title: Assessing the impact of immunosuppressive therapies on the risk of hypertension
Creators: name: Alosaimi, Hani Eid
Publisher: name: University of Glasgow
Year: 2024

description: Background

Although it has a significant impact on morbidity and mortality, hypertension is a major global health concern that is frequently neglected. Despite its prevalence, the role of inflammation in hypertension is often overlooked. However, earlier research suggested a link between hypertension and specific inflammatory biomarkers, proposing that these biomarkers may play a pivotal role in the development and progression of hypertension. This was initially observed through the effects of immunosuppressive therapies, which were found to affect development of hypertension. This led to a growing interest in the role of inflammation in hypertension and its potential as a therapeutic target.

Inflammation is now recognised as an important contributor to the development and progression of hypertension. The immune system plays a key role in regulating inflammation and dysregulation of the immune response can lead to chronic low-grade inflammation that can contribute to hypertension and target organ damage. As a result, there is a growing interest in developing anti-inflammatory drugs to treat hypertension, particularly in patients who have not responded to traditional blood pressure-lowering medications.

Methodology for answering the research questions: Systematic review and meta-analysis of randomised-control trials (RCTs). It aimed to assess pre-specified outcomes including hypertension risk and evaluated particular pre-specified subgroups of patients, including drug subclasses, comparator drugs, population clinical setting and follow-up duration. This analysis was designed to investigate the differential varying benefits and risks when comparing different classes of immunosuppressive therapies.

Results
The thesis is divided into seven main results chapters (Chapters 4 to 10) based on the immunosuppressive therapies classes evaluated for risk of hypertension in the systematic review and meta-analysis. Risk was assessed in comparison to placebo or separately to other active drugs used to treat immune/inflammatory disorders. Altogether, the qualitative and quantitative analysis includes 141 RCTs that enrolled 60,580 participants in total with an average follow-up of 3.5 years.


Methotrexate (MTX) and risk of hypertension: This meta-analysis found that when Methotrexate (MTX) was compared to the placebo, there was no significant difference in the risk of hypertension (RR = 0.93, 95% CI, 0.61; 1.44, P = 0.75). Meanwhile, low and nonstatistically significant heterogeneity between studies (I2 = 14%, P = 0.33). When MTX was compared to other active drugs, MTX reduced the hypertension risk (RR = 0.47, 95% CI, 0.34; 0.65, P = 0.00001), while heterogeneity was observed between studies (I2 = 29%, P = 0.11). These findings suggest that compared to other active drugs, MTX may reduce the risk of hypertension, but no significant difference was found when it was compared to a placebo.

Tumornecrosis factor inhibitors (Anti-TNF) and risk of hypertension: The findings for anti-TNF inhibitors were significantly different. The risk of hypertension was elevated for participants on anti-TNF inhibitors compared to those given a placebo (RR = 1.31, 95% CI 1; 1.73, P = 0.05); however, low heterogeneity was observed between studies (I2 = 2%, P = 0.43). Meanwhile, when compared with other active drugs, the hypertension risk did not significantly differ (RR = 1.14, 95% CI 0.73; 1.78, P = 0.56) and minimal heterogeneity was observed between studies (I2 = 38%, P = 0.11). These results suggest that while the use of anti-TNF inhibitors may increase the risk of hypertension compared to a placebo, this difference is not statistically significant when compared to other active drugs.

Interleukin – 17 inhibitors (Anti-IL17) and risk of hypertension: This study’s meta-analysis showed that the risk of hypertension was not significantly different between Anti-IL17 and a placebo drug (RR = 1.09, 95% CI 0.75, 1.58, P = 0.65). Similarly, the risk of hypertension was not significantly different between Anti-IL17 and other active drugs (RR = 0.89, 95% CI 0.60, 1.31, P = 0.54). This analysis observed low heterogeneity between studies comparing Anti-IL17 to a placebo drug (I2 = 9, P = 0.34), as well as between studies that compared AntiIL17 to other active drugs (I2 = 9, P =0.33). The present study’s findings suggest that Anti-IL17 drugs do not significantly increase the risk of hypertension compared to placebo or other active drugs.

Interleukin – 6 inhibitors (Anti-IL6) and risk of hypertension: In the Anti-IL6 group, the results of the meta-analysis found no statistically significant difference in the risk of hypertension between Anti-IL6 and a placebo (RR = 1.2, 95% CI 0.82; 1.73, P = 0.35) also finding no heterogeneity between studies (I2 = 0%, P = 0.89). When Anti-IL6 was compared to other active drugs, this study found no statistically significant difference in the risk of hypertension between groups (RR = 1.48, 95% CI 0.97; 2.25, P = 0.07) and observed low heterogeneity between studies (I2 = 7%, P = 0.37). Thus, this study’s results showed that in both groups (placebo and active drugs), there was no significant increase in the risk of hypertension.

Purine and Pyrimidine synthesis inhibitors and risk of hypertension: There was no statistically significant difference in the risk ratio when the results of the Purine and Pyrimidine synthesis inhibitors groups were compared to the placebo group (RR = 1.37, 95% CI 0.78; 2.44, P = 0.28) and no heterogeneity was observed between studies (I 2= 0%, P = 0.96). However, Purine and Pyrimidine synthesis inhibitors can reduce the hypertension risk when compared to other active drugs (RR = 0.81, 95% CI 0.65; 0.99, P = 0.04), while substantial heterogeneity could be observed between studies (I2 = 76%, P = 0.00001). These findings suggest that Purine and Pyrimidine synthesis inhibitors may be effective in reducing the risk of hypertension when compared to other active drugs, although no significant difference was found when compared to a placebo.

Interleukin 1 Beta inhibitors (Anti-1B) and risk of hypertension: The results of this paper’s analysis for Anti-IL 1B showed that compared to the placebo group, the risk of hypertension was not significantly different between the groups (RR = 0.74, 95% 0.35; 1.6, P = 0.45) and no heterogeneity was observed between studies (I2 = 0%, P = 0.87). These findings suggest that the use of anti-IL 1B drugs does not significantly affect the risk of hypertension compared to a placebo.

Colchicine and risk of hypertension : The present study compared the impact of colchicine and the placebo on the risk of hypertension and found no significant differences between the groups (RR = 0.50, 95% CI 0.10; 2.38, P = 0.38), also finding no heterogeneity between studies (I2 = 0%, P = 0.96). When colchicine was compared to other active drugs, the present study did not observe any statistically significant differences in the risk of hypertension between groups (RR = 0.44, 95% CI 0.09; 2.11, P = 0.31) and found low heterogeneity between studies (I2 = 35%, P = 0.21). These results suggest that the use of colchicine does not significantly affect the risk of hypertension compared to either a placebo or other active drugs.

Conclusions

The overall risk of hypertension associated with each of the seven groups of drugs differs, with anti-Interlukin-6 agents, anti-Interlukin17, anti-Interleukin-1beta and colchicine appearing not to affect the risk of the occurrence of hypertension when compared to either a placebo or other active drugs. In contrast, both Methotrexate and Purine and Pyrimidine synthesis inhibitors appear to reduce the risk of hypertension in comparison to other anti-inflammatory treatments. Anti-TNF medications, in turn, may borderline increase the risk of developing hypertension compared to placebo. The groups also differ in their heterogeneity with some having very low heterogeneity, while others have significant internal differences; nevertheless, most are highly homogeneous, with the results of similar studies being almost identical. These findings have important implications for clinical practice, suggesting that when healthcare professionals select immunosuppressive therapies for their patients, they should take into account the hypertensive effect those therapies have. Medications that inhibit the synthesis of purine and pyrimidine or methotrexate might be suitable choices for patients who have an elevated higher risk of hypertension. Further research is needed to understand the long-term effects and clinical significance of these findings, as well as to explore mechanisms, patient-specific factors, and the potential benefits or risks associated with specific populations or treatment durations. Overall, this study contributes valuable insights that may guide clinical decision-making, as well as stimulate further research in the fields of immunosuppression therapies and hypertension.