Everything You Need to Know about Immunosuppressants

The pros and cons of immunosuppressant medications are relatively well known, but there’s considerable debate about which drugs actually fit this description. 

By Linda Rath | Dec. 8, 2022

Immunosuppressant drugs are designed to suppress or tamp down part of the immune system. Many were originally developed to prevent organ rejection in transplant patients, but some are now also used to treat cancer and autoimmune diseases such as rheumatoid arthritis (RA), psoriatic arthritis and lupus.

In autoimmune forms of arthritis, the immune system loses the ability to distinguish between invading pathogens and healthy tissue. The result is surging inflammation attacking the body — usually starting with the joints — instead of viruses and bacteria. Immunosuppressants slow or stop the attack by disabling parts of the immune system. For many arthritis patients, the drugs can help reduce chronic inflammation and pain and slow the destruction of joint tissue. The trade-off is a higher risk of both common and serious infections and, depending on the medication, a subpar response to vaccinations, including COVID-19 vaccines and boosters.

Immunosuppressants Use a Broad Brush
Some of the most prescribed medications for autoimmune arthritis are immune suppressants. They include conventional disease-modifying antirheumatic drugs (DMARDs), such as methotrexate and leflunomide (Arava). Not all immunosuppressant drugs work the same way. Methotrexate prevents the production of one inflammatory protein, or “cytokine,” and reduces others; leflunomide interferes with the rapid growth of immune cells. Although they work differently, many conventional DMARDs affect the immune system broadly.

Targeted Therapies
Other arthritis medications, such as biologic DMARDs (or biologics) and Janus kinase (JAK) inhibitors target specific parts of the immune system. They selectively block certain immune pathways and interfere with cytokine production, but don’t affect the whole immune system. They include:
    •    Tumor necrosis factor (TNF) blockers, such as adalimumab (Humira)
    •    Interleukin (IL)-6 blockers such as tocilizumab (Actemra)
    •    IL-17 blockers such as secukinumab (Cosentyx)
    •    IL-23 blockers such as guselkumab (Tremfya)
    •    JAK inhibitors like tofacitinib (Xeljanz)
    •    Selective T-cell costimulation blockers, such as abatacept (Orencia)
    •    Autoreactive B-cell inhibitors like belimumab (Benlysta)
    •    The interferon receptor blocker anifrolumab (Saphnelo)

Targeted drugs are sometimes called immune modulators instead of immune suppressants, but these classifications are far from settled. In its new vaccination guideline, the American College of Rheumatology (ACR) refers to all arthritis medications that act on the immune system as “immunosuppressants” except for hydroxychloroquine (Plaquenil), sulfasalazine (Azulfidine), apremilast (Otezla) and intravenous immunoglobulin (IVIG), an infusion to boost low antibodies. The European Alliance of Associations for Rheumatology (EULAR, formerly known as the European League Against Rheumatism), the European equivalent of the ACR, considers all arthritis drugs that act on the immune system immunosuppressants. Meanwhile, the U.S. National Institutes of Health calls TNF blockers and interleukin blockers “immune modulators” but not JAK inhibitors, which it considers immunosuppressants.

The important thing isn’t so much what a drug is called but rather its effect on the immune system. All of these arthritis medicines weaken some aspect of immunity and increase the risk of serious infections. The risk is highest with biologics, which, according to some research, are significantly more likely to lead to infections in standard or high doses than are conventional DMARDs like methotrexate. Some biologics can also reactivate dormant tuberculosis and hepatitis B infections and worsen hepatitis C.

Choosing an Arthritis Drug: Weighing Cost and Convenience
The decision to try an immunosuppressant should be one you and your doctor make together, and you should fully understand the potential risks and benefits of your options. Methotrexate is the first drug most people with inflammatory arthritis try. But other factors may come into play, too, including the severity and type of your arthritis, any additional health problems you may have, and the drug’s effectiveness, side effects and cost. Methotrexate, for example, comes in tablet form and is relatively inexpensive – less than $10 a month for pills compared to adalimumab, which costs more than $6,000 for a month’s supply of pre-filled injectable syringes.

Side Effects and Other Cautions
Different immunosuppressants have different side effects, but because immune systems are complicated, there is no way to predict how you will respond to a particular medication or how bothersome side effects might be for you. Many people end up switching medications over time because they don’t work as well as hoped or the side effects become too troubling. Here’s a closer look at two of the most common conventional DMARDs:
    •Methotrexate. About half of patients quit methotrexate after a year due to side effects, such as fatigue, mouth sores, nausea and vomiting. These can be severe even when the B vitamin folic acid is taken to help offset them. Patients surveyed about their experiences with methotrexate reported fatigue within a day of taking it as well as stomach upset, hair thinning and trouble sleeping. Yet nearly 70% also said they felt methotrexate helped control their disease.

Methotrexate can be toxic, even at the recommended dose, so you’ll need regular blood tests to check the health of your liver and kidneys.

    •Leflunomide. This drug is sometimes used when methotrexate doesn’t work well enough or the patient doesn’t tolerate it well. Leflunomide has many of the same potential side effects, including liver toxicity, nausea, vomiting and hair loss, which occur in about 10% to 15% of patients.

Both methotrexate and leflunomide can cause severe birth defects and must be stopped before you try to become pregnant. Be sure to tell your doctor if you’re thinking about pregnancy, even if it’s far in the future. Also keep in mind that immunosuppressants won’t give you instant relief. It may take a few weeks or months before you see any benefit.

Nondrug Options
For many people with arthritis, regular exercise and an anti-inflammatory eating pattern like the Mediterranean diet can help relieve pain and inflammation well enough without medications. Exercise has other significant benefits, building strength and flexibility, staving off muscle loss, disability and depression and helping sleep. Whether nondrug treatments can slow joint damage isn’t clear, although several small studies suggest that probiotics — microorganisms that benefit health — may improve disease activity as well as abnormal gut function that’s implicated in chronic inflammatory diseases.