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Practical use of biologic therapy in dermatology: Some considerations and checklists

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https://doi.org/10.5070/D39r3171q1
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Practical use of biologic therapy in dermatology: Some considerations and checklists
Melanie Ortleb1 MD, Jacob Levitt2 MD
Dermatology Online Journal 18 (2): 2

1. University of Nebraska Medical Center, Omaha, Nebraska
2. Department of Dermatology, Mount Sinai School of Medicine, New York, New York

Abstract

BACKGROUND: Practice varies with respect to biologic therapy counseling and monitoring of biologic therapy. Because of the complexity, many physicians shy away from prescribing biologic therapy. OBJECTIVE: To create checklists and discuss considerations behind various counseling and monitoring issues. METHODS: The full prescribing information of infliximab, etanercept, adalimumab, golimumab, certolizumab, alefacept, ustekinumab, rituximab, and IVIg were reviewed in addition to National Psoriasis Foundation guidelines to create the checklists. RESULTS: Considerations of counseling for biologics includes explaining benefits, relative risks of not treating or alternative therapies, consequence of risk, preventability of risk, and likelihood of risk. Considerations regarding vaccination, viral hepatitis screening, tuberculosis screening, skin cancer screening, pregnancy, and anti-nuclear antibody screening are discussed. LIMITATIONS: Consensus is unavailable as to the extent of counseling or monitoring. This manuscript provides one perspective. CONCLUSIONS: This article reviews monitoring and patient counseling considerations for the use of biologics in dermatology. Tables for each drug are provided with checklists for counseling and monitoring.


Capsule Summary

  • General guidelines, published in separate places, describe monitoring of one or another biologic agent used in dermatology. Ambiguity remains, causing insecurity among those physicians who feel more comfortable with more structured guidance.
  • This article discusses the rationale behind suggested counseling and screening and checklists for each biologic for counseling and screening.
  • The checklists are intended to be adapted to the office setting, allowing for a standardized approach to counseling and monitoring.

Introduction

The therapeutic ladder for psoriasis and autoimmune blistering diseases, such as pemphigus vulgaris and bullous pemphigoid, has evolved from using biologics as a last resort to using biologics as first and second line agents. The use of these medications has revolutionized the therapeutic landscape and has provided for levels of benefit not seen in past times. As with all medications, the biologics come with their fair share of risks, which require pre-treatment screening and ongoing monitoring. The package inserts of these agents are often long and cumbersome. Unfortunately, because of the intricacies of each individual agent and the growing variety of agents, some physicians shy away from their use. The low level of comfort and lack of use translates into a denial of life-altering therapy for patients in need. This manuscript hopes to facilitate the adoption of biologic agents into the practice of the physician who is compassionate enough to employ these modalities for the patient in need.

Using a checklist approach, we have attempted to streamline the package inserts and provide a means to navigate the biologics in a safe, efficient, and thorough manner. This manuscript presupposes that: a) the physician is very familiar with the effects of the agents in question, b) a guide cannot replace such familiarity, c) a decision has been made by the physician that a biologic would be appropriate, and d) the physician requires guidance through the minefield of items that might prevent their safe administration. We hope our approach helps minimize medical errors and provides a framework for appropriate history and physical exam, laboratory work-up, and follow-up. Unfortunately, few sources provide for evidence-based guidance beyond that of the package inserts.

We supplement with our own clinical experience and cautious common sense and indicate where we do so. Package inserts are constantly evolving documents. Although we feel we have accurately captured the majority of monitoring issues for each drug, it is always prudent to keep abreast of the latest information and changes.

We use the following overarching themes in deciding how to counsel:

  1. Is the physician convinced it is a safe and good choice given a non-risk averse patient?
  2. Is the patient aware of the magnitude and extent of benefits of the medication?
  3. Does the patient understand the relative magnitude of risk of treating versus not treating?
  4. Does the patient understand the relative risks of alternative therapies?
  5. To help the patient understand risk magnitudes, one should consider:
    • Consequence of Risk (e.g., irreversible/death versus treatable infection)
    • Ability to Mitigate Risk (e.g., vaccination, proper screening to avoid high risk individuals)
    • Likelihood of Risk (rare – e.g., lymphoma, multiple sclerosis; versus uncommon – e.g., some types of infection; versus common – e.g., injection site reaction)
  6. Is the risk worthwhile mentioning at all? It is confusing and neither feasible nor practical to review every single risk with the patient. We tend to screen for and elaborate on those risks that result in death or severe disability or that are extremely common.

Considerations Common To Most Biologics


Vaccination

Whether to give a vaccine in a biologic patient depends on whether one would truly withhold the biologic in the face of the patient’s not getting the vaccine. No pre-administration vaccine is mandated by the package inserts of these medications. We are influenced to give the influenza vaccine annually in light of a recent death at our center from influenza in an infliximab patient [1]. It is recommended to avoid giving live or attenuated live vaccines for patients on biologic therapies. Table 1 [2] lists available live vaccines. Zostavax® would appear to be the most likely to be given inadvertently in an adult population on biologics, followed by the Yellow Fever vaccine prior to travel to endemic areas.

If administration of a live vaccine to the patient or household member of a patient is desired prior to initiating a biologic, one month appears to be a reasonable interval between vaccination and initiation of therapy. IVIg may interfere with the response to live viral vaccines and may confound results of serological testing related to passive antibody transfer. Delay administration of live viral vaccines at least three months prior to IVIg. With respect to when to administer a live viral vaccine to the patient or household member of a patient after a patient’s discontinuation of a biologic, the half-life of the biologic should dictate timing, with four half-lives being a conservative guide. Indeed, five half-lives ensures 97 percent clearance of a drug; however, long term effects of the drugs might last beyond five half-lives (for example, rituximab may cause a decrease in B-cell counts for up to a year after a single dose). A rare scenario is brought to light by a recent update to the package insert of infliximab, whereby infants born to mothers taking infliximab should wait six months before receiving live vaccines [3]. We believe this precaution should be applicable to the other biologics barring IVIg.

In general, non-live vaccines (e.g., the human papilloma virus vaccine) can be given safely and effectively during biologic therapy. Study results vary with respect to relative efficacy on and off biologic therapy. However, most agree that biologic therapy does not interfere in a clinically significant way with immunogenicity [4, 5, 6, 7].


Tuberculosis (TB) screening

Pre-therapy and annual TB screening thereafter is encouraged for TNF-alpha and IL12/23 inhibitors. Common practice is to do so with alefacept as well. Increase in TB reactivation is seen in patients treated with infliximab and adalimumab, and less so with etanercept, implying the risk is greatest with TNF antibodies rather than TNF receptor inhibitors [8]. The CDC recommends TB testing prior to starting a TNF blocker [9].

Because of the difficulty of having patients return for their purified protein derivative (PPD) readings and subsequent delays in initiation of therapy and because of potential false-negative PPD readings while on anti-TNF therapy, we employ an interferon-gamma release assay (IGRA) (QuantiFERON®-TB Gold test), which is a blood test done on a single visit. We accept negative readings as true negatives. In spite of manufacturer claims, we have experienced a number of false positive readings with the IGRA. In the event the IGRA is used and is positive, we place a PPD, repeat the IGRA, and perform a chest x-ray (posterior-anterior (PA) and lateral). If repeat IGRA is positive, we consider that a true positive. If repeat IGRA is negative, but PPD is positive, we consider that a true positive. If a PPD is used as the initial screening, a positive PPD is verified with an IGRA and chest x-ray (PA and lateral). A positive IGRA in the face of a positive PPD is considered a true positive. Chest x-rays in both cases are done to rule out active disease.

Patients with positive tuberculosis screens and negative chest x-rays are asked if they have had nine months of isoniazid therapy. Although we do not do so routinely, in this instance one should at least ask the patient about past atypical mycobacterial infections, because these are known causes of a false positive IGRA and PPD [10, 11]. If the patient states so with certainty, we do not in our practice seek medical record verification. Of course, a more conservative approach would be to demand medical-record verification or retreat. If the patient is uncertain, we refer to the pulmonology department for treatment with nine months of isoniazid (or another comparable regimen). In those with treated tuberculosis on biologic therapy, we screen with a chest x-ray (PA and lateral) yearly. In latent TB carriers, National Psoriasis Foundation guidelines suggest waiting until the full course of isoniazid has been finished prior to initiating anti-TNF alpha therapy if practicable. In patients who we deem to be reliable with severe psoriasis and no alternatives, the Guidelines do defend initiation of biologic therapy one month into the isoniazid course (with follow-up to confirm that the patient finishes the nine-month course) [12]. For new converters to latent TB carriage while on biologic therapy, we favor initiating isoniazid with a pulmonologist while continuing biologic therapy (i.e., no one month delay). In those with active TB, we do not initiate therapy until a full course of an appropriate regimen is completed and prefer to avoid anti-TNF therapy altogether if possible [12, 13].


Screening for hepatitis B and C

We try to screen for hepatitis B virus (HBV) at baseline for all biologics except IVIg, but especially in those we feel are high risk. However, only the package inserts for infliximab and rituximab could be interpreted to require it. We screen with hepatitis B surface antigen, surface antibody, and core antigen. A frequent outcome is surface antigen negative, but surface antibody positive AND core antibody positive (indicating a possible carrier state). If core antibody is positive, test HBV DNA. If HBV DNA is positive, we defer anti-TNF therapy and manage with a hepatologist. If HBV DNA negative, there is no need to prophylax with tenofovir or entecavir. Rarely, IVIg given immediately prior to measurement may yield false positive HBV core antibody. Of course, hepatitis B surface antigen positivity indicates either active or chronic infection, in which case we defer anti-TNF therapy while managing with a hepatologist.

If baseline ALT and AST are elevated or if risk factors are identified, we screen for Hepatitis B and C. Indeed, hepatitis C appears to be stable or improve with some TNF-alpha inhibitors [14]. If possible, we avoid infliximab because of its rarely reported hepatotoxicity.


Pregnancy

The TNF-alpha antagonists, ustekinumab and alefacept are pregnancy category B, which expands the options for a pregnant patient with severe psoriasis or psoriatic arthritis. Rituximab and IVIg are pregnancy category C. However, at least one study demonstrated safety of IVIg for pemphigus vulgaris in eight pregnant females [15] and anecdotal drug registry data indicate that rituximab has been used safely in pregnancy as well [16].


Non-melanoma skin cancer

All biologics for psoriasis and psoriatic arthritis appear to increase the incidence of basal cell cancer and squamous cell cancer. To that end, baseline and periodic total body skin exams are warranted for these therapies. The interval varies with the individual dermatologist, but anywhere from 3-12 months seems reasonable. We try to do them every six months.


Malignancy

Where possible, we prefer to avoid biologics in patients with prior histories of malignancy. Little research has been published regarding the risk of inducing a recurrence of previously treated, dormant cancers. As such, we must rely on the known cancer risks as a guide in these patients. TNF-alpha inhibitors are associated with some degree of risk for lymphoma, breast cancer, colorectal cancer, melanoma, leukemia, and head and neck cancers in smokers. Alefacept is associated with solid organ malignancies, lymphomas, and melanomas. Ustekinumab is associated with breast, colon, head and neck, kidney, prostate, and thyroid cancers. Common sense appears to dictate that patients with histories of the above malignancies should avoid the agents with which they have been associated. Our practice has been that in patients in remission from a cancer with a low risk of recurrence (e.g., a completely resected thin melanoma), we proceed cautiously with the use of these therapies. If a patient is in remission with a cancer with a less predictable recurrence rate, consultation with an oncologist is sought for a risk/benefit analysis.


Considerations For TNF-alpha Antagonists

Among the most difficult conundrums encountered when counseling a patient about TNF-alpha inhibitors are whether to consider the risks of any one agent as unique to that agent or to attribute them to the class as a whole. The most onerous risks come from infliximab, in which use with azathioprine is associated with fatal hepatosplenic T-cell lymphoma and use in chronic obstructive pulmonary disease is associated with lung and head and neck malignancy.

Upper respiratory tract infections are the most common infection [14]. Reactivation of latent hepatitis B infection is a concern and should be screened for at baseline (some will screen everyone, others will screen only individuals at risk). Some instances of lymphoma and multiple sclerosis resolve with discontinuation of the drug; however, some are persistent and fatal [14].

Chemistry and CBC monitoring can be done every three months for the first year, then biannually thereafter for all but infliximab, for which monitoring should occur with each infusion [4]. There is wide variability among practitioners in timing of blood monitoring. Incidence of elevated liver enzymes and liver complications is somewhat higher with infliximab than with other TNF-alpha inhibitors [4].

We limit ANA screening to infliximab patients and arguably one could eliminate such screening altogether. However, in the rare instance that a lupus-like syndrome occurs, it is always reassuring and even clinically helpful to have a baseline, pre-biologic ANA on file.

Not all side effects are negative. Some literature suggests that TNF-alpha inhibition improves the risk of coronary artery disease [17, 18]. Such positive information, along with beneficial efficacy profiles for psoriasis and/or psoriatic arthritis, ought to enter into the discussion, especially for those patients metabolically at risk.

Table 2 [3, 14, 19-28] compares the mechanisms of action, indications, dosing, and half-lives of the biologics currently used in dermatology. Tables 3-11 [3, 4, 14, 21-31] present the exhaustive checklist of considerations that the package inserts suggest to do for each drug. Such rigorous full disclosure, screening, and monitoring is both impractical in a busy clinic and unnecessary in light of the themes for counseling cited above. Furthermore, it may raise unnecessary doubts about safety and precipitate refusal of drug by a patient who otherwise might have benefited greatly from it. As such, in bold are the questions and considerations we feel are essential and practical, whereas in normal text are the remainder of the totality of considerations as might be inferred from the package inserts. We take the opinion that idiosyncratic risks associated with individual agents (i.e., risk of head and neck malignancy with history of COPD for infliximab) are unique to that drug and not class effects, but we keep them unbolded in Tables 4-7 for those who take the stance that indeed these risks should be considered a class-effect. With respect to timing of follow up blood counts and chemistries and whether or not to perform hepatitis screening or influenza vaccination, we acknowledge the lack of firm guidance and a wide variation in individual practice. The time points offered reflect our practice and what we feel is reasonable. Table 12 [32-39] contains a comparison of available IVIg preparations in the U.S., mainly created to compare the sugar contents of the various preparations.


Tables Legends:

  1. Table 1. Live vaccines available in the U.S. [2] (Click for PDF)
  2. Table 2. Comparison of biologic agents: mechanisms of action, indications, dosing, and half-lives [3, 14, 19-28] (Click for PDF)
  3. Table 3. Remicade® (infliximab) [3, 4, 14] (Click for PDF)
  4. Table 4. Humira® (adalimumab) [4, 21] (Click for PDF)
  5. Table 5. Enbrel® (etanercept) [4, 14, 21] (Click for PDF)
  6. Table 6. Cimzia® (cetolizumab) [4, 23] (Click for PDF)
  7. Table 7. Simponi® (golimumab) [4, 24] (Click for PDF)
  8. Table 8. Stelara® (ustekinumab) [25] (Click for PDF)
  9. Table 9. Amevive® (alefacept) [26, 29, 30, 31] (Click for PDF)
  10. Table 10. Rituxan® (rituximab) [27] (Click for PDF)
  11. Table 11. IVIg (Gamunex, Gammaguard, others) (Click for PDF)
  12. Table 12. Sugar content of available IVIg preparations in the U.S. (Click for PDF)

References

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