Elsevier

Cytokine

Volume 44, Issue 2, November 2008, Pages 207-220
Cytokine

Review Article
Giant cell arteritis and polymyalgia rheumatica: Role of cytokines in the pathogenesis and implications for treatment

https://doi.org/10.1016/j.cyto.2008.09.004Get rights and content

Abstract

Objective: To summarize the contribution of cytokines to pathogenesis, clinical manifestations and prognosis of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA).

Methods: MEDLINE database search for studies published between 1980 and April 2008.

Results: PMR and GCA are characterized by a hyperproduction of IL-6. The role of other circulating cytokines in their pathogenesis remains unclear. Cytokine mRNA in the arterial wall of GCA can distinguish different clinical subgroups of patients. The profile of T cell-derived cytokines in GCA suggests that it is a Th1-driven disease. The scarce number of studies makes difficult to evaluate the exact contribution of cytokine polymorphisms to their pathogenesis. Small studies have suggested the utility of TNF antagonists in patients with refractory PMR and GCA. However, these data have not been confirmed in controlled studies in patients with recent onset disease.

Conclusion: Further studies are needed to evaluate the role of circulating cytokines in PMR and GCA. The study of tissue cytokines has provided important insights into the mechanisms implicated in the local inflammatory response that occurs in GCA. The important advance in the knowledge of the role of cytokines in PMR and GCA will have clear implications for treatment.

Introduction

Polymyalgia rheumatica (PMR)1 and giant cell arteritis (GCA) are chronic inflammatory disorders of unknown etiology that affect elderly people [1]. GCA is a chronic granulomatous vasculitis preferentially targeting large and medium-sized arteries. The clinical manifestations range from the classic symptoms resulting from the involvement of the carotid artery branches such as headache, jaw claudication, scalp tenderness, visual involvement or stroke, to aortic arch syndrome or less specific manifestations such as fever, malaise, weight loss, or a polymyalgic syndrome [2], [3], [4], [5], [6]. PMR is characterized by pain and stiffness in the neck, shoulder and pelvic girdles [7], [8]. Around 50% of the patients with GCA have polymyalgic symptoms and it has been reported that 15% of PMR patients without cranial symptoms of the disease have an underlying GCA [2], [4], [9]. PMR and GCA, in addition to the clear predilection for the elderly, also present an excellent and characteristic response to corticosteroid (CS) therapy. Whereas GCA usually needs treatment with high-dose CS to prevent ischemic complications, PMR has an almost diagnostic response to low-dose CS therapy [4], [7], [10]. Despite the similarities regarding age distribution, some clinical manifestations, laboratory abnormalities and the excellent response to CS therapy, the relationship between GCA and PMR is still not clearly established. In fact, it is not understood why some patients with PMR develop a systemic vasculitis and why the disease process remains limited to the musculoskeletal system in others.

Cytokines are involved in the pathogenesis of most inflammatory diseases and since 1993 an increasing number of studies have addressed the role of cytokines in the pathogenesis of PMR and GCA. Such studies have been complicated by the number of new cytokines that are continuously being described. As the peripheral compartment is more accessible, the majority studies have searched for differences in the circulating cytokine profile, and also for the utility of monitoring cytokine levels in the clinical management and prognosis of PMR and GCA. Many studies have been conducted to investigate whether a genetic basis for these diseases may be found in polymorphisms of cytokine genes. The reasoning behind the proposed involvement of cytokine gene polymorphisms in susceptibility or disease severity is that they may influence in vivo cytokine levels [11]. And finally, several key studies have addressed the cytokine profile in the inflamed vessels. On the other hand, the importance of clarifying the role of cytokines in PMR and GCA comes from the implications for treatment, as we now have available an increasing number of effective biologic agents directed against cytokines that could be used in these patients.

The objective of this review is to summarize the contribution of cytokines to the pathogenesis and their possible relationships with the clinical manifestations and prognosis of GCA and PMR. Furthermore, the possible implications for treatment are also discussed.

Section snippets

Review of the literature

We searched the MEDLINE database for studies published between 1980 and April 2008. Paired medical subject headings (MeSH) used for keyword and text word searching included giant cell arteritis, temporal arteritis, polymyalgia rheumatica, cytokines, lymphokines, genes, and polymorphisms. We also reviewed the reference lists of all articles obtained to identify additional articles of interest. We reviewed only English language articles and when possible, the following aspects of each article

Interleukin-6 (IL-6)

Several reports have suggested that increased serum levels of IL-6 can be detected in patients with PMR and GCA (Table 1). Three major messages might be extracted from these studies. First, the majority of the studies have found a significant increased of circulating IL-6 in patients with active disease [12], [13], [14], [15], [16], [17], [18], [19], [20], [21]. Second, most of the studies have also shown a significant decrease of circulating IL-6 levels that correlate with remission of

Circulating cytokines

As chronic inflammatory diseases, PMR and GCA represent a model for studying an imbalance in cytokine production and their kinetics during treatment. The study of circulating cytokines in these two conditions may be relevant in several aspects. First of all, as PMR and GCA are closely related syndromes, the circulating cytokine profile may help to distinguish both conditions, and also to predict which patients are at high risk of developing ischemic complications. Secondly, nowadays there is a

Acknowledgments

This work was supported by grants from Fundación Marqués de Valdecilla, Fundación Mutua Madrileña, and Fondo de Investigación Sanitaria (PI050475). Lorena Alvarez was supported by a grant for Research Aid from Wyeth Pharma.

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