Hydroxychloroquine may reduce risk of Pneumocystis pneumonia in lupus patients: a Nationwide, population-based case-control study

Pneumocystis pneumonia (PCP), caused by Pneumocystis jirovecii, is a potentially life-threatening infection and is increasingly diagnosed in the immunocompromised patient without human immunodeficiency virus infection, including transplant recipients and the patient with malignancies or autoimmune diseases [1, 2]. Glucocorticoids (GC) and a number of immunosuppressants, mainly cyclophosphamide, and have been identified to be associated with an increased risk for PCP in patients with systemic lupus erythematosus (SLE) [3]. Notably, hydroxychloroquine (HCQ) and sulfasalazine (SSZ) have been found to have anti-fungal activities; therefore, it is crucial to address the risk for PCP in lupus patients receiving HCQ or SSZ [4‐6]. One recently published Japanese multicenter study reported a reduced risk for PCP in patients with rheumatoid arthritis (RA) receiving SSZ [7]. HCQ is a frequently used medication in patients with SLE; therefore, there is a crucial need to determine the distinct risks for PCP among medications, including HCQ and immunosuppressants, in patients with SLE. In this study, we aimed to explore the individual risks for PCP of frequently administered medications including GC as well as immunosuppressants and to determine the potential protective effect of HCQ against PCP among patients with SLE by using a Taiwanes population-based claim database.

To the best of our knowledge, the present study is the first research to address the association between HCQ use and the risk for PCP in lupus patients using a population-based claim database. We found that the use of HCQ with a 3-month cumulative dose of > 14 g was associated with a reduced risk of PCP, whereas the use of GC, CYC and MMF/MPA was associated with an increased risk for PCP in lupus patients. These findings indicated the distinct risk for PCP in lupus patients receiving GC and immunosuppressants and suggested a potential protective role of HCQ against PCP.

HCQ was originally developed as an antimalarial medication and is currently widely used as an immunomodulation agent for autoimmune diseases, mainly SLE, RA and Sjögren’s syndrome [13]. In addition to the antimalarial properties, HCQ also has antibacterial activities, which were mainly exerted by pH-dependent iron depletion and by an increased pH of phagosome, which in turn inhibit the growth of intracellular organisms [4]. Owing to the aforementioned antibacterial effect, HCQ has been found to be associated with a decreased risk of major bacterial infections in lupus patients [14, 15]. In addition to the antimalarial and antibacterial effects, HCQ also exhibits antifungal activities. Henriet et al., conducting an in vivo study with Aspergillus fumigatus and Aspergillus nidulans, demonstrated that chloroquine may increase the antifungal activity of leucocytes isolated in those with chronic granulomatous disease (CGD) at a low concentration through regulating the production of interleukin-1β and tumor necrosis factor-α [16]. Another in vitro study also found the synergistic effect of chloroquine and fluconazole against fluconazole-resistant Candida spp. including Candida tropicalis as well as Candida krusei [5]. Although data regarding Pneumocystis jirovecii are still lacking, Podrebarac et al. reported two subjects with SLE receiving high-dose GC developed PCP shortly after discontinuation of HCQ [17]. Taken together, these evidence highlight the anti-fungal effect of HCQ and at least partly explain the protective effect of HCQ against PCP in lupus patients as shown in this study.

The prevalence of PCP in lupus patients has varied over the past two decades. Gupta D. et al., analyzing 18 studies conducted in the United States between 1987 and 2006, found that merely 0.16% (121/76,156) of patients with SLE had PCP [18]. Recently, Kapoor TM et al. reported that approximately 0.45% (9/2000) of hospitalized patients with SLE had PCP using data collected from a database for the period 2000–2014 at Columbia University Medical Center-New York Presbyterian Hospital [19]. In the present study, we found that 0.24% (58/24,348) of patients with SLE between 2001 and 2013 had PCP in Taiwan. In line with our data, Weng CT et al., investigating 858 hospitalised lupus patient in southern Taiwan, found that only 0.58% (5/858) of them had PCP with identified Pneumocystis organisms in the lung (2 by lung biopsy and the other three by bronchoalveolar lavage) [20]. Taken together, the diagnosis of PCP appears to have increased gradually in the past two decades; however, the prevalence remains low. Given that we used a conservative definition for PCP, including both ICD-9-CM codes of PCP and medication for PCP to define the diagnosis of PCP, we may have underestimated, rather than overestimated, the prevalence of PCP infection in the present Taiwanese research.

In the present study, we identified an elevated risk of PCP in lupus patients taking MMF/MPA or in taking CYC with 3-month cumulative dose > 1.4 g. However, the use of CS, AZA or MTX was not significantly associated with the risk for PCP. Indeed, discrepant findings have been noted in the risk for infection among immunosuppressants in lupus patients [3, 21]. MMF was initially reported to have fewer severe infections as the induction therapy for lupus nephritis when compared with CYC [22, 23]. However, one recently published study conducted by Feldman CH et al., using the Medicaid beneficiaries with patients with SLE in 28 U.S. states, found that the risk for severe infections was not increased among new users of CYC and MMF/MPA, and AZA [21]. Similarly, Mok CC et al. conducted a long-term follow-up research among 803 patients with SLE and showed that CYC and MMF/MPA had similar impacts on survival [24]. However, it is somehow difficult to disentangle the effects of the complex interaction among disease activities, the sequential/combinational usage of immunosuppressants, and dosage of each medication on the risks for PCP. Therefore, CS and AZA did not confer any significant independent risks for PCP in this study, although these two medications tended to increase the risk of PCP in the univariable analysis. Intriguingly, in the aforementioned study conducted by Mok CC et al., the use of HCQ had a survival benefit in patients with SLE (HR 0.59, 95% CI 0.37–0.93) [24]. Moreover, Feldman CH et al., using Medicaid database between 2000 and 2006, also found that HCQ user had a decreased risk of infections than non-user (HR 0.73, 95% CI 0.68–0.77) [10], and these findings are largely consistent with our findings in the present study.

Moderate to severe renal disease was an independent risk for PCP in the present study. In line with our findings, Feldman CH et al., analyzing 33,565 patients with SLE and 7113 with lupus nephritis, found that the incidence rate of serious infections requiring hospitalization per 100 person-years was 10.8 in SLE and 23.9 in those with lupus nephritis [10]. Although we could not specify lupus nephritis using ICD, the moderate to severe renal disease in lupus patients should be reasonably attributed to lupus nephritis given that underlying moderate to severe renal disease is uncommon in subjects aged 40. The high risk for PCP in lupus patients with moderate to severe renal disease highlights that lupus patients with renal involvement are particularly vulnerable to infectious diseases, including PCP. A number of studies have explored the efficacy and safety profile of using trimethoprim-sulfamethoxazole as PCP prophylaxis in high-risk lupus patients, particularly those receiving medium-to-high dose GC [25, 26]. However, there is currently no consensus regarding routine PCP prophylaxis in lupus patients, and we think PCP prophylaxis might potentially be feasible in high-risk patients [18].

There are limitations in this study. First, our results were derived from a population-based claim database in Taiwan; therefore, further investigations involving other populations are needed for the generalizability. Second, we could not assess the causality of HCQ-associated reduced risk for PCP; however, the finding of this study warrant more mechanistic studies. Third, the accuracy of diagnoses is a concern in the claim database. However, we think that regular quality control surveys of NHIRD among all medical facilities by the BNHI has much improved the accuracy of coding in NHIRD [27], and bias attributed by the misclassification was hence minimised. Additionally, the prevalence of PCP infection in the present Taiwanese research was quite similar to those in other studies [19, 20].

PCP is a life-threatening fungal infection with an increasing prevalence in patients with SLE. We have identified a potentially protective effect of HCQ against PCP and demonstrated the distinct risks for PCP conferred by GC and various immunosuppressants in lupus patients. The decreased risk of PCP in lupus patients receiving HCQ as we showed should be clinically relevant, such as the prescription of HCQ for lupus patients with a high risk for PCP and the less indicated for PCP prophylactics in patients already receiving HCQ. The distinct risks for PCP among GC and immunosuppressants should be taken into account with regards to the vigilance for PCP and the implementation of PCP prophylaxis in lupus patients. Further mechanistic studies are required to address the underlying mechanisms.