Correspondence
Pneumocystis Pneumonia Associated with Infliximab in Japan
N Engl J Med 2007; 357:1874-1876November 1, 2007
- Article
To the Editor:
Infliximab, a monoclonal antibody against tumor necrosis factor α (TNF-α), is used in Japan for the treatment of patients with active rheumatoid arthritis that is resistant to methotrexate.1 Methotrexate is used only for patients who do not have a response to or cannot tolerate other disease-modifying antirheumatic drugs, such as sulfasalazine. Infliximab is not used as primary therapy for rheumatoid arthritis in Japan.
Strict postmarketing surveillance of infliximab and etanercept, a drug that blocks the action of TNF, revealed incidences of pneumocystis pneumonia in Japanese patients with rheumatoid arthritis that were higher (0.4% and 0.2%, respectively) than those in Western countries.2 We therefore conducted a multicenter, case–control study of pneumocystis pneumonia in patients with rheumatoid arthritis who were receiving infliximab therapy.
The study protocol was approved by the institutional review board at our hospital; informed oral consent was obtained from all patients. Included in the study were patients who met the 1987 American College of Rheumatology criteria for rheumatoid arthritis3 and who were receiving 3 mg of infliximab per kilogram of body weight every 8 weeks with concomitant methotrexate. A total of 21 patients with pneumocystis pneumonia were collected through postmarketing surveillance or voluntary case reports from 14 hospitals. Another 102 patients without pneumocystis pneumonia were selected at random from a consecutive series of patients from three hospitals participating in the study. A diagnosis of pneumocystis pneumonia was definitive if Pneumocystis jiroveci was found on microscopical analysis of respiratory samples from patients with clinical manifestations (pyrexia, dry cough, or dyspnea), hypoxemia, and radiologic findings compatible with pneumocystis pneumonia. The diagnosis of pneumocystis pneumonia was presumptive if a patient met all three criteria and had either a positive polymerase-chain-reaction test for P. jiroveci DNA or an increased serum level of (1→3) β-D-glucan with an appropriate response to the standard treatments for pneumocystis pneumonia.4,5 We did not test for the presence or absence of human immunodeficiency virus.
The diagnosis of pneumocystis pneumonia was definitive in 2 patients and presumptive in 19 patients. As compared with patients who did not have pneumocystis pneumonia, patients with pneumocystis pneumonia were significantly older (median age, 65 years vs. 55 years; P<0.001); had a higher prevalence of coexisting pulmonary disease, including interstitial pneumonia, chronic obstructive pulmonary disease, bronchiectasis, chronic bronchitis, follicular bronchiolitis, and old pulmonary tuberculosis (47.6% vs. 10.8%, P<0.001); and were treated with a higher daily dose of prednisolone (median dose, 7.5 mg vs. 5.0 mg; P=0.001).
Among patients with pneumocystis pneumonia, the hazard ratio for an age of at least 65 years was 3.77 (95% confidence interval [CI], 1.54 to 9.25), the hazard ratio for a daily dose of prednisolone of at least 6 mg was 3.76 (95% CI, 1.37 to 10.3), and the hazard ratio for the presence of coexisting pulmonary disease was 2.54 (95% CI, 1.00 to 6.46). All comparisons were calculated with the use of Cox proportional-hazards regression. The Cox model with age and the use of prednisolone as continuous variables and coexisting pulmonary disease as a categorical variable provided similar results. Pneumocystis pneumonia developed more frequently in patients with two or three of the risk factors than in the other patients (Figure 1Figure 1
Cumulative Probability of Pneumocystis Pneumonia in Patients with Rheumatoid Arthritis Associated with Infliximab Therapy, According to the Number of Risk Factors.). More research is needed to determine precisely which patients with rheumatoid arthritis who are receiving infliximab therapy have a risk of pneumocystis pneumonia that is high enough to warrant prophylaxis.Masayoshi Harigai, M.D., Ph.D.
Ryuji Koike, M.D., Ph.D.
Nobuyuki Miyasaka, M.D., Ph.D.
Tokyo Medical and Dental University, Tokyo 113-8519, Japan
mharigai.mpha@tmd. ac. jp for the Pneumocystis Pneumonia under Anti–Tumor Necrosis Factor Therapy (PAT) Study Group
Dr. Harigai reports receiving lecture fees and grant support from Tanabe Seiyaku, Wyeth, and Takeda Pharmaceutical; Dr. Koike, receiving lecture fees and grant support from Tanabe Seiyaku; and Dr. Miyasaka, receiving lecture fees and grant support from Tanabe Seiyaku, Wyeth, and Takeda Pharmaceutical and serving on advisory boards for Tanabe Seiyaku and Wyeth. No other potential conflict of interest relevant to this letter was reported.
5 References1
Miyasaka N ,Takeuchi T ,Eguchi K . Proposed [corrected] Japanese guidelines for the use of infliximab for rheumatoid arthritis. Mod Rheumatol 2005;15:4-8[Erratum, Mod Rheumatol 2005;15:322.]
CrossRef | Medline2
Takeuchi T, Tatsuki Y, Nogami Y, et al. Post-marketing surveillance of the safety profile of infliximab in 5,000 Japanese patients with rheumatoid arthritis. Ann Rheum Dis (in press).
3
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
CrossRef | Web of Science | Medline4
Ledergerber B ,Mocroft A ,Reiss P , et al. Discontinuation of secondary prophylaxis against Pneumocystis carinii pneumonia in patients with HIV infection who have a response to antiretroviral therapy. N Engl J Med 2001;344:168-174
Full Text | Web of Science | Medline5
Yasuoka A ,Tachikawa N ,Shimada K ,Kimura S ,Oka S . (1→3) beta-D-glucan as a quantitative serological marker for Pneumocystis carinii pneumonia. Clin Diagn Lab Immunol 1996;3:197-199
Medline
- Citing Articles (22)
Citing Articles
1
Matthew R Gingo, Lorrie Lucht, Kieran R Daly, Kpandja Djawe, Frank J Palella, Alison G Abraham, Jay H Bream, Mallory D Witt, Lawrence A Kingsley, Karen A Norris, Peter D Walzer, Alison Morris. (2011) Serologic Responses to Pneumocystis Proteins in HIV Patients With and Without Pneumocystis jirovecii Pneumonia. JAIDS Journal of Acquired Immune Deficiency Syndromes 57:3, 190-196
CrossRef2
Gustavo Wissmann, Rubén Morilla, Isabel Martín-Garrido, Vicente Friaza, Nieves Respaldiza, Juan Povedano, Juan M. Praena-Fernández, Marco A. Montes-Cano, Francisco J. Medrano, Luciano Z. Goldani, Carmen de la Horra, José M. Varela, Enrique J. Calderón. (2011) Pneumocystis jirovecii colonization in patients treated with infliximab. European Journal of Clinical Investigation 41:3, 343-348
CrossRef3
Sophia Koo, Francisco M. Marty, Lindsey R. Baden. (2011) Infectious Complications Associated with Immunomodulating Biologic Agents. Hematology/Oncology Clinics of North America 25:1, 117-138
CrossRef4
William G Dixon, Samy Suissa, Marie Hudson. (2011) The association between systemic glucocorticoid therapy and the risk of infection in patients with rheumatoid arthritis: systematic review and meta-analyses. Arthritis Research & Therapy 13:4, R139
CrossRef5
Nobuyuki Miyasaka. (2011) Treatment trends of rheumatoid arthritis in Japan: Changes toward globalization and its unique innovation. Inflammation and Regeneration 31:1, 25-32
CrossRef6
Hidekazu IKEUCHI, Azusa UMEMOTO, Mayuko TSUKIDA, Noriyuki SAKURAI, Akito MAESHIMA, Takashi KUROIWA, Keiju HIROMURA, Yoshihisa NOJIMA. (2011) Pneumocystis pneumonia developed in two patients with rheumatoid arthritis during treatment of adalimumab. Japanese Journal of Clinical Immunology 34:5, 420-425
CrossRef7
A Nakajima, E Inoue, E Tanaka, G Singh, E Sato, D Hoshi, K Shidara, M Hara, S Momohara, A Taniguchi, N Kamatani, H Yamanaka. (2010) Mortality and cause of death in Japanese patients with rheumatoid arthritis based on a large observational cohort, IORRA. Scandinavian Journal of Rheumatology 39:5, 360-367
CrossRef8
James Tschudy, Sonia Michail. (2010) Disseminated Histoplasmosis and Pneumocystis Pneumonia in a Child With Crohn Disease Receiving Infliximab. Journal of Pediatric Gastroenterology and Nutrition 51:2, 221-222
CrossRef9
Sophia Koo, Francisco M. Marty, Lindsey R. Baden. (2010) Infectious Complications Associated with Immunomodulating Biologic Agents. Infectious Disease Clinics of North America 24:2, 285-306
CrossRef10
Shin-ya Kawashiri, Atsushi Kawakami, Noriho Sakamoto, Yuji Ishimatsu, Katsumi Eguchi. (2010) A fatal case of acute exacerbation of interstitial lung disease in a patient with rheumatoid arthritis during treatment with tocilizumab. Rheumatology International
CrossRef11
Sachiko ONISHI, Masahiro IWMOTO, Seiji MINOTA. (2010) Management of Elderly-onset Rheumatoid Arthritis. Japanese Journal of Clinical Immunology 33:1, 1-7
CrossRef12
Waqqas Afif, Edward V. Loftus. (2010) Safety Profile of IBD Therapeutics: Infectious Risks. Medical Clinics of North America 94:1, 115-133
CrossRef13
L.-S. Tam, Y.-Y. Leung, E. K. Li. (2009) Psoriatic arthritis in Asia. Rheumatology 48:12, 1473-1477
CrossRef14
Waqqas Afif, Edward V. Loftus. (2009) Safety Profile of IBD Therapeutics: Infectious Risks. Gastroenterology Clinics of North America 38:4, 691-709
CrossRef15
Siba P. Raychaudhuri, Caroline T. Nguyen, Smriti K. Raychaudhuri, M. Eric Gershwin. (2009) Incidence and nature of infectious disease in patients treated with anti-TNF agents. Autoimmunity Reviews 9:2, 67-81
CrossRef16
Bryan J. Krajicek, Charles F. Thomas, Andrew H. Limper. (2009) Pneumocystis Pneumonia: Current Concepts in Pathogenesis, Diagnosis, and Treatment. Clinics in Chest Medicine 30:2, 265-278
CrossRef17
Yousuke Murakami, Tohru Akahoshi, Naoko Aoki, Masayasu Toyomoto, Nobuyuki Miyasaka, Hitoshi Kohsaka. (2009) Intervention of an inflammation amplifier, triggering receptor expressed on myeloid cells 1, for treatment of autoimmune arthritis. Arthritis & Rheumatism 60:6, 1615-1623
CrossRef18
Yukiko Komano, Masayoshi Harigai, Ryuji Koike, Haruhito Sugiyama, Jun Ogawa, Kazuyoshi Saito, Naoya Sekiguchi, Masayuki Inoo, Ikuko Onishi, Hiroyuki Ohashi, Fujio Amamoto, Masayuki Miyata, Hideo Ohtsubo, Kazuko Hiramatsu, Masahiro Iwamoto, Seiji Minota, Naoki Matsuoka, Goichi Kageyama, Kazuyoshi Imaizumi, Hitoshi Tokuda, Yasumi Okochi, Koichiro Kudo, Yoshiya Tanaka, Tsutomu Takeuchi, Nobuyuki Miyasaka. (2009) Pneumocystis jiroveci pneumonia in patients with rheumatoid arthritis treated with infliximab: A retrospective review and case-control study of 21 patients. Arthritis & Rheumatism 61:3, 305-312
CrossRef19
Silvia Odorcic, Edward C Keystone, Joseph J K Ma. (2009) Infliximab for the Treatment of Refractory Progressive Sterile Peripheral Ulcerative Keratitis Associated With Late Corneal Perforation: 3-Year Follow-Up. Cornea 28:1, 89-92
CrossRef20
Shunsuke Mori, Isamu Cho, Hidenori Ichiyasu, Mineharu Sugimoto. (2008) Asymptomatic carriage of Pneumocystis jiroveci in elderly patients with rheumatoid arthritis in Japan: a possible association between colonization and development of Pneumocystis jiroveci pneumonia during low-dose MTX therapy. Modern Rheumatology 18:3, 240-246
CrossRef21
Bryan J Krajicek, Andrew H Limper, Charles F Thomas. (2008) Advances in the biology, pathogenesis and identification of Pneumocystis pneumonia. Current Opinion in Pulmonary Medicine 14:3, 228-234
CrossRef22
(2008) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 17:5, i-xvi
CrossRef
