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
- Atrial fibrillation (ICD-9: 427.31)
- Hypertension (ICD-9: 401-405)
- Acute myocardial infarction: Any hospitalization with a diagnosis of
ICD-9: 410.x
- Coronary heart disease (ICD-9: 410–414)
- Heart failure (ICD-9: 398.91, 402.01, 402.11, 402.91, 404.01, 404.03,
404.11, 404.13, 404.91, 404.93, or 428)
- Cerebral vascular incident (CVA) (ICD-9: 430–438)
- Deep vein thrombosis (DVT) and pulmonary thromboembolism (PE): PE
(ICD-9: 415.1), iatrogenic PE (ICD-9: 415.11), and DVT (ICD-9: 453.8)
- Hyperlipidemias (ICD-9: 272)
- Diabetes mellitus (ICD-9: 250)
- Thyroid disorders: thyroid cancer (ICD-9: 193), hypothyroidism (ICD-9:
244), hyperthyroidism (ICD-9: 242), and thyroiditis (ICD-9: 245)
Rheumatic or orthopedics:
- Gout (ICD-9: 274)
- Hip fracture (ICD-9: 820) and operation codes 7855, 7925, 7935, 7995,
or 8152
- Inflammatory bowel disease: ulcerative colitis (ICD-9: 556) and
Crohn’s disease (ICD-9: 555)
- Psoriasis (ICD-9: 696, 696.1 or 696.8)
- Malignancy (ICD-9: 140–208)
- Lymphoma (ICD-9: 200, 201, 202, or 203)
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)
- Chronic obstructive pulmonary disease (ICD-9: 491, 492, or 496)
- Asthma (ICD-9: 493)
- Chronic kidney disease (ICD-9: 582, 583, 585, 586, or 588)
- Chronic liver diseases (ICD-9: 456.0–456.2, 571.2, 571.4–571.6, or
572)
- Table 2. Demographic data of patients with rheumatoid
arthritis, their incidence rates of comorbidities, and their treatment
status with or without biologic agents.