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Journal ArticleDOI

Emergence of Legionella pneumophila Pneumonia in Patients Receiving Tumor Necrosis Factor–α Antagonists

TL;DR: In patients receiving anti-TNF-alpha who develop pneumonia, legionellosis should be systematically investigated, and first-line antibiotic therapy should be efficient against L. pneumophila.
Abstract: Background Patients treated with tumor necrosis factor-alpha (TNF-alpha) antagonists have an increased risk of infection, but infection due to Legionella pneumophila has rarely been described in patients receiving such therapy. Methods A registry involving 486 clinical departments in France was designed by a multidisciplinary group (Recherche Axee sur la Tolerance des Biotherapies [RATIO]) to collect data on opportunistic and severe infections occurring in patients treated with TNF-alpha antagonists. All cases are reported to RATIO in accordance with national health authorities and validated by infectious disease experts. The legionellosis rate among patients treated with TNF-alpha antagonists was compared with the rate in France overall. Results We report a 1-year consecutive series of 10 cases of L. pneumophila pneumonia in France in 2004, including 6 cases treated with adalimumab, 2 treated with etanercept, and 2 treated with infliximab. The median patient age was 51 years (range, 40-69 years). Eight patients were treated for rheumatoid arthritis, 1 was treated for cutaneous psoriasis, and 1 was treated for pyoderma gangrenosum. The median duration of TNF-alpha antagonist treatment at onset of infection was 38.5 weeks (range, 3-73 weeks). Eight patients were receiving concomitant treatment with corticosteroids, and 6 were receiving treatment with methotrexate. The relative risk of legionellosis when receiving treatment with a TNF-alpha antagonist, compared with the relative risk in France overall, was estimated to be between 16.5 and 21.0. We also report a second episode of confirmed legionellosis following the reintroduction of infliximab therapy. Conclusions L. pneumophila pneumonia is a potentially severe but curable infection that might complicate anti-TNF-alpha therapy. In patients receiving anti-TNF-alpha who develop pneumonia, legionellosis should be systematically investigated, and first-line antibiotic therapy should be efficient against L. pneumophila.
Citations
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Journal ArticleDOI
TL;DR: There is good evidence for the efficacy of biological agents in patients with RA and safety data confirm an increased risk of bacterial infection and TB with TNFi compared with conventional DMARDs.
Abstract: Objectives To review the evidence for the efficacy and safety of biological agents in patients with rheumatoid arthritis (RA) to provide data to develop treatment recommendations by the European League Against Rheumatism (EULAR) Task Force. Methods Medline, Embase and Cochrane databases were searched for relevant articles on infliximab (IFX), etanercept (ETN), adalimumab (ADA), certolizumab-pegol (CZP), golimumab (GLM), anakinra (ANA), abatacept (ABT), rituximab (RTX) and tocilizumab (TCZ) published between 1962 and February 2009; published abstracts from the 2007–2008 American College of Rheumatology (ACR) and EULAR conference were obtained. Results 87 articles and 40 abstracts were identified. In methotrexate (MTX) naive patients, biological therapy with IFX, ETN, ADA, GLM or ABT has been shown to improve clinical outcomes (level of evidence 1B). In MTX/other synthetic disease-modifying antirheumatic drug (DMARD) failures all nine biological agents confer benefit (1B), with lower efficacy noted for ANA. RTX, ABT, TCZ and GLM demonstrate efficacy in tumour necrosis factor inhibitor (TNFi) failures (1B). Less evidence exists for switching between IFX, ETN and ADA (3B). Biological and MTX combination therapy is more efficacious than a biological agent alone (1B). A safety review shows no increased malignancy risk compared with conventional DMARDs (3B). TNFi are generally associated with an increased risk of serious bacterial infection, particularly within the first 6 months of treatment initiation; increased tuberculosis (TB) rates with TNFi are highest with the monoclonal antibodies (3B). Conclusions There is good evidence for the efficacy of biological agents in patients with RA. Safety data confirm an increased risk of bacterial infection and TB with TNFi compared with conventional DMARDs.

418 citations

Journal ArticleDOI
TL;DR: Various and severe OIs, especially those with intracellular micro-organisms, may develop in patients receiving anti-TNF treatment and steroid use >10 mg/day are independently associated with OI.
Abstract: Background Anti-tumour necrosis factor (TNF) therapy may be associated with opportunistic infections (OIs). Objective To describe the spectrum of non-tuberculosis OIs associated with anti-TNF therapy and identify their risk factors. Methods A 3-year national French registry (RATIO) collected all cases of OI in patients receiving anti-TNF treatment for any indication in France. A case–control study was performed with three controls treated with anti-TNF agents per case, matched for gender and underlying inflammatory disease. Results 45 cases were collected of non-TB OIs in 43 patients receiving infliximab (n=29), adalimumab (n=10) or etanercept (n=4) for rheumatoid arthritis (n=26), spondyloarthritides (n=3), inflammatory colitis (n=8), psoriasis (n=1) or other conditions (n=5). One-third (33%) of OIs were bacterial (4 listeriosis, 4 nocardiosis, 4 atypical mycobacteriosis, 3 non-typhoid salmonellosis), 40% were viral (8 severe herpes zoster, 3 varicella, 3 extensive herpes simplex, 4 disseminated cytomegalovirus infections), 22% were fungal (5 pneumocystosis, 3 invasive aspergillosis, 2 cryptococcosis) and 4% were parasitic (2 leishmaniasis). Ten patients (23%) required admission to the intensive care unit, and four patients (9%) died. Risk factors for OIs were treatment with infliximab (OR=17.6 (95% CI 4.3 - 72.9); p 10 mg/day or intravenous boluses during the previous year (OR=6.3 (2.0 to 20.0); p=0.002). Conclusion Various and severe OIs, especially those with intracellular micro-organisms, may develop in patients receiving anti-TNF treatment. Monoclonal anti-TNF antibody rather than soluble TNF receptor therapy and steroid use >10 mg/day are independently associated with OI.

273 citations

Journal ArticleDOI
TL;DR: Although suggestive, data for abatacept and rituximab are less definitive and longer periods of patient exposure to these agents are needed before an assessment of their risks can be made, all marketed TNF inhibitors appear to increase the risk of serious and nonserious infections compared with DMARDs.

268 citations

Journal ArticleDOI
TL;DR: The establishment of biological registries in rheumatic diseases, in France, with their different methods, has already provided additional data to controlled trials, mainly on the risk of severe infections and lymphoma.
Abstract: Objectives. Clinical registries have shown their effectiveness in capturing the long-term benefit of drugs in routine care. In France, two types of registry have been established to analyse the safety and efficacy of biological agents. Methods. The Research Axed on Tolerance of Biotherapies (RATIO) registry was designed to prospectively collect all cases of lymphoma and opportunistic infections occurring in patients receiving anti-TNF blockers for any indication. We also examined the results from nationwide prospective cohorts in order to investigate the safety and efficacy of rituximab (RTX), abatacept (ABA) and tocilizumab in RA and other autoimmune diseases. Results. Analysis of the RATIO registry demonstrated an increased risk of Legionella pneumophila infection in patients receiving anti-TNF therapy, a higher risk of tuberculosis [odds ratio (OR) (95% CI): 13.3 (2.6, 69.0) and 17.1 (3.6, 80.6) for infliximab and adalimumab vs etanercept, respectively], opportunistic infections and incidence of lymphoma, with mAb than with soluble-receptor anti-TNF. The characteristics of RA patients in RTX and ABA registries showed that some patients did not receive previous TNF blockers [20% in autoimmunity and RTX (AIR) and 13% in Orencia and RA (ORA)] and one-third of them were treated without concomitant DMARDs. Patients receiving RTX showed an increased proportion of severe infections (5.0/100 patient-years). Lung and cardiac comorbidities, extra-articular involvement and low immunoglobulin G before RTX were predictive factors of severe infections. In addition, the AIR registry suggested the effectiveness of RTX in patients with SLE. Conclusion. The establishment of biological registries in rheumatic diseases, in France, with their different methods, has already provided additional data to controlled trials, mainly on the risk of severe infections and lymphoma.

163 citations

References
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Journal ArticleDOI
TL;DR: Infliximab is a humanized antibody against tumor necrosis factor α (TNF-α) that is used in the treatment of Crohn's disease and rheumatoid arthritis but there is no direct evidence of a protective role of TNF- α in patients with tuberculosis.
Abstract: Background Infliximab is a humanized antibody against tumor necrosis factor α (TNF-α) that is used in the treatment of Crohn's disease and rheumatoid arthritis. Approximately 147,000 patients throughout the world have received infliximab. Excess TNF-α in association with tuberculosis may cause weight loss and night sweats, yet in animal models it has a protective role in the host response to tuberculosis. There is no direct evidence of a protective role of TNF-α in patients with tuberculosis. Methods We analyzed all reports of tuberculosis after infliximab therapy that had been received as of May 29, 2001, through the MedWatch spontaneous reporting system of the Food and Drug Administration. Results There were 70 reported cases of tuberculosis after treatment with infliximab for a median of 12 weeks. In 48 patients, tuberculosis developed after three or fewer infusions. Forty of the patients had extrapulmonary disease (17 had disseminated disease, 11 lymph-node disease, 4 peritoneal disease, 2 pleural dis...

3,405 citations

Journal ArticleDOI
TL;DR: Current slow-acting antirheumatic drugs have limited efficacy and many side effects and do not improve the long-term prognosis of rheumatoid arthritis.
Abstract: Rheumatoid arthritis is a common chronic inflammatory and destructive arthropathy that cannot be cured and that has substantial personal, social, and economic costs. The long-term prognosis is poor: 80 percent of affected patients are disabled after 20 years,1 and life expectancy is reduced by an average of 3 to 18 years.2 The medical cost of rheumatoid arthritis averages $5,919 per case per year in the United States3 and approximately £2,600 per case per year in the United Kingdom.4 Current slow-acting antirheumatic drugs have limited efficacy and many side effects. Moreover, they do not improve the long-term prognosis of rheumatoid arthritis. . . .

2,180 citations


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Journal ArticleDOI
TL;DR: With increasing doses the rate of occurrence of infectious complications increased in Patients given corticosteroids as well as in patients given placebo, a finding suggesting that not only the Corticosteroid but also the underlying disease state account for the steroid-associated infectious complications observed in clinical practice.
Abstract: The association between corticosteroid therapy and subsequent infections was calculated by pooling data from 71 controlled clinical trials. The overall rate of infectious complications was 12.7% in the 2,111 patients randomly allocated to systemic corticosteroids and 8.0% in the 2,087 controls (relative risk [RR], 1.6; 95% confidence interval [CI], 1.3-1.9; P less than .001). The risk of infection was particularly high in patients with neurologic diseases (RR, 2.8; 95% CI, 1.9-4.3; P less than .001) and less pronounced in patients with intestinal (RR, 1.4; 95% CI, 1.1-1.7; P = .02), hepatic (RR, 1.4; 95% CI, 0.9-2.3; P = .25), and renal (RR greater than 1; P = .03) diseases. The rate was not increased in patients given a daily dose of less than 10 mg or a cumulative dose of less than 700 mg of prednisone. With increasing doses the rate of occurrence of infectious complications increased in patients given corticosteroids as well as in patients given placebo, a finding suggesting that not only the corticosteroid but also the underlying disease state account for the steroid-associated infectious complications observed in clinical practice.

764 citations


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  • ...therapy [24–26]....

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Journal ArticleDOI
TL;DR: Tuberculin skin testing (TST) should be undertaken before any significant immunosuppressive therapy including these agents, though the possibility of false-negative reactions in immunocompromised populations must be borne in mind.
Abstract: Cases of active tuberculosis have been reported worldwide with the use of therapeutic agents that inhibit tumour necrosis factor (TNF) alpha. TNFalpha has a central role in mycobacterial infection and disease. Accordingly, progression of recently acquired tuberculosis infection or reactivation of remotely acquired infection should be expected with the use of anti-TNF agents. The available in-vitro and epidemiological evidence for the two currently approved agents, infliximab and etanercept, shows that the risk of development of active tuberculosis is greater with infliximab. Tuberculin skin testing (TST) should be undertaken before any significant immunosuppressive therapy including these agents, though the possibility of false-negative reactions in immunocompromised populations must be borne in mind. A positive TST should be followed by medical assessment and chest radiography, as well as by other tests judged appropriate by the physician to identify active disease. Active tuberculosis must be treated appropriately before initiation of treatment with an anti-TNF agent. Treatment of latent tuberculosis can be considered on an individual basis for TST-negative patients receiving anti-TNF agents when significant risk factors for infection are present.

740 citations

Journal ArticleDOI
TL;DR: Synovial fluids from 6 of 12 patients with rheumatoid arthritis and from 3 of 11 patients with reactive arthritis contained measurable levels of tumor necrosis factor alpha (TNF alpha), and Gamma-interferon was detected in the synovial fluid and sera of only the RA patients.
Abstract: Synovial fluids from 6 of 12 patients with rheumatoid arthritis (RA) and from 3 of 11 patients with reactive arthritis contained measurable levels of tumor necrosis factor α (TNFα). Seven of 12 sera from RA patients contained TNFα, while only 1 of those from reactive arthritis patients was positive. Gamma-interferon was detected in the synovial fluids and sera of only the RA patients. Tumor necrosis factor β was not detected in any sera or synovial fluids. RA patients with detectable TNFα had higher erythrocyte sedimentation rates and synovial fluid leukocyte counts.

580 citations


Additional excerpts

  • ...eases [1–3], and TNF-a antagonists are increasingly...

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