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Diseases and Conditions

Diseases and Conditions

Can small fiber neuropathy mimic fibromyalgia?

July 19, 2017
Small fiber neuropathy can feel like your legs and feet are on fire. Can small fiber neuropathy mimic fibromyalgia?

Can small fiber neuropathy (SFN) mimic fibromyalgia?  The simple answer is yes, but it’s more complicated… So why does a rheumatologist care about small fiber neuropathy?  The answer is very simple.  Many people get referred to a rheumatologist for fibromyalgia, which is a disease that causes widespread pain, brain fog, non-restorative sleep, and various other unexplained symptoms such as headaches.  While fibromyalgia IS NOT an autoimmune disease, small fiber neuropathy can present very similarly but CAN BE caused by autoimmune diseases.

There’s a lot of controversy in the medical community about fibromyalgia.  One group believes that it’s a separate entity, some do not believe in its existence, and some people are somewhere in the middle.  Personally, I believe that fibromyalgia likely represents many diseases that we haven’t identified yet.  Until we can categorize them into distinct entities, we’re going to have a hard time understanding them, let alone come up with effective treatments.

First, let’s review the clinical criteria that doctors use to make a diagnosis of fibromyalgia.

2010 ACR criteria for fibromyalgia

Criteria A patient satisfies diagnostic criteria for fibromyalgia if the following 3 conditions are met:

  1. Widespread pain index (WPI) ≥ 7 and symptom severity (SS) scale score ≥5 or WPI 3–6 and SS scale score ≥ 9.
  2. Symptoms have been present at a similar level for at least 3 months.
  3. The patient does not have a disorder that would otherwise explain the pain.

Number #1 are various validated pain scores.  These are rarely used in clinic but are often used for clinical trials.  It helps researchers objectively quantify pain levels at any given time.  As you can see, we don’t use trigger points to check for fibromyalgia anymore.

Small fiber neuropathy in people with fibromyalgia

So is small fiber neuropathy a feature of fibromyalgia, just like it is for diseases like Sjogren’s syndrome or are patient’s with small fiber neuropathy mistakenly diagnosed with fibromyalgia?

In one study, 46 patients with fibromyalgia and 34 normal controls were tested for small fiber neuropathy with a specialized skin biopsy.  I’ll talk more about this later on.  The researchers measured pain intensity with a survey called the Neuropathic Pain Symptom Inventory. They found that 32.6% of patients with fibromyalgia had reduced nerve fiber density on their biopsy, i.e, they had small fiber neuropathy.  Interestingly, they also didn’t find any correlation between pain scores and nerve density.

This implies three things.  First of all, the level of pain and symptoms experienced by people with fibromyalgia was the same as those with small fiber neuropathy.  So you can’t distinguish between fibromyalgia and small fiber neuropathy based on symptoms alone.  Second, about 1/3 of people diagnosed with fibromyalgia have small fiber neuropathy.  Finally, having worse nerve density doesn’t necessarily mean you’ll experience more pain.  Other studies have also found similar results.

Now this still doesn’t answer all our questions but I think it’s safe to say that testing for small fiber neuropathy should happen when there is a clinical diagnosis of fibromyalgia. Now let’s talk about small fiber neuropathy.

What is Small Fiber Neuropathy?

Small fiber neuropathy results from damage to the small, unmyelinated nerve fibers that send pain and temperature and control autonomic functions like sweating.  The following are some of the symptoms caused by SFN:

  • Burning pain
  • Numbness and tingling
  • Pain that is out of proportion
  • Cramping
  • Unexplained itching
  • Lack of sweating
  • Temperature dysregulation
  • Dryness

How to diagnose small fiber neuropathy?

The first step to diagnose small fiber neuropathy is taking a care history, reviewing risk factors, and performing a detailed physical examination.  On physical exam, deep tendon reflexes (e.g., knee jerk reflex) are normal and there’s no loss of strength.  If there is a suspicion for SFN your doctor may send you for electrodiagnostic tests (EMGs).  These are colloquially called nerve conduction tests.

Small fiber neuropathy affects small myelinated A-delta and unmyelinated C fibers, NOT large fibers.  This means that EMGs are typically negative because these are good for looking for problems affecting large fibers like carpal tunnel syndrome.

One way to diagnose small fiber neuropathy is with a skin biopsy, more specifically epidermal nerve fiber density testing (ENFD).  This technique allows direct visualization, quantification, and morphologic assessment of small sensory fibers innervating the skin.  This technique has a sensitivity of 88% and a specificity of 95 – 97%.  In layman’s terms, the test will miss 12% of cases of small fiber neuropathy, but if the test is positive, there’s a 3 – 5% chance that it’s a mistake (false positive).   These are actually pretty good values.    A report by the European Federation of Neurological Societies states that ENFD is a reliable and efficient tool to assess for SFN.

How is epidermal fiber density testing done?

Epidermal fiber density testing is done by taking 2-4 three mm punch biopsies.  This test happens in clinic.  It’s quick and safe.  Your doctor can only do these in areas that have been validated: near the ankle, upper thigh, the foot, near the wrist, and the upper arm.

The biopsy is then sent to a specialized pathologist and stained with anti-protein gene product 9.5 antibody (PGP 9.5), which stains all the axons.  The pathologist can then painstakingly count all the nerves and calculate the density.  The density is then compared to age and sex matched control values to decide whether it’s abnormal.

Common causes of small fiber neuropathy

Once your doctor makes a diagnosis of small fiber neuropathy, then the question is whether there is an underlying cause.  About 50% of small fiber neuropathy cases are idiopathic, meaning that doctors can’t find an underlying cause.  As a result that leaves us with the other 50%.  Of those cases, the most common cause is diabetes mellitus.  In fact, autoimmune diseases make a relatively small proportion of cases, so it’s important to look for other causes first.  There are MANY other causes but these are some of the more common conditions that can cause small fiber neuropathy.

Non-autoimmune causes

  • Diabetes mellitus
  • Lyme disease
  • Hepatitis C infection
  • HIV
  • Celiac disease
  • Chronic kidney disease
  • Hypo/hyperthyroidism
  • Alcohol abuse
  • Medications, especially chemotherapy
  • Vitamin B12, B6, B1 deficiency
  • Paraneoplastic syndromes
  • Amyloidosis
  • Exposure to heavy metals

Autoimmune causes

  • Sjögren’s syndrome
  • Systemic lupus erythematosus
  • Sarcoidosis
  • Rheumatoid arthritis
  • Scleroderma
  • Inflammatory bowel disease (Crohn’s disease and ulcerative colitis)
  • Vasculitis
  • Psoriasis and psoriatic arthritis

Some genetic conditions can also cause small fiber neuropathy, like Fabry’s, but these are very rare.

Treatment

I won’t talk too much about treatment because it really depends on the underlying cause.  If you’re dealing with an autoimmune disease… treat it.  Sometimes symptomatic treatment is also necessarily. The following are some medications that are often used:

  • Tricyclic antidepressants
  • Serotonin norephinephrine re-uptake inhibitors (SNRIs)
  • Pregabalin
  • Gabapentin
  • Topical lidocaine
  • Topical capsaicin

Doctors sometimes use intravenous immunoglobulin (IVIG) in extreme situation, particularly in situations where an autoimmune disease is the culprit. The evidence supporting this type of treatment isn’t great.  Sometimes it works, sometimes it doesn’t.  Moreover, there are no large randomized controlled studies looking at IVIG treatment for small fiber neuropathy.

Ultimately, we’re going to need to understand why and how small fiber neuropathy happens to come up with effective treatments.

Conclusion

I hope this helps explain how small fiber neuropathy (SFN) mimics fibromyalgia and why it’s important to distinguish between both.  For those who want to learn more about small fiber neuropathy and how to live with it, I’ve included a link to a great YouTube video.

Please leave your comments below!

References

Lauria G, Devigili G. Skin biopsy as a diagnostic tool in peripheral neuropathy. Nature Clinical Practice Neurology. 2007 Oct 3;3(10):546-57.

Devigili G, Tugnoli V, Penza P, Camozzi F Lombordi R, Milli G, Broglio , Granieri E, Lauria G. The diagnostic criteria for small fibre neuropathy : from symptoms to neuropathology. Brain 2008; 131; 1912-19.

Lauria G, Hsieh ST, Johansson O, Kennedy WR, Leger JM, Mellgren SI, Nolano M, Merkies IS, Polydefkis M, Smith AG, Sommer C, Valls-Sole J. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on he use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the peripheral nerve society. J Peripher Nerv Syst. 2010 Jun;15(2):79-92.

Giannoccaro MP, DonadioV, Incensi A, Avoni P, Liguori R. Small nerve fiber involvement in patients referred for fibromyalgia. Muscle Nerve. 2014 May;49(5):757-9.

Kosmidis ML, Koutsogeorgopoulou L, Alexopoulos H, Mamali I, Vlachoyiannopoulos PG, Voulgarelis M, Moutsopoulos HM, Tzioufas AG, Dalakas MC. Reduction of intraepidermal nerve fiber density (IENFD) in the skin biopsies of patients with fibromyalgia: a controlled study. J Neurol Sci. 2014 Dec 15;347(1-2):143-7.

Chan AC, Wilder-Smith EP. Small fiber neuropathy: getting bigger! Muscle Nerve. 2016 Feb 13. [Epub ahead of print]

UpToDate 2017

Uceyler N, Zeller D, Kahn AK, Kewenig S, Kittel-Schneider A, Casanova-Molla J, Reiners K, Sommer C. Small fibre pathology in patients with fibromyalgia syndrome. Brain. 2013 Jun;136(Pt 6):1857-67.

Medical Disclaimer

This information is offered to educate the general public. The information posted on this website does not replace professional medical advice, but for general information purposes only. There is no Doctor – Patient relationship established. We strongly advised you to speak with your medical professional if you have questions concerning your symptoms, diagnosis and treatment.

Diseases and Conditions Overcoming Inflammation

Can UV light trigger lupus flares?

July 12, 2017
Can UV light trigger lupus flares?

Now that summer is finally in full swing, I’d like to remind everyone to use broad spectrum sunscreen while enjoying the sun!  This is especially important for people living with systemic lupus erythematosus (SLE). Ultraviolet (UV) light is a known trigger of SLE flares BOTH involving the skin and major organs.  Many people also report joint pain, weakness, and headaches.  These flares can be very serious.

Although we know UV light is a trigger for SLE flares, we still don’t fully know how it happens.  This is what we do know.

  • UV light directly damages the DNA of skin cells.
  • The cells release inflammatory cytokines, most notably interleukin-1α and tumor necrosis factor-α.
  • UV light also increases interferon-α signaling. People with high levels of interferon-α signaling often develop fevers, fatigue, and low white cell count (leukopenia).  Interferon-α signaling is thought to be an important part in the development of SLE.

Take home points

So while you’re enjoying the sun remember to:

  1. Avoid the sun when UV light is strongest, between 10 AM and 3 PM. If you use IFTTT, check out this app.  You will get a notification on your phone when the UV index is high… and it’s free!
  2. Use broad spectrum UVA/UVB sunscreen.  Try to aim for a SPF higher than 30.
  3. Try wearing clothing that have vivid colors and a tight weave. The Skin Cancer Foundation has a great article regarding this topic: “What is Sun-Safe Clothing?”
  4. Wear a broad-brimmed hat when spending time in the sun.

Be safe and please leave your comments below!

References

 Fernandez D, Kirou KA. What causes lupus flares?  2016 Mar;18(3):14. doi: 10.1007/s11926-016-0562-3.

Medical Disclaimer

This information is offered to educate the general public. The information posted on this website does not replace professional medical advice, but for general information purposes only. There is no Doctor – Patient relationship established. We strongly advised you to speak with your medical professional if you have questions concerning your symptoms, diagnosis and treatment.

Diseases and Conditions Featured

Guide to living with rheumatoid arthritis: Part 1

July 5, 2017
Have you recently been diagnosed with rheumatoid arthritis? RheumDoctor presents a guide to living with rheumatoid arthritis

Rheumatoid arthritis…  Your rheumatologist diagnosed you with rheumatoid arthritis and you have a lot questions.  What’s rheumatoid arthritis?  Can I get rid of it or will I live with this disease for the rest of my life?  What should I expect?  How do I fight it?  This week I’ll present to you Part 1 of a Guide to living with rheumatoid arthritis.  I’m going to present this as a three-part series.  Part 1 will cover the basics: what is rheumatoid arthritis, the cause, symptoms, diagnosis, treatment, etc.  In Part 2 I’ll cover prognosis, what to expect, diet and exercise.  In Part 3, I’ll be covering the financial side of rheumatoid arthritis: How to get access to medications and how to deal with insurance companies.

I hope you find this information useful.  Be strong, be brave, and know that you’re not alone.

What is rheumatoid arthritis?

Rheumatoid arthritis is an autoimmune disease that causes inflammation throughout the body but mainly affect joints. Without treatment, rheumatoid arthritis can eventually lead to permanent joint destruction.  Autoimmune diseases occur when the immune system loses “tolerance to self”.  What this means is that the immune system can no longer distinguish between healthy cells and cells that don’t belong like bacteria or cancerous cells.

According to the CDC, about 1% of people living in the US suffer from rheumatoid arthritis.  It tends to occur 2-3 times more often in women and tends to start in your sixties but it can start at any age.  [1]

Some common signs and symptoms include:

  • Pain and swelling in the joints. Particularly small joints like the knuckles, wrists, and toes.
  • Morning stiffness that lasts more than one hours
  • Having difficulty opening jars. Weakness in the hands.
  • Fatigue, fevers, unintentional weight loss.

What causes rheumatoid arthritis?

We’re actually unsure.  We do know that in certain cases there is a genetic link. People that have a certain HLA class II genotype (shared epitope) tend to get rheumatoid arthritis more often.  Especially, if they smoke cigarettes.  Moreover, we know that rheumatoid arthritis tends to run in families.  However, most cases of RA happen spontaneously and not everyone who has a genetic risk factor develops RA.

There’s still a lot of work that needs to be done to fully understand what causes rheumatoid arthritis.  Like most autoimmune diseases, our best guess is that people who have RA probably were born with some sort of genetic predisposition for the disease.  Then they get exposed to something in the environment like a virus, trauma, stress, hormonal change, which then triggers the disease to come online.

What are the symptoms of rheumatoid arthritis?

Usually rheumatoid arthritis presents with pain, swelling, and prolonged stiffness involving small joints, like the ones in your hands or feet.  When I mean prolonged, I mean more than one hour.  But RA can present in many ways. These can be divided into typical (90% of cases) and atypical presentations (10% of cases).

Typical

Insidious (55% – 65%): People develop pain, swelling, and prolonged stiffness mainly involving small joints like the toes and knuckles. This progressively worsens over months.

Subacute (15% – 20%): Again small joints are painful, swollen, and stiff but the this develops over weeks. Usually people experience some fatigue.

Acute (10%): Joints suddenly become swollen and tender over days. Some people have a fever, drenching night sweats, and sometimes can lose weight without trying.

Atypical (10% of cases)

Palindromic pattern: This type of presentation isn’t technically considered rheumatoid arthritis. It’s just that 33% to 50% of people with this type of presentation progress to full-blown rheumatoid arthritis. Typically, one joint is involved. It becomes tender and swollen for a few days then gets better on its own. Then a few weeks to a few months later it happens again. The flare can happen in the same joint but not necessarily. Treatment with hydroxychloroquine can decrease the risk of developing full-blown rheumatoid arthritis, so it’s important to start treatment as this stage.

Insidious onset of the elderly: As the name suggests this type of presentation occurs in the elderly, so people aged greater than 65 years. People experience extreme pain and stiffness shoulders and the hips. Sometimes you can see whole hand or foot swelling. Sometimes it’s very difficult to differentiate from polymyalgia rheumatica or remitting seronegative symmetrical synovitis with pitting edema (RS3PE).  People with polymyalgia rheumatica and RS3PE typically do NOT have any positive antibodies.

Rheumatoid nodulosis: Rheumatoid arthritis can cause nodules and bone cysts on radiographs. Usually people also have joint pain and swelling but sometimes all they have are nodules.

Arthritis robustus: This is rather rare. I’ve only seen it once. It typically occurs in men. Essentially the person develops horrible rheumatoid arthritis hand deformities but experiences little or no pain.  I know it’s hard to believe, but it’s possible!

Untreated rheumatoid arthritis

By James Heilman, MD (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)], via Wikimedia Commons

How is rheumatoid arthritis diagnosed?

The diagnosis of rheumatoid arthritis, contrary to popular belief, is primarily a clinical diagnosis. Having a positive antibodies like a rheumatoid factor (RF) does not necessarily mean that you have rheumatoid arthritis because MANY conditions can have a positive rheumatoid factor. Some of these include:

Rheumatoid arthritis, mixed cryoglobulinemia types II and III, sarcoidosis, and other autoimmune diseases like Sjogren’s syndrome. Other non-rheumatology diseases that can cause someone to have a positive rheumatoid factor include infections most notably hepatitis C, tuberculosis, syphilis, HIV, and endocarditis. People suffering from cancer and people with chronic pulmonary and liver diseases, can also have a positive rheumatoid factor.

It’s also important to mention that about 5 – 25% of people aged 60 years and older have a positive rheumatoid factor without any underlying causative disease.

This is why my job as a rheumatologist is so interesting 🙂

The American College of Rheumatology classification criteria for rheumatoid arthritis is as follows:

The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis[2]

Who to test?

  • People that have at least 1 joint with definite swelling.
  • And the swelling cannot be better explained by another disease.

Classification criteria for RA (a score of ≥ 6/10 is needed for someone to have definite RA)

Category   Score
A Joint involvement

1 large joint

2 – 10 large joints

1 – 3 small joints

4 – 10 small joints

> 10 joints (at least one small joint)

 

0

1

2

3

5

B Antibodies

Negative RF and negative CCP antibodies

Low positive RF or low positive CCP antibodies *

High-positive RF or high positive CCP antibodies #

 

0

2

3

C Inflammation markers

Normal CRP and normal ESR

Abnormal CRP or abnormal ESR

 

0

1

D Duration of symptoms

< 6 weeks

≥ 6 weeks

 

0

1

* Low positive antibodies means any value that is above normal but less than 3 standard deviations above the upper limit of normal.

# High positive antibodies means any value that is 3 standard deviations above the upper limit of normal.

It’s important to note that these criteria were NOT meant for clinical practice but rather, were really meant for research trials. Sometimes, rheumatologists do deviate. Other conditions should be ruled out and let’s face it, not everyone fits perfectly into the mold. The criteria also does not account for musculoskeletal ultrasound testing. This imaging test can detect very subtle inflammation of a joint.[3]

Positive antibodies without RA

Now sometimes the workup is completely negative including x-rays. This is not uncommon. It can mean many things. It could mean that the rheumatoid factor is not clinically significant. 5–25% of the population can have a positive rheumatoid factor without any underlying condition or any symptoms. Typically the rheumatoid factor levels are low. It could also mean that you will develop rheumatoid arthritis in the future. Studies have shown that antibodies associated with rheumatoid arthritis can be present over a decade before onset of clinical disease. [4]Unfortunately, we don’t have the tools to precisely determine who will convert and who will not. In this situation, your rheumatologist can help you watch for any change in your condition.

How is rheumatoid arthritis treated?

We treat rheumatoid arthritis with medications called disease modifying anti-rheumatic drugs (DMARDs).  These medications slow down or stop the natural progression of rheumatoid arthritis.

Except for a few special situations, EVERYONE should with rheumatoid arthritis should be treated with a DMARD as soon as possible because permanent joint damage can happen in as little as 3 months after symptoms start.[5]

The following are the medications used to treat rheumatoid arthritis in the United States.  It’s important to work closely with your rheumatologist because they all have possible risks and what may be good for your neighbor may not be safe for you.

I’ve broken them down into conventional DMARDs, biologic DMARDs, and pipeline medications that have not been approved as of yet.

Conventional

  • Methotrexate
  • Leflunomide
  • Sulfasalazine
  • Hydroyxchloroquine

Biologics

  • Etanercept, TNF inhibitor
  • Adalimumab, TNF inhibitor
  • Golimumab, TNF inhibitor
  • Certolizumab pegol, TNF inhibitor
  • Infliximab, TNF inhibitor
  • Abatacept, Co-stimulation inhibitor
  • Tocilizumab, IL-6 inhibitor
  • Sarilumab, IL-6 inhibitor
  • Tofacitinib – JAK inhibitor
  • Rituximab – B cell depletion

Pipeline

  • ABT 494, a new JAK inhibitor
  • Baricitinib, another JAK inhibitor
  • Sirukumab, another IL-6 inhibitor

Biosimilars

It’s also important to note that we are starting to see biosimilar medications in the States. These are medications that are sort of copied from existing biologic medications.  They are NOT generic medications. The problem with biosimilars is that because of their complexity, it literally is impossible to exactly copy a biologic medication. If you want to learn more about biosimilar medications, please check this article.

Supplements

If you’re interested in supplementing, there is some research that suggests high dose turmeric/curcuma and high dose fish oil/omega-3 fatty acids may also be helpful.[6][7] However, supplementation should be used in combination with FDA approved medications that I listed above.

Is there a cure for rheumatoid arthritis?

I honestly wish I had better news for you. Unfortunately there is no cure for rheumatoid arthritis. Treatment primarily focuses on arresting the natural progression of the disease with the use of disease modifying anti-rheumatic agents (DMARDs). Conventional DMARDs such as methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine, modulate the immune system to decrease rheumatoid arthritis activity.  Biologic medications like etanercept use a targeted approach, i.e., suppress a specific cytokine.

The goal of treatment is to put rheumatoid arthritis into remission and decrease the frequency of flares.

This may seem very pessimistic, but recent advances have really improved the prognosis of people living with rheumatoid arthritis.

Nevertheless, DMARDs do not cure rheumatoid arthritis.

How do we win the war against rheumatoid arthritis? Before we can win the war and find a cure, we need to know exactly what causes rheumatoid arthritis in the first place and we need to understand its exact pathophysiology. Believe it or not, despite all our advances, we still cannot answer these two questions. Don’t despair, researchers are actively trying to answer these questions.

Can rheumatoid arthritis become fatal?

Rheumatoid arthritis is a systemic autoimmune mediated disease that primarily affect the joints. Note the primarily bit. It can affect a host of different organs including the eyes, lungs, heart, skin, and bone marrow to name a few.

Untreated or poorly controlled rheumatoid arthritis can cause serious conditions such as interstitial lung disease (i.e., inflammation of the lungs), pericarditis (i.e., inflammation of the “sac” surrounding the heart), as well as something called Felty’s syndrome (i.e., a hematologic condition that can cause white cells to dramatically decrease and causes the spleen to enlarge). These severe manifestations of rheumatoid arthritis that can lead to death are hardly ever seen anymore mainly because we have many highly effective medications called disease modifying anti-rheumatic medications (DMARDs). These medications have completely changed people’s prognosis.

Cardiovascular disease and infection

The most common cause of death in people with rheumatoid arthritis these days includes cardiovascular disease and infection – primarily from medications.[8]

Rheumatoid arthritis increases cardiovascular risk via the interplay of inflammation and lipid metabolism. Studies have shown that people who receive treatment with methotrexate and or tumor necrosis factor inhibitors reduce their cardiovascular risk.[9] A British study also demonstrated that cardiovascular was not increased regardless of the choice of DMARD provided that rheumatoid arthritis was well controlled.[10]

Infection remains an ever-present problem in the world of rheumatology. To treat autoimmunity you need to suppress the immune system. Not too much, not too little, but just right. In some cases this has the unfortunate result in causing serious infections that can lead to death in extreme cases.

Rheumatoid arthritis can become fatal in many other ways, however, for the most part it is medication induced – although the pharmaceutical companies don’t really want you to know that. Just read a package insert. They’re terrifying.

However, I’ve been talking about rheumatoid arthritis fatalities. Untreated or undertreated rheumatoid arthritis is HIGHLY debilitating leading to a significant drop in your quality of life. Early treatment with a DMARD is the best way to improve your odds. You have to fight fire with fire!

Can I stop my medications if I’m feeling better?

No. Rheumatoid arthritis is a life-long disease.  If you’re feeling better, great!  However, it’s probably your medications that are keeping you that way.  If you stop your medications the rheumatoid arthritis will come back.  Maybe not now but soon.  Rheumatoid arthritis subsides spontaneously in a VERY small subset of people.

If your medication is making you feel sick, talk to your rheumatologist.  They’re there to make you feel better and they want to find the perfect treatment plan tailored for you.

Do not stop your medications without consulting your rheumatologist.

Next steps

We’ve covered a lot of material today and there’s a lot more coming your way!  Stay tuned for Part 2.  I’ll be covering topics such as what to expect, what to eat, how to exercise, and strategies on how to reduce stress.  Please leave your comments below.

References

[1] https://www.cdc.gov/arthritis/basics/rheumatoid-arthritis.html

[2] https://www.rheumatology.org/Portals/0/Files/2010_revised_criteria_classification_ra.pdf

[3] Horton SC, et al. Ultrasound-detectable grey scale synovitis predicts future fulfilment of the 2010 ACR/EULAR RA classification criteria in patients with new-onset undifferentiated arthritis. RMD Open. 2017 Mar 30;3(1):e000394. doi: 10.1136/rmdopen-2016-000394. eCollection 2017.

[4] Brink M, et al. Rheumatoid factor isotypes in relation to antibodies against citrullinated peptides and carbamylated proteins before the onset of rheumatoid arthritis. Arthritis Res Ther. 2016 Feb 9;18:43. doi: 10.1186/s13075-016-0940-2.

[5] Raza K, et al. Treating very early rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2006 Oct;20(5):849-63.

[6] van der Tempel H, et al. Effects of fish oil supplementation in rheumatoid arthritis. Ann Rheum Dis. 1990 Feb; 49(2): 76–80.

[7] Ramadan G Al-Kahtani MA, El-Sayed WM. Anti-inflammatory and anti-oxidant properties of Curcuma longa (turmeric) versus Zingiber officiale (ginger) rhizomes in rat adjuvant-induced arthritis. Inflammation. 2011 Aug;34(4):291-301. doi: 10.1007/s10753-010-9278-0.

[8] https://www-ncbi-nlm-nih-gov.elibrary.amc.edu/pubmed/26472415

[9] https://www-ncbi-nlm-nih-gov.elibrary.amc.edu/pubmed/28455580

[10] https://www-ncbi-nlm-nih-gov.elibrary.amc.edu/pubmed/28160488

Medical Disclaimer

This information is offered to educate the general public. The information posted on this website does not replace professional medical advice, but for general information purposes only. There is no Doctor – Patient relationship established. We strongly advised you to speak with your medical professional if you have questions concerning your symptoms, diagnosis and treatment.

Diseases and Conditions

Tocilizumab: the new wonder drug for giant cell arteritis

June 7, 2017
People aged 50 years and above can develop giant cell arteritis

On May 22nd 2017 the FDA approved weekly subcutaneous tocilizumab (trade name Actemra®) to treat giant cell arteritis, a type of vasculitis that can cause blindness and in some cases death.  Why is this so important and how does this change everything?  The answer is simple.  Previously there were no effective treatments.  Rheumatologists used steroids like prednisone at high doses for months on end.  Many people would get lot’s of side effects due to the steroids and even this did not guarantee success.  Typically it takes many years for a medication to get FDA approval.  Although it did take more than a year to get approval, the process in this particular situation was fast-tracked.  Before I get into how we got to where we are today, let’s start with some background.

What is giant cell arteritis?

Giant cell arteritis is a type of large vessel vasculitis that tends to affect people aged 50 years and above.

Pay attention to the spelling, a-r-T-E-r-i-t-i-s. This is completely different from a-r-T-H-r-i-t-i-s.

Giant cell arteritis is an autoimmune disease that inflames blood vessels not joints.  More specifically, it inflames the aorta and the branches of the aorta.  Sometimes it’s also called temporal arteritis, but that’s not a good name for it because the temporal arteries are one type of artery that giant cell arteritis can affect.  We call this autoimmune disease giant cell arteritis because if you biopsy an artery you will find “giant cells” also called “granulomatous inflammation”, when you look at it under a microscope.  In fact, this is one way rheumatologists make the diagnosis.

This is an image of the human arterial system. Giant cell arteritis can affect any artery coming off the aorta

By LadyofHats, Mariana Ruiz Villarreal [Public domain], via Wikimedia Commons

What are the symptoms of giant cell arteritis?

Giant cell arteritis can present in many ways.  It really depends on the affected blood vessel(s).  If there is vasculitis in a temporal artery, then people tend to have a bad headache and a cramping pain when chewing food.  Maybe the blood vessels supplying the ears has vasculitis? This can cause a change in hearing and vertigo.  If the blood vessels supplying the eyes is affected, then it can cause blindness.  In some cases, people aren’t even aware of it.  They get a CT scan for some unrelated issue and the radiologist finds a large aortic aneurysm.  Giant cell arteritis is a condition that causes inflammation throughout the body, so many people present with fevers, drenching night sweats, and weight loss.

One of the most common presentations of giant cell arteritis is polymyalgia rheumatica.  Sometimes doctors simply call it “PMR”.  While 40% of people with giant cell arteritis have polymyalgia rheumatica, 10-20% of people with polymyalgia rheumatic develop giant cell arteritis.  Polymyalgia rheumatica is an autoimmune disease that causes muscle pain and stiffness in the shoulders, neck, hips, and thighs.  Finally, like giant cell arteritis, it affects people aged 50 years and above.

How do you diagnose giant cell arteritis?

There are many ways to diagnose giant cell arteritis.  First of all, blood tests like the CRP and the sed rate are usually very high.  These are tests that measure the amount of inflammation in your body.   Ideally you want to have a biopsy of the affected blood vessel but sometimes that’s not possible.  The biopsy should show giant cells but this only occurs in about 50% of cases so having a negative biopsy does not necessarily completely exclude disease.  When a biopsy is not possible, certain imaging studies can help like ultrasound, CT angiography, and PET scans.

How is giant cell arteritis treated?

Steroids, steroids, and more steroids.  If a doctor suspects that someone has giant cell arteritis, they immediately start treatment with high doses of steroids.  This happens even before the workup!  Once the diagnosis is firmly made the steroids are slowly tapered.  This happens over months.  It’s not uncommon to still be on steroids for YEARS after the diagnosis.  In many cases, the vasculitis returns.  This can be very frustrating and upsetting.  Rheumatologists have tried to treat people with medications like methotrexate in addition to steroids, but these haven’t really worked.

That is until now…

How it began

In 1990 researchers tested the blood of 15 people who had untreated giant cell arteritis.  They found high levels of a cytokine called interleukin 6 (IL-6) in their blood.  After treatment with steroids, their interleukin 6 levels decreased except for a few people.  Which is unsurprising since many people with giant cell arteritis relapse.

At that time, we didn’t have any medications that specifically blocked interleukin 6.

Flash forward to 1997.  A company based in Japan called Chugai Pharmaceuticals began research on tocilizumab to treat rheumatoid arthritis.  Tocilizumab is biologic humanized monoclonal antibody that blocks interleukin 6. Then in 2003 Genentech co-developed the medication.  Genentech’s tocilizumab is called Actemra®. Finally in 2010 the FDA approved Actemra® for to treat moderate to severe rheumatoid arthritis.

Giant cell arteritis and tocilizumab

Now remember how researchers found high levels of interleukin 6 in the blood of people with giant cell arteritis? What would happen if you treated someone who has giant cell arteritis with tocilizumab?  Would they go into remission?  Maybe you could taper off steroids more quickly?  That’s exactly what some Swiss scientists showed in 2011.  They treated 5 people with giant cell arteritis with tocilizumab.  All of them went into remission and all of them were able to taper off the steroids quickly.  The elevation and blockade of interleukin 6 appeared to be especially relevant for the treatment of giant cell arteritis.  But this was a case series with a very short follow-up time.  Was this a fluke or were they onto something?

In 2012, researchers started a larger phase 2 study.  This time they studied 30 people and they randomized them to either receive tocilizumab+prednisone or placebo+prednisone. The results were favorable:

  • 85% of the people who received tocilizumab and 40% of the people who received placebo went into remission by week 12.
  • 15 % of the people who received tocilizumab relapsed, where 80% of the people who received placebo relapsed by week 52.
  • People who received tocilizumab on average stopped prednisone 12 weeks in advance compared to people who received placebo.
  • 35% of people who received tocilizumab had a serious side effect, where 50% of people who received placebo had a serious side effect.

The last act

At last year’s American College of Rheumatology conference, Dr. John Stone presented data from the GiACTA trial, which was a randomized, double-blind, placebo-controlled trial.  This was a phase 3 study.  So they looked at more people from various locations.  There were 251 people placed into 4 different groups.

  • A short course of prednisone (26 weeks) + a weekly subcutaneous placebo
  • A long course of prednisone (52 weeks) + a weekly subcutaneous placebo
  • A short course of prednisone + weekly subcutaneous tocilizumab
  • A short course of prednisone + every other week subcutaneous tocilizumab

The results

  • 56% of people who received weekly tocilizumab achieved and stayed in remission after 12 months.
  • 53.1% of people who received every other week tocilizumab achieved and stayed in remission after 12 months.
  • 14% of people who received a short course prednisone + placebo were in remission after 12 months (p <0.0001).
  • 17.6% of people who received a long course of prednisone + placebo were in remission after 12 months (p ≤ 0.0002).
  • People who received tocilizumab received about half as much prednisone overall.
  • Adverse events were about the same in all groups and there were no deaths or vision loss.

The conclusion

Due to these extraordinary results and the dire need for effective treatment for giant cell arteritis, the FDA approved weekly subcutaneous tocilizumab.  I don’t know about you, but I’m very excited about this!  Finally a medication that works!  Mind you, it doesn’t work in every single case but this is definitely is a step forward.  And to add icing on the cake, although tocilizumab doesn’t eliminate the need for steroids, it does drastically decrease the total amount people get…another big plus.

To continue learning more about rheumatology and how to read research articles from their original source, please read on!

References

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm559791.htm

Rheumatology Secrets, 3rd edition

Dasgupta B, Panayi GS. Interleukin-6 in serum of patients with polymyalgia rheumatica and giant cell arteritis. Br J Rheumatol. 1990 Dec;29(6):456-8.

https://www.drugs.com/history/actemra.html

Seitz M, Reichenbach S, Bonel HM, Adler S, Wermelinger F, Villiger PM. Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series.Swiss Med Wkly. 2011 Jan 17;141:w13156. doi: 10.4414/smw.2011.13156.

Villiger PM, Adler S, Kuchen S, Wermelinger F, Dan D, Fiege V, Bütikofer L, Seitz M, Reichenbach. Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial.Lancet. 2016 May 7;387(10031):1921-7. doi: 10.1016/S0140-6736(16)00560-2. Epub 2016 Mar 4.

Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, Brouwer E, Cid MC, Dasgupta B, Rech J, Salvarani C, Spiera RF, Unizony SH, Collinson N. Efficacy and Safety of Tocilizumab in Patients with Giant Cell Arteritis: Primary and Secondary Outcomes from a Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). http://acrabstracts.org/abstract/efficacy-and-safety-of-tocilizumab-in-patients-with-giant-cell-arteritis-primary-and-secondary-outcomes-from-a-phase-3-randomized-double-blind-placebo-controlled-trial/. Accessed May 29, 2017.

Diseases and Conditions

Will hydroxychloroquine hurt my eyes?

May 24, 2017
Will hydroxychloroquine damage my eyes?

I love hydroxychloroquine.  Honestly, I really do.  It’s simple, easy, it works, and for the most part it’s benign especially when compared to the rest of the medications I prescribe.  Rheumatologists use hydroxychloroquine (Plaquenil) to treat of lupus, mild cases of rheumatoid arthritis, and many other autoimmune diseases.

Now I said benign.  Well I actually said, “for the most part it’s benign”.  Allergic reactions are always a concern but the main concern I have with hydroxychloroquine is the possibility of developing eye toxicity.  More specifically, hydroxychloroquine maculopathy.  But before I continue, I think it’s important to go through some anatomy.

Anatomy of the Eye

The following is a simplified version of the human eye.  The cornea is the clear part of the eye that lets you focus light into your eye.  The iris regulates the amount of light you let into your eye.  The pupil is the dark part of the eye.  This is where light actually goes into the eye.  The lens focuses light so that it hits the retina just right and the retina actually senses light.  This info is then condensed onto the optic disc and then sent to the optic nerve then into your brain.

Where does hydroxychloroquine fit in?

Now this is the important part because this is where hydroxychloroquine can cause problems: the macula.  The macula is a specialized place on your retina that has cells that enable you to see fine details with high acuity.  We call these specialized cells cones and they are found in high density in this area.  The macula is then made up of the fovea, foveal avascular zone, parafovea, and the perifovea.  The following is a real life example courtesy of Danny Hope.

By Photograph: Danny Hope from Brighton & Hove, UK Diagram: User:Zyxwv99 [CC BY 2.0 (http://creativecommons.org/licenses/by/2.0)], via Wikimedia Commons


Now the prospect of losing the ability to see things clearly sounds absolutely terrible. I’ve been wearing glasses since I was 13.  Without them, everything is blurry.  I can’t even imagine the blow to my quality of life, if I didn’t have my glasses.  Hydroxychloroquine is kind of like that.  Your vision becomes blurry, except glasses won’t help, and the vision loss is permanent.

So why would anyone go on this medication and why would your doctor even suggest it?

Well… because it’s actually a pretty good medication.  Just like most medications, you need to take it as safely as possible.  The American Academy of Ophthalmology released a statement last year about monitoring hydroxychloroquine.  Let’s go over these recommendations together!

Recommendations on Screening for Hydroxychloroquine Retinopathy (2016 Revision)

First of all, it’s still unclear how exactly hydroxychloroquine causes eye toxicity.  In a nutshell the outer layer of the retina gets damaged and then it deepens and spreads around the fovea.  People tend not to notice anything at this stage. Over time, if the medication is not stopped, the fovea becomes involved and visual acuity drops.  It’s also important to note that hydroxychloroquine can worsen even after stopping the medication.  If it’s caught early on, it probably won’t affect vision.  If there already was a lot of damage to begin with, then the risk is higher.  So the real question is what is the real risk of developing toxicity, what are the factors that increase that risk, and how often should you get screened by an ophthalmologist?

What is the real risk of developing hydroxychloroquine eye toxicity?

In the past, we thought the risk of developing eye toxicity from hydroxychloroquine was very low.  New data suggests otherwise.  Although the risk is still low, we were probably underestimating the risk.  Researchers following 2,361 people using hydroxychloroquine, found that about 7.5% of those people had eye toxicity.  The most important risk factors included the daily dose of hydroxychloroquine and duration of use.

People who took 4 to 5 mg/kg/day of hydroxychloroquine had a much lower cumulative risk as compared to people you took a higher dose: 1% risk in the first 5 years and less than 2% up to 10 years.  After 20 years the risk dramatically increased to 20%.

When I mean mg/kg/day, I mean the amount of drug for every kilogram of body weight over a 24 hour period.  To calculate the dosage of hydroxychloroquine you need to use your real weight, NOT your ideal weight.  For some medications, it’s the opposite.  Let’s say you were taking hydroxychloroquine 200 mg twice a day and then you started dieting and exercising, and then you shed a lot of weight.  You now may need to decrease your daily dose of hydroxychloroquine because your real weight decreased.  In the study, the researchers found that thin people tended to have more eye toxicity because they tended to get more than 4 – 5 mg/kg/day of hydroxychloroquine.


FYI When calculating your body weight to verify your hydroxychloroquine dose, you need to use metric.  This is not optional.

1 kilogram = 2.2 pounds


Other Significant Risks

Initially we thought hydroxychloroquine gets stored in fat cells.  In actuality, recent lab studies show that the medication is mostly stored in melanotic tissue, liver, and in the kidneys.  Muscle, fat, and other organs not so much.  That being said, people with severe kidney disease are at higher risk of developing eye toxicity.  These people may need more frequent eye testing and they may not need as high of a dose.

Other significant risks includes concurrent use of tamoxifen, which is a medication commonly used to help treat breast cancer.  The researchers found that there was a 5-fold increase of toxicity in people taking tamoxifen and hydroxychloroquine.  Why?  Tamoxifen itself can affect the retina, so maybe having both on board simultaneously isn’t such a great idea.

Finally, people with macular or retinal issues, like having macular degeneration, may also be at higher risk.  There wasn’t enough results to confirm this, but it kind of makes sense.  If he retina isn’t too hot to begin with, it’ll probably be difficult for the ophthalmologist to decide whether future changes are medication-related versus disease-related, in this case macular degeneration.  Do you need to stop hydroxychloroquine?  Or do you need to start ranibizumab (i.e., a medication FDA approved for macular degeneration)?

Screening Schedule

As I mentioned before, hydroxychloroquine eye toxicity is not reversible.  Once it happens, it happens.  So the trick is to catch it early.  Fortunately, the changes occur VERY slowly.  The American Academy of Ophthalmology recommends the following:

  • Obtain a baseline eye exam within the first year of starting hydroxychloroquine to document any complicating eye problem.
  • Annual screening beginning after 5 years of use.
  • Sooner if there are major risk factors.
  • Check the dose of hydroxychloroquine based on your weight at your doctor’s appointment.
  • Inform your doctor if there’s been any significant change in your health: significant weight loss (intentional or unintentional), kidney disease, or if you’ve been prescribed tamoxifen.

Now you may wonder why your rheumatologist insists on annual eye checks even though you’ve been on hydroxychloroquine for less than 5 years.  This is probably a matter of style.  Personally, I’m one of those rheumatologists that insists on annual eye checks.  I wouldn’t feel comfortable NOT seeing my ophthalmologist if I was taking a medication that had retinal toxicity.

Screening Tests

There are many different techniques to screen for toxicity.  I won’t go into specifics because, well, I’m not an ophthalmologist.  However, here is a list of techniques that the American Academy of Ophthalmology approved to screen for hydroxychloroquine eye toxicity.

  • Automated visual fields
  • Spectral-domain optical coherence tomography
  • Multifocal electroretinogram
  • Fundus autofluorescence
  • Microperimetry – newer test, possible value in future
  • Adaptive optics retinal imaging – newer test, possible value in future

These tests are not recommended for screening

  • Fundus examination
  • Time-domain optical coherence tomography
  • Fluorescein angiography
  • Full-field electroretinogram
  • Amsler grid
  • Color testing
  • Electro-oculogram

If you have any questions about these tests, please ask you ophthalmologist.

Conclusion

Hydroxychloroquine is truly wonderful and useful medication for the treatment of multiple different types of autoimmune diseases.  Although eye toxicity is a real danger, the risk is usually small especially in the short-term.  But like I said at the beginning, like medications you need to take it safely and responsibly.  To learn more about medication safety, please read my article regarding the 10 most frequently asked questions when starting methotrexate.

Please leave your comments below!


By Jessica Chapman, M.D.

References

https://commons.wikimedia.org/wiki/File:Schematic_diagram_of_the_human_eye_en.svg

https://commons.wikimedia.org/wiki/File:Macula.svg

Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF, American Academy of Ophthalmology. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology. 2016 Jun;123(6):1386-94.

UpToDate

Diseases and Conditions Featured

Biosimilars: How they may affect your autoimmune disease?

May 10, 2017
Biosimilars: How they may affect your autoimmune disease?

You may have recently heard about biosimilars for many autoimmune diseases like rheumatoid arthritis, psoriatic arthritis, and Crohn disease or maybe you haven’t even hear about biosimilars at all! A biosimilar is a medication that is a “copycat” version of a biologic but may have some small differences. The patent, which prevents other companies from making a product, on many biologics will expire soon opening a new opportunity for the development of biosimilars. While these medications are just beginning to come into the US market they you can already find them in Europe.

What are biosimilars and what can I expect when I use them? Are they better than the real medication, what is the cost? Read on to get the answer to all these questions and more!

What is a Biosimilar?

First of all, to understand biosimilars you must first understand what biologics are. Biologics are a class of medication used to treat many different autoimmune diseases.  Scientist make biologics with living cells or tissues inside a yeast or bacteria.  They are very complex molecules. Conventional medications, like methotrexate and hydroxychloroquine, are produced through specific reactions which produces a very precise molecule with a distinct structure. These medications are the same every time, the same materials, used in the same way produce the same drug.  These molecules are NOT complex. Biologics don’t always make an exact replica as living cells make them.  These are sensitive to the environment including light, temperature and nutrients.

Now add in the addition of a biosimilar. A biosimilar is a biologic that if it can show that it is “highly similar” to another, already approved biologic.  The original biologic is the “reference product”. The FDA requires these products to meet strict safety and efficacy standards just like biologics. The company then needs to prove that their biosimilar is a match for the already approved product for a particular disease.  After this happens, the biosimilar automatically gets approval to treat other diseases the reference product already has approval for.  For example, a biosimilar that has approval for rheumatoid arthritis would then automatically get approval for psoriatic arthritis if the reference product has approval for both.

Isn’t this the same as a generic?

The reality is that it’s a little bit more complicated than that. Think of a brand and generic medication as the recipe for a hamburger at a fast food chain. If you follow the same recipe you get the same hamburger every time, a hamburger in China tastes the same as one made in Albany, NY. Biologics and biosimilars are more like the recipe for sourdough bread. You can follow the same recipe every time but if the weather is different the bread may turn out different. The bread may have a slightly different texture but it will still fulfill its purpose. So biosimilars are not generics because they are NOT exactly the same as their reference medication.  It’s just that the difference is so small that it really should work about the same.

Cost savings?

Treatment with biologics is expensive. But the benefits, like an increase in quality of life, far outweighs the cost. What if you could get similar effects at a decreased cost? That is where biosimilars come into the picture. After the patent on a biologic has expired other companies are able to create drugs using the same process to get a biosimilar medication. Multiple companies producing the same product forces competition and a decrease in price.  This is what theoretically should happen.  In reality, we actually don’t anticipate a significant decrease in cost partly due to the complex process to produce the product.

How will I know what the medication is?

Biosimilars will have the same base name as the biologic they replicate. They will have an extra suffix after the name to differentiate them from the replicated drug. Naming the products in this way ensures you know what drug it replicated (through the base name) and that it is not the “real thing”, but in fact a biosimilar (through the suffix). For example, infliximab is the generic name for Remicade- the branded version. The biosimilar produced by Janssen Biotech is infliximab-dyyb. The addition of the “dyyb” shows that it is a biosimilar to infliximab.

If I have an allergy to the reference medication, am I allergic the biosimilar medication?

Just because you are allergic to the reference medication does not mean you will be allergic to the biosimilar, but it also does not mean you won’t be. True antibody derived allergic reactions are uncommon. Injection site reactions are much more common. There are many factors that can affect if you will have a reaction and what type of reaction it will be.

Some of these factors include:

  • Source of the protein used to make the biosimilar
  • What type of cell the protein was made in
  • Alteration in the protein structure. This can occur from something as simple as a change in storage temperate to changes in the manufacturing process.

As always, if you experience any type of reaction, call your doctor or get to an emergency center right away.

What biosimilars are approved in the U.S.?

At the time of this post there 4 products which have FDA approved biosimilars. This includes

  • adalimumab-atto, biosimilar to Humira (adalimumab)
  • etanercept-szzs, biosimilar to Enbrel (etanercept)
  • infliximab-abda and infliximab-dyyb, biosimilar to Remicade (infliximab)
  • filgrastim-sndz, biosimilar to Neupogen (filgrastim)

There are many other products currently being studied and this list will soon grow larger.

Is it as good as the real thing? What should I expect?

This is probably your biggest concern with using a biosimilar. When you find a treatment that works, you don’t want to jeopardize your health by changing your medications. Believe me, neither does your doctor. Maybe you are wondering if a biosimilar will do the same and possibly save you money? The FDA approval process ensures that biosimilars are just as effective (AND SAFE) as the biologic being replicated. Researchers need to prove that their product has the same clinical effect as the reference product. In the U.S., the FDA require strict safety and efficacy studies prior to approval and post-marketing studies.  These efforts help clinicians keep track of real-world experience with newly approved medications. Over the next few years it will be important for both patients and providers to stay up-to-date with post-marketing information related to the use and experience with biosimilars.

Do you have any experiences using biosimilars? Share them below!

 

Author: Alexis Bruno, Doctor of Pharmacy Candidate graduating May 2017 from Albany College of Pharmacy and Health Sciences.

Reviewed and approved by:  Jessica Farrell, PharmD.  Clinical Pharmacist, The Center for Rheumatology/Associate Professor, Albany College of Pharmacy and Health Sciences

 

References

  1. Center for Biologics Evaluation and Research. What Are “Biologics” Questions and Answers [Internet]. U S Food and Drug Administration. Center for Drug Evaluation and Research; 2015 [cited 2017Mar26]. Available from: https://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cber/ucm133077.htm
  2. Center for Drug Evaluation and Research. Information on Biosimilars [Internet]. U S Food and Drug Administration. Center for Drug Evaluation and Research; 2016 [cited 2017Mar26]. Available from: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/
  3. Biosimilars: More Treatment Options Are on the Way [Internet]. U S Food and Drug Administration. Office of the Commissioner; 2016 [cited 2017Mar27]. Available from: https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm436399.htm
  4. What is a biosimilar medicine? Supplemental Guide. NHS England. 2015 September 24.
  5. How biosimilars are approved [Internet]. 2017 [cited 2017 May 1]. Available from: http://www.amgenbiosimilars.com/the-basics/how-biosimilars-are-approved/
  6. Christl L. Biosimilar product labeling [Internet]. U S Food and Drug Administration. Center for Drug Evaluation and Research; 2016 [cited 2017Mar27]. Available from: https://www.fda.gov/Drugs/NewsEvents/ucm493240.htm
  7. Center for Drug Evaluation and Research. List Of Licensed Biological Products With (1) Reference Product Exclusivity And (2) Biosimilarity Or Interchangeability Evaluations To Date. US Food and Drug Administration, 2017. [cited 2017 May 1] Available from : https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM549201.pdf

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