These articles have been accepted for publication in the British Journal of Dermatology and are currently being edited and typeset. Readers should note that articles published below have been fully refereed, but have not been through the copy-editing and proof correction process. WileyBlackwell and the British Association of Dermatologists cannot be held responsible for errors or consequences arising from the use of information contained in these articles; nor do the views and opinions expressed necessarily reflect those of Wiley-Blackwell or the British Association of Dermatologists This article is protected by copyright. All rights reserved. Received Date : 27-Aug-2014 Revised Date : 28-Oct-2014 Accepted Date : 23-Nov-2014 Article type : Correspondence
Combining biologics with methotrexate in psoriasis: a systematic review J.S. van Bezooijen,1,2 E.P. Prens,2 M.S. Pradeepti3, R. Atiqi,4 M.W.J. Schreurs,1 B.C.P. Koch,3 T. van Gelder,1,3 M.B.A. van Doorn 2 Department of Hospital Pharmacy, 2Department of Dermatology, 3Department of Internal
1
Medicine, 4Department of Immunology, Erasmus MC, Rotterdam, the Netherlands.
Potential conflicts of interest: M. van Doorn has acted as a consultant for Abbott, Janssen, LEO Pharma and Pfizer, and has been an investigator for Eli Lilly, Idera Pharmaceuticals and Novartis. T. van Gelder has been on the speakers’ bureau or worked as consultant for Sandoz, Novartis, Astellas and Roche. E. Prens has acted as a consultant for AbbVie, AstraZeneca, Baxter, Janssen-Cilag, Novartis and Pfizer and has received investigator-initiated research grants from Pfizer, Janssen-Cilag and AbbVie.
Financial support: none
This article is protected by copyright. All rights reserved. Correspondence: J.S. van Bezooijen, Department of Dermatology and Hospital Pharmacy, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands ([email protected], phone +31 633048922). Key words: immunogenicity, psoriasis, biologics, methotrexate, combination therapy, review.
Dear Editor, Biologic drugs (‘biologics’), have revolutionized the treatment of patients with extensive and therapy-resistant psoriasis 1. Unfortunately, biologics (the anti-TNFα agents adalimumab, infliximab and etanercept, and the anti-p40(IL12/23) ustekinumab) appear to lose efficacy over time and many patients are eventually switched to another biologic 2. For the monoclonal antibody (MAb) based anti-TNFα drugs, this loss of efficacy has been partly attributed to immunogenicity. Neutralizing anti-drug antibody (ADA) formation against the biologic drug leads to inhibition of function and formation of drug-antibody complexes, resulting in accelerated clearance from the circulation 3. To overcome both these efficacy problems, the feasibility of off-label therapies that combine biologics with traditional systemic agents are being explored. However, there is insufficient evidence to suggest that these agents can significantly prevent immunogenicity in psoriasis 4. In contrast, combined treatment with MTX may improve short-term clinical efficacy and drug survival in particular. The latter effect may be due to MTX’s ability to reduce neutralizing ADA formation and thus maintain adequate biologic drug levels. However, European S3 guidelines on the systemic treatment of psoriasis do not recommend this combination therapy 5. In this letter, we review the combined therapy of biologics and MTX in psoriasis. Pivotal electronic databases were searched up to October 27th 2014 to identify studies on the combination therapy of methotrexate and biologics for the treatment of psoriasis (Fig. 1). The searches were limited to English-language articles. Two independent investigators performed a
This article is protected by copyright. All rights reserved. preliminary selection of eligible trials based on the title and abstract, followed by a second selection based on the full text (see the flow chart in Fig. 1). Any discrepancies were resolved by discussion or by referral to a third investigator. Eight studies were selected and reviewed (see Table 1). These studies generally showed that combination therapy of a biologic and MTX had higher efficacy than biologic monotherapy. Combination therapy was well tolerated and not associated with higher rates of clinically relevant adverse events. However, the following limitations of the studies reviewed should be taken into account. Firstly, most studies were performed in relatively small numbers of patients (range 11-32). The only exception was the randomized controlled trial (RCT) by Gottlieb et al., which prospectively investigated the efficacy and safety of etanercept monotherapy versus MTX combination treatment in a relatively large number of patients (239) 6. Secondly, most treatment durations were short (24 weeks) and had a retrospective design, with the inherent disadvantage that factors such as the dosing regimen and duration of treatment were not the same for individual patients. In contrast to this paucity of studies in psoriasis, large prospective studies with a long follow-up have been performed in rheumatoid arthritis (RA). These studies have shown that, when compared with biologic monotherapy, combination therapy of biologics (e.g. etanercept, adalimumab and infliximab) and MTX yields better clinical efficacy and has a comparable tolerability and safety profile
7-9
. Consequently, combination regimens with MTX are included in the EULAR
recommendations for the treatment of RA 10. From a theoretical point of view, the timing of MTX co-treatment initiation might be a factor that influences the success of combination therapy. However, there is insufficient evidence from the literature reviewed to support this concept (Table 1). There is also no consensus in the current literature on the most effective and safe dose of MTX for combination treatment. Although the longterm safety results of MTX combination therapy in RA are reassuring, the situation may not be the
This article is protected by copyright. All rights reserved. same in psoriasis because of their inherent higher risk of non-alcoholic fatty liver disease
11,12
. In
view of the results in Table 1, a MTX dose ranging from 5-15 mg/week may be considered for improving efficacy and drug survival while limiting the risk of hepatotoxicity 6,13,14 We conclude that the available evidence on combination treatment of biologics and MTX in psoriasis is currently not sufficient to propose an amendment of the current treatment guidelines. However, our findings do support the initiation of adequately powered RCTs to compare biologic monotherapy versus MTX combination therapy in psoriasis. Based on the RA studies, we propose a trial of 12-24 weeks to assess the short-term clinical outcomes, and have a follow-up of at least five years to assess long-term safety and drug survival.
References 1 Vincent FB, Morand EF, Murphy K et al. Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: A real issue, a clinical perspective. Ann Rheum Dis 2013; 72: 165-78. 2 Zandvliet ML, van Bezooijen JS, Bos MA et al. Monitoring antigen-specific biologics: current knowledge and future prospects. Ther Drug Monit 2013; 35: 588-94. 3 Carrascosa JM, van Doorn MB, Lahfa M et al. Clinical relevance of immunogenicity of biologics in psoriasis: Implications for treatment strategies. J Eur Acad Dermatol Venereol 2014. 4 Jani M, Barton A, Warren RB et al. The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases. Rheumatology (Oxford) 2013. 5 Pathirana D, Ormerod AD, Saiag P et al. European S3-guidelines on the systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol Venereol 2009; 23 Suppl 2: 1-70. 6 Gottlieb AB, Langley RG, Strober BE et al. A randomized, double-blind, placebo-controlled study to evaluate the addition of methotrexate to etanercept in patients with moderate to severe plaque psoriasis. Br J Dermatol 2012; 167: 649-57. 7 Klareskog L, van der Heijde D, de Jager JP et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004; 363: 675-81. 8 Keystone EC, van der Heijde D, Kavanaugh A et al. Clinical, Functional, and Radiographic Benefits of Longterm Adalimumab Plus Methotrexate: Final 10-year Data in Longstanding Rheumatoid Arthritis. J Rheumatol 2013. 9 St Clair EW, van der Heijde DM, Smolen JS et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 2004; 50: 3432-43. 10 Smolen JS, Landewe R, Breedveld FC et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014; 73: 492-509. 11 Gisondi P, Targher G, Zoppini G et al. Non-alcoholic fatty liver disease in patients with chronic plaque psoriasis. J Hepatol 2009; 51: 758-64.
This article is protected by copyright. All rights reserved. 12 van der Voort EA, Koehler EM, Dowlatshahi EA et al. Psoriasis is independently associated with nonalcoholic fatty liver disease in patients 55 years old or older: Results from a population-based study. J Am Acad Dermatol 2014; 70: 517-24. 13 Lopez-Ferrer A, Vilarrasa E, Gich IJ et al. Adalimumab for the treatment of psoriasis in real life: A retrospective cohort of 119 patients at a single Spanish centre. Br J Dermatol 2013; 169: 1141-7. 14 Antoniou C, Dessinioti C, Vergou T et al. Sequential treatment with biologics: Switching from efalizumab to etanercept in 35 patients with high-need psoriasis. J Eur Acad Dermatol Venereol 2010; 24: 1413-20.
This article is protected by copyright. All rights reserved. Table 1. Selected publications on combination therapy of biologics with MTX in psoriasis
Referenc e
Type study
No. of patient s with biologi c and MTX
LopezFerrer et al. Br J Dermatol 2013; 169: 1141-7
Retro
26
Mean treat ment duratio n in weeks
Biologic and MTX average dose
Timing of MTX
Efficacy
Tolerability
24
Adalimumab 40mg eow
Add-on MTX when insufficient response to adalimumab
After 24 weeks Combination group
AEs not specified for each group
spectiv e
5 –12.5 mg MTX/week2
73.5% PASI 75 67.5% PASI 90 Monotherapy group 43,5% PASI 75 34,8% PASI 90
Philipp et al. J Dtsch Dermatol Ges 2012; 10: 82137
Retro spectiv e
32
43
Adalimumab 40mg eow
20 patients received MTX concomitantly
85% PASI 50-751
12 patients received addon MTX when insufficient response to adalimumab
67% PASI 50-75 1
No serious AEs No treatmentrelated AEs
12.4±4.5 mg MTX/week
This article is protected by copyright. All rights reserved. Van den Reek et al. J Dermatolo g Treat 2013
Prospe c
Dalaker et al. J Eur Acad Dermatol Venereol 2009; 23: 277-82
Retros
Driessen et al. Br J Dermatol 2008; 159: 460-3
Prospe c
11
24
Adalimumab 40mg eow 9.5±3.2 mg MTX/week
tive
18
106
pective
Infliximab 3-5 mg/kg
Add-on MTX when insufficient response to adalimumab
After 12 weeks 9% PASI 50 After 24 weeks 18% PASI 50
MTX started concomitantly
11.66 mg MTX/week2
After 14 weeks 91.3% PASI 50 69.6% PASI 75 39.1% PASI 90
No serious AEs No treatmentrelated AEs
No serious AEs No treatmentrelated AEs
After 1 year 80% PASI 50 60% PASI 75 33.3% PASI 90
tive
14
40
Etanercept 50mg twice weekly the first 12 weeks, than 25mg twice weekly
8 patients started with MTX and received add-on etanercept
Discontinuation of MTX in 6 of these patients resulted in a decrease in clinical efficacy in 5 patients 3
12.5 mg MTX/week2
6 patients received add-on MTX when insufficient response to etanercept
67% improvement efficacy 3
No serious AEs 8 possible treatment-related AEs to MTX (gastro-intestinal complaints and liver enzyme elevation)
This article is protected by copyright. All rights reserved. Zachariae et al. Acta Derm Venereol 2008; 88: 495-501
Prospe c
31
24
tive
Etanercept 50mg twice weekly the first 12 weeks, than 25mg twice weekly
Add-on etanercept when insufficient response to MTX
After 24 weeks Combination group 76.4% PASI 75
13.4mg 2 MTX/week
Etanercept with MTX tapered treatment
50 AEs 2 serious treatment-related AEs (infection and vomiting) were considered treatment-related. (infection and
Tapered MTX group
51 AEs
51.3% PASI 75
5 serious treatment-related AEs (infection, pustular psoriasis, heart failure and atrial fibrillation)
Antoniou et al. J Eur Acad Dermatol Venereol 2010; 24: 1413-20
Retro
Gottlieb et
Prospe
11
24
spectiv e
Etanercept 50mg twice weekly the first 12 weeks, than 25mg twice weekly
MTX started concomitantly
Combination group 36.4% PASI 75 27.2% PASI 50
15 mg MTX/week2
239
24
Etanercept 50mg
After 24 weeks
AEs not specified for each group
Monotherapy group 41.7% PASI 75 8.3% PASI 50 MTX started concomitantly
After 12 weeks
Combination
This article is protected by copyright. All rights reserved. al. Br J Dermatol 2012; 167: 649-57
c tive
twice weekly the first 12 weeks, than 50mg once weekly MTX ranging 7.515mg/ week 2
Combination group 70.2% PASI 75 Monotherapy group 54.3% PASI 75 After 24 weeks Combination group 77.3% PASI 75 Monotherapy group 60.3% PASI 75
group 179 AE 3 serious AEs (lumbar spinal stenosis, synovial cyst and bacterial pneumonia) 7 treatmentrelated AEs (liver enzyme elevation) Monotherapy group 143 AE 3 serious AEs (asthma, cholecystitis and myocardial infarction) 4 treatmentrelated AEs (liver enzyme elevation)
eow, every other week; PASI, Psoriasis Activity Severity Index; AE; Adverse Events
This article is protected by copyright. All rights reserved. 1
The average time period of achieving PASI 50-75 is not mentioned in the original paper.
2
Standard deviation not reported.
3
Specific PASI score were not mentioned.
This article is protected by copyright. All rights reserved. Fig. 1 Flowchart of the search and selection process. IDENTIFICATION – Embase, Medline, Cochrane Central, PubMed and Web of Science
Inclusion criteria: Types of patients: • Adults (≥18 years) with psoriasis vulgaris
Exclusion criteria: N = 2309 Other forms of psoriasis: • Erythrodermic psoriasis • Pustular psoriasis • Psoriatic arthritis
Types of intervention: • Combination biologic and MTX • Dose of biologics stated • Dose of MTX stated • Treatment duration stated
Types of studies: • Reviews • Guidelines • Case reports • Case series
Combining biologics with methotrexate in psoriasis: a systematic review J.S. van Bezooijen,1,2 E.P. Prens,2 M.S. Pradeepti3, R. Atiqi,4 M.W.J. Schreurs,1 B.C.P. Koch,3 T. van Gelder,1,3 M.B.A. van Doorn 2 Department of Hospital Pharmacy, 2Department of Dermatology, 3Department of Internal
1
Medicine, 4Department of Immunology, Erasmus MC, Rotterdam, the Netherlands.
Potential conflicts of interest: M. van Doorn has acted as a consultant for Abbott, Janssen, LEO Pharma and Pfizer, and has been an investigator for Eli Lilly, Idera Pharmaceuticals and Novartis. T. van Gelder has been on the speakers’ bureau or worked as consultant for Sandoz, Novartis, Astellas and Roche. E. Prens has acted as a consultant for AbbVie, AstraZeneca, Baxter, Janssen-Cilag, Novartis and Pfizer and has received investigator-initiated research grants from Pfizer, Janssen-Cilag and AbbVie.
Financial support: none
This article is protected by copyright. All rights reserved. Correspondence: J.S. van Bezooijen, Department of Dermatology and Hospital Pharmacy, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands ([email protected], phone +31 633048922). Key words: immunogenicity, psoriasis, biologics, methotrexate, combination therapy, review.
Dear Editor, Biologic drugs (‘biologics’), have revolutionized the treatment of patients with extensive and therapy-resistant psoriasis 1. Unfortunately, biologics (the anti-TNFα agents adalimumab, infliximab and etanercept, and the anti-p40(IL12/23) ustekinumab) appear to lose efficacy over time and many patients are eventually switched to another biologic 2. For the monoclonal antibody (MAb) based anti-TNFα drugs, this loss of efficacy has been partly attributed to immunogenicity. Neutralizing anti-drug antibody (ADA) formation against the biologic drug leads to inhibition of function and formation of drug-antibody complexes, resulting in accelerated clearance from the circulation 3. To overcome both these efficacy problems, the feasibility of off-label therapies that combine biologics with traditional systemic agents are being explored. However, there is insufficient evidence to suggest that these agents can significantly prevent immunogenicity in psoriasis 4. In contrast, combined treatment with MTX may improve short-term clinical efficacy and drug survival in particular. The latter effect may be due to MTX’s ability to reduce neutralizing ADA formation and thus maintain adequate biologic drug levels. However, European S3 guidelines on the systemic treatment of psoriasis do not recommend this combination therapy 5. In this letter, we review the combined therapy of biologics and MTX in psoriasis. Pivotal electronic databases were searched up to October 27th 2014 to identify studies on the combination therapy of methotrexate and biologics for the treatment of psoriasis (Fig. 1). The searches were limited to English-language articles. Two independent investigators performed a
This article is protected by copyright. All rights reserved. preliminary selection of eligible trials based on the title and abstract, followed by a second selection based on the full text (see the flow chart in Fig. 1). Any discrepancies were resolved by discussion or by referral to a third investigator. Eight studies were selected and reviewed (see Table 1). These studies generally showed that combination therapy of a biologic and MTX had higher efficacy than biologic monotherapy. Combination therapy was well tolerated and not associated with higher rates of clinically relevant adverse events. However, the following limitations of the studies reviewed should be taken into account. Firstly, most studies were performed in relatively small numbers of patients (range 11-32). The only exception was the randomized controlled trial (RCT) by Gottlieb et al., which prospectively investigated the efficacy and safety of etanercept monotherapy versus MTX combination treatment in a relatively large number of patients (239) 6. Secondly, most treatment durations were short (24 weeks) and had a retrospective design, with the inherent disadvantage that factors such as the dosing regimen and duration of treatment were not the same for individual patients. In contrast to this paucity of studies in psoriasis, large prospective studies with a long follow-up have been performed in rheumatoid arthritis (RA). These studies have shown that, when compared with biologic monotherapy, combination therapy of biologics (e.g. etanercept, adalimumab and infliximab) and MTX yields better clinical efficacy and has a comparable tolerability and safety profile
7-9
. Consequently, combination regimens with MTX are included in the EULAR
recommendations for the treatment of RA 10. From a theoretical point of view, the timing of MTX co-treatment initiation might be a factor that influences the success of combination therapy. However, there is insufficient evidence from the literature reviewed to support this concept (Table 1). There is also no consensus in the current literature on the most effective and safe dose of MTX for combination treatment. Although the longterm safety results of MTX combination therapy in RA are reassuring, the situation may not be the
This article is protected by copyright. All rights reserved. same in psoriasis because of their inherent higher risk of non-alcoholic fatty liver disease
11,12
. In
view of the results in Table 1, a MTX dose ranging from 5-15 mg/week may be considered for improving efficacy and drug survival while limiting the risk of hepatotoxicity 6,13,14 We conclude that the available evidence on combination treatment of biologics and MTX in psoriasis is currently not sufficient to propose an amendment of the current treatment guidelines. However, our findings do support the initiation of adequately powered RCTs to compare biologic monotherapy versus MTX combination therapy in psoriasis. Based on the RA studies, we propose a trial of 12-24 weeks to assess the short-term clinical outcomes, and have a follow-up of at least five years to assess long-term safety and drug survival.
References 1 Vincent FB, Morand EF, Murphy K et al. Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: A real issue, a clinical perspective. Ann Rheum Dis 2013; 72: 165-78. 2 Zandvliet ML, van Bezooijen JS, Bos MA et al. Monitoring antigen-specific biologics: current knowledge and future prospects. Ther Drug Monit 2013; 35: 588-94. 3 Carrascosa JM, van Doorn MB, Lahfa M et al. Clinical relevance of immunogenicity of biologics in psoriasis: Implications for treatment strategies. J Eur Acad Dermatol Venereol 2014. 4 Jani M, Barton A, Warren RB et al. The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases. Rheumatology (Oxford) 2013. 5 Pathirana D, Ormerod AD, Saiag P et al. European S3-guidelines on the systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol Venereol 2009; 23 Suppl 2: 1-70. 6 Gottlieb AB, Langley RG, Strober BE et al. A randomized, double-blind, placebo-controlled study to evaluate the addition of methotrexate to etanercept in patients with moderate to severe plaque psoriasis. Br J Dermatol 2012; 167: 649-57. 7 Klareskog L, van der Heijde D, de Jager JP et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004; 363: 675-81. 8 Keystone EC, van der Heijde D, Kavanaugh A et al. Clinical, Functional, and Radiographic Benefits of Longterm Adalimumab Plus Methotrexate: Final 10-year Data in Longstanding Rheumatoid Arthritis. J Rheumatol 2013. 9 St Clair EW, van der Heijde DM, Smolen JS et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 2004; 50: 3432-43. 10 Smolen JS, Landewe R, Breedveld FC et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014; 73: 492-509. 11 Gisondi P, Targher G, Zoppini G et al. Non-alcoholic fatty liver disease in patients with chronic plaque psoriasis. J Hepatol 2009; 51: 758-64.
This article is protected by copyright. All rights reserved. 12 van der Voort EA, Koehler EM, Dowlatshahi EA et al. Psoriasis is independently associated with nonalcoholic fatty liver disease in patients 55 years old or older: Results from a population-based study. J Am Acad Dermatol 2014; 70: 517-24. 13 Lopez-Ferrer A, Vilarrasa E, Gich IJ et al. Adalimumab for the treatment of psoriasis in real life: A retrospective cohort of 119 patients at a single Spanish centre. Br J Dermatol 2013; 169: 1141-7. 14 Antoniou C, Dessinioti C, Vergou T et al. Sequential treatment with biologics: Switching from efalizumab to etanercept in 35 patients with high-need psoriasis. J Eur Acad Dermatol Venereol 2010; 24: 1413-20.
This article is protected by copyright. All rights reserved. Table 1. Selected publications on combination therapy of biologics with MTX in psoriasis
Referenc e
Type study
No. of patient s with biologi c and MTX
LopezFerrer et al. Br J Dermatol 2013; 169: 1141-7
Retro
26
Mean treat ment duratio n in weeks
Biologic and MTX average dose
Timing of MTX
Efficacy
Tolerability
24
Adalimumab 40mg eow
Add-on MTX when insufficient response to adalimumab
After 24 weeks Combination group
AEs not specified for each group
spectiv e
5 –12.5 mg MTX/week2
73.5% PASI 75 67.5% PASI 90 Monotherapy group 43,5% PASI 75 34,8% PASI 90
Philipp et al. J Dtsch Dermatol Ges 2012; 10: 82137
Retro spectiv e
32
43
Adalimumab 40mg eow
20 patients received MTX concomitantly
85% PASI 50-751
12 patients received addon MTX when insufficient response to adalimumab
67% PASI 50-75 1
No serious AEs No treatmentrelated AEs
12.4±4.5 mg MTX/week
This article is protected by copyright. All rights reserved. Van den Reek et al. J Dermatolo g Treat 2013
Prospe c
Dalaker et al. J Eur Acad Dermatol Venereol 2009; 23: 277-82
Retros
Driessen et al. Br J Dermatol 2008; 159: 460-3
Prospe c
11
24
Adalimumab 40mg eow 9.5±3.2 mg MTX/week
tive
18
106
pective
Infliximab 3-5 mg/kg
Add-on MTX when insufficient response to adalimumab
After 12 weeks 9% PASI 50 After 24 weeks 18% PASI 50
MTX started concomitantly
11.66 mg MTX/week2
After 14 weeks 91.3% PASI 50 69.6% PASI 75 39.1% PASI 90
No serious AEs No treatmentrelated AEs
No serious AEs No treatmentrelated AEs
After 1 year 80% PASI 50 60% PASI 75 33.3% PASI 90
tive
14
40
Etanercept 50mg twice weekly the first 12 weeks, than 25mg twice weekly
8 patients started with MTX and received add-on etanercept
Discontinuation of MTX in 6 of these patients resulted in a decrease in clinical efficacy in 5 patients 3
12.5 mg MTX/week2
6 patients received add-on MTX when insufficient response to etanercept
67% improvement efficacy 3
No serious AEs 8 possible treatment-related AEs to MTX (gastro-intestinal complaints and liver enzyme elevation)
This article is protected by copyright. All rights reserved. Zachariae et al. Acta Derm Venereol 2008; 88: 495-501
Prospe c
31
24
tive
Etanercept 50mg twice weekly the first 12 weeks, than 25mg twice weekly
Add-on etanercept when insufficient response to MTX
After 24 weeks Combination group 76.4% PASI 75
13.4mg 2 MTX/week
Etanercept with MTX tapered treatment
50 AEs 2 serious treatment-related AEs (infection and vomiting) were considered treatment-related. (infection and
Tapered MTX group
51 AEs
51.3% PASI 75
5 serious treatment-related AEs (infection, pustular psoriasis, heart failure and atrial fibrillation)
Antoniou et al. J Eur Acad Dermatol Venereol 2010; 24: 1413-20
Retro
Gottlieb et
Prospe
11
24
spectiv e
Etanercept 50mg twice weekly the first 12 weeks, than 25mg twice weekly
MTX started concomitantly
Combination group 36.4% PASI 75 27.2% PASI 50
15 mg MTX/week2
239
24
Etanercept 50mg
After 24 weeks
AEs not specified for each group
Monotherapy group 41.7% PASI 75 8.3% PASI 50 MTX started concomitantly
After 12 weeks
Combination
This article is protected by copyright. All rights reserved. al. Br J Dermatol 2012; 167: 649-57
c tive
twice weekly the first 12 weeks, than 50mg once weekly MTX ranging 7.515mg/ week 2
Combination group 70.2% PASI 75 Monotherapy group 54.3% PASI 75 After 24 weeks Combination group 77.3% PASI 75 Monotherapy group 60.3% PASI 75
group 179 AE 3 serious AEs (lumbar spinal stenosis, synovial cyst and bacterial pneumonia) 7 treatmentrelated AEs (liver enzyme elevation) Monotherapy group 143 AE 3 serious AEs (asthma, cholecystitis and myocardial infarction) 4 treatmentrelated AEs (liver enzyme elevation)
eow, every other week; PASI, Psoriasis Activity Severity Index; AE; Adverse Events
This article is protected by copyright. All rights reserved. 1
The average time period of achieving PASI 50-75 is not mentioned in the original paper.
2
Standard deviation not reported.
3
Specific PASI score were not mentioned.
This article is protected by copyright. All rights reserved. Fig. 1 Flowchart of the search and selection process. IDENTIFICATION – Embase, Medline, Cochrane Central, PubMed and Web of Science
Inclusion criteria: Types of patients: • Adults (≥18 years) with psoriasis vulgaris
Exclusion criteria: N = 2309 Other forms of psoriasis: • Erythrodermic psoriasis • Pustular psoriasis • Psoriatic arthritis
Types of intervention: • Combination biologic and MTX • Dose of biologics stated • Dose of MTX stated • Treatment duration stated
Types of studies: • Reviews • Guidelines • Case reports • Case series
