Discussion
Such factors as data collection interval, race, provider type (general
physician vs. specialist), and type of drug coverage are associated with
the use of DMARDs or biological agents among RA patients [10], and
financial burden of certain expensive biological agents, usually leads
to insufficient treatment among RA patients [10]. The data
collection interval in this study was between 1998 and 2012, and during
which period, the most available biologics agents for RA were etanercept
(etanercept was available in Taiwan was since May 12, 2005) and
adalimumab (adalimumab was available in Taiwan was since Aug 19, 2008).
All the other currently available biologic agents for RA were neither
available nor reimbursed by health insurance during the interval.
Considering the study method, the cumulative dosage of analgesics for
treating lower back pain has been reported in a previous study [21].
This similar method of cumulative days of administering a certain drug
was applied in this present study to appropriately represent the
severity of RA, since the medications were entirely reimbursed by
Taiwan’s health insurance, and all the medications prescribed are
recorded and could be processed in the future, as in this study.
Therefore, this study focused on the changes of cumulative days of the
three aforementioned types of oral medication within 12 months before
and after biological agents in the same RA patient. As a result, we were
able to evaluate whether the use of a biological agent could taper the
subsequent cumulative days of the aforementioned medications.
The most frequent causes of death in RA patients are cardiovascular
disease, neoplasms, and sepsis [22], but none of these were
considered as a covariate in this study because treatment of these
diseases is irrelevant to the aforementioned medication, and we excluded
patients that had passed away during the follow-up period. We focused on
comparing cumulative days of oral medication in the same individual.
Previous studies have suggested that both smoking [23] and genes
[24] may be involved in increased RA severity. However, due to the
limitation of the NIHR database, we could not include these two
variables in this current study. Furthermore, temperature and humidity
are also claimed to influence RA severity, with both sunny conditions
and less humid conditions significantly lowering RA activity [25].
We believe that these factors have a limited influence in this study due
to the similar climate cycle throughout Taiwan. One interesting finding
that we did not show in our result is that some patients started use
biologics agent before his adulthood, which is before 18 years old,
which by definition was juvenile RA.
The footnote in Table 1, we mark the early use of biologics and late use
of biologics as either before or after 2.24 years (equals to 27 months)
diagnosis of RA, which we combine the idea of two-year treatment window
of opportunity from previous recommendation and evidence [16, 17],
and the real-world situation in Taiwan that all the reimbursement cases
of biologics are required to be authorized first before the prescription
of biologics, and the average processing period is around 3 months (0.24
years). These patients who use biologics agent within 2.24 years of
diagnosis of RA are representatives those patients within 2-year
treatment window of opportunity. Otherwise, if we pick up those patients
treated with biologics with exact 2 years within diagnosis of RA, we
might pick up those patients with only 1.76 years (21 months) of RA
duration, which could exaggerate the results in Table 2, and make the
comparison of oral medication 1 year before and after the use of
biologics unreliable.
In Table 3, we demonstrate the advantages between giving biological
treatment in the first 2.24 years, compared to those who receive it
later, which shows that the number of patients using glucocorticoids
could be reduced significantly compared to the other group. (p=0.047)
Those patients with delayed use of biologics have a tendency to increase
use glucocorticoids. Despites of the statistics of difference of NSAIDs
dose not reach significance, we still can see there is a trend of using
more NSAIDs in those patients with delayed treatment with biologics
(p=0.06). In delayed treatment subgroup, the NSAIDs tend to be
prescribed more; 236 patients (57.42% of overall 411 patients) were
having more than 75% of NSAIDs prescription days even after treated
with biologics. It gives us the hint that delayed treatment with
biologics might hinder the process of tapering glucocorticoids and
NSAIDs.[16, 26, 27]
Indication bias, comorbidities, and adherence rates (differences between
oral prescribed agents and how much patients actually took) are listed
as our study limitations. The reimbursement of biologics other than the
Etanercept and the Adalimumab as first-line biologics treatment was not
available in Rituximab and Tocilizumab by 2013, and the Golimumab was
not available until the end of 2012, which could limit the case numbers
in this research. Even though early treatment with an immune modulation
agent has been proven to be beneficial in rheumatic patients, the
adherence rates and comorbidities could be biased. However, due to
increased risk of infectious diseases [28] to those with TB, have
active or suspected infections, or easily get infected are not
recommended to receive early full-dose DMARD agents and glucocorticoids
treatment unless infections are under control.
Although biological agents have been considered appropriate
pharmaceutical treatment for RA, immunological tolerance, which results
in long-term remission, has not yet been established [29], despites
several choices of biologics currently available. The search for
alternative cures is still needed, and our study has provided some hints
that early treatment with biologics may be a better choice than
conventional oral medication, and this was the main purpose of our
study.
We set the study period to 12 months prior to and 12 months following a
one-month washout period after a biological agent in a bid to avoid such
time varying covariates as adverse drug effects due to long-term use or
progression of disease severity. Residence type (city/country), age,
gender, community/nursing home, type of healthcare, and comorbidities
[30] are commonly considered, and the current study focused on the
efficacy of biologics and treatment timing by comparing changes of days
of related drug administration in the same individual. Only gender and
age were found to be independent factors that could decrease days of
prescription of both steroids and NSAIDs in early use of biologics
agents, preferentially Etanercept and Adalimumab after three months’
treatment. This study indicates that younger patients only need
short-term (2.53±1.92 years, p=0.03) and early treatment with biologics
(within 2.24 years of diagnosis of RA) in order to taper steroids and
NSAIDs to less than 50% than before biologics treatment. This result
has an important clinical implication that reflects updated treatment
guidelines to use steroids at the lowest dose possible [31].