Personalised Therapy Based on Immunopathogenesis to Improve Outcome of At-Risk and Established Systemic Lupus Erythematosus

Background: Pathogenesis of systemic lupus erythematosus (SLE) is thought to be closely related to B-cell dysfunction, and accordingly this is the usual target for therapies. However, non-B-cell mechanisms such as tumour necrosis factor (TNF) and interferons may also be important in the onset as well as established disease. Objectives: (i) To assess biomarkers of progression from At-Risk (ANA-positive but limited symptoms) to connective tissue disease (AI-CTD); (ii) to identify predictors of non-response and serious infections with rituximab; and (iii) to assess new therapies to overcome rituximab deficiency with respect to anti-rituximab antibodies and B-cell-independent inflammation in discoid lupus erythematosus (DLE). Methods: Prospective observational studies were conducted in (i) At-Risk of AI-CTD and (ii) SLE patients treated with rituximab. Patients with anti-rituximab antibodies were treated with alternative humanised anti-CD20 agents. (iii) A single arm, phase II open label trial of intra-dermal injection of etanercept for remission induction in DLE (TARGET-DLE) was undertaken. Results: (i) Higher IFN-Score-B and a family history of autoimmune rheumatic diseases at baseline were predictive of progression from At-Risk to AI-CTD. (ii) B-cell depletion at 6 weeks post-rituximab was predictive of major response to rituximab and was not associated with increased serious infection post-therapy in SLE. During repeat rituximab cycles, 12% of SLE patients lost depletion, which was attributed to anti-rituximab antibodies. These patients were switched to humanised agents, and all depleted and responded. (iii) For TARGET-DLE, the primary and most of the key secondary endpoints were met. Therapy was tolerable without inducing systemic autoimmunity. Conclusion: In this thesis, a personalised approach to treatment based on immunopathogenesis in At-Risk and established SLE led to better outcomes for patients. The predictive values of the biomarkers presented may allow stratification of patients for disease progression. While results from the use of novel therapies presented support further development in multi-centre trials

Repeat cycles of rituximab on clinical relapse in ANCA-associated vasculitis: identifying B cell biomarkers for relapse to guide retreatment decisions

OBJECTIVE: To assess clinical and B cell biomarkers to predict relapse after rituximab in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) using retreatment on clinical relapse strategy. METHODS: 35 patients with AAV received treatment with 2×1000 mg rituximab, repeated on clinical relapse (up to 5 cycles). Disease activity was assessed by Birmingham Vasculitis Activity Score (BVAS) and peripheral B cell subsets using highly sensitive flow cytometry (HSFC) as previously described; both performed at baseline and every 3 months. RESULTS: Response rates were high: >83%, with median time-to-relapse of 82 weeks for cycle 1 (C1) and >54 weeks for all cycles. Prior to rituximab, AAV was characterised by naïve B-lymphopenia compared to healthy controls. This dysregulation was more marked in patients with raised C-reactive protein (CRP) (p<0.05). In C1, no clinical feature predicted relapse. However, repopulation of naïve B cell at 6 months was associated with a reduced risk of relapse (HR: 0.326, 95% 0.114 to 0.930, p=0.036). Relapse rates at 12 and 18 months were 0% and 14% with naïve repopulation at 6 months, and 31% and 54% without naïve repopulation. CONCLUSIONS: Responses to B cell depletion therapy are long-lasting and relapse post-treatment may be predicted by absence of naïve B cell repopulation at 6 months. Naïve B-lymphopenia may be a biomarker of disease activity in AAV

Ultrasound to identify systemic lupus erythematosus patients with musculoskeletal symptoms who respond best to therapy: the US Evaluation For mUsculoskeletal Lupus longitudinal multicentre study

Abstract Objective To determine whether SLE patients with inflammatory joint symptoms and ultrasound-synovitis/tenosyovitis achieve better clinical responses to glucocorticoid compared with patients with normal scans. Secondary objectives included identification of clinical features predicting ultrasound-synovitis/tenosynovitis. Methods In a longitudinal muticentre study, SLE patients with physician-diagnosed inflammatory joint pain received intramuscular methylprednisolone 120 mg once. Clinical assessments, patient-reported outcomes, and bilateral hands/wrist ultrasound were collected at 0-, 2- and 6-weeks. The primary outcome (determined via internal pilot) was early morning stiffness visual analogue scale (EMS-VAS) at 2-weeks, adjusted for baseline, comparing patients with positive (Grey-scale ≥2 and/or Power-Doppler ≥1) and negative ultrasound. Post-hoc analyses excluded fibromyalgia. Results Of 133 patients, 78 had positive ultrasound. Only 53/78 (68%) of these had ≥1 swollen joint. Of 66/133 patients with ≥1 swollen joint, 20% had negative ultrasound. Positive ultrasound was associated with joint swelling, symmetrical small joint distribution and serology. The primary end point was not met: in the full analysis set (n = 133) there was no difference in baseline-adjusted EMS-VAS at week-2 (-7.7 mm 95% CI -19.0 mm, 3.5 mm, p= 0.178). After excluding 32 patients with fibromyalgia, response was significantly better in patients with positive ultrasound at baseline (baseline-adjusted EMS-VAS at 2-weeks -12.1 mm, 95% CI -22.2 mm, -0.1 mm, p= 0.049). This difference was greater when adjusted for treatment (-12.8 mm (95% CI -22mm, -3mm), p= 0.007). BILAG and SLEDAI responses were higher in ultrasound-positive patients. Conclusions In SLE patients without fibromyalgia, those with positive ultrasound had better clinical response to therapy. Imaging-detected synovitis/tenosynovitis may be considered to decide on therapy and enrich clinical trials

Recommendations for physical activity and exercise in persons living with Systemic Lupus Erythematosus (SLE): consensus by an international task force

Objective: This international task force aimed to provide healthcare professionals and persons living with systemic lupus erythematosus (SLE) with consensus-based recommendations for physical activity and exercise in SLE. Methods: Based on evidence from a systematic literature review and expert opinion, 3 overarching principles and 15 recommendations were agreed on by Delphi consensus. Results: The overarching principles highlight the importance of shared decision-making and the need to explain the benefits of physical activity to persons living with SLE and other healthcare providers. The 15 specific recommendations state that physical activity is generally recommended for all people with SLE, but in some instances, a medical evaluation may be needed to rule out contraindications. Pertaining to outdoor activity, photoprotection is necessary. Both aerobic and resistance training programmes are recommended, with a gradual increase in frequency and intensity, which should be adapted for each individual, and ideally supervised by qualified professionals. Conclusion: In summary, the consensus reached by the international task force provides a valuable framework for the integration of physical activity and exercise into the management of SLE, offering a tailored evidence-based and eminence-based approach to enhance the well-being of individuals living with this challenging autoimmune condition

Management and treatment of children, young people and adults with systemic lupus erythematosus: British Society for Rheumatology guideline scope

Lay Summary: Systemic lupus erythematosus (SLE) is a lifelong condition in which the immune system damages the body’s own tissues, causing various symptoms including rashes, hair loss, mouth ulcers, joint pain and overwhelming tiredness. It can also affect major organs including the kidneys, heart, lungs and brain. SLE can present during childhood, but most commonly affects young and middle-aged females. It is approximately nine times more common in females than males. The disease can lead to disability, poor quality of life and even death in severe cases. Treatments can often be difficult to tolerate and can cause both short- and long-term side effects. Guidelines developed by the British Society for Rheumatology aim to provide guidance for diagnosing and treating people with SLE. This is necessary to ensure that the most up-to-date approach is followed, utilising the safest and most effective treatments. This article describes the plan for a guideline in SLE that is being updated to cover new evidence that has been published since 2017 relating to the treatment and management of SLE. The guideline will take a whole life course approach, from childhood to adulthood, and is being undertaken by a working group consisting of paediatric and adult rheumatologists and nephrologists, SLE experts, general practitioners, specialist nurses and other healthcare professionals, together with people with SLE and representatives from patient organizations. The guideline will be developed using the methods and processes outlined in the British Society for Rheumatology document ‘Creating Clinical Guidelines: Our Protocol’

Efficacy and safety of obinutuzumab in systemic lupus erythematosus patients with secondary non-response to rituximab.

OBJECTIVES Secondary inefficacy with infusion reactions and anti-drug antibodies (2NDNR) occurs in 14% of SLE patients receiving repeated rituximab courses. We evaluated baseline clinical characteristics, efficacy and safety of obinutuzumab, a next-generation humanised type-2 anti-CD20 antibody licensed for haematological malignancies in SLE patients with 2NDNR to rituximab. METHODS We collated data from SLE patients receiving obinutuzumab for secondary non-response to rituximab in BILAG centres. Disease activity was assessed using BILAG-2004, SLEDAI-2K and serology before, and 6 months after, obinutuzumab 2x1000mg infusions alongside methylprednisolone 100 mg. RESULTS All 9 patients included in the study received obinutuzumab with concomitant oral immunosuppression. At 6 months post-obinutuzumab, there were significant reductions in median SLEDAI-2K from 12 to 6 (p= 0.014) and total BILAG-2004 score from 21 to 2 (p= 0.009). Complement C3 and dsDNA titres improved significantly (both p= 0.04). Numerical, but not statistically significant improvements were seen in C4 levels. Of 8/9 patients receiving concomitant oral prednisolone at baseline (all >10mg/day), 5/8 had their dose reduced at 6 months. 4/9 patients were on 5 mg/day and were in Lupus Low Disease Activity State following obinutuzumab. After obinutuzumab, 6/9 patients with peripheral B cell data achieved complete depletion including 4/4 assessed with highly-sensitive assays. 1/9 obinutuzumab non-responder required cyclophosphamide therapy. 1 unvaccinated patient died from COVID-19. CONCLUSIONS Obinutuzumab appears to be effective and steroid-sparing in renal and non-renal SLE patients with secondary non-response to rituximab. These patients have severe disease with few treatment options but given responsiveness to B cell depletion, switching to humanised type-2 anti-CD20 therapy is a logical approach

Gene expression and autoantibody analysis reveals distinct ancestry-specific profiles associated with response to rituximab in refractory systemic lupus erythematosus

Objective Gene expression profiles are associated with the clinical heterogeneity of SLE but are not well studied as biomarkers for therapy. Many clinical and demographic features influence treatment responses. We studied gene expression and response to rituximab in a multi-ethnic UK cohort refractory to standard therapy. Methods Baseline expression of transcripts known to associate with clinical features of SLE was evaluated in whole blood by 96-probe Taqman® array in patients (n=213) with active SLE, prospectively enrolled in British Isles Lupus Assessment Group (BILAG) Biologics Registry. Autoantibodies were measured using immunoprecipitation and ELISA. Response to first cycle rituximab (n=110) was determined by BILAG-2004 criteria at 6 months. Results Interferon scores were lower in European ancestry patients than all other groups. The relationship between blood interferon scores and plasmablast, neutrophil, myeloid, inflammation and erythropoiesis-annotated scores differed between patients of European and non-European ancestries. Hierarchical clustering revealed 3 distinct non-European ancestry patient subsets with stratified response to rituximab which was not explained by sociodemographic and clinical variables. Response was lowest in an interferon-low, neutrophil-high cluster and highest in a cluster with high expression across all signatures (p<0.001). Clusters within European ancestry patients did not predict response to rituximab but segregated patients by global disease activity and renal involvement. In both ancestral groups, interferon-high clusters associated with U1RNP-Sm antibodies. Conclusion Ancestry appears central to the immunological and clinical heterogeneity in SLE. These results suggest that ancestry, disease activity and transcriptional signatures could each assist predict the effectiveness of B-cell depletion

Primary myocardial disease in scleroderma – a comprehensive review of the literature to inform the UK Systemic Sclerosis Study Group cardiac working group

Cardiac disease is prevalent in Systemic Sclerosis (SSc) and associated with a poor prognosis. Differentiating primary myocardial disease (SSc-cardiomyopathy) from ischaemic heart disease (IHD) is difficult, and the disease phenotype most at risk is unclear. A comprehensive literature review was performed to inform the UK Systemic Sclerosis Study Group for cardiac disease tasked with producing a best practice pathway for the management of cardiac disease in SSc. This review describes the prevalence of SSc-cardiomyopathy, its associated greater mortality, and various manifestations, for example, heart failure, arrhythmias and diastolic dysfunction. The limited evidence suggests SSc-cardiomyopathy is associated with other poor prognostic indicators such as diffuse cutaneous disease, positive SSc-specific serology, black ethnicity, older age at disease onset, tendon friction rubs, abnormal nail-fold capillaroscopy and worse quality of life scores. Differentiating SSc-cardiomyopathy from IHD requires well planned studies. Non-invasive investigative techniques are improving the understanding of its pathophysiological basis