Side Effects of Enbrel

Enbrel (etanercept) is a biologic medication used for autoimmune conditions like rheumatoid arthritis, psoriatic arthritis, and plaque psoriasis. It works by blocking tumor necrosis factor (TNF), a protein that causes inflammation. By reducing inflammation, Enbrel helps manage symptoms and improve quality of life.

However, TNF also plays a role in fighting infections. Blocking it can weaken the immune system, making infections more likely. Some people experience mild injection site reactions, while others may develop more serious complications, such as infections or neurological issues.

This article breaks down the side effects of Enbrel, including the serious risks that require medical attention, and provides guidance on what to do if you experience adverse reactions.

What are the side effects of Enbrel?

Like any medication, Enbrel can cause side effects ranging from mild to serious. While many users tolerate it well, some may experience infections, injection site reactions, or other health concerns.

Understanding these potential side effects can help you monitor for any issues and seek medical advice if needed.

Long-Term Side Effects of Enbrel

Long-term use of Enbrel can pose certain risks that require medical attention if they occur, including:

1. Increased Risk of Infections

Enbrel has a boxed warning for an increased risk of serious infections that can affect different parts of the body. Reports include bacterial, viral, and fungal infections, including invasive and opportunistic ones.

Invasive fungal infections happen when fungi spread deep into the body, affecting the bloodstream, organs, or tissues. Unlike common fungal infections like athlete’s foot or yeast infections, these can be life-threatening.

Signs of a serious infection may include:

• • High temperature or fever
  • Symptoms similar to the flu
  • Body aches and muscle soreness
  • Diarrhea, with or without stomach discomfort
  • Sweating excessively at night
  • Difficulty breathing
  • Frequent urination or a burning sensation while urinating

Enbrel can also reactivate latent tuberculosis (TB), which is an inactive TB infection.

One study found that, on average, TB developed about 11.5 months after starting Enbrel. More than 50% of these cases involved “extrapulmonary” TB, meaning the infection spread beyond the lungs to areas like the bones, joints, or other organs.

A case report described a 57-year-old woman with rheumatoid arthritis (RA) who developed swelling, pain, and warmth in her right elbow after taking Enbrel for three months. Before starting, her TB skin test and chest X-ray showed no signs of TB, and she had no history of infection or exposure.

Despite this, lab tests confirmed TB in her elbow joint fluid and tissue, leading to a diagnosis of tuberculous arthritis. Enbrel was stopped immediately, and her symptoms significantly improved within three weeks.

Recommendation

Before starting Enbrel, your doctor should evaluate you if:

• • You frequently get infections or have long-lasting ones
  • You’ve been exposed to tuberculosis
  • You’ve had serious infections in the past
  • You’ve lived or traveled in areas where certain fungal infections (like histoplasmosis or blastomycosis) are common
  • You have a condition like uncontrolled diabetes that makes infections more likely

2. Reactivation of Hepatitis B

If you’ve had hepatitis B before, your immune system may have kept the virus inactive. However, taking Enbrel can sometimes cause the virus to reactivate. Although this is very rare (less than 0.01% of cases), it can be serious or even fatal. The risk is higher if you’re also taking other immune-suppressing medications.

An analysis of 17 studies found that the hepatitis B virus reactivation rate for etanercept (Enbrel) was 2.4%. Another study reported a slightly higher rate of 3.9%.

Early symptoms of hepatitis B are similar to the flu, including:

• • Fatigue
  • Fever
  • Loss of appetite
  • Nausea or vomiting
  • Muscle or joint pain
  • Headache

Symptoms may not appear until several weeks to months after infection. Some people, especially children, may have no symptoms at all.

3. Cancer Risk

This is another boxed warning for Enbrel, although the link between etanercept and cancer remains unclear. Lymphomas were the most commonly reported malignancies, followed by melanoma and other skin cancers.

Findings from multiple studies indicate the following risks for patients treated with Enbrel:

• • In rheumatology patients (rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis), the lymphoma rate was approximately three times higher.

• • Leukemia was observed in 2 out of 5,445 patients (0.06 cases per 100 patient-years), with no cases in the control group.

• • The melanoma rate was 0.043 cases per 100 patient-years.

• • Rheumatology patients have about an 11% higher risk of non-melanoma skin cancer, while psoriasis patients have about a 2.8 times higher risk.

• • Rare cases of Merkel cell carcinoma have been reported postmarketing.

In pediatric patients taking Enbrel:

• • On average, cancer cases developed after approximately 30 months of Enbrel treatment.

• • The reported overall cancer rate was nearly twice as high compared to children in the general US population.

• • Hodgkin lymphoma was about 10 times more common than in the general population.

However, it is difficult to determine whether Enbrel is the direct cause of these malignancies since severe or uncontrolled rheumatoid arthritis itself increases the risk of certain cancers.

Cancer symptoms vary, but these are some of the most common early warning signs:

• • Unexplained weight loss
  • Feeling extremely tired all the time
  • Lumps or swelling especially in the neck, armpits, groin, or breasts
  • Changes in the skin like new moles, changes in existing moles, sores that don’t heal
  • Unusual bleeding or bruising
  • Persistent cough or hoarseness
  • Difficulty swallowing or persistent indigestion
  • Long-lasting pain especially in the bones or abdomen
  • Frequent infections or slow-healing wounds

If you notice any of these unusual, persistent symptoms, see your doctor immediately for further evaluation.

4. Neurological Disorders

Treatment with TNF-blocking agents, including Enbrel, has been linked to rare cases (less than 0.1%) of new or worsening central nervous system demyelinating disorders. These are conditions where the protective coating around nerve fibers (called myelin) gets damaged.

Myelin helps nerves send signals quickly and efficiently. When it’s damaged, nerve signals slow down or get disrupted, leading to problems with movement, sensation, vision, or thinking.

Early symptoms to watch for include:

• • Vision problems like blurred vision, double vision, or partial vision loss
  • Numbness or tingling especially in the arms, legs, or face
  • Difficulty walking, frequent tripping, or feeling unsteady
  • Persistent exhaustion that isn’t relieved by rest
  • Dizziness or balance issues
  • Bladder or bowel changes
  • Memory problems, trouble concentrating, or brain fog

A 2017 case report described a possible link between etanercept and rheumatoid meningitis, a rare and serious condition that causes inflammation of the membranes covering the brain and spinal cord.

The case involved a 65-year-old man who developed neurological symptoms six months after starting etanercept. He initially experienced a brief loss of consciousness, followed by seizures, speech impairment, and limb weakness.

A brain biopsy confirmed features consistent with rheumatoid meningitis. Symptoms improved after stopping etanercept and switching to tocilizumab.

Reported Cases of Neurological Disorders Linked to Enbrel

Reported cases in postmarketing experience include:

• • Transverse Myelitis – Inflammation in the spinal cord that can cause pain, muscle weakness, numbness, and sometimes paralysis.

• • Optic Neuritis – Inflammation of the optic nerve, which can lead to eye pain and vision problems, including temporary or permanent vision loss.

• • Multiple Sclerosis (MS) – A disease where the immune system attacks the protective covering of nerves, leading to symptoms like fatigue, trouble walking, numbness, and muscle weakness.

• • Guillain-Barré Syndrome (GBS) – A rare disorder where the immune system mistakenly attacks the nerves, causing weakness, tingling, and, in severe cases, paralysis.

5. New or Worsening Heart Failure

It is not entirely clear why Enbrel has an adverse effect on the heart. A study suggested that by blocking TNF, etanercept might increase TNF levels in the bloodstream, triggering inflammation in a way that negatively impacts the heart.

Heart failure develops gradually, so watch for symptoms like:

• • Shortness of breath especially during activity or when lying down
  • Unusual fatigue
  • Swelling in the legs, ankles, or feet
  • Frequent coughing or wheezing especially with white or pink-tinged mucus
  • Palpitations or feeling like your heart is racing
  • Sudden weight gain
  • Loss of appetite or nausea

In a case report, a 42-year-old man with ankylosing spondylitis developed severe heart failure while taking etanercept. His heart function improved after stopping the drug, suggesting a possible link.

In another report, a 47-year-old man with rheumatoid arthritis and no history of heart disease developed sudden, severe heart failure shortly after starting etanercept.

His echocardiogram (heart ultrasound) showed an irregular heartbeat with abnormal electrical activity and an extremely weak heart, with his left ventricular ejection fraction (LVEF) at just 10% (normal is 55-70%). Since other causes were ruled out, etanercept was suspected as the likely cause.

Reported Cases of Heart Failure Linked to Enbrel

Researchers analyzed data from the US MedWatch Program, which tracks adverse drug reactions, and identified 47 cases of heart failure linked to TNF inhibitors. Among them 29 patients had received etanercept and 26 of them developed new-onset heart failure, including:

• • 12 with no known heart disease risk factors
  • 14 with existing cardiovascular risk factors

For those under 50 years old, symptoms appeared around 8.5 months after starting etanercept.

6. Blood Disorders

Rare cases of pancytopenia (fewer than 0.1%) and aplastic anemia (fewer than 0.01%) have been reported in patients taking Enbrel. Some of these cases were fatal, but it’s unclear whether Enbrel directly caused them.

Pancytopenia is a condition where red, white blood cells, and platelets are all low. While aplastic anemia is a severe condition where the bone marrow stops making enough blood cells. Other blood disorders that could occur with Enbrel include:

• • Thrombocytopenia (low platelet levels)
  • Leukopenia (low white blood cells)
  • Myelodysplastic syndrome, a group of bone marrow disorders that can sometimes progress to acute leukemia (a type of blood cancer)

Warning signs to watch for include:

• • Persistent fever
  • Unusual bruising or bleeding
  • Paleness or extreme fatigue

In one case report, a 62-year-old woman with rheumatoid arthritis was admitted to the hospital with fatigue, high fever, gingival bleeding, and a rash on her legs. Enbrel 50 mg was introduced 23 days before admission.

One week after receiving the injection, she developed malaise, fatigue, and low-grade fever. Her symptoms worsened over two weeks, leading to a high fever and rash, which prompted hospitalization.

Her lab tests showed:

• • Severe pancytopenia
  • Very low neutrophil count
  • Bone marrow aplasia (failure to produce blood cells)

She had no signs of viral infections or other common causes of cytopenia. Methotrexate levels were undetectable, ruling it out as the cause, and Enbrel was suspected as the likely trigger of her condition.

7. Autoimmune Reactions

Enbrel can sometimes cause the body to produce autoantibodies (proteins that attack its own tissues). In rare cases (less than 0.1%), this can lead to:

• • Lupus-like syndrome (a condition with symptoms similar to lupus)
  • Autoimmune hepatitis (liver inflammation caused by the immune system)
  • Vasculitis (inflammation of blood vessels)

Some of the most common warning signs include:

• • Unexplained fatigue
  • Fever
  • Muscle aches and joint pain
  • Weight loss or loss of appetite

In a case report, a 72-year-old man with psoriatic arthritis developed a serious lung condition while taking etanercept. He had fluid buildup around the lungs, but initial tests and a tissue biopsy did not identify a clear cause.

Further investigation revealed that he had drug-induced lupus erythematosus, triggered by etanercept. This condition mimics lupus, causing inflammation and fluid accumulation in the body.

Reported Cases of Autoimmune Diseases Linked to Enbrel

Using MEDLINE data, cases associated with etanercept include:

• • 59 cases of vasculitis
  • 37 cases of lupus or lupus-like syndrome

Interstitial lung disease–a group of lung disorders that cause scarring and inflammation in the lung’s thin tissue surrounding the air sacs–was also reported, though less frequently.

Common Side Effects of Enbrel

Infections were the most common side effect of Enbrel, occurring in up to 50% of treated patients. Another common issue is injection site reactions.

Enbrel is injected under the skin once or twice a week, depending on the condition being treated. Because of this, injection site reactions are prevalent, particularly in the first few months of use.

According to clinical trials, about 37% of people using it for rheumatologic conditions and 15% of adults and 7% of children using it for psoriasis had these reactions in the first three months. Most reactions at the site of injection were mild to moderate and included redness, itching, pain, swelling, bleeding, and bruising. On average, they lasted 3 to 5 days and did not require stopping the medication.

Other common side effects observed with Enbrel use include:

• • Upper respiratory infections, primarily upper respiratory tract infections, sinusitis, and influenza
  • Diarrhea
  • Rash
  • Pruritus (itchy skin)
  • Fever
  • Hives (raised, itchy, red welts on the skin)

Children had similar side effects to adults, both in how often they happened and what types they were. The infections reported were usually mild and like those commonly seen in kids.

Other Side Effects of Enbrel Injections

Aside from the other side effects of Enbrel, allergic reactions were also reported. In clinical trials, fewer than 2% of patients experienced an allergic reaction to enbrel. While most were mild, serious reactions like anaphylaxis can occur. If a severe allergic reaction happens, stop using Enbrel immediately and seek medical care.

What are the side effects of Enbrel and methotrexate together?

Methotrexate is a disease-modifying antirheumatic drug (DMARD) that slows the immune system to reduce inflammation and prevent long-term joint damage. It is often prescribed alongside Enbrel to better manage autoimmune diseases like rheumatoid arthritis and psoriatic arthritis.

Since both Enbrel and methotrexate suppress the immune system, they can increase the risk of serious infections, liver problems, and low blood cell counts, as mentioned earlier.

A 16-week study compared the effectiveness and safety of Enbrel alone and Enbrel combined with methotrexate. Both groups showed significant symptom improvement, and the rates of side effects and serious side effects were similar, indicating no major safety concerns with either approach.

Let’s Wrap Up

Enbrel is effective for autoimmune conditions but comes with risks. Common side effects include injection site reactions and mild infections, while serious risks involve severe infections, tuberculosis reactivation, cancer, neurological issues, heart failure, and blood disorders.

If you’re taking Enbrel, regular monitoring is essential, especially if you’re using other immunosuppressive medications like methotrexate. If you notice any unusual symptoms, contact your doctor immediately. Knowing the risks allows you to make informed decisions about your treatment.

Frequently Asked Questions