Secondary Immunodeficiencies and Infectious Considerations of Biologic Immunomodulatory Therapies

Abstract

Biologic immunomodulatory medications have rapidly expanded in the previous decades, providing new treatment options for individuals with a spectrum of oncologic, allergic, rheumatologic, and neurologic conditions. Biologic therapies alter immune function and can impair key host defense mechanisms, resulting in secondary immunodeficiency and increased infectious risks. Biologic medications can increase general risk for upper respiratory tract infections, but can also be associated with unique infectious risks due to distinct mechanisms of action. With their widespread use, providers in every area of medicine will likely care for individuals receiving biologic therapies and understanding of their potential infectious complications can help mitigate these risks. This practical review discusses the infectious implications of biologics by class of medication and provides recommendations regarding the evaluation and screening both prior to therapy initiation and while the patient is receiving the medication. With this knowledge and background, providers can reduce risk while patients receive the treatment benefits of these biologic medications.

Introduction

Biologic immunomodulatory medications, defined here as monoclonal antibodies (mAbs) and fusion proteins, have advanced the treatment landscape of many oncologic, allergic, rheumatologic, and neurologic conditions. For immunologists, biologic modifiers have allowed precision medicine-based therapy for the growing number of monogenic primary immune dysregulation disorders (1).The number of biologics has rapidly expanded in the last two decades and continues to multiply with over 70 monoclonal antibodies used in clinical practice (2). Providers in every specialty will likely encounter and care for patients receiving biologic medications.

The overarching goal of biologic therapies is to restore balance between pro- and anti-inflammatory responses of the immune system. An overabundance of pro-inflammatory response with loss of self-tolerance can result in autoimmune disease, while too much anti-inflammatory response will lead to infectious and neoplastic complications. Biologic medications typically work in three different ways: 1) soluble receptor antagonism acting as decoy receptors inhibiting free cytokines, 2) cell surface receptor antagonist preventing cytokine-mediated receptor activation, and 3) through a combination of soluble cytokine and bound receptor inhibition. Given that biologics target a number of cytokines and cellular interactions within the immune system and can impair important host defense functions (Figures 1 and 2), secondary immunodeficiency and increased infectious risk are important considerations. Providers should be aware of the general and unique infectious risks and preventative measures for the different biologics. Here, we aim to provide for the clinician a practical review of the more widely used biologic medications including their mechanism of action, indication for use, infectious implications, and recommendations for monitoring and screening for infectious complications.

Figure 1.

Overview of cytokine-targeting and anti-IgE biologic immunomodulatory therapies.

Figure 2.

Biologic immunomodulatory therapies targeting key T-cell and B-cell receptors and molecules.

TNF-α Inhibitors

Tumor necrosis factor-α (TNF-α) is a potent pro-inflammatory cytokine of innate immunity and involved in the pathophysiology of a myriad of inflammatory conditions. TNF-α inhibitors (TNFi) were among the first biologics used to treat autoimmune disorders and include mAbs adalimumab, golimumab, infliximab, and certolizumab and the soluble TNF receptor etanercept (Figure 1, Table 1). TNFi are currently approved for treating a range of autoimmune diseases including rheumatoid arthritis (RA), polyarticular juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), psoriasis, psoriatic arthritis (PsA), ankylosing spondylitis (AS), hidradenitis suppurativa, and uveitis (3–8). Though TNFi are highly effective and have revolutionized treatment of many autoimmune conditions leading to improved outcomes, infectious risks are a significant consideration (2, 9, 10). Many factors contribute to an individual’s risk including age, comorbid medical conditions, and use of adjunctive immunosuppressive therapies (9–11).

Table 1.

Infectious Considerations and Recommended Screening for Biologic Agents

Class of Biologic	Reference Product Brand Name	FDA Approved Indications	Unique Infections Considerations	Recommended Screening Prior to Initiation
TNF inhibitors
Adalimumab	Humira	RA, pJIA, Crohn’s disease, UC, psoriasis, PsA, AS, uveitis, hidradenitis suppurativa	Reactivation of LTBI Reactivation of viral hepatitis Less commonly fungal infection	Testing for TB, HBV, HCV, VZV, and HIV Consider stool testing for Clostridiodes difficile and Strongyloides in IBD patients Review vaccination history and provide non-live vaccinations
Certolizumab	Cimzia	RA, Crohn’s disease, psoriasis, PsA, AS
Etanercept	Enbrel	RA, pJIA, psoriasis, PsA, AS
Golimumab	Aria, Simponi	RA, pJIA, PsA, AS, UC
Infliximab	Remicade
IL-1 Inhibitors
Anakinra	Kineret	RA, NOMID, DIRA	Mild upper respiratory tract viral infections	Consider testing for TB Review vaccination history and provide non-live vaccinations
Canakinumab	Ilaris	Systemic JIA, AOSD, CAPS, FMF, HIDS/MKD, TRAPS
Rilonacept	Arcalyst	DIRA, recurrent pericarditis
IL-6 Inhibitors
Tocilizumab	Actemra	RA, giant cell arteritis, pJIA, systemic JIA	Upper respiratory tract viral infections Bacterial skin infections	Consider testing for TB and HBV Review vaccination history and provide non-live vaccinations
Sarilumab	Kevzara	RA
Siltuximab	Sylvant	Castleman’s disease
IL-12/IL-23 Inhibitors
Risankizumab	Skyrizi	Crohn’s disease, psoriasis, PsA	Upper respiratory tract viral infections and nasopharyngitis Monitor for Candida infections	Testing for TB and HBV Review vaccination history and provide non-live vaccinations
Tildrakizumab	Ilumya	Psoriasis
Guselkumab	Tremfya	Psoriasis, PsA
Ustekinumab	Stelara	Crohn’s disease, UC, psoriasis, PsA
IL-17 Inhibitors
Secukinumab	Cosentyx	Psoriasis, PsA, AS, ERA	Upper respiratory tract viral infections Increased risk of Candida infections	Testing for TB Consider antifungal prophylaxis for patients with chronic candidiasis Review vaccination history and provide non-live vaccinations
Ixekizumab	Taltz	Psoriasis, PsA, AS
Brodalumab	Siliq	Psoriasis
IL-4/IL-13 Inhibitors
Dupilumab	Dupixent	Atopic dermatitis, asthma, CRSwNP, EoE, PN	Potential increased risk for parasitic infections	Evaluate and treat for parasitic infections Review vaccination history and provide non-live vaccinations
IL-5 Inhibitors
Mepolizumab	Nucala	CRSwNP, EGPA, HES, severe asthma with eosinophilic phenotype	Potential increased risk for parasitic infections	Evaluate and treat for parasitic infections Review vaccination history and provide non-live vaccinations
Reslizumab	Cinqair	severe asthma with eosinophilic phenotype
Benralizumab	Fasenra	severe asthma with eosinophilic phenotype
Anti-IgE Therapy
Omalizumab	Xolair	Moderate to severe persistent asthma, CSU, nasal polyps	Potential increased risk for parasitic infections	Evaluate and treat for parasitic infections Review vaccination history and provide non-live vaccinations

AS, ankylosing spondylitis; AOSD, adult-onset Still’s disease; CAPS, cryopyrin-associated periodic syndromes; CRSwNP, chronic rhinosinusitis with nasal polyposis; CSU, chronic spontaneous urticaria; DIRA, deficiency of interleukin-1 receptor antagonist; EGPA, eosinophilic granulomatosis with polyangiitis; EoE, eosinophilic esophagitis; ERA, enthesitis related arthritis; FDA, food and drug administration; FMF, familial Mediterranean fever; HBV, hepatitis B virus; HCV, hepatitis C virus; HES, hypereosinophilic syndrome; HIDS, hyperimmunoglobulin D syndrome; HIV, human immunodeficiency virus; IBD, inflammatory bowel disease; IL, interleukin; JIA, juvenile idiopathic arthritis; MKD, mevalonate kinase deficiency; NOMID, neonatal-onset multisystemic inflammatory disease; pJIA, polyarticular juvenile idiopathic arthritis; PN, prurigo nodularis; PsA, psoriatic arthritis; RA, rheumatoid arthritis; TB, tuberculosis; TNF, tumor necrosis factor; TRAPS, tumor necrosis factor receptor associated periodic syndrome; UC, ulcerative colitis; VZV, varicella zoster virus.

Overall infectious risk is different among TNFi, with the highest risk associated with infliximab followed by adalimumab and lowest risk with etanercept (2, 10, 12, 13). Given TNF-α’s key and pleiotropic role in host defense, its inhibition can increase risk for common viral and bacterial infections and, to a lesser extent, opportunistic fungal and rare parasitic infections (11). A French national registry found that 40% of infections were viral, 33% were bacterial, 22% were fungal, and the remaining 4% were parasitic in patients receiving TNFi (14). Herpes simplex virus (HSV), hepatitis B virus (HBV), and varicella zoster virus (VZV) reactivation have been reported and are important considerations when administering TNFi (15, 16). HBV reactivation rates in patients positive for HB surface antigen (HBsAg) are higher with the mAb (12–39%) than etanercept (1–5%) (17). TNF-activated macrophages are critical in phagocytosing and killing mycobacteria and controlling granuloma formation and maintenance (18). Reactivation of latent tuberculosis infection (LTBI) is therefore a well-known concern with TNFi, with the greatest risk occurring with infliximab. One meta-analysis determined the absolute rate of TB infection in RA patients treated with infliximab was 0.7% (10, 19). TNF-α also enhances neutrophil fungicidal activity, and invasive fungal infections have been observed with TNFi use, including Histoplasma, Candida, Pneumocystis, Aspergillus, and Cryptococcus (20).

Given the infectious risk profile of TNFi, clinicians need to perform screening prior to starting treatment. A thorough history should be performed and include vaccination status and special attention for TB exposure and chronic viral infections (21). Testing for TB, HBV, hepatitis C virus (HCV), VZV, and human immunodeficiency virus (HIV) should be completed prior to therapy initiation. Prophylactic anti-HBV therapy is recommended for patients with higher risk of reactivation. Patients treated specifically for IBD may also need stool testing for Clostridiodes difficile and Strongyloides if in a high prevalence area (22). The need for routine vaccinations should be reviewed, and all recommended vaccinations based on age and immune status ideally administered prior to treatment. Vaccine responses may be weakened, and live-attenuated vaccines are typically avoided with TNFi. If disease activity allows, TNFi therapy should be held one dosing interval before and four weeks after live-attenuated vaccine administration (23).

While TNFi have drastically improved the outcomes of patients with several inflammatory conditions, they are not without modest infectious risks. Patients should undergo a thorough infectious history, individualized screening for infection, and optimization of immunization status prior to therapy initiation. Due to their demonstrated effectiveness in many inflammatory conditions, however, the benefit of TNFi therapy outweighs risk when measures are taken to mitigate infectious complications.

IL-1 Inhibitors

The interleukin (IL)-1 pathway is a crucial part of the innate immune system’s response to infection, and dysregulated IL-1 activity also plays a role in autoinflammatory conditions. Three agents that block the IL-1 pathway include anakinra, canakinumab, and rilonacept (Figure 1, Table 1) (2, 24). Anakinra is approved for treatment of RA, neonatal-onset multisystemic inflammatory disease (NOMID), and deficiency of interleukin-1 receptor antagonist (DIRA). Canakinumab is approved for treatment of systemic JIA, adult-onset Still’s disease (AOSD), and several periodic fever syndromes: cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), hyperimmunoglobulin D syndrome/mevalonate kinase deficiency (HIDS/MKD), and TNF receptor associated periodic syndrome (TRAPS). Rilonacept is currently approved for CAPS, DIRA, and recurrent pericarditis.

Studies of patients being treated with IL-1 inhibitors have overall been favorable and reassuring from an infectious perspective. In one large study of RA patients treated with anakinra, infections occurred in 12% of the placebo-treated group compared to 15–17% of those receiving anakinra, with mild respiratory infections being most common (25). Similarly, in studies of anakinra and canakinumab where patients also received concomitant immunosuppression, infections were most commonly upper respiratory tract infections (URTI), with severe infections occurring less frequently (26–29).

Given a potential risk and case reports of TB reactivation with IL-1 inhibition, providers should consider screening for LTBI prior to starting therapy (30). Patients should be up-to-date on all non-live vaccinations according to age (31, 32). Avoiding live vaccinations while receiving IL-1 inhibitors is recommended, so ensuring an individual is up-to-date prior to therapy initiation if disease activity allows would be ideal (33).

Overall infectious risk is small with IL-1 inhibitors, and respiratory infections are the most commonly observed infectious complication. Though overall risk is considered minimal, individuals should be evaluated for their own particular factors such as diabetes, underlying lung disease, or treatment with additional immunosuppression which may increase risk for more serious complications (28, 29, 34) and will also help individualize screening and medication monitoring.

IL-6 Inhibitors

IL-6 is critically important to both innate and adaptive immune responses and is implicated in a number of different acute and chronic inflammatory processes. Given its multifaceted role in the immune system, IL-6 inhibition has been used to treat several different systemic rheumatic inflammatory conditions. (2, 35). Approved IL-6 pathway inhibitors include tocilizumab and sarilumab, mAbs against the IL-6 receptor, and siltuximab, a mAb against the IL-6 cytokine (Figure 1, Table 1). Tocilizumab is approved for RA resistant to first-line disease-modifying antirheumatic drugs (DMARDs), giant cell arteritis, polyarticular and systemic JIA, and cytokine release syndrome from chimeric antigen receptor (CAR)-T cell therapy. Sarilumab is approved for RA resistant to DMARDs, and siltuximab for multicentric Castleman’s disease.

Understanding of the infectious complications of IL-6 inhibitors is largely derived from studies with tocilizumab, where most infections reported are skin and URTIs, without reported cases of TB (36). Though fewer, studies with sarilumab and siltuximab have demonstrated similar findings with upper respiratory infection being most commonly observed (37, 38). When compared to RA patients being treated with TNFi, those receiving tocilizumab had a higher risk of serious bacterial infection and skin and soft tissue infection, but there was no difference for infections requiring hospitalization (39). In contrast to some of the other mAb agents, reactiviating LTBI has not been associated with tocilizumab, and reactivation of viral hepatitis has also not been consistently associated with IL-6 inhibition (9, 40).

Skin and respiratory infections are most commonly observed with IL-6 inhibitors, so providers should pay particular attention to these organ systems prior to initiating therapy and appropriate counseling should be provided to patients. Providers may have a lower threshold to initiate antimicrobial therapy for presumed bacterial pneumonia or cellulitis in patients receiving IL-6 inhibitors. Vaccination history should be reviewed to confirm the patient is up-to-date on all non-live vaccinations according to age (31, 32). Live vaccines should not be administered (23). Some groups do advocate screening for TB and HBV in all patients, but providers may decide to take an individualized approach based on both being rarely observed in studies (41). In summary, IL-6 inhibitors have advanced treatment of numerous inflammatory conditions, but they are not without infectious risk, specifically respiratory and skin infections requiring thorough screening and vigilant monitoring to diminish likelihood of complications.

IL-12/IL-23 Inhibitors

The IL-12 and IL-23 cytokines play a key role in T-cell differentiation and are important drivers in autoimmunity. Currently, three agents selectively block IL-23, and one blocks both IL-12 and IL-23 (Figure 1, Table 1). Risankizumab, tildrakizumab, and guselkumab are mAbs targeting the P19 subunit of IL-23 and are indicated in moderate to severe plaque psoriasis. Ustekinumab is a human IgG1 mAb targeting the P40 subunit of both IL-12 and IL-23 and is indicated for moderate to severe plaque psoriasis, active PsA, and treatment-resistant Crohn’s disease (2).

Since the IL-12/23 pathways are involved in T- and natural killer (NK)-cell activation, it is plausible that IL-12/23 inhibition can increase infection risk, particularly from intracellular pathogens. Recent trials have shown that nasopharyngitis and URTIs are the most common infections with IL-12/23 inhibitor therapy (42). Trials of guselkumab in psoriasis patients, however, showed comparable low rates of nasopharyngitis and URTIs as compared to groups receiving adalimumab and placebo (43–45). Additional studies support minimal risk of intracellular pathogen and viral infections with IL-12/23 inhibitors.

Patients treated with IL-23 inhibitors do not have increased risk of TB and have low rates of TB reactivation (46, 47). In a pooled study assessing the safety of guselkumab and anti-TB treatment, no cases of active TB including reactivation of LTBI were reported in patients with or without LTBI treated for up to 2 years (48, 49). Few cases of HBV reactivation in HBsAg-positive patients and herpes zoster infection have been reported, but these have not been demonstrated in large clinical trials (50).

Inhibition of IL-23 also results in indirect inhibition of IL-17. IL-17 is important in immune defense against fungal and extracellular bacterial infections. Consequently, some studies report an increased incidence of mucocutaneous Candida infections with ustekinumab at 2.3%. The risk of mucocutaneous Candida infections, however, seems to be lower with ustekinumab than with direct IL-17 inhibitors (51, 52).

In conclusion, the data for IL-12/IL-23 inhibitors suggests an increased risk of URTIs. Although the risk of TB and HBV reactivation seems to be low, it is recommended to screen for latent and active TB prior to therapy initiation and antiviral prophylaxis is recommended in HBsAg-positive patients, respectively (2). If possible, routine vaccinations should also be completed prior to starting therapy.

IL-17 Inhibitors

IL-17 is a proinflammatory cytokine produced mainly by CD4+ T helper 17 (Th17) cells and is essential in defense against bacteria and fungi by phagocytic cell recruitment and activation. Th17 cells and IL-17 also play a key role in the pathogenesis of several autoimmune diseases. Secukinumab and ixekizumab are anti-17A mAbs, and brodalumab is an anti-IL17 receptor mAb (Figure 1, Table 1). IL-17 inhibitors are currently approved to treat plaque psoriasis, PsA, and/or ankylosing spondylitis.

Given the role of the IL-17 pathway in antifungal immunity, IL-17 inhibitor therapy is not surprisingly associated with an increased risk of mild candidiasis infection (2, 53). Similar to primary immunodeficiencies with impaired Th17-mediated immunity, IL-17 inhibitors are associated with an increased susceptibility to chronic mucocutaneous candidiasis (CMC) (54). Consistent with previous studies, a recent global real-world observational study found a strong association between IL-17 inhibitors and cutaneous, oropharyngeal, and esophageal candidiasis. Incidence rates were 4–6.5% for brodalumab, 1.7–4.7% for secukinumab, and 3.3–3.6% for ixekizumab. The risk of Candida infection was 4 to 10-fold higher in patients treated with IL-17 inhibitors than in patients treated with TNFi. The Candida infections, however, were successfully treated with antifungals and did not lead to therapy discontinuation, resistant candidiasis, or increased morbidity (51).

IL-17 inhibitors are generally considered safe in patients with LTBI (47). A pooled cohort study of over 12,000 patients treated with secukinumab for 5 years reported 13 patients (0.1%) with LTBI as an adverse effect. Of those 13 patients, 6 had prior positive LTBI and 7 were new findings. No active TB cases were reported. These results suggest that new LTBI is rare during long-term secukinumab treatment (55). Secukinumab has very rarely been associated with opportunistic infections such as herpes zoster, toxoplasmosis, and Mycobacterium avium complex infections (56). Like other biologic agents, two large studies showed an increased risk of URTIs with IL-17 inhibitors (57, 58).

In summary, patients treated with IL-17 inhibitors are at increased risk of Candida infections compared to other biologic agents. The risk of other infections including URTIs and opportunistic infections, however, is similar to other classes. Prior to therapy initiation, screening for latent and active TB is recommended. Additionally, patients should be screened and treated for mucocutaneous candidiasis prior to and during IL-17 inhibitor therapy. Antifungal prophylaxis can be considered in patients with recurrent or chronic candidiasis. More studies, however, are needed to identify potential predisposing risk factors (2, 51).

IL-4/IL-13 and IL-5 Inhibitors and anti-IgE Therapy

Type 2 immune responses are critical for host defense against parasitic infections, and when dysregulated, can underpin allergic inflammation. Type 2 cytokines include IL-4, IL-5, and IL-13, which promote eosinophil recruitment and IgE production (59). Dupilumab is a mAb that inhibits IL-4 and IL-13 signaling by targeting the shared receptor subunit IL-4Rα (Figure 1, Table 1) (59, 60). Mepolizumab, reslizumab, and benralizumab target the IL-5 pathway, and omalizumab is an anti-IgE mAb (Figure 1, Table 1) (59, 60). These medications are approved to treat a spectrum of atopic disorders including, but not limited to, atopic dermatitis, asthma, chronic rhinitis with nasal polyposis, eosinophilic esophagitis, chronic spontaneous urticaria, eosinophilic granulomatosis with polyangiitis, and hypereosinophilic syndrome (59).

There is particular concern for an increased risk of parasitic infection given the importance of type 2 immunity in defending against parasitic infections. While parasitic infections were observed in 2.6% of pediatric patients receiving dupilumab in an RCT for asthma, these infections were mild, did not result in drug discontinuation, and were not considered related to dupilumab by trial investigators (61). In addition, a meta-analysis of RCTs of dupilumab for atopic dermatitis showed that the rate of overall infections was similar to placebo (62–64). Similarly, systematic reviews of RCTs for anti-IL-5 and anti-IgE therapies demonstrated no increased rate of adverse effects compared to placebo (65). Most clinical trials were limited in that they occurred in modern settings and excluded individuals with parasitic infections. To better address the concern, a RCT of omalizumab was conducted in subjects with asthma and allergic rhinitis with a high risk of geohelminth infection (66). There was slightly increased, but not statistically significant, risk for acquiring a parasitic infection compared to placebo (66).

Prior studies have showed an increase rate of HSV exacerbation with dupilumab. In a pooled data analysis of seven RTCs of dupilumab in atopic dermatitis, rates of HSV infections were slightly higher with dupilumab and mostly due to oral herpes. Clinically important infections like eczema herpeticum and zoster were less common with dupilumab (67).

For agents targeting type 2 cytokines and IgE, safety has been demonstrated and infectious complications are overall rare. There is limited data regarding the safety and efficacy of live vaccines with these agents, but it is generally recommended to complete all age-appropriate vaccinations prior to initiating treatment and to avoid live vaccines during treatment. Although there is no robust evidence of increased risk, evaluation and treatment for parasitic infections should be considered prior to starting therapy. Patients with recurrent HSV may also benefit from antiviral prophylaxis.

Anti-T-Lymphocyte Therapies

T-lymphocytes coordinate and regulate cell-mediated adaptive immunity and are paramount in response to intracellular organisms such as viruses, mycobacteria, and fungi (2). Basiliximab is the one T-cell-targeted therapy marketed as an immunosuppressive agent. Basiliximab prevents T-lymphocyte activation by antagonism of CD25, the alpha subunit of the IL-2 receptor (Figure 2). Its only indication is for induction therapy in patients undergoing renal transplant (68). Basiliximab’s infectious risk is difficult to fully ascertain since it is typically used in conjunction with other immunomodulatory therapies. Studies in renal and liver transplant have had favorable findings when examining basiliximab versus placebo, with no increase in infection rates after addition of basiliximab (69–72).

Abatacept is another T-lymphocyte therapy and is a fusion molecule consisting of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the Fc portion of IgG1. Abatacept prevents T-cell activation by blocking the costimulatory signal between antigen-presenting cells and T-cells (Figure 2) (73). It is approved for use in RA, PsA, and JIA.

Reported infections with abatacept are largely respiratory and skin infections with common organisms. In one large meta-analysis, the rate of infection with abatacept was 3% versus 1.9% in the placebo group (74). In a cohort study comparing abatacept to other biologics, there was no significant difference in risk of serious bacterial infection in the abatacept group compared to individuals receiving other biologics (75). There are several reports of HBV reactivation in individuals receiving abatacept (76–78). Regarding TB, there seems to be an exceptionally minimal risk of TB reactivation with abatacept therapy (79, 80).

Given that basiliximab is not typically used as a single agent, infection prevention strategies do not need to be altered with addition of basiliximab based on the available evidence. Patients starting or receiving abatacept should be counseled on general infection prevention strategies. Depending on the individual, HBV serologies should be considered. There is no data to support the need for TB screening prior to abatacept initiation (2).

Overall, the rates of viral, bacterial, or fungal infections have been observed to be no different with basiliximab compared to placebo. Abatacept is associated with small risk of infection, particularly skin or respiratory tract infections. Providers should be aware of the potential for HBV reactivation in patients on abatacept and provide appropriate monitoring and counseling. Vaccination history should be reviewed to optimize vaccinations prior to initiating therapy, and live vaccinations should be avoided while on therapy (23).

Anti-B-Lymphocyte Therapies

B-lymphocytes are vital in adaptive immunity with main functions including immunoglobulin production, antigen presentation, and T-cell activation/regulation (2). Given their broad functions, B-lymphocytes have a key role in immune response to viral, bacterial, and fungal infections. Anti-B-lymphocyte therapies include six monoclonal antibodies. Rituximab, ocrelizumab, ofatumumab, and obinutuzumab are mAbs directed against the CD20 antigen (Figure 2). Inebilizumab works against CD19 found primarily on B-cell precursors, and belimumab targets B-cell-activating factor (BAFF) which promotes formation and survival of memory B-cells and plasma cells (Figure 2). These agents are primarily approved for the treatment of several oncologic and autoimmune conditions.

The risks and type of infectious complications are similar across this drug group except for belimumab. By neutralizing BAFF, belimumab reduces B-cell differentiation and survival, but does not fully deplete B-cell numbers. This may be a reason belimumab has lower infectious risks than the B-cell depleting therapies. The overall rates of serious infection reported with belimumab are comparable to rates with placebo (81, 82). This contrasts with the remaining agents in this group where infectious risks are more significant.

Of the B-lymphocyte targeting therapies, rituximab has been studied the most in depth regarding infectious complications. Given the similar target and mechanism of action, however, the infectious risks are considered similar across agents. Reported risk does vary based on indication, with higher rates observed for treatment of hematological malignancy than autoimmune disease which is likely due to higher cumulative dose and more concomitant immunosuppressive therapy (83–85). The indication for treatment will also likely impact screening and monitoring.

Rituximab carries an FDA black box warning for HBV reactivation. HBV reactivation occurs less often in those with autoimmune disease being treated with rituximab as compared to malignancy with one long term study of 3,595 RA patients not having a single case of HBV reactivation (86, 87). The rates of HBV reactivation vary greatly based on indication and concomitant immunosuppressive therapy. Rituximab also has an FDA black box warning for progressive multifocal leukoencephalopathy (PML). In one large report of confirmed PML cases in patients who received rituximab, reported occurrence was very low in RA patients with 2.56 cases per 100,000 with RA (88).

Apart from viral infections and reactivation, bacterial infections are a concern in patients receiving anti-B-lymphocyte therapies. Bacterial infections were the most common infectious complication of patients treated with rituximab for malignancies, with Escherichia coli and coagulase-negative staphylococci being the two most common organisms (89). Other types of infections have been reported as well. Fungal infections are uncommon with rituximab though Pneumocystis pneumonia has been reported in case reports and case series and other studies finding increased risk in lymphoma patients (90–92). Unlike many other biologic agents, TB is a rare complication (93).

Hypogammaglobulinemia following B-cell-depleting therapy may include low IgG, IgM, and/or IgA levels. A subset of children and adults develop secondary immunodeficiency and persistent hypogammaglobulinemia and failure of B-cell recovery which can persist for years, predisposing to serious infections and potentially requiring immunoglobulin replacement (94). One large study of children and young adults receiving rituximab demonstrated 13% with low IgG levels and 33% had persistently low IgM levels one year after stopping rituximab (95). Possible risk factors for developing persistent or symptomatic hypogammaglobulinemia include low immunoglobulin levels at baseline, cumulative dose, and concomitant immunosuppression (96, 97).

Prior to initiation of therapy, screening for HBV infection given the risk of reactivation and screening for HCV infection are recommended. This can guide the need for any vaccinations or if antiviral therapy is indicated. Routine vaccinations should be up-to-date prior to starting therapy, ideally giving vaccinations several weeks before therapy initiation. Live vaccinations are contraindicated while receiving anti-B-lymphocyte therapies (23). Immunoglobulin levels and B-cell numbers should be monitored prior to, during, and after treatment.

Though anti-B-lymphocyte agents are effective for several oncologic and autoimmune conditions, they are associated with secondary immunodeficiency including persistent hypogammaglobulinemia and increased infectious risk including bacterial infection, viral hepatitis reactivation, and PML. Providers must be vigilant about the patient’s individual risk factors with close monitoring while patients are receiving this therapy.

Conclusion

Biologic immunomodulatory therapies have contributed to a paradigm shift and revolutionized the treatment of numerous inflammatory conditions over the preceding decades. While their therapeutic effectiveness is absolute, appropriate vigilance is necessary due to safety concerns with the potential for secondary immunodeficiency and increased infectious risk. There is a general increased infectious risk as well as specific risk profiles given the unique mechanisms of action for the different classes. Although not covered in this review, another area of rapid growth is small molecule inhibition including janus kinase (JAK) inhibitors and proteasome inhibitors each with their own unique infectious risk profiles (98, 99). As immunomodulatory therapies continue to expand, providers caring for patients receiving biologic and other immunomodulatory medications should familiarize themselves with the associated risks and the recommended or required screenings prior to use. Other individual risk factors such as concomitant immunosuppressive therapy, age, and comorbid medical conditions should also factor into determination of risk and screening. Ultimately, the benefit of these therapies must be weighed with each agent’s risk profile. With appropriate screening and monitoring, these risks can be mitigated, and patients can safely and effectively receive biologic agents.

Key Messages.

• Biologic immunodulatory medications have rapidly expanded in the previous decades and are approved for a wide variety of conditions, necessitating providers familiarize themselves with their indications and individual risks and side effects.

• Biologic medications target different pathways in the immune system and can impair host defense mechanisms, causing potential secondary immunodeficiency and increased risk of infection. The infectious risks and typical pathogens differ depending on the specific agent and its mechanism of action.

• Infectious risks with biologic medications can be mitigated by a comprehensive evaluation prior to therapy initiation and should include a thorough history of existing comorbid medical conditions, history of infections, screening for appropriate infections, assessment of risk for future infection, review of vaccination history, and optimizing immunization status.

• Treatment of secondary immunodeficiency and infections due to biologic medications may include timely antimicobrial therapy, antimicrobial prophylaxis, and possibly immunoglobulin replacement when indicated.

Abbreviations/Acronyms:

AOSD

adult-onset Still’s disease

AS

ankylosing spondylitis

BAFF

B-cell activating factor

CAPS

cryopyrin-associated periodic syndromes

CAR

chimeric antigen receptor

CMC

chronic mucocutaneous candidiasis

CTLA-4

cytotoxic T-lymphocyte-associated antigen 4

DIRA

deficiency of interleukin-1 receptor antagonist

DMARDs

disease-modifying antirheumatic drugs

FMF

familial Mediterranean fever

HBV

hepatitis B virus

HBsAg

hepatitis B surface antigen

HCV

hepatitis C virus

HIDS

hyperimmunoglobulin D syndrome

HIV

human immunodeficiency virus

HSV

herpes simplex virus

IBD

inflammatory bowel disease

Ig

immunoglobulin

IL

interleukin

JIA

juvenile idiopathic arthritis

LTBI

latent tuberculosis infection

mAb

monoclonal antibody

MKD

mevalonate kinase deficiency

NK

natural killer

NOMID

neonatal-onset multisystemic inflammatory disease

PML

progressive multifocal leukoencephalopathy

PsA

psoriatic arthritis

RA

rheumatoid arthritis

RCT

randomized controlled trial

Th17

T helper 17

TB

tuberculosis

TRAPS

tumor necrosis factor receptor associated periodic syndrome

TNF-α

tumor necrosis factor α

TNFi

tumor necrosis factor inhibitor

URTI

upper respiratory tract infection

VZV

varicella zoster virus