Closer Look at Giant Cell Arteritis

At last year’s American College of Rheumatology Annual Meeting, preliminary results of the GiACTA study made a splash among clinicians who deal with giant cell arteritis. The findings offered tangible hope that tocilizumab might be the next step in GCA therapy that rheumatologists have been looking for since prednisone hit the market some 70 years ago.

“We have not identified an effective steroid-sparing medication since prednisone became the standard of therapy in the 1950s,” Kenneth J. Warrington, MD, professor of Medicine and chair of the Division of Rheumatology at the Mayo Clinic in Rochester, Minn., told Healio Rheumatology in an interview. “There have been so many drugs investigated but none were of significant benefit.”

Although the full data set has yet to emerge, there has been enough optimism that other trials of tocilizumab (Actemra/RoActemra, Roche) are underway.

Measuring Advances

A useful way of measuring advances in giant cell arteritis (GCA) was proposed by Peter Grayson, MD, head of the Vasculitis Translational Research Program at the NIH. He suggested that treatment advances in GCA lags years, if not decades, behind the advancements in other forms of vasculitis, particularly small vessel vasculitides.

Gary S. Hoffman, MD, MS, MACR, professor emeritus in the Department of Rheumatic and Immunologic Diseases and founder of the Center for Vasculitis Care and Research at the Cleveland Clinic/Lerner College of Medicine, weighed in. “That is a complex question,” he said. “GCA is a simpler disease than most small vessel vasculitides (SVV), eg, [granulomatosis with polyangiitis] GPA, [Fmicroscopic polyangiitis] MPA, [eosinophilic granulomatosis with polyangiitis] EGPA or Churg Strauss. GCA almost exclusively targets vessels, and the others target tissue parenchyma and vessels.”

According to Hoffman, important strides have been made in all types of vasculitides in recent years.

“The prognosis for GCA is better than for most examples of SVV because deaths from GCA usually do not occur apart from those cases complicated by aortic aneurysms that may dissect or rupture,” he said. “If not diagnosed or properly treated, GPA and MPA are often fatal conditions, but that has changed with better treatment for those diseases.”

For Warrington, there are practical considerations.

“GCA is more common, which means that larger trials can be conducted,” he said. “On the other hand, when one considers the move to biologic therapies, it was done earlier in small vessel vasculitis.”

Warrington said the search for immunosuppressive agents to supplement steroids has moved slower in GCA.

“The good news is that in GCA, we are on the cusp of having biologic therapies available,” he said. “Some folks hypothesized that infliximab or adalimumab would work, but in clinical trials of those drugs with GCA, [these] failed to show significant benefit. Efforts have been made with methotrexate, but there has not been evidence of significant efficacy until tocilizumab.”

For Hoffman, the issue comes down to one fundamental problem. “We still do not know the cause of GCA,” he said. “Without knowing that, identifying a cure is unlikely.”

Key Findings

John H. Stone, MD, and colleagues presented 52-week data for the GiACTA study at last year’s American College of Rheumatology (ACR) Annual Meeting. The study included 251 patients randomly assigned one of four treatment groups. One group was the short-course prednisone group, which underwent a 26-week prednisone taper plus weekly subcutaneous placebo); another group was the long-course prednisone group, which included a 52-week prednisone taper plus weekly subcutaneous placebo; another group was treated with weekly subcutaneous tocilizumab 162 mg plus a 26-week prednisone taper; and a fourth group received subcutaneous tocilizumab at 162 mg every other week plus a 26-week prednisone taper.

The proportion of patients in sustained remission served as the primary endpoint. Primary comparison results indicated that 56% of patients in the weekly tocilizumab group and 53.1% of patients who received this drug every other week achieved sustained remission at 12 months. Comparatively, 14% of patients in the short-course prednisone arm reached this endpoint. Secondary comparison results showed the sustained remission rates in both tocilizumab arms were significantly superior to the rate of 17.6% which was reported for patients treated with long-course prednisone. Use of tocilizumab also resulted in less than half of the median cumulative steroid exposure than in the long-course prednisone group. Adverse event profiles were comparable for the four study groups. As of the time of study presentation at the ACR Annual Meeting in 2016, the researchers said there was no mortality or new vision loss.

Stone initially investigated the drug in a small cohort of patients and published the results in 2012. Warrington highlighted the favorable response in terms of symptoms and inflammatory markers in that cohort and suggested this was the reason the group continued with GiACTA.

“GiACTA was easily one of the biggest things to come out of the ACR Annual Meeting last year,” Grayson said. “It was a real breakthrough because of how long we have been looking for an effective steroid-sparing medication in giant cell arteritis. This study showed that tocilizumab has efficacy in giant cell arteritis.”

The key is that the IL-6 cytokine is relevant in the pathogenesis of GCA, according to Warrington.

“IL-6 correlates with disease activity,” he said. “When you look at an inflamed artery, you see that IL-6 is expressed in the vessel.”

Despite the largely favorable results, Warrington expressed some caution. “First off, we are still waiting for the full manuscript,” he said. “Beyond that, there are a number of unanswered questions. We still do not know the optimal duration of treatment with tocilizumab. It was observed that some patients may develop vascular complications, such as aneurysms, and it is unclear if the drug has an impact on that.”

That said, the clinical community is moving forward with investigation of tocilizumab. Villiger and colleagues randomly assigned 20 patients to tocilizumab at a dose of 8 mg/kg along with oral prednisolone, starting at 1 mg/kg per day and tapered to 0 mg, and 10 patients to receive placebo plus the same prednisolone regimen. This treatment was administered during the course of 52 weeks, with a total of 13 infusions each given every 4 weeks. The proportion of patients who achieved complete remission with a prednisolone dose of 0.1 mg/kg per day in an intention-to-treat analysis served as the primary outcome measure. The study was conducted between Mar. 3, 2012 and Sept. 9, 2014. Complete remission rates were 85% for the tocilizumab group and 40% for the placebo group. The relapse-free survival rates were 85% for tocilizumab plus prednisone group and 20% for prednisone plus placebo group.

Other findings indicated the mean survival-time difference for cessation of steroids was 12 weeks in favor of the study drug compared with placebo. Cumulative prednisolone doses were 43 mg/kg for tocilizumab and 110 mg/kg for placebo. Serious adverse event rates were 35% for tocilizumab and 50% for placebo.

“Our findings show, for the first time in a trial setting, the efficacy of tocilizumab in the induction and maintenance of remission in patients with giant cell arteritis,” the researchers concluded.

“The unpublished GiACTA data confirm these findings,” Hoffman said.

Closer Look at Methotrexate

Koster and colleagues conducted a retrospective review of patients diagnosed with GCA between 1998 and 2013 to determine usage patterns of methotrexate (MTX) and outcomes among patients treated with that drug. The study included 84 patients who received MTX and 84 patients treated only with prednisone. The initial prednisone doses were 53.5 ± 15.8 mg/day among patients in the MTX arm compared with 55.0 ± 13.5 mg/day among controls. The median duration between diagnosis of GCA and initiation of MTX was 0.7 years (interquartile range[IQR], 0.3-1.6). The median dose was 13.5 mg (IQR, 10-15) per week. Before MTX initiation, the relapse rate was 11.8 relapses per 10 person-years. After initiation, this decreased to 3.69 relapses per 10 person-years. When the researchers performed a rate ratio comparing relapse rates before and after MTX initiation, it was observed that this ratio significantly decreased.

Among controls, there were 3.42 relapses per 10 person-years before the index date and 2.27 after. A significantly greater reduction in relapse rate occurred in the MTX group compared with the non-MTX group. Patients in the MTX group discontinued glucocorticoid therapy at a significantly greater rate than those not taking MTX. “MTX should be considered as adjunct therapy in patients with relapsing GCA to decrease the risk of further relapse events,” the researchers concluded.

“After a lot of time and effort to find other medications beyond prednisone, the next best thing is methotrexate,” Warrington said. “But the data are still inconclusive. There have essentially been three clinical trials of methotrexate. There was no evidence of efficacy in two of these, and one showed efficacy. In a meta-analysis of the three trials, there was evidence of a reduction in relapse risk with methotrexate.”

Grayson addressed these findings. “There just are not a lot of therapeutic options for these diseases,” he said.

That said, Hoffman noted some of his own previous research investigated these drugs prospectively. In a study from 2002, for example, 98 patients treated with MTX or placebo reached similar levels of treatment failure, with 57.5% in the MTX group failing and 77.3% in the placebo group failing. Multivariate analysis results indicated MTX did not decrease the risk of failure in the study population (RR = 0.72).

“The results of this randomized, multicenter trial do not support the adjunctive use of MTX to control disease activity or to decrease the cumulative dose and toxicity of [corticosteroid] CS in patients with GCA,” the researchers concluded.

Conversely, in 2001, Jover and colleagues investigated 42 patients with new-onset GCA. Eligible participants were treated with a tapered dose of corticosteroids and then MTX or placebo for 24 months. Results indicated the combination of prednisone and MTX yielded a 45% relapse rate compared with 84.2% for prednisone and placebo. The MTX regimen also reduced the ratio of patients with more than one relapse event. “Treatment with methotrexate plus corticosteroid is a safe alternative to corticosteroid therapy alone in patients with giant-cell arteritis and is more effective in controlling disease,” the researchers concluded.

Warrington said MTX has been the most studied drug, apart from tocilizumab. “The data are not robust enough yet,” he said. “This is why we are so excited about the signs of efficacy with tocilizumab.”

Advances in Imaging

Reichenbach and colleagues assessed magnetic resonance angiograms (MRA) to evaluate inflammatory signals in the vessel walls in a cohort of patients who underwent tocilizumab therapy. The study included 20 patients treated with the study drug at 8 mg/kg of body weight plus glucocorticoids and eight patients treated with placebo plus glucocorticoids. The number of patients with complete remission as assessed by MRA at week 12 served as the primary endpoint, while remission at 52 weeks plus change in vasculitis score served as the secondary endpoint. There were nine MRAs performed in the tocilizumab group and two performed in the placebo group at baseline. There were no signs of vasculitis. At week 12, nine patients in the tocilizumab group and four patients in the placebo Fgroup underwent these imaging tests. No signs of vasculitis were observed among nine patients in the tocilizumab group and two in the placebo group who had baseline MRAs. Twelve-week angiogram results showed all nine patients who underwent this imaging procedure were in clinical remission, while two of four patients in the placebo group were in remission.

Complete remission was reported in three patients in the tocilizumab arm and in one patient in the placebo arm. Week 52 results indicated additional improvement, but three patients remained in complete remission in the study drug group. These patients experienced a median change in vasculitis score of -1.0. No additional improvement was reported in the two patients in the placebo group who were in remission. They experienced a median change in vasculitis score of -0.5.

“Tocilizumab induces and sustains clinical remission of GCA but does not completely suppress [magnetic resonance] signals of vessel inflammation,” the researchers concluded. “Whether these signals are of prognostic importance remains to be determined and should be further evaluated in long-term studies.”

Nielsen and colleagues wrote that fluorine-18-fluorodeoxyglucose (18F-FDG) PET/CT is being used more frequently. However, steroid treatment is often delayed at least inpart because of limited availability of PET.

“PET is not performed for many reasons a part from availability. One example is that insurers may not allow payment for it, as it is not considered standard of care in their eyes,” he said.

Nielsen and colleagues aimed to find an 18F-FDG PET/CT diagnostic window after steroid treatment begins. The analysis included 20 patients who had confirmed GCA by 18F-FDG PET/CT. Ten patients were randomly assigned to repeat this imaging procedure after 3 days of treatment with oral prednisone 60 mg daily, while the other 10 were assigned to repeat the procedure after 10 days of the same therapy. Results prior to treatment included mean C-reactive protein was 77.2 mg/L, while the mean erythrocyte sedimentation rate was 77.3 mm/h. ACR criteria for GCA were fulfilled by 14 patients. Researchers observed a positive TAB in 13 patients. The mean number of prednisolone doses before the post-therapeutic image was 3.1 for the 3-day arm and 10.2 for the 10-day arm. No decrease in vascular composite score in the aorta was reported in the 3-day group. However, a significant in supra-aortic branches occurred in this group. All vascular domains significantly decreased FDG signal was noted in the 10-day treatment group. Despite a decrease in 18F-FDG, uptake decreased in supra-aortic branches after 3 days and all 10 patients were able to be diagnosed accurately in this arm. However, five of 10 patients could be diagnosed based on imaging criteria in the 10-day group.

“In LV-GCA, high-dose steroid treatment for 3 [days] or 10 days differentially attenuates the regional uptake of 18F-FDG, but diagnostic properties remain within the first 3 days,” the researchers concluded.

“A big push in the field currently is toward understanding the clinical utility of advanced imaging techniques in large vessel vasculitis, including PET scans that are traditionally used to detect cancer rather than vascular inflammation,” Grayson said. “A number of researchers are trying to figure out if PET scans provide complementary and useful information about disease activity beyond what can be gained by clinical assessment.”

More Targeted Imaging

Busquet and colleagues conducted a meta-analysis of 16 previously published studies to evaluate ultrasonography-derived signs of the temporal artery as a diagnostic tool for GCA. The study included 964 patients, of whom 448 were diagnosed by ACR criteria and 764 by temporal biopsy. All patients had undergone ultrasound. Clinicians observed the halo sign in 29% of the cohort. A positive biopsy was reported in 76% of the halo cases. In the ACR-criteria-positive group, the ultrasound halo sign had an overall sensitivity of 68.2% and specificity of 93.2%. However, when associated with Brefeldin A (BFA), the halo sign yielded an overall sensitivity of 64.2% and specificity of 93.4%. Also in the ACR-positive group, the bilateral halo sign was associated with an overall sensitivity of 58.2% and a specificity of about 100%.

However, this was only estimated in one study, according to the findings. In the positive biopsy group, an overall sensitivity of 82.4% and specificity of 86.8% was observed for the unilateral halo sign. However, no improvement was reported in association with BFA. An overall sensitivity of 51.7% and specificity of 82.4% was reported for the bilateral halo sign. The researchers reported significant heterogeneity was observed between studies.

“Among all ultrasonography-derived signs, the unilateral halo sign may be sufficient in GCA diagnosis,” they wrote. “However, this meta-analysis did not confirm the infallibility of these signs, in particular in case of an absence of ultrasonographic signs.”

“It is often necessary to periodically use imaging to detect or screen for damage in the aorta,” Warrington said. “Periodic imaging should be part of evaluation of many patients, particularly those at risk for aortic aneurysm.”

Hoffman wrote a comprehensive paper covering all aspects of GCA, which may be useful in putting this imaging information into context.

“The diagnosis of GCA should be considered in patients older than 50 years who present with new-onset, localized, unilateral headache; ischemic symptoms in the cervicocranial and upper vascular territories (eg, jaw claudication, vision aberration or loss); and muscle stiffness of the neck, shoulder or pelvic girdle,” he wrote. “Typical physical examination findings may include tenderness, swelling and erythema over the temporal artery and flow abnormalities of large vessels (eg, bruits, asymmetrical pulse or blood pressure).”

He noted most patients show elevations in ESR or CRP. “GCA involvement of large vessels is common and subclinical in most patients,” he wrote. “Temporal artery biopsy is considered the gold standard for diagnosis but may not be essential in all cases.”

More Standards of Care

Hoffman wrote that corticosteroid therapy should be initiated as soon as suspicion of GCA is high enough to warrant a temporal artery biopsy. This is particularly true when visual symptoms are present.

It is with this in mind that Warrington urged vigilance for clinicians who may potentially encounter GCA in day-to-day practice. “We should keep a high suspicion for disease when evaluating potential patients,” he said. “The most important potential complication is vision loss or blindness. The best way to reduce that risk is to diagnose and treat promptly and urgently.”

“Symptoms and acute-phase reactants typically respond promptly to effective treatment,” Hoffman wrote. However, he noted flares are common, especially when tapering corticosteroid therapy. “Although controversial, low-dose aspirin seems to decrease the risk of vision loss and cardiovascular ischemic events and should be provided to all patients who do not have contraindications. Patients should be followed closely for clinical signs of relapse or large vessel involvement and for development of corticosteroid-related complications.”

Some centers have fast-track clinics where patients who are at risk for vision loss can be treated right away, according to Warrington, who echoed Hoffman’s point that patients also should be followed closely for side effects of prednisone. “We need to educate patients that it is common to have relapses, and we as clinicians need to watch for those,” he said.

Immunosuppressive agents currently are adjunctive therapy to corticosteroids, the effects of which are almost immediate, according to Hoffman. “Monitoring therapy and disease progression for large vessel vasculitis should be clinical, include imaging modalities and measurement of inflammatory markers,” he said.

Warrington commented on this point. “It is important for clinicians to perform a thorough vascular exam on potential patients,” he said. “As rheumatologists, we are used to examining patients’ joints. In this case, we have to check pulses in upper and lower extremities, blood pressure in both arms and listen for bruits over all large vessels. One sign of vascular complications is discrepancy or loss of pulse in one arm.”

It is for all of these reasons that Hoffman recommends lifetime surveillance of patients with GCA. For Grayson, it is about reliably assessing each of the individual parameters that the disease presents.

“Large vessel vasculitis can be confusing and challenging even for rheumatologists with a lot of experience with these diseases,” Grayson said. “In some situations, it is hard to tell if a patient’s disease is active or in remission, which makes treatment decisions difficult and makes the conduction of clinical trials a challenge.”

There is reason for optimism, according to Hoffman. “Until tocilizumab came along, we had made no progress beyond steroids for more than 60 years,” he said. “Now we are making some progress.” – by Rob Volansky

• References:
• Busquet F, et al. Abstract #1958. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.
• http://acrabstracts.org/abstract/efficacy-and-safety-of-tocilizumab-in-patients-with-giant-cell-arteritis-primary-and-secondary-outcomes-from-a-phase-3-randomized-double-blind-placebo-controlled-trial/
• Hoffman GS. Ann Intern Med. 2016;doi:10.7326/AITC201611010.
• Koster MJ, et al. Abstract #861. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.
• Nielsen BD, et al. Abstract #3182. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.
• Reichenbach S, et a. Abstract #3183. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.
• Stone JH, et al. Abstract #911. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.
• Villiger PM, et al. Lancet. 2016;doi:10.1016/S0140-6736(16)00560-2.

• For more information:
• Peter Grayson, MD, can be reached at 1 AMS Circle, Bethesda, MD 20892; email: peter.grayson@nih.gov.
• Gary S. Hoffman, MD, MS, MACR, can be reached at 30060 Bolingbrook Rd, Pepper Pike, OH 44124; email: hoffmag@ccf.org.
• Kenneth J. Warrington, MD, can be reached at the Mayo Clinic, 200 First St. SW, Rochester, MN 55905; email: warrington.kenneth@mayo.edu.

Disclosures: Hoffman reports he has served on the independent Data Safety and Monitoring Board for GiACTA. Grayson reports no relevant financial disclosures. Warrington reports he has received clinical trial support from GlaxoSmithKline and Eli Lilly.