Functionally Heterogenous Macrophage Subsets in the Pathogenesis of Giant Cell Arteritis: Novel Targets for Disease Monitoring and Treatment.
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ABSTRACT:
SUBMITTER: Esen I
PROVIDER: S-EPMC8585092 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Monocytes/macrophages are critical in systemic and local inflammation in giant cell arteritis (GCA) and possibly in clinically overlapping polymyalgia rheumatica (PMR). Therefore, we aimed to understand the contribution of monocyte subsets and the CX3CR1-CX3CL1 and CCR2-CCL2 migratory pathways, to the pathology of GCA. Peripheral blood monocytes were enumerated in samples from newly-diagnosed, untreated GCA and PMR patients and after prednisone-induced remission. The distribution of classical (CD14brightCD16neg) and the more pro-inflammatory, intermediate (CD14brightCD16+) and non-classical (CD14dimCD16+) monocyte subsets was analysed by flow cytometry. The phenotype of macrophages in temporal artery biopsies (TABs) from GCA patients was studied by immunohistochemistry and immunofluorescence. A clear monocytosis was seen in newly diagnosed GCA and PMR patients caused by elevated numbers of classical monocytes. Prednisone treatment suppressed numbers of non-classical monocytes. Both chemokine CX3CL1 and CCL2 were highly expressed in the TAB. Most macrophages in the TAB of GCA patients expressed non-classical monocyte markers CD16 and CX3CR1 whereas co-localisation of CD16 with classical monocyte marker CCR2 was infrequent. In conclusion, we report an altered distribution of monocyte subsets in both GCA and PMR patients. The majority of macrophages in TABs of GCA patients were CD68 + CD16 + CX3CR1 + CCR2- and thereby resembled the phenotype of non-classical monocytes.
| S-EPMC5529580 | biostudies-literature
Project description:ObjectiveIdentify predictors of treatment failure in patients with giant cell arteritis (GCA) receiving tocilizumab in combination with glucocorticoids and in patients with GCA receiving only glucocorticoids.MethodsPosthoc analysis of the Giant-Cell Arteritis Actemra trial including 250 patients who received tocilizumab every week plus a 26-week prednisone taper (n=100), tocilizumab every-other-week plus a 26-week prednisone taper (n=49) or placebo plus a 26-week (n=50) or 52-week (n=51) prednisone taper in the intention-to-treat population. Responders for this analysis were patients who maintained remission (no GCA signs/symptoms and no erythrocyte sedimentation rate elevation) through week 52. Treatment failure was defined as inability to achieve remission by week 12 or relapse between weeks 12 and 52. Predictors investigated in univariate and multivariable analyses included patient characteristics, disease-related and treatment-related factors and patient-reported outcomes (PROs).Results149 patients received tocilizumab plus prednisone (TCZ/PDN) and 101 received placebo plus prednisone (PBO+PDN). After adjustment for confounders, treatment failure was significantly less likely in the TCZ/PDN group than the PBO/PDN group (OR, 0.2; 95% CI, 0.1 to 0.3; p<0.0001). Risk for treatment failure was significantly higher in women than men in the PBO/PDN group (OR, 5.2; 95% CI, 1.6 to 17.2; p=0.007) but not in the TCZ/PDN group. Predictors of treatment failure in the TCZ/PDN group included lower baseline prednisone doses and worse PROs at baseline.ConclusionThe strongest risk factors for treatment failure in GCA are treatment with prednisone alone and female sex. Lower starting prednisone doses and impaired PROs are associated with failure to respond to tocilizumab.Trial registration numberNCT01791153.
| S-EPMC8522464 | biostudies-literature
Project description:Giant cell arteritis (GCA) is the most frequent primary large-vessel vasculitis in individuals older than 50. Glucocorticoids (GCs) are considered the cornerstone of treatment. GC therapy is usually tapered over months according to clinical symptoms and inflammatory marker levels. Considering the high rate of GC-related adverse events in these older individuals, immunosuppressive treatments and biologic agents have been proposed as add-on therapies. Methotrexate was considered an alternative option, but its clinical impact was limited. Other immunosuppressants failed to demonstrate a significant favourable benefit/risk ratio. The approval of tocilizumab, an anti-interleukin 6 (IL-6) receptor inhibitor brought significant improvement. Indeed, tocilizumab had a noticeable effect on cumulative GCs' dose and relapse prevention. After the improvement in pathophysiological knowledge, other targeted therapies have been proposed, with anti-IL-12/23, anti-IL-17, anti-IL-1, anti-cytotoxic T-lymphocyte antigen 4, Janus kinase inhibitors or anti-granulocyte/macrophage colony stimulating factor therapies. These therapies are currently under evaluation. Interestingly, mavrilimumab, ustekinumab and, to a lesser extent, abatacept have shown promising results in phase 2 randomised controlled trials. Despite this recent progress, the value, specific condition and optimal application of each treatment remain undecided. In this review, we discuss the scientific rationale for each treatment and the therapeutic strategy.
| S-EPMC8999932 | biostudies-literature
Project description:GCA, a systemic vasculitis, is characterized by an IL-6-dependent acute-phase response. This response is typically suppressed by treatment rendering CRP/ESR unreliable for monitoring vascular inflammation. Also, there are no accurate biomarkers predicting a non-favourable disease course. Here we investigated macrophage products and markers of angiogenesis as biomarkers for prognosis and monitoring of vascular inflammation. Forty-one newly diagnosed, glucocorticoid-naive GCA patients were prospectively followed for relapses and glucocorticoid requirement for a median of 30 months (range 0-71). Serum markers at baseline and during follow-up were compared with 33 age-matched healthy controls and 13 infection controls. Concentrations of IL-6, serum amyloid A, soluble CD163, calprotectin, YKL-40, VEGF, angiopoietin-1 and -2 and sTie2 were determined by ELISA/Luminex assay. Serum concentrations of all markers, but not angiopoietin-1, were elevated in GCA patients at baseline when compared with healthy controls. High VEGF (P = 0.0025) and angiopoietin-1 (P = 0.0174) and low YKL-40 (P = 0.0369) levels at baseline were predictive of a short time to glucocorticoid-free remission. Elevated angiopoietin-2 levels were associated with an imminent relapse during treatment (P < 0.05). IL-6 correlated strongly with acute-phase markers and soluble CD163 but not with markers of angiogenesis, YKL-40 or calprotectin. Glucocorticoid treatment down-modulated all markers except for calprotectin and YKL-40. Tissue expression of markers in temporal arteries was confirmed. Markers of angiogenesis at baseline and during treatment predict GCA disease course, suggesting utility in patient stratification for glucocorticoid-sparing therapy. Calprotectin and YKL-40 are candidate markers for monitoring vessel wall inflammation.
| S-EPMC6649803 | biostudies-literature
Project description:Background: Giant cell arteritis (GCA) is the most common primary systemic vasculitis predominantly affecting large and medium sized vessels. In rare cases, the vasculitis can affect the vessels of the brain. Results: We describe four cases of GCA with involvement of the cerebral vessels causing stroke. These cases were unresponsive to aggressive immunosuppression and we opted to treat with endovascular balloon dilatation of the stenotic areas. The procedure was safe. The four patients were treated in nine sessions and a total of 16 vessels were treated. We observed two dissections with no clinical influence on the patients. Discussion: In patients with stroke due to progressive GCA that is non-responsive to immunosuppression, endovascular therapy is feasible.
| S-EPMC7177021 | biostudies-literature
Project description:Giant cell arteritis (GCA) is the most common idiopathic systemic vasculitis in persons aged 50 years or greater. Treatment options for GCA, to-date, have been limited and have consisted primarily of glucocorticoids. Significant advances in the understanding of the genetic and cellular mechanisms in GCA are leading to identification of potential pathogenic targets. The recent success of interleukin-6 blockade in the treatment of GCA has opened the landscape to targeted biologic therapy. T cells, particularly T helper 1 and T helper 17 cell lineages have been identified as key inflammatory cells in both active and chronic vascular inflammatory lesions. Therapeutic agents, including abatacept and ustekinumab, which can impede both vasculitogenic cell lines are of particular interest. Inhibition of signalling pathways, including the janus kinase-signal tranducers and activation of transcription (JAK-STAT) and Notch pathways are evolving options. Tocilizumab has shown clear benefit in both newly diagnosed and relapsing patients with GCA and approval of this medication for treatment of GCA has led to rapid incorporation into treatment regimens. More information is required to understand the long-term outcomes of tocilizumab and other investigational targeted therapeutics in the treatment of GCA.
| S-EPMC6383596 | biostudies-literature
Project description:Giant cell arteritis (GCA) is an autoimmune vasculitis affecting large and medium-sized arteries. Ample evidence indicates that GCA is a heterogeneous disease in terms of symptoms, immune pathology, and response to treatment. In the current review, we discuss the evidence for disease subsets in GCA. We describe clinical and immunologic characteristics that may impact the risk of cranial ischemic symptoms, relapse rates, and long-term glucocorticoid requirements in patients with GCA. In addition, we discuss both proven and putative immunologic targets for therapy in patients with GCA who have an unfavorable prognosis. Finally, we provide recommendations for further research on disease subsets in GCA.
| S-EPMC6175064 | biostudies-literature
Project description:The peritoneal cavity (PerC) is a unique compartment within which a variety of immune cells reside, and from which macrophages (MØ) are commonly drawn for functional studies. Here we define two MØ subsets that coexist in PerC in adult mice. One, provisionally called the large peritoneal MØ (LPM), contains approximately 90% of the PerC MØ in unstimulated animals but disappears rapidly from PerC following lipopolysaccharide (LPS) or thioglycolate stimulation. These cells express high levels of the canonical MØ surface markers, CD11b and F4/80. The second subset, referred to as small peritoneal MØ (SPM), expresses substantially lower levels of CD11b and F4/80 but expresses high levels of MHC-II, which is not expressed on LPM. SPM, which predominates in PerC after LPS or thioglycolate stimulation, does not derive from LPM. Instead, it derives from blood monocytes that rapidly enter the PerC after stimulation and differentiate to mature SPM within 2 to 4 d. Both subsets show clear phagocytic activity and both produce nitric oxide (NO) in response to LPS stimulation in vivo. However, their responses to LPS show key differences: in vitro, LPS stimulates LPM, but not SPM, to produce NO; in vivo, LPS stimulates both subsets to produce NO, albeit with different response patterns. These findings extend current models of MØ heterogeneity and shed new light on PerC MØ diversity, development, and function. Thus, they introduce a new context for interpreting (and reinterpreting) data from ex vivo studies with PerC MØ.
| S-EPMC2823920 | biostudies-literature
Project description:Glucocorticoids remain the cornerstone of medical therapy in giant cell arteritis (GCA) and should be started immediately to prevent severe consequences of the disease, such as blindness. However, glucocorticoid therapy leads to significant toxicity in over 80% of the patients. Various steroid-sparing agents have been tried, but robust scientific evidence of their efficacy and safety is still lacking. Tocilizumab, a monoclonal IL-6 receptor blocker, has shown promising results in a number of case series and is now being tested in a multi-centre randomized controlled trial. Other targeted treatments, such as the use of abatacept, are also now under investigation in GCA. The need for surgical treatment is rare and should ideally be performed in a quiescent phase of the disease. Not all patients follow the same course, but there are no valid biomarkers to assess therapy response. Monitoring of disease progress still relies on assessing clinical features and measuring inflammatory markers (C-reactive protein and erythrocyte sedimentation rate). Imaging techniques (e.g., ultrasound) are clearly important screening tools for aortic aneurysms and assessing patients with large-vessel involvement, but may also have an important role as biomarkers of disease activity over time or in response to therapy. Although GCA is the most common form of primary vasculitis, the optimal strategies for treatment and monitoring remain uncertain.
| S-EPMC4468893 | biostudies-other
Project description:Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are two interrelated inflammatory diseases affecting patients above 50 years of age. Patients with GCA suffer from granulomatous inflammation of medium- to large-sized arteries. This inflammation can lead to severe ischemic complications (e.g., irreversible vision loss and stroke) and aneurysm-related complications (such as aortic dissection). On the other hand, patients suffering from PMR present with proximal stiffness and pain due to inflammation of the shoulder and pelvic girdles. PMR is observed in 40-60% of patients with GCA, while up to 21% of patients suffering from PMR are also affected by GCA. Due to the risk of ischemic complications, GCA has to be promptly treated upon clinical suspicion. The treatment of both GCA and PMR still heavily relies on glucocorticoids (GCs), although novel targeted therapies are emerging. Imaging has a central position in the diagnosis of GCA and PMR. While [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) has proven to be a valuable tool for diagnosis of GCA and PMR, it possesses major drawbacks such as unspecific uptake in cells with high glucose metabolism, high background activity in several non-target organs and a decrease of diagnostic accuracy already after a short course of GC treatment. In recent years, our understanding of the immunopathogenesis of GCA and, to some extent, PMR has advanced. In this review, we summarize the current knowledge on the cellular heterogeneity in the immunopathology of GCA/PMR and discuss how recent advances in specific tissue infiltrating leukocyte and stromal cell profiles may be exploited as a source of novel targets for imaging. Finally, we discuss prospective novel PET radiotracers that may be useful for the diagnosis and treatment monitoring in GCA and PMR.
| S-EPMC9207253 | biostudies-literature