Discussion
This large RA cohort study demonstrates that patients that have been prescribed biologics have a significantly decreased rate of cardiovascular comorbidity, metabolic comorbidity, rheumatologic comorbidity, and miscellaneous comorbidity (all p<0.05), but with a similar rate of oncology and infectious comorbidity incidence (both p>0.05) (Table 2). The extra-joint benefitfrom being treated with the biologics has been documented by previous studies, including improved cardiovascular outcome [5], improved insulin resistance [6], improved trabecular bone mass, and decreased bone loss [7, 8], but with a stable malignancy rate [9]. Furthermore, a recent article mentioned that patients with RA appeared to be at a higher risk of lung cancer and lymphoma, but a lower risk of colorectal and breast cancer [10], which contribute equally to the malignancy rate. Also, that the biologic agents did not induce malignancy was demonstrated in another meta-analysis research [11]. On the other hand, the infection comorbidities, which should be increased in patients treated with biologics [12, 13], was not seen in our current study. This finding may have been because the risk management program arose before all the biologic agents could be issued by physicians, thus making the incidence rate of infections too low to be detected in this cohort.
The prescription of biologic agents to RA patients was not affected byage discrimination (p=0.61), but it was affected bygender, with female being predominant (p<0.0001) (Table 2). One possible explanation for this phenomenon is that the female RA patients may have higher pain scores [14], which could be a surrogate marker for higher disease activity, implying a much higher chance to get access to biologics treatment. Regarding the age effect of comorbidities (Table 3), a selection bias may arise in treating juvenile RA or adult RA patients [15, 16], but age itself is still a risk factor for all the comorbidities in treating RA patients [17].
In the current study, the infection outcome comparison between biologics users and non-biologics users seems to be neutral, which differs from previous studies on the deteriorated effect of biologics with regard to tuberculosis infection [11], bacterial infection [18], and other opportunistic infections [19-21]. The different results of infection rate could be a bias related to a mixture of different mechanisms of biologics [22, 23] or different components of the biologics [23].
Regarding miscellaneous comorbidities, whether exposure to biologics has a deteriorating [24] or neutral [25] effect on kidney function is still debated, but biologics may have benefits related to reducing chronic obstructive pulmonary disease in RA patients [26]. Furthermore, other studies have been performed on biologics in cardiovascular events [5, 27], hepatoma [28], cancers [5], and atherothrombosis [29]. To the best of our knowledge, no specific research dealing with the biologics effect on miscellaneous comorbidities has yet been published.
Likewise, respiratory failure is mostly caused by inflammation [30] and increased oxidative stress [31]. Biologics may be significantly associated with lung disease in RA patients [32-34]. Another review article mentioned that MTX, LEF, TNFi, RTX, and TCZ may cause pneumonitis [35], which was not demonstrated in our current study and warrants further investigation.
Our study has certain limitations that should be mentioned at this point. This study is designed to evaluate an organ system-oriented comorbidity in RA, which limits the individual causative etiology of comorbidity results. Furthermore, this retrospective observation cohort study only reflects a particular interval of time, which certain types of biologic agents available in Taiwan. Different time inveral and a different mixture of patients could have different results. In general, we found that biologics may be associated with decreasing several comorbidities in RA patients in this particular cohort study.
-         Table 1. Comorbidities of rheumatoid arthritis, categorized by system
Cardiovascular:
Endocrine:
Rheumatic or orthopedics:
Oncology:
Infection:
Tuberculosis (ICD-9: 010.x–018.x)
Viral hepatitis: HBV (ICD-9: 070.2, 0.70.3, or V02.61) and HCV (ICD-9: 070.41, 070.44, 070.51, 070.54, or V02.62)
Miscellaneous:
-        Table 2. Demographic data of patients with rheumatoid arthritis, their incidence rates of comorbidities, and their treatment status with or without biologic agents.