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Posts Tagged ‘Disease-modifying antirheumatic drug’

I’ve been on seven – count them – seven different biologic medicines since being diagnosed with rheumatoid arthritis. I started with several anti-TNF biologics and then moved to several others even bouncing back to try another anti-TNF before eventually trying Rituxan. I’ve self-injected with auto-inject pens, self-injected with needles, and seems like I’ve had every type of infusion possible. This is probably something of a record although similar stories emerge on discussion boards from time to time. With some of the biologics, I would respond for a period of time and then it would stop working. With others, there was never a response. With yet others, there would be some adverse side-effect causing cessation. This is not all to unusual as it is widely know in the rheumatology community that upwards of 30% of RA patients do not positively respond to anti-TNF biologic medicines.

Read the rest at … http://rheumatoidarthritis.net/living/switching-ra-medicines-dont-wait-long-try-many/

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In the five some years since being diagnosed with RA, I’ve tried a boatload of treatment options including various NSAIDS (chewed up my stomach), multiple DMARDs (one caused an allergic reaction and am currently injecting methotrexate), and I’m currently on my 7th biological medication – Rituxan infusions.

My rheumatologist always says that the treatment goal is that I hardly pay attention to my joints throughout the day. This sounds like everyday language for the ultimate target for RA treatment which is called clinical remission. This is defined as one or less than on tender joint, one or less than one swollen joint, low inflammation blood tests, and a strong patient self-assessment. Over the five years of treatment, I’ve never gotten anywhere close to these goals. But over the past couple of weeks it’s become clear that Rituxan is working like no other treatment combination has! Pain, swelling, and tenderness are hardly noticeable. My hip doesn’t hurt when sleeping or walking. My knee can pull me up steps. I can get out of bed relatively quickly without much stiffness. My right ankle that’s had 2 surgeries lets me know it’s there but it doesn’t scream at me all day along. The bottom line is that RA is starting to take a back seat in daily life…just like my rheumatologist hoped for! This is the first time in five year to have this experience and for this I am very grateful. It was a long time coming and many starts and stops and trying dozens of drug combinations. Of course, I’ll temper the joy just a little and take each pain free day at a time as you never know what lurks around the bend.

It took a while for me to figure out what was going on with Rituxan. These complex biological processes take time – in fact it’s been 4 months since my first infusion and I was already giving up hope for Rituxan to work. But I was also quite distracted over the past month fighting a battle with chronic and almost daily migraines. We’re not sure what’s causing them although my neurologist believes that genetics, a fight with an autoimmune disease, and the medications used to treat RA may all be contributing. So while RA is finally getting under control after 5 years, we’re busy trying to find the best treatment for the migraines. In addition to the emergency triptans (like Imitrex) to take when a migraine comes on, I’ve been on three different long term preventative medications, and have been into the infusion clinic two times for a cocktail of meds in an effort to break a long migraine cycle – the latest was a 4 day killer over the weekend. I have an MRI/MRA  (image of brain and blood vessels) scheduled next week to rule out any functional issues and we’re seeking insurance approval for botox injections which my doctor said works very well for his patients.

Two steps forward for RA treatment success after five long years and dozens of drugs! For this I will truly thank God as I was getting close to giving up hope as the options were getting few and far between. One step back with the nasty migraines. Such seems to be the life of a patient with a chronic disease. But just like what happened with RA, I believe that the migraines will eventually get under control. Two steps forward and one step back still equals forward progress.

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There are several blood tests that rheumatologists currently use to diagnose and monitor rheumatoid arthritis disease activity. Rheumatoid factor (RF) is an antibody identified with RA and other autoimmune diseases. A newer test specific to RA called anti-cyclic citrullinated peptide, or anti-CCP, has been found to have more predictive value than rheumatoid factor tests.1 Since RA involves inflammation, general tests of systemic inflammation including erythrocyte sedimentation rate (ESR) and c-reactive protein may be used. These tests are not specific to RA and are used for a variety of diseases and conditions. But these tests are not completely accurate and they may fail to identify disease activity.

Read more at …http://rheumatoidarthritis.net/living/better-diagnostic-and-individualized-tests-for-ra-needed/

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It is my thesis that the symptoms of rheumatoid arthritis, it’s real impact on people, and the lack of a cure and highly effective treatments is not being accurately portrayed in various forms of the press and media.

Pharmaceutical companies, primarily those with biological treatments for RA, have print and TV ads that show happy, active people easily engaged in physical activities such as cooking in the kitchen, playing soccer with children, and living carefree lifestyles. For example, watch this recent TV ad for Humira. The Enbrel ads featuring golf professional Phil Mickelson, which he takes for psoriatic arthritis (an autoimmune relative of RA), make it sound like he’s licked the disease and is better than ever. One review of these ads points out the caution that must be taken from this story. Nevermind the potential paid spokesperson issues involved in such ads. A recent article in USA Today portrayed a person with RA who is taking a current biological treatment and lives a very active physical lifestyle. The author used language that made it sound like the person was cured. The article received scathing reviews from numerous groups and people (read the posted comments) and the story was slightly modified although the main misrepresentations remain. A recent issue of the magazine Arthritis Today published by the large patient advocacy non-profit Arthritis Foundation features a cover story where a person with RA competes professionally as a triathlete. Upon seeing and reading such portrayals as those listed above, the general public would be prone to believe that rheumatoid arthritis is not that big of a deal.

It may be true that some RA patients do quite well due to low levels of disease activity, natural remission (a rarity), or symptoms well controlled by treatments. Biological treatments developed over the past 15-20 years resulted in many patients doing well and with rheumatologists indicating that they’ve seen a dramatic change in their practices. But the reality for a large proportion of RA patients is that they suffer everyday with uncontrolled or poorly controlled symptoms and do not adequately respond to treatment combinations. Up to 40% of RA patients are not helped by RA treatments or cannot continue treatments due to side effects (see this study by Rubbert-Roth and Finckh, 2009). One recent study reported that higher priced biologic drugs have had the same impact on time lost at work as older DMARD treatments. A meta-analysis (a statistical analysis of many studies) by Callhoff, et al (2013) demonstrated that the use of biologics help RA patients in physical functioning but that improvement was only seen in 50% of patients.

Disease remission is the goal of rheumatologists and advances in treatments help towards this goal (see this article by Collins in 2012). The currently accepted standard for remission as reported in Felson, et. al, 2011, p 581 is…

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)

These are stringent criteria and it would be difficult for many RA patients to meet this even on biological treatments. In 2011, Sokka et al stated that remission “…is not a common phenomenon in real life due to many hurdles.” And the rate of remission depends on the criteria used (Mäkinen, et al., 2005) with rates of remission ranging from 17-55% with only 13% reported as obtaining remission on all three sets of standards used. Many clinical trials are considered a success and the drug receives governmental approval for public use if the patients met older 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. It stands to reason that hundreds of thousands of RA patients in the U.S. alone do not meet “remission” criteria and that does not include the untold millions throughout the world.

The reality of unfettered disease activity is clearly evident in the RA patient online community. Read any of the discussion forums at the popular sites listed below and the norm will be discussions of patient suffering, unrelenting symptoms, lack of treatment efficacy, and side effects preventing them from taking prescribed treatments.

One could argue that these communities may be populated primarily by patients with uncontrolled disease activity and who are seeking help and relief. Even if this is the case, there are still tens or hundreds of thousands of patients who visit and post on these sites.

Read some of the most popular blogs written by people with RA and it will be clear RA is a constant companion that has had a great impact on life. Lene at the Seated View is in a wheel chair due to permanent joint damage and has been fighting RA symptoms for years. Carla at Carla’s Corner just had a knee replacement and this is not her first joint surgery due to RA. Mariah at her blog From This Point. Forward is changing medications once again due to unrelenting disease activity. All of these bloggers are taking some of the most current and sophisticated treatments for RA. These blogs and others (see this list) represent the patient voice of how the disease is really affecting their lives.

Could there be some people with rheumatoid arthritis who are in remission and leading physically active lives? Should these cases be celebrated? Can the stories of their lives be used to bring hope? The answer to all of these questions is a resounding yes. But it must be clear to medical professionals, pharmaceutical companies, government health funding agencies, researchers, non-profit agencies, advocacy groups, and the general public that such cases are the exception and not the norm. The vast majority of RA patients never reach clinical remission. Large portions of RA patients are not helped by the current RA treatments on the market or suffer side effects preventing them from continuing treatment.

Some organizations and individuals in the media may have underlying promotional and marketing purposes that drive their messages. But all I ask for is a balanced and realistic portrayal with integrity (see the journalistic code of ethics) in popular press and media. Anything other than that will only lead to misunderstanding, underrepresentation, and lack of advocacy for a disease that has no cure and whose current line of treatments that are not completely effective.

Postscript: Scott S commented on this article and left a wonderful quote from now deceased Deb Butterfield from her post titled Perceptions vs. Reality in Insulin-Free Times – “By showing the world only the happy face, and not the tragic disease beneath, we are endorsing the prevailing philosophy of tolerating, rather than curing, diabetes.”

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For those who live with type I diabetes, injecting insulin multiple times a day becomes a regular routine. But rheumatoid arthritis patients are also likely to face using needles to administer a variety of medications.

After receiving a diagnosis, there is a progression of RA treatments recommended by the American College of Rheumatology (ACR)[i] that usually begin with chemical-based disease modifying drugs (DMARDs) like methotrexate, sulfasalazine, leflunomide (Arava), and hydroxychloroquine (Plaquenil). All of these drugs are available in pill form. Even though available in pill form, many people cannot tolerate the side effects of the most commonly used DMARD, methotrexate, as it is prone to cause nausea. Methotrexate is also available in an injectable liquid form and many rheumatologists will prescribe this form when side effects can’t be tolerated. If this is the case, the patient must learn to self-inject…

…Read more at http://rheumatoidarthritis.net/living/prepare-poked-needles-ra-treatments-go-hand-hand/

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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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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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