10 years ago, the mother of all RA trials was published, which paved the way for management strategies like "Early & Aggressive" (some call it "Hit Early, Hit Hard", I christened it "Fast & Furious" after the movie franchise that emerged about the same time) and "Treat-to-Target" (which I define for myself as deep sonographic remission), which have become the standard of care nowadays.
Titled Behandel Strategieen (BeSt) ~management strategies, this Dutch study sought to replicate real life clinical practice in 4 strategies:
1) sequential monotherapy (switching csDMARDs) starting with MTX;
2) step-up combination therapy (add-on csDMARDs) starting with MTX;
3) initial MTX combined with high-dose steroid;
4) initial MTX combined with an anti-TNF (Infliximab).
The primary outcome measure at 1 year (and at later timepoints) was clinical remission (DAS44 <2.4). Other measures included functional status (HAQ) and structural damage (SHS). They also looked at patient preference, drug survival, drug-free remission (DFR) and mortality rate. Patients were switched between arms at 3-monthly reviews if the primary outcome was not attained. At the end of the second year, patients in deep remission of DAS <1.6 could stop all treatment (drug-free).
Results at earlier timepoints showed that the initial biologic arm:
1) achieved remission and functional improvement faster;
2) needed fewer strategy switches to achieve primary outcome;
3) was preferred by patients over steroids;
4) accrued less structural damage (also the steroid arm) compared to the initial sequential and step-up arms;
5) attained DFR in about 17% by the end of the third year (but there were relapses).
At the end of the first year, all arms converged in terms of DAS and HAQ. By the end of the second year, even the SHS differences narrowed. I quipped then that this is analogous to flying Economy, Premium Economy, Business or Suite (corresponding respectively to arms 1-4): everyone eventually arrives at the same destination, but you arrive in different shape depending on whether you initially chose to pay forward (costly treatment) or pay back (treatment side effects and joint damage).
Now, 10 years later, my analogy needs some (minor) tweaking. It appears that, between arms:
1) the DAS & HAQ remained low and the differences are not statistically significant;
2) the difference in structural deterioration (SHS), though statistically significant, is small and not clinically relevant (5 points over 10 years, between arms 1 & 4);
3) DFR averaged 14% in all arms without statistical difference;
4) mortality rates regressed to the norm of the general population;
5) major adverse events from treatment were rare and did not differ between arms;
6) dropout rate was lowest in arm 4.
So, the price difference in the airfare pertains to the enjoyment on the journey (and not even the state of well-being at arrival): faster pain relief and functional restoration. You therefore choose to pay how much you deem your near-term quality of life is worth😉
With this, I modify and justify my management mantra:
1) Fast & Furious
2) Treat To Target
3) Whatever It Takes.
This review in 2011 highlights the findings of the BeSt study at the end of years 4 and 5.
An earlier review at year 3 end gave DFR rate at 10%, 5%, 9% & 17% for arms 1-4 respectively, averaging 13%:
DFR remained 17% for arm 4 at the end of year 4.
At year 5 end, DFR rates were 14%, 16%, 10%, 19% in the 4 arms respectively, averaging 14%:
The earlier 10-year result gave DFR of 14% for the whole cohort, without a breakdown for the 4 individual arms, but said the differences were not statistically significant. I presume then that the DFR rates of the 4 arms converged sometime between years 5 and 10.
3.6%-22% of RA patients appropriately managed with current strategies (Fast & Furious, Treat-To-Target) can expect to go off all medication.
Predictors of SUSTAINED biologic and/or drug-free remission include:
1) negative serologies (RF, anti-CCP) & shared epitope;
2) male gender;
4) low disease activity (DAS) at baseline;
5) better functional status (HAQ) at baseline;
6) short duration of active disease;
7) no or minimal radiographic joint damage.
Be psychologically prepared that there is a 50:50 chance RA may flare after going off all medicines. But it's a chance I personally would take, especially if this is my first remission, and even if I fall on the wrong side of the predictives in the previous post. Fortunately, should I flare, my previous effective medications should work on resumption.
If I flare and get into full remission again, I may either stay in drug-induced remission much longer before trying again, or I may opt to maintain on low-dose csDMARD indefinitely.
I pitch it the same way to my patients.
This study is an offshoot of the 10-year BeSt study, examining the effect of the 4 management strategies in RA patients who are seronegative. The results are not different.