Biosimilars – “Generics” for Biological Treatments for RA

Etanercept (Enbrel) structure (Photo credit: Wikipedia)

It was recently announced that Etacept was being launched in India by the generic drug company Cipla as a “biosimilar” to Enbrel (Etanercept). This new biological drug is designed to treat rheumatoid arthritis and other rheumatic conditions and is being manufactured by China-based Shanghai CP Guojian Pharmaceutical Company Ltd. It is supposed to cost 30% less than Enbrel. The approval of this biosimilar in India is not without controversy as biotechnology companies are complaining that Cipla did not follow the standards for approval (see this article).

In the United States, patent exclusivity for biological drugs is set at 12 years. This is designed to protect the expensive and time consuming processes involved in developing and testing these complex biological treatments. However, there is an approaching “patent cliff” (see this excellent article on biosimilars). Of all biologicals used for a variety of diseases, Humira, Enbrel, Remicade, and Rituxan are among the most profitable biologicals on the market. These drugs will lose their patent protection in the next few years. Once the patent cliff is reached, large pharmaceutical companies stand to lose billions of dollars in sales (see this article). The Biologics Price Competition and Innovation Act (BPCIA) of 2009 was built into the Patient Protection and Affordable Care Act (“Obamacare”) and is designed to speed up the process of approval for biosimilars. Large generic drug manufacturers are beginning to ramp up to enter the biosimilar market

Over the next few years, we will likely begin to see a slew of biosimilars for RA begin to hit the market worldwide. The potential savings to patients and insurance companies will competitively drive the market (see this article). Decisions about starting or switching to the biosimilars will need to be made. The efficacy and safety of these look-alike drugs will be questioned. This will also drive large pharmaceutical drug companies to research and develop new drugs for RA in order to maintain a competitive edge.

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Refractory RA – When Treatments Fail to Work

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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Sub-Types of Rheumatoid Arthritis?

My rheumatologist believes that I may have a combination of rheumatoid arthritis (RA) and ankylosing spondylitis (AS). I have had a positive rheumatoid factor (RF) test and I present classic examples of inflammation and damage in joints commonly associated with RA including in the proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints in both hands. Add to that list, symmetrical joint presentation in the wrists, shoulders, hips, and knees along with fatigue and it seems like RA. At the same time, my rheumatologist noted limited spinal mobility and many problems with my ankles and Achilles’ tendons which are common with AS. My first autoimmune symptom, which occurred years before joint problems, was inflammatory uveitis in both eyes. While Achilles tendon problems and uveitis can be associated with RA, they are more commonly seen in AS patients. But a test for HLA-B27, a common genetic test related to ankylosing spondylitis (AS), was negative. These blood tests are not 100% accurate and the official diagnosis in my chart is RA (diagnosis code 714).

Muddying the water is the fact that I have been through a slew of RA treatments over the past four years in an effort to find a combination that works for the long term. I’m currently on Actemra infusions and now going back to add leflunomide (Arava) in an effort to capture the earlier success with Actemra. While many RA patients find relief from the most common treatments like methotrexate, Enbrel, and Humira, it seems to elude 30-40% of patients.[i] Every person seems to respond differently to various medicines and doses.

This personal evidence leads me to believe that there may be different sub-types of RA. In a recent conversation at the RA site on HealthCentral, the notion of sub-types of RA was mentioned. We already know that there are different types of inflammatory arthritis including RA, AS, psoriatic arthritis.[ii] And each of these diseases presents different patterns and may be treated with similar and/or different medications. But there seems to be a lack of scientifically defined sub-types of RA.

According to researchers from the Netherlands, “Rheumatoid arthritis (RA) is a heterogeneous disease with unknown cause.“[iii] Differences in genetic expressions of RA patients were seen by these researchers lending some credence to a genetic link to sub-types of RA. In an earlier study of the genetics of RA in 1989, researchers found a gene called HLA-DR was found in 83% of 149 patients with classical or definite RA.[iv] But no explanation is given for the 17% of RA patients who did not show the gene. In 2010, a group of researchers found four genetic sub-types of RA.[v] Japanese scientists found genetic differences at the molecular level. They stated, “Data from genome-wide screening, transcriptional profiling, and animal models indicate that RA consists with heterogeneous disease subsets.”[vi] Some researchers even found different emotional responses in RA patients.[vii]

While the causes of RA are not completely evident, most scientists suspect a combination of factors including genetic and environmental (see earlier post on the triggers of RA). Scientists are now beginning to unravel the complexities of RA and find that there may actually be a variety of sub-types of the disease. I hypothesize that future research into RA and other autoimmune diseases will reveal that genetics and environmental factors impact the way individuals present symptoms and respond to treatments. This knowledge may lead to definitions of RA sub-types and better treatments in the future. In the meantime, I’ll keep experimenting with treatments in order to find a combination that works.

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[i] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669237/

[ii] http://www.arthritisresearchuk.org/arthritis-information/inflammatory-arthritis-pathway.aspx

[iii] http://www.ncbi.nlm.nih.gov/pubmed/17223656

[iv] http://www.ncbi.nlm.nih.gov/pubmed/2481309

[v] http://www.blackwellpublishing.com/acrmeeting/abstract.asp?MeetingID=774&id=90254

[vi] http://cdn.intechopen.com/pdfs/25397/InTech-Molecular_mechanisms_of_rheumatoid_arthritis_revealed_by_categorizing_subtypes_of_fibroblast_like_synoviocytes.pdf

[vii] http://arthritis-research.com/content/15/2/R45/abstract

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Traveling with RA

With RA, routines are a necessary fact of life in order to function. But those routines may get pushed aside for various life events. Traveling is one of those times. I’m currently on a trip to Orlando, Florida for a work related conference. Many friends and colleagues in Seattle expressed jealousy at the notion of escaping winter and heading to a sunny climate. But for me, RA adds many dimensions that makes it difficult to travel to the point where it’s hard to enjoy the pleasures associated with travel. On the way out the door, my wife wished me well and that the RA would not kick back at me too hard. Below are some strategies that may help while traveling with RA.

1. Check bags instead of carrying them on the plane. It may cost a baggage fee but this avoids the extra work on your joints from hauling and lifting heavy objects.

2. Take an extra supply of medicines. Several weeks before leaving, check your supplies and refill prescriptions. You never know if you’ll get stuck in an airport or need to spend a few extra days due to unseen circumstances.

3. Pull out the “big gun” medicines and bring them along just in case they are needed. For me, this includes Vicodin for pain and Ambien for sleep. I store these in a safe at home and rarely use them but you never know when they may be needed.

4. Carry medicines with you on the plane just in case you need them or your luggage gets lost. I use pill boxes which I label for each medication because they take up less space than the original pharmacy bottles.

5. For those on a biological treatment or injectable methotrexate, extra planning may be needed. If you self-inject on a regular basis, your next injection may fall in the middle of the trip. You will need to carry-on your meds in a cooler, plan for cold storage upon arrival, and include alcohol swabs and other related items. While using Enbrel and Humira, I used a nice little cooler pack that the makers of Enbrel sent me. Extra foam was added to the inside and I used one of the ice packs that the pharmacy used to ship the medicine. The syringes or injector pens can be kept in a water proof zip lock bag. I kept the medicine cold for over 8 hours on one trip using this technique. Most hotel rooms have refrigerators that can be used for storage until the day of injection but it’s a good idea to check ahead of time. One time while taking Cimzia I was traveling for the holidays. The specialty pharmacy directly shipped the syringes to my in-law’s house. Not only was this convenient, it became an educational tool for my extended family since they were able to see what the treatments were like. If you are on an medicine administered via infusion, schedule your infusions around the trip.

6. On long flights, get up and stretch those stiff, achy joints from time to time.

7. While traveling for either pleasure or business, it’s easy to overdo it so schedule times of rest and avoid pushing yourself. While on this short four day trip, I plan to treat myself to some sun at the pool at least once (see photo). Don’t feel the need to attend every conference session, side tour, family outing, late night dinner with the gang, etc. Know your limits and stick to them.

8. Eat healthy foods and drink plenty of liquids. This is sometimes hard to do but helps keep your body functioning as well as possible.

The longer I have RA, the less inclined I am to travel. But sometimes it can’t be avoided. Now I need to go give a presentation at the conference followed by some more sun!

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Is RA Remission Possible and Permanent?

In 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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“Oh No I Can’t”…Changing RA Treatment Regimen Again

I received an official rheumatoid arthritis diagnosis almost four years ago. In that period of time I went through multiple treatment schemes (see the My Meds page) including four biologicals (Enbrel, Cimzia, Humira, and Orencia) and three DMARD chemicals (sulphsalazine, methotrexate, and Arava) in addition to numerous NSAIDS and the obligatory prednisone. As mentioned in blog posts over the past couple of months, it became increasingly apparent that the combination of Orencia and Arava was just not working. Sticking my head in the sand and ignoring the signs could only last so long while my wife and doctor tried to convince me that it was time to try something else. The evidence was becoming overwhelming…unrelenting fatigue beyond comprehension, increase in the number and intensity of swollen and tender joints, new joints including one shoulder and both hips presenting with signs of attack by RA, missed work, and a level of brain fog never experienced before. In addition, it felt like the monthly Orencia infusions might just as well have been plain saline solution as there was no improvement afterwards. On top of that, Arava was wrecking havoc on my digestive system and the bathroom and I became quite friendly.

While driving into the doctor’s office today, the inevitable started sinking in and I got nervous wondering what would happen. Most of this anxiety is probably grounded in the fact that I’ve been through a slew of treatments and I was feeling like options were beginning to run out. After an exam and conversation about symptoms, my rheumatologist emphatically stated that it’s time to change treatment. She continually expresses hope that we can find a medicine combination that will work for me. She got out a piece of paper and made two lists. The one on the left was for DMARDS that I haven’t tried yet and she wrote down Imuran and Cellcept. On the right she listed biologicals that I haven’t tried and she listed Remicade, Rituxin, and Actemra. In the middle she listed the newly approved oral biological Xeljanz which she dismissed as a possibility for now stating that she wanted to see more long-term data on efficacy and safety before widely using it. She recommended Imuran since it’s been around longer and has better efficacy data for treating RA. Imuran is an immunosuppressant commonly used to help organ transplant patients avoid tissue rejection. It is also used to treat many autoimmune diseases including RA, lupus, and MS. Since three TNF blockers didn’t seem to work well for me, she argued against Remicade but said that we’d keep that option on the list just in case we want to try it later. She said that Rituxan helps some of her RA patients but not as many as she would like. Actemra is the newest antibody biological for RA approved in the United States and she said that she’s seen it help some of her patients. It’s different from the TNF blockers and Orencia in that it targets interleukin 6 which is part of the autoimmune processes linked to RA. So we landed on the Imuran/Actemra combination and await insurance approval to begin the infusions. A trip to the lab for blood tests to establish baselines were ordered. In the meantime, doses of prednisone are prescribed to knock down inflammation.

Changing treatments brings about many questions but also hope that maybe it will provide some relief. Because relief would be a good thing right now!

Creative Commons photo credit: http://www.flickr.com/photos/busy-pochi/5170100206/

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Brain Fog (Cognitive Dysfunction) Caused by RA Medicines

Several years ago I wrote a post about brain fog caused by the biochemical processes of rheumatoid arthritis. The inflammatory chemicals, including cytokines, produced during an autoimmune response can impact nervous system functioning and cause brain fog – or more accurately, cognitive dysfunction. The best way to describe this for someone who doesn’t have RA is to think about how their brain feels while they have a bad case of influenza.

Lately I’ve been wondering about cognitive dysfunction caused by the vast array of medications used to treat RA. This wondering is grounded in the fact that for the past few months I’ve just not felt sharp in thinking and the timing of that goes along with some changes in medication and dosing. I was also reminded of a colleague years ago who was battling multiple sclerosis, another autoimmune disease, and how the medications he was taking caused changes in his cognitive functioning to the point where he could no longer perform his job effectively resulting in his taking disability leave. At the time I didn’t understand what was going on with him but now I have empathy.

I spent a little time exploring the side effects of various medications used to treat RA and its symptoms. Below is a list of side effects related to brain functioning. This confirms what I hypothesized…these drugs can impact cognitive functioning. I suspect that part of my recent “fogginess” is a combination of the biochemical processes of RA coupled with the side effects of my treatment regimen. Like with any side effect, one must consider the tradeoffs. If I don’t take the RA meds, I’m more prone to permanent tissue damage. If I take the meds, I have to learn to manage the brain fog. I’m done writing this post now as I can’t focus any more attention to complex tasks!

Disease Modifying (DMARDs)

Methotrexate[i]

• dizziness
• drowsiness
• headache
• confusion

Plaquenil (hydroxycholoroquine)[ii]

• Blurred vision or eye problems
• Headache

Arava (lefunomide)[iii]

• Headache

Imuran (azathioprine)[iv]

• Lightheadedness or fainting

Biologicals

Enbrel[v]

• Blurred vision or sudden change in vision
• Lightheadedness, fainting, seizure, or trouble thinking
• Depression, or mood or behavior changes
• Mild headache or dizziness

Humira[vi]

• Changes in vision or eye pain
• Headache

Orencia[vii]

• Dizziness, drowsiness, or lightheadedness.
• Headache

Rituxan[viii]

• Changes in vision
• Confusion
• Dizziness, lightheadedness, or drowsiness
• Problems with coordination or speech
• Anxiety
• Trouble sleeping

Anti-Inflammatory

Prednisone[ix]

• Nervousness
• Trouble sleeping
• Confusion, depression, or mood changes
• Seeing or hearing unusual things

Pain Killers

Tramadol[x]

• Lightheadedness, dizziness, or fainting
• Severe sleepiness or unusual drowsiness
• Feeling nervous, anxious, shaky, or unusually happy
• Feeling of constant movement of self or surroundings
• Headache
• Trouble sleeping

Tylenol 3 (with codeine)[xi]

• Hallucinations or unusual thoughts
• Lightheadedness
• Sleepiness

Vicodin (hydrocodone)

• Drowsiness
• Feeling faint
• Dizzy
• Confused
• Feeling unhappy or unwell
• Head pain
• Nervousness
• Sluggishness
• Mood changes
• Anxious
• False sense of well-being

Sleep Aides

Ambien (zolpidem)[xii]

• Lightheadedness
• Seeing, hearing, or feeling things that are not really there
• Unusual or disturbing thoughts or behavior
• Confusion, blurred vision, or problems with balance
• Dizziness
• Headache
• Memory loss

Lunesta (eszopiclone)[xiii]

• Abnormal thinking and behavior
• Anxiety, aggressiveness, confusion, depression, or dizziness
• Headache
• Memory loss

Elavil (amitriptyline)[xiv]

• confusion, agitation, hallucinations
• Changes in vision such as trouble focusing
• Drowsiness or dizziness
• Seeing, hearing, or feeling things that are not there

Creative Commons Photo Credit: http://commons.wikimedia.org/wiki/File:50mgtramadolhclakyma.jpg

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[i] http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000547/

[ii] http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010621/?report=details#side_effects

[iii] http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010881/?report=details#side_effects

[iv] http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0009164/?report=details

[v] http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010203/?report=details#side_effects

[vi] http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0008825/?report=details#side_effects

[vii] http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0008771/?report=details#side_effects

[viii] http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0012019/?report=details#side_effects

[ix] http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0011828/?report=details#side_effects

[x] http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0012486/?report=details#side_effects

[xi] http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0009704/?report=details#side_effects

[xii] http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0012721/?report=details#side_effects

[xiii] http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010201/

[xiv] http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0008944/?report=details#side_effects

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Orencia Infusion – Play by Play

Today was a scheduled Orencia infusion. I began this medication last January after Humira stopped working. Orencia is different than Humira and Enbrel, the most common biological medicines for RA, in that it is designed to inhibit T-lymphocyte cells in the immune system while Humira and Enbrel block TNF-alpha. It’s usually used as a second line biological treatment if TNF blockers don’t work.

The treatment begins with three loading sessions every two weeks and then moves to once a month infusions. For my weight, the normal dose is 750mg. However, my new rheumatologist wanted to up the dose to 1,000mg as it wasn’t having the full anticipated impact and some recent research shows that an increased dose is beneficial for some patients. She also added 10mg of Arava (leflunomide) in an effort to combine a disease modifying drug with a biological.

The morning began like any other day except that I tried to keep myself hydrated and I took some Tylenol and 50mg of Tramadol before leaving the house. This was an effort to keep headaches at bay since I’ve experienced them after infusions in the past. I also had similar reactions with Humira injections. I recently switched rheumatologists at a new clinic. Orencia must be administered in an infusion clinic and this would be my first visit. The infusion clinic is on the 5^th floor of a brand new building and is near the Oncology offices. That is because many cancer patients are receiving chemotherapy via infusion. It feels a little strange walking into such a place as you know that many of the patients around you are in serious and life threatening situations. The clinic itself was bright and cheery with small and private cubicles for each patient. Unlike other doctor offices, you just walk in and immediately meet a nurse who escorts you to a cubicle.

Once settled into a comfortable lounge-like chair, blood pressure measurements were taken and then an infusion needle was inserted into a vein. I’ve had infusions in my elbow, arm and hand. Today the choice site was the hand. The stick began with a slight sting that then grew more painful to the point of major discomfort. The nurse said that there are many nerve endings in the back of the hand and that the needle must be irritating them. She placed a warm compress on the site but the pain was almost unbearable. She offered to re-stick me but the pain subsided a little. Four vials of blood were drawn as is typical with each infusion. These samples will be used to run typical RA blood tests like complete blood count (CBC), sed rates, and liver panels all in an effort to make sure that everything is normal since the array of RA medicines can impact these markers.

Orencia

Infusion Pump

The medicine is contained in a solution and is infused, not dripped, meaning that a pump provides the force pushing it into your body. The pump makes a whirring sound every few seconds. At this point, I could pull out my iPad, listen to music, and read a book. For Orencia, the infusion takes about 45 minutes. That’s not bad compared to 3-4 hours for Remicade, another TNF blocker used for RA. When the medicine is gone out of the bag, a beeping on the pump alerts the nurse. Some saline solution is pushed through the drip line to flush all of the expensive medicine into your body. I can always feel a cold sensation in my arm during this time. Finally, a pressure bandage is wrapped to keep the site from bleeding and they advise leaving it on for 30 minutes.

View of Space Needle from Gates Foundation

It’s all over in a pretty short period and after setting up an appointment for the next infusion, I’m out the door. Today I was fortunate enough to be able to meet a friend for lunch. He works at the Gates Foundation – the largest non-profit in the world. I was able to put the infusion behind and take a tour of the amazing, environmentally friendly building before enjoying some sushi. There was no headache today and for that, I’m thankful. But the real story will be if Orencia impacts RA symptoms over the long term.

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More Genetic Connections with RA

Chromosomes

My curiosity about genetics and RA was peaked again today when I saw a post on the Facebook page of the American Autoimmune Related Diseases Association (AARDA). A publication from 2004 suggested a possible genetic link between an immune response to tuberculosis over the past few hundred years and autoimmune diseases including rheumatoid arthritis.[i] The notion is that survival of bacteria-induced tuberculosis resulted in the genetic selection of proteins connected with RA including TNF-alpha and HLA. In other words, people that survived tuberculosis had the genes to produce more of these proteins. And people whose genes resulted in the production of certain proteins resulted in more cases of RA. While the exact causes of RA are complex and not entirely known, this study lends more evidence to the notion that there is an underlying genetic connection. Some evidence also exists for environmental and even bacterial triggers for RA (see my earlier posts). Most scientists believe that RA is caused by both genetic and environmental triggers.

For anyone on Humira, Enbrel, or Remicade, TNF-alpha should be familiar since those biological medicines work to block TNF-alpha in the biochemical processes. TNF alpha is a cytokine (protein) that causes inflammation. People with RA and other autoimmune diseases show an overproduction of TNF-alpha. Thus, blocking TNF became a recent mainstay in the treatment of RA.

The human leukocyte antigens (HLA) are a group of genes on chromosome 6 that are connected with the immune system.[ii] There are many autoimmune diseases connected with HLA genes and a scientist in the UK maintains a website is devoted to the topic –  http://www.hladiseaseassociations.com/. Multiple HLA genes are connected with rheumatoid arthritis including HLA-DR4 and HLA-DRB. While HLA genes are commonly connected with RA, some scientists demonstrated that other genes also play a role.[iii] One gene called, HLA-B27, is associated with ankylosing spondylitis (AS), an autoimmune disease that impacts the spine, hips, and ankles. I tested negative for this gene several years ago although my rheumatologist noted that some of my symptoms resemble AS. But not all people with AS have the gene and not all people with the gene have AS.

My rheumatologist really grabbed my attention recently when she suggested that I participate in a genetic study since I display symptoms of multiple autoimmune diseases along with mixed genetic and blood tests (rheumatoid factor positive, HLA-B27 negative). Consumer-based companies will conduct basic genetic testing for a cost (e.g. https://www.23andme.com). Kelly at RA Warrior wrote an informative blog about consumer testing last year.  I would prefer to engage in a scientific study and I plan to raise this topic at my next doctor appointment. Stay tuned for test results!

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[i] http://www.ncbi.nlm.nih.gov/pubmed/15082117

[ii] http://www.uptodate.com/contents/human-leukocyte-antigens-hla-a-roadmap?source=see_link

[iii] http://www.ncbi.nlm.nih.gov/pubmed/12687532

photo credit: http://commons.wikimedia.org/wiki/File:Karyotype_color_chromosomes_white_background.png

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Hope Springs Eternal

I’ve been absent from this blog for almost 1 ½ years, I decided to jump back and start writing again. And much has transpired since the last post. After stringing it out as long as possible, I had my third ankle surgery in late November 2011. The orthopedic surgeon cleaned up bone erosion on the top side of the heel bone, removed a bone spur poking into my Achilles tendon, removed a bursa sac, and repaired mores tears in the Achilles tendon. Tissues samples were sent to pathology and the lab results noted bone erosion and inflammation caused by rheumatoid arthritis.

Stopping Humira injections in early November 2011 was necessitated by the pending ankle surgery but also by the fact that it just wasn’t helping that much anymore. In addition, a 3 cm swollen lymph node in my armpit needed to be checked out. Short story – saw a great oncologist and after many blood tests, an ultrasound, and a CT scan with iodine contrast, everything came back negative with no lymphoma! One interesting blood test result was that I had a positive Rheumatoid Factor test for the first time. I was finally seropositive and felt like I was no longer the seronegative stepchild of RA. Although I know that upwards of 30% of folk don’t have positive RA blood tests.

I was started on Orcenia infusions in January 2012. I was done with TNF blockers after using Enbrel, Cimzia, and Humira. After insurance approval, I had three loading doses every two weeks before moving to a regular schedule of once a month. Having a nurse administered infusion at a clinic was a new experience compared to self-injections of Enbrel and Humira. It was a rough few months but I began to get back some energy and have less joint pain and stiffness.

By this point, I decided to pursue a new rheumatologist. I had been with my original rheumatologist from the beginning and he made the initial diagnosis. But over time I began to realize that it was time for a change. I sought out a new rheumy by asking around, checking out published lists of top doctors in the region, and looking at patient reviews online. A choice was made and an appointment with a new rheumy scheduled. As an added advantage, her clinic just relocated to a brand new, clean, and cheery building. I had all medical records sent to her.

The first appointment was a pleasant experience from the beginning with smiling staff, caring nurses, and the fact that I didn’t have to wait. The first thing the doctor told me was that she spent considerable time reading all of my medical records. That was a refreshing to know – she already had an idea about my case before I arrived. She then asked me to tell my story in my own words. Given my history, my new rheumy suspects that I may have a combination of RA and ankylosing spondylitis – an autoimmune condition which commonly affects ankles, hips, and backs. She joked that I would be a good subject for genetic testing! We discussed how Orencia was working and she felt like I would benefit from the addition of a disease modifying drug (DMARD). Since methotrexate and I didn’t have a good relationship a few years ago, she wanted to try leflunomide (Arava). In fact, she suspects that one reason that TNF blockers stopped working was that I wasn’t on combination therapy resulting in the building up of antibodies to Enbrel and Humira. I appreciated her optimism about being able to help and compassion about my experiences.

New adventures lie ahead with a new doctor, new medicines, and new possible side effects. But hope springs eternal just like the sun finally coming out in Seattle.

Photo taken by my daughter on a sunny day in Puget Sound.

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