Skip to main content
  • Research article
  • Open access
  • Published:

Impact of tapering targeted therapies (bDMARDs or JAKis) on the risk of serious infections and adverse events of special interest in patients with rheumatoid arthritis or spondyloarthritis: a systematic analysis of the literature and meta-analysis



To systematically review the impact of tapering targeted therapies (bDMARDs or JAKis) on the risk of serious infections and severe adverse events (SAEs) in patients with rheumatoid arthritis (RA) or axial spondyloarthritis (axSpA) in remission or low disease activity (LDA) state.

Materials and methods

A meta-analysis based on a systematic review of PubMed, Embase, Cochrane, until August 2019, as well as relevant databases of international conferences, was used to evaluate the risk difference (RD) at 95% confidence interval (95% CI) of incidence density of serious infections, SAEs, malignancies, cardiovascular adverse events (CV AEs), or deaths after tapering (dose reduction or spacing) compared to continuation of targeted therapies.


Of the 1957 studies initially identified, 13 controlled trials (9 RA and 4 SpA trials) were included in the meta-analysis. 1174 patient-years were studied in the tapering group (TG) versus 1086 in the usual care group (UC). There were 1.7/100 patient-year (p-y) serious infections in TG versus 2.6/100 p-y in UC (RD (95% CI) 0.01 (0.00 to 0.02), p = 0.13) and 7.4/100 p-y SAEs in TG versus 6.7/100 p-y in UC (RD 0.00 (− 0.02 to 0.02), p = 0.82). The risk of malignancies, CV AEs, or deaths did not differ between the tapering and the usual care groups. Subgroup analysis (RA and SpA) detected no significant differences between the two groups.


We could not show significant impact of tapering bDMARD or JAKi over continuation concerning the risk of serious infections, SAEs, malignancies, CV AEs, or deaths in RA and SpA patients in remission or LDA state.

Key message

What is already known about this subject?

Current guidelines recommend tapering of targeted therapies for RA or SpA patients in remission.

What does this study add?

No change in serious infection risk, SAEs, CV AEs, malignancies while tapering targeted therapies.

How might this impact on clinical practice?

Physicians should still try to taper targeted therapies for efficiency and financial advantages.


Current best practice in the treatment of chronic inflammatory rheumatisms such as rheumatoid arthritis (RA) and spondyloarthritis (SpA) focusses on a tight control strategy (treat-to-target strategy) to prevent joint destruction and improve patients’ functional prognosis. The objective of this management strategy is to establish remission or a low disease activity (LDA) ((a) RA: Disease Activity Score28 ESR (DAS28-ESR) < 3.2 for LDA and < 2.6 for remission [1], (b) axSpA: Ankylosing Spondylitis Disease Activity Score (ASDAS) < 2.1 for LDA and < 1.3 for inactive disease [2]).

The first-line treatment for RA consists of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) [3], whereas initial treatment for SpA is based on non-steroidal anti-inflammatory drugs (NSAIDs) [4, 5]. Thereafter, in both diseases, biological DMARDs (bDMARDS) are employed, and the use of bDMARDs and more recently targeted synthetic DMARDs (tsDMARDs) has been part of the clear improvement in the therapeutic management of these diseases, leading to sustained LDA or remission in a large number of patients [6, 7].

Nonetheless, many studies have drawn attention to the increased AE risk occurring as a result of these treatments compared to csDMARD or no treatment, of which infectious disorders [8,9,10] are the most frequently reported. Patients on bDMARDs do not have an increased risk of malignancies in general [11, 12], but the risk of melanoma may be slightly increased. As for cardiovascular AE (CV AE), it is well-established [13, 14] that certain targeted therapies help improve cardiovascular comorbidities. The economic burden of these expensive therapies [15] should also not be underestimated and ought to be taken into consideration by the prescribing physician. The European League Against Rheumatisms (EULAR) and the American College of Rheumatology (ACR) have addressed these issues by publishing recommendations for the management of chronic inflammatory rheumatisms once remission or LDA has been established, based on a tapering strategy [3,4,5, 16,17,18].

Several studies [19,20,21,22] have highlighted that discontinuation of targeted therapies, more so in RA than in SpA, leads to an increased risk of relapse and radiographic progression, while tapering strategies does not seem to increase this risk when compared with continuing the initial treatment.

Although there is extensive evidence to support that tapering of targeted therapies does not significantly increase the risk of relapse nor of radiographic progression, a beneficial effect on the rate of infectious AEs, and most importantly on serious infectious, is yet to be proven. A recent meta-analysis [23] reassessed the effectiveness of down-titration compared with the continuation of the standard dose of anti-TNF for RA treatment in patients with LDA. Their study evaluated safety events as a secondary outcome and concluded that it was uncertain whether anti-TNF tapering influenced the number of SAE observed due to the very low certainty of the evidence obtained. This study was restricted to RA patients treated with anti-TNF and did not extend to SpA patients or any other targeted therapies.

The aim of our study was therefore to assess the impact of tapering targeted therapies (bDMARDs or JAKis), compared to continuation of the initial treatment regimen, on the risk of serious infectious and AEs of special interest (SAEs, malignancies, CV AEs, and deaths) in patients with RA or SpA, in remission or LDA, by conducting a systematic analysis of the literature and a meta-analysis.

Materials and methods

This meta-analysis is reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 statement [24] (see Supplementary Text 1).

Selection of articles

We carried out a systematic analysis of the literature to identify controlled trials, preferentially prospective and randomized trials, which compared tapering targeted therapies (bDMARDs or JAKis) versus continuation of the initial treatment regimen, in patients with RA or SpA in remission or LDA. The PubMed, Embase, and Cochrane databases were searched from their date of inception to August 2019 using a Boolean association of keywords (see Supplementary Text 2). Abstracts from articles submitted to international conferences (ACR, EULAR, and SFR) between 2016 and 2019 were also queried.

This search was carried out independently by two investigators (DV and LMB). The title and abstract of articles identified from database searches were subsequently reviewed for the following inclusion criteria: (1) controlled trials, randomized or not; (2) involving rheumatoid arthritis (RA) or spondyloarthritis (SpA) patients; (3) treated by targeted therapies: bDMARDs (anti-TNF (adalimumab, certolizumab, etanercept, golimumab, infliximab) or abatacept or anti-IL6 (sarilumab, tocilizumab) or rituximab or anti IL 12/23 (ustekinumab) or anti IL 17 (secukinumab, ixekizumab) or anti-IL 23) or JAKis (tofacitinib, baricitinib or upadacitinib); (4) in remission or LDA under targeted therapies; and (5) comparing tapering (dose reduction or spacing [3]) targeted therapies (tapering group (TG)) versus continuation of the initial treatment regimen (usual care group (UC)).

The other inclusion criteria applied after full text reading were (1) description of targeted therapies tapering protocol and (2) assessing at least one of the following AE: serious infections, SAEs, CV AEs, malignancies, or death. We did not include any restrictions concerning disease duration, period of remission or LDA, duration of treatment, or concomitant use of csDMARDs. The limits were English or French language. The exclusion criteria were (1) retrospective trials, (2) case reports, (3) trials without tapering of targeted therapies, (4) trials without control arms, and (5) trials with no data on AE.

Data extraction

Data was collated using a standardized grid. For each selected study, predefined data were extracted (see Supplementary Text 3).

If data were missing in the article, the corresponding authors were contacted by e-mail. Details of data collected are available in Supplementary Table 1 and 2.

Patient and public involvement was not appropriate in our study.

Study quality assessment

Risk of bias was assessed using the Cochrane Risk of Bias Tool [25] and is available in Supplementary Figure 1.


For the meta-analysis, the primary endpoint was the incidence density of serious infections in each treatment group (TG or UC). The secondary endpoints were the incidence density of SAEs, CV AEs, malignancies, or deaths.

A risk difference (RD) was calculated for each study included in the meta-analysis. All meta-analyses were performed using the inverse variance approach, which assumes a fixed effect model, to determine the weight given to each study. This provided a common weighted RD estimate with a 95% CI, taking into account weighting of the different samples. RD and 95% CIs are expressed as forest plots. Statistical heterogeneity of the selected studies was tested using the Q test (χ2), applying a 0.05 statistical significance cut-off, and reported with the I2 statistic in which high values of I2, ranging from 0 to 100%, represent strong heterogeneity. In case of a significant heterogeneity, a random effect model was applied to take into account heterogeneity. Publication bias was searched using funnel plots and Egger test, no significant bias was found (Supplementary Figure 2). All computations were performed using the RevMan V.5.3 software package developed by Nordic Cochrane Centre (Review Manager (computer program), V.5.3. Copenhagen: The Nordic Cochrane Centre, the Cochrane Collaboration, 2011). P values lower than 0.05 were considered significant.


Study selection

1957 records were screened in our systematic analysis of the literature. 1854 records were excluded based on title and abstract reading, leaving a total of 103 relevant articles to be further examined. Full-text assessments excluded an additional 89 references. Among the remaining 14 studies, one study [26], corresponding to an extension phase of another included study which already described AEs, was excluded in order to avoid duplicated data. Thirteen references were finally included in our systematic review and meta-analysis (Fig. 1).

Fig. 1
figure 1

Flow chart of systematic review and meta-analysis

We contacted 11 corresponding authors by e-mail to complete safety data that was omitted from the corresponding publications (values and details). Five authors [27,28,29,30,31] responded and were able to provide us with the necessary information to complete our data set.

Population characteristics

Among the 13 studies included in the analysis, there were 9 RA trials [27, 28, 30, 32,33,34,35,36,37] and 4 SpA trials [29, 31, 38, 39], more precisely axial SpA. All were controlled trials, 11 were randomized controlled trials [26,27,28, 30,31,32,33,34,35,36,37,38], whereas 2 studies followed a longitudinal observational design using a propensity score matching method [29, 39].

A total of 2196 patients were included. Disease duration extended from 2.2 to 16.6 years, the sex ratio was 65% female, and mean patient age in both groups ranged from 30 to 59 years. Disease activity was low in both groups (TG and UC): DAS 28-CRP ranging from 1.6 to 2.3 in RA patients and BASDAI SpA patients from 1 to 2.

Duration of the trials

1174 patient-years were studied in the targeted therapies tapering group (TG) versus 1086 in the usual care group (UC). The study period extended from 6 months in 2 trials [28, 37] to 12 months in 8 trials [29,30,31,32,33,34,35, 39] and to approximately 18 months in 3 trials [27, 36, 38].

Studied drugs

In RA patients, the studied targeted therapies were predominantly anti-TNF: certolizumab [32], adalimumab [27, 28, 36, 37], and etanercept [27, 28, 34,35,36]. Abatacept, a selective modulator of T cell co-stimulation, was studied in one trial [30], and baricitinib, a targeted synthetic DMARD (JAK-inhibitor), was also evaluated in one trial [33]. SpA patient drug treatments were based on anti-TNF: adalimumab [29, 31], etanercept [29, 31, 38, 39], infliximab [29, 31], and golimumab [31].

Previous treatment and duration of targeted therapies

Patients were bDMARD-naive prior to their inclusion in 6 trials [27, 29, 30, 32, 35, 38], whereas they received bDMARDs before the investigation in 4 trials [31, 33, 36, 37]. This information was not available for 3 studies [28, 34, 39]. No study included patients treated with tsDMARDs prior to inclusion in the trials.

In bDMARD-naive patients, the duration of targeted therapies ranged from 37 weeks to 6 years, with a preponderance of patients taking targeted therapies for more than 3 years. For patients previously treated with bDMARDs prior to their inclusion in the trial, data relating to the total duration of the targeted therapy could not be retrieved.

Evaluating the primary outcome: serious infections in studies comparing tapering of targeted therapies (TG) versus usual care (UC)

Our meta-analysis comparing tapering of targeted therapies (TG) versus continuation of usual care (UC) was performed on 13 trials and showed no significant difference in relation to the incidence density of serious infections reported between TG (20 patients presented serious infections among 1174 patient-years, corresponding to 1.7/100 patient-year (p-y)) and UC groups (28 patients presented serious infections among 1087 patient-years (2.6/100 p-y)), with a total risk difference (RD) (95% CI) of 0.01 (0.00 to 0.02), p = 0.13 (I2 heterogeneity score, 0%) (Fig. 2).

Fig. 2
figure 2

Forest plot of serious infections: difference of risk of serious infections in TG versus UC

The subgroup analysis, performed separately on RA or SpA trials, did not show any significant difference in the risk of serious infections in RA patients, 0.01 (0.00 to 0.02), p = 0.10 (I2, 0%), nor in SpA patients, 0.00 (− 0.02 to 0.02), p = 0.95 (I2, 0%) (Fig. 2).

Evaluation of secondary outcomes: SAEs

Our meta-analysis did not show a decreased risk in SAEs (RD (95% CI), 0.00 (− 0.02 to 0.02), p = 0.82 (I2, 0%)), when comparing 87 patients with SAEs among 1174 patient-years (7.4/100 p-y) in the TG group to 73 patients with SAEs among 1085 patient-years (6.7/100 p-y) in the UC group (Fig. 3). There was also no statistically significant difference between the two subgroups: RD in RA patients (95% CI) was 0.00 (− 0.02 to 0.02), p = 0.93 (I2, 24%), compared to RD in SpA patients (95% CI) 0.00 (− 0.03 to 0.03), p = 0.79 (I2, 0%) (Fig. 3).

Fig. 3
figure 3

Forest plot of severe adverse events: risk difference of TG versus UC

Meta-analysis of other safety events in studies comparing TG versus UC

Six studies [27,28,29,30,31, 37] reported the incidence of CV AEs. Among these, 4 studies [27, 28, 30, 37] focused on RA patients and 2 studies [29, 31] on SpA patients. There was no significant difference in the incidence of CV AE (RD (95% CI), 0.00 (− 0.02 to 0.02), p = 0.84 (I2, 3%)), when comparing 5 patients with CV AE among 383 patients-years (1.3/100 p-y) in TG, to 7 patients with CV AE among 331 patients-years (2.1/100 p-y) in UC (Fig. 4). There was no significant difference in each subgroup either: in RA patients, RD (95% CI) was 0.02 (− 0.02 to 0.05), p = 0.37 (I2, 23%), whereas in SpA patients RD (95% CI) was − 0.01 (− 0.03 to 0.02), p = 0.68 (I2, 0%) (Fig. 4).

Fig. 4
figure 4

Forest plot of cardiovascular adverse events: risk difference of TG versus UC

Eight studies [27,28,29,30,31,32, 35, 37] reported malignancies which developed during the study period. Among these, 6 studies [27, 28, 30, 32, 35, 37] involved RA patients and 2 studies [29, 31] SpA patients; 13 patients with malignancies among 712 patients-years (1.8/100 p-y) in TG and 5 patients with malignancies among 616 patients-years (0.8/100 p-y) in UC. Our meta-analysis did not detect any significant differences when all 8 studies were examined (RD (95% CI), − 0.01 (− 0.02 to 0.01), p = 0.33 (I2, 0)) and also not in the subgroup analysis (RA patients: RD (95% CI), − 0.01 (− 0.03 to 0.00), p = 0.17 (I2, 0%); SpA patients: RD (95% CI), 0.01 (− 0.02 to 0.03), p = 0.68, (I2, 0%)) (Fig. 5).

Fig. 5
figure 5

Forest Plot of Malignancy: Risk difference of TG versus UC

Three deaths were reported in the trials, 2 in one RA trial [35] in the UC group (0.2/100 p-y) and 1 in one RA trial (0.1/100 p-y) in the TG group [30], with no significant differences detected (RD (95% CI), 0.00 (0.00 to 0.01), p = 0.76 (I2, 0%)) (Fig. 6).

Fig. 6
figure 6

Forest Plot of Deaths: Risk difference of TG versus UC


Our meta-analysis focused on controlled trials in RA and SpA patients that achieved remission or LDA and showed that tapering targeted therapies was not associated with a statistically significant difference in risk of developing serious infections, SAEs, CV AEs, malignancies, or death when compared with continuation of the initial treatment regimen. This result was also confirmed in the subgroup analyses (of RA and SpA). Our results are consistent with the only other meta-analysis [23] published on the issue.

Our meta-analysis has several strengths. Compared to the previously published meta-analysis, it includes SpA patients next to RA patients and expands on the number and type of drugs used (bDMARDS and JAKis) and finally assesses specific subgroups of AE outcomes. Also, all studies included in our meta-analysis were prospective, controlled trials, and eleven [27, 28, 30,31,32,33,34,35,36,37,38] out of thirteen studies randomly assigned patients into groups, thereby granting the absence of heterogeneity.

We expected to see a decrease of the risk of serious infections due to a reduction of the therapeutic pressure. However, although we observed a numerical trend with less serious infections in tapering versus continuation of the initial treatment schedule (1.7/100 p-y versus 2.6/100 p-y), our study was not able to show a statistical difference. The range of serious infections observed in our meta-analysis is consistent with a previous one focused on bDMARDs in RA patients [10]. A recent meta-analysis [23] published in 2019, which focused on down-titration compared with continuation of the standard dose of TNFi for RA in patients with LDA, evaluated safety events as secondary outcomes and concluded that it was uncertain whether dose tapering affected the number of SAEs observed due to the low certainty of the evidence. Another meta-analysis [10] assessing the risk of serious infections in RA patients treated with targeted therapies was conducted in 2015 and also did not detect any differences. Indeed, the initial course of treatment with targeted therapies may represent an increased risk of infectious events [40]. However, the absence of statistical difference may be explained by a lack of power. Indeed, we calculated the statistical power of our meta-analysis, based on the primary endpoint (serious infections), which was about 26.6%. This is relatively low and can be explained by the assessed endpoint being rare and by the fact that the clinical trials included in our meta-analysis were not designed to achieve an objective of tolerance. To increase the power, it would require a greater number of patients and would jeopardize the feasibility of these types of trials. Indeed, to reach a statistical power of 80% in our meta-analysis, it would require 10,084 patient-year. In addition, the difference in frequency is very low between the two groups (TG vs UC) for each tolerance endpoints, and this also contributes to the requirement for greater patient numbers in order to show a significant difference. Despite its good internal validity, our meta-analysis has several limitations.

Only one study analyzing a tsDMARD (Baricitinib) was included in our meta-analysis, which makes the evaluation of infectious risk in this therapeutic subclass precarious, even though the results were consistent with a non-significant difference.

Another concern is the healthy survivor bias. After excluding subjects with numerous comorbidities, which may potentially influence the risk of infection [41, 42], most of all in RA patients, this risk may be lowered. Accordingly, it may become more difficult to point out a difference between patient populations that are already closely followed for any signs of AEs, during a longer follow-up and with better tolerance. Moreover, patients in these trials had been taking targeted therapies for at least more than a year, before initiating the tapering phase. However, the critical phase for AE is in the first months [43,44,45]. Indeed, a safety issue (serious infection and SAE) is more likely to happen in the initiating phase, rather than after a long period under treatment, thus leading to the exclusion of the patient. The population included in the trials is therefore highly selected and might explain the absence of any difference in risk between the TG and UC group.

The same argument holds for the selection of subjects regarding cardiovascular and tumoral status.

As for CV AE, it is well-established [13, 14] that certain targeted therapies help improve cardiovascular comorbidities in patients, yet no increase in CV AE was detected in the TG strategy. This may potentially be explained by the persistence of the remission/LDA state, imparting lower cardiovascular risk [46].

Regarding malignancy, the duration of the studies was too short and the events too rare to detect any statistical difference. Trials with a longer follow-up period would be needed to be able to point out a statistical difference.


In conclusion, our meta-analysis highlights no remarkable difference in the rate of infectious events, in patients in the tapering treatment group or patients continuing their initial treatment schedule.

Nevertheless, other benefits of a tapering strategy, including alleviating patient burden due to self-injection, medication costs, and the safety of these strategies in relation to flare-ups leads us to support this therapeutic approach.

Availability of data and materials

This study involved data that are available in published papers used for this systematic review. Additional data were also got directly from authors.



American College of Rheumatology


Ankylosing Spondylitis Disease Activity Score


Axial spondyloarthritis


Cardiovascular adverse events


Disease Activity Score28 ESR


Disease-modifying anti-rheumatic drugs


Biological DMARDs


Conventional synthetic disease-modifying anti-rheumatic drugs


Targeted synthetic DMARDs


European League Against Rheumatisms




Low disease activity


Non-steroidal anti-inflammatory drugs




Rheumatoid arthritis


Risk difference


Severe adverse events


Tapering group


Usual care group


  1. Fransen J, Creemers MCW, Van Riel PLCM. Remission in rheumatoid arthritis: agreement of the disease activity score (DAS28) with the ARA preliminary remission criteria. Rheumatol (Oxford). 2004;43(10):1252–5.

    Article  CAS  Google Scholar 

  2. Machado P, Landewé R, Lie E, Kvien TK, Braun J, Baker D, et al. Ankylosing Spondylitis Disease Activity Score (ASDAS): defining cut-off values for disease activity states and improvement scores. Ann Rheum Dis. 2011;70(1):47–53.

    Article  PubMed  Google Scholar 

  3. Josef S Smolen, Robert Landewé, Johannes Bijlsma, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update | Annals of the Rheumatic Diseases. Disponible sur: [cité 15 juin 2019].

  4. van der Heijde D, Ramiro S, Landewe R, Baraliakos X, Van den Bosch F, Sepriano A, et al. 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis. 2017;76(6):978–91.

    Article  PubMed  Google Scholar 

  5. Gossec L. European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. - PubMed - NCBI. Disponible sur: [cité 18 juin 2019].

  6. van Tuyl LH, Sadlonova M, Davis B, Flurey C, Goel N, Hewlett SE, et al. Remission in rheumatoid arthritis: working toward incorporation of the patient perspective at OMERACT 12. J Rheumatol janv. 2016;43(1):203–7.

    Article  Google Scholar 

  7. Lubrano E, Mesina F, Caporali R. Clinical remission in rheumatoid arthritis and psoriatic arthritis. Clin Exp Rheumatol. 2018;36(5):900–10.

    PubMed  Google Scholar 

  8. Singh JA, Wells GA, Christensen R, Tanjong Ghogomu E, Maxwell L, Macdonald JK, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011;(2):CD008794.

  9. Minozzi S, Bonovas S, Lytras T, Pecoraro V, González-Lorenzo M, Bastiampillai AJ, et al. Risk of infections using anti-TNF agents in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: a systematic review and meta-analysis. Expert Opin Drug Saf. 2016;15(sup1):11–34.

    Article  CAS  PubMed  Google Scholar 

  10. Singh JA, Cameron C, Noorbaloochi S, Cullis T, Tucker M, Christensen R, et al. Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis. Lancet Lond Engl. 2015;386(9990):258–65.

    Article  Google Scholar 

  11. Ramiro S, Sepriano A, Chatzidionysiou K, Nam JL, Smolen JS, van der Heijde D, et al. Safety of synthetic and biological DMARDs: a systematic literature review informing the 2016 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis. 2017;76(6):1101–36.

    Article  PubMed  Google Scholar 

  12. Dreyer L, Cordtz RL, Hansen IMJ, Kristensen LE, Hetland ML, Mellemkjaer L. Risk of second malignant neoplasm and mortality in patients with rheumatoid arthritis treated with biological DMARDs: a Danish population-based cohort study. Ann Rheum Dis. 2018;77(4):510–4.

    Article  PubMed  Google Scholar 

  13. Ursini F, Ruscitti P, Caio GPI, Manfredini R, Giacomelli R, De Giorgio R. The effect of non-TNF-targeted biologics on vascular dysfunction in rheumatoid arthritis: a systematic literature review. Autoimmun Rev. 2019;18(5):501–9.

    Article  CAS  PubMed  Google Scholar 

  14. England BR, Thiele GM, Anderson DR, Mikuls TR. Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications. BMJ. 2018;361:k1036.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Stevenson M, Archer R, Tosh J, Simpson E, Everson-Hock E, Stevens J, et al. Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for the treatment of rheumatoid arthritis not previously treated with disease-modifying antirheumatic drugs and after the failure of conventional disease-modifying antirheumatic drugs only: systematic review and economic evaluation. Health Technol Assess. 2016;20(35):1–610.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Singh JA, Saag KG, Bridges SLJ, Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American College of Rheumatology Guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):1–26.

    Article  PubMed  Google Scholar 

  17. Singh JA, Guyatt G, Ogdie A, Gladman DD, Deal C, Deodhar A, et al. 2018 American College of Rheumatology/National Psoriasis Foundation guideline for the treatment of psoriatic arthritis. Arthritis Care Res. 2019;71(1):2–29.

    Article  Google Scholar 

  18. Ward MM, Deodhar A, Akl EA, Lui A, Ermann J, Gensler LS, et al. American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 recommendations for the treatment of ankylosing spondylitis and nonradiographic axial Spondyloarthritis. Arthritis Rheumatol. 2016;68(2):282–98.

    Article  PubMed  Google Scholar 

  19. Henaux S, Ruyssen-Witrand A, Cantagrel A, Barnetche T, Fautrel B, Filippi N, et al. Risk of losing remission, low disease activity or radiographic progression in case of bDMARD discontinuation or tapering in rheumatoid arthritis: systematic analysis of the literature and meta-analysis. Ann Rheum Dis. 2018;77(4):515–22.

    Article  PubMed  Google Scholar 

  20. Couvaras L, Barnetche T, Constantin A, Pham T. Tapering TNF Inhibitors in Axial Spondyloarthritis: Systematic analysis of the literature and meta-Analysis. ACR Meeting Abstracts. 2018. Disponible sur: [cité 3 juill 2019].

  21. Park JW, Kim H-A, Shin K, Park Y-B, Kim T-H, Song YW, et al. Effects of tapering tumor necrosis factor inhibitor on the achievement of inactive disease in patients with axial spondyloarthritis: a nationwide cohort study. Arthritis Res Ther. 2019;21(1):163.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Tanaka Y, Smolen JS, Jones H, Szumski A, Marshall L, Emery P. The effect of deep or sustained remission on maintenance of remission after dose reduction or withdrawal of etanercept in patients with rheumatoid arthritis. Arthritis Res Ther. 2019;21(1):164.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Verhoef LM, van den Bemt BJ, van der Maas A, Vriezekolk JE, Hulscher ME, van den Hoogen FH, et al. Down-titration and discontinuation strategies of tumour necrosis factor-blocking agents for rheumatoid arthritis in patients with low disease activity. Cochrane Database Syst Rev. 2019;5:CD010455.

    PubMed  Google Scholar 

  24. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4(1):1.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials | The BMJ. Disponible sur: [cité 15 juin 2019].

  26. Bouman CA, van Herwaarden N, van den Hoogen FH, Fransen J, van Vollenhoven RF, Bijlsma JW, et al. Long-term outcomes after disease activity-guided dose reduction of TNF inhibition in rheumatoid arthritis: 3-year data of the DRESS study - a randomised controlled pragmatic non-inferiority strategy trial. Ann Rheum Dis. 2017;76(10):1716–22.

    Article  CAS  PubMed  Google Scholar 

  27. van Herwaarden N, van der Maas A, Minten MJM, van den Hoogen FHJ, Kievit W, van Vollenhoven RF, et al. Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised controlled, non-inferiority trial. BMJ. 2015;350:h1389.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Ibrahim F, Lorente-Canovas B, Dore CJ, Bosworth A, Ma MH, Galloway JB, et al. Optimizing treatment with tumour necrosis factor inhibitors in rheumatoid arthritis-a proof of principle and exploratory trial: is dose tapering practical in good responders? Rheumatol (Oxford). 2017;56(11):2004–14.

    Article  CAS  Google Scholar 

  29. Zavada J, Uher M, Sisol K, Forejtova S, Jarosova K, Mann H, et al. A tailored approach to reduce dose of anti-TNF drugs may be equally effective, but substantially less costly than standard dosing in patients with ankylosing spondylitis over 1 year: a propensity score-matched cohort study. Ann Rheum Dis. 2016;75(1):96–102.

    Article  PubMed  Google Scholar 

  30. Westhovens R, Robles M, Ximenes AC, Wollenhaupt J, Durez P, Gomez-Reino J, et al. Maintenance of remission following 2 years of standard treatment then dose reduction with abatacept in patients with early rheumatoid arthritis and poor prognosis. Ann Rheum Dis. 2015;74(3):564–8.

    Article  CAS  PubMed  Google Scholar 

  31. Gratacos J, Pontes C, Juanola X, Sanz J, Torres F, Avendano C, et al. Non-inferiority of dose reduction versus standard dosing of TNF-inhibitors in axial spondyloarthritis. Arthritis Res Ther. 2019;21(1):11.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Weinblatt ME, Bingham CO 3rd, Burmester G-R, Bykerk VP, Furst DE, Mariette X, et al. A phase III study evaluating continuation, tapering, and withdrawal of certolizumab pegol after one year of therapy in patients with early rheumatoid arthritis. Arthritis Rheumatol. 2017;69(10):1937–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Takeuchi T, Genovese MC, Haraoui B, Li Z, Xie L, Klar R, et al. Dose reduction of baricitinib in patients with rheumatoid arthritis achieving sustained disease control: results of a prospective study. Ann Rheum Dis. 2019;78(2):171–8.

    Article  CAS  PubMed  Google Scholar 

  34. van Vollenhoven RF, Ostergaard M, Leirisalo-Repo M, Uhlig T, Jansson M, Larsson E, et al. Full dose, reduced dose or discontinuation of etanercept in rheumatoid arthritis. Ann Rheum Dis. 2016;75(1):52–8.

    Article  PubMed  CAS  Google Scholar 

  35. Smolen JS, Nash P, Durez P, Hall S, Ilivanova E, Irazoque-Palazuelos F, et al. Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial. Lancet Lond. 2013;381(9870):918–29.

    Article  CAS  Google Scholar 

  36. Fautrel B, Pham T, Alfaiate T, Gandjbakhch F, Foltz V, Morel J, et al. Step-down strategy of spacing TNF-blocker injections for established rheumatoid arthritis in remission: results of the multicentre non-inferiority randomised open-label controlled trial (STRASS: Spacing of TNF-blocker injections in Rheumatoid ArthritiS Study). Ann Rheum Dis. 2016;75(1):59–67.

    Article  PubMed  Google Scholar 

  37. l’Ami MJ, Krieckaert CL, Nurmohamed MT, van Vollenhoven RF, Rispens T, Boers M, et al. Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial. Ann Rheum Dis. 2018;77(4):484–7.

    Article  PubMed  CAS  Google Scholar 

  38. Cantini F, Niccoli L, Cassara E, Kaloudi O, Nannini C. Duration of remission after halving of the etanercept dose in patients with ankylosing spondylitis: a randomized, prospective, long-term, follow-up study. Biol Targets Ther. 2013;7:1–6.

    CAS  Google Scholar 

  39. Li K-P, Jin J-Y, Yang J-S, Li Y, Zhao W, Luo G, et al. Full dose, half dose, or discontinuation of etanercept biosimilar in early axial spondyloarthritis patients: a real-world study in China. Arch Med Sci AMS. 2019;15(3):700–5.

    Article  CAS  PubMed  Google Scholar 

  40. Bernatsky S, Habel Y, Rahme E. Observational studies of infections in rheumatoid arthritis: a metaanalysis of tumor necrosis factor antagonists. J Rheumatol. 2010;37(5):928–31.

    Article  CAS  PubMed  Google Scholar 

  41. Jani M, Barton A, Hyrich K. Prediction of infection risk in rheumatoid arthritis patients treated with biologics: are we any closer to risk stratification? Curr Opin Rheumatol. 2019;31(3):285–92.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Curtis JR, Winthrop K, O’Brien C, Ndlovu MN, de Longueville M, Haraoui B. Use of a baseline risk score to identify the risk of serious infectious events in patients with rheumatoid arthritis during certolizumab pegol treatment. Arthritis Res Ther. 2017;19(1):276.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Ruderman EM. Overview of safety of non-biologic and biologic DMARDs. Rheumatology. 2012;51(suppl_6):vi37–43.

    PubMed  Google Scholar 

  44. Galloway JB, Hyrich KL, Mercer LK, Dixon WG, Fu B, Ustianowski AP, et al. Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatol (Oxford). 2011;50(1):124–31.

    Article  CAS  Google Scholar 

  45. Askling J, Fored CM, Brandt L, Baecklund E, Bertilsson L, Feltelius N, et al. Time-dependent increase in risk of hospitalisation with infection among Swedish RA patients treated with TNF antagonists. Ann Rheum Dis. 2007;66(10):1339–44.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Solomon DH, Reed GW, Kremer JM, Curtis JR, Farkouh ME, Harrold LR, et al. Disease activity in rheumatoid arthritis and the risk of cardiovascular events. Arthritis Rheumatol. 2015;67(6):1449–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references


We are grateful to the professors and organizers of ASLER seminary (for Systematic Analysis of the Literature in Rheumatology) for their useful advice in the writing of this manuscript. We wish to thank AbbVie who provided logistic support in the organization of sessions about the implementation of meta-analysis and remained independent of the collection, analysis, and interpretation of data. We are grateful to Mrs. Weill C. who helped us in the Embase bibliographic research.

Patient and public involvement

Was not appropriate in our study

Patient consent

Not required.


The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations



DV and LM-B: contributed to the conception of the study, the article selection process, the data collection, the data analysis, the results interpretation, and the manuscript writing and approval. AC and AR-W: contributed to the conception of the study, results interpretation, and manuscript approval. YD, AdB, FI, CP, RW, JZ, TP, and TB: contributed to the results interpretation and manuscript approval. TB: was in charge of the statistical analyses. All authors take responsibility for the integrity of the work as a whole, from inception to published article, and they should indicate that they had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. They give permission to reproduce published material, to report sensitive personal information, to use illustrations of identifiable persons, or to name persons for their contributions.

Corresponding author

Correspondence to D. Vinson.

Ethics declarations

Ethics approval and consent to participate

This study, as a meta-analysis, does not involve directly human participants but used data from trials performed on human participants. Indeed, the Ethics Committee approvals of each trial were obtained for all the studies selected in this meta-analysis.

Competing interests

The authors declare that they have no competing interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Additional file 1 : Supplementary text 1

: Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) 2015 statement [24]. Supplementary text 2: Boolean association of keywords used in PubMed (Medline database). Supplementary text 3: List of data extracted for each selected study. Supplementary Table 1: Population characteristics of studies included in the Meta-Analysis. Supplementary Table 2: Adverse Event (AE) characteristics of studies included in the Meta-Analysis. Supplementary Figure 1: Cochrane Risk of Bias Tool [25]. Supplementary Figure 2: Publication bias and Funnel plots.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vinson, D., Molet-Benhamou, L., Degboé, Y. et al. Impact of tapering targeted therapies (bDMARDs or JAKis) on the risk of serious infections and adverse events of special interest in patients with rheumatoid arthritis or spondyloarthritis: a systematic analysis of the literature and meta-analysis. Arthritis Res Ther 22, 97 (2020).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: