Down titration and discontinuation strategies of tumor necrosis factor blocking agents for rheumatoid arthritis in patients with low disease activity

  • Protocol
  • Intervention



This is the protocol for a review and there is no abstract. The objectives are as follows:

To evaluate the benefits and harms on disease activity, functioning, costs, safety and radiographic damage of down titration (dose reduction, interval increase or discontinuation) of tumor necrosis factor blocking (anti-TNF) agents (adalimumab, etanercept, infliximab, golimumab, certolizumab pegol) compared with usual care in patients with rheumatoid arthritis (RA) and low disease activity.


Description of the condition

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by symmetric joint inflammation often leading to joint damage. Tumor necrosis factor blocking (anti-TNF) agents have proven to be effective therapies for RA (Blumenauer 2002; Blumenauer 2003; Navarro-Sarabia 2005; Ruiz Garcia 2011; Singh 2009; Singh 2010). They improve clinical symptoms and functioning, inhibit joint destruction, and have become an important part of the treatment of RA.

Description of the intervention

Treatment of RA has been evolving from traditional step-up regimens to more aggressive step-down strategies. Pivotal to these changes are the early start of treatment (hit early), the use of combination therapy including steroids and rapid escalation to biologics (hit hard) and most importantly, frequently assessing disease activity and changing treatment accordingly. Strategies incorporating these concepts lead to the swift achievement of low disease activity or remission in most patients, which prevents joint damage and improves function and quality of life. An important disadvantage of the hit-hard approach compared with the traditional step-up approach, however, is that the former method does not allow for individual titration of the minimal effective treatment. Indeed, the traditional step-up approach largely prevents over-treatment, but the high(er) disease activity at the beginning of the disease has to be accepted. To prevent over-treatment when using high-dose or multi-drug strategies, treatment must be tapered down when low disease activity is reached up to the point that either the disease activity increases again or medication can be stopped. This way, the minimal effective dose is found and over-treatment is prevented. Optimal dosing of biologics is especially important due to the risk of dose-dependent adverse effects and moreover, risk of low cost-effectiveness due to high cost (den Broeder 2010).

The intervention that is the subject of this review is therefore dose reduction of anti-TNF agents (either by adaptation of dose or dosing interval) and/or discontinuation in patients with RA and low disease activity status.

How the intervention might work

Successful dose reduction or discontinuation of anti-TNF agents can be expected for several reasons. Firstly, amongst patients who seemingly respond to treatment with anti-TNF agents, there are patients who have spontaneous improvement (regression to the mean) (den Broeder 2010; van Vollenhoven 2004), and this phenomenon applies to 10% to 30% of all patients as shown by proportion of placebo group response (Doherty 2009; St Claire 2004). Secondly, often concomitant medication is given that might induce a response. Both mechanisms are supported by the fact that a proportion of patients seemingly doing well on the drug have (neutralizing) antibodies (< 5% to 43%) (Bartelds 2007; Klareskog 2011; Wolbink 2006).

Research has shown that discontinuation or down titration (lowering the dose or widening the interval) of anti-TNF agents can be successful in a relevant proportion of patients. For example, in the BeSt study (van der Bijl 2007), the fourth treatment arm (120 patients) started with methotrexate (MTX) and infliximab. The infliximab (initially often raised up to 10 mg/kg) was reduced when the disease activity score (DAS) was lower than 2.4 for > six months (n = 77); 87% of these patients were able to discontinue infliximab without loss of response (DAS > 2.4). Tanaka et al (Tanaka 2010) described 102 patients with a DAS28 (a modified version of the original DAS) < 3.2 for more than six months and MTX co-medication in whom infliximab was discontinued. After one year, 55% of patients had a DAS28) < 3.2. Another infliximab study (van den Bemt 2008), focused on reducing infliximab (5 to 3 mg/kg), 16 of 18 patients (89%) could be reduced. Of note, in this study patients with low disease activity, but a DAS28 above 3.2 were also included. In a randomized controlled trial (RCT) involving 105 patients with RA and a DAS <1.6 for at least three months, patients were randomized to continue etanercept 25 mg twice a week or to 25 mg once a week. After six months 89% and 73% of the respective groups were still in remission (Botsios 2007). One study evaluated lowering high-dose adalimumab (den Broeder 2002). In this study, 15 of 21 patients (71%) could lower the dose, sometimes up to equivalent of 40 mg/12 weeks. This resulted in 67% reduction of total anti-TNF dose in these patients, with an unchanged mean DAS28. Another study with anti-TNFs (Brocq 2009) showed 21 patients in whom anti-TNF was discontinued when they were in DAS28 remission for six months. After six months, 45% were still in remission, and after one year 25%. In a recent study (van der Maas 2012),16% and 45% respectively of included patients could discontinue or down-titrate infliximab.

Why it is important to do this review

Although the adverse effects of anti-TNF agents reported in clinical trials were generally mild in severity, these drugs are associated with unintended effects including increased risk of infections and perhaps a dose-dependent increased risk of malignancies and rare severe adverse events (Bongartz 2006).The introduction of anti-TNF agents – and also other biologic drugs - has also led to an increase in cost because they are much more expensive than the traditional disease-modifying anti-rheumatic drugs (DMARDs) (van Vollenhoven 2009).

At this time it is appropriate to conduct a systematic review of RCTs of anti-TNF down titration and discontinuation studies, because a number of RCTs are emerging concerning this subject.


To evaluate the benefits and harms on disease activity, functioning, costs, safety and radiographic damage of down titration (dose reduction, interval increase or discontinuation) of tumor necrosis factor blocking (anti-TNF) agents (adalimumab, etanercept, infliximab, golimumab, certolizumab pegol) compared with usual care in patients with rheumatoid arthritis (RA) and low disease activity.


Criteria for considering studies for this review

Types of studies

All randomized controlled trials (RCTs) and controlled clinical trials (CCTs) comparing down titration of tumor necrosis factor blocking (anti-TNF) agents with usual care/no down titration will be reviewed.

The minimal required follow-up will be six months.

Types of participants

Patients with RA (either 1987 (Arnett 1988) and/or 2010 (Aletaha 2010) ACR (American College of Rheumatology) criteria) using anti-TNF agents in a standard dosing regimen (adalimumab 40 mg every other week, etanercept 50 mg every week or 25 mg twice a week, infliximab 3 mg/kg every eight weeks, golimumab 50 mg every month, certolizumab pegol 200 mg every other week) for more than six months and with a low disease activity state (clinical judgement of rheumatologist or DAS28 < 3.2/DAS < 2.4/CDAI (Clinical Disease Activity Index) < 10/SDAI (Simplified Disease Activity Index) < 11 or DAS28 < 2.6/DAS < 1.6/CDAI < 2.8/SDAI < 3.3 (Aletaha 2005; Fransen 2005) or 2011 ACR/EULAR (European League Against Rheumatism) remission (Felson 2011)).

Types of interventions

Protocollised down titration or discontinuation of the anti-TNF agent for optimal dose finding (not for other reasons, including reduction of side effects, availability, planned surgery, pregnancy). The intervention should include the option for a patient to restart the anti-TNF agent in case of loss of response. Non-protocollised change in medication (DMARDs, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids) is allowed.

Comparison is usual care/no down titration/continuation of anti-TNF.

Types of outcome measures

The following seven major outcomes will be presented in the 'Summary of findings' table.

Major outcomes
  • Mean disease activity score; DAS28/DAS/CDAI/SDAI at 6,12,18, 24 months (Aletaha 2005; Prevoo 1995; Smolen 2003; van der Heijde 1990)

  • Proportion of patients with a flare (or loss of response) (defined as any composite disease activity index based flare criteria) during the follow-up time

  • Proportion of patients with persistent loss of response, refractory to re-installment of the tapered anti-TNF

  • Radiographic progression; measured by Larsen (Larsen 1973), Sharp (Sharp 1971) or modified Sharp-van der Heijde Score (van der Heijde 2000)

  • Function (measured by Health Assessment Questionnaire (HAQ)/Arthritis Impact Measurement Scale (AIMS)

  • Number of serious adverse events

  • Withdrawals due to adverse events

Minor outcomes
  • Proportion of patients with persistent low disease activity (as specified above) after six, 12, 18 and 24 months

  • Quality of life measured by SF12/36, Health Utilities Index (HUI) or EuroQoL Quality of Life Scale (EQ5D)

  • Costs (direct and indirect)

  • Decremental cost effectiveness ratio (difference in (direct and indirect) costs divided by difference in quality of life expressed as utility)

  • Time to flare

  • Change in other medication (including DMARDs, NSAIDs, corticosteroids)

Search methods for identification of studies

Electronic searches

The following electronic databases will be searched: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and Web of Science. The specific search strategy for each of the databases is shown in the appendices (Appendix 1, Appendix 2, Appendix 3, Appendix 4). The search will not be limited by language, year of publication or type of publication. The search period for all the databases will be from inception to present.

Searching other resources

We will also search conference proceedings, 2005 to 2012, of the American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) for abstracts of RCTs and CCTs.

Reference lists from identified clinical trials will be searched and citation tracking of the included trials in the ISI Web of Knowledge citation index will be performed. We will search trial registries for completed trials and for our ongoing trials table.

We will contact experts for any additional trials.

Data collection and analysis

Selection of studies

Two review authors (NvH, AdB) will independently screen titles and abstracts for inclusion. Full articles will be obtained if necessary. Differences will be resolved by discussion and consensus, and by consulting a referee (BvdB) if needed. In case the same study population is described in more than one publication, all publications will be used, but for the analysis, they will be grouped into one study with the most informative publication as the primary reference and other publications being secondary references. A record of reasons for excluding studies will be kept.

Data extraction and management

Two review authors (NvH and AdB) will independently abstract data from each study using a data extraction form. Differences will be resolved by discussion and consensus, and by consulting a referee (BvdB) if needed. The data extraction form will be pilot tested on a selection of trials. If necessary, we will contact the authors of a study to obtain missing data.

The following data will be extracted.

  • General study information: first author, author affiliation, publication source and publication year.

  • Study characteristics: design, setting, patient selection, method of randomization, allocation procedure, blinding, inclusion/exclusion criteria and study duration.

  • Population characteristics: age, sex, diagnostic criteria, disease duration, DMARD co-medication, previous DMARD use, previous anti-TNF use, rheumatoid factor status, anti-CCP (cyclic citrullinated peptide) status, disease activity state, total number of patients recruited, total number of patients randomized, total number of patients followed and numbers in each group.

  • Intervention characteristics: anti-TNF agent, type of intervention (dose reduction/interval widening/discontinuation), treatment comparators.

  • Outcome measures as noted above.

  • Analysis: statistical technique used, intention-to-treat analyses and/or per protocol analyses used.

  • Results with number, mean and standard deviation.

Assessment of risk of bias in included studies

The risk of bias in the included studies will be assessed by two review authors (NvH, AdB). This will be done using the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) (Appendix 5).

The domains that will be assessed are:

I Random sequence generation

II Allocation concealment

III Blinding of participants and personnel

IV Blinding of outcome assessment

V Incomplete outcome data

V Selective reporting

VI Other sources of bias (none)

Each of these domains will be judged using: "low risk", "high risk" or unclear risk" of bias.

Measures of treatment effect

The results of the studies will be analyzed using RevMan 5.1. Continuous data will be expressed as mean difference (MD) or standardized mean difference (SMD). Dichotomous data will be expressed as risk ratio (RR). Rates will be expressed as rate ratio (RR). Data will be summarized in a meta-analyses if they are sufficiently homogeneous, both clinically and statistically.

Unit of analysis issues

The unit of analysis will be the patient.

Dealing with missing data

Missing clinical data in trials will be accepted when they are less than 20%. If more than 20% of the data are missing, a sensitivity analysis will be performed to explore the impact of including or excluding these studies. Attempts will be made to obtain missing information about parameter variability through contacting the authors of the particular trial. In the event that study authors are not able or willing to provide this information it will be estimated from ranges if provided or estimated from comparable trials.

Assessment of heterogeneity

Heterogeneity will first be evaluated clinically by considering the comparability across trials on the following variables: type of intervention (dose reduction/interval widening/discontinuation), disease duration and DMARD co-medication.

Forest plots will be reviewed. We will test for heterogeneity using the Chi-square test with a P value of < 0.10 indicating significant heterogeneity. Also, we will use the I2 statistic (Higgins 2003) to describe the percentage of variability in effect estimates that is due to heterogeneity rather than chance. A value greater than 50% may indicate substantial heterogeneity (Higgins 2011). If significant heterogeneity exists, we will not pool data but perform subgroup analyses in an attempt to explain the heterogeneity.

Assessment of reporting biases

Publication bias implies that studies that report favorable results are more likely to be published than negative or inconclusive (non-significant) results, leading to a bias in the overall published literature. To minimize the effect of selective reporting of results, we will search trial registries for ongoing and unpublished studies. A funnel plot will be used to assess potential publication bias.

Reporting bias at the outcome level will be assessed by comparing the outcomes intended to be analyzed using published protocols of the studies with the published results of the study.

Data synthesis

When possible, data will be analyzed using an intention-to-treat model and for non-inferiority studies, also using a per protocol model. This is because intention-to-treat analyses can lead to false conclusion of non-inferiority in non-inferiority trials.

Outcomes of included studies will be analyzed using a random-effects model.

Subgroup analysis and investigation of heterogeneity

We will conduct a subgroup analyses for the following candidate effect modifiers: disease duration, baseline disease activity (low disease activity versus remission), anti-TNF agent, duration of anti-TNF use, presence or absence of concomitant DMARDs and dose reduction versus withdrawal.

Sensitivity analysis

The following sensitivity analyses are planned.

  • Effect of risk of bias of included studies

  • Effect of imputation of missing data or statistical transformations

'Summary of findings' table

'Summary of findings' tables included in RevMan 5.2 will be completed in order to improve the readability of the review. Three different tables will be made for the interventions: down titration, discontinuation and dose tapering until flare or discontinuation. Population: patients with RA with low disease activity using a standard dose of anti-TNF, intervention: down titration, discontinuation or dose tapering until flare or discontinuation, comparison: usual care (continuation or no formalized dose reduction of anti-TNF).

In addition to the absolute and relative magnitude of effect, the number needed to treat to benefit (NNTB) and number needed to treat to harm (NNTH) will be calculated from the intervention group compared with the control group.

GRADE software will be used to provide an overall grading of the quality of evidence.

The GRADE approach specifies four levels of quality (High, Moderate, Low and Very low) The highest quality rating is for randomized trial evidence. Randomized trial evidence can be downgraded to Moderate, Low or Very Low depending on the presence of five factors.

  1. Limitations in the design and implementation of available studies suggesting high likelihood of bias

  2. Indirectness of evidence

  3. Unexplained heterogeneity or inconsistency of results

  4. Imprecision of results

  5. High probability of publication bias


Drs R.A.H. Schrijnemakers for help with developing the search strategy.


Appendix 1. Cochrane Library search strategy

#1 MeSH descriptor Arthritis, Rheumatoid explode all trees in MeSH products

#2 caplan near/2 syndrome in All Fields in all products

#3 felty near/2 syndrome in All Fields in all products

#4 rheumatoid nodule in All Fields in all products

#5 rheumatoid vasculitis in All Fields in all products

#6 sjogren* near/2 syndrome in All Fields in all products

#7 still* next disease in All Fields in all products

#8 artritis near/2 juvenile near/2 rheumat* in All Fields in all products

#9 arthritis near/2 rheumat* in All Fields in all products

#10 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9)

#11 anti-tumor necrosis factor

#12 anti-tumour necrosis factor

#13 anti-tnf

#14 adalimumab

#15 humira

#16 etanercept

#17 enbrel

#18 infliximab

#19 remicade

#20 golimumab

#21 simponi

#22 certolizumab near/2 pegol

#23 cimzia

#24 (#11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23)

#25 down titration

#26 dose reduction

#27 dose de-escalation

#28 discontinuation

#29 dose tapering

#30 spacing

#31 cessation

#32 stopping

#33 interval widening)

#34 (#25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33)

#35 ( #10 AND #24 AND #34)

Appendix 2. MEDLINE search strategy

1. exp arthritis, rheumatoid/

2. (caplan$ adj2 syndrome). tw.

3. (felty$ adj2 syndrome).tw.

4. rheumatoid nodule. tw.

5. rheumatoid

6. (sjogren$ adj2 syndrome).tw.

7. still$

8. (arthritis adj2 juvenile adj2 rheumat$).tw.

9. (arthritis adj2 rheumat$).tw.

10. or/1-9

11. anti-tumor necrosis

12. anti-tumour necrosis










22. certolizumab adj2


24. or/11-23

25. 10 AND 24

26. down

27. dose

28. dose


30. dose




34. interval

35 or/26-34

36. 25 and 35

37. clinical

38. randomized.ab.

39. clinical trials/

40. randomly.ab.

41. trial.ti.

42. groups.ab.

43. or/37-42

44. animals/

45. humans/

46. 44 and 45

47. 44 not 46

48. 43 not 47

49. 36 and 48

Appendix 3. EMBASE search strategy

1. exp arthritis, rheumatoid/

2. (caplan$ adj2 syndrome). tw.

3. (felty$ adj2 syndrome).tw.

4. rheumatoid nodule. tw.

5. rheumatoid

6. (sjogren$ adj2 syndrome).tw.

7. still$

8. (arthritis adj2 juvenile adj2 rheumat$).tw.

9. (arthritis adj2 rheumat$).tw.

10. or/1-9

11. anti-tumor necrosis

12. anti-tumour necrosis


14. adalimumab/



17. etanercept/



20. infliximab/



23. golimumab/



26. certolizumab adj2 pegol/

27. certolizumab adj2


29. or/11-28

30. down

31. dose

32. dose


34. dose

35. spacing. tw.



38. interval

39. or/30-38

40. random$.ti,ab.

41. allocat$.ti,ab

42. (double$ adj blind$).ti,ab.

43. (single$ adj blind$).ti,ab.

44. randomized controlled

45. double blind

46. single blind

47. or/40-46

48. exp animal/ or nonhuman/ or exp animal experiment

49. exp human/

50. 48 and 49

51. 48 not 50

52. 47 not 451

51. 10 and 29 and 39 and 52

Appendix 4. Web of Science search strategy

#1 rheumatoid artrhritis or caplan syndrome or felty syndrome or rheumatoid nodule or rheumatoid vasculitis or sjogren* syndrome or still* disease or juvenile rheumatoid arthritis

#2 anti-tumor necrosis factor* or anti-tumour necrosis factor* or anti-tnf or adalimumab or humira or etanercept or enbrel or infliximab or remicade or golimumab or simponi or certolizumab pegol or cimzia

#3 down titration or dose reduction or dose de-escalation or discontinuation or dose tapering or spacing or cessation or stopping or interval widening

#4 trial* or random* or control*

#5 #1 AND #2 AND #3 AND #4

Appendix 5. Risk of bias

Article nr:


Reviewer: AdB / NvH




DomainSupport for judgement


low risk of bias, high risk of bias or unclear risk of bias

Selection bias
Random sequence generation  
Allocation concealment  
Performance bias
Blinding of participants and personnel



Detection bias
Blinding of outcome assessment



Attrition bias
Incomplete outcome data



Reporting bias
Selective reporting  
Other bias
Other sources of bias





Contributions of authors

NvH, WJ and AdB wrote the first version of the protocol. BvdB, RvV and JB provided comments and suggestions.

Declarations of interest


Noortje van Herwaarden: none known.

Alfons A den Broeder: none known.

Wilco Jacobs: none known.

Johannes W.J. Bijlsma: consultant and/or speaker to Abbott, Roche, BMS, UCB, Pfizer and Merck (all < 10.000 US).

Ronald F van Vollenhoven: research support and/or honoraria: Abbott, MSD, Pfizer, Roche, UCB Pharma.

Bart.J.F. van den Bemt: payment for educational lectures for Roche and MSD.

We are currently performing a dose reduction RCT with etanercept and adalimumab in RA patients in the Sint Maartenskliniek in Nijmegen, The Netherlands (Dutch Trial Register NTR3216).