FDA Approves First Biologic Treatment for Polymyalgia Rheumatica
Medscape
Lucy Hicks
Gerry Gajadharsingh writes:
There are various diagnostic categories that fall under the heading of rheumatology (inflammatory joint and soft tissue disease) and polymyalgia rheumatica (PMR) is relatively common. It tends to present, predominantly in women > 60 years of age, normally with stiffness in pain affecting the neck and shoulder girdle, sometimes the pelvis and hips. Sometimes presentations can be atypical, and sometimes, including the related manifestation of giant cell arteritis (GCA), inflammation within the arterial vessels, of which temporal arteritis is the most concerning, because it tends to supply the eye. Initial medical treatment tends to be with prednisolone (oral steroids).
Blood test results can be suggestive, especially if there are raised inflammatory markers. The two most common inflammatory markers used in haematology and biochemistry blood tests tend to be ESR, Erythrocyte Sedimentation Rate and CRP, C reactive protein.
Both ESR and CRP are markers for inflammation but should be interpreted differently. Due to a basic physiological difference, CRP is more sensitive, as an accurate reflection of the acute phase of inflammation, compared to ESR. CRP concentration peak rapidly after the inflammatory stimulus and when the stimulus stops CRP decreases rapidly.
Levels of CRP begin to rise within 2 hours of an insult and has a half-life of about 18 hours. The rapid action of CRP makes it a participant in the acute or first phase of the inflammatory process, which is why it is often called an “acute-phase protein. ESR is an indirect measure of inflammation and increases at a slower rate in response to inflammation and can often take weeks to return to normal levels. Even after the inflammatory stimulation has ceased. The ESR rate increases as a result of any cause or focus of inflammation. When an inflammatory process is present, fibrinogen enters the blood in high amounts and causes red cells to stick to each other, which raises the ESR.
It is unclear whether chronic pain can exist without some inflammation. ESR and CRP may not be sensitive enough to detect small amounts of inflammation that may occur with neuropathic pain or other local causes of inflammation. In fact, ESR and CRP levels are normal in the majority of chronic back pain cases. In patients with osteoarthritis, ESR is usually normal, but CRP may be elevated. In fact, the CRP level in osteoarthritis may be a predictive biomarker for severity and duration of the disease. The presence of elevated ESR and CRP levels also can indicate the presence of an infection, so neither test can be used as a definitive diagnostic tool for pain or inflammation.
Normal results from an ESR test may show a range of range 0 to 22 mm/hr for men and 0 to 29 mm/hr for women. The upper threshold for a normal rate value may vary among testing labs and tends to increase with age and obesity. Inflammation tends to underpin most disease processes, and in fact, obesity with an increase in the size and number of fat cells within the body, tends to pump out lots of inflammatory cytokines. Just for reference when there is severe inflammation/infection, it’s not uncommon to see ESR > 100 mm/Hr.
A person’s CRP values may vary over time. Normal results from a CRP test may show a common range of 1 mg/L to 3mg/L but are not considered elevated until reaching over 5 mg/L. Just for reference when there is severe inflammation/infection, it’s not uncommon to see CRP > 200 mg/L.
There is also a subtype of CRP called high sensitivity CRP , hs-CRP. This is normally used for assessment for heart related problems. Results for an hs-CRP test may vary from a level less than 2.0 mg/L (lower risk of heart disease) to a level equal or greater than 2 mg/L (higher risk of heart disease).
There are other inflammatory markers such as interleukin-6 (IL6) and TNF Alpha. However, they tend to be much more expensive than ESR and CRP, for example, IL6 costs approximately £200 and a turnaround time from the lab is between one and two weeks, TNF Alpha approximately £170, with a turnaround time of two weeks.
The research below is focused on a monoclonal antibody ( an IL-6 blocker) in relation to PMR.
Monoclonal antibodies have been in the news because of their use in COVID-19 infection. They are approved in the UK but are incredibly expensive and the UK NICE guidelines are understandably, quite restrictive because of the cost. Protocols suggest the screening for TB prior to commencement of these drugs for certain patient groups, which can add to the complexity.
The majority of PMR patients start on a relatively high dose of prednisolone, which then tends to be tapered off over the next few weeks or months onto a maintenance dose, it’s not uncommon for people to be on a load of prednisolone for several years. However, long-term steroid use has its complications and side-effects, and one of those tends to be on the effect of bone density. Therefore, other drugs are often used such as the disease modifying antirheumatic drugs DMARDS. So called Biologics such as monoclonal antibodies are a relatively new addition with the research below suggesting their approval for PMR (in the USA).
Like many medical conditions, PMR is classified as autoimmune the body is attacking itself. Stress and viral infections can often be triggers. On a more holistic level, it’s often worthwhile supporting the patient and exploring the other factors that might be causing the immune systems to overreact. Diet plays a big part in aggravating inflammation, manual treatment and can often be used but not applied over vigorously, especially when the inflammatory load is high. I’m a big fan of the impact of the autonomic nervous system on many of these autoimmune problems, and this can be explored in a variety of ways, usually initially on a diagnostic level, measuring heart rate variability (HRV) and intervening using breathing exercises and being aware of the concepts of central nervous system sensitisation, often present in chronic pain.
The US Food and Drug Administration (FDA) approved sarilumab (Kevzara), monoclonal antibodies similar to tocilizumab (both also known as biologics), today for the treatment of polymyalgia rheumatica (PMR) in adults who have had an inadequate response to corticosteroids or could not tolerate a corticosteroid taper, joint developers Sanofi and Regeneron announced. The drug is the first and only FDA-approved biologic treatment for this inflammatory rheumatic disease.
The FDA previously approved sarilumb, an interleukin-6 receptor antagonist, in May 2017 for the treatment of moderate-to-severe active rheumatoid arthritis in adults who do not respond well or have an intolerance to disease-modifying antirheumatic drugs (DMARDs), like methotrexate.
The FDA approval for this new indication was based on results from the multicenter, phase 3 SAPHYR trial in patients with corticosteroid resistant, active PMR. In the randomized, double-blind, placebo-controlled study, 59 participants received 200 mg of sarilumab plus a 14-week taper of corticosteroid treatment and 58 participants received placebo every 2 weeks along with a 52-week taper of corticosteroid treatment.
After 1 year, 28% of sarilumab patients achieved sustained remission, compared with 10% of the placebo group (P = .0193). Medscape Medical News previously reported these trial results in November when they were presented at the 2022 American College of Rheumatology Annual Meeting.
The most common adverse events in the sarilumab group were neutropenia (15%), leukopenia (7%), constipation (7%), pruritic rash (5%), myalgia (7%), fatigue (5%), and injection site pruritus (5%). Two patients had serious adverse reactions of neutropenia, which resolved after discontinuing treatment.
“Polymyalgia rheumatica can be an incapacitating disease, causing painful disease flares in multiple parts of the bodies that leave people fatigued and unable to fully perform everyday activities. Corticosteroids have been the primary treatment to date, but many patients do not adequately respond to steroids or cannot be tapered off steroids, which puts such patients at risk of complications from long-term steroid therapy,” George D. Yancopolous, MD, PHD, president and chief scientific officer at Regeneron, said in the announcement. “With the approval of Kevzara for polymyalgia rheumatica, patients now have an FDA-approved treatment to help offer relief from the disabling symptoms of this disease and long-term dependence on steroids.”