A Review on Comparison of Effectiveness and Safety of Disease Modifying Anti-Rheumatoid Drugs Used in Patients with Rheumatoid Arthritis
Objective: To compare the safety and effectiveness of monotherapy as well as combination therapy with disease modifying anti rheumatoid drugs (DMARDs) in rheumatoid arthritis patients.
Data sources: Study works limited to the English language and more concentrated to adults by using Google Scholar, PubMed and The Cochrane library.
Summary: Some head to head trial works, retrospective studies and prospective cohort studies were used to compare the safety and effectiveness of the therapy. Here we go through the comparison in between each disease modifying anti rheumatoid drug (DMARD) monotherapy, combination with monotherapy and also combination with combination therapy.
Conclusion: Among the synthetic DMARDs monotherapy, methotrexate would be the preferred DMARD. Biological DMARDs have more efficacy than synthetic agents and have comparable safety profile. Rituximab would be the preferred agent among the bDMARDs. Since synthetic agents are more economical as compared to biologicals, hence these are preferred over biological agents. Combinations of biological DMARDs with methotrexate have improved efficacy and safety than methotrexate monotherapy. Combination of biological DMARDs have no advantage over biological monotherapy, there was an increased safety risk and no therapeutic benefit. Combination of biological DMARDs with methotrexate have better efficacy than monotherapy with either bDMARDs or methotrexate alone. A triple combination therapy of synthetic DMARDs (methotrexate, sulfasalazine and hydroxychloroquine) had better safety, effectiveness and high tolerability than double combination therapy or monotherapy.
Keywords: Rheumatoid arthritis, disease modifying antirheumatoid drugs
2. Buckley F, Finckh A, Huizinga TW, Dejonckheere F, Jansen JP. Comparative efficacy of novel DMARDs as monotherapy and in combination with methotrexate in rheumatoid arthritis patients with inadequate response to conventional DMARDs: a network meta-analysis. Journal of managed care & specialty pharmacy. 2015 May; 21(5):409-23.
3. Malysheva OA, Wahle M, Wagner U, Pierer M, Arnold S, Haentzschel H, Baerwald CG. Low-dose prednisolone in rheumatoid arthritis: adverse effects of various disease modifying antirheumatic drugs. The Journal of rheumatology. 2008 Jun 1; 35(6):979-85.
4. Farheen K, Agarwal SK. Assessment of disease activity and treatment outcomes in rheumatoid arthritis. Journal of Managed Care Pharmacy. 2011 Nov; 17(9 Supp B):S09-13.
5. Singh G, Ramey DR, Morfeld D, Shi H, Hatoum HT, Fries JF. Gastrointenstinal tract complications of nonsteroidal anti inflammatory drug treatment in rheumatoid arthritis: a prospective observational cohort study. Archives of internal medicine. 1996 Jul 22; 156(14)1530-6.
6. Caldwell JR, Furst DE. The efficacy and safety of low dose corticosteroids for rheumatoid arthritis. Inseminars in arthritis and rheumatism 1991 Aug 1; (21):1-11
7. Strand V, Tugwell P, Bombardier C, Maetzel A, Crawford B, Dorrier C, Thompson A, Wells G. Function and health‐related quality of life: results from a randomized controlled trial of leflunomide versus methotrexate or placebo in patients with active rheumatoid arthritis. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 1999 Sep; 42(9):1870-8.
8. Emery P, Breedveld FC, Lemmel EM, Kaltwasser JP, Dawes PT, Gömör B, Van den Bosch F, Nordström D, Bjørneboe O, Dahl R, Hørslev‐Petersen K. A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. Rheumatology. 2000 Jun 1; 39(6):655-65.
9. Strand V, Cohen S, Schiff M, Weaver A, Fleischmann R, Cannon G, Fox R, Morland L, Olsen N, Furst D, Caldwell J. treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Archives of internal medicine. 1999 nov 22; 159(21):2542-50.
10. Cohen S, Cannon GW, Schiff M, Weaver A, Fox R, Olsen N, Furst D, Sharp J, Moreland L, Caldwell J, Kaine J. Two‐year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 2001 Sep; 44(9):1984-92.
11. Egsmose C, Hansen TM, Andersen LS, Beier JM, Christensen L, Peters ND, Van der Heijde DM. Limited effect of sulfasalazine treatment in reactive arthritis. A randomized double blind placebo controlled trial. Annals of the rheumatic diseases. 1997 Jan 1; 56(1):32-6
12. Haagsma CJ, Van Riel, De Jong AJ, Van De Putte LB. Combination of sulfasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized controlled, double blind, 52 week clinical trial. British journal of rheumatology. 1997 Oct 1; 36(10):1082-8
13. Gaujoux-Viala C, Smolen JS, Landewé R, Dougados M, Kvien TK, Mola EM, Scholte-Voshaar M, van Riel P, Gossec L. Current evidence for the management of rheumatoid arthritis with synthetic disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis. Annals of the rheumatic diseases. 2010 Jun 1; 69(6):1004-9.
14. Haraoui B, Keystone EC, Thorne JC, Pope JE, Chen I, Asare CG, Leff JA. Clinical outcomes of patients with rheumatoid arthritis after switching from infliximab to etanercept. The journal of rheumatology. 2004 Dec 1; 31(12):2356-9
15. Flouri I, Markatseli TE, Voulgari PV, Boki KA, Papadopoulos I, Settas L, Zisopoulos D, Skopouli FN, Iliopoulos A, Bertsias GK, Geborek P. Comparative effectiveness and survival of infliximab, adalimumab, and etanercept for rheumatoid arthritis patients in the Hellenic Registry of Biologics: Low rates of remission and 5-year drug survival. InSeminars in arthritis and rheumatism 2014 Feb 1; 43(4):447-457). WB Saunders.
16. Greenberg JD, Reed G, Decktor D, Harrold L, Furst D, Gibofsky A, DeHoratius R, Kishimoto M, Kremer JM. A comparative effectiveness study of adalimumab, etanercept and infliximab in biologically naive and switched rheumatoid arthritis patients: results from the US CORRONA registry. Annals of the rheumatic diseases. 2012 Jul 1; 71(7):1134-42.
17. Salliot C, Finckh A, Katchamart W, Lu Y, Sun Y, Bombardier C, Keystone E. Indirect comparisons of the efficacy of biological antirheumatic agents in rheumatoid arthritis in patients with an inadequate response to conventional disease-modifying antirheumatic drugs or to an anti-tumour necrosis factor agent: a meta-analysis. Annals of the rheumatic diseases. 2011 Feb 1; 70(2):266-71.
18. Singh JA, Christensen R, Wells GA, Suarez-Almazor ME, Buchbinder R, Lopez-Olivo MA, Ghogomu ET, Tugwell P. A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview. Cmaj. 2009 Nov 24; 181(11):787-96.
19. Malottki K, Barton P, Tsourapas A, Uthman AO, Liu Z, Routh K, Connock M, Jobanputra P, Moore D, Fry-Smith A, Chen YF. Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a tumour necrosis factor inhibitor: a systematic review and economic evaluation. InNIHR Health Technology Assessment programme: Executive Summaries 2011. NIHR Journals Library.
20. Brownish JL. B cells move to centre stage: novel opportunities for auto immune disease treatment. Nature reviews drug discovery. 2006 Jul; 5(7):564.
21. Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA4 is a second receptor for the B cell activation antigen B7. Journal of experimental medicine. 1991 Sep 1; 174(3):561-9
22. Smolen JS, Aletaha D, Koelller M, Weisman H, Emery P. New therapies for treatment of rheumatoid arthritis. The lancet. 2007 Dec 1; 370(9602):1861-74.
23. Ramiro S, Sepriano A, Chatzidionysiou K, Nam JL, Smolen JS, Van Der Heijde D, Dougados M, Van Vollenhoven R, Bijlsma JW, Burmester GR, Scholte-Voshaar M. Safety of synthetic and biological DMARDs: a systematic literature review informing the 2016 update of the EULAR recommendations for management of rheumatoid arthritis. Annals of the rheumatic diseases. 2017 Jun 1; 76(6):1101-36.
24. Barrera P, van Der Maas A, Van Ede AE, Kiemeney BA, Laan RF, Van de Putte LB, van Riel PL. Drug survival, efficacy and toxicity of monotherapy with a fully human anti‐tumour necrosis factor‐α antibody compared with methotrexate in long‐standing rheumatoid arthritis. Rheumatology. 2002 Apr 1; 41(4):430-9.
25. Chen YF, Jobanputra P, Barton P, Jowett S, Bryan S, Clark W, Fry-Smith A, Burls A. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness. InNIHR Health Technology Assessment programme: Executive Summaries 2006. NIHR Journals Library.
26. Jones G, Sebba A, Gu J, Lowenstein MB, Calvo A, Gomez-Reino JJ, Siri DA, Tomšič M, Alecock E, Woodworth T, Genovese MC. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Annals of the rheumatic diseases. 2010 Jan 1; 69(01):88-96.
27. Katchamart W, Trudeau J, Phumethum V, Bombardier C. Methotrexate monotherapy versus methotrexate combination therapy with non‐biologic disease modifying anti‐rheumatic drugs for rheumatoid arthritis. Cochrane database of systematic reviews. 2010(4).
28. Weinblatt ME, Kremer JM, Coblyn JS, Maier AL, Helfgott SM, Morrel M, Byrne VM, Kaymakcian MV, Strand V. Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis. Arthritis and Rheumatism: Official Journal of American College of Rheumatology. 1999 Jul; 42(7):1322-8
29. Gerards AH, Landewe RB, Prins AP, Bruijn GA, Laan RF, Dijkmans BA. Cyclosporin A monotherapy versus cyclosporin A and methotrexate combination therapy in patients with early rheumatoid arthritis: a double blind randomisedplacebo controlled trial. Annals of the rheumatic diseases. 2003 Apr 1; 62(4):291-6.
30. Capell, H.A., Madhok, R., Porter, D.R., Munro, R.A., McInnes, I.B., Hunter, J.A., Steven, M., Zoma, A., Morrison, E., Sambrook, M. and Poon, F.W., Combination therapy with sulfasalazine and methotrexate is more effective than either drug alone in patients with rheumatoid arthritis with a suboptimal response to sulfasalazine: results from the double-blind placebo-controlled MASCOT study. Annals of the rheumatic diseases, 2007; 66(2):235-241.
31. Rau R, Schleusser B, Herborn G, Karger T. Longterm combination therapy of refractory and destructive rheumatoid arthritis with methotrexate (MTX) and intramuscular gold or other disease modifying antirheumatic drugs compared to MTX monotherapy. The Journal of rheumatology. 1998 Aug; 25(8):1485-92.
32. Calgüneri M, Pay S, Caliskaner Z, Apras S, Kiraz S, Ertenli I, Cobankara V. Combination therapy versus monotherapy for the treatment of patients with rheumatoid arthritis. Clin Exp Rheumatol. 1999; 17(6):699-704.
33. Klareskog L, van der Heijde D, de Jager JP, Shoor S. Etanercept plus methotrexate reduced symptoms and disease activity in adult-onset rheumatoid arthritis/COMMENTARY. ACP Journal Club. 2004 Sep 1; 141(2):42.
34. Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, Jackson CG, Lange M, Burge DJ. A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. New England Journal of Medicine. 1999 Jan 28; 340(4):253-9.
35. Burmester GR, Mariette X, Montecucco C, Monteagudo-Sáez I, Malaise M, Tzioufas AG, Bijlsma JW, Unnebrink K, Kary S, Kupper H. Adalimumab alone and in combination with disease-modifying antirheumatic drugs for the treatment of rheumatoid arthritis in clinical practice: the Research in Active Rheumatoid Arthritis (ReAct) trial. Annals of the rheumatic diseases. 2007 Jun 1; 66(6):732-9.
36. Lipsky PE, van der Heijde DM, St. Clair EW, Furst DE, Breedveld FC, Kalden JR, Smolen JS, Weisman M, Emery P, Feldmann M, Harriman GR. Infliximab and methotrexate in the treatment of rheumatoid arthritis. New England Journal of Medicine. 2000 Nov 30; 343(22):1594-602.
37. Cohen S, Hurd E, Cush J, Schiff M, Weinblatt ME, Moreland LW, Kremer J, Bear MB, Rich WJ, McCabe D. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin‐1 receptor antagonist, in combination with methotrexate: results of a twenty‐four–week, multicenter, randomized, double‐blind, placebo‐controlled trial. Arthritis & Rheumatism. 2002 Mar; 46(3):614-24.
38. Genovese MC, Cohen S, Moreland L, Lium D, Robbins S, Newmark R, Bekker P, 20000223 Study Group. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis & Rheumatism. 2004 May; 50(5):1412-9.
39. Klareskog L, van der Heijde D, de Jager JP, Shoor S. Etanercept plus methotrexate reduced symptoms and disease activity in adult-onset rheumatoid arthritis/COMMENTARY. ACP Journal Club. 2004 Sep 1; 141(2):42.
40. Horneff G, De Bock F, Foeldvari I, Girschick HJ, Michels H, Moebius D, Schmeling H, German and Austrian Paediatric Rheumatology Collaborative Study Group. Safety and efficacy of combination of etanercept and methotrexate compared to treatment with etanercept only in patients with juvenile idiopathic arthritis (JIA): preliminary data from the German JIA Registry. Annals of the rheumatic diseases. 2009 Apr 1; 68(4):519-25.
41. Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, Vollenhoven RV, Sharp J, Perez JL, Spencer‐Green GT. The PREMIER study: a multicenter, randomized, double‐blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 2006 Jan; 54(1):26-37
42. Combe B, Codreanu C, Fiocco U, Geusens PP, Kvien TK, Pavelka K, Sambrook PN, Smolen JS, Wajdula J, Fatenejad S. Etanercept and sulfasalazine, alone and combined in patients with active rheumatoid arthritis despite receiving sulfasalazine: a double blind comparison. Annals of rheumatic diseases. 2006 Oct 1; 65(10):1357-62.
43. O'Dell JR, Haire CE, Erikson N, Drymalski W, Palmer W, Eckhoff PJ, Garwood V, Maloley P, Klassen LW, Wees S, Klein H. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. New England Journal of Medicine. 1996 May 16; 334(20):1287-91.
44. O'Dell JR, Leff R, Paulsen G, Haire C, Mallek J, Eckhoff PJ, Fernandez A, Blakely K, Wees S, Stoner J, Hadley S. Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: results of a two‐year, randomized, double‐blind, placebo‐controlled trial. Arthritis & Rheumatism. 2002 May; 46(5):1164-70.
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