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OP27. THE TREATMENT OF GIANT CELL ARTERITIS WITH BIOLOGIC AGENTS
Center for Vasculitis Care and Research, Lerner College of Medicine, Harold C. Schott Chair of Rheumatic and Immunologic Diseases, The Cleveland Clinic Foundation, Cleveland, OH, USA
Giant Cell (Temporal) Arteritis (GCA)
Background: Although the signs and symptoms of GCA are exquisitely sensitive to treatment with high doses of glucocorticosteroids (GCS), morbidity from treatment and GCA itself is substantial. Morbidity includes visual loss in 5–25% of patients, which although better than in the era preceding GCS (30–60% blindness), is still a terrible handicap for the already impaired elderly patient [1–7]. In one population-based study, 17% of GCA patients developed aortic aneurysms that were sometimes associated with dissection or vessel rupture [8]. Aortic branch vessel stenoses may cause extremity (upper>lower) claudication (15%). Patients may also experience polymyalgia rheumatica (PMR) (
50%), constitutional symptoms (50%) and stroke (0–5%) [3].
Whereas some early reports of GCA treatment suggested that GCS may only be necessary for 6–12 months, in 1973, Beevers et al. [9] recognized the chronic nature of this illness and noted that in many cases GCS therapy may be required for several years. Indeed, this is now a widely accepted observation. Relapse rates in the course of GCS tapering have been reportedly 30 – >80% over 1–4 years of follow up [6–13]. After 2–3 years of therapy about 50% of patients remain GCS-dependent. The risk of fractures and cataracts are 5 and 3 times greater, respectively, in patients with GCA compared to age-matched controls not treated with GCS [14]. Nesher et al. [15, 16] found that among 43 patients followed for a mean period of 3 years, 35% had fractures and 21% had severe infections, which in 2/3 of cases lead to death. An important role for GCS could be implicated in 37% of all deaths. The need for prolonged GCS therapy to control GCA, and the goal of reducing disease- and treatment-related morbidity and mortality, has lead investigators to explore the use of adjunctive agents to improve outcomes.
Adjunctive Therapy in GCA: Numerous studies have explored the utility of either methotrexate or azathioprine as a means of achieving improved disease control and less dependence on GCS therapy. Two randomized, double-blind, placebo-controlled studies of weekly methotrexate (MTX) have been completed. In both, the rate of GCS taper was rapid, so that in the absence of relapse, GCS withdrawal could be accomplished in four months [17] or 6 months [18]. In both studies relapses were frequent and the first relapse occurred with equal frequency in the GCS-only and GCS + MTX groups. However, the frequency with which more than one relapse occurred differed between groups in one study and not the other. Jover et al. [17] found that MTX diminished second relapses and cumulative GCS use, whereas Hoffman et al. [18] did not find MTX to be beneficial. The reason for these different conclusions is uncertain. Consequently, what role MTX or other adjunctive therapies may play in GCA remains unsettled.
Rationale for Biologic Agents in the Treatment of GCA: Although the pathogenesis of GCA has not been completely elucidated, our understanding of the disease has grown substantially. Biopsy specimens obtained at different stages in the evolution of vascular lesions have revealed that inflammatory cells are initially concentrated in the adventitia and are absent or sparse in the intima, and there being an intermediate presence in the media. Mononuclear cells migrate into the vessel wall from the adventitia [19, 20]. Slow flow of blood in the adventitial microcirculation (vasa vasorum) compared to the larger vessel lumen favors developing initial vessel wall inflammation in this location. CD4+ T cells, and CD68+ macrophages are more commonly found in the adventitia and the intima than in the media. Giant cells appear to be formed from macrophages that are recruited from the adventitia and traverse the media, later also appearing in the intima of the large vessel lumen [19, 20]. CD4+ T cells are prevalent in this infiltrate, and may play a key role in driving the inflammatory attack. Production of IL-2, TNF
and IFN
, by CD4+ T cells indicates a predominant Th1 response [19, 20]. Products of activated macrophages include IL-1 and TNF, which are proinflammatory cytokines that further stimulate the Th1 response. Granuloma formation depends on Th1 cytokines, and in animal models, anti-TNF therapy has been shown to block granuloma formation. Blockade of these cytokines could theoretically play an important role in selective interference with disease progression.
TNF inhibitors such as infliximab, eternacept, adalimumab and IL-1 receptor antagonist (IL-1ra) have been shown to abrogate inflammatory responses and limit tissue damage in patients with rheumatoid arthritis and are being studied in other illnesses in which macrophage and Th1-mediated responses may be important. Our current understanding of the pathogenesis of GCA suggests that interfering with vascular injury due to the products of activated macrophages and Th1 lymphocytes would be worthy of investigation. Because of their apparent important roles in GCA pathogenesis, blockade of either IL-1, IFN, and TNF are particularly attractive considerations.
The use of infliximab (IFX) as adjunctive therapy to GCS in new onset GCA has recently been investigated in a multicenter, randomized, double-blind, controlled trial [21]. Forty-four patients were randomized in a 1:2 ratio (placebo, n = 16, IFX, n = 28) at 22 centers in 5 countries. Mean age in both groups was 71.0 years (range: 50–93). After a 22 week interim analysis, the study was terminated. There were no differences between groups in regard to: (1) proportion of patients remaining relapse-free (50% placebo vs. 43% IFX, p = 0.651), (2) cumulative doses of GCS therapy (placebo mean±SD = 3117±971 mg vs. IFX = 3051±70 mg, p = NS) and (3) among patients who had 1st relapse, days to 1st relapse (placebo median = 84.5, IFX median = 96.5, p = NS). There was one case of heart failure in an IFX-treated patient. Infections were infrequent and limited to upper respiratory tract (12.5% placebo vs. 14.3% IFX). In this elderly population of patients with newly diagnosed GCA, IFX 5 mg/kg every 8 weeks, was well-tolerated, but during 22 weeks of treatment did not reduce number of 1st relapses or cumulative GCS dosage.
While these results were unexpected and disappointing, they should not discourage further exploration of blockade of other seemingly critical cytokines in the future. The morbidity of GCA and current therapies are far too great to accept the status quo.
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  J. Andrews and J. C. Mason Takayasu's arteritis--recent advances in imaging offer promise Rheumatology, January 1, 2007; 46(1): 6 - 15. [Abstract] [Full Text] [PDF]
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