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Posts Tagged ‘Tocilizumab’

My rheumatologist reiterated with me yesterday that I have a tough to treat case of RA – called refractory RA. She displayed disappointment that all of the treatment plans we’ve tried over the years have not had the intended impact. We’ve cycled through four TNF inhibitors (Enbrel, Cimzia, Humira, and Remicade), Orencia, and Actemra. And that’s in addition to various DMARDs including sulphasalzine, azathioprine, and leflunomide (Arava). The reasons for stopping the use of these drugs runs the gamut of lack of efficacy to intolerable side effects. My doctor was apologetic, felt bad I wasn’t helped by all of the treatment plans, and genuinely expressed concern for the impact RA has had on my life recently. But I reassured her that I trusted her medical judgement and that the impact comes over time allowing time to adjust. I appreciated her empathy and deep desire to help.

We discussed the few remaining options which includes Xeljanz, Kineret, and Rituxan. Xeljanz (tofacitinib) was approved in the United States but not approved in Europe. We both felt that more data was needed on this “oral biologic” before giving it a try. Kineret, or anakinra is a biological response modifier that targets interleukin 1. My rheumy said that is not used that much anymore because of more effective options. A recently published report indicates that a Swedish company just purchased the rights for Kineret from biological pharmaceutical giant Amgen. Such a move seems like Amgen is dumping the drug likely because it is not profitable and is moving onto other new drugs. After much discussion, we both agreed to try Rituxan and I will continue to inject 20mg of methotrexate weekly. 

As I was describing my new treatment regimen to friends and family, I found myself trying to explain the drugs, how they are administered, how they act to treat RA, and the possible side effects. As I read more about these drugs, it struck me as interesting that both medicines were originally developed to treat certain forms of cancer. Methotrexate is a chemotherapy drug developed in the 1950s and is still used to treat forms of leukemia, breast cancer, lung cancer, non-Hodgkin lymphoma, and head and neck cancers (see American Cancer Society). It stops the growth of cancer cells by affecting their metabolism. Given the immunosuppressing nature of methotrexate, it is now commonly used in lower doses to treat various autoimmune diseases including rheumatoid arthritis. It’s also used to treat tubal ectopic pregnancies by inducing abortion. In spite of the low doses used in treating RA, some of the chemotherapy side effects remain including hair loss and nausea. This paints a picture of a rather toxic medicine! But I’ve been injecting 20mg weekly for some time now and seem to tolerate it rather well.

Rituxan is also known by the names MabThera and Rituxamab. This monoclonal antibody is a biological medicine that was originally developed in the late 1990s to target the protein CD20 present in certain phases of B lymphocytes. It was originally approved for the treatment of B cell related lymphomas and leukemias (see the Rituxan website). In the early 2000s, it was shown in clinical trials to be effective in treating rheumatoid arthritis and gained FDA approval for use in refractory RA cases in 2006. The involvement of B cells in autoimmune diseases likely led to the investigation of Rituxan as a treatment for RA. The side effect profile appears similar to other biologicals but with some additional infusion side effects requiring some pre-medications along with a few more rare serious infections.

The use of cancer drugs to treat RA points to the connection of both diseases to the immune system. It also demonstrates the serious nature of RA. Given the fact that both methotrexate and Rituxan were originally designed to treat certain cancers, and that they are now secondarily being used to treat RA, may point to the fact that a much larger proportion of research funding goes to cancer (see this earlier post). While I don’t mind receiving the “leftovers” or being an “afterthought” if the medicines effectively treat RA, the ideal would be for the development of new treatments or even cures specifically designed for the processes involved in autoimmune diseases. In the meantime, I’ll go to the infusion clinic and begin Rituxan infusions along with cancer patients and see if it can take care of this refractory case of RA!

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fragment of antibodyWith the research net being cast widely and deeply by researchers and pharmaceutical companies, it’s clear that the currently approved treatments for rheumatoid arthritis are not having the intended impact on all patients (see this recent post on lack of remission). Unlike some infectious diseases where there is a treatment that often results in a cure (e.g. tuberculosis) or eradication via a vaccine (e.g. polio), no such remedy currently exists for RA. Last year I wrote a post about the large variety of biological treatments for RA that are currently in the development and testing pipeline. And this did not even include the myriad of small molecule drugs being developed to target the so-called JAK-STAT pathways of which Xeljanz (tofacitinib) is the only one currently approved in the United States but not approved in Europe.

The vast majority of approved RA biological treatments focus on inhibiting the tumor necrosis factor (TNF) alpha molecule which is overactive in autoimmune patients. The TNF blockers Enbrel, Remicade, and Humira account for the majority of biological prescriptions and control a vast portion of the market. The newer TNF blockers Simponi and Cimzia have recently joined the fray. Other parts of the involved biological pathways have been targeted for treatment including costimulatory protein CD-40 (Rituxan), interleukin 6 or IL-6 (Actemra), and T cell lymphocytes (Orencia).

In spite of the major focus on TNF alpha, a Belgium company called Ablynx now proposes that over the next few years, the “Anti-IL-6 pathway will dominate as the preferred biologic after anti-TNFα treatment.” They predict that 16% of the RA biological market will consist of IL-6 inhibitors by the year 2021. This focusing on IL-6 signaling pathways was proposed in 2008. In addition to Actemra (tocilizumab) which is currently approved in the U.S. and Europe, other antibody treatments targeting IL-6 are being developed including sarilumab by Sanofi and Regeneron, sirukumab by GlaxoSmithKline, and clazakizumab by Bristol Myers Squibb.

Ablynx is currently completing Phase II clinical trials of an IL-6 inhibitor called ALX-0061 and the results show strong treatment efficacy and safety profiles. Instead of being made of large monoclonal antibody (MAB) molecules like most of the current biological medicines, the company Ablynx focuses on producing smaller components called “nanobodies” or fragments of antibodies (FAB) (see this Scientific American article). FABs are cheaper to produce, may produce fewer side effects, and are less prone to breakdown in harsh environments. Ablynx clones the human FABs in llamas before isolating the molecules (see this report).

It is heartening that much research continues on the development and testing of treatments for RA.

Creative Commons photo credit, public domain: http://commons.wikimedia.org/wiki/File:1K4C.png

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A weird thing happened at my Actemra (tocilizumab) infusion last Friday…I was dog tired and started dozing off in the chair when all of a sudden about half way through the infusion I got a rapid burst of energy. I went home feeling great and even mowed my front yard! But by Saturday night it was all over and I was back to feeling terrible – it was a great tease!

My rheumatologist always states that her goal is for me to not pay much attention to RA throughout the day. If the RA is causing issues to which I must attend during the day, then she believes that the medications aren’t working well. For the past five months since starting Actemra, I can clearly state that RA persistently reminds me that it’s present. I knew in the back of my mind that a change may be needed. But after being through so many RA treatments over the past 4 ½ years, I’m very hesitant to switch medications because I’m getting to the point where choices are limited. Below are some factors that are working towards a change.

  1. Doctor recommendation. I don’t tend raise the issue of switching medicines and instead rely on my rheumatologist to broach the subject. Call me gun shy – I just want to make sure that we give a treatment a fair shot before moving on. Part of that hesitancy is based on the fact that we’re running out of options. After last month’s discussion and a recent set of blood tests a few days ago, my rheumatologist contacted me and wants me to stop the current combination of Actemra infusions and leflunomide (Arava).
  2. Your body. My rheumatologist always asks me how I’m feeling in terms of joint pain, swelling, fatigue. She understands that I know my body better than anyone else and takes that into account. She even asked me yesterday, “Do you think the Actemra is working – if not, I’m fleshing out a super Plan B.” I have to admit that it does not seem to be working well. I’ve had increasing joint pain and swelling with over 28 joints impacted. Using the ubiquitous DAS28 tool for measuring RA disease activity (an online calculator is available), I currently have high disease activity.
  3. Increase in Inflammatory Blood Markers. A sharp increase in inflammatory blood markers may demonstrate that the disease is becoming more active (see this study on the correlation). For the first time ever since being diagnosed with RA, I had a high C Reactive Protein test last week. While blood tests like sedimentation rate and C reactive protein are not always accurate indicators of disease as some RA patients like myself tend to not show high results (see this study), they can serve as some gauge of disease activity and are used for clinical trials (see this post from RA Warrior for more info). If the level of general inflammation in my body is increasing while taking certain medications, it may be a sign that they are not working well.
  4. Side Effects. Many side effects of RA medications are tolerable. But sometimes side effects can have too great of an impact. Such is my case with Actemra as we’ve seen a steady increase in cholesterol, triglycerides, and blood pressure since starting infusions. Roche, the maker of Actemra, lists these side effects in the prescribing information as “Adverse Reactions” seen in at least 5% of the population taking the drug. While these side effects are not listed as “Warnings” which include more acute issues like serious infections and gastrointestinal perforations, my rheumatologist believes that they are serious enough to warrant a switch in medication.
  5. Others Around You. Sometimes we can’t see the “forest for the trees” so to speak and we need others to observe how we are doing. I will tend to put my head in the sand and march on like nothing is wrong. As the British say, “hold a stiff upper lip” or “keep calm and carry on.” I’m fortunate to have a wife who can observe changes over time and call it like it is. She recently questioned the efficacy of the Actemra/Arava combination.

4109461394_1be7f99342All of the information above tends to be pointing towards the fact that Actemra is not working for me and that it’s time to move on. The choices are becoming limited as it appears that Rituxin infusions and the newly approved Xeljanz are the only biological treatments currently on the market that I haven’t yet tried. Rituxan is an entirely different kind of biological which is usually reserved for patients who don’t respond to the more common biological treatments. Xeljanz is brand new and lacks long term efficacy and safety data in the open market.

Last December I wrote a post about how Orencia was not working and the switch over to Actemra. Five short months later I’m at the same place of limbo trying to figure out the next plan of attack.

Creative Commons Photo Credit: http://www.flickr.com/photos/carolyncoles/4109461394/sizes/m/

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626px-Michael_Ancher_001I’m currently sitting in an infusion center getting a dose of Actemra. This is a double dose, 640mg, as the single dose did not appear to be working well for me. My rheumatologist decided this action based on several key factors. It’s been a rough couple of months as I’ve experienced an increase in joint pain and swelling, been constantly tired, and lacked energy and motivation. Many of the patients around me in the infusion center are cancer patients who are receiving chemotherapy. As I look around at these folk, it is clear that they have some of the same symptoms.

This recent episode caused me to investigate why I felt so bad and I stumbled upon something called “sickness behavior”. The best way for the general population to understand this feeling is to think about what it’s like while fighting an infection like influenza or pneumonia. In summarizing the source and symptoms of sickness behavior, researchers stated,

“It was subsequently shown that physiological concentrations of proinflammatory cytokines that occur after infection act in the brain to induce common symptoms of sickness, such as loss of appetite, sleepiness, withdrawal from normal social activities, fever, aching joints and fatigue.”[i]

According to researchers at the University of Illinois, it was reiterated that sickness behavior can be brought about by pro-inflammatory cytokines. They stated,

“The behavioral repertoire of humans and animals changes dramatically following infection. Sick individuals have little motivation to eat, are listless, complain of fatigue and malaise, loose interest in social activities and have significant changes in sleep patterns. They display an inability to experience pleasure, have exaggerated responses to pain and fail to concentrate. Proinflammatory cytokines acting in the brain cause sickness behaviors.”[ii]

The same cytokines that are involved in autoimmune diseases like rheumatoid arthritis – TNF alpha, Interleukin-1 (IL-1), and Interleukin-6 (IL-6) – are implicated in sickness behavior.[iii] Increased levels of these cytokines are observed in patients with RA. In one study, sickness behavior was even observed in volunteers who received a typhoid vaccine which increased the levels of IL-6 in the blood.[iv] The same symptoms are observed in patients with diseases that involve the immune system such as AIDS, coronary heart disease, cancer, systemic infections, etc.[v] People might act like such symptoms are “all in your head” but there are biochemical reasons behind these symptoms.

This brings me back to Actemra. It is designed to block the signaling processes of IL-6 which are thought to be overactive in RA patients. If IL-6 can be blocked, then symptoms of RA such as joint destruction can be controlled. In addition, Actemra may assist with reducing fatigue experienced by RA patients.[vi] All of this makes sense in light of the sickness behavior theories discussed above. My rheumatologist once told me that the first sign that a biological treatment was working was a patient experiencing more energy.

Within the first month of receiving Actemra infusions, my energy levels skyrocketed and joint pain was reduced. But that experience was short-lived. I’m hoping that the double dose brings a return of that wonderful feeling. In the meantime, I just feel sick!

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5195232402_d7914561e0_nThe past few weeks have been a real pain in the neck literally. The lymph nodes under my jaws and neck are swollen and quite painful. This is not uncommon when fighting a cold or flu but I have no symptoms of any such infection. The pain was bad enough that it woke me up early this morning. I’m not too concerned as I’ve been down this road before.

About a year and a half ago, while taking Humira, a series of lymph nodes from under the jaw, down the neck, across the chest, and under the armpits were swollen and at times, quite painful. My rheumatologist called it lymphadenopathy which simply means “disease of the lymph nodes.”[i] This rather general definition doesn’t get at the cause of the changes in the lymph nodes. After a physical exam, my rheumatologist said that I probably had some sort of infection caused by the immune-suppressing medications used to treat RA. This made sense at the time since the lymph system is part of the immune system and includes liquid containing white blood cells that attack foreign invaders like bacteria and viruses.[ii]He called for a chest x-ray to rule out sarcoidosis[iii] which is an autoimmune disease of the lymph system and commonly shows up as many swollen lymph nodes deep in the chest. The x-rays were negative and he told me to keep an eye on the nodes. After a few months, I returned to the rheumatologist and told him that the nodes were the same. He found some nodes that were rather large including one being 3 centimeters. He called for an ultrasound to image the culprit. The ultrasound technician could not find it and she called in the radiologist on staff that day. She poked and prodded and moved the ultrasound wand all over the place without finding anything. She mentioned that a 3 centimeter node was rather large and wanted to be sure that she didn’t miss it. I went away not thinking about it much anymore. After another 6 months, I mentioned them again to my rheumatologist and this time he recommended that I see a hematologist since they are experts on blood and lymph system disorders. Little did I know that hematologists are also oncologists…doctors who treat cancers. That sent the stress level up a bit since I knew that Humira and other immune-suppressing treatments for RA were linked to higher levels of lymphoma. The oncologist was wonderful and very reassuring stating this is was likely not lymphoma but he wanted to rule it out. He ordered a CT scan with contrast and ran a large amount of blood tests…9 vials in all! At the follow-up, he told me the good news that he could not find anything and didn’t want to do a biopsy of the nodes. He did find an increased level of rheumatoid factor (RF) in my blood and said that I was probably experiencing an increase of disease activity and that lymph nodes can be impacted like this in RA patients. According to rheumatology researchers,

“Lymph node enlargement is
an important physical finding associated with RA and SLE
[lupus] disease activity. Atypical locations and unusually
large lymph nodes should raise clinical suspicion of another
underlying disease.”
[iv]

So it seems that lymphadenopathy is common with autoimmune diseases and that makes sense given the fact that the lymph nodes are part of the immune system. I’ve been down this road before and won’t think too much about it. But I’ll keep an eye on things since starting a new combination of Actemra and Imuran both of which impact the immune system. I just wish it wasn’t such a pain in the neck!

Creative Commons Photo Credit: http://www.bartleby.com/107/illus602.html

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4880117233_085f24e9b3_nThe sun was out in full force in Seattle today. In fact, it’s been a good week of sunshine and the extended forecast is for more sun. It’s a rare event when a high pressure takes control in January and blesses us with extended sunshine and cool, crisp Canadian air. During such events, Seattlites’ behavior changes with more energy, outdoor activities and improved moods. The snow speckled Cascade and Olympic mountains are visible making a nice contrast in colors. Mt. Rainier, that 14,400 foot volcano, shows itself to the south. We know that the weather won’t stay this way forever as the usual pattern in the winter is clouds with only periodic sun-breaks  But we know that spring and summer are coming with wonderful weather and a beautiful landscape.

This experience is much like living with rheumatoid arthritis. It’s been a long and draining “rainy season” as various medications failed to provide relief. I’ve tried various DMARD and biological treatments (Enbrel, Humira, Cimzia, Orencia) over the past four years. There were times of relief and times of bad flares. The past year seemed particularly bad as the combination of Orencia and Arava failed to make much of a dent in RA symptoms. After an extended time period like this, I begin to forget what it’s like to be “normal”. In December I began a new combination of Actemra infusions and Imuran as a DMARD. After about 2-3 weeks I began to notice a change. By the time of the second infusion I felt about 30-40% better. Two months into this treatment I feel like I haven’t in several years! I have almost a full day of energy, sleep is more restful, joint pain is reduced, and stiffness decreased. I forgot what it was like to feel this way. The sun is shining at the moment and I’m going to take advantage of it because you never know when the clouds will roll back in. Those clouds could be a failure of the medications over time, side effects, or long term tissue damage not stopped by the treatment.

Actemra acts on Interleukin 6 which is a unique cytokine that has a dual role in the immune system as both anti and pro-inflammatory. It’s also the first biological that raises the cholesterol levels of some patients and we’ve already noticed a spike in my recent blood test. Dietary changes were in order…watch fat and cholesterol consumption, eat foods that lower LDL and raise HDL, and exercise. I haven’t been able to exercise in almost three years. But this week I felt good enough to start some low level sessions on our elliptical.

I have hope that this combination will provide strong and long term relief. For the time being, I’m enjoying this time of sun-breaks. But with RA, those hopes are always tempered by the reality that RA is a sneaky beast.

Creative Commons Photo Credit: http://www.flickr.com/photos/okadayoichi/4880117233/

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2154575545_f58be7229d

As the New Year comes upon us, it’s time to reflect on the previous year and consider the upcoming
year. Here is a summary of topics from this blog – both general and personal.

  1. A third ankle surgery and other RA symptoms was the straw that broke the camel’s back on being physically active. My snow skiing days seem to be over but I won’t give up fishing.
  2. I went through a variety of medicines this year. It began with Humira, then Orencia for 11 months, and ended with Actemra in the search for a treatment that would work. In terms of DMARDs, I stopped using Arava and am now taking Imuran. I’m not alone because many RA patients experience the same search for the right treatment.
  3. I experienced receiving monthly infusions in a clinic. The process is not bad, the nurses are knowledgeable and nice, and I’m pretty well off compared to the some of the cancer patients in the clinic.
  4. Biological treatments are crazy expensive and I’m so thankful for health insurance.
  5. RA and its treatments bring about many side effects. The immune suppressing drugs contributed to recurring sinus infections and ultimately, sinus surgery.
  6. A change in rheumatologist was the best decision made in years. Lesson learned – don’t always go with the first doctor you find and spend time seeking out recommendations, patient reviews, and nominations by regional media for best doctor awards
  7. I met many other bloggers who struggle with RA. A close relationship and support system exists among the RA blog community and I’m very thankful for these friends.
  8. Misinformation and incomplete information about RA continues to pervade media. We must continue to work at advocating for RA patients.
  9. This blog was listed as one of the best 22 RA blogs by Healthline and summarily nominated for their best health blog of 2012.
  10. The first new oral medication for RA, Xeljanz, received approval by the United States Food and Drug Administration.
  11. There are numerous new biological treatments for RA in the clinical trial pipeline bringing the possibility of new treatment options.
  12. Much research continues into the genetic and biochemical processes involved with RA which may eventually lead to better treatments or even a cure.
  13. Autoimmune diseases including RA, while impacting a large proportion of the population, continue to receive a disproportionate amount of research funding when compared to cancer and heart disease.
  14. While the currently available biological treatments for RA bring much needed relief, they do not work for approximately 20-40% of RA sufferers.

Thanks to all those who took time to read and comment on this blog. I wish everyone a wonderful and healthy 2013!

Andrew

Creative Commons Photo Credit: http://www.flickr.com/photos/sally_12/2154575545/sizes/m/

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