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Diseases and Conditions

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.

UpToDate

Diseases and Conditions Featured

Biosimilars: How they may affect your autoimmune disease?

May 10, 2017
Biosimilars: How they may affect your autoimmune disease?

You may have recently heard about biosimilars for many autoimmune diseases like rheumatoid arthritis, psoriatic arthritis, and Crohn disease or maybe you haven’t even hear about biosimilars at all! A biosimilar is a medication that is a “copycat” version of a biologic but may have some small differences. The patent, which prevents other companies from making a product, on many biologics will expire soon opening a new opportunity for the development of biosimilars. While these medications are just beginning to come into the US market you can already find them in Europe.

What are biosimilars and what can I expect when I use them? Are they better than the real medication, what is the cost? Read on to get the answer to all these questions and more!

What is a Biosimilar?

First of all, to understand biosimilars you must first understand what biologics are. Biologics are a class of medication used to treat many different autoimmune diseases.  Scientist make biologics with living cells or tissues inside a yeast or bacteria.  They are very complex molecules. Conventional medications, like methotrexate and hydroxychloroquine, are produced through specific reactions which produces a very precise molecule with a distinct structure. These medications are the same every time, the same materials, used in the same way produce the same drug.  These molecules are NOT complex. Biologics don’t always make an exact replica as living cells make them.  These are sensitive to the environment including light, temperature and nutrients.

Now add in the addition of a biosimilar. A biosimilar is a biologic that if it can show that it is “highly similar” to another, already approved biologic.  The original biologic is the “reference product”. The FDA requires these products to meet strict safety and efficacy standards just like biologics. The company then needs to prove that their biosimilar is a match for the already approved product for a particular disease.  After this happens, the biosimilar automatically gets approval to treat other diseases the reference product already has approval for.  For example, a biosimilar that has approval for rheumatoid arthritis would then automatically get approval for psoriatic arthritis if the reference product has approval for both.

Isn’t this the same as a generic?

The reality is that it’s a little bit more complicated than that. Think of a brand and generic medication as the recipe for a hamburger at a fast food chain. If you follow the same recipe you get the same hamburger every time, a hamburger in China tastes the same as one made in Albany, NY. Biologics and biosimilars are more like the recipe for sourdough bread. You can follow the same recipe every time but if the weather is different the bread may turn out different. The bread may have a slightly different texture but it will still fulfill its purpose. So biosimilars are not generics because they are NOT exactly the same as their reference medication.  It’s just that the difference is so small that it really should work about the same.

Cost savings?

Treatment with biologics is expensive. But the benefits, like an increase in quality of life, far outweighs the cost. What if you could get similar effects at a decreased cost? That is where biosimilars come into the picture. After the patent on a biologic has expired other companies are able to create drugs using the same process to get a biosimilar medication. Multiple companies producing the same product forces competition and a decrease in price.  This is what theoretically should happen.  In reality, we actually don’t anticipate a significant decrease in cost partly due to the complex process to produce the product.

How will I know what the medication is?

Biosimilars will have the same base name as the biologic they replicate. They will have an extra suffix after the name to differentiate them from the replicated drug. Naming the products in this way ensures you know what drug it replicated (through the base name) and that it is not the “real thing”, but in fact a biosimilar (through the suffix). For example, infliximab is the generic name for Remicade- the branded version. The biosimilar produced by Janssen Biotech is infliximab-dyyb. The addition of the “dyyb” shows that it is a biosimilar to infliximab.

If I have an allergy to the reference medication, am I allergic the biosimilar medication?

Just because you are allergic to the reference medication does not mean you will be allergic to the biosimilar, but it also does not mean you won’t be. True antibody derived allergic reactions are uncommon. Injection site reactions are much more common. There are many factors that can affect if you will have a reaction and what type of reaction it will be.

Some of these factors include:

  • Source of the protein used to make the biosimilar
  • What type of cell the protein was made in
  • Alteration in the protein structure. This can occur from something as simple as a change in storage temperate to changes in the manufacturing process.

As always, if you experience any type of reaction, call your doctor or get to an emergency center right away.

What biosimilars are approved in the U.S.?

At the time of this post there 4 products which have FDA approved biosimilars. This includes

  • adalimumab-atto, biosimilar to Humira (adalimumab)
  • etanercept-szzs, biosimilar to Enbrel (etanercept)
  • infliximab-abda and infliximab-dyyb, biosimilar to Remicade (infliximab)
  • filgrastim-sndz, biosimilar to Neupogen (filgrastim)

There are many other products currently being studied and this list will soon grow larger.

Is it as good as the real thing? What should I expect?

This is probably your biggest concern with using a biosimilar. When you find a treatment that works, you don’t want to jeopardize your health by changing your medications. Believe me, neither does your doctor. Maybe you are wondering if a biosimilar will do the same and possibly save you money? The FDA approval process ensures that biosimilars are just as effective (AND SAFE) as the biologic being replicated. Researchers need to prove that their product has the same clinical effect as the reference product. In the U.S., the FDA require strict safety and efficacy studies prior to approval and post-marketing studies.  These efforts help clinicians keep track of real-world experience with newly approved medications. Over the next few years it will be important for both patients and providers to stay up-to-date with post-marketing information related to the use and experience with biosimilars.

Do you have any experiences using biosimilars? Share them below!

 

Author: Alexis Bruno, 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. Center for Biologics Evaluation and Research. What Are “Biologics” Questions and Answers [Internet]. U S Food and Drug Administration. Center for Drug Evaluation and Research; 2015 [cited 2017Mar26]. Available from: https://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cber/ucm133077.htm
  2. Center for Drug Evaluation and Research. Information on Biosimilars [Internet]. U S Food and Drug Administration. Center for Drug Evaluation and Research; 2016 [cited 2017Mar26]. Available from: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/
  3. Biosimilars: More Treatment Options Are on the Way [Internet]. U S Food and Drug Administration. Office of the Commissioner; 2016 [cited 2017Mar27]. Available from: https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm436399.htm
  4. What is a biosimilar medicine? Supplemental Guide. NHS England. 2015 September 24.
  5. How biosimilars are approved [Internet]. 2017 [cited 2017 May 1]. Available from: http://www.amgenbiosimilars.com/the-basics/how-biosimilars-are-approved/
  6. Christl L. Biosimilar product labeling [Internet]. U S Food and Drug Administration. Center for Drug Evaluation and Research; 2016 [cited 2017Mar27]. Available from: https://www.fda.gov/Drugs/NewsEvents/ucm493240.htm
  7. Center for Drug Evaluation and Research. List Of Licensed Biological Products With (1) Reference Product Exclusivity And (2) Biosimilarity Or Interchangeability Evaluations To Date. US Food and Drug Administration, 2017. [cited 2017 May 1] Available from : https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM549201.pdf
Diseases and Conditions

How much alcohol is safe with methotrexate?

April 26, 2017
Is it safe to drink while taking methotrexate?

Can I drink alcohol when I take methotrexate?  This is one of the most often asked questions I’m asked in clinic when starting methotrexate.  I also suspect it is one of the reasons people sometime decline treatment with methotrexate.  This is a shame, because methotrexate the cornerstone medication for rheumatoid arthritis.

You would think the answer to this question is obvious.  Alcohol can cause liver failure and cirrhosis.  Methotrexate can also cause liver inflammation and fibrosis/cirrhosis.  So combining the two doesn’t sound like such a hot idea.  It turns out the answer to the question isn’t so black and white.

Yes, alcohol can cause liver failure, however, not everyone who drinks alcohol gets cirrhosis.  It tends to happen when someone drinks excessively for years.  The same goes for methotrexate.  Not everyone who takes methotrexate gets liver inflammation.

The real question is, how MUCH alcohol is safe to take with methotrexate?  Shockingly there was little if any data addressing this question until recently.  How much alcohol is too much?  How much alcohol is likely safe?

Science to the rescue!  A recent study from the UK specifically addressed this question¹.  But before I get into that, let’s quickly review what a standard unit of alcohol actually is.  “I drink alcohol socially” simply isn’t going to cut it.  “Social” is highly variable!


What is a standard unit of alcohol?

This depends on the country you’re talking about.  Every country defines a unit of alcohol differently.  Since I’m writing based from the US, I define a unit of alcohol as follows:

“NIH standard drink comparison” by the National Institutes of Health is in the public domain in the United States.  This file has been identified as being free of known restrictions under copyright law, including all related and neighboring rights.

Moreover, each country has their own definition for the maximum amount of alcohol per week.  Some countries are more permissive than others.  In the US, defines low risk drinking for women as no more than 3 drinks on a single day and no more than 7 drinks per week.  Men can drink no more than 4 drinks on a single day and no more than 14 drinks per week².

Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate

Researchers in the UK recently looked into this matter.  As I alluded to, our current guidelines actually offer no specific guidance about alcohol and methotrexate.  In the UK, “patients taking methotrexate should limit their alcohol intake to well within the UK national recommendations”… whatever that means.  The American College of Rheumatology offers similar non-specific guidance.  When I was training, some mentors would have a strict “no alcohol” policy and some would say, a glass of wine or two per week should be okay.

The aim of the recent study was to quantify the risk of alcohol consumption on hepatotoxicity (liver damage) in a contemporary group of methotrexate users with rheumatoid arthritis, in a large national primary care database.

Methods

The researchers recruited people from the Clinical Practice Research Datalink (CPRD) which is a large database of information gathered by primary care providers.  They looked at all patients identified as having rheumatoid arthritis and starting methotrexate after 1987 up until Feb 2016.  People were included if their liver enzymes were measured at least six times per year.

The researchers want to measure any episode of liver inflammation (transaminitis) defined as a level that was three times the upper limit of normal.  This was called the primary definition of transaminitis.  Since we know that persistently elevated liver inflammation can lead to liver fibrosis, the researchers were also interested in identifying people that that have three back-to-back levels that were above the upper limit of normal.  This was called the secondary definition of transaminitis.

Alcohol consumption was measured first by seeing whether the person drinks alcohol, yes or no.  Then the person’s alcohol consumption was categorized:

  1. Mild: 1-7 units per week
  2. Moderate: 8-14 units per week
  3. Moderate-high: 15-21 units per week
  4. High: > 21 units per week

Results

The researchers identified 44 586 people but only included 11 839 people in the study.  The people that were excluded typically were a little younger, were female, and tended to drink no alcohol or very little alcohol.

Using the primary definition of transaminitis, there were 530 first episodes in 47 090 person-years.  That’s about 11.26 per 1000 person-years.  This rate was similar between drinkers of alcohol and non-drinkers of alcohol.  There was no increased risk in the occurrence of transaminitis in drinkers compared with non-drinkers.  But this is pulling all the data together.  What about people who drank mildly vs moderately vs high?

After analyzing the data ever further, the researchers found, unsurprising, that the rate of transaminitis increased with increasing levels of alcohol consumption.  Drinking mild to moderate amounts of alcohol was not associated with transaminitis.  Drinking more than 21 units of alcohol per week tended to be associated with transaminitis.

Alcohol consumption below 14 units per week was associated with a very low probability (0.93%) of having clinically important risk of transaminitis.  Alcohol consumption in excess of 14 units per week was associated with increasing risk of transaminitis.  More specifically, the risk was 33% with moderate-high consumption (15 – 21 units weekly) and 81% with high (>21 units weekly) consumption.

When the researchers used the secondary definition of transaminitis, i.e., 3 or more consecutive episodes of increased liver enzymes above the upper limit of normal, they found similar data: Mild = 0.01%, moderate-high = 8%, and high 17%.

Limitations

No study is perfect.

First, the data came from a primary care database.  This means, it was the PCP or rather the general practitioner that was responsible for coding the diagnosis appropriately, not a rheumatologist.  That being said, some misclassification may have occurred inadvertently.

Another issue was that the amount of amount of alcohol consumption was self-reported.  Most people tend to under report their alcohol consumption, so we can kind of assume that the levels of alcohol reported by the people in the study were actually a lot more than stated.

Another limitation included the fact that many people were excluded because their liver enzymes were measured less than 6 times per year.  Things get a little muddled up here.  People that have their blood tested less often statistically have a decreased chance of having an abnormal test simply because they get tested less.  Then again, having your blood tested 6 times a year is a bit much, unless that person has risk factors that put them at increased risk of developing liver problems.

An important limitation is the fact that the dose of methotrexate was not included.  There could be an increased risk of hepatotoxicity if someone were to take 25 mg of methotrexate weekly versus someone who takes 10 mg.

It’s also unclear whether these results are generalizable to other autoimmune diseases.  Methotrexate is also used to treat psoriasis and psoriatic arthritis.  The study only included people with rheumatoid arthritis.  People with rheumatoid arthritis and psoriasis are not the same.  People with psoriasis tend to have more liver problems in general.  For example, they tend to develop fatty liver.  So the risk of hepatotoxicity with alcohol could be different.

Lastly, some people say that measuring liver function tests (AST and ALT) may be insufficient to actually assess long-term damage from methotrexate because some people develop liver fibrosis without having transaminitis.  The problem with the studies that look at methotrexate and liver fibrosis are for the most part, dated and most looked at people with psoriasis.  As I mentioned, people with psoriasis tend to have more liver problems than people with rheumatoid arthritis.  It’s also important to note that since the 80’s, we’ve changed the way we prescribe methotrexate as well as changed the way we check labs.  Measuring liver function tests, NOT performing serial liver biopsies to monitor methotrexate toxicity, remains current best practice.

On a side note, liver function tests is kind of misnomer because the AST and ALT actually don’t measure liver function.  They measure liver inflammation.

Conclusion

According to this study modest amounts of alcohol consumption when taking methotrexate may not be as harmful as once though.  I would like to remind you that the information provided today does not constitute medical advice.  Please talk to your doctor.  Everyone’s health is unique.  Please leave comments below!

References

  1. Humphreys JH, Warner A, Costello R, Lunt M, Verstappen SM, Dixon WG. Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate. Ann Rheum Dis.2017 Mar 23. pii: annrheumdis-2016-210629. doi: 10.1136/annrheumdis-2016-210629. [Epub ahead of print]
  2. https://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/alcohol-facts-and-statistics
Diseases and Conditions

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

April 12, 2017

Foreword

As a rheumatologist, I regularly depend on the expertise and advice of pharmacists.  Medicine has gotten unbelievably complex.  I truly believe that using a team-based approach is the best way of providing quality-care.  In the clinic, I’m often asked questions about osteoporosis medications.  Bisphosphonates are a class of medications that are commonly used to treat osteoporosis and they’ve come under a lot of scrutiny lately. One of the potential side effects is osteonecrosis of the jaw.  For this week’s edition of RheumDoctor, one of our pharmacy students, Amy DeGennaro, teaches us: what is osteoporosis, what are bisphosphonates, and what is the real risk of osteonecrosis of the jaw.


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

Bisphosphonates work very well at inhibiting the breakdown of bone which results in an increase in the density of bone. Bisphosphonates 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.

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.
Diseases and Conditions

How do autoimmune diseases affect pregnancy?

April 5, 2017

By Jessica Chapman, M.D.

This past week I was asked to discuss the topic of pregnancy and rheumatic diseases.  This is a major issue as many people that develop autoimmune disease are young women.  If you so happen to be one of those young women and you thought that pregnancy was out of the question for you because of your illness… think again.

For the most part, most women with autoimmune disease can have successful pregnancies.  That is, with careful plan and coordination between your doctors.

General tips

It’s extremely important to have a frank discussion with your rheumatologist before thinking about conceiving.  If you have a hematologist, nephrologist, pulmonologist, cardiologist, or any other specialist that also plays a role in caring for your autoimmune, then they should be involved as well.  It’ll also me crucial for you to establish care with a high risk OB-GYN. I did say that it is possible to have a successful pregnancy, but it won’t be your average type of pregnancy.  All this should be done between 6 -12 months prior to attempting conception.

The following are typically recommended.

  • For best outcome, conception should be attempted during periods of low disease activity.
  • All high risk or teratogenic medications should be replaced with low risk medications.  This one can be tricky at times.  Remember that most of the medication have very very long washout periods.  So just because you stopped methotrexate a week ago, it’s still there lingering.
  • You should be assessed for high risk autoantibodies.  These include SSA (anti-Ro) and SSB (anti-La) antibodies as well as all the antiphospholipid antibodies.
  • If you plan on breastfeeding, the choice of medication should also factor into the decision.

Antibodies

SSA and SSB antibodies

These antibodies are typically associated with Sjogren’s syndrome but can also be present in a variety of different conditions such as lupus and rheumatoid arthritis.  It’s important to know whether you have these antibodies because they increase the chance of neonatal lupus.  Maternal SSA and SSB antibodies can passively transfer in utero to the baby.  The risk is small, 1-2% of cases but the risk significantly increases in women who have already borne a child with neonatal lupus.

Children that are born with neonatal lupus may have a rash, liver problems, and low blood cell counts but thankfully, these symptoms disappear completely after about six months.  I did not find research finding that have neonatal lupus increases the chance of the child developing systemic lupus erythematosus (SLE).  Research is research and things may change with time.

The most dreaded complication of neonatal lupus is complete heart block, which typically occurs at weeks 20 – 22.  It’s currently not recommended to use prophylactic steroids to prevent this from happening, but rather to get frequent cardiac monitoring.  This is where the high risk OB-GYN comes into play.

Antiphospholipid antibodies

There are three types of antiphospholipids: lupus anticoagulant, anticardiolipin antibodies, and beta-2 glycoproteins.  The presence of these antibodies, particularly at high titers, are associated with something called the antiphospholipid syndrome.  People that have this condition are  higher risk of developing bother arterial and/or venous blood clots.  Other complications include: miscarriage, stillbirth, pre-term delivery, and preeclampsia.  In an effort to try to prevent some of these complications, women that have antiphospholipids typically treated with prophylactic “pregnancy-safe” blood thinners.

High risk medications

Because it would be completely and utterly unethical to conduct a randomized controlled study on pregnancy outcomes and exposure to disease modifying agents (DMARDs), the vast majority of evidence regarding the safety of medications during pregnancy comes from animal models.  There are also a few registries that capture human data.  As we all know, not all pregnancies are necessarily planned and for some women having active disease may be worse for the baby or the mother, so the benefits of the medication may outweigh the risks.  Every situation is unique.

The American College of Rheumatology has a nice table listing medications that typically are used to treat rheumatic conditions.  Which is considered safe in pregnancy and breastfeeding.  In general the antimalarials, like hydroxychloroquine, are safe as well as azathioprine and sometimes sulfasalazine.  Mounting evidence also suggests that the TNF-alpha inhibitors may also be safe, but this isn’t set in stone.  Many rheumatologists are still on the fence regarding this one.  If a TNF-alpha inhibitor is absolutely required, it may be a good idea to use certolizumab as this medication is pegylated and technically should not cross the placenta.  It is VERY important to have a discussion with your rheumatologist regarding your medications!

How does pregnancy affect disease activity?

It all depends on the disease we are talking about.  Typically SLE becomes more active during pregnancy, whereas rheumatoid arthritis and psoriatic arthritis tends to improve.  Typically vasculitis, polymyositis, dermatomyositis, and systemic sclerosis are unaffected by pregnancy.

High risk clinical situations

HOWEVER, there are a few notable circumstances where pregnancy is risky for both the mother and the child.  It’s generally not safe to conceive during a period of very high disease activity.  This includes lupus nephritis.  It’s generally discouraged to conceive when lupus nephritis is active, but when things are controlled it’s okay with very close monitoring.  Patients with lupus nephritis commonly flare, are at higher risk of preeclampsia, and HELLP syndrome during pregnancy but these can be reversed with prompt treatment.

Another very important high risk situation is pulmonary hypertension.  This can occur in variety of disease such as systemic sclerosis, SLE, myositis, mixed connective tissue disease, Sjogren’s syndrome, and rheumatoid arthritis.  When pulmonary hypertension is caused by an autoimmune disease, we call it connective tissue disease-related pulmonary arterial hypertension.  For those who want to get technical, pulmonary hypertension is defined as a mean pulmonary arterial pressure higher than 25 mmHg at rest, associated with a pulmonary capillary wedge pressure lower than 12 mmHg diagnosed by right heart catheterization. Symptoms include:

  • Shortness of breath particularly while exercising.  Like more than what you would expect.  At one point the shortness of breath even when you are at rest.
  • Fatigue
  • Dizziness, passing out.
  • Chest pain
  • Swollen legs or swollen abdomen (ascites)
  • Palpitations
  • Bluish color

So why is this especially important for pregnancy-related matters?

A study by Qian et al. aimed to evaluate the survival of patient with SLE-associated pulmonary arterial hypertension.  This was a systematic review and meta-analysis.  They identified 6 studies which included a total of 323 patients.  They found that 1-, 3-, and 5-year survival rates were 88%, 81%, and 68% respectively.  The more severe the pulmonary hypertension, the worse the outcome.  These are not good odds.

High pulmonary hypertension peripartal mortality is not an isolated incident related to SLE alone.  It is elevated for all connective tissue disease-related caused of pulmonary arterial hypertension.

Conclusion

We’ve come a long way when it comes to rheumatic diseases and pregnancy.  Way back when, it was generally discouraged in practically all circumstances.  But things have changed.  With careful planning and monitoring, many women with autoimmune diseases can now have safe pregnancies.

References

Kelley and Firestein’s Textbook of Rheumatology, tenth edition

American College of Rheumatology

Pasut G. Pegylation of biological molecules and potential benefits: pharmacological properties of certolizumab pegol.BioDrugs. 2014 Apr;28 Suppl 1:S15-23.

Moroni G, et al. Maternal outcome in pregnancy women with lupus nephritis. A prospective multicenter study. J Autoimmun. 2016 Nov;74:194-200.

Thakkar V, Lau EM. Connective tissue disease-related pulmonary arterial hypertension. Best Pract Res Clin Rheumatol. 2016 Feb;30(1):22-38.

Qian J, et al. Survival and prognostic factors of systemic lupus erythematosus-associated pulmonary arterial hypertension: A PRISMA-compliant systematic review and meta-analysis. Autoimmun Rev. 2016 Mar;15(3):250-7.

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