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.

Overcoming Inflammation

How to read and analyze medical research

January 16, 2017

Reading medical journal articles is not considered light reading. They’re written in a funny sort of way, they have a lot of statistics, and they tend to be devoid of “normal English”. Sometimes I feel they were actually written for robots as opposed to human beings. The thing is, evidence-based medicine offers us the most unbiased scientific information out there. It’s important to note that not all research is unbiased. A lot of it is! Knowing how to read, understand, and analyze primary scientific research is paramount. It’s the difference between getting a story from a friend of a friend, as opposed to actually being in the story.

This week I’d like to invite you to go through the process I use to read through a medical journal so that when someone tells you, “research says”, you can read, understand, and analyze that actual data yourself.

Rheumatoid Arthritis

One of the most common conditions encountered in a rheumatology practice is rheumatoid arthritis (RA). This is not your typical type of arthritis. RA is a systemic autoimmune disease that tends to first attack small joints in the hands and feet. If left untreated, it can spread to other joints, other organs, and can lead to permanent joint destruction.

Rheumatoid arthritis is treated with medications collectively called, disease-modifying agents (DMARDs). These are medications that change the way the immune system works. Fight fire with fire. Simple right? Problem is, most of these medications have scary potential side effects. They’re the ones with the commercials ending with, “risks may include nausea, vomiting, hair loss… oh yes and death. Please consult your physician for further information”. Oh yes, I totally want that medication. Don’t get me wrong, these medications have GREATLY improved the health and lives of people suffering from autoimmune diseases.

Increasingly, people have been interested in complementing their prescribed treatment with more natural interventions. Notice, I said complementing, not replacing. The CDC actually looked into this and did what they always do… crunch numbers. They wanted to know what percentage of people suffering from musculoskeletal pain disorders use complementary health approaches. What they found was that 54.5% of people have a musculoskeletal pain disorder in the US and of these, 24.7% use natural products. Now, RA only accounts for a small fraction of people suffering from joint diseases but other reports have shown a similar trend in RA sufferers.

So without further adieu…

A multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of Tong Luo Hua Shi capsule, a modernized Tibetan medicine, in patients with rheumatoid arthritis

Let me put this out there, doctors like to be really descriptive and unoriginal when choosing a title for their article. So sorry for the never-ending header.

Tong luo hua shi is a modern herbal supplement akin to wu-wei-gan-lu, an herb that has been used in Chinese medicine to treat RA for hundreds of years. Chinese researchers conducted a multicenter, randomized, double-blind, placebo-controlled, dose-finding trial with tong luo hua shi (TLHS) in people suffering from RA. This is the type of info you want: multicenter, randomized, double-blind, and you want the study drug to be compared to a placebo. The researchers are basically trying to decrease bias.

They studied 236 people with RA according to guidelines set by the American College of Rheumatology. People were excluded if they had another autoimmune conditions, if their RA was very advanced, if they had another severe disease like advanced kidney disease, if they were pregnant – duh, or if they had a psychological disease. Basically, you want all your participants to be the same, compare apples with apples, and you want the study to be safe.

The participants had to come off their inflammatory meds like ibuprofen but they were allowed to stay on a stable dose of steroids and their DMARD.

The participants were then randomized to the following groups: TLHS 4.8 grams/daily, TLHS 3.6 grams/daily, TLHS 2.4 grams/daily, and placebo. It’s important to have a placebo group. Sometimes the placebo can be a fake pill and more often researchers use a medication that is considered standard of care. When reading an article, you want to make sure that both the researchers and the participants were blinded. This means that the people doing the research and the people receiving the intervention, did not know who was getting what. This reduces a considerable amount of bias.

The study lasted 8 weeks. If they were doing terribly 2 weeks into the study, the treating physician was allowed to prescribe diclofenac (i.e., a powerful anti-inflammatory) and/or leflunomide (i.e., a DMARD). The baseline characteristics of the participants were similar across all four treatment groups.

This is the beauty of randomization. It’s essential for treatment groups to be similar. For example, if the study group had a lot more women, then you could blame whatever outcome because of sex instead of the actual intervention.

What they found was that people who received TLHS 4.8 grams daily did better compared to all groups. Moreover, the TLHS groups tended to use less diclofenac. Importantly, there weren’t any serious side effects. Some insomnia, gastrointestinal intolerance, a minor liver lesion, and a participant in the placebo group experienced some minor liver dysfunction. Then again, a lot of these people were being exposed to diclofenac and leflunomide, both of which are known to cause liver problems. So really, who knows what caused what.

Study Evaluation

Study findings

TLHS seems to be effective in relieving symptoms caused by rheumatoid arthritis, especially at higher doses.
TLHS appears to be safe up to a dose of 4.6 grams daily. More than that, who knows?
Pregnancy safety data is not available.

Limitations

Participants were allowed to stay on their prior existing DMARD. They never said, which ones exactly. Were the people receiving the higher dose of TLHS, also receiving a more powerful DMARD than the people who received placebo? I can see that confusing the picture.
The sample size was rather small.
The study lasted only 8 weeks. This is VERY short. RA studies typically last 30+ weeks because the medications typically takes months to take effect.
Participants were allowed to have leflunomide and diclofenac added to their treatment plan, two weeks into the study. This is a big no-no for very obvious reasons. How are you supposed to know what’s causing what? Typically if participants are doing terribly in a study, they either have to a. white knuckle through, b. opt out of the study, or c. depending on the study design are allowed to crossover to the treatment group if they were on placebo.

Parting Words

Now this is the part where I’m supposed to tell you whether tong luo hua shi is effective in complementing standard rheumatoid arthritis treatment. But, I’m not going to do that.

I want you to analyze the data yourself.

I want you to think for yourself.

Happy researching and stay safe!

If you want to keep on learning, please subscribe to my mailing list.

References

Clarke TC. Use of complementary health approaches for musculoskeletal pain disorders among adults: United States, 2012. Available at: http://www.cdc.gov/nchs/data/nhsr/nhsr098.pdf. Accessed October 18, 2016

Liu W, et al. A multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of Tong Luo Hua Shi capsule, a modernized Tibetan medicine, in patients with rheumatoid arthritis. Trials. 2016 Jul 27;17:359.

Pubmed: https://www.ncbi.nlm.nih.gov/pubmed

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