Worried about side effects of arthritis medications? Your DNA is the key to long-term safety of treatmentRuslan Dorfman, PhD, MBA
People with arthritis take medications to manage pain and stem disease progression. However, long-term use of these drugs poses risks of severe complications including tuberculosis, increased risk of leukemia, heart disease and bleeding. Here we describe how the science of pharmacogenetics can help to improve the safety of treatment with common arthritis medications.
Types of Arthritis Medications
There are several kinds of arthritis and many different medications used to treat it. Three of the main types of arthritis are osteoarthritis, rheumatoid arthritis, and metabolic arthritis, all of which manifest as pain in joints. Metabolic arthritis, also known as gout, is caused by the reduced elimination of uric acid from the body.
Rheumatoid arthritis (RA) is an autoimmune condition. With RA, the immune system attacks the connective tissue causing inflammation and degradation, affecting small joints. Osteoarthritis is a degenerative disease that is the result of increased degradation of weight-bearing joints. Osteoarthritis may manifest inflammatory symptoms as well but isn’t an autoimmune disease.
Commonly used arthritis medications suppress the immune system or block local inflammatory response. Unfortunately, long-term use of these drugs poses some health risks. The table below summarizes different arthritis medication types and known complications.
|Medication type||Common medications||Therapy problems|
|Urate transporter inhibitors||· allopurinol (Zyloprim)
· lesinurad (Zurampic)
|· Severe skin toxicity
· GERD (gastroesophageal reflux disease)
(TNF blockers, IL-6 blockers)
|· adalimumab (Humira)
· etanercept (Enbrel)
· Increased risk of infections
|Conventional synthetic disease-Modifying Antirheumatic Drugs (DMARDs)||· azathioprine (Imuran)
· leflunomide (Arava)
· hydroxychloroquine (Plaquenil)
· methotrexate (Metoject, Rheumatrex, Trexall)
· sulfasalazine (Salazopyrin)
|· Increased risk of infections
· Increased blood pressure
|Targeted synthetic DMARDs
|· ruxolitinib (Jakavi)
· tofacitinib (Xeljanz)
· upadacitinib (Rinvoq)
· Increased risk of infections
|NSAIDs||· celecoxib (Celebrex)
· diclofenac (Voltaren)
· ibuprofen (Advil, Motrin)
· naproxen (Aleve, Anaprox)
· meloxicam (Mobicox)
· tenoxicam (Mobiflex)
|· Gastrointestinal bleeding
· Heart failure
|Opioids||· tramadol (Zytram, Ultram)
· codeine (Tylenol #3)
· Low effectiveness
The newer and more expensive arthritis drugs are not always the best choice. Biologics, such as Remicade and Enbrel, are typically reserved for more severe and rapidly progressing cases. Although biological medications are quite effective, immunosuppressing drugs, particularly TNF inhibitors, have been shown to increase the risk of cancer, and opportunistic fungal and bacterial infections, including tuberculosis. People with a diagnosis of Rheumatoid Arthritis are twice as likely to contract COVID-19 and have an increased risk of mortality independent of other complications.
Even over-the-counter painkillers such as ibuprofen and celecoxib can increase your risk of gastrointestinal bleeding, kidney and heart failure. In addition, both NSAIDs and glucocorticoids can increase the risk of heart complications. On the positive side, hydroxychloroquine has been shown to normalize lipid and glucose levels and reduce heart disease risk.
How to balance long-term arthritis medication risks?
Although there are no reliable tests that predict how well arthritis medications will work for you, several liver enzymes have been linked to the risk of side effects and long-term safety. Pharmacogenetic testing can help you and your doctors to assess which medications may pose a higher risk for you based on your genetics. In the table below, we summarize genetic variations in which enzymes impact long-term treatment safety. Knowledge of your genetic metabolic profile for these critical liver enzymes can help you and your healthcare providers reduce the risk of drug-induced complications.
|Commonly used arthritis drugs||Genes / Enzymes|
methotrexate (Metoject, Rheumatrex, Trexall)
|upadacitinib (Rinvoq)||CYP3A4, CYP2D6|
ibuprofen (Advil, Motrin)
naproxen (Aleve, Anaprox)
|tramadol (Zytram, Ultram)
codeine (Tylenol #3)
Azathioprine and TPMT and NUDT15 enzymes
Clinical studies have shown that people who have reduced or absent TPMT or NUDT15 enzymes are at high risk of infections due to low white blood cell count (myelosuppression). Up to 15% of people in Canada have reduced function of these enzymes. Clinical guidelines recommend azathioprine dose reductions for people with reduced function of these enzymes (called Intermediate Metabolizers). People with the absent activity of one of the two enzymes should avoid azathioprine and similar drugs.
NSAIDs and CYP2C9
NSAIDs include celecoxib, meloxicam, ibuprofen, and many others. Ibuprofen and naproxen can quickly cause stomach problems and require co-prescription of Proton Pump Inhibitors (PPIs) to make long-term treatment more tolerable. However, over 30% of Canadians clear PPIs too fast and are at increased risk of NSAID-induced stomach damage.
Celecoxib and other COX-2 blockers spare the stomach and reduce arthritis pain levels. However, long-term use of these drugs has been linked to a high risk of gastrointestinal bleeding and heart complications due to drug build-up. Most NSAIDs are affected by variations in the CYP2C9 gene. Up to 15% of people in Canada have reduced CYP2C9 activity and should avoid using long-acting NSAIDs such as meloxicam and tenoxicam but may use a lower dose of short-acting drugs. Additionally, 3-5% of people have very low or absent CYP2C9 activity. For them, using naproxen or diclofenac, which are considered less affected by this enzyme, or taking low doses of celecoxib is the safest route.
Methotrexate and SLCO1B1, MTHFR, MTR
Methotrexate is one of the most used arthritis medications. However, it has many drug-induced side effects. Methotrexate (MTX) affects folic acid metabolism, and concentrations of folic acid metabolites affect the risk of side effects and MTX efficacy. Variations in the genes responsible for the synthesis and metabolism of folic acid (MTHFR, MTR) have been linked to poor methotrexate tolerability.
A key drug transporter, called SLCO1B1, also affects the absorption and clearance of methotrexate. Up to 18% of people in Canada have reduced SCLO1B1 function and are at higher risk of MTX-induced side effects. Additionally, 5% have a significantly reduced SLCO1B1 are much more likely to experience methotrexate toxicity. Therefore, if you are taking methotrexate, you should consult with a pharmacist before starting any other medications or even supplements to assess whether these drugs could cause drug interactions and increase methotrexate levels. In addition to metabolism risks, methotrexate has also been linked to increased risk of cancer and infections.
Upadacitinib, leflunomide and CYP3A4
Upadacitinib is for patients with moderate to severe rheumatoid arthritis after other treatments (mainly methotrexate) have failed or could not be tolerated. Both upadacitinib and leflunomide can cause severe bleeding. These drugs are eliminated from circulation by the CYP3A4 that can be blocked or induced by many other medications. People with reduced CYP3A4 activity are more sensitive to such drug-drug interactions. If you are taking one of these medications, you should consult with a pharmacist before starting any other medication.
Codeine, tramadol and CYP2D6
Although opioids are not advised for treating rheumatoid arthritis, they can help to manage pain flare-ups. Tylenol #3 contains codeine which is an inactive drug. For codeine to provide pain relief, it must be transformed into morphine by the CYP2D6 liver enzyme. Over 32% of Canadians have reduced or absent CYP2C6 activity, making Tylenol #3, tramadol, and similar narcotic medications less effective. For an additional 6-8%, these medications do not work at all. 3% of Canadians have an elevated risk of addiction and accidental overdose because of higher morphine levels.
Understanding your safety of arthritis medications through DNA testing
Genetic testing can highlight which arthritis medications may pose a higher risk of side effects for you. Getting a pharmacogenetic profile earlier in disease progression can help you avoid adverse events and ensure long-term treatment safety.
The Pillcheck service includes genetic testing for key enzymes clearing many of the non-biologic arthritis medications, and an expert medication review by a clinical pharmacist. The pharmacist will review your medications and provide recommendations on which arthritis drugs can be used safely and if drug dose adjustment is needed because of drug-drug or drug-gene interactions.
- Long term use of arthritis medications can cause serious complications
- Many arthritis drugs are metabolized by liver enzymes
- Inherently reduced drug metabolism and drug-drug interactions significantly increase the risk of medications side effects
- Pharmacogenetic testing can show which medications may increase your risk of complications and guide you and your doctor in selecting safer treatment options
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