Abstract
Introduction
Pneumocystis jirovecii pneumonia (PJP) is a severe, life-threatening complication in patients treated with rituximab. However, there is no consensus on the primary prophylaxis for it in rituximab-treated pemphigus patients. Therefore, we sought to investigate the prophylactic efficacy and safety profile of cotrimoxazole for reducing the risk of developing PJP in pemphigus patients receiving rituximab.
Methods
This single-center retrospective study investigated 148 pemphigus patients undergoing a first cycle of rituximab between 2008 and 2021 at a tertiary referral center in northern Taiwan. Patients were divided into the prophylaxis group (N = 113) and the control group (N = 35) according to whether or not cotrimoxazole was administered. The primary outcome was the 1-year incidence of PJP in the two groups, while the secondary outcome was the incidence of cotrimoxazole-related adverse events.
Results
Of the 148 patients enrolled in this study, three patients, all in the control group, developed PJP during the 1-year follow-up. The incidence of PJP (8.6%) in the control group was significantly higher than that in the prophylaxis group (0%) (p = 0.012). The incidence of cotrimoxazole-related adverse events was 2.7%, and none of the cases were associated with life-threatening conditions. In addition, the cumulative prednisolone dose was associated with a trend of a higher risk of PJP (p = 0.0483).
Conclusions
Prophylactic cotrimoxazole significantly reduces the risk of PJP in a certain high-risk population and has a tolerable safety profile.
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Avoid common mistakes on your manuscript.
Although Pneumocystis pneumonia is a life-threatening complication following rituximab therapy, no consensus regarding the necessity of primary prophylaxis for it in rituximab-treated pemphigus patients has been established. |
We assessed the efficacy and safety profile of prophylactic cotrimoxazole in pemphigus patients receiving rituximab. |
The incidence of Pneumocystis jirovecii pneumonia (PJP) in patients not receiving prophylactic cotrimoxazole was significantly higher (8.6%) compared to those receiving prophylaxis (0%), and cotrimoxazole-related adverse events occurred in 2.7% of the patients, none of which were associated with life-threatening conditions. |
Patients who received concomitant moderate-to-high doses of corticosteroids might be predisposed to a higher risk of Pneumocystis pneumonia. |
Since our result shows that cotrimoxazole significantly reduces the incidence of PJP and has a tolerable safety profile, we recommend that prophylactic cotrimoxazole might be indicated in rituximab-treated pemphigus patients, especially for those receiving concomitant moderate- to high-dose corticosteroids. |
Introduction
Pemphigus consists of a group of chronic, life-threatening autoimmune blistering diseases characterized by flaccid blisters and erosions on the skin and mucous membranes. It has been treated with systemic corticosteroids along with various immunosuppressive agents for decades [1, 2]. However, in spite of the rapid and significant therapeutic effect of systemic corticosteroids, their long-term use is recognized as a double-edged sword because they can cause severe or even life-threatening adverse events [3, 4]. Therefore, additional therapies with high long-term efficacies and fewer systemic adverse effects have been investigated [5, 6].
Rituximab, a chimeric monoclonal antibody targeting CD20 antigens, removes CD20-expressing B lymphocytes from the circulation for 6–12 months, and has been widely used to treat various immune-related diseases [7, 8]. With regard to the pathogenic role of autoantibodies against desmoglein 1 and/or desmoglein 3 in pemphigus, the depletion of B lymphocytes seems a rational and promising therapeutic approach. Numerous studies have demonstrated that rituximab may be an effective treatment for pemphigus with a potential steroid-sparing effect [7, 9, 10]. Recent guidelines have recommended rituximab with systemic corticosteroids as the first-line therapy for managing moderate-to-severe pemphigus [11, 12].
Despite the advantages of rituximab for treating pemphigus, several serious adverse effects have been reported [13]. Among these, Pneumocystis jirovecii pneumonia (PJP) is a life-threatening event of clinical importance [13, 14]. PJP is well known as an opportunistic infection in HIV patients and was formerly considered to be mainly attributable to impaired T cell function [15]. However, recent studies have demonstrated the specific role of B cell depletion in PJP, and have found that anti-CD20 antibody alone permits PJP occurrence [15, 16]. Because the mortality rate of PJP in non-HIV patients reaches 30%, which is significantly higher than that reported in HIV patients, PJP has become a thorny problem for rituximab-treated patients [17,18,19,20,21].
Fortunately, despite the high mortality associated with PJP, it is preventable with multiple prophylactic modalities [22]. Among these, cotrimoxazole is the recommended first-line treatment because of its outstanding efficacy [22, 23]. A Cochrane review showed that cotrimoxazole was associated with an 85% reduction in PJP occurrence and an 83% reduction in PJP-related mortality, emphasizing the potential benefit of PJP prophylaxis for non-HIV immunocompromised patients [24]. However, despite its high efficacy as a PJP prophylaxis, cotrimoxazole has numerous side effects, including urticaria, skin rash, loss of appetite, and more rare but severe adverse reactions, such as Stevens–Johnsons syndrome, Henoch–Schönlein purpura, aplastic anemia, myocarditis, and hepatic necrosis [25], which have led to debates about the necessity of prescribing it for immunocompromised patients [26].
Several studies have investigated the incidence of PJP and the efficacy of prophylactic cotrimoxazole following rituximab administration for various diseases, including Wegener’s granulomatosis, B cell lymphoma, antineutrophil cytoplasm antibody-associated vasculitis, and rheumatoid arthritis, as well as in kidney transplant recipients, and have suggested regular Pneumocystis prophylaxis after rituximab treatment [15, 27,28,29,30]. However, only a few studies have examined the role of prophylactic cotrimoxazole in pemphigus patients, and the results remain controversial [31, 32]. Therefore, the aim of this study was to evaluate the incidence of PJP, describe the risk and benefit profile of prophylactic cotrimoxazole, and identify the risk factors for developing PJP in rituximab-treated pemphigus patients.
Methods
Study Population
This study was a single-center retrospective investigation of pemphigus patients undergoing a first cycle of rituximab therapy between 2008 and 2021 at a tertiary referral center in northern Taiwan. All patients in this cohort were followed up for more than 3 months. PJP occurrence was monitored from the date of administration of the first dose of rituximab to the date of PJP infection, death, loss to follow-up, or for 52 weeks from the start of the observation, whichever came first. This study was conducted in accordance with the Declaration of Helsinki and received approval from the Institutional Review Board (202210001RINC).
Diagnosis
Clinical suspicion prompted the diagnosis of pemphigus, which was confirmed by histopathological assessments by a trained pathologist, intercellular IgG and C3 deposits in a direct immunofluorescence assay, and a high titer of autoantibodies against desmoglein 1 and/or desmoglein 3 demonstrated by enzyme-linked immunosorbent assay. The precise pemphigus subtype (pemphigus vulgaris, pemphigus foliaceus, and pemphigus erythematosus) was determined for all patients following the evaluation.
Evaluation of PJP was based on clinical presentation, radiological findings, polymerase chain reaction or an antigen test for PJP, and the treatment response to therapeutic doses of cotrimoxazole. For all patients diagnosed with PJP in our study, we routinely consulted infectious disease specialists and excluded any other well-established probable etiology before the diagnosis was made.
Exposure to Prophylaxis for PJP
Since there is no consensus on prescribing prophylactic cotrimoxazole to pemphigus patients treated with rituximab, some patients in our cohort received prophylaxis while others did not due to different clinical judgements of different clinicians. The protocol for cotrimoxazole dosage was one single-strength tablet daily according to the current recommendation [33]. Moreover, we thoroughly reviewed the drug history of all patients to determine whether second-line therapies for PJP prophylaxis were given during the observation period.
Clinical Data
We collected the following information for each patient: demographic data (age, sex, body weight, diagnosis, and comorbidities) and clinical information associated with rituximab therapy (PJP occurrence, disease duration prior to rituximab, previous or concurrent therapies, total dose of rituximab, and complications of rituximab). Because systemic corticosteroids are reported to be the most common medication associated with PJP in non-HIV patients [34], we further calculated the cumulative dose of systemic corticosteroids received within 6 months after the first administration of rituximab and converted it to an equivalent dose of prednisolone. Moreover, to evaluate the potential risk posed by the PJP prophylaxis, cotrimoxazole-related adverse events, determined based on the timing of occurrence, clinical profile, and response after the cessation of cotrimoxazole, were also recorded.
Statistical Analysis
Categorical variables were compared using the χ2 test, but Fisher’s exact test was used instead when the sample size was small. Continuous variables were compared using Student’s t test or Wilcoxon’s rank-sum test, as appropriate. All tests were two-tailed and performed using STATA software, version 14. A p value of < 0.05 was considered statistically significant.
Ethical Clearance
This study protocol was reviewed and approved by the National Taiwan University Hospital Research Ethics Committee, approval number 202210001RINC. Written informed consent was obtained from the participants included in the study. The study was in accordance with the ethical standards of the institutional and national research committee and with the World Medical Association Declaration of Helsinki.
Results
Baseline Characteristics and Clinical Data
One hundred forty-eight pemphigus patients undergoing a first cycle of rituximab were enrolled in our study; 67 were male (45.3%) and 81 were female (54.7%). The mean age at rituximab administration was 51.7 years (standard deviation (SD) = 13.9). The majority of the patients (N = 118, 79.7%) were diagnosed as having pemphigus vulgaris, while 29 patients (19.6%) were diagnosed as having pemphigus foliaceus, and 1 patient (0.7%) was diagnosed with pemphigus erythematosus. During follow-up, 144 patients (97.3%) were taking concomitant oral prednisolone and 77 patients (52.0%) were also taking azathioprine. Other previous or concurrent immunosuppressive therapies included hydroxychloroquine (N = 12, 8.1%), minocycline (N = 2, 1.4%), colchicine (N = 10, 6.6%), cyclosporin (N = 4, 2.7%), tacrolimus (N = 2, 1.4%), intravenous immunoglobulin (N = 1, 0.7%), methotrexate (N = 9, 6.1%), sulfasalazine (N = 2, 1.4%), levamisole (N = 1, 0.7%), mycophenolate mofetil (N = 2, 1.4%), and cyclophosphamide (N = 1, 0.7%).
Prophylaxis for PJP
Of the 148 patients in our study, 113 (76.4%) received concurrent cotrimoxazole as prophylaxis for PJP, while 35 (23.6%) received no prophylaxis. None of the patients received atovaquone, pentamidine, dapsone, or any other known second-line therapy for PJP prophylaxis during observation. The baseline demographic data and clinical information are presented in Table 1. Statistically significant differences in disease duration prior to rituximab therapy (p = 0.0001), total rituximab dose (p = 0.0029), and cumulative prednisolone dose within 6 months after rituximab administration (p = 0.0001) were found between the prophylaxis group and the control group. Other baseline characteristics were comparable between the two groups.
Pneumocystis jirovecii Pneumonia
Overall, of the 148 patients, three (2.0%), all in the control group, were diagnosed with PJP during follow-up. The incidence of PJP was 8.6% in patients in the control group and 0% in patients receiving prophylaxis; this was a statistically significant difference (p = 0.012). None of the PJP cases had a fatal outcome after receiving aggressive treatment with therapeutic cotrimoxazole.
Risk Factors for Developing PJP
To demonstrate the potential risk factors contributing to PJP in pemphigus patients receiving rituximab, we carried out a further evaluation of the control group (Table 2). The 35 patients not receiving prophylaxis showed a trend of a higher risk of developing PJP (p = 0.0483) when the cumulative prednisolone dose was increased. Apart from the prednisolone dose, none of the variables showed a statistically significant impact on PJP occurrence.
Second to Fourth Cycles of Rituximab
We further examined patients who experienced disease flare-ups, and thus underwent a second to fourth cycle of rituximab, using the same inclusion criteria. Baseline characteristics and clinical data are presented in Table 3. Of the 148 patients enrolled in our study, 93 (62.8%) received a second cycle of rituximab, 41 (27.7%) a third, and 23 (15.5%) a fourth. However, none of the patients were diagnosed with PJP within 1 year after each rituximab cycle, regardless of the prophylaxis profile. Moreover, both the prophylaxis group and the control group received a lower cumulative prednisolone dose in subsequent cycles compared to the dose administered in the first cycle.
Safety of Prophylactic Cotrimoxazole
Of the 113 patients receiving cotrimoxazole as prophylaxis for PJP, three cases (2.7%) experienced cotrimoxazole-related adverse events. None of the adverse effects were correlated with life-threatening events, and all of them spontaneously resolved after discontinuation of cotrimoxazole.
Discussion
Although cotrimoxazole has been widely used as prophylaxis for PJP, the experience is mainly based on HIV-infected patients [35, 36]. Therefore, whether prophylactic cotrimoxazole is indicated for patients receiving rituximab remains unclear. Although several studies have investigated rituximab use in various diseases [24], currently there is no consensus on the necessity of prescribing prophylactic cotrimoxazole to pemphigus patients undergoing rituximab treatment [31]. Therefore, we conducted this retrospective study to evaluate the effects of cotrimoxazole as the primary prophylaxis for PJP in rituximab-treated pemphigus patients.
Several studies investigating the incidence of PJP in pemphigus patients treated with rituximab have reported inconsistent results. Chen et al. [37] evaluated 38 pemphigus patients treated with rituximab without PJP prophylaxis and found one patient (2.6%) that developed PJP. Amber et al. [38] evaluated 801 patients with autoimmune blistering diseases, of whom 140 patients underwent rituximab therapy, and found that one patient (0.7%) treated with rituximab developed PJP during follow-up. In an observational epidemiological study conducted by Wei et al. [32] in Taiwan, the incidence of PJP in rituximab-treated pemphigus patients approached 3.8%. Considering the high prevalence and high mortality rate, the authors concluded that prophylaxis for PJP might be warranted for pemphigus patients receiving rituximab. In contrast, Faraji et al. [31] evaluated 494 rituximab-treated pemphigus patients, of whom 235 (47.6%) received prophylactic cotrimoxazole and 259 (52.4%) did not; the PJP incidence was 0.4% in both groups. Due to the low incidence of PJP in their study, the authors declared that prophylactic cotrimoxazole was not mandatory for all pemphigus patients receiving rituximab.
The incidence of PJP in our cohort was 8.6% in patients not receiving prophylaxis, and was significantly higher than the incidence reported for the prophylaxis group (0%) (p = 0.012). Since none of the PJP cases received prophylaxis in our study, the result demonstrated the high efficacy of cotrimoxazole in preventing PJP, a result consistent with the findings of previous studies [24, 39]. Although several variables were significantly different between the prophylaxis group and the control group (Table 1), apart from the cumulative corticosteroid dosage, most were not considered to be noteworthy risk factors for PJP development [40,41,42]. Moreover, these variables did not differ significantly between patients with PJP and patients without PJP. Therefore, instead of these variables, the use of cotrimoxazole may be the main reason for the lower incidence of PJP in the prophylaxis group in the present study.
It is worth noting that the incidence of PJP among pemphigus patients receiving rituximab in our cohort was much higher than that shown in previous studies [31, 32, 37, 38]. Although previous studies have not described the geographic distribution of PJP in pemphigus patients, one study found that the PJP incidence among HIV-infected patients in Taiwan (2.8%) was four times higher than that in the USA (0.7%) [43, 44]. Another study also pointed out that Asian ethnicity might be a potential risk factor for developing PJP [45]. Based on these findings, we suggest that the higher incidence of PJP in our cohort might be attributed to a regional or ethnic difference compared to previous studies. However, further studies are required to accurately determine the difference in PJP incidence between pemphigus patients of different geographic and ethnic characteristics.
Our study also demonstrated that a higher cumulative prednisolone dose was associated with a trend of developing PJP in rituximab-treated pemphigus patients without prophylaxis. Previous studies have also described probable risk factors contributing to PJP occurrence in patients with autoimmune and inflammatory diseases, revealing that corticosteroids, immunosuppressants, interstitial lung disease, high disease activity, lymphopenia, hypoalbuminemia, and advanced age (≥ 65 years) may all predispose patients to a higher risk of developing PJP [40, 46, 47]. Among these factors, corticosteroid use is well established [48, 49]. However, there is no consensus on the threshold corticosteroid dose that warrants routine prophylaxis for PJP. One study suggested that patients receiving ≥ 20 mg of prednisolone for ≥ 4 weeks might be appropriately indicated for prophylaxis for PJP [50]. Since pemphigus patients treated with rituximab are likely to receive concomitant high-dose corticosteroids, which is recommended as the first-line-treatment in new-onset moderate-to-severe pemphigus by current guidelines [11, 12], and considering the increased risk of developing PJP associated with both rituximab and corticosteroids, prophylaxis for these patients seems rational. Furthermore, PJP tends to develop in specific populations, including patients taking more than one immunosuppressant with concomitant moderate- to high-dose corticosteroids and patients with serious comorbidities [51]. Our study showed that high corticosteroid doses might be a risk factor of PJP in rituximab-treated pemphigus patients, suggesting that these patients may require specific monitoring for the development of PJP.
Our study also revealed that no patients developed PJP following the second to fourth cycles of rituximab. Based on previous studies and our findings emphasizing the importance of concomitant corticosteroids for triggering PJP development, we hypothesize that the lower risk of PJP in pemphigus patients undergoing rituximab retreatment might be attributed to both lower disease activity and lower concomitant corticosteroid doses. This result again emphasizes the potential role of concomitant corticosteroids in PJP development. Therefore, we suggest that, although routine prophylaxis for rituximab-treated pemphigus patients has been a dilemma, prophylaxis in patients receiving rituximab with concomitant moderate- to high-dose corticosteroids is warranted. However, further studies are required for determining the threshold dose of concomitant corticosteroids.
It is worth noting that although the prophylaxis group in our study was treated with a higher dose of concomitant corticosteroids compared to the control group (p = 0.0001), the incidence of PJP in the former was actually lower. This observation emphasizes the outstanding efficacy of prophylactic cotrimoxazole, and again highlights its role in preventing PJP in patients at risk of the disease.
Although some previous studies have described a high incidence of cotrimoxazole-related adverse events, which necessitated the cessation of prophylaxis [24, 38, 52], more recent studies of patients with autoimmune bullous disorders have shown a relatively low risk [31, 46]. In our study, three patients (2.7%) experienced cotrimoxazole-related complications. Since the incidence of cotrimoxazole-related adverse events was much lower than the incidence of PJP in the control group (8.6%), prophylactic cotrimoxazole may be beneficial to pemphigus patients treated with a first cycle of rituximab, especially to those receiving concomitant moderate- to high-dose corticosteroids. Moreover, we found that most of the cotrimoxazole-related adverse events were reversible [53,54,55], whereas serious PJP might have a fatal outcome [15], further emphasizing the importance of adequate prophylaxis for PJP in these high-risk patients.
Limitations
Our study has several limitations. First, owing to its retrospective nature, baseline characteristics in the prophylaxis group and the control group could not be well balanced. However, patients receiving prophylactic cotrimoxazole still showed a significantly lower risk of PJP despite receiving higher doses of corticosteroids. Second, due to the small study population, our data were insufficient to identify additional risk factors for developing PJP, apart from higher corticosteroid doses. Larger studies may be required to identify further risk factors. Third, since not all patients with clinical suspicion underwent bronchoalveolar lavage at our hospital, the diagnosis of PJP in patients without adequate respiratory specimens for microorganism identification was based on clinical presentation, radiological findings, treatment response, and the infectious disease specialist’s opinion. Fourth, as a few patients did not have a long-term regular follow-up, we could not determine whether PJP developed after their last visit. In addition, regional or ethnic differences might be a risk factor for higher incidence of PJP in certain geographic areas, which could be a limitation, as this study is only a single-center investigation. Finally, because none of the cases in the prophylaxis group were diagnosed with PJP, our study could not identify the minimum duration of prophylaxis required for PJP, which needs further investigation.
Conclusion
Since PJP is often described as having a grave prognosis [20, 56, 57], the consideration of prophylaxis for rituximab-treated immunocompromised patients is warranted. We demonstrated that cotrimoxazole may significantly reduce the incidence of PJP among pemphigus patients receiving a first cycle of rituximab. Meanwhile, the incidence of adverse events due to prophylaxis for PJP was low, and all such events were reversible after the cessation of cotrimoxazole. In addition, a trend for a higher cumulative concomitant corticosteroid dose to lead to a higher risk of developing PJP was revealed. Since the incidence of PJP among pemphigus patients who did not receive prophylaxis surpassed the incidence of cotrimoxazole-related adverse events, we consider cotrimoxazole to be an effective prophylaxis for PJP with a tolerable safety profile, and we recommend its use for pemphigus patients treated with a first cycle of rituximab, especially for those receiving concomitant moderate- to high-dose corticosteroids.
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Acknowledgements
The authors would like to express their gratitude to the staff of National Taiwan University Hospital—Statistical Consulting Unit (NTUH-SCU) for statistical consultation and analyses. The authors would also like to thank the participants of this study.
Funding
No funding or sponsorship was received for this study or the publication of this article.
Author Contributions
All authors were involved in the study conception and design. All authors analyzed and interpreted the data. Hao-Chen Hsu first drafted the manuscript, and all authors provided substantial knowledge-based revisions and editing of previous versions of the manuscript. All authors read and approved the final manuscript for submission.
Disclosures
Hao-Chen Hsu, Po-Wei Huang, Yung-Tsu Cho, and Chia-Yu Chu declare that they have no competing interests.
Compliance with Ethics Guidelines
This study protocol was reviewed and approved by the National Taiwan University Hospital Research Ethics Committee, approval number 202210001RINC. Written informed consent was obtained from the participants included in the study. The study was in accordance with the ethical standards of the institutional and national research committee and with the World Medical Association Declaration of Helsinki.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Hsu, HC., Huang, PW., Cho, YT. et al. Cotrimoxazole as a Preventative Intervention for Pneumocystis Pneumonia in Pemphigus Patients Treated with Rituximab: A Retrospective Study. Dermatol Ther (Heidelb) 13, 1561–1576 (2023). https://doi.org/10.1007/s13555-023-00953-9
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DOI: https://doi.org/10.1007/s13555-023-00953-9