Quality, Safety, and Practical Considerations of Using Biologic Therapies

Fig. 18.1

Practical strategies for improving safety of biologic therapies

Choice of Biologic Agents

There are eight FDA-approved biologic agents to treat IBD, generally indicated for patients with active disease despite conventional therapy or corticosteroids, or for those patients at increased risk for disease complications [7, 8], including five anti-TNF agents. These agents include infliximab (Remicade^®) for CD and UC, adalimumab (Humira^®) for CD and UC, certolizumab pegol (Cimzia^®) for CD, golimumab (Simponi^®) for UC, and one biosimilar to infliximab (Inflectra^®); two integrin receptor antagonists, including natalizumab (Tysabri^®) for CD and vedolizumab (Entyvio^®) for CD and UC; and one anti IL12/23 agent , ustekinumab (Stelara^®) for CD. Anti-TNF-α agents are the most widely used first-line biologic agents, although vedolizumab is an appropriate first-line biologic treatment for UC [7]. The positioning of ustekinumab for CD has yet to be determined in guidelines and clinical practice. The uptake of natalizumab has been limited by an associated small increased incidence of PML. There are no head-to-head prospective, randomized trials of biologic agents to guide decision-making for positioning one anti-TNF over another on the basis of safety or efficacy [9]. The mode of the administration and cost of therapy have become important factors to be considered when choosing a biologic agent. The number and frequency of injections or infusions, the type and ease of injections, access and time for intravenous therapies, and insurance company formulary restrictions can all impact the decision of which biologic to start. Another consideration for distinguishing among biologic therapies is the availability of commercial assays for drug and antidrug antibody assays . Thus, in addition to safety and efficacy considerations, patients should be informed of the advantages and disadvantages of the different options and be involved in the decision as to which biologic may be best for them [10].

Notably, over one-third of patients do not respond to the initial anti-TNF-α agents at all, and among those with an initial response, 23–46% of patients lose response over time [11]. In cases of loss of response to anti-TNF-α therapy, reduction in interval between doses or dose escalation may be appropriate strategies before switching to another agent [12]. Measurement of drug concentration and antidrug antibody levels has been shown to be a cost-effective strategy given the ability to optimize biologic therapies [13]. The use of therapeutic drug monitoring to guide decision-making [14] is beyond the scope of this chapter and is discussed elsewhere (Chap. 8).

Appropriate Administration

Currently, all biologic agents for IBD are administered either by intravenous (IV) infusion or subcutaneous injection. Infliximab is given through IV infusion over 2 h; adalimumab, certolizumab pegol, and golimumab are administered by subcutaneous injection; natalizumab and vedolizumab are given through IV infusion over 30 or 60 min; and ustekinumab is administered via single intravenous loading dose followed by subcutaneous maintenance doses. Quality control around drug handling and administration is critically important for the safe use of biologics. Product mishandling includes exposure to extremes of temperature or pH, agitation, pumping operations, freeze-thawing, and exposure to light, which can cause protein aggregation, potentially triggering immunogenicity in a patient after months of successful treatment, and may contribute to the loss of response and infusion reactions to biologic agents. Thus, clinical staff in infusion centers must carefully follow the product instructions to minimize product degradation [15]. Subcutaneously administered agents also require proper training to patients and/or their caregivers on the right way to prepare and inject these agents. Patients should be comfortable and confident with their ability to self-administer injections at home and to comply with manufacturer instructions regarding the need for appropriate temperature control, light exposure, and undue manipulation/shaking of biologic products.

Before Starting Biologic Therapies

Appropriate Patient Selection

Before starting biologic therapy, contraindications should first be considered. A thorough history should be obtained to exclude any active untreated infection, untreated latent tuberculosis, known hypersensitivity to the biologic agents, and congenital or acquired immunodeficiency [16]. Anti-TNF should not be used in patients with moderate-to-severe heart failure (New York Heart Association [NYHA] functional class III/IV) or a personal history of multiple sclerosis or optic neuritis [3–6]. Integrin receptor antagonists are contraindicated in patients who have or have had progressive multifocal leukoencephalopathy (PML) [17, 18]. Ustekinumab, approved for moderate-to-severe Crohn’s disease, binds to p40, a common subunit of the IL12 and IL23 receptors, and should not be used in those with reversible posterior leukoencephalopathy syndrome (RPLS) [19] (Table 18.1).

Table 18.1

Checklist of contraindications to assess before starting biologic therapy

Contraindications	Anti-TNF	Anti-integrin	Anti IL12/IL23
Any active untreated infection	X	X	X
Untreated latent tuberculosis	X	?	X
Moderate-to-severe heart failure (NYHA class III/IV)	X
Personal history of multiple sclerosis or optic neuritis	X
Known hypersensitivity to biologic agents	X	X	X
Present or prior malignancy or history of lymphoma	?	?	?
Have or have had progressive multifocal leukoencephalopathy (PML)	?	X	?
Have reversible posterior leukoencephalopathy syndrome (RPLS)	?	?	X

Patient Education

Due to the potential serious risks and significant cost of biologic therapies, it is important for patients to make an informed decision after thoroughly understanding potential risks, the benefits to their disease and quality of life, and the high cost associated with these therapies.

Patients should receive adequate education on the expected course of their disease state without biologic therapy, the anticipated benefits to disease activity from appropriate treatment, potential benefit to their quality of life from biologic therapy, and the risks of therapy [20]. Clinicians play a critical role in patient education about the risks of their disease and the benefits and risks of therapy, to facilitate decisions that are in line with their personal preferences for treatment [21]. In addition, patients should be familiar with the medication administration, prescribed regimen, and the importance of treatment adherence. Furthermore, financial implications of treatment should be discussed, given the expense of treatment and the need for maintenance therapy; these can be contrasted to the costs of uncontrolled disease and potential complications [22].

Patient education can take many forms, including face-to-face discussions with the physician and/or nurse, provision of educational materials [20], referral to professional organizations such as the Crohn’s & Colitis Foundation of America (CCFA, http://ccfa.org) and European Crohn’s and Colitis Organisation (ECCO, https://www.ecco-ibd.eu), and reputable Internet sites. Although patients can get reliable and easily understandable information about almost all aspects of IBD from these resources, they should be encouraged to discuss questions and concerns with their prescribing healthcare provider.

Screening Tests

Prior to starting biologic therapy, appropriate screening to identify active and latent infections should be performed. When any active or latent infection such as Clostridium difficile (C. difficile), Cytomegalovirus (CMV), or Epstein-Barr virus (EBV) is identified, biologic therapies should generally be deferred until appropriate treatment has been initiated or until clinical resolution of the active infection.

Anti-TNF Therapy

Before starting anti-TNF therapy , screening for latent tuberculosis (TB) and hepatitis B virus (HBV) should be performed, and doing so is an indicator of good quality of care [23]. In addition, screening for other infections should be considered based on patient-specific factors (i.e., travel to endemic areas for various infectious) and geographic risk (i.e., histoplasmosis in high-risk regions) (Table 18.2).

Table 18.2

Suggested checklist of screening and baseline tests before starting biologic therapy

• Appropriate screening to identify active and latent infections as clinically warranted

• Anti-TNF therapy screening tests

− Latent tuberculosis (TB)—PPD^a skin test or IGRA^btest, CXR as indicated for higher-risk individuals

− Hepatitis B virus (HBV)—HBsAg, HBsAb, HBcAb

• Anti-integrin therapy screening test

− Anti-JCV antibody test (prior to initiation of natalizumab)

− Screening of TB (according to the local practice before vedolizumab)

− Screening of HBV and other hepatitis viruses (provider discretion)

• Anti-IL12/IL23 (ustekinumab)

− Latent tuberculosis (TB)—PPD^a skin test or IGRA^btest, CXR as indicated for higher-risk individuals

• Baseline tests before all biologics

− Complete blood counts, chemistries with liver enzymes, inflammatory markers (sedimentation rate, CRP, with or without fecal calprotectin)

− Consider colonoscopy and/or small bowel imaging, as clinically warranted

^aPurified protein derivative

^bInterferon-γ release assays

Risk factors for latent TB include a prolonged stay (>3 months) in a high TB incidence area, close contact with patients with active TB, radiological evidence of previous TB infection or having undergone previous treatment for active TB or latent TB infection [24]. There are no 100% specific or 100% sensitive methods for diagnosing latent TB infection. All patients should have a tuberculin skin test (TST) or interferon-γ release assay (IGRA) test and a chest X-ray as indicated for higher-risk individuals. It is important to recognize that concurrent immunosuppressive therapies such as corticosteroids are associated with anergy and false-negative skin test results can occur [25]. It is generally recommended to replace the TST with IGRA, which is more specific and sensitive [24]. Patients screening positive for latent TB should begin a 6-month course of antituberculosis therapy prior to initiation of biologic therapy, and while the duration of treatment for latent TB prior to initiation of anti-TNF therapy has not been definitively defined, common practice suggests at least 1 month of antituberculosis therapy prior to anti-TNF therapy is prudent in most cases.

Anti-TNF therapy may increase the risk of reactivation of HBV in patients who are chronic carriers of this virus. Guidelines recommend screening all patients for HBV prior to starting anti-TNF therapy. Serologic assessment for HBV should include hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb) with levels, and hepatitis B core antibody (HBcAb). If active HBV is found, it should be treated and controlled before anti-TNF initiation. In HBsAg + carrier patients, prophylactic antiviral treatment is recommended and ideally started at least 2 weeks prior to the introduction of anti-TNF therapy and continued for at least 6 months after its cessation [23, 26] to reduce the risk of HBV reactivation.

Anti-integrin Therapy

Clinical trial data suggest that anti-integrin therapies overall have a favorable safety profile, with low rates of serious infections over an extended treatment period [27]. However, the occurrence of progressive multifocal leukoencephalopathy (PML) due to reactivation of John Cunningham (JC) virus in approximately 1:1000 patients treated with natalizumab both in clinical trials and in post-marketing surveillance has limited the uptake of natalizumab for Crohn’s disease. Risk factors for PML include positive JCV antibody status at baseline, concomitant immunosuppression, and more than 2 years of exposure to natalizumab [28]. Therefore, testing for JCV prior to starting natalizumab can identify those patients at lowest risk (i.e., negative antibody status) for subsequent PML. Furthermore, patients treated with natalizumab should not be on concomitant immunosuppressives, and those on concomitant steroids should be weaned off of steroids within 6 months of initiation of natalizumab [17].

Although natalizumab and vedolizumab are both anti-integrins that prevent leukocyte adhesion via blockade of α4 integrin, vedolizumab is more selective due to additional β7 inhibition which is specific to leukocyte trafficking to the gut. To date, no cases of PML have been reported in patients receiving vedolizumab [29], and JCV testing is not indicated prior to initiation of vedolizumab therapy.

With regard to tuberculosis, active TB has infrequently occurred in vedolizumab-exposed patients, and all cases occurred in endemic regions. Therefore, while there is likely no TB reactivation risk on vedolizumab, screening for TB should be considered according to the local practice [18], and patients should be asked about exposure to tuberculosis. There were no cases of HBV reactivation in the vedolizumab pivotal trials; however, due to the potential risk of hepatotoxicity among vedolizumab-treated patients [18], screening of HBV and other hepatitis viruses before vedolizumab initiation may be prudent.

Anti-IL12/IL23 (Ustekinumab)

Ustekinumab should generally be avoided in patients with active infections, with special concern for patients at risk for mycobacterial infections and those with Salmonella infection due to increased infection risks among patients genetically deficient in IL12/IL23 [19]. Testing for latent tuberculosis should be performed prior to initiation of ustekinumab.

Baseline Tests

Complete blood counts, chemistries with liver enzymes, and inflammatory markers (sedimentation rate, CRP, with or without fecal calprotectin) should be assessed to establish baseline values prior to starting therapy and periodically during the course of treatment for response and safety [2, 30]. Oftentimes a baseline colonoscopy may be useful to establish disease activity, with a follow-up colonoscopy approximately 6 months later to determine treatment response especially when clinical symptoms do not clearly correlate with endoscopic disease activity [31] (Table 18.2).

Vaccination Strategies

Vaccinations can effectively prevent or reduce the risk of certain infections, particularly among patients with IBD patients treated with immunosuppressive therapies. However, this appears to be significant underutilization of recommended immunizations in the adult IBD population [32, 33].

All patients being considered for biologics should have their vaccination status thoroughly assessed. Inactivated influenza vaccination is recommended annually, and updated guidelines suggest pneumococcal vaccination with both the 23-valent polysaccharide and the 13-valent conjugate vaccines 8 weeks apart [34, 35]. All adults should also undergo vaccination with tetanus toxoid every 10 years [36]. Hepatitis B vaccination should be offered to at-risk nonimmune individuals, and levels of anti-HBs >100 IU/l are advisable to achieve adequate seroprotection when anti-TNF treatment is planned [37]. In addition, HPV vaccination in women and men ≤26 years should be considered, due to increased frequency of abnormal Pap smears in women with IBD on immunosuppressive therapy [38]. Other vaccinations should be administered based on recommended intervals and specific indications, and evaluation of antibodies to some infectious diseases (e.g., varicella) might be performed to determine if specific vaccines are required. In general, live virus vaccines (such as varicella, herpes zoster, measles, mumps and rubella vaccines, BCG vaccine) should be generally avoided while on any biologic therapy [39, 40] (Table 18.3).

Table 18.3

Checklist of recommended vaccinations before starting biologic therapy

• Non-live vaccines (can be given before or during therapy)

− Inactivated influenza vaccination (during “flu” season)

− Pneumococcal vaccination with both the 23-valent polysaccharide and the 13-valent conjugate vaccines, per guidelines

− Tetanus toxoid (if not in prior 10 years)

− Hepatitis B (if not immune)

− HPV (age appropriate)

• Live vaccines (should generally not be administered while on biologic therapy)

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