Methods
Study design
This retrospective cohort study used the Taiwan National Health
Insurance Research (NHIR) database from January 1, 1997 to December 31,
2013. Subjects are those RA patients who use biologics after 18 years
old. The medication before and after 1 year of biologics will be
recorded. We defined early use of biologics as biologics prescribed
within 2.24 years after the RA diagnosis, and the late use of biologics
was defined as those prescribed after 2.24 years of the RA diagnosis.
These definitions are based on previous studies defining early arthritis
as the onset of symptoms within 2 years of diagnosis [14-17], while
we needed another 3 months for application biologics here in Taiwan,
which equals a total of 2.24 years. We further defined the cut-off value
of a 50% reduction in days of using DMARDs, steroids, or NSAIDs as the
clinically meaningful tapering of medication [18], a protocol found
in other studies.
Data source
Taiwan’s National Health Insurance (NHI) Program began to be implemented
on March 1, 1995. This program provides broad health insurance, and more
than 99% of Taiwan’s 23 million citizens have been included and
received various healthcare services under this program, including
physical therapy, inpatient and outpatient care, dental care,
childbirth, Chinese medicine, etc. This NHIR provides information
regarding hospitalization, epidemiological research, information on
prescribed medication, diagnostic information, etc., all of which is
considered high quality [19]. The NHIR randomly sampled a database
of 1,000,000 subjects from all of its beneficiaries and database of
subjects with major illnesses and has been releasing the data set to the
public for studies since 1997.
Each person has been assigned a distinct identity number in the NHIR
database, and identification data of the beneficiaries has been
randomized to protect their privacy. This current study used the
database of subjects with major illnesses and was financially supported
by Kaohsiung Chang Gung Memorial Hospital, Taiwan (CMRP: CFRPG8H0231;
IRB: 201801196B0).
Study cohort
The International Classification of Diseases, 9thversion (ICD-9) code was used for encoding diseases of interest.
Patients aged at least 16 years old who were diagnosed with RA (ICD-9
code 714.0) in the NHI database at least three times in an outpatient
department or at least one time in an inpatient department within 12
months were defined as RA patients in this study. RA patients who used
one biological agent at least three times within 6 months to treat RA
were defined as biologics users and have been included in this study
starting from March 1997. We calculated the total days of prescribing
NSAIDs, oral steroids, intra-articular steroid, MTX, and DMARDs by
physicians. Furthermore, the overall medication prescribed days within
12 months before the initiation of biologics and 12 months following a
one-month washout after discontinuation of a biological agent were
recorded and analyzed. Exclusion criteria were as follows: the use of a
biological agent prior to diagnosis of RA; a diagnosis of ulcerative
colitis (ICD-9 code 556.9, 556.8, 556) , Crohn’s disease (ICD-9
code 555, 555.0, 555.1, 555.2, 555.9), psoriasis, and/or psoriatic
arthritis (ICD-9 code 696.0, 696.1, 696.2, 6961, 696) within 5
years before the use of a biological agent [20]; RA patients who had
never used any biological agent; and a follow-up period less than 12
months.
Statistical Analysis
We used t-tests and chi-square tests to compare baseline characteristics
between these two groups. Logistic regression was used to estimate crude
and adjusted odds ratios (OR) and 95% confidence intervals. All
statistical analyses were performed using commercial software (SAS 9.4,
SAS Institute, Cary, NC).