Enbrel alternatives: What can I take instead of Enbrel?

Compare Enbrel alternatives | Otrexup | Orencia | Actemra | Rituxan | Xeljanz | Natural alternatives | How to switch meds

Those with autoimmune diseases, such as rheumatoid arthritis (RA), Crohn’s Disease, ulcerative colitis, and plaque psoriasis not only suffer the symptoms of their diagnosis but often multiple trials of prescription drugs until they settle upon one (or a combination) that best fits their lifestyle and manages their symptoms. Enbrel (etanercept) is a member of a biologic drug class known as Tumor Necrosis Factor (TNF) inhibitors used to treat rheumatoid arthritis and other autoimmune conditions like polyarticular juvenile idiopathic arthritis, ankylosing spondylitis, or psoriatic arthritis. 

TNF inhibitors are initiated after failure or contraindication to first-line, conventional disease-modifying anti-rheumatic drugs (DMARDs). TNF inhibitors make up 90% of patients’ first biologic treatment. Selecting a TNF inhibitor may be influenced by price or health insurance copay, route of administration and patient’s comfort level, dosing frequency, other concomitant conditions, and adverse effects. Enbrel can be self-administered and is dosed once weekly, and while a common side effect includes injection-site reactions, this option may be desirable over infusions that must be administered in a healthcare setting. 

For patients on immunosuppressants and at high risk of serious infections, Enbrel may be preferable to other TNF inhibitors because it causes lower infection rates than alternatives in its class. On the flip side, Enbrel isn’t the ideal choice for the management of RA in the setting of concomitant inflammatory bowel disease or inflammatory eye disease because it is known to be inferior to other members in the TNF inhibitor class for these conditions. Additionally, TNF inhibitors are just one subset of DMARDs. Here we will discuss Enbrel and its alternatives in the management of RA. 

What can I take in place of Enbrel?

The American College of Rheumatology (ACR) recommends a treat-to-target approach for patients with RA, meaning that patients should begin treatment as soon as RA is diagnosed to slow irreversible joint damage. Oral methotrexate remains the first-line treatment unless a patient can’t tolerate it or has a contraindication to it and is considered a conventional synthetic DMARD (csDMARD) that was developed without a specific target within the immune system. Targeted synthetic DMARDs (tsDMARDs) contrast with methotrexate since they specifically target proinflammatory molecules. Biologic DMARDs (bDMARDs) are large molecules and highly specific to certain immune pathways. Drug classes within the bDMARD umbrella category include TNF inhibitors like Enbrel, CD80/86 costimulatory modulators, IL-6 inhibitors, CD20 inhibitors, and within tsDMARDs are the JAK inhibitors. After methotrexate and other csDMARDs, alternative available options within bDMARDs may be more suitable than Enbrel for certain individuals due to cost, side effects, and concomitant conditions.

Top 5 Enbrel alternatives

The following are some of the most common alternatives to Enbrel.

1.  Otrexup (methotrexate)

Methotrexate remains the first line therapy in the management of RA unless a patient has a specific reason they shouldn’t receive it. Contraindications for methotrexate include pregnancy, chronic kidney disease, and liver disease. Methotrexate is recommended over other tsDMARDs and bDMARDs due to its extensive data on safety, efficacy, low cost, and flexibility in administration-it is available as tablets and a self-injectable subcutaneous formulation. Methotrexate is also convenient since the most common dose for RA is 15 mg once weekly, which is the goal dose to achieve within four to six weeks of initiation of therapy. 

Methotrexate does come with many side effects, including GI effects like diarrhea, nausea, oral ulcers, and vomiting. It is recommended to take methotrexate with folic acid which may reduce some of these effects. If patients continue to experience significant side effects, the dose can be split and taken as two separate doses on the same day or the subcutaneous formulation may offer some relief. Methotrexate also comes with the potential for quite a few serious drug interactions and cannot be taken with a wide range of both prescription and over-the-counter medication or supplements. Methotrexate should never be given in conjunction with live vaccines, for example. 

Always seek medical advice when starting new medications or supplements while on methotrexate. Patients may be apprehensive to read about methotrexate since it is considered an oral chemotherapy, but the doses used to treat RA are significantly lower than the doses used for the management of different types of cancer. 

2. Orencia (abatacepte)

Orencia is considered a selective T-cell costimulatory modulator and binds to receptors CD80 and CD86 on cells known as antigen-presenting cells. This prevents T-cell proliferation and B-cell stimulation-a phenomenon which contributes to joint inflammation experienced in RA. While initially approved for intravenous infusion in patients who do not respond or could not tolerate/take methotrexate and TNF inhibitors, it is now FDA approved for use as a self-injectable subcutaneous formulation providing patients with greater autonomy for its use. The intravenous formulation only needs to be administered every four weeks, whereas the subcutaneous (self-injectable) must be administered weekly. Patients with chronic obstructive pulmonary disorder (COPD) may experience worsening of symptoms while receiving this therapy and may not be ideal candidates for this therapy.

3. Actemra (tocilizumab)

Actemra is in an additional class of bDMARDs for the treatment of RA known as IL-6 receptor inhibitors. IL-6 concentrations are known to be elevated in RA, which in turn is associated with immune activation. Actemra is administered either by intravenous infusion or is available as a prefilled syringe and is able to be self-injected subcutaneously. Like all bDMARDs, Actemra use will also come with a range of possible side effects, the most serious being increasing the risk of infection and increased risk of GI perforation. Given the prior, patients must be ruled out for certain respiratory infections prior to use, like tuberculosis, and hepatitis B. Given the latter, Actemra should be avoided in patients with a known underlying indication that may additively contribute to this risk, such as a history of diverticulitis. Patients taking this medication will require frequent monitoring of white blood cells and platelets, as well as labs to indicate any level of liver damage or hyperlipidemia.

4. Rituxan (rituximab)

Rituxan is an anti-CD20 monoclonal antibody with several indications in addition to treatment refractory RA nonresponsive to other DMARDs. It shouldn’t be an initial bDMARD, whereas a TNF inhibitor like Enbrel is. However, if a patient goes through several lines of therapy without achieving remission, this option has a good chance of success. The benefit of this medication over many others includes its relatively infrequent dosing-most patients receive two doses every six months. Rituxan is only available as an IV infusion in comparison to several other alternatives which offer a self-injectable route of administration, and even the infusion itself comes with warnings and precautions for causing reactions. Rituxan, given its profound effect on the immune system, greatly increases the risk of infections-it minimizes a person’s ability to mount an immune response to vaccines, contributing to its place in therapy as more of a last-line agent.

5. Xeljanz (tofacitinib)

Xeljanz is a type of tsDMARD and is a member of one of the newest classes of agents used to treat RA known as JAK inhibitors. Xeljanz is different from many of the available treatment options for RA in that it is a tablet and has a much more targeted mechanism of action than cDMARDs. Unfortunately, Xeljanz does also come with safety concerns when used, including major adverse events like increased risk of heart attack stroke, blood clots, certain viral infections, malignancies like lymphoma, and even death. The incidence of overall infections with tsDMARDs is similar to those seen with bDMARDs, but another benefit of this class of drugs is a slightly lower incidence of severe infections. Screening for tuberculosis is still required prior to initiation of therapy, and herpes zoster vaccination is highly recommended because of an increased risk of reactivation on therapy in comparison to bDMARDs. All these risks combined must be weighed against its pros as a tablet and targeted mechanism in comparison to biologics like Enbrel after lack of remission on first-line therapies. 

Natural alternatives to Enbrel

Lifestyle modifications like exercise are critical in people affected by RA to decrease fatigue and pain of RA. Other more natural approaches to the management of RA might include the addition of probiotics, which have some benefits in inflammatory conditions by providing a healthy balance of “good bacteria” in your gut. A well-balanced diet may be important for similar reasons. Arnica, which is a plant that has been used to manage pain and inflammation, may provide some symptom relief when applied in topical formulations to aching joints. Any alternative approaches to the management of RA should always be made under the medical advice of a healthcare professional. 

How to switch to an Enbrel alternative

Conventional synthetic DMARDs, like methotrexate, are first-line in the management of RA. Failure to achieve remission after a trial of these medications, or absolute contraindications to receive them, would give a rheumatologist the go-ahead to move down the prescription drug list to trial either a bDMARD or tsDMARD. Studies have demonstrated that reduced doses in combination with methotrexate may prolong low disease severity, and others have introduced the possibility of trialing off all medications with sustained remission. No therapy should be discontinued without the advice of a healthcare professional, as discontinuation may result in an increase in symptoms and a return to a higher level of disease severity.

Biosimilars are also a consideration when taking biologic agents like brand-name Enbrel. While guidelines consider biosimilars equivalent to their FDA-approved counterparts, there are currently no recommendations on changing patients currently taking bDMARDS to an equivalent biosimilar. The most cost-effective option is ideal, but health insurance mandated changes to biosimilars pose potential concerns. Patients and healthcare providers should always be made aware before any automated changes in therapy occur. 

The COVID-19 pandemic highlighted some issues with biologic DMARDs when shortages arose as it related to the management of RA and other autoimmune disorders. Actemra was granted emergency use authorization (EUA) by the FDA to treat hospitalized patients in response to the Delta variant, resulting in a global shortage of the biologic. This forced patients to face an inability to remain in adherence to their regimens, so the ACR has made recommendations to change within drug classes if necessary (versus changing to a biologic drug in a different class).