Vasculitis is a heterogeneous group of inflammatory disorders of the circulatory system. The size of the blood vessels involved, the predominant organs or tissues affected, histopathological features, and serologic biomarkers vary considerably among different entities and are the basis of the classification system used in clinical practice. Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are the most common forms of large-vessel vasculitis (LVV). Although important similarities, particularly their shared chronic granulomatous inflammation of the aorta and main branches, support their grouping within the same disease spectrum, demographic differences distinguish them. Better characterization of the roles that different inflammatory and resident vascular cells play in the pathogenesis of LVV has improved our therapeutic possibilities. In this review, we briefly describe novel treatment strategies emphasizing the most recent findings.
GIANT CELL ARTERITIS
GCA, the most common form of LVV, occurs primarily in elderly individuals of European ancestry . Inflammation in this disease affects medium to large-sized arteries, and involves the aorta and great vessels, with predilection for the extracranial branches of the carotid arteries. GCA carries a substantial morbidity burden in relation to both the disease itself and its treatment. One of the most feared consequences is vision loss , but several other inflammatory complications can ensue including arterial aneurysms and dissections [3,4].
Since its first description in the early 1930s, no clearly defined alternative to long-term treatment with glucocorticoids has been defined for GCA . Glucocorticoids are highly effectively at controlling systemic inflammation and preventing acute damage (i.e. vision loss), but generally fail to cure the disease or to induce long-term, treatment-free remissions . More than half of the patients relapse upon weaning steroids, and therefore require prolonged treatments that are invariably associated with an array of toxic effects including bone fractures, cataracts, diabetes, and mood swings . The results of treatment trials with conventional immunosuppressive agents including methotrexate have been generally disappointing, and tumor necrosis factor α (TNF-α) antagonists have failed to spare glucocorticoids .
The antigen that triggers an autoimmune response against the arterial components in GCA has remained elusive. However, disease mechanisms that involve the cellular branch of the adaptive and innate immune systems have been partially clarified . In untreated patients, an expanded repertoire of autoreactive CD4-positive T lymphocytes, including IFN-γ producing T helper (Th) 1 cells and IL-17-secreting Th17 cells, orchestrates the formation of a granulomatous inflammatory process. Moreover, the number of Foxp3+ regulatory T cells (Treg), which normally serve to limit an immunologic response, appears to be decreased . GCA is associated with the upregulation of multiple proinflammatory cytokines, such as IL-6, which is secreted by a wide variety of cell types including T-cells, macrophages, and endothelial cells. Thus, inhibition of IL-6 may be an alternative strategy for treating GCA.
ANTIINTERLEUKIN-6 THERAPY (TOCILIZUMAB) FOR GIANT CELL ARTERITIS
IL-6 exerts a wide variety of biological functions depending on its target cell . 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 . 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 . Serum IL-6 levels mirror the activity of the disease, and decline with effective glucocorticoid therapy . 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 ; and targeting downstream aspects of the inflammatory cascade .
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 . 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.
TAK is a relatively rare form of vasculitis with tropism for the aorta and its main branches as well as the pulmonary vasculature . TAK primarily affects women of childbearing-age across all races and geographic locations, but Asians and South Americans demonstrate higher incidence . As in GCA, glucocorticoids are still the mainstay of treatment for TAK . Unfortunately, relapses, glucocorticoid dependence, and subclinical radiographic progression are seen in more than two-thirds of the patients, and, as in GCA, there is no proven glucocorticoid-sparing alternative. Conventional immunosuppression (e.g. methotrexate, azathioprine, mycophenolate mofetil) has shown limited potential for glucocorticoid sparing in uncontrolled series [32–34]. Retrospective and open-label studies [35–38] suggest that TNF-α-directed therapies might have a role in the treatment of TAK, but confirmatory controlled studies are lacking.
In TAK, early vascular lesions consist of T cells, natural killer (NK) cells, and macrophages. Granuloma formation and giant cells can subsequently be found in the media of elastic arteries. Late-stage (‘burned out’) damage demonstrates extensive fibrosis, and intimal hyperplasia, which may lead to aneurysm formation or arterial stenosis. In contrast with GCA, a pathogenic role for B cells has also been suggested in TAK by not only the identification of nonspecific polyclonal hypergammaglobulinemia and circulating antiendothelial antibodies , but also the demonstration of increased numbers of plasmablasts in peripheral blood [40▪▪] and the presence of B cells infiltrating the adventitia of patients’ aortic samples .
B-CELL DEPLETION (RITUXIMAB) FOR TAKAYASU ARTERITIS
Lessons from B-cell depletion therapy (BCDT) in clinical practice and experimental models have confirmed the expanded repertoire of B-cell functions . Apart from differentiating into antibody producing plasma cells, B cells have ‘antibody-independent’ effects that can influence the magnitude and quality of immune reactions against foreign and self-antigens [42,43]. B cells present antigens efficiently, express costimulatory molecules , and represent a source of mediators that can polarize effector CD4 responses , maintain T-cell memory, and modulate regulatory T cells. Furthermore, subpopulations of B cells with intrinsic regulatory capacity have been recently described .
Rituximab is a chimeric IgG1 antibody that binds to CD20 expressed on the surface of B-lymphocytes and depletes circulating naive and memory B cells for 6–12 months via FcγR-mediated antibody dependent cell cytotoxicity and complement dependent cytotoxicity. Galarza et al. reported good clinical response to rituximab, evidenced by improvement in clinical signs and symptoms, in one of two patients with TAK refractory to methotrexate and TNF-α inhibitors. Hoyer et al.[40▪▪] reported three patients with refractory TAK despite prednisone, mycophenolic acid, cyclosporine and adalimumab, who responded to rituximab. Of note, anti-CD20 therapy normalized the number of peripheral plasma cell precursors, which subsequently increased during relapse in two patients that were successfully retreated with B-cell depletion.
ANTI-INTERLEUKIN-6 THERAPY (TOCILIZUMAB) FOR TAKAYASU ARTERITIS
As in GCA, IL-6 is highly expressed within inflamed arteries in TAK , and serum IL-6 levels correlate with disease activity . During the early stages of the disease, IL-6 might be important in stimulating T cells and recruiting monocytes to the sites of inflammation. Later, IL-6 could be involved in angiogenesis and fibrosis.
Nishimoto et al. reported successful use of tocilizumab in a patient with refractory TAK in 2008. Since then, eight additional cases of TAK treated with tocilizumab have been reported [21▪,22▪▪,26▪▪,51▪,52]. For these nine cases (Table 2), IL-6R therapy was utilized for a mean period of 11 months (range 4–41 months). One case was treatment naive and received tocilizumab monotherapy, and eight patients were refractory to concomitant prednisone (mean dose 23 mg/day; range 5–40 mg/day) and other immunosuppressants (methotrexate, n = 5; azathioprine, n = 3; mycophenolate mofetil, n = 3; cyclophosphamide n = 2; cyclosporine n = 1; infliximab, n = 4; and adalimumab n = 1). All patients achieved disease control, and those on glucocorticoids were able to either discontinue or significantly taper prednisone after 3–6 months of tocilizumab therapy. Serial imaging in eight patients (MRA, n = 2; CT, n = 2; PET/CT, n = 4)showed improvement of vasculitic features in seven patients, evidenced by decreased vascular 18-fluordeoxyglucose uptake (n = 4), decreased vascular paramagnetic contrast enhancement (n = 2) or decreased aortic wall thickness (n = 1). One patient was shown to have a decrease in the thickness of the aortic wall following tocilizumab treatment, but progressive narrowing of the lumens of the renal, subclavian, and vertebral arteries was also observed [51▪]. One patient relapsed after 8 months of treatment while still receiving tocilizumabat 8 mg/kg every 4 weeks. A second patient relapsed within 3 months of discontinuing treatment.
LEFLUNOMIDE FOR TAKAYASU ARTERITIS
Immunity is dependent on rapidly dividing cells that require continuous synthesis of DNA. Leflunomide, an agent widely used in rheumatoid arthritis, has immunomodulatory effects by inhibiting pyrimidine synthesis. In a recent prospective study from Brazil , favorable clinical response to leflunomide at 20 mg/day was seen in 12 of 15 TAK patients whose disease had been refractory to glucocorticoids (100%), methotrexate (100%), azathioprine (30%), cyclosporine (30%), mycophenolate mofetil (25%), and TNF-α antagonists (7%). Disease activity scores, CRP levels and prednisone use significantly declined after a median treatment period of 9 months. However, at the end of follow up, patients still required a mean daily prednisone dose of 13.9 mg (SD 8.5 mg), although it is unclear how many of these patients still required glucocorticoids. In addition, two cases had radiographic progression despite being classified in remission by clinical examination and laboratory analysis. Three patients experienced mild side effects.
RITUXIMAB AND TOCILIZUMAB WITH OTHER LARGE-VESSEL VASCULITIDES
IgG4-related disease (IgG4-RD) is a disorder characterized by elevated serum IgG4 levels and the infiltration of tissue by increased numbers of IgG4-expressing plasma cells along with fibrosis. Although almost any organ may be involved, IgG4-RD involvement of the aorta results in a lymphoplasmacytic aortitis or periaortitis . Khosroshahi et al.[55▪▪] recently reported treatment with rituximab in 10 patients with IgG4-RD, including three patients with aortitis. All three patients showed a positive response to rituximab as evidenced by improvement in clinical signs and symptoms, and decreases in acute phase reactants and serum IgG4 levels. Prednisone treatment, which ranged from 10 to 60 mg/day before rituximab, could be discontinued in all three patients following treatment with rituximab. However, approximately 6 months following the initial course of rituximab, two of these patients experienced disease recurrences, characterized by worsening clinical symptoms and elevation of serum IgG4 levels, that responded to additional courses of BCDT.
Relapsing polychondritis is characterized by destructive inflammation targeting cartilaginous tissues, with aortic involvement in some cases. TNF-α blockers have been shown to have some benefit in a small number of these patients with refractory disease . Narshi and Allard  described a patient with refractory relapsing polychondritis with aortitis who failed TNF-α blockade, but responded to tocilizumab administered at 8 mg/kg per month. As with GCA and TAK, administration of tocilizumab resulted in marked reduction in the CRP level and allowed a substantial decrease in the glucocorticoid dose. The effect of tocilizumab treatment on the aortic inflammation in this patient was not reported. Recently, Shibuya et al. reported a patient with refractory Cogan's syndrome with involvement of the ascending aorta by PET-CT, who had failed TNF-α blockade, but responded to treatment with tocilizumab 8 mg/kg every 4 weeks. Six months of therapy resulted in clinical improvement, and (not surprisingly) normalization of CRP, but no decrease in aortic 18-fluordeoxyglucose uptake by PET-CT was seen.
There is a great unmet need for better treatments in LVV. IL-6 and CD20 are novel targets susceptible to specific pharmacologic modulation in these conditions. At this juncture, adequately powered controlled trials are required to rigorously evaluate the efficacy of tocilizumab and rituximab for LVV aiming for clinically meaningful endpoints (e.g. remission maintenance, glucocorticoid-sparing, radiographic response, cost-effectiveness), and controlling for specific clinical parameters (i.e. newly diagnosed vs. relapsing/refractory patients). Correct subclassification of the specific LVV being treated in these studies will be essential. Mechanistic studies are also needed not only to assess the biologic impact that new therapies may have on the immunopathogenic mechanisms of these disorders, but also to identify new biomarkers to monitor disease activity and predict response to treatment.
This work was supported by Massachusetts General Hospital.
Conflicts of interest
Dr James R. has received fees for consulting from Merck and fees for consulting and expert testimony from GlaxoSmithKline. Dr John H. Stone is the Principal Investigator of a Roche-funded trial of tocilizumab in giant cell arteritis and has received consulting fees on study design from Roche for that trial. Dr John H. Stone has also received research grants from Genentech for the study of IgG4-related disease and the utility of rituximab in treating that condition.
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