Comparing the burdens of opportunistic infections among patients with systemic rheumatic diseases: a nationally representative cohort study

Infection remains a leading cause of morbidity, hospitalization, and mortality among patients with autoimmune rheumatic disease [1, 2]. Furthermore, the estimated rates of infectious complications can be 26–50% among patients with polymyositis/dermatomyositis (PM/DM) or systemic lupus erythematosus (SLE) [3‐5]. Several factors may influence the vulnerability of patients with rheumatic diseases, with infectious diseases being strongly associated with their frequent use of corticosteroids and immunosuppressive agents. There is also evidence that innate and adaptive immunity against various pathogens is impaired in patients with SLE [6]. Moreover, the development of infection in patients with rheumatic diseases leads to a much poorer prognosis relative to that of patients without infectious diseases [2, 7].

In addition to common infections, opportunistic infection (OI) has emerged as an important complication in developed countries [8]. Interestingly, the risks of herpes zoster and Pneumocystis jiroveci pneumonia are elevated among SLE patients [9, 10], while DM was recently shown to be associated with elevated rates of herpes zoster and tuberculosis [11, 12]. However, most previous studies regarding the relationship between rheumatic diseases and OI were focused on SLE and were limited by their small-scale or single-centre designs. Furthermore, there is scarce research regarding the incidence rates (IRs) of OI in other major connective tissue diseases, such as systemic sclerosis (SSc) and primary Sjögren’s syndrome (pSS). Moreover, among patients with PM/DM or SLE, there are no large-scale studies regarding the incidences of other OIs (e.g. aspergillosis, cryptococcosis, non-tuberculous mycobacteria, and cytomegalovirus infection). We are also unaware of any studies regarding whether the burden of OI varies among different connective tissue diseases. Therefore, the present study aimed to determine the incidence rates of various OIs in real-world practice among Taiwanese patients with five systemic rheumatic diseases (SLE, PM/DM, SSc, pSS, and rheumatoid arthritis [RA]). We also compared the risks of OIs between these rheumatic diseases.

To the best of our knowledge, this is the first nationally representative study to investigate the incidence of various OI types, including invasive fungal infection, mycobacterium infection, salmonellosis, and cytomegalovirus infection, among patients with five major immune-mediated diseases (PM/DM, SLE, RA, SSc, and pSS). Our study is also the first to demonstrate that the risks of OI vary for each specific disease, with the highest risk observed for PM/DM, followed by SLE, SSc, RA, and pSS. In addition, we found that the risk of OI was highest during the first year after the diagnosis of rheumatic disease, with the risk subsequently decreasing at longer intervals after the diagnosis.

Previous studies have indicated that SLE patients have higher rates of bacterial infection or OI than the general population [1, 2], which has been attributed to various factors. For example, several immune abnormalities have been reported in SLE patients, including complement deficiency [27], complement receptor deficiency [9, 28], defective chemotaxis and phagocytosis [7], decreased production of interleukin-8 by polymorphonuclear leukocytes [29], and impaired activity of T-helper cells against viral antigens [30]. Furthermore, disease-related factors can also increase the risk of OI in patients with SLE, with their lupus activity index independently predicting the risk of hospitalization for infectious disease [9]. Frequent use of glucocorticoids and immunosuppressive agents is also an important risk factor for unusual infection, and it has been reported that cyclophosphamide use for serious SLE manifestations is linked to fatal OIs [31]. A recent observational study also revealed that corticosteroid use had a dose-dependent effect on the rate of OIs [10].

One of the present study’s main findings was that the IR of OI was significantly higher for PM/DM than for SLE, even after adjusting for age, sex, and comorbidities. There are several possible explanations for this result. First, interstitial lung disease is a serious complication in up to 40–65% of PM/DM cases [32, 33], and patients with interstitial lung disease may be vulnerable to pulmonary infections by Mycobacterium and Aspergillus species [34, 35]. Second, PM/DM patients often require more intensive immunosuppression than SLE patients, and fatal refractory interstitial lung disease associated with PM/DM is not uncommon, with Kameda et al. [36] reporting that treatment using cyclophosphamide plus glucocorticoids was only effective in 25% of these critical patients. Triple therapy using cyclophosphamide, cyclosporin A, and glucocorticoids has been suggested to increase the response rate in these refractory patients [37], although no combination treatments (e.g. > 2 immunosuppressive agents) have been suggested for SLE patients, even in cases with lupus nephritis [38]. Thus, intensive immunosuppression may expose PM/DM patients to a significantly higher risk of OI than SLE patients. Third, PM/DM are strongly associated with a broad range of malignancies [39], which could contribute to the increased risk of OI through the use of cytotoxic anti-cancer therapies. Interestingly, malignancy can be present at the onset of idiopathic inflammatory myositis or may develop before or after the diagnosis of PM/DM [39], although we found that the risk of OI remained higher for PM/DM patients than for SLE patients, even after adjusting our regression model for various cancer types. Fourth, involvement of the striated muscle at the oropharynx and upper third of the oesophagus can be observed in PM/DM patients, which can alter their ability to swallow and increase their risk of aspiration pneumonia [40]. Similarly, a small proportion of PM/DM patients experience thoracic muscle myopathy, which leads to ventilatory compromise, difficulty managing respiratory secretions, and an elevated risk of respiratory infection [3, 41].

Although infectious complications are more common in patients with connective tissue diseases, it is unclear whether the risk of OI varies over time. The present study revealed that the risk of OI was highest during the first year after the diagnosis of systemic rheumatic disease, especially among PM/DM patients, where the IR of OI during the first year after diagnosis was approximately 5.4 times greater than the IR at > 5 years after diagnosis. Similarly, a French study of 156 PM/DM patients revealed that 62.5% of the OI events occurred during the first year after the PM/DM diagnosis [42]. Another cohort study explored the risk of herpes virus infection in 134 DM patients and also indicated that the IR was highest during the first year after DM diagnosis [43]. Other research has evaluated the courses of adult and juvenile DM patients, and the results suggested that disease activity was highest during the 6–12 months after the DM diagnosis, with improvement apparently accompanied by corticosteroid treatment [44‐46]. Moreover, the required dosage of corticosteroid immunosuppression for DM was lower after 12 months of use and remained relatively constant until 36 months of use [46]. However, some studies have indicated that 11–30% of PM/DM patients developed OI before starting immunosuppressive therapy [42, 47]. Therefore, both high-dose corticosteroid treatment and high disease activity may contribute to the enhanced risk of OI during the first year after PM/DM diagnosis.

The introduction of biological agents has been a major advance in the treatment of RA [48]. For example, tumour necrosis factor alpha (TNF-α) inhibitors have potent immunosuppressive effect in this setting and can prevent radiographic progression or induce clinical remission in RA patients [49]. However, infectious complications are important concerns when patients are receiving anti-TNF therapies [50], and there is evidence that anti-TNF therapies are associated with increased risks of serious infections that may require hospitalization [51‐53]. In this context, etanercept and adalimumab were the first biologic agents approved for the treatment of severe RA in Taiwan and were widely used after 2004. However, we did not perform separate analyses of the risks of OI before and after the era of biological therapy in Taiwan, and caution should be exercised when interpreting our data regarding the incidence of OI in RA cases. It is important to note that RA patients receiving anti-TNF therapy or other biological agents may experience a higher risk of OI, relative to their apparent risk based on our findings.

Taiwan is a country with an intermediate burden of tuberculosis, based on an estimated IR of 68 cases per 100,000 population in 2011 [54]. Our study revealed that incidences of tuberculosis in all five rheumatic diseases were several times higher than that in the general population, with the highest risk observed in the PM/DM cohort. These findings agree with the results from previous record-linkage studies conducted in Western countries [55, 56].

The strength of the present study lies in the use of a nationally representative data source with long-term follow-up data, which allowed us to examine the risks of overall and specific OIs according to five systemic rheumatic diseases. Nevertheless, our findings must be interpreted in the light of several limitations. First, the dataset lacked information regarding the activity or severity of the rheumatic diseases. Second, we did not incorporate variables regarding the exposure of glucocorticoids and immunosuppressants into our regression model, which precluded an analysis of their influence on the risk of OI. However, given the time-varying nature of medication use, it would be more appropriate to adopt a case-control study design for assessing the impact of immunosuppressive drugs. Third, we only counted the first episode in cases with multiple episodes of the same OI, which suggests that our calculated IR values might be underestimated.

This nationally representative cohort study revealed that patients with PM/DM had the highest risk of OI, followed by SLE, SSc, RA, and pSS, in order of decreasing risk. Furthermore, the highest risk of OI was observed during the first year after the diagnosis of systemic rheumatic disease, especially in cases of PM/DM. These findings highlight the importance of monitoring for OI development during the treatment of these autoimmune rheumatic diseases, especially for patients with PM/DM.