It is well-known that HIV patients with a CD4+ cell counts less than 200 cells/mm3 are likely to develop PCP, and the most common identifiable risk factor for developing PCP in patients with autoimmune disease or malignancy is glucocorticoid use [9, 10]. Ogawa et al. reported that the number of peripheral lymphocytes at 2 weeks after initiation of glucocorticoid treatment, not the number at the initiation of treatment, was a risk factor for PCP in patients with rheumatic diseases [11]. Other reports and some postmarketing surveillance studies have revealed that a low lymphocyte count is not a risk factor for PCP in patients with RA. Thus, we excluded the number of lymphocytes as a risk factor from the analysis.
The postmarketing surveillance of IFX revealed that the development of PCP in RA patients treated with IFX was best predicted by an age of at least 65 years, dose of glucocorticoids (≥6 mg of PSL) and coexisting pulmonary disease [12]. However, that report was restricted to patients treated with IFX and did not include patients receiving other TNFα inhibitors or an IL-6 inhibitor. After analyzing the patients treated with biologic therapy who developed PCP in this study, we found that four of nine patients had fewer than two of the above-mentioned risk factors.
In our present study, we identified various risk factors for PCP in patients treated with biologics, including not only TNFα inhibitors but also the IL-6 inhibitor, to establish a new and useful prophylactic TMP/SMX procedure for PCP. We retrospectively compared a PCP group with a non-PCP group in patients who did not receive prophylaxis, and the multivariate analysis revealed that an age of at least 65 years, coexisting pulmonary disease and use of glucocorticoids were risk factors for PCP. An age of at least 65 years and coexisting pulmonary disease were also risk factors in the IFX postmarketing surveillance report; however, in our present study, the use of glucocorticoids alone was abstracted as a risk factor without regard to the dose administered. Other researchers have shown that, among patients with interstitial pneumonia or autoimmune disease, the glucocorticoid dose (≥30 mg of PSL) was a risk factor for PCP development [3, 11]. In our study, eight of the nine patients who developed PCP were receiving glucocorticoids, but only two patients were given at least 6 mg of PSL. The other six patients were treated with less than 6 mg of PSL (1.0 mg to 5.0 mg), suggesting that patients treated with glucocorticoids can benefit from primary TMP/SMX prophylaxis of PCP, regardless of glucocorticoid dose.
A previous report revealed that patients treated with high-dose glucocorticoids, those receiving immunosuppressive agents and those with lower serum IgG levels had a significantly higher risk for developing PCP [13]. Another recent report identified an advanced radiographic stage as a risk factor for PCP in RA patients treated with ADA [14]. In the present study, however, there were no significant differences in the serum IgG level or the radiographic stage between the patients with versus without PCP. Although concomitant MTX treatment was identified as an independent risk factor for PCP in a report of RA patients in Japan who were treated with ETN [15], the use (yes or no) or dose of MTX was not found to be a risk factor for the development of PCP in our patient cohort.
The duration between the initiation of biologics and PCP development varied widely, from 2 weeks to 20 months. In previous reports of RA patients treated with biologics, 76% to 90% of the cases of PCP developed within 6 months after the initiation of biologics [14–16]. In our present study, PCP developed in two of nine patients more than 12 months after biologics were started. That finding suggests that TMP/SMX prophylaxis needs to be continued for long periods.
A total of 250 (35.6%) of the 702 patients had two or three risk factors for PCP in this study. If patients with at least one risk factor were started on TMP/SMX prophylaxis in our study, 513 (73.1%) of the patients would have been included in the prophylaxis group. We thought that including these patients would have been difficult because of the adverse effects of the prophylactic treatment.
In the analysis of 214 patients, the duration of RA was shorter and the DAS28 score (ESR) was lower than those of the 702 patients. These findings could be due to our becoming more proactive about using biologic agents in patients with RA during the early stage of the disease. After adoption of the inclusion criteria for PCP prophylaxis, the ratio of glucocorticoid use decreased and the MTX dose increased, suggesting that an adequate dosage of MTX led to a tendency toward decreased glucocorticoid use in patients with RA. Almost all of the patients underwent CT, and we were more proactive about using biologic agents in patients with complications after the adoption of the prophylactic criteria. This is why the percentage of pulmonary disease was much higher in the 214 patients than that in the analysis of 702 patients.
Under the new prophylactic criteria, 94 (43.9%) of 214 patients were given prophylaxis and no severe adverse events occurred. After the adoption of the criteria for PCP prophylaxis, none of the patients developed PCP and the incidence of PCP was reduced from 0.93/100 patient-years to 0.00, confirming the validity and the safety of the primary prophylactic procedure in daily clinical practice. Authors of a previous report found that 3.1% of patients were forced to stop TMP/SMX prophylaxis because of adverse events [17]. The development of adverse events following TMP/SMX treatment were unavoidable in our present study, but we found that inhaled aerosolized pentamidine could be used as an alternative prophylactic treatment, rather than biologics, for PCP in patients with RA.
There are some limitations associated with this study. First, we treated only nine patients with PCP A larger number of patients and a longer observation period are necessary to confirm the effectiveness of our protocol. By the statistical calculation, we found that we needed 369 patients to confirm the statistical significance of the difference in the incidence of PCP in the first cohort (1.28%). Second, Pneumocystis colonization, which was previously reported to be a possible risk factor for PCP, was not analyzed in this study. The number of lymphocytes also was not analyzed. In the first cohort evaluated to identify the risk factors for PCP development, we excluded 141 patients who received TMP/SMX, although this exclusion might have led to biased results regarding the identification of risk factors. The serum level of IgG and the ratio of patients with DM complications were significantly different between the excluded 141 patients and 561 patients, respectively. These results suggest that if all 141 patients had not received the prophylaxis and the incidence of PCP had been much higher than 1.28%, the lower IgG level or the complication with DM might have been risk factors for PCP.
The incidence of PCP is much lower in Western countries than in Japan. Given the adverse effects of TMP/SMX, the prophylaxis criteria used in this study cannot be applied to patients in other countries in which the incidence of PCP is quite different from that in Japan. Additional studies are required to determine the incidence and risk factors for PCP in Western countries.