From clinical trials to the bedside: how can we treat patients with rheumatoid arthritis and concurrent morbidities who are generally excluded from randomised controlled clinical trials?

In the last few years management of rheumatoid arthritis (RA) has changed substantially due to the availability of new drugs and newer therapeutical strategies. Controlled randomised clinical trials (RCT) have allowed us to analyse the efficacy and safety of all these innovative approaches. Unfortunately, these RCTs are not free from criticisms and their rigid inclusion and exclusion criteria may increase the differences between the ideal patients enrolled and the majority of patients seen in standard clinical care. This review focuses on actual clinical practice, with particular attention on patient comorbidities and all the conditions which have been designated as exclusion criteria in the most important registration RCTs. We will attempt to provide an overview of the most widely used strategies in RA therapy.

[1]  J. Rodés,et al.  Bone mass and mineral metabolism in liver transplant patients treated with FK506 or cyclosporine A , 2001, Calcified Tissue International.

[2]  P. Peloso,et al.  Long term safety of etanercept in elderly subjects with rheumatic diseases , 2005, Annals of the rheumatic diseases.

[3]  G. Mela,et al.  [Comorbidities in rheumatoid arthritis: analysis of hospital discharge records]. , 2011, Reumatismo.

[4]  U. Müller-Ladner,et al.  Increase in bone mineral density of patients with rheumatoid arthritis treated with anti-TNF-alpha antibody: a prospective open-label pilot study. , 2005, Rheumatology.

[5]  J. Angel,et al.  Mycobacterium abscessus infection after use of tumor necrosis factor alpha inhibitor therapy: case report and review of infectious complications associated with tumor necrosis factor alpha inhibitor use. , 2005, Diagnostic microbiology and infectious disease.

[6]  A. Murasawa,et al.  Autoantibodies against oxidized low-density lipoprotein (LDL) and carotid atherosclerosis in patients with rheumatoid arthritis. , 2005, Clinical and experimental rheumatology.

[7]  C. Botsios Safety of tumour necrosis factor and interleukin-1 blocking agents in rheumatic diseases. , 2005, Autoimmunity reviews.

[8]  A. Delle Sedie,et al.  Disease-modifying antirheumatic drugs and bone mass in rheumatoid arthritis. , 2005, Clinical and experimental rheumatology.

[9]  B. Dijkmans,et al.  Bone mineral density in patients with rheumatoid arthritis treated with infliximab , 2005, Annals of the rheumatic diseases.

[10]  M. Dougados,et al.  Body weight, body composition, and bone turnover changes in patients with spondyloarthropathy receiving anti-tumour necrosis factor α treatment , 2005, Annals of the rheumatic diseases.

[11]  N. Hajjaj-Hassouni,et al.  Prevalence and clinical characteristics of tuberculosis in rheumatoid arthritis patients , 2005, Clinical Rheumatology.

[12]  W. Lems,et al.  Bone mineral density in patients with rheumatoid arthritis: relation between disease severity and low bone mineral density , 2004, Annals of the rheumatic diseases.

[13]  D. M. van der Heijde,et al.  Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. , 2004, Arthritis and rheumatism.

[14]  S. Abramson,et al.  Overview of benefit/risk of biological agents. , 2004, Clinical and experimental rheumatology.

[15]  A. Kavanaugh,et al.  Tuberculosis and opportunistic infections: relevance to biologic agents. , 2004, Clinical and experimental rheumatology.

[16]  R. Rau,et al.  Benefit and risk of methotrexate treatment in rheumatoid arthritis. , 2004, Clinical and experimental rheumatology.

[17]  A. Bitton,et al.  Newer disease-modifying antirheumatic drugs and the risk of serious hepatic adverse events in patients with rheumatoid arthritis. , 2004, The American journal of medicine.

[18]  P. Wiland,et al.  Renal function in rheumatoid arthritis patients treated with methotrexate and infliximab. , 2004, Clinical and experimental rheumatology.

[19]  J. O'dell,et al.  Therapeutic strategies for rheumatoid arthritis. , 2004, The New England journal of medicine.

[20]  M. Dougados,et al.  Leflunomide: a manageable safety profile. , 2004, The Journal of rheumatology. Supplement.

[21]  J. Lacki,et al.  [Change in biomarkers of osteoporosis in rheumatoid arthritis patients treated with infliximab]. , 2004, Polskie Archiwum Medycyny Wewnetrznej.

[22]  M. Kurosaki,et al.  Fulminant hepatitis in an asymptomatic chronic carrier of hepatitis B virus mutant after withdrawal of low-dose methotrexate therapy for rheumatoid arthritis. , 2004, Clinical and experimental rheumatology.

[23]  M. Østensen New insights into sexual functioning and fertility in rheumatic diseases. , 2004, Best practice & research. Clinical rheumatology.

[24]  T. Taniguchi,et al.  The antirheumatic drug leflunomide inhibits osteoclastogenesis by interfering with receptor activator of NF-kappa B ligand-stimulated induction of nuclear factor of activated T cells c1. , 2004, Arthritis and rheumatism.

[25]  F. Wolfe,et al.  Heart failure in rheumatoid arthritis: rates, predictors, and the effect of anti-tumor necrosis factor therapy. , 2004, The American journal of medicine.

[26]  J. Pawlotsky,et al.  Infliximab therapy for rheumatic diseases in patients with chronic hepatitis B or C. , 2004, The Journal of rheumatology.

[27]  L. Hallberg,et al.  Well-being in children with juvenile chronic arthritis. , 2004, Clinical and experimental rheumatology.

[28]  B. Fernández-Gutiérrez,et al.  Leflunomide-induced acute hepatitis. , 2004, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[29]  G. Bianchi,et al.  [Kidney involvement in rheumatoid arthritis]. , 2011, Reumatismo.

[30]  M. Droździk,et al.  The urinary excretion of pyridinoline and deoxypyridinoline during rheumatoid arthritis therapy with infliximab , 2004, Clinical Rheumatology.

[31]  W. Roberts,et al.  Hepatitis C and methotrexate. , 2003, Arthritis and rheumatism.

[32]  K. Shimotohno,et al.  Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes , 2003, Hepatology.

[33]  M. Wener,et al.  Effect of tumour necrosis factor α antagonists on serum transaminases and viraemia in patients with rheumatoid arthritis and chronic hepatitis C infection , 2003, Annals of the rheumatic diseases.

[34]  P. Emery,et al.  Bone mineral density improvement in spondyloarthropathy after treatment with etanercept , 2003, Annals of the rheumatic diseases.

[35]  P. Emery,et al.  Role of biologics in early arthritis. , 2003, Clinical and experimental rheumatology.

[36]  J. Smolen,et al.  DMARD use in early rheumatoid arthritis. Lessons from observations in patients with established disease. , 2003, Clinical and experimental rheumatology.

[37]  E. Keystone,et al.  The safety of biologic agents in early rheumatoid arthritis. , 2003, Clinical and experimental rheumatology.

[38]  M. Dougados,et al.  Combination therapy for early rheumatoid arthritis , 2003, Clinical and experimental rheumatology.

[39]  T. Pincus,et al.  Methotrexate as the "anchor drug" for the treatment of early rheumatoid arthritis. , 2003, Clinical and experimental rheumatology.

[40]  P. Wiland,et al.  [Renal tubular dysfunction in patients with rheumatoid arthritis starting with low dose of methotrexate]. , 2003, Polskie Archiwum Medycyny Wewnetrznej.

[41]  J. Smolen,et al.  Therapeutic strategies for rheumatoid arthritis , 2003, Nature Reviews Drug Discovery.

[42]  R. Porcher,et al.  Increase in bone mineral density of patients with spondyloarthropathy treated with anti-tumour necrosis factor α , 2003, Annals of the rheumatic diseases.

[43]  L. Klareskog,et al.  Risk of malignant lymphomas in patients with rheumatoid arthritis and in their first-degree relatives. , 2003, Arthritis and rheumatism.

[44]  A. Icardi,et al.  Coinvolgimento renale in corso di artrite reumatoide Kidney involvement in rheumatoid arthritis , 2003 .

[45]  A. Drosos Methotrexate Intolerance in Elderly Patients with Rheumatoid Arthritis , 2003, Drugs & aging.

[46]  M. Weisman,et al.  Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. , 2003, Arthritis and rheumatism.

[47]  Tsunamasa Watanabe,et al.  Combined interferon α2b and cyclosporin A in the treatment of chronic hepatitis C: controlled trial , 2003, Journal of Gastroenterology.

[48]  U. Neumann,et al.  Significance of mycophenolate mofetil treatment in patients with HCV reinfection after liver transplantation: impact on clinical course and histologic damage. , 2002, Transplantation Proceedings.

[49]  A. Legras,et al.  Fatal hepatitis with leflunomide and itraconazole. , 2002, The American journal of medicine.

[50]  S. Gabriel,et al.  Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. , 2002, Arthritis and rheumatism.

[51]  Richard W. Martin,et al.  Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. , 2002, Arthritis and rheumatism.

[52]  N. Sookvanichsilp,et al.  Anti-implantation effects of indomethacin and celecoxib in rats. , 2002, Contraception.

[53]  J. Stoner,et al.  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. , 2002, Arthritis and rheumatism.

[54]  Stanley B. Cohen,et al.  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. , 2002, Arthritis and rheumatism.

[55]  L. Biancone,et al.  Immunomodulatory drugs in Crohn's disease patients with hepatitis B or C virus infection. , 2002, Gastroenterology.

[56]  M. Østensen Drugs in pregnancy. Rheumatological disorders. , 2001, Best practice & research. Clinical obstetrics & gynaecology.

[57]  M. Brännström,et al.  Induction of delayed follicular rupture in the human by the selective COX-2 inhibitor rofecoxib: a randomized double-blind study. , 2001, Human reproduction.

[58]  K. Saag,et al.  Comorbidity in rheumatoid arthritis. , 2001, Rheumatic diseases clinics of North America.

[59]  R. Cooper,et al.  Late reactivation of spinal tuberculosis by low-dose methotrexate therapy in a patient with rheumatoid arthritis. , 2001, Rheumatology.

[60]  B. Rojkovich,et al.  Rheumatoid arthritis and hepatitis B virus: evaluating the pathogenic link. , 2001, The Journal of rheumatology.

[61]  S. Campbell,et al.  Infliximab therapy for Crohn's disease in the presence of chronic hepatitis C infection. , 2001, European journal of gastroenterology & hepatology.

[62]  M. Weinblatt,et al.  Serious liver disease in a patient receiving methotrexate and leflunomide. , 2000, Arthritis and rheumatism.

[63]  I. Kawamura,et al.  LESSER REDUCTION IN BONE MINERAL DENSITY BY THE IMMUNOSUPPRESSANT, FK506, COMPARED WITH CYCLOSPORINE IN RATS , 2000, Transplantation.

[64]  M. Govoni,et al.  Elderly onset rheumatoid arthritis: clinical aspects. , 2000, Clinical and experimental rheumatology.

[65]  M. Yuen,et al.  Safety of disease modifying anti-rheumatic agents in rheumatoid arthritis patients with chronic viral hepatitis. , 2000, Clinical and experimental rheumatology.

[66]  N. M. Janssen,et al.  The effects of immunosuppressive and anti-inflammatory medications on fertility, pregnancy, and lactation. , 2000, Archives of internal medicine.

[67]  W. O'brien,et al.  Tumor necrosis factor (TNF)-alpha and TNF receptors in viral pathogenesis. , 2000, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[68]  W M O'Fallon,et al.  Comorbidity in arthritis. , 1999, The Journal of rheumatology.

[69]  C. Suh,et al.  Lipid profiles in untreated patients with rheumatoid arthritis. , 1999, The Journal of rheumatology.

[70]  H. Moutsopoulos,et al.  Rheumatoid arthritis in the elderly , 1999, Experimental Gerontology.

[71]  V. Rodríguez-Valverde,et al.  Insufficiency fractures of the tibia and fibula. , 1999, Seminars in arthritis and rheumatism.

[72]  D. Furst,et al.  Etanercept Therapy in Rheumatoid Arthritis , 1999, Annals of Internal Medicine.

[73]  J. Rivera,et al.  Arthritis in patients with chronic hepatitis C virus infection. , 1999, The Journal of rheumatology.

[74]  J. Kremer,et al.  A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. , 1999, The New England journal of medicine.

[75]  E. Díaz-Jouanen,et al.  Tuberculosis prophylaxis in patients with steroid treatment and systemic rheumatic diseases. A case-control study. , 1999, Clinical and experimental rheumatology.

[76]  J. Smolen Efficacy and safety of the new DMARD leflunomide: comparison to placebo and sulfasalazine in active rheumatoid arthritis. , 1999, Scandinavian journal of rheumatology. Supplement.

[77]  Nina Singh,et al.  Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. , 1998, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[78]  Y. El Miedany,et al.  Effect of low dose methotrexate on markers of bone metabolism in patients with rheumatoid arthritis. , 1998, The Journal of rheumatology.

[79]  G. Alarcón,et al.  Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: implications for cardiovascular disease prevention. , 1998, The Journal of rheumatology.

[80]  S. Epstein,et al.  Mycophenolate mofetil: a promising new immunosuppressant that does not cause bone loss in the rat. , 1998, Transplantation.

[81]  J. Sibley,et al.  Rheumatoid arthritis and the risk of malignancy. , 1997, Arthritis and rheumatism.

[82]  S. van der Linden,et al.  Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis , 1997, The Lancet.

[83]  E. Tindall,et al.  Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. , 1997, The New England journal of medicine.

[84]  C. Ponticelli,et al.  Effects of three immunosuppressive regimens on vertebral bone density in renal transplant recipients: a prospective study. , 1997, Transplantation.

[85]  J. Dequeker,et al.  Methotrexate osteopathy, does it exist? , 1996, The Journal of rheumatology.

[86]  E. Bartoli,et al.  Increase of bone mineral density and anabolic variables in patients with rheumatoid arthritis resistant to methotrexate after cyclosporin A therapy. , 1996, The Journal of rheumatology.

[87]  J. Olsen,et al.  Rheumatoid arthritis and cancer risk. , 1996, European journal of cancer.

[88]  C. Haire,et al.  Efficacy of triple DMARD therapy in patients with RA with suboptimal response to methotrexate. , 1996, The Journal of rheumatology. Supplement.

[89]  P. Tugwell,et al.  Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The Methotrexate-Cyclosporine Combination Study Group. , 1995, The New England journal of medicine.

[90]  S. Epstein,et al.  AzaThioprine alone is bone sparing and does not alter cyclosporin A‐induced osteopenia in the rat , 1995, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[91]  F. Breedveld,et al.  Elderly-onset rheumatoid arthritis. , 1994, Seminars in arthritis and rheumatism.

[92]  R. Müller-Suúr,et al.  Renal effects of low dose methotrexate in rheumatoid arthritis. , 1993, The Journal of rheumatology.

[93]  G. Appel,et al.  Cyclosporine: nephrotoxic effects and guidelines for safe use in patients with rheumatoid arthritis. , 1992, Seminars in arthritis and rheumatism.

[94]  D. Heijde,et al.  Older versus younger onset rheumatoid arthritis: results at onset and after 2 years of a prospective followup study of early rheumatoid arthritis. , 1991 .

[95]  B. Julian,et al.  Rapid loss of vertebral mineral density after renal transplantation. , 1991, The New England journal of medicine.

[96]  Q. Whiting-O'Keefe,et al.  Methotrexate and histologic hepatic abnormalities: a meta-analysis. , 1991, The American journal of medicine.

[97]  A. Lok,et al.  Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study. , 1991 .

[98]  M. Elstein,et al.  The effect of prostaglandin synthetase inhibitors on human preovulatory follicular fluid prostaglandin, thromboxane, and leukotriene concentrations. , 1990, The Journal of clinical endocrinology and metabolism.

[99]  A. Silman,et al.  Mortality and survival in rheumatoid arthritis: a 25 year prospective study of 100 patients. , 1990, Annals of the rheumatic diseases.

[100]  S. Epstein,et al.  Cyclosporin-A in vivo produces severe osteopenia in the rat: effect of dose and duration of administration. , 1988, Endocrinology.

[101]  C. Christiansen,et al.  Bone mass in rheumatoid arthritis , 1987 .

[102]  M. Guttadauria,et al.  Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial. , 1985, Arthritis and rheumatism.

[103]  C. O'Morain,et al.  Reversible male infertility due to sulphasalazine: studies in man and rat. , 1984, Gut.

[104]  P. Rokkanen,et al.  Chloroquine treatment and bone changes in rheumatoid arthritis. , 1976, Scandinavian journal of rheumatology.

[105]  V. Fischer,et al.  Affinity of chloroquine for bone , 1975, The Journal of pharmacy and pharmacology.

[106]  J. Graef,et al.  Methotrexate-induced congenital malformations. , 1968, The Journal of pediatrics.