Drug-induced immunosuppression

What is drug-induced immune suppression?

Drug-induced immune suppression, also known as medication-induced immunosuppression, refers to impaired immune system function as the result of medications used in the treatment of systemic diseases. This typically manifests as recurrent, severe, unusual, or opportunistic infections [1].

There are several medications used to treat dermatological conditions that affect the immune system to a variable extent.

Chronic drug-induced immune suppression for other reasons (for example, to prevent rejection in organ transplantation patients) is also associated with a number of dermatological complications [2].

Who gets drug-induced immune suppression?

The main medications used in dermatology that cause significant drug-induced immune suppression include [3]:

• Azathioprine
• Ciclosporin
• Mycophenolate mofetil
• Cyclophosphamide
• Systemic corticosteroids, such as prednisone.

Prednisone tablets

Azathioprine tablets

Mycophenolate capsule

Other medications that result in a milder impairment of immune function, especially if in conjunction with other agents, include:

• Methotrexate
• Biological agents [4].

Methotrexate injection

Methotrexate tablets

Examples of biological agents are:

• Tumour necrosis factor (TNF) alpha antagonists (infliximab, etanercept, adalimumab)
• Interleukin (IL) 12/23 antibodies (ustekinumab)
• IL 17 antibodies (secukinumab, ixekizumab, brodalumab)
• IL 4 receptor antibodies (dupilumab)
• Immunoglobulin (Ig) E antibodies (omalizumab)
• Janus kinase (JAK) receptor inhibitors (tofacitinib)
• Phosphodiesterase (PD) E4 inhibitors (apremilast).

Adalimumab pen

Ustekinumab injection

Omalizumab syringe

Immunosuppressive therapy is used in a variety of dermatological conditions, including psoriasis, atopic dermatitis, autoimmune bullous diseases, and cutaneous lupus erythematosus [3,4]. In some patients, drug-induced immune suppression involves multiple agents with synergistic effects on immune suppression [5,6].

What causes drug-induced immune suppression?

Drug-induced immune suppression can occur by one or more mechanisms, including [1,5]:

• T-cell inhibition — with ciclosporin, and to a lesser extent, corticosteroids
• Cytokine inhibition — with corticosteroids (their main mechanism) and biological agents
• Antimetabolite impairment of immune cell function and production — with azathioprine, mycophenolate mofetil, and to a lesser extent, methotrexate
• Alkylating agents that impair immune cell function and production — such as cyclophosphamide.

What are the clinical features of drug-induced immune suppression?

Drug-induced immune suppression can lead to bacterial, viral, fungal, or parasitic infections, with different medications predisposing to specific types of organisms [6]. Many of these result in cutaneous disease or signs, notably bacterial abscesses, herpes zoster, herpes simplex, cytomegalovirus, and viral warts [2].

Bacterial infections

Bacterial infections associated with drug-induced immune suppression include [6]:

• Mycobacterium species
• Listeria species
• Staphylococcus species
• Nocardia species
• Escherichia coli
• Salmonella species
• Legionella pneumophilia
• Clostridium difficile.

Viral infections

Viral infections associated with drug-induced immune suppression include [6]:

• Hepatitis B virus
• Hepatitis C virus
• Human immunodeficiency virus (HIV)
• Influenza
• Varicella-zoster virus (VZV) (chickenpox, herpes zoster)
• Herpes simplex virus (HSV)
• Epstein-Barr virus (EBV)
• Human papillomavirus (HPV) which can be sexually acquired (genital warts) or nonsexually acquired (viral warts)
• Cytomegalovirus.

Fungal and parasite infections

Fungal and parasitic infections associated with drug-induced immune suppression include [6]:

• Candida species
• Histoplasmosis
• Aspergillus species
• Cryptococcus species
• Coccidioides immitis
• Blastomycoses
• Pneumocystis jiroveci
• Toxoplasma gondii.

High-dose chronic drug-induced immune suppression is associated with non-infectious dermatological problems, such as acne, gingival enlargement, hypertrichosis, and induction of skin cancer, in particular cutaneous squamous cell carcinoma [2].

What are the complications of drug-induced immune suppression?

Infections associated with drug-induced immune suppression can cause serious morbidity and potentially mortality, particularly in those with a poor functional state at baseline [6,7]. Immunosuppressive therapy can also change the clinical features of an infection, making it more difficult to diagnose [6].

The development of a serious infection can lead to complex clinical management decisions regarding the immune-suppressive treatment of the underlying condition [5,6].

Drug-induced immune suppression prevents the administration of live vaccines — because they might be hazardous — and limits the efficacy of other vaccines [6]. If practical, it is best to have any recommended vaccinations prior to initiating immunosuppressive drug treatment [5,6].

How is drug-induced immune suppression diagnosed?

Drug-induced immune suppression is a clinical diagnosis based on the known effects of the patient’s medications.

To quantify the extent of drug-induced immune suppression, antibody response can be measured before and after vaccination for pneumococcus. However, this predominantly assesses humoral immunity, not cell-mediated immunity, and is rarely performed [8].

What is the treatment for drug-induced immune suppression?

The effects of drug-induced immune suppression can be limited by taking preventative measures such as [5,6]:

• Update vaccinations prior to initiation of immune suppression
• Annual influenza vaccination
• Screening for infections or immunity to specific pathogens prior to initiation (eg, tuberculosis, viral hepatitis, HIV)
• Patient education regarding the risk of infections and the need for prompt medical treatment
• Specialist consultation and risk management prior to international travel.

Antibiotics, antivirals (such as aciclovir), or antifungals should be prescribed promptly in response to symptoms and signs consistent with infection.

If infections are severe or recurrent, the immunosuppressive therapy may need to be reduced or stopped and alterative drug management options considered [1,6].

What is the outcome for drug-induced immune suppression?

Drug-induced immune suppression has a variable prognosis. This can be based on the characteristics of the drug, the patient, and the disease being treated [1,5,7].

Drug characteristics include:

• The type of medication
• The dose of the medication
• The duration of treatment
• Synergistic effect of multiple immunosuppressive medications.

Patient characteristics include:

• Their baseline functional state
• Their age
• The indication for immunosuppressive therapy
• Their co-morbidities and vaccination status
• Their adherence to preventative measures and management.

Low-dose, single-agent immunosuppressive therapy for a short duration carries only a minor risk of serious infection and mortality [1,2,9].