Monocyte and macrophage heterogeneity in Giant Cell Arteritis and Polymyalgia Rheumatica:central in Pathology and a Source of Clinically Relevant Biomarkers

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are chronic inflammatory diseases that frequently overlap and often require long-term treatment with prednisolone. Prednisolone is a drug that suppresses the immune system, but also has serious side effects. GCA and PMR patients suffer from inflammation in their arteries (vasculitis) and joints, respectively. White blood cells such as macrophages play a major role in the initiation and continuation of inflammation. To find new clues for treatment, this thesis focuses on the involvement of macrophages, and on their blood monocyte precursors in these diseases. Both monocytes and macrophages consist of various subtypes that can be distinguished by phenotype (the way they look) and function (the way they behave). We implicated macrophage subtypes, and their likely monocyte precursors, in the development of vasculitis and destruction of the arterial wall. Macrophages in affected tissues also release numerous factors, which can be measured in the blood of patients. We discovered that one of these factors, angiopoietin-2, could aid in detecting vasculitis (GCA) in PMR patients. This is important for patients as GCA is associated with severe complications such as vision loss and aortic rupture. Using these factors in follow-up studies of patients also revealed that the disease may be still ongoing in affected tissues, despite treatment with prednisolone. Finally, we also discovered a profile of factors in the blood that could predict whether GCA and PMR patients require short- or long-term treatment with prednisolone, thereby reducing the side effects in individual patients

Biomarkers in the era of targeted therapy in giant cell arteritis and polymyalgia rheumatica:is it possible to replace acute-phase reactants?

Research into giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) has become more important in the last few decades. Physicians are facing several challenges in managing the diagnosis, treatment, and relapses of GCA and PMR patients. The search for biomarkers could provide elements to guide a physician’s decision. In this review, we aim to summarize the scientific publications about biomarkers in GCA and PMR in the past decade. The first point raised by this review is the number of clinical situations in which biomarkers could be useful: differential diagnosis of either GCA or PMR, diagnosis of underlying vasculitis in PMR, prediction of relapse or complications, disease activity monitoring, choice, and modification of treatments. The second point raised by this review is the large number of biomarkers studied, from common markers like C-reactive protein, erythrocyte sedimentation rate, or elements of blood count to inflammatory cytokines, growth factors, or immune cell subpopulations. Finally, this review underlines the heterogeneity between the studies and proposes points to consider in studies evaluating biomarkers in general and particularly in the case of GCA and PMR.</p

Need and value of targeted immunosuppressive therapy in giant cell arteritis

Despite the heterogeneity of the giant cell arteritis (GCA) at the level of clinical manifestations and the cellular and molecular players involved in its pathogenesis, GCA is still treated with standardised regimens largely based on glucocorticoids (GC). Long-term use of high dosages of GC as required in GCA are associated with many clinically relevant side effects. In the recent years, the interleukin-6 receptor blocker tocilizumab has become available as the only registered targeted immunosuppressive agent in GCA. However, immunological heterogeneity may require different pathways to be targeted in order to achieve a clinical, immunological and vascular remission in GCA. The advances in the targeted blockade of various molecular pathways involved in other inflammatory and autoimmune diseases have catalyzed the research on targeted therapy in GCA. This article gives an overview of the studies with targeted immunosuppressive treatments in GCA, with a focus on their clinical value, including their effects at the level of vascular inflammation

Effect of DMARDs on the immunogenicity of vaccines

Vaccines are important for protecting individuals at increased risk of severe infections, including patients undergoing DMARD therapy. However, DMARD therapy can also compromise the immune system, leading to impaired responses to vaccination. This Review focuses on the impact of DMARDs on influenza and SARS-CoV-2 vaccinations, as such vaccines have been investigated most thoroughly. Various data suggest that B cell depletion therapy, mycophenolate mofetil, cyclophosphamide, azathioprine and abatacept substantially reduce the immunogenicity of these vaccines. However, the effects of glucocorticoids, methotrexate, TNF inhibitors and JAK inhibitors on vaccine responses remain unclear and could depend on the dosage and type of vaccination. Vaccination is aimed at initiating robust humoral and cellular vaccine responses, which requires efficient interactions between antigen-presenting cells, T cells and B cells. DMARDs impair these cells in different ways and to different degrees, such as the prevention of antigen-presenting cell maturation, alteration of T cell differentiation and selective inhibition of B cell subsets, thus inhibiting processes that are necessary for an effective vaccine response. Innovative modified vaccination strategies are needed to improve vaccination responses in patients undergoing DMARD therapy and to protect these patients from the severe outcomes of infectious diseases.</p

Effect of DMARDs on the immunogenicity of vaccines

Vaccines are important for protecting individuals at increased risk of severe infections, including patients undergoing DMARD therapy. However, DMARD therapy can also compromise the immune system, leading to impaired responses to vaccination. This Review focuses on the impact of DMARDs on influenza and SARS-CoV-2 vaccinations, as such vaccines have been investigated most thoroughly. Various data suggest that B cell depletion therapy, mycophenolate mofetil, cyclophosphamide, azathioprine and abatacept substantially reduce the immunogenicity of these vaccines. However, the effects of glucocorticoids, methotrexate, TNF inhibitors and JAK inhibitors on vaccine responses remain unclear and could depend on the dosage and type of vaccination. Vaccination is aimed at initiating robust humoral and cellular vaccine responses, which requires efficient interactions between antigen-presenting cells, T cells and B cells. DMARDs impair these cells in different ways and to different degrees, such as the prevention of antigen-presenting cell maturation, alteration of T cell differentiation and selective inhibition of B cell subsets, thus inhibiting processes that are necessary for an effective vaccine response. Innovative modified vaccination strategies are needed to improve vaccination responses in patients undergoing DMARD therapy and to protect these patients from the severe outcomes of infectious diseases.</p

Effect of DMARDs on the immunogenicity of vaccines

Vaccines are important for protecting individuals at increased risk of severe infections, including patients undergoing DMARD therapy. However, DMARD therapy can also compromise the immune system, leading to impaired responses to vaccination. This Review focuses on the impact of DMARDs on influenza and SARS-CoV-2 vaccinations, as such vaccines have been investigated most thoroughly. Various data suggest that B cell depletion therapy, mycophenolate mofetil, cyclophosphamide, azathioprine and abatacept substantially reduce the immunogenicity of these vaccines. However, the effects of glucocorticoids, methotrexate, TNF inhibitors and JAK inhibitors on vaccine responses remain unclear and could depend on the dosage and type of vaccination. Vaccination is aimed at initiating robust humoral and cellular vaccine responses, which requires efficient interactions between antigen-presenting cells, T cells and B cells. DMARDs impair these cells in different ways and to different degrees, such as the prevention of antigen-presenting cell maturation, alteration of T cell differentiation and selective inhibition of B cell subsets, thus inhibiting processes that are necessary for an effective vaccine response. Innovative modified vaccination strategies are needed to improve vaccination responses in patients undergoing DMARD therapy and to protect these patients from the severe outcomes of infectious diseases.</p

Effect of DMARDs on the immunogenicity of vaccines

Vaccines are important for protecting individuals at increased risk of severe infections, including patients undergoing DMARD therapy. However, DMARD therapy can also compromise the immune system, leading to impaired responses to vaccination. This Review focuses on the impact of DMARDs on influenza and SARS-CoV-2 vaccinations, as such vaccines have been investigated most thoroughly. Various data suggest that B cell depletion therapy, mycophenolate mofetil, cyclophosphamide, azathioprine and abatacept substantially reduce the immunogenicity of these vaccines. However, the effects of glucocorticoids, methotrexate, TNF inhibitors and JAK inhibitors on vaccine responses remain unclear and could depend on the dosage and type of vaccination. Vaccination is aimed at initiating robust humoral and cellular vaccine responses, which requires efficient interactions between antigen-presenting cells, T cells and B cells. DMARDs impair these cells in different ways and to different degrees, such as the prevention of antigen-presenting cell maturation, alteration of T cell differentiation and selective inhibition of B cell subsets, thus inhibiting processes that are necessary for an effective vaccine response. Innovative modified vaccination strategies are needed to improve vaccination responses in patients undergoing DMARD therapy and to protect these patients from the severe outcomes of infectious diseases.</p

Effect of DMARDs on the immunogenicity of vaccines

Vaccines are important for protecting individuals at increased risk of severe infections, including patients undergoing DMARD therapy. However, DMARD therapy can also compromise the immune system, leading to impaired responses to vaccination. This Review focuses on the impact of DMARDs on influenza and SARS-CoV-2 vaccinations, as such vaccines have been investigated most thoroughly. Various data suggest that B cell depletion therapy, mycophenolate mofetil, cyclophosphamide, azathioprine and abatacept substantially reduce the immunogenicity of these vaccines. However, the effects of glucocorticoids, methotrexate, TNF inhibitors and JAK inhibitors on vaccine responses remain unclear and could depend on the dosage and type of vaccination. Vaccination is aimed at initiating robust humoral and cellular vaccine responses, which requires efficient interactions between antigen-presenting cells, T cells and B cells. DMARDs impair these cells in different ways and to different degrees, such as the prevention of antigen-presenting cell maturation, alteration of T cell differentiation and selective inhibition of B cell subsets, thus inhibiting processes that are necessary for an effective vaccine response. Innovative modified vaccination strategies are needed to improve vaccination responses in patients undergoing DMARD therapy and to protect these patients from the severe outcomes of infectious diseases.</p

Effect of DMARDs on the immunogenicity of vaccines

Vaccines are important for protecting individuals at increased risk of severe infections, including patients undergoing DMARD therapy. However, DMARD therapy can also compromise the immune system, leading to impaired responses to vaccination. This Review focuses on the impact of DMARDs on influenza and SARS-CoV-2 vaccinations, as such vaccines have been investigated most thoroughly. Various data suggest that B cell depletion therapy, mycophenolate mofetil, cyclophosphamide, azathioprine and abatacept substantially reduce the immunogenicity of these vaccines. However, the effects of glucocorticoids, methotrexate, TNF inhibitors and JAK inhibitors on vaccine responses remain unclear and could depend on the dosage and type of vaccination. Vaccination is aimed at initiating robust humoral and cellular vaccine responses, which requires efficient interactions between antigen-presenting cells, T cells and B cells. DMARDs impair these cells in different ways and to different degrees, such as the prevention of antigen-presenting cell maturation, alteration of T cell differentiation and selective inhibition of B cell subsets, thus inhibiting processes that are necessary for an effective vaccine response. Innovative modified vaccination strategies are needed to improve vaccination responses in patients undergoing DMARD therapy and to protect these patients from the severe outcomes of infectious diseases.</p

Disease stratification in giant cell arteritis to reduce relapses and prevent long-term vascular damage

For years, clinicians and researchers working on giant cell arteritis have been battling with the conundrum of a disease that displays a short-term steroid responsiveness but is burdened by a remarkable risk of flares and chronic damage in the long term. This issue should be addressed by a change in the direction of research and clinical practice. Evidence suggests that giant cell arteritis is not a monolithic disease; it varies in extent and severity. Hence, treatment should be guided by disease stratification. The current one-size-fits-all strategy leads to overreliance on glucocorticoids and progression of glucocorticoid-related and disease-related complications. A new approach requires disease stratification using clinical, laboratory, histology, and imaging parameters. A giant cell arteritis registry might offer opportunities to scrutinise disease course and prognostic variables early; however, more studies that directly incorporate disease stratification through the above parameters are required. This Series paper also suggests that future clinical trials should be targeted at patients with different disease strata of giant cell arteritis and should incorporate ultrasound, PET-CT scanning, and other imaging modalities as key outcomes