Secondary Logo

New treatment strategies in large-vessel vasculitis

Unizony, Sebastiana; Stone, John H.a; Stone, James R.b

Current Opinion in Rheumatology: January 2013 - Volume 25 - Issue 1 - p 3–9
doi: 10.1097/BOR.0b013e32835b133a
VASCULITIS SYNDROMES: Edited by Curry L. Loening

Purpose of review Recent advancements in the understanding of the pathogenesis of large-vessel vasculitis may broaden our currently limited therapeutic possibilities. This review summarizes the available evidence for new treatment strategies in this spectrum of diseases.

Recent findings Interleukin (IL) 6 appears to be an important mediator of the pathology in large-vessel vasculitis. IL-6 is upregulated in inflamed arteries of patients with giant cell arteritis and Takayasu arteritis, and serum levels of this cytokine mirror disease activity. Encouraging preliminary results have been obtained with the IL-6 receptor (IL-6R) antagonist tocilizumab for the treatment of large-vessel vasculitides, including both giant cell arteritis and Takayasu arteritis, and the aortitis of Cogan syndrome and relapsing polychondritis. A small number of patients with Takayasu arteritis and IgG4-related aortitis have also been successfully treated with the B-cell depleting agent rituximab, and some patients with refractory Takayasu arteritis have responded to the immunomodulator leflunomide.

Summary The possibility of biologic therapy in large vessel vasculitis has emerged. At this time, better delineation of the immunopathogenic mechanisms of this spectrum of diseases and prospective randomized clinical trials are required to move the field forward and decrease the cumulative glucocorticoid toxicity seen in these disorders.

aRheumatology Unit, Division of Rheumatology, Allergy, and Immunology, Department of Medicine

bDepartment of Pathology, Center for Systems BiologyMassachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

Correspondence to James R. Stone, MD, PhD, Massachusetts General Hospital, Simches Research Building Room 8236, 185 Cambridge Street CPZN, Boston, MA 02114, USA. Tel: +1 617 726 8303; fax: +1 617 643 3566; e-mail:

Back to Top | Article Outline


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.

Back to Top | Article Outline


GCA, the most common form of LVV, occurs primarily in elderly individuals of European ancestry [1]. 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 [2], 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 [5]. 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 [6]. 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 [7]. 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 [8].

Box 1

Box 1

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 [9]. 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 [10]. 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.

Back to Top | Article Outline


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.

Table 1

Table 1

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.

Back to Top | Article Outline


TAK is a relatively rare form of vasculitis with tropism for the aorta and its main branches as well as the pulmonary vasculature [30]. TAK primarily affects women of childbearing-age across all races and geographic locations, but Asians and South Americans demonstrate higher incidence [31]. As in GCA, glucocorticoids are still the mainstay of treatment for TAK [5]. 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 [39], 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 [41].

Back to Top | Article Outline


Lessons from B-cell depletion therapy (BCDT) in clinical practice and experimental models have confirmed the expanded repertoire of B-cell functions [42]. 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 [44], and represent a source of mediators that can polarize effector CD4 responses [45], maintain T-cell memory, and modulate regulatory T cells. Furthermore, subpopulations of B cells with intrinsic regulatory capacity have been recently described [46].

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.[47] 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.

Back to Top | Article Outline


As in GCA, IL-6 is highly expressed within inflamed arteries in TAK [48], and serum IL-6 levels correlate with disease activity [49]. 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.[50] 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.

Table 2

Table 2

Back to Top | Article Outline


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 [53], 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.

Back to Top | Article Outline


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 [54]. 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 [8]. Narshi and Allard [56] 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.[57] 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.

Back to Top | Article Outline


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.

Back to Top | Article Outline


This work was supported by Massachusetts General Hospital.

Back to Top | Article Outline

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.

Back to Top | Article Outline


Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 145–146).

Back to Top | Article Outline


1. Gonzalez-Gay MA, Vazquez-Rodriguez TR, Lopez-Diaz MJ, et al. Epidemiology of giant cell arteritis and polymyalgia rheumatica. Arthritis Rheum 2009; 61:1454–1461.
2. Borg FA, Salter VL, Dasgupta B. Neuro-ophthalmic complications in giant cell arteritis. Curr Allergy Asthma Rep 2008; 8:323–330.
3. Garcia-Martinez A, Hernandez-Rodriguez J, Arguis P, et al. Development of aortic aneurysm/dilatation during the followup of patients with giant cell arteritis: a cross-sectional screening of fifty-four prospectively followed patients. Arthritis Rheum 2008; 59:422–430.
4. Wang H, Smith RN, Spooner AE, et al. Giant cell aortitis of the ascending aorta without signs or symptoms of systemic vasculitis is associated with elevated risk of distal aortic events. Arthritis Rheum 2012; 64:317–319.
5. Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis 2009; 68:318–323.
6. Mazlumzadeh M, Hunder GG, Easley KA, et al. Treatment of giant cell arteritis using induction therapy with high-dose glucocorticoids: a double-blind, placebo-controlled, randomized prospective clinical trial. Arthritis Rheum 2006; 54:3310–3318.
7. Proven A, Gabriel SE, Orces C, et al. Glucocorticoid therapy in giant cell arteritis: duration and adverse outcomes. Arthritis Rheum 2003; 49:703–708.
8. Schafer VS, Zwerina J. Biologic treatment of large-vessel vasculitides. Curr Opin Rheumatol 2012; 24:31–37.
9. Weyand CM, Younge BR, Goronzy JJ. IFN-gamma and IL-17: the two faces of T-cell pathology in giant cell arteritis. Curr Opin Rheumatol 2011; 23:43–49.
10. Terrier B, Geri G, Chaara W, et al. IL-21 modulates Th1 and Th17 responses in giant cell arteritis. Arthritis Rheum 2012; 64:2001–2011.
11. Naka T, Nishimoto N, Kishimoto T. The paradigm of IL-6: from basic science to medicine. Arthritis Res 2002; 4 (Suppl 3):S233–S242.
12. Jones SA. Directing transition from innate to acquired immunity: defining a role for IL-6. J Immunol 2005; 175:3463–3468.
13. Weyand CM, Hicok KC, Hunder GG, Goronzy JJ. Tissue cytokine patterns in patients with polymyalgia rheumatica and giant cell arteritis. Ann Intern Med 1994; 121:484–491.
14. Emilie D, Liozon E, Crevon MC, et al. Production of interleukin 6 by granulomas of giant cell arteritis. Hum Immunol 1994; 39:17–24.
15. Garcia-Martinez A, Hernandez-Rodriguez J, Espigol-Frigole G, et al. Clinical relevance of persistently elevated circulating cytokines (tumor necrosis factor alpha and interleukin-6) in the long-term followup of patients with giant cell arteritis. Arthritis Care Res 2010; 62:835–841.
16. Weyand CM, Fulbright JW, Hunder GG, et al. Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity. Arthritis Rheum 2000; 43:1041–1048.
17. Fujimoto M, Serada S, Mihara M, et al. Interleukin-6 blockade suppresses autoimmune arthritis in mice by the inhibition of inflammatory Th17 responses. Arthritis Rheum 2008; 58:3710–3719.
18. Serada S, Fujimoto M, Mihara M, et al. IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 2008; 105:9041–9046.
19. Haruta H, Ohguro N, Fujimoto M, et al. Blockade of interleukin-6 signaling suppresses not only th17 but also interphotoreceptor retinoid binding protein-specific Th1 by promoting regulatory T cells in experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci 2011; 52:3264–3271.
20. Korn T, Mitsdoerffer M, Croxford AL, et al. IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A 2008; 105:18460–18465.
21▪. Salvarani C, Magnani L, Catanoso M, et al. Tocilizumab: a novel therapy for patients with large-vessel vasculitis. Rheumatology 2012; 51:151–156.

In this case series the authors utilized PET-CT in the follow-up of patients with LVV, including patients with both refractory and naive TAK, treated with tocilizumab.

22▪▪. Seitz M, Reichenbach S, Bonel HM, et al. Rapid induction of remission in large vessel vasculitis by IL-6 blockade: a case series. Swiss Med Wkly 2011; 141:w13156.

This is the first case series demonstrating the utility of tocilizumab in large-vessel vasculitis.

23. Sciascia S, Rossi D, Roccatello D. Interleukin 6 blockade as steroid-sparing treatment for 2 patients with giant cell arteritis. J Rheumatol 2011; 38:2080–2081.
24▪▪. Beyer C, Axmann R, Sahinbegovic E, et al. Antiinterleukin 6 receptor therapy as rescue treatment for giant cell arteritis. Ann Rheum Dis 2011; 70:1874–1875.

This was the first case series to use PET-CT in a cohort of patients to show improvement in LVV during treatment with tocilizumab.

25. Vinit J, Bielefeld P, Muller G, Besancenot JF. Efficacy of tocilizumab in refractory giant cell arteritis. Joint Bone Spine 2012; 79:317–318.
26▪▪. Unizony S, Arias-Urdaneta L, Miloslavsky E, et al. Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica. Arthritis Care Res (in press).

This is the largest series yet published on the use of tocilizumab in large-vessel vasculitis and describes for the first time the persistence in vasculitis on pathology during tocilizumab treatment in one patient.

27. Besada E, Nossent JC. Ultrasonographic resolution of the vessel wall oedema with modest clinical improvement in a large-vessel vasculitis patient treated with tocilizumab. Clin Rheum 2012; 31:1263–1265.
28. Christidis D, Jain S, Gupta BD. Successful use of tocilizumab in polymyalgic onset biopsy positive GCA with large vessel involvement. BMJ Case Rep 2011. doi:10.1136/bcr.04.2011.4135.
29. Deng J, Younge BR, Olshen RA, et al. Th17 and Th1 T-cell responses in giant cell arteritis. Circulation 2010; 121:906–915.
30. Kerr GS. Takayasu's arteritis. Rheum Dis Clin North Am 1995; 21:1041–1058.
31. Numano F. Differences in clinical presentation and outcome in different countries for Takayasu's arteritis. Curr Opin Rheumatol 1997; 9:12–15.
32. Hoffman GS, Leavitt RY, Kerr GS, et al. Treatment of glucocorticoid-resistant or relapsing Takayasu arteritis with methotrexate. Arthritis Rheum 1994; 37:578–582.
33. Maksimowicz-McKinnon K, Clark TM, Hoffman GS. Limitations of therapy and a guarded prognosis in an American cohort of Takayasu arteritis patients. Arthritis Rheum 2007; 56:1000–1009.
34. Goel R, Danda D, Mathew J, Edwin N. Mycophenolate mofetil in Takayasu's arteritis. Clin Rheumatol 2010; 29:329–332.
35. Tanaka F, Kawakami A, Iwanaga N, et al. Infliximab is effective for Takayasu arteritis refractory to glucocorticoid and methotrexate. Intern Med 2006; 45:313–316.
36. Molloy ES, Langford CA, Clark TM, et al. Antitumour necrosis factor therapy in patients with refractory Takayasu arteritis: long-term follow-up. Ann Rheum Dis 2008; 67:1567–1569.
37. Mekinian A, Neel A, Sibilia J, et al. Efficacy and tolerance of infliximab in refractory Takayasu arteritis: French multicentre study. Rheumatology 2012; 51:882–886.
38. Comarmond C, Plaisier E, Dahan K, et al. Anti TNF-alpha in refractory Takayasu's arteritis: cases series and review of the literature. Autoimmun Rev 2012; 11:678–684.
39. Wang H, Ma J, Wu Q, et al. Circulating B lymphocytes producing autoantibodies to endothelial cells play a role in the pathogenesis of Takayasu arteritis. J Vasc Surg 2011; 53:174–180.
40▪▪. Hoyer BF, Mumtaz IM, Loddenkemper K, et al. Takayasu arteritis is characterized by disturbances of B cell homeostasis and responds to B cell depletion therapy with rituximab. Ann Rheum Dis 2012; 71:75–79.

This report showed efficacy of rituximab in a small number of patients with TAK and also proposed a rationale for the use of BCDT in this disease by showing elevated levels of circulating plasmablasts in patients with active TAK.

41. Inder SJ, Bobryshev YV, Cherian SM, et al. Immunophenotypic analysis of the aortic wall in Takayasu's arteritis: involvement of lymphocytes, dendritic cells and granulocytes in immuno-inflammatory reactions. Cardiovasc Surg 2000; 8:141–148.
42. Lund FE, Randall TD. Effector and regulatory B cells: modulators of CD4(+) T cell immunity. Nat Rev Immunol 2010; 10:236–247.
43. Shlomchik MJ, Craft JE, Mamula MJ. From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol 2001; 1:147–153.
44. Griffin DO, Rothstein TL. A small CD11b(+) human B1 cell subpopulation stimulates T cells and is expanded in lupus. J Exp Med 2011; 208:2591–2598.
45. Barr TA, Shen P, Brown S, et al. B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells. J Exp Med 2012; 209:1001–1010.
46. Mauri C, Blair PA. Regulatory B cells in autoimmunity: developments and controversies. Nat Rev Rheumatol 2010; 6:636–643.
47. Galarza C, Valencia D, Tobon GJ, et al. Should rituximab be considered as the first-choice treatment for severe autoimmune rheumatic diseases? Clin Rev Allergy Immunol 2008; 34:124–128.
48. Seko Y, Sato O, Takagi A, et al. Restricted usage of T-cell receptor Valpha-Vbeta genes in infiltrating cells in aortic tissue of patients with Takayasu's arteritis. Circulation 1996; 93:1788–1790.
49. Park MC, Lee SW, Park YB, Lee SK. Serum cytokine profiles and their correlations with disease activity in Takayasu's arteritis. Rheumatology 2006; 45:545–548.
50. Nishimoto N, Nakahara H, Yoshio-Hoshino N, Mima T. Successful treatment of a patient with Takayasu arteritis using a humanized antiinterleukin-6 receptor antibody. Arthritis Rheum 2008; 58:1197–1200.
51▪. Bredemeier M, Rocha CM, Barbosa MV, Pitrez EH. One-year clinical and radiological evolution of a patient with refractory Takayasu's arteritis under treatment with tocilizumab. Clin Exp Rheumatol 2012; 30:S98–S100.

This is an important case report that documents the progression of vascular stenoses in a patient with TAK while being treated with tocilizumab.

52. Salvarani C, Magani L, Catanoso M, et al. Rescue treatment with tocilizumab for Takayasu arteritis resistant to TNF-alpha blockers. Clin Exp Rheumatol 2012; 30:S90–S93.
53. de Souza AW, da Silva MD, Machado LS, et al. Short-term effect of leflunomide in patients with Takayasu arteritis: an observational study. Scand J Rheumatol 2012; 41:227–230.
54. Stone JR. Aortitis, periaortitis, and retroperitoneal fibrosis as manifestations of IgG4-related systemic disease. Curr Opin Rheumatol 2011; 23:88–94.
55▪▪. Khosroshahi A, Carruthers MN, Deshpande V, et al. Rituximab for the treatment of IgG4-related disease: Lessons from 10 consecutive patients. Medicine 2012; 91:57–66.

This is the largest case series published on the use of rituximab in patients with aortitis due to IgG4-RD.

56. Narshi CV, Allard SA. Sustained response to tocilizumab, anti-IL-6 antibody, following anti-TNF-alpha failure in a patient with relapsing polychondritis complicated by aortitis. Rheumatol 2012; 51:952–953.
57. Shibuya M, Fujio K, Morita K, et al. Successful treatment with tocilizumab in a case of Cogan's syndrome complicated with aortitis. Mod Rheumatol (in press).

aortitis; giant cell arteritis; IgG4-related disease; leflunomide; rituximab; Takayasu arteritis; tocilizumab

© 2013 Lippincott Williams & Wilkins, Inc.