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• Re: Identification of Pneumocystis colonization in patients treated with Infliximab
  Tsutomu Takeuchi
  Published on: 26 May 2008
• Identification of Pneumocystis colonization in patients treated with Infliximab
  Gustavo Wissmann
  Published on: 4 February 2008

• Published on: 26 May 2008

  Re: Identification of Pneumocystis colonization in patients treated with Infliximab

  • Tsutomu Takeuchi, Professor of Rheumatology/Clinical Immunology

  Dear Editor,

  We thank Dr Wissmann for the eLetter concerning Pneumocystis jiroveci pneumonia (PCP) to our article, "Postmarketing surveillance of the safety profile of infliximab in 5000 Japanese patients with rheumatoid arthritis. Ann Rheum Dis 2008;67:189-194.

  We reported that PCP developed in 22 patients among 5,000 patients with RA treated with infliximab. The organism of Pneumocysits jiroveci was not i...

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  Dear Editor,

  We thank Dr Wissmann for the eLetter concerning Pneumocystis jiroveci pneumonia (PCP) to our article, "Postmarketing surveillance of the safety profile of infliximab in 5000 Japanese patients with rheumatoid arthritis. Ann Rheum Dis 2008;67:189-194.

  We reported that PCP developed in 22 patients among 5,000 patients with RA treated with infliximab. The organism of Pneumocysits jiroveci was not identified in any of the patients with PCP, but they have been diagnosed as PCP by typical clinical manifestation such as dyspnea, fever, characteristic chest X-ray as well as chest CT findings showing diffuse alveolar shadows, and elevation of blood beta-D glucan. In addition, polymerase chain reaction for Pneumocystis jiroveci in sputa or alveolar lavage fluids has been analyzed, and the results were positive for 21 out of 22 patients diagnosed as having PCP. Unfortunately, we did not routinely check the colonalization of PCP before starting infliximab. We agree that a screening for pneumocystis jiroveci and prophylactic treatment with cotrimoxazol before starting infliximab treatment would be a useful method for prevention of PCP development.

  In this regard, we routinely follow-up the blood beta-D glucan level as a monitoring of the expanding colonalization of Pneumocystis jiroveci. Although beta-D glucan is not specific for Pneumocystis jiroveci, as Dr. Wissmann pointed out, only few cases with severe fungal infection had been reported in the 5000 RA cohorts, while those with PCP was found in 0.4% of the patients. Consequently 117 RA patient (14 male and 105 female) treated with infliximab with 3mg/kg, at 0, 2, 6 week, followed by every 8 weeks, and observed for 30 weeks or more in our institution were checked for blood beta-D glucan level at every visit (Table 1). The patient demographics were follows: 24-71 years old (53.5 +/- 11.9; the mean +/- S.D.) and 3-624 contraction period months (100.3 +/- 100.0; the mean +/- S.D.). MTX 8.8 mg/week, in average, has been administered together with infliximab, and prednisolone (6.3 +/- 2.6 mg/day; the mean +/- S.D.) was administered to 90 patients. At the time of screening before the introduction of infliximab, blood beta-D glucan level was abnormally high in 2 patients (22.7 pg/mL and 27.4 pg/mL; normal less than 20 pg/mL). At week 14, 4 patients showed the elevation of blood beta-D glucan level, and prophylactic cotrimoxazol was initiated in 3 of them, which successfully decreased blood beta-D glucan level. The co-incidence of the peak in the elevation of blood beta-D glucan level in our patients with the development of PCP in 5,000 Japanese RA patients, as well as the efficacy of cotrimoxazol to beta-D glucan, collectively support a hypothesis that colonalization of Pneumocystis jiroveci is not rare and PCP subsequently develops in Japanese RA patients with colonization of Pneumocystis jiroveci during treatment with infliximab.

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  Conflict of Interest:
  None declared.

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• Published on: 4 February 2008

  Identification of Pneumocystis colonization in patients treated with Infliximab

  • Gustavo Wissmann, Postdoctoral fellow
  • Other Contributors:
    • Isabel M Garrido, Nieves Respaldiza, Jose M. Varela, and Enrique Calderón

  Dear Editor,

  The introduction of biological agents resulted in a paradigm shift in the treatment of rheumatoid arthritis (RA). Infliximab, a chimeric anti-tumor necrosis factor (TNF)-α monoclonal antibody, has become an established effective therapy for RA. However, despite its role in chronic inflammatory diseases, evidence shows that TNF-α is also a critical factor in host defense. TNF-α initiates the inflammator...

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  Dear Editor,

  The introduction of biological agents resulted in a paradigm shift in the treatment of rheumatoid arthritis (RA). Infliximab, a chimeric anti-tumor necrosis factor (TNF)-α monoclonal antibody, has become an established effective therapy for RA. However, despite its role in chronic inflammatory diseases, evidence shows that TNF-α is also a critical factor in host defense. TNF-α initiates the inflammatory cascade by stimulating the production of other pro-inflammatory cytokines and influencing the maturation of cytokines that provide defense against pathogens. For this reason infliximab is contraindicated in patients with ongoing infections and its use should be delayed until a full improvement of acute infections [1,2].

  The frequent use of infliximab in clinical practice has identified Pneumocystis jiroveci pneumonia (PcP) as a serious complication [3], even though initial clinical trials failed to find this association. In this study that included 5,000 Japanese patients treated with infliximab, there was a higher incidence of PcP than of Tuberculosis [1]. Clinical practice guidelines recommend the systematic screening for Tuberculosis before starting the treatment, but there is no strategy for screening patients for PcP [4]. A recent Japanese Guideline has proposed screening patients through the blood beta-D-glucan test, but this essay is non specific for PcP [2].

  Another study identified age of at least 65 years, use of corticosteroids and coexisting of chronic pulmonary diseases as risk factors for PcP in patients treated with infliximab [5]. This association can be explained because of the high prevalence of colonization by Pneumocystis jiroveci in patients with chronic pulmonary disease [6,7]. The use of corticosteroids is also related to a higher prevalence of colonization [8]. Because of these findings we think that patients treated with infliximab that develop PcP might have been previously colonized by P. jiroveci.

  The identification of patients colonized by P. jiroveci before starting the treatments with infliximab could be a strategy for PcP prevention. Oral washes have been confirmed to be an useful high specificity and sensibility non invasive procedure for the detection of Pneumocystis colonization through the use of molecular techniques [9]. Thereby, detection of Pneumocystis colonization by PCR on oral washes and treatment with cotrimoxazol could be a practical strategy for PcP prevention in patients undergo infliximab therapy. This strategy for PcP prevention deserves further research to assess its clinical usefulness.

  References

  1. Takeuchi T, Tatsuki Y, Nogami Y, Ishiguro N, Tanaka H, Yamanaka H, et al. Post-marketing surveillance of the safety profile of infliximab in 5,000 Japanese patients with rheumatoid arthritis. Ann Rheum Dis 2008;67:189-194.

  2. Koike R, Takeuchi T, Eguchi K, Miyasaka N. Update on the Japanese guidelines for the use of infliximab and etanercept in rheumatoid arthritis. Mod Rheum 2007;17:451-458.

  3. Kaur N, Mahl TC. Pneumocystis jiroveci (carinii) pneumonia alter Infliximab therapy: a review of 84 cases. Dig Dis Sci 2007;52:1481-1484.

  4. Ledingham J, Dheigton C, British Society for Rheumatology standards, guidelines and audit working group. Update on the British Society for Rheumatology guidelines for prescribing TNF alpha blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology (Oxford) 2005;44:157-163.

  5. Harigai M, Koike R, Miyasaka N. Pneumocystis pneumonia associated with Infliximab in Japan. N Engl J Med 357;1874-1876.

  6. Calderón E, de la Horra C, Medrano FJ, López-Suárez A, Montes-Cano MA, Respaldiza N, et al. Pneumocystis jiroveci isolates with dihydropteroate synthase mutations in patients with chronic bronchitis. Eur J Clin Microbiol Infect Dis 2004;23:545-549.

  7. Morris A, Wei K, Afshar K, Huang L. Epidemiology and clinical ignificance of Pneumocystis colonization. J Infect Dis 2008;197:10-17.

  8. Maskell NA, Waine DJ, Lindley A, Pepperell JC, Wakefield AE, MillerRF and Davies RJ. Thorax 2003;58:594-597.

  9. Respaldiza N, Montes-Cano MA, Friaza V, Muñoz-Lobato F, Medrano FJ, Varela JM, Calderón E, and de la Horra C. Usefulness of Oropharyngela Washings for identifying Pneumocystis jirovecii carriers. J Eukaryot Microbiol 2006;53:100S-101S.

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  Conflict of Interest:
  None declared.

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