New Treatment Strategies in Large-vessel Vasculitis

Sebastian Unizony; John H. Stone; James R. Stone

Disclosures

Curr Opin Rheumatol. 2013;25(1):3-9. 

In This Article

Antiinterleukin-6 Therapy (Tocilizumab) for Giant Cell Arteritis

IL-6 exerts a wide variety of biological functions depending on its target cell.[11] During physiologic inflammatory responses, IL-6 triggers the synthesis of acute phase proteins, promotes the transition from acute-to-chronic inflammation, and facilitates the development of specific immunity.[12] IL-6 modulates the activation, proliferation and differentiation of different T-cell subsets including CD8, Th17 and Treg cells. IL-6 also stimulates the terminal differentiation of B cells, enhances the survival of plasma cells, and induces cells of the monocyte, endothelial and stromal lineages to acquire a 'proinflammatory' phenotype.

In GCA patients, IL-6 is upregulated within the inflamed arteries[13,14] and in the peripheral circulation.[15] Serum IL-6 levels mirror the activity of the disease, and decline with effective glucocorticoid therapy.[16] It has been proposed that the pharmacologic inhibition of the IL-6 system can ameliorate vascular inflammation in this setting through different mechanisms that include: altering upstream differentiation of autoreactive lymphocytes;[17–19] promoting the generation of Treg cells;[20] and targeting downstream aspects of the inflammatory cascade.[14]

In published reports, approximately two dozen GCA patients have shown positive responses upon treatment with tocilizumab, a humanized monoclonal anti-IL-6 receptor (IL-6R) antibody.[21,22,23,24,25,26,27,28] The majority of these patients have had relapsing/refractory disease ( Table 1 ), although a smaller number, newly diagnosed patients have also been treated. Two patients received tocilizumab at 4 mg/kg,[26] but the majority were infused with 8 mg/kg every 4 weeks. So far, this medication has been tolerated without major adverse events. Common side effects include cytopenias (leucopenia and neutropenia), and transaminitis. No infusion reactions were reported.

Salvarani et al.[21] reported a series of four LVV cases, including one patient with GCA whose disease had been refractory despite treatment with prednisone, methotrexate, and etanercept. After treatment with tocilizumab at 8 mg/kg for 6 months, this patient had significant clinical improvement, normalization of acute phase reactants, and decreased signs of inflammation on PET/computed tomography (CT). Five months after discontinuing tocilizumab, this patient experienced a disease flare, as evidenced by myoarthralgias and increased acute phase reactants, whereas on methotrexate 15 mg/week and prednisone 2.5 mg/day. Seitz et al.[22] reported rapid and complete clinical improvement in five GCA patients treated with tocilizumab for 7–8 months. Two patients, who were naive to any treatment for vasculitis, both received biologic monotherapy. For the other three cases (two previously failing methotrexate), tocilizumab was added to a background of glucocorticoids. Patients achieved and maintained disease remission while on tocilizumab and were able to taper their prednisone dose from a mean of 19 mg/day (range 10–40 mg) at the first tocilizumab administration to 3 mg/day (range 0–5 mg) 12 weeks after starting tocilizumab. Surrogate evidence of large vessel inflammation, identified by paramagnetic contrast enhancement on MRA, resolved after 3 months of treatment in three individuals, including one patient with refractory GCA.

Beyer et at.[24] reported good clinical and radiographic response in three patients with refractory GCA who received tocilizumab for 6 months. Before biologic therapy was initiated, all three patients could not decrease their prednisone dose below 30 mg/day without relapse of disease activity, despite the use of oral immunosuppression (azathioprine, mycophenolate mofetil, and methotrexate). Once on IL-6R blockade, these patients were able to reduce their glucocorticoid to 7.5 mg/day or less without experiencing disease exacerbation. PET/CT scans, which had previously shown increased 18-fluorodeoxyglucose uptake at baseline in two cases, normalized after 24 weeks of treatment with tocilizumab.

We recently published the largest open label experience to date using tocilizumab for LVV.[26] Within a cohort of 10 cases, seven patients with GCA whose disease had been highly refractory to glucocorticoids and multiple other immunosuppressive agents (azathioprine, methotrexate, cyclophosphamide, and TNF-α inhibitors) rapidly entered and maintained remission, while receiving tocilizumabat 4–8 mg/kg every month for a mean period of 8 months (range 6–12 months). Given their excellent clinical responses, as evidenced by the absence of clinical signs and symptoms of active GCA, this cohort was able to reduce their prednisone intake from an average daily dose of 25.5 mg at baseline (range 8–60 mg) to 2.2 mg at the end of follow-up (range 0–6 mg). Of note, active GCA was observed pathologically in the autopsy of an 81-year-old woman who died from an unrelated cause. This patient had been in clinical and serologic remission for 4 months while on tocilizumab and low-dose prednisone.

Despite encouraging results from case reports and small-uncontrolled series, important questions remain. Some patients with LVV treated with glucocorticoids have persistent vascular inflammation despite the resolution of clinical symptoms.[29] The explanation for this subclinical activity remains unknown, but it may represent a differential sensitivity of Th1 and Th17 cells to the effects of glucocorticoids. Mechanistic studies will be required to clarify the effects of IL-6 inhibition on specific inflammatory cell populations in LVV. IL-6 blockade will presumably target Th17 cells efficiently, but the effects of this drug on the Th1 and Treg populations are less predictable. In the only tocilizumab-treated patient for whom follow-up pathology has been available thus far, inflammation was still present in the arteries after months of treatment.[26] Moreover, as any IL-6R antagonist in adequate doses will by default normalize the levels of traditional inflammatory markers by directly inhibiting the hepatocyte production of acute phase reactants (i.e. fibrinogen, CRP), should tocilizumab prove to be an effective alternative to glucocorticoids in GCA, then monitoring disease activity will have to rely on clinical, radiologic and pathologic grounds until more accurate biomarkers are discovered and validated. Finally, three of four patients with refractory GCA who showed adequate response with tocilizumab relapsed after this agent was discontinued ( Table 1 ), suggesting that long-term therapy may be required in many of these patients.

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