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Treatment of Giant Cell Arteritis With Tocilizumab: A Historical Perspective

Issue: November 2017

ByGary S. Hoffman, MD, MS, MACR

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Editor’s Note:

I am thrilled to have Gary S. Hoffman, MD, MS, MACR, write this month’s Guest Editorial for Healio Rheumatology. No one, in my judgment, is better qualified to help us consider how the recent advances in giant cell arteritis will ultimately effect the way we treat the disease and, of course, ultimately how our patients can potentially benefit from these changes. New therapies must be critically appraised based on a skillful weighing of benefits and risk. We are fortunate to have one of the sages of vasculitis guide us through this process.

— Leonard H. Calabrese, DO
Chief Medical Editor, Healio Rheumatology

Some have attributed the first written account of giant cell arteritis and temporal artery excision to Ali ibn Isa (940 to 1010 A.D.). In his text Memorandum Book of a 10th Century Oculist, Isa notes that “By cautery or removal of arteries one treats not only migraine and headache ... but also the acute sharp catarrhal affections, including those showing heat and inflammation in the temporal muscles.” He adds that “These conditions may terminate in loss of eye sight.”

During the ensuing 9 centuries, numerous descriptions of giant cell arteritis (GCA) have emphasized demographics and outcomes of those afflicted. The most seminal accounts include recognition of large vessel disease and the first use of corticosteroids (CS). Unfortunately, the following 6 decades of GCA history have been marked by a plethora of studies documenting both efficacy and toxicity of CS, but not new effective therapies. Toxicity has limited duration of high-dose therapy and prospective studies have revealed that tapering of CS leads to upward of 80% of patients experiencing relapses and disease progression.

Pathogenesis

This period has not been without efforts to explore predisposition and etiology of GCA, as well as attempts to identify better therapies. Based on genetic frequencies that exceed chance, GCA has been linked to several gene polymorphisms that either increase or decrease disease risk. Examples for increased risk include HLA-DRB1*04 (both alleles 04:01, 04:04) and non-HLA polymorphisms (eg, PTPN22). While these genes may play important roles in affecting GCA susceptibility, the associations are not so precise as to conclude that anyone or combination these polymorphisms are by themselves essential for disease expression.

The search for an etiological agent has produced many suspects, but confirmation by others has been absent. Numerous studies have provided insights into the nature of cells, cytokines and proinflammatory agents within the GCA lesion. The findings have been an impetus to examine immunoinflammatory antagonists in vasculitis in general, including GCA. The results have been enlightening and have reminded us of certain aspects of evidence and inflammation that are akin to human behavior. For example, being at the scene of a crime is not proof of committing that crime. We learned that finding abundant tumor necrosis factor-alpha in GCA lesions did not predict that anti-TNF-alpha therapy would be palliative for GCA. Do such findings suggest that some proinflammatory mediators may have other roles, such as being reactive or compensatory in certain settings or just not being major factors in a multifaceted attack on a target?

Would strategies to block interleukin-6 (IL-6) in GCA have the same fate as anti-TNF agents? What is known that might predict a positive clinical trial? New-onset GCA is associated with Th1 and Th17 cells populating lesions in affected arteries and expansion of these cells in blood. IL-6 stimulates differentiation of naïve CD4+ T cells into Th17 cells and decreases Treg function. IL-6 is present in inflamed GCA arteries and concentrations are increased in the blood of patients with active disease. Miyabe and colleagues have demonstrated that tocilizumab (TCZ), a monoclonal antibody to the IL-6 receptor, corrects the reduction of Tregs in GCA and diminishes circulating Th17 cells and IL-17.

Seminal Study

In a seminal study, Stone and colleagues have almost brought us full circle in the TCZ-GCA treatment story. In the GiACTA study, the largest prospective GCA trial to date, the authors enrolled 251 patients. Of these, 86% completed the trial at 52-week follow-up. Patients were randomly assigned in a double-blind fashion to groups that received CS plus TCZ (Actemra, Genentech, Roche) (162 mg subcutaneously) either every week (qwk) or every other week (q2wk). The TCZ groups underwent a 26-week CS taper and were compared to groups that received TCZ-placebo plus CS with either a 26-week or 52-week taper to 0. Sustained remission was defined as the absence of relapse and ability to taper off CS at week 52. This endpoint was achieved in 14% of placebo-treated patients who underwent a 26-week taper of CS and in 18% who had the longer 52-week CS taper. The two TCZ groups (26-week CS taper) achieved sustained remission in 56% (qwk TCZ) and 53% (q2wk TCZ) of cases. In addition, at 52-week follow-up, the TCZ groups had received about 50% less CS than controls.

Total adverse events were similar between all groups. However, serious adverse events were more common in the placebo groups and that included infections, especially in those undergoing a 52-week CS taper. Physical components of quality of life assessments (SF-36) in the TCZ groups were superior to that noted for the placebo CS-treated patients. Patient global assessments of disease activity were also superior for TCZ-treated groups. It was based on these results that the FDA approved TCZ for the treatment of GCA in May 2017.

Remaining Questions

What questions remain for those who plan to prescribe TCZ for GCA? Should it be used for all patients with GCA from the start of therapy? Not knowing long-term outcomes in this elderly cohort with multiple comorbidities, the authors deferred recommending TCZ for all patients with GCA. Nonetheless, given the striking results from the GiACTA trial, I would be inclined to consider TCZ with CS at the time of diagnosis for patients in whom there is a history of poor CS tolerance or for those who have conditions likely to be aggravated by prolonged CS use. This may include patients with a history of CS-induced-psychosis or severe mental status changes, severe metabolic bone disease, difficult-to-control diabetes and severe congestive heart failure made worse by CS.

In patients for whom TCZ has allowed effective CS tapering and sustained remissions, should TCZ be continued indefinitely? We are now familiar with GCA usually not “burning out” or being fully controlled by CS. Indeed, in the GiACTA trial, more than 80% of CS plus placebo-treated patients relapsed by 52 weeks. One can only speculate about whether the remainder would relapse with time. However, we do know that clinically inapparent active GCA may be discovered at post-mortem or surgery for thoracic aortic aneurysms requiring reconstruction. This question can only be answered after we learn more from follow up of the GiACTA study and others like it.

Future Studies

The reader should also be encouraged to know that studies are planned or ongoing to evaluate the efficacy of other cell or cytokine inhibitors in GCA. Examples include abatacept (CTLA4-Ig), for which there has already been a positive phase 2 study; sirukumab, a direct acting IL-6 inhibitor; baricitnib, a Janus kinase inhibitor; ustekinumab, an inhibitor of IL-12 and IL-23; and secukinumab, an IL-17 antagonist.

Thus, after a painfully prolonged era of CS therapy for GCA, we are reaping the rewards of decades of work devoted to pathogenesis. We now have the tools to design targeted therapies, but mysteries still abound. What is responsible for female gender bias in GCA? Why are certain vessels (eg, the aorta and aortic arch arteries) favored as targets? Why are the elderly so vulnerable (eg, mean age 74 years)? What changes accompany aging that enhance vulnerability? While immune function becomes more abnormal with aging, antigens are less efficiently cleared, low-grade inflammation and autoimmune events increase, and our microbiome changes, still only a small percent of the geriatric population develops GCA. What is the antigen driving the multipronged attack on vulnerable vessels? Is it endogenous, exogenous, a native antigen or a modified native protein? How might it interface with genetic susceptibility markers?

We have learned from the oncology community that cancer cures may be achieved without always knowing cause, but we have also learned from the history of infectious diseases that knowledge of causation is the most certain path to designing curative therapies. It is not unrealistic for us to be excited about the dawning of the next era for autoimmunity being discovery of cause and cures. Until then, we can be grateful for the addition of TCZ to GCA care.

• References:
• Carmona FD, et al. Amer J Hum Gen. 2015;96:565–580.
• Chavany JA, et al. La Presse Medicale. 1948;69:835.
• Cooke WT, et al. Quarterly J Med. 1946;15:47-75.
• Franceschi C, et al. Trends Endocrinol Metab. 2017;doi:10.1016/j.tem.2016.09.005.
• Hoffman GS. Ann Intern Med. 2016;doi:10.7326/AITC201611010.
• Hoffman GS, et al. Ann Intern Med. 2007;146(9):621-630.
• Hoffman GS, et al. Arthritis Rheum. 2002;46:1309-1318.
• Jover JA, et al. Ann Intern Med. 2001;134:106-114.
• Mackie SL, et al. Arthritis Res Ther. 2015;doi:10.1186/s13075-015-0692-4.
• Miyabe C, et al. Ann Rheum Dis. 2014;doi:10.1136/annrheumdis-2016-210070.
• Ostberg G. Acta Med Scand Suppl. 1972;533:135-159.
• Seror R, et al. Ann Rheum Dis. 2014;doi:10.1136/annrheumdis-2013-203586.
• Shick RM, et al. Proc Staff Meet Mayo Clin. 1950;16;25:492-494.
• Stone JH, et al. N Engl J Med. 2017;doi:10.1056/NEJMc1711031.
• Svensson LG, et al. J Thorac Cardiovasc Surg. 2015;doi:10.1016/j.jtcvs.2014.08.003.
• Tuckwell K, et al. Sem Arthritis Rheum. 2017;doi:10.1016/j.semarthrit.2016.11.002.
• Wood C. Northwestern University. Memorandum Book of a 10th Century Oculist. Translated from Arabic. Chapter 25, “Excision of Arteries and their Cauterization.” 1936.

• For more information:
• Gary S. Hoffman MD, MS, MACR, is professor emeritus at the Cleveland Clinic Lerner College of Medicine, Center for Vasculitis Care and Research in Cleveland. He can be reached at hoffmag@ccf.org.

Disclosure: Hoffman reports service on the GiACTA Independent Monitoring Committee and advisory boards for Genentech and Roche.