Tuberculosis Associated with Infliximab, a Tumor Necrosis Factor α–Neutralizing Agent

Keane, Joseph; Gershon, Sharon K.; Wise, Robert P.; Mirabile-Levens, Elizabeth; Kasznica, John; Schwieterman, William D.; Siegel, Jeffrey; Braun, M. Miles

doi:10.1056/nejmoa011110

Cited by 3,404 publications

(2,193 citation statements)

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“…Although anti-TNF␣ therapy seems to be generally well tolerated, severe side effects of both etanercept and infliximab have occurred in some rare cases (42)(43)(44)(45). The actual status of reported adverse events can be obtained from the FDA Web site at www.fda.gov.…”

Section: Discussionmentioning

confidence: 99%

Six‐month results of a double‐blind, placebo‐controlled trial of etanercept treatment in patients with active ankylosing spondylitis

Brandt

Khariouzov

Listing

et al. 2003

Arthritis & Rheumatism

420

268

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Objective. There is increasing evidence that tumor necrosis factor ␣ (TNF␣) is centrally involved in the pathogenesis of ankylosing spondylitis (AS) and other spondylarthritides. This study was designed to investigate the efficacy of anti-TNF␣ therapy with etanercept, a 75-kd receptor fusion protein, in active AS.Methods. This multicenter trial had 2 phases: an initial placebo-controlled period of 6 weeks' duration and an observational phase lasting 24 weeks. Thirty patients with active AS were included. They were randomized into 2 groups, which received either etanercept (25 mg twice weekly) (n ‫؍‬ 14) or placebo (n ‫؍‬ 16) for 6 weeks. Then both groups were treated with etanercept. Nonsteroidal antiinflammatory drug (NSAID) treatment could be continued, but disease-modifying antirheumatic drugs (DMARDs) and steroids had to be withdrawn prior to the study. All patients received etanercept for a total of 12 weeks and were followed up for at least 24 weeks. The Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index, Bath AS Metrology Index, pain level on a numeric rating scale, quality of life by the Short Form 36, and C-reactive protein (CRP) level were assessed. The primary outcome parameter was a >50% improvement in the BAS-DAI.Results. Treatment with etanercept resulted in at least a 50% regression of disease activity in 57% of these patients at week 6, versus 6% of the placebo-treated patients (P ‫؍‬ 0.004). After the placebo-treated patients switched to etanercept, 56% improved. The mean ؎ SD BASDAI improved from 6.5 ؎ 1.2 at baseline to 3.5 ؎ 1.9 at week 6 in the etanercept group, with no improvement in the placebo group (P ‫؍‬ 0.003 between groups). Similarly, pain, function, mobility, and quality of life improved with etanercept but not with placebo at week 6 (P < 0.05). Mean CRP levels decreased significantly with etanercept but not with placebo (P ‫؍‬ 0.001). There was ongoing improvement in all parameters in both groups until week 12 and week 18, respectively (i.e., throughout the period of etanercept treatment). Disease relapses occurred a mean ؎ SD of 6.2 ؎ 3.0 weeks after cessation of etanercept. No severe adverse events, including major infections, were observed during the trial.Conclusion. This study shows that on a shortterm basis (3 months), treatment with etanercept is clearly efficacious in patients with active AS who are receiving NSAID therapy but not DMARDs or steroids. After cessation of therapy, almost all patients experienced a relapse within a few weeks. Thus, it seems probable that etanercept must be administered continuously in most AS patients to achieve permanent inhibition of the inflammatory process.Ankylosing spondylitis (AS), the prototype of the spondylarthritides (SpA), is a chronic inflammatory rheumatic disease. In the past, the prevalence of SpA has been underestimated (1); more recently, the prevalence of the group of SpA as a whole has been calculated

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Section: Discussionmentioning

confidence: 99%

Six‐month results of a double‐blind, placebo‐controlled trial of etanercept treatment in patients with active ankylosing spondylitis

Brandt

Khariouzov

Listing

et al. 2003

Arthritis & Rheumatism

420

268

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“…One might assume that the risk of infection begins with the first dosage of a TNF␣ antagonist ( Figure 1A). This would seem to be a reasonable assumption, based on prior case series regarding mycobacterial infections among patients taking TNF␣ antagonists (10). However, in other drug-toxicity relationships, there may be a lag period between drug initiation and onset of risk ( Figure 1B).…”

Section: Exposure Risk Windowmentioning

confidence: 93%

The risk of infection associated with tumor necrosis factor α antagonists: Making sense of epidemiologic evidence

Solomon¹,

Lunt²,

Schneeweiß³

2008

Arthritis & Rheumatism

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“…Since OSM does not act in isolation in the granuloma, which is a cytokine-rich environment, MRC5 lung fibroblasts were stimulated with OSM and/or TNF-a, a cytokine secreted by Mtbinfected monocytes that is critical for an effective immune response to TB [38]. OSM induced a small non-statistically significant increase in MMP-1 and MMP-3 secretion by fibroblasts, while TNF-a induced a greater response ( Fig.…”

Section: Erk Map Kinase Regulates Osm Secretion In Mtb-infected Monocmentioning

confidence: 99%

Monocyte‐dependent oncostatin M and TNF‐α synergize to stimulate unopposed matrix metalloproteinase‐1/3 secretion from human lung fibroblasts in tuberculosis

2008

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Leukocyte-derived matrix metalloproteinases (MMP) are implicated in the tissue destruction characteristic of tuberculosis (TB). The contribution of lung stromal cells to MMP activity in TB is unknown. Oncostatin M (OSM) is an important stimulus to extrapulmonary stromal MMP induction, but its role in regulation of pulmonary MMP secretion or pathophysiology of TB is unknown. We investigated OSM secretion from Mycobacterium tuberculosis (Mtb)-infected human monocytes/macrophages and the networking effects of such OSM on lung fibroblast MMP secretion. Mtb increased monocyte OSM secretion dose dependently in vitro. In vivo tuberculous granulomas immunostained positively for OSM. Further, conditioned media from Mtb-infected monocytes (CoMTb) induced monocyte OSM secretion (670 AE 55 versus 166 AE 14 pg/mL in controls), implicating an autocrine loop. Mtbinduced OSM secretion was prostaglandin (PG) sensitive, and required activation of surface G-protein coupled receptors. OSM induction was ERK MAP kinase dependent, p38-requiring but JNK-independent. OSM synergized with TNF-a, a key cytokine in TB granuloma formation, to stimulate pulmonary fibroblast MMP-1/-3 secretion, while suppressing secretion of tissue inhibitors of metalloproteinases-1/-2. In summary, Mtb infection of monocytes results in PG-dependent OSM secretion, which synergizes with TNF-a to drive functionally unopposed fibroblast MMP-1/-3 secretion, demonstrating a previously unrecognized role for OSM in TB.Key words: Human Á Inflammation Á Monocytes/macrophages Á Stromal cells Introduction Tuberculosis (TB) remains a major global health problem with over 8 million cases of overt clinical infection, and 2 million deaths annually. The pathological response to Mycobacterium tuberculosis (Mtb) infection is characterised by extensive tissue breakdown including caseous necrosis, and later fibrosis. Tissue destruction in TB requires degradation of matrix proteins including collagen and elastin, and several studies have implicated matrix metalloproteinases (MMP) in pathogenesis [1][2][3]. MMP are a group of 23 related zinc-dependent enzymes that together are capable of degrading all components of the extracellular matrix (ECM) [4]. MMP are inhibited in vivo by the tissue inhibitors of metalloproteinases (TIMP), and in general, overall proteolytic activity is determined by the molar ratio of MMP:TIMP. MMP secretion is induced by inflammatory cytokines, physical stimuli, or directly by some bacterial components [5]. Direct infection of mononuclear cells with Mtb has been shown to induce MMP-9 (gelatinase B), a process that depends in part on 6].In the lung, the principal structural supporting collagen is type I [7,8]. MMP-1 (interstitial collagenase) is the most abundant pulmonary enzyme capable of degrading type I collagen [5]. Several cell types secrete MMP-1 in TB [9,10] but there are no data on the role of fibroblast-derived MMP-1 in TB. However, stimulated fibroblasts are the most potent source of MMP-1 in the lung [11] and may cause type IV collagen and prote...

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Tuberculosis Associated with Infliximab, a Tumor Necrosis Factor α–Neutralizing Agent

Abstract: Active tuberculosis may develop soon after the initiation of treatment with infliximab. Before prescribing the drug, physicians should screen patients for latent tuberculosis infection or disease.

Cited by 3,404 publications

References 32 publications

Six‐month results of a double‐blind, placebo‐controlled trial of etanercept treatment in patients with active ankylosing spondylitis

Six‐month results of a double‐blind, placebo‐controlled trial of etanercept treatment in patients with active ankylosing spondylitis

The risk of infection associated with tumor necrosis factor α antagonists: Making sense of epidemiologic evidence

Monocyte‐dependent oncostatin M and TNF‐α synergize to stimulate unopposed matrix metalloproteinase‐1/3 secretion from human lung fibroblasts in tuberculosis

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