Diseases and Conditions Overcoming Inflammation

Can UV light trigger lupus flares?

July 12, 2017

Now that summer is finally in full swing, I’d like to remind everyone to use broad spectrum sunscreen while enjoying the sun! This is especially important for people living with systemic lupus erythematosus (SLE). Ultraviolet (UV) light is a known trigger of SLE flares BOTH involving the skin and major organs. Many people also report joint pain, weakness, and headaches. These flares can be very serious.

Although we know UV light is a trigger for SLE flares, we still don’t fully know how it happens. This is what we do know.

UV light directly damages the DNA of skin cells.
The cells release inflammatory cytokines, most notably interleukin-1α and tumor necrosis factor-α.
UV light also increases interferon-α signaling. People with high levels of interferon-α signaling often develop fevers, fatigue, and low white cell count (leukopenia). Interferon-α signaling is thought to be an important part in the development of SLE.

Take home points

So while you’re enjoying the sun remember to:

Avoid the sun when UV light is strongest, between 10 AM and 3 PM. If you use IFTTT, check out this app. You will get a notification on your phone when the UV index is high… and it’s free!
Use broad spectrum UVA/UVB sunscreen. Try to aim for a SPF higher than 30.
Try wearing clothing that have vivid colors and a tight weave. The Skin Cancer Foundation has a great article regarding this topic: “What is Sun-Safe Clothing?”
Wear a broad-brimmed hat when spending time in the sun.

Be safe and please leave your comments below!

References

Fernandez D, Kirou KA. What causes lupus flares? 2016 Mar;18(3):14. doi: 10.1007/s11926-016-0562-3.

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.

Diseases and Conditions Featured

Guide to living with rheumatoid arthritis: Part 1

July 5, 2017

Have you recently been diagnosed with rheumatoid arthritis? RheumDoctor presents a guide to living with rheumatoid arthritis

Rheumatoid arthritis… Your rheumatologist diagnosed you with rheumatoid arthritis and you have a lot questions. What’s rheumatoid arthritis? Can I get rid of it or will I live with this disease for the rest of my life? What should I expect? How do I fight it? This week I’ll present to you Part 1 of a Guide to living with rheumatoid arthritis. I’m going to present this as a three-part series. Part 1 will cover the basics: what is rheumatoid arthritis, the cause, symptoms, diagnosis, treatment, etc. In Part 2 I’ll cover prognosis, what to expect, diet and exercise. In Part 3, I’ll be covering the financial side of rheumatoid arthritis: How to get access to medications and how to deal with insurance companies.

I hope you find this information useful. Be strong, be brave, and know that you’re not alone.

What is rheumatoid arthritis?

Rheumatoid arthritis is an autoimmune disease that causes inflammation throughout the body but mainly affect joints. Without treatment, rheumatoid arthritis can eventually lead to permanent joint destruction. Autoimmune diseases occur when the immune system loses “tolerance to self”. What this means is that the immune system can no longer distinguish between healthy cells and cells that don’t belong like bacteria or cancerous cells.

According to the CDC, about 1% of people living in the US suffer from rheumatoid arthritis. It tends to occur 2-3 times more often in women and tends to start in your sixties but it can start at any age. [1]

Some common signs and symptoms include:

Pain and swelling in the joints. Particularly small joints like the knuckles, wrists, and toes.
Morning stiffness that lasts more than one hours
Having difficulty opening jars. Weakness in the hands.
Fatigue, fevers, unintentional weight loss.

What causes rheumatoid arthritis?

We’re actually unsure. We do know that in certain cases there is a genetic link. People that have a certain HLA class II genotype (shared epitope) tend to get rheumatoid arthritis more often. Especially, if they smoke cigarettes. Moreover, we know that rheumatoid arthritis tends to run in families. However, most cases of RA happen spontaneously and not everyone who has a genetic risk factor develops RA.

There’s still a lot of work that needs to be done to fully understand what causes rheumatoid arthritis. Like most autoimmune diseases, our best guess is that people who have RA probably were born with some sort of genetic predisposition for the disease. Then they get exposed to something in the environment like a virus, trauma, stress, hormonal change, which then triggers the disease to come online.

What are the symptoms of rheumatoid arthritis?

Usually rheumatoid arthritis presents with pain, swelling, and prolonged stiffness involving small joints, like the ones in your hands or feet. When I mean prolonged, I mean more than one hour. But RA can present in many ways. These can be divided into typical (90% of cases) and atypical presentations (10% of cases).

Typical

Insidious (55% – 65%): People develop pain, swelling, and prolonged stiffness mainly involving small joints like the toes and knuckles. This progressively worsens over months.

Subacute (15% – 20%): Again small joints are painful, swollen, and stiff but the this develops over weeks. Usually people experience some fatigue.

Acute (10%): Joints suddenly become swollen and tender over days. Some people have a fever, drenching night sweats, and sometimes can lose weight without trying.

Atypical (10% of cases)

Palindromic pattern: This type of presentation isn’t technically considered rheumatoid arthritis. It’s just that 33% to 50% of people with this type of presentation progress to full-blown rheumatoid arthritis. Typically, one joint is involved. It becomes tender and swollen for a few days then gets better on its own. Then a few weeks to a few months later it happens again. The flare can happen in the same joint but not necessarily. Treatment with hydroxychloroquine can decrease the risk of developing full-blown rheumatoid arthritis, so it’s important to start treatment as this stage.

Insidious onset of the elderly: As the name suggests this type of presentation occurs in the elderly, so people aged greater than 65 years. People experience extreme pain and stiffness shoulders and the hips. Sometimes you can see whole hand or foot swelling. Sometimes it’s very difficult to differentiate from polymyalgia rheumatica or remitting seronegative symmetrical synovitis with pitting edema (RS3PE). People with polymyalgia rheumatica and RS3PE typically do NOT have any positive antibodies.

Rheumatoid nodulosis: Rheumatoid arthritis can cause nodules and bone cysts on radiographs. Usually people also have joint pain and swelling but sometimes all they have are nodules.

Arthritis robustus: This is rather rare. I’ve only seen it once. It typically occurs in men. Essentially the person develops horrible rheumatoid arthritis hand deformities but experiences little or no pain. I know it’s hard to believe, but it’s possible!

By James Heilman, MD (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)], via Wikimedia Commons

How is rheumatoid arthritis diagnosed?

The diagnosis of rheumatoid arthritis, contrary to popular belief, is primarily a clinical diagnosis. Having a positive antibodies like a rheumatoid factor (RF) does not necessarily mean that you have rheumatoid arthritis because MANY conditions can have a positive rheumatoid factor. Some of these include:

Rheumatoid arthritis, mixed cryoglobulinemia types II and III, sarcoidosis, and other autoimmune diseases like Sjogren’s syndrome. Other non-rheumatology diseases that can cause someone to have a positive rheumatoid factor include infections most notably hepatitis C, tuberculosis, syphilis, HIV, and endocarditis. People suffering from cancer and people with chronic pulmonary and liver diseases, can also have a positive rheumatoid factor.

It’s also important to mention that about 5 – 25% of people aged 60 years and older have a positive rheumatoid factor without any underlying causative disease.

This is why my job as a rheumatologist is so interesting 🙂

The American College of Rheumatology classification criteria for rheumatoid arthritis is as follows:

The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis[2]

Who to test?

People that have at least 1 joint with definite swelling.
And the swelling cannot be better explained by another disease.

Classification criteria for RA (a score of ≥ 6/10 is needed for someone to have definite RA)

Category

Score

Joint involvement

1 large joint

2 – 10 large joints

1 – 3 small joints

4 – 10 small joints

> 10 joints (at least one small joint)

Antibodies

Negative RF and negative CCP antibodies

Low positive RF or low positive CCP antibodies *

High-positive RF or high positive CCP antibodies #

Inflammation markers

Normal CRP and normal ESR

Abnormal CRP or abnormal ESR

Duration of symptoms

< 6 weeks

≥ 6 weeks

* Low positive antibodies means any value that is above normal but less than 3 standard deviations above the upper limit of normal.

# High positive antibodies means any value that is 3 standard deviations above the upper limit of normal.

It’s important to note that these criteria were NOT meant for clinical practice but rather, were really meant for research trials. Sometimes, rheumatologists do deviate. Other conditions should be ruled out and let’s face it, not everyone fits perfectly into the mold. The criteria also does not account for musculoskeletal ultrasound testing. This imaging test can detect very subtle inflammation of a joint.[3]

Positive antibodies without RA

Now sometimes the workup is completely negative including x-rays. This is not uncommon. It can mean many things. It could mean that the rheumatoid factor is not clinically significant. 5–25% of the population can have a positive rheumatoid factor without any underlying condition or any symptoms. Typically the rheumatoid factor levels are low. It could also mean that you will develop rheumatoid arthritis in the future. Studies have shown that antibodies associated with rheumatoid arthritis can be present over a decade before onset of clinical disease. [4]Unfortunately, we don’t have the tools to precisely determine who will convert and who will not. In this situation, your rheumatologist can help you watch for any change in your condition.

How is rheumatoid arthritis treated?

We treat rheumatoid arthritis with medications called disease modifying anti-rheumatic drugs (DMARDs). These medications slow down or stop the natural progression of rheumatoid arthritis.

Except for a few special situations, EVERYONE should with rheumatoid arthritis should be treated with a DMARD as soon as possible because permanent joint damage can happen in as little as 3 months after symptoms start.[5]

The following are the medications used to treat rheumatoid arthritis in the United States. It’s important to work closely with your rheumatologist because they all have possible risks and what may be good for your neighbor may not be safe for you.

I’ve broken them down into conventional DMARDs, biologic DMARDs, and pipeline medications that have not been approved as of yet.

Conventional

Methotrexate
Leflunomide
Sulfasalazine
Hydroyxchloroquine

Biologics

Etanercept, TNF inhibitor
Adalimumab, TNF inhibitor
Golimumab, TNF inhibitor
Certolizumab pegol, TNF inhibitor
Infliximab, TNF inhibitor
Abatacept, Co-stimulation inhibitor
Tocilizumab, IL-6 inhibitor
Sarilumab, IL-6 inhibitor
Tofacitinib – JAK inhibitor
Rituximab – B cell depletion

Pipeline

ABT 494, a new JAK inhibitor
Baricitinib, another JAK inhibitor
Sirukumab, another IL-6 inhibitor

Biosimilars

It’s also important to note that we are starting to see biosimilar medications in the States. These are medications that are sort of copied from existing biologic medications. They are NOT generic medications. The problem with biosimilars is that because of their complexity, it literally is impossible to exactly copy a biologic medication. If you want to learn more about biosimilar medications, please check this article.

Supplements

If you’re interested in supplementing, there is some research that suggests high dose turmeric/curcuma and high dose fish oil/omega-3 fatty acids may also be helpful.[6][7] However, supplementation should be used in combination with FDA approved medications that I listed above.

Is there a cure for rheumatoid arthritis?

I honestly wish I had better news for you. Unfortunately there is no cure for rheumatoid arthritis. Treatment primarily focuses on arresting the natural progression of the disease with the use of disease modifying anti-rheumatic agents (DMARDs). Conventional DMARDs such as methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine, modulate the immune system to decrease rheumatoid arthritis activity. Biologic medications like etanercept use a targeted approach, i.e., suppress a specific cytokine.

The goal of treatment is to put rheumatoid arthritis into remission and decrease the frequency of flares.

This may seem very pessimistic, but recent advances have really improved the prognosis of people living with rheumatoid arthritis.

Nevertheless, DMARDs do not cure rheumatoid arthritis.

How do we win the war against rheumatoid arthritis? Before we can win the war and find a cure, we need to know exactly what causes rheumatoid arthritis in the first place and we need to understand its exact pathophysiology. Believe it or not, despite all our advances, we still cannot answer these two questions. Don’t despair, researchers are actively trying to answer these questions.

Can rheumatoid arthritis become fatal?

Rheumatoid arthritis is a systemic autoimmune mediated disease that primarily affect the joints. Note the primarily bit. It can affect a host of different organs including the eyes, lungs, heart, skin, and bone marrow to name a few.

Untreated or poorly controlled rheumatoid arthritis can cause serious conditions such as interstitial lung disease (i.e., inflammation of the lungs), pericarditis (i.e., inflammation of the “sac” surrounding the heart), as well as something called Felty’s syndrome (i.e., a hematologic condition that can cause white cells to dramatically decrease and causes the spleen to enlarge). These severe manifestations of rheumatoid arthritis that can lead to death are hardly ever seen anymore mainly because we have many highly effective medications called disease modifying anti-rheumatic medications (DMARDs). These medications have completely changed people’s prognosis.

Cardiovascular disease and infection

The most common cause of death in people with rheumatoid arthritis these days includes cardiovascular disease and infection – primarily from medications.[8]

Rheumatoid arthritis increases cardiovascular risk via the interplay of inflammation and lipid metabolism. Studies have shown that people who receive treatment with methotrexate and or tumor necrosis factor inhibitors reduce their cardiovascular risk.[9] A British study also demonstrated that cardiovascular was not increased regardless of the choice of DMARD provided that rheumatoid arthritis was well controlled.[10]

Infection remains an ever-present problem in the world of rheumatology. To treat autoimmunity you need to suppress the immune system. Not too much, not too little, but just right. In some cases this has the unfortunate result in causing serious infections that can lead to death in extreme cases.

Rheumatoid arthritis can become fatal in many other ways, however, for the most part it is medication induced – although the pharmaceutical companies don’t really want you to know that. Just read a package insert. They’re terrifying.

However, I’ve been talking about rheumatoid arthritis fatalities. Untreated or undertreated rheumatoid arthritis is HIGHLY debilitating leading to a significant drop in your quality of life. Early treatment with a DMARD is the best way to improve your odds. You have to fight fire with fire!

Can I stop my medications if I’m feeling better?

No. Rheumatoid arthritis is a life-long disease. If you’re feeling better, great! However, it’s probably your medications that are keeping you that way. If you stop your medications the rheumatoid arthritis will come back. Maybe not now but soon. Rheumatoid arthritis subsides spontaneously in a VERY small subset of people.

If your medication is making you feel sick, talk to your rheumatologist. They’re there to make you feel better and they want to find the perfect treatment plan tailored for you.

Do not stop your medications without consulting your rheumatologist.

Next steps

We’ve covered a lot of material today and there’s a lot more coming your way! Stay tuned for Part 2. I’ll be covering topics such as what to expect, what to eat, how to exercise, and strategies on how to reduce stress. Please leave your comments below.

References

[1] https://www.cdc.gov/arthritis/basics/rheumatoid-arthritis.html

[2] https://www.rheumatology.org/Portals/0/Files/2010_revised_criteria_classification_ra.pdf

[3] Horton SC, et al. Ultrasound-detectable grey scale synovitis predicts future fulfilment of the 2010 ACR/EULAR RA classification criteria in patients with new-onset undifferentiated arthritis. RMD Open. 2017 Mar 30;3(1):e000394. doi: 10.1136/rmdopen-2016-000394. eCollection 2017.

[4] Brink M, et al. Rheumatoid factor isotypes in relation to antibodies against citrullinated peptides and carbamylated proteins before the onset of rheumatoid arthritis. Arthritis Res Ther. 2016 Feb 9;18:43. doi: 10.1186/s13075-016-0940-2.

[5] Raza K, et al. Treating very early rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2006 Oct;20(5):849-63.

[6] van der Tempel H, et al. Effects of fish oil supplementation in rheumatoid arthritis. Ann Rheum Dis. 1990 Feb; 49(2): 76–80.

[7] Ramadan G Al-Kahtani MA, El-Sayed WM. Anti-inflammatory and anti-oxidant properties of Curcuma longa (turmeric) versus Zingiber officiale (ginger) rhizomes in rat adjuvant-induced arthritis. Inflammation. 2011 Aug;34(4):291-301. doi: 10.1007/s10753-010-9278-0.

[8] https://www-ncbi-nlm-nih-gov.elibrary.amc.edu/pubmed/26472415

[9] https://www-ncbi-nlm-nih-gov.elibrary.amc.edu/pubmed/28455580

[10] https://www-ncbi-nlm-nih-gov.elibrary.amc.edu/pubmed/28160488

Medical Disclaimer

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Recipes

Buckwheat pancake: galettes de sarrasin

June 28, 2017

A picture of the moulin Legare the oldest functional water powered mill in North America. The mill produces 4 tons of wheat and buckwheat flour annually.

Last weekend I took some much needed time off and spent it celebrating la Fête de la Saint-Jean-Baptiste with my family up in my hometown of Saint-Eustache, Quebec. This is akin to the 4th of July for French Canadians. Saint-Eustache was founded in 1770 and boasts two famous historical sites: the church and the buckwheat water mill.

Historical Sites

The church gained notoriety for its significance during the battle of the Lower Canada Rebellion on December 14th, 1837. After rebelling against the English following multiple failures at political reform, seventy rebels were shot or burnt alive inside the church while the English bombarded its facade. The English then pillaged the city and burnt the majority of the city to the ground. Many see the rebellion of the Patriotes Canadiens as an example of what could have happened in the United States had the American Revolutionary War failed.

By Vincent Poirier (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

Every June 24th the entire province gathers to celebrate our independence and express our gratitude for those who made the ultimate sacrifice.

Now the second famous historical site in Saint-Eustache is the moulin Légaré. It was built in 1762 and has been in constant operation since then. In fact, it’s the oldest functional water-powered mill in North America. The mill, to this day, produces about 40 tons of wheat and buckwheat flour annually!

What’s buckwheat and how do I use it?

Contrary to popular belief, buckwheat is NOT a grain. It just has grain-like seeds which are milled into a flour. That being said, buckwheat flour is gluten-free and has many trace minerals as well as vitamin B6, pantothenic acid, niacin, folate, thiamine, and choline. Moreover, you will find 4 grams of soluble fiber, 8 grams of protein, and 15% of your daily iron requirements in 1/3 of a cup of buckwheat flour. Needless to say buckwheat is very healthy and should be part of your diet.

In Quebec, we use buckwheat in our traditional cooking. This is probably because we have a shorter growing season. Buckwheat likes cold weather, acidic and low fertility soil.

One of the most popular ways to use buckwheat flour is to make pancakes. We call them galettes de sarrasin. Essentially it’s a thin pancake, more like a Parisian crêpe. It’s cooked on a sizzling hot cast iron pan and then drizzled with molasses or maple syrup. But really you can dress it with almost anything: swiss cheese, a fried egg, bechamel, etc. Sweet or savory, whatever you fancy.

Buckwheat Pancake – Galette de sarrasin

Adapted from Recettes de la famille Légaré

2 cups of buckwheat flour

1 tsp of baking powder

1/2 tsp of salt

2 cups of water

Butter

Instructions

In a large bowl, whisk together the water, buckwheat flour, baking powder, and salt.
Heat a cast iron pan on medium heat. When hot, add about 1/2 tsp of butter. If you want to be ultra traditional, use lard.
Ladle a spoonful of batter onto the sizzling hot pan. Flip the pancake once you see holes forming but only for a few seconds. Serve immediately.

Recipes

Chive Blossom Butter

June 14, 2017

My mom is what you would call a busy body. Always out and about: gardening, cooking, cleaning… running a business. She also happens to be an amazing cook. This Saturday morning as I was doing my errands, she texted me images of her latest creation.

Very pretty. Why aren’t mine like that?

Interesting, show me more.

This does not look appetizing.

Yum!

I can see this tasting great with mashed potatoes, toasted bread, or on a steak. Although this is not the healthiest recipe, something like this should definitely be shared.

Chive Blossom Butter

Adapted from Popayan www.recettes.qc.ca

50 – 60 Chive flowers with ½ inch of the stem attached, finely minced

1 lb Unsalted butter, room temperature

1 ½ Lemons, juiced

¼ cup Extra-virgin olive oil

Salt as desired

In a large bowl, mix the butter, lemon juice, and the olive oil together with a wooden spoon. Then, add the minced chive blossoms.
At this point you can either fill ramequins with the butter-chive blossom mixture or you can mold them into individual sized portions as seen above.

Individual sized portions

Mold the butter-chive blossom mixture into a roll and wrap in wax paper and then in plastic wrapping.
Place in the freezer.
When the mixture has hardened, unwrap, and cut into individual sized portions

Makes one pound of butter.

Bon appetit!

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.

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

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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