Can Rheumatoid
Arthritis treatment ever
be stopped?
Robert L. DiGiovanni, DO, FACOI
Program Director Largo Medical Center Rheumatology Fellowship
[email protected]
I have no financial
relationship in regard
to the content of this
presentaion.
“Do not pour strange
medicines into your
patients.”
Sir William Osler
New treatment
paradigm
Recognize RA as a heterogenous group of diseases.
Identify patients with aggressive disease.
Early window of opportunity to achieve remission
Use best therapies up front. MTX as anchor.
Treat to a pre-identified target (DAS28 < 2.6).
Maintain tight control of the disease.
Can treatment be stopped at any point?
Can remission be maintained with fewer Rx?
Traditional DMARDS
Methotrexate
Hydroxychloroquine
Sulfasalazine
Azathioprine
Gold Salts
D-penicillamine
Can the traditional synthetic
DMARDs induce sustained
remission?
Six RCT of RA patients on DMARD monotherapy published
prior to 2000 were reviewed by Scott, et. al. in Clin. Exp.
Rheumatology in a 2013 supplement.
Total 501 patients deemed under good control evaluated
Flares occurred in 43/248 (17%) of patients who continued
DMARDS vs. 117/253 (46%) of patients who discontinued
DMARDS.
Risk of flare 3x greater in those that stopped DMARDs
Restarting DMARDs was usually successful.
Step down therapy
Scott further evaluated 4 RCT of step down combination
therapy compared to monotherapy
COBRA: early RA patients; group I aggressive treatment
with high dose prednisilone tapered over 28 weeks + MTX
7.5mg for 40 weeks and sulfasalazine as the anchor Rx.
Group II was sulfasalazine monotherapy.
Aggressive group had superior clinical and radiographic
response that was maintained.
Step down therapy
(continued)
BeSt (Behandel Strategieen) study: 508 patients in four
treatment groups with early RA
One group was DMARD monotherapy, next was a Step-up
protocol, next was a step-down based on COBRA and last
was a MTX + infliximab group.
The last two groups did the best as one might predict
When patients achieved DAS remission, DMARDS were
tapered and stopped and patients followed for 5 years
Step Down therapy
(continued)
23% of patients had drug free remission during the five year
period of study observation
Subsequently, 46% of these had to go back on a DMARD
The results were similar across all the four initial treatment
groups.
Hence, this data suggests that DMARD-free remission is rare.
The best predictors of disease reactivation in Scott’s review were
IgM-RF and ACPA-positivity
Further data from BeSt
Groups 1,2,3 were allowed to go on infliximab later on if
they failed
77/120 (64%) of the initial infliximab group (4) were able to
stop infliximab compared to only 27/109 (25%) of the
delayed infliximab start (groups 1-3)
After D/C infliximab, 59% of groups 1-3 and 44% of group
4 suffered a flare with DAS>2.4 and had to restart
infliximab.
Median time off infliximab was 17 months (range 3-47
months)!
Further BeSt data
(continued)
Restarting Infliximab resulted in DAS28 < 2.4 in all
patients and no radiographic progression.
Therefore, inflixamab discontinuation was possible in 1 in
4 patients following 6 months of LDA.
If MTX is continued, 50% could permanently stop
infliximab.
Hmmmmmmm!
Biologicals
TNF target: etanercept, adalimumab, infliximab,
certulizumab pegol, golimumab
Co-stimulatory inhibitor: abatacept
Interleukin-6 target: tocalizumab
B-cell depletion: rituximab
Jak inhibitor: tofacitanib
Interleukin-17 target: on its way
Biologicals
Revolutionized the treatment of Rheumatoid Arthritis
Often used in combination with methotrexate
Can we use a cancer chemotherapy model of “induction”
followed by maintenance with fewer medication? Then retreat if disease activity flares?
Problem: inflammatory disease is due to “dysregulation” of
the immune system. Can the biologicals “re-boot” the
immune system to a more normal status?
Studies
OPTIMA: Optimal Protocol for Treatment Initiation with
Methotrexate and Adalimumab
ORION: Orencia Remission Induction and Outcome
Navigation
DREAM: Drug-free REmission/low disease activity after
cessation of tocilizumab (Actemra) Monotherapy
IDEA: Infliximab as in-Duction therapy in Early
rheumatoid Arthritis
Studies (continued)
HIT HARD: High Induction THerapy with AntiRheumatic Drugs
PRESERVE: Maintain low disease activity (LDA) with
reduced doses or withdrawal of entanercept in patients
with moderately active RA despite MTX.
CERTAIN, PRIZE, HONOR, RRR, TNF-20
PRESERVE
604 patients with moderate RA disease activity while
taking MTX (MTX-IR)
All received etanercept 50mg/week in an open phase for 9
months
More than 80% achieved LDA with DAS28 < 2.6
They were maintained on therapy for 6 months further
If they maintained LDA (DAS28 < 3.2), they were further
randomized in a double-blinded fashion.
PRESERVE (continued)
Three groups: MTX + full dose etanercept, MTX + reduced
etanercept (25mg), MTX + placebo
One year later: 57% of MTX monotherapy lost their LDA
state compared to 18% on full dose etanercept and 21% on
the half dose of etanercept
Progression of joint damage did not occur on either
etanercept dose. Some of the MTX monotherapy patients
had progression of joint damage radiographically.
PRESERVE (continued)
Thus, in patients with established RA, withdrawal of an
anti-TNF agent following good control usually led to
disease flare
However, 90% of the reduced dose patients maintained
LDA status
Results are essentially confirmed by the CERTAIN
(certolizumab pegol) study wherein patients with
established RA (MTX-IR) flared with withdrawal of the
biological
OPTIMA
Early RA patients (mean duration of disease 3.9 months)
MTX-naïve
Over 1,000 patients randomized to MTX + adalimumab vs. MTX
+ placebo
Former group had better outcomes in terms of DAS, structural
damage, etc.
Of the 466 patients with stable LDA at 24 weeks on MTX +
adalimumab, 207 were randomized to MTX + continued
adalimumab vs. MTX + placebo
OPTIMA (continued)
At week 78, 86% of the combination group and 66% of the
MTX/placebo group maintained DAS28 remission. (<2.6)
LDA was maintained in 91% of the combination group and
81% of the MTX monotherapy group (adalimumab-free)
Work productivity was better in the group that continued
on adalimumab
Similar results in the German study of MTX-naïve early RA
(mean 1.7 months) with MTX + adalimumab HIT HARD
Some differences between
PRESERVE and OPTIMA
Early RA vs. established RA
MTX-IR vs. MTX-naïve
MOA of the anti-TNF medication: Soluble TNF-receptor
vs. Monoclonal Antibody
Can the monoclonal antibody “re-boot” the regulation of
the immune response in the MTX-naïve early RA patient?
It appears to be the case in a subset of patients.
DREAM STUDY
Patients on tocilizumab monotherapy for a mean of 4 yrs
who met DAS28 remission criteria (previous MTX-IR) at
the time the biological was discontinued
LDA maintained without DMARDS was 35% at 24 weeks
and 13.4% at 52 weeks
Remission (DAS28 criteria) without DMARDS was 9.1% at
52 weeks
Comparable to the anti-TNF meds for true drug-free
remission
Official Recommendations
EULAR: (2012) After remission has been maintained for 12
months, gradual dosage reduction of the biological should
be attempted (van den Broek, et al)
ACR: No official recommendations on withdrawal of
biologicals
Possible strategy for a
“Drug Holiday”
Early aggressive treatment with MTX + biological to a
target (DAS28)
LDA/remission for 6 months; consider tapering dose of the
biological. (Tanaka, et. al.) Patient should be brought into
this decision. I say remission not LDA.
Once biological stopped, continue to monitor for disease
activity and radiographic joint progression
Resume biological as soon as it appears RA is relapsing
Personal practice experience over
30 years
In the case of RA, the disease is far worse than the treatment.
The consequences of unchecked systemic inflammtion include
structural damage, disability, extra-articular organ involvement
(e.g., pulmonary, ASHD, SAA amyloid)
Select carefully patients you believe can retain LDA off biologics
but follow them very closely for increase in DAS28 or
radiographic/ultrasound progression. Low disease activity is,
after all, still smoldering disease activity.
Don’t hesitate to resume biologics if need be. We have never
had better treatments for RA as we do now.
“The desire to take
medicine is perhaps the
greatest feature which
distinguishes man from
animals.”
Sir William Olser
“One of the first duties of
the physician is to train the
masses not to take
medicine”
Sir William Osler
References
Tanaka et al, Discontinuation of biologics in patients with rheumatoid
arthritis, Clin Exp Rheumatol. 2013, 31 supp 78
Kavanaugh et al, The when and how of biologic agent withdrawal in
rheumatoid arthritis, Clin Exp Rheumatol. 2013, 31 supp 78
Yoshida et al, Use of data from multiple registries in studying biologic
discontinuation, Clin Exp Rheumatol. 2013, 31 supp 78
Pincus, et al, Possible discontinuation of therapies in inflammatory
rheumatic diseases.
Scott, et al, Can we discontinue synthetic disease-modifying antirheumatic drugs in rheumatoid arthritis? Clin Exp Rheumotol. 2013, 31
supp 78
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