Dear Editor,

In October 2011, Beyer and colleagues published an interesting article on the use of tocilizumab as rescue treatment for 3 patients with giant cell arteritis(1). Their patients had a high systemic inflammatory response and involvement of the aorta and its main branches, showing Takayasu-like features. The authors noted that, perhaps, tocilizumab might be less effective for 'classical' giant cell arteritis (GCA) patients with limited cranial involvement. In other case reports, tocilizumab has also been used successfully in patients with giant-cell arteritis and elevated acute phase reactants(2). In a series of cases recently published by Seitz et al(3,4), interestingly, two of their patients had almost normal acute phase reaction before starting treatment with tocilizumab and they did respond quickly upon treatment. The results in these case reports may indicate a good correlation between recent advances in the understanding of the pathogenic mechanisms of GCA and the favorable response to tocilizumab. At least two distinct CD4+ T-cell subsets, namely Th17 and Th1 cells, promote vascular inflammation in GCA. Th17 cells are explicitly corticosteroid-sensitive. However, Th1 cells are corticosteroid-resistant and abnormal Th1 responses continue, unaffected by corticosteroids, identifying GCA as a long-term, chronic immune-mediated disease(5). Interferon-gamma, the signature cytokine produced by the Th1 cell lineage, is expressed in high amounts in patients who experiment ischaemic complications. Thus, a major therapeutic challenge in controlling GCA disease activity lies in persistent Th1 responses. A recent study(6) has shown that in peripheral blood of active GCA patients Th1 and Th17 cells are markedly expanded and regulatory T cells are decreased. In experimental models, interleukin-6 (IL-6) is a potent inhibitor of transforming growth factor beta (TGF-beta)-driven induction of Foxp3+ regulatory T cells(7). IL-6 not only suppresses the generation of these regulatory T cells, but together with TGF-beta, it also induces naive T cells to express interleukin-17 and to become pathogenic Th17 cells(7). Theoretically, given that IL-6 regulates the balance between Th17 and regulatory T cells(8), it is possible that blocking IL-6-induced intracellular signals by the anti-IL-6 receptor antibody tocilizumab ameliorates the function of regulatory T cells, thereby helping to bring the immune system into physiologic balance.

Thus, besides its possible use as a rescue treatment or steroid sparing agent, perhaps, tocilizumab could have an additional role in modifying the natural history of this disorder.

References

1.Beyer C, Axmann R, Sahinbegovic E, et al. Anti-interleukin 6 receptor therapy as rescue treatment for giant cell arteritis. Ann Rheum Dis 2011;70:1874-5.

2.Sciascia S, Rossi D, Roccatello. Interleukin 6 blockade as steroid- sparing treatment for 2 patients with giant cell arteritis. J Rheumatol 2011;38:2080-1.

3.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.

4.Seitz M. Reply to the Letter to the Editor of Francisco Jose Fernandez-Fernandez et al. Swiss Med Wkly 2012;142:w13504.

5.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;23:43-9.

6.Terrier B, Geri G, Chaara W, et al. IL-21 modulates Th1 and Th17 responses in giant cell arteritis. Arthritis Rheum 2011 Dec 6. doi: 10.1002/art.34327.

7.Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441:235-8.

8.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 USA 2008;105:18460-5.