Background/Purpose:  
Combination therapy with methotrexate (MTX), sulfasalazine (SUL), and
hydroxychloroquine (HCQ) [triple therapy] is an effective treatment for rheumatoid
arthritis (RA).   Randomized controlled trials (RCTs) evaluating triple therapy
have concomitantly added either SUL+HCQ to MTX or started all three drugs concurrently. 
Nevertheless, the frequency that providers actually initiate triple therapy in
this manner is unknown.  Understanding provider practices with the initiation
of triple drug therapy is important as these practices might impact treatment
effectiveness.

Objectives:
 To explore patterns of initiation of MTX, SUL and HCQ employed in patients who
received triple therapy in real-world settings.

Methods:  
Using national Veterans Affairs (VA) databases, RA patients receiving triple
therapy at any time between January 1, 2006 and December 31, 2012 were
identified.  Triple therapy was defined by evidence of any overlapping prescription
of all three drugs within a 90-day period.  Drug prescribing was considered concurrent
(e.g. SUL+HCQ) if the initial prescriptions for the agents occurred within 30
days of each other, with subsequent prescription refills demonstrating intent
to continue to prescribe all agents simultaneously.  DMARD use in the six months
prior to initiation of triple therapy was described herein to better understand
treatment patterns leading to triple therapy.   

Results:  
Triple therapy was prescribed in 1,160 patients.   This cohort had a mean
age of 62, was 91% male, 65% positive for RF and 59% positive for anti-CCP antibodies.  
Only 59 (5%) patients initiated all 3 drugs simultaneously; 171 (14%) had SUL
and HCQ added concurrently to MTX (Table).  There were 657 (57%) patients who were
on MTX either alone or in combination with SUL or HCQ as a foundation to which
other agent(s) were added.  There were 666 (57%) patients who received drugs in
a step-up fashion where the 3 drugs were added sequentially over time with more
than 30 days between initiating each drug.  In 38 (3%) patients, 2 drugs were
added to either background HCQ or SUL.  Triple therapy was started in 229 (19%)
patients who were initially started on dual therapy then later escalated to triple therapy.

Conclusion:
The spectrum of utilization patterns involved in initiation of individual drugs
that comprise triple therapy is much wider in clinical practice than in RCTs.  In
contrast to initiation strategies evaluated in RCTs, only 20% of US Veterans
initiating triple therapy either initiated all agents simultaneously or stepped
up from MTX by concomitantly adding SUL/HCQ together.  Rather, the additional
drugs were commonly added in sequence rather than concurrently.  Since clinical
response and patient experience during sequential DMARD initiation may affect decisions
to progress to triple therapy, RCT results describing the benefits of triple
therapy may not generalize to clinical practice.