Rheumatoid Arthritis and risk of infection: The role of disease-modifying anti-inflammatory drugs

The development of infection is far more common in rheumatoid arthritis (RA) patients than in the general population. It is probably one of the most important consequences of RA. It is shown that RA can also increase the rate of serious infection (SI), from less than one per hundred patient years (100PYs) in the normal population to around five per 100PYs in the RA population. The risk of infection in RA increases due to several factors. Some of these include (i) the nature of RA disease and the pathophysiological changes in the immune system, (ii) RA medications, a number of which suppress the immune system, and (iii) coexisting genetic factors, such as Mannose binding lectin (MBL) deficiency, which increases the risk of immunodeficiency through well-known or unknown mechanism(s).

In this project, data were collected from the Australian Rheumatology Association Database (ARAD), in which a cohort of 3569 RA patients (960 males and 2609 females), who had completed related questionnaires 28176 times (during 200 to 2014) were investigated for the development of infections. Among the 3569 patients, 459 patients were eliminated because they had filled out the questionnaire only once, after which 3110 patients remained. Eight duplicates were eliminated, leaving 27709 visits from 3110 patients. All these visits were examined, to capture self-reported infections in different organs and the medications that were being taken at the time. ARAD reports were statistically analysed using the Chi-square test, Fisher’s exact test and logistic or multinomial logistical regression modelling. The thesis is divided into five chapters:
•Chapter 1 provides a detailed overview of the entire thesis, including a comprehensive background of the topic and the project hypothesis, goals, objectives, and strategies.

•Chapter 2 outlines a comprehensive systematic review in which the implications of the development of infection in RA patients and strategies for the prevention of infection are discussed. This chapter was published as a review article in 2017. This chapter provides a background on the subject of this thesis and provides a comprehensive review of the relevant studies that have been undertaken in this area.

•Chapter 3 outlines a descriptive analysis of the infection status of RA patients, in which the role of disease modifying anti-inflammatory drugs (DMARDs) are investigated. ARAD reports are examined with respect to demographic and treatment categories. Observed differences were then subjected to descriptive statistical appraisal. This chapter is an introduction to the more complex inferential analysis outlined in chapter 4.

•Chapter 4 outlines an inferential analysis of the association between the risk of infection and each anti-RA medication. The analysis provides valuable information concerning the relative frequency of self-reported infections in users of diverse anti-rheumatic therapies. Various organs, including eyes, ears, nose, throat, lungs, urinary tract, heart, gastrointestinal tract, and the central nervous system (CNS) are examined, as well as systemic infections of a viral and pyogenic nature (sepsis /septicaemia). This provides an introduction to the use of adjusted equations for predicting the risk of infection, presented in the next chapter.

•Chapter 5 presents more complex assessments around the incidence of serious infection, its demographic characteristics, and potential risk factors. Patient reports taken from 27709 visits by 3110 patients during 2001 to 2014 were searched for evidence of hospitalisation or intravenous (IV) infusion for infection. Resultant data were tested using inferential and descriptive analyses, and odds ratios for potential risk factors were calculated. A few studies indicate that RA disease and anti RA medication can specifically increase the risk of serious infections. Serious infection (SI) is still the number one cause of death in RA, globally, and so investigating the basis for SIs is important because of the risk of immediate mortality, ongoing morbidity, and health economic burdens. Moreover, an increased understanding of SIs may lead to the development of improved strategies for the prevention of infection. In Chapter 5, serious infection, with all its potential risk factors, is discussed and analysed in detail.
Based on the systematic literature research, we have found that SI is far more common in RA than in the general population. In addition, anti RA medications have different impacts on serious infections, with corticosteroids demonstrating a huge impact on infection followed by bDMARDs and csDMARDs. The time of prescribing bDMARDs in the first year or after, higher dosage of bDMARDs, and combination therapy with bDMARDs all increase the risk of infection. Although it seems that, in the Australian database, csDMARDs alone, during prescription, can evoke higher rates of infection than bDMARDs alone; this difference is statistically significant in self-reports of heart infection, lung infection (p-value = 0.0156), urinary system infection (p-value = 0.0002), and GIT infection. Both csDMARDs and bDMARDs are associated with a higher risk of infection in RA. All in all, without isolating the first year of taking bDMARDs, it seems that bDMARDs causes less infection but more serious infection. The impact of various medications on infection depends on the type and severity of infection.