- Email: [email protected]
Benefit-risk analysis of adalimumab versus methotrexate and placebo in the treatment of moderate to severe psoriasis: Comparison of adverse event–free response days in the CHAMPION trial
Benefit-risk analysis of adalimumab versus methotrexate and placebo in the treatment of moderate to severe psoriasis: Comparison of adverse eventefree response days in the CHAMPION trial Kristian Reich, MD, PhD,a James Signorovitch, PhD,b Karthik Ramakrishnan, MPH,b Andrew P. Yu, PhD,b Eric Q. Wu, PhD,b Shiraz R. Gupta, PharmD, MPH,c Yanjun Bao, PhD,c and Parvez M. Mulani, PhDc Hamburg, Germany; Boston, Massachusetts; and Abbott Park, Illinois Background: The Comparative Study of Humira versus Methotrexate (MTX) versus Placebo in Psoriasis Patients (CHAMPION) demonstrated superior efficacy of biologic over conventional systemic immunosuppressant therapy in psoriasis. Objective: We sought to compare the risk-benefit profile of adalimumab (ADA), MTX, and placebo using data from CHAMPION. Methods: Patients randomized to ADA (n = 107), MTX (n = 110), or placebo (n = 53) were followed up for 16 weeks. Response ( $ 75% improvement in Psoriasis Area and Severity Index), days free of adverse events (AEs), moderate to severe AEs, infection-related AEs, and study drugerelated AEs were analyzed. Results: ADA treatment was associated with substantially more days (SD) of AE-free response compared with MTX or placebo treatment, respectively: 36.9 (31.1) versus 8.3 (15.9) or 6.7 (18.1) days of response free of any AEs, 43.8 (31.9) versus 11.1 (19.9) or 7.9 (19.9) days of response free of moderate to severe AEs, 48.5 (29.2) versus 12.4 (21.7) or 9.2 (21.8) days of response free of infection-related AEs, and 44.6 (31.4) versus 11.8 (21.1) or 10.0 (24.0) days free of study drugerelated AEs (all P \ .0001 for ADA vs MTX or placebo). Limitations: This clinical trialebased analysis may not have captured the full spectrum of AEs in the actual clinical setting. The short (16-week) duration of the trial limited the ability to capture some important but uncommon AEs associated with long-term ADA or MTX use. Conclusion: With 4 times as many AE-free response days, ADA demonstrated a superior benefit-risk profile. ( J Am Acad Dermatol 2010;63:1011-8.) Key words: adalimumab; adverse events; benefit-risk analysis; global benefit-risk; health-related quality of life; methotrexate; psoriasis. From Dermatologikum Hamburga; Analysis Group Inc, Bostonb; and Abbott Laboratories, Abbott Park.c The work reported here was performed under contract with Abbott Laboratories by Analysis Group Inc. Disclosure: Dr Reich has acted as a consultant and speaker for and/or participated in clinical trials sponsored by Abbott, Biogen Idec, Bristol-Myers-Squibb, Centocor, Merck Serono, Schering-Plough, UCB, and Wyeth. Drs Signorovitch, Ramakrishnan, Yu, and Wu are employees of Analysis Group Inc. Drs Gupta, Bao, and Mulani are employees of Abbott Laboratories. Accepted for publication December 1, 2009. Reprint requests: Kristian Reich, MD, PhD, Dermatologikum Hamburg, Stephansplatz 5, Hamburg, Germany 20354. E-mail: [email protected]. Published online October 8, 2010. 0190-9622/$36.00 ª 2010 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2009.12.029
P
soriasis is a chronic, inflammatory, multisystem disorder affecting 1% to 3% of the worldwide population, with the highest prevalence in North America and Europe.1,2 In the United States, an estimated 5.8 million to 7.5 million people have psoriasis, of whom approximately 1.5 million adults are affected by moderate to severe psoriasis.3,4 Psoriasis substantially reduces health-related quality of life (HRQOL), with impairments of physical and mental functioning that are comparable with those of patients with other chronic conditions, such as cancer, arthritis, hypertension, heart disease, diabetes, and depression.5,6 In addition, psoriasis imposes a significant economic burden. Direct medical care for psoriasis in the United States is estimated to cost from 1011
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$650 million to $4.3 billion annually after adjusting treatment of moderate to severe chronic plaque for inflation and population growth.7 psoriasis in adult patients who are candidates for The goals of psoriasis treatment are to gain initial systemic therapy or phototherapy and when other and rapid control of the disease, reduce the extent systemic therapies are medically less appropriate.13 and severity of plaque lesions, achieve and maintain To date, only one clinical trial has been published long-term remission, minimize adverse events (AEs) comparing the efficacy and safety of a biologic of treatment, and improve quality of life.8 A variety of versus an active systemic therapy for the treatment systemic treatments available of psoriasis: the Comparative for moderate to severe psoStudy of Humira versus MTX CAPSULE SUMMARY riasis can result in complete versus Placebo in Psoriasis and long-lasting clearance of Patients (CHAMPION) trial.12 A combined measure of benefits and physical symptoms, but each In this trial, ADA was associrisks may provide a more comprehensive treatment also carries a difated with a greater and more and clinically relevant comparison of ferent set of risks of AE.8 rapid reduction of psoriasis treatment options for patients with Thus, it is important for clinisymptoms compared with psoriasis. cians to evaluate treatment MTX. At the end of 16 weeks, risks and the benefits to This benefit-risk analysis compared approximately 80% of ADAachieve optimal improvement adalimumab versus methotrexate and treated patients achieved a in patients’ quality of life. placebo by rate of achieving a clinical substantial clinical response, Current pharmacotherresponse without adverse events to as indicated by a 75% or apies for moderate to severe assist patients and physicians in greater improvement in psoriasis include convenchoosing an optimal treatment for Psoriasis Area and Severity tional systemic agents and psoriasis. Index (PASI) score (PASI immunomodulating bio75). In comparison, signifiWith 4 times as many adverse logics.4 Conventional syscantly smaller percentages of eventefree response days, adalimumab temic agents considered to MTX- and placebo-treated demonstrated a superior benefit-risk be first-line treatment for patients achieved a PASI 75 profile compared with methotrexate or moderate to severe psoriasis response (36% and 19%, replacebo. include methotrexate (MTX), spectively). In addition, sigcyclosporine, retinoids, and nificantly more ADA-treated psoralen ultraviolet therapy. Although these medipatients achieved complete clearance of psoriasis cations may be effective and well tolerated for a short (100% improvement in PASI score). Overall rates of duration, they are associated with serious toxicities AEs in CHAMPION were comparable across treatthat can limit their long-term use.9 The most widely ment arms, although the frequencies of individual used systemic therapy is MTX,8 which was approved types of AEs differed. In particular, liver function by the US Food and Drug Administration (FDA) for abnormalities affected a higher percentage of patreatment of psoriasis in 1971.10 Toxicities associated tients in the MTX arm compared with the ADA and with MTX include acute hematologic toxicity, acute placebo arms. The most frequent AEs in each arm and chronic hepatotoxicity (eg, fibrosis and cirrhowere nonserious infections. There were no serious sis), lung disease, severe skin reactions, serious infections in any treatment arm and serious AEs in opportunistic infections, lymphoproliferative disorgeneral were rare, affecting less than 2% of patients ders, and severe gastrointestinal toxicity.1 In recent in each treatment arm. years, biologics targeting tumor necrosis factor have Published comparisons of treatment arms in the demonstrated efficacy in reducing psoriasis sympCHAMPION trial have reported efficacy and safety toms while causing fewer and less severe toxicities as separate outcomes. However, individual patients than MTX. Potential safety concerns regarding the may experience clinical response with or without use of such tumor necrosis factor antagonists include concurrent AEs. Because the therapeutic goal in reactivation of tuberculosis, development of other psoriasis treatment is to achieve and maintain opportunistic infections, malignancies, demyelinatclinical response with minimal AEs,8 a combined 2,11 ing diseases, and congestive heart failure. measure of benefits and risks may provide a more Adalimumab (ADA), a fully human monoclonal comprehensive and clinically relevant comparison antibody against tumor necrosis factor, has demonof treatment options. To assist patients and physistrated efficacy and tolerability in treating patients cians in choosing a treatment with the optimal with psoriasis across several randomized trials.5,12 In benefit-risk profile, the objective of this benefit-risk 2008, the FDA approved the use of ADA for analysis was to compare ADA versus MTX and d
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Abbreviations used: ADA: adalimumab AE: adverse event CHAMPION: Comparative Study of Humira versus Methotrexate versus Placebo in Psoriasis Patients EQ: EuroQOL FDA: Food and Drug Administration HRQOL: health-related quality of life MTX: methotrexate NNH: number needed to harm NNT: number needed to treat PASI: Psoriasis Area and Severity Index PASI 75: 75% or greater improvement in Psoriasis Area and Severity Index
placebo in terms of the rate of achieving a clinical response without AEs.
METHODS Data source The current benefit-risk analysis was conducted using data from the CHAMPION trial.12 In this 16week, multicenter, randomized, placebo-controlled, double-blind clinical trial patients with greater than or equal to 10% body surface area involvement and a PASI score of greater than or equal to 10 at baseline were randomized to 3 treatment groups: ADA subcutaneous injection 80 mg at week 0, followed by 40 mg every other week from weeks 1 through 15 (n = 108); oral MTX 7.5 to 25 mg/wk for 16 weeks (n = 110); or placebo for 16 weeks (n = 53). All patients received oral folic acid, and 24 patients received prophylactic treatment for tuberculosis during the study. The primary efficacy end point in CHAMPION was the percentage of patients achieving a PASI 75 response after 16 weeks of treatment. Patients were evaluated for PASI score at baseline and at the end of weeks 1, 2, 4, 8, 12, and 16. Safety assessments, including AEs, standard laboratory tests, and vital signs, were conducted throughout the trial and continued after week 16 through 70 days after the final dose of study drug. The details of the study design and inclusion/exclusion criteria used during CHAMPION have been previously reported.12 End points A single composite metric combining both safety and efficacy was used as the primary end point for the current benefit-risk analyses: the total number of days a patient had PASI 75 response and was free of AEs during the 16-week study period. At each day of follow-up, a patient was considered to have an AEfree response if they: (1) experienced PASI 75 response; and (2) had no active AEs. The total
Fig 1. Graphic illustration of incidence of serious adverse events (SAE ).
number of PASI 75 response days, regardless of AEs, was also studied. Missing PASI 75 response was imputed by carrying forward the PASI 75 response from the most recent study visit (last observation carried forward). To ensure that all study visits contributed substantially to the cumulative number of PASI 75 response days and AE-free response days, the last PASI 75 assessment at week 16 was carried through week 17 for all treatment arms. The time covered by an active AE was identified from the start and stop dates recorded on the AE report form. AEs with missing end dates were assumed to continue up to week 17. The total numbers of PASI 75 response days and AE-free response days during the 16-week study period were summed for each patient. Separate analyses were conducted for 3 specific AE categories: (1) response days free of moderate to severe AEs; (2) response days free of infectionrelated AEs; and (3) response days free of study drugerelated AEs. Response free of moderate to severe AEs is of particular interest because, by definition, moderate to severe AEs have a high potential to worsen patient HRQOL. Per CHAMPION study protocol, moderate AEs were defined as those causing discomfort and interrupting usual activities and severe AEs were defined as those causing considerable interference with the patient’s usual activities and those that may be incapacitating or life threatening.12 Infection-related AEs were analyzed because they are of particular clinical concern for biologic and systemic immunotherapies. Drug-related AEs were included because these events may be more likely to reflect clinically
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Fig 2. Cumulative number of any (A), infectious (B), moderate to severe (C), and study drugerelated (D) adverse event (AE )-free response days during 16-week study period. ADA, Adalimumab; MTX, methotrexate; PBO, placebo.
relevant differences between treatments. Serious AEs, defined as events that are life threatening, cause or prolong hospitalization, or require medical or surgical intervention to prevent a serious outcome, were also considered. However, because serious AEs were extremely rare in the trial across treatment arms and occurred in approximately 0.4% per patientmonth,12 the analyses of AE-free response days did not stratify by this subtype of AE (Fig 1 and 2). The impact of moderate to severe and mild AEs on HRQOL was also measured using the EuroQOL (EQ)-5D, a preference-based health status that measures the 5 dimensions of health (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression). The scores range from 0 to 1, with 0 being death and 1 being perfect health; a score may
have a value less than 0, which indicates that the health state is worse than death. The EQ-5D scores were converted to a scale of 0 to 100 for this analysis. EQ-5D was assessed at weeks 0, 12, and 16 in the CHAMPION trial.12 Statistical analysis Analyses included all randomized patients who had at least one postbaseline PASI assessment. Baseline characteristics including patient demographics (age, sex, race) and clinical characteristics (percent body surface area, PASI score) and AE rates during the 16-week study period were summarized for patients in each treatment group. Comparisons were made using x 2 tests for categorical variables and 1-way analysis of variance for continuous
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Table I. Demographics, clinical characteristics, and adverse event profiles of intention-to-treat patients in Comparative Study of Humira versus Methotrexate versus Placebo in Psoriasis Patients (N = 271) Characteristics
Baseline Age, y, mean (SD) Male, n (%) White, n (%) BSA affected by psoriasis, mean (SD) PASI score, mean (SD) Double-blind study period Any AE, n (%) Infection-related AEs (nonserious), n (%) AE by severity, n (%) Mild Moderate Severe AE by closest relationship to study drug, n (%) Not related Probably not related Possibly related Probably related
Placebo (n = 53)
40.7 35 49 28.4 19.2
(11.4) (66.0) (92.5) (16.1) (6.9)
MTX (n = 110)
41.6 73 105 32.4 19.4
(12.0) (66.4) (95.5) (20.6) (7.4)
ADA (n = 108)*
42.9 69 102 33.6 20.2
P value
(12.6) (64.5) (95.4) (19.9) (7.5)
.427 .955 .687 .262 .598 .355 .677 .687
42 (79.2) 23 (43.4)
90 (81.8) 46 (41.8)
79 (73.8) 51 (47.7)
27 (50.9) 14 (26.4) 1 (1.9)
60 (54.6) 26 (23.6) 4 (3.6)
52 (48.6) 26 (24.3) 1 (0.93) .345
17 (32.1) 18 (34.0) 6 (11.3) 1 (1.9)
34 26 18 12
(30.9) (23.6) (16.4) (10.9)
28 24 19 8
(26.2) (22.4) (17.8) (7.5)
ADA, Adalimumab; AE, adverse event; BSA, body surface area; MTX, methotrexate; PASI, Psoriasis Area and Severity Index. *One patient was randomized to ADA treatment (n = 108), but was withdrawn from study before receiving dose of study medication. Therefore, safety analysis included 107 patients who received ADA.
variables. The outcome measures of AE-free response days were compared among the 3 treatment arms for the 16-week study period and the first 30 days after treatment initiation. Differences between treatment groups were assessed using the Wilcoxon rank sum test for statistical significance. The level of significance was set at P less than .05. The impact of moderate to severe or mild AEs on EQ-5D scores at each visit was assessed using a longitudinal regression model that included categorical variables indicating whether a moderate to severe or mild AE was occurring on the visit date. The model was further adjusted for concurrent PASI score, duration of psoriasis, history of psoriatic arthritis, age, and sex. For each patient, every study visit from week 0 onward with an available EQ-5D assessment was considered in the analysis. Statistical inference was based on generalized estimating equations to account for correlation across multiple assessments of the same patient.
RESULTS As previously reported, baseline characteristics were well balanced across the 3 treatment groups in CHAMPION, with no significant differences noted in age, sex, race, or disease severity (percent body surface area affected by psoriasis and PASI score) (Table I).12 During the 16-week study period, 73.8%
of patients in the ADA group, 81.8% in the MTX group, and 79.2% in the placebo groups experienced at least one AE.12 Infection-related AEs occurred in 47.7% of patients in the ADA group, 41.8% in the MTX group, and 43.4% in the placebo group.12 The rate of moderate to severe AEs and drug-related AEs were 25.2% and 25.3%, respectively, in the ADA group and 27.2% and 27.3%, respectively, in the MTX group. None of these differences was statistically significant. Over the 16-week study period, the mean number of PASI 75 response days was highest for the ADAtreated patients (52.3 days) compared with MTX (13.3 days) or placebo (10.4 days) (P\.0001 for ADA vs MTX and ADA vs placebo; P = .04 for MTX vs placebo). When AEs were taken into account, the mean number of response days free of any AE was higher for ADA-treated patients (36.9 days) compared with MTX-treated patients (8.3 days, P \ .0001) and the placebo group (6.7 days, P \ .0001) (Table II). The mean number of AE-free response days did not differ significantly between the MTX and placebo groups. For ADA-treated patients, the mean numbers of response days free of moderate to severe AEs (43.8 days), free of infection-related AEs (48.5 days), and free of study drugerelated AEs (44.6 days) were all significantly greater than in the MTX group (11.1, 12.4, and 11.8 days, respectively) or the
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Table II. Comparisons of adverse eventefree response days in adalimumab, methotrexate, and placebo groups during 16-week study period and first 30 days of treatment P valuey
AE-free response d,* mean (SD) Type of AE-free response
16-wk Study period Any AEs Infectious AEs Moderate to severe AEs AEs related to study drug First 30 d of treatment Any AEs Infectious AEs Moderate to severe AEs AEs related to study drug
ADA (n = 107)
MTX (n = 110)
Placebo (n = 53)
ADA vs MTX
ADA vs placebo
MTX vs placebo
36.9 48.5 43.8 44.6
(31.1) (29.2) (31.9) (31.4)
8.3 12.4 11.1 11.8
(15.9) (21.7) (19.9) (21.1)
6.7 9.2 7.9 10.0
(18.1) (21.8) (19.9) (24.0)
\.0001 \.0001 \.0001 \.0001
\.0001 \.0001 \.0001 \.0001
.0742 .0574 .0454 .0632
1.05 1.13 1.13 1.11
(3.43) (3.43) (3.43) (3.43)
0.03 0.07 0.05 0.05
(0.29) (0.44) (0.34) (0.40)
0.08 0.08 0.08 0.08
(0.38) (0.38) (0.38) (0.38)
\.0001 \.0001 \.0001 \.0001
.0127 .0034 .0034 .0047
.2121 .7398 .4632 .4713
ADA, Adalimumab; AE, adverse event; MTX, methotrexate. *Total number of days on which patients had $ 75% improvement in Psoriasis Area and Severity Index score and were free of AEs; computed by carrying last observation forward. y Wilcoxon rank sum test.
placebo group (7.9, 9.2, and 10.0 days, respectively) (all P \ .0001) (Table II). Among all the studied benefit-risk end points, only the mean number of response days free of moderate to severe AEs was significantly different between MTX and placebo. The mean number of PASI 75 response days was also highest for ADA during the initial 30 days of treatment (1.2 days) compared with MTX (0.07 days, P \ .0001) or placebo (0.08 days, P \ .0001). The difference in PASI 75 response days between MTX and placebo was not statistically significant. Taking AEs into account, a benefit in terms of additional AEfree response days for ADA versus MTX and placebo was evident during the first 30 days of therapy: ADAtreated patients had a greater mean number of AEfree response days (1.05 days) in this period than both the MTX (0.03 days, P \ .0001) and placebo (0.08 days, P = .0127) groups. Treatment with ADA versus MTX was also associated with a greater mean number of response days free of moderate to severe AEs (1.13 vs 0.05 days, P \.0001), response days free of infection-related AEs (1.13 vs 0.07 days, P \ .0001), and response days free of study drugerelated AEs (1.11 vs 0.05 days, P \.0001). Mean number of AE-free response days did not differ significantly between ADA- and MTX-treated patients during the first 30 days. The longitudinal regression model for the effect of AEs on EQ-5D showed that patients with moderate to severe AEs experienced clinically meaningful and statistically significant mean reductions from baseline to week 16 in their EQ-5D scores (e10.97 U, P = .0039, 95% confidence interval e18.42 to e3.52), whereas such reduction was insignificant for mild AEs (0.66 U, P = .7108, 95% confidence interval e2.85 to 4.18) (Table III).
Table III. Impact of adverse events on EuroQOL-5D scores by severity: longitudinal regression analysis AE severity
Effect on mean EQ-5D score*
Mild Moderate to severe
0.66 10.97
95% CI
2.85 to 4.18 18.42 to e3.52
P value
.7108 .0039
Impact of each AE type on HRQOL was assessed using longitudinal models. AE, Adverse event; CI, confidence interval; EQ, EuroQOL. *Coefficients for recent AE covariates are reported. Negative coefficient indicates association with worse health-related quality of life (HRQOL).
DISCUSSION Traditionally, clinical studies comparing psoriasis therapies have analyzed efficacy and safety outcomes separately. Treatment comparisons are usually focused on the PASI 75 response, whereas safety end points are given a lower priority.14 However, in clinical practice, occurrence of AEs may not be independent of a patient’s clinical response to therapy, and treatments may differ in terms of how much of the AE burden falls on patients who respond versus do not respond to therapy.15 In particular, for flexibly dosed systemic therapies such as MTX, risks increase concurrently with dose such that patients with clinical response may experience a higher rate of AEs.16 Separate comparisons of average risks and benefits therefore may not accurately represent the benefit-risks tradeoffs for individual patients with psoriasis. A single composite metric that combines both safety and efficacy data can better inform clinical decision-making in psoriasis.14,15 Moderate to severe
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psoriasis can be treated with a number of therapies, including phototherapy, topical medications, conventional systemic agents, biologics, or a combination of them all.8,10 These drug classes vary widely in mode of action, efficacy, and potential toxicities, making it more complicated for clinicians to compare the benefits with risks/AEs directly. Hence, a standardized, composite risk-benefit metric, measured at the patient level, would be clinically useful and allow clinicians to balance the tradeoff between the risks (safety and tolerability) and the benefits (efficacy) of the various treatment options. This analysis chose the number of AE-free response days as a metric to compare ADA with MTX and placebo for treating moderate to severe psoriasis. Methodologically, this analysis used a novel metric to study the combination of risks and benefits at the patient level. Prior studies in other diseases, such as hypertension and depression, have used a global benefit-risk assessment to study patient-level risk and benefits.17,18 This method involves classifying patients into ordered categories according to their experience of risks and benefits ranging from the most desirable outcome (patient receives benefits with no AEs) to the least desirable outcome (patients does not benefit and experiences AEs). Global benefit-risk scores are obtained by weighting these benefit-risk categories.17 However, the choices of benefit-risk categories needed to implement this method and the weighting scheme are subjective, and sensitivity analyses are often needed to test the robustness of these components. Another frequently used measure is the number-needed-to-treat (NNT) and the number-needed-to-harm (NNH) values, which are computed by taking the reciprocal of the absolute risk difference between the experimental treatment group and placebo or another comparator treatment.15 The results are expressed as the average number of patients needed to encounter an occurrence of a treatment benefit (NNT) or treatment harm (NNH).15,19 Although NNT and NNH provide informative measures of population risks and benefits, these quantities are measured separately and cannot describe the correlation between benefits and risks that can occur, for example, when efficacy and risk are dose related.15 Therefore, combined measures of benefits and risks can complement comparisons of NNT and NNH. The AE-free response outcome studied in the current analysis combines benefits and risks at the patient level but avoids assigning weights to multiple benefit-risk categories, as in the global benefit-risk approach. By focusing on AE-free response, the ideal patient-level benefit-risk outcome, the current analysis provides a transparent comparison of risks
and benefits that may be more interpretable for patients and physicians. By measuring AE-free response days over time, the current analysis also describes the full patient experience, rather than just using a summary of efficacy at a single time point. Response free of moderate to severe AEs may be of particular interest, as moderate to severe AEs were found to reduce patients’ quality of life, as would be expected. This analysis found that treatment with ADA was associated with a superior benefit-risk profile compared with MTX or placebo through 16 weeks, and the advantage was statistically significant as early as the first 30 days of treatment. Although the absolute numbers of AE-free response days were small during the initial treatment period, reflecting the fact that many patients had not yet responded to treatment, there was a large relative difference in early benefitrisk profiles favoring ADA over MTX or placebo. During the 16-week study period, the ADA group had 4 times as many AE-free response days as the MTX and placebo groups, largely because of approximately 4 additional weeks in PASI 75 response. The other end points involving specific types of AEs also consistently favored ADA over MTX and placebo, whereas MTX did not differ significantly from placebo in most end points. These findings complement previously published studies showing superior efficacy and tolerability of ADA for treating moderate to severe psoriasis over traditional systemic therapy.12 In CHAMPION, the MTX dosing regimen started at a low dose of 7.5 mg/wk and was slowly titrated up to 25 mg/wk under careful assessment to minimize MTX-related AEs. Accordingly, the rate of AE-related discontinuation in CHAMPION was 5.5%,12 much lower than the 27.9% rate of discontinuation caused by hepatic AEs in a previous study in which MTX was started at 15 mg/wk and titrated up to 22.5 mg/wk.20 The rate of AEs observed on the MTX arm of CHAMPION therefore reflects conservative dosing. This analysis has several limitations. First, data were analyzed from a clinical trial, which may not have captured the full spectrum of AEs in the actual clinical setting.21 In particular, MTX has many known drugedrug interactions22 that could lead to a higher AE risk in real-world practice. Furthermore, because the CHAMPION trial lasted 16 weeks, some important but uncommon AEs associated with the longterm use of ADA or MTX in patients with chronic psoriasis may not be captured in the trial results. A well-designed, large-scale, long-term study can provide better insights on the safety and benefits of continuous treatment. Second, the last-observationcarried-forward method was used to impute the
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missing clinical response (PASI 75) scores between scheduled visits. Consequently, this resulted in assignment of a constant PASI 75 score between scheduled visits, which in reality could have fluctuated day by day. Nevertheless, all 3 treatment groups were treated the same to avoid any systematic biases. Third, the actual individual AEs in various treatment groups may have been different. Although efforts were made in this analysis to analyze subtypes of AEs by severity, infection, and relatedness to study drug, the AEs in each group could still have different impact on patients’ quality of life. Future analysis to better differentiate AEs and more accurately assess patients’ overall experience may allow more informative comparisons. Finally, in this analysis, benefits were described solely on the basis of efficacy comparisons between treatments. However, it is also important to measure treatment benefits by looking at improvements in patients’ HRQOL end points. Composite measures, such as the Safe Psoriasis Control, have been proposed that evaluate psoriasis treatments on multiple dimensions, including efficacy, quality of life, and safety data.14 Future studies prospectively incorporating HRQOL outcomes will be a step forward in comparing the combined benefit-risk outcomes for various psoriasis treatments.
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CONCLUSIONS This analysis demonstrated that the benefit-risk profile of ADA was superior to MTX and placebo in treating moderate to severe psoriasis. Patients treated with ADA had approximately 4 times as many AE-free response days as MTX. MTX did not differ significantly from placebo in most measures of AE-free response days. The authors thank Arbor Communications Inc, Ann Arbor, MI, for editorial support in the development of this article. REFERENCES 1. Naldi L, Griffiths CE. Traditional therapies in the management of moderate-to-severe chronic plaque psoriasis: an assessment of the benefits and risks. Br J Dermatol 2005;152:597-615. 2. Gordon KB, Langley RG, Leonardi C, Toth D, Menter MA, Kang S, et al. Clinical response to adalimumab treatment in patients with moderate-to-severe psoriasis: double-blind, randomized controlled trial and open-label extension study. J Am Acad Dermatol 2006;55:598-606. 3. National Psoriasis Foundation. Statistics. Available from: URL:http://www.psoriasis.org/about/stats/. Accessed June 9, 2009. 4. Bhosle MJ, Feldman SR, Camacho FT, Timothy Whitmire J, Nahata MC, Balkrishnan R. Medication adherence and health
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22.
care costs associated with biologics in Medicaid-enrolled patients with psoriasis. J Dermatolog Treat 2006;17:294-301. Revicki D, Willian MK, Saurat JH, Papp KA, Ortonne JP, Sexton C, et al. Impact of adalimumab treatment on health-related quality of life and other patient-reported outcomes: results from a 16-week randomized controlled trial in patients with moderate-to-severe plaque psoriasis. Br J Dermatol 2008;158: 549-57. Rapp SR, Feldman SR, Exum ML, Fleischer AB Jr, Reboussin DM. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol 1999;41:401-7. Kimball AB, Jacobson C, Weiss S, Vreeland MG, Wu Y. The psychosocial burden of psoriasis. Am J Clin Dermatol 2005;6: 383-92. Lebwohl MA. clinician’s paradigm in the treatment of psoriasis. J Am Acad Dermatol 2005;53(Suppl):S59-69. Thac¸i D. Long-term data in the treatment of psoriasis. Br J Dermatol 2008;159:18-24. McClure SL, Valentine J, Gordon KB. Comparative tolerability of systemic treatments for plaque-type psoriasis. Drug Saf 2002;25:913-27. Saini R, Tutrone WD, Weinberg JM. Advances in therapy for psoriasis: an overview of infliximab, etanercept, efalizumab, alefacept, adalimumab, tazarotene, and pimecrolimus. Curr Pharm Des 2005;11:273-80. Saurat JH, Stingl G, Dubertret L, Papp K, Langley RG, Ortonne JP, et al. CHAMPION Study Investigators. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs methotrexate vs placebo in patients with psoriasis (CHAMPION). Br J Dermatol 2008;158:558-66. Humira [package insert]. Chicago, IL: Abbott Laboratories; 2008. Papp KA, Henninger E. Safe psoriasis control: a new outcome measure for the composite assessment of the efficacy and safety of psoriasis treatment. J Cutan Med Surg 2005;9:276-83. Schulzer M, Mancini GBJ. ‘Unqualified success’ and ‘unmitigated failure’: number-needed-to-treaterelated concepts for assessing treatment efficacy in the presence of treatmentinduced adverse events. Int J Epidemiol 1996;25:704-12. Yamauchi PS, Rizk D, Kormeili T. Current systemic therapies for psoriasis: where are we now? J Am Acad Dermatol 2003; 49(Suppl):S66-77. Pritchett YL, Tamura R. Global benefit-risk assessment in designing clinical trials and some statistical considerations of the method. Pharm Stat 2008;7:170-8. Entsuah R, Gorman JM. Global benefit-risk assessment of antidepressants: venlafaxine XR and fluoxetine. J Psychiatr Res 2002;36:111-8. Osiri M, Saurez-Almazor ME, Wells GA, Robinson V, Tugwell P. Number needed to treat (NNT): implication in rheumatology clinical practice. Ann Rheum Dis 2003;62:316-21. Heydendael VM, Spuls PI, Opmeer BC, de Borgie CA, Reitsma JB, Goldschmidt WF, et al. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N Engl J Med 2003;349:658-65. Vandenbroucke JP, Psaty BM. Benefits and risks of drug treatments: how to combine the best evidence on benefits with the best data about adverse effects. JAMA 2008;300: 2417-9. National Psoriasis Foundation. Methotrexate. Available from: URL:http://www.psoriasis.org/treatment/psoriasis/systemics/ methotrexate.php. Accessed June 9, 2009.
P
soriasis is a chronic, inflammatory, multisystem disorder affecting 1% to 3% of the worldwide population, with the highest prevalence in North America and Europe.1,2 In the United States, an estimated 5.8 million to 7.5 million people have psoriasis, of whom approximately 1.5 million adults are affected by moderate to severe psoriasis.3,4 Psoriasis substantially reduces health-related quality of life (HRQOL), with impairments of physical and mental functioning that are comparable with those of patients with other chronic conditions, such as cancer, arthritis, hypertension, heart disease, diabetes, and depression.5,6 In addition, psoriasis imposes a significant economic burden. Direct medical care for psoriasis in the United States is estimated to cost from 1011
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$650 million to $4.3 billion annually after adjusting treatment of moderate to severe chronic plaque for inflation and population growth.7 psoriasis in adult patients who are candidates for The goals of psoriasis treatment are to gain initial systemic therapy or phototherapy and when other and rapid control of the disease, reduce the extent systemic therapies are medically less appropriate.13 and severity of plaque lesions, achieve and maintain To date, only one clinical trial has been published long-term remission, minimize adverse events (AEs) comparing the efficacy and safety of a biologic of treatment, and improve quality of life.8 A variety of versus an active systemic therapy for the treatment systemic treatments available of psoriasis: the Comparative for moderate to severe psoStudy of Humira versus MTX CAPSULE SUMMARY riasis can result in complete versus Placebo in Psoriasis and long-lasting clearance of Patients (CHAMPION) trial.12 A combined measure of benefits and physical symptoms, but each In this trial, ADA was associrisks may provide a more comprehensive treatment also carries a difated with a greater and more and clinically relevant comparison of ferent set of risks of AE.8 rapid reduction of psoriasis treatment options for patients with Thus, it is important for clinisymptoms compared with psoriasis. cians to evaluate treatment MTX. At the end of 16 weeks, risks and the benefits to This benefit-risk analysis compared approximately 80% of ADAachieve optimal improvement adalimumab versus methotrexate and treated patients achieved a in patients’ quality of life. placebo by rate of achieving a clinical substantial clinical response, Current pharmacotherresponse without adverse events to as indicated by a 75% or apies for moderate to severe assist patients and physicians in greater improvement in psoriasis include convenchoosing an optimal treatment for Psoriasis Area and Severity tional systemic agents and psoriasis. Index (PASI) score (PASI immunomodulating bio75). In comparison, signifiWith 4 times as many adverse logics.4 Conventional syscantly smaller percentages of eventefree response days, adalimumab temic agents considered to MTX- and placebo-treated demonstrated a superior benefit-risk be first-line treatment for patients achieved a PASI 75 profile compared with methotrexate or moderate to severe psoriasis response (36% and 19%, replacebo. include methotrexate (MTX), spectively). In addition, sigcyclosporine, retinoids, and nificantly more ADA-treated psoralen ultraviolet therapy. Although these medipatients achieved complete clearance of psoriasis cations may be effective and well tolerated for a short (100% improvement in PASI score). Overall rates of duration, they are associated with serious toxicities AEs in CHAMPION were comparable across treatthat can limit their long-term use.9 The most widely ment arms, although the frequencies of individual used systemic therapy is MTX,8 which was approved types of AEs differed. In particular, liver function by the US Food and Drug Administration (FDA) for abnormalities affected a higher percentage of patreatment of psoriasis in 1971.10 Toxicities associated tients in the MTX arm compared with the ADA and with MTX include acute hematologic toxicity, acute placebo arms. The most frequent AEs in each arm and chronic hepatotoxicity (eg, fibrosis and cirrhowere nonserious infections. There were no serious sis), lung disease, severe skin reactions, serious infections in any treatment arm and serious AEs in opportunistic infections, lymphoproliferative disorgeneral were rare, affecting less than 2% of patients ders, and severe gastrointestinal toxicity.1 In recent in each treatment arm. years, biologics targeting tumor necrosis factor have Published comparisons of treatment arms in the demonstrated efficacy in reducing psoriasis sympCHAMPION trial have reported efficacy and safety toms while causing fewer and less severe toxicities as separate outcomes. However, individual patients than MTX. Potential safety concerns regarding the may experience clinical response with or without use of such tumor necrosis factor antagonists include concurrent AEs. Because the therapeutic goal in reactivation of tuberculosis, development of other psoriasis treatment is to achieve and maintain opportunistic infections, malignancies, demyelinatclinical response with minimal AEs,8 a combined 2,11 ing diseases, and congestive heart failure. measure of benefits and risks may provide a more Adalimumab (ADA), a fully human monoclonal comprehensive and clinically relevant comparison antibody against tumor necrosis factor, has demonof treatment options. To assist patients and physistrated efficacy and tolerability in treating patients cians in choosing a treatment with the optimal with psoriasis across several randomized trials.5,12 In benefit-risk profile, the objective of this benefit-risk 2008, the FDA approved the use of ADA for analysis was to compare ADA versus MTX and d
d
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Abbreviations used: ADA: adalimumab AE: adverse event CHAMPION: Comparative Study of Humira versus Methotrexate versus Placebo in Psoriasis Patients EQ: EuroQOL FDA: Food and Drug Administration HRQOL: health-related quality of life MTX: methotrexate NNH: number needed to harm NNT: number needed to treat PASI: Psoriasis Area and Severity Index PASI 75: 75% or greater improvement in Psoriasis Area and Severity Index
placebo in terms of the rate of achieving a clinical response without AEs.
METHODS Data source The current benefit-risk analysis was conducted using data from the CHAMPION trial.12 In this 16week, multicenter, randomized, placebo-controlled, double-blind clinical trial patients with greater than or equal to 10% body surface area involvement and a PASI score of greater than or equal to 10 at baseline were randomized to 3 treatment groups: ADA subcutaneous injection 80 mg at week 0, followed by 40 mg every other week from weeks 1 through 15 (n = 108); oral MTX 7.5 to 25 mg/wk for 16 weeks (n = 110); or placebo for 16 weeks (n = 53). All patients received oral folic acid, and 24 patients received prophylactic treatment for tuberculosis during the study. The primary efficacy end point in CHAMPION was the percentage of patients achieving a PASI 75 response after 16 weeks of treatment. Patients were evaluated for PASI score at baseline and at the end of weeks 1, 2, 4, 8, 12, and 16. Safety assessments, including AEs, standard laboratory tests, and vital signs, were conducted throughout the trial and continued after week 16 through 70 days after the final dose of study drug. The details of the study design and inclusion/exclusion criteria used during CHAMPION have been previously reported.12 End points A single composite metric combining both safety and efficacy was used as the primary end point for the current benefit-risk analyses: the total number of days a patient had PASI 75 response and was free of AEs during the 16-week study period. At each day of follow-up, a patient was considered to have an AEfree response if they: (1) experienced PASI 75 response; and (2) had no active AEs. The total
Fig 1. Graphic illustration of incidence of serious adverse events (SAE ).
number of PASI 75 response days, regardless of AEs, was also studied. Missing PASI 75 response was imputed by carrying forward the PASI 75 response from the most recent study visit (last observation carried forward). To ensure that all study visits contributed substantially to the cumulative number of PASI 75 response days and AE-free response days, the last PASI 75 assessment at week 16 was carried through week 17 for all treatment arms. The time covered by an active AE was identified from the start and stop dates recorded on the AE report form. AEs with missing end dates were assumed to continue up to week 17. The total numbers of PASI 75 response days and AE-free response days during the 16-week study period were summed for each patient. Separate analyses were conducted for 3 specific AE categories: (1) response days free of moderate to severe AEs; (2) response days free of infectionrelated AEs; and (3) response days free of study drugerelated AEs. Response free of moderate to severe AEs is of particular interest because, by definition, moderate to severe AEs have a high potential to worsen patient HRQOL. Per CHAMPION study protocol, moderate AEs were defined as those causing discomfort and interrupting usual activities and severe AEs were defined as those causing considerable interference with the patient’s usual activities and those that may be incapacitating or life threatening.12 Infection-related AEs were analyzed because they are of particular clinical concern for biologic and systemic immunotherapies. Drug-related AEs were included because these events may be more likely to reflect clinically
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Fig 2. Cumulative number of any (A), infectious (B), moderate to severe (C), and study drugerelated (D) adverse event (AE )-free response days during 16-week study period. ADA, Adalimumab; MTX, methotrexate; PBO, placebo.
relevant differences between treatments. Serious AEs, defined as events that are life threatening, cause or prolong hospitalization, or require medical or surgical intervention to prevent a serious outcome, were also considered. However, because serious AEs were extremely rare in the trial across treatment arms and occurred in approximately 0.4% per patientmonth,12 the analyses of AE-free response days did not stratify by this subtype of AE (Fig 1 and 2). The impact of moderate to severe and mild AEs on HRQOL was also measured using the EuroQOL (EQ)-5D, a preference-based health status that measures the 5 dimensions of health (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression). The scores range from 0 to 1, with 0 being death and 1 being perfect health; a score may
have a value less than 0, which indicates that the health state is worse than death. The EQ-5D scores were converted to a scale of 0 to 100 for this analysis. EQ-5D was assessed at weeks 0, 12, and 16 in the CHAMPION trial.12 Statistical analysis Analyses included all randomized patients who had at least one postbaseline PASI assessment. Baseline characteristics including patient demographics (age, sex, race) and clinical characteristics (percent body surface area, PASI score) and AE rates during the 16-week study period were summarized for patients in each treatment group. Comparisons were made using x 2 tests for categorical variables and 1-way analysis of variance for continuous
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Table I. Demographics, clinical characteristics, and adverse event profiles of intention-to-treat patients in Comparative Study of Humira versus Methotrexate versus Placebo in Psoriasis Patients (N = 271) Characteristics
Baseline Age, y, mean (SD) Male, n (%) White, n (%) BSA affected by psoriasis, mean (SD) PASI score, mean (SD) Double-blind study period Any AE, n (%) Infection-related AEs (nonserious), n (%) AE by severity, n (%) Mild Moderate Severe AE by closest relationship to study drug, n (%) Not related Probably not related Possibly related Probably related
Placebo (n = 53)
40.7 35 49 28.4 19.2
(11.4) (66.0) (92.5) (16.1) (6.9)
MTX (n = 110)
41.6 73 105 32.4 19.4
(12.0) (66.4) (95.5) (20.6) (7.4)
ADA (n = 108)*
42.9 69 102 33.6 20.2
P value
(12.6) (64.5) (95.4) (19.9) (7.5)
.427 .955 .687 .262 .598 .355 .677 .687
42 (79.2) 23 (43.4)
90 (81.8) 46 (41.8)
79 (73.8) 51 (47.7)
27 (50.9) 14 (26.4) 1 (1.9)
60 (54.6) 26 (23.6) 4 (3.6)
52 (48.6) 26 (24.3) 1 (0.93) .345
17 (32.1) 18 (34.0) 6 (11.3) 1 (1.9)
34 26 18 12
(30.9) (23.6) (16.4) (10.9)
28 24 19 8
(26.2) (22.4) (17.8) (7.5)
ADA, Adalimumab; AE, adverse event; BSA, body surface area; MTX, methotrexate; PASI, Psoriasis Area and Severity Index. *One patient was randomized to ADA treatment (n = 108), but was withdrawn from study before receiving dose of study medication. Therefore, safety analysis included 107 patients who received ADA.
variables. The outcome measures of AE-free response days were compared among the 3 treatment arms for the 16-week study period and the first 30 days after treatment initiation. Differences between treatment groups were assessed using the Wilcoxon rank sum test for statistical significance. The level of significance was set at P less than .05. The impact of moderate to severe or mild AEs on EQ-5D scores at each visit was assessed using a longitudinal regression model that included categorical variables indicating whether a moderate to severe or mild AE was occurring on the visit date. The model was further adjusted for concurrent PASI score, duration of psoriasis, history of psoriatic arthritis, age, and sex. For each patient, every study visit from week 0 onward with an available EQ-5D assessment was considered in the analysis. Statistical inference was based on generalized estimating equations to account for correlation across multiple assessments of the same patient.
RESULTS As previously reported, baseline characteristics were well balanced across the 3 treatment groups in CHAMPION, with no significant differences noted in age, sex, race, or disease severity (percent body surface area affected by psoriasis and PASI score) (Table I).12 During the 16-week study period, 73.8%
of patients in the ADA group, 81.8% in the MTX group, and 79.2% in the placebo groups experienced at least one AE.12 Infection-related AEs occurred in 47.7% of patients in the ADA group, 41.8% in the MTX group, and 43.4% in the placebo group.12 The rate of moderate to severe AEs and drug-related AEs were 25.2% and 25.3%, respectively, in the ADA group and 27.2% and 27.3%, respectively, in the MTX group. None of these differences was statistically significant. Over the 16-week study period, the mean number of PASI 75 response days was highest for the ADAtreated patients (52.3 days) compared with MTX (13.3 days) or placebo (10.4 days) (P\.0001 for ADA vs MTX and ADA vs placebo; P = .04 for MTX vs placebo). When AEs were taken into account, the mean number of response days free of any AE was higher for ADA-treated patients (36.9 days) compared with MTX-treated patients (8.3 days, P \ .0001) and the placebo group (6.7 days, P \ .0001) (Table II). The mean number of AE-free response days did not differ significantly between the MTX and placebo groups. For ADA-treated patients, the mean numbers of response days free of moderate to severe AEs (43.8 days), free of infection-related AEs (48.5 days), and free of study drugerelated AEs (44.6 days) were all significantly greater than in the MTX group (11.1, 12.4, and 11.8 days, respectively) or the
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Table II. Comparisons of adverse eventefree response days in adalimumab, methotrexate, and placebo groups during 16-week study period and first 30 days of treatment P valuey
AE-free response d,* mean (SD) Type of AE-free response
16-wk Study period Any AEs Infectious AEs Moderate to severe AEs AEs related to study drug First 30 d of treatment Any AEs Infectious AEs Moderate to severe AEs AEs related to study drug
ADA (n = 107)
MTX (n = 110)
Placebo (n = 53)
ADA vs MTX
ADA vs placebo
MTX vs placebo
36.9 48.5 43.8 44.6
(31.1) (29.2) (31.9) (31.4)
8.3 12.4 11.1 11.8
(15.9) (21.7) (19.9) (21.1)
6.7 9.2 7.9 10.0
(18.1) (21.8) (19.9) (24.0)
\.0001 \.0001 \.0001 \.0001
\.0001 \.0001 \.0001 \.0001
.0742 .0574 .0454 .0632
1.05 1.13 1.13 1.11
(3.43) (3.43) (3.43) (3.43)
0.03 0.07 0.05 0.05
(0.29) (0.44) (0.34) (0.40)
0.08 0.08 0.08 0.08
(0.38) (0.38) (0.38) (0.38)
\.0001 \.0001 \.0001 \.0001
.0127 .0034 .0034 .0047
.2121 .7398 .4632 .4713
ADA, Adalimumab; AE, adverse event; MTX, methotrexate. *Total number of days on which patients had $ 75% improvement in Psoriasis Area and Severity Index score and were free of AEs; computed by carrying last observation forward. y Wilcoxon rank sum test.
placebo group (7.9, 9.2, and 10.0 days, respectively) (all P \ .0001) (Table II). Among all the studied benefit-risk end points, only the mean number of response days free of moderate to severe AEs was significantly different between MTX and placebo. The mean number of PASI 75 response days was also highest for ADA during the initial 30 days of treatment (1.2 days) compared with MTX (0.07 days, P \ .0001) or placebo (0.08 days, P \ .0001). The difference in PASI 75 response days between MTX and placebo was not statistically significant. Taking AEs into account, a benefit in terms of additional AEfree response days for ADA versus MTX and placebo was evident during the first 30 days of therapy: ADAtreated patients had a greater mean number of AEfree response days (1.05 days) in this period than both the MTX (0.03 days, P \ .0001) and placebo (0.08 days, P = .0127) groups. Treatment with ADA versus MTX was also associated with a greater mean number of response days free of moderate to severe AEs (1.13 vs 0.05 days, P \.0001), response days free of infection-related AEs (1.13 vs 0.07 days, P \ .0001), and response days free of study drugerelated AEs (1.11 vs 0.05 days, P \.0001). Mean number of AE-free response days did not differ significantly between ADA- and MTX-treated patients during the first 30 days. The longitudinal regression model for the effect of AEs on EQ-5D showed that patients with moderate to severe AEs experienced clinically meaningful and statistically significant mean reductions from baseline to week 16 in their EQ-5D scores (e10.97 U, P = .0039, 95% confidence interval e18.42 to e3.52), whereas such reduction was insignificant for mild AEs (0.66 U, P = .7108, 95% confidence interval e2.85 to 4.18) (Table III).
Table III. Impact of adverse events on EuroQOL-5D scores by severity: longitudinal regression analysis AE severity
Effect on mean EQ-5D score*
Mild Moderate to severe
0.66 10.97
95% CI
2.85 to 4.18 18.42 to e3.52
P value
.7108 .0039
Impact of each AE type on HRQOL was assessed using longitudinal models. AE, Adverse event; CI, confidence interval; EQ, EuroQOL. *Coefficients for recent AE covariates are reported. Negative coefficient indicates association with worse health-related quality of life (HRQOL).
DISCUSSION Traditionally, clinical studies comparing psoriasis therapies have analyzed efficacy and safety outcomes separately. Treatment comparisons are usually focused on the PASI 75 response, whereas safety end points are given a lower priority.14 However, in clinical practice, occurrence of AEs may not be independent of a patient’s clinical response to therapy, and treatments may differ in terms of how much of the AE burden falls on patients who respond versus do not respond to therapy.15 In particular, for flexibly dosed systemic therapies such as MTX, risks increase concurrently with dose such that patients with clinical response may experience a higher rate of AEs.16 Separate comparisons of average risks and benefits therefore may not accurately represent the benefit-risks tradeoffs for individual patients with psoriasis. A single composite metric that combines both safety and efficacy data can better inform clinical decision-making in psoriasis.14,15 Moderate to severe
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psoriasis can be treated with a number of therapies, including phototherapy, topical medications, conventional systemic agents, biologics, or a combination of them all.8,10 These drug classes vary widely in mode of action, efficacy, and potential toxicities, making it more complicated for clinicians to compare the benefits with risks/AEs directly. Hence, a standardized, composite risk-benefit metric, measured at the patient level, would be clinically useful and allow clinicians to balance the tradeoff between the risks (safety and tolerability) and the benefits (efficacy) of the various treatment options. This analysis chose the number of AE-free response days as a metric to compare ADA with MTX and placebo for treating moderate to severe psoriasis. Methodologically, this analysis used a novel metric to study the combination of risks and benefits at the patient level. Prior studies in other diseases, such as hypertension and depression, have used a global benefit-risk assessment to study patient-level risk and benefits.17,18 This method involves classifying patients into ordered categories according to their experience of risks and benefits ranging from the most desirable outcome (patient receives benefits with no AEs) to the least desirable outcome (patients does not benefit and experiences AEs). Global benefit-risk scores are obtained by weighting these benefit-risk categories.17 However, the choices of benefit-risk categories needed to implement this method and the weighting scheme are subjective, and sensitivity analyses are often needed to test the robustness of these components. Another frequently used measure is the number-needed-to-treat (NNT) and the number-needed-to-harm (NNH) values, which are computed by taking the reciprocal of the absolute risk difference between the experimental treatment group and placebo or another comparator treatment.15 The results are expressed as the average number of patients needed to encounter an occurrence of a treatment benefit (NNT) or treatment harm (NNH).15,19 Although NNT and NNH provide informative measures of population risks and benefits, these quantities are measured separately and cannot describe the correlation between benefits and risks that can occur, for example, when efficacy and risk are dose related.15 Therefore, combined measures of benefits and risks can complement comparisons of NNT and NNH. The AE-free response outcome studied in the current analysis combines benefits and risks at the patient level but avoids assigning weights to multiple benefit-risk categories, as in the global benefit-risk approach. By focusing on AE-free response, the ideal patient-level benefit-risk outcome, the current analysis provides a transparent comparison of risks
and benefits that may be more interpretable for patients and physicians. By measuring AE-free response days over time, the current analysis also describes the full patient experience, rather than just using a summary of efficacy at a single time point. Response free of moderate to severe AEs may be of particular interest, as moderate to severe AEs were found to reduce patients’ quality of life, as would be expected. This analysis found that treatment with ADA was associated with a superior benefit-risk profile compared with MTX or placebo through 16 weeks, and the advantage was statistically significant as early as the first 30 days of treatment. Although the absolute numbers of AE-free response days were small during the initial treatment period, reflecting the fact that many patients had not yet responded to treatment, there was a large relative difference in early benefitrisk profiles favoring ADA over MTX or placebo. During the 16-week study period, the ADA group had 4 times as many AE-free response days as the MTX and placebo groups, largely because of approximately 4 additional weeks in PASI 75 response. The other end points involving specific types of AEs also consistently favored ADA over MTX and placebo, whereas MTX did not differ significantly from placebo in most end points. These findings complement previously published studies showing superior efficacy and tolerability of ADA for treating moderate to severe psoriasis over traditional systemic therapy.12 In CHAMPION, the MTX dosing regimen started at a low dose of 7.5 mg/wk and was slowly titrated up to 25 mg/wk under careful assessment to minimize MTX-related AEs. Accordingly, the rate of AE-related discontinuation in CHAMPION was 5.5%,12 much lower than the 27.9% rate of discontinuation caused by hepatic AEs in a previous study in which MTX was started at 15 mg/wk and titrated up to 22.5 mg/wk.20 The rate of AEs observed on the MTX arm of CHAMPION therefore reflects conservative dosing. This analysis has several limitations. First, data were analyzed from a clinical trial, which may not have captured the full spectrum of AEs in the actual clinical setting.21 In particular, MTX has many known drugedrug interactions22 that could lead to a higher AE risk in real-world practice. Furthermore, because the CHAMPION trial lasted 16 weeks, some important but uncommon AEs associated with the longterm use of ADA or MTX in patients with chronic psoriasis may not be captured in the trial results. A well-designed, large-scale, long-term study can provide better insights on the safety and benefits of continuous treatment. Second, the last-observationcarried-forward method was used to impute the
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missing clinical response (PASI 75) scores between scheduled visits. Consequently, this resulted in assignment of a constant PASI 75 score between scheduled visits, which in reality could have fluctuated day by day. Nevertheless, all 3 treatment groups were treated the same to avoid any systematic biases. Third, the actual individual AEs in various treatment groups may have been different. Although efforts were made in this analysis to analyze subtypes of AEs by severity, infection, and relatedness to study drug, the AEs in each group could still have different impact on patients’ quality of life. Future analysis to better differentiate AEs and more accurately assess patients’ overall experience may allow more informative comparisons. Finally, in this analysis, benefits were described solely on the basis of efficacy comparisons between treatments. However, it is also important to measure treatment benefits by looking at improvements in patients’ HRQOL end points. Composite measures, such as the Safe Psoriasis Control, have been proposed that evaluate psoriasis treatments on multiple dimensions, including efficacy, quality of life, and safety data.14 Future studies prospectively incorporating HRQOL outcomes will be a step forward in comparing the combined benefit-risk outcomes for various psoriasis treatments.
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CONCLUSIONS This analysis demonstrated that the benefit-risk profile of ADA was superior to MTX and placebo in treating moderate to severe psoriasis. Patients treated with ADA had approximately 4 times as many AE-free response days as MTX. MTX did not differ significantly from placebo in most measures of AE-free response days. The authors thank Arbor Communications Inc, Ann Arbor, MI, for editorial support in the development of this article. REFERENCES 1. Naldi L, Griffiths CE. Traditional therapies in the management of moderate-to-severe chronic plaque psoriasis: an assessment of the benefits and risks. Br J Dermatol 2005;152:597-615. 2. Gordon KB, Langley RG, Leonardi C, Toth D, Menter MA, Kang S, et al. Clinical response to adalimumab treatment in patients with moderate-to-severe psoriasis: double-blind, randomized controlled trial and open-label extension study. J Am Acad Dermatol 2006;55:598-606. 3. National Psoriasis Foundation. Statistics. Available from: URL:http://www.psoriasis.org/about/stats/. Accessed June 9, 2009. 4. Bhosle MJ, Feldman SR, Camacho FT, Timothy Whitmire J, Nahata MC, Balkrishnan R. Medication adherence and health
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