Skip to main content
Top
Published in: Rheumatology International 3/2017

Open Access 01-03-2017 | Safety and Pharmacovigillance

Long-term use of biologic agents does not increase the risk of serious infections in elderly patients with rheumatoid arthritis

Authors: Hirotoshi Kawashima, Shin-ichiro Kagami, Daisuke Kashiwakuma, Kentaro Takahashi, Masaya Yokota, Shunsuke Furuta, Itsuo Iwamoto

Published in: Rheumatology International | Issue 3/2017

Login to get access

Abstract

This study aimed to determine whether the long-term use of biologic agents increases serious infections in elderly patients with rheumatoid arthritis (RA) and to determine the risk factors of serious infections in biologics-treated elderly RA patients. We retrospectively analyzed the incidence rate of serious infections that required hospitalization between biologics-treated and non-biologic disease-modifying antirheumatic drug (DMARD)-treated elderly RA patients (aged over 65 years). We examined the risk factors for serious infections in biologics-treated elderly RA patients. We found that, during a 3-year observation period, the incidence rate of serious infections was not significantly different between biologics-treated and non-biologic DMARD-treated elderly RA patients [8.0 (95% CI 4.7–13.5) and 6.3 (95% CI 4.1–9.5) events per 100 person-years of follow-up, respectively, P = 0.78]. The time to the first serious infection did not significantly differ between the two groups by the analysis of the Kaplan–Meier curves, either (P = 0.46). We then found that prednisolone doses alone were significantly associated with serious infections in biologics-treated elderly RA patients. Furthermore, we found that prednisolone at 1–4 mg/day was associated with serious infections in biologics-treated patients, but not non-biologic DMARD-treated patients. On the other hand, prednisolone at greater than 5 mg/day was associated with serious infections in both biologics-treated and non-biologics-treated patients. We show that there is not a significant difference between the incidence of serious infections between biologics group and non-biologics group in elderly RA patients (≧65 years) and that even very low-dose glucocorticoid use (prednisolone 1–4 mg/day) is a risk factor for serious infections in biologics-treated elderly RA patients.
Literature
1.
go back to reference 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 64:625–639CrossRef 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 64:625–639CrossRef
2.
go back to reference Smolen JS, Landewe R, Breedveld FC, Buch M, Burmester G, Dougados M et al (2014) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 73:492–509CrossRefPubMed Smolen JS, Landewe R, Breedveld FC, Buch M, Burmester G, Dougados M et al (2014) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 73:492–509CrossRefPubMed
3.
go back to reference Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE (2002) Predictors of infection in rheumatoid arthritis. Arthritis Rheum 46:2294–2300CrossRefPubMed Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE (2002) Predictors of infection in rheumatoid arthritis. Arthritis Rheum 46:2294–2300CrossRefPubMed
4.
go back to reference Lacaille D, Guh DP, Abrahamowicz M, Anis AH, Esdaile JM (2008) Use of nonbiologic disease-modifying antirheumatic drugs and risk of infection in patients with rheumatoid arthritis. Arthritis Rheum 59:1074–1081CrossRefPubMed Lacaille D, Guh DP, Abrahamowicz M, Anis AH, Esdaile JM (2008) Use of nonbiologic disease-modifying antirheumatic drugs and risk of infection in patients with rheumatoid arthritis. Arthritis Rheum 59:1074–1081CrossRefPubMed
5.
go back to reference Salliot C, van der Heijde D (2009) Long-term safety of the methotrexate monotherapy in patients with rheumatoid arthritis: a systemic literature research. Ann Rheum Dis 68:1100–1104CrossRefPubMed Salliot C, van der Heijde D (2009) Long-term safety of the methotrexate monotherapy in patients with rheumatoid arthritis: a systemic literature research. Ann Rheum Dis 68:1100–1104CrossRefPubMed
6.
go back to reference Crowson CS, Hoganson DD, Fitz-Gibbon PD, Matteson EL (2012) Development and validation of a risk score for serious infection in patients with rheumatoid arthritis. Arthritis Rheum 64:2847–2855CrossRefPubMedPubMedCentral Crowson CS, Hoganson DD, Fitz-Gibbon PD, Matteson EL (2012) Development and validation of a risk score for serious infection in patients with rheumatoid arthritis. Arthritis Rheum 64:2847–2855CrossRefPubMedPubMedCentral
7.
go back to reference 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 295:2275–2285CrossRefPubMed 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 295:2275–2285CrossRefPubMed
8.
go back to reference Askling J, Fored CM, Brandt L, Baecklund E, Bertilsson L, Feltelius N et al (2007) Time dependent increase in risk of hospitalization with infection among Swedish RA patients treated with TNF antagonists. Ann Rheum Dis 66:1339–1344CrossRefPubMedPubMedCentral Askling J, Fored CM, Brandt L, Baecklund E, Bertilsson L, Feltelius N et al (2007) Time dependent increase in risk of hospitalization with infection among Swedish RA patients treated with TNF antagonists. Ann Rheum Dis 66:1339–1344CrossRefPubMedPubMedCentral
9.
go back to reference Galloway JB, Hyrich KL, Mercer LK, Dixon WG, Fu B, Ustianowski AP et al (2011) Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatology (Oxford) 50:124–131CrossRef Galloway JB, Hyrich KL, Mercer LK, Dixon WG, Fu B, Ustianowski AP et al (2011) Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatology (Oxford) 50:124–131CrossRef
10.
go back to reference Curtis JR, Xie F, Chen L, Baddley JW, Beukelman T, Saag KG et al (2011) The comparative risk of serious infections among rheumatoid arthritis patients starting or switching biological agents. Ann Rheum Dis 70:1401–1406CrossRefPubMedPubMedCentral Curtis JR, Xie F, Chen L, Baddley JW, Beukelman T, Saag KG et al (2011) The comparative risk of serious infections among rheumatoid arthritis patients starting or switching biological agents. Ann Rheum Dis 70:1401–1406CrossRefPubMedPubMedCentral
11.
go back to reference Dixon WG, Watson K, Lunt M, Hyrich KL, Silman AJ, Symmons DP et al (2006) Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum 54:2368–2376CrossRefPubMed Dixon WG, Watson K, Lunt M, Hyrich KL, Silman AJ, Symmons DP et al (2006) Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum 54:2368–2376CrossRefPubMed
12.
go back to reference Grijalva CG, Chen L, Delzell E, Baddley JW, Beukelman T, Winthrop KL et al (2011) Initiation of tumor necrosis factor-α antagonists and the risk of hospitalization for infection in patients with autoimmune diseases. JAMA 306:2331–2339CrossRefPubMedPubMedCentral Grijalva CG, Chen L, Delzell E, Baddley JW, Beukelman T, Winthrop KL et al (2011) Initiation of tumor necrosis factor-α antagonists and the risk of hospitalization for infection in patients with autoimmune diseases. JAMA 306:2331–2339CrossRefPubMedPubMedCentral
14.
go back to reference Grubeck-Loebenstein B, Berger P, Saurwein-Teissl M, Zisterer K, Wick G (1998) No immunity for the elderly. Nat Med 4:870CrossRefPubMed Grubeck-Loebenstein B, Berger P, Saurwein-Teissl M, Zisterer K, Wick G (1998) No immunity for the elderly. Nat Med 4:870CrossRefPubMed
15.
go back to reference Schneeweiss S, Setoguchi S, Weinblatt ME, Katz JN, Avorn J, Sax PE (2007) Anti-tumor Necrosis Factor α therapy and the risk of serious bacterial infections in elderly patients with rheumatoid arthritis. Arthritis Rheum 56:1754–1764CrossRefPubMed Schneeweiss S, Setoguchi S, Weinblatt ME, Katz JN, Avorn J, Sax PE (2007) Anti-tumor Necrosis Factor α therapy and the risk of serious bacterial infections in elderly patients with rheumatoid arthritis. Arthritis Rheum 56:1754–1764CrossRefPubMed
16.
go back to reference Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al (1998) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324CrossRef Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al (1998) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324CrossRef
17.
go back to reference Smitten AL, Choi HK, Hochberg MC, Suissa S, Simon TA, Testa MA et al (2008) The risk of hospitalized infection in patients with rheumatoid arthritis. J Rheumatol 35:387–393PubMed Smitten AL, Choi HK, Hochberg MC, Suissa S, Simon TA, Testa MA et al (2008) The risk of hospitalized infection in patients with rheumatoid arthritis. J Rheumatol 35:387–393PubMed
18.
go back to reference Wolfe F, Caplan L, Michaud K (2006) Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia; association with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy. Arthritis Rheum 54:628–634CrossRefPubMed Wolfe F, Caplan L, Michaud K (2006) Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia; association with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy. Arthritis Rheum 54:628–634CrossRefPubMed
19.
go back to reference Kroesen S, Widmer AF, Tyndall A, Hasler P (2003) Serious bacterial infections in patients with rheumatoid arthritis under anti-TNF-α therapy. Rheumatology (Oxford) 42:617–621CrossRef Kroesen S, Widmer AF, Tyndall A, Hasler P (2003) Serious bacterial infections in patients with rheumatoid arthritis under anti-TNF-α therapy. Rheumatology (Oxford) 42:617–621CrossRef
20.
go back to reference Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schweiterman WD et al (2001) Tuberculosis associated with infliximab, a tumor necrosis factor α—neutralizing agent. N Engl J Med 345:1098–1104CrossRefPubMed Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schweiterman WD et al (2001) Tuberculosis associated with infliximab, a tumor necrosis factor α—neutralizing agent. N Engl J Med 345:1098–1104CrossRefPubMed
21.
go back to reference Gomez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD, BIOBADASER Group (2003) Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum 48:2122–2127CrossRefPubMed Gomez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD, BIOBADASER Group (2003) Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum 48:2122–2127CrossRefPubMed
22.
go back to reference Takeuchi T, Tatsuki Y, Nogami Y, Ishiguro N, Tanaka Y, Yamanaka H et al (2008) Postmarketing surveillance of the safety profile of infliximab in 5000 Japanese patients with rheumatoid arthritis. Ann Rheum Dis 67:189–194CrossRefPubMed Takeuchi T, Tatsuki Y, Nogami Y, Ishiguro N, Tanaka Y, Yamanaka H et al (2008) Postmarketing surveillance of the safety profile of infliximab in 5000 Japanese patients with rheumatoid arthritis. Ann Rheum Dis 67:189–194CrossRefPubMed
23.
go back to reference St Clair EW, van der Heijde DM, Smolen JS, Maini RN, Bathon JM, Emery P et al (2004) Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 50:3432–3443CrossRefPubMed St Clair EW, van der Heijde DM, Smolen JS, Maini RN, Bathon JM, Emery P et al (2004) Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 50:3432–3443CrossRefPubMed
24.
go back to reference Greenberg JD, Reed G, Kremer JM, Tindall E, Kavanaugh A, Zheng C et al (2010) Association of methotrexate and tumor necrosis factor antagonists with risk of infectious outcomes including opportunistic infections in the CORRONA registry. Ann Rheum Dis 69:380–386CrossRefPubMed Greenberg JD, Reed G, Kremer JM, Tindall E, Kavanaugh A, Zheng C et al (2010) Association of methotrexate and tumor necrosis factor antagonists with risk of infectious outcomes including opportunistic infections in the CORRONA registry. Ann Rheum Dis 69:380–386CrossRefPubMed
25.
go back to reference Au K, Reed G, Curtis JR, Kremer JM, Greenberg JD, Strand V et al (2011) High disease activity is associated with an increased risk of infection in patients with rheumatoid arthritis. Ann Rheum Dis 70:785–791CrossRefPubMed Au K, Reed G, Curtis JR, Kremer JM, Greenberg JD, Strand V et al (2011) High disease activity is associated with an increased risk of infection in patients with rheumatoid arthritis. Ann Rheum Dis 70:785–791CrossRefPubMed
26.
go back to reference Strangfeld A, Eveslage M, Schneider M, Bergerhausen HJ, Klopsch T, Zink A et al (2011) Treatment benefit or survival of the fittest: what drives the time-dependent decrease in serious infection rates under TNF inhibition and what does this imply for the individual patient? Ann Rheum Dis 70:1914–1920CrossRefPubMedPubMedCentral Strangfeld A, Eveslage M, Schneider M, Bergerhausen HJ, Klopsch T, Zink A et al (2011) Treatment benefit or survival of the fittest: what drives the time-dependent decrease in serious infection rates under TNF inhibition and what does this imply for the individual patient? Ann Rheum Dis 70:1914–1920CrossRefPubMedPubMedCentral
27.
go back to reference Listing J, Gerhold K, Zink A (2013) The risk of infections associated with rheumatoid arthritis, with its comorbidity and treatment. Rheumatology (Oxford) 52:53–61CrossRef Listing J, Gerhold K, Zink A (2013) The risk of infections associated with rheumatoid arthritis, with its comorbidity and treatment. Rheumatology (Oxford) 52:53–61CrossRef
Metadata
Title
Long-term use of biologic agents does not increase the risk of serious infections in elderly patients with rheumatoid arthritis
Authors
Hirotoshi Kawashima
Shin-ichiro Kagami
Daisuke Kashiwakuma
Kentaro Takahashi
Masaya Yokota
Shunsuke Furuta
Itsuo Iwamoto
Publication date
01-03-2017
Publisher
Springer Berlin Heidelberg
Published in
Rheumatology International / Issue 3/2017
Print ISSN: 0172-8172
Electronic ISSN: 1437-160X
DOI
https://doi.org/10.1007/s00296-016-3631-z

Other articles of this Issue 3/2017

Rheumatology International 3/2017 Go to the issue