Biologicals in the Treatment of Plaque Psoriasis: Drug Selection by Means of the SOJA Method

The SOJA method is a model for rational drug selection. The relevant selection criteria for a certain group of drugs are defined and judged (Table 1). The more important a selection criterion is considered, the higher the relative weight that is given to that criterion. The ideal properties for each selection criterion are determined and each drug is scored as a percentage of the relative weight for all selection criteria. The criteria, which were used in the present SOJA method and the weighting of the authors, are presented below. A Medline and Embase search was performed, as well as a search for studies in the Cochrane library. As well as these searches, the references of review articles on this subject were obtained and incorporated in the analysis when appropriate. All relevant data were included in the manuscript. The drugs with the highest total score are most suitable for formulary inclusion [1].


Introduction
The treatment of plaque psoriasis is changing because of the introduction of new treatment options. The goal of this SOJA is to allow a transparent and rational choice of medicines.
The SOJA method is a model for rational drug selection. The relevant selection criteria for a certain group of drugs are defined and judged ( Table 1). The more important a selection criterion is considered, the higher the relative weight that is given to that criterion. The ideal properties for each selection criterion are determined and each drug is scored as a percentage of the relative weight for all selection criteria. The criteria, which were used in the present SOJA method and the weighting of the authors, are presented below. A Medline and Embase search was performed, as well as a search for studies in the Cochrane library. As well as these searches, the references of review articles on this subject were obtained and incorporated in the analysis when appropriate. All relevant data were included in the manuscript. The drugs with the highest total score are most suitable for formulary inclusion [1].
The following medicines were included: • Adalimumab (Humira ® ) Alefacept, which is not available in the Netherlands, was not included in the analysis.
The evaluation of the criteria in the SOJA method is highly standardized in order to promote unbiased judgement of drugs from various pharmacotherapeutic categories based on clinically relevant criteria. There will of course always be room for debate whether or not the correct scoring system was used for each criterion and judgement may be arbitrary for most, if not all, criteria. This is the case with any method used to quantify properties of drugs. The SOJA method is intended as a tool for rational drug decision making, forcing clinicians and pharmacists to include all relevant aspects of a certain group of drugs, thereby preventing formulary decisions being based on only one or two criteria. Also, possible "hidden criteria" are excluded from the decision making process. The outcome of this study should be seen as the basis for discussions within formulary committees and not as the absolute truth.

Psoriasis
Psoriasis is a frequently occurring inflammatory condition of the skin. Its prevalence in the Netherlands is estimated at 2-3%. This review focusses on plaque psoriasis, which is by far the most frequent form of psoriasis [2][3][4]. Psoriatic arthritis occurs to a much more limited extent [5].
First line therapy consists of locally acting agents, such as calcitriol, calcipotriol or class 3 or 4 corticosteroids or ditranol [3,4]. When these drugs are not sufficient, rotation therapy using the above agents can be applied [6,7]. Local therapy can be combined with narrow spectrum UV-B or acitretine. PUVA therapy is an option in case of insufficient efficacy. As the next step methotrexate or ciclosporine can be used. Both treatments may have serious adverse effects [2, 4,5,8]. Combinations may be used to optimise results [9]. The present analysis is limited to those patients in which all above agents are not effective or not tolerated [8,10,11].

Dosage frequency
Subcutaneous administration is more patient-friendly than iv administration. Twenty percent is deducted for iv infusion compared to sc.

Documentation
The score for this criterion was divided over 4 sub criteria. The first two sub criteria are indicative of the overall clinical documentation of the drugs in randomized controlled clinical studies. A large number of clinical studies and a large number of patients included in these studies leave no doubt about the clinical efficacy and safety of this drug in the studied population. The latter two criteria are indicative of the overall clinical experience with the drug. These sub criteria may introduce a bias to the advantage of older drugs, but this is done intentionally. The safety of a newly introduced drug cannot be guaranteed from the results of clinical studies, in which only a relatively small number of patients were included and most patients at risk for the development of adverse reactions (e.g. patients with diminished renal function) were excluded. Both the number of patients that has been treated on a worldwide basis and the period that a certain drug has been available are of importance, as it may take time until adverse reactions occur.

Number of randomized comparative studies
The number of randomized comparative clinical studies is an important determinant of the clinical documentation.
5% of the relative weight for this sub criterion was awarded for each randomized comparative study.

Number of patients in these studies
Besides the number of clinical studies, the number of patients that were treated with the drug in question must also be taken into consideration.
1% of the relative weight for this sub criterion was awarded for every 10 patients enrolled in randomised comparative studies.

Number of years marketed
The number of years that a product has been marketed in any country in the world provides information on the clinical experience with the drug. If a product is on the market for more than 10 years it is very unlikely that serious adverse reactions will be observed that have not been seen in the first 10 years after its introduction. 10% of the relative weight for this sub criterion was awarded for every year that the product is available on the market.

Number of patients treated worldwide
Besides the number of years that a product is on the market, also the number of patient days experience with the drug plays a role. 10% of the relative weight for this sub criterion was awarded for every million patients treated with the drug in question worldwide.

Approved indications
Adalimumab Rheumatoid arthritis: Adalimumab in combination with methotrexate is indicated for: • The treatment of moderate to severe, active rheumatoid arthritis in adult patients when the response to disease-modifying antirheumatic drugs including methotrexate has been inadequate.
• The treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate.
Adalimumab can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.
Adalimumab has been shown to reduce the rate of progression of

Polyarticular juvenile idiopathic arthritis
Adalimumab in combination with methotrexate is indicated for the treatment of active polyarticular juvenile idiopathic arthritis, in children and adolescents from the age of 2 years who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs). Adalimumab can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate. Humira has not been studied in children aged less than 2 years.

Ankylosing spondylitis (AS)
Adalimumab is indicated for the treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to conventional therapy.

Axial spondyloarthritis without radiographic evidence of AS
Adalimumab is indicated for the treatment of adults with severe axial spondyloarthritis without radiographic evidence of AS but with objective signs of inflammation by elevated CRP and / or MRI, who have had an inadequate response to, or are intolerant to Nonsteroidal anti-inflammatory drugs.

Psoriatic arthritis
Adalimumab is indicated for the treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying anti-rheumatic drug therapy has been inadequate. Adalimumab has been shown to reduce the rate of progression of peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of the disease and to improve physical function.

Psoriasis
Adalimumab is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or PUVA.

Crohn's disease
Adalimumab is indicated for treatment of moderately to severely active Crohn's disease, in adult patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/ or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies.

Pediatric Crohn's Disease
Adalimumab is indicated for the treatment of severe active Crohn's disease in paediatric patients (from 6 years of age) who have had an inadequate response to conventional therapy including primary nutrition therapy, a corticosteroid, and an immunomodulatory, or who are intolerant to or have contraindications for such therapies.

Ulcerative colitis
Adalimumab is indicated for treatment of moderately to severely active ulcerative colitis in adult patients who have had an inadequate response to conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medical contraindications for such therapies.

Etanercept
Rheumatoid arthritis: Etanercept in combination with methotrexate is indicated for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to disease-modifying antirheumatic drugs, including methotrexate (unless contraindicated), has been inadequate.
Etanercept can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.
Etanercept is also indicated in the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate.
Etanercept, alone or in combination with methotrexate, has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function.
Juvenile idiopathic arthritis: Treatment of polyarthritis (rheumatoid factor positive or negative) and extended oligoarthritis in children and adolescents from the age of 2 years who have had an inadequate response to, or who have proved intolerant of, methotrexate.
Psoriatric arthritis: Treatment of psoriatic arthritis in adolescents from the age of 12 years who have had an inadequate response to, or who have proved intolerant of, methotrexate.
Enthesis-related arthritis: Treatment of enthesitis-related arthritis in adolescents from the age of 12 years who have had an inadequate response to, or who have proved intolerant of, conventional therapy. Etanercept has not been studied in children aged less than 2 years.
Psoriatic arthritis: Treatment of active and progressive psoriatic arthritis in adults when the response to previous disease modifying antirheumatic drug therapy has been inadequate. Etanercept has been shown to improve physical function in patients with psoriatic arthritis, and to reduce the rate of progression of peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of the disease.
Ankylosing spondylitis: Treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to conventional therapy.
Plaque psoriasis: Treatment of adults with moderate to severe plaque psoriasis who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy, including ciclosporin, methotrexate or psoralen and ultraviolet-A light (PUVA).
Pediatric plaque psoriasis: Treatment of chronic severe plaque psoriasis in children and adolescents from the age of 6 years who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies.

Infliximab
Rheumatoid arthritis: Infliximab, in combination with methotrexate, is indicated for the reduction of signs and symptoms as well as the improvement in physical function in: • Adult patients with active disease when the response to disease-modifying antirheumatic drugs (DMARDs), including methotrexate, has been inadequate.
• Adult patients with severe, active and progressive disease not previously treated with methotrexate or other DMARDs.
In these patient populations, a reduction in the rate of the progression of joint damage, as measured by X-ray, has been demonstrated Adult Crohn's disease: Infliximab is indicated for: • treatment of moderately to severely active Crohn's disease, in adult patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies.
• Treatment of fistulising, active Crohn's disease, in adult patients who have not responded despite a full and adequate course of therapy with conventional treatment (including antibiotics, drainage and immunosuppressive therapy).
Pediatric Crohn's disease: Infliximab is indicated for treatment of severe, active Crohn's disease, in children and adolescents aged 6 to 17 years, who have not responded to conventional therapy including a corticosteroid, an immunomodulator and primary nutrition therapy; or who are intolerant to or have contraindications for such therapies.
Infliximab has been studied only in combination with conventional immuno-suppressive therapy.
Ulcerative colitis: Infliximab is indicated for treatment of moderately to severely active ulcerative colitis in adult patients who have had an inadequate response to conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medical contraindications for such therapies.
Pediatric ulcerative colitis: Infliximab is indicated for treatment of severely active ulcerative colitis, in children and adolescents aged 6 to 17 years, who have had an inadequate response to conventional therapy including corticosteroids and 6-MP or AZA, or who are intolerant to or have medical contraindications for such therapies.
Ankylosing spondylitis: Infliximab is indicated for treatment of severe, active ankylosing spondylitis, in adult patients who have responded inadequately to conventional therapy.
Psoriatic arthritis: Infliximab is indicated for treatment of active and progressive psoriatic arthritis in adult patients when the response to previous DMARD therapy has been inadequate.
Infliximab should be administered -In combination with methotrexate -Or alone in patients who show intolerance to methotrexate or for whom methotrexate is contraindicated Infliximab has been shown to improve physical function in patients with psoriatic arthritis, and to reduce the rate of progression of peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of the disease.
Psoriasis: Infliximab is indicated for treatment of moderate to severe plaque psoriasis in adult patients who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or PUVA.

Ustekinumab
Plaque psoriasis: Ustekinumab is indicated for the treatment of moderate to severe plaque psoriasis in adults who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapies including ciclosporin, methotrexate (MTX) and PUVA (psoralen and ultraviolet A).
Psoriatic arthritis: Ustekinimab, alone or in combination with MTX, is indicated for the treatment of active psoriatic arthritis in adult patients when the response to previous non-biological disease-modifying anti-rheumatic drug (DMARD) therapy has been inadequate.
Adalimumab and infliximab are approved for all indications and are awarded 100%. Etanercept is not approved for IBD and scores 90%. Ustekinumab is only approved for plaque psoriasis and psoriatic arthritis and scores 70%.
Interactions: Unless otherwise specified, all data are derived from the Summaries of Product Characteristics.

Adalimumab
Adalimumab has been studied in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and psoriatic arthritis patients taking adalimumab as monotherapy and those taking concomitant methotrexate. Antibody formation was lower when adalimumab was given together with methotrexate in comparison with use as monotherapy. Administration of adalimumab without methotrexate resulted in increased formation of antibodies, increased clearance and reduced efficacy of adalimumab. The combination of adalimumab and anakinra or abatacept is not recommended.

Etanercept
Concurrent treatment with anakinra: Adult patients treated with etanercept and anakinra were observed to have a higher rate of serious infection when compared with patients treated with either etanercept or anakinra alone (historical data). In addition, in a double-blind, placebocontrolled trial in adult patients receiving background methotrexate, patients treated with etanercept and anakinra were observed to have a higher rate of serious infections (7%) and neutropenia than patients treated with etanercept. The combination etanercept and anakinra has not demonstrated increased clinical benefit, and is therefore not recommended.

Concurrent treatment with abatacept:
In clinical studies, concurrent administration of abatacept and etanercept resulted in increased incidences of serious adverse events. This combination has not demonstrated increased clinical benefit; such use is not recommended.

Concurrent treatment with sulfasalazine:
In a clinical study of adult patients who were receiving established doses of sulfasalazine, to which etanercept was added, patients in the combination group experienced a statistically significant decrease in mean white blood cell counts in comparison to groups treated with etanercept or sulfasalazine alone. The clinical significance of this interaction is unknown. Physicians should use caution when considering combination therapy with sulfasalazine.

Non-interactions:
In clinical trials, no interactions have been observed when etanercept was administered with glucocorticoids, salicylates (except sulfasalazine), Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), analgesics, or methotrexate.

Infliximab: No interaction studies have been performed.
In rheumatoid arthritis, psoriatic arthritis and Crohn's disease patients, there are indications that concomitant use of methotrexate and other immunomodulators reduces the formation of antibodies against infliximab and increases the plasma concentrations of infliximab. However, the results are uncertain due to limitations in the methods used for serum analyses of infliximab and antibodies against infliximab.
Corticosteroids do not appear to affect the pharmacokinetics of infliximab to a clinically relevant extent.
The combination of infliximab with other biological therapeutics used to treat the same conditions as infliximab, including anakinra and abatacept, is not recommended.
It is recommended that live vaccines not be given concurrently with infliximab.
It is recommended that therapeutic infectious agents not be given concurrently with infliximab.
Ustekinumab: Live vaccines should not be given concurrently with ustekinumab. No interaction studies have been performed in humans. In the population pharmacokinetic analyses of the phase III studies, the effect of the most frequently used concomitant medicinal products in patients with psoriasis (including paracetamol, ibuprofen, acetylsalicylic acid, metformin, atorvastatin, levothyroxine) on pharmacokinetics of ustekinumab was explored. There were no indications of an interaction with these concomitantly administered medicinal products. The basis for this analysis was that at least 100 patients (>5% of the studied population) were treated concomitantly with these medicinal products for at least 90% of the study period. The pharmacokinetics of ustekinumab was not impacted by concomitant use of MTX, NSAIDs and oral corticosteroids, or prior exposure to anti-TNFα agents, in patients with psoriatic arthritis.
The results of an in vitro study do not suggest the need for dose adjustments in patients who are receiving concomitant CYP450 substrates.
In psoriasis studies, the safety and efficacy of ustekinumab in combination with immunosuppressants, including biologics or phototherapy have not been evaluated. In psoriatic arthritis studies, concomitant MTX use did not appear to influence the safety or efficacy of ustekinumab.
There are few, if any, drug interactions relevant for the treatment of plaque psoriasis. All medicines are awarded 90%.

Efficacy
Score for determination of efficacy: The PASI-score (Psoriasis Area and Severity Index) is the most common and most accepted score for the determination of efficacy for medicines in the treatment of plaque psoriasis. This score combines dermal symptoms: erythema, induration, desquamation (rated 0 to 4) and the percentage of the body surface area affected (rated 0 to 6). These are evaluated separately for head, trunk and the upper and lower extremities. PASI score ranges from 0 (no lesions) to 72 (most severe psoriasis). Psoriasis is considered severe when affects at least 20% of the body and/or in case of a PASIscore of at least 10.
A reduction of at least 75% in the PASI score (PASI-75) is the most usual primary endpoint in therapeutic studies in psoriasis. This reflects a clinically meaningful improvement of disease severity. Other endpoints include PASI-50 and PASI 90, as well as the percentage improvement in PASI [2]. The determination of PASI is labour intensive however, that is why other endpoints have been used in clinical trials, such as Overall Lesion Severity Scale (OLS) and Physician Global Assessment (PGA). Validated patient reported outcomes include Dermatology Life Quality Index (DLQI), visual analogue scale for the judgement of pruritis (VAS), Skindex-29 and the Psoriasis Symptom Assessment (PSA) [15][16][17]. A combined endpoint of effects on the skin, (PASI), joints (ACR) and quality of life (Euro EQ-50) has been proposed as well [18].
All biologicals have a limited indication in plaque psoriasis: "moderate to severe plaque psoriasis in adults who did not respond to other systemic therapies (methotrexate, ciclosporin or PUVA) or who have a contraindication to, or are intolerant for these drugs" and this limitation was assigned by the authorities. Most clinical studies with biologicals were however performed in another population. Only few studies were explicitly performed in patients who were pretreated with ciclosporin, methotrexate or PUVA and response to these agents was usually not described in the Materials and Methods sections of these studies. This makes is hard to judge the efficacy of biologicals in the correct population of patients ( Table 3).
The most usual inclusion criteria were: plaque psoriasis patients of 18 years or older, stable plaque psoriasis during at least 6 months, minimal PASI of 10 or 12 and at least 10% of body surface area affected by plaque psoriasis. Use of biologicals in the last 4 weeks before randomization was not allowed.

Review double-blind studies and methodology
Efficacy Adalimumab: Several studies were performed with adalimumab [19][20][21]. One study [43] was not included in the analysis because of a low number of patients per treatment arm (n=23).
The first study compared adalimumab to placebo. Patients who completed the double-blind phase could continue adalimumab in an open setting. Patients randomized in the placebo arm received an 80 mg loading dose, followed by 40 mg every two weeks. Patients could be switched to a higher dose when PASI-50 was not achieved. No differences were observed in response rates of patients with moderate and with severe plaque psoriasis. PASI-75 was reached in 64% of patients treated with the higher dose and in 56% of patients treated every two weeks [19]. A sub analysis also showed an improvement of depressive symptoms compared to placebo [44]. Adalimumab was also better than placebo in patient-reported outcomes [45].
The double-blind phase of the second study lasted 15 weeks. Patients who reached PASI-75 could continue adalimumab once every two weeks for another 17 weeks in an open-label fashion. After this, patients who were originally treated with adalimumab were rerandomized to adalimumab (n=250) or placebo (n=240) for 19 weeks [20]. The primary endpoint "loss of adequate response" was not well specified, what makes it difficult to interpret the results ( Table 4).
The third study compared adalimumab with oral methotrexate (7.5 mg titrated to 25 mg when well tolerated) and placebo during 16 weeks. Adalimumab was more effective than methotrexate on all endpoints [21] as well as quality of life [46].

Efficacy etanercept
The first study compared etanercept with placebo for 12 weeks. Patients in the etanercept group continued etanercept for another 12 weeks, whereas patients in the placebo group were changed to etanercept 25 mg twice per week in a blinded fashion [23].   [23]. PASI-75 response in the groups originally randomized to 50 mg, 25 mg or placebo twice weekly at 24 weeks was 54%, 45% and 28%, respectively. Response rates at 24 weeks were at least as good as at 12 weeks. Of patients achieving PASI-75 at 12 weeks at the higher dose, 77% maintained PASI-75 at 24 weeks after 12 weeks of treatment with the lower dose; 32% of 88 patients who did not achieve PASI-75 at 12 weeks did so at 24 weeks [23]. DLQI remained constant at 12 and 24 weeks in patients originally treated with the higher dose [41].
The fourth study also investigated effect on tiredness and depressive complaints. Depression was seen in 33% and 3% for etanercept and placebo at baseline. After 12 weeks of treatment improvement was seen in 55% and 39%, respectively. Using the Hamilton rating scale, improvement was seen in 43% and 32% [28].
In a follow-up study all patients were changed to etanercept after 12 weeks in an open label setting. Results at 24 weeks were similar for patients originally treated with etanercept or with placebo. PASI-75 at 48 weeks was 62%, whereas this was 51% at 96 weeks [49].
An analysis of studies 21 and 23 showed no major effects on PASI-75 regarding disease duration, previous treatment, presence or psoriatric arthritis and gender. A trend was observed of lower efficacy in European vs. American studies in patients with a baseline PASI of 16 or higher. A relatively poor effect was seen in patients with higher body weight (median>90 kg) [50].
Studies with etanercept included patients with moderate to severe plaque psoriasis, pretreated with systemic medicines or in whom such treatment was indicated. In the 3 studies judged by EMA [23][24][25]   A more recent study compared etanercept and placebo in children and adolescents [49]. The double blind phase lasted for 12 weeks, after which all patients received weekly etanercept for 24 weeks. At 36 weeks patients were rerandomised to study the effects of treatment cessation. One study compared etanercept 50 mg once per week with placebo for 12 weeks. The results are summarized in the Table 6. After the double-blind phase all patients received 50 mg etanercept once per week. PASI at 24 weeks values were similar in both groups. PASI-90 in patients originally treated with etanercept increased from 14% to 42% in this period [27].
Other studies compared higher (100 mg per week) and lower   (Table 7).
Etanercept was also less effective than briakinumab in a doubleblind, placebo controlled study [31].

Efficacy Infliximab
The most important results of the studies are summarized in the Table 8.
One study was too limited in size to be included and another study was excluded because it was a phase II study [52,53]. In the first study an induction therapy with three dosages of (3 mg/kg or 5 mg/kg at 0, 2 en 6 weeks was compared to placebo. An additional dose could be given in patients with a recurrence after 26 weeks. The initial results at 10 weeks were favourable. The clinical response decreased with time after 10 weeks in the 3 mg/kg group and after 14 weeks in the 5 mg/kg group. PASI-75 was about 10% in the 3 mg/kg group and 25% in the 5 mg/kg group. In patients receiving retreatment after 26 weeks, 38% and 64% in the 3 mg/kg and 5 mg/kg infliximab groups reached a PGA of less than 3, compared to 18% with placebo [33].
The second study applied a 5 mg/kg dosage at 0, 2 and 6 weeks, which was repeated every 8 weeks afterwards. Patients in the placebo group switched to infliximab at 24 weeks. Despite continued treatment, the percentage of patients with PASI-75 decreased gradually from 80% at 10 weeks to 61% at 50 weeks. PASI-50 decreased from 91% to 69% at 10 and 50 weeks, respectively. Especially patients with nondetectable trough levels and patients with high concentrations of antibodies showed a low response rate [34]. This study also showed a significant effect on nail psoriasis: 56% improvement in the infliximab group versus -3% in the placebo group at 24 weeks. Quality of life was also favourably influenced by infliximab, expressed as DLQI or SF-36. The DLQI index decreased 87% in the infliximab group versus 3% for placebo. A significant improvement was seen in all 8 SF36 subscales for infliximab compared to placebo [54].
The third study randomized patients to induction treatment with infliximab 3 mg/kg, infliximab 5 mg/kg or placebo at weeks 0, 2 and 6. Patients assigned to infliximab were rerandomised to continuous treatment (every 8 weeks) or intermittent treatment, based on complaints at 14 weeks. PASI-75 scores were 76% in the 5 mg/kg group and 70% in the 3 mg/kg group, compared to 2% for placebo at 10 weeks. PASI-90 was reached in 45%, 37% and 0.5%, respectively. Continuous treatment was more effective than intermittent therapy, with PASI-75 of 25% and 38% for intermittent use of 3 mg/kg and 5 mg/kg and 44% (3 mg/kg) and 55% (5 mg/kg) for continued use (235). Infliximab improved disease-related quality of life as well [55].
A Chinese study randomized patients to induction treatment with infliximab 5 mg/kg or placebo at weeks 0, 2, 6, 14 and 22. The primary endpoint was PASI-75 at 10 weeks. The results at 10 weeks are summarized in the Tables. PASI-75 responses increased to 93% at week 26. Subjects in the placebo group received infliximab induction therapy at week 10; PASI-75 at 26 weeks was 80% in these patients [36].
One study was not included in the analysis, because the number of patients in the placebo arm was too low [56].

Efficacy ustekinumab
The Phoenix studies compared ustekinumab 45 mg or 90 mg at time 0, at 4 weeks and every 12 weeks thereafter to placebo [37,38]. Patients in the placebo group were switched to ustekinumab 45 mg or 90 mg after 12 weeks treatment. The overall effects were judged after 28 weeks of treatment and treatment was stopped in all patients who had not achieved PASI-50 and dosage frequency was increased to every 8 weeks in all patients between PASI-50 and PASI-75. A randomized withdrawal phase started at 40 weeks.
The most important results of the studies at 12 weeks are summarized in the Table 8. PASI-75 was reached in 71% and 79% of patients treated with 45 mg and 90 mg respectively. A difference in response between both dosages was seen between the two dosages in patients originally assigned to placebo. PASI-75 was reached in 66% for the 45 mg and in 85% for 90 mg. This was also reflected in a better PASI-90: 45% vs. 62% [37]. The effects were maintained during 3 years treatment [57].
The Phoenix 2 study randomized patients showing a response between -50 and PASI-75 at 28 weeks to ustekinumab every 8 or 12 weeks. No advantage was seen for the shorter dosage interval for 45 mg, whereas a better efficacy was seen for 90 mg every 8 weeks [38].

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Ustekinumab 45 and/or 90 mg were more effective than placebo in studies with Asian patients [39,40]. In a Japanese study PASI-75 remained constant during in open label treatment of 1 year [39]. Etanercept 50 mg (n=347) twice per week was less effective than ustekinumab (45 mg (n=209) or 90 mg (n=347) at weeks 0 and 4) in a direct open-label comparative study. This study included patients with moderate to severe plaque psoriasis, 57% of patients received previous systemic therapy and 65% light therapy and 97% had used dermal treatment. Eleven percent had used previous biologicals. Baseline PASI was 19. The mean age was 45 years. The mean weight (91 kg) was rather high. The primary endpoint was PASI-75. A secondary endpoint was the fraction of patients with a clear skin or minimal lesions, judged by the physician. Patients randomized to etanercept were switched to ustekinumab after 12 weeks. PASI-75 at 12 weeks was achieved in 68% and 74% of patients treated with 45 mg and 90 mg ustekinumab, respectively vs. 57% for etanercept, p=0.01 and p<0.001, respectively). Of all patients showing insufficient response to etanercept, 49% achieved PASI-75 after 12 weeks of treatment with ustekinumab 90 mg. A clear skin was seen in 65% and 71% for both dosages of ustekunimab vs. 49% for etanercept, p<0.001 [32].

Discussion
It is difficult to draw conclusions concerning the relative clinical efficacy of the four drugs. Adalimumab has not been extensively studied in psoriasis, but appears to be effective. Etanercept showed a more limited effect concerning PASI-75 at 12 weeks. Most clinicians used PASI-50 more often in daily practice and no major differences between adalimumab and etanercept become apparent using this endpoint.
Infliximab was also more effective than etanercept, which was confirmed in two meta-analyses [58,59]. One of these analyses also showed superiority of adalimumab to etanercept [59]. One direct openlabel comparative study between ustekinumab and etanercept showed superiority of ustekinumab regarding PASI-75 [32]. Other metaanalysis concluded that ustekinunab and infliximab were the most efficacious agents, followed by adalimumab and etanercept [60][61][62]. Because only one (open label) direct comparative study was performed, these results must be interpreted with caution.
Limited data are available concerning long-term efficacy of the drugs [61,62]. The efficacy of adalimumab and infliximab seems to decrease over time [19], while there are no data indicating a decreased efficacy over time for etanercept. It should however be noted that the maximal approved treatment period for etanercept is 24 weeks. One study compared drug survival rates for adalimumab, etanercept and infliximab in patients with psoriasis vulgaris. The drug survival rates were most favourable for infliximab, followed by adalimumab and etanercept [63].

Sheets for the presentation
Safety: Safety data should be interpreted with caution, because plaque psoriasis has been linked to increased risk of the development of diabetes, cardiovascular diseases and cancer. One systematic review and meta-analysis found a pooled odds ratio for the development of diabetes of 1.53 for mild psoriasis and of 1.97 for severe psoriasis [64].
Two systematic reviews and meta-analysis investigated the association between psoriasis and adverse cardiovascular events. One study showed a significantly increased risk of myocardial infarction (RR 1.29) and stroke (RR 1.12) for mild psoriasis. For patients with severe psoriasis, an association was found with cardiovascular mortality (RR 1.39), myocardial infarction (RR 1.70) and stroke (RR 1.56) [65]. Another study was a meta-analyses of observational studies of psoriasis as study variable and cardiovascular disease and associated risk factors as outcome. The following odds ratios were found: ischaemic heart disease (1.5) and peripheral vascular disease (1.5). No significant effect on cerebrovascular disease and cardiovascular mortality was observed [66]. Another study combined plaque psoriasis and psoriatic arthritis. Increased odds ratios were found for coronary artery disease (1.19 for cross-sectional studies and 1.84 for case-control studies) [67]. So far, there are no indications that anti-TNF agents contribute to an increased cardiovascular risk in patients with plaque psoriasis [68].
Another meta-analysis found an increased risk of the development of various forms of cancer [69]. PUVA treatment increases the risk of cutaneous squamous cell carcinoma and malignant melanoma. Other treatments, methotrexate, cyclosporin and mycophenolate may be associated with increased risk of lymphoproliferative disorders. The situation is less clear concerning biologicals, but most studies suggest a slightly increased risk of non-melanoma skin cancer and lymphoma [70][71][72]. One study showed a higher incidence of lymphoma for adalimumab (SIR 4.1) and infliximab ((SIR) 3.6 than for etanercept (SIR 0.9) in patients with rheumatoid arthritis [73].
Antidrug antibodies may occur in patients treated with infliximab or adalimumab. The presence of antibodies reduce efficacy of infliximab and adalimumab in the treatment of rheumatoid arthritis. Etanerept does not give rise to the presence of anti-drug antibodies [74]. A metaanalysis of these studies showed a relationship between the presence of antibodies and infusion reactions on infliximab and hypersensitivity reactions on adalimumab [75]. Presence of antibodies is lower when the drugs are combined with methotrexate or azathioprine. This combination is usual in the treatment of rheumatoid arthritis and inflammatory bowel disease, respectively, but much less so in the treatment of psoriasis.   Limited data are available regarding safety of TNF-α blockers concerning patients with plaque psoriasis. The number of patients included in clinical studies is limited and the average duration was short compared to studies in rheumatology or inflammatory bowel disease.

Adalimumab:
In a relatively large-scale placebo-controlled study, the incidence of serious adverse events was similar to placebo. One cases each of tuberculosis and opportunistic infections were observed in 540 patient years of treatment with adalimumab [20]. The incidence of malignancies was similar to placebo, although number of nonmelanoma skin cancers (NMSC) (0.013 vs. 0.008) was numerically higher than for placebo. This should be related to the very low incidence (only 1 case in the placebo-group). No lupus-like disorders or demyelinating disorders were observed in this study [20] (Table 9).
An overview of all clinical studies with adalimumab was published in 2011. Total exposure was 370 patient years during the double-blind phases and 4844 patient years in overall adalimumab-treated patients. None of the serious adverse events, such as malignancies, opportunistic infections and congestive heart failure occurred significantly more frequent with adalimumab than with placebo. NMSC (1.35 vs. 0.58 per 100 patient years) occurred numerically higher than for placebo, but it was not stated whether this was statistically significantly different.
In the overall database, the SIR for NMSC was 1.51 (1.04-2.11) for the largest dataset. Only one case of lymphoma (0.02 per 100 patient years) was observed in adalimumab-treated patients. There were no indications for an increased risk for heart failure, lupus-like syndrome and demyelinating disorders. Serious adverse events were seen to a similar extent as for placebo (8.6 vs. 7.5 per 100 patient years). There were no indications at all that adalimumab increased mortality rates [76].
Another, more recent, study evaluated all (25,000) patients involved in clinical trials with adalimumab, of which 3,000 patients with psoriasis (5061 patient years). The results were quite similar to the above study. The incidence of serious infections (1.7 per 100 years) was lower than for rheumatoid arthritis (4.6 per 100 patient years). Active tuberculosis was seen in 0.1 per 100 years. Mortal adverse events occurred in 0.2 per 100 patient years [77].

Etanercept:
One study provided an overview of reported adverse events in clinical trials with etanercept. Serious adverse events were reported at a rate of 7.9 reports per 100 patient years (total exposure 1305 patient years). Serious infections adverse events were uncommon: 0.9 per 100 patient years. No case of tuberculosis was reported. Malignancies were reported in 0.8 per 100 patient years. Cardiovascular events were reported in 1.3 per 100 patient years, mostly myocardial infarction (0.6 per 100 patient years). No data from the placebo groups were reported [78].
Another study compared pooled etanercept and placebo groups. Serious adverse events were seen in 6.2 to 6.7 cases per 100 treatment years for etanercept vs. 9.8 for placebo. The rate of serious infections was similar to that of placebo. The standardized incidence ratios for malignancies excluding NMSC were not significantly higher than expected. The incidence of NMSC was higher than expected in the etanercept groups [79] (Table 9).
One US database study consisting of 2511 patients taking etanercept for the treatment of psoriasis showed 290 adverse events in up to 5 years. Quantitatively the most important adverse events included cellulitis and pneumonia (17 cases each), myocardial infarction [13], coronary heart disease [9], osteoarthritis [7] and angina pectoris, atrial fibrillation, cholecystitis, diverticulitis, intervertebral disk protrusion, nephrolithiasis, staphylococcal infections and death (6 cases each). The incidence of cancer was not higher than that was expected for the database population [80]. In clinical studies, patients with latent tuberculosis who were concurrently treated with isoniazid did not develop tuberculosis [81].
In the controlled and non-controlled periods of psoriasis and psoriatic arthritis clinical studies, representing 9,548 patient-years of exposure in 4,031 patients, the median follow up was 3.2 years for psoriasis studies. The rate of serious infections was 0.01 per patient-year of follow-up in ustekinumab-treated patients (104 serious infections in 9,548 patient-years of follow-up) and serious infections reported included diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis and sepsis (SPC ustekinumab).

Malignancies:
In the placebo-controlled period of the psoriasis and psoriatic arthritis clinical studies, the incidence of malignancies excluding non-melanoma skin cancer was 0.16 per 100 patient-years of follow-up for ustekinumab-treated patients (1 patient in 615 patientyears of follow-up) compared with 0.35 for placebo-treated patients (1 patient in 287 patient-years of follow-up). The incidence of nonmelanoma skin cancer was 0.65 per 100 patient-years of follow-up for ustekinumab-treated patients (4 patients in 615 pa-tient-years of follow-up) compared to 0.70 for placebo-treated patients (2 patients in 287 patient-years of follow-up) (SPC ustekinumab).
In the controlled and non-controlled periods of psoriasis and psoriatic arthritis clinical studies, representing 9,548 patient-years of exposure in 4,031 patients, the median follow-up was 1.0 year; 3.2 years for psoriasis studies and 0.5 year for psoriatic arthritis studies. Malignancies excluding non-melanoma skin cancers were reported in 54 patients in 9,530 patient-years of follow-up (incidence of 0.57 per 100 patient-years of follow-up for ustekinumab-treated patients). This incidence of malignancies reported in ustekinumab-treated patients

Hypersensitivity reactions
During the controlled periods of the psoriasis and psoriatic arthritis clinical studies of ustekinumab, rash and urticaria have each been observed in<1% of patients.
Immunogenicity: Approximately 6% of ustekinumab-treated patients in psoriasis and psoriatic arthritis clinical studies developed antibodies to ustekinumab, which were generally low-titer. No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions was observed. The majority of patients who were positive for antibodies to ustekinumab had neutralizing antibodies. Efficacy tended to be lower in patients positive for antibodies to ustekinumab; however, antibody positivity did not preclude a clinical response (SPC ustekinumab).

Cardiovascular events Ustekinumab:
An analysis of controlled clinical trials with ustekinumab showed an incidence of major cardiovascular events (MACE) of 0.44 per 100 patient years [82]. An analysis also including another IL12/23 antagonist (briakinumab) showed a significantly increased incidence of MACE vs. placebo [83]. Patients with a history of cardiovascular disease should be treated with caution [84].

Common, but non-serious adverse events
Reactions at the Injection site Adalimumab : Local reactions at the injection site (erythema, itching, bleeding, pain or swelling) were seen in 20% of adalimumabtreated patients' vs. 14% for placebo. A trend towards a lower incidence of local reactions was seen in patients also using methotrexate [85]. However, in one study in which 34% of patients also received methotrexate, injection site reactions were seen in 20% of adalumumabtreated patients vs. 12% in placebo [86]. Keystone [87] did not find a difference in the incidence of reactions in patients receiving methotrexate or not. A trend towards a gradual decrease of injection site reactions with time was observed in one study [19].
An overview of all clinical studies with adalimumab was published in 2011. Total exposure was 370 patient years during the doubleblind phases and 4844 patient years in overall adalimumab-treated patients. The incidence of adverse events was 657 per 100 patient years for adalimumab vs. 557 for placebo (no data provided concerning statistical significance). Infectious adverse events were seen more often as well: 154 vs. 115 per 100 patient years [76].

Etanercept:
One study provided an overview of reported adverse events in clinical trials with etanercept. Adverse events were reported at a rate of 243 reports per 100 patient years (total exposure 1305 patient years). Infectious adverse events had a major contribution: 97 per 100 patient years. Withdrawal due to adverse events occurred in 2.6% of patients [78].
Another study compared the incidence of adverse events in clinical trials with etanercept with placebo. The incidence of headache, injection site hemorrhage and infections was similar to placebo during short-term use. Arthralgia was observed more frequently for placebo (5-9.5 vs. 19 per 100 patient years) and fatigue was seen more often for etanercept (12-23 cases vs. 6 per 100 patient years. The total incidence of adverse events was between 550 and 650 cases per 100 patient years for all dosages of etanercept vs. 600 cases for placebo [79]. Infliximab: Infliximab was associated with an increased risk of doubling the upper normal aspartate amino transferase levels (OR 1.87) and alanine amino transferase levels (OR 1.74), whereas adalimumab and etanercept were not associated with increased liver enzyme levels. No significant effects on lipid levels or blood pressure were observed for any of the anti-TNF agents [89].
Ustekinumab: In the placebo-controlled studies of patients with psoriasis and/or psoriatic arthritis, the rates of infection or serious infection were similar between ustekinumab-treated patients and those treated with placebo: 1.27 per patient-year of follow-up in ustekinumab-treated patients, and 1.17 in placebo-treated patients (SPC ustekinumab). The most frequently reported adverse events in patients treated with ustekinumab in clinical trials were nasopharyngitis (27%), upper respiratory tract infection (22%), headache (11%), arthralgia (7%), back pain (6%), influenza (6%) and sinusitis (5%). Treatment was discontinued because of adverse events in 3%. No difference in side-effect profile was observed between 45 and 90 mg ustekinumab. Analyses of three comparative studies with ustekinumab showed no difference in the incidence of adverse events compared to placebo or etancercept [90][91][92].

Overview of adverse events in the treatment of psoriasis in placebo-controlled studies
There are no clear indications of meaningful differences in the safety profile of the medicines. All are awarded an identical score of 80%.

Dosage frequency
Documentation: De documentation concerning randomized clinical trials is summarized below (

20%
Infliximab 5 mg / kg as intravenous infusion during 2 hours, at baseline, 2 and 6 weeks and every 8 weeks thereafter. 80% Ustekinumab 45 mg subcutaneously, repeated after 4 weeks, and then every 12 weeks. 90 mg is used in patients with body weight of 100 kg or above.

SOJA score
The SOJA score is presented below Infliximab and ustekinumab show the highest scores. The choice between these compounds mainly depends on the patient's (and physician's) preference for iv or sc administration. Both medicines score better than adalimumab and etanercept concerning clinical efficacy and dosage frequency (Table 14).
Of course the final score depends on the relative weights assigned to the selection criteria and on the judgement of the medicines per criterion. The outcome of this analysis should certainly not been seen as the "truth", but much more as a starting point of a discussion on the pros and cons of the various treatment options.