Obesity and psoriasis: body weight and body mass index influence the response to biological treatment

Transcription

1 DOI: /j x JEADV REVIEW ARTICLE Obesity and psoriasis: body weight and body mass index influence the response to biological treatment L. Puig* Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain *Correspondence: L. Puig. lpuig@santpau.cat Abstract Patients with psoriasis, in particular those requiring systemic treatment, tend to be above normal weight. Obesity is associated with psoriasis and contributes significantly to the increased cardiovascular risk in these patients. Most biologics used to treat psoriasis in the European Union are fixed dosed treatments: etanercept, adalimumab and ustekinumab. Apart from infliximab, dosing regimens do not account for weight, with the exception of ustekinumab, the dose of which should be doubled in patients weighing more than 100 kg. The aim of this study was to review the available evidence on the association of obesity and psoriasis, and the effect of body weight or obesity on the efficacy of biologics as well as their practical implications in daily practice. A review was performed of the literature relating to obesity and psoriasis and weight effect, including subgroup analyses, on the efficacy of the biologicals available for treatment of psoriasis in the European Union, namely adalimumab, etanercept, infliximab and ustekinumab. Optimal responses with fixed dose biological agents are less frequent in patients with increasing weight, especially above 100 kg, who account for approximately 25% to 30% of patients in clinical trials. Body weight effect on drug clearance might partly account for this fact. The data are limited to subgroup analyses, often with no statistical significance reported. Further studies, including weight-based subanalysis of clinical trials and pharmacoeconomic evaluations, are required to assess the issue of body weight and response to therapy of the biologics. Infliximab response appears to be independent of body mass index. Possible weight-based dose adjustments and the impact of treatment on body weight changes also require additional study. Received: 1 November 2010; Accepted: 18 March 2011 Conflicts of interest Dr. Puig has participated in clinical trials promoted by and/or received consultancy fees, speaker s honoraria and travel grants from: Abbott, Janssen, Merck and Pfizer. Over the years, dermatologists have become increasingly aware of the association between psoriasis and risk factors for cardiovascular disease, including obesity and metabolic syndrome, and the need for a global approach to comorbidities in patients with psoriasis. On the other hand, there is increasing evidence that body weight and body mass index may influence the outcome of therapy in patients with moderate to severe psoriasis and the available evidence has recently been the object of a systematic review by the Medical Board of the National Psoriasis Foundation. 1 Conversely, treatment with some biologics may lead to weight increase in some patients, and a critical review of the available literature can behelpfultodermatologistsconfrontedwiththerapeuticdecisions in their daily practice. To review the available evidence on the association of obesity and psoriasis and the effect of body weight or obesity on the efficacy of biological treatment for psoriasis as well as their practical implications in daily practice, MEDLINE and PubMed were searched using the strategy (obes* or weight or body mass index) AND psoriasis and complementary papers were retrieved from the selected references. Lindegård 2 first described an association between obesity and psoriasis in a study of Swedish citizens over a 10-year period. Recently, Neimann et al. 3 published a population-based study of individuals with mild and severe psoriasis. Their multivariate analysis demonstrated significant independent associations between psoriasis and hypertension, diabetes mellitus, hyperlipidaemia, obesity and smoking. Multiple studies have demonstrated that patients with psoriasis are more frequently overweight (BMI > 25 kg m 2 and 30 kg m 2 )orobese(bmi>30kg m 2 ) compared with patients without psoriasis. 3 6 Irrespective of cause and effect, the relationship between obesity and advancing psoriatic disease has been noted in a number of cross-sectional studies in

2 1008 Puig which increased BMI coincides with a greater degree of psoriasis disease severity. 3,4 Obesity may occur prior to the onset of psoriasis and be risk factor for development of the disease: in a case control study of 560 psoriasis patients seen by dermatologists, obesity was found to be an independent risk factor for the development of psoriasis. 5 Similarly, a cohort study from the General Practice Research Database in the UK of almost 4000 incident cases of psoriasis confirmed that obesity is an independent risk factor for developing psoriasis. 6 A large cohort study of over nurses from the US demonstrated a dose response relationship for obesity on the risk of developing incident psoriasis. 7 Furthermore, the results of a population-based case control study 8 including 373 cases with onset of first-time plaque psoriasis within 12 months and matched healthy controls indicate that excessive body weight and smoking are risk factors for onset of psoriasis and that higher body mass index increases the Psoriasis Area and Severity Index (PASI) of plaque psoriasis at onset. In multivariable analyses, for each unit increment in body mass index, there was a statistically significant 9% increased risk for psoriasis onset and 7% higher risk for increased PASI. 8 Obesity (BMI 30) compared with normal body weight was associated with a two-fold increased risk for psoriasis onset. 8 In addition, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis characterized by steatosis, inflammation and progressive fibrosis are closely associated with metabolic syndrome, obesity and an increased risk of incident cardiovascular disease. 9 NAFLD is frequent in patients with chronic plaque psoriasis affecting up to nearly half of these patients and is strongly associated with psoriasis severity. 10 The association between NAFLD and psoriasis has been explored in an unselected cohort of 142 adult Italian outpatients with psoriasis vulgaris that were compared with an age- and body mass indexmatched retrospective cohort of 125 non-psoriasis patients with biopsy proven NAFLD. 11 Based on histories, laboratory tests and ultrasound studies, 84 (59.2%) received a clinical diagnosis of NAFLD, which was found to be closely associated with obesity (overall and abdominal), metabolic syndrome, and psoriatic arthritis and more likely to cause severe liver fibrosis (compared with non-psoriatic-nafld). 11 Body weight and efficacy of treatment The association between psoriasis, obesity and cardiovascular morbidity and mortality has been extensively studied in recent years. Co-occurrence of obesity and psoriasis could lead to interactions of both diseases in which adipokines, at least in part, are involved and may contribute to associated comorbidities of psoriasis; their pathogenic implications are beyond the scope of this manuscript, but have been the subject of a recent review. 12 From a clinical perspective, the potential impact of obesity on therapeutic response to psoriasis treatments has been less studied but is likely to have important implications regarding therapeutic choices in daily dermatological practice. Obesity and high body mass index have been demonstrated to have a significant impact ontheresponsetosystemictreatments and specifically to biologics: high body mass index has been associated with a reduced short-term clinical response to all systemic treatments. 13 In this cohort study that assessed the role of BMI in the clinical response to systemic treatment for psoriasis, PASI 75 response rate in the overall population was 34.5% at 8 weeks and 50.6% at 16 weeks, and it was lower in obese patients compared with normal weight patients. The adjusted odds ratio at 8 weeks was 0.73 (95% CI = ) and at 16 weeks 0.62 (95% CI = ). The impact of the BMI did not show remarkable variations according to the drug prescribed at entry in this registry study; 13 the detrimental effect of obesity or body mass on therapeutic response might be explained in part by pharmacokinetic considerations, being greater in drugs prescribed at a fixed dose than in those that are dosed according to patient s weight, but registry studies, because of frequent dose adjustments and combination therapy, would be less likely to show this effect than clinical trials. On the other hand, even if the effect of body weight is too subtle to attain statistical significance, it might be better appreciated in selected subpopulations of patients with weight or BMI greater than a hypothetical threshold. The evidence supporting this hypothesis will be reviewed below. Body weight, rather than body mass index, has been shown to have a marked impact on the pharmacokinetics of at least some biologics. 14,15 In the case of patients with rheumatoid arthritis treated with adalimumab, there is a tendency towards a slight increase in total serum clearance with an increase in body weight; 14 the predictability of this association was low, although statistically significant. There was a statistically significant difference in total serum clearance between men and women, which was attributed mainly to differences in body weight (23%). 14 In the case of ustekinumab, a population pharmacokinetics study has shown that body weight, diabetes and positive immune response (antibodies to ustekinumab) are important covariates affecting the apparent clearance and or apparent volume of distribution of ustekinumab. 15 The apparent clearance of ustekinumab was approximately 55% higher for patients weighing more than 100 kg compared with those 100 kg or less. 15 Pharmacokinetic analyses in the PHOENIX 1 and PHOENIX 2 studies have revealed a distinct relationship between systemic exposure to ustekinumab and weight. 16 A decrease in serum ustekinumab concentration with increasing weight was seen for both the 45 mg and the 90 mg doses. Median trough serum ustekinumab concentrations for the 45-mg group decreased below the lower limit of quantification (LLOQ) in 10-kg increment subpopulations greater than 100 kg. By contrast, the median trough serum ustekinumab concentration for the 90-mg group generally remained above the LLOQ at a body weight greater than 100 kg, with the exception of the subpopulation of patients weighing between 120 and 130 kg in which the serum concentrations were undetectable. 16

3 Psoriasis and biologicals in heavy patients 1009 Although corresponding data from population pharmacokinetics studies are not available for etanercept or infliximab, 17 pharmacokinetic considerations might justify, at least in part, the acknowledged fact that biologics with a fixed-dose regimen (etanercept, alefacept and adalimumab) may have a compromised efficacy in heavier individuals. 18 Inthecaseofetanercept,theeffectofweightandBMIon therapeutic efficacy has been examined in at least two studies, but no statistical analysis has been made available. Strober et al. 19 presented in a poster the results of a clinical trial in which 618 patients were randomized to receive twice weekly doses of etanercept 50 mg or placebo in a 12-week double-blind phase followed by a 36-week open trial of etanercept 50 mg twice weekly for a total of 48 weeks of treatment. About 70% of the patients were overweight and 10% were extremely obese (BMI 40). A superior response defined as a PASI 90 response at 3 or more postbaseline visits or 2 for those who received placebo for 12 weeks was achieved by 40.57% of normal-weight patients and 28.57%, 18.29% and 15.25% of overweight, obese and extremely obese individuals respectively. Suboptimal response defined as PASI 50 at less than three postbaseline visits, or two for those who received placebo for 12 weeks was noted in only 9.43% of normal-weight individuals but noted in 20.73% and 27.12% of obese patients and extremely obese patients respectively. A subgroup analysis of a pooled study by Gordon et al. 20 of 1187 patients blinded to placebo or etanercept (50 or 100 mg week) showed a strong dose- and weight-related response. The median weight of the patients included in the study was kg. At week 12, in the group receiving 50 mg week of etanercept, PASI 75 was achieved by 25% of patients weighing kg (vs. 41% of patients weighing less than the median). In the group randomized to 50 mg twice weekly of etanercept, the corresponding rates were 43% vs. 53%. These results imply that patients with low weight may have a greater response to etanercept than patients who are heavier than the median, and show a clear relationship between increasing BMI and decreasing response rates in clinical trials. In the case of adalimumab, results of subanalyses according to baseline weight quartiles are available for the REVEAL, 21,22 BELIEVE 23 and CHAMPION 24 studies, showing in all cases a weight-dependent decrease of treatment efficacy for patients corresponding to the third and fourth quartiles (in the case of the CHAMPION study, this applies also to the placebo and methotrexate arms) (Table 1). Univariate analyses of a variety of baseline variables in the REVEAL study 21,22 demonstrated that mean change in PASI at week 16 was statistically significantly associated with only treatment group, age, weight and BMI. Multivariate analysis based on stepwise selection identified treatment received, weight and age as the most influential factors for mean percentage change in PASI at week ,22 In patients receiving adalimumab, PASI 75 response at week 16 was achieved by 74.1% of patients weighing <100 kg (31.3% of all those included in the study) vs. 63.8% of those weighing 100 kg. When the subanalysis was based on BMI, the corresponding percentages were 79.2%, 75.5% and 65.1% for normal weight, overweight and obese patients respectively. 21 In the BELIEVE study, 23 lower body weight was determined by logistic regression analysis to be an independent significant predictor of PASI 75 response at week 16 (P < 0.001) and PASI 75 response rates were slightly lower for patients weighing 95 kg (26.6% of all patients) than for other weight groups. In the CHAMPION study, 24 themeanpercentagedecreasein PASI from weeks 0 to 16 by baseline weight quartile in patients treated with adalimumab were 79% for patients in the first quartile ( 68 kg), 88% in the second (68 to 82 kg), 83% in the third (82 to 92 kg) and 71% in the fourth ( 92 kg). As regards ustekinumab, in phase 2 studies (PHOENIX 1 and PHOENIX 2), lower efficacy was observed in higher weight patients who received a single 45 mg dose, and phase 3 studies therefore investigated the potential for weight-based dosing to optimize efficacy in higher weight patients. 25 Subjects were stratified to receive ustekinumab 45 mg or 90 mg and a prespecified efficacy analysis by body weight (in 10 kg increments) was performed, showing correlation between body weight and efficacy, but no correlation between BMI and efficacy. 25 Across the two studies, for patients weighing more than 100 kg, the PASI 75 response rate was about 20% higher in the 90-mg group than in the 45-mg group [74.2% ( ) and 54.6% ( ) respectively; P < ]. By contrast, for lighter patients ( 100 kg), PASI 75 response rates were similar between the 90-mg and Table 1 Responses at week 16 according to baseline weight quartiles in the REVEAL, 21 BELIEVE, 23 and CHAMPION 24 studies Study Response parameter Q1 Q2 Q3 Q4 REVEAL % of patients achieving PGA PASI improvement with respect to baseline (%) PASI 75 response rate (% of patients): adalimumab BELIEVE PASI 75 response rate (% of patients): adalimumab + vehicle PASI 75 response rate (% of patients): adalimumab + calcipotriol betamethasone CHAMPION PASI 75 response rate (% of patients): placebo PASI 75 response rate (% of patients): methotrexate PASI 75 response rate (% of patients): adalimumab

4 1010 Puig 45-mg groups [80.8% ( ) and 76.9% ( ) respectively; P = ]. 26 An impact of weight on response was also observed when measured by a response of at least 90% improvement from baseline in PASI score or a Physician s Global Assessment (PGA) of cleared or minimal (score of 0 or 1, respectively) and this was eventually reflected in the EMEA summary of product characteristics. 26 Weight-related differences in efficacy at 12 weeks were also shown in the ACCEPT study, both for etanercept and ustekinumab at the doses of 45 mg and 90 mg: the corresponding PASI 75 rates were 61%, 72% and 77% for patients weighing 100 kg and 45%, 55% and 65% for those weighing >100 kg ( , or 28.46% of total). 26 Interestingly enough, 50 of 177 patients (28.2%) treated with etanercept 50 mg biw did not achieve a PGA <3 response at week 12 and their mean weight was nearly 10 kg higher (99.3 vs kg) than that of those who did. 27,28 In the case of infliximab, a subgroup analysis of three randomized placebo-controlled trials in 1462 patients with moderate to severe psoriasis showed that PASI 75 response rates at 10 weeks were similar regardless of BMI: 77.5%, 78.3% and 74.4%, for normal weight, overweight and obese patients treated with infliximab vs. 5.0%, 1.7% and 2.6% of patients given placebo respectively. 29 Practical implications Weight loss is advisable in all patients who are overweight or obese, as this is the most important factor in improving metabolic syndrome and reducing its impact on cardiovascular morbidmortality, in combination with smoking cessation. On the other hand,itcanbeinferredfromtheabovementionedevidencethat weight loss might improve the response to therapy in obese patients with moderate severe psoriasis, regardless of the therapeutic modality, but especially in patients being treated with a fixed dose biologic. As a matter of fact, diet-associated weight loss has been shown to improve the response of obese patients with moderate-to-severe chronic plaque psoriasis to low-dose cyclosporine therapy, 30 and there are several reports of psoriasis improvement following jejunoileal 31 and gastric by-pass surgery. On the other hand, there are case reports demonstrating worsening of psoriasis after weight loss surgery, 35,36 and in one study rapid weight reduction (10% to 14% over 3 to 5 weeks) has been associated with worsening of psoriasis in seven of eight patients. 37 The issue of obesity and psoriasis is further compounded by the fact that anti-tnf-a therapy increases body weight in patients with chronic plaque psoriasis 38 and there appears to be some variation among the different agents as regards the duration and reversibility of this weight increase, which does not occur in patients treated with other systemic agents such as methotrexate. 38 The weight gain seems to be more intense and persistent in patients treated with etanercept. 39,40 Interestingly, these authors did not find a negative correlation between BMI and drug efficacy (measured as PASI improvement) at weeks 12 and 24 in their patients. 39,40 Further studies are needed to identify which subpopulations of patients are more amenable to get a detrimental effect as regards both health-related quality of life and self-image (a 10% increase in body weight might have a more significant impact on self-image in a young lady weighing 55 kg than in an elderly man weighing 105 kg) and therapeutic effect. In clinical practice, therapeutic goals are biased towards achievement of excellent response, and the decreased likelihood of eventually achieving this therapeutic goal in patients weighing more than kg using etanercept (even at high dose: 50 mg twice weekly for 48 weeks) suggests that this TNF blocking agent might not be the best therapeutic choice at least in some cases in this subpopulation of patients. On the other hand, the economic implications of the dose adjustments that may be necessary in those patients (e.g. administering adalimumab every week to improve efficacy, as recommended in patients with Crohn s disease or rheumatoid arthritis 41 or doubling the dose of ustekinumab according to the EMEA summary of product characteristics 26 ) are expected to be significant and require specific pharmacoeconomic analyses that have not yet been published. The size of the patient populations where dose adjustment, or dose doubling according to the ustekinumab label, would be needed to achieve optimal efficacy is significant and can be extrapolated from clinical trials data: the percentages of patients weighing more than 100 kg were 31.35% in the REVEAL trial, % in the PHOENIX1, % in the PHOENIX2 26 and 28.46% in the ACCEPT trial, 26 whereas 24.35% (66 271) of patients in the CHAMPION trial 24 and 26.62% ( ) of patients included in the BELIEVE trial 23 had body weights included in the fourth quartile (>92 kg and 95 kg respectively). In conclusion, the therapeutic and possibly pharmacoeconomic advantage of infliximab in comparison with other biologicals might be more marked in patients with body weight greater than kg, obesity or associated metabolic syndrome, that are very prevalent in patients with psoriasis. Further studies are warranted to better identify the subpopulations of patients who would obtain the maximum benefit, as well as the impact of treatment on body weight changes and metabolic syndrome-associated cardiovascular risk in patients with psoriasis. References 1 Bremmer S, Van Voorhees AS, Hsu S et al. National Psoriasis Foundation. Obesity and psoriasis: from the Medical Board of the National Psoriasis Foundation. J Am AcadDermatol 2010; 63: Lindegård B. Diseases associated with psoriasis in a general population of 159,200 middle-aged, urban, native Swedes. Dermatologica 1986; 172: Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB, Gelfand JM. Prevalence of cardiovascular risk factors in patients with psoriasis. JAm Acad Dermatol 2006; 55:

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