Vascular disease persistence in giant cell arteritis: are stromal cells neglected?

Giant cell arteritis (GCA), the most common systemic vasculitis, is characterised by aberrant interactions between infiltrating and resident cells of the vessel wall. Ageing and breach of tolerance are prerequisites for GCA development, resulting in dendritic and T-cell dysfunction. Inflammatory cytokines polarise T-cells, activate resident macrophages and synergistically enhance vascular inflammation, providing a loop of autoreactivity. These events originate in the adventitia, commonly regarded as the biological epicentre of the vessel wall, with additional recruitment of cells that infiltrate and migrate towards the intima. Thus, GCA-vessels exhibit infiltrates across the vascular layers, with various cytokines and growth factors amplifying the pathogenic process. These events activate ineffective repair mechanisms, where dysfunctional vascular smooth muscle cells and fibroblasts phenotypically shift along their lineage and colonise the intima. While high-dose glucocorticoids broadly suppress these inflammatory events, they cause well known deleterious effects. Despite the emerging targeted therapeutics, disease relapse remains common, affecting >50% of patients. This may reflect a discrepancy between systemic and local mediators of inflammation. Indeed, temporal arteries and aortas of GCA-patients can show immune-mediated abnormalities, despite the treatment induced clinical remission. The mechanisms of persistence of vascular disease in GCA remain elusive. Studies in other chronic inflammatory diseases point to the fibroblasts (and their lineage cells including myofibroblasts) as possible orchestrators or even effectors of disease chronicity through interactions with immune cells. Here, we critically review the contribution of immune and stromal cells to GCA pathogenesis and analyse the molecular mechanisms by which these would underpin the persistence of vascular disease.

A real-world assessment of mycophenolate mofetil for remission induction in eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a form of ANCA-associated vasculitis (AAV). Clinical trials demonstrating the efficacy of mycophenolate mofetil (MMF) for remission induction in AAV excluded patients with EGPA. Despite this, MMF is commonly used in these patients. The objective of this study was to evaluate, for the first time, the effectiveness and tolerance of MMF in EGPA remission induction. A retrospective, two-center, real-world study was conducted in patients with EGPA who received MMF in addition to prednisolone for newly diagnosed or relapsing disease between 2009 and 2019. Baseline, 3-, 6- and 12-month outcome data were extracted from electronic health records. The primary outcome was disease remission, defined as a Birmingham Vasculitis Activity Score of 0 at 6 months. Secondary outcomes included disease relapse, median prednisolone dose at 12 months and drug tolerance. In total, 15 patients (73% male, median age 57) with EGPA (11 newly diagnosed/4 relapsing) were identified. At 6 months, 67% had achieved disease remission. At 12 months, this was maintained (66.7%) and 4 patients had relapsed. All but one patient remained on MMF at study completion and all patients tolerated MMF. Our real-world data suggest that MMF is an effective and well-tolerated agent for achieving disease remission in EGPA. A future randomized controlled trial of MMF in this neglected orphan disease is now warranted.

Quantifying and predicting the effect of anti-TNF therapy on axSpA-related fatigue: results from the BSRBR-AS registry and meta-analysis.

OBJECTIVES: Effective management of axial spondyloarthritis (axSpA)-related fatigue is a major unmet clinical need. Anti-TNF therapy may reduce fatigue levels, although any effect has yet to be definitively quantified and predictors of any such improvements are unknown. METHODS: The British Society of Rheumatology Register in Axial Spondyloarthritis (BSRBR-AS) prospectively recruited axSpA patients across the UK. Changes in fatigue levels (measured using the Chalder Fatigue Scale) >1 year were compared between those starting anti-TNF therapy at the time of recruitment and those not. Differences between treatment groups were adjusted using propensity score matching. Results were meta-analysed with the extant literature to calculate pooled estimates. Then, among those BSRBR-AS anti-TNF commencers with clinically relevant fatigue, baseline predictors of response were investigated. RESULTS: Of the 998 BSRBR-AS recruits with complete fatigue data, 310 were anti-TNF commencers. At 1-year follow-up, the former group reported a mean fatigue change of -2.6 (95% CI -4.1, -1.9) points while the latter reported a mean worsening of fatigue by 0.2 points. Following propensity score adjustment, those commencing anti-TNF therapy reduced fatigue by 3.0 points compared with those not. Of those with significant fatigue and commencing anti-TNF, poor sleep quality at baseline predicted fatigue improvement. In the meta-analysis, including 1109 subjects, treatment with anti-TNF therapy resulted in a significant improvement in fatigue [Standardized mean difference (SMD) = 0.36, 95% CI 0.15, 1.56]. CONCLUSION: Anti-TNF therapy results in a significant but modest reduction in fatigue amongst axSpA patients, with those reporting poor sleep quality most likely to report improvement. Effective management will likely require additional approaches.

Large-vessel vasculitis.

Large-vessel vasculitis (LVV) manifests as inflammation of the aorta and its major branches and is the most common primary vasculitis in adults. LVV comprises two distinct conditions, giant cell arteritis and Takayasu arteritis, although the phenotypic spectrum of primary LVV is complex. Non-specific symptoms often predominate and so patients with LVV present to a range of health-care providers and settings. Rapid diagnosis, specialist referral and early treatment are key to good patient outcomes. Unfortunately, disease relapse remains common and chronic vascular complications are a source of considerable morbidity. Although accurate monitoring of disease activity is challenging, progress in vascular imaging techniques and the measurement of laboratory biomarkers may facilitate better matching of treatment intensity with disease activity. Further, advances in our understanding of disease pathophysiology have paved the way for novel biologic treatments that target important mediators of disease in both giant cell arteritis and Takayasu arteritis. This work has highlighted the substantial heterogeneity present within LVV and the importance of an individualized therapeutic approach. Future work will focus on understanding the mechanisms of persisting vascular inflammation, which will inform the development of increasingly sophisticated imaging technologies. Together, these will enable better disease prognostication, limit treatment-associated adverse effects, and facilitate targeted development and use of novel therapies.

Risk Factors for Severe Outcomes in Patients With Systemic Vasculitis and COVID-19: A Binational, Registry-Based Cohort Study.

OBJECTIVE: COVID-19 is a novel infectious disease with a broad spectrum of clinical severity. Patients with systemic vasculitis have an increased risk of serious infections and may be at risk of severe outcomes following COVID-19. We undertook this study to establish the risk factors for severe COVID-19 outcomes in these patients, including the impact of immunosuppressive therapies. METHODS: A multicenter cohort was developed through the participation of centers affiliated with national UK and Ireland vasculitis registries. Clinical characteristics and outcomes are described. Logistic regression was used to evaluate associations between potential risk factors and a severe COVID-19 outcome, defined as a requirement for advanced oxygen therapy, a requirement for invasive ventilation, or death. RESULTS: The cohort included 65 patients with systemic vasculitis who developed COVID-19 (median age 70 years, 49% women), of whom 25 patients (38%) experienced a severe outcome. Most patients (55 of 65 [85%]) had antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Almost all patients required hospitalization (59 of 65 [91%]), 7 patients (11%) were admitted to intensive care, and 18 patients (28%) died. Background glucocorticoid therapy was associated with severe outcomes (adjusted odds ratio [OR] 3.7 [95% confidence interval 1.1-14.9]; P = 0.047), as was comorbid respiratory disease (adjusted OR 7.5 [95% confidence interval 1.9-38.2]; P = 0.006). Vasculitis disease activity and nonglucocorticoid immunosuppressive therapy were not associated with severe outcomes. CONCLUSION: In patients with systemic vasculitis, glucocorticoid use at presentation and comorbid respiratory disease were associated with severe outcomes in COVID-19. These data can inform clinical decision-making relating to the risk of severe COVID-19 in this vulnerable patient group.

Stratified glucocorticoid monotherapy is safe and effective for most cases of giant cell arteritis.

OBJECTIVES: High-dose glucocorticoids anchor standard care in GCA but are associated with significant toxicity. We aimed to evaluate the safety and effectiveness of a stratified approach to glucocorticoid tapering. The strategy aggressively reduced glucocorticoid doses in those manifesting an adequate early response to treatment, with a view to minimizing glucocorticoid complications. METHODS: A retrospective, population-based study of GCA was performed. All cases were confirmed by temporal artery biopsy between November 2010 and November 2015. Baseline and outcome data were extracted from secondary and primary care records at diagnosis and 1 year follow-up. The primary outcome was loss of vision. Secondary outcomes included remission and relapse rates and CS-related complications. RESULTS: The cohort consisted of 73 patients (76% female; mean age 73.5 years, s.d. 7.6 years). At presentation, a reduction in visual acuity was recorded in 17 patients (22.3%). The median CRP at diagnosis was 69.5 mg/l [interquartile range (IQR) 40.5-101 mg/l], with a median ESR of 80 mm/h (IQR 60-91 mm/h). At 1 year, remission was achieved in 64 patients (87.7%), whereas 10 patients (13.7%) relapsed. A single patient sustained visual loss after initiation of therapy. The median CRP at 1 year was 4 mg/l (IQR 4-9.5 mg/l) and the mean prednisolone dose was 5.4 mg (0-15 mg). CS-related complications were observed in 10 patients (13.7%). CONCLUSION: A stratified approach to CS tapering appeared safe and effective in GCA. It was associated with a high rate of remission and promisingly low rates of relapse at 1 year follow-up. These real-world data indicate that glucocorticoid exposure can be minimized safely in some patients with GCA.

Evaluation of adjunctive mycophenolate for large vessel giant cell arteritis.

OBJECTIVES: GCA patients with large vessel involvement (LV-GCA) experience greater CS requirements and higher relapse rates compared with classical cranial GCA. Despite the distinct disease course, interventions in LV-GCA have yet to be investigated specifically. This study aimed to evaluate the CS-sparing effect and tolerability of first-line mycophenolate in LV-GCA. METHODS: A retrospective cohort study was conducted in patients with LV-GCA identified from a regional clinical database between 2005 and 2019. All cases were prescribed mycophenolate derivatives (MYC; MMF or mycophenolic acid) at diagnosis and were followed up for ≥2 years. The primary outcome was the cumulative CS dose at 1 year. Secondary outcomes included MYC tolerance, relapse rates and CRP levels at 1 and 2 years. RESULTS: A total of 37 patients (65% female; mean age 69.4 years, SD 7.9 years) were identified. All cases demonstrated large vessel involvement via CT/PET (n = 34), CT angiography (n = 5) or magnetic resonance angiography (n = 2). After 2 years, 31 patients remained on MYC, whereas 6 had switched to MTX or tocilizumab owing to significant disease relapse. The mean (±SD) cumulative prednisolone dose at 1 year was 4960 (±1621) mg. Relapse rates at 1 and 2 years were 16.2 and 27%, respectively, and CRP levels at 1 and 2 years were 4 [interquartile range (IQR) 4-6] and 4 (IQR 4-4) mg/l, respectively. CONCLUSION: To our knowledge, this is the first attempt to assess the effectiveness of any specific agent in LV-GCA. MYC might be both effective in reducing CS exposure and well tolerated in this subpopulation. A future randomized controlled trial is warranted.