SAT0052 THERAPEUTIC STRATEGIES IN DIFFICULT-TO-TREAT RHEUMATOID ARTHRITIS: PRELIMINARY RESULTS OF A SYSTEMATIC LITERATURE REVIEW INFORMING THE 2020 EULAR RECOMMENDATIONS FOR THE MANAGEMENT OF DIFFICULT-TO-TREAT RHEUMATOID ARTHRITIS

Background:Rheumatoid arthritis (RA) patients treated according to European League Against Rheumatism (EULAR) recommendations failing ≥2 biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) with a different mode of action who still have complaints which may be suggestive of active disease may be defined as suffering from ‘difficult-to-treat RA’. Management recommendations for RA focus predominantly on the earlier phases of the disease and specific recommendations for difficult-to-treat RA patients are currently lacking.1Objectives:To systematically summarise evidence in the literature on pharmacological and non-pharmacological therapeutic strategies for difficult-to-treat RA patients, informing the 2020 EULAR recommendations for the management of difficult-to-treat RA.Methods:A systematic literature review (SLR) was performed: PubMed, Embase and Cochrane databases were searched up to December 2019. Relevant papers were selected and appraised.Results:Thirty articles were selected for therapeutic strategies in patients with limited DMARD options due to contraindications, 73 for patients in whom previous b/tsDMARDs were not effective (‘true refractory RA’), and 51 for patients with predominantly non-inflammatory complaints. For patients with limited DMARD options, limited evidence was found on effective DMARD options for patients with concomitant obesity, and on safe DMARD options for patients with concomitant hepatitis B and C. In patients who failed ≥2 bDMARDs, tocilizumab, tofacitinib, baricitinib, upadacitinib and filgotinib were found to be more effective than placebo, but evidence was insufficient to prioritise. In patients who failed ≥1 bDMARD, there was a tendency of non-tumour necrosis factor inhibitor (TNFi) bDMARDs to be more effective than TNFi (Figure 1). Generally, b/tsDMARDs become less effective when patients failed more bDMARDs, this tendency was not clear for upadacitinib and filgotinib (Figure 2). In patients with predominantly non-inflammatory complaints (mainly function, pain and fatigue), exercise, education, psychological and self-management interventions were found to be of additional benefit.Conclusion:This SLR underscores the scarcity of evidence on the optimal treatment of difficult-to-treat RA patients. As difficult-to-treat RA is a newly defined disease state, all evidence is to an extent indirect. Several b/tsDMARDs were found to be effective in patients who failed ≥2 bDMARDs and generally effectiveness decreased with a higher number of failed bDMARDs. Additionally, a beneficial effect of non-pharmacological interventions was found on non-inflammatory complaints.References:[1] Smolen JSet al. Ann Rheum Dis2020. Epub ahead of print.Disclosure of Interests:Nadia M. T. Roodenrijs: None declared, Attila Hamar: None declared, Melinda Kedves: None declared, György Nagy: None declared, Jacob M. van Laar Grant/research support from: MSD, Genentech, Consultant of: MSD, Roche, Pfizer, Eli Lilly, BMS, Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead Sciences, Inc., Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma; Director of Imaging Rheumatology BV, Paco Welsing: None declared

Download Full-text

Pharmacological and non-pharmacological therapeutic strategies in difficult-to-treat rheumatoid arthritis: a systematic literature review informing the EULAR recommendations for the management of difficult-to-treat rheumatoid arthritis

RMD Open ◽

10.1136/rmdopen-2020-001512 ◽

2021 ◽

Vol 7 (1) ◽

pp. e001512

Author(s):

Nadia M T Roodenrijs ◽

Attila Hamar ◽

Melinda Kedves ◽

György Nagy ◽

Jacob M van Laar ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Literature Review ◽

Goal Setting ◽

Systematic Literature Review ◽

Functional Disability ◽

Therapeutic Strategies ◽

Self Management ◽

Eular Recommendations ◽

Management Interventions ◽

Pregnancy And Lactation

ObjectivesTo summarise, by a systematic literature review (SLR), the evidence regarding pharmacological and non-pharmacological therapeutic strategies in difficult-to-treat rheumatoid arthritis (D2T RA), informing the EULAR recommendations for the management of D2T RA.MethodsPubMed, Embase and Cochrane databases were searched up to December 2019. Relevant papers were selected and appraised.ResultsTwo hundred seven (207) papers studied therapeutic strategies. Limited evidence was found on effective and safe disease-modifying antirheumatic drugs (DMARDs) in patients with comorbidities and other contraindications that limit DMARD options (patients with obesity, hepatitis B and C, risk of venous thromboembolisms, pregnancy and lactation). In patients who previously failed biological (b-)DMARDs, all currently used b/targeted synthetic (ts-)DMARDs were found to be more effective than placebo. In patients who previously failed a tumour necrosis factor inhibitor (TNFi), there was a tendency of non-TNFi bDMARDs to be more effective than TNFis. Generally, effectiveness decreased in patients who previously failed a higher number of bDMARDs. Additionally, exercise, psychological, educational and self-management interventions were found to improve non-inflammatory complaints (mainly functional disability, pain, fatigue), education to improve goal setting, and self-management programmes, educational and psychological interventions to improve self-management.The identified evidence had several limitations: (1) no studies were found in patients with D2T RA specifically, (2) heterogeneous outcome criteria were used and (3) most studies had a moderate or high risk of bias.ConclusionsThis SLR underscores the scarcity of high-quality evidence on the pharmacological and non-pharmacological treatment of patients with D2T RA. Effectiveness of b/tsDMARDs decreased in RA patients who had failed a higher number of bDMARDs and a subsequent b/tsDMARD of a previously not targeted mechanism of action was somewhat more effective. Additionally, a beneficial effect of non-pharmacological interventions was found for improvement of non-inflammatory complaints, goal setting and self-management.

Download Full-text

Current evidence for a strategic approach to the management of rheumatoid arthritis with disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis

Annals of the Rheumatic Diseases ◽

10.1136/ard.2009.126748 ◽

2010 ◽

Vol 69 (6) ◽

pp. 987-994 ◽

Cited By ~ 96

Author(s):

R Knevel ◽

M Schoels ◽

T W J Huizinga ◽

D Aletaha ◽

G R Burmester ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Literature Review ◽

Clinical Outcome ◽

Physical Function ◽

Systematic Literature Review ◽

Structural Damage ◽

Task Force ◽

Treatment Strategies ◽

Current Evidence ◽

Eular Recommendations

ObjectivesTo perform a systematic literature review of effective strategies for the treatment of rheumatoid arthritis (RA).MethodsAs part of a European League Against Rheumatism (EULAR) Task Force investigation, a literature search was carried out from January 1962 until February 2009 in PubMed/Ovid Embase/Cochrane and EULAR/American College of Rheumatism (ACR)) abstracts (2007/2008) for studies with a treatment strategy adjusted to target a predefined outcome. Articles were systematically reviewed and clinical outcome, physical function and structural damage were compared between intensive and less intensive strategies. The results were evaluated by an expert panel to consolidate evidence on treatment strategies in RA.ResultsThe search identified two different kinds of treatment strategies: strategies in which the reason for treatment adjustment differed between the study arms (‘steering strategies’, n=13) and strategies in which all trial arms used the same clinical outcome to adjust treatment with different pharmacological treatments (‘medication strategies’, n=7). Both intensive steering strategies and intensive medication strategies resulted in better outcome than less intensive strategies in patients with early active RA.ConclusionIntensive steering strategies and intensive medication strategies produce a better clinical outcome, improved physical function and less structural damage than conventional steering or treatment. Proof in favour of any steering method is lacking and the best medication sequence is still not known.

Download Full-text

Efficacy of glucocorticoids, conventional and targeted synthetic disease-modifying antirheumatic drugs: a systematic literature review informing the 2016 update of the EULAR recommendations for the management of rheumatoid arthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2016-210711 ◽

2017 ◽

Vol 76 (6) ◽

pp. 1102-1107 ◽

Cited By ~ 63

Author(s):

Katerina Chatzidionysiou ◽

Sharzad Emamikia ◽

Jackie Nam ◽

Sofia Ramiro ◽

Josef Smolen ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Literature Review ◽

Systematic Literature Review ◽

Treat To Target ◽

Tight Control ◽

Disease Modifying Antirheumatic Drugs ◽

Antirheumatic Drugs ◽

Eular Recommendations ◽

Synthetic Dmards ◽

Disease Modifying

ObjectivesTo perform a systematic literature review (SLR) informing the 2016 update of the recommendations for the management of rheumatoid arthritis (RA).MethodsAn SLR for the period between 2013 and 2016 was undertaken to assess the efficacy of glucocorticoids (GCs), conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and targeted synthetic DMARDs (tsDMARDs) (tofacitinib and baricitinib) in randomised clinical trials.ResultsFor GCs, four studies were included in the SLR. Patients without poor prognostic factors experienced benefit when GCs were added to methotrexate (MTX). Lower doses of GCs were similar to higher doses. For csDMARDs, two new studies comparing MTX monotherapy with combination csDMARD were included in the SLR. In the tREACH trial at the end of 12 months no difference between the groups in disease activity, functional ability and radiographic progression was seen, using principles of tight control (treat-to-target). In the CareRA trial, combination therapy with csDMARDs was not superior to MTX monotherapy and monotherapy was better tolerated.For tsDMARDs, tofacitinib and baricitinib were shown to be more effective than placebo (MTX) in different patient populations.ConclusionsAddition of GCs to csDMARD therapy may be beneficial but the benefits should be balanced against the risk of toxicity. Under tight control conditions MTX monotherapy is not less effective than combination csDMARDs, but better tolerated. Tofacitinib and baricitinib are efficacious in patients with RA, including those with refractory disease.

Download Full-text

Safety of synthetic and biological DMARDs: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2013-204575 ◽

2014 ◽

Vol 73 (3) ◽

pp. 529-535 ◽

Cited By ~ 223

Author(s):

Sofia Ramiro ◽

Cécile Gaujoux-Viala ◽

Jackie L Nam ◽

Josef S Smolen ◽

Maya Buch ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Literature Review ◽

Systematic Literature Review ◽

Observational Studies ◽

Certolizumab Pegol ◽

Eligibility Criteria ◽

Biological Dmards ◽

Eular Recommendations ◽

Increased Risk ◽

Safety Outcomes

ObjectivesTo update the evidence for the safety of synthetic disease-modifying antirheumatic drugs (sDMARDs), glucocorticoids (GC) and biological DMARDs (bDMARDs) in patients with rheumatoid arthritis (RA) to inform the European League Against Rheumatism (EULAR) recommendations for the management of RA.MethodsSystematic literature review (SLR) of observational studies (including registries). Interventions were any bDMARD (anakinra, infliximab, etanercept, adalimumab, rituximab, abatacept, tocilizumab, golimumab or certolizumab pegol) or sDMARD (methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, gold/auranofin, azathioprine, chlorambucil, chloroquine, cyclosporin, cyclophosphamide, mycophenolate, minocycline, penicillamine, tacrolimus or tofacitinib) and a comparator was required. Information on GCs was collected from the included studies. All safety outcomes were included.ResultsForty-nine observational studies addressing diverse safety outcomes of therapy with bDMARDs met eligibility criteria. Substantial heterogeneity precluded meta-analysis of any of the outcomes. Patients on tumour necrosis factor inhibitors (TNFi) compared to patients on conventional sDMARDs had a higher risk of serious infections (adjusted HR (aHR) 1.1–1.8), a higher risk of tuberculosis, and an increased risk of infection by herpes zoster cannot be excluded. Patients on TNFi did not have an increased risk for malignancies in general, lymphoma or non-melanoma skin cancer, but the risk of melanoma may be slightly increased (aHR 1.5). From the studies identified on conventional sDMARDs, no new safety signals were found.ConclusionsThe findings from this SLR confirm the known safety pattern of sDMARDs and bDMARDs for the treatment of RA.

Download Full-text

Safety of synthetic and biological DMARDs: a systematic literature review informing the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2019-216653 ◽

2020 ◽

pp. annrheumdis-2019-216653 ◽

Cited By ~ 25

Author(s):

Alexandre Sepriano ◽

Andreas Kerschbaumer ◽

Josef S Smolen ◽

Désirée van der Heijde ◽

Maxime Dougados ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Literature Review ◽

Systematic Literature Review ◽

Observational Studies ◽

Janus Kinase ◽

Jak Inhibitors ◽

Eular Recommendations ◽

Increased Risk ◽

Safety Outcomes ◽

Risk Of Cancer

ObjectivesTo perform a systematic literature review (SLR) concerning the safety of synthetic (s) and biological (b) disease-modifying anti rheumatic dugs (DMARDs) to inform the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis (RA).MethodsAn SLR of observational studies comparing safety outcomes of any DMARD with another intervention for the management of RA. A comparator group was required for inclusion. For treatments still without registry data (eg, sarilumab and the Janus kinase (JAK) inhibitors baricitinib, upadacitinib), randomised controlled trials (RCTs) and long-term extensions (LTEs) were used. Risk of bias (RoB) was assessed according to standard procedures.ResultsForty-two observational studies fulfilled the inclusion criteria, addressing safety outcomes with bDMARDs and sDMARDs. Nine studies showed no difference in the risk of serious infections across bDMARDs and two studies (high RoB) showed an increased risk with bDMARDs compared with conventional synthetic (cs) DMARDs (adjusted incidence rate ratio 3.1–3.9). The risk of Herpes zoster infection was similar across bDMARDs, but one study showed an increased risk with tofacitinib compared with abatacept (adjusted HR (aHR) 2.0). Five studies showed no increased risk of cancer for bDMARDs compared with csDMARDs. An increased risk of lower intestinal perforation was found for tocilizumab compared with csDMARDs (aHR 4.5) and tumour necrosis factor inhibitor (TNFi) (aHR 2.6–4.0). Sixty manuscripts reported safety data from RCTs/LTEs. Overall, no unexpected safety outcomes were found, except for the possibly increased risk of venous thromboembolism (VTE) with JAK inhibitors.ConclusionData obtained by this SLR confirm the known safety profile of bDMARDs. The risk of VTE in RA, especially in patients on JAK inhibitors, needs further evaluation.

Download Full-text

Diagnostic issues in difficult-to-treat rheumatoid arthritis: a systematic literature review informing the EULAR recommendations for the management of difficult-to-treat rheumatoid arthritis

RMD Open ◽

10.1136/rmdopen-2020-001511 ◽

2021 ◽

Vol 7 (1) ◽

pp. e001511

Author(s):

Nadia M T Roodenrijs ◽

Melinda Kedves ◽

Attila Hamar ◽

György Nagy ◽

Jacob M van Laar ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Literature Review ◽

Diagnostic Test ◽

Systematic Literature Review ◽

Direct Evidence ◽

Inflammatory Activity ◽

High Quality ◽

Eular Recommendations ◽

Detailed Assessment ◽

Additional Value

ObjectivesTo summarise the evidence on diagnostic issues in difficult-to-treat rheumatoid arthritis (D2T RA) informing the EULAR recommendations for the management of D2T RA.MethodsA systematic literature review (SLR) was performed regarding the optimal confirmation of a diagnosis of rheumatoid arthritis (RA) and of mimicking diseases and the assessment of inflammatory disease activity. PubMed and Embase databases were searched up to December 2019. Relevant papers were selected and appraised.ResultsEighty-two papers were selected for detailed assessment. The identified evidence had several limitations: (1) no studies were found including D2T RA patients specifically, and only the minority of studies included RA patients in whom there was explicit doubt about the diagnosis of RA or presence of inflammatory activity; (2) mostly only correlations were reported, not directly useful to evaluate the accuracy of detecting inflammatory activity in clinical practice; (3) heterogeneous, and often suboptimal, reference standards were used and (4) (thus) only very few studies had a low risk of bias.To ascertain a diagnosis of RA or relevant mimicking disease, no diagnostic test with sufficient validity and accuracy was identified. To ascertain inflammatory activity in patients with RA in general and in those with obesity and fibromyalgia, ultrasonography (US) was studied most extensively and was found to be the most promising diagnostic test.ConclusionsThis SLR highlights the scarcity of high-quality studies regarding diagnostic issues in D2T RA. No diagnostic tests with sufficient validity and accuracy were found to confirm nor exclude the diagnosis of RA nor its mimicking diseases in D2T RA patients. Despite the lack of high-quality direct evidence, US may have an additional value to assess the presence of inflammatory activity in D2T RA patients, including those with concomitant obesity or fibromyalgia.

Download Full-text