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Secondary immunodeficiency induced by biologic therapies

Secondary immunodeficiency induced by biologic therapies
Authors:
Mark Ballow, MD
Thomas A Fleisher, MD
Section Editor:
Jordan S Orange, MD, PhD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: Nov 2022. | This topic last updated: Apr 02, 2021.

INTRODUCTION — Biologic therapies typically do not cause the global immunosuppression that is characteristic of traditional immunosuppressive drugs, such as glucocorticoids, cyclosporine, methotrexate, and azathioprine. However, biologics can have unintended effects on immune function that can compromise host defenses and lead to serious infections. Other manifestations of immunosuppression, such as the development of autoimmune diseases or malignancies, may also occur with some of these therapies. Biologics that cause immunosuppression, either as the primary therapeutic goal or as an unintended side effect, and the immunologic mechanisms through which this occurs will be reviewed here. This topic is not comprehensive. Only representative examples of biologics resulting in a consistent and marked impairment in immune function are discussed. In addition, many new biologics targeting the immune system are under development with varying degrees of infectious complications [1-3].

The management of drug-induced immunodeficiency may include regimens of prophylactic antibiotics or antivirals or immune globulin for the treatment of hypogammaglobulinemia. These issues are discussed elsewhere in the program in relation to specific diseases, and links are provided throughout this topic.

OVERVIEW — Biologic therapies that can increase the risk of infectious diseases include antithymocyte globulin, monoclonal antibodies to T and B cells, anticytokine therapies, agents that disrupt T cell costimulation signals, and agents that interfere with T cell inhibitory (checkpoint) signals. These agents selectively target cells and pathways of the immune system to achieve specific therapeutic effects and are used primarily in the treatment of rheumatic, inflammatory, and malignant diseases. Overview discussions of the use of these agents in rheumatic disorders and oncologic diseases are found separately. (See "Overview of biologic agents and kinase inhibitors in the rheumatic diseases" and "Principles of cancer immunotherapy", section on 'Checkpoint inhibitor immunotherapy' and "Toxicities associated with checkpoint inhibitor immunotherapy".)

Factors that increase the risk of infectious complications — With any biologic agent, the likelihood of clinically significant infection primarily depends upon the actions of the drug in question, its dose, and the duration of treatment. In addition, there are other patient-specific factors that contribute to the risk. The most important are:

The nature of the underlying disease process – For example, a patient who is given an immunosuppressive drug shortly after undergoing hematopoietic cell transplantation for malignancy may be at greater risk than a patient receiving the same drug for chronic, stable rheumatologic disease.

The functional status and medical fragility of the patient – Studies have shown that hospitalized patients, those with poor functional status or comorbid conditions, and older adults are more likely to develop immune complications when treated with glucocorticoids, and this is likely to be the case for other immunosuppressant drugs [4].

The concomitant use of other immunosuppressive medications with synergistic adverse immunologic effects – In addition, the use of multiple biologic agents is rarely studied formally but is becoming increasingly common in clinical practice. Clinicians must be cognizant of the possibility of acquired immune defects resulting from combinations of biologics affecting the same or different targets. (See "Overview of therapeutic monoclonal antibodies", section on 'Co-administration of more than one mAb'.)

The use of biologics to modulate the immune system has become a major therapeutic approach in the setting of inflammatory disorders. As with all therapeutics, there are untoward effects associated with these agents, and one of the most common is increased susceptibility to infection. The impact in terms of altering host defense and infectious susceptibility varies depending on the specific agent(s) used. In general, infections with common bacterial pathogens may become more frequent with agents targeting the B cell system, whereas intracellular pathogens, including opportunistic microbes, are often seen in treatment that is more focused on T cell immunity. It is important to recognize that use of biologics is also associated with additional adverse effects that often include an increased risk of developing a malignancy or autoimmunity as well as others, but these are not the focus of this section.

Interventions to prevent infections — Whenever possible, the potential complications of these drugs should be considered in advance of their use. Patients can be immunized against some pathogens and tested for other pathogens that may reactivate after immunosuppression, such as hepatitis B virus and tuberculosis:

(See "Immunizations in solid organ transplant candidates and recipients".)

(See "Immunizations in hematopoietic cell transplant candidates and recipients".)

ANTITHYMOCYTE GLOBULIN — Antithymocyte globulin (ATG) is a preparation of polyclonal immunoglobulin obtained by immunizing rabbits (Thymoglobulin [brand name]) or horses (Atgam [brand name]) with human lymphoid cells derived from the thymus or cultured B cell lines. It is used to reverse acute rejection, in induction regimens for transplant, and in the treatment of various hematologic disorders.

ATG contains antibodies to a number of different T cell surface determinants, although its mechanism of action is not fully defined.

Immunologic effects of ATG include the following:

It appears to disrupt the interaction of T cells with antigen-presenting cells [5]. T cells are depleted in the peripheral blood both by cell death from complement-dependent lysis or Fc receptor-mediated lysis and opsonization.

ATG inhibits cutaneous delayed hypersensitivity.

ATG causes B cell depletion and dysfunction, which results in a beneficial lowering in the risk of Epstein-Barr virus lymphoproliferative disease compared with therapy with OKT3 (muromonab-CD3) [6,7]. (See 'OKT3' below.)

ATG given before a vaccine will inhibit vaccine-induced antibody response, but ATG given after will not.

Pre-existing antibody levels are not affected by ATG.

ATG causes increased susceptibility to herpes virus infections (especially cytomegalovirus [CMV]). Prophylaxis against CMV is discussed in more detail separately. (See "Prophylaxis of infections in solid organ transplantation", section on 'Viral infections' and "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients" and "Prevention of cytomegalovirus infection in lung transplant recipients" and "Infectious complications in liver transplantation", section on 'Cytomegalovirus'.)

ATG may also cause acute allergic (IgE mediated) reactions, serum sickness reactions, and thrombocytopenia.

MONOCLONAL ANTIBODIES TO B CELLS

Rituximab — Rituximab is a chimeric immunoglobulin (Ig)G1 CD20-specific monoclonal antibody. Rituximab targets B cells from the pre-B cell stage to the preplasma cell stage via antibody-dependent, cell-mediated lysis. The primary use of rituximab is in the treatment of B cell malignancies and in selected autoimmune disorders, including rheumatoid arthritis, autoimmune cytopenias, autoimmune skin disease (pemphigus, pemphigoid), Sjögren syndrome, and some forms of vasculitis. It also disrupts B and T cell interactions, resulting in impaired cellular immunity and increased risk of viral reactivation [8].

Rituximab depletes peripheral blood B cells, and subsequent normalization of B cell numbers typically requires six to nine months or longer [9], with significant variability among patients. The recovery of B cells recapitulates B cell ontogeny, with CD27- (naïve) B cells returning before CD27+ (memory) B cells [10]. In a study of patients with different types of vasculitides, B cell recovery occurred over a range of 8 to 44 months [11]. While B cells are depleted, the patient’s ability to respond to vaccines is impaired and some degree of transient hypogammaglobulinemia is common.

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'.)

Since rituximab is an IgG1 chimeric murine/human monoclonal antibody, it passes through the placenta during the third trimester with the mother's serum IgG. Newborns whose mothers were treated during pregnancy with rituximab have a marked reduction in B cells during the first few weeks of life, with normal numbers of peripheral blood B cells appearing by six months of age [12]. Kappa-deleting recombination excision circles may be low or absent in rituximab-exposed infants, and such infants may test erroneously positive on neonatal screening for B cell immunodeficiencies [13]. (See "Newborn screening for primary immunodeficiencies", section on 'Screening for B cell defects'.)

Impact on vaccination — Available studies suggest that rituximab may impair vaccine responses to some degree, particularly responses to polysaccharide vaccines. Therefore, whenever possible, polysaccharide vaccines and primary non-live immunizations should be administered at least four weeks prior to rituximab therapy to maximize responses and enhance protection during the period of B cell immunosuppression. Note that safety data are lacking about live vaccines (eg, measles-mumps-rubella or varicella zoster virus [VZV]) in close proximity to rituximab, so these should not be given just before or for at least six months after the end of treatment [8].

The impact on vaccinations given before, during, and after rituximab therapy was evaluated in a study of 75 patients with type 1 diabetes mellitus 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) [14]. The following were observed during the one-year study:

Pre-existing immunity to standard vaccinations was not affected by treatment: Measles, mumps, and rubella vaccine was not given during the study and titers to these were unchanged by treatment (ie, not different in the rituximab and placebo groups).

Most patients were able to respond to vaccines given 12 months after rituximab therapy, but titers were lower than in the placebo group: Tetanus titers were low at the start of the study, and a dose of tetanus/diphtheria vaccine was given at 12 months, with titers measured one month later. The majority of patients in the rituximab and placebo groups achieved protective titers (defined as a twofold or greater increase), although the mean titers were lower in the rituximab group. A similar pattern of response was seen with hepatitis A vaccination.

Vaccine responsiveness returns with B cell recovery, and immunization after the completion of rituximab therapy does not appear to interfere with a later normal response if the vaccine is readministered: The response to the neoantigen phiX174 was measured in a subset of patients vaccinated with four doses during the study (two doses just after rituximab, and two doses at the end of the year) [14]. Response to the first two doses was severely blunted in the rituximab group, but after the third and fourth doses, subjects responded with levels that were equivalent to those of the first two doses in the placebo groups, suggesting neoantigen exposure during the period of rituximab-induced immune suppression does not lead to anergy following B cell recovery.

Other observations from studies of patients with rheumatoid arthritis (RA) include the following [15,16]:

In a study of patients with RA, the response to influenza vaccination was markedly reduced in patients treated with rituximab, compared with methotrexate-treated patients and healthy controls, when vaccines were administered 4 to 8 weeks after rituximab therapy [15]. However, if immunization was given 6 to 10 months after rituximab therapy, patients had a partial response, even in the absence of B cell repopulation at the time of vaccination.

T cell-driven responses, such as recall responses to tetanus toxoid, as well as delayed-type hypersensitivity responses, were preserved 6 months after therapy in a study of patients with RA treated with rituximab plus methotrexate or methotrexate alone, as would be expected [16]. In contrast, responses to neoantigen (keyhole limpet hemocyanin) and pneumococcal polysaccharide vaccine were decreased, although many patients were still able to mount responses.

It is possible that vaccine response during rituximab therapy may be further compromised in patient populations with underlying immune disorders or in those receiving additional immunosuppressant drugs. As an example, in a study of 67 patients with lymphoma given the H1N1 influenza vaccine within 6 months of completing therapy, none who had received rituximab-containing regimens achieved protective antibody titers, while 82 percent of control lymphoma patients (not receiving rituximab) responded adequately [17].

Hypogammaglobulinemia — In most patients, rituximab does not significantly reduce levels of existing antibodies because antigen-specific IgG is produced by plasma cells, which do not express surface CD20 [18,19]. However, a subset of patients develop hypogammaglobulinemia, which can be persistent and clinically significant, resulting in serious infections and necessitating antibiotic prophylaxis or immune globulin replacement therapy to prevent infections [11,20-29]. Possible risk factors for more significant and prolonged hypogammaglobulinemia are reviewed below. (See 'Possible risk factors' below.)

The incidence of new hypogammaglobulinemia after treatment with rituximab is not precisely known, in part because measurement of serum immunoglobulin levels prior to treatment has not been standard-of-care in many of the specialties that use rituximab extensively.

In a study of 179 patients with B cell lymphoma who initially had normal serum IgG levels, 39 percent developed hypogammaglobulinemia and 6.6 percent developed recurrent sinopulmonary infections [27]. Approximately 7 percent required immune globulin replacement therapy to control infections.

In a retrospective review of 114 patients who had received rituximab for any condition over a one-year period at four London hospitals, 24 percent developed hypogammaglobulinemia (IgG <580 mg/dL or 5.8 g/L) [28]. Nineteen patients were subsequently evaluated for persistent and symptomatic hypogammaglobulinemia in the absence of neutropenia. In nearly two-thirds of this subgroup, IgG, IgA, and IgM were all decreased. Specific antibodies to Haemophilus influenzae type b, tetanus toxoid, and pneumococcus were all reduced, and patients failed to mount an antibody response following vaccination. Most experienced recurrent bronchitis, rhinosinusitis, and pneumonia, but three patients had enteroviral meningoencephalitis, with one fatality. Although most were initially managed with prophylactic antibiotics, 18 (16 percent) eventually required immune globulin replacement therapy.

Additional issues surrounding rituximab-induced hypogammaglobulinemia were examined in a large cohort study of nearly 5000 patients [30]. Rituximab was administered for the treatment of malignancies, autoimmune or hematologic disorders, or for autoimmune manifestations in patients with primary immunodeficiency (77, 28, 8, and 1 percent, respectively). In the entire group, nearly 30 percent experienced severe infections requiring hospitalization during the 18 months following initial rituximab treatment, most of which occurred in the first six months. Pretreatment IgG levels were measured in only 15 percent (655 of 4479 patients), among whom nearly one-half had pre-existing hypogammaglobulinemia, indicating that this may not be an uncommon finding. Among this subset, immunoglobulin levels generally declined further during treatment and the rate of severe infections remained high even after rituximab discontinuation. This high-risk group appeared to benefit from immunoglobulin replacement therapy.

Possible risk factors — Several studies have identified possible risk factors for the development of hypogammaglobulinemia and infections during/following rituximab therapy [24,29-35]. These include repeated courses of rituximab, cancer, rituximab treatment in combination with chemotherapy, older age, and pre-existing hypogammaglobulinemia.

Repeated courses of rituximab, older age, and concomitant glucocorticoid therapy were factors that led to decreases in serum IgG levels in a long-term safety study of rituximab use in patients with rheumatoid arthritis (RA) [34]. Data were analyzed from 2578 patients who received at least one dose of rituximab. Serum immunoglobulin levels decreased below the lower limit of normal of the assaying laboratory for some patients during follow-up (5 percent for IgG, 23 percent for IgM, and 1 percent for IgA). The number of patients with decreasing immunoglobulin levels increased with the number of treatment courses, particularly for IgM. Serious infections were reported in 7 percent, with an overall rate of 4.3 per 100 patient-years. The most common serious infection was pneumonia. The rates of serious infection were greater (but not significantly) following the development of low serum IgG levels.

Low levels of IgG prior to rituximab treatment, as well as sustained hypogammaglobulinemia (longer than four months) after treatment, were associated with higher rates of serious infections in other studies of patients with autoimmune disorders [36]. This led to a consensus statement recommending that patients with RA who are to be treated with rituximab should have pretreatment levels of IgG measured, and that IgG should be measured before each additional rituximab dose [37]. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Hypogammaglobulinemia and infection'.)

The combination of fludarabine with rituximab was an independent predictor of hypogammaglobulinemia and non-neutropenic infections in a retrospective study of 97 patients who received rituximab as part of chemotherapy regimens for various B cell malignancies [31]. Twenty percent (19 patients) were found to have one or more infectious complications (predominantly sinopulmonary bacterial infections not associated with neutropenia). Of these 19 patients, 15 had measurement of serum immunoglobulins, and all had either low IgG, IgM, or IgA. Some patients received one or two doses of immune globulin, which reduced the frequency and severity of these infections. None required prolonged immune globulin therapy.

Pre-treatment evaluation — We would strongly advocate for obtaining baseline serum immunoglobulin levels (IgG, IgA, and IgM) and enumerating peripheral blood B cells using flow cytometry prior to initiation of rituximab therapy, as this is a readily-assessed risk factor for rituximab-induced hypogammaglobulinemia and infectious complications. However, pre-treatment evaluation is not uniformly recommended in treatment protocols for rheumatic and malignant diseases, although this may become more routine as the prevalence of subsequent hypogammaglobulinemia is better appreciated.

Detecting pre-existing hypogammaglobulinemia may be especially relevant in patients with lymphoma or certain autoimmune diseases (eg, inflammatory arthritis, warm autoimmune hemolytic anemia, or Evan's syndrome), which can be presenting disorders of humoral immunodeficiencies. Low levels of IgG, accompanied by low levels of IgA or IgM or both, should be evaluated further, as this finding is one of the diagnostic criteria for the most common form of antibody deficiency, common variable immunodeficiency. It is important to understand that many of the patients with a diagnosis of common variable immunodeficiency present initially with an autoimmune process, commonly autoimmune cytopenias, before they have problems with recurrent infections [38]. Once rituximab has been initiated, diagnostic studies of the patient's B cells and immunoglobulins may not be possible for months or years, complicating subsequent diagnosis. If hypogammaglobulinemia is uncovered, further evaluation (eg, antibody responses to vaccines) and close monitoring for infections is helpful in identifying those patients with an underlying immune deficiency and who might benefit from immune globulin replacement therapy. In patients with persistent hypogammaglobulinemia, genetic analysis for an immune deficiency can be important for determining further therapies [39,40]. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults", section on 'Autoimmune disease'.)

Immune globulin therapy — Our approach to the use of immune globulin in patients previously treated with rituximab is to offer this therapy to any patient with recurrent infections in the setting of either reduced IgG levels or impaired vaccine responses. We would also advocate for periodic monitoring for recovery of B cell numbers and serum immunoglobulins (ie, IgG, IgM, and IgA) after rituximab therapy is completed, in an effort to identify patients who develop persistent hypogammaglobulinemia before they have significant infections, although recommendations from professional societies in different specialties vary. However, patients who have already developed infections following rituximab therapy should have both serum immunoglobulins and a complete blood count with differential (to evaluate for neutropenia) checked. Several series have reported reductions in infections with immune globulin therapy [27,28,31,41,42]. Consultation with a clinical immunologist is helpful.

One study of patients treated with rituximab for non-Hodgkin lymphoma found that even when serum immunoglobulins were normal or only slightly reduced, vaccine response was frequently impaired, and that patients with impaired vaccine response appeared to benefit from immune globulin therapy [41]. In this prospective cohort study, 15 patients were enrolled. Serum IgG was mildly decreased (median of 628 mg/dL) for the group, and 13 had impaired responses to vaccination. All were offered one year of immune globulin therapy, and nine accepted. The number of serious non-neutropenic infections prior to immune globulin in this group was reduced from 16 in the year prior to immune globulin (with two life-threatening infections) to six during the treatment period (none were life-threatening), and treatment was well tolerated. Thus, this study suggests that, following rituximab therapy, patients should be actively screened for hypogammaglobulinemia and impaired vaccine response, rather than waiting until infections have developed. The evaluation of vaccine response is discussed in detail separately. (See "Assessing antibody function as part of an immunologic evaluation".)

To prevent recurrent infections, either prophylactic antibiotics or immune globulin can be administered.

Regimens of prophylactic antibiotics are discussed in detail separately. (See "Primary immunodeficiency: Overview of management", section on 'Prophylactic antimicrobial therapy'.)

Both intravenous and subcutaneous immune globulin have been administered to patients with rituximab-induced hypogammaglobulinemia [27,28,41]. Dosing is the same as that used for primary immunodeficiency (eg, 400 mg/kg monthly for IVIG and 100 mg/kg weekly for subcutaneous immune globulin). (See "Immune globulin therapy in primary immunodeficiency" and "Subcutaneous and intramuscular immune globulin therapy".)

Deciding when to discontinue immunoglobulin replacement therapy can be challenging. It may be difficult or impossible to distinguish between the long-lasting effects of rituximab or a possible diagnosis of immune deficiency. A genetic panel for the gene mutations associated with immune deficiencies can be helpful. Following peripheral B cell counts and serum levels of IgM and IgA over time can also provide useful information in deciding whether or not to continue therapy. In a retrospective review of 17 cases of hypogammaglobulinemia following rituximab therapy, 5 patients recovered their B cell counts but had continued hypogammaglobulinemia and decreased switched or unswitched memory B cells. This study emphasizes the potential utility of monitoring B cell subsets focused on memory B cells in addition to following serum IgM and IgA levels to help decide when to discontinue immunoglobulin replacement therapy [43].

Considerations during the coronavirus pandemic — For patients who have rituximab-induced hypogammaglobulinemia and develop coronavirus disease 2019 (COVID-19), case reports and small series suggest convalescent plasma may be of benefit [44,45]. In a series of 17 consecutive patients with prolonged COVID-19 (ie, median duration of illness of 53 days), 15 of whom had B cell depletion due to rituximab therapy, infusion of four units of convalescent plasma was associated with rapid clinical improvement in 16 [45]. SARS-CoV-2 RNA levels in the blood decreased to below the sensitivity of the assay in nine evaluated patients. Patients also received a variety of other therapies and controlled trials are needed. The use of convalescent plasma in COVID-19 is reviewed separately. (See "COVID-19: Convalescent plasma and hyperimmune globulin" and "COVID-19: Management in hospitalized adults", section on 'Antibody-based therapies (anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma)'.)

Specific infections — When rituximab results in hypogammaglobulinemia, sinopulmonary infections are the most common manifestation. However, rituximab therapy has been associated with serious and fatal infections, such as progressive multifocal leukoencephalopathy (PML), reactivation of latent hepatitis B infection, and severe cytomegalovirus infection [46], which are not known to be related to hypogammaglobulinemia. This may result from impaired antigen presentation, reduced B cell costimulation of T cells, and impaired interactions with other immune effector cells [47,48].  

PML due to reactivation of latent JC virus infection is a rare opportunistic infection that occurs in patients with autoimmune rheumatic diseases, especially in patients with systemic lupus erythematosus (SLE). A report from the US Food and Drug Administration Adverse Event Reporting System database listed 34 reports of PML in association with patients receiving a biologic. The majority of the patients with SLE and rheumatoid arthritis who developed PML had received rituximab [49]. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)

Hepatitis B virus (HBV) reactivation is discussed separately. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy", section on 'How to assess risk'.)

Other infectious complications include anecdotal reports of cerebral toxoplasmosis [50], granulomatous Acanthamoeba encephalitis [51], and relapsing babesiosis [52].

Ofatumumab — Ofatumumab is a fully human monoclonal anti-CD20 monoclonal antibody, which targets a distinct epitope on the CD20 molecules of B cells. It has utility in treating patients with chronic lymphocytic leukemia (CLL) that is refractory to other therapies and is in clinical trials for other malignant and rheumatologic diseases [53-55]. Ofatumumab depletes peripheral blood B cells [53]. Limited information is available from clinical studies on the immune effects of this drug. In one uncontrolled trial of 33 patients with CLL, 51 percent experienced infections, although most were mild or moderate [54]. Other toxicities included thrombocytopenia (9 percent), neutropenia (6 percent), and anemia (3 percent) [54]. Reactivation of hepatitis B has also been reported. Preventative measures are discussed separately. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Anti-CD20 monoclonal antibodies' and "Prevention of infections in patients with chronic lymphocytic leukemia" and "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Others — Other anti-CD20 agents include ocrelizumab, veltuzumab, 90Y-ibritumomab tiuxetan, 131I-tositumomab, and obinutuzumab. These each likely increase the risk of severe respiratory tract infections and HBV reactivation, and may increase the risk of hepatitis C reactivation and VZV [8].

Inotuzumab ozogamicin — Inotuzumab ozogamicin is an antibody-drug conjugate used to treat relapsed or refractory B cell precursor acute lymphoblastic leukemia. The humanized monoclonal antibody component (inotuzumab) is directed against CD22 and is linked to a cytotoxic agent of the calicheamicin class, ozogamicin. This biologic was approved in the United States in 2017 for the treatment of adults with relapsed or refractory B cell precursor acute lymphoblastic leukemia. In a large, open-label phase 3 randomized trial comparing inotuzumab ozogamicin with standard intensive chemotherapy, cytopenias were the most common adverse effect [56]. The incidence of infection (eg, sepsis or pneumonia) was similar between both study groups. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Inotuzumab ozogamicin'.)

MONOCLONAL ANTIBODIES TO T CELLS

OKT3 — OKT3 (muromonab-CD3) is a murine IgG2 monoclonal antibody that binds to the CD3-epsilon chain of the T cell receptor-CD3 complex. It was introduced in the mid-1980s and used for treatment of acute allograft rejection and steroid-resistant cardiac or hepatic allograft rejection. Following administration, OKT3 causes a transient activation of T cells, the release of cytokines, and the subsequent blocking of T cell proliferation. Thereafter, a rapid and profound T cell lymphopenia ensues. With the initial dose, patients may experience an acute cytokine release phenomenon with a flu-like illness, capillary leak, hypotension, and even multiorgan failure [57]. OKT3 is no longer used as induction therapy in lung transplantation in the United States and Europe due to these severe toxicities, although it is still in use in some other countries. The prevention and treatment of OKT3 reactions is reviewed separately. (See "Induction immunosuppression following lung transplantation", section on 'Muromonab-CD3'.)

OKT3 immunosuppression results in increased susceptibility to infection, particularly with herpes viruses and bacteria. Patients treated with OKT3 should receive prophylaxis for cytomegalovirus (CMV) infection and for Pneumocystis jirovecii pneumonia. Patients with confirmed prior tuberculosis (TB) infection may reactivate disease, and those who develop TB post-OKT3 therapy have more problems than individuals who never received OKT3. [58]. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis' and "Tuberculosis in solid organ transplant candidates and recipients".)

Alemtuzumab — Alemtuzumab (anti-CD52) is a humanized T cell-depleting monoclonal antibody that has been used for induction therapy of solid organ transplantation [59]. It is only available in the United States directly from the manufacturer for B cell chronic lymphocytic leukemia (CLL) and select off-label uses [60]. It is also used in the treatment of CLL and other lymphoid malignancies, as well as in some preparative regimens for nonmyeloablative stem cell transplantation [61,62]. Alemtuzumab therapy can result in lymphopenia and neutropenia [63]. Following administration, there is profound depletion of T (and B) cells for a period of several months or longer. In a review of the lymphocyte subset data from phase 3 trials comparing the efficacy of alemtuzumab and interferon beta-1a for multiple sclerosis, there was a more marked depletion of CD4 T cells compared with CD8 T cells. More importantly, there was a rapid hyper-repopulation of immature B cells in the absence of regulatory CD4 T cells that led to the generation of secondary autoimmune disease, including antidrug antibodies and other antibody-mediated autoimmune diseases [64].

Infectious complications of alemtuzumab therapy include bacteremia, sepsis, CMV, Pneumocystis pneumonia, and Epstein-Barr virus infections [63,65]. These adverse effects may be more problematic when using alemtuzumab for rejection episodes compared with its use for induction therapy [66]. In one study, there was evidence that some memory cells are resistant to depletion, potentially providing patients with some protection against severe viral infections [67]. The possibility of increased risk of malignancy after alemtuzumab therapy is not known.

Prophylaxis for prevention of infections in specific patient groups receiving alemtuzumab is presented separately. (See "Overview of the complications of chronic lymphocytic leukemia", section on 'Infection' and "Treatment of aplastic anemia in adults" and "Prevention of infections in patients with chronic lymphocytic leukemia", section on 'Alemtuzumab'.)

Patients receiving alemtuzumab should receive Pneumocystis pneumonia prophylaxis for a minimum of two months after completion of therapy or until the CD4 count is >200 x 107 cells/microL (whichever occurs later). This is reviewed separately. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Indications'.)

Basiliximab and daclizumab — Basiliximab and daclizumab are monoclonal antibodies to the interleukin (IL)-2 receptor alpha chain (CD25). T cell activation normally leads to upregulation of the high-affinity IL-2 receptor involving the expression of the IL-2 receptor alpha chain (CD25) that associates with the IL-2 receptor beta and gamma chains. Daclizumab (Zenapax [brand name]) was voluntarily withdrawn from the market in 2008 due to low demand. In 2018, daclizumab was voluntarily withdrawn worldwide because of an association with immune-mediated encephalitis and liver toxicity [68,69].

Basiliximab (Simulect [brand name]) is a chimeric monoclonal antibody with an estimated elimination half-life of seven days used in renal transplant patients. Basiliximab inhibits the generation of antigen-specific cytotoxic T cells. Basiliximab is as effective as OKT3 in preventing graft rejection but has fewer side effects associated with cytokine release syndrome [70,71]. It may also be useful in the prevention of graft-versus-host disease (GVHD), following hematopoietic stem cell transplantation, and in the treatment of certain autoimmune diseases. Blocking the IL-2 receptor is immunosuppressive and appeared to increase the risk of infection in patients with GVHD in one study, although the frequency of serious infections is not well-reported [72]. However, in a three-year follow-up study of renal transplant patients, the use of daclizumab did not result in an increased risk of death from infection or malignancy [73].

ANTICYTOKINE THERAPY

Biologics that inhibit B cell function — A number of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus (SLE), and Sjögren syndrome, exhibit evidence of overactive humoral immune responses thought to be mediated by cytokines that are important in B cell homeostasis and growth [74]. These cytokines include interleukin (IL)-6, IL-21, and B cell-activating factor or B lymphocyte stimulator (BlyS) [75].

Tocilizumab — Tocilizumab is a humanized monoclonal antibody to the IL-6 receptor that is used in the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. The drug competitively blocks the interaction of IL-6 with its receptor. IL-6 functions in the regulation of the immune response, specifically in the proliferation and differentiation of T cells and the terminal differentiation of B cells. IL-6, together with transforming growth factor-beta, also has a role in the development of regulatory T cells and has been implicated in autoimmune diseases. IL-6, like IL-1, is important for both systemic and local inflammation that is often associated with symptoms like fever, fatigue, and anorexia, with changes in acute-phase proteins in the plasma (eg, C-reactive protein and fibrinogen).

Based on available data, the risk of serious infections with tocilizumab therapy is lower than that with agents that suppress B cells more globally, and an increased risk of malignancy or autoimmunity has not been observed. In long-term safety studies of tocilizumab in patients with rheumatoid arthritis, the serious adverse event rate was 27.5 events per 100 patient-years and 5.7 serious infections per 100 patient-years [76]. Infections (eg, pneumonia, herpes zoster, and bronchitis) were the most frequent serious adverse effects , although most patients recovered with appropriate treatment, and outcomes were comparable with that of patients treated with tumor necrosis factor (TNF) inhibitors. Because tocilizumab is anti-inflammatory, there is a theoretical concern for a delay in the diagnosis of infection due to reduced fever and inflammation. In a 2011 meta-analysis, opportunistic infections developed at a rate of 0.23 episodes per 100 patient-years. Infections included active tuberculosis, nontuberculous mycobacteria, invasive candidiasis, P. jirovecii pneumonia, and cryptococcosis, especially with higher doses of tocilizumab [77].

In a subsequent postmarketing surveillance study of 5573 patients with rheumatoid arthritis treated with tocilizumab in Japan, the overall incidence of serious infection was 3.67 per 100 patient-years. Risk factors included advanced age, long disease duration, and respiratory comorbidities. Most infections were bacterial in nature, including pneumonia, cellulitis, and sepsis, although atypical mycobacterial infections, P. jirovecii pneumonia, and herpes zoster infections occurred as well [78,79]. Studies of tocilizumab in patients with rheumatoid arthritis are reviewed in more detail separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Methotrexate plus IL-6 inhibitor/IL-6 inhibitor monotherapy' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tocilizumab'.)

Siltuximab is a chimeric anti-IL-6 monoclonal antibody approved for the treatment of patients with multicentric Castleman disease who do not have HIV or human herpesvirus-8. Siltuximab may mask signs and symptoms of acute inflammation (suppression of fever and acute-phase reactants, such as C-reactive protein) and should not be given to patients with severe infections. However, in a long-term safety study of up to seven years treatment, there were very few serious infections [80]. (See "HHV-8-negative/idiopathic multicentric Castleman disease", section on 'IL-6 inhibitors'.)

Belimumab — Belimumab is a human monoclonal antibody that binds to soluble human BlyS and inhibits its biologic activity. It is approved for the treatment of patients with SLE. In a long-term safety study of four years of belimumab treatment (248 patients completed four years of treatment), the rate of serious and/or severe infections was highest in the first year (8.3 per 100 patient-years) and declined in years 2 to 4. Cellulitis and pneumonia were the most common serious infections. Two opportunistic infections were reported (coccidioidomycosis and cytomegalovirus pneumonia) [81].

Biologics that neutralize or block cytokines

IL-1-blocking agents — The blockade of IL-1 has been an important therapeutic approach in the treatment of several autoimmune and autoinflammatory diseases [82,83]. Several recombinant drugs act as competitive inhibitors by binding to the IL-1 receptor. Anakinra is a recombinant IL-1 receptor antagonist that is similar to the human native molecule and acts by blocking the binding of IL-1-alpha and IL-1-beta to the IL-1 receptor. Other biologics that achieve similar effects are canakinumab, a fully human IgG1 monoclonal antibody targeting IL-1-beta and rilonacept, a fusion protein of the ligand-binding domain of the extracellular portion of the IL-1 receptor and the IL-1 receptor accessory protein linked to the Fc portion of human IgG1. Rilonacept acts by inhibiting the binding of IL-1-alpha and IL-1-beta to the IL-1 receptor. As a proinflammatory cytokine, IL-1 plays a major role in the protection against many pathogens. In clinical trials with these IL-1 inhibitors in patients with rheumatoid arthritis, infections were mild-to-moderate, especially in those patients concomitantly treated with other immunosuppressive drugs [84]. In the autoinflammatory diseases, these biologics are associated with increased respiratory infections but are usually well-tolerated. Opportunistic infection and tuberculosis have only been reported rarely. In a large clinical trial of canakinumab for a 48-month period in the setting of atherosclerotic disease, the incidence of fatal infection or sepsis was higher in the canakinumab group compared with placebo (0.31 versus 0.18 episodes per 100 patient-years). Risk factors included older age and diabetes [85].

IL-5 blocking agents — Mepolizumab, a humanized IgG1 monoclonal antibody, and reslizumab, a humanized IgG4 monoclonal antibody, are biologic agents that block IL-5 from binding to its receptor. These are used in eosinophilic asthma and other eosinophilic disorders (eg, eosinophilic granulomatosis with polyangiitis). Published studies have not shown any significant increase in infection. In two clinical studies of mepolizumab, two patients developed herpes zoster infection [86,87]. The package insert suggests vaccination with herpes zoster vaccine and to treat patients with pre-existing helminth infections before starting therapy. Benralizumab is a humanized, afucosylated monoclonal antibody directed at the alpha chain of the IL-5 receptor and is approved by the US Food and Drug Administration for the treatment of severe eosinophilic asthma. No significant increase in infection was seen in the phase III clinical trial [88].

IL-4 and IL-13 blocking agents — IL-4 and IL-13 signal through a shared receptor component, IL-4 receptor alpha. Signaling through the receptors for IL-4 and IL-13 contribute to the immune pathways involved in allergic disease (eg, asthma and atopic dermatitis). Dupilumab, a fully human monoclonal antibody directed at the alpha subunit of the IL-4 receptor that blocks both IL-4 and IL-13 signaling, has been approved for moderate-to-severe atopic dermatitis in adults not adequately controlled with topical therapies [89,90] and as an add-on maintenance therapy in moderate to severe asthma in patients 12 years and older [91]. In a phase IIb trial, there was a 12 percent incidence of herpes virus infection in the 100 mg dupilumab group [92]. However, the rates of eczema herpeticum and herpes zoster were similar between the placebo and treatment groups in other atopic dermatitis trials.

IL-17A blocking agents — IL-17A blocking agents include secukinumab, ixekizumab, and brodalumab.

Secukinumab is a fully human IgG1k monoclonal antibody that selectively targets the binding of IL-17A to its receptor, inhibiting the downstream release of proinflammatory cytokines and chemokines that contribute to autoimmune and inflammatory diseases [93]. Secukinumab was the first IL-17A-targeted agent approved for the treatment of moderate-to-severe plaque psoriasis in 2015. Subsequently, it has been used in the treatment of adults with active ankylosing spondylitis and psoriatic arthritis.

Ixekizumab is a humanized IgG4 monoclonal antibody targeting IL-17A, which is also used for moderate-to-severe plaque psoriasis.

Brodalumab is a fully human IgG2 monoclonal antibody targeting the IL-17 receptor, which also blocks the activity of other IL-17 cytokines (eg, IL-17F, IL-17E [also known as IL-25], and the IL-17A/F heterodimer). Brodalumab is approved for use in adults with moderate-to-severe plaque psoriasis who have failed to respond or had lost response to other systemic therapies.

A pooled analysis of a number of studies encompassing 3993 patients with moderate-to-severe plaque psoriasis treated with secukinumab at various doses or etanercept found that upper respiratory tract infections were the most common infectious events [94]. Mucosal or cutaneous candidiasis was higher among patients receiving secukinumab, and this correlated with the cumulative dose. No serious systemic infections or opportunistic infections were observed. Neutropenia occurred rarely and was mostly grade 1. The infection rates and the increased prevalence for mucocutaneous candidiasis with brodalumab and ixekizumab were similar to secukinumab. A systematic review of 13 trials of IL-17-targeted agents for psoriasis or psoriatic arthritis found that mucocutaneous Candida infection occurred in 4, 1.7, and 3.3 percent of patients treated with brodalumab, secukinumab, and ixekizumab (compared with 0.3, 2.3, and 0.8 percent for those receiving placebo, ustekinumab, or etanercept, respectively) [95]. Similarly, in two trials of secukinumab in patients with active ankylosing spondylitis, candidiasis was more common in the secukinumab group (0.9 events per 100 patient-years) [96]. Candida infection did not lead to discontinuation of the study and resolved with standard antifungal therapy. Grade 3 and grade 4 neutropenia was also low (0.7 events per 100 patient-years). In a review of the data from a Danish registry of patients with moderate-to-severe psoriasis treated with biologics, biosimilars, or novel small molecule agents, secukinumab had the highest rate of infections, while ustekinumab was well-tolerated [97].

IL-12 and IL-23 blocking agents — Ustekinumab is a fully human IgG1 monoclonal antibody that binds to the common p40 subunit of the receptor shared by IL-12 and IL-23, inhibiting the biologic functions of both cytokines. Ustekinumab was first approved for the treatment of moderate-to-severe plaque psoriasis or active psoriatic arthritis and subsequently for severe Crohn disease refractory to other biologic therapies. There was no significant increase in the incidence of infections in several randomized, controlled studies [98-100]. Postmarketing surveillance studies of patients with psoriasis showed that the rates of serious infection were lower than in patients receiving anti-TNF-alpha agents or conventional chemotherapy [101].

AGENTS DISRUPTING T CELL COSTIMULATION — T cells need two signals to undergo activation. The first involves direct binding of the T cell antigen receptor by antigenic peptide presented by antigen-presenting cells (APCs) in the context of the major histocompatibility complex (human-leukocyte antigen surface proteins). The second signal involves specific costimulatory pathways. CD28 on T cells bind its ligands, CD80 (B7-1) and CD86 (B7-2), on APCs. The presence of both signals provides an activation signal to T cells. In contrast, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4 or CD152) competes for binding to CD80/CD86, and this interaction results in suppression of T cell activation. (See "The adaptive cellular immune response: T cells and cytokines".)

Abatacept — Abatacept targets T cell activation by disrupting CD28 costimulation [102]. It is a fusion protein of the extracellular domain of human CTLA-4 linked to a modified Fc portion of human IgG1 (CTLA-4-Ig). Abatacept as monotherapy has been shown to be effective in refractory rheumatoid arthritis [103] and juvenile idiopathic arthritis (JIA). (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Methotrexate plus abatacept' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Abatacept'.)

Abatacept does not appear to greatly increase the risk of infectious complications in most patients with rheumatoid arthritis. The safety of abatacept was assessed in several trials [104,105]. Serious infection occurred at an incidence rate of 4.3 per 100 patient-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) observed in seven patients in one study of psoriasis and three patients in another. 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) [106]. In a compilation of eight clinical trials of patients with rheumatoid arthritis, there was no difference in the infection rate between those patients receiving abatacept versus placebo [107]. Using a Medicare database of patients with rheumatoid arthritis who had prior treatment with a biologic, the risk of infections in hospitalized patients was significantly higher for tumor necrosis factor inhibitors and rituximab compared with subjects receiving abatacept [108].

These results may not be applicable to a healthier, younger cohort of patients with rheumatoid arthritis who have not had prior therapy with a biologic, and fewer data are available about this group of patients. In a long-term extension study of 190 patients with JIA ages 6 to 17 years, there were no cases of tuberculosis or malignancies. Five patients developed serious infections, and one patient developed multiple sclerosis [109].

Abatacept was not associated with a higher frequency of autoimmune serologies, and the frequency of malignancies was the same as the placebo group in these studies [104,105].

Belatacept — Belatacept is a second-generation CTLA-4-Ig that has superior binding to CD80 and CD86, compared with abatacept. This medication has been used primarily in organ transplantation [110]. It is frequently used as a component of a triple drug regimen (often with prednisone and mycophenolate mofetil) for patients who do not tolerate calcineurin inhibitors. Belatacept should not be administered to patients who are Epstein-Barr virus (EBV)-seronegative and who received a transplant from an EBV-seropositive donor or to recipients with unknown EBV status, because of the risk of EBV-associated post-transplant lymphoproliferative disorder (PTLD). This is discussed more elsewhere. (See "Kidney transplantation in children: Immunosuppression".)

AGENTS INHIBITING LEUKOCYTE MOVEMENT — Agents that inhibit leukocyte movement include natalizumab, efalizumab, and fingolimod.

Natalizumab and efalizumab — Natalizumab (anti-alpha-4 integrin) and efalizumab (anti-CD11-alpha) inhibit the normal migration of leukocytes. The agents have been used in the treatment of multiple sclerosis, Crohn disease, and chronic moderate-to-severe plaque psoriasis [111,112]. Both agents have been associated with progressive multifocal leukoencephalopathy (PML), and efalizumab was withdrawn from the American and Canadian markets for this reason [113]. Natalizumab and PML are discussed separately. (See "Disease-modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse effects", section on 'Natalizumab' and "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease", section on 'Other biologic agents'.)

Fingolimod — Fingolimod is a sphingosine-1-phosphate-receptor modulator, which acts by preventing lymphocyte egress from lymph nodes. This agent has been approved for use in the management of relapsing multiple sclerosis, although it is associated with life-threatening herpes virus infections and malignancies. There was also a higher rate of lower respiratory tract infections (including bronchitis and pneumonia) in the fingolimod study groups [114]. Specific measures to prevent varicella-zoster infections are reviewed separately. (See "Disease-modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse effects", section on 'Fingolimod'.)

TUMOR NECROSIS FACTOR INHIBITORS — Several inhibitors of tumor necrosis factor-alpha (TNF-alpha) have been developed:

Infliximab – A chimeric (mouse/human) anti-TNF-alpha monoclonal antibody

Adalimumab – A fully human monoclonal anti-TNF-alpha antibody

Certolizumab pegol – A PEGylated Fab fragment of a humanized monoclonal antibody to TNF-alpha

Golimumab – A human monoclonal anti-TNF-alpha antibody

Etanercept – A soluble TNF-alpha receptor fusion protein

The risk of infection, malignancy, and autoimmune disorders associated with these agents is reviewed in detail separately in various topics:

(See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections".)

(See "Tumor necrosis factor-alpha inhibitors and mycobacterial infections".)

(See "Hepatitis B virus reactivation associated with immunosuppressive therapy", section on 'Categorizing level of risk'.)

(See "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)

(See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases".)

MONOCLONAL ANTIBODIES TO COMPLEMENT PROTEINS — Biologic agents that interfere with the function of specific complement components have been developed. Adverse immunologic effects potentially mimic deficiency of that complement protein.

Eculizumab — Eculizumab is a humanized monoclonal antibody that binds to the C5 component of complement and inhibits terminal complement activation. This drug is used in the treatment of paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), adult patients with generalized myasthenia gravis who are anti-acetyl choline receptor antibody positive, and adult patients with neuromyelitis optica spectrum disorder who are anti-aquaporin-4 antibody positive. It theoretically increases the risk of serious infections with neisserial organisms, including Neisseria meningitidis and N. gonorrhoeae, as discussed separately. (See "Treatment and prevention of meningococcal infection", section on 'Patients receiving C5 inhibitors'.)

SMALL MOLECULE KINASE INHIBITORS

Ibrutinib — Ibrutinib is a small molecule inhibitor of Bruton tyrosine kinase (BTK), which has antineoplastic potential. BTK is a member of the src-related BTK/Tec family of cytoplasmic tyrosine kinases. Ibrutinib binds to and irreversibly inhibits BTK activity, thereby preventing both B cell activation and B cell-mediated signaling. This leads to an inhibition of the growth of malignant B cells that overexpress BTK. BTK is required for B cell receptor signaling, plays a key role in B cell maturation, and is overexpressed in a number of B cell malignancies. Ibrutinib is given orally for refractory chronic lymphocytic leukemia (CLL), other B cell malignancies, and Waldenstrom macroglobulinemia. It is usually given with other agents, notably rituximab, so its effect on the immune system is not well-defined. Neutropenia and hypogammaglobulinemia have been reported [115,116]. The risk of infections in patients with CLL is discussed in detail separately. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Ibrutinib'.)

Idelalisib — Idelalisib disrupts B cell receptor signaling, similar to ibrutinib, although through inhibition of the delta isoform of phosphatidylinositol 3-kinase. Idelalisib is associated with an increase in opportunistic infections, and the manufacturer recommends prophylaxis for P. jirovecii pneumonia and monitoring for cytomegalovirus. (See "Prevention of infections in patients with chronic lymphocytic leukemia", section on 'Bruton tyrosine kinase and phosphatidylinositol 3-kinase inhibitors' and "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Idelalisib'.)

Janus kinase inhibitors — Janus kinases (JAK) are a family of nonreceptor tyrosine kinases that are important for cytokine receptor triggering of signals through the signal transducer and activator of transcription (STAT) proteins. Phosphorylated STATs dissociate from their receptor subunits, homo- or hetero-dimerize, and translocate to the cell nucleus to regulate gene transcription. The JAK family is comprised of four members: JAK1, JAK2, JAK3, and tyrosine kinase 2 (Tyk2). Each cytokine receptor requires a pair of two associated JAKs to signal through the cytokine receptor. The JAK pathways are important for both immune and hematopoietic cells [117].

Tofacitinib — Tofacitinib is the first small molecule selective JAK inhibitor drug approved in the United States for the treatment of rheumatoid arthritis in patients with moderate-to-severe disease after disease-modifying antirheumatic drug (DMARD) therapy. In a phase 3b/4 randomized, controlled clinical trial, tofacitinib was well-tolerated [118]. In a retrospective cohort study of databases containing over 20,000 patients, the rate of serious infection in patients on tofacitinib was not significantly higher than DMARDs, tumor necrosis factor (TNF) inhibitors, and non-TNF biologics [119].

Tofacitinib inhibits JAK1 and JAK3 more completely than JAK2 and inhibits Tyk2 to a lesser degree. Tofacitinib was shown to inhibit interleukin (IL)-4-dependent T helper type 2 cell differentiation and interfere with T helper type 17 cell differentiation when naïve human and mouse T cells were stimulated with IL-6 and IL-23 in vitro. In addition, activation of STAT1 and the generation of T helper type 1 cells are blocked. The authors concluded that the modulation of immune pathways was likely based on the ability of tofacitinib to block multiple cytokine pathways, particularly those of the gamma-c-cytokine signaling pathways [120]. In clinical studies, there is a slight-to-moderate decrease in total lymphocyte and T cell numbers, a dose-dependent decrease in natural killer cells, and an increase in B cell numbers. Although there may be a slight decrease in serum immunoglobulins, this observation may be due to the decrease in systemic inflammation associated with tofacitinib therapy. Immune responses following immunization with influenza appears to be intact [121]. Decreased responses to pneumococcal immunization, especially in combination with methotrexate, have been observed [122]. Tofacitinib therapy is associated with an increased risk of herpes zoster infection [123]. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tofacitinib'.)

Ruxolitinib — Ruxolitinib is a JAK inhibitor drug used in the treatment of intermediate or high-risk myelofibrosis and for polycythemia vera when there has been an inadequate response to or intolerance of hydroxyurea [124,125]. It is also under evaluation for hair loss, especially autoimmune alopecia, both orally and topically [126]. Adverse immune effects are discussed separately. (See "Management of primary myelofibrosis", section on 'Ruxolitinib'.)

CHECKPOINT INHIBITORS — Checkpoint inhibitors represent a new class of biologics that have emerged primarily in the immunotherapy of cancer. These agents block the normal T cell inhibitory signals thereby removing T cell down-regulatory signals and increasing the immunologic response to a variety of malignant cells. Checkpoint inhibitors are directed at two different pathways, one involves inhibition of cytotoxic T-lymphocyte associated protein 4 (CTLA4/CD152) (ipilimumab) and the other via inhibition of the program cell death protein 1 (PD-1/CD279) (pembrolizumab, nivolumab, cemiplimab) or its partner protein PD-L1 (atezolizumab, avelumab, durvalumab). As a class of agents, the major side effects include rash, diarrhea, and fatigue, as well as signs of widespread organ inflammation involving the skin, lung, gastrointestinal tract, liver, heart, pancreas, thyroid, pituitary, or nervous system associated with an overall increase in the immunologic response including autoreactivity. In general, these agents are not associated with increased rates of infection that can be directly linked to their inhibition of normal down regulation of the immune response. (See "Toxicities associated with checkpoint inhibitor immunotherapy" and "Principles of cancer immunotherapy", section on 'Checkpoint inhibitor immunotherapy'.)

SUMMARY AND RECOMMENDATIONS

Biologic therapies that suppress immune function have the potential to cause serious unintended immunologic effects, such as an increased risk of infection or the development of malignant or autoimmune diseases. The risk of immune complications is influenced by the specific agent used and its dose and duration, as well as patient-specific factors, such as the nature of the underlying disease, the patient's functional status and medical fragility, and the use of combinations of immunosuppressive agents. Whenever possible, the potential complications of these drugs should be considered in advance of their use. Patients can be immunized against some pathogens and tested for other pathogens that may reactivate after immunosuppression, including hepatitis B virus and tuberculosis. (See 'Overview' above.)

Antithymocyte globulin (ATG) is used to deplete T cells in the peripheral blood and inhibit T and B cell interactions. Its use increases susceptibility to herpes virus, especially cytomegalovirus (CMV), and inhibits vaccine response if given before vaccination. (See 'Antithymocyte globulin' above.)

Rituximab is a monoclonal antibody to B cells that depletes peripheral blood B cells for a period of months. When possible, immunizations should be administered prior to rituximab therapy. Rituximab may cause hypogammaglobulinemia in a subset of patients, especially if given in multiple cycles or with glucocorticoids or fludarabine. Although usually transient, this adverse effect can be persistent and clinically significant. For patients with recurrent infections following rituximab therapy, combined with either low serum IgG or impaired vaccine response, we suggest either antibiotic prophylaxis or immune globulin replacement (Grade 2C). These patients should be further evaluated for a possible underlying primary immunodeficiency disorder, such as common variable immunodeficiency. Rituximab therapy has been also been associated with fatal progressive multifocal leukoencephalopathy (PML), reactivation of latent hepatitis B infection, and severe CMV infection, and it can cause late-onset neutropenia. (See 'Monoclonal antibodies to B cells' above.)

Monoclonal antibodies to T cells include alemtuzumab and basiliximab. Alemtuzumab therapy can result in lymphopenia and neutropenia and a profound depletion of T and B cells for several months. Infectious complications of alemtuzumab therapy include bacteremia, sepsis, CMV, Pneumocystis pneumonia, and Epstein-Barr virus (EBV). (See 'Monoclonal antibodies to T cells' above.)

Monoclonal antibodies that inhibit B cell function include tocilizumab (anti-interleukin-6) and belimumab (anti-soluble human B lymphocyte stimulator) have a lower risk of serious infections than that with drugs that suppress B cells more globally. In addition, an increased risk of malignancy or autoimmunity has not been observed. (See 'Anticytokine therapy' above.)

Abatacept and belatacept are agents that interfere with T cell costimulation. Abatacept has been used primarily in patients with rheumatoid arthritis and juvenile idiopathic arthritis, and infectious complications in patients with rheumatoid arthritis appear to be less common than with tumor necrosis factor inhibitors or rituximab. Belatacept has been used mostly in renal transplantation and should not be given to patients who are EBV-seronegative and who received a transplant from an EBV-seropositive donor or to recipients with unknown EBV status, because of the risk of EBV-associated post-transplant lymphoproliferative disorder. (See 'Agents disrupting T cell costimulation' above.)

Agents that inhibit leukocyte movement include natalizumab and fingolimod. Natalizumab is used in multiple sclerosis, Crohn disease, and plaque psoriasis and has been associated with PML. Fingolimod is administered to patients with multiple sclerosis and is associated with life-threatening herpes virus infections and malignancies. (See 'Agents inhibiting leukocyte movement' above.)

Small molecule kinase inhibitors include ibrutinib, which inhibits Bruton tyrosine kinase, and the Janus kinase inhibitors, tofacitinib and ruxolitinib. Ibrutinib inhibits B cell activation and B cell-mediated signaling and can cause neutropenia and hypogammaglobulinemia. (See 'Small molecule kinase inhibitors' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.

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