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Dr Jessica Chapman

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 hydroxychloroquine hurt my eyes?

May 24, 2017
Will hydroxychloroquine damage my eyes?

I love hydroxychloroquine.  Honestly, I really do.  It’s simple, easy, it works, and for the most part it’s benign especially when compared to the rest of the medications I prescribe.  Rheumatologists use hydroxychloroquine (Plaquenil) to treat of lupus, mild cases of rheumatoid arthritis, and many other autoimmune diseases.

Now I said benign.  Well I actually said, “for the most part it’s benign”.  Allergic reactions are always a concern but the main concern I have with hydroxychloroquine is the possibility of developing eye toxicity.  More specifically, hydroxychloroquine maculopathy.  But before I continue, I think it’s important to go through some anatomy.

Anatomy of the Eye

The following is a simplified version of the human eye.  The cornea is the clear part of the eye that lets you focus light into your eye.  The iris regulates the amount of light you let into your eye.  The pupil is the dark part of the eye.  This is where light actually goes into the eye.  The lens focuses light so that it hits the retina just right and the retina actually senses light.  This info is then condensed onto the optic disc and then sent to the optic nerve then into your brain.

Where does hydroxychloroquine fit in?

Now this is the important part because this is where hydroxychloroquine can cause problems: the macula.  The macula is a specialized place on your retina that has cells that enable you to see fine details with high acuity.  We call these specialized cells cones and they are found in high density in this area.  The macula is then made up of the fovea, foveal avascular zone, parafovea, and the perifovea.  The following is a real life example courtesy of Danny Hope.

By Photograph: Danny Hope from Brighton & Hove, UK Diagram: User:Zyxwv99 [CC BY 2.0 (http://creativecommons.org/licenses/by/2.0)], via Wikimedia Commons


Now the prospect of losing the ability to see things clearly sounds absolutely terrible. I’ve been wearing glasses since I was 13.  Without them, everything is blurry.  I can’t even imagine the blow to my quality of life, if I didn’t have my glasses.  Hydroxychloroquine is kind of like that.  Your vision becomes blurry, except glasses won’t help, and the vision loss is permanent.

So why would anyone go on this medication and why would your doctor even suggest it?

Well… because it’s actually a pretty good medication.  Just like most medications, you need to take it as safely as possible.  The American Academy of Ophthalmology released a statement last year about monitoring hydroxychloroquine.  Let’s go over these recommendations together!

Recommendations on Screening for Hydroxychloroquine Retinopathy (2016 Revision)

First of all, it’s still unclear how exactly hydroxychloroquine causes eye toxicity.  In a nutshell the outer layer of the retina gets damaged and then it deepens and spreads around the fovea.  People tend not to notice anything at this stage. Over time, if the medication is not stopped, the fovea becomes involved and visual acuity drops.  It’s also important to note that hydroxychloroquine can worsen even after stopping the medication.  If it’s caught early on, it probably won’t affect vision.  If there already was a lot of damage to begin with, then the risk is higher.  So the real question is what is the real risk of developing toxicity, what are the factors that increase that risk, and how often should you get screened by an ophthalmologist?

What is the real risk of developing hydroxychloroquine eye toxicity?

In the past, we thought the risk of developing eye toxicity from hydroxychloroquine was very low.  New data suggests otherwise.  Although the risk is still low, we were probably underestimating the risk.  Researchers following 2,361 people using hydroxychloroquine, found that about 7.5% of those people had eye toxicity.  The most important risk factors included the daily dose of hydroxychloroquine and duration of use.

People who took 4 to 5 mg/kg/day of hydroxychloroquine had a much lower cumulative risk as compared to people you took a higher dose: 1% risk in the first 5 years and less than 2% up to 10 years.  After 20 years the risk dramatically increased to 20%.

When I mean mg/kg/day, I mean the amount of drug for every kilogram of body weight over a 24 hour period.  To calculate the dosage of hydroxychloroquine you need to use your real weight, NOT your ideal weight.  For some medications, it’s the opposite.  Let’s say you were taking hydroxychloroquine 200 mg twice a day and then you started dieting and exercising, and then you shed a lot of weight.  You now may need to decrease your daily dose of hydroxychloroquine because your real weight decreased.  In the study, the researchers found that thin people tended to have more eye toxicity because they tended to get more than 4 – 5 mg/kg/day of hydroxychloroquine.


FYI When calculating your body weight to verify your hydroxychloroquine dose, you need to use metric.  This is not optional.

1 kilogram = 2.2 pounds


Other Significant Risks

Initially we thought hydroxychloroquine gets stored in fat cells.  In actuality, recent lab studies show that the medication is mostly stored in melanotic tissue, liver, and in the kidneys.  Muscle, fat, and other organs not so much.  That being said, people with severe kidney disease are at higher risk of developing eye toxicity.  These people may need more frequent eye testing and they may not need as high of a dose.

Other significant risks includes concurrent use of tamoxifen, which is a medication commonly used to help treat breast cancer.  The researchers found that there was a 5-fold increase of toxicity in people taking tamoxifen and hydroxychloroquine.  Why?  Tamoxifen itself can affect the retina, so maybe having both on board simultaneously isn’t such a great idea.

Finally, people with macular or retinal issues, like having macular degeneration, may also be at higher risk.  There wasn’t enough results to confirm this, but it kind of makes sense.  If he retina isn’t too hot to begin with, it’ll probably be difficult for the ophthalmologist to decide whether future changes are medication-related versus disease-related, in this case macular degeneration.  Do you need to stop hydroxychloroquine?  Or do you need to start ranibizumab (i.e., a medication FDA approved for macular degeneration)?

Screening Schedule

As I mentioned before, hydroxychloroquine eye toxicity is not reversible.  Once it happens, it happens.  So the trick is to catch it early.  Fortunately, the changes occur VERY slowly.  The American Academy of Ophthalmology recommends the following:

  • Obtain a baseline eye exam within the first year of starting hydroxychloroquine to document any complicating eye problem.
  • Annual screening beginning after 5 years of use.
  • Sooner if there are major risk factors.
  • Check the dose of hydroxychloroquine based on your weight at your doctor’s appointment.
  • Inform your doctor if there’s been any significant change in your health: significant weight loss (intentional or unintentional), kidney disease, or if you’ve been prescribed tamoxifen.

Now you may wonder why your rheumatologist insists on annual eye checks even though you’ve been on hydroxychloroquine for less than 5 years.  This is probably a matter of style.  Personally, I’m one of those rheumatologists that insists on annual eye checks.  I wouldn’t feel comfortable NOT seeing my ophthalmologist if I was taking a medication that had retinal toxicity.

Screening Tests

There are many different techniques to screen for toxicity.  I won’t go into specifics because, well, I’m not an ophthalmologist.  However, here is a list of techniques that the American Academy of Ophthalmology approved to screen for hydroxychloroquine eye toxicity.

  • Automated visual fields
  • Spectral-domain optical coherence tomography
  • Multifocal electroretinogram
  • Fundus autofluorescence
  • Microperimetry – newer test, possible value in future
  • Adaptive optics retinal imaging – newer test, possible value in future

These tests are not recommended for screening

  • Fundus examination
  • Time-domain optical coherence tomography
  • Fluorescein angiography
  • Full-field electroretinogram
  • Amsler grid
  • Color testing
  • Electro-oculogram

If you have any questions about these tests, please ask you ophthalmologist.

Conclusion

Hydroxychloroquine is truly wonderful and useful medication for the treatment of multiple different types of autoimmune diseases.  Although eye toxicity is a real danger, the risk is usually small especially in the short-term.  But like I said at the beginning, like medications you need to take it safely and responsibly.  To learn more about medication safety, please read my article regarding the 10 most frequently asked questions when starting methotrexate.

Please leave your comments below!


By Jessica Chapman, M.D.

References

https://commons.wikimedia.org/wiki/File:Schematic_diagram_of_the_human_eye_en.svg

https://commons.wikimedia.org/wiki/File:Macula.svg

Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF, American Academy of Ophthalmology. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology. 2016 Jun;123(6):1386-94.

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