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Table 2 Potential biomarkers associated with successful treatment withdrawal in rheumatoid arthritis

From: Tailored therapeutic decision of rheumatoid arthritis using proteomic strategies: how to start and when to stop?

Cohorts

Previous treatments

Inclusion criteria (definition of remission)

Interventions

No. of patients

Primary outcomes

Clinical implications

Refs.

Leiden EAC and ERAS

csDMARDs

defined by rheumatologist

Stop all csDMARDs

1349

Sustained DFR > 1y until last follow up

RF â–¼ anti-CCP â–¼

Patients positive for RF and/or anti-CCP were less likely to reach sustained DFR

[119]

Spain

bDMARDs for 2 m

Boolean definition

at least 12 m

Taper bDMARDs

77

Taper failure in 40 m

RF ▼ anti-CCP ʘ

Patients positive for RF were associated with taper failure, but the association was not observed in anti-CCP

[120]

RETRO

TNFi or tocilizumab > 6 m

DAS28-ESR < 2.6

at least 6 m

Taper or stop TNFi and tocilizumab

101

Flare:

DAS28-ESR ≥ 2.6 in 12 m

anti-CCP â–¼

anti-CCP-positive patients were more likely to relapse

[121]

94

Flare:

DAS28-ESR > 2.6 in 12 m

anti-CCP â–¼ MBDA â–¼

Patients with lower MBDA score (< 30 units) and negative anti-CCP are at higher risk of relapse after treatment withdrawal

[122]

94

Flare:

DAS28-ESR > 2.6 in 12 m

Diverse autoantibodies â–¼

The risk of relapse increased with more autoantibody reactivities, regardless of specific isotypes or targets

[123]

57

Flare:

DAS28-ESR > 2.6 in 12 m

Calprotectin â–¼

Patients with higher calprotectin levels at the moment of treatment withdrawal were prone to relapse

[127]

IMPROVED

csDMARDs (methotrexate and prednisolone) for 4 m

DAS44 < 1.6

Taper and stop methotrexate at 8 m

399

Sustained DFR between the 1st–2nd year of follow up

Diverse autoantibodies â–¼

Patients with more diverse autoantibodies were less likely to achieve DFR

[19]

610

Sustained DFR > 1y until last follow up (2y)

RF â–¼ anti-CCP â–¼

RF and/or anti-CCP positive patients were less likely to reach DFR

[124]

104

Flare:

DAS44 ≥ 1.6 in 12 m

Calprotectin â–¼

Patients with higher calprotectin levels at the moment of treatment withdrawal were prone to relapse

[127]

RRRR trial

infliximab (TNFi) for 1y

SDAI ≤ 3.3

Stop infliximab

337

Sustained DFR > 1y until last follow up (2y)

RF ▼ TNF-α ▲

Patients with lower RF and higher TNF-α have a higher likelihood of sustained DFR

[125]

BioRRA

csDMARDs alone, no prior bDMARDs

DAS28-CRP < 2.4

Stop all csDMARDs without tapering

44

Flare:

DAS28-CRP ≥ 2.4 in 6 m

39 serum proteins; RF ▲ anti-CCP ʘ IL-27 ▼

RF status, two cytokines/chemokines (IL-27, MCP-1), and three CD4 + T cell genes were associated with the risk of flare after DMARD cessation. Patients with lower IL-27 were more likely to remain remission

[126]

POET

TNFi > 1y

DAS28-ESR < 3.2

at least 6 m

Stop TNFi

439

Flare:

ΔDAS > 0.6 and DAS28-ESR ≥ 3.2 in 12 m

MBDA â–¼

Patients with higher MBDA score at the moment of treatment withdrawal were more likely to relapse

[129]

STRASS

TNFi

sustained DAS28 remission

Taper TNFi

137

Flare:

ΔDAS > 0.6 and DAS28 > 2.6 in 18 m

MBDA ʘ

No significant difference in MBDA scores between relapsing and non-relapsing patients

[130]

DRESS

stable adalimumab or etanercept (TNFi) > 6 m

DAS28-ESR < 3.2

at least 6 m

Taper and strop adalimumab and etanercept

115

Flare:

ΔDAS > 0.6 and DAS28 ≥ 3.2 OR ΔDAS > 1.2 in 18 m

MBDA ʘ

The MBDA scores at the moment of tapering were not associated with the risk of relapse after TNFi withdrawal

[131]

SURPRISE

tocilizumab ± methotrexate for 1y

DAS28 < 2.6

Stop tocilizumab, keep methotrexate

105

Sustained DFR > 1y

RF â–¼ MMP-3 â–¼

Patients with negative RF and lower MMP-3 were more likely to achieve DFR

[139]

FLAIR

bDMARDs for 2y

SDAI ≤ 3.3

at least 3 m

Stop bDMARDs

36

Flare:

∆DAS28-ESR > 0.6 and DAS28-ESR ≥ 3.2 in 24 m

12 cytokines: soluble TNFR1 â–¼ IL-2 â–²

Patients with lower levels of soluble TNFR1 and higher levels of IL-2 were more likely to remain remission

[140]

UMIN

000044434

TNFi or tocilizumab

DAS28-CRP < 2.3

at least 1y

Stop TNFi and tocilizumab, keep other medication

40

Flare:

DAS28-CRP ≥ 2.3 in 24 m

73-plex cytokine array: IL-34 â–¼ IL-19 â–²

Upon treatment withdrawal, the IL-34 was significantly up-regulated and IL-19 was significantly down-regulated in patients experiencing subsequent relapses

[141]

U-Act-Early

tocilizumab

DAS28 < 2.6

at least 24 wk

Taper and stop tocilizumab

24

Sustained DFR ≥ 3 m until last follow up (2y)

85 inflammatory proteins (Luminex multiplex assay):

14 proteins corresponding to leukocyte activation pathway are associated with sustained DFR

[142]

  1. bDMARDs biological DMARDs, csDMARDs conventional synthetic DMARDs, DFR DMARD-free remission, i.e., fulfilling the definition of remission after DMARD cessation; TNFi TNF inhibitors; SDAI Simple Disease Activity Index, MBDA multi-biomarker disease activity, MCP-1 monocyte chemoattractant protein-1, TNFR1 tumor necrosis factor receptor 1, wk week(s), m month(s), y year(s)
  2. â–² Suggests that elevated levels of designated biomarkers are associated with higher rates of successful treatment withdrawal (favorable)
  3. â–¼ Indicates that elevated levels of designated biomarkers are associated with higher rates of relapse (unfavorable)
  4. ʘ Implies that the levels of designated biomarkers are less relevant to the success rates of treatment withdrawal
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Clinical Proteomics

ISSN: 1559-0275