Arch Dermatol Res (2014) 306:921–925 DOI 10.1007/s00403-014-1495-1
ORIGINAL PAPER
Impact of obesity on the efficacy of ustekinumab in Japanese patients with psoriasis: a retrospective cohort study of 111 patients Koichi Yanaba • Yoshinori Umezawa • Toshihiro Ito • Mitsuha Hayashi • Sota Kikuchi • Osamu Fukuchi • Hidehisa Saeki • Hidemi Nakagawa
Received: 14 July 2014 / Revised: 22 August 2014 / Accepted: 29 August 2014 / Published online: 6 September 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Obesity is thought to be involved in the pathogenesis of psoriasis, although its impact on the therapeutic response to systemic treatments remains unclear. The aim of this study was to examine the association of body mass index (BMI) with the efficacy of ustekinumab in Japanese patients with psoriasis. Clinical data from a cohort of 111 Japanese patients treated with ustekinumab 45 mg between July 2011 and March 2014 were retrospectively evaluated. The measured outcome was improvement in the psoriasis area and severity index (PASI) score at week 16. Patients with BMI C 25 and BMI \ 25 had comparable rates of C50 and 75 % improvement in PASI (PASI-50 and PASI75, respectively), whereas patients with BMI C 25 had significantly lower PASI-90 and PASI-100 response rates. Patients with BMI C 25 also showed significantly lower percent reduction in PASI than those with BMI \ 25 at week 16 (85 vs. 74 %, P \ 0.004). BMI was negatively correlated with percent reduction in PASI, whereas body weight was not. These results show that a higher BMI, but not body weight, is associated with lower effectiveness of ustekinumab for psoriasis. BMI C 25 could therefore be a negative predictor of achieving PASI-90 and PASI-100 in patients with psoriasis when starting ustekinumab. Keywords Psoriasis Ustekinumab Obesity Body mass index Psoriasis area and severity index K. Yanaba (&) Y. Umezawa T. Ito M. Hayashi S. Kikuchi O. Fukuchi H. Nakagawa Department of Dermatology, The Jikei University School of Medicine, 3-25-8 Nishishimbashi, Minato-Ku, Tokyo 105-8641, Japan e-mail: [email protected] H. Saeki Department of Dermatology, Nippon Medical School, Bunkyo, Tokyo, Japan
Introduction Psoriasis is a chronic inflammatory skin disorder affecting approximately 1–3 % of the general population [19], although the prevalence is lower in Asian populations [24]. The pathogenesis of psoriasis has yet to be clarified, but obesity is thought to play a critical role in its development [12, 14, 16, 23]. Patients with psoriasis are more frequently overweight or obese compared with healthy individuals [12, 14, 16, 23]. Furthermore, body mass index (BMI), which is widely used to evaluate the degree of obesity, is positively correlated with the severity of psoriasis [14, 23]. The association between psoriasis and obesity has been extensively examined; however, the impact of obesity on the therapeutic response to systemic treatments, and biologics in particular, is still controversial. Although several studies have shown that BMI does not affect the clinical response of psoriasis to tumor necrosis factor (TNF) a inhibitors such as adalimumab, etanercept, and infliximab [1, 6, 9], high BMI (C30) has been shown to affect the clinical response to TNF a inhibitors [13]. Ustekinumab (Stelara; Janssen Biotech Inc., Horsham, PA), a human immunoglobulin G1j monoclonal antibody that binds to the common p40 subunit shared by interleukin (IL)-12 and IL-23, is an effective and well-tolerated treatment of moderate-to-severe plaque psoriasis [4, 7, 11, 18]. However, the relationship between obesity and its efficacy for patients with psoriasis remains unclear. Furthermore, rates of overweight and obesity are lower for the adult Japanese population than for the adult American population: 33 and 36 % of the adult population in the USA have BMI 25 to\30 and BMI C 30, respectively [2], whereas approximately 20–30 % of the adult Japanese have BMI 25 to \30 and only about 3 % have BMI C 30, according to data from the Ministry of Health, Labour and
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Welfare in 2010. Therefore, the impact of high BMI on the efficacy of biologics in Japanese patients might be different from the impact on Western populations. Therefore, we examined the association of BMI with the efficacy of ustekinumab in 111 Japanese patients with psoriasis.
Materials and methods Patients and methods This retrospective study evaluated the clinical records of 111 Japanese patients with psoriasis treated with ustekinumab for at least 16 weeks at the Department of Dermatology, the Jikei University Hospital, Tokyo, Japan, between July 2011 and March 2014. The evaluated data included demographic characteristics, medical history, presence of psoriatic arthritis, and previous systemic treatment for psoriasis. BMI was used to evaluate the degree of obesity and was calculated as weight in kilograms divided by height in meters squared. Obesity was defined as BMI C 25. Severity of psoriasis was assessed from psoriasis area and severity index (PASI) score. Patients received subcutaneous injections of ustekinumab 45 mg at weeks 0, 4, and 16. We evaluated the clinical efficacy by the percent reduction in PASI score (D PASI) from baseline to week 16. We also assessed the proportion of patients achieving a PASI score reduction of C50 % (PASI-50), C75 % (PASI-75), C90 % (PASI-90), and 100 % (PASI-100) at week 16 compared with baseline. We compared D PASI, PASI-50, PASI-75, PASI-90, and PASI-100 between patients with BMI \ 25 and BMI C 25. Statistical analysis The Mann–Whitney U test was used to compare means. The Chi-square test was performed to compare proportions. When the minimum expected value (number of patients) was \5, Fisher’s exact probability test was adopted. Bonferroni’s test was used for multiple comparisons. Spearman’s rank correlation coefficient was used to examine the relationship between continuous variables. A probability (P) value \0.05 was considered to be significant.
Results BMI in patients with psoriasis Between July 2011 and March 2014, 111 patients with psoriasis were treated with ustekinumab (Table 1): 73 (66 %) had BMI \ 25 and 38 (34 %) had BMI C 25. Only three patients (3 %) had BMI C 30. At baseline, no
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Arch Dermatol Res (2014) 306:921–925 Table 1 Clinical and demographic characteristics of the study population All patients N = 111
BMI \ 25 n = 73
BMI C 25 n = 38
Age, years (mean ± SD)
58 ± 17
59 ± 18
57 ± 15
Male:female
83:28
54:19
29:9
Body weight (kg)
65 ± 12
59 ± 8
75 ± 11
Height (cm)
164 ± 8
164 ± 8
165 ± 10
BMI (mean ± SD)
23.9 ± 3.3
22.1 ± 1.9
27.6 ± 2.2 \0.001
Baseline PASI (mean ± SD)
12.0 ± 6.8
11.1 ± 5.5
13.8 ± 8.4
0.180
PASI \ 10
46 (51)a
49 (36)
39 (15)
0.324
PASI C 10
54 (60)
51 (37)
61 (23)
0.324
Psoriatic arthritis
5 (5)
4 (3)
5 (2)
0.781
P value
0.513 0.787 \0.001 0.448
Smoking habit
28 (31)
19 (14)
45 (17)
0.004
Diabetes
16 (18)
12 (9)
24 (9)
0.124
Hypertension
46 (51)
34 (25)
68 (26)
Previous biologic treatment
15 (17)
16 (12)
13 (5)
\0.001 0.649
SD standard deviation, BMI body mass index, PASI psoriasis area and severity index a
Unless noted otherwise, values are percentages. Patient numbers are given in parentheses
significant differences were observed between the two groups in age, sex distribution, height, presence of psoriatic arthritis or diabetes, or previous biologic treatment. In contrast, patients with BMI C 25 had more hypertension and smoking habit compared with those with BMI \ 25 (P \ 0.001 and P = 0.004, respectively). As expected, the mean body weight was significantly higher in patients with BMI C 25 than in those with BMI \ 25 (P \ 0.001). Correlation between BMI and ustekinumab efficacy Baseline PASI score was similar in both groups. PASI-50 and PASI-75 response rates were comparable between patients with BMI \ 25 and those with BMI C 25 at week 16 (93 vs. 87 %, P = 0.306 and 81 vs. 71 %, P = 0.338, respectively; Table 2 and Fig. 1a). However, PASI-90 and PASI-100 response rates were significantly higher in patients with BMI \ 25 than in those with BMI C 25 (52 vs. 24 %; P = 0.005 and 32 vs. 5 %; P = 0.002, respectively). The adjusted odds ratios for achieving PASI-50, PASI-75, PASI-90, and PASI-100 in patients with BMI C 25 compared with those with BMI \ 25 were 0.485, 0.582, 0.286, and 0.121, respectively. Consistent with this, patients with BMI \ 25 exhibited higher D PASI than those with BMI C 25 at week 16 (85 vs. 74 %;
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Table 2 Evaluation of PASI at week 16 following the start of ustekinumab treatment All patients N = 111
BMI \ 25 N = 73
BMI C 25 N = 38
P value
81 ± 23
85 ± 20
74 ± 27
0.004
PASI-50
91 (101)a
93 (68)
87 (33)
0.306
0.485 (0.131–1.800)
PASI-75
77 (86)
81 (59)
71 (27)
0.338
0.582 (0.234–1.450)
PASI-90
42 (47)
52 (38)
24 (9)
0.005
0.286 (0.119–0.688)
PASI-100
23 (25)
32 (23)
5 (2)
0.002
0.121 (0.027–0.545)
D PASI
Odds ratio (95 % CI)
(mean ± SD)
Odds ratios are for achieving PASI-50, PASI-75, PASI-90, or PASI-100 in patients with BMI C 25 compared with BMI \ 25 PASI psoriasis area and severity index, D PASI percent reduction in PASI, SD standard deviation, BMI body mass index, CI confidence interval a
Unless noted otherwise, values are percentages. Patient numbers are given in parentheses
Fig. 1 The effect of obesity on the efficacy of ustekinumab treatment in patients with psoriasis. a PASI-50, PASI-75, PASI-90, and PASI100 response rates at week 16 following the start of ustekinumab treatment. b D PASI at week 16 following the start of ustekinumab treatment. Significant differences between sample means are indicated: *P \ 0.01
Fig. 2 Correlation between D PASI and BMI (a) or body weight (b) at week 16 following the start of ustekinumab
P \ 0.004; Table 2 and Fig. 1b). Also consistent with the association of BMI with the efficacy of ustekinumab in psoriasis, D PASI correlated negatively with BMI (r = -
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0.204, P = 0.032; Fig. 2a). By contrast, D PASI did not correlate with body weight (r = -0.094, P = 0.322; Fig. 2b).
Discussion To our knowledge, this is the first study to evaluate the association of BMI with the efficacy of ustekinumab in patients with psoriasis. Irrespective of the degree of BMI, PASI-50 and PASI-75 were achieved by more than 91 %, and 77 % in patients receiving ustekinumab treatment at week 16, respectively. By contrast, patients with BMI C 25 had significantly lower PASI-90 and PASI-100 response rates and significantly lower D PASI than patients with BMI \ 25. BMI, but not body weight, was negatively correlated with D PASI, indicating that a higher BMI may be linked to a lower clinical response to ustekinumab in patients with psoriasis. Although the effect of obesity on therapeutic response to ustekinumab has been unclear, high body weight was shown to have a negative impact. The apparent clearance of PASI by ustekinumab is higher in patients weighing [100 kg than in those weighing B100 kg [25]. PASI-75 response was lower in patients weighing [100 kg than in those weighing B100 kg, but those weighing B100 kg had similar PASI-75 response rates to treatment with 45 or 90 mg [10]. Therefore, treatment with ustekinumab 90 mg may be appropriate for those weighing [100 kg. However, the prevalence of excess body weight, particularly weight [100 kg, is lower in Japan and other Asian countries than in Western countries; in the present study, only 1 of the 111 patients with psoriasis weighed [100 kg (0.9 %), and this patient successfully achieved PASI-90 but not PASI-100. Consequently, parameters other than body weight would be useful to predict the clinical response to ustekinumab of Japanese or other Asian patients. In this study, patients with BMI C 25 were less likely to achieve PASI-90 and PASI-100, suggesting that dosing by BMI may improve the clinical response to ustekinumab. Further studies are needed to determine the impact of high BMI on the efficacy of ustekinumab for the treatment of psoriasis in each ethnic group. Obesity is thought to be a chronic low-grade inflammatory disorder. The adipose tissue produces various proinflammatory immune mediators, including cytokines (e.g., TNF-a and IL-6), chemokines, and adipokines [20], suggested to be involved in the pathogenesis of psoriasis [17]. Moreover, circulating levels of TNF-a, IL-17, and IL-23 are higher in obese subjects than in non-obese subjects [21, 22], suggesting that obese patients with psoriasis are likely to be more resistant to therapies targeting these immune mediators. Accumulating evidence indicates that weight loss
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interventions, including a low-calorie diet, physical exercise, and gastric bypass surgery, ameliorate the severity of psoriasis [5, 8, 15]. A low-calorie diet also increases the clinical responses of obese patients with psoriasis to cyclosporine [3]. Therefore, weight loss interventions are likely to enhance the efficacy of ustekinumab treatment for psoriasis, although this warrants further study. There are several potential limitations to this study. First, the efficacy of ustekinumab was evaluated only at week 16. Further studies should investigate the long-term efficacy of ustekinumab in patients with psoriasis and assess the association with BMI. Second, the effects of BMI on the efficacy of other biological agents, such as infliximab and adalimumab, should be compared. Third, all patients were treated with ustekinumab 45 mg; additional studies should confirm whether these findings can be extended to those treated with ustekinumab 90 mg. Fourth, the significance of hypertension and smoking habit is unclear; it is essential to assess its association with BMI and the efficacy of ustekinumab in future studies. Lastly, the precise mechanism by which a higher BMI contributes to the efficacy of ustekinumab in psoriasis has not been clarified. Nonetheless, the results of this study suggest that patients with BMI C 25 may be more resistant to ustekinumab treatment for psoriasis compared with those with BMI \ 25, indicating that evaluation of BMI in patients with psoriasis initiating ustekinumab treatment may be useful for therapeutic stratification.
Conflict of interest H. Nakagawa has received consultant and speaker fees from Janssen Pharmaceuticals K K.
References 1. Driessen RJ, Boezeman JB, van de Kerkhof PC, de Jong EM (2009) Three-year registry data on biological treatment for psoriasis: the influence of patient characteristics on treatment outcome. Br J Dermatol 160:670–675 2. Flegal KM, Carroll MD, Kit BK, Ogden CL (2012) Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA 307:491–497 3. Gisondi P, Del Giglio M, Di Francesco V, Zamboni M, Girolomoni G (2008) Weight loss improves the response of obese patients with moderate-to-severe chronic plaque psoriasis to lowdose cyclosporine therapy: a randomized, controlled, investigator-blinded clinical trial. Am J Clin Nutr 88:1242–1247 4. Griffiths CE, Strober BE, van de Kerkhof P et al (2010) Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med 362:118–128 5. Hossler EW, Wood GC, Still CD, Mowad CM, Maroon MS (2013) The effect of weight loss surgery on the severity of psoriasis. Br J Dermatol 168:660–661 6. Iannone F, Fanizzi R, Scioscia C, Anelli MG, Lapadula G (2013) Body mass does not affect the remission of psoriatic arthritis patients on anti-TNF-a therapy. Scand J Rheumatol 42:41–44
Arch Dermatol Res (2014) 306:921–925 7. Igarashi A, Kato T, Kato M, Song M, Nakagawa H (2012) Efficacy and safety of ustekinumab in Japanese patients with moderate-to-severe plaque-type psoriasis: long-term results from a phase 2/3 clinical trial. J Dermatol Sci 39:242–252 8. Jensen P, Zachariae C, Christensen R et al (2013) Effect of weight loss on the severity of psoriasis: a randomized clinical study. JAMA Dermatol 149:795–801 9. Lafuente-Urrez RF, Perez-Pelegay J (2014) Impact of obesity on the effectiveness of adalimumab for the treatment of psoriasis: a retrospective study of 30 patients in daily practice. Eur J Dermatol 24:217–223 10. Lebwohl M, Yeilding N, Szapary P et al (2010) Impact of weight on the efficacy and safety of ustekinumab in patients with moderate to severe psoriasis: rationale for dosing recommendations. J Am Acad Dermatol 63:571–579 11. Leonardi CL, Kimball AB, Papp KA et al (2008) Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 371:1665–1674 12. Lindegard B (1986) Diseases associated with psoriasis in a general population of 159,200 middle-aged, urban, native Swedes. Dermatologica 172:298–304 13. Naldi L, Addis A, Chimenti S et al (2008) Impact of body mass index and obesity on clinical response to systemic treatment for psoriasis. Evidence from the psocare project. Dermatology 217:365–373 14. Naldi L, Chatenoud L, Linder D et al (2005) Cigarette smoking, body mass index, and stressful life events as risk factors for psoriasis: results from an Italian case-control study. J Invest Dermatol 125:61–67 15. Naldi L, Conti A, Cazzaniga S et al (2014) Diet and physical exercise in psoriasis: a randomized controlled trial. Br J Dermatol 170:634–642
925 16. Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB, Gelfand JM (2006) Prevalence of cardiovascular risk factors in patients with psoriasis. J Am Acad Dermatol 55:829–835 17. Nestle FO, Kaplan DH, Barker J (2009) Psoriasis. N Engl J Med 361:496–509 18. Papp KA, Langley RG, Lebwohl M et al (2008) Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 371:1675–1684 19. Schon MP, Boehncke WH (2005) Psoriasis. N Engl J Med 352:1899–1912 20. Shoelson SE, Lee J, Goldfine AB (2006) Inflammation and insulin resistance. J Clin Invest 116:1793–1801 21. Sumarac-Dumanovic M, Stevanovic D, Ljubic A et al (2009) Increased activity of interleukin-23/interleukin-17 proinflammatory axis in obese women. Int J Obes (Lond) 33:151–156 22. Tanaka S, Isoda F, Ishihara Y, Kimura M, Yamakawa T (2001) T lymphopaenia in relation to body mass index and TNF-a in human obesity: adequate weight reduction can be corrective. Clin Endocrinol (Oxf) 54:347–354 23. Wolk K, Mallbris L, Larsson P, Rosenblad A, Vingard E, Stahle M (2009) Excessive body weight and smoking associates with a high risk of onset of plaque psoriasis. Acta Derm Venereol 89:492–497 24. Yip SY (1984) The prevalence of psoriasis in the Mongoloid race. J Am Acad Dermatol 10:965–968 25. Zhu Y, Hu C, Lu M et al (2009) Population pharmacokinetic modeling of ustekinumab, a human monoclonal antibody targeting IL-12/23p40, in patients with moderate to severe plaque psoriasis. J Clin Pharmacol 49:162–175
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ORIGINAL PAPER
Impact of obesity on the efficacy of ustekinumab in Japanese patients with psoriasis: a retrospective cohort study of 111 patients Koichi Yanaba • Yoshinori Umezawa • Toshihiro Ito • Mitsuha Hayashi • Sota Kikuchi • Osamu Fukuchi • Hidehisa Saeki • Hidemi Nakagawa
Received: 14 July 2014 / Revised: 22 August 2014 / Accepted: 29 August 2014 / Published online: 6 September 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Obesity is thought to be involved in the pathogenesis of psoriasis, although its impact on the therapeutic response to systemic treatments remains unclear. The aim of this study was to examine the association of body mass index (BMI) with the efficacy of ustekinumab in Japanese patients with psoriasis. Clinical data from a cohort of 111 Japanese patients treated with ustekinumab 45 mg between July 2011 and March 2014 were retrospectively evaluated. The measured outcome was improvement in the psoriasis area and severity index (PASI) score at week 16. Patients with BMI C 25 and BMI \ 25 had comparable rates of C50 and 75 % improvement in PASI (PASI-50 and PASI75, respectively), whereas patients with BMI C 25 had significantly lower PASI-90 and PASI-100 response rates. Patients with BMI C 25 also showed significantly lower percent reduction in PASI than those with BMI \ 25 at week 16 (85 vs. 74 %, P \ 0.004). BMI was negatively correlated with percent reduction in PASI, whereas body weight was not. These results show that a higher BMI, but not body weight, is associated with lower effectiveness of ustekinumab for psoriasis. BMI C 25 could therefore be a negative predictor of achieving PASI-90 and PASI-100 in patients with psoriasis when starting ustekinumab. Keywords Psoriasis Ustekinumab Obesity Body mass index Psoriasis area and severity index K. Yanaba (&) Y. Umezawa T. Ito M. Hayashi S. Kikuchi O. Fukuchi H. Nakagawa Department of Dermatology, The Jikei University School of Medicine, 3-25-8 Nishishimbashi, Minato-Ku, Tokyo 105-8641, Japan e-mail: [email protected] H. Saeki Department of Dermatology, Nippon Medical School, Bunkyo, Tokyo, Japan
Introduction Psoriasis is a chronic inflammatory skin disorder affecting approximately 1–3 % of the general population [19], although the prevalence is lower in Asian populations [24]. The pathogenesis of psoriasis has yet to be clarified, but obesity is thought to play a critical role in its development [12, 14, 16, 23]. Patients with psoriasis are more frequently overweight or obese compared with healthy individuals [12, 14, 16, 23]. Furthermore, body mass index (BMI), which is widely used to evaluate the degree of obesity, is positively correlated with the severity of psoriasis [14, 23]. The association between psoriasis and obesity has been extensively examined; however, the impact of obesity on the therapeutic response to systemic treatments, and biologics in particular, is still controversial. Although several studies have shown that BMI does not affect the clinical response of psoriasis to tumor necrosis factor (TNF) a inhibitors such as adalimumab, etanercept, and infliximab [1, 6, 9], high BMI (C30) has been shown to affect the clinical response to TNF a inhibitors [13]. Ustekinumab (Stelara; Janssen Biotech Inc., Horsham, PA), a human immunoglobulin G1j monoclonal antibody that binds to the common p40 subunit shared by interleukin (IL)-12 and IL-23, is an effective and well-tolerated treatment of moderate-to-severe plaque psoriasis [4, 7, 11, 18]. However, the relationship between obesity and its efficacy for patients with psoriasis remains unclear. Furthermore, rates of overweight and obesity are lower for the adult Japanese population than for the adult American population: 33 and 36 % of the adult population in the USA have BMI 25 to\30 and BMI C 30, respectively [2], whereas approximately 20–30 % of the adult Japanese have BMI 25 to \30 and only about 3 % have BMI C 30, according to data from the Ministry of Health, Labour and
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Welfare in 2010. Therefore, the impact of high BMI on the efficacy of biologics in Japanese patients might be different from the impact on Western populations. Therefore, we examined the association of BMI with the efficacy of ustekinumab in 111 Japanese patients with psoriasis.
Materials and methods Patients and methods This retrospective study evaluated the clinical records of 111 Japanese patients with psoriasis treated with ustekinumab for at least 16 weeks at the Department of Dermatology, the Jikei University Hospital, Tokyo, Japan, between July 2011 and March 2014. The evaluated data included demographic characteristics, medical history, presence of psoriatic arthritis, and previous systemic treatment for psoriasis. BMI was used to evaluate the degree of obesity and was calculated as weight in kilograms divided by height in meters squared. Obesity was defined as BMI C 25. Severity of psoriasis was assessed from psoriasis area and severity index (PASI) score. Patients received subcutaneous injections of ustekinumab 45 mg at weeks 0, 4, and 16. We evaluated the clinical efficacy by the percent reduction in PASI score (D PASI) from baseline to week 16. We also assessed the proportion of patients achieving a PASI score reduction of C50 % (PASI-50), C75 % (PASI-75), C90 % (PASI-90), and 100 % (PASI-100) at week 16 compared with baseline. We compared D PASI, PASI-50, PASI-75, PASI-90, and PASI-100 between patients with BMI \ 25 and BMI C 25. Statistical analysis The Mann–Whitney U test was used to compare means. The Chi-square test was performed to compare proportions. When the minimum expected value (number of patients) was \5, Fisher’s exact probability test was adopted. Bonferroni’s test was used for multiple comparisons. Spearman’s rank correlation coefficient was used to examine the relationship between continuous variables. A probability (P) value \0.05 was considered to be significant.
Results BMI in patients with psoriasis Between July 2011 and March 2014, 111 patients with psoriasis were treated with ustekinumab (Table 1): 73 (66 %) had BMI \ 25 and 38 (34 %) had BMI C 25. Only three patients (3 %) had BMI C 30. At baseline, no
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Arch Dermatol Res (2014) 306:921–925 Table 1 Clinical and demographic characteristics of the study population All patients N = 111
BMI \ 25 n = 73
BMI C 25 n = 38
Age, years (mean ± SD)
58 ± 17
59 ± 18
57 ± 15
Male:female
83:28
54:19
29:9
Body weight (kg)
65 ± 12
59 ± 8
75 ± 11
Height (cm)
164 ± 8
164 ± 8
165 ± 10
BMI (mean ± SD)
23.9 ± 3.3
22.1 ± 1.9
27.6 ± 2.2 \0.001
Baseline PASI (mean ± SD)
12.0 ± 6.8
11.1 ± 5.5
13.8 ± 8.4
0.180
PASI \ 10
46 (51)a
49 (36)
39 (15)
0.324
PASI C 10
54 (60)
51 (37)
61 (23)
0.324
Psoriatic arthritis
5 (5)
4 (3)
5 (2)
0.781
P value
0.513 0.787 \0.001 0.448
Smoking habit
28 (31)
19 (14)
45 (17)
0.004
Diabetes
16 (18)
12 (9)
24 (9)
0.124
Hypertension
46 (51)
34 (25)
68 (26)
Previous biologic treatment
15 (17)
16 (12)
13 (5)
\0.001 0.649
SD standard deviation, BMI body mass index, PASI psoriasis area and severity index a
Unless noted otherwise, values are percentages. Patient numbers are given in parentheses
significant differences were observed between the two groups in age, sex distribution, height, presence of psoriatic arthritis or diabetes, or previous biologic treatment. In contrast, patients with BMI C 25 had more hypertension and smoking habit compared with those with BMI \ 25 (P \ 0.001 and P = 0.004, respectively). As expected, the mean body weight was significantly higher in patients with BMI C 25 than in those with BMI \ 25 (P \ 0.001). Correlation between BMI and ustekinumab efficacy Baseline PASI score was similar in both groups. PASI-50 and PASI-75 response rates were comparable between patients with BMI \ 25 and those with BMI C 25 at week 16 (93 vs. 87 %, P = 0.306 and 81 vs. 71 %, P = 0.338, respectively; Table 2 and Fig. 1a). However, PASI-90 and PASI-100 response rates were significantly higher in patients with BMI \ 25 than in those with BMI C 25 (52 vs. 24 %; P = 0.005 and 32 vs. 5 %; P = 0.002, respectively). The adjusted odds ratios for achieving PASI-50, PASI-75, PASI-90, and PASI-100 in patients with BMI C 25 compared with those with BMI \ 25 were 0.485, 0.582, 0.286, and 0.121, respectively. Consistent with this, patients with BMI \ 25 exhibited higher D PASI than those with BMI C 25 at week 16 (85 vs. 74 %;
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Table 2 Evaluation of PASI at week 16 following the start of ustekinumab treatment All patients N = 111
BMI \ 25 N = 73
BMI C 25 N = 38
P value
81 ± 23
85 ± 20
74 ± 27
0.004
PASI-50
91 (101)a
93 (68)
87 (33)
0.306
0.485 (0.131–1.800)
PASI-75
77 (86)
81 (59)
71 (27)
0.338
0.582 (0.234–1.450)
PASI-90
42 (47)
52 (38)
24 (9)
0.005
0.286 (0.119–0.688)
PASI-100
23 (25)
32 (23)
5 (2)
0.002
0.121 (0.027–0.545)
D PASI
Odds ratio (95 % CI)
(mean ± SD)
Odds ratios are for achieving PASI-50, PASI-75, PASI-90, or PASI-100 in patients with BMI C 25 compared with BMI \ 25 PASI psoriasis area and severity index, D PASI percent reduction in PASI, SD standard deviation, BMI body mass index, CI confidence interval a
Unless noted otherwise, values are percentages. Patient numbers are given in parentheses
Fig. 1 The effect of obesity on the efficacy of ustekinumab treatment in patients with psoriasis. a PASI-50, PASI-75, PASI-90, and PASI100 response rates at week 16 following the start of ustekinumab treatment. b D PASI at week 16 following the start of ustekinumab treatment. Significant differences between sample means are indicated: *P \ 0.01
Fig. 2 Correlation between D PASI and BMI (a) or body weight (b) at week 16 following the start of ustekinumab
P \ 0.004; Table 2 and Fig. 1b). Also consistent with the association of BMI with the efficacy of ustekinumab in psoriasis, D PASI correlated negatively with BMI (r = -
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0.204, P = 0.032; Fig. 2a). By contrast, D PASI did not correlate with body weight (r = -0.094, P = 0.322; Fig. 2b).
Discussion To our knowledge, this is the first study to evaluate the association of BMI with the efficacy of ustekinumab in patients with psoriasis. Irrespective of the degree of BMI, PASI-50 and PASI-75 were achieved by more than 91 %, and 77 % in patients receiving ustekinumab treatment at week 16, respectively. By contrast, patients with BMI C 25 had significantly lower PASI-90 and PASI-100 response rates and significantly lower D PASI than patients with BMI \ 25. BMI, but not body weight, was negatively correlated with D PASI, indicating that a higher BMI may be linked to a lower clinical response to ustekinumab in patients with psoriasis. Although the effect of obesity on therapeutic response to ustekinumab has been unclear, high body weight was shown to have a negative impact. The apparent clearance of PASI by ustekinumab is higher in patients weighing [100 kg than in those weighing B100 kg [25]. PASI-75 response was lower in patients weighing [100 kg than in those weighing B100 kg, but those weighing B100 kg had similar PASI-75 response rates to treatment with 45 or 90 mg [10]. Therefore, treatment with ustekinumab 90 mg may be appropriate for those weighing [100 kg. However, the prevalence of excess body weight, particularly weight [100 kg, is lower in Japan and other Asian countries than in Western countries; in the present study, only 1 of the 111 patients with psoriasis weighed [100 kg (0.9 %), and this patient successfully achieved PASI-90 but not PASI-100. Consequently, parameters other than body weight would be useful to predict the clinical response to ustekinumab of Japanese or other Asian patients. In this study, patients with BMI C 25 were less likely to achieve PASI-90 and PASI-100, suggesting that dosing by BMI may improve the clinical response to ustekinumab. Further studies are needed to determine the impact of high BMI on the efficacy of ustekinumab for the treatment of psoriasis in each ethnic group. Obesity is thought to be a chronic low-grade inflammatory disorder. The adipose tissue produces various proinflammatory immune mediators, including cytokines (e.g., TNF-a and IL-6), chemokines, and adipokines [20], suggested to be involved in the pathogenesis of psoriasis [17]. Moreover, circulating levels of TNF-a, IL-17, and IL-23 are higher in obese subjects than in non-obese subjects [21, 22], suggesting that obese patients with psoriasis are likely to be more resistant to therapies targeting these immune mediators. Accumulating evidence indicates that weight loss
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interventions, including a low-calorie diet, physical exercise, and gastric bypass surgery, ameliorate the severity of psoriasis [5, 8, 15]. A low-calorie diet also increases the clinical responses of obese patients with psoriasis to cyclosporine [3]. Therefore, weight loss interventions are likely to enhance the efficacy of ustekinumab treatment for psoriasis, although this warrants further study. There are several potential limitations to this study. First, the efficacy of ustekinumab was evaluated only at week 16. Further studies should investigate the long-term efficacy of ustekinumab in patients with psoriasis and assess the association with BMI. Second, the effects of BMI on the efficacy of other biological agents, such as infliximab and adalimumab, should be compared. Third, all patients were treated with ustekinumab 45 mg; additional studies should confirm whether these findings can be extended to those treated with ustekinumab 90 mg. Fourth, the significance of hypertension and smoking habit is unclear; it is essential to assess its association with BMI and the efficacy of ustekinumab in future studies. Lastly, the precise mechanism by which a higher BMI contributes to the efficacy of ustekinumab in psoriasis has not been clarified. Nonetheless, the results of this study suggest that patients with BMI C 25 may be more resistant to ustekinumab treatment for psoriasis compared with those with BMI \ 25, indicating that evaluation of BMI in patients with psoriasis initiating ustekinumab treatment may be useful for therapeutic stratification.
Conflict of interest H. Nakagawa has received consultant and speaker fees from Janssen Pharmaceuticals K K.
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