True infliximab resistance in rheumatoid arthritis: a role for lymphotoxin α?

Background: The combination of methotrexate and the anti-tumour necrosis factor (TNF) antibody infliximab is a very effective treatment for rheumatoid arthritis (RA). However, a proportion of patients are not responsive to this treatment. Inefficacy may represent a TNF independent disease or insufficient drug at the site of action. Case report: A patient with RA resistant to repeated high dose infliximab infusions and intra-articular infliximab into an inflamed knee is described. No beneficial clinical effect was observed. Pre-injection arthroscopic biopsy of the study knee demonstrated TNF staining but also confirmed the presence of lymphotoxin (LT or TNFß) on immunohistochemistry. Subsequent treatment with etanercept (which blocks LT as well as TNF) resulted in clinical remission of disease. Conclusion: This case suggests that resistance to TNF blockade may occur when TNF is not the dominant inflammatory cytokine and suggests that LT may have a pathogenic role in RA

Domains and outcome measures for the assessment of limited cutaneous systemic sclerosis: a scoping review protocol

Introduction: Limited cutaneous systemic sclerosis (lcSSc) is the most frequent subset of systemic sclerosis. Despite this, lcSSc is not the major focus of clinical studies. The lack of interventional studies in lcSSc is due, in part, to a paucity of relevant outcome measures to effectively evaluate this subset. A combined response index dedicated to lcSSc would facilitate development of well-designed trials and approval of new drugs. The objective of this scoping review is to perform a broad and comprehensive identification of the outcome measures (core set items) within relevant domains, which have been used so far to assess lcSSc. Methods and analysis: The planned scoping review will be based on the approach proposed by Arksey et al and further developed by Levac et al. Development and reporting will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses—Extension for Scoping Reviews checklist and guidelines. The development of the search strategy was guided by the concepts of domains and outcomes based on the Outcome Measures in Rheumatology approach and by the different names and definitions of SSc, with a specific emphasis on their occurrence in clinical trial studies. Two databases will be searched: MEDLINE and Embase. Studies in English, published from the year 1988 onwards, will be included, since 1988 corresponds to the publication of LeRoy’s first consensus definition of lcSSc. Data will be extracted and analysed using a standardised charting tool. Ethics and dissemination: No ethical approval is required for this study. The results will be submitted to an international peer-reviewed journal and scientific conferences, informing the discussion on which items should be included in a combined response index dedicated to lcSSc (the CRISTAL project: Combined Response Index for Scleroderma Trial Assessing lcSSc)

Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis

Background Since initial approval for the treatment of rheumatoid arthritis (RA), rituximab has been evaluated in clinical trials involving various populations with RA. Information has also been gathered from registries. This report therefore updates the 2007 consensus document on the use of rituximab in the treatment of RA. Methods Preparation of this new document involved many international experts experienced in the treatment of RA. Following a meeting to agree upon the core agenda, a systematic literature review was undertaken to identify all relevant data. Data were then interrogated by a drafting committee, with subsequent review and discussion by a wider expert committee leading to the formulation of an updated consensus statement. These committees also included patients with RA. Results The new statement covers wide-ranging issues including the use of rituximab in earlier RA and impact on structural progression, and aspects particularly pertinent to rituximab such as co-medication, optimal dosage regimens, repeat treatment cycles and how to manage non-response. Biological therapy following rituximab usage is also addressed, and safety concerns including appropriate screening for hepatitis, immunoglobulin levels and infection risk. This consensus statement will support clinicians and inform patients when using B-cell depletion in the management of RA, providing up-to-date information and highlighting areas for further research. Conclusion New therapeutic strategies and treatment options for RA, a chronic destructive and disabling disease, have expanded over recent years. These have been summarised in general strategic suggestions and specific management recommendations, emphasising the importance of expedient disease-modifying antirheumatic drug implementation and tight disease control. This consensus statement is in line with these fundamental principles of management

Rituximab versus tocilizumab and b-cell status in tnf-alpha inadequate-responder rheumatoid arthritis patients: the r4-ra rct

Background Although biological therapies have transformed the outlook for those with rheumatoid arthritis, there is a lack of any meaningful response in approximately 40% of patients. The role of B cells in rheumatoid arthritis pathogenesis is well recognised and is supported by the clinical efficacy of the B-cell-depleting agent rituximab (MabThera, F. Hoffman La-Roche Ltd, Basel, Switzerland). Rituximab is licensed for use in rheumatoid arthritis following failure of conventional synthetic disease-modifying antirheumatic drugs and tumour necrosis factor inhibitor therapy. However, over 50% of patients show low/absent synovial B-cell infiltration, suggesting that, in these patients, inflammation is driven by alternative cell types. This prompted us to test the hypothesis that, in synovial biopsy B-cell-poor patients, tocilizumab (RoActemra, F. Hoffman La-Roche Ltd, Basel, Switzerland) (targeting interleukin 6) is superior to rituximab (targeting CD20+/B cells). Design The R4–RA (A Randomised, open-labelled study in anti-TNFalpha inadequate responders to investigate the mechanisms for Response, Resistance to Rituximab versus Tocilizumab in Rheumatoid Arthritis patients) trial is a 48-week Phase IV, open-label, randomised controlled trial conducted in 19 European centres that recruited patients failing on or intolerant to conventional synthetic disease-modifying antirheumatic drug therapy and at least one tumour necrosis factor inhibitor. Participants Synovial tissue was obtained at trial entry and classified histologically as B-cell rich or B-cell poor to inform balanced stratification. Patients were randomised on a 1 : 1 basis to receive standard therapy with rituximab or tocilizumab. B-cell-poor/-rich molecular classification was also carried out. The study was powered to test the superiority of tocilizumab over rituximab at 16 weeks in the B-cell-poor population. Main outcome measures The primary end point was defined as an improvement in the Clinical Disease Activity Index (CDAI) score of ≥ 50% from baseline. In addition, patients were considered to be non-responders if they did not reach an improvement in CDAI score of ≥ 50% and a CDAI score of < 10.1, defined for simplicity as CDAI major treatment response (CDAI-MTR). Secondary outcomes included the assessment of CDAI response in the B-cell-rich cohort, in which the non-inferiority of rituximab compared with tocilizumab was evaluated. Safety data up to week 48 are reported. Results In total, 164 patients were randomised: 83 patients received rituximab and 81 received tocilizumab. Eighty-one out of 83 rituximab patients and 73 out of 81 tocilizumab patients completed treatment up to week 16 (primary end point). Baseline characteristics were comparable between the treatment groups. In the histologically classified B-cell-poor population (n = 79), no significant difference was observed in the primary outcome, an improvement in CDAI score of ≥ 50% from baseline (risk ratio 1.25, 95% confidence interval 0.80 to 1.96). A supplementary analysis of the CDAI-MTR, however, did reach statistical significance (risk ratio 1.96, 95% confidence interval 1.01 to 3.78). In addition, when B-cell-poor classification was determined molecularly, both the primary end point and the CDAI-MTR were statistically significant (risk ratio 1.72, 95% confidence interval 1.02 to 2.91, and risk ratio 4.12, 95% confidence interval 1.55 to 11.01, respectively). Moreover, a larger number of secondary end points achieved significance when classified molecularly than when classified histologically. In the B-cell-rich population, there was no significant difference between treatments in the majority of both primary and secondary end points. There were more adverse events and serious adverse events, such as infections, in the tocilizumab group than in the rituximab group. Conclusion To our knowledge, this is the first biopsy-based, multicentre, randomised controlled trial of rheumatoid arthritis. We were unable to demonstrate that tocilizumab was more effective than rituximab in patients with a B-cell-poor pathotype in our primary analysis. However, superiority was shown in most of the supplementary and secondary analyses using a molecular classification. These analyses overcame possible unavoidable weaknesses in our original study plan, in which the histological method of determining B-cell status may have misclassified some participants and our chosen primary outcome was insufficiently sensitive. Given the significant results observed using the molecular classification, future research will focus on refining this stratification method and evaluating its clinical utility

Unmet need in rheumatology: reports from the Advances in Targeted Therapies meeting, 2023

The Advances in Targeted Therapies meets annually, convening experts in the field of rheumatology to both provide scientific updates and identify existing scientific gaps within the field. To review the major unmet scientific needs in rheumatology. The 23rd annual Advances in Targeted Therapies meeting convened with more than 100 international basic scientists and clinical researchers in rheumatology, immunology, infectious diseases, epidemiology, molecular biology and other specialties relating to all aspects of immune-mediated inflammatory diseases. We held breakout sessions in five rheumatological disease-specific groups including: rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpa), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and vasculitis, and osteoarthritis (OA). In each group, experts were asked to identify and prioritise current unmet needs in clinical and translational research. An overarching theme across all disease states is the continued need for clinical trial design innovation with regard to therapeutics, endpoint and disease endotypes. Within RA, unmet needs comprise molecular classification of disease pathogenesis and activity, pre-/early RA strategies, more refined pain profiling and innovative trials designs to deliver on precision medicine. Continued scientific questions within PsA include evaluating the genetic, immunophenotypic, clinical signatures that predict development of PsA in patients with psoriasis, and the evaluation of combination therapies for difficult-to-treat disease. For axSpA, there continues to be the need to understand the role of interleukin-23 (IL-23) in pathogenesis and the genetic relationship of the IL-23-receptor polymorphism with other related systemic inflammatory diseases (eg, inflammatory bowel disease). A major unmet need in the OA field remains the need to develop the ability to reliably phenotype and stratify patients for inclusion in clinical trials. SLE experts identified a number of unmet needs within clinical trial design including the need for allowing endpoints that reflect pharmacodynamic/functional outcomes (eg, inhibition of type I interferon pathway activation; changes in urine biomarkers). Lastly, within SSc and vasculitis, there is a lack of biomarkers that predict response or disease progression, and that allow patients to be stratified for therapies. There remains a strong need to innovate clinical trial design, to identify systemic and tissue-level biomarkers that predict progression or response to therapy, endotype disease, and to continue developing therapies and therapeutic strategies for those with treatment-refractory disease. This document, based on expert consensus, should provide a roadmap for prioritising scientific endeavour in the field of rheumatology.Pathophysiology and treatment of rheumatic disease

The 2024 British Society for Rheumatology guideline for management of systemic sclerosis

This guideline was developed according to the British Society for Rheumatology Guidelines Protocol by a Guideline Development Group comprising healthcare professionals with expertise in SSc and people with lived experience, as well as patient organization representatives. It is an update of the previous 2015 SSc guideline. The recommendations were developed and agreed by the group and are underpinned by published evidence, assessed by systematic literature review and reinforced by collective expert opinion of the group. It considers all aspects of SSc including general management, treatment of organ-based complications, including cardiopulmonary, renal and gastrointestinal tract manifestations, as well as broader impact of disease. Whilst it is focused on adults with SSc we expect that the guideline will be relevant to people of all ages and expert input and review by paediatric rheumatologists and other relevant specialists considered where the guideline was, or may not be, applicable to young people with SSc and juvenile-onset disease. In addition to providing guidance on disease assessment and management the full guideline also considers service organization within the National Health Service and future approaches to audit of the guideline. The lay summary that accompanies this abstract can be found in Supplemental information 1

The 2024 British Society for Rheumatology guideline for management of systemic sclerosis—executive summary

This guideline was developed according to the British Society for Rheumatology Guidelines Protocol by a Guideline Development Group comprising healthcare professionals with expertise in SSc and people with lived experience, as well as patient organization representatives. It is an update of the previous 2015 SSc guideline. The recommendations were developed and agreed by the group and are underpinned by published evidence, assessed by systematic literature review and reinforced by collective expert opinion of the group. It considers all aspects of SSc including general management, treatment of organ-based complications, including cardiopulmonary, renal and gastrointestinal tract manifestations, as well as broader impact of disease. Whilst it is focused on adults with SSc we expect that the guideline will be relevant to people of all ages and expert input and review by paediatric rheumatologists and other relevant specialists considered where the guideline was, or may not be, applicable to young people with SSc and juvenile-onset disease. In addition to providing guidance on disease assessment and management the full guideline also considers service organization within the National Health Service and future approaches to audit of the guideline. The lay summary that accompanies this abstract can be found in Supplemental information 1

EULAR definition of difficult-to-treat rheumatoid arthritis

Background: Despite treatment according to the current management recommendations, a significant proportion of patients with rheumatoid arthritis (RA) remain symptomatic. These patients can be considered to have ‘difficult-to-treat RA’. However, uniform terminology and an appropriate definition are lacking. Objective: The Task Force in charge of the „Development of EULAR recommendations for the comprehensive management of difficult-to-treat rheumatoid arthritis” aims to create recommendations for this underserved patient group. Herein, we present the definition of difficult-to treat RA, as the first step. Methods: The Steering Committee drafted a definition with suggested terminology based on an international survey among rheumatologists. This was discussed and amended by the Task Force, including rheumatologists, nurses, health professionals and patients, at a face-to-face meeting until sufficient agreement was reached (assessed through voting). Results: The following three criteria were agreed by all Task Force members as mandatory elements of the definition of difficult-to-treat RA: 1) Treatment according to EULAR rec-ommendation and failure of ≥2 b/tsDMARDs (with different mechanisms of action) after failing csDMARD therapy (unless contraindicated); 2) presence of at least one of the follow-ing: at least moderate disease activity; signs and/or symptoms suggestive of active disease; inability to taper glucocorticoid treatment; rapid radiographic progression; RA symptoms that are causing a reduction in quality of life; 3) the management of signs and/or symptoms is perceived as problematic by the rheumatologist and/or the patient. Conclusions: The proposed EULAR definition for difficult-to-treat RA can be used in clinical practice, clinical trials and can form a basis for future research

EULAR points to consider for the management of difficult-to-treat rheumatoid arthritis

Objective: To develop evidence-based European Alliance of Associations for Rheumatology (EULAR) points to consider (PtCs) for the management of difficult-to-treat rheumatoid arthritis (D2T RA). Methods: A EULAR Task Force was established comprising 34 individuals: 26 rheumatologists, patient partners and rheumatology experienced health professionals. Two systematic literature reviews addressed clinical questions around diagnostic challenges, and pharmacological and non-pharmacological therapeutic strategies in D2T RA. PtCs were formulated based on the identified evidence and expert opinion. Strength of recommendations (SoR, scale A-D: A typically consistent level 1 studies, D level 5 evidence or inconsistent studies) and level of agreement (LoA, scale 0-10: 0 completely disagree, 10 completely agree) of the PtCs were determined by the Task Force members. Results: Two overarching principles and eleven PtCs were defined concerning diagnostic confirmation of RA, evaluation of inflammatory disease activity, pharmacological and nonpharmacological interventions, treatment adherence, functional disability, pain, fatigue, goal setting and self-efficacy and the impact of comorbidities. The SoR varied from level C to D. The mean LoA with the overarching principles and PtCs was generally high (8.4-9.6). Conclusions: These points to consider for D2T RA can serve as a clinical roadmap to support healthcare professionals and patients to deliver holistic management and more personalised pharmacological and non-pharmacological therapeutic strategies. High-quality evidence was scarce. A research agenda was created to guide future research