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I had a follow-up appointment with my rheumatologist to see how the Rituxan/Methotrexate combination is working. Since the time I started Rituxan, an MRI of my right elbow revealed a 50% tear in a tendon and active inflammation in the joint space. A cortisone shot from the orthopedic surgeon seems to have calmed things down for the time being. My right ankle displays regular sharp pain feeling much like it did a couple of years ago when I had surgery to remove bone erosion and repair soft tissue damage. Under examination from the rheumatologist, my toes were tender and painful – something I never noticed since I don’t regularly inspect my toes. I still experience considerable overall stiffness, joint pain, and fatigue. But the good news was that my rheumatologist noticed that I had less tenderness and swelling in my finger joints (it amazes me how she distinctly remembers such things). I agreed as I had noticed the same thing. My wife, one of the best and objective observers, also noticed some improvement over the past few weeks.

When I started other biological treatments, it was pretty clear whether or not it was working within the first few weeks. But that is not the case with Rixutan. Unlike anti-TNF drugs like Enbrel and Humira that can work more quickly, the full effect of Rituximab may not be seen for 16-24 weeks (National Rheumatoid Arthritis Society). My first Rituxan infusion was on September 23rd and I’m sitting at about 11 weeks since I started. According to the Rituxan frequently asked questions (FAQ) website,

At the time of their first checkup—8 weeks after starting treatment—many of those people had seen an improvement in their symptoms. And 6 months later, many were still experiencing improvement.”

The hope remains that this combination will continue to cause an improvement in symptoms. My rheumatologist believes that with the RA out of control for so long, it may take some time for a treatment to catch up and put out the inflammatory fire.

Rituxima Binding to CD20 on a B Cell Surface

Rituxima Binding to CD20 on a B Cell Surface (Photo credit: NIAID)

In this fast-paced, electronic society, we demand everything instantly. It’s difficult to wait for a treatment to take effect. But with the complex biological processes involved with rheumatoid arthritis, the immune system, and Rituxan, we must be patient. While scientists aren’t completely sure about the exact details, it is believed that Rituxan works by depleting the production of B cell lymphocytes by targeting an antigen called CD20 (see graphic) (Pescovitz, 2006). Since B cell production takes time and Rituxan only works on a portion of the production line (see graphic below from the Rituxan website), it stands to reason that it will take time for the therapeutic action to take hold. Slow and steady, hold the course, wait and see…these are all operative words at this time.

moa-illustration

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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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Twelfth_century_headache_-_geograph_org_uk_-_456584Monday afternoon was spent receiving a Remicade infusion. No, it was not regularly scheduled infusion- it was moved up two weeks as my rheumatologist increased the frequency to every 4 weeks and increased the dose from 300mg to 500mg. This is due to the fact that the Remicade/methotrexate combination does not seem to be having the desired impact on RA as evidenced by increased joint pain/swelling, fatigue, and continuously high C-reactive protein tests over the past few months. After trying multiple treatment regimens over the past five years, this result does not surprise me and I knew that the adjustment was coming. Given past experience, I also knew that the chance of getting a “killer” headache after the infusion was high.

My rheumatologist has been working with a neurologist to tackle the headaches. The neurologist mentioned that at the basic level, many headaches are caused by some type of inflammation (see this overview) and he suspects that my body is reacting to the medications in a negative way. There is research to support the idea that inflammatory cytokines including tumor necrosis factor (TNF) may be implicated in causing migraines (see this review of research). Furthermore, it is suggested that anti-TNF medications may be beneficial in treating headaches although no data currently exists to support this notion (for example, see Bo, et al, 2009). But in fact, just the opposite seems to be occurring with some patients taking anti-TNF medications like Humira and Remicade. TNF inhibitor medications used in inflammatory autoimmune diseases are associated with causing headaches. Read any medication guide for these class of biological medications and you’ll see that headaches are one of the most commonly listed side effects (for example, see the FDA guide for Remicade).

My neurologist indicated that two ways to treat headaches include abortive – knock it down after it starts, or preventative-stop it from happening in the first place. I keep a small pill box of sumitriptan (Imitrex) handy at all times in case a bad headache sneaks up on me. I also take a very low dose, 10mg daily, of nortriptyline as a preventative. This old class of tricyclic antidepressant is also noted as helping manage pain and many rheumatologists use it for fibromyalgia and RA. But the “big guns” come out at the time that I receive an infusion. Last month I was given an injection of 150mg of solu-medrol (methylprednisolone) corticosteroid as a powerful anti-inflammatory headache preventative. The nurse slowly injects it into the infusion line and I could feel a tingling move up my arm, my heart rate increase, and a blast of energy come out of nowhere. Just for perspective, the first day on a Medrol dose pack (see my last post) is a total of 24mg of methylprednisolone. 150mg is a high dose of steroids coming all at once! Forget getting any sleep that evening as insomnia is a classic side effect. Last month the solu-medrol injection seemed to help prevent Remicade-induced headaches. But within two hours of receiving the 500mg dose of Remicade on Monday, a massive headache bore down and lasted for the next 24 hours (of course, the lack of sleep probably didn’t help). Two days later it still feels like I received a big butt whipping.

Side effects are one of many reasons that RA patients stop taking medications. Uncontrolled and debilitating headaches certainly are causing me to think carefully about what’s going with my treatment regimen. I can still recall a month or so early last spring when I stopped Actermra infusions and was waiting to start Remicade infusions. It was a wonderful time as my mind was clear and I had no headaches. Yet, the RA was not under control. While taking no treatment for a while helped reduce headaches, the alternative of receiving permanent damage and disability from uncontrolled RA sounds even worse. Of course, my RA is not under control right now anyway!

Creative Commons photo credit: http://www.geograph.org.uk/photo/456584

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struktura infliximabu

struktura infliximabu (Photo credit: Wikipedia)

It is becoming increasingly clear that a substantial proportion of RA patients fail to respond to the more common treatment regimens including combinations of DMARDs (methotrexate, Arava, etc.) and TNF inhibitors (Enbrel, Humira, Remicade, etc). As recently noted by researchers,

“However, about 20% to 40% of patients treated with a TNF inhibitor fail to achieve a 20% improvement in American College of Rheumatology criteria, and more lose response over time (secondary failure or acquired therapeutic resistance) or experience adverse events following treatment with a TNF inhibitor.” (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669237/)

The television advertisements in the United States for these drugs show happy, active people. It is heartening that many RA patients receive excellent results from DMARDs and anti-TNF medications. But I seem to have found myself in the 20-40% group of non-responders. Apparently there is a name for this…Refractory RA.

Refractory in the medical sense means “resistant to treatment or cure” (http://www.merriam-webster.com/dictionary/refractory). According to the National Institutes of Health,

“Refractory disease is defined as failure to attain a predefined target, which is now accepted to be remission or, at least, a low disease activity state.” (http://www.ncbi.nlm.nih.gov/pubmed/21570496)

Since remission is embedded within this definition, it must be clearly operationalized. The predefined target for remission of RA is from the recently revised ACR-EULAR criteria. In order to be technically in remission,

At any time point, patient must satisfy all of the following:

Tender joint count – equal or less than 1
Swollen joint count – equal or less than1
C-reactive protein – equal or less than 1 mg/dl
Patient global assessment – equal or less than 1 (on a 0–10 scale) (p. 581)

These are the stringent criteria applied for clinical trials of newly developed drugs. But applied to currently approved drugs, do patients on these drugs reach remission status? In a review of several studies, the use of traditional DMARDs like methotrexate result in between 35-65% of patients reaching remission. Other comparison studies demonstrated remission rates within a range of 24% with methotrexate alone to 64% with Humira. In one recently published study in China, only 25% of patients achieved remission status using the ACR-EULAR criteria. Many of the remission rate studies were conducted using the old criteria before 2010. Whatever standard is used, it is clear that there are a considerable number of patients who are not in remission.

Biological medicines that are not in the TNF inhibitor class like Xeljanz, Rituxan, and Actemra, are commonly recommended for refractory RA (see studies linked to each medicine above). In the United Kingdom, failure of TNF inhibitors leads to a recommendation to use Rituxan (see http://guidance.nice.org.uk/TA195). But these “second tier” biologicals don’t always result in patients reaching remission status. All one needs to do is read the prescribing information for each of these drugs to quickly realize that many patients in the clinical trials did not reach ACR-EULAR remission status. This is actually the case for all approved RA drugs.

Rheumatology researchers in Portugal recently stated,

“During the last decade we have experienced exciting developments regarding the approval of new treatment options but few patients are reaching sustained remission and refractory patients continue to be a problem. Thus, it is critical to understand how clinicians can decrease the risk of refractoriness by closely monitoring disease activity, using well defined and accepted composite measures, and by early and optimized use of DMARDs, including biologics.” (http://www.ncbi.nlm.nih.gov/pubmed/21570496)

This quote sums up the problem which remains. A large proportion of RA patients who are currently on biological and DMARD medication combinations do not achieve remission status – they have Refractory RA. This evidence lends credence to the fact that more work needs to be done in order to develop treatments that result in true remission. Ultimately, a cure should be the goal for this insidious disease.

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8101257735_8338a4603dIn an article recently published in USA Today, the author discusses the possibility of remission in rheumatoid arthritis. It presents a case of a women who takes Enbrel and methotrexate and is living an active lifestyle. The advent of biological treatments for RA in the last 10-15 years has indeed made a huge impact on RA patients. In fact, my rheumatologist told me that she’s seen things change dramatically in her practice and patients. For this I am truly glad.

However, this author fails to accurately report the whole story. These amazing and expensive treatments are just that…they treat but don’t cure the disease. Remission is an elusive and perhaps temporary state. In 2011, the American College of Rheumatology (ACR) in collaboration with the European League Against Rheumatism (EULAR), updated the criteria for remission. Using the ubiquitous measure of disease activity, the DAS28 ACR-EULAR, the new criteria are as follows:

At any time point, patient must satisfy all of the following:
Tender joint count - equal or less than 1
Swollen joint count – equal or less than1
C-reactive protein – equal or less than 1 mg/dl
Patient global assessment – equal or less than 1 (on a 0–10 scale)

(Felson, et. al, 2011, p 581)

That’s much more strict than the previous criteria and it would be difficult for many RA patients to meet this even on biological treatments. These new criteria are to be used for clinical trials for RA medications to be approved by the FDA. In fact, many previous clinical trials are considered a success if the patients met the old ACR criteria oftentimes reported as ACR 20, ACR 50, or ACR 70 meaning that the patient reported a 20%, 50%, or 70% improvement in symptoms. In most clinical trails, the majority of patients don’t meet the ACR 70 (see this package insert which reports clinical study results). This is not remission, only an improvement in symptoms.

In the USA Today article, it was reported that one study with Enbrel and methotrexate combination resulted “more than 75% of those treated with Enbrel and Methotrexate experienced no progression of joint damage after three years.” That is one study, for one drug combination of which there are many, and was likely based on the less stringent ACR criteria used before 2011. Even if this data was applicable to all RA patients and medication combinations, that would still leave 25% of 1.5 million RA patients in the U.S. alone who do not meet “remission”. That is 375,000 patients! And that does not include the untold millions throughout the world.

Finally, there is the issue of failure of biological treatments. It is well documented that some patients don’t respond to biological treatments for a variety of reasons. In a recent research review, the researchers stated,

“However, about 20% to 40% of patients treated with a TNF inhibitor fail to achieve a 20% improvement in American College of Rheumatology criteria, and more lose response over time (secondary failure or acquired therapeutic resistance) or experience adverse events following treatment with a TNF inhibitor.”

This failure from a large proportion of RA patients can be from lack of initial response, loss in response over time as the patient builds antibodies against the biological treatment proteins, or from severe side effects.

While I am so thankful for the advent of biological treatments and the huge impact that they have on RA patients, we must remain cognizant of the reality that these treatments are not cures, they don’t work for many patients, may fail to work over time, and they may give severe side effects. For these reasons, we must treat this chronic illness as not yet defeated or cured and scientific research must continue.

Postscript December 23, 2012…after many people commented on the article and sent letters to the author and editor, some changes were made to the title and article text. However, the author still does not scientifically define RA remission using current ACR criteria, does not detail the many other RA treatments, and avoids the topic of the large proportion of patients who do not respond to biologicals or fail to respond over time.  

Creative Commons Photo Credit: http://www.flickr.com/photos/meganschuirmann/8101257735/

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