Background: The incidence of severe infections is increased under biologic therapies and the skin is the second localization. Objective: To appraise the factors associated with severe skin infections (SSI) in patients under biologic therapies for inflammatory rheumatic diseases (IRD). Methods: We performed a case-control (ratio 1:3) study nested in a prospective cohort of patients with IRD. SSI was defined as requiring hospitalization or intravenous anti-infectious therapy. We defined two imbedded periods: period A was the time window between the first biologic therapy and the SSI; period B was the last 3 or 12 months (for tumor necrosis factor blockers or rituximab, respectively) before the SSI. Results: Among 4,361 patients with IRD, 29 had a SSI under biologic therapy. In multivariate analyses, SSI were significantly associated with smoking, baseline C-reactive protein and gammaglobulinemia, non-steroidal anti-inflammatory drugs before biologic therapy, cumulative dose of steroids, concomitant steroids during period A, number of different biologic therapies during period A, treatment with infliximab during period A, period B or as first biologic therapy and treatment at high dose during period B. Conclusion: In patients under biologic therapies for IRD, the risk of SSI is associated with several factors including tobacco, treatment with infliximab or high dose range.

1.
Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M, Lipsky P: Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999;354:1932–1939.
2.
Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh A, Racewicz AJ, van Vollenhoven RF, Li NF, Agarwal S, Hessey EW, Shaw TM: The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 2006;54:1390–1400.
3.
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. N Engl J Med 1999;340:253–259.
4.
Genovese MC, Bathon JM, Fleischmann RM, Moreland LW, Martin RW, Whitmore JB, Tsuji WH, Leff JA: Longterm safety, efficacy, and radiographic outcome with etanercept treatment in patients with early rheumatoid arthritis. J Rheumatol 2005;32:1232–1242.
5.
Furst DE, Schiff MH, Fleischmann RM, Strand V, Birbara CA, Compagnone D, Fischkoff SA, Chartash EK: Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). J Rheumatol 2003;30:2563–2571.
6.
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, Maini RN: Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 2000;343:1594–1602.
7.
Weinblatt ME, Keystone EC, Furst DE, Kavanaugh AF, Chartash EK, Segurado OG: Long term efficacy and safety of adalimumab plus methotrexate in patients with rheumatoid arthritis: ARMADA 4 year extended study. Ann Rheum Dis 2006;65:753–759.
8.
van de Putte LB, Atkins C, Malaise M, Sany J, Russell AS, van Riel PL, Settas L, Bijlsma JW, Todesco S, Dougados M, Nash P, Emery P, Walter N, Kaul M, Fischkoff S, Kupper H: Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Ann Rheum Dis 2004;63:508–516.
9.
van der Heijde D, Klareskog L, Rodriguez-Valverde V, Codreanu C, Bolosiu H, Melo-Gomes J, Tornero-Molina J, Wajdula J, Pedersen R, Fatenejad S: Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: two-year clinical and radiographic results from the TEMPO study, a double-blind, randomized trial. Arthritis Rheum 2006;54:1063–1074.
10.
Moreland LW, Weinblatt ME, Keystone EC, Kremer JM, Martin RW, Schiff MH, Whitmore JB, White BW: Etanercept treatment in adults with established rheumatoid arthritis: 7 years of clinical experience. J Rheumatol 2006;33:854–861.
11.
Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ, Weaver AL, Keystone EC, Furst DE, Mease PJ, Ruderman EM, Horwitz DA, Arkfeld DG, Garrison L, Burge DJ, Blosch CM, Lange ML, McDonnell ND, Weinblatt ME: Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med 1999;130:478–486.
12.
Kroesen S, Widmer AF, Tyndall A, Hasler P: Serious bacterial infections in patients with rheumatoid arthritis under anti-TNF-alpha therapy. Rheumatology (Oxford) 2003;42:617–621.
13.
Dixon WG, Symmons DP, Lunt M, Watson KD, Hyrich KL, Silman AJ: Serious infection following anti-tumor necrosis factor alpha therapy in patients with rheumatoid arthritis: lessons from interpreting data from observational studies. Arthritis Rheum 2007;56:2896–2904.
14.
Listing J, Strangfeld A, Kary S, Rau R, von Hinueber U, Stoyanova-Scholz M, Gromnica-Ihle E, Antoni C, Herzer P, Kekow J, Schneider M, Zink A: Infections in patients with rheumatoid arthritis treated with biologic agents. Arthritis Rheum 2005;52:3403–3412.
15.
Salliot C, Gossec L, Ruyssen-Witrand A, Luc M, Duclos M, Guignard S, Dougados M: Infections during tumour necrosis factor-alpha blocker therapy for rheumatic diseases in daily practice: a systematic retrospective study of 709 patients. Rheumatology (Oxford) 2007;46:327–334.
16.
Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V: 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 2006;295:2275–2285.
17.
Alonso-Ruiz A, Pijoan JI, Ansuategui E, Urkaregi A, Calabozo M, Quintana A: Tumor necrosis factor alpha drugs in rheumatoid arthritis: systematic review and metaanalysis of efficacy and safety. BMC Musculoskelet Disord 2008;9:52.
18.
Dixon WG, Watson K, Lunt M, Hyrich KL, Silman AJ, Symmons DP: 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 2006;54:2368–2376.
19.
Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE: Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum 2002;46:2287–2293.
20.
Curtis JR, Patkar N, Xie A, Martin C, Allison JJ, Saag M, Shatin D, Saag KG: Risk of serious bacterial infections among rheumatoid arthritis patients exposed to tumor necrosis factor alpha antagonists. Arthritis Rheum 2007;56:1125–1133.
21.
Leombruno JP, Einarson TR, Keystone EC: The safety of anti-tumour necrosis factor treatments in rheumatoid arthritis: meta and exposure-adjusted pooled analyses of serious adverse events. Ann Rheum Dis 2009;68:1136–1145.
22.
Mohrbacher A: B cell non-Hodgkin’s lymphoma: rituximab safety experience. Arthritis Res Ther 2005;7(suppl 3):S19–S25.
23.
Salliot C, Dougados M, Gossec L: Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of randomised placebo-controlled trials. Ann Rheum Dis 2009;68:25–32.
24.
Teichmann LL, Woenckhaus M, Vogel C, Salzberger B, Scholmerich J, Fleck M: Fatal Pneumocystis pneumonia following rituximab administration for rheumatoid arthritis. Rheumatology (Oxford) 2008;47:1256–1257.
25.
Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T: Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572–2581.
26.
Arnett FC, Edworthy SM, Bloch DA, et al: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–324.
27.
Amor B, Dougados M, Listrat V, et al: Are classification criteria for spondylarthropathy useful as diagnostic criteria? Rev Rhum Engl Ed 1995;62:10–15.
28.
Braun J, Pham T, Sieper J, Davis J, van der Linden S, Dougados M, van der Heijde D: International ASAS consensus statement for the use of anti-tumour necrosis factor agents in patients with ankylosing spondylitis. Ann Rheum Dis 2003;62:817–824.
29.
Prevoo ML, van ’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL: Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38:44–48.
30.
Xu Z, Seitz K, Fasanmade A, Ford J, Williamson P, Xu W, Davis HM, Zhou H: Population pharmacokinetics of infliximab in patients with ankylosing spondylitis. J Clin Pharmacol 2008;48:681–695.
31.
Weisman MH, Moreland LW, Furst DE, Weinblatt ME, Keystone EC, Paulus HE, Teoh LS, Velagapudi RB, Noertersheuser PA, Granneman GR, Fischkoff SA, Chartash EK: Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully human anti-tumor necrosis factor-alpha monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant methotrexate: a pilot study. Clin Ther 2003;25:1700–1721.
32.
Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, DeWoody KL, Schaible TF, Rutgeerts PJ: A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 1997;337:1029–1035.
33.
den Broeder A, van de Putte L, Rau R, Schattenkirchner M, Van Riel P, Sander O, Binder C, Fenner H, Bankmann Y, Velagapudi R, Kempeni J, Kupper H: A single dose, placebo controlled study of the fully human anti-tumor necrosis factor-alpha antibody adalimumab (D2E7) in patients with rheumatoid arthritis. J Rheumatol 2002;29:2288–2298.
34.
Moore A, Gordon KB, Kang S, Gottlieb A, Freundlich B, Xia HA, Stevens SR: A randomized, open-label trial of continuous versus interrupted etanercept therapy in the treatment of psoriasis. J Am Acad Dermatol 2007;56:598–603.
35.
Breedveld F, Agarwal S, Yin M, Ren S, Li NF, Shaw TM, Davies BE: Rituximab pharmacokinetics in patients with rheumatoid arthritis: B-cell levels do not correlate with clinical response. J Clin Pharmacol 2007;47:1119–1128.
36.
Strangfeld A, Listing J, Herzer P, Liebhaber A, Rockwitz K, Richter C, Zink A: Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA 2009;301:737–744.
37.
Perez-Sola MJ, Torre-Cisneros J, Perez-Zafrilla B, Carmona L, Descalzo MA, Gomez-Reino JJ: Infections in patients treated with tumor necrosis factor antagonists: incidence, etiology and mortality in the BIOBADASER registry. Med Clin (Barc) 2011;137:533–540.
38.
Kinder A, Stephens S, Mortimer N, Sheldon P: Severe herpes zoster after infliximab infusion. Postgrad Med J 2004;80:26.
39.
Manzano V, Ruiz P, Torres M, Gomez F: Severe pneumonia by aciclovir-resistant varicella-zoster virus during etanercept therapy. Rheumatology (Oxford) 2010;49:1791–1793.
40.
Failla V, Nikkels AF: Ustekinumab and herpes zoster. Dermatology 2011;222:119–122.
41.
Arcavi L, Benowitz NL: Cigarette smoking and infection. Arch Intern Med 2004;164:2206–2216.
42.
Dupuy A, Benchikhi H, Roujeau JC, Bernard P, Vaillant L, Chosidow O, Sassolas B, Guillaume JC, Grob JJ, Bastuji-Garin S: Risk factors for erysipelas of the leg (cellulitis): case-control study. BMJ 1999;318:1591–1594.
43.
Bjornsdottir S, Gottfredsson M, Thorisdottir AS, Gunnarsson GB, Rikardsdottir H, Kristjansson M, Hilmarsdottir I: Risk factors for acute cellulitis of the lower limb: a prospective case-control study. Clin Infect Dis 2005;41:1416–1422.
44.
Mokni M, Dupuy A, Denguezli M, Dhaoui R, Bouassida S, Amri M, Fenniche S, Zeglaoui F, Doss N, Nouira R, Ben Osman-Dhahri A, Zili J, Mokhtar I, Kamoun MR, Zahaf A, Chosidow O: Risk factors for erysipelas of the leg in Tunisia: a multicenter case-control study. Dermatology 2006;212:108–112.
45.
Halpern J, Holder R, Langford NJ: Ethnicity and other risk factors for acute lower limb cellulitis: a U.K.-based prospective case-control study. Br J Dermatol 2008;158:1288–1292.
46.
Franklin J, Lunt M, Bunn D, Symmons D, Silman A: Risk and predictors of infection leading to hospitalisation in a large primary-care-derived cohort of patients with inflammatory polyarthritis. Ann Rheum Dis 2007;66:308–312.
47.
Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE: Predictors of infection in rheumatoid arthritis. Arthritis Rheum 2002;46:2294–2300.
48.
Harrison BJ, Silman AJ, Wiles NJ, Scott DG, Symmons DP: The association of cigarette smoking with disease outcome in patients with early inflammatory polyarthritis. Arthritis Rheum 2001;44:323–330.
49.
Symmons DP, Bankhead CR, Harrison BJ, Brennan P, Barrett EM, Scott DG, Silman AJ: Blood transfusion, smoking, and obesity as risk factors for the development of rheumatoid arthritis: results from a primary care-based incident case-control study in Norfolk, England. Arthritis Rheum 1997;40:1955–1961.
50.
Sugiyama D, Nishimura K, Tamaki K, Tsuji G, Nakazawa T, Morinobu A, Kumagai S: Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis 2010;69:70–81.
51.
Manfredsdottir VF, Vikingsdottir T, Jonsson T, Geirsson AJ, Kjartansson O, Heimisdottir M, Sigurdardottir SL, Valdimarsson H, Vikingsson A: The effects of tobacco smoking and rheumatoid factor seropositivity on disease activity and joint damage in early rheumatoid arthritis. Rheumatology (Oxford) 2006;45:734–740.
52.
Masdottir B, Jonsson T, Manfredsdottir V, Vikingsson A, Brekkan A, Valdimarsson H: Smoking, rheumatoid factor isotypes and severity of rheumatoid arthritis. Rheumatology (Oxford) 2000;39:1202–1205.
53.
Averns HL, Oxtoby J, Taylor HG, Jones PW, Dziedzic K, Dawes PT: Smoking and outcome in ankylosing spondylitis. Scand J Rheumatol 1996;25:138–142.
54.
Ward MM, Weisman MH, Davis JC Jr, Reveille JD: Risk factors for functional limitations in patients with long-standing ankylosing spondylitis. Arthritis Rheum 2005;53:710–717.
55.
Hassett JM: Humoral immunodeficiency: a review. Pediatr Ann 1987;16:404–411.
56.
Salmon-Ceron D, Tubach F, Lortholary O, Chosidow O, Bretagne S, Nicolas N, Cuillerier E, Fautrel B, Michelet C, Morel J, Puechal X, Wendling D, Lemann M, Ravaud P, Mariette X: Drug-specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3-year prospective French RATIO registry. Ann Rheum Dis 2011;70:616–623.
57.
Dixon WG, Hyrich KL, Watson KD, Lunt M, Galloway J, Ustianowski A, Symmons DP: Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis 2010;69:522–528.
58.
Tubach F, Salmon D, Ravaud P, Allanore Y, Goupille P, Breban M, Pallot-Prades B, Pouplin S, Sacchi A, Chichemanian RM, Bretagne S, Emilie D, Lemann M, Lortholary O, Mariette X: Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: the three-year prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum 2009;60:1884–1894.
59.
Wallis RS, Broder MS, Wong JY, Hanson ME, Beenhouwer DO: Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 2004;38:1261–1265.
60.
Westhovens R, Yocum D, Han J, Berman A, Strusberg I, Geusens P, Rahman MU: The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis Rheum 2006;54:1075–1086.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.