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Biologic therapies and infections in the daily practice of three Italian rheumatologic units: a prospective, observational study

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Abstract

Since the introduction of biologics, many concerns about the increased risk of infections have been reported and, to date, the real impact of infections on the daily practice in the rheumatologic centers is still largely unknown. In this work, we evaluated the infection rates associated with the use of biologics in a large cohort of patients. A prospective study, between January 2010 and December 2013, enrolling 731 rheumatic patients, was performed. Demographic and disease characteristics, therapies, comorbidities, and infectious events were recorded and statistically analyzed by multivariate analysis. Two-hundred thirty-five infectious episodes were observed in 28.4 % of patients. About total infections, bacteria were identified in 70.6 % of total cases and viruses in 18.3 %. The most common site of not-serious infection was the urinary tract. Duration of disease, longer follow-up, concomitant steroid therapy, and comorbidities were significantly associated with not-serious infection. In our cohort, 17 episodes fulfilled the criteria of serious infection and occurred in 17 different patients (2.3 %), the majority involving the lower respiratory tract. Serious infections were associated with the beginning of biologics in older age. Our prospective, observational study showed that, in daily practice, a lesser rate of serious as well as not-serious infections may be observed in rheumatic patients treated with biologics than those reported in previous papers. The most common sites of not-serious infections are both the urinary and the respiratory tracts, and for serious infections, the respiratory tract. When pathogens were isolated, we did not find any multidrug-resistant organism.

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References

  1. Singh JA, Wells GA, Christensen R, Tanjong Ghogomu E, Maxwell L, Macdonald JK et al (2011) Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev 16:CD008794

    Google Scholar 

  2. Listing J, Gerhold K, Zink A (2013) The risk of infections associated with rheumatoid arthritis, with its comorbidity and treatment. Rheumatology (Oxford) 52:53–61

    Article  CAS  Google Scholar 

  3. Ruderman EM (2012) Overview of safety of non-biologic and biologic DMARDs. Rheumatology (Oxford) 51:vi37–vi43

    Article  Google Scholar 

  4. Singh JA, Cameron C, Noorbaloochi S, Cullis T, Tucker M, Christensen R et al (2015) Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis. Lancet 18(386):258–265

    Article  Google Scholar 

  5. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V (2006) Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295:2275–2285

    Article  CAS  PubMed  Google Scholar 

  6. Leombruno JP, Einarson TR, Keystone EC (2009) The safety of anti-tumour necrosis factor treatments in rheumatoid arthritis: meta and exposure-adjusted pooled analyses of serious adverse events. Ann Rheum Dis 68:1136–1145

    Article  CAS  PubMed  Google Scholar 

  7. Salliot C, Dougados M, Gossec L (2009) Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of randomised placebo-controlled trials. Ann Rheum Dis 68:25–32

    Article  CAS  PubMed  Google Scholar 

  8. Thompson AE, Rieder SW, Pope JE (2011) Tumor necrosis factor therapy and the risk of serious infection and malignancy in patients with early rheumatoid arthritis: a meta-analysis of randomized controlled trials. Arthritis Rheum 63:1479–1485

    Article  CAS  PubMed  Google Scholar 

  9. Sokka T, Pincus T (2003) Most patients receiving routine care for rheumatoid arthritis in 2001 did not meet inclusion criteria for most recent clinical trials or American College of Rheumatology criteria for remission. J Rheumatol 30:1138–1146

    PubMed  Google Scholar 

  10. Sokka T, Pincus T (2003) A historical perspective concerning population-based and clinical studies of early arthritis and early rheumatoid arthritis. Clin Exp Rheumatol 21:S5–14

    CAS  PubMed  Google Scholar 

  11. Dixon WG, Symmons DP, Lunt M, Watson KD, Hyrich KL, British Society for Rheumatology Biologics Register Control Centre Consortium, AJ S, British Society for Rheumatology Biologics Register (2007) Serious infection following anti-tumor necrosis factor alpha therapy in patients with rheumatoid arthritis: lessons from interpreting data from observational studies. Arthritis Rheum 56:2896–2904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Salliot C, Gossec L, Ruyssen-Witrand A, Luc M, Duclos M, Guignard S et al (2007) Infections during tumour necrosis factor-alpha blocker therapy for rheumatic diseases in daily practice: a systematic retrospective study of 709 patients. Rheumatology (Oxford) 46:327–334

    Article  CAS  Google Scholar 

  13. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd et al (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62:2569–2581

    Article  PubMed  Google Scholar 

  14. van der Linden S, Valkenburg HA, Cats A (1984) Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 27:361–368

    Article  PubMed  Google Scholar 

  15. Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, European Study Group on Classification Criteria for Sjögren’s Syndrome et al (2002) Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 61:554–558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H, CASPAR Study Group (2006) Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum 54:2665–2673

    Article  PubMed  Google Scholar 

  17. Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM et al (2012) 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 64:625–639

    Article  CAS  Google Scholar 

  18. Gossec L, Smolen JS, Gaujoux-Viala C, Ash Z, Marzo-Ortega H, van der Heijde D, European League Against Rheumatism et al (2012) European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies. Ann Rheum Dis 71:4–12

    Article  CAS  PubMed  Google Scholar 

  19. Smolen JS, Landewé R, Breedveld FC, Dougados M, Emery P, Gaujoux-Viala C et al (2010) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 69:964–975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Favalli EG, Desiati F, Atzeni F, Sarzi-Puttini P, Caporali R, Pallavicini FB et al (2009) Serious infections during anti-TNFalpha treatment in rheumatoid arthritis patients. Autoimmun Rev 8:266–273

    Article  CAS  PubMed  Google Scholar 

  21. Furst DE, Breedveld FC, Kalden JR, Smolen JS, Antoni CE, Bijlsma JW et al (2002) Updated consensus statement on biological agents for the treatment of rheumatoid arthritis and other rheumatic diseases (May 2002). Ann Rheum Dis 61:ii2–ii7

    Article  PubMed  PubMed Central  Google Scholar 

  22. Volkmann ER, Rezai S, Tarp S, Woodworth TG, Furst DE (2013) We still don’t know how to taper glucocorticoids in rheumatoid arthritis, and we can do better. J Rheumatol 40(10):1646–1649

    Article  CAS  PubMed  Google Scholar 

  23. Boers M, Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen JC et al (1997) Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 350(9074):309–318

    Article  CAS  PubMed  Google Scholar 

  24. Tengstrand B, Larsson E, Klareskog L, Hafström I (2007) Randomized withdrawal of long-term prednisolone treatment in rheumatoid arthritis: effects on inflammation and bone mineral density. Scand J Rheumatol 36(5):351–358

    Article  CAS  PubMed  Google Scholar 

  25. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM et al (2005) Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum 52(11):3381–3390

    Article  CAS  PubMed  Google Scholar 

  26. Choy EH, Smith CM, Farewell V, Walker D, Hassell A, Chau L, Scott DL, CARDERA (Combination Anti-Rheumatic Drugs in Early Rheumatoid Arhritis) Trial Group (2008) Factorial randomised controlled trial of glucocorticoids and combination disease modifying drugs in early rheumatoid arthritis. Ann Rheum Dis 67(5):656–663

    Article  CAS  PubMed  Google Scholar 

  27. Pincus T, Swearingen CJ, Luta G, Sokka T (2009) Efficacy of prednisone 1-4 mg/day in patients with rheumatoid arthritis: a randomised, double-blind, placebo controlled withdrawal clinical trial. Ann Rheum Dis 68(11):1715–1720

    Article  CAS  PubMed  Google Scholar 

  28. Hickling P, Jacoby RK, Kirwan JR (1998) Joint destruction after glucocorticoids are withdrawn in early rheumatoid arthritis. Arthritis and Rheumatism Council Low Dose Glucocorticoid Study Group. Br J Rheumatol 37(9):930–936

    Article  CAS  PubMed  Google Scholar 

  29. Furst DE (2010) The risk of infections with biologic therapies for rheumatoid arthritis. Semin Arthritis Rheum 39:327–346

    Article  CAS  PubMed  Google Scholar 

  30. Pincus T, Sokka T (2004) Should contemporary rheumatoid arthritis clinical trials be more like standard patient care and vice versa? Ann Rheum Dis 63:ii32–ii39

    PubMed  PubMed Central  Google Scholar 

  31. Strand V, Sokolove J (2009) Randomized controlled trial design in rheumatoid arthritis: the past decade. Arthritis Res Ther 11:205

    Article  PubMed  PubMed Central  Google Scholar 

  32. Vieira R, Fonseca R, Pinto JA, Costa L. Infections in an inpatient rheumatology unit: how big is the problem? Acta Reumatol Port 2015

  33. Bernatsky S, Hudson M, Suissa S (2007) Anti-rheumatic drug use and risk of serious infections in rheumatoid arthritis. Rheumatology (Oxford) 46:1157–1160

    Article  CAS  Google Scholar 

  34. Schneeweiss S, Setoguchi S, Weinblatt ME, Katz JN, Avorn J, Sax PE et al (2007) Anti-tumor necrosis factor alpha therapy and the risk of serious bacterial infections in elderly patients with rheumatoid arthritis. Arthritis Rheum 56:1754–1764

    Article  CAS  PubMed  Google Scholar 

  35. Dixon WG, Abrahamowicz M, Beauchamp ME, Ray DW, Bernatsky S, Suissa S et al (2012) Immediate and delayed impact of oral glucocorticoid therapy on risk of serious infection in older patients with rheumatoid arthritis: a nested case-control analysis. Ann Rheum Dis 71:1128–1133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. van der Goes MC, Jacobs JW, Bijlsma JW (2014) The value of glucocorticoid co-therapy in different rheumatic diseases—positive and adverse effects. Arthritis Res Ther 16:S2

    Article  PubMed  PubMed Central  Google Scholar 

  37. McMaster A, Ray DW (2008) Drug insight: selective agonists and antagonists of the glucocorticoid receptor. Nat Clin Pract Endocrinol Metab 4:91–101

    Article  CAS  PubMed  Google Scholar 

  38. Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE (2002) Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum 46(9):2287–2293

    Article  PubMed  Google Scholar 

  39. Sokka T, Kautiainen H, Toloza S, Mäkinen H, Verstappen SM, Lund Hetland M, QUEST-RA Group et al (2007) QUEST-RA: quantitative clinical assessment of patients with rheumatoid arthritis seen in standard rheumatology care in 15 countries. Ann Rheum Dis 66:1491–1496

    Article  PubMed  PubMed Central  Google Scholar 

  40. Sokka T, Kautiainen H, Pincus T, Toloza S, da Rocha Castelar Pinheiro G, Lazovskis J et al (2009) Disparities in rheumatoid arthritis disease activity according to gross domestic product in 25 countries in the QUEST RA database. Ann Rheum Dis 68:1666–1672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Putrik P, Ramiro S, Kvien TK, Sokka T, Pavlova M, Uhlig T, Working Group ‘Equity in access to treatment of rheumatoid arthritis in Europe’ et al (2014) Inequities in access to biologic and synthetic DMARDs across 46 European countries. Ann Rheum Dis 73:198–206

    Article  CAS  PubMed  Google Scholar 

  42. Putrik P, Ramiro S, Kvien TK, Sokka T, Uhlig T, Boonen A, Equity in Clinical Eligibility Criteria for RA treatment Working Group (2014) Variations in criteria regulating treatment with reimbursed biologic DMARDs across European countries. Are differences related to country’s wealth? Ann Rheum Dis 73:2010–2021

    Article  PubMed  Google Scholar 

  43. Gvozdenović E, Wolterbeek R, Allaart CF, Brenol C, Dougados M, Emery P et al (2015) Assessment of global disease activity in rheumatoid arthritis by patients and physicians: differences across countries in the METEOR database. J Clin Rheumatol 21:349–354

    Article  PubMed  Google Scholar 

  44. Au K, Reed G, Curtis JR, Kremer JM, Greenberg JD, Strand V, CORRONA Investigators et al (2011) High disease activity is associated with an increased risk of infection in patients with rheumatoid arthritis. Ann Rheum Dis 70:785–791

    Article  PubMed  Google Scholar 

  45. Wallis D, Thavaneswaran A, Haroon N, Ayearst R, Inman RD (2015) Tumour necrosis factor inhibitor therapy and infection risk in axial spondyloarthritis: results from a longitudinal observational cohort. Rheumatology (Oxford) 54:152–156

    Article  Google Scholar 

  46. Burmester GR, Panaccione R, Gordon KB, McIlraith MJ, Lacerda AP (2013) Adalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn’s disease. Ann Rheum Dis 72:517–524

    Article  CAS  PubMed  Google Scholar 

  47. Cantini F, Niccoli L, Goletti D (2014) Adalimumab, etanercept, infliximab, and the risk of tuberculosis: data from clinical trials, national registries, and postmarketing surveillance. J Rheumatol Suppl 91:47–55

    Article  CAS  PubMed  Google Scholar 

  48. Emery P, Gallo G, Boyd H, Morgan CL, Currie CJ, Poole CD et al (2014) Association between disease activity and risk of serious infections in subjects with rheumatoid arthritis treated with etanercept or disease-modifying anti-rheumatic drugs. Clin Exp Rheumatol 32:653–660

    PubMed  Google Scholar 

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Acknowledgments

The authors thank Mrs. Federica Sensini for her technical assistance.

Authors’ contributions

PC, OB were involved in the study conception and design, data interpretation, literature search, table creation, writing, paper revision, and acceptance. LN, PR, NM, and FC performed the data collection, data interpretation, literature search, paper revision, and acceptance. FM and MV performed the statistical analysis, revision, and acceptance. FDO, DPEM, VL, and PDB performed the data collection, literature search, paper revision, and acceptance. FPC, AA, and RG was involved in the study design, data interpretation, writing, paper revision, and acceptance. All authors gave their final approval for submitting the manuscript for review and agreed to be accountable for all aspects of the work.

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Authors and Affiliations

  1. Rheumatology Division, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Delta 6 Building, PO Box 67100, L’Aquila, Italy

    Paola Cipriani, Onorina Berardicurti, Piero Ruscitti, Vasiliki Liakouli, Paola Di Benedetto, Francesco Carubbi & Roberto Giacomelli

  2. Division of Medical Statistic Unit, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy

    Francesco Masedu & Marco Valenti

  3. Rheumatologic Clinic, University of Foggia, Foggia, Italy

    Francesca D’Onofrio, Nicola Maruotti & Francesco Paolo Cantatore

  4. Unit of Allergology, Immunology, Rheumatology, Campus Bio-Medico University, Rome, Italy

    Luca Navarini, Domenico Paolo Emanuele Margiotta & Antonella Afeltra

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  1. Paola Cipriani
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  2. Onorina Berardicurti
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  3. Francesco Masedu
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Correspondence to Paola Cipriani.

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Cipriani, P., Berardicurti, O., Masedu, F. et al. Biologic therapies and infections in the daily practice of three Italian rheumatologic units: a prospective, observational study. Clin Rheumatol 36, 251–260 (2017). https://doi.org/10.1007/s10067-016-3444-1

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