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Posts Tagged ‘TNF blocker’

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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A group of researchers at the Max Planck Institute of Immunobiology and Epigenetics in Germany released research results that implicate the lack of a protein in B lymphocytes in autoimmune diseases including rheumatoid arthritis. The original research was published in the Journal of Experimental Medicine.

In reporting on this research, an article published in a popular press outlet in Germany used the headline “German Scientists Discover ‘Anti-Arthritis’ Protein”. Such a headline pulls in the reader thinking that a cure for RA is just around the corner. However, such a response is much too premature and all too common when reading about research being conducted on autoimmune diseases. The researchers found a protein called PTP1B was linked to autoimmunity processes. As with most initial studies, the first part of the research was conducted with mice and results don’t always extrapolate to people. These researchers did, however, follow-up with examining RA patients in a clinic. This protein is not newly discovered as scientists connected it to metabolism and insulin years ago. The PTP1B protein is also connected to B cell activating factor (BAFF) which scientists implicated in RA processes and connect to tumor necrosis factor (TNF) which has been the target of many RA treatments for years.

Personally, the most interesting part of this research is the role of B cells in rheumatoid arthritis since I am currently taking Rituximab which reduces the B cells in the body. In reporting the results on the university website, the scientists noted the potential role of Rituxamab in impacting the PTP1B protein in the following statement,

“The B-cells produced after the Rituximab therapy possess similar amount of the PTP1B protein as cells in healthy people. This may contribute to the less severe autoimmune reaction.”

While this research is interesting in terms of potential interest of determining why Rituxan works to treat RA, there remains much speculation about the biochemical processes involved and new treatments based on the role of the PTP1B protein remain hypothetical and likely many years away. As one of the scientists stated,

“Finding out how the protein works was an important discovery, but it doesn’t come with a solution to help heal arthritis, Michael Reth said. For that, scientists would need to artificially stimulate the PTP1B protein, and they are yet to find a simple way to do that.”

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

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

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

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

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

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

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If anything, RA is interesting in that there is never a dull moment as some new adventure waits around every bend. Those adventures may be in the form of a medication that works well, the failure of a medication, new symptoms that appear, etc. Earlier this week I happened to be rubbing my right elbow since it’s been in a lot of pain lately. While rubbing it, I noticed a lump and looked down to see a protuberance that was not there before. I inspected it and compared it to my left elbow determining that it was only presenting on the right side. It was clearly not part of the normal elbow joint. Then it dawned on me, this could be a rheumatoid nodule.

According to the National Rheumatoid Arthritis Society (NRAS) in the UK,

Rheumatoid nodules are firm lumps that appear subcutaneously (ie under the skin) in about 20% of patients with rheumatoid arthritis. These nodules usually occur over exposed joints that are subject to trauma, such as the fingers joints and elbows, though occasionally they can occur elsewhere such as the back of the heel.

In a study of almost 800 RA patients in Spain, the most prevalent extra-articular (outside the joint) presentation was nodules appearing in 24.5% of the sample.

According to a dermatological overview on the topic, the nodules consist of inflammatory tissue called necrobiotic granulomas which contains inflammatory cells such as lymphocytes and other white blood cells. The lumps are usually hard and painless and do not typically require any treatment although they may be removed surgically if needed. Nodules are usually benign but sometimes get infected. Nodules tend to be more common with patients with severe and aggressive RA disease symptoms, who are rheumatoid factor (RF) positive, and who display additional extra-articular symptoms including vasculitis (inflammation of blood vessels) and lung disease. Nodules can even develop in the lungs (see this case study).

The exact source of nodules is unknown but some researchers are beginning to argue that rheumatoid nodules may be related to genetic material which originated from the mother during pregnancy – called microchimerism (see this genetic study). According to Dr. Paget at the Hospital for Special Surgery in New York, patients who use high doses of methotrexate are more prone to develop nodules and the reasons for this are unclear (see also this article on MTX induced nodules). But there has been a decline in the presentation of nodules over the past few years probably attributed to the use of biological treatments. However, one group of researchers exhibited cases where increases of lung nodules were seen in patients using TNF blockers which then decreased after stopping the TNF blocker and switching to Rituxan. Supporting this study, other researchers documented that the use of Rituxan effectively treated subcutaneous nodules.

Rheumatoid nodules are an oft neglected area of research (see this recent review on nodules). In a recently published article in the prestigious international journal Rheumatolgy, Highton, Hessian, and Stamp (2007) pointed out that nodules may serve an important role in understanding RA. They stated,

In conclusion, the rheumatoid nodule is a much-ignored lesion in RA. This is despite the fact that it is a lesion that is destructive of tissue, a key feature shared with the joint lesion. Could this usually peripherally situated lesion be central to understanding which are the core lesions of RA leading to tissue destruction, and which are additional amplification mechanisms? Definition of the seemingly simpler and less diverse inflammatory mechanisms leading to tissue destruction in the rheumatoid nodule might be one way of addressing the increasing complexity of RA pathogenic mechanisms and getting to the centre of the matter.

While rheumatoid nodules tend to get pushed to the back burner, perhaps more research is needed about their pathology, how they develop, and how they are connected to other aspects of RA.

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8198569526_3f28555551Having gone through a slew of treatments options for rheumatoid arthritis in the past four years, it’s easy to begin to feel like a failure especially as I read about other fortunate RA sufferers who receive great benefit or even remission from first line medications like methotrexate and TNF blockers such as Enbrel and Humira. This feeling was exacerbated today when staying home because I felt too bad to go into work. In a period of no less than one hour, four commercials for Orencia and Humira came on the television (oh, as I was writing this sentence, a fifth commercial just came on!). These commercials show healthy, happy, and energetic looking people engaged in all types of activities that may be difficult for those with RA. Funny thing is, both of these medications failed to bring much impact let alone remission to me. I’m not alone as researchers discovered that 30% of patients on TNF blockers fail to reach even the minimal threshold for efficacy.[i] For some, including myself, there is some initial positive response but the impact diminishes over time. And for others, negative side effects or a reaction to the drug prevents them from taking it any longer.

After trying a boatload of RA treatments, I’m off to try a combination of RA medications that tend to be reserved for “failures” like me! My insurance approved Actemra in a fairly short time period – six days! I will have my first infusion tomorrow afternoon. According Genentech’s website,

“Actemra is the first humanized IL-6 receptor-inhibiting monoclonal antibody approved for the treatment of adult patients with moderately to severely active RA who have had an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).”[ii]

And the American College of Rheumatology repeats this “failure” mantra…

“Tocilizumab has been approved by the Food and Drug Administration (FDA) for use in patients with rheumatoid arthritis who have active disease despite having been treated with one or more of five other biologic modifier drugs that block another cytokine, tumor necrosis factor (TNF), or who have been unable to tolerate such drugs.”[iii]

The good thing is that I should know fairly quickly if it is working since it is reported to start working within a few weeks.[iv]

The other medication that I started taking today is azathioprine (trade name Imuran). Once again, it appears that this drug, originally designed as an immunosuppressant for organ transplants, tends to be reserved for RA patients who do not respond or cannot take other more common DMARDS like methotrexate and leflunomide (Arava).[v]

Rheumatoid arthritis affects everyone differently as do the various treatments. This is evident in the many new medications being tested (see earlier post) and the recent approval of Xeljanz. I just have to keep reminding myself that I’m not a failure and that some combination of treatments will work! I’ll write a post about tomorrow’s Actemra infusion.

Creative Commons Photo Credit: http://www.flickr.com/photos/quinnanya/8198569526/

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It seems that with the FDA approval of Xeljanz this week, most of the attention for new treatments for RA is focused on orally administered protein kinase inhibitors.[i] This attention is not unwarranted in that Xeljanz is the first oral treatment for RA approved in over 10 years. The kinase inhibitor drugs are complex molecules that impact some part of the biological pathways involved in cancer and immune diseases.[ii] With all the hoopla around Xeljanz, I wondered what was going on in the world of new biological treatments for RA.

antibodies

Most biological treatments for autoimmune diseases are focused on signaling pathways involved with immune cells. These signals are typically carried by proteins including cytokines. In autoimmune diseases, it is thought that the pathways and associated cytokines are out of whack resulting in an overactive immune response in which a person’s own tissue comes under attack. Tumor necrosis factor (TNF) is a cytokine that has been the target of many recent biological treatments for RA. The most popular biological treatments for RA are Enbrel, Humira, and Remicade which all attempt to block TNF with antibody proteins. The large size of these sensitive proteins means that they must be injected or infused into the body rather than be ingested orally. Other biological treatments approved for RA include Orencia targeting the protein called B7 which reduces T cell stimulation, Rituxan which targets the protein CD-20 in B cell pathways, and the newest one Actemera which targets interleukin 6 (IL-6).

There are literally thousands of clinical trials related to RA occurring around the world[iii] and finding specific information related to new possible biological treatments is difficult for someone outside the research community. It seems that pharmaceutical companies are somewhat elusive with drug development. They want to maintain some level of trade secrecy, publish results in the peer-reviewed research world, and give out just enough information for investors to get excited. With a little snooping that would not have been possible 15 years ago in the early stages of the internet, I found that there are some important clinical trials going on for new biological treatments. In some cases, I had to create a login to access certain journals or use my university library access to find information.

B cell lymphocytes and their signaling proteins appear to be one of the main targets of recent biological drug development.[iv][v]. It seems that IL-6 and CD-20 are the most researched parts of the RA biochemical pathway. I found 17 biologicals that show promise and are in various stages of testing. Below is a list of some of the biologicals I found. Most of their scientific names end in “MAB” because they are monoclonal antibodies meaning that they are cloned proteins coming from one type of immune cell. Genetically engineered mice are used in the complex production process.

We see the usual set of major pharmaceutical players, who already have the lion’s share of the RA drug market, doing most of the testing of these new drugs demonstrating that there is big money to be had in this area. Sometimes smaller companies develop the drug and the rights are purchased by a large company who then funds the extensive clinical trails. Not all of these experimental drugs will obtain approval and make it to market.

It is a good thing for patients that the search for new biological and chemical treatments for RA continues. The wide variety of biologicals targeting different biochemical pathways may ultimately result in more patients responding to treatment. With over 1.5 million RA patients and as one of the leading causes of disability in the United States, treatments are needed that improve the quality of life and reduce disability. In spite of the proliferation of treatments, I still hold out hope for a real cure to this insidious disease.

IL-6 Inhibitors

Sarilumab is being developed by Sanofi in Europe. It shows promise in clinical trials in treating RA with infections the most common side effect.[vi]

BMS-945429 is an experimental drug from Bristol Meyers Squibb that also targets IL-6.[vii] It is made in yeast cells instead of the standard medium for making other biologicals-hamster ovaries. It shows promise in treating RA.[viii]

Sirukumab, being tested by GlaxoSmithKline, is an IL-6 inhibitor to which RA patients show a good response.[ix] Side effects include infections, gastrointestinal problems, and blood problems.[x]

Olokizumab is being developed in Europe by UCB which also developed the TNF blocker Cimzia. [xi] It shows promise in early trials with side effects including headache and blood problems.[xii]

GSK315234, also from GlaxoSmithKline, targets interleukin 6 (IL-6) and is in early clinical trials. [xiii] [xiv]

CD-20 Inhibitors

Like Rituxin, the antibody Ofatumumab (trade name Azerra also known as HuMax-CD20) targets the B cell protein CD-20. It is already approved for leukemia but is being tested in clinical trials for rheumatoid arthritis.[xv] It is produced by GlaxoSmithKline.

Pfizer, in partnership with Emergent, announced the development of a biological which also targets CD-20. It is currently called SBI-087 (PF-05230895).[xvi] It is in clinical trial for the treatment of RA.[xvii]

While not a completely new biological, Pfizer is testing an antibody called PF-05280586 that is similar to Rituxin. These are called “biosimilars” and other companies around the world are trying to get in on the action by developing their own Rituxin look-alikes.[xviii]

IL-20 Inhibitors

The monoclonal antibody NNC 0109-0012 targets interleukin 20 (IL-20). Clinical trials occurred in Europe and are funded by the company Novo Nordisk. Early results show that this biological positively impacted RA symptoms while showing the typical safety profile of other biologicals including increased infections and injection reactions.[xix]

IL-17 Inhibitors

Secukinumab, developed by Novartis, targets the cytokine interleukin 17 (IL-17).[xx] It is in clinical trial for several autoimmune diseases including RA in which some improvement was seen with typical side effect profiles for other biologicals.[xxi] [xxii]

Ixekizumab, from Eli Lily and Co., also targets IL-17 and is being tested for RA and plaque psoriasis.[xxiii] Early results demonstrate impact on RA symptoms along with typical side effects including infections.[xxiv]

B Cell Activating Factor (BAFF) Inhibitors

Tabalumab, from Eli Lily and Co., is being developed as a treatment for autoimmune diseases and some cancers. It shows some efficacy at reducing RA symptoms yet includes infections as a side effect.[xxv]

Others

Pateclizumab, by Genentech and Roche, targets a set of cytokines called lymphotoxin (LT)-alpha Inhibitors. It shows promise in treating RA. It is also being tested by co-administering it along with a TNF blocker like Enbrel. Side effects include headache and gastrointestinal issues but no serious infections.[xxvi]

Denosumab is an antibody from Amgen that targets the production of RANKL, a protein that signals bone erosion. It is currently approved under the trade name Prolia for the treatment of osteoporosis and is currently under clinical trial for the treatment of RA.[xxvii] But problems with the drug have held up the use of Denosumab for osteoporosis let alone other diseases.[xxviii]

Ozoralizumab, developed by Ablynx in Europe, is a new TNF blocker that shows promise in treating RA and may compete with Humira and Enbrel if approved.[xxix][xxx]

Stelara (Ustekinumab), developed by Janssen, is already approved for the treatment of psoriasis. It targets interleukins 12 and 23 (IL-12, IL-23). It is in clinical trial for RA.[xxxi]

Fezakinumab, being developed by Pfizer, targets interleukin 22 and is in clinical trial for RA.[xxxii]

Creative Commons Photo Credit: http://commons.wikimedia.org/wiki/File:Chimeric_and_humanized_antibodies.svg

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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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