Giant cell arteritis: An updated review of an old disease
Release date: July 1, 2019
Expiration date: June 30, 2020
Estimated time of completion: 1 hour
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ABSTRACT
Giant cell arteritis is a common systemic vasculitis that affects the elderly and has a variable clinical presentation. Physicians should be aware of its different clinical phenotypes so that they can recognize it early and promptly initiate glucocorticoids, the mainstay of therapy. Clinicians should also be familiar with the toxicity of glucocorticoids and how to manage adverse effects. Tocilizumab, an interleukin 6 receptor inhibitor, is emerging as a glucocorticoid-sparing treatment, though its long-term safety and efficacy are still under study.
KEY POINTS
- Giant cell arteritis can present with cranial symptoms, extracranial large-vessel involvement, or polymyalgia rheumatica.
- Temporal artery biopsy is the standard for diagnosis.
- Adverse effects of glucocorticoid treatment, particularly bone loss, need to be managed.
- In patients treated with glucocorticoids alone, the relapse rate is high when the drugs are tapered; thus, prolonged treatment is required.
TOCILIZUMAB: A STEROID-SPARING MEDICATION
Due to the adverse effects of long-term use of glucocorticoids and high rates of relapse, there is a pressing need for medications that are more efficacious and less toxic to treat GCA.
The European League Against Rheumatism, in its 2009 management guidelines for large-vessel vasculitis, recommend using an adjunctive immunosuppressant agent.19 In the case of GCA, they recommend using methotrexate 10 to 15 mg/week, which has shown modest evidence of reducing the relapse rate and lowering the cumulative doses of glucocorticoids needed.35,36
Studies of tumor necrosis factor inhibitors and abatacept have not yielded significant reductions in the relapse rate or decreased cumulative doses of prednisone.37,38
,Advances in treatment for GCA have stagnated, but recent trials39,40 have evaluated the IL-6 receptor alpha inhibitor tocilizumab, given the central role of IL-6 in the pathogenesis of GCA. Case reports have revealed rapid induction and maintenance of remission in GCA using tocilizumab.41,42
Villiger et al39 performed a randomized, placebo-controlled trial to study the efficacy and safety of tocilizumab in induction and maintenance of disease remission in 30 patients with newly diagnosed GCA. The primary outcome, complete remission at 12 weeks, was achieved in 85% of patients who received tocilizumab plus tapered prednisolone, compared with 40% of patients who received placebo plus tapering prednisolone. The tocilizumab group also had favorable results in secondary outcomes including relapse-free survival at 52 weeks, time to first relapse after induction of remission, and cumulative dose of prednisolone.
The GiACTA trial. Stone et al40 studied the effect of tocilizumab on rates of relapse during glucocorticoid tapering in 251 GCA patients over the course of 52 weeks. Patients were randomized in a 2:1:1:1 ratio to 4 treatment groups:
- Tocilizumab weekly plus prednisone, with prednisone tapered over 26 weeks
- Tocilizumab every other week plus prednisone tapered over 26 weeks
- Placebo plus prednisone tapered over 26 weeks
- Placebo plus prednisone tapered over 52 weeks.
The primary outcome was the rate of sustained glucocorticoid-free remission at 52 weeks. Secondary outcomes included the remission rate, the cumulative glucocorticoid dose, and safety measures. At 52 weeks, the rates of sustained remission were:
- 56% with tocilizumab weekly
- 53% with tocilizumab every other week
- 14% with placebo plus 26-week prednisone taper
- 18% with placebo plus 52-week taper.
Differences between the active treatment groups and the placebo groups were statistically significant (P < .001).
The cumulative dose of prednisone in tocilizumab recipients was significantly less than in placebo recipients. Rates of adverse events were similar. Ultimately, the study showed that tocilizumab, either weekly or every other week, was more effective than prednisone alone at sustaining glucocorticoid-free remission in patients with GCA.
However, the study also raised questions about tocilizumab’s toxic effect profile and its long-term efficacy, as well as who are the optimal candidates for this therapy. Data on long-term use of tocilizumab are primarily taken from its use in rheumatoid arthritis.43 As of this writing, Stone et al are conducting an open-label trial to help provide long-term safety and efficacy data in patients with GCA. In the meantime, we must extrapolate data from the long-term use of tocilizumab in rheumatoid arthritis.
Tocilizumab and lower gastrointestinal tract perforation
One of the major adverse effects of long-term use of tocilizumab is lower gastrointestinal tract perforation.
Xie et al,44 in 2016, reported that the risk of perforation in patients on tocilizumab for rheumatoid arthritis was more than 2 times higher than in patients taking a tumor necrosis factor inhibitor. However, the absolute rates of perforation were low overall, roughly 1 to 3 per 1,000 patient-years in the tocilizumab group. Risk factors for perforation included older age, history of diverticulitis or other gastrointestinal tract condition, and prednisone doses of 7.5 mg or more a day.
Does tocilizumab prevent blindness?
Another consideration is that tocilizumab may not prevent optic neuropathy. In the GiACTA trial, 1 patient in the group receiving tocilizumab every other week developed optic neuropathy.40 Prednisone had been completely tapered off at the time, and the condition resolved when glucocorticoids were restarted. Thus, it is unknown if tocilizumab would be effective on its own without concomitant use of glucocorticoids.
Vision loss is one of the most severe complications of GCA, and it is still unclear whether tocilizumab can prevent vision loss in GCA. Also, we still have no data on the effect of tocilizumab on histopathologic findings, and whether biopsy yield diminishes over time. We hope future studies will help guide us in this regard.
No guidelines on tocilizumab yet
Clinical guidelines on the appropriate use of tocilizumab in GCA are lacking. The American College of Rheumatology and the European League Against Rheumatism have yet to publish updated guidelines with comments on use of tocilizumab. Therefore, it is unclear if tocilizumab is a first-line treatment in GCA, as its efficacy alone without glucocorticoids and its long-term safety in GCA patients have not been studied.
Treatment with tocilizumab should be individualized; it should be considered in patients who have had adverse effects from glucocorticoids, and in patients who experience a flare or cannot have their glucocorticoid dose lowered to an appropriate range.
The optimal duration of tocilizumab therapy is also unknown. However, using the GiACTA study as a rough guide, we try to limit its use to 1 year until additional data are available.
Patients on IL-6 inhibition may have suppressed C-reactive protein regardless of disease activity.43 Therefore, this laboratory value may not be reliable in determining active disease in patients on tocilizumab.
The GiACTA trial has shown an impressive improvement in the relapse-free remission period in patients with GCA taking tocilizumab. However, much work needs to be done to define the safety of this medication and determine which patients should be started on it. In the meantime, we recommend starting high-dose glucocorticoid therapy as soon as the diagnosis of GCA is suspected. In patients who do not tolerate glucocorticoids or whose disease flares during glucocorticoid taper, we recommend starting treatment with tocilizumab either once a week or every other week for at least 1 year.
