Correspondence
Tuberculosis and Treatment with Infliximab
N Engl J Med 2002; 346:623-626February 21, 2002
- Article
To the Editor:
In support of the findings of Keane et al. (Oct. 11 issue),1 we describe the reactivation of latent tuberculosis in a 19-year-old Pakistani man treated with infliximab for sight-threatening uveitis of unknown cause despite extensive investigation. The patient presented with a 3-week history of fever, sweats, dry cough, and breathlessness 60 days after the first of three intravenous boluses of infliximab at a dose of 5 mg per kilogram of body weight. Upper and midzone interstitial lung shadowing and extensive lymphadenopathy were noted on computed tomographic scanning. Lymph-node biopsy revealed heavy infiltration with acid-fast bacilli. The patient's symptoms improved after the initiation of treatment with rifampin, pyrazinamide, and isoniazid, but his temperature continued to spike (39.5°C) for a further six weeks. Immune-function testing demonstrated that his T cells were able to make interferon-γ in response to stimulation with purified protein derivative. No other immunodeficiency was noted.
Twenty months earlier, the patient had been screened according to the guidelines of the British Thoracic Society2 as a close contact of a patient with smear-positive pulmonary tuberculosis and deemed not to be infected. A grade 2 response to a Heaf test at the time was thought to be consistent with prior bacille Calmette–Guérin vaccination. The timing of events, extent of disease, and clinical course described are all consistent with an association between infliximab and the reactivation of tuberculosis.
2 ReferencesWei Shen Lim, M.D.
R.J. Powell, M.D.
I.D. Johnston, M.D.
University Hospital, Nottingham NG7 2UH, United Kingdom
weishen@doctors.org. uk 1
Keane J ,Gershon S ,Wise RP , et al. Tuberculosis associated with infliximab, a tumor necrosis factor α-neutralizing agent. N Engl J Med 2001;345:1098-1104
Full Text | Web of Science | Medline2
Joint Tuberculosis Committee of the British Thoracic Society
CrossRef | Web of Science | Medline
To the Editor:
Keane et al. reported that active tuberculosis may develop soon after the initiation of treatment with infliximab. We describe a case of disseminated histoplasmosis after similar treatment.
A 19-year-old man had Crohn's disease (diagnosed at the age of 12 years) that was not controlled by conventional treatment. While still receiving mercaptopurine he was given infliximab (5 mg per kilogram) in June 2000. Symptoms of Crohn's disease improved, and a second dose of infliximab was given in September 2000. Three weeks later he presented with fever (temperature, 40.0°C), followed over the next four weeks by a nonproductive cough, abdominal discomfort, watery stools, and massive hepatosplenomegaly, with progressive leukopenia (cell count, 2.31×109 per liter) and thrombocytopenia (cell count, 79×109 per liter). A workup revealed no evidence of active Crohn's disease, a malignant condition, tuberculosis, or infection with Epstein–Barr virus, cytomegalovirus, or bacteria. Histopathological examination of biopsy specimens of the colon, liver, and bone marrow showed noncaseating granulomas. Fungus-like organisms were detected within the granulomas, and cultures were positive for Histoplasma capsulatum. Therapy with amphotericin B (15 mg per kilogram) was administered, followed by itraconazole (200 mg per day). The patient recovered uneventfully.
The patient had grown up in Louisiana and had attended college in Ohio, areas where histoplasmosis is endemic. This fact and the short interval between the infliximab infusion and the appearance of symptoms suggest that our patient had a reactivation of prior infection.
Tumor necrosis factor α (TNF-α) is an important immune modulator, and neutralization of this cytokine significantly suppresses the immune response. Inhibition of TNF-α resulted in delayed clearance of Pneumocystis carinii in the lungs of immunocompetent mice.1 Blockade of TNF-α exacerbated chronic infection in CD4+ cell–depleted mice. In addition to neutralizing secreted TNF-α, infliximab exerts an immunosuppressive effect by attacking immune effector cells that express membrane-bound TNF-α,2 further impairing host defenses.
2 ReferencesZili Zhang, M.D., Ph.D.
Hernán Correa, M.D.
Rodolfo E. Bégué, M.D.
Louisiana State University Health Sciences Center, New Orleans, LA 70112
rbegue@lsuhsc.edu 1
Kolls JK ,Lei D ,Vasquez C , et al. Exacerbation of murine Pneumocystis carinii infection by adenoviral-mediated gene transfer of a TNF inhibitor. Am J Respir Cell Mol Biol 1997;16:112-118
Web of Science | Medline2
Scallon BJ ,Moore MA ,Trinh H ,Knight DM ,Ghrayeb J . Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine 1995;7:251-259
CrossRef | Web of Science | Medline
To the Editor:
Keane et al. report that tuberculosis developed in some patients with Crohn's disease or rheumatoid arthritis after treatment with infliximab. We believe that these patients need to be described separately, especially with respect to their clinical characteristics and the interval between infliximab treatment and the appearance of tuberculosis. There is a possibility that some patients who have been given a diagnosis of Crohn's disease actually have abdominal tuberculosis. Both conditions can present with transmural spread and penetration through the muscle coat, although this presentation is relatively less common in Crohn's disease. These conditions have a similar microscopic appearance that includes granulomas, and the caseation that is characteristic of tuberculosis is often difficult to identify.1 In areas where abdominal tuberculosis is more frequent, some criteria must be fulfilled to differentiate intestinal tuberculosis from Crohn's disease: there must be histologic evidence of tubercles with caseation necrosis; there must be a good typical gross description of operative findings, with biopsy of mesenteric nodes showing histologic evidence of tuberculosis; inoculation into animals or culture of the suspected tissue must result in the growth of tubercle bacilli; and histologic examination must show Mycobacterium tuberculosis in a lesion.2 In an urban British population with a large number of Asian immigrants, abdominal tuberculosis was not infrequent, whereas Crohn's disease occurred rarely in Asian immigrants.3 A clear distinction in describing the general characteristics of patients with Crohn's disease and rheumatoid arthritis in whom tuberculosis developed will be useful, given that when we diagnose Crohn's disease we are at risk of underdiagnosing abdominal tuberculosis.
3 ReferencesFrancesco G. De Rosa, M.D.
Stefano Bonora, M.D.
Giovanni Di Perri, M.D., Ph.D.
University of Turin, 10149 Turin, Italy
fgderosa@hotmail.com 1
Tandon HD ,Prakash A . Pathology of intestinal tuberculosis and its distinction from Crohn's disease. Gut 1972;13:260-269
CrossRef | Web of Science | Medline2
Paustian FF. Tuberculosis of the intestines. In: Bockus HL. Gastroenterology. 2nd ed. Vol. 2. Philadelphia: W.B. Saunders, 1964:311-34.
3
Palmer KR ,Patil DH ,Basran GS ,Riordan JF ,Silk DBA . Abdominal tuberculosis in urban Britain -- a common disease. Gut 1985;26:1296-1305
CrossRef | Web of Science | Medline
To the Editor:
Keane et al. describe the occurrence of active tuberculosis soon after the initiation of treatment with infliximab. We describe a nine-year-old girl with classic systemic-onset juvenile idiopathic arthritis,1 who was given a diagnosis of osteoarticular tuberculosis shortly after commencing treatment with etanercept. She had been treated with corticosteroids (initially intravenous methylprednisolone, then oral corticosteroids) and methotrexate. However, owing to poor control of the disease, etanercept (0.4 mg per kilogram) was substituted for methotrexate, with a good response initially (the active-joint count and levels of acute-phase reactants were decreased and her sense of well-being improved). Five weeks later, a painful swollen left ankle developed, but the patient remained well and afebrile. Clear synovial fluid was aspirated from the joint (which was sterile on routine culture). Etanercept was recommenced, and she remained well. However, three weeks later M. tuberculosis complex was isolated, and its identity was confirmed by a gene probe; it then was found to be a fully sensitive strain of M. tuberculosis. An isotopic bone scan revealed additional sites of presumed infection, but the chest radiograph was normal. Tracing of the patient's contacts identified no source of infection. Etanercept was stopped. Antituberculosis treatment included standard triple therapy, extended for 12 months, with rifampin and isoniazid continued as maintenance therapy, since the reactivation of systemic juvenile idiopathic arthritis necessitated the resumption of methotrexate therapy. She continues to take corticosteroids (<0.5 mg per kilogram every other day), and 18 months later, she is well and her arthritis is clinically inactive.
Osteoarticular tuberculosis is uncommon in children in Britain. Tuberculosis should be considered in immunocompromised patients, especially those with monoarthropathy, and in patients who have received anti-TNF therapy, since such therapy may suppress the classic signs of infection.
1 ReferencesAndrea Myers, M.B., Ch.B.
University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, United Kingdom
andrea.myers@ncl. ac. uk Julia Clark, B.M., B.S.
Newcastle Hospitals National Health Service Trust, Newcastle upon Tyne NE4 4HH, United KingdomHelen Foster, M.D.
University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, United Kingdom1
Petty RE ,Southwood TR ,Baum J , et al. Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 97. J Rheumatol 1998;25:1991-1994
Medline
To the Editor:
Study of animal models has provided a guide to the safety of the inhibition of TNF in humans, including its effect on susceptibility to tuberculosis.1,2 The report by Keane and colleagues highlights important safety concerns regarding the reactivation of tuberculosis in recipients of TNF inhibitors, but we found that the absence of TNF had no adverse effect on morbidity or overall survival in TNF-deficient mice that had not previously been exposed to M. tuberculosis.
We conducted a prospective age- and sex-matched 30-month study of morbidity and mortality in a cohort of 106 wild-type C57BL/6 mice and 98 C57BL/6 mice rendered TNF-deficient by gene targeting (Riminton DS, et al., unpublished data). The cohorts were divided into two groups: one housed under pathogen-free conditions and the other under conventional conditions. Survival of TNF-deficient mice was equivalent to that of controls (P=0.9 by the log-rank test; hazard ratio, 1.02; 95 percent confidence interval, 0.66 to 1.6), irrespective of environmental variations. The same TNF-deficient mice, however, had greatly increased susceptibility to disease on inhalational challenge with virulent M. tuberculosis.2
2 ReferencesSean Riminton, M.B., Ch.B., Ph.D.
Nicholas Pearce, Ph.D.
Antony Basten, M.B., B.S., D.Phil.
Centenary Institute of Cancer Medicine and Cell Biology, Sydney, NSW 2050, Australia
s.riminton@centenary. usyd. edu. au 1
Flynn JL ,Goldstein MM ,Chan J , et al. Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 1995;2:561-572
CrossRef | Web of Science | Medline2
Bean AG ,Roach DR ,Briscoe H , et al. Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin. J Immunol 1999;162:3504-3511
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: The findings of Lim et al. support our finding of an association between infliximab and tuberculosis. Since our report was published, the Food and Drug Administration (FDA) has received 47 additional reports of infliximab-associated tuberculosis, for a total of 117 cases through November 30, 2001. Given that the amount of underreporting is unknown, the estimated rate of tuberculosis reported to the FDA for the first year of treatment with infliximab is approximately 41 per 100,000 in U.S. patients with rheumatoid arthritis, 9 per 100,000 in U.S. patients with Crohn's disease, and 224 per 100,000 in all non-U.S. patients with rheumatoid arthritis or Crohn's disease. The infliximab package insert states that screening for and treatment of latent tuberculosis are indicated before the drug is prescribed.1 This precaution is important because cases of tuberculosis influence public health as well as the health of the patient. Our data do not rule out an association between etanercept and tuberculosis, and the case reported by Myers et al. highlights the need for continued surveillance for tuberculosis with the use of all anti-TNF agents.
The case reported by Zhang et al. of histoplasmosis in association with infliximab emphasizes the possibility that infections that are dormant in granulomas may become susceptible to reactivation when TNF is neutralized. Of the 11 cases of histoplasmosis after infliximab that have been reported to the FDA, 10 required care in the intensive care unit and 1 was fatal. This experience highlights the importance of the early diagnosis and treatment of histoplasmosis.
We acknowledge the difficulty in differentiating Crohn's disease from enteric tuberculosis, as mentioned by De Rosa et al. Indeed, mycobacterial infection has been suggested as a possible etiologic agent of Crohn's disease.2 To date, 27 cases of tuberculosis have been reported in patients with Crohn's disease after treatment with infliximab for a median of 10 weeks (range, 4 to 52). Sixteen of these patients had extrapulmonary disease, and five had disseminated tuberculosis. In our study, one patient who was initially considered to have Crohn's disease was reclassified as having enteric tuberculosis and was excluded from the analysis. Available data suggest that these cases of tuberculosis were not from an otherwise high-risk group, such as inner-city Asian immigrants. The possibility of occasional mistaken diagnoses does not detract from the importance of testing for tuberculosis infection in patients with Crohn's disease before the initiation of infliximab therapy.
The immunologic events that explain the possible link between blockade of TNF and the failure of granuloma to contain bacilli are poorly understood. We have seen an interferon-γ–independent mycobactericidal effect of macrophages that is mediated by host-cell apoptosis and dependent on TNF.3 Consistent with this finding is the report of Lim et al. that the secretion of IFN-γ by T cells was normal after stimulation with purified protein derivative in their patient who was receiving infliximab. Bean et al. have demonstrated normal T-cell activation in tuberculosis-infected mice that have a disruption of the TNF gene.4 Given the pleiotropic nature of TNF, it most likely influences many aspects of the immune response to tuberculosis.
4 ReferencesJoseph Keane, M.D.
Boston University School of Medicine, Boston, MA 02118
jkeane@lung.bumc. bu. edu Sharon K. Gershon, Pharm.D.
M. Miles Braun, M.D., M.P.H.
Food and Drug Administration, Rockville, MD 208521
Remicade (infliximab, recombinant). Malvern, Pa.: Centocor, Inc., 2001 (package insert).
2
Mishina D ,Katsel P ,Brown ST ,Gilberts EC ,Greenstein RJ . On the etiology of Crohn disease. Proc Natl Acad Sci U S A 1996;93:9816-9820
CrossRef | Web of Science | Medline3
Keane J, Shurtleff B, Kornfeld H. TNF-dependent BALB/c murine macrophage apoptosis following Mycobacterium tuberculosis infection inhibits bacillary growth in an IFN-gamma independent manner. Tuberculosis (in press).
4
Bean GA ,Roach DR ,Briscoe H , et al. Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin. J Immunol 1999;162:3504-3511
Web of Science | Medline
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