Comparison of Ustekinumab and Etanercept for Moderate-to-Severe Psoriasis

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1 The new england journal of medicine original article Comparison of Ustekinumab and Etanercept for Moderate-to-Severe Psoriasis Christopher E.M. Griffiths, M.D., Bruce E. Strober, M.D., Ph.D., Peter van de Kerkhof, M.D., Vincent Ho, M.D., Roseanne Fidelus-Gort, Ph.D., Newman Yeilding, M.D., Cynthia Guzzo, M.D., Yichuan Xia, Ph.D., Bei Zhou, Ph.D., Shu Li, M.S., Lisa T. Dooley, Dr.P.H., Neil H. Goldstein, M.D., and Alan Menter, M.D., for the ACCEPT Study Group* ABSTRACT From the University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom (C.E.M.G.); New York University Medical Center, New York (B.E.S.); University Hospital Nijmegen, Nijmegen, the Netherlands (P.K.); University of British Columbia, Vancouver, BC, Canada (V.H.); Incyte Corporation, Wilmington, DE (R.F.-G.); Centocor Research and Development (N.Y., C.G., Y.X., B.Z., S.L., L.T.D.) and Precision Research (N.H.G.) both in Malvern, PA; and the Psoriasis Research Unit, Baylor University Medical Center, Dallas (A.M.). Address reprint requests to Dr. Griffiths at the Dermatology Centre, Salford Royal Hospital, University of Manchester, Manchester M6 8HD, United Kingdom, or at *The investigators participating in the Active Comparator (CNTO 1275/Enbrel) Psoriasis Trial (ACCEPT) study group are listed in the Supplementary Appendix, available with the full text of this article at NEJM.org. This article (1.156/NEJMoa81652) was updated on January 25, 21, at NEJM.org. N Engl J Med 21;362: Copyright 21 Massachusetts Medical Society. Background Biologic agents offer a range of new therapeutic options for patients with psoriasis; however, the relative benefit risk profiles of such therapies are not well known. We compared two biologic agents, ustekinumab (an interleukin-12 and interleukin-23 blocker) and etanercept (an inhibitor of tumor necrosis factor α), for the treatment of psoriasis. Methods We randomly assigned 93 patients with moderate-to-severe psoriasis to receive subcutaneous injections of either 45 or 9 mg of ustekinumab (at weeks and 4) or high-dose etanercept (5 mg twice weekly for 12 weeks). The primary end point was the proportion of patients with at least 75% improvement in the psoriasis area-andseverity index (PASI) at week 12; a secondary end point was the proportion with cleared or minimal disease on the basis of the physician s global assessment. Assessors were unaware of the treatment assignments. The efficacy and safety of a crossover from etanercept to ustekinumab were evaluated after week 12. Results There was at least 75% improvement in the PASI at week 12 in 67.5% of patients who received 45 mg of ustekinumab and 73.8% of patients who received 9 mg, as compared with 56.8% of those who received etanercept (P =.1 and P<.1, respectively). Similarly, 65.1% of patients who received 45 mg of ustekinumab and 7.6% of patients who received 9 mg of ustekinumab had cleared or minimal disease according to the physician s global assessment, as compared with 49.% of those who received etanercept (P<.1 for both comparisons). Among patients who did not have a response to etanercept, 48.9% had at least 75% improvement in the PASI within 12 weeks after crossover to ustekinumab. One or more adverse events occurred through week 12 in 66.% of patients who received 45 mg of ustekinumab and 69.2% of patients who received 9 mg of ustekinumab and in 7.% who received etanercept; 1.9%, 1.2%, and 1.2%, respectively, had serious adverse events. Safety patterns were similar before and after crossover from etanercept to ustekinumab. Conclusions The efficacy of ustekinumab at a dose of 45 or 9 mg was superior to that of highdose etanercept over a 12-week period in patients with psoriasis. (ClinicalTrials.gov number, NCT ) 118

2 Psoriasis is a chronic, inflammatory skin disease affecting approximately 2% of the world s population. 1,2 Therapeutic agents used for the management of psoriasis commonly target the underlying inflammation. Immunosuppressive agents such as methotrexate and cyclosporine have proved effective in the treatment of psoriasis. 3 Biologic agents that selectively block steps in the inflammatory cascade have provided additional therapies for psoriasis and have led to a better understanding of its immunologic and pathophysiological basis. 4-9 Proinflammatory cytokines such as tumor necrosis factor α (TNF-α) play a central role in the inflammation underlying psoriasis. Agents that selectively block TNF-α have proved highly effective in treating psoriasis More recently, interleukin-12 and interleukin-23, cytokines that induce naive CD4+ lymphocytes to differentiate into type 1 helper T cells (Th1 cells) and type 17 helper T cells (Th17 cells), respectively, have been identified as key mediators of psoriasis A new class of biologic agents that block both interleukin-12 and interleukin-23 has been shown to be effective for the treatment of psoriasis. 19,2 The phase 3 Active Comparator (CNTO 1275/ Enbrel) Psoriasis Trial (ACCEPT) was designed to compare the efficacy of two effective biologic agents, one that inhibits TNF-α (etanercept [Enbrel, Amgen and Wyeth]) and one that blocks interleukin-12 and interleukin-23 (ustekinumab [Stelara, Centocor Ortho Biotech Services, a subsidiary of Johnson & Johnson]). Methods Patients We conducted this study at 67 sites worldwide, and the study protocol was approved by the institutional review board or ethics committee at each site. Written informed consent was obtained from each patient. The first patient was enrolled on March 26, 27, and the last patient visit occurred on January 15, 29. Patients were eligible for the study if they were adults ( 18 years of age) who had received a diagnosis of plaque psoriasis at least 6 months earlier, were candidates for phototherapy or systemic treatment, had a score on the psoriasis area-and-severity index (PASI) of 12 or higher (on a scale of to 72, with higher scores indicating more severe disease), had a score of at least 3 on the physician s global assessment (on a scale of to 5, with indicating no disease and 5 severe disease), and had involvement of at least 1% of body-surface area at baseline. Additional eligibility criteria were an inadequate response, intolerance, or contraindication to at least one conventional systemic agent for the treatment of psoriasis (i.e., methotrexate, cyclosporine, or psoralen plus ultraviolet A) and no previous treatment with ustekinumab or etanercept. Patients were ineligible for participation in the study if they had nonplaque (i.e., pustular, guttate, or erythrodermic) or drug-induced forms of psoriasis, a recent serious infection or a history of chronic or recurrent infectious disease, or a known malignant condition (with the exception of treated basal-cell or squamous-cell skin cancer or cervical cancer in situ with no evidence of recurrence for 5 years). Patients could not have received conventional systemic therapy or phototherapy within 4 weeks before enrollment, topical psoriasis agents within 2 weeks, investigational drugs within 4 weeks or five half-lives, whichever was longer, or biologic agents within 3 months or five half-lives, whichever was longer. Study Design We randomly assigned patients (in a 3:5:5 ratio) to one of three treatment groups (ustekinumab at a dose of 45 or 9 mg at weeks and 4 or etanercept at a dose of 5 mg twice weekly [hereafter called high-dose etanercept] for 12 weeks), using an adaptive randomization scheme that was stratified according to investigational site and baseline weight (<9 kg or 9 kg). 21 Patients in the etanercept group who did not have a response (i.e., patients who had moderate, marked, or severe psoriasis) at week 12 received 9 mg of ustekinumab at weeks 16 and 2, and patients who did not have a response to ustekinumab received one additional dose of ustekinumab at week 16 (Fig. 1). Treatment was interrupted starting at week 12 in all patients with cleared, minimal, or mild psoriasis; patients were retreated with ustekinumab if psoriasis recurred and was classified as moderate, marked, or severe disease (Fig. 1). Patients were aware of their treatment assignment, although patients who were randomly assigned to ustekinumab received double injections (one injection of active treatment and one injection of placebo) to maintain blinding for the dose. All study personnel, except those who dispensed or administered a study agent, remained unaware 119

3 The new england journal of medicine Controlled period Treatment interruption Crossover and retreatment Follow-up 5 mg of etanercept twice weekly Crossover to 9 mg of ustekinumab Randomization 45 mg of ustekinumab at wk and 4 Retreatment with 45 mg of ustekinumab 9 mg of ustekinumab at wk and 4 Retreatment with 9 mg of ustekinumab Figure 1. Schematic Representation of the Study Design. Patients who were randomly assigned to receive ustekinumab and who had a physician s global assessment score of 3 or higher at week 12 received one additional dose of ustekinumab at week 16 and no further therapy. of the treatment assignments throughout the study. The study was sponsored by Centocor Research and Development. The academic authors and Centocor representatives designed the study, and Centocor conducted the data analyses. The authors interpreted the data and, with support from a professional medical writer employed by Centocor Ortho Biotech Services, collaborated in the preparation of the manuscript. The academic authors had access to the data and vouch for the completeness and accuracy of the data and data analyses. The lead author served as guarantor of the analyses, which were verified by the Biostatistics Department at Centocor Research and Development. Efficacy and Safety Evaluations Efficacy evaluations included the PASI and the physician s global assessment. The PASI score is based on the extent of psoriatic involvement of body-surface area on the head, trunk, arms, and legs, as well as the severity of scale formation, erythema, and plaque induration in each region of the body. 22 The physician s global assessment score reflects the overall status of psoriatic lesions (induration, erythema, and scaling) at a given time point. Safety was evaluated by assessing adverse events and routine hematologic and laboratory values. Possible major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) were adjudicated by an independent panel of academic cardiologists. In addition, serum samples were evaluated for antibodies to ustekinumab. Statistical Analysis Efficacy data for all patients who underwent randomization were analyzed according to the assigned treatment, and safety data were summarized according to the actual treatment received. The prespecified data-analysis plan was finalized before the treatment assignments were revealed. The primary end point was the proportion of patients who had at least 75% improvement in the PASI score from baseline to week 12. A total enrollment of 85 patients was planned on the basis of a step-down test procedure in which the proportions of patients with at least 75% improvement in the PASI score were assumed to be 64%, 65%, and 5% in the groups receiving 45 mg of ustekinumab, 9 mg of ustekinumab, and etanercept, respectively. With 325 patients each in the group receiving 9 mg of ustekinumab and the group receiving etanercept, the power to detect a significant treatment difference at an alpha level of.5 was 97%; with 2 patients in the group receiving 45 mg of ustekinumab, the power to further detect a significant treatment difference between 45 mg of ustekinumab and etaner- 12

4 cept was 87%, with an overall type I error rate of.5. Major secondary end points included the proportion of patients with a physician s global assessment score of (clearance of disease) or 1 (minimal disease) at week 12, the proportion with at least 9% improvement in the PASI score from baseline to week 12, and the difference between the PASI score at week 12 and the score 12 weeks after retreatment on recurrence of psoriasis. To maintain an overall type I error rate of.5, a step-down test procedure was applied, first comparing 9 mg of ustekinumab with etanercept, and then comparing 45 mg of ustekinumab with etanercept only if the 9-mg dose was significantly superior to etanercept. A twosided Cochran Mantel Haenszel chi-square test stratified according to the patient s weight (<9 kg or 9 kg) was conducted to evaluate each superiority hypothesis. All tests were two-sided. Results Patient Characteristics Of the 1175 patients screened for enrollment, 93 were randomly assigned in a 3:5:5 ratio to one of three treatment groups: 29 patients to 45 mg of ustekinumab, 347 patients to 9 mg of ustekinumab, and 347 patients to high-dose etanercept (Fig. 2). Baseline demographic and disease characteristics of the patients were similar among the three treatment groups (Table 1). More than two thirds of the patients were male, the mean age was approximately 45 years, and the average duration of psoriasis was approximately 19 years. The mean body-surface area affected by psoriasis was approximately 25%, and the mean PASI score was approximately 2. Approximately one quarter of patients reported a history of psoriatic arthritis. The vast majority of patients had used topical agents previously, and more than 1% had used biologic agents (Table 1). Efficacy At week 12, a total of 67.5% of patients who received 45 mg of ustekinumab and 73.8% of patients who received 9 mg of ustekinumab had at least 75% improvement in the PASI score, as compared with 56.8% of those who received highdose etanercept (P =.1 and P<.1, respectively) (Table 2). A 9% improvement in the PASI score was achieved at week 12 by a higher proportion of patients who received 45 mg or 9 mg of ustekinumab (36.4% and 44.7%, respectively) than by patients who received etanercept (23.1%) (P<.1 for both comparisons) (Table 2, and Figure 1 of the Supplementary Appendix). The proportion of patients who had cleared disease (a score of ) or minimal disease (a score of 1) based on the physician s global assessment score at week 12 was also significantly higher in each ustekinumab group; 65.1% of patients who received 45 mg and 7.6% of patients who received 9 mg of ustekinumab, as compared with 49.% of patients who received high-dose etanercept, had cleared or minimal disease (P<.1 for both comparisons with etanercept) (Table 2). The onset of a clinical response was more rapid in patients treated with ustekinumab than in patients treated with etanercept (Fig. 3A, 3B, and 3C). Among patients who did not have a response to etanercept, 48.9% had at least 75% improvement in the PASI score and 23.4% had at least 9% improvement after crossing over to 9 mg of ustekinumab for 12 weeks; 4.4% achieved cleared or minimal disease according to the physician s global assessment during this period (Fig. 3D, 3E, and 3F). For patients who received a physician s global assessment score indicating cleared, minimal, or mild disease at week 12, the treatment was interrupted until psoriasis recurred and was classified as moderate, marked, or severe disease. The median time to recurrence was 14.4 weeks among patients who received 45 mg of ustekinumab, 18.1 weeks among those who received 9 mg of ustekinumab, and 7.3 weeks among those who received etanercept. Of the 633 patients who were treated with ustekinumab again after the recurrence of psoriasis, 534 (84.4%) had a physician s global assessment score of to 2 within 12 weeks after retreatment. Safety During the first 12 weeks of the trial, the proportions of patients who had at least one adverse event were similar in the etanercept group (7.%) and both ustekinumab groups (66.% in the group that received 45 mg of ustekinumab and 69.2% in the group that received 9 mg) (Table 3, and Table 1 of the Supplementary Appendix, available with the full text of this article at NEJM.org), and similar proportions of patients discontinued treatment because of adverse events (2.3% of patients in the etanercept group, as compared with 1.9% of those who received 45 mg of usteki- 121

5 The new england journal of medicine 1175 Patients were screened 93 Underwent randomization 347 Were assigned to 5 mg of etanercept twice weekly 29 Were assigned to 45 mg of ustekinumab at and 4 wk 347 Were assigned to 9 mg of ustekinumab at and 4 wk 11 Discontinued treatment 5 Had adverse event 1 Was lost to follow-up 5 Had other reason 8 Discontinued treatment 2 Had adverse event 2 Were lost to follow-up 4 Had other reason 5 Discontinued treatment 1 Had adverse event 2 Were lost to follow-up 2 Had other reason 336 Completed 12-wk treatment 41 Did not cross over to 9 mg of ustekinumab after wk Discontinued treatment 5 Had adverse event 1 Was lost to follow-up 11 Had other reason 1 Did not report reason 23 Completed treatment without requiring additional treatment 21 Completed 12-wk treatment 27 Did not receive retreatment with 45 mg of ustekinumab after wk 12 1 Discontinued treatment 3 Had adverse event 2 Were lost to follow-up 5 Had other reason 17 Completed treatment without requiring additional treatment 342 Completed 12-wk treatment 72 Did not receive retreatment with 9 mg of ustekinumab after wk Discontinued treatment 6 Had adverse event 5 Were lost to follow-up 14 Had other reason 47 Completed treatment without requiring additional treatment 295 Crossed over to 9 mg of ustekinumab 5 Did not have PGA response at wk 12 and received 9 mg of ustekinumab at wk 16 and Had a PGA response at wk 12 and received 9 mg of ustekinumab at wk and 4 when psoriasis recurred 174 Received additional ustekinumab treatment 2 Did not have PGA response at wk 12 and received an additional dose at wk Had a PGA response at wk 12 and received two retreatment doses when psoriasis recurred 27 Received additional ustekinumab treatment 25 Did not have PGA response at wk 12 and received an additional dose at wk Had a PGA response at wk 12 and received two retreatment doses when psoriasis recurred 8 Discontinued treatment 4 Had adverse event 1 Was lost to follow-up 3 Had other reason 2 Discontinued treatment Had adverse event 2 Were lost to follow-up Had other reason 7 Discontinued treatment 3 Had adverse event 1 Was lost to follow-up 3 Had other reason 287 Completed treatment 172 Completed treatment 263 Completed treatment Figure 2. Enrollment, Randomization, and Treatment through 64. Treatment was interrupted in patients who had a response based on a physician s global assessment (PGA) score of 2 or less (cleared, minimal, or mild psoriasis) at week 12. Patients in the etanercept group crossed over to receive two 9-mg doses of ustekinumab 4 weeks apart, beginning at week 16, if they did not have a response to etanercept (PGA score, 3 [moderate, marked, or severe psoriasis]) or if psoriasis recurred as moderate or more severe disease after they had had a response. Patients in the ustekinumab group were treated again with their original ustekinumab dose if psoriasis recurred as moderate or more severe disease. 122

6 Table 1. Baseline Characteristics of the Patients.* Variable Etanercept Group (N = 347) Ustekinumab Group 45 mg (N = 29) 9 mg (N = 347) Age yr 45.7± ± ±12.3 Male sex no. (%) 246 (7.9) 133 (63.6) 234 (67.4) White race no. (%) 316 (91.1) 193 (92.3) 39 (89.) Weight kg 9.8± ± ±22.8 Duration of psoriasis yr 18.8± ± ±11.8 Involved body-surface area % 23.8± ± ±17.6 Psoriasis area-and-severity index score 18.6± ± ±8.4 Marked or severe psoriasis based on physician s global assessment no. (%) 148 (42.7) 98 (46.9) 144 (41.5) Psoriatic arthritis no. (%) 95 (27.4) 62 (29.7) 95 (27.4) Previous treatment no. (%) Topical agents 336 (96.8) 22 (96.7) 336 (96.8) Phototherapy 224 (64.6) 138 (66.) 23 (66.3) Conventional systemic agents 199 (57.3) 129 (61.7) 182 (52.4) Biologic agents 41 (11.8) 26 (12.4) 36 (1.4) Unsuitable conventional systemic agents no. (%) 1 Agent 347 (.) 29 (.) 346 (99.7) 2 Agents 186 (53.6) 118 (56.5) 185 (53.3) 3 Agents 52 (15.) 31 (14.8) 47 (13.5) * Plus minus values are means ±SD. Race was self-reported. Phototherapy included ultraviolet B light and psoralen plus ultraviolet A (PUVA). Conventional systemic agents included PUVA, methotrexate, and cyclosporine. Biologic agents included alefacept, efalizumab, infliximab, and adalimumab. Unsuitable conventional systemic agents were those for which patients had an inadequate response, a lack of tolerance, or a contraindication. Categories were not mutually exclusive. For example, patients with intolerance to three agents were also included as having intolerance to one or more agents and two or more agents. numab and 1.2% of those who received 9 mg of ustekinumab). The greatest disparity in adverse events was observed in the proportions of patients who reported injection-site reactions (24.8% of patients who received etanercept as compared with 4.3% of patients who received 45 mg of ustekinumab and 3.7% of patients who received 9 mg of ustekinumab); the majority of these reactions were mild, and no anaphylaxis or serum sickness like reactions were reported. Through week 12, serious adverse events occurred in four patients in each treatment group (Table 3). In the etanercept group, one patient each had upper abdominal pain, bacterial meningitis, nephrolithiasis, and the rotator-cuff syndrome. In the group of patients who received 45 mg of ustekinumab, one patient each had pancreatitis, psychotic disorder, and hypertension with chest pain, and one patient with a family history of breast cancer received a diagnosis of breast cancer at week 7 of the study. In the group of patients who received 9 mg of ustekinumab, one patient each had appendicitis, gastrointestinal infection due to food poisoning, and uvulitis, and one patient was hospitalized twice: initially for urosepsis complicated by acute renal failure, gastritis, peptic-ulcer hemorrhage, nosocomial pneumonia, and chest pain (reported as a myocardial infarction by the investigator but determined not to be a myocardial infarction by 123

7 The new england journal of medicine Table 2. Clinical Responses at 12.* Variable Etanercept (N = 347) Ustekinumab 45 mg (N = 29) 9 mg (N = 347) Improvement in PASI score At least 75% no. (%) 197 (56.8) 141 (67.5) 256 (73.8) P value.1 <.1 Treatment difference (95% CI) 1.7 ( ) 17. (1. 24.) At least 9% no. (%) (23.1) 76 (36.4) 155 (44.7) P value <.1 <.1 Treatment difference (95% CI) 13.3 ( ) 21.6 ( ) Physician s global assessment Cleared or minimal disease no. (%) 17 (49.) 136 (65.1) 245 (7.6) P value <.1 <.1 Treatment difference (95% CI) 16.1 ( ) 21.6 ( ) Cleared disease no. (%) 3 (8.6) 34 (16.3) 91 (26.2) P value.6 <.1 Treatment difference (95% CI) 7.7 ( ) 17.6 ( ) * P values are for the comparison of rates between each ustekinumab group and the etanercept group. Treatment differences are percentage-point differences between each ustekinumab group and the etanercept group. CI denotes confidence interval, and PASI psoriasis area-and-severity index. adjudication) and subsequently for angina. Infections occurred at similar rates in the three treatment groups (29.1%, 3.6%, and 29.7% in the groups that received etanercept, 45 mg of ustekinumab, and 9 mg of ustekinumab, respectively). Nonmelanoma skin cancers occurred in two patients in the group that received 45 mg of ustekinumab and in one patient in the group that received 9 mg of ustekinumab; all cases occurred in areas of cleared psoriatic plaques. Through week 64, the rates and types of common adverse events were similar in the lowerdose and higher-dose ustekinumab groups and also before and after crossover from etanercept to ustekinumab, with the exception of injectionsite reactions through week 12, noted above (Table 3, and Table 1 of the Supplementary Appendix). Three deaths occurred, one each in the etanercept group (from a motor vehicle accident), the lower-dose ustekinumab group (from a gunshot wound), and the higher-dose ustekinumab group (from multisystem organ failure and sepsis in a patient who was retrospectively shown to be positive for the human immunodeficiency virus at study entry and who had methicillinresistant Staphylococcus epidermidis bacteremia). Serious infections of a common bacterial or viral origin occurred in 4 patients in the etanercept group (1.2%) (3 before crossover to ustekinumab and 1 after crossover), 2 patients in the group that received 45 mg of ustekinumab (1.%), and 1 patients in the group that received 9 mg of ustekinumab (2.9%) (P =.23 for the comparison between the group that received 45 mg of ustekinumab and the group that received 9 mg) (see Table 1 in the Supplementary Appendix). Nonmelanoma skin cancers were reported in nine patients, and other malignant conditions were reported in five patients treated with ustekinumab, including one case of mycosis fungoides, which the investigator retrospectively concluded was present before randomization but had been incorrectly diagnosed as psoriasis (Table 3). Major adverse cardiovascular events were reported in three patients overall: one patient each had a myocardial infarction in the etanercept group after crossover to ustekinumab, in the lower-dose ustekinumab group, and in the higher-dose ustekinumab group. The proportions of patients with abnormalities in hematologic and laboratory measures, including tests of liver and renal function, were 124

8 A At Least 75% Improvement in PASI Score D At Least 75% Improvement in PASI Score mg ustekinumab (N=347) 45 mg ustekinumab (N=29) Etanercept (N=347) P<.1 P= Crossover to 9 mg of ustekinumab after no response to etanercept B Physician s Global Assessment of Cleared or Minimal Disease 4 2 P=.2 P=.8 P<.1 P<.1 E Physician s Global Assessment of Cleared or Minimal Disease C At Least 9% Improvement in PASI Score F At Least 9% Improvement in PASI Score 4 2 P=.3 P< No. of Patients Figure 3. Clinical Response to Treatment, as Measured by the Psoriasis Area-and-Severity Index (PASI) and the Physician s Global Assessment, over Time. The proportions of patients randomly assigned to receive ustekinumab, at a dose of either 45 or 9 mg, or etanercept, at a dose of 5 mg twice weekly through week 12, who had at least 75% improvement in the score on the psoriasis area-and-severity index (PASI) (Panel A), a physician s global assessment of cleared or minimal disease (Panel B), and at least 9% improvement in the PASI score (Panel C) are shown. Patients who were randomly assigned to receive etanercept at baseline and who did not have a response at week 12 crossed over to receive 9 mg of ustekinumab at weeks 16 through week 32. The proportions of these patients who had at least 75% improvement in the PASI (Panel D), the physician s global assessment of cleared or minimal disease (Panel E), and at least 9% improvement in the PASI (Panel F) are shown. similar among the groups (see Table 1 in the Supplementary Appendix). Antibodies to ustekinumab developed in 32 of 835 patients treated with ustekinumab (3.8%); 26 of these 32 patients had low titers (<1:32), and the presence of antibodies was not associated with injection-site reactions. 125

9 The new england journal of medicine Table 3. Adverse Events and Other Key Safety Data through 64. Variable Wk 12 Wk 64 Etanercept Ustekinumab Etanercept with Crossover to 9 mg Ustekinumab Episodic Treatment with Ustekinumab 45 mg 9 mg Before Crossover After Crossover 45 mg 9 mg Total no. of patients Mean duration of follow-up wk Mean no. of doses Adverse event no. of patients (%) 243 (7.) 138 (66.) 24 (69.2) 275 (79.3) 191 (64.7) 182 (87.1) 39 (89.) Common adverse events no. of patients (%)* Nasopharyngitis 3 (8.6) 21 (1.) 34 (9.8) 52 (15.) 38 (12.9) 5 (23.9) 84 (24.2) Upper respiratory tract infection 2 (5.8) 13 (6.2) 22 (6.3) 39 (11.2) 35 (11.9) 37 (17.7) 71 (2.5) Headache 38 (11.) 31 (14.8) 42 (12.1) 41 (11.8) 9 (3.1) 35 (16.7) 55 (15.9) Back pain 7 (2.) 14 (6.7) 15 (4.3) 9 (2.6) 3 (1.) 17 (8.1) 36 (1.4) Injection-site reaction 86 (24.8) 9 (4.3) 13 (3.7) 86 (24.8) 5 (1.7) 12 (5.7) 18 (5.2) Adverse event leading to withdrawal of study 8 (2.3) 4 (1.9) 4 (1.2) 11 (3.2) 2 (.7) 5 (2.4) 1 (2.9) agent no. of patients (%) 1 Serious adverse event no. of patients (%) 4 (1.2) 4 (1.9) 4 (1.2) 12 (3.5) 1 (3.4) 17 (8.1) 25 (7.2) Adverse events of interest no. of patients (%) Infection 11 (29.1) 64 (3.6) 13 (29.7) 15 (43.2) 116 (39.3) 133 (63.6) 229 (66.) Infection requiring treatment 34 (9.8) 18 (8.6) 33 (9.5) 56 (16.1) 33 (11.2) 59 (28.2) 99 (28.5) Malignant condition other than nonmelanoma 1 (.5) 1 (.3) 2 (1.) 2 (.6) skin cancer Nonmelanoma skin cancer 2 (1.) 1 (.3) 1 (.3) 2 (1.) 6 (1.7) * Common adverse events were those that occurred in at least 1% of patients in any treatment group. Malignant conditions other than nonmelanoma skin cancer included breast cancer in one patient and an oral neoplasm in one patient in the group of patients who received 45 mg of ustekinumab, chronic lymphocytic leukemia in one patient and mycosis fungoides in one patient in the group of patients who received 9 mg of ustekinumab, and prostate cancer in one patient who received etanercept followed by crossover to 9 mg of ustekinumab. A total of nine patients had nonmelanoma skin cancers: six with basal-cell carcinoma, one with squamous-cell carcinoma, and two with basal-cell and squamous-cell carcinoma. Discussion Biologic agents offer a range of new therapeutic options for patients with psoriasis; however, the relative benefit risk profiles of such therapies are not well known. A direct comparison between a systemic medication (methotrexate) and a biologic agent (adalimumab) 23 showed the superiority of adalimumab 16 weeks after the start of treatment. Our comparison of two biologic agents, ustekinumab and high-dose etanercept, showed that ustekinumab has superior efficacy in patients with moderate-to-severe psoriasis, according to both the PASI score and the physician s global assessment, over a 12-week period. The safety of ustekinumab and etanercept, including the rates and types of adverse events and laboratory abnormalities, appeared to be generally similar with short-term treatment, with the exception of injection-site reactions, which were more common (albeit mild in the majority of cases) with etanercept than with ustekinumab. Patients in the etanercept group received more injections than did those in the ustekinumab groups, which may account for the disparity in the number of patients with injection-site reactions. Through 64 weeks, the rate of serious infections was higher among patients who received 9 mg of ustekinumab than among patients who received 45 mg of ustekinumab, but the difference was not significant. Rates of noncutaneous malignant conditions were low in all groups, pre- 126

10 cluding meaningful comparisons, and the majority of skin cancers were basal-cell carcinomas. The safety of ustekinumab did not appear to be compromised by crossover after treatment with etanercept or retreatment with ustekinumab after a treatment interruption. The size and duration of the study do not eliminate the potential for differences between these agents with regard to safety events that occur infrequently or after a longer period of treatment. In addition, although TNF-α inhibitory agents have been used in clinical practice for the past decade and their safety is generally well understood, 4,7-9 data on the use of ustekinumab are more limited. The results of this study provide additional evidence of the central role of proinflammatory cytokines in psoriasis and suggest that agents targeting interleukin-12 and interleukin-23 provide effective treatment of psoriasis. TNF-α is produced by a wide range of immune and nonimmune cells and has broad inflammatory effects, up-regulating both innate and adaptive immunity and activating a range of nonimmune tissues, including keratinocytes. Accordingly, TNF-α blockers have broad antiinflammatory effects that may be important in their therapeutic effect In contrast, interleukin-12 and interleukin-23 are produced primarily by activated antigen-presenting cells, including dermal dendritic cells, and they serve to activate natural killer cells, CD8+ T cells, and CD4+ T cells, inducing the differentiation of CD4+ T cells into Th1 and Th17 cells. Th1 cells produce proinflammatory cytokines, most prominently interferon-γ and TNF-α. 4,7,8 Th17 cells produce a different profile and a wider range of proinflammatory cytokines, which include TNF-α, interleukin-17, and interleukin The activities of these cytokines affect many cell types, including epithelial tissues and keratinocytes, possibly providing communication between the immune system and the epidermis that results in the keratinocyte hyperplasia observed in psoriasis. 12,24,25 An intriguing aspect that gives credence to the clinical use of interleukin-12 and interleukin-23 antibodies in psoriasis is the recent discovery in a genomewide association study that polymorphisms in interleukin-12 and interleukin-23 genes are associated with psoriasis. 26 The results of our direct comparison of two biologic agents, ustekinumab and high-dose etanercept, in the treatment of psoriasis suggest that ustekinumab provides superior efficacy with similar safety over a 12-week period. Our findings are generally consistent with those of previous studies. 4,19,27,28 The high level of efficacy of ustekinumab treatment that we observed was achieved with only two injections during the 12-week period, as compared with twice-weekly injections of etanercept, which may be important for improved treatment compliance. Furthermore, the results of this study could have implications for determining the optimal approach to the treatment of psoriasis and, in particular, the need for therapeutic strategies targeting Th1 cells, Th17 cells, or both to provide optimal benefit and safety. Supported by Centocor Research and Development. Dr. Griffiths reports receiving consulting and lecture fees from Abbott, Janssen-Cilag, Merck Serono, Novartis, Schering-Plough, and Wyeth and grant support from Merck Serono; Dr. Strober, receiving consulting and lecture fees from Centocor, Johnson & Johnson, Amgen, and Abbott Laboratories and grant support from Amgen and Abbott Laboratories; Dr. van de Kerkhof, receiving consulting fees from Schering-Plough, Celgene, Centocor, Almirall, UCB, Wyeth, Pfizer, Soffinova, Abbott, Actelion, Galderma, Novartis, Janssen-Cilag, and Leo Pharma; Dr. Ho, receiving advisory-board and lecture fees from Schering, Abbott, Janssen- Ortho, Pfizer, Amgen, and Wyeth and grant support from Centocor, Abbott, Amgen, and Wyeth; Dr. Menter, receiving advisoryboard, consulting, and lecture fees from Abbott, Amgen, Astellas, Biogen Idec, Celgene, Centocor, Genentech, Warner Chilcott, and Wyeth; Drs. Yeilding, Guzzo, Xia, and Dooley and Ms. Li, being employees of Johnson & Johnson and having equity and holding stock options in Johnson & Johnson; Dr. Zhou, being an employee of Johnson & Johnson, having equity and holding stock options in Johnson & Johnson, and having equity in Wyeth; Dr. Fidelus-Gort, being a former employee of Johnson & Johnson and having equity and holding stock options in Johnson & Johnson; and Dr. Goldstein, receiving consulting fees from Centocor. No other potential conflict of interest relevant to this article was reported. We thank C. Arnold of Centocor Ortho Biotech Services Research and Development for her writing support and editorial assistance, J. Krueger of Rockefeller University and J. Benson of Centocor Research and Development for their critical review of an earlier version of the manuscript, Y. 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