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Profile of tocilizumab and its potential in the treatment of giant cell arteritis.

ABSTRACT: Giant cell arteritis (GCA) remains a medical emergency due to the threat of permanent sight loss. High-dose glucocorticoids (GCs) are effective in inducing remission in the majority of patients, however, relapses are common which lengthen GC therapy. GC toxicity remains a major morbidity in this group of patients, and conventional steroid-sparing therapies have not yet shown enough of a clinical benefit to change the standard of care. As the understanding of the underlying immunopathophysiology of GCA has increased, positive clinical observations have been made with the use of IL-6 receptor inhibitor therapies, such as tocilizumab (TCZ). This has led to prospective randomized control trials that have highlighted the safety and efficacy of TCZ in both new-onset and relapsing GCA.

SUBMITTER: Mollan SP

PROVIDER: S-EPMC5790065 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Profile of tocilizumab and its potential in the treatment of giant cell arteritis.

Mollan Susan Patricia SP Horsburgh John J Dasgupta Bhaskar B

Eye and brain 20180123

Giant cell arteritis (GCA) remains a medical emergency due to the threat of permanent sight loss. High-dose glucocorticoids (GCs) are effective in inducing remission in the majority of patients, however, relapses are common which lengthen GC therapy. GC toxicity remains a major morbidity in this group of patients, and conventional steroid-sparing therapies have not yet shown enough of a clinical benefit to change the standard of care. As the understanding of the underlying immunopathophysiology ...[more]

PMID: 29416384

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Tocilizumab for giant cell arteritis.

Project description: Not available

| S-EPMC9105486 | biostudies-literature

Improvement of Treg immune response after treatment with tocilizumab in giant cell arteritis.

Project description:ObjectivesTo study the percentage, suppressive function and plasticity of Treg in giant cell arteritis (GCA), and the effects of glucocorticoids and tocilizumab.MethodsBlood samples were obtained from 40 controls and 43 GCA patients at baseline and after treatment with glucocorticoids + IV tocilizumab (n = 20) or glucocorticoids (n = 23). Treg percentage and phenotype were assessed by flow cytometry. Suppressive function of Treg was assessed by measuring their ability to inhibit effector T-cell (Teff) proliferation and polarisation into Th1 and Th17 cells.ResultsTreg (CD4+CD25highFoxP3+) frequency in total CD4+ T cells was decreased in active GCA patients when compared to controls (2.5% vs. 4.7%, P < 0.001) and increased after treatment with tocilizumab but worsened after treatment with glucocorticoids alone. Treg lacking exon 2 of FoxP3 were increased in GCA patients when compared to controls (23% vs. 10% of total Treg, P = 0.0096) and normalised after treatment with tocilizumab + glucocorticoids but not glucocorticoids alone. In GCA patients, Treg were unable to control Teff proliferation and induced ˜50% increase in the amount of IL-17+ Teff, which was improved after in vitro blockade of the IL-6 pathway by tocilizumab.ConclusionThis study reports quantitative and functional disruptions in the regulatory immune response of GCA patients and demonstrates that, unlike glucocorticoids, tocilizumab improves Treg immune response.

| S-EPMC8435365 | biostudies-literature

Treatment failure in giant cell arteritis.

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

Treatment of Giant Cell Arteritis (GCA).

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

Quantitative ultrasound to monitor the vascular response to tocilizumab in giant cell arteritis.

Project description:ObjectivesTo characterize the effect of ultra-short glucocorticoids followed by Tocilizumab monotherapy on the intima-media thickness (IMT) in GCA.Methods18 GCA patients received 500mg methylprednisolone intravenously on days 0-2, followed by Tocilizumab (8mg/kg) intravenously on day 3 and thereafter weekly subcutaneous Tocilizumab injections (162 mg) over 52 weeks. Ultrasound of temporal (TA), axillary (AA) and subclavian (SA) arteries was performed at baseline, on days 2-3, at week 4, 8, 12, 24 and 52. The largest IMT of all segments and IMT at landmarks of AA/SA were recorded. IMT was scaled by mean normal values and averaged. Each segment was classified according to diagnostic cut-offs.Results16 patients had TA and 6 had extracranial large artery involvement. The IMT showed a sharp decline on day 2/3 in the TA and AA/SA. In TA, this was followed by an increase to baseline levels at week 4 and a subsequent slow decrease, which was paralleled by decreasing symptoms and achievement of clinical remission. The AA/SA showed a new signal of vasculitis at week 4 in three patients with an IMT increase up to week 8.ConclusionsGlucocorticoid pulse therapy induced a transient decrease of the IMT in TA and AA/SA. Tocilizumab monotherapy resulted in a slow and steady decrease in IMT of the TA and a smaller and delayed effect on the AA/SA. The data strongly support a remission-inducing effect of Tocilizumab and argue for an important role of ultrasound in monitoring disease activity in GCA.

| S-EPMC8566271 | biostudies-literature

Endovascular Treatment of Intracerebral Giant Cell Arteritis.

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

Giant cell arteritis: Current treatment and management.

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

Is Tocilizumab Effective and Safe in Polymyalgia Rheumatica and Giant-Cell Arteritis With Polymyalgia Rheumatica?

Project description:Polymyalgia rheumatica (PMR) and giant-cell arteritis (GCA) with symptoms of PMR share some pathophysiologic features. Interleukin 6 (IL-6) levels are elevated in both groups. We investigated the effect of tocilizumab (TCZ), an IL-6 inhibitor, in both populations and whether there were any differences regarding effectiveness and safety between them. We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines by searching the following databases: PubMed, PMC, Medline, Scopus, Cochrane Library, and ClincalTrials.gov. We found eight articles including one systematic review, one randomized controlled trial (RCT), one posthoc analysis of an RCT, and five observational studies. A total of 668 patients were included in this study. After a comprehensive analysis, we can only infer that there is insufficient evidence to suggest TCZ as monotherapy. Nevertheless, using TCZ in combination with glucocorticoid can be an effective therapeutic option.

| S-EPMC9435397 | biostudies-literature

Giant cell arteritis: pathogenic mechanisms and new potential therapeutic targets.

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

Biologic Therapy for the Treatment of Giant Cell Arteritis.

Project description:Giant cell arteritis (GCA), a vasculitis of the medium and large arteries, is traditionally managed with glucocorticoids. However, the side effects of chronic glucocorticoid use and the occurrence of refractory cases warrant the consideration of steroid-sparing agents, including biologic agents. Interleukin-6 (IL-6) inhibition shows the most promise as biologic therapy for refractory cases of GCA, but data to support the use of other existing biologic agents are currently lacking. A better understanding of the pathogenesis of GCA as well as clinical trials investigating both existing and emerging biologic agents is needed to expand therapeutic options for the treatment of GCA.

| S-EPMC5123077 | biostudies-other

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