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Diseases and Conditions

Tocilizumab: the new wonder drug for giant cell arteritis

June 7, 2017
People aged 50 years and above can develop giant cell arteritis

On May 22nd 2017 the FDA approved weekly subcutaneous tocilizumab (trade name Actemra®) to treat giant cell arteritis, a type of vasculitis that can cause blindness and in some cases death.  Why is this so important and how does this change everything?  The answer is simple.  Previously there were no effective treatments.  Rheumatologists used steroids like prednisone at high doses for months on end.  Many people would get lot’s of side effects due to the steroids and even this did not guarantee success.  Typically it takes many years for a medication to get FDA approval.  Although it did take more than a year to get approval, the process in this particular situation was fast-tracked.  Before I get into how we got to where we are today, let’s start with some background.

What is giant cell arteritis?

Giant cell arteritis is a type of large vessel vasculitis that tends to affect people aged 50 years and above.

Pay attention to the spelling, a-r-T-E-r-i-t-i-s. This is completely different from a-r-T-H-r-i-t-i-s.

Giant cell arteritis is an autoimmune disease that inflames blood vessels not joints.  More specifically, it inflames the aorta and the branches of the aorta.  Sometimes it’s also called temporal arteritis, but that’s not a good name for it because the temporal arteries are one type of artery that giant cell arteritis can affect.  We call this autoimmune disease giant cell arteritis because if you biopsy an artery you will find “giant cells” also called “granulomatous inflammation”, when you look at it under a microscope.  In fact, this is one way rheumatologists make the diagnosis.

This is an image of the human arterial system. Giant cell arteritis can affect any artery coming off the aorta

By LadyofHats, Mariana Ruiz Villarreal [Public domain], via Wikimedia Commons

What are the symptoms of giant cell arteritis?

Giant cell arteritis can present in many ways.  It really depends on the affected blood vessel(s).  If there is vasculitis in a temporal artery, then people tend to have a bad headache and a cramping pain when chewing food.  Maybe the blood vessels supplying the ears has vasculitis? This can cause a change in hearing and vertigo.  If the blood vessels supplying the eyes is affected, then it can cause blindness.  In some cases, people aren’t even aware of it.  They get a CT scan for some unrelated issue and the radiologist finds a large aortic aneurysm.  Giant cell arteritis is a condition that causes inflammation throughout the body, so many people present with fevers, drenching night sweats, and weight loss.

One of the most common presentations of giant cell arteritis is polymyalgia rheumatica.  Sometimes doctors simply call it “PMR”.  While 40% of people with giant cell arteritis have polymyalgia rheumatica, 10-20% of people with polymyalgia rheumatic develop giant cell arteritis.  Polymyalgia rheumatica is an autoimmune disease that causes muscle pain and stiffness in the shoulders, neck, hips, and thighs.  Finally, like giant cell arteritis, it affects people aged 50 years and above.

How do you diagnose giant cell arteritis?

There are many ways to diagnose giant cell arteritis.  First of all, blood tests like the CRP and the sed rate are usually very high.  These are tests that measure the amount of inflammation in your body.   Ideally you want to have a biopsy of the affected blood vessel but sometimes that’s not possible.  The biopsy should show giant cells but this only occurs in about 50% of cases so having a negative biopsy does not necessarily completely exclude disease.  When a biopsy is not possible, certain imaging studies can help like ultrasound, CT angiography, and PET scans.

How is giant cell arteritis treated?

Steroids, steroids, and more steroids.  If a doctor suspects that someone has giant cell arteritis, they immediately start treatment with high doses of steroids.  This happens even before the workup!  Once the diagnosis is firmly made the steroids are slowly tapered.  This happens over months.  It’s not uncommon to still be on steroids for YEARS after the diagnosis.  In many cases, the vasculitis returns.  This can be very frustrating and upsetting.  Rheumatologists have tried to treat people with medications like methotrexate in addition to steroids, but these haven’t really worked.

That is until now…

How it began

In 1990 researchers tested the blood of 15 people who had untreated giant cell arteritis.  They found high levels of a cytokine called interleukin 6 (IL-6) in their blood.  After treatment with steroids, their interleukin 6 levels decreased except for a few people.  Which is unsurprising since many people with giant cell arteritis relapse.

At that time, we didn’t have any medications that specifically blocked interleukin 6.

Flash forward to 1997.  A company based in Japan called Chugai Pharmaceuticals began research on tocilizumab to treat rheumatoid arthritis.  Tocilizumab is biologic humanized monoclonal antibody that blocks interleukin 6. Then in 2003 Genentech co-developed the medication.  Genentech’s tocilizumab is called Actemra®. Finally in 2010 the FDA approved Actemra® for to treat moderate to severe rheumatoid arthritis.

Giant cell arteritis and tocilizumab

Now remember how researchers found high levels of interleukin 6 in the blood of people with giant cell arteritis? What would happen if you treated someone who has giant cell arteritis with tocilizumab?  Would they go into remission?  Maybe you could taper off steroids more quickly?  That’s exactly what some Swiss scientists showed in 2011.  They treated 5 people with giant cell arteritis with tocilizumab.  All of them went into remission and all of them were able to taper off the steroids quickly.  The elevation and blockade of interleukin 6 appeared to be especially relevant for the treatment of giant cell arteritis.  But this was a case series with a very short follow-up time.  Was this a fluke or were they onto something?

In 2012, researchers started a larger phase 2 study.  This time they studied 30 people and they randomized them to either receive tocilizumab+prednisone or placebo+prednisone. The results were favorable:

  • 85% of the people who received tocilizumab and 40% of the people who received placebo went into remission by week 12.
  • 15 % of the people who received tocilizumab relapsed, where 80% of the people who received placebo relapsed by week 52.
  • People who received tocilizumab on average stopped prednisone 12 weeks in advance compared to people who received placebo.
  • 35% of people who received tocilizumab had a serious side effect, where 50% of people who received placebo had a serious side effect.

The last act

At last year’s American College of Rheumatology conference, Dr. John Stone presented data from the GiACTA trial, which was a randomized, double-blind, placebo-controlled trial.  This was a phase 3 study.  So they looked at more people from various locations.  There were 251 people placed into 4 different groups.

  • A short course of prednisone (26 weeks) + a weekly subcutaneous placebo
  • A long course of prednisone (52 weeks) + a weekly subcutaneous placebo
  • A short course of prednisone + weekly subcutaneous tocilizumab
  • A short course of prednisone + every other week subcutaneous tocilizumab

The results

  • 56% of people who received weekly tocilizumab achieved and stayed in remission after 12 months.
  • 53.1% of people who received every other week tocilizumab achieved and stayed in remission after 12 months.
  • 14% of people who received a short course prednisone + placebo were in remission after 12 months (p <0.0001).
  • 17.6% of people who received a long course of prednisone + placebo were in remission after 12 months (p ≤ 0.0002).
  • People who received tocilizumab received about half as much prednisone overall.
  • Adverse events were about the same in all groups and there were no deaths or vision loss.

The conclusion

Due to these extraordinary results and the dire need for effective treatment for giant cell arteritis, the FDA approved weekly subcutaneous tocilizumab.  I don’t know about you, but I’m very excited about this!  Finally a medication that works!  Mind you, it doesn’t work in every single case but this is definitely is a step forward.  And to add icing on the cake, although tocilizumab doesn’t eliminate the need for steroids, it does drastically decrease the total amount people get…another big plus.

To continue learning more about rheumatology and how to read research articles from their original source, please read on!

References

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm559791.htm

Rheumatology Secrets, 3rd edition

Dasgupta B, Panayi GS. Interleukin-6 in serum of patients with polymyalgia rheumatica and giant cell arteritis. Br J Rheumatol. 1990 Dec;29(6):456-8.

https://www.drugs.com/history/actemra.html

Seitz M, Reichenbach S, Bonel HM, Adler S, Wermelinger F, Villiger PM. Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series.Swiss Med Wkly. 2011 Jan 17;141:w13156. doi: 10.4414/smw.2011.13156.

Villiger PM, Adler S, Kuchen S, Wermelinger F, Dan D, Fiege V, Bütikofer L, Seitz M, Reichenbach. Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial.Lancet. 2016 May 7;387(10031):1921-7. doi: 10.1016/S0140-6736(16)00560-2. Epub 2016 Mar 4.

Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, Brouwer E, Cid MC, Dasgupta B, Rech J, Salvarani C, Spiera RF, Unizony SH, Collinson N. 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 [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). 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/. Accessed May 29, 2017.

Diseases and Conditions

Will I get osteonecrosis of the jaw if I take medications for osteoporosis?

April 12, 2017
Will I get osteonecrosis of the jaw if I take medications for osteoporosis?

Believe it or not, our bones are alive. Bones, in our bodies, are constantly renewing just like how our skin is constantly turning over. Our body’s ability to constantly build and breakdown bone is what allows us to grow and heal. This normal bone process over time results in our bones to get slightly thicker, however, we reach peak bone density in early adulthood.  As we age we gradually start to lose bone though.  Reduced bone mass puts us at risk for fractures which can be prevented by treatment.  It’s important to regularly perform weight-bearing exercise to prevent osteoporosis but sometimes it’s just not enough.  One of our best treatments (a group of drugs called bisphosphonates) slows the breakdown of bone and reduces the risk of a fracture, which is exactly what we want when treating osteoporosis.

What is Osteoporosis?

Osteoporosis is a disease in which bone density and quality are reduced, which means our bones become more porous and fragile, increasing the risk of fractures greatly. However, this bone loss occurs silently. Often there are no symptoms you would experience until your first fracture. It’s estimated that 200 million people worldwide suffer from osteoporosis. In the United States and in Europe, about 30% of all postmenopausal women have osteoporosis, and even worse at least 40% of these women will sustain one or more fragility fractures in their remaining lifetime.

But it is important not to forget that men suffer as well from osteoporosis.1

What is Osteonecrosis of the Jaw?

Exposed bone, in our mouths, that has persisted for more than 8 weeks. If a section of bone is fractured and does not heal it can cause blood flow to the bone to be interrupted causing bone death.

What Type of Treatment for Osteoporosis is related to Osteonecrosis of the Jaw?

Bisphosphonates work very well at slowing down the breakdown of bone which results in an increase in the density of bone. They have FDA approved indications for the treatment and prevention of post-menopausal osteoporosis, osteoporosis in men, and glucocorticoid (steroid) induced-osteoporosis. All bisphosphonates on the market have demonstrated reductions in vertebrae fractures and the majority of bisphosphonates show additional reduction in non-vertebral and hip fractures as well.

Bisphosphonates include: alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), zoledronic acid (Reclast)

Such strong inhibition of bone breakdown may theoretically lead to an accumulation of microdamage to the bone which might compromise bone strength or delay fracture healing. However, we have seen, from studying the bones of women on long-term bisphosphonates that there is no increased microdamage, and clinical trials of bisphosphonates did not show evidence of altered healing.2

What are Risk Factors for Osteonecrosis of the Jaw for Patients?

  • Drug-related risk factors
    • Bisphosphonate potency (oral therapies less potent than intravenous)
    • Duration of bisphosphonate treatment
  • Individual risk factors
    • Dental surgery
    • Concomitant oral disease
    • Periodontal disease
    • Ill-fitted dental prosthesis
  • Demographic factors
    • Genetic factors
  • Aggravating factors
    • Heavy smoking
    • Infection

What is the Real Risk of Osteonecrosis?

Osteonecrosis of the jaw (ONJ) is an extremely rare adverse event for patients taking bisphosphonates for osteoporosis.  Reports of bisphosphonate induced ONJ date back to the early 2000’s.  Reviews of current data support that up to 80% of ONJ cases occurred in patients with various cancers. These patients were also treated for a long period of time with high-dose injectable bisphosphonates. It is important to note that these doses were 10x higher than doses used to treat osteoporosis.3

Cases, of ONJ in osteoporotic patients, are extremely rare – not one case was found in more than 3000 patients participating in the clinical trials with zoledronic acid and alendronate. And no causal link between ONJ and bisphosphonate therapy, in these patients, has been convincingly demonstrated.4  

Although there are limitations to all studies, based on this information, the risk of ONJ in patients treated with bisphosphonates for osteoporosis is very low.

What does the American Dental Association Recommend?4

  • Routine Dental Care
  • Not modifying dental care solely because of bisphosphonates
  • Recommend AGAINST discontinuing bisphosphonates just before dental procedures

Conclusion

You should not stop taking your osteoporosis medication without talking to your medical provider. Osteoporosis is a serious but very treatable medical condition. The risk of fractures in people suffering from osteoporosis is very real and serious, while the risk of bisphosphonate-induced osteonecrosis of the jaw is rare. Also, there are  steps you and your doctor can take to help further reduce your risk by ensuring good dental hygiene and  preventive dental checkups  before starting and during treatment with these medications.    

Remember it’s always about benefit versus risk!

Author: Amy R. DeGennaro, Doctor of Pharmacy Candidate graduating May 2017 from Albany College of Pharmacy and Health Sciences.

Reviewed and approved by:  Jessica Farrell, PharmD.  Clinical Pharmacist, The Center for Rheumatology/Associate Professor, Albany College of Pharmacy and Health Sciences

References

  1. International Osteoporosis Foundation. Available at:  iofbonehealth.org
  2. Chapurlat RD, Arlot M, Burt-Pichat B, Chavassieux P, Roux JP, Portero-Muzy N, Delmas PD. Microcrack frequency and bone remodeling in postmenopausal osteoporotic women on long-term bisphosphonates: a bone biopsy study. J Bone Miner Res. 2007; 22:1502-1509.
  3. Hough FS, Brown SL, Cassim B, Davey MR. The safety of osteoporosis medication. South African Medical Journal. 2014;104.4: p279.
  4. Florence R, Allen S, Benedict L, Compo R, Jensen A, Kalogeropoulou D, Kearns A, Larson S, Mallen E, O’Day K, Peltier A, Webb B. Institute for Clinical Systems Improvement. Diagnosis and Treatment of Osteoporosis.  Updated July 2013.

Medical Disclaimer

This information is offered to educate the general public. The information posted on this website does not replace professional medical advice, but for general information purposes only. There is no Doctor – Patient relationship established. We strongly advised you to speak with your medical professional if you have questions concerning your symptoms, diagnosis and treatment.