Immunosuppressive Medication for the Treatment of Autoimmune Disease

Diseases in allergy, immunology, and rheumatology are often caused by problems with the immune system. The drugs to treat autoimmune and allergic disease target different components of the immune system. The treatments may weaken the entire immune system or only very specific parts of it. How each of these drugs target specific parts of the immune system may make the patient more likely to get certain infections. Here, we will discuss a wide range of medications used to treat autoimmune disease, the components of the immune system targeted by these medications, and the kinds of infections (if any) that may be more common in people taking these immune suppressive medications.

The immune system has two parts: innate and adaptive. The innate immune system is the first line of defense against bacteria and viruses. These defenses include cells and molecules located at sites of entry for foreign invaders (the nose, lungs, gut, and skin). Immune cells make molecules called cytokines to communicate between different parts of the body. These cytokines, such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6) can be targeted to treat autoimmune disease, where the immune system attacks the body’s own cells.

The adaptive immune system develops over time. Two types of white blood cells called T cells and B cells are important parts of adaptive immunity. When the body sees a new bacteria or virus, it makes T cells and B cells that recognize the invader and help the body to get rid of the infection. If the immune system is working well, the body then remembers that bacteria or virus after fighting off the first infection. Parts of the adaptive immune system are also targets to treat autoimmune disease. We have medications to remove B cells and to slow down B cells and T cells.  Some cytokines such as interleukin-17 (IL-17), interleukin-12 (IL-12), and interleukin-23 (IL-23) are important for adaptive immunity as well.

There are different ways to get these medications into your body. Certain medicines such as steroids, azathioprine, and methotrexate can be taken by mouth. Other medicines, called biologics, need to be injected either into the blood through the vein or subcutaneously into the fat under the skin.

Also, keep in mind that research into autoimmune disease and its treatment is very active, and medications and indications for treatment evolve frequently. This discussion does not include a full list of indications or side effects for these medications. For example, pregnancy (whether as a would-be father or mother) should be avoided on many of these medications. If you have specific questions regarding the following medications or conditions, be sure to speak with your personal physician, immunologist, or rheumatologist.

General Immune Suppressants

Steroids
Examples: Prednisone, methylprednisolone, dexamethasone
Indications for use: Numerous uses in many autoimmune diseases, asthma, urticaria
Medication target: Steroids have broad effects to block inflammation
How it works: Steroids stop the body from making cytokines that cause inflammation, deplete certain immune cells called T and B cells and eosinophils, and make it more difficult for immune cells to travel to spots of infection or injury though the body. They are different from the “anabolic steroids” that are sometimes abused by athletes.
What to look out for: Using steroids for a long time puts you at risk for many issues related to bone health, high blood pressure, blood sugar control, cataracts, and infections. Depending on how much steroid you are taking and how long you will be on it, you will be monitored for certain types of infections, including rare types of pneumonia. You may need to use antibiotics to help prevent some types of infections. These measures are normally not needed if you are on steroids for a short time. For those on long-term steroids, you should speak with your physician before receiving vaccinations.
Colchicine
Indications for use: Gout flares, Familial Mediterranean Fever (FMF), other autoinflammatory disorders
Medication target: Inhibits neutrophil (a type of white blood cell) function
How it works: By reducing the function of neutrophils, it works by reducing inflammation in specific diseases.
What to look out for: Colchicine can commonly cause diarrhea, nausea and vomiting. It may also cause liver, kidney or muscle damage and can lead to low blood cell counts. This medication may cause dangerous interactions with other medications, so a full medication check is necessary. It should not be taken with grapefruit juice.

Hydroxychloroquine (Plaquenil)
Indications for use: Lupus, rheumatoid arthritis, malaria, chronic hives and other autoimmune conditions
Medication target: Immune cell signaling
How it works: By reducing signaling in the immune system, it reduces the inflammatory response. It may prevent activation of certain immune cells called dendritic cells.
What to look out for: Hydroxychloroquine may cause diarrhea, nausea, vomiting and abdominal pain. It may also cause a rash, vision changes and low blood cell counts. It is not associated with an increased risk for infection. Patients should have regular eye examinations while taking this medication. It has many drug interactions.

Sulfasalazine
Indications for use: Rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ulcerative colitis and other autoinflammatory conditions
Medication target: Inhibits the formation of chemicals called prostaglandins
How it works: The active component of sulfasalazine, 5-aminosalicylate, helps to gradually reduce inflammation.
What to look out for: This medication may cause nausea, headache, sun sensitivity and a rash. It should be avoided in patients allergic to sulfa antibiotics or salicylates and used with caution in patients with G6PD deficiency. Patients should use sun protection when taking this medication. It may temporarily reduce sperm counts and cause orange urine. Since it may rarely lead to reduced blood counts and risk for infection, you may have blood tests checked while taking this medication.

Dapsone
Indications for use: Leprosy and other infections, dermatitis herpetiformis, other autoimmune conditions
Medication target: Interferes with bacterial folate synthesis
How it works: It also prevents cellular injury from free radicals, and inhibits chemicals called leukotrienes or prostaglandins for an anti-inflammatory effect.
What to look out for: This medication may cause gastrointestinal upset, a rash, and headache. Less commonly it may cause mood changes, low blood cell counts, kidney and liver damage, and male infertility. It should be used with caution in patients with G6PD deficiency and avoided in patients with a sulfa-allergy. It may have many drug interactions.

Methotrexate
Indications for use: Rheumatoid arthritis, many other autoimmune diseases and certain cancers
Medication target: Blocks how cells use folic acid, a specific nutrient. This is a key part of making DNA and RNA that are important for T cells and B cells to grow, divide, and survive.
How it works: T cells and B cells need to make DNA and RNA to live and grow. Slowing this process helps to control inflammation in autoimmune conditions.
What to look out for: Methotrexate is an immune suppressing drug. It is used at low doses for treatment of autoimmune disease. You are more likely to get bacterial and viral infections when you are taking methotrexate because it lowers your body's ability to make T and B cells. You should be checked for viral infections such as hepatitis B and C, as well as for your kidney and liver function before starting this drug. Your kidney and liver tests will be checked while you are taking this medication. Patients are often prescribed folic acid to reduce the side effects of this medication, such as mouth sores, diarrhea or nausea.

Mycophenolate Mofetil (Cellcept, Myfortic)
Indications for use: Used in many other autoimmune diseases and prevention of rejection in solid organ transplantation
Medication target: Inosine-5′-monophosphate dehydrogenase (IMPDH) enzyme
How it works: The IMPDH enzyme is important for making DNA and RNA. T cells and B cells need this enzyme to grow and divide, and blocking it helps to control immune responses in autoimmune conditions.
What to look out for: There is a higher risk of getting infections from bacteria or viruses when you are taking mycophenolate because it lowers your body's ability to make T and B cells. You should be checked for viral infections such as hepatitis B and C before starting this medication. Your blood cell counts, kidney, and liver tests will be checked while you are taking this drug. Live vaccines should be avoided.

Azathioprine (Imuran)
Indications for use: Used in many other autoimmune diseases and prevention of transplant rejection
Medication target: This drug is broken into a molecule that is built into DNA as it is being put together and stops DNA from being made correctly. This causes T and B cells to grow and divide more slowly.
How it works: T cells and B cells need to make DNA and RNA to grow and divide. Slowing this process down helps to control immune responses in autoimmune diseases.
What to look out for: There is a higher risk of getting infections from bacteria or viruses when you are taking azathioprine because it lowers your body's ability to make T and B cells. You should be checked for viral infections, such as hepatitis B and C, before starting this medication. Your doctor may check whether your body makes a protein called thiopurine methyltransferase (TPMT) before you start this medication to make sure your body can get rid of it normally. Your blood cell counts, kidney, and liver tests will be checked while you are taking this drug. It may increase your risk for malignancy.

Innate Immunity

Anti-IL-1 Biologics
Examples: Anakinra (Kineret), Canakinumab (Ilaris), Rilonacept (Arcalyst)
Indications for use: Cryopyrin-Associated Periodic Syndromes (CAPS), including
Familial Cold Autoinflammatory Syndrome and Muckle-Wells Syndrome, Systemic Juvenile Idiopathic Arthritis (canakinumab), rheumatoid arthritis (anakinra)
Medication target: Interleukin-1 (IL-1)
How it works: IL-1 helps your body respond right away when microbes come into contact with cells. This causes fever and tells other cells to help join and fight the infection. By blocking the IL-1, we can reduce fever, inflammation in the joints and skin, and help to reduce the overall inflammation caused by these conditions.
What to look out for: Because IL-1 is important for protection against microbes, you may be more likely to get infections (bacterial and viral), such as upper respiratory infections and urinary tract infections, with long-term treatment with an IL-1 blocking drug. Reactivation of disease such as tuberculosis is rare, but getting a test for tuberculosis infection is recommended before you start this drug. It is recommended to avoid live vaccines while on these medications and to receive all required vaccinations of any type before starting the medication because it is not known how well the body makes a response to the vaccine while you are taking this type of medication. Your white blood cell count is often monitored while taking these medications.

Anti-TNF Biologics (TNF Inhibitors)
Examples: Infliximab (Remicade), Adalimumab (Humira), Golimumab (Simponi), Etanercept (Enbrel), Certolizumab (Cimzia)
Indications for use: Rheumatoid arthritis, plaque psoriasis/arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis
Medication target: Tumor necrosis factor (TNF)
How it works: TNF is important for inflammation that starts when the body comes into contact with microbes. TNF activates inflammation throughout the body, causes fever, and recruits other white blood cells to the part of the body where there is an infection. In inflammatory conditions such as rheumatoid arthritis and inflammatory bowel disease, TNF can cause damage to joints, skin, and the digestive tract. Blocking TNF can help to keep these inflammatory diseases under control.
What to look out for: TNF is also an important part of the body’s ability to get rid of invading bacteria, viruses, and fungi. There is a higher risk of serious infections when taking a TNF blocking therapy. Additionally, you should be tested for tuberculosis, hepatitis B and C, HIV, and screened for any risk of fungal infection because if you have these infections, they can become active when we block TNF.  You should also avoid live vaccines when taking this family of medications. The long-term risk of cancers such as lymphoma may also be higher in patients taking anti-TNF therapy.

Anti-IL-6 Biologics
Examples: Tocilizumab (Actemra), Sarilumab (Kevzara)
Indications for use: Rheumatoid arthritis, giant cell arteritis, juvenile idiopathic arthritis
Medication target: Interleukin-6 (IL-6) receptor
How it works: IL-6 is an important cytokine that causes T cells and B cells to be activated. It is also important for inflammation throughout the body leading to fever. In autoimmune disease such as rheumatoid arthritis, IL-6 causes inflammation that damages joints and other parts of the body.  
What to look out for: Because IL-6 is an important cytokine for many white blood cells and inflammation in general, there is a higher risk of infection with common infections, such as upper respiratory viruses, and with less common infections, such as tuberculosis. As with TNF blocking therapies, you should be tested for tuberculosis before starting an IL-6 blocking treatment.

Complement
Examples: Eculizumab
Indications for use: Paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (a-HUS)
Medication target: Complement C5
How it works: Complement is part of the innate immune system that binds to and destroys certain types of bacteria (such as Neisseria—the family of bacteria that causes gonorrhea and meningococcal meningitis). In normal circumstances, the body keeps complement in check by having proteins to prevent complement from being activated. In certain conditions, such as PNH and a-HUS, the body cannot stop complement from being activated and the body destroys its own cells. Eculizumab helps to prevent this type of spontaneous complement activation.
What to look out for: Because complement is very important for the body’s defense against Neisseria, individuals taking eculizumab are more likely to get this infection. You should be vaccinated against meningococcus before starting this drug and take antibiotics to prevent infections while on this drug.

Adaptive Immunity – B cells

Anti-CD20 Biologics
Examples: Rituximab (Rituxan)
Indications for use: Non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, vasculitis (such as granulomatosis with polyangiitis and microscopic polyangiitis), autoimmune skin disease
Medication target: CD20, a surface protein on B cells
How it works: Rituximab binds to the CD20 protein on B cells and destroys the B cells in the bloodstream. The diseases that are treated with rituximab all require B cells to either grow (such as lymphoma) or make antibodies that bind to certain parts of our body and cause inflammation (such as rheumatoid arthritis, vasculitis, and autoimmune skin disease). When the B cells are removed by rituximab, the body gets rid of the growing B cells and the B cells that are making the antibodies causing the disease.
What to look out for: When B cells are removed from the body, there is a higher risk of diseases that are normally cleared by antibodies. These include infections in the sinuses and lungs. Specific diseases such as hepatitis B can become re-activated after rituximab and you should be tested for hepatitis B before treatment. Other types of viral infections have also been seen, such as herpes. The response to vaccines is also limited after rituximab and all indicated vaccinations should be given before its use. In most people who get rituximab, the B cells return within one year. However, in a subset of individuals treated with rituximab, B cells do not return and you may have low antibody levels for many years or lifelong. This can put you at higher risk for infection.

B Cell Growth Factor Targeting Biologics
Examples: Belimumab (Benlysta)
Indications for use: Systemic lupus erythematosus
Medication target: BLyS (B lymphocyte stimulator, also called BAFF)
How it works: Belimumab targets the cytokine BLyS, which is an important protein for B cell survival and growth. By blocking this growth factor in patients with lupus, you can reduce some of the autoimmune antibodies that are made by B cells.
What to look out for: In patients using belimumab, skin infections and pneumonia are the most common infections. Patients on belimumab who develop decreased immune function are also more likely to develop pneumonia caused by fungi or cytomegalovirus. Live vaccines should be avoided when taking belimumab.

Adaptive Immunity – T Cells
Examples: Cyclosporine
Indications for use: Prevent organ transplant rejection, graft versus host disease, rheumatoid arthritis, psoriasis, chronic urticaria
Medication target: Calcineurin, which gives signals to activate T cells
How it works: Cyclosporine is an oral medication that is taken up into T cells where it binds a protein called calcineurin. When this happens, the T cells cannot make cytokines or make more T cells.
What to look out for: The most frequent side effects of cyclosporine are high blood pressure and decreased kidney function and these need to be closely monitored. Because cyclosporine blocks T cells, it is an immune-suppressing medication. It may increase the risk for malignancy. You are at higher risk of infections in general when on this medication. For this reason, it is recommended that you avoid all live vaccines when you are taking this medication.

T Cell Co-stimulation and Activation
Examples: Abatacept (Orencia)
Indications for use: Rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis
Medication target: CTLA-4/CD28
How it works: T cells are activated by two signals. The first signal is when the T cell receptor binds a specific part of a microbe (antigen) brought to it by an immune cell called an antigen presenting cell (APC). The second signal occurs when the T cell and APC communicate by a second set of proteins when these cells interact. An example of this second signal is a T cell protein called CD28 that binds to APC proteins CD80/86 activating both the T cell and the APC. To turn itself off, the T cell will bring in CTLA-4 that blocks the binding of CD28 to CD80/86. Abatacept is a drug form of CTLA-4. By using this medication, we are able to turn off the T cell immune response. In inflammatory arthritis, this helps to calm the inflammation caused by T cells that causes joint pain and swelling.
What to look out for: Because abatacept is helping to turn off all T cell responses, you are at a higher risk of infections when taking this medication. You should be tested for tuberculosis and hepatitis B and C because if you have these infections, they can become active when we turn down the activity of T cells.  Live vaccines should not be given concurrently or within 3 months of stopping this medication.

Adaptive Immunity – Cytokines

Anti-IL-17 Biologics
Examples: Secukinumab (Cosentyx), Ixekizumab (Taltz), Brodalumab (Siliq)
Indications for use: Psoriasis, psoriatic arthritis, ankylosing spondylitis
Medication target: IL-17 (secukinumab, ixekizumab), IL-17 receptor (brodalumab)
How it works: IL-17 is an important cytokine in autoimmune disease. It is important in diseases like psoriasis and ankylosing spondylitis. Normally, IL-17 is an important part of our defense against bacterial and fungal infections by recruiting other types of white blood cells called neutrophils to sites of infections.
What to look out for: When IL-17 blocking treatments are used there is a higher likelihood of infections, mostly including upper respiratory tract infections. Serious infections and fungal infections were rare in studies of these types of medications. Live vaccines should be avoided while using an IL-17 blocking therapy.

Anti-IL-23 Biologics
Examples: Guselkumab (Tremfya)
Indications for use: Psoriasis
Medication target: IL-23 cytokine
How it works: IL-23 is a cytokine important for keeping a type of T cell called Th17 cells (that make IL-17) alive. By keeping these cells alive and active, IL-23 is an important part of the body’s defense against bacterial infection and other infections in the gut. In autoimmune diseases like psoriasis, IL-23 can be part of the inflammatory response causing skin inflammation and symptoms.
What to look out for: Blocking IL-23 does not have a big effect on the number of infections that patients had during clinical trials.

Anti-IL-12/23 Biologics
Examples: Ustekinumab (Stelara)
Indications for use: Psoriasis, psoriatic arthritis, Crohn’s disease
Medication target: IL-12 and IL-23 cytokine receptors
How it works: Ustekinumab binds to a part of the IL-12 and IL-23 receptors that is shared, called IL-12p40. IL-12 is an important cytokine to activate T cells and other white blood cells called natural killer cells that help to clear bacterial and viral infections. When these cytokines are abnormally regulated in autoimmune disease, it can cause damage to tissues, as seen in psoriasis and Crohn’s disease.
What to look out for: Because IL-12 is an important part of the immune system to activate T cells, this may put patients at higher risk of infection from mycobacteria, salmonella, and tuberculosis or BCG. This appears to be very rare. Testing for tuberculosis is recommended before starting therapy with ustekinumab.

Anti-IL-5 Biologics
Examples: Mepolizumab (Nucala), Reslizumab (Cinqair), Benralizumab (Fasenra)
Indications for use: Severe eosinophilic asthma, other eosinophilic related disorders
Medication target: IL-5 (mepolizumab and reslizumab), IL-5 receptor (benralizumab)
How it works: IL-5 is an important cytokine for a specific type of white blood cells called eosinophils. Eosinophils are important for the body to fight off worm (helminth) infections and are activated in allergic conditions such as asthma.
What to look out for: If you have a helminth infection, it should be treated before starting these medications. If you get a helminth infection that does not clear with treatment while on the IL-5 targeted medications, you should stop these medications.

Anti-IL-4/IL-13 Biologics
Examples: Dupilumab (Dupixent)
Indications for use: Atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps
Medication target: IL-4 Receptor alpha (Part of the IL-4 and IL-13 receptor)
How it works: The cytokines IL-4 and IL-13 are involved in the immune response that leads to production of allergy antibodies (IgE), mucous in the airways, and activation of the allergic immune response.  
What to look out for: The recommendations are to avoid live vaccines (such as MMR and varicella) when you are using dupilumab. The responses to killed or inactive vaccines (such as the meningitis vaccine) are normal when on this medication. There is likely no or a very small increased risk for getting skin infections, flu, or cold virus infections. IL-4 and IL-13 are likely important in the control of worm (helminth) infections. Studies have not measured the effect of dupilumab on these types of infections. If you are living in an area where there are helminths, you should be monitored periodically or tested if you have symptoms.

Biologics Targeting IgE
Examples: Omalizumab (Xolair)
Indications for use: Allergic asthma, Chronic urticaria
Medication target: IgE – allergy antibody
How it works: IgE is often referred to as the “allergy antibody”. When IgE binds to an allergen, it causes release of histamine and other molecules that cause an allergic response (itching, redness, hives).
What to look out for: Blocking IgE does not have a large impact on the body’s ability to fight off typical bacterial and viral infections. IgE may be important to attack other types of infections such as helminths (also called worms, such as roundworm, hookworm, whipworm, threadworm). Studies have shown a slightly increased risk for infection in areas of the world where these parasites live if you are using omalizumab. If you are living in an area where there are helminths, you should be monitored periodically or tested if you have symptoms.

Lymphocyte (White Blood Cell) Movement
Examples: Vedolizumab (Entyvio)
Indications for use: Inflammatory bowel disease (ulcerative colitis and Crohn’s)
Medication target: α4β7 integrin (a protein on the outside of white blood cells that help them get to the gut)
How it works: White blood cells with α4β7 integrins go to the gut where they can have inflammatory effects in inflammatory bowel disease. Vedolizumab blocks these cells from going to the gut, reducing the amount of inflammation.
What to look out for: Rates of overall infection (including sinus infections and urinary infections) are slightly higher in patients using vedolizumab. For infections in the gut, there are reports of abscesses in the lower digestive tract and bacterial infections in patients using this medication.

Small Molecule Targeting Medications

JAK Inhibitors
Examples: Tofacitinib (Xeljanz), Upadacitinib (Rinvoq), Baricitinib (Olumiant)
Indications for use: Rheumatoid arthritis, psoriatic arthritis, ulcerative colitis
Medication target: JAK (Janus Kinase) Enzymes
How it works: JAK enzymes are important proteins inside of cells that relay signals from the outside of the cell to the nucleus, or the machinery inside the cell. Many different cytokine signals use JAKs to transmit messages in the cells. In diseases where there is too much inflammation, blocking JAKs can help to lower the amount of inflammation by decreasing the signals that tell the cell to make and release inflammatory molecules like cytokines.
What to look out for: As with other immune-suppressing medications, there is an increased amount of infections with JAK inhibitors. One virus that has been found more often in patients using JAK inhibitors is herpes zoster. Live vaccines should not be given concurrently.


This article has been reviewed by Andrew Moore, MD, FAAAAI

Reviewed: 9/28/20