Advanced therapies to treat the underlying disease
Advances in therapy for people with inflammatory arthritis over the last 25 years have led to better disease management strategies and improved patient outcomes. The term “advanced therapies” is commonly used to describe medications (conventional synthetic DMARDs, originator biologics, biosimilar biologics, and targeted small molecule) that treat some of the specific molecules that have been found to drive the inflammation, pain, and disability in inflammatory types of arthritis.
Each class of medication works differently, providing various benefits and risks. Regular monitoring and close communication with health care providers are essential to ensure safe and effective treatment. These medications can significantly improve quality of life for people with arthritis by reducing symptoms, preventing joint damage, and maintaining joint function.
There’s no single treatment plan for inflammatory arthritis – it is very “person dependent” – and chances are you will need to adjust the dosage or change your medication one or more times during your disease journey.
There are many reasons why you may need to try something new. Inflammatory arthritis affects people in different ways, and the disease can get worse or improve over time. A medication or medications that once kept your symptoms under control can stop working. Side effects may become serious enough that taking the medication puts other aspects of your health at risk. Sometimes, the way a medicine is given doesn’t fit with your lifestyle, or it interacts with another medicine you’re taking. For these reasons, your rheumatologist may suggest a different or new treatment. You may transition to a different drug in the same class or step up from a conventional synthetic DMARD to a biologic or targeted small molecule therapy. Think of your medication regime as a “cocktail” of medications, like it is referred to in HIV or cancer treatment (both are also autoimmune diseases).
Advanced therapies used to treat the underlying disease include:
Disease-modifying anti-rheumatic drugs (DMARDs) are a class of medications used to treat underlying inflammatory arthritis diseases such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and lupus. These DMARD medications alter the natural course of the disease by suppressing the inflammation, decreasing autoantibody levels and can help prevent long-term damage.
DMARDs now come in all “shapes and sizes” and can be taken by pill, self-injection and infusion (or “IV”). Each DMARD works in a unique way and the decision about which one(s) is best for you is perhaps the most important conversation you can have with your rheumatologist.
Disease-modifying anti-rheumatic drugs are divided into different classifications:
Conventional synthetic DMARDs
Conventional synthetic DMARDs work by slowing down or stopping the immune system from attacking the joints, which helps to reduce inflammation, pain, and long-term joint damage.
They are typically taken in pill form and are considered the first line of treatment before biologic or targeted synthetic DMARDs are introduced if these medications do not work effectively.
Biologic DMARDs (originator and biosimilar)
Biologic DMARDs are complex, large molecule medicines. The first version of a biologic developed is known as the "originator" because it is the original version of a drug that a biosimilar is based on.
As patents expire for originator biologics, other manufacturers may produce new, similar versions shown to be as safe and effective called biosimilar biologic DMARDs. Since the originator biologics are large and complex, biosimilar biologics can be highly similar, but not identical.
Targeted synthetic DMARDs
Targeted synthetic DMARDs include only those medications that were specifically developed to target a particular molecular structure such as tofacitinib, baricitinib or apremilast, or agents not focused primarily on rheumatic diseases, such as imatinib or ibrutinib.
Conventional synthetic DMARDs (csDMARDs)
How they work
Other than glucocorticoids (steroids), csDMARDs have been on the market the longest and have the most evidence to support their use. In inflammatory arthritis, the immune system mistakenly attacks the joints, leading to pain and swelling. Conventional synthetic DMARDs work by targeting the immune system to slow or halt the underlying processes that cause inflammation. Rheumatologists sometimes prescribe short-term use of steroids or NSAIDs to help bridge the gap while waiting for DMARDs or biologic therapies to take effect.
Conventional synthetic DMARDs and anti-inflammatories
Conventional synthetic DMARDs are often prescribed with other medications – such as corticosteroids or NSAIDs – for quick relief of inflammation and pain. This is particularly important during the time it takes conventional synthetic DMARDs to take effect, which can be several weeks or months.
Early and consistent use of conventional synthetic DMARDs to treat inflammatory arthritis is necessary for best results. Research has shown that there is a short "window of opportunity" at the beginning of the disease process when these medications work best to slow or halt the inflammatory process. For this reason, treatment should begin as early as possible after diagnosis, ideally within the first 3 months after the disease starts. It may take 3-12 months for these medications to provide full benefit.
Common conventional synthetic DMARDs
Benefits
Research has clearly shown that in addition to controlling symptoms, conventional synthetic DMARDs make a long-term difference in preventing or minimizing the joint damage that can cause devastating disability and improving joint function and quality of life.
Initiation of disease-modifying anti-rheumatic drugs (DMARDs)
DMARD therapy should be initiated as soon as persistent synovitis is identified to prevent disease progression. Methotrexate (MTX) is the preferred first-line DMARD due to its proven efficacy and safety profile. MTX should be started at an oral or subcutaneous dose of 10-15 mg/week, titrated up to 25 mg/week if tolerated. Regular monitoring of liver enzymes, renal function, and blood cell counts is essential to minimize toxicity.
Conventional synthetic DMARD combination therapy
Sometimes a single medication is all that’s needed to control inflammatory arthritis. But more commonly, early treatment with a combination of DMARDs or a DMARD-biologic combination can be more effective than using a single medication to relieve symptoms and prevent long-term joint damage and disability.
Combination DMARD therapy
Methotrexate is often used in combination with other DMARDs for patients with high disease activity. Conventional synthetic DMARDs that have been paired with methotrexate include sulfasalazine, hydroxychloroquine, cyclosporine, leflunomide and azathioprine. Although studies of these combinations have shown differing levels of benefit, the combinations of methotrexate plus leflunomide and methotrexate plus sulfasalazine are among the most effective.
Conventional synthetic DMARD plus a biologic
In some cases, the effectiveness of biologics is improved by adding a conventional synthetic DMARD, most commonly methotrexate.
Triple therapy
For the treatment of rheumatoid arthritis, if one or two medications are not enough, doctors can turn to triple therapy. The most common combination is methotrexate, sulfasalazine and hydroxychloroquine. Research shows that in some cases, using three conventional synthetic DMARDs together is just as effective as using a conventional synthetic DMARD in combination with a biologic drug.
The American College of Rheumatology has developed guidelines recommending the following approach for people living with rheumatoid arthritis starting medication treatment that also respects the “window of opportunity”:
While conventional synthetic DMARDs are effective, they can have side effects, including:
Regular monitoring through blood tests is essential to check for potential side effects of conventional synthetic DMARDs. People should follow their health care provider's instructions closely and report any unusual symptoms.
Most important, you need to inform your doctor immediately if you experience any side effect, especially nausea, vomiting, fever, rash, or symptoms of infection. Call your doctor if you think you are pregnant or if you are planning on becoming pregnant.
Choosing a biologic for treatment (originator or biosimilar)
As Health Canada approves more biologic medicines for sale – originators and biosimilars – and public and private drug plans provide reimbursement for them, it’s important that people with arthritis and their health care providers understand the facts around these therapies.
People understandably have many questions when prescribed a biologic. When a person with inflammatory arthritis and their rheumatologist discuss whether to take a biologic therapy, they should be able to assess treatment (or no treatment) risk against benefit and have tools to enable them to discuss the pros and cons of the treatment with their healthcare team.
This places a great deal of importance on the patient-rheumatologist conversation about biologics when deciding on a treatment plan. The conversation should consider all available therapy options, the safety, benefits and risks, patient treatment goals and tolerance for side effects, and the accessibility and affordability of medications.
People who feel they understand the choice of a biologic treatment and why it’s necessary, who trust their health care professionals, and who understand that there is a support plan in place are likely to achieve better outcomes.
Medication treatment plans should be tailored to an individual’s disease, treatment response, and potential side effects. Patients should work closely with health care providers to adjust medications as needed. To achieve effective disease management, adherence to prescribed medications is essential. Missing doses or stopping medication without medical advice can lead to worsened symptoms and disease progression.
Benefits and risks
Each advanced therapy has benefits and risks. Benefits include good control of disease activity, significantly reduced inflammation and pain, maintaining quality of life, among others. Advanced therapy treatment should be tailored considering patient comorbidities such as cardiovascular disease, liver disease, and infections. Side effects can be broken down into two forms: serious and rare, such as severe infections, liver problems, or an increased risk of certain cancers, and common and less worrisome, like injection site reactions, mild infections, or headaches.
Monitoring
Regular monitoring by a health care provider is essential when using DMARDs to catch any serious issues early while managing the more common side effects like liver enzyme elevation or blood count changes. When starting a new medication regimen for inflammatory arthritis, the rheumatologist may order routine blood tests to monitor a person’s response to the treatment and help make sure the treatment is working effectively while keeping any potential risks under control. These tests help check if inflammation is decreasing and ensure the medication is safe, keeping an eye on possible side effects, such as liver or blood cell issues. After about 6 to 12 months, if everything is stable, the frequency of these tests is usually reduced to every two or three months. Patients in remission or with well-controlled disease may be assessed at longer intervals, as determined by their health care provider.
Biologic DMARDs
Over the past 23 years in Canada, biologics have become a life-changing treatment options for people living with inflammatory arthritis whose disease does not respond, or respond well enough, to conventional synthetic DMARDs such as hydroxychloroquine or sulfasalazine.
Biologic DMARDs are made from living organisms, such as living cells that have been modified using biotechnology. This allows these living organisms or cells to produce the active substance of the biological medicine. This active substance is then harvested from the cells. The active substance is commonly called a “protein.” Biologics are much larger and more complex in nature than conventional, small molecule medicines such as over-the-counter ibuprofen (e.g., Advil) or by-prescription conventional synthetic DMARDS like methotrexate or targeted synthetic DMARDS like a JAK inhibitor. Biologics are administered in two ways; by subcutaneous self-injection under the skin or into muscle, or by intravenous (IV) infusion into a vein in the hand, wrist or arm.
The first version of a biologic DMARD developed is known as the “originator.” This is because they are the original version of a drug that a biosimilar is based on.
How they work
Biologics work by targeting specific molecules or cells of the immune systems. For example, they may block tumor necrosis factor alpha (TNF), interleukin-6 (IL-6), or B-cells, all of which play a role in inflammation.
TNF inhibitors
TNF inhibitors are typically the first-line biologics. TNF biologics work by targeting something called tumor necrosis factor proteins. TNF is a protein that sends signals to your body, eventually leading to inflammation that causes swelling, pain, and stiffness. By inhibiting, or stopping TNF, these medications can reduce inflammation. That’s why they are often called TNF inhibitors.
Some common originator TNF biologics include:
Non-TNF biologics may be used after failure of TNF inhibitors.
Other common biologics target the immune system in different ways from TNF medications by interacting with different kinds of white blood cells, such as T cells or B cells, in the immune system. They can also block chemicals called cytokines known as interleukin that cause inflammation.
White blood cells and cytokines are made by your immune system to fight off infection. But in inflammatory arthritis diseases, they may be out of control and cause inflammation. These drugs can suppress specific parts of the immune system, ease inflammation, stop disease progress, and ease symptoms.
Some common originator biologics that interact with T cells or B cells or block cytokines include:
Biologics are proved to effectively address disease signs and symptoms – like inflammation, pain and fatigue – but also can prevent long-term joint damage and improve mortality and reduce heart disease and other complications of inflammatory arthritis. Some patients in sustained remission may be able to taper off biologic treatment under medical supervision. However, complete withdrawal of therapy is not recommended due to the risk of disease flare.
Side effects and risks
Because biologic medications (originator or biosimilar) suppress the immune system, the greatest risk while taking a biologic is infection. The likelihood of experiencing infection or any other side effects vary from person to person. Common infections include upper respiratory tract infections, urinary tract infections, and skin infections.
Here are some of the other most common side effects:
To minimize risks, people taking biologics should be closely monitored by their health care provider. This includes regular blood tests to check liver function, blood cell counts, and signs of infection. People should report any unusual symptoms or side effects to their health care provider immediately. It is also important for people to avoid live vaccines while on biologics due to the suppressed immune response. Vaccinations should be updated before starting treatment. Regular follow-ups and open communication with health care providers help manage these side effects effectively and ensure the best possible outcomes.
If you feel you are experiencing a side effect, your specialist will be able to assess whether it is the medication or another health issue.
Biosimilar biologic DMARDs
When the patent of an originator biologic DMARD expires, other manufacturers are allowed to make a biosimilar version of the medicine, much like a generic medicine does when a small molecule brand name medicine loses its patent. Health Canada defines a biosimilar as a biologic medicine that is highly similar to its originator biologic with no expected meaningful differences in safety or how well it works compared to the originator biologic, and so delivers the same therapeutic benefits to patients. Biosimilar biologics, like originator biologics, may be administered at home by injection (known as “self-injection”) or by intravenous infusion (IV) in a doctor’s office or an infusion clinic.
The type of data required to support biosimilar approval from Health Canada differs from that required for an originator biologic medicine. Biosimilar manufacturers do not have to recreate the originator biologic’s research and development. Instead, biosimilar manufacturers must perform comparative studies to demonstrate similarity. This means manufacturers that make biosimilars of other originator biologic medicines typically do not have the same costs to bring the product to market and can therefore offer it at a lower price. The savings generated by biosimilars may be reinvested into health care resources needed by Canadians.
Biosimilars have been approved for use in Canada since 2009, and in arthritis since 2014. Fifty-five biosimilars are currently approved by Health Canada for chronic diseases, including inflammatory arthritis, cancer, inflammatory bowel disease, diabetes, multiple sclerosis, psoriasis and age-related macular degeneration.
Biosimilars are typically prescribed to people living with inflammatory arthritis by a rheumatologist. The biosimilar versions of originator biologics currently available to Canadians living with inflammatory arthritis include:
Biosimilar biologics
Biosimilars work in the same way as the originator biologics. They target specific components of the immune system to reduce inflammation and prevent joint damage.
Benefits
Biosimilars offer the same benefits as their originator biologics, including symptom reduction, improved joint function, and prevention of joint damage. Biosimilars are also more cost-effective, making treatment more accessible.
Side effects and risks
Biologics – originator or biosimilar - make it harder for your body’s immune system to fight off infections. If you take an originator or biosimilar biologic, your specialist will ask you to go for regular lab tests to monitor your blood and watch out for side effects, such as infections.
The side effects of biosimilars are like those of the originator biologics, including:
As with originator biologics, to minimize risks, people taking biosimilars should be closely monitored by their health care provider. This includes regular blood tests to check liver function, blood cell counts, and signs of infection. People should report any unusual symptoms or side effects to their health care provider immediately. It is also important for people to avoid live vaccines while on biosimilars due to the suppressed immune response. Vaccinations should be updated before starting treatment. Regular follow-ups and open communication with health care providers help manage these side effects effectively and ensure the best possible outcomes.
If you feel you are experiencing a side effect, your specialist will be able to assess whether it is the medication or another health issue.
Targeted synthetic DMARDs
Targeted Synthetic DMARDs are a class of DMARDs designed to target specific molecules involved in the inflammatory process. They are not biologics, but they do target specific parts of the immune system — unlike conventional synthetic DMARDs, which have a dampening effect on the whole immune system.
How they work
Targeted synthetic DMARDs are administered as daily tablets which pass through the digestive system and work from within the immune cells.
To date, janus kinase (JAK) inhibitors are the only sub-classification of tsDMARDs available in Canada, although there are others being researched globally.
JAK inhibitors work by inhibiting the activity of one or more of the Janus kinase family of enzymes JAK1, JAK2, JAK3 and tyrosine kinase, which are parts of the immune system that can be related to inflammatory arthritis symptoms. JAK inhibitors are only used to treat inflammatory types of arthritis; they are not used in the management of osteoarthritis.
JAK inhibitors may be taken alone or in combination with another drug.
Common tsDMARDs
JAK inhibitors can be very effective for people who do not respond well to traditional conventional synthetic DMARDs or who are not able to tolerate methotrexate. They can reduce symptoms, improve joint function, and prevent further joint damage. They are also administered orally, which makes them a good option for people who prefer the convenience of a daily oral tablet instead of taking an injection or infusion of a biologic. Some patients in sustained remission may be able to taper off targeted synthetic DMARDs under medical supervision.
Side effects and risks
JAK-inhibitors have been associated with an increased risk of serious heart-related events such as heart attack, stroke, blood clots and rarely cancer and death, particularly in those with risk factors such as having a history of smoking, past heart attack, known malignancy or cancer, stroke, or blood clots. Ensure your doctor is aware if you have any of these risk factors and discuss the risk and benefits of using this medication.
Other potential side effects include:
People taking JAK inhibitors need to get periodic blood tests so their doctor can monitor different values. This is to ensure that the medication is working effectively and to keep track of whether there are any negative side effects. People will also need to have their heart rate and blood pressure periodically monitored, have regular skin tests, and monitor for signs and symptoms of any potential infections.
Advances in therapy for people with inflammatory arthritis over the last 25 years have led to better disease management strategies and improved patient outcomes. The term “advanced therapies” is commonly used to describe medications (conventional synthetic DMARDs, originator biologics, biosimilar biologics, and targeted small molecule) that treat some of the specific molecules that have been found to drive the inflammation, pain, and disability in inflammatory types of arthritis.
Each class of medication works differently, providing various benefits and risks. Regular monitoring and close communication with health care providers are essential to ensure safe and effective treatment. These medications can significantly improve quality of life for people with arthritis by reducing symptoms, preventing joint damage, and maintaining joint function.
There’s no single treatment plan for inflammatory arthritis – it is very “person dependent” – and chances are you will need to adjust the dosage or change your medication one or more times during your disease journey.
There are many reasons why you may need to try something new. Inflammatory arthritis affects people in different ways, and the disease can get worse or improve over time. A medication or medications that once kept your symptoms under control can stop working. Side effects may become serious enough that taking the medication puts other aspects of your health at risk. Sometimes, the way a medicine is given doesn’t fit with your lifestyle, or it interacts with another medicine you’re taking. For these reasons, your rheumatologist may suggest a different or new treatment. You may transition to a different drug in the same class or step up from a conventional synthetic DMARD to a biologic or targeted small molecule therapy. Think of your medication regime as a “cocktail” of medications, like it is referred to in HIV or cancer treatment (both are also autoimmune diseases).
Advanced therapies used to treat the underlying disease include:
- conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs)
- biologic DMARDs
- biosimilar biologic DMARDs
- targeted synthetic DMARDs
Disease-modifying anti-rheumatic drugs (DMARDs) are a class of medications used to treat underlying inflammatory arthritis diseases such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and lupus. These DMARD medications alter the natural course of the disease by suppressing the inflammation, decreasing autoantibody levels and can help prevent long-term damage.
DMARDs now come in all “shapes and sizes” and can be taken by pill, self-injection and infusion (or “IV”). Each DMARD works in a unique way and the decision about which one(s) is best for you is perhaps the most important conversation you can have with your rheumatologist.
Disease-modifying anti-rheumatic drugs are divided into different classifications:
Conventional synthetic DMARDs
Conventional synthetic DMARDs work by slowing down or stopping the immune system from attacking the joints, which helps to reduce inflammation, pain, and long-term joint damage.
They are typically taken in pill form and are considered the first line of treatment before biologic or targeted synthetic DMARDs are introduced if these medications do not work effectively.
Biologic DMARDs (originator and biosimilar)
Biologic DMARDs are complex, large molecule medicines. The first version of a biologic developed is known as the "originator" because it is the original version of a drug that a biosimilar is based on.
As patents expire for originator biologics, other manufacturers may produce new, similar versions shown to be as safe and effective called biosimilar biologic DMARDs. Since the originator biologics are large and complex, biosimilar biologics can be highly similar, but not identical.
Targeted synthetic DMARDs
Targeted synthetic DMARDs include only those medications that were specifically developed to target a particular molecular structure such as tofacitinib, baricitinib or apremilast, or agents not focused primarily on rheumatic diseases, such as imatinib or ibrutinib.
Conventional synthetic DMARDs (csDMARDs)
How they work
Other than glucocorticoids (steroids), csDMARDs have been on the market the longest and have the most evidence to support their use. In inflammatory arthritis, the immune system mistakenly attacks the joints, leading to pain and swelling. Conventional synthetic DMARDs work by targeting the immune system to slow or halt the underlying processes that cause inflammation. Rheumatologists sometimes prescribe short-term use of steroids or NSAIDs to help bridge the gap while waiting for DMARDs or biologic therapies to take effect.
Conventional synthetic DMARDs and anti-inflammatories
Conventional synthetic DMARDs are often prescribed with other medications – such as corticosteroids or NSAIDs – for quick relief of inflammation and pain. This is particularly important during the time it takes conventional synthetic DMARDs to take effect, which can be several weeks or months.
Early and consistent use of conventional synthetic DMARDs to treat inflammatory arthritis is necessary for best results. Research has shown that there is a short "window of opportunity" at the beginning of the disease process when these medications work best to slow or halt the inflammatory process. For this reason, treatment should begin as early as possible after diagnosis, ideally within the first 3 months after the disease starts. It may take 3-12 months for these medications to provide full benefit.
Common conventional synthetic DMARDs
- Methotrexate (Trexall®, Rasuvo®, Otrexup®): Often the first DMARD prescribed for rheumatoid arthritis (RA). It can be taken orally or by injection and is usually taken once a week.
- Leflunomide (Araya®): Another common DMARD that helps reduce inflammation and slow joint damage.
- Sulfasalazine (Azulfidine®): Used for various inflammatory conditions, including RA.
- Hydroxychloroquine (Plaquenil®): Originally used to treat malaria, it is also effective in reducing arthritis symptoms.
- Apremilast (Otezla®): Used to treat psoriatic arthritis.
Benefits
Research has clearly shown that in addition to controlling symptoms, conventional synthetic DMARDs make a long-term difference in preventing or minimizing the joint damage that can cause devastating disability and improving joint function and quality of life.
Initiation of disease-modifying anti-rheumatic drugs (DMARDs)
DMARD therapy should be initiated as soon as persistent synovitis is identified to prevent disease progression. Methotrexate (MTX) is the preferred first-line DMARD due to its proven efficacy and safety profile. MTX should be started at an oral or subcutaneous dose of 10-15 mg/week, titrated up to 25 mg/week if tolerated. Regular monitoring of liver enzymes, renal function, and blood cell counts is essential to minimize toxicity.
Conventional synthetic DMARD combination therapy
Sometimes a single medication is all that’s needed to control inflammatory arthritis. But more commonly, early treatment with a combination of DMARDs or a DMARD-biologic combination can be more effective than using a single medication to relieve symptoms and prevent long-term joint damage and disability.
Combination DMARD therapy
Methotrexate is often used in combination with other DMARDs for patients with high disease activity. Conventional synthetic DMARDs that have been paired with methotrexate include sulfasalazine, hydroxychloroquine, cyclosporine, leflunomide and azathioprine. Although studies of these combinations have shown differing levels of benefit, the combinations of methotrexate plus leflunomide and methotrexate plus sulfasalazine are among the most effective.
Conventional synthetic DMARD plus a biologic
In some cases, the effectiveness of biologics is improved by adding a conventional synthetic DMARD, most commonly methotrexate.
Triple therapy
For the treatment of rheumatoid arthritis, if one or two medications are not enough, doctors can turn to triple therapy. The most common combination is methotrexate, sulfasalazine and hydroxychloroquine. Research shows that in some cases, using three conventional synthetic DMARDs together is just as effective as using a conventional synthetic DMARD in combination with a biologic drug.
The American College of Rheumatology has developed guidelines recommending the following approach for people living with rheumatoid arthritis starting medication treatment that also respects the “window of opportunity”:
- Step 1:
A person newly or recently diagnosed with moderate to severe rheumatoid arthritis is typically started on methotrexate, and possibly 1 or 2 other conventional synthetic DMARDs in combination with methotrexate, such as sulfasalazine and hydroxychloroquine (also called “combination” or “triple therapy”). While waiting for the medications to take effect (the full effect is usually seen in 12 weeks), symptom management medications such as a NSAID, or in some cases, prednisone, may be used to help reduce inflammation quickly. - Step 2:
If a person does not respond or does not respond well enough to the above combination therapy (i.e., their inflammation is not well controlled), biologic DMARD or targeted synthetic DMARD (only 1 is used at a time) should be started. Some biologic DMARDs are more effective when used in combination with methotrexate. Some biologic DMARDs and tsDMARDs are just as effective without methotrexate.
While conventional synthetic DMARDs are effective, they can have side effects, including:
- Nausea and gastrointestinal issues: Many conventional synthetic DMARDs, such as methotrexate and sulfasalazine, can cause nausea, vomiting, and diarrhea. Some people may also experience stomach pain or upset.
- Liver toxicity: Conventional synthetic DMARDs, such as leflunomide, can affect liver function. Regular blood tests are necessary to monitor liver health. Symptoms of liver issues can include yellowing of the skin or eyes (jaundice), dark urine, and fatigue.
- Increased risk of infections: Because conventional synthetic DMARDs suppress the immune system, they can make people more susceptible to infections. It's important to report signs of infection, such as fever, chills, or persistent cough, to a health care provider.
- Bone marrow suppression: Some conventional synthetic DMARDs can affect bone marrow, leading to low levels of blood cells. This can cause anemia (low red blood cells), increased risk of bleeding or bruising (low platelets), and higher susceptibility to infections (low white blood cells).
- Hair loss: Methotrexate and other conventional synthetic DMARDs can sometimes cause hair thinning or loss.
- Rashes and skin reactions: Skin rashes or reactions are possible with conventional synthetic DMARDs such as sulfasalazine. These should be reported to a health care provider, especially if they are severe or persistent.
- Lung problems: Some conventional synthetic DMARDs, like methotrexate and leflunomide, can cause lung issues, such as shortness of breath or a persistent cough. This is a rare but serious side effect.
- Mouth sores: Ulcers or sores in the mouth can occur, particularly with methotrexate.
- Fatigue: Feeling unusually tired or weak is a common side effect of many conventional synthetic DMARDs.
- Allergic reactions: While rare, some people may have allergic reactions to conventional synthetic DMARDs, which can include hives, swelling, or difficulty breathing.
Regular monitoring through blood tests is essential to check for potential side effects of conventional synthetic DMARDs. People should follow their health care provider's instructions closely and report any unusual symptoms.
Most important, you need to inform your doctor immediately if you experience any side effect, especially nausea, vomiting, fever, rash, or symptoms of infection. Call your doctor if you think you are pregnant or if you are planning on becoming pregnant.
Choosing a biologic for treatment (originator or biosimilar)
As Health Canada approves more biologic medicines for sale – originators and biosimilars – and public and private drug plans provide reimbursement for them, it’s important that people with arthritis and their health care providers understand the facts around these therapies.
People understandably have many questions when prescribed a biologic. When a person with inflammatory arthritis and their rheumatologist discuss whether to take a biologic therapy, they should be able to assess treatment (or no treatment) risk against benefit and have tools to enable them to discuss the pros and cons of the treatment with their healthcare team.
This places a great deal of importance on the patient-rheumatologist conversation about biologics when deciding on a treatment plan. The conversation should consider all available therapy options, the safety, benefits and risks, patient treatment goals and tolerance for side effects, and the accessibility and affordability of medications.
People who feel they understand the choice of a biologic treatment and why it’s necessary, who trust their health care professionals, and who understand that there is a support plan in place are likely to achieve better outcomes.
Medication treatment plans should be tailored to an individual’s disease, treatment response, and potential side effects. Patients should work closely with health care providers to adjust medications as needed. To achieve effective disease management, adherence to prescribed medications is essential. Missing doses or stopping medication without medical advice can lead to worsened symptoms and disease progression.
Benefits and risks
Each advanced therapy has benefits and risks. Benefits include good control of disease activity, significantly reduced inflammation and pain, maintaining quality of life, among others. Advanced therapy treatment should be tailored considering patient comorbidities such as cardiovascular disease, liver disease, and infections. Side effects can be broken down into two forms: serious and rare, such as severe infections, liver problems, or an increased risk of certain cancers, and common and less worrisome, like injection site reactions, mild infections, or headaches.
Monitoring
Regular monitoring by a health care provider is essential when using DMARDs to catch any serious issues early while managing the more common side effects like liver enzyme elevation or blood count changes. When starting a new medication regimen for inflammatory arthritis, the rheumatologist may order routine blood tests to monitor a person’s response to the treatment and help make sure the treatment is working effectively while keeping any potential risks under control. These tests help check if inflammation is decreasing and ensure the medication is safe, keeping an eye on possible side effects, such as liver or blood cell issues. After about 6 to 12 months, if everything is stable, the frequency of these tests is usually reduced to every two or three months. Patients in remission or with well-controlled disease may be assessed at longer intervals, as determined by their health care provider.
Biologic DMARDs
Over the past 23 years in Canada, biologics have become a life-changing treatment options for people living with inflammatory arthritis whose disease does not respond, or respond well enough, to conventional synthetic DMARDs such as hydroxychloroquine or sulfasalazine.
Biologic DMARDs are made from living organisms, such as living cells that have been modified using biotechnology. This allows these living organisms or cells to produce the active substance of the biological medicine. This active substance is then harvested from the cells. The active substance is commonly called a “protein.” Biologics are much larger and more complex in nature than conventional, small molecule medicines such as over-the-counter ibuprofen (e.g., Advil) or by-prescription conventional synthetic DMARDS like methotrexate or targeted synthetic DMARDS like a JAK inhibitor. Biologics are administered in two ways; by subcutaneous self-injection under the skin or into muscle, or by intravenous (IV) infusion into a vein in the hand, wrist or arm.
The first version of a biologic DMARD developed is known as the “originator.” This is because they are the original version of a drug that a biosimilar is based on.
How they work
Biologics work by targeting specific molecules or cells of the immune systems. For example, they may block tumor necrosis factor alpha (TNF), interleukin-6 (IL-6), or B-cells, all of which play a role in inflammation.
TNF inhibitors
TNF inhibitors are typically the first-line biologics. TNF biologics work by targeting something called tumor necrosis factor proteins. TNF is a protein that sends signals to your body, eventually leading to inflammation that causes swelling, pain, and stiffness. By inhibiting, or stopping TNF, these medications can reduce inflammation. That’s why they are often called TNF inhibitors.
Some common originator TNF biologics include:
- adalimumab (Humira®): administered through subcutaneous injection
- certolizumab pegol (Cimzia®): administered through subcutaneous injection
- etanercept (Enbrel®): administered through subcutaneous injection
- tolimumab (Simponi®): administered by either subcutaneous injection or IV infusion
- infliximab (Remicade®): administered through intravenous infusion
Non-TNF biologics may be used after failure of TNF inhibitors.
Other common biologics target the immune system in different ways from TNF medications by interacting with different kinds of white blood cells, such as T cells or B cells, in the immune system. They can also block chemicals called cytokines known as interleukin that cause inflammation.
White blood cells and cytokines are made by your immune system to fight off infection. But in inflammatory arthritis diseases, they may be out of control and cause inflammation. These drugs can suppress specific parts of the immune system, ease inflammation, stop disease progress, and ease symptoms.
Some common originator biologics that interact with T cells or B cells or block cytokines include:
- abatacept (Orencia®): Abatacept works by blocking signaling to a special kind of white blood cell called a T cell. It is administered through either subcutaneous injection or intravenous infusion.
- anakinra (Kineret®): Anakinra works by blocking interleukin-1 (IL-1). It is administered through subcutaneous injection.
- anifrolumab (Saphnelo®): Anifrolumab works by targeting the type I interferon receptor, which plays a role in inflammatory and immune responses. It is administered through intravenous infusion.
- belimumab (Benlysta®): Belimumab works by inhibiting B-lymphocyte stimulator (BLyS), a protein that can cause the immune system to attack healthy cells. It can be administered by either IV infusion or subcutaneous injection.
- bimekizumab (Bimzelx®): Bimekizumab works by inhibiting interleukin-17A (IL-17A) and interleukin-17F (IL-17F) cytokines. It is administered through subcutaneous injection.
- canakinumab (Ilaris®): Canakinumab works by blocking interleukin-1 beta (IL-1β). It is administered through subcutaneous injection.
- denosumab (Prolia®): Denosumab works by inhibiting RANK ligand (RANKL), a protein involved in the formation, function, and survival of osteoclasts, which break down bone. It is administered through subcutaneous injection.
- guselkumab (Tremfya®): Guselkumab works by targeting interleukin-23 (IL-23). It is administered through subcutaneous injection.
- ixekizumab (Taltz®): Ixekizumab works by inhibiting interleukin-17A (IL-17A). It is administered through subcutaneous injection.
- rituximab (Rituxan®): Rituximab works by blocking a special kind of white blood cell known as B cells. Rituximab is given by IV infusion.
- romosozumab (Evenity®): Romosozumab works by inhibiting sclerostin, a protein that negatively regulates bone formation, leading to increased bone formation and decreased bone resorption. It is administered through subcutaneous injection.
- sarilumab (Kevzara®): Sarilumab works by blocking IL6, a pivotal cytokine that drives inflammation. It is available as subcutaneous injections every 2 weeks.
- secukinumab (Cosentyx®): Secukinumab works by inhibiting interleukin-17A (IL-17A). It is administered through subcutaneous injection.
- tocilizumab (Actemra®): Tocilizumab works by blocking a cytokine known as Il-6 that can cause inflammation. It can be given by either IV infusion or self-injected.
- ustekinumab (Stelara®): Ustekinumab works by targeting interleukin-12 (IL-12) and interleukin-23 (IL-23). It is administered through subcutaneous injection.
Biologics are proved to effectively address disease signs and symptoms – like inflammation, pain and fatigue – but also can prevent long-term joint damage and improve mortality and reduce heart disease and other complications of inflammatory arthritis. Some patients in sustained remission may be able to taper off biologic treatment under medical supervision. However, complete withdrawal of therapy is not recommended due to the risk of disease flare.
Side effects and risks
Because biologic medications (originator or biosimilar) suppress the immune system, the greatest risk while taking a biologic is infection. The likelihood of experiencing infection or any other side effects vary from person to person. Common infections include upper respiratory tract infections, urinary tract infections, and skin infections.
Here are some of the other most common side effects:
- Injection site reactions: For biologics administered via injection, reactions at the injection site are common. These can include redness, swelling, itching, and pain at the site of injection. These reactions are typically mild and resolve on their own.
- Infusion reactions: For biologics administered through intravenous (IV) infusion, some people may experience infusion reactions. These can include fever, chills, rash, itching, or difficulty breathing during or shortly after the infusion.
- Allergic reactions: Although rare, some people may experience allergic reactions to biologics. Symptoms can include hives, swelling of the face or lips, and difficulty breathing. Severe allergic reactions require immediate medical attention.
- Headaches: Some people may experience headaches while taking biologics. These are usually mild and can be managed with over-the-counter pain relievers.
- Gastrointestinal issues: Nausea, abdominal pain, and diarrhea can occur with biologic DMARDs. These side effects are generally mild but should be reported to a health care provider if they persist.
- Fatigue: Feeling unusually tired or weak is a common side effect of biologics. This fatigue can affect daily activities and should be discussed with a health care provider if it becomes bothersome.
- Liver enzyme elevations: Biologics can cause increases in liver enzymes, indicating potential liver irritation or damage. Regular blood tests are needed to monitor liver function.
- Blood disorders: Some biologics can affect blood cell counts, leading to conditions like anemia (low red blood cells), leukopenia (low white blood cells), or thrombocytopenia (low platelets). Regular blood tests are necessary to monitor these levels.
- Vaccination considerations: Patients on biologics should receive recommended vaccines before starting treatment, as live vaccines should generally be avoided during therapy.
- Serious infections: Including tuberculosis (TB) and fungal infections. People should be tested for TB before starting biologics.
- Malignancies: There is a potential increased risk of certain cancers, such as lymphoma and skin cancer, with long-term use of biologics.
- Heart failure: Some biologics can worsen or contribute to the development of heart failure.
- Neurological conditions: Rarely, biologics can be associated with demyelinating diseases, such as multiple sclerosis.
To minimize risks, people taking biologics should be closely monitored by their health care provider. This includes regular blood tests to check liver function, blood cell counts, and signs of infection. People should report any unusual symptoms or side effects to their health care provider immediately. It is also important for people to avoid live vaccines while on biologics due to the suppressed immune response. Vaccinations should be updated before starting treatment. Regular follow-ups and open communication with health care providers help manage these side effects effectively and ensure the best possible outcomes.
If you feel you are experiencing a side effect, your specialist will be able to assess whether it is the medication or another health issue.
Biosimilar biologic DMARDs
When the patent of an originator biologic DMARD expires, other manufacturers are allowed to make a biosimilar version of the medicine, much like a generic medicine does when a small molecule brand name medicine loses its patent. Health Canada defines a biosimilar as a biologic medicine that is highly similar to its originator biologic with no expected meaningful differences in safety or how well it works compared to the originator biologic, and so delivers the same therapeutic benefits to patients. Biosimilar biologics, like originator biologics, may be administered at home by injection (known as “self-injection”) or by intravenous infusion (IV) in a doctor’s office or an infusion clinic.
The type of data required to support biosimilar approval from Health Canada differs from that required for an originator biologic medicine. Biosimilar manufacturers do not have to recreate the originator biologic’s research and development. Instead, biosimilar manufacturers must perform comparative studies to demonstrate similarity. This means manufacturers that make biosimilars of other originator biologic medicines typically do not have the same costs to bring the product to market and can therefore offer it at a lower price. The savings generated by biosimilars may be reinvested into health care resources needed by Canadians.
Biosimilars have been approved for use in Canada since 2009, and in arthritis since 2014. Fifty-five biosimilars are currently approved by Health Canada for chronic diseases, including inflammatory arthritis, cancer, inflammatory bowel disease, diabetes, multiple sclerosis, psoriasis and age-related macular degeneration.
Biosimilars are typically prescribed to people living with inflammatory arthritis by a rheumatologist. The biosimilar versions of originator biologics currently available to Canadians living with inflammatory arthritis include:
Biosimilar biologics
- adalimumab (Abrilada®), adalimumab (Amgevita®), adalimumab (Hadlima®), adalimumab (Hulio®), adalimumab (Hyrimoz®), adalimumab (Idacio®), adalimumab (Simlandi®), and adalimumab (Yuflyma®) are biosimilar versions of the originator adalimumab (Humira®)
- etanercept (Brenzys®), etanercept (Erelzi®), and etanercept (Rymti®) are biosimilar versions of the originator etanercept (Enbrel®)
- infliximab (Avsola®), infliximab (Inflectra®), infliximab (Renflexis®), and infliximab (Remsima®SC) are biosimilar versions of the originator infliximab (Remicade®)
- rituximab (Riabni®), rituximab (Riximyo®), rituximab (Ruxience®), and rituximab (Truxima®) are biosimilar versions of the originator rituximab (Rituxan®)
- ustekinumab (Jamteki®) and ustekinumab (Wezlana®) are biosimilar versions of the originator ustekinumab (Stelara®)
Biosimilars work in the same way as the originator biologics. They target specific components of the immune system to reduce inflammation and prevent joint damage.
Benefits
Biosimilars offer the same benefits as their originator biologics, including symptom reduction, improved joint function, and prevention of joint damage. Biosimilars are also more cost-effective, making treatment more accessible.
Side effects and risks
Biologics – originator or biosimilar - make it harder for your body’s immune system to fight off infections. If you take an originator or biosimilar biologic, your specialist will ask you to go for regular lab tests to monitor your blood and watch out for side effects, such as infections.
The side effects of biosimilars are like those of the originator biologics, including:
- Injection site reactions: For biosimilars administered via injection, reactions at the injection site are common. These can include redness, swelling, itching, and pain at the site of injection. These reactions are typically mild and resolve on their own.
- Infusion reactions: For biosimilars administered through intravenous (IV) infusion, some people may experience infusion reactions. These can include fever, chills, rash, itching, or difficulty breathing during or shortly after the infusion.
- Allergic reactions: Although rare, some people may experience allergic reactions to biologics. Symptoms can include hives, swelling of the face or lips, and difficulty breathing. Severe allergic reactions require immediate medical attention.
- Headaches: Some people may experience headaches while taking biosimilars. These are usually mild and can be managed with over-the-counter pain relievers.
- Gastrointestinal issues: Nausea, abdominal pain, and diarrhea can occur with biosimilars. These side effects are generally mild but should be reported to a health care provider if they persist.
- Fatigue: Feeling unusually tired or weak is a common side effect of biosimilars. This fatigue can affect daily activities and should be discussed with a health care provider if it becomes bothersome.
- Liver enzyme elevations: Biosimilars can cause increases in liver enzymes, indicating potential liver irritation or damage. Regular blood tests are needed to monitor liver function.
- Blood disorders: Some biosimilars can affect blood cell counts, leading to conditions like anemia (low red blood cells), leukopenia (low white blood cells), or thrombocytopenia (low platelets). Regular blood tests are necessary to monitor these levels.
- Serious infections: Including tuberculosis (TB) and fungal infections. People should be tested for TB before starting biologic DMARDs.
- Malignancies: There is a potential increased risk of certain cancers, such as lymphoma and skin cancer, with long-term use of biosimilars.
- Heart failure: Some biosimilars can worsen or contribute to the development of heart failure.
- Neurological conditions: Rarely, biosimilars can be associated with demyelinating diseases, such as multiple sclerosis.
As with originator biologics, to minimize risks, people taking biosimilars should be closely monitored by their health care provider. This includes regular blood tests to check liver function, blood cell counts, and signs of infection. People should report any unusual symptoms or side effects to their health care provider immediately. It is also important for people to avoid live vaccines while on biosimilars due to the suppressed immune response. Vaccinations should be updated before starting treatment. Regular follow-ups and open communication with health care providers help manage these side effects effectively and ensure the best possible outcomes.
If you feel you are experiencing a side effect, your specialist will be able to assess whether it is the medication or another health issue.
Targeted synthetic DMARDs
Targeted Synthetic DMARDs are a class of DMARDs designed to target specific molecules involved in the inflammatory process. They are not biologics, but they do target specific parts of the immune system — unlike conventional synthetic DMARDs, which have a dampening effect on the whole immune system.
How they work
Targeted synthetic DMARDs are administered as daily tablets which pass through the digestive system and work from within the immune cells.
To date, janus kinase (JAK) inhibitors are the only sub-classification of tsDMARDs available in Canada, although there are others being researched globally.
JAK inhibitors work by inhibiting the activity of one or more of the Janus kinase family of enzymes JAK1, JAK2, JAK3 and tyrosine kinase, which are parts of the immune system that can be related to inflammatory arthritis symptoms. JAK inhibitors are only used to treat inflammatory types of arthritis; they are not used in the management of osteoarthritis.
JAK inhibitors may be taken alone or in combination with another drug.
Common tsDMARDs
- tofacitinib (Xeljanz®), (Auro-Tofacitinib®), (JAMP-Tofacitinib®), (PMS-Tofacitinib®), (TARO-Tofacitinib®)
- baricitinib (Olumiant®)
- upadacitinib (Rinvoq®)
JAK inhibitors can be very effective for people who do not respond well to traditional conventional synthetic DMARDs or who are not able to tolerate methotrexate. They can reduce symptoms, improve joint function, and prevent further joint damage. They are also administered orally, which makes them a good option for people who prefer the convenience of a daily oral tablet instead of taking an injection or infusion of a biologic. Some patients in sustained remission may be able to taper off targeted synthetic DMARDs under medical supervision.
Side effects and risks
JAK-inhibitors have been associated with an increased risk of serious heart-related events such as heart attack, stroke, blood clots and rarely cancer and death, particularly in those with risk factors such as having a history of smoking, past heart attack, known malignancy or cancer, stroke, or blood clots. Ensure your doctor is aware if you have any of these risk factors and discuss the risk and benefits of using this medication.
Other potential side effects include:
- Increased risk of infections: JAK inhibitors suppress the immune system, making it easier for infections to take hold. Common infections include upper respiratory tract infections, urinary tract infections, and shingles (herpes zoster). It's crucial to seek medical advice at the first sign of an infection, such as fever, chills, or persistent cough.
- Liver enzyme changes: JAK inhibitors can cause elevated liver enzymes, indicating potential liver damage. Regular blood tests are needed to monitor liver function. Symptoms of liver issues include yellowing of the skin or eyes (jaundice), dark urine, and abdominal pain.
- Gastrointestinal issues: Some people may experience nausea, diarrhea, or stomach pain while taking JAK inhibitors.
- Increased cholesterol levels: JAK inhibitors can raise levels of cholesterol and triglycerides in the blood. Regular monitoring of blood lipid levels is recommended.
- Anemia: A reduction in red blood cells, leading to anemia, can occur. Symptoms include fatigue, weakness, and shortness of breath.
- Elevated blood pressure: Some people may experience increased blood pressure while on JAK inhibitors, necessitating regular monitoring.
- Headaches: Headaches are a relatively common side effect and can usually be managed with over-the-counter pain relievers.
- Vaccination considerations: Patients on JAK inhibitors should receive recommended vaccines before starting treatment, as live vaccines should generally be avoided during therapy.
People taking JAK inhibitors need to get periodic blood tests so their doctor can monitor different values. This is to ensure that the medication is working effectively and to keep track of whether there are any negative side effects. People will also need to have their heart rate and blood pressure periodically monitored, have regular skin tests, and monitor for signs and symptoms of any potential infections.
Arthritis Consumer Experts
ACE thanks Arthritis Research Canada (ARC) for its scientific review of ACE and JointHealth™ information and education programs.