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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Objective

To establish proper management of Pneumocystis jiroveci pneumonia (PCP) in rheumatoid arthritis (RA) patients treated with infliximab. PCP has been observed in 0.4% of patients with RA treated with infliximab in Japan.

Methods

Data from patients with RA (n = 21) who were diagnosed with PCP during infliximab treatment and from 102 patients with RA who did not develop PCP during infliximab therapy were collected from 14 rheumatology referral centers in Japan. A retrospective review of these patients and a case–control study to compare patients with and without PCP were performed.

Results

The median length of time from the first infliximab infusion to the development of PCP was 8.5 weeks. At the onset of PCP, the median dosages of prednisolone and methotrexate were 7.5 mg/day and 8 mg/week, respectively. Pneumocystis jiroveci was microscopically identified in only 2 patients, although the polymerase chain reaction test for the organism was positive in 20 patients. The patients with PCP had significantly lower serum albumin levels (P < 0.001) and lower serum IgG levels (P < 0.001) than the patients without PCP. Computed tomography of the chest in all patients with PCP revealed ground-glass opacity either with sharp demarcation by interlobular septa or without interlobular septal boundaries. Sixteen of the 21 patients with PCP developed acute respiratory failure, but all survived.

Conclusion

PCP is a serious complication that may occur early in the course of infliximab therapy in patients with RA. For the proper clinical management of this infectious disease, physicians need to be aware of the possibility of PCP developing during infliximab therapy.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Rheumatoid arthritis (RA) is a systemic inflammatory disease that is characterized by chronic synovitis and the destruction of articular structures of multiple joints. The discovery that high levels of tumor necrosis factor α (TNFα) contribute to chronic inflammation and joint destruction in patients with RA heralded a new era of targeted and highly effective therapy for this disease.

Several clinical trials have demonstrated excellent efficacy for the treatment of RA with infliximab, an anti-TNFα chimeric monoclonal antibody (1, 2). Because TNFα is one of the key molecules protecting against microorganisms in vivo, treatment with infliximab has been associated with increased risk of opportunistic and serious infections in cohort studies using RA patient registries, as well as in the meta-analysis of clinical trials (3–6). In Japan, a strict postmarketing surveillance program was implemented that mandated the registration of all patients with RA receiving infliximab, with a tracking period of 6 months for each patient. Of the 5,000 patients tracked, this postmarketing surveillance program identified 108 patients (2.2%) with bacterial pneumonia and 14 patients (0.3%) with tuberculosis (7). Notably, 22 patients (0.4%) with Pneumocystis jiroveci pneumonia (PCP) were identified in the same postmarketing surveillance program (7), a much higher number than was found in corresponding studies in the US (3). In addition, another anti-TNFα agent, etanercept, has been subject to a similarly strict postmarketing surveillance program in Japan, which identified 16 patients (0.23%) with PCP out of 7,091 patients with RA receiving etanercept (8). These 2 postmarketing surveillance programs show PCP to be more common than expected in patients receiving anti-TNF therapy in Japan (9).

PCP is an infectious disease caused by P jiroveci, and has received increased attention since the emergence of the human immunodeficiency virus (HIV) infection more than 20 years prior (10). More recently, PCP has increasingly been reported in immunocompromised patients with connective tissue diseases, patients with malignancies, or in patients after organ transplantation (11, 12). The postmarketing surveillance data in Japan and some anecdotal reports of PCP in patients receiving infliximab (13–16) suggest that patients receiving infliximab comprise a novel high-risk group for development of PCP. A thorough knowledge of the clinical and laboratory characteristics of PCP in patients treated with infliximab is indispensable for prophylaxis, early diagnosis, and proper treatment of this infectious disease.

In a previous report (17), we compared 21 patients with RA receiving infliximab who developed PCP and 102 patients with RA receiving infliximab who did not develop PCP, and identified risk factors for PCP in patients with RA treated with infliximab. We demonstrated that patients with 2 or 3 risk factors showed significantly higher probability of developing PCP than those with 1 or those without risk factors. In this study, we report detailed clinical, laboratory, and radiographic features along with a case–control study of PCP in these 21 patients with RA treated with infliximab.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

The PCP Under Anti-TNF Therapy (PAT) study group was organized for the investigation of PCP in patients with RA treated with infliximab in Japan. Included in the present study were those patients who fulfilled the 1987 American College of Rheumatology (formerly the American Rheumatism Association) criteria for RA (18) and received infliximab (3 mg/kg every 8 weeks) with concomitant methotrexate (MTX). Between August 2003 and June 2006, 21 patients with PCP were selected from 14 hospitals through either the postmarketing surveillance program (n = 15) or through voluntary case reports by attending physicians either at scientific meetings or to a pharmaceutical company (n = 6). Patients without PCP (n = 102) were selected at random from a consecutive series of 523 patients with RA who did not develop PCP during infliximab therapy. These patients were selected from 3 hospitals: the University Hospital of Occupational and Environmental Health, the Saitama Medical Center, and the Tokyo Medical and Dental University Hospital. To increase the statistical power of the case–control study, the number of patients in the control group was designed to provide ∼5 times the number of patients with PCP (19). Two pulmonologists (HS and KK) participated in the PAT study group.

Diagnostic criteria for PCP.

Previously established diagnostic criteria for PCP (20, 21) were used for the present study, with some modifications (17). A diagnosis of PCP was deemed definitive if P jiroveci was found on microscopic analysis of respiratory samples with concurrent clinical manifestations (fever, dry cough, or dyspnea), hypoxemia, and radiologic findings indicative of PCP. The diagnosis of PCP was considered presumptive if a patient fulfilled these conditions in the absence of evidence of bacterial pneumonia and presence of either a positive polymerase chain reaction (PCR) test for P jiroveci DNA or increased serum 1,3-β-D-glucan levels (Fungitec G test MK; Seikagaku, Tokyo, Japan or Wako β-D-glucan test; Wako Pure Chemical industries, Tokyo, Japan) with response to standard treatments for PCP (22, 23). The HIV status of the patient was not examined.

Collection and analysis of the clinical data.

RA patients with definitive or presumptive PCP (n = 21) and those without PCP (n = 102) were referred to as the PCP group and the non-PCP group, respectively. Patient records were evaluated to determine demographic information, comorbidities, concomitant drugs, laboratory data, radiographic data, treatment, and outcome. Chest radiographs and computed tomography (CT) scans of the thorax were evaluated by the 2 pulmonologists. Inclusion in the study required that the patient be followed until January 31, 2006 (the date established as the common close-out date for the non-PCP group) or that the patient stopped receiving infliximab before that date.

Ethics.

The guidelines of Helsinki declaration and the ethical guidelines for epidemiologic research in Japan were followed. The study protocol was approved by the Institutional Ethical Committee of the Tokyo Medical and Dental University Hospital.

Statistical analyses.

Fisher's exact test was used for categorical variables and the Mann-Whitney U test was used for continuous variables with Bonferroni correction for multiple pair comparisons. All analyses were performed using SPSS software, version 15.0 (SPSS Japan, Tokyo, Japan).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Diagnosis and clinical characteristics of RA patients with PCP.

We evaluated the cases of 21 patients with RA who were receiving infliximab treatment using the above diagnostic criteria. Two of the 21 cases were considered to have a definitive PCP diagnosis and 19 had a presumptive PCP diagnosis. The clinical characteristics of each patient are summarized in Table 1. The mean age of the patients was 64 years (range 52–80 years) and 17 (81%) were women.

Table 1. Characteristics of rheumatoid arthritis patients with PCP who were treated with infliximab*
PatientAge, yearsSexNo. of infusionsTreatment duration, weeksMTX, mg/weekPSL, mg/dayLung diseaseDiabetes mellitusClinical symptoms
  • *

    PCP = Pneumocystis jiroveci pneumonia; MTX = methotrexate; PSL = prednisolone; IP = interstitial pneumonia; cough = dry cough; DOE = dyspnea on effort; COPD = chronic obstructive pulmonary disease.

  • Infliximab infusions prior to the diagnosis of PCP.

  • With infliximab before the onset of PCP.

152F3127.57.5IP-fever/cough/DOE
276F12620IP-fever/cough/DOE
361M3815.56--fever/cough/DOE
469F416620IP+cough/DOE
554F27208--fever
660F2465--fever/cough
780F1687.5-+fever/cough/DOE
866F3667bronchiectasis-fever/DOE
952M251010follicular bronchiolitis-fever/cough
1065F3910.57.5old tuberculosis-fever/cough/DOE
1164F13901010--fever/cough
1264M5261015COPD-fever/DOE
1371F41785--fever/cough/DOE
1456F31268IP+fever/DOE
1571M3988chronic bronchitis-fever/cough/DOE
1656F2355--fever/cough/DOE
1768F2611--fever/cough/DOE
1869F391010-+fever/cough/DOE
1967F3985--fever/cough/DOE
2071F7542.52.5old tuberculosis-cough/DOE
2156F387.57.5-+DOE

All patients were receiving both corticosteroids and MTX. At the onset of PCP, the median dosages of prednisolone and MTX were 7.5 mg/day (range 1–20 mg/day) and 8 mg/week (range 6–20 mg/week), respectively. None of the patients were receiving other immunosuppressive drugs. Ten patients had pulmonary comorbidities, including interstitial pneumonia (n = 4), chronic obstructive pulmonary disease (n = 1), bronchiectasis (n = 1), chronic bronchitis (n = 1), follicular bronchiolitis (n = 1), and prior pulmonary tuberculosis (n = 2). Five patients had diabetes mellitus. None of the patients were receiving chemoprophylaxis for PCP at the time of PCP diagnosis. The median interval between the first infusion of infliximab and the onset of PCP was 9 weeks (range 2–90 weeks). Sixteen patients (76%) developed PCP within 14 weeks after the first infusion (before the scheduled fourth infusion) and 19 patients (90%) developed PCP within 26 weeks. Fever was the most common clinical symptom, observed in 18 patients (86%), followed by effort-induced dyspnea (81%) and dry cough (76%).

Laboratory and radiographic features of the patients with PCP.

Laboratory results data for the PCP group are summarized in Table 2. Sixteen patients either had severe hypoxia (with PaO2 <60 mm Hg on room air) or required immediate oxygen therapy at the onset of PCP. Peripheral blood lymphocyte (PBL) counts at the onset of PCP were <500 cells/μl in 3 patients, 500–1,000 cells/μl in 7 patients, and >1,000 cells/μl in 10 patients. The PCR test to detect P jiroveci was conducted in 19 patients, using either induced sputum (14 patients) or bronchoalveolar lavage fluid (5 patients). All test results were positive, although P jiroveci was microscopically identified in samples from only 2 patients (patients 18 and 19). Serum levels of 1,3-β-D-glucan, one of the major components of the cell walls of fungi and reportedly a reliable serum maker for PCP (22, 23), were elevated in 19 patients. Results of sputum culture performed on 20 patients revealed no causative bacteria or fungus. The median serum levels of IgG, lactate dehydrogenase, and KL-6 antigen were 1,191.5 mg/dl (range 626–2,112 mg/dl, n = 12), 439.0 IU/liter (range 214–1,011 IU/liter, n = 16), and 521.5 units/ml (range 156–1,480 units/ml, n=20), respectively. KL-6 antigen is a mucinous high molecular weight glycoprotein that is produced by type II pneumonocytes and is reported to increase in patients with active interstitial pneumonitis as well as in those with PCP (24).

Table 2. Laboratory data of patients with rheumatoid arthritis treated with infliximab at the onset of PCP*
PatientWBC, cells/μlLymphocytes, cells/μlPaO2 mm Hg (O2 liter/minute)Serum β-D- glucan, pg/mlPneumocystis jiroveci PCR
  • *

    PCP = Pneumocystis jiroveci pneumonia; WBC = white blood cell; PCR = polymerase chain reaction; NA = not assessed.

  • Oxygen therapy during the measurement of PaO2.

  • Normal ranges: <20 pg/ml by Fungitec G test (Seikagaku) for patients 1, 2, 8, 12, and 14–17, ≤11 pg/ml by Wako β-D-glucan test (Pure Chemical Industries) for patients 3–7, 9–11, 13, and 18–21.

  • §

    Oxygen saturation measured by a pulse oximeter was 93%.

  • Pneumocystis jiroveci were microscopically detected in bronchoalveolar lavage fluid (patient 18) or sputum (patient 19).

17,9505394639.0+
26,9001,2494430.5+
38,4001,00881 (5)67.1+
46,5002,21056 (10)27.2+
55,70057071 (2)325.3NA
614,80074047 (3)204.0+
79,700854507.9+
87,8801,56055<5+
913,100524761,720.0+
107,40059274 (10)928.0+
118,2801,52044 (15)241.0+
127,2002886336.1+
1311,5001,84062256.0+
144,9001474335.7+
1510,660320NA§863.0+
166,3001,34853267.5+
179,700NA41180.0+
188,4001,1006641.3+
1911,9508362877.8NA
206,9001,57334334.0+
2111,6001,856102 (4)103.5+

Chest radiographs and CT scans were analyzed in all 21 patients. The most common CT finding was ground-glass opacity (in 21 patients), either with sharp demarcation by interlobular septa (in 7 patients) or without interlobular septal boundaries (in 15 patients) (Figure 1). One patient demonstrated both patterns.

thumbnail image

Figure 1. Representative computed tomography scans of patients with Pneumocystis jiroveci pneumonia taken at the time of diagnosis. A, Ground-glass opacity with sharp demarcation by interlobular septa (patient 21), and B, ground-glass opacity without interlobular septal boundaries (patient 9).

Download figure to PowerPoint

Treatment and clinical course of PCP in patients with RA treated with infliximab.

All of the patients were hospitalized on the same day that PCP was suspected. Eighteen patients (all except patients 9, 15, and 18) received oxygen therapy on admission. MTX and infliximab were discontinued in all patients. Twenty patients received therapeutic doses of trimethoprim/sulfamethoxazole (TMP/SMX) and 1 was given a therapeutic dose of pentamidine isethionate immediately after the laboratory and radiologic examinations. Because of adverse drug reactions that included skin eruptions, renal toxicity, and thrombocytopenia, therapy with TMP/SMX was changed to pentamidine isethionate in 7 patients. Nineteen patients were treated with high-dose corticosteroids within a few days after admission. Sixteen patients were empirically treated with antibiotics and 7 with antifungal agents. A 68-year-old woman (patient 17) was intubated on the day of admission because of progressive respiratory failure, but was successfully weaned from the respirator 4 days later. All of the patients responded well to treatment and all survived.

Case–control study.

In order to characterize the PCP group of patients with RA more precisely, we compared demographic information, comorbidities, treatments, and laboratory data between the PCP and non-PCP groups (Table 3). We have previously reported that the PCP group was significantly older (P < 0.001), had a higher percentage of pulmonary diseases (P < 0.001), and was treated with a higher prednisolone dose (P = 0.001) than the non-PCP group at baseline (i.e., at the initiation of treatment with infliximab) (17). The percentage of patients with diabetes mellitus was higher (P = 0.046) and serum IgG levels were lower (P = 0.008) in the PCP group; however, these differences were not considered to be statistically significant after Bonferroni correction.

Table 3. Baseline characteristics of patients with rheumatoid arthritis treated with infliximab*
CharacteristicPCP group (n = 21)Non-PCP group (n = 102)P
  • *

    Values are the median (range) unless otherwise indicated. PCP = Pneumocystis jiroveci pneumonia; NS = not significant.

  • Bonferroni correction was applied; difference considered significant if P ≤ 0.005.

  • Interstitial pneumonia (n = 4), chronic obstructive pulmonary disease (n = 1), bronchiectasis (n = 1), chronic bronchitis (n = 1), follicular bronchiolitis (n = 1), old pulmonary tuberculosis (n = 2).

  • §

    Interstitial pneumonia (n = 1), chronic obstructive pulmonary diseases (n = 2), bronchiectasis (n = 2), chronic bronchitis (n = 3), old pulmonary tuberculosis (n = 3).

  • PCP group n = 19, non-PCP group n = 95.

  • #

    PCP group n = 17, non-PCP group n = 94.

  • **

    PCP group n = 12, non-PCP group n = 89.

Age, mean ± SD years64 ± 854 ± 12< 0.001
Women, n (%)17 (81.0)93 (91.2)NS
Diabetes, n (%)5 (23.8)8 (7.8)0.046
Pulmonary disease, n (%)10 (47.6)11 (10.8)§< 0.001
Disease duration, years8.9 (2.6–29)7 (0.3–35)NS
Methotrexate, mg/week8 (6–20)8 (2–15)NS
Prednisolone, mg/day7.5 (1–20)5 (0–20)0.001
Peripheral lymphocyte counts, cells/μl1,148 (420–2,439)1,192 (170–3,200)NS
Serum albumin, gm/dl#3.7 (2.9–4.4)3.8 (2.9–4.6)NS
Serum IgG, mg/dl**1,192 (626–2,112)1,540 (932–3,460)0.008

We compared the treatment and laboratory data of the PCP group at the onset of PCP with those of the non-PCP group at the most recent visit during infliximab therapy (as of January 31, 2006). The PCP group received higher prednisolone dosages than the non-PCP group (median 7.5 mg/day [range 1–15] and median 4 mg/day [range 0–15], respectively; P < 0.001). The PCP group also exhibited lower PBL counts compared with the non-PCP group (median 931 cells/μl [range 147–2,210] and median 1,330 cells/μl [range 119–4,788], respectively; P = 0.015), lower serum albumin levels than the non-PCP group (median 3.3 gm/dl [range 2.3–4.0] and 4.0 gm/dl [range 2.9–4.8], respectively; P < 0.001), and lower serum IgG levels than the non-PCP group (944 mg/dl [range 518–1,474] and 1,394 mg/dl [range 799–3,269], respectively; P < 0.001).

We prepared 21 case–control matches. In each match we collected data from 2 patients from the non-PCP group at the same point in time at which a patient from the PCP group was first diagnosed with PCP. Analyzing these data, we found that at time of onset of PCP, the PCP group had significantly lower serum albumin levels than the non-PCP group (median 3.3 gm/dl, n = 20 and median 3.9 gm/dl, n = 32, respectively; P < 0.001) and lower serum IgG levels than the non-PCP group (median 944 mg/dl, n =13 and 1,347 mg/dl, n =32, respectively; P < 0.001).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

We accumulated the largest possible number of patients with RA who developed PCP during treatment with infliximab, and described clinical and radiologic characteristics of the 21 patients that we found. Sixteen patients presented with severe hypoxia and/or required immediate oxygen therapy, and all 21 patients were hospitalized. PCP in these patients with RA presented an acute and progressive course, which should alert clinicians to recognize PCP as an important opportunistic infection during infliximab therapy.

The incidences of PCP during the postmarketing surveillance programs of infliximab and etanercept in Japan were 0.4% and 0.23%, respectively (7, 8). The corresponding incidence reported in the US is ∼0.01% (25). Although the US incidence was derived from voluntary reports to the Food and Drug Administration, a 20–40-fold higher incidence of PCP with the use of anti-TNF therapy in Japan suggests that this phenomenon might be unique to Japanese patients. Possible explanations for the difference include: 1) anti-TNF therapy may more severely affect host defenses in Japanese patients with RA in vivo due to genetic or environmental differences, 2) Japanese patients with RA may have a higher prevalence of prolonged colonization of P jiroveci, or 3) the incidence of PCP in patients with RA receiving anti-TNF therapy in Western countries may be underestimated due to the voluntary reporting system for adverse events.

Several lines of evidence have suggested that TNFα plays a critical role in host defenses against a Pneumocystis infection. First, Pneumocystis murina was found to directly stimulate the secretion of TNFα from murine alveolar macrophages by activation of the Toll-like receptor (26). Second, Pneumocystis-induced TNFα in turn enhanced the production of the reactive nitrogen intermediates that are important mediators for killing the microorganism (27). Finally, adenoviral gene transfer of mouse IgG/p55 TNF receptor in immunocompetent mice delayed clearance of P jiroveci after intratracheal inoculation (28). These data clearly indicate that TNFα serves as a key cytokine in the host defenses during a Pneumocystis infection, and they explain the association between PCP and treatment with infliximab. In the 21 patients with PCP, 76% developed the disease within 14 weeks after the first infusion of infliximab and 90% developed PCP within 26 weeks (or 6 months). Although patients with RA who are prescribed MTX alone sometimes develop PCP during their clinical course, the relatively short interval between the first infusions of infliximab and the onset of PCP indicate a strong causal relationship between the two.

Previous studies have revealed that there are significant differences in clinical presentations of PCP between patients with HIV infection and those without. PCP in patients with HIV infection develops insidiously, taking a subacute to chronic course that usually does not progress to respiratory failure (29). In contrast, patients without HIV infection develop PCP abruptly and progress to acute fulminating pneumonia with a high incidence of acute respiratory failure (30, 31). Mortality due to PCP in patients with HIV infection ranges from 9.6–20%, whereas it exceeds 50% in patients without HIV infection (32, 33). These differences probably resulted not only from the older age, more frequent comorbidities, and less standardized management of PCP in patients without HIV infection (31, 32, 34), but also from differing immunologic responses to P jiroveci (35). In our cohort, the clinical features of PCP are similar to those of previously reported cases without HIV infection (32) in terms of the high rate of progressive respiratory failure (observed in 16 [76%] of 21 patients) as well as the low rate of the microscopic detection of P jiroveci (found in 2 [9.5%] of 21 patients). All of our patients survived, which is distinctly different from the much higher mortality reported in PCP patients without HIV infection. Prompt diagnosis and treatment by attending physicians who have prior experience and are alert for the possible development of PCP probably contributed to the excellent prognosis for the patients in this study (36).

Double-blind, placebo-controlled trials have shown that adjunctive treatment with corticosteroids reduces the need for mechanical ventilation and mortality due to moderate-to-severe PCP in patients with HIV infection. An officially recommended regimen of adjunctive corticosteroid therapy for PCP in patients with HIV infection has been proposed (37). However, the clinical benefit of adjunctive corticosteroid therapy for PCP patients without HIV infection has not been established (35, 38). In our study, 19 of 21 patients received adjunctive corticosteroid therapy, including intravenous pulse methylprednisolone. Secondary infections were not observed in these patients, only 1 required mechanical ventilation, and all recovered rapidly. Based on the limited existing reports and our sample of patients, adjunctive corticosteroid therapy for PCP in patients with RA treated with infliximab who show respiratory failure may have some clinical benefit, including an improved prognosis. Further studies will be required to establish an optimal regimen for adjunctive corticosteroid therapy in these patients.

Microscopic evidence of P jiroveci is required to make a definitive diagnosis of PCP. Studies have shown that the organism is detectable on microscopic examination of induced sputum in 55–92% of PCP patients with HIV infection (39, 40). In patients with PCP but without HIV infection, detectability is <10%; thus, bronchoalveolar lavage fluid examination is often required (38). We included the PCR test for P jiroveci (41) or serum 1,3-β-D-glucan (22, 42) in the diagnostic criteria for presumptive PCP diagnosis in the current study. Several studies have demonstrated that the PCR test has greater sensitivity and specificity for the diagnosis of PCP compared with direct staining of P jiroveci (43). β-D-glucan, the major component of fungi cell walls (including the Pneumocystis cyst wall), has been also recognized as a useful serum marker for PCP (23). Because the PCR test results are sometimes positive in patients with colonization of P jiroveci, and because patients can have elevated serum β-D-glucan levels with various fungal infections, combining the results of these tests with clinical findings, laboratory data, and radiologic findings is mandatory for the presumptive diagnosis of PCP.

Monitoring and prophylaxis for PCP in patients with RA receiving infliximab is an important and challenging issue. There are no clinically useful biologic markers that guide the initiation of chemoprophylaxis for PCP in these patients. In individuals with HIV infection, the risk of developing PCP increases with a CD4+ T cell count <200/μl; this number serves as a clinically useful marker to identify patients at high risk for PCP (44). In patients with rheumatic diseases who are starting corticosteroid therapy, a PBL count of <500/μl proved to be a major predictor for PCP infection (12). In the current study, however, only 3 of the 21 patients had lymphocyte counts <500/μl at the time of disease onset, indicating that PCP can develop in patients with RA receiving infliximab both in a T cell-independent (i.e., TNF-dependent) and a T cell-dependent status. Recently, we reported that development of PCP in patients with RA treated with infliximab was best predicted by age (≥65 years), dosage of prednisolone (≥6 mg/day), and pulmonary comorbidities. Patients with 2 or 3 of the above risk factors developed PCP more frequently than those with only 1 or none.

In the present study we demonstrated that levels of serum albumin and serum IgG decreased upon onset of PCP. Therefore, prophylaxis should begin with a standard regimen in patients with 2 or 3 risk factors for PCP when results of serum albumin level or serum IgG level are seen to decrease. PBL counts could prove useful as a general predictor for PCP. Considering the seriousness and the relatively high incidence of PCP in RA patients in Japan, we also recommend that prophylaxis be initiated before treating patients with infliximab, at least in Japanese patients with RA, with 3 of these risk factors. Appropriate timing and length of PCP prophylaxis, as well as its efficacy in patients with RA receiving infliximab, need to be investigated.

In summary, the results of this study show that PCP is a serious complication in patients with RA who receive infliximab therapy. PCP developed early in the course of infliximab treatment and progressed to respiratory failure. The severity of PCP in the present series emphasizes the importance of the clinician's awareness of this opportunistic infection in patients treated for RA with infliximab. Early diagnosis and prompt intervention with specific antimicrobial drugs is vital. The evaluation of risk factors before treatment, as well as careful monitoring of clinical manifestations and laboratory tests, is beneficial for early diagnosis.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Dr. Harigai had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Komano, Harigai, Koike, Miyasaka.

Acquisition of data. Komano, Harigai, Sugiyama, Ogawa, Saito, Sekiguchi, Inoo, Oonishi, Ohashi, Amamoto, Miyata, Ohtsubo, Hiramatsu, Iwamoto, Minota, Matsuoka, Kageyama, Imaizumi, Tokuda, Okochi, Kudo, Tanaka, Takeuchi.

Analysis and interpretation of data. Komano, Harigai, Koike, Sugiyama, Ogawa, Saito, Sekiguchi, Inoo, Oonishi, Ohashi, Amamoto, Miyata, Ohtsubo, Hiramatsu, Iwamoto, Minota, Matsuoka, Kageyama, Imaizumi, Tokuda, Okochi, Kudo, Tanaka, Takeuchi, Miyasaka.

Manuscript preparation. Komano, Harigai, Koike, Sugiyama, Ogawa, Saito, Sekiguchi, Inoo, Oonishi, Ohashi, Amamoto, Miyata, Ohtsubo, Hiramatsu, Iwamoto, Minota, Matsuoka, Kageyama, Imaizumi, Tokuda, Okochi, Kudo, Tanaka, Takeuchi, Miyasaka.

Statistical analysis. Komano, Harigai, Koike, Ogawa, Miyasaka.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

We would like to thank Drs. Tatsuya Atsumi (Hokkaido University), Hiroaki Ida (Nagasaki University), and Mitsuhiro Iwahashi (Higashi Hiroshima Memorial Hospital) for their critical comments on this manuscript, and Drs. Yoshikazu Yamamoto (Tokyo Metropolitan Fuchu General Hospital), Takemasa Matsuda (Kagoshima Red Cross Hospital), Yoshinori Hasegawa (Nagoya University), and Seizo Yamana (Higashi Hiroshima Memorial Hospital) for supplementation of the clinical data for the patients. We also would like to thank Dr. Takahiro Nakamura (National Defense Medical College) for his help with the statistical analyses.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES
  • 1
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