Efficacy of several biological therapies for treating moderate to severe psoriasis: A network meta‑analysis
- Authors:
- Published online on: October 15, 2018 https://doi.org/10.3892/etm.2018.6859
- Pages: 5085-5095
-
Copyright: © Geng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Psoriasis is a common immune-mediated skin disease. The prevalence of psoriasis in adults ranges between 0.91 and 8.5% worldwide and the incidence of psoriasis is higher in adults than in children (1). Psoriasis is characterized by symptoms of plaque, pustular and other skin lesions. Chronic plaque psoriasis accounts for 90% of all psoriasis cases (2,3).
A number of biological therapies are used to treat moderate to severe psoriasis, including etanercept, briakinumab, ustekinumab, adalimumab and infliximab (4–8). Etanercept, adalimumab and infliximab are monoclonal antibodies against tumor necrosis factor (TNF), which function by neutralizing the biological activity of TNF for treating the TNF-mediated inflammation (5,9). By contrast, ustekinumab and briakinumab are human monoclonal antibodies against interleukin (IL)-12/23p40 (8). These biological therapies are used to treat psoriasis and improved clinical outcomes have been observed. However, the efficacy of these therapies has been not systematically reviewed.
In the present study, a network meta-analysis was performed to review and compare the efficacy of these aforementioned biological therapies of psoriasis. The Psoriasis Area and Severity Index (PASI) response (10) was used as an indicator for assessing the effect of treatment on the severity of psoriasis. PASI 50, PASI 75 and PASI 90 responses for the therapies were systematically assessed. The pooled results provide further information on selecting the most suitable treatments for moderate to severe psoriasis.
Materials and methods
Data sources
The PubMed (www.ncbi.nlm.nih.gov/pubmed) and Embase (www.elsevier.com/solutions/embase-biomedical-research) databases were systematically searched in order to select relevant studies up to February 2015. The search terms included the following: Psoriasis, methotrexate (MTX), cyclosporin A (CSA), ustekinumab, etanercept, infliximab, briakinumab and adalimumab.
Inclusion and exclusion criteria
Studies with the following characteristics were included in the current meta-analysis: i) Randomized controlled trials (RCTs) reporting the treatment of moderate to severe psoriasis with the aforementioned drugs. Moderate to severe psoriasis is defined as body surface area >10 or psoriasis area and severity index >10 and dermatology life quality index >10 (11); ii) studies including the adults as participants; and iii) studies reporting the PASI response rate (50, 75 and 90%). Any reviews, case reports and letters were excluded from the meta-analysis. Any studies investigating patients with mild psoriasis and those written in a language other than English were also excluded.
Data extraction and quality assessment
Two reviewers independently extracted the following data: The name of the first author, publication year, sample size, intervention, demographic characteristics of the included patients and PASI response rate. The controversies were discussed with a third reviewer to reach consensus. The methodological quality of the included studies was evaluated by the Cochrane Collaboration Risk of Bias Tool (12).
Statistical analysis
All analyses were performed using the ADDIS software version 1.16.5 (Drug Information and Monitoring Systems, Groningen, The Netherlands). Odds ratios (ORs) and their 95% confidence intervals (CIs) were pooled. The network analysis performed was based on the Bayesian framework. Data were evaluated by Markov chain Monte Carlo methods and all analyses were performed using the random effects model. The consistency of the RCTs was assessed by Node-splitting analysis, and the consistency model was used if P>0.05. Otherwise, the inconsistency model was used to pool the odd ratios (13).
Results
Study selection
As presented in Fig. 1, a total of 897 studies were identified from PubMed and 917 studies from Embase by the initial search. Subsequent to excluding any duplicates, 1,113 studies remained. A total of 831 irrelevant studies were excluded by reviewing the titles and abstracts. In addition, 249 studies that did not meet the inclusion criteria were excluded. Finally, 33 RCTs were included in the present study (4–9,14–40).
Characteristics of the included studies
As presented in Table I, the demographic characteristics, including age, sex and weight of the patients in the included studies were similar. Included RCTs were published between 1994 and 2015. The mean duration of psoriasis of the included patients ranged between 11.1 and 21.5 years. Quality assessment demonstrated that the quality of the included RCTs was relatively high. With respect to random sequence generation (selection bias), a number of studies were assessed as having an unclear risk of bias. With regards to blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias) and incomplete outcome data (attrition bias), a small proportion of studies were assessed as having high risk of bias (Fig. 2) and were excluded from the current study. However, the studies by Laburte et al (25) and Cassano et al (15) were not excluded as they met with the inclusion criteria despite having quite a poor rating.
Network meta-analysis
Based on the results of node-splitting analysis (Table II), the effect sizes were pooled using an inconsistency model. Regarding the PASI 75 response rate, infliximab (5 mg) was the most effective option for the treatment of moderate to severe psoriasis (Table III and Fig. 3). The pooled results of the PASI 50 response rate demonstrated that infliximab (5 mg) and ustekinumab (90 mg) may be superior to other drugs for treating moderate to severe psoriasis (Table IV). In addition, regarding the PASI 90 response rate, treatment with infliximab (5 mg), ustekinumab (90 mg) and briakinumab (weeks 0 and 4, 200 mg; week 8, 100 mg) indicated improved results compared with other agents (Table V). Finally, the drugs can be ranked in the following order according to their efficacy, defined as their PASI 90 response rate: Briakinumab > ustekinumab (90 mg) > infliximab (5 mg)> ustekinumab (45 mg) > adalimumab > infliximab (3 mg)> etanercept (50 mg BIW) > CSA (5 mg) > etanercept (25 mg BIW) > MTX > etanercept (25 mg QW) > placebo (Table VI). The odds ratio value of infliximab (5 mg) compared with the other drugs was >1, therefore, infliximab (5 mg) was regarded as the best treatment agent, although it ranked as third in terms of efficacy.
Table V.Network meta-analysis of PASI 90 response rate between different drugs used to treat psoriasis. |
Discussion
In the present study, a network meta-analysis was performed to systematically review and compare the efficacy of seven drugs used at different doses for treating moderate to severe psoriasis. Based on the results of the network analysis, infliximab (5 mg) may be an appropriate option to treat moderate to severe psoriasis.
Psoriasis has been reported to be associated with a high concentration of TNF-α (41) and infliximab treatment can neutralize the biological activity of TNF-α (42). However, the role of the TNF-α in the pathogenesis of psoriasis remains unclear. Previous studies have reported that TNF-α may serve an important role in the upstream of the inflammatory responses of psoriasis (43,44). An in vitro study determined that infliximab was able to inhibit the activation of skin-homing T cells and impair the antigen-presenting capacity of immature dendritic cells in psoriasis patients (43). However, another TNF-α inhibitor, etanercept, has been found to be effective in the treatment of psoriasis by reducing the Th17 cell products, as well as the production of IL-17, IL-22, IL-23 and inducible NO synthase from dendritic cells (44). Thus, it has been suggested that the infliximab may serve a different role with other treatments on moderate to severe psoriasis.
Although the present meta-analysis indicated that infliximab treatment had a high PASI score, a higher percentage of adverse events were observed in infliximab-treated patients compared with those in the placebo group (18), indicating that infliximab treatment induces adverse effects. In addition, infliximab treatment increases the incidence of infusion reactions (45). However, these outcomes were not considered to be important due to the small sample size of each study or the fact that the data were unavailable. Thus, the therapeutic effect of the infliximab should be systematically assessed in further studies. Besides, the dosage and treatment duration of infliximab should be optimized according to the disease severity of psoriasis.
In the present study, briakinumab and ustekinumab (90 mg) treatments were superior to other treatments for PASI 90 response. Thus, anti-IL-12/23 monoclonal antibodies appear to be more appropriate compared with anti-TNF-α treatment for treating moderate to severe psoriasis. However, briakinumab and ustekinumab showed no significantly improved therapeutic effect in PASI 75 and PASI 50 responses when compared with the anti-TNF-α treatments. In addition, the long-term safety profile, including severe infections and cardiac disorders, should be evaluated in further studies with large sample sizes and strict study design.
To the best of our knowledge, the present study is the first network meta-analysis for evaluating the efficacy of various treatments for moderate to severe psoriasis. The current results may provide information for clinician and patients on the selection of the suitable treatment for moderate to severe psoriasis. However, there were also several limitations in the present meta-analysis. Firstly, due to unavailable data in certain included studies, confounding variables could not be adjusted and subgroup analysis was not performed to reduce the effect of the confounding variables. Secondly, due to unknown bias, the network analyses of PASI 75 and PASI 50 responses were performed using an inconsistency model. Finally, the results of the network meta-analysis should be pooled only by a random effects model. Thus, the pooled results may be conservative and certain borderline significant effects may have been ignored (46).
In conclusion, the present meta-analysis results suggested that infliximab (5 mg) may be a superior option compared with other drugs for treating moderate to severe psoriasis due to the relatively high PASI scores of patients. However, despite the high PASI 90 responses, the efficacy of ustekinumab (90 mg) and briakinumab were also high and therefore should be investigated in further studies.
References
Parisi R, Symmons DP, Griffiths CE and Ashcroft DM; Identification and Management of Psoriasis and Associated ComorbidiTy (IMPACT) project team, . Global epidemiology of psoriasis: A systematic review of incidence and prevalence. J Invest Dermatol. 133:377–385. 2013. View Article : Google Scholar : PubMed/NCBI | |
Menter A, Gottlieb A, Feldman SR, Van Voorhees AS, Leonardi CL, Gordon KB, Lebwohl M, Koo JY, Elmets CA, Korman NJ, et al: Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 58:826–850. 2008. | |
Griffiths CE and Barker JN: Pathogenesis and clinical features of psoriasis. Lancet. 370:263–271. 2007. View Article : Google Scholar : PubMed/NCBI | |
Antoni CE, Kavanaugh A, Kirkham B, Tutuncu Z, Burmester GR, Schneider U, Furst DE, Molitor J, Keystone E, Gladman D, et al: Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: Results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum. 52:1227–1236. 2005. View Article : Google Scholar : PubMed/NCBI | |
Asahina A, Nakagawa H, Etoh T and Ohtsuki M; Adalimumab M04-688 Study Group, . Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: Efficacy and safety results from a Phase II/III randomized controlled study. J Dermatol. 37:299–310. 2010. View Article : Google Scholar : PubMed/NCBI | |
Griffiths C, Sterry W, Brock F, Dilleen M, Stefanidis D, Germain JM and Mallbris L: Pattern of response in patients with moderate-to-severe psoriasis treated with etanercept. Br J Dermatol. 172:230–238. 2015. View Article : Google Scholar : PubMed/NCBI | |
Sterry W, Ortonne JP, Kirkham B, Brocq O, Robertson D, Pedersen RD, Estojak J, Molta CT and Freundlich B: Comparison of two etanercept regimens for treatment of psoriasis and psoriatic arthritis: PRESTA randomised double blind multicentre trial. BMJ. 340:c1472010. View Article : Google Scholar : PubMed/NCBI | |
Strober BE, Crowley JJ, Yamauchi PS, Olds M and Williams DA: 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. Br J Dermatol. 165:661–668. 2011. View Article : Google Scholar : PubMed/NCBI | |
Bagel J, Lynde C, Tyring S, Kricorian G, Shi Y and Klekotka P: Moderate to severe plaque psoriasis with scalp involvement: A randomized, double-blind, placebo-controlled study of etanercept. J Am Acad Dermatol. 67:86–92. 2012. View Article : Google Scholar : PubMed/NCBI | |
Schäfer I, Hacker J, Rustenbach SJ, Radtke M, Franzke N and Augustin M: Concordance of the psoriasis area and severity index (PASI) and patient-reported outcomes in psoriasis treatment. Eur J Dermatol. 20:62–67. 2010.PubMed/NCBI | |
Mrowietz U, Kragballe K, Reich K, Spuls P, Griffiths CE, Nast A, Franke J, Antoniou C, Arenberger P, Balieva F, et al: Definition of treatment goals for moderate to severe psoriasis: A European consensus. Arch Dermatol Res. 303:1–10. 2011. View Article : Google Scholar : PubMed/NCBI | |
Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA, et al: The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 343:d59282011. View Article : Google Scholar : PubMed/NCBI | |
Dias S, Welton NJ, Caldwell DM and Ades AE: Checking consistency in mixed treatment comparison meta-analysis. Stat Med. 29:932–944. 2010. View Article : Google Scholar : PubMed/NCBI | |
Barker J, Hoffmann M, Wozel G, Ortonne JP, Zheng H, van Hoogstraten H and Reich K: 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). Br J Dermatol. 165:1109–1117. 2011. | |
Cassano N, Miracapillo A, Coviello C, Loconsole F, Bellino M and Vena GA: Treatment of psoriasis vulgaris with the two-compound product calcipotriol/betamethasone dipropionate followed by different formulations of calcipotriol. Clin Drug Investig. 26:227–233. 2006. View Article : Google Scholar : PubMed/NCBI | |
Flytstrom I, Stenberg B, Svensson A and Bergbrant IM: Methotrexate vs. ciclosporin in psoriasis: effectiveness, quality of life and safety. A randomized controlled trial. Br J Dermatol. 158:116–121. 2008. | |
Gordon KB, Langley RG, Leonardi C, Toth D, Menter MA, Kang S, Heffernan M, Miller B, Hamlin R, Lim L, et al: Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: Double-blind, randomized controlled trial and open-label extension study. J Am Acad Dermatol. 55:598–606. 2006. View Article : Google Scholar : PubMed/NCBI | |
Gottlieb AB, Evans R, Li S, Dooley LT, Guzzo CA, Baker D, Bala M, Marano CW and Menter A: Infliximab induction therapy for patients with severe plaque-type psoriasis: A randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. 51:534–542. 2004. View Article : Google Scholar : PubMed/NCBI | |
Gottlieb AB, Leonardi C, Kerdel F, Mehlis S, Olds M and Williams DA: Efficacy and safety of briakinumab vs. etanercept and placebo in patients with moderate to severe chronic plaque psoriasis. Br J Dermatol. 165:652–660. 2011. | |
Gottlieb AB, Matheson RT, Lowe N, Krueger GG, Kang S, Goffe BS, Gaspari AA, Ling M, Weinstein GD, Nayak A, et al: A randomized trial of etanercept as monotherapy for psoriasis. Arch Dermatol. 139:1627–1632. 2003. View Article : Google Scholar : PubMed/NCBI | |
Griffiths CE: Comparing biological therapies in psoriasis: Implications for clinical practice. J Eur Acad Dermatol Venereol. 24 (Suppl 6):S10–S14. 2010. View Article : Google Scholar | |
Heydendael VM, Spuls PI, Opmeer BC, de Borgie CA, Reitsma JB, Goldschmidt WF, Bossuyt PM, Bos JD and de Rie MA: Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N Engl J Med. 349:658–665. 2003. View Article : Google Scholar : PubMed/NCBI | |
Ho SG, Yeung CK and Chan HH: Methotrexate versus traditional Chinese medicine in psoriasis: A randomized, placebo-controlled trial to determine efficacy, safety and quality of life. Clin Exp Dermatol. 35:717–722. 2010. View Article : Google Scholar : PubMed/NCBI | |
Igarashi A, Kato T, Kato M, Song M and Nakagawa H; Japanese Ustekinumab Study Group, . 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. J Dermatol. 39:242–252. 2012. View Article : Google Scholar : PubMed/NCBI | |
Laburte C, Grossman R, Abi-Rached J, Abeywickrama K and Dubertret L: Efficacy and safety of oral cyclosporin A (CyA; Sandimmun) for long-term treatment of chronic severe plaque psoriasis. Br J Dermatol. 130:366–375. 1994. View Article : Google Scholar : PubMed/NCBI | |
Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, Li S, Dooley LT and Gordon KB; PHOENIX 1 study investigators, . 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). Lancet. 371:1665–1674. 2008. View Article : Google Scholar : PubMed/NCBI | |
Leonardi CL, Powers JL, Matheson RT, Goffe BS, Zitnik R, Wang A and Gottlieb AB; Etanercept Psoriasis Study Group, . Etanercept as monotherapy in patients with psoriasis. N Engl J Med. 349:2014–2022. 2003. View Article : Google Scholar : PubMed/NCBI | |
McInnes IB, Kavanaugh A, Gottlieb AB, Puig L, Rahman P, Ritchlin C, Brodmerkel C, Li S, Wang Y, Mendelsohn AM, et al: Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet. 382:780–789. 2013. View Article : Google Scholar : PubMed/NCBI | |
Menter A, Feldman SR, Weinstein GD, Papp K, Evans R, Guzzo C, Li S, Dooley LT, Arnold C and Gottlieb AB: A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis. J Am Acad Dermatol. 56(31): e1–e15. 2007.PubMed/NCBI | |
Menter A, Tyring SK, Gordon K, Kimball AB, Leonardi CL, Langley RG, Strober BE, Kaul M, Gu Y, Okun M and Papp K: Adalimumab therapy for moderate to severe psoriasis: A randomized, controlled phase III trial. J Am Acad Dermatol. 58:106–115. 2008. View Article : Google Scholar : PubMed/NCBI | |
Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N, Guzzo C, Hsu MC, Wang Y, Li S, et al: 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). Lancet. 371:1675–1684. 2008. View Article : Google Scholar : PubMed/NCBI | |
Papp KA, Tyring S, Lahfa M, Prinz J, Griffiths CE, Nakanishi AM, Zitnik R, van de Kerkhof PC and Melvin L; Etanercept Psoriasis Study Group, . A global phase III randomized controlled trial of etanercept in psoriasis: Safety, efficacy and effect of dose reduction. Br J Dermatol. 152:1304–1312. 2005. View Article : Google Scholar : PubMed/NCBI | |
Reich K, Nestle FO, Papp K, Ortonne JP, Evans R, Guzzo C, Li S, Dooley LT and Griffiths CE: EXPRESS study investigators: Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: A phase III, multicentre, double-blind trial. Lancet. 366:1367–1374. 2005. View Article : Google Scholar : PubMed/NCBI | |
Revicki D, Willian MK, Saurat JH, Papp KA, Ortonne JP, Sexton C and Camez A: Impact of adalimumab treatment on health-related quality of life and other patient-reported outcomes: Results from a 16-week randomized controlled trial in patients with moderate to severe plaque psoriasis. Br J Dermatol. 158:549–557. 2008. View Article : Google Scholar : PubMed/NCBI | |
Torii H and Nakagawa H; Japanese Infliximab Study investigators, . Infliximab monotherapy in Japanese patients with moderate-to-severe plaque psoriasis and psoriatic arthritis. A randomized, double-blind, placebo-controlled multicenter trial. J Dermatol Sci. 59:40–49. 2010. View Article : Google Scholar : PubMed/NCBI | |
Tsai TF, Ho JC, Song M, Szapary P, Guzzo C, Shen YK, Li S, Kim KJ, Kim TY, Choi JH, et al: 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). J Dermatol Sci. 63:154–163. 2011. View Article : Google Scholar : PubMed/NCBI | |
Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A, Lalla D, Woolley M, Jahreis A, Zitnik R, et al: Etanercept and clinical outcomes, fatigue, and depression in psoriasis: Double-blind placebo-controlled randomised phase III trial. Lancet. 367:29–35. 2006. View Article : Google Scholar : PubMed/NCBI | |
van de Kerkhof PC, Segaert S, Lahfa M, Luger TA, Karolyi Z, Kaszuba A, Leigheb G, Camacho FM, Forsea D, Zang C, et al: 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. Br J Dermatol. 159:1177–1185. 2008.PubMed/NCBI | |
Yang HZ, Wang K, Jin HZ, Gao TW, Xiao SX, Xu JH, Wang BX, Zhang FR, Li CY, Liu XM, et al: Infliximab monotherapy for Chinese patients with moderate to severe plaque psoriasis: A randomized, double-blind, placebo-controlled multicenter trial. Chin Med J (Engl). 125:1845–1851. 2012.PubMed/NCBI | |
Cassano N, Loconsole F, Miracapillo A, Travaglini M, Digiuseppe MD, Congedo M, Galluccio A, Buquicchio R, Mastrandrea V, Filieri M, et al: Treatment of psoriasis with different dosage regimens of etanercept: Preliminary results from the Tαranta plastic study group. Int J Immunopathol Pharmacol. 23:797–802. 2010. View Article : Google Scholar : PubMed/NCBI | |
Mussi A, Bonifati C, Carducci M, D'Agosto G, Pimpinelli F, D'Urso D, D'Auria L, Fazio M and Ameglio F: Serum TNF-alpha levels correlate with disease severity and are reduced by effective therapy in plaque-type psoriasis. J Biol Regul Homeost Agents. 11:115–118. 1997.PubMed/NCBI | |
Cooper C, Shafran S, Greenbloom S, Enns R, Farley J, Hilzenrat N, Williams K, Elkashab M, Abadir N and Neuman M: Single-dose infliximab in hepatitis C genotype 1 treatment-naive patients with high serum tumour necrosis factor-alpha does not influence the efficacy of pegylated interferon alpha-2b/ribavirin therapy. Can J Gastroenterol Hepatol. 28:35–40. 2014. View Article : Google Scholar : PubMed/NCBI | |
Bedini C, Nasorri F, Girolomoni G, Pità Od and Cavani A: Antitumour necrosis factor-alpha chimeric antibody (infliximab) inhibits activation of skin-homing CD4+ and CD8+ T lymphocytes and impairs dendritic cell function. Br J Dermatol. 157:249–258. 2007. View Article : Google Scholar : PubMed/NCBI | |
Gottlieb AB, Chamian F, Masud S, Cardinale I, Abello MV, Lowes MA, Chen F, Magliocco M and Krueger JG: TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques. J Immunol. 175:2721–2729. 2005. View Article : Google Scholar : PubMed/NCBI | |
Steenholdt C, Svenson M, Bendtzen K, Thomsen OØ, Brynskov J and Ainsworth MA: Severe infusion reactions to infliximab: aetiology, immunogenicity and risk factors in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 34:51–58. 2011. View Article : Google Scholar : PubMed/NCBI | |
Van Valkenhoef G, Tervonen T, Zwinkels T, de Brock B and Hillege H: ADDIS: A decision support system for evidence-based medicine. Decis Support Syst. 55:459–475. 2013. View Article : Google Scholar |