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The time necessary for a treatment to become effective is crucial for patients and physicians but has been largely neglected in the reporting and comparison of clinical trials in dermatology. The aim of this systematic review is to determine the time until the onset of action (TOA) of systemic agents approved for moderate-to-severe psoriasis. Primary outcome is the TOA defined as the weighted mean time until 25% of the patients achieved a psoriasis area and severity index (PASI) 75 response. Among the biologics, infliximab has the shortest TOA (3.5 weeks), followed by ustekinumab (high dose 4.6/low dose 5.1 weeks/not weight adapted), adalimumab (4.6 weeks), etanercept (high dose 6.6/low dose 9.5 weeks), and alefacept (high dose 15.4 weeks/low dose: no data). Among the conventional treatments, good data are available for cyclosporine A (CsA; TOA: 6.0 weeks) and limited data are found for methotrexate (MTX; TOA: high dose 3.2/low dose 9.9 weeks). No data are available for fumaric acid esters and retinoids. This systematic review provides clinically relevant information on the onset of action of antipsoriatic agents, although the data currently available allow only a limited assessment. Psoriasis trials should consider including TOA as an additional outcome measure.
Abbreviations
CsA
cyclosporine A
MTX
methotrexate
PASI
psoriasis area and severity index
TOA
time until onset of action
INTRODUCTION
Different treatment options are available for the treatment of psoriasis, including topical treatments, UV therapy, and systemic treatments. For moderate or severe disease, UV treatment or systemic treatment is usually recommended (
). Many different aspects have to be considered when choosing an appropriate antipsoriatic treatment for a patient. The current guidelines suggest taking efficacy, safety, practicability for physicians and patients, as well as costs into consideration (
). However, the time necessary for a patient to achieve a significant improvement in the skin disease has been an aspect largely neglected in existing reviews and guidelines. Discreet choice experiments have shown that the time necessary to achieve moderate improvements is of large importance to the patients and it is favored over aspects such as time until relapse (
). Very acute and severe forms of psoriasis will require a treatment with a very rapid onset of action, whereas patients with a long-standing history of psoriasis with a stable disease may be more willing to accept a slow onset of action if the treatment offers other advantages or a better safety profile.
In clinical trials on psoriasis, the Psoriasis Area and Severity Index (PASI) is usually used to measure disease severity. The PASI 75 response, which means the percentage of patients achieving at least a PASI reduction of 75%, serves as an efficacy parameter in psoriasis treatment guidelines (
). Another parameter addressing changes in the PASI is the mean reduction in the PASI of all patients in the trial. A reduction in the PASI by 50% or by 75% in individual patients have been suggested and discussed as clinical meaningful outcomes (
Two considerations for patients with psoriasis and their clinicians: what defines mild, moderate, and severe psoriasis? What constitutes a clinically significant improvement when treating psoriasis?.
Estimates on how long a treatment requires to become effective can be given based on data on the course of the mean PASI or derived from the curve of the percentage of the patients achieving at least a PASI 75 response after a certain time. We aim to determine the time needed for specific antipsoriatic drugs to achieve a given treatment goal.
RESULTS
After systematic literature search and screening for eligibility, 49 studies with 66 relevant study arms on biologics (adalimumab, alefacept, etanercept, infliximab, and ustekinumab) and nonbiologic systemic monotherapies (cyclosporine A (CsA), fumaric acid esters, methotrexate (MTX), and retinoids) were included in this review (Figure 1). Alefacept, CsA, etanercept, MTX, and ustekinumab were investigated in different dosages, which were not dependent on body weight.
Figure 1Flow of information through the different phases of literature evaluation.
Of the 49 included studies, 44 were placebo controlled, verum controlled, or both placebo and verum controlled, and the remaining 5 studies were uncontrolled. As measured by the Cochrane Risk of Bias Tool, the quality of studies within each drug group ranged mainly from low to high (data available on request). Because of the low number of trials, sensitivity analysis could not be performed to evaluate bias rising from trials with different methodological quality.
The reported mean baseline PASI ranged from 13 to 32 in the study populations. Minimal washout periods of 2 weeks for low-to-moderate-potency topical steroids and of 4 weeks for systemic therapies, high-potency topical steroids, or UVB/psoralen plus UVA were stated in most of the studies. A 1-week washout period for topical treatment was reported in four study arms and a 2-week washout period for any treatment was reported in four study arms. Any information regarding washout periods was not given in almost half of the study arms. Concurrent topical treatment (emollients, low-to-mid-potency corticosteroids) was allowed in 16 of 38 study arms investigating biologics, in 2 of 3 study arms with fumaric acid esters, in 3 of 9 MTX study arms, and in 2 of 13 study arms evaluating CsA. Topical treatment was not permitted in four study arms with biologics, in three investigating MTX, in both with retinoids, and in seven study arms of CsA. No information on concurrent topical treatment was provided for 27 of all evaluated study arms. Detailed information on characteristics of the included study arms is available as Supplementary Table S1 online.
Primary outcomes—time until 25% of patients achieve PASI 75
In all, 34 study arms provided data on the time necessary for 25% of the patients to achieve a reduction in PASI of at least 75%. In the studies with adalimumab (3 study arms, n=933), time until 25% of patients achieved a PASI 75 response was 4.6 weeks (
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.
Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION).
A randomized controlled study of combination therapy with alefacept and narrow band UVB phototherapy (UVB) for moderate to severe psoriasis: efficacy, onset, and duration of response.
). During treatment with low-dose etanercept (2 × 25mg or 1 × 50mg per week), a duration of 9.5 weeks was necessary to achieve a PASI 75 response in 25% of the patients (2 study arms, n=153) (
Once weekly administration of etanercept 50 mg is efficacious and well tolerated in patients with moderate-to-severe plaque psoriasis: a randomized controlled trial with open-label extension.
A randomized, double-blind, placebo-controlled study to evaluate the addition of methotrexate to etanercept in patients with moderate to severe plaque psoriasis.
Efficacy and safety results from a phase III, randomized controlled trial comparing the safety and efficacy of briakinumab with etanercept and placebo in patients with moderate to severe chronic plaque psoriasis.
A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis.
Infliximab monotherapy in Japanese patients with moderate-to-severe plaque psoriasis and psoriatic arthritis. A randomized, double-blind, placebo-controlled multicenter trial.
Efficacy and safety of infliximab vs. methotrexate in patients with moderate-to-severe plaque psoriasis: results of an open-label, active-controlled, randomized trial (RESTORE1).
Infliximab monotherapy for Chinese patients with moderate to severe plaque psoriasis: a randomized, double-blind, placebo-controlled multicenter trial.
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.
Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION).
Efficacy and safety of infliximab vs. methotrexate in patients with moderate-to-severe plaque psoriasis: results of an open-label, active-controlled, randomized trial (RESTORE1).
). During treatment with MTX with an initial dosage of 7.5mg and an immediate increase to 15mg in the second week, the patients showed a very quick onset of action within 3.2 weeks (1 study arm, n=18) (
Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1).
Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2).
Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: a phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL).
Efficacy and safety of ustekinumab in Japanese patients with moderate-to-severe plaque-type psoriasis: long-term results from a phase 2/3 clinical trial.
Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1).
Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2).
Efficacy and safety of ustekinumab in Japanese patients with moderate-to-severe plaque-type psoriasis: long-term results from a phase 2/3 clinical trial.
A randomized, double-blind study comparing the efficacy, safety and optimal dose of two formulations of cyclosporin, Neoral and Sandimmun, in patients with severe psoriasis. OLP302 Study Group.
Combined treatment with low-dose cyclosporine and calcipotriol/betamethasone dipropionate ointment for moderate-to-severe plaque psoriasis: a randomized controlled open-label study.
). No suitable data for this outcome were available for low-dose alefacept, fumaric acid esters, and retinoids. Individual study results can be seen in Figure 2 and in the Supplementary Table S2 online.
Figure 2Time until 25% of patients achieve a PASI 75 response—distribution of the individual study results. CsA, cyclosporine A; MTX, methotrexate; PASI, psoriasis area and severity index.
Secondary outcomes—time necessary for 25% reduction in the mean initial PASI and time necessary for 50% reduction in the mean initial PASI
A total of 38 study arms provided data on the mean PASI reduction. Of these, 36 study arms were suitable for data extraction with respect to the time necessary for a mean PASI reduction by 25% and 35 study arms were suitable with respect to the time necessary for a mean PASI reduction by 50%. Results of this secondary outcome are shown in Figures 3 and 4. Detailed information on individual study results are presented in Supplementary Table S2 online.
Figure 3Time necessary for 25% reduction in the mean initial PASI—distribution of the individual study results. CsA, cyclosporine A; MTX, methotrexate; PASI, psoriasis area and severity index.
Figure 4Time necessary for 50% reduction in the mean initial PASI—distribution of the individual study results. CsA, cyclosporine A; MTX, methotrexate; PASI, psoriasis area and severity index.
In patients treated with adalimumab (1 study arm, n=108), time periods of 1.6 and 3.5 weeks were necessary to lower the mean PASI by 25% and 50%, respectively (
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.
Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION).
A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis.
). No suitable data were found for low-dose alefacept with respect to a 50% mean PASI reduction. Treatment with high-dose alefacept needed a period of 6.7 weeks to reduce the mean PASI by 25% (1 study arm, n=46) (
Clinical effectiveness and safety experience with alefacept in the treatment of patients with moderate-to-severe chronic plaque psoriasis in Taiwan: results of an open-label, single-arm, multicentre pilot study.
). In this study, a mean PASI reduction by 50% was not achieved within the whole study period of 24 weeks and no assumption could be made on how much longer it would have taken to reach this result. That is why the weighted mean PASI reduction by 50% was not calculated for high-dose alefacept, although two other study arms provided 50% mean PASI reduction data (
). During treatment with low-dose CsA, a period of 2.3 weeks was required for a 25% reduction and a period of 5.4 weeks was required for a 50% reduction in the mean PASI (8 study arms, n=359) (
A novel therapeutic approach to psoriasis with combination calcipotriol ointment and very low-dose cyclosporine: results of a multicenter placebo-controlled study.
Combined treatment with low-dose cyclosporine and calcipotriol/betamethasone dipropionate ointment for moderate-to-severe plaque psoriasis: a randomized controlled open-label study.
). Patients treated with high-dose CsA achieved a reduction in the mean PASI by 25% within a period of 1.6 weeks and a reduction in the mean PASI by 50% within a period of 3.1 weeks (4 study arms, n=211) (
Efficacy of sirolimus (rapamycin) administered concomitantly with a subtherapeutic dose of cyclosporin in the treatment of severe psoriasis: a randomized controlled trial.
). Patients treated with low-dose etanercept (3 study arms, n=811) required time periods of 3.5 and 10.9 weeks to lower the mean PASI by 25% and 50%, respectively (
Once weekly administration of etanercept 50 mg is efficacious and well tolerated in patients with moderate-to-severe plaque psoriasis: a randomized controlled trial with open-label extension.
). With high-dose etanercept, a period of 2.9 weeks was necessary for a 25% reduction and a period of 6.5 weeks was required for a 50% reduction in the mean PASI (2 study arms, n=226) (
). Fumaric acid esters (3 study arms, n=250) required a period of 3.7 weeks for a 25% reduction and a period of 8.1 weeks for a 50% reduction in the mean PASI (
Efficacy and safety profile of fumaric acid esters in oral long-term therapy with severe treatment refractory psoriasis vulgaris. A study of 83 patients.
Topical calcipotriol plus oral fumaric acid is more effective and faster acting than oral fumaric acid monotherapy in the treatment of severe chronic plaque psoriasis vulgaris.
). On treating patients with infliximab (2 study arms, n=21), a period of 1.5 weeks was necessary to achieve a PASI reduction by 25% and a period of 3.7 weeks was necessary to lower the PASI by 50% (
The effect of folic acid supplementation on the pharmacokinetics and pharmacodynamics of oral methotrexate during the remission-induction period of treatment for moderate-to-severe plaque psoriasis.
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.
Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION).
Efficacy and safety of systemic methotrexate in two fixed doses of 10 mg or 25 mg orally once weekly in adult patients with severe plaque-type psoriasis: a prospective, randomized, double-blind, dose-ranging study.
). During treatment with high-dose MTX (3 study arms, n=92), a 25% reduction in the mean PASI was achieved within a period of 1.9 weeks and a 50% reduction was achieved within a period of 3.9 weeks (
Efficacy and safety of systemic methotrexate in two fixed doses of 10 mg or 25 mg orally once weekly in adult patients with severe plaque-type psoriasis: a prospective, randomized, double-blind, dose-ranging study.
). With retinoids (acitretin), a period of 2.9 weeks was required to reduce the mean PASI by 25% reduction and a period of 6.5 weeks was required for a reduction in the mean PASI by 50% (2 study arms, n=79) (
). No suitable data were found for ustekinumab with respect to secondary outcomes.
DISCUSSION
A good knowledge of the time necessary until an antipsoriatic treatment becomes effective is important to select a treatment that corresponds to the patients’ needs and expectations.
The rapidity of the onset of a treatment has rarely been taken into consideration as a specific outcome in the clinical trials. Current guidelines do not consider time until the onset of action (TOA) as a criterion for drug selection (
Our review provides a summarized comparison of TOA between different treatments for psoriasis. For adalimumab, etanercept, infliximab, CsA, low-dose MTX, and ustekinumab, at least two study groups were available for the outcome “25% of the patients achieving a PASI 75 response.” Among biologics, infliximab needs the shortest time until a PASI 75 response is reached by 25% of the patients, followed by ustekinumab, adalimumab, etanercept, and alefacept. The results correspond well with our experiences from clinical practice. For etanercept and ustekinumab, the primary outcome could be analyzed for low and high dosages. The expected faster response on the high dosage occurs only with etanercept. The TOA results of low-dose ustekinumab do not differ from the results from study arms investigating high dosage, although the dosage in the studies was not dependent on the body weight, and the distribution of weight between the study groups was similar. As both TOA values were quite fast (by ∼5 weeks), a saturation may be reached where a dosage increase had no influence on the result anymore.
Among nonbiologics, CsA in a low dosage needs more time compared with high-dose MTX but less time compared with low-dose MTX to reach the PASI 75 response in 25% of the patients. The very fast onset seen with a dosage of 15mg per week MTX after 3.2 weeks is surprising. This result, which is based on one study only, is likely to be biased because of the very small sample size (n=18) (
), the subgroup of responders also showed a rather fast onset of action after increasing the dose, leading to a mean PASI reduction of 21.2% within a time period of 2 weeks. In a subgroup of patients who respond well to MTX, the onset of action may therefore be seen rather fast. More data are necessary to draw reliable conclusions on the onset of action of high-dose MTX. As expected, TOA for low-dose MTX is longer compared with that for high-dose MTX and corresponds well with the onset of action seen in our clinical practice. Results of low-dose CsA are based on more reliable data compared with high-dose MTX and show that CsA is faster than etanercept but needs more time to act compared with infliximab, adalimumab, or ustekinumab.
For the secondary outcome, the mean PASI reduction in all patients, more data were available. Again, infliximab, adalimumab, and ustekinumab show very fast onsets of action. CsA data on the time necessary for 25 or 50% reduction in the mean PASI support the primary outcome that patients treated with CsA also experience a fast improvement in symptoms. The possibly fast onset of action of high-dose MTX seen in the data generated for the primary outcome is corroborated in this analysis by a second trial. As seen in the primary outcome analysis, etanercept, fumaric acid esters, low-dose MTX, and alefacept required more time to act when compared with infliximab, adalimumab, and CsA for the secondary outcomes.
The data available to perform such a comparison are limited and the taken approach provides a general estimate on the TOA of the different drugs. Important methodological limitations apply. The review assumes a linear course of the PASI response between the different measured time points. Most PASI data were provided at time points in a 4-week interval, limiting precision of the estimation of the TOA. If PASI data at more frequent time points within the first weeks of treatment had been provided, the generated results could have been more precise. Another limitation associated with the approach of reading out the PASI response and corresponding time data from the graphs is that measures of variation (e.g., SD) were not available and confidence intervals of the TOA outcome could not be calculated.
To a certain extent, this analysis is influenced by the overall response rate of a drug. This applies especially to the mean PASI reduction, because the nonresponders do delay the measurable response of the responders. For this reason, the time until 25% of patients reach a PASI 75 response was chosen as the primary outcome, as the nonresponder population does not influence this part of the outcome curve. The PASI 75 response is accepted as a clinically relevant improvement and considered as an efficacy parameter in psoriasis guidelines. Our primary outcome might not be assumed as a meaningful parameter if only a quarter of patients achieve the 75% reduction in the initial PASI. The time until PASI 75 response or PASI 50 response is achieved in 50% of patients might be a more relevant indicator. However, the outcome selection was done with respect to the availability and comparability of the data in the trials, especially as with some drugs a PASI 75 response is not even achieved by 50% of the patients. The secondary outcomes, time until 25 or 50% reduction in the mean PASI, relate to clinical relevant targets, but look at the responders and nonresponders together. The 25% reduction is less affected by nonresponders than the 50% reduction, and can therefore be considered the more reliable secondary outcome. A low efficacy in many patients would be more visible in the mean PASI reduction results, whereas a small group of fast responders with many nonresponders would become more evident in the 25% PASI 75 response group.
A possible bias due to heterogeneity of the studies on the calculated TOA data cannot be excluded. Homogeneity of the trials has been tried to be assured by a comparison of the initial PASI, washout phases, and concurrent topical treatments that might influence the study outcomes. A very high initial PASI may allow for a more significant and faster reduction in the first weeks. Recently, attention has been turned to the so-called “eligibility creep,” describing a tendency of patients to have higher measured severity at initial assessment visits when eligibility is determined and inclusion criteria have to be met (
). This influences overall efficacy of the drug and also the rapidity of the onset of action. In the included study arms, patients suffered from moderate-to-severe psoriasis with differences between trials of ∼20 points in the initial PASI. Looking at the same antipsoriatic drugs, TOA results of individual studies with initial PASI ≥25 obviously do not differ from data of studies with initial PASI <25. However, because of the low number of trials for the different drugs, sensitivity analysis could not be performed and the possibility of a bias derived from this aspect has to be considered when interpreting the results.
Small differences between the studies were found in the use of concurrent topical treatment. Although in some trials any concurrent topical treatment was prohibited, several studies allowed applying emollients or corticosteroids with low to mild potency. We still considered the influence of low and moderate topical steroids on the TOA as marginal. Unfortunately, a lack of information for some trials does not allow evaluating the impact of any potent concomitant medication in the related study arms.
Reported washout phases of 2 to 4 weeks for topical and of 4 to 12 weeks for systemic therapies were quite similar. Four studies (
Efficacy and safety of systemic methotrexate in two fixed doses of 10 mg or 25 mg orally once weekly in adult patients with severe plaque-type psoriasis: a prospective, randomized, double-blind, dose-ranging study.
) differ from this approach with shorter washout periods, but it does not seem to affect the outcome as the TOA results of these studies were in the range of other studies investigating the drugs. Because of missing information in a large proportion of the included studies, potential influence of different washout phases on the results cannot be excluded.
By grouping of drugs in low and high dosages, the comparability of the study interventions should be improved. Looking at the primary and secondary outcomes, the effect of an increased dosage can be seen for all drugs by a faster TOA, with the exception of ustekinumab as mentioned before. Grouping of alefacept, CsA, etanercept, and ustekinumab follows the standard dosage regime recommended by the manufacturers, but low and high doses of MTX were defined by authors on the basis of clinical experience and can be a source of bias. However, the manufacturer’s recommendation of MTX allows a high variability in dosage regime, which could not be completely controlled by grouping. Grouping of retinoid trials by dosage was not possible because of the small number of studies. The dosage differences between the retinoid studies resulted in less comparability, which can cause some imprecision in the weighted mean of TOA.
Unfortunately, because of limited studies providing data for the different outcomes, we were not able to perform a sensitivity analysis and could not evaluate bias that arise from different study quality. However, we tried to control bias based on small trials by calculating a weighted mean, taking into account the number of patients.
So far, the TOA has been neglected as an outcome criterion in clinical trials. The right choice of a treatment that is suitable to a patient’s need is a prerequisite for adherence. As the scope of this review was to determine TOA in a first approach, we do not provide data on general efficacy and safety of systemic antipsoriatic drugs (
Efficacy and tolerability of biologic and nonbiologic systemic treatments for moderate-to-severe psoriasis: meta-analysis of randomized controlled trials.
). Existing reviews on safety and general efficacy should be used in addition to this review to complete the view on the discussed drugs. Taken together, time until onset, final improvement, and adverse events of drugs are highly relevant for therapeutic decisions and should be considered when weighting benefit and harm. However, for such a comprehensive analysis, more precise study data are necessary to draw a valid conclusion.
In summary, our review gives information on time until antipsoriatic drugs become effective. TOA should be considered as a part of the reporting of clinical trials in the future to gain more valid data. If a drug with a slow onset of action is chosen, the patient should be informed and should agree with this, or a combination treatment should be chosen, adding a fast therapy such as UV therapy or high-potency corticosteroids.
MATERIALS AND METHODS
We systemically reviewed original articles reporting on clinical trials for licensed biologic and nonbiologic systemic monotherapies for patients suffering from moderate-to-severe psoriasis vulgaris with respect to available data for TOA.
Identification of articles
All relevant trials published until November 2009 were identified using the results of the systematic search done by our group for the German S3 psoriasis guidelines (
). As alefacept was not part of the German guidelines, a complete de novo search for the time period until December 2008 was performed, with the search terms “psoriasis” and “alefacept.” We then updated both the literature searches for the dates January 2009 to 13 July 2011. The search was done using the terms “psoriasis” and “acitretin” or “adalimumab” or “alefacept” or “cyclosporine” or “etanercept” or “fumaric acid esters” or “infliximab” or “methotrexate” or “ustekinumab.” MeSH terms and title and abstracts were searched. A second update of the literature search was done on 18 October 2012 using the same search strategy (see also Figure 1). All searches were performed in Medline, Embase, and the Cochrane Library.
The selection criteria for relevant interventions for the treatment of moderate-to-severe chronic plaque psoriasis were in accordance with the German and European psoriasis guidelines (
). Studies had to be clinical trials investigating at least 10 adult patients in each treatment group with moderate-to-severe psoriasis vulgaris and were treated with one of the included systemic. The studies were included in this review if a baseline PASI of at least eight was an inclusion criterion for patients or a PASI of eight was the minimal reported initial value in the study population. Relevant outcome data (mean PASI reduction or PASI 75 response) had to be provided for at least three time points at least every 4 weeks during the observed treatment period either in tables, texts, or graphs.
Primary outcome for this systematic review was the time necessary for 25% of the patients in a trial population to achieve at least a PASI 75 response.
Secondary outcomes were the time necessary to achieve a reduction of 25% and 50% of the mean PASI in the included patient populations.
Because of the lack of sufficient data in the included trials to allow for a comparative analysis, other relevant outcomes such as PASI 90 or DLQI (Dermatology Life Quality Index) data were not further analyzed after initial check for availability.
The abstracts were independently screened by two investigators (DP and SR); differences were resolved by discussion.
Data extraction
Data extraction was done independently by two investigators (SR and BS). Differences were resolved by discussion. Whenever possible, PASI response and mean PASI reduction data were directly extracted for the relevant time points from the tables or texts of the included trials. In most cases, data were provided within graphs only. In these cases, we used Engauge Digitizer Software (http://digitizer.sourceforge.net/, accessed 5 September 2012) to read out these data from the graphs. The Engauge Software allows to match a graph with a given scale and to extract the displayed values. The software was validated performing 25 read outs on six different studies where data were provided in a graphic form as well as in tables or text (
Topical calcipotriol plus oral fumaric acid is more effective and faster acting than oral fumaric acid monotherapy in the treatment of severe chronic plaque psoriasis vulgaris.
Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1).
;). The mean deviation of the Engauge-extracted data from data provided in texts or tables is considered to be negligible (0.24% (-0.16 to 0.64)).
Only study arms with licensed dosages were considered for these analyses. For those drugs, where different dosages are licensed or commonly used, study arms were grouped according to the applied dosage in low and high doses: low-dose (7.5mg) and high-dose (15mg) alefacept; low-dose (<5mg/kg bodyweight) and high-dose (≥5mg/kg bodyweight) cyclosporine; low-dose (2 × 25 or 1 × 50mg) and high-dose (2 × 50mg) etanercept; low-dose (<15mg) and high-dose (≥15mg) MTX; and low-dose (45mg) and high-dose (90mg) ustekinumab. If dosage adjustments were performed during the course of the treatment, the dosage that was used most of the time during the time period in focus was used for the grouping.
Data analysis
A linear course of PASI response between the provided time points (e.g., between baseline and week 4) was assumed as a model for this analysis and the PASI data and their corresponding time value were used to calculate the TOA for the drugs in each trial. Study arms on the same drug and with comparable dosages providing the same outcome criteria were grouped. After checking for sufficient comparability, e.g., with respect to disease severity, the TOA data were summarized for each drug. Summarizing was done by means of calculating a weighted mean, taking into account the number of patients in every study arm. Results are presented in table form and displayed graphically.
The quality of the trials included was assessed using the Cochrane Risk of Bias Tool (
). We aimed to perform sensitivity analysis to control bias arising from trials with different methodological quality. This review was performed in accordance with the requirement set forth by the PRISMA statement (
Efficacy and safety profile of fumaric acid esters in oral long-term therapy with severe treatment refractory psoriasis vulgaris. A study of 83 patients.
Efficacy and safety of infliximab vs. methotrexate in patients with moderate-to-severe plaque psoriasis: results of an open-label, active-controlled, randomized trial (RESTORE1).
The effect of folic acid supplementation on the pharmacokinetics and pharmacodynamics of oral methotrexate during the remission-induction period of treatment for moderate-to-severe plaque psoriasis.
Efficacy and safety of systemic methotrexate in two fixed doses of 10 mg or 25 mg orally once weekly in adult patients with severe plaque-type psoriasis: a prospective, randomized, double-blind, dose-ranging study.
Topical calcipotriol plus oral fumaric acid is more effective and faster acting than oral fumaric acid monotherapy in the treatment of severe chronic plaque psoriasis vulgaris.
A randomized, double-blind, placebo-controlled study to evaluate the addition of methotrexate to etanercept in patients with moderate to severe plaque psoriasis.
A novel therapeutic approach to psoriasis with combination calcipotriol ointment and very low-dose cyclosporine: results of a multicenter placebo-controlled study.
Clinical effectiveness and safety experience with alefacept in the treatment of patients with moderate-to-severe chronic plaque psoriasis in Taiwan: results of an open-label, single-arm, multicentre pilot study.
Efficacy and safety of ustekinumab in Japanese patients with moderate-to-severe plaque-type psoriasis: long-term results from a phase 2/3 clinical trial.
A randomized, double-blind study comparing the efficacy, safety and optimal dose of two formulations of cyclosporin, Neoral and Sandimmun, in patients with severe psoriasis. OLP302 Study Group.
Two considerations for patients with psoriasis and their clinicians: what defines mild, moderate, and severe psoriasis? What constitutes a clinically significant improvement when treating psoriasis?.
A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis.
Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1).
A randomized controlled study of combination therapy with alefacept and narrow band UVB phototherapy (UVB) for moderate to severe psoriasis: efficacy, onset, and duration of response.
A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis.
Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2).
Efficacy of sirolimus (rapamycin) administered concomitantly with a subtherapeutic dose of cyclosporin in the treatment of severe psoriasis: a randomized controlled trial.
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Efficacy and safety results from a phase III, randomized controlled trial comparing the safety and efficacy of briakinumab with etanercept and placebo in patients with moderate to severe chronic plaque psoriasis.
Infliximab monotherapy in Japanese patients with moderate-to-severe plaque psoriasis and psoriatic arthritis. A randomized, double-blind, placebo-controlled multicenter trial.
Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: a phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL).
Once weekly administration of etanercept 50 mg is efficacious and well tolerated in patients with moderate-to-severe plaque psoriasis: a randomized controlled trial with open-label extension.
Combined treatment with low-dose cyclosporine and calcipotriol/betamethasone dipropionate ointment for moderate-to-severe plaque psoriasis: a randomized controlled open-label study.
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accepted article preview online 20 February 2013 published online 19 May 2013
Footnotes
AN has received honoraria for CME certified educational talks that received indirect sponsoring from Abbott, Pfizer, and Jansen Cilag. AN, BS, SR, DP, AJ, and RNW: The Division of Evidence based Medicine has received research grants from Wyeth (now Pfizer) and Abbott. JS has received research grants from Wyeth and from Novartis, honoraria for CME certified educational talks that received indirect sponsoring from Abbott and Novartis, and has received honoraria as an advisory board member from Novartis. The mentioned pharmaceutical companies did not influence this work. The selection of the primary and secondary outcomes as well as the performance of the analysis was done independently from industrial interest.
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