Discontinuation of biologics in patients with rheumatoid arthritis - Clinical and Experimental Rheumatology
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Discontinuation of biologics in patients with
rheumatoid arthritis
Y. Tanaka1, S. Hirata1, B. Saleem2, P. Emery3,4
1
The First Department of Internal ABSTRACT introduction of biological agents target-
Medicine, School of Medicine, University The use of early aggressive treatment ing TNF and other cytokines have revo-
of Occupation and Environmental Health, combined with the availability of bio- lutionised RA treatment (1-5). Clinical
Japan; 2York Teaching Hospital NHS
logical agents targeting pro-inflam- remission is perceived as an appropriate
Foundation Trust, York, United Kingdom;
3
Leeds Institute of Rheumatic & matory cytokines such TNF and IL-6 and realistic primary goal in many pa-
Musculoskeletal Medicine, University of has greatly advanced the treatment of tients, and its maintenance – especially
Leeds, Leeds, United Kingdom; rheumatoid arthritis (RA). Clinical re- with biological agents – leads to struc-
4
NIHR Leeds Musculoskeletal Biomedical mission is a realistic primary goal and tural and functional remission. Caution
Research Unit, Leeds Teaching Hospitals its maintenance leads to stabilisation is required concerning decisions to dis-
NHS Trust, Leeds, United Kingdom. of structural deterioration and func- continue synthetic DMARDs, as dis-
Yoshiya Tanaka, MD, PhD tional remission. With the achievement continuation results in twice as many
Shintaro Hirata, MD, PhD of sustained remission, discontinua- flare-ups, difficulty in reintroducing
Benazir Saleem, MD, PhD
tion of biological agents has emerged remission, and a halt in damage preven-
Paul Emery, MD, PhD
as an important consideration, with tion (6). However, similar studies are
Please address correspondence
and reprint requests to:
subsequent reductions in medication- just becoming available for biological
Prof. Paul Emery, induced side effects and health costs. agents. The possibility of discontinua-
Arthritis Research UK, Evidence from studies suggests that tion of biological agents after achieving
Leeds Institute of Rheumatic MTX-naïve, early RA patients can remission must be considered, because
& Musculoskeletal Medicine, achieve sustained biologic-free remis- of both the potential long-term safety
Chapel Allerton Hospital, sion with no functional or radiographic issues and the economic burden associ-
Chapeltown Road, progression, after treatment with com- ated with their expense. Multiple stud-
Leeds LS7 4SA, United Kingdom.
E-mail: p.emery@leeds.ac.uk
bination TNF inhibitors and MTX. ies have recently investigated whether
For patients with long-standing RA and remission can be sustained after a bio-
Received on July 18, 2013; accepted in
revised form on August 19, 2013.
who have previous inadequate respons- logical agent is discontinued, namely,
es to MTX, the evidence for sustained “biologic-free remission.” This article
Clin Exp Rheumatol 2013; 31 (Suppl. 78):
S22-S27.
biologic-free remission is less con- provides an overview of the literature
vincing. The discontinuation of TNF- regarding the discontinuation of TNF
© Copyright Clinical and
Experimental Rheumatology 2013. inhibitors after sustained remission inhibitors and other biological agents in
has been shown to be possible in some RA patients, after obtaining low disease
Key words: rheumatoid arthritis, long-standing RA patients with inad- activity or clinical remission.
biological agent, treatment holiday, equate response to MTX, particularly in
remission, TNF-inhibitor Japanese patients. However, high flare Discontinuation of TNF inhibitors
rates and adverse long-term outcomes in patients with an inadequate
have been documented in other studies. response to MTX (MTX-IR)
Competing interests: For these patients a biologic dose-re- The initial management of patients with
Y. Tanaka, has received consulting fees, duction regimen may be preferable. newly diagnosed RA is aimed at control-
speaking fees, and/or honoraria from The combination of early treatment ling inflammation, maintaining function
Mitsubishi-Tanabe Pharma, Eisai, Chugai with TNF inhibitors and MTX plus and preventing structural joint dam-
Pharma, Abbott Japan, AstellasPharma,
tight control of inflammation provide age. For the majority of patients world-
Daiichi-Sankyo, Abbvie, Janssen Pharma,
Pfizer, Takeda Pharma, Astra-Zeneca, the best chance of a biologic-free re- wide, MTX is now used as the first-line
Eli Lilly Japan, GlaxoSmithKline, mission or at least the possibility of DMARD, with slight differences in
Quintiles, MSD, Asahi-Kasei Pharama “biologic treatment holidays”. regional and national algorithms for
and has received research grants from further DMARD and biological agents
Bristol-Myers, Mitsubishi-Tanabe Introduction (7). The success of TNF-inhibitors in
Pharma, Abbvie, MSD, Chugai Pharma, Rheumatoid arthritis (RA) is a systemic patients with inadequate responses to
AstellasPharma, Daiichi-Sankyo;
inflammatory disease that causes signifi- MTX is well documented (8, 9).
P. Emery has received consulting fees and
honoraria from AbbVie, BMS, MSD, Pfizer, cant morbidity and premature mortality. A Japanese group conducted a mul-
Roche, and UCB; However, the early use of disease-mod- ti-centre prospective study, RRR
the other co-authors have declared no ifying anti-rheumatic drugs (DMARDs) (Remission induction by Remicade in
competing interests. such as methotrexate (MTX) and the RA patients), aimed at the possibility of
S-22Discontinuation of biologics in patients with RA / Y. Tanaka et al. biologic-free remission in RA patients
Discontinuation of biologics in patients with RA / Y. Tanaka et al.
tained with reduced doses or withdraw- 12 month follow-up. These patients all BeSt, OPTIMA, HIT HARD, IDEA and
al of etanercept in patients with mod- had received tocilizumab as part of dif- PRIZE have recently been undertaken
erately active RA despite MTX (18). ferent trial protocols, i.e. some patients to investigate whether remission can
After treatment with 50 mg etanercept received tocilizumab after failing TNF be sustained even if a TNF-inhibitor is
plus MTX for 36 weeks, 604 patients inhibitors, some after DMARD fail- discontinued after controlling disease
were randomised to 3 groups in equal ures, and others were MTX-naïve. activity in early RA patients
numbers: 50 mg etanercept plus MTX; The DREAM [Drug-free REmission/ A pivotal study concerned with bio-
25 mg etanercept plus MTX; or placebo low disease activity after cessation of logic-free remission was performed
plus MTX. At week 88, 52 weeks after tocilizumab (Actemra) Monotherapy] by Quinn et al. (22, 23). Patients with
randomisation, LDA had been main- study investigated remission and LDA early, active RA were recruited into a
tained in 84 (42.6%) of 197 patients after cessation of tocilizumab mono- 12-month randomised placebo-con-
randomised to placebo plus MTX, ver- therapy in patients with previous inad- trolled double-blind trial of infliximab
sus 166 (82.6%) of 201 patients who equate response to MTX (21). At the with MTX, with the aim of inducing
had received at least one dose of 50 time of stopping tocilizumab, patients remission. The primary outcome was
mg etanercept and 159 (79.1%) of 201 had received a mean 4 years of treat- synovitis as measured by MRI. At 12
given 25 mg etanercept. From these re- ment. The rate of LDA without con- months, all MRI scores were signifi-
sults, conventional or reduced doses of comitant use of synthetic DMARDs cantly better, with no new erosions
etanercept with MTX in patients with was 35.1% at 24 weeks and 13.4% at in the infliximab+MTX group. The
moderately active RA more effectively 52 weeks according to the Kaplan- patients in the active treatment arm
maintain LDA than does MTX alone Meier estimate. DAS28 remission and also achieved higher ACR 50 and 70
after withdrawal of etanercept, but 2011 ACR/EULAR remission criteria responses. Importantly, one year after
LDA was sustained with MTX alone (Boolean approach) were maintained stopping induction therapy, response
in 42.6% of patients after discontinuing in 17 patients (9.1%) and 14 patients was sustained in 70% of patients who
etanercept. (7.5%), respectively, at 52 weeks. In had received infliximab+MTX, with a
patients who flared after cessation of median DAS28 of 2.05.
Discontinuation of Abatacept tocilizumab, 88.5% regained remission Saleem et al. published a sustained re-
in patients with an inadequate after restarting tocilizumab and therapy mission rate of 60% after discontinua-
response to MTX (MTX-IR) was well tolerated. tion of TNF inhibitor therapy in MTX-
The ORION (Orencia Remission The rate of drug-free remission after naïve patients in DAS28 remission
Induction and Outcome Navigation) tocilizumab monotherapy seems com- after one year of combination therapy.
study group assessed abatacept-free parable to rates of sustained remission Evidence was found that sustained
remission in 51 RA patients with a after stopping TNF inhibitor therapy TNF-inhibitor-free remission was as-
DAS28 2.4 (moderate to high disease
Discontinuation of Tocilizumab logic agents targeting TNF, IL-6 and T activity), change or addition of medi-
in patients with an inadequate cells have proven that intensive initial cations is required; if DAS44 ≤2.4 (re-
response to MTX (MTX-IR) biologic therapy in early RA patients mission or LDA), current medication
Mexican patients in DAS28 remission who have never been treated with MTX is continued; and if DAS44 ≤2.4 con-
discontinued tocilizumab and continued results in the improvement of clinical, tinued over 6 months, decrease and/or
MTX therapy (20). Forty patients were structural and physiological outcomes discontinue concomitant medications
recruited, mean disease duration 14 over both the short and long terms. including infliximab (see Allaart et al.
years, and 44% maintained remission at Several studies, including TNF20, p. S14-S18).
S-24Discontinuation of biologics in patients with RA / Y. Tanaka et al.
Ninety (75%) patients of 120 in the maintained or improved work produc- 63.5% of patients with ETAN25/MTX,
fourth group who started treatment with tivity, whilst those who did not sustain 38.5% with MTX (those who discontin-
infliximab achieved DAS44 ≤2.4; inf- LDA worsened with respect to these ued etanercept) and 23% with placebo
liximab was withdrawn in 77 patients outcomes. However, continued use of (those who discontinued etanercept and
because DAS44 ≤2.4 was maintained adalimumab+MTX yields better ben- MTX). There was no significant radio-
for 6 months. LDA was maintained and efits with respect to work productivity graphic progression in any treatment
progress of joint damage was inhibited than discontinuation of adalimumab for group (34).
in 67 of 77 (87%) patients who were patients who achieve LDA following 26
treated with MTX monotherapy for weeks of adalimumab+MTX. Discontinuation of TNF inhibitors
2 years after infliximab withdrawal. The withdrawal of adalimumab in in MTX naïve very early RA patients
Furthermore, 5 years after receiving in- early RA patients with mean RA du- With accumulating evidence in sup-
fliximab and MTX as initial treatment ration of 1.7 months was also as- port of early treatment with combina-
for RA, 58% of 120 patients discon- sessed in a German study, HIT HARD tion TNF inhibitor/biological agent and
tinued infliximab and 19% of patients (High Induction THerapy with Anti- MTX therapy, identification of patients
have discontinued all DMARD and Rheumatic Drugs) (31). During the with very early disease is paramount,
remained in clinical remission, with first 24 weeks, 172 patients were and the question arises to whether
minimal joint damage progression. In treated with adalimumab+MTX or treatment in the at the onset of IA can
addition, the total cost of work loss and placebo+MTX. After week 24, both prevent or delay the development of
medical expenses could be suppressed groups were treated with MTX alone RA. The results so far are inconclu-
to less than half in the fourth group for 24 weeks. During the induction sive, with evidence that abatacept may
which was treated with MTX and in- phase, 47.0% of patients treated with reduce the progression to RA (35), but
fliximab initially, compared to other adalimumab+MTX achieved DAS28 a 6-month course of infliximab mono-
groups whose initial therapy involved remission, and at week 48, 43.8% were therapy was unsuccessful (36). The
only DMARD. still in remission after 24 weeks of EMPIRE (Etanercept and Methotrexate
The withdrawal of adalimumab in ear- adalimumab-free treatment. in Patients to Induce Remission in
ly RA patients (with a mean RA dura- Other studies have been designed to Early Arthritis) trial aimed to investi-
tion of 3.9 months) was also assessed determine rates of TNF-inhibitor-free gate clinical, radiographic and func-
in a randomised, placebo-controlled, remission in MTX-naïve patients with tional outcomes, comparing the ef-
double-blind trial OPTIMA (Optimal early RA. The IDEA (Infliximab as in- ficacy of combination therapy with
Protocol for Treatment Initiation with Duction therapy in Early rheumatoid MTX+ETAN versus MTX monother-
Methotrexate and Adalimumab) (29, Arthritis) study was a randomised con- apy, in subjects with DMARD-naïve
30). The OPTIMA study showed a trolled trial in DMARD-naïve early RA very early inflammatory arthritis with
significant advantage of initial treat- to compare the efficacy of MTX plus a the minimum of one synovitic joint.
ment with adalimumab+MTX vs. TNF inhibitor versus MTX combined One hundred and ten DMARD-naïve
placebo+MTX to achieve improved dis- with IV steroid therapy as remission- patients were recruited into this 78-
ease activity, structural changes, patient- induction, followed by a treat-to-target week multicentre randomised con-
reported outcomes and work productivi- approach. A treat-to-target approach trolled trial and were randomised 1:1 to
ty outcomes in patients with MTX-naïve was used with treatment escalation if receive MTX+ETAN or MTX+placebo
RA. The requirement for randomisation DAS44 >2.4. In the IFX group, IFX (PBO) for 52 weeks. Injections were
to discontinuation was achievement of was discontinued for sustained remis- stopped in all patients at week 52; in
LDA at both 22 and 26 weeks. sion (DAS44 26 weeks, injections were
adalimumab+MTX for 24 weeks, 207 IFX due to sustained (>6 months) re- stopped early. If patients had NTSJ
(44%) achieved the stable LDA and mission and 78.6% (11/14) of them >12 weeks after stopping the injec-
were re-randomised to placebo+MTX maintained remission (32). tions, MTX was weaned. Initial re-
or adalimumab+MTX. At week 78, 86% The PRIZE study aimed to determine sults suggest that of the patients in the
treated with adalimumab+MTX and the effectiveness of etanercept (ETAN) MTX+ETN group, 41.9% remained
66% treated placebo+MTX maintained and MTX therapy in MTX-naïve early in DAS28 remission from week 52 to
DAS28 remission. SDAI-remission and RA patients who had moderately ac- week 78 and 57.7% remained in LDA
ΔmTSS remission were comparable for tive disease (33). DAS28 remission according to DAS28 (37).
both groups. More patients with con- was achieved by 70% of patients, and
tinuous adalimumab maintained LDA these patients were subsequently ran- Tight control and treatment holiday
(91%) than did patients in the adalimum- domised to a double-blind 39-week Although there are limited studies, “a
ab-free group (81%). In the combined period of reduced-dose etanercept (25 biologic treatment holiday” not only in
group (consisting of placebo+MTX or mg) plus MTX, or MTX plus place- patients with early RA but also some
adalimumab+MTX), patients with sus- bo sc, or placebo PO and placebo sc. select group of patients with long-
tained LDA between weeks 26 and 78 Sustained remission was observed in established RA is possible. Infliximab
S-25Discontinuation of biologics in patients with RA / Y. Tanaka et al.
and adalimumab seem to have a better sustained for at least 12 months, grad- 3. REDLICH K, SMOLEN JS: Inflammatory bone
loss: pathogenesis and therapeutic interven-
potential for their discontinuation than ual dose reduction should be attempted.
tion. Nat Rev Drug Discovery 2012; 11: 234-
certolizumab pegol or etanercept as van den Broek et al. recently published 50.
shown in the studies of TNF20, BeSt, three recommendations for discontinu- 4. TANAKA Y: Intensive treatment and treat-
HIT HARD, OPTIMA and PRIZE in ation of biological drugs (41): ment holiday of TNF-inhibitors in rheuma-
toid arthritis. Curr Opin Rheumatol 2012;
early RA, and RRR and HONOR in es- 1. If patients have low disease activity 24: 319-26.
tablished RA (10-37). However, there or been in remission for at least 6 5. TANAKA Y: Next stage of RA treatment:
is evidence that etanercept dose reduc- months, consider trying it. TNF-inhibitor-free remission will be a pos-
tion can maintain sustained remission 2. Once biologics are discontinued,
sible treatment goal? Ann Rheum Dis 2013;
72: ii124-ii127.
(18, 34). A direct comparison of the keep monitoring disease activity, 6. SMOLEN JS, ALETAHA D, BIJLSMA JWJ et al.:
studies presented here is not possible functional ability and radiological Treating rheumatoid arthritis to target: rec-
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mission criteria. Further work is also clinical assessment of patients with rheuma-
required to determine the effect of ces- Conclusion toid arthritis seen in standard rheumatology
sation of other biological drugs such care in 15 countries. Ann Rheum Dis 2007;
For patients with established disease 66: 1491-6.
as tocilizumab and abatacept, and the (MTX-IR), the evidence suggests that 8. KLARESKOG L, van der HEIJDE D, de JAGER
roles their different mechanisms of ac- for some patients, especially in Japan, JP et al.; TEMPO (Trial of Etanercept
tion may play. successful biological drug cessation and Methotrexate with Radiographic
Patient Outcomes) study investigators:
There are pharmacologic differences is possible but dose reduction is more Therapeutic effect of the combination of
between the available TNF inhibitor consistently successful. For MTX- etanercept and methotrexate compared with
drugs. A monoclonal antibody to the naïve patients, treatment with combi- each treatment alone in patients with rheu-
TNF, such as infliximab or adalimum- nation TNF inhibitor therapy and MTX matoid arthritis: double-blind randomised
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TNF via binding to not only soluble a 60–70% chance of sustaining remis- Demonstration of response in rheuma-
TNF but also transmembrane TNF, sion after cessation of TNF inhibitor toid arthritis patients who are nonrespond-
whose binding induces complement- therapy. Such an early intensive ap-
ers according to the American College of
Rheumatology 20% criteria: the paradox of
dependent cytotoxicity, antibody-de- proach to patients with new-onset beneficial treatment effects in nonresponders
pendent cell-mediated cytotoxicity, and RA, with limited biologic use, would in the ATTRACT trial. Anti-Tumor Necrosis
outside-to-in signaling, which would have the potential of reducing drug- Factor Trial in Rheumatoid Arthritis with
produce apoptosis to pathogenetic cells Concomitant Therapy. Arthritis Rheum 2001;
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bearing membrane-bound TNF (38- long-term health costs – although the 10. NAWATA M, SAITO K, NAKAYAMADA S,
40). Therefore, biologic-free remission risks of worsening clinical, functional TANAKA Y: Discontinuation of infliximab
might be highly expected in infliximab and radiographic outcomes must be in rheumatoid arthritis patients in clinical re-
and adalimumab with the mechanisms mission. Mod Rheumatol 2008; 18: 460-4.
considered, with measures in place for 11. TANAKA Y, TAKEUCHI T, MIMORI T et al.:
of action to be able to eradicate the root careful monitoring of status, prompt Discontinuation of infliximab after attaining
cause of joint inflammation. re-assessment and re-introduction of low disease activity in patients with rheu-
After achieving LDA or remission the therapy. Further data are eagerly await- matoid arthritis, RRR (remission induction
by remicade in RA) study. Ann Rheum Dis
goal of therapy is to maintain a clini- ed that will provide evidence for the 2010; 69: 1286-91.
cal, functional and structural remis- ideal remission induction regime and 12. TANAKA Y, HIRATA S, NAWATA M et al.:
sion state. For some patients this is predictors for successful cessation of Discontinuation of adalimumab without
possible even after the cessation of therapy. Such data could provide ob-
functional and structural progress after at-
taining remission in patients with rheumatoid
the biological drug. However, there jective markers of disease to enable an arthritis (an interim report of HONOR study)
are no guidelines or reliable predictive individualised approach to the manage- [abstract]. Arthritis Rheum 2011; 63, S962
markers that allow the identification of ment of patients in remission. 13. SALEEM B, KEEN H, GOEB V et al.: Patients
such patients. Questions arise as to the with RA in remission on TNF blockers:
when and in whom can TNF blocker therapy
optimal method of defining remission Acknowledgements be stopped? Ann Rheum Dis 2010; 69: 1636-
and whether there is a need for more The authors thank all medical staff in 42.
objective assessments of remission that all institutions for providing the data. 14. BUCH MH, SETO Y, BINGHAM SJ et al.:
would include imaging (MRI, US) and C-reactive protein as a predictor of inf-
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