Video Editor's Note: Tocilizumab and Disease Activity in Patients With Polymyalgia Rheumatica Receiving Glucocorticoid Therapy

I’m Dr Mary McDermott, JAMA Deputy Editor and Professor of Medicine at Northwestern University’s Feinberg School of Medicine. Welcome to this JAMA video editor’s note for the SEMAPHORE trial, published in the September 20th, 2022 issue of JAMA. Based on data from 2016, the lifetime risk of polymyalgia rheumatica, also know as PMR, in the US is 2.4% for women and 1.7% for men. Glucocorticoids are the primary treatment. However, relapse of PMR is common, and approximately 25% of patients require treatment with glucocorticoids for four to eight years. Glucocorticoids have adverse effects, and effective alternative therapies are needed.

Preliminary evidence suggests that tocilizumab might improve disease activity and reduce the need for glucocorticoid therapy in patients with PMR. Tocilizumab is a monoclonal antibody that blocks the cytokine interleukin-6 receptor, and has been approved to treat giant-cell arteritis. Interleukin-6 may be involved in the pathology of PMR. 

The SEMAPHORE Trial, a randomized, double-blinded, parallel-group, placebo-controlled clinical trial, studied the ability of tocilizumab, compared to placebo, to improve disease activity in patients with PMR and glucocorticoid dependence.  

The SEMAPHORE trial was conducted at 17 medical centers in France. Eligible participants were adults older than 50 years who responded to prednisone therapy but subsequently developed glucocorticoid dependency during prednisone tapering.

101 eligible participants were randomized to either intravenous tocilizumab or intravenous placebo, administered every four weeks for 24 weeks. The intervention was added to a standard tapering regimen of oral prednisone. 

The primary outcome was a composite of low disease activity and prednisone dose less than or equal to 5 mg/d or dose decrease by more than or equal to 10 mg/d from baseline at week 24. The composite primary endpoint occurred in 67.3% of patients treated with tocilizumab compared to 31.4% of those treated with placebo. Of 11 secondary outcomes, seven were statistically significant, favoring treatment with tocilizumab. The secondary outcomes included the finding that 49% of those randomized to tocilizumab, compared to about 19.6% of those randomized to placebo, discontinued prednisone during the trial. Infections were the most common adverse event, and occurred in 46.9% of patients in the tocilizumab group, and 39.2% in the placebo group. 

The results of the SEMAPHORE Trial support using tocilizumab to treat patients with PMR who are receiving chronic steroid therapy. This trial was important because a relatively large proportion of people with PMR require long-term therapy with glucocorticoids. However, these results do not apply to people with PMR who are not dependent on chronic steroids. Additional study is needed to determine whether patients who have not previously been treated with medications for PMR might benefit from tocilizumab. It’s also important to consider that tocilizumab has immunosuppressive effects, while PMR is not associated with increased risk of mortality or other major organ pathology. As noted in a related editorial by Dr Brendan Antiochos, many patients with PMR can be treated with relatively low doses of prednisone. In contrast to rheumatoid arthritis, it is difficult to envision universal treatment with a steroid-sparing agent such as tocilizumab in all patients presenting with PMR, because most likely this would represent overtreatment, both with regard to costs and risk of infection. A reasonable approach would be for clinicians to first evaluate a patient’s initial response to modest doses of glucocorticoids instead of prescribing biologic therapy at the time of diagnosis of PMR. Therefore, a treatment strategy for patients with refractory disease, or for patients with comorbidities that make even modest doses of prednisone over a long timeframe highly undesirable, should be the focus of future studies of novel approaches to managing PMR. While this trial suggests great promise for use of tocilizumab in patients with PMR on chronic glucocorticoids, further studies with longer term follow-up are needed before tocilizumab can be routinely prescribed long term for patients with PMR.