveolens129. HESA-A has been combination of fish oil or marine oil (omega-3 tested in patients with chronic plaque psoriasis. source) and EPSO (omega-6 source) was used. Ahmadi et al130 reported complete or substantial No substantial difference was reported in the remission of the plaques after 4-6 months of treatment of psoriasis when compared with pla- treatment in all treated subjects. Although Barik- cebo (Table II). Curcuma longa L. (C. longa), bin et al131 reported contradictory results when the spice turmeric, is a sterile domesticated plant the treatment period was reduced to 4 weeks, a not found in the wild, and thought to originate in significant correlation between duration of the South or Southeast Asia by selective and vegeta- treatment and improved PASI score consistently tive propagation of a hybrid between wild tur- suggests HESA-A is more suitable for long-term meric (Curcuma aromatica) and another closely therapy (Table II). Overall, despite the prospec- related species (http://www.plantsoftheworldon- tive efficacy of several of the above-mentioned line.org). This species has been used for millen- CAM agents in the treatment of psoriasis, addi- nia in TCM and Ayurveda due to its wide range tional clinical trials are needed in the future to of medicinal benefits96,117. However, the efficacy better understand the activity of these agents, of curcumin, the main bioactive compound in C. considering the increased use of CAM remedies longa, has been refuted by Nelson et al118 on the among patients. basis of instability, reactivity, and poor bioavail- ability, as well as the inadequacy of most trials. In terms of treatment for psoriasis, curcumin has Conclusions been suggested in published RCTs to have an adjuvant instead of a main role. According to Anti- The multifactorial causes and the chronic nature ga et al119, oral curcumin acts as an adjuvant in of psoriasis require a systematic approach based topical steroid treatment by reducing serum IL- on an adequate interaction between nutrition and 22 levels and leading to lower PASI scores. Car- supplementation that might act synergistically to

8546 Nutritional strategies for psoriasis: current scientific evidence in clinical trials prevent the onset or reduce psoriasis severity and Acknowledgments consequently, improve the quality of life and mit- We thank Ilaria Cabrini and the Universitiamo staff of the igate the symptomatology of psoriasis diseases. A University of Pavia for supporting in our crowdfunding bidirectional connection exists between psoriasis “Noi coltiviamo la memoria”. We thank Istituto Per Lo and obesity. For this reason, weight loss combined Studio e La Cura Del Diabete S.r.l. (Caserta), Guna S.p.A, Named S.p.A, Miconet S.r.l., A.V.D Reform, Bromatech with a healthy lifestyle has been proven beneficial S.r.l, METEDA S.r.l., for supporting us as donors. We for patients with moderate to severe disease to ob- thank experts from BioMed Proofreading® LLC for a first tain a significant reduction of PASI score. Several English editing, and we also thank Dr. Alexander Salerno questions remain regarding the role of a hypocalor- for English editing of the final version of the review. ic diet on psoriatic condition: • Is psoriasis severity reduced by the type of diet Conflict of Interests and/or the weight reduction? The Authors declare that they have no conflict of interests. • What is the amount of weight reduction neces- sary for clinical efficacy? • What is the efficacy of different diets and their References long-term benefits? World Health Organization. • What is the effect of weight reduction in nor- 1) Global report on psoriasis, 2016. mal-weight patients? 2) Reich K. The concept of psoriasis as a systemic in- • What is the role of exercise in conjunction flammation: implications for disease management. J with dietary weight reduction? Eur Acad Dermatol Venereol 2012; 26: 3-11. Education regarding modifiable environmen- 3) Napolitano M, Megna M, Monfrecola G. 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Clinical evaluation of a more rapid and sensitive psoriasis assessment severity score This research was supported by the Italian Ministry of Ed- (PASS), and its comparison with the classic method ucation, University and Research (MIUR): Dipartimenti di of psoriasis area and severity index (PASI), before Eccellenza Program (2018-2022) – Department of Biology and after climatotherapy at the Dead-Sea. Int J and Biotechnology “L. Spallanzani”, University of Pavia. Dermatol 2000; 39: 913-918.

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