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A Dermatologist's Guide to Infection Screening Prior to Initiating Immunosuppressive Therapy

Marisa G. Ponzo, MD, PhD1 and Chih-Ho Hong, MD, FRCPC1,2
1Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
2Division of Dermatology, St. Paul's Hospital, Vancouver, BC, Canada

Conflicts of interest: None Reported.

ABSTRACT

Dermatologists have within their armamentarium numerous immunosuppressant agents, both traditional and new, that are useful in the treatment of chronic cutaneous disorders such as autoimmune bullous diseases and psoriasis. It is imperative that users of these agents are aware of potential sequelae from therapy, particularly infections. In this review, we summarize the most common immunosuppressant medications currently used in dermatology, and provide recommendations for infection screening prior to initiating treatment.

Key Words: immunosuppression, infection, TNF-α inhibitors, IL-12/23 inhibitors, IL-17 inhibitors, clinical protocol, drug therapy, skin diseases

Introduction

Psoriasis, connective tissue diseases, and autoimmune bullous diseases such as bullous pemphigoid and pemphigus are but a few examples of the dermatological indications for which immunomodulatory/immunosuppressive therapy may be indicated. Treating patients with these inflammatory cutaneous diseases often involves one or more immunosuppressive agents, either sequentially or in combination, which increases the risk of infection-related morbidity and mortality. One of the main safety concerns for the dermatologist prior to initiating therapy is the risk of infection. Risk factors for infection include age, medical comorbidities, travel history, location of residence, occupation, as well as the type, duration and extent of immunosuppression. Although pretreatment infection-testing guidelines exist for the disciplines of gastroenterology, hepatology, rheumatology, and transplant medicine, no specific guidelines have been developed for the dermatologist wishing to begin immunosuppressive therapy. This discussion is timely and of interest within the dermatology literature, as multiple publications have emerged within the last 5 years.1-3 The dermatologist has a therapeutic armamentarium of immunosuppressive drugs including traditional therapies such as systemic corticosteroids, methotrexate, cyclosporine, azathioprine, mycophenolate mofetil as well as novel therapeutics known as biologics. Within the last decade or so there has been an emergence of novel biologic therapeutics including inhibitors of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1, CD20, p40 subunit of IL-12/23, and more recently IL-17. Herein, we discuss the current pre-treatment infection guidelines for the dermatologist prior to beginning immunosuppressive therapy.

Non-biologic immunosuppressive therapy

The non-biologic immunosuppressive therapies that will be discussed are corticosteroids, methotrexate, azathioprine, cyclosporine and mycophenolate mofetil (Table 1). Since their introduction in the 1950s, corticosteroids have revolutionized the management of inflammatory diseases.4 Corticosteroids are among the oldest immunosuppressants; their mechanism of action is through inhibition of gene transcription and downregulation of secreted inflammatory cytokines.5,6 The risk of infection with corticosteroid use depends upon the patient's underlying disease state, duration, dose and route of administration.7 A lower dose of corticosteroids as well as a shorter duration are associated with a reduction in infectious complications.8 Corticosteroid use in combination with other immunosuppressive agents, such as methotrexate or azathioprine, increases the risk of serious infections as evidenced in inflammatory bowel disease and rheumatoid arthritis.9 However, given the short half-life of systemic corticosteroids (e.g., prednisone plasma half-life is 60 minutes, prednisolone plasma half-life is 115-212 minutes), it is reasonable to start these medications, if needed, while awaiting infection screening results.

Agent Mechanism of Action Immunosuppressive Effect
Azathioprine Purine anti-metabolite Apoptosis of T-cells
Corticosteroids Inhibition of transcription of genes response for secretion of inflammatory cytokines Multiple cytokine alterations; overall effects are decreased leukocyte migration and phagocytosis; decreased T-cell function
Cyclosporine Inhibition of cytosolic enzyme calcineurin Suppression of cell-mediated immunity
Methotrexate Folic acid antagonist; inhibition of purine synthesis; JAK/STAT inhibitor Mechanism for immunosuppression not fully elucidated
Mycophenolate mofetil Inhibitor of purine biosynthesis Decreased migration of inflammatory cells; decreased immunoglobulin production by B-cells
Table 1: Traditional immunosuppressive agents and their mechanism of action

Azathioprine and its derivative 6-mercatopurine are structurally similar to the endogenous purines adenine and guanine. The exact mechanism of action of this immunosuppressive agent is unknown, however it is thought that the structural similarity to endogenous purines allows it to be incorporated into DNA and RNA with subsequent inhibition of purine metabolism and cell division. Azathioprine use is associated with increased bacterial, fungal and viral infections.10 Prior to initiating azathioprine, the dermatologist should ascertain whether the patient has been immunized or previously infected with varicella zoster virus and if not, immunization prior to commencing immunosuppression should be recommended.10 Furthermore, azathioprine in combination with prednisolone is associated with an increased risk of infection which can be fatal in the elderly.11

Methotrexate is a potent competitive inhibitor of dihydrofolate reductase and a partially reversible inhibitor of thymidylate synthetase, which ultimately acts by inhibiting purine synthesis. However, the definitive mechanism of action of methotrexate is, to date, incompletely understood, as novel modes of action continue to be published; most recently its role as a Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway inhibitor has been described.12 In patients receiving long-term treatment with methotrexate, hepatotoxicity is an important consideration and patients should be screened for hepatitis B and C infection prior to initiating treatment. In addition, untreated chronic tuberculosis and active tuberculosis infections are contraindications to treating with methotrexate.

Cyclosporine is postulated to act by inhibition of the intracellular enzyme calcineurin, resulting in reduced activity of the transcription factor nuclear factor of activated T-cells (NFAT-1). With decreased NFAT-1 activity, the transcription of a number of downstream cytokine genes, most notably IL-2, are suppressed. Furthermore, impaired production of IL-2 leads to a decline in the number of activated T-cells within the epidermis. Thus, cyclosporine results in decreased functional T-cell mediated immunity, leading to increased susceptibility to cytosolic microorganisms, including atypical Mycobacterium, and viruses.13,14

Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid that inhibits inosine monophosphate dehydrogenase (IMPDH). Inhibition of this critical enzyme, IMPDH, subsequently deprives T- and B-cells of purine metabolites necessary for growth and replication. The net effect is selective immunosuppression. MMF is associated with an increased risk of infection especially when doses in excess of 2 g daily are used.15,16 Serious infections are most common in renal and cardiac (2%) and hepatic (5%) transplant patients at doses of 2-3 g daily. Viral (herpes zoster, herpes simplex), bacterial, atypical mycobacterial and fungal infections have been reported in the literature.17-20

Biologic Immunosuppressive Therapy

The biologics account for a relatively novel class of medications refered to as specialty drugs or specialty pharmaceuticals.21 Biologics are derived from living cells and are administered by injection, infusion or oral route, and are used to treat a variety of rare conditions. Biologic immunosuppressive therapies include TNF-α inhibitors (infliximab, adalimumab, etanercept), IL-12/23 inhibitors (ustekinumab), CD20 inhibitors (rituximab) and most recently the IL-17 pathway inhibitors (secukinumab, ixekizumab, brodalumab) (Table 2). Given the relative success of TNF-α inhibitors and ustekinumab in the treatment of psoriasis, there has been an emergence of biologics targeting various other cytokines. Inhibitors of IL-17 are the latest wave of therapeutics developed for the treatment of psoriasis and psoriatic arthritis, which deplete the Th17 population of T-cells. Other types of IL-17 inhibitors are currently in various phases of clinical trials for psoriasis and psoriatic arthritis.22 The clinical trials for these agents are currently ongoing and data pertaining to incidence and type of infections have not yet been published.

Biologic Class Generic Name/Trade Name Monoclonal Ab vs. Receptor Mechanism of Action
TNF-α inhibitors Infliximab (Remicade®) Monoclonal Ab (chimeric), IgG1κ Binds TNF-α only, inhibits binding to soluble and transmembrane TNF receptor
Adalimumab (Humira®) Monoclonal Ab (fully human), IgG1 Binds TNF-α only, inhibits TNF binding to p55 and p75 transmembrane TNF receptor
Etanercept (Enbrel®) Receptor, dimeric fusion protein, p75 TNF receptor linked to Fc IgG1 Binds to both TNF-α and TNF-β; binding to soluble and membrane bound TNF-α
IL-12/23 inhibitor Ustekinumab (Stelara®) Monoclonal Ab (fully human), IgG1 Binds the common p40 subunit of IL-12 and IL-23 preventing interaction with IL-12Rβ1; decreased Th1 and Th17 signalling
IL-17 pathway inhibitors Secukinumab (Cosentyx®) Monoclonal Ab (fully human), IgG1κ Neutralizes IL-17A; decreased IL-23 signalling pathway downstream of Th17 cells
Ixekizumab (Talz®) Monoclonal Ab (fully human), IgG4 Neutralizes IL-17A; decreased IL-23 signalling pathway downstream of Th17 cells
CD20 inhibitor Rituximab (Rituxan®) Monoclonal Ab (chimeric), IgG1κ Binds CD20 surface molecule on B-cells
Table 2: Biologic immunosuppressive therapy. Ab = antibody; IgG = immunoglobulin G antibody; Th = T helper cells

Rituximab, a biologic that targets the B-cell surface antigen CD20, can be used in several dermatologic conditions including pemphigus vulgaris. Rituximab became the first monoclonal antibody approved by the US FDA for the treatment of cancer. Since rituximab depletes CD20+ B-cells, it should not be administered to patients with active infections. Live vaccines should not be given to patients taking rituximab, and recombinant or killed vaccines should be given at least 4 weeks prior to initiating treatment. Patients should undergo screening for active and latent infections. Rituximab has been associated in particular with reactivation of hepatitis B virus (HBV).23 The time from last rituximab dose to reactivation of HBV was 3 months, although 29% occurred >6 months after last rituximab. Patients with previous exposure to HBV should be screened prior to initiating rituximab. Carriers should be closely monitored for clinical and laboratory signs of infection as reactivation may lead to liver failure and death in the months following therapy. There is an argument for the consideration of prophylactic treatment in selected patients.24 Reactivation of the JC virus (a type of human polyomavirus), leading to progressive multifocal leukoencephalopathy (PML) has also been associated with rituximab treatment.25 Among human immunodeficiency virus (HIV)-negative patients, the median time to diagnosis of PML was 5.5 months following the last dose of rituximab and a 90% fatality was reported. These data warrant vigilant monitoring for new onset neurologic findings during and after the course of treatment.

Pretreatment Infection Workup

Recent publications within the dermatology literature have provided recommendations for an infection workup for the dermatologist prior to initiating immunosuppressive agents.2,3 In general, the suggested steps apply to all immunosuppressants, whether non-biologic or biologic. Table 3 provides a summary of these and our recommendations.

Although the morbidity and mortality from infectious complications can be significant, careful patient selection and monitoring can mitigate risk and reduce potential harm. General recommendations include conducting a thorough history and physical exam, with particular focus on country of birth and residence, travel history, sexual and social risk factors and exposure to sick contacts. Vaccination records should be reviewed and, if feasible, age-appropriate vaccinations should be updated prior to initiating immunosuppressive therapy. Patients should be educated on the importance of general hygiene (i.e., handwashing), signs and symptoms of early infection and when they should seek urgent medical care. Likewise, the dermatologist should be vigilant for early signs and symptoms of infection, and have a low threshold to treat bacterial, fungal and viral illness. Physicians should assess patients at each visit for impetiginization and treat appropriately.

1. Screen patient for risk factors of infection:
  • Comorbid medical conditions (i.e., organ/hematopoietic transplant, active malignancy, renal or liver failure, diabetes mellitus etc.)
  • Age
  • Occupation
  • History of travel to areas of endemic disease
  • History of high risk sexual activity, drug abuse
  • History of exposure to tuberculosis
  • History of blood transfusion
2. On a case by case basis, consider laboratory screening for patients at risk:
  • Hepatitis B (HBsAg, anti-HBc, IgM anti-HBc, anti-HBs)
  • Hepatitis C (HCV enzyme immunoassay)
  • HIV (HIV ELISA)
  • Strongyloides (stool culture for ova and parasites; Strongyloides ELISA)
  • Tuberculosis (PPD tests; interferon-gamma release assay; chest x-ray, for patients with a positive PPD test from previous Bacillus Calmette-GuĂ©rin vaccination)
  • Systemic fungal infections, such as cryptococcosis, histoplasmosis, coccidiomycosis, blastomycosis, and paracoccidioidomycosis (serum and/or urine test; chest x-ray)
  • Consider pneumocystis pneumonia prophylaxis
3. Ensure immunizations are up-to-date according to latest recommendations (www.cdc.gov/vaccines/schedules/)
  • Seasonal influenza vaccination (non-live vaccine; avoid live vaccine after immunosuppressive therapies have been initiated)
  • Pneumococcus vaccination (non-live vaccine)
  • Herpes zoster vaccination (live vaccine; initiate prior to starting immunosuppressive therapy)
  • Tetanus/diphtheria vaccination (non-live vaccine)
4. Patient education in regards to:
  • Frequent handwashing
  • Avoiding high-risk infectious exposures if possible (i.e., over-crowded areas, child care centres, nursing homes, farms, compost, travel to countries where aforementioned diseases are endemic)
  • Early signs and symptoms of infection (e.g., including impetiginization, and systemic bacterial, fungal and viral infections)
Table 3: A dermatologist's checklist to infection screening prior to initiating immunosuppressive therapy (adapted from Lehman JS et al.2) Anti-HBc = hepatitis B virus core antibody; anti-HBs= hepatitis B virus surface antibody; ELISA = enzyme-linked immunosorbent assay; HBsAg = hepatitis B virus surface antigen; HCV = hepatitis C virus; PPD = purified protein derivative

All patients should undergo HIV, HBV, and hepatitis C virus (HCV) testing. Furthermore, testing and diagnosis of tuberculosis should be undertaken as per Centers for Disease Control and Prevention (CDC) and Health Canada recommendations (Health Canada: http://www.phac-aspc.gc.ca/tbpc-latb/pubs/tbcanada-7/tb-standards-tb-normes-ch3-eng.php and CDC: http://www.cdc.gov/tb/topic/testing/).

Testing for parasitic infections, particularly Strongyloides stercoralis (S. stercoralis) should be considered and done on an individualized basis. Infection with S. stercoralis is usually chronic and asymptomatic in immunocompetent patients and may persist undetected for many years. In immunosuppressed patients, strongyloidiasis can cause hyperinfection and dessimination and carries a high mortality rate. It is reasonable to screen those who have resided in an endemic area for a prolonged period even if it was in the distant past (i.e., southeastern United States and subtropical areas, Europe) and those who possess other risk factors (i.e., occupation, activities). Unexplained hypereosinophilia should also trigger the physician to screen for Strongyloides. Conversely, the physician should be mindful that prolonged corticosteroid use can suppress hypereosinophilia. Stool microscopy for ova and parasites is currently the gold standard for diagnosis, however, up to seven collections may be required in order to reach a sensitivity of 100%.26 A single stool sample collection has a low sensitivity of 30-75%.27,28 Sensitivity for the enzyme-linked immunosorbent assay (ELISA) for S. stercoralis serology is 83-93% with 95-97% specificity.29

Conclusion

We have provided an overview of some of the major immunosuppressant drugs used in dermatology and have presented a summary of recommendations prior to initiating these medications (Table 3). Regardless of the immunosuppressive agent used, the type of infections that the dermatologist needs to screen for and prevent are similar. Overall, the risk of infection is likely to be directly proportional to the dose and duration of immunosuppressant therapy.

References

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In this issue:

  1. A Dermatologist's Guide to Infection Screening Prior to Initiating Immunosuppressive Therapy
  2. Update on Drugs and Drug News - January-February 2017