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Posts Tagged ‘cytokine’

Given the fact that there are a slew of RA medications laying on the failure heap, I’m willing to move outside the box and so is my doctor. The latest drug to be tried will be secukinumab – brand name Cosentyx by Norvartis. This biologic is currently approved by the United States Food and Drug Administration (FDA) for the autoimmune diseases psoriasis, psoriatic arthritis (PSA), and ankylosing spondylitis (AS). Cosentyx is an interleukin 17 (IL-17) inhibitor. IL-17 is a cytokine produced by T cell lymphocytes and is connected with autoimmune inflammatory responses. I reported on clinical trials with secukinumab for RA back in 2012. In a recently reported clinical trial being conducted for RA, patients demonstrated improvement over a one year treatment period. Safety and side effect profiles match other biologics with increased risk of infections, allergic reactions, changes in liver and blood tests, and cases of inflammatory bowel disease.

My official diagnosis has been seropositive rheumatoid arthritis due to positive rheumatoid factor (RF) tests, classic RA symptoms like symmetrical bilateral presentation, and bone erosions. But I’ve also shown symptoms more associated with AS like tendon insertion tearing, large joint involvement, and uveitis but without a positive genetic marker for AS (HLA-B27). In addition, my grandmother dealt with psoriasis and her brother had a debilitating case of ankylosing spondylitis. My insurance approved this drug for my use and I will begin the weekly loading dose self-injections as soon as they are shipped. We’ll see how I respond to this newest option.

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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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In my last post, I briefly discussed how various metabolic systems are involved with RA and how something called Metabolic Syndrome is more common in RA patients and is implicated in increased risk for cardiovascular disease. A recent article written by Spanish researchers (Amaro, et al., 2013) provides an excellent overview of the connection between metabolic syndrome and rheumatoid arthritis. They stated that metabolic syndrome is characterized by high blood glucose, low HDL cholesterol, high triglycerides, obesity, and hypertension. Up to 39% of RA patients display symptoms of metabolic syndrome placing them at greater risk for cardiovascular diseases. They noted that something called insulin resistance is connected with RA, increased inflammation, cardiovascular disease, and type II diabetes. According to the U.S. National Institutes of Health,

“Insulin resistance is a condition in which the body produces insulin but does not use it effectively. When people have insulin resistance, glucose builds up in the blood instead of being absorbed by the cells, leading to type 2 diabetes or prediabetes.”

A review of research conducted by European rheumatologic researchers (Amaro, et al., 2011) connected insulin resistance to RA. They revealed that insulin resistance was more common in RA patients with higher inflammatory blood markers (c-reactive protein, ESR) and disease activity measured by the DAS28. In addition to helping curb joint destruction, these researchers also noted that the use of biologics that impact inflammatory cytokines, primarily the TNF inhibitors (e.g. Humira and Remicade), may benefit those with insulin resistance. For RA patients on TNF inhibitor treatment, improvements were seen in the insulin resistance in multiple studies over the past few years. In summarizing the topic, Amaro, et al, concluded,

“The role of chronic inflammation is becoming more and more important in the development of atherosclerosis. Likewise, the latter seems increasingly important as a determinant of mortality in patients with RA. In light of the observations, there seems to be ample evidence supporting a relationship between insulin resistance, inflammation and RA, as is also the case in other chronic diseases. In addition, such insulin resistance plays an initial role in vascular damage and appears to be (along with other mechanisms such as endothelial dysfunction, cellular adhesion, etc.) a link between inflammation and atherosclerosis. For all these reasons, rheumatologists should know insulin resistance better, become familiar with its concepts, learn how to measure it, relate it to other disease parameters and consider it as a another systemic manifestation of patients with RA.”

If you have RA, it is a good idea to pay attention to metabolic systems since you are at an increased risk for insulin resistance, increased inflammation, and cardiovascular disease. Below are some strategies that will likely benefit all RA patients.

  • Speak to your rheumatologist about this topic.
  • Get your lipids checked out. Traditional cholesterol tests do not provide enough detailed information. It is important to know LDL levels (“bad” cholesterol), HDL levels (“good” cholesterol), triglycerides, and insulin resistance. There are newer tests like the nuclear magnetic resonance (NMR) lipoprofile test which provides detailed information about the number and type of LDL particles. It also calculates an insulin resistance score. Ask your doctor to order this test. It’s not that expensive and most insurance companies cover it.
  • Watch your diet in terms of refined sugars and starches which rapidly increase blood glucose levels, cause insulin levels to spike, and add stored fat to the midsection. Such a diet increases the chances of developing insulin resistance. This is especially true for RA patients given the inflammatory connections. It is proposed that balancing low fat proteins with whole grain carbohydrates and small amounts of quality fats is the best diet for those with metabolic syndrome (see The Insulin Resistance Diet book by doctor and registered dietician Hart and Grossman for an excellent overview). In general, a low carb diet is suggested to lower levels of inflammation (see Forsythe, et al., 2008).
  • Exercise if possible. You don’t need to be a long distance runner or champion body builder. It is believed that muscle resistance exercise is better for insulin resistance as it burns excess glucose in the bloodstream (see this article).

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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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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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Humira - sunday week 12

Image by pollyalida via Flickr

Things are pretty hectic these days and that typically brings an increase in fatigue and joint symptoms. It doesn’t help that my Humira injection is due tomorrow but I’m itching to take it today with the notion that it may help me feel better. Of course, today I read of a study demonstrating that stress increases the release of inflammatory proteins like TNF alpha.[i] But I was more intrigued by the Arthritis Foundation article about how long it takes for rheumatic diseases to be diagnosed.[ii] Average time to diagnosis varies (see table below) but it is clear that folks with these diseases suffer for a long time before getting proper treatments. The article states, “Many rheumatic diseases have symptoms that overlap, and blood tests are rarely conclusive.”

Rheumatoid arthritis 6 to 9 months
Juvenile arthritis             5 months
Fibromyalgia                    2 to 5 years
Sjögren’s syndrome         3 to 7 years
Ankylosing spondylitis    6 to 9 years

Such was the case with me. After being referred by my general practitioner (an internist), my rheumatologist first suspected ankylosing spondylitis since my primary symptoms at the time were uveitis (inflammation of the iris) and achilles tendon problems. But my blood test for HLA-B27, the common genetic marker for this disease, was negative. About the same time, other tell-tale symptoms of RA began appearing…middle finger joints, wrists, elbows, knees – all occurring symmetrically on both sides. Bone erosion was noted via x-rays. Morning stiffness (what’s that? I’m stiff all day long!) and overwhelming fatigue (the truck running over you type) wrapped it up for the rheumy and he diagnosed me with RA.

This diagnosis was made in spite of negative RA factor blood tests. My RA factor tests have always been “borderline”…it’s not a black and white test. Another antibody test, anti-cyclic citrullinated peptide (anti-CCP) is another one used to determine RA. So far, I’ve been negative on that one as well. Therefore, I have what is called “seronegative RA.” I met the criteria using the now outdated diagnostic criteria.[iii] The diagnosis criteria were recently updated[iv] and according this new system, I still meet the diagnostic critieria without having positive blood tests. My rheumy regularly mentions that seronegative RA patients tend to fare better with symptoms over the long run and this is borne out by research.[v] Some seronegative RA patients “convert” over time…they end up with positive tests. Interestingly, a large proportion of folks diagnosed with RA are seronegative…up to 30% in some studies.[vi]

Being seronegative makes me feel somewhat like the stepchild to those who are seropositive. Maybe I’m not “official enough”. But then I have to step back and remember that my symptoms are real, I have permanent joint damage, and I’m forking out upwards of $20,000 a year for biological treatments (well ok, my insurance covers most of it). Perhaps I will seroconvert someday. But in the meantime I’ll hang onto the research that says that us seronegative RA types have a better long term prognosis.


[i] http://www.arthritistoday.org/news/social-rejection-stress-inflammation080.php

[ii] http://www.arthritistoday.org/daily-living/relationships/you-and-your-doctor/rheumatic-diseases-misdiagnosed.php

[iii] http://www.hopkins-arthritis.org/physician-corner/education/acr/acr.html

[iv] http://www.rheumatology.org/practice/clinical/classification/ra/2010_revised_criteria_classification_ra.pdf

[v] http://www.ncbi.nlm.nih.gov/pubmed/3855618

[vi] http://onlinelibrary.wiley.com/doi/10.1111/j.0105-2896.2009.00856.x/full

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A colleague recently was describing his experience fighting pneumonia. In addition to the hideous, non-stop coughing and the serious antibiotics he was taking, he began to describe how tired it made him feel. He would do a few hours of work and then feel totally wiped out. He could barely walk up a long set of stairs and then broke out in a sweat. Long naps and going early to bed were common. At that point, I thought to myself, “That’s exactly what RA induced fatigue feels like.” Interestingly, he asked me how I was doing with RA (he regularly displays compassion and understanding). I proceeded to give some general thoughts about joints being affected and about the medicines I’m taking. Later on, I kicked myself for not describing other symptoms such as the fatigue. I tend to avoid this topic. While many people can understand joint pain and damage associated with RA, they tend to not understand the general malaise that comes with it.

The fatigue my friend with pneumonia was experiencing is actually rooted to the same causes of RA fatigue – an immune response. During an immune response, either from an infection or autoimmunity, the body produces proteins called cytokines which are the cause of inflammation (see earlier post). This can lead to the fatigue commonly associated with autoimmune diseases. And, unfortunately, like I did with my colleague, this symptom of RA routinely gets swept aside or dismissed.

Here’s a list of some of the ways RA induced fatigue impacts me.

  1. It’s really hard to get going. This usually occurs in the morning and evening.
  2. I have less stamina and wear out more quickly.
  3. Bedtime gets earlier (or at least climbing into bed to rest if not yet fall asleep).
  4. My wife drives more often especially on longer trips.
  5. My limbs feel heavy.
  6. My brain gets foggy and it’s harder to concentrate.
  7. I have to force myself to do certain things and maintain attention.
  8. Some activities fall by the wayside. I have to choose my “battles”.
  9. Being over fatigued makes for less restful sleep.

And I just ran out of energy preparing this post… 🙂

Photo credit: Creative Commons License http://www.flickr.com/photos/codedragon/

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