Version May 2024
INTRODUCTION — Biologic agents are a rapidly expanding therapeutic strategy for a wide range of medical conditions. These targeted approaches have improved outcomes for many chronic diseases but, at the same time, induce unique immunologic deficits that may increase the risk for common and opportunistic infections.
This topic provides an overview of the various classes of biologic agents along with janus kinase (JAK) inhibitors, their associated infections, and approaches to mitigate risk. The number of biologic agents is constantly expanding; the more commonly used nononcologic biologic agents are discussed here.
A more detailed overview of the mechanism of action and the secondary immunodeficiency caused by many of these agents is found elsewhere. (See "Overview of biologic agents in the rheumatic diseases".)
GENERAL PRINCIPLES
Immunologic mechanisms — Biologic agents are designed to interfere with the biological activity of a component of the immune system, typically a cytokine or a cellular receptor. Cytokines are soluble proteins that interact with immune cells to control proinflammatory responses, cellular activation, and cell migration. Cell receptors reside on the surface of immune cells and can initiate cellular activation or drive cell migration upon recognizing their respective cognate ligand. By interfering with the normal activities of these molecules, biologic agents disrupt signaling pathways that drive activation and migration of immune cells to sites of infection, thereby interfering with the host immune response and increasing risk for infection.
Many biologic therapies are associated with an increased risk of opportunistic infections. As an example, in a meta-analysis of 70 randomized controlled trials that included over 32,000 patients with rheumatoid arthritis, use of a biologic agent (tumor necrosis factor [TNF]-alpha inhibitors, anakinra, tocilizumab, abatacept, and rituximab) was associated with higher incidence of opportunistic infections compared with placebo (odds ratio [OR] 1.79, 95% CI 1.17-2.74; one additional opportunistic infection for every 582 patients treated with a biologic agent) [1]. Consequently, we test and/or vaccinate for certain latent and/or chronic infections prior to the start of these biologic agents.
Pretreatment infectious testing — Biologic agents can increase the risk for serious and potentially fatal infections from bacteria, viruses, fungi, and occasionally parasites [1-5]. The risk varies depending on the type of immunosuppressive agent, the condition being treated, and the concomitant use of other immunosuppressants (eg, corticosteroids). For some conditions, there may be additional infectious testing necessary (eg, cytomegalovirus [CMV] in select cases of ulcerative colitis) for diagnostic purposes.
●Baseline testing – Baseline testing for some latent infections is recommended prior to initiating therapy with many of the medications in this section. In general, most of the biologic agents discussed here warrant testing for the following infections:
•Tuberculosis infection (TBI), previously known as latent tuberculosis infection (table 1 and algorithm 1 and algorithm 2) (see "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)")
•Hepatitis B virus (HBV) (algorithm 3) (see "Hepatitis B virus: Screening and diagnosis in adults", section on 'Approach to screening and testing')
•Hepatitis C virus (HCV) (algorithm 4) (see "Screening and diagnosis of chronic hepatitis C virus infection")
For patients who do not have a negative human immunodeficiency virus (HIV) test documented in their records or are at increased risk of acquiring HIV (eg, men who have sex with men, engagement in sex work), the pretreatment infectious testing process is a good opportunity to provide routine HIV screening prior to the initiation of immunosuppression. (See "Screening and diagnostic testing for HIV infection", section on 'Preferred approach'.)
Specific testing recommendations for each biologic agent are discussed in the corresponding sections below.
●Management of identified infections – If any infections are discovered on pretreatment testing, we treat the underlying infection and hold off on starting the biologic agent until the infection is controlled, if possible. Close monitoring is paramount to make sure there is no worsening of the underlying infection once the biologic agent is started.
•Tuberculosis infection – Those who test positive for TBI warrant tuberculosis (TB) treatment prior to initiating the biologic agent. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection".)
•Hepatitis B – Those who test positive for chronic HBV infection may require antiviral prophylaxis to prevent HBV reactivation while they are on the biologic agent. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
Timing of vaccinations
Prior to initiating biologics — We make sure that all patients initiating biologics have age-appropriate routine vaccinations (including severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] vaccine series and annual influenza vaccination, if applicable) completed prior to starting therapy when feasible, because some vaccinations may be less effective during and after therapy or may be contraindicated (eg, live vaccines) (figure 1) [6-9]. Routine vaccinations should be administered at least two weeks before starting these immunomodulatory therapies if possible, and timing should be extended to at least four weeks for live vaccines (table 2) [10,11]. Although concrete efficacy data are limited, therapeutic agents that target down-regulation of immune responses (eg, antigen presenting cells [dendritic cells and macrophages], T cells, and B cells) could potentially impair the immunogenicity and/or effectiveness of newly administered vaccines.
Additional recommended vaccinations for some biologic agents may include:
●Pneumococcal vaccination (see "Immunizations in autoimmune inflammatory rheumatic disease in adults", section on 'Pneumococcal vaccines' and "Pneumococcal vaccination in adults", section on 'Approach to vaccination')
●Varicella/herpes zoster vaccination – Generally, assessing for prior varicella zoster virus (VZV) infection by history and/or medical records is sufficient to document prior exposure to VZV. If a patient has been exposed to VZV (either by vaccination or by natural infection), we administer the nonlive recombinant zoster vaccine (RZV) to adult patients at least two weeks prior to initiating immunosuppressive therapy.
If a patient has never been exposed to varicella, some experts administer the live VZV vaccine, barring any contraindications, with the goal to complete the whole series at least four weeks prior to initiating immunosuppressive therapy, while others administer RZV irrespective of prior exposure history. (See "Vaccination for the prevention of shingles (herpes zoster)", section on 'Immunocompromised persons' and "Vaccination for the prevention of chickenpox (primary varicella infection)", section on 'Immunocompromised hosts'.)
During treatment with biologics — Vaccination with nonlive vaccines during therapy may be considered if the benefit of vaccination outweighs the risk (eg, annual influenza vaccination) [12,13]. Although vaccine efficacy may be attenuated, the humoral response often remains intact, and some protective antibody levels can be achieved.
When possible, vaccination should be given at the nadir of immunosuppression. This is often achieved by administering the nonlive vaccine midcycle of each dose interval (eg, at two weeks for a four-week dose interval). In general, we do not hold back treatments required for managing the associated chronic medical condition in order to optimize immune responses. However, with some treatments, such as rituximab, one can consider temporary discontinuation of the drug [9]. If treatment is discontinued, the length of time should be guided by the drug's pharmacokinetics and the expected time to immune recovery, as there are limited real-world data to provide specific guidance for this practice for any given drug.
Live vaccinations are typically contraindicated while receiving biologic agents. Specific vaccination recommendations for each biologic agent are discussed in the corresponding sections below.
Further detailed discussion of vaccine administration timing while the patient is taking immunosuppressive therapy for rheumatic diseases is found elsewhere. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".)
Active infections during treatment — In the event of a new serious infection while on treatment, the biologic agent should be stopped while the infection is treated [14]. Therapy can resume after the active infection is controlled, with close monitoring. If active M. tuberculosis infection is diagnosed during therapy, many of the drugs discussed in this section should be discontinued while treatment is initiated [15-21]. This is discussed in detail elsewhere. (See "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors", section on 'Management'.)
Differentiating symptoms of infection versus medication adverse effects — Often, it may be difficult to distinguish symptoms of infection from symptoms caused by adverse effects of the biologic agent [22]. Since many drugs discussed here predispose a patient to infections, it is important to complete a comprehensive evaluation for infection prior to attributing the patient's symptoms to the medication.
TUMOR NECROSIS FACTOR (TNF)-ALPHA INHIBITORS (TNFI) — TNF is a pleiotropic cytokine that is an important component of innate immunity. TNF receptor binding leads to the release of proinflammatory cytokines, chemokines, and adhesion factors. The primary TNFi that have been US Food and Drug Administration (FDA)-approved are monoclonal antibodies (mAbs; eg, infliximab, adalimumab, certolizumab, and golimumab) and engineered antibody fragments (certolizumab pegol), which function by binding and inhibiting soluble and membrane-bound TNF. Etanercept is a fusion protein that acts as a soluble TNF receptor to bind TNF. TNFi therapies disrupt the immune system's capacity to clear intracellular pathogens and those sequestered in granulomas. (See "Overview of biologic agents in the rheumatic diseases", section on 'TNF inhibition' and "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors".)
●Risk of infection – Treatment with TNFi predisposes individuals to the following infections (table 3) [23-29]:
•Tuberculosis (TB) and other mycobacterial infections
•Listeria monocytogenes, Nocardia spp, and Legionella spp
•Hepatitis B virus (HBV) and hepatitis C virus (HCV)
•Herpes zoster virus
•Endemic mycoses
•Candidal infections
•Cryptococcal infection
•Aspergillosis
•Toxoplasmosis (rare)
•Common viral and bacterial infections (sinopulmonary infections, pneumonia, urinary tract infections, cellulitis)
TNFi particularly predispose an individual to acquisition and/or reactivation of mycobacterial infections (including TB), hepatitis B, and endemic mycoses such as histoplasmosis. Detailed discussions of the risk of infections seen with TNFi are discussed separately. (See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections" and "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors".)
●Pretreatment infectious testing – We test patients initiating TNF inhibitors for tuberculosis infection (TBI) (algorithm 1), HBV (algorithm 3), and HCV (algorithm 4 and table 3). In regions endemic to specific mycoses, we obtain history of symptoms that would suggest active or recent infection in the past two years and inquire about potential exposures. In patients with risk factors of being exposed to histoplasmosis in the last two years, we obtain a chest radiograph (see "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections", section on 'Histoplasmosis'). In coccidioidomycosis endemic regions, we obtain coccidioides serology to test for previous exposure to Coccidioides spp. (See "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients", section on 'Patients receiving immunomodulatory agents'.)
●Vaccinations – We administer the routine and additional vaccinations (pneumococcal and varicella/herpes zoster vaccines) for individuals starting TNFi, as discussed above (table 3) (see 'Timing of vaccinations' above). Vaccine responses may be attenuated while on therapy.
ABATACEPT — Abatacept is an anti-T cell therapy that inhibits the costimulatory signal by competitively interacting with CD80/CD86 on antigen-presenting cells, blocking binding to T cell-expressed CD28. This prevents T cell activation and proinflammatory cytokine release. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Abatacept'.)
●Risk of infection – Although abatacept is not thought to be severely immunocompromising, it may predispose individuals to the following infections [26-29] (table 3):
•Tuberculosis (TB) and other mycobacterial infections
•Hepatitis B virus (HBV) and hepatitis C virus (HCV)
•Epstein-Barr virus and cytomegalovirus (CMV) infection
•Common viral and bacterial infections (sinopulmonary infections, pneumonia, urinary tract infections, cellulitis)
Abatacept does not appear to greatly increase the risk of infectious complications in most patients. A 2009 meta-analysis of five trials that included 2945 patients found similar rates of serious infection with abatacept compared with placebo (2.5 versus 1.7 percent) [30]. In another compilation of eight clinical trials of patients with rheumatoid arthritis, there was no difference in the infection rate between patients receiving abatacept versus placebo [31]. However, case reports and small retrospective analyses have demonstrated reactivation of hepatitis B with use of abatacept [26-29]. Using a Medicare database of patients with rheumatoid arthritis who had prior treatment with a biologic agent, the risk of infections in hospitalized patients was significantly higher for tumor necrosis factor-alpha inhibitors (TNFi) and rituximab compared with subjects receiving abatacept [32]. (See 'Tumor necrosis factor (TNF)-alpha inhibitors (TNFi)' above and 'Anti-B cell agents' below.)
The safety of abatacept was assessed in several trials [5,33]. Serious infections occurred at an incidence rate of 4.3 per 100 person-years. The most frequent infections were pneumonia, bronchitis, cellulitis, and urinary tract infections. The increased risk of respiratory tract infections mostly occurred in patients with underlying pulmonary disease (eg, chronic obstructive pulmonary disease).
●Pretreatment infectious testing – We test patients initiating abatacept for TBI (algorithm 1), HBV (algorithm 3), and HCV (algorithm 4 and table 3).
●Vaccinations – We administer the routine and additional vaccinations (pneumococcal and varicella/herpes zoster vaccines) for individuals starting abatacept, as discussed above (table 3) (see 'Timing of vaccinations' above). Vaccine responses may be attenuated while on therapy.
ANTI-B CELL AGENTS — Rituximab and other anti-B cell antibodies (eg, ocrelizumab, ofatumumab) are monoclonal antibodies (mAbs) that bind to the CD20 receptor on B cells [34], resulting in B cell depletion. Belimumab confers less risk of infection because it prevents activation of B cells instead of depleting them [35].
Class-wide risk assessment
●Risk of infection – Treatment with anti-B cell agents predisposes individuals to the following infections [36-42] (table 4):
•Tuberculosis (TB) and other mycobacterial infections
•Hepatitis B virus (HBV) [43,44] and hepatitis C virus (HCV)
•Herpes zoster virus
•Epstein-Barr virus and cytomegalovirus (CMV) infection
•Severe coronavirus disease 2019 (COVID-19) [45-47] (except belimumab)
•Progressive multifocal leukoencephalopathy (PML; mostly rituximab, although has been reported with belimumab)
•Endemic mycoses
•Cryptococcal infection
•Pneumocystis pneumonia (only rituximab) [48]
•Common viral and bacterial infections (sinopulmonary infections, pneumonia, urinary tract infections, cellulitis) [49]
Out of all the anti-B cell agents, rituximab is associated with the highest risk of serious infections, while belimumab is associated with the lowest risk for serious infections.
Risk is highest for hepatitis B reactivation. For patients with evidence of active HBV (positive surface antigen) or inactive HBV (positive core antibody, negative surface antigen), we try to avoid anti-B cell agents when possible. If treatment with an anti-B cell agent is necessary, HBV prophylaxis should be initiated prior to treatment to prevent HBV reactivation (see "Hepatitis B virus reactivation associated with immunosuppressive therapy", section on 'Preventing HBV reactivation'). If HBV reactivation is detected, therapy with the CD20 inhibitor should be stopped temporarily until antiviral therapy is initiated and HBV deoxyribonucleic acid (DNA) and alanine aminotransferase decrease to lower levels. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
Infection with SARS-CoV-2 has been a serious complication for those on anti-CD20 therapies, which increases the risk of COVID-19-related hospitalization and death [45,46]. Patients with SARS-CoV-2 infection should be promptly evaluated for treatment. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Treatment with COVID-19-specific therapies'.)
People with HIV receiving anti-CD20 therapies should be closely monitored and strictly adhere to antiviral therapy; guidelines recommend withholding anti-CD20 therapies in patients with a CD4 cell counts ≤50 cells/microL [50].
The risk of infection is increased when CD20 inhibitors are used in the context of hematological malignancies [51] or solid organ transplants [52,53] compared with the treatment of autoimmune disorders [54]. There is also a risk of developing hypogammaglobulinemia while taking rituximab, which can further increase infection risk. (See "Secondary immunodeficiency induced by biologic therapies".)
●Pretreatment infectious testing – We test patients initiating anti-B cell agents for tuberculosis infection (TBI) (algorithm 1), HBV (algorithm 3), and HCV (algorithm 4 and table 4).
●Vaccinations – We administer the routine and additional vaccinations (pneumococcal and varicella/herpes zoster vaccines) for patients starting anti-B cell agents, as discussed above (table 4) (see 'Timing of vaccinations' above). Vaccine responses may be attenuated while on therapy and for 6 to 12 months after cessation of therapy. When administering nonlive attenuated vaccines (with the exception of the annual influenza vaccine) during rituximab therapy, one can optimize immunogenicity by administering the vaccine at the time the rituximab dose is due and holding rituximab for at least two weeks after vaccination, if disease activity allows [9].
Drug-specific risks
Rituximab — Rituximab is a mAb that binds to the CD20 receptor on B cells [34], resulting in B cell depletion. It also disrupts B and T cell interactions, resulting in impaired cellular immunity and increased risk of viral reactivation [55] (see "Rituximab: Principles of use and adverse effects in rheumatoid arthritis"). Usage in the setting of malignancy is reviewed in other chapters. (See "Treatment protocols for lymphoma".)
Out of all the anti-B cell agents, rituximab is associated with the highest risk of serious infections, especially with HBV reactivation. Some experts choose to initiate Pneumocystis spp prophylaxis in patients taking rituximab monotherapy, although the absolute risk is low (see "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Indications'). PML has been observed in patients taking rituximab, but the absolute risk is quite low [56]. There are no recommendations to test for John Cunningham virus (JCV) antibody prior to initiating rituximab. Rituximab should be discontinued if PML is suspected and/or confirmed.
In addition to increasing risk of bacterial, viral, and fungal infections, rituximab is also associated with attenuated response to vaccines administered during and after discontinuation of the drug [57]. This phenomenon is due to the prolonged time needed for the repletion of B cells within the body. On average, it typically requires six to nine months after discontinuing rituximab for B cells numbers to return to normal [48]. In a study of 120 patients with different types of vasculitides, B cell recovery occurred over a range of 8 to 44 months [58]. Even after normalization of B cell numbers, vaccine response may be attenuated. In a study of 75 patients who received four injections of rituximab or placebo over one month, titers to vaccines administered 12 months after rituximab therapy were lower in patients who received rituximab versus placebo [59].
Pre-existing immunity to vaccinations administered previously is not affected by treatment. As an example, in a study of 75 patients with type 1 diabetes treated with four injections of rituximab or placebo over one month and then followed for 12 months (ie, a period sufficient for B cell recovery), measles, mumps, and rubella titers before rituximab and after were unchanged between the rituximab group and placebo [59].
Additionally, some degree of transient hypogammaglobulinemia is common and rituximab can also cause "late-onset" neutropenia, appearing one to five months after the end of therapy, which is reviewed separately. (See "Drug-induced neutropenia and agranulocytosis", section on 'Rituximab' and "Secondary immunodeficiency induced by biologic therapies".)
Ocrelizumab — Ocrelizumab is a humanized monoclonal anti-CD20 antibody therapy that triggers antibody-dependent cellular cytolysis. This will deplete circulating immature and mature B cells, not the CD20-negative plasma cells [60,61].
Ocrelizumab has been associated with a higher risk of infection in comparison to interferon-beta and placebo for treatment of multiple sclerosis. In phase II trials, ocrelizumab was associated with higher rates of nonserious infections, including upper respiratory tract infections, nasopharyngitis, urinary tract infections, skin infections, and herpesvirus infections [43,49]. Cases of osteomyelitis, urosepsis, cystitis, and pyelonephritis have been reported [49]. Additionally, there is a possible correlation between ocrelizumab administration and more severe COVID-19 outcomes [47]. Opportunistic infections appear relatively infrequently, except for serious HBV infections [43]. At least one case of PML was associated with ocrelizumab monotherapy in a patient without prior immunosuppressive therapy [62].
Ofatumumab — Ofatumumab is a fully human monoclonal anti-CD20 monoclonal antibody, which targets a distinct epitope on the CD20 molecules of B cells and induces apoptosis [63]. Limited information is available from clinical studies on the immune effects of this drug. In one uncontrolled trial of 33 patients with chronic lymphocytic leukemia, 51 percent experienced infections, although most were mild or moderate [40]. Reactivation of hepatitis B has also been reported.
Belimumab — Belimumab, a mAb that inhibits B cell activating factor, reduces B cell development and survival [64]. Compared with the other anti-B cell treatments and rheumatic disease immunomodulators, belimumab is less likely to increase the risk for serious infections, because it prevents activation of B cells but does not deplete them [35]. Belimumab treatment does not appear to substantially impact the risk for severe COVID-19 [65] or reduce the immune response to vaccination [66]. A low incidence of PML has been observed in patients taking belimumab [56].
Others — Obinutuzumab and inebilizumab are other anti-B cell agents. Although data on these agents are limited, we expect similar risks for infection compared with other anti-B cell agents and provide the same pretreatment testing and vaccinations for patients initiating these agents as other anti-B cell agents.
JANUS KINASE (JAK) INHIBITORS — The JAK-signal transducer and activator of transcription pathway transduces cytokine signaling, making it critical to inflammatory responses [67-69]. The JAK family is comprised of four members: JAK1, JAK2, JAK3, and tyrosine kinase 2. Each cytokine receptor requires a pair of two associated JAKs to signal through the cytokine receptor. These kinases are important for proper immune function and hematopoiesis due to their effect on the signaling of numerous cytokines and growth factors [70]. JAK inhibitors include ruxolitinib, baricitinib, tofacitinib, upadacitinib, and filgotinib. (See "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders".)
Class-wide risk assessment
●Risk of infection – Treatment with JAK inhibitors predisposes individuals to the following infections [71-76] (table 3):
•Tuberculosis (TB) [77,78] and other mycobacterial infections
•Hepatitis B virus (HBV) [79] and hepatitis C virus (HCV)
•Herpes zoster virus
•Epstein-Barr virus and cytomegalovirus (CMV)
•Progressive multifocal leukoencephalopathy (PML)
•Endemic mycoses
•Cryptococcal infection
•Pneumocystis pneumonia
•Common viral and bacterial infections (sinopulmonary infections, pneumonia, urinary tract infections, cellulitis) [68,78]
●Pretreatment infectious testing – We test patients initiating JAK inhibitors for tuberculosis infection (TBI) (algorithm 1), HBV (algorithm 3), and HCV (algorithm 4 and table 3). In coccidioidomycosis-endemic regions, we also obtain Coccidioides serology if the individual will be starting ruxolitinib, based on observational data that this agent predisposes patients to reactivation of previous Coccidioides infection. (See "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients", section on 'Patients receiving immunomodulatory agents'.)
●Vaccinations – We administer the routine and additional vaccinations (pneumococcal and varicella/herpes zoster vaccines) for patients initiating JAK inhibitors, as discussed above (table 3). (See 'Timing of vaccinations' above.)
Drug-specific risks
Ruxolitinib — Ruxolitinib inhibits JAK1 and JAK2, which disrupts cytokine and growth factor signaling to attenuate immune responses.
Serious bacterial, viral, and fungal infections have been reported in patients treated with ruxolitinib, including mycobacterial infections, reactivation of HBV, PML, herpes zoster, and coccidioidomycosis [69,80]. Neutropenia may occur, and patients should be closely monitored during treatment.
Baricitinib — Baricitinib, like ruxolitinib, is a JAK1/JAK2 inhibitor that blocks plasmablast, Th1, and Th17 differentiation and innate stimulation of T cells [81].
Patients receiving baricitinib most commonly report respiratory infections, bronchitis, and urinary tract infections [71-73]. Herpes zoster occurred more frequently in patients receiving baricitinib compared with placebo in clinical trials [71-73].
Tofacitinib — Tofacitinib inhibits JAK1, JAK2, and JAK 3 to disrupt cytokine and growth factor signaling, thereby reducing lymphocyte activation, differentiation, and function [68].
Infections reported in patients treated with tofacitinib include pneumonia, cellulitis, herpes zoster, and urinary tract infections [74-76]. Other common infections include upper respiratory tract infections [68,78]. Opportunistic infections have been reported, including M. tuberculosis, P. jirovecii pneumonia, and cryptococcosis, as well as the reactivation of other viruses. Patients with HBV and HCV were excluded from clinical trials, but HBV reactivation has been observed [79]. It is unclear if risk of TB reactivation is lower with JAK inhibitors compared with tumor necrosis factor (TNF)-alpha inhibitor or other biologic agents.
Decreased responses to pneumococcal immunization, especially in combination with methotrexate, have been observed [82].
INTERLEUKIN-1 INHIBITORS — Interleukin (IL)-1 inhibitors prevent the activation of potent proinflammatory cytokine cascades. (See "Interleukin 1 inhibitors: Biology, principles of use, and adverse events".)
Class-wide risk assessment
●Risk of infection – Treatment with IL-1 inhibitors predisposes individuals to the following infections (table 5):
•Tuberculosis (TB) and other mycobacterial infections
•Hepatitis B virus (HBV) and hepatitis C virus (HCV)
•Herpes zoster virus
•Candidal infections
•Cryptococcal infection
•Aspergillosis
•Common viral and bacterial infections (sinopulmonary infections, pneumonia, urinary tract infections, cellulitis)
Since risk of infections with IL-1 inhibitors seems to be lower than with some other biologic agents (eg, tumor necrosis factor-alpha inhibitors [TNFi]), these agents can be a useful treatment option for patients who are undergoing evaluation for occult infections but would benefit from starting a biologic agent earlier than the time frame in which the evaluation for infection can be completed. Nevertheless, IL-1 inhibitors should not be initiated in patients with known active infections and should be held in the context of active infections that arise during treatment. IL-1 inhibitors should not be used in combination with TNFi [83].
●Pretreatment infectious testing – We test patients initiating IL-1 inhibitors for tuberculosis infection (TBI) (algorithm 1), HBV (algorithm 3), and HCV (algorithm 4 and table 5).
●Vaccinations – We administer the routine and additional vaccinations (pneumococcal and varicella/herpes zoster vaccines) for patients starting IL-1 inhibitors, as discussed above (table 5). (See 'Timing of vaccinations' above.)
Drug-specific risks
Anakinra — Anakinra is an IL-1 receptor antagonist that prevents IL-1 from binding to IL-1 receptors [84]. IL-1 has a multitude of signaling responsibilities in the cell, and blocking this leads to reduced proinflammatory cytokine cascades.
The most commonly observed infections among patients treated with anakinra include upper respiratory tract infections, cellulitis, nasopharyngitis, and bone and joint infections [84-86]. Additional opportunistic infections reported in postmarketing studies include fungal, mycobacterial, and bacterial infections. Reactivation of M. tuberculosis infection has been reported but appears infrequent when appropriate testing and treatment are implemented [86]. The risk for HBV reactivation in patients receiving anakinra has not been studied.
Canakinumab — Canakinumab is a humanized monoclonal antibody (mAb) directed against IL-1 beta. Canakinumab specifically binds to IL-1 beta and inhibits its downstream effector functions by blocking its ability to bind to IL-1 receptors [87]. This signal inhibition decreases the proinflammatory immune response.
The most common infections seen in patients on canakinumab include nasopharyngitis, upper respiratory tract infections, and influenza [88-90]. Opportunistic infections with aspergillosis, mycobacterial infections, herpes zoster, and cytomegalovirus (CMV) have been reported. Patients with TBI, HBV, and HCV were excluded from all canakinumab trials, and the risk for reactivation of chronic bacterial and viral infections is unclear [89,90].
Rilonacept — Rilonacept is a bispecific humanized mAb directed against IL-1 beta to limit IL-1 signaling and reduce inflammatory responses [91,92].
Upper respiratory tract infection is the most common infection in patients undergoing treatment. However, many other serious infections can occur due to the consequences of preventing the IL-1 signaling pathways, such as M. tuberculosis infection [91-93]. Injection site reactions are common and should be monitored for infection.
INTERLEUKIN-4 INHIBITORS (DUPILUMAB) — Dupilumab is a humanized monoclonal antibody (mAb) directed against interleukin (IL)-4 receptor subunit alpha. Dupilumab inhibits the downstream signaling of both IL-4 and IL-13, critical drivers of the type II inflammatory response [94,95]. Studies are ongoing to determine the safety of long-term usage [96]. (See "Treatment of severe asthma in adolescents and adults", section on 'Anti-lL-4 receptor alpha subunit antibody (dupilumab)' and "Evaluation and management of severe refractory atopic dermatitis (eczema) in adults", section on 'Dupilumab'.)
●Risk for infection – Generally, dupilumab is associated with less infectious risk compared with other immunomodulators, such as methotrexate [97] (table 6). Serious infections leading to drug discontinuation are infrequent, but patients should be monitored closely [98]. Herpes simplex virus infections have been reported in patients undergoing therapy with dupilumab. Most conjunctivitis seen in patients taking dupilumab is noninfectious, although bacterial and viral conjunctivitis can rarely occur [97]. Infection severity due to SARS-CoV-2 does not appear to be increased [99-101].
The impact of dupilumab on infections due to helminths and chronic infections with hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV are unknown, as patients with these conditions were excluded from clinical trials [95]. However, subsequent case reports of patients with chronic HBV and HCV treated with dupilumab have been reassuring [102,103].
●Pretreatment infectious testing – Testing for tuberculosis infection (TBI) (algorithm 1), HBV (algorithm 3), and HCV (algorithm 4) can be decided on a case-by-case basis, based on the patient's risk factors and prior testing history for each of these infections, since there are no data indicating increased risk of reactivation with TBI and HBV in patients taking dupilumab (table 6) [102-104]. Since dupilumab selectively suppresses Th2 immune responses, it is unlikely to cause reactivation of HBV, HCV, or tuberculosis (TB). In a case series of five patients with atopic dermatitis and positive hepatitis B surface antigen who were treated with dupilumab, there were no cases of hepatitis B reactivation after two years of treatment [102]. (See 'Pretreatment infectious testing' above.)
●Vaccinations – No vaccinations are necessary prior to initiating dupilumab (table 6).
INTERLEUKIN-5 AND IMMUNOGLOBULIN E INHIBITORS — Eosinophil and mast cell activation are critical aspects of the immune response to allergens and parasitic pathogens, causing inflammation and tissue damage. Interleukin (IL)-5, secreted by Th2 cells and mast cells, is a critical regulator of eosinophil differentiation, stimulation, and survival; activation and signaling occur upon IL-5-specific binding to its receptor (IL-5R). Monoclonal antibodies (mAbs) designed to inhibit this interaction by binding circulating IL-5 (mepolizumab, reslizumab) or competitively binding to IL-5R (benralizumab) have been shown to deplete blood and tissue eosinophil counts [105-107]. Omalizumab is a competitive inhibitor of immunoglobulin E (IgE), leading to inhibition of mast cell activation and release of inflammatory proteins [108]. (See "Treatment of severe asthma in adolescents and adults", section on 'Persistently uncontrolled asthma'.)
Class-wide risk assessment
●Risk of infection – Due to the known effect of IL-5 and IgE signaling on helminth clearance, there is a theoretical increased risk for parasitic infections (table 6). Thus, in a patient presenting with signs and symptoms of infection, we consider the possibility and evaluate for parasitic infections, especially within an appropriate clinical context. If a parasitic infection is discovered following the start of therapy, treatment should be stopped until the infection is resolved.
Due to the theoretical increased risk for parasitic infections, the major clinical trials for benralizumab [70,107,109-112], mepolizumab [106,113-119], reslizumab [105,120-122], and omalizumab [123-128] excluded patients with active parasitic infections and we do not know how much of an increased risk to parasitic infections these drugs confer. In a small randomized, double-blinded study of 137 participants in Brazil who were at high risk for helminth infection, there was a statistically nonsignificant trend toward higher incidence of parasitic infection in those who received omalizumab compared with placebo (50 versus 41 percent, OR 1.47, 95% CI 0.74-2.95) [129].
●Pretreatment infectious testing – For patients at increased risk for parasitic infections (eg, patients who live in or recently traveled from endemic countries), we test for possible quiescent parasitic infections with a Strongyloides spp immunoglobulin G (IgG) antibody and stool microscopy for ova, cysts, and helminths prior to initiation of these agents (table 6). If any parasitic infections are found, they should be treated prior to the initiation of IL-5 inhibitor or anti-IgE monoclonal antibody agents. (See "Strongyloidiasis", section on 'Screening' and "Approach to stool microscopy".)
●Vaccinations – We administer the herpes zoster vaccine to patients (especially those above the age of 50) starting mepolizumab, given the increased risk for herpes zoster infections (table 6).
Drug-specific risks
Benralizumab — Benralizumab is a humanized cytolytic IgG1 mAb directed against the IL-5R alpha subunit. Due to a direct apoptotic effect on eosinophils via antibody-mediated cellular cytotoxicity [130], benralizumab results in greater depletion of circulating and tissue-resident eosinophils compared with drugs that bind IL-5 directly [131]. In a review of the Vigibase database, parasitic infections were more prevalent in patients taking benralizumab (0.23 percent) compared with mepolizumab (0.07 percent), omalizumab (0.06 percent), dupilumab (0.04 percent), or placebo (0.02 percent) [132]. However, in most clinical trials, infections occurred at a similar rate in the benralizumab and placebo arms [70,107,109-112].
Mepolizumab — Mepolizumab is a humanized IgG1 kappa mAb directed against IL-5. The overall incidence of infections was similar in clinical trials of patients receiving mepolizumab compared with placebo [106,113-116,118,119]. However, multiple studies report cases of herpes zoster in patients taking mepolizumab [106,113,114]. Based on a small number of case studies, there is no clear evidence of increased COVID-19 severity in patients taking mepolizumab [133,134]. Nonetheless, the risk of hospitalization may be elevated in patients infected with SARS-CoV-2 [135].
Reslizumab — Reslizumab is a humanized IgG4 kappa mAb directed against IL-5. The incidence of infections in clinical trials was similar among patients receiving reslizumab and placebo [105,120-122].
Omalizumab — Omalizumab is a humanized IgG1 mAb that targets circulating IgE. Most studies have demonstrated a similar incidence of infections in patients receiving omalizumab compared with placebo [123-128]. A few case studies suggest that omalizumab does not increase the risk for SARS-CoV-2 infection or the development of severe COVID-19 [136]. In a randomized controlled trial exploring the rate of helminth infection in patients receiving omalizumab, there was a small increase in the incidence of helminth infections but no apparent difference in the severity of infection [129]. Omalizumab has also been associated with adverse effects that mimic infections, such as fever, arthralgias, and urticaria [22,137]. These symptoms have been reported in some individuals even after a year into the course of therapy [22].
OTHER INTERLEUKIN INHIBITORS (IL-6, IL-12, IL-17, IL-23) — Interleukin (IL)-6, IL-12, IL-17, and IL-23 are all cytokines involved in inflammatory and immune response pathways. The discussed monoclonal antibodies (mAbs) are directed against these cytokines and interfere with downstream signaling processes, preventing the release of proinflammatory cytokines. These cytokines are produced in a vast array of cells, including those involved in T cell activation and stimulation of hematopoietic precursor cell proliferation and differentiation. The cytokines can also be found locally at sites of infection and inflammation. Continual production of these cytokines is involved in the pathogenesis of some autoimmune diseases, and targeting these cytokines through neutralization or antagonization is an effective strategy to treat these diseases [138]. (See "Overview of biologic agents in the rheumatic diseases", section on 'Biologic cytokine inhibitors'.)
Sarilumab and tocilizumab — Sarilumab and tocilizumab bind to soluble and membrane-bound IL-6 receptors and interfere with IL-6 signaling via the receptor [139,140] (table 5). (See "Overview of biologic agents in the rheumatic diseases", section on 'IL-6 inhibition'.)
●Risk of infection – Patients treated with IL-6 inhibitors are at increased risk of the following infections:
•Tuberculosis (TB) and other mycobacterial infections
•Hepatitis B virus (HBV) and hepatitis C virus (HCV)
•Herpes zoster virus [141]
•Candidal infections
•Pneumocystis pneumonia
•Common viral and bacterial infections (sinopulmonary infections, pneumonia, urinary tract infections, cellulitis) [142,143]
Long-term studies suggest that risk for infections is similar to other biologic agents, including tumor necrosis factor (TNF)-alpha inhibitors [144-148]. However, many of the opportunistic bacterial, viral, and fungal infections often occur during coadministration with other immunosuppressive medications [149,150]. Patients with HBV and HCV were excluded from trials using sarilumab and tocilizumab; however, reactivation of HBV has been reported [151].
●Pretreatment infectious testing – For patients starting IL-6 inhibitors, we test for tuberculosis infection (TBI) (algorithm 1), HBV (algorithm 3), and HCV (algorithm 4 and table 5).
●Vaccinations – We administer the routine and additional vaccinations (pneumococcal and varicella/herpes zoster vaccines) for patients starting IL-6 inhibitors, as discussed above (table 5). (See 'Timing of vaccinations' above.)
Ixekizumab, secukinumab, brodalumab, and bimekizumab — These mAbs are directed against IL-17. In particular, ixekizumab and secukinumab selectively bind IL-17A and inhibit its ability to interact with the IL-17 receptor [15,16]. Brodalumab binds IL-17RA and prevents its interactions with other IL-17-related proteins [17]. These actions prevent cytokine signaling and the subsequent release of proinflammatory cytokines. Bimekizumab is not available in the United States. (See "Overview of biologic agents in the rheumatic diseases", section on 'IL-17 inhibition'.)
●Risk of infections – Patients treated with IL-17 inhibitors are at increased risk of the following infections (table 5):
•TB and other mycobacterial infections [15-20]
•Candidal infections, especially oral candidiasis [18]
•Dermatologic fungal infections (eg, tinea)
•Common viral and bacterial pathogens (eg, nasopharyngitis, upper respiratory tract infections, urinary tract infections) [19,20]
Based on case reports, secukinumab has been used in patients with HBV and HCV infection without viral reactivation [152]. Very few cases of TB and other mycobacterial infections have been reported with these agents, and the overall risk is likely very low [153].
●Pretreatment infectious testing – For patients initiating IL-17 inhibitors, we test for TBI (algorithm 1) prior to initiating treatment (table 5).
●Vaccinations – We administer the routine and additional vaccinations (pneumococcal and varicella/herpes zoster vaccines) for patients starting IL-17 inhibitors, as discussed above (table 5). (See 'Timing of vaccinations' above.)
Guselkumab, ustekinumab, and others — Guselkumab is a mAb directed against IL-23 to prevent binding to its receptor, which inhibits downstream signaling to dampen proinflammatory cytokine responses [154]. Ustekinumab is a mAb directed against IL-12 and IL-23, interfering with natural killer cell activation and CD4+ T cell differentiation [155]. Risankizumab and mirikizumab are other IL-23 inhibitors with similar mechanism of action to guselkumab. (See "Overview of biologic agents in the rheumatic diseases", section on 'IL-12/23 blockade'.)
●Risk for infections – Patients treated with IL-23 inhibitors are at increased risk of candidal and dermatologic fungal infections (eg, tinea) (table 5).
Although the drug labels for these agents warns that the risk of TBI and HBV reactivation may be increased, postmarketing data have not shown a significantly increased risk of infection with these agents [153,156]. Nevertheless, we continue to test for these infections, because the benefit of testing outweighs the harms.
Risankizumab (an IL-23 inhibitor) appears to have a lower risk for HBV and HCV reactivation compared with guselkumab or ustekinumab.
●Pretreatment infectious testing – We test for TBI (algorithm 1), HBV (algorithm 3), and HCV (algorithm 4) in patients initiating guselkumab or ustekinumab (table 5). Since there are no reports of HBV or HCV reactivation in patients taking isankizumab, we do not test patients starting isankizumab for HBV or HCV.
●Vaccinations – We administer the routine and additional vaccinations (pneumococcal and varicella/herpes zoster vaccines) for patients starting IL-23 inhibitors, as discussed above (table 5). (See 'Timing of vaccinations' above.)
INTEGRIN INHIBITORS
Vedolizumab — Vedolizumab is a monoclonal antibody (mAb) that binds alpha 4 beta 7 integrin and prevents its interaction with MAdCAM-1, which hinders the migration of memory T cells into the gastrointestinal tract [157]. (See "Medical management of moderate to severe Crohn disease in adults" and "Management of moderate to severe ulcerative colitis in adults", section on 'Vedolizumab'.)
●Risk of infection – In clinical trials and postmarketing studies, infection rates were not significantly higher in patients receiving vedolizumab compared with placebo [157-161]. However, certain serious infections have been rarely reported in those taking vedolizumab, including [71] (table 7):
•Tuberculosis (TB) and other mycobacterial infections
•Cytomegalovirus (CMV) disease (eg, colitis) and Epstein-Barr virus
•Progressive multifocal leukoencephalopathy (PML)
•Common viral and bacterial pathogens (eg, nasopharyngitis, sinopulmonary infections, gastroenteritis, perirectal abscesses) [162,163]
Vedolizumab does not seem to affect the incidence of complications due to SARS-CoV-2 infection [164].
Vedolizumab treatment should not be started in patients with severe infections nor be administered concomitantly with natalizumab or tumor necrosis factor (TNF)-alpha inhibitors due to additive infection risk [14].
Vedolizumab appears to carry a low risk for opportunistic infections. In a pooled analysis of six trials that included 2830 patients, there was no increased risk of serious infection associated with vedolizumab exposure compared with placebo [157]. Both TB and CMV infections were reported in 1 person per 1000 person-years in the vedolizumab group.
●Pretreatment infectious testing – Prior to administering vedolizumab, we test for tuberculosis infection (TBI) (algorithm 1), as the benefits of TBI preemptive treatment in those who test positive outweigh the risks associated with testing (table 7). (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".)
●Vaccinations – We administer the routine and additional vaccinations (pneumococcal and varicella/herpes zoster vaccines) for patients starting vedolizumab, as discussed above (table 7) (see 'Timing of vaccinations' above). Administration of live vaccines before initiating vedolizumab is preferred. Live vaccines can be administered during therapy if the benefit outweighs the risk [14]. Vedolizumab does not appear to reduce parenterally delivered vaccine responses, but the response to oral vaccines may be lower [165,166].
Natalizumab — Natalizumab is a selective adhesion molecule inhibitor, functioning as a humanized mAb that binds to alpha 4 beta 1 integrins on nonneutrophil leukocytes. This prevents alpha 4 beta 1 from interacting with vascular cell adhesion molecule 1 (VCAM-1) found in blood vessel lumens. By blocking the interaction of alpha 4 beta 1 to VCAM-1, leukocyte migration across the blood-brain barrier and interactions with extracellular matrix proteins are inhibited [167,168].
●Risk for infections – Patients treated with natalizumab are at increased risk of the following infections (table 7):
•TB [169] and other mycobacterial infections
•PML and John Cunningham virus (JCV; can occur in both seropositive and seronegative patients) [167,169,170]
•Herpes simplex virus meningoencephalitis [169]
•Varicella zoster virus (VZV) and other herpesviruses (eg, acute retinal necrosis) [171,172]
•Hepatitis B virus (HBV) and hepatitis C virus (HCV) [173]
•Aspergillosis [169]
•Cryptococcal infection [169]
•Common viral and bacterial infections (nasopharyngitis, upper respiratory tract infections, urinary tract infections) [169,174,175]
Natalizumab should not be administered to patients with severe infections nor in combination with other immunomodulatory therapies. Corticosteroids should be discontinued prior to natalizumab initiation. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Natalizumab'.)
In a nationwide Swedish cohort of 1573 patients taking natalizumab, the risk of developing a serious infection within the first six years of treatment was 11.4 per 1000 person-years (95% CI 8.3-15.3) compared with the general population [170]. Although the risk is elevated, it was still lower than the infection risk associated with use of fingolimod or rituximab in this study. (See 'Sphingosine-1-phosphate receptor modulators (fingolimod)' below and 'Rituximab' above.)
Although rare, PML is a significant concern in patients taking natalizumab due to its high mortality rate and moderate to severe disability among survivors. The risk of natalizumab-associated PML for an individual patient varies according to JCV antibody status, prior immunosuppressant treatment, and the duration of natalizumab exposure (table 8). (See "Progressive multifocal leukoencephalopathy (PML): Treatment and prognosis", section on 'Morbidity and mortality'.)
●Pretreatment infectious testing – We test for TBI (algorithm 1), HBV (algorithm 3), HCV (algorithm 4), and JCV prior to starting natalizumab (table 7) [169,176,177]. We also obtain baseline brain magnetic resonance imaging (MRI) prior to initiating therapy, continue to monitor JCV antibodies every six months, and repeat the brain MRI annually during therapy. If JCV antibody is positive at any time, some experts opt to not initiate or discontinue natalizumab due to the increased risk of PML incidence [167,169,170,178]. As an example, in a multinational observational study of over 6500 patients started on natalizumab, 44 (0.7 percent) developed PML over the five-year follow-up period [178]. Half of these patients had positive JCV antibodies recorded in the previous six months, while another 47 percent did not have JCV antibody results recorded.
Surveillance for PML in patients with a positive JCV antibody who remain on natalizumab is discussed separately. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Surveillance for PML'.)
●Vaccinations – We administer the routine and additional vaccinations (pneumococcal and varicella/herpes zoster vaccines) in patients starting natalizumab, as discussed above (table 7). (See 'Timing of vaccinations' above.) Live vaccines should be avoided during the treatment period and for four months following the cessation of therapy [11].
Others — Etrolizumab is similar to vedolizumab in mechanism of action and increased susceptibility to infections (see 'Vedolizumab' above). Efalizumab is similar to natalizumab and also increases the risk of PML. It is no longer available in the United States or Canada due to fatal PML infections [179].
SPHINGOSINE-1-PHOSPHATE RECEPTOR MODULATORS (FINGOLIMOD) — Drugs belonging to the sphingosine-1-phosphate (S1P) modulators class include fingolimod, ozanimod, siponimod, and ponesimod. All of them have similar risk of infection; patients taking S1P receptor modulators other than fingolimod should be managed similar to patients taking fingolimod. (See "Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults", section on 'Sphingosine 1-phosphate (S1P) receptor modulators' and "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'S1PR modulators'.)
Fingolimod binds to S1P receptors, downregulating S1P signaling to inhibit the exit of naive T cells and central memory T cells from lymph nodes [180,181]. Expression of cytokines on CD4+ T cells is also inhibited [181,182].
●Risk of infection – Patients taking fingolimod are at increased risk for the following infections [183,184] (table 7):
•Tuberculosis (TB) and other mycobacterial infections
•Varicella zoster virus (VZV) and herpes simplex virus infections
•Progressive multifocal leukoencephalopathy (PML)
•Human herpesvirus-8-associated tumors
•Cryptococcal infection
•Common viral and bacterial infections (sinopulmonary infections, pneumonia, urinary tract infections, cellulitis)
A significant increase in risk for lower respiratory tract infections and herpesvirus infections was identified in clinical trials, with two fatal cases of disseminated VZV reported [185-188]. Patients should be carefully monitored during treatment for lower respiratory infections and herpesvirus infections [189,190].
Although risk of PML with fingolimod is lower than with natalizumab, cases of PML have been reported [191,192]. No fingolimod dose-dependent increase in infection risk has been noted [181]. Fingolimod should not be used with natalizumab due to increased risk of PML. (See 'Natalizumab' above and "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)
●Pretreatment infectious testing – For patients starting S1P receptor modulators, we test for tuberculosis infection (TBI) (algorithm 1), hepatitis B virus (HBV) (algorithm 3), and hepatitis C virus (HCV) (algorithm 4 and table 7). We prefer to test for John Cunningham virus (JCV), similar to the approach used in patients receiving natalizumab, due to the increased risk for PML in patients receiving fingolimod [193]. However, testing for JCV is not routine among all clinicians, and no guidelines are available to guide testing. Fingolimod should be held if any signs or symptoms of PML develop while further work-up is pursued [193]. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Surveillance for PML'.)
●Vaccinations – We administer the routine and additional vaccinations (pneumococcal and herpes zoster vaccines) for patients starting S1P receptor modulators, as discussed above (table 7). (See 'Timing of vaccinations' above.)
COMPLEMENT PATHWAY INHIBITORS (ECULIZUMAB) — Eculizumab is a monoclonal antibody (mAb) directed against protein C5 of the membrane attack complex (MAC). The binding of eculizumab to C5 reduces the number of terminal complement components (C5b-9) that form the MAC, thereby decreasing the cytolysis of targeted encapsulated bacteria [194-196].
●Risk of infection – Patients treated with eculizumab are at increased risk for (table 9):
•Serious infections due to encapsulated bacteria (eg, Neisseria meningitidis, S. pneumoniae, and Haemophilus influenzae type b (Hib) [194,197]), particularly severe or fatal meningococcal infections [194,195]
•Common bacterial and viral infections (eg, upper respiratory infections, urinary tract infections) [197]
The severity of SARS-CoV-2 infection does not appear to be higher in patients treated with eculizumab [198].
●Pretreatment infectious testing – No testing is necessary for patients prior to starting eculizumab (table 9).
●Vaccinations – Due to the high risk of bacterial infections, initial or booster vaccinations for N. meningitidis (both for ACWY serogroups and serogroup B) and S. pneumoniae are recommended at least two weeks before the start of treatment or as soon as possible (table 9). Children receiving eculizumab treatment may be at particularly increased risk for infection with S. pneumoniae or Hib, and age-appropriate vaccinations should be administered according to standard guidelines. (See "Pneumococcal vaccination in children" and "Pneumococcal vaccination in adults" and "Prevention of Haemophilus influenzae type b infection" and "Meningococcal vaccination in children and adults", section on 'Immunization of persons at increased risk'.)
●Other considerations – Antibacterial prophylaxis with penicillin, or a macrolide if penicillin allergic, can be considered while receiving this treatment, but the risks and benefits are not well evaluated [197]. This is discussed in further detail elsewhere. (See "Treatment and prevention of meningococcal infection", section on 'Patients receiving C5 inhibitors'.)
Close monitoring for serious infections is warranted in all patients receiving eculizumab since infection is still possible (although less likely) in a patient who has been vaccinated and/or is receiving antimicrobial prophylaxis [195].
MONOCLONAL ANTIBODIES WITH NO KNOWN EFFECT ON THE IMMUNE SYSTEM — Certain monoclonal antibodies (mAbs) are designed to not affect the immune system and thus do not predispose the patients taking these agents to infections. Agents in this category include evolocumab, abciximab, and calcitonin gene-related peptide antagonists (eg, erenumab, galcanezumab, atogepant).
SUMMARY AND RECOMMENDATIONS
●Immunologic mechanisms – Biologic agents are designed to interfere with the biological activity of a component of the immune system, typically a cytokine or a cellular receptor. By interfering with the normal activities of these molecules, biologic agents disrupt signaling pathways that drive activation and migration of immune cells to sites of infection, thereby interfering with the host immune response and increasing risk for infection. (See 'Immunologic mechanisms' above.)
●Pretreatment testing for infections – Baseline testing for some latent infections is recommended prior to initiating therapy with many of the medications in this section (table 3 and table 4 and table 5 and table 6 and table 9 and table 7). In general, most of the biologic agents discussed here warrant testing for tuberculosis infection (TBI), hepatitis B virus (HBV), and hepatitis C virus (HCV). If any infections are discovered on pretreatment testing, we treat the underlying infection and hold off on starting the biologic agent until the infection is controlled. Close monitoring is paramount to make sure there is no worsening of the underlying infection once the biologic agent is started. (See 'Pretreatment infectious testing' above.)
●Pretreatment vaccinations
•We administer age-appropriate routine vaccinations (including SARS-CoV-2 vaccine series and annual influenza vaccination) to all patients starting biologic agents or a janus kinase (JAK) inhibitor prior to initiation of therapy when feasible, because vaccination may be less effective during and after therapy or may be contraindicated (eg, live vaccines) (table 3 and table 4 and table 5 and table 6 and table 9 and table 7).
•For some drugs, pneumococcal and herpes zoster virus vaccines should also be administered prior to initiation of biologic agent, if possible (table 3 and table 4 and table 5 and table 6 and table 9 and table 7).
•Live vaccines should generally be avoided during treatment with immunomodulatory agents. (See 'Prior to initiating biologics' above.)
●Administration of vaccines during treatment – Vaccination with nonlive vaccines during therapy may be considered if the benefit of vaccination outweighs the risk. When possible, vaccination should be given at the nadir of immunosuppression. (See 'During treatment with biologics' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
