88 Biologics

Introduction

Biologic therapies have revolutionized nearly every discipline of medicine. As our understanding of the relevant immunologic pathways of cancer, rheumatologic disease, hematopoietic and solid organ transplantation has evolved, so has the discovery of new monoclonal antibodies for targeted therapy. Currently, over 100 monoclonal antibodies have been approved for clinical use. This chapter highlights two commonly used monoclonal antibodies and their associated infectious complications. We outline the immunologic mechanism of action and indications of use of these important biologic therapies. We also examine the commonly reported infectious complications and summarize the role for pre-implementation diagnostics, post-implementation surveillance, and antimicrobial prophylaxis.

Lymphocyte-depleting therapies

Monoclonal antibodies that target surface proteins found on lymphocytes including alemtuzumab (humanized chimeric monoclonal antibody that recognizes CD52) and rituximab (chimeric murine/human monoclonal antibody directed against the CD20) have been used successfully in the management of lymphoproliferative disorders and autoimmune diseases. We focus on rituximab because of the propensity of available data. Rituximab is constructed with human IgG1 and kappa-chain constant regions and heavy and light chain variable regions from a murine antibody to the CD20 antigen, a hydrophobic transmembrane protein which is present on mature B lymphocytes but absent from the surface of normal plasma cells. Rituximab eliminates mature B cells. Although the CD20 antigen is absent from the surface of mature plasma cells, rituximab can be complicated by hypogammaglobulinemia; the precise mechanism is incompletely understood. Rituximab is currently approved for the treatment of non-Hodgkin’s lymphoma (NHL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. In addition, rituximab is approved as second-line therapy for rheumatoid arthritis (RA) not responsive to tumor necrosis factor (TNF)-blocking agents. This anti-CD20 monoclonal antibody has also been widely used off-label for lupus, autoimmune hematologic diseases (including primary idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia), multiple sclerosis, bullous dermatologic disorders, immune-mediated glomerular disease, and cryoglobulinemia.

The B-cell immunomodulatory effects of rituximab can be long lasting. Rituximab persists in the serum for many months after the drug is initially administered and can cause sustained depletion of B cells for 6 to 9 months after completion of therapy. One year after completion of rituximab, even when the quantitative number of B cells has recovered, these populations of B cells are often functionally nonequivalent to pre-rituximab B cells, with decreased expression of CD27, suggesting a relative deficiency in memory B-cell populations. Additionally, late-onset neutropenia can complicate rituximab therapy, with the median time to onset of neutropenia around 102 days, often coinciding with B-lymphocyte depletion.

The nature and duration of these immunomodulatory effects of rituximab have implications for infectious complications. In a study evaluating the pre-emptive use of rituximab in treating Epstein–Barr virus (EBV)-related post-transplantation lymphoproliferative disorder (PTLD), individuals receiving rituximab had a significantly higher incidence of bacterial infections, predominantly from gram-negative bacilli (including Pseudomonas and Haemophilus), gram-positive cocci, and atypical mycobacteria, as compared to controls. Increased rates of post-rituximab viral infections have also been reported, with hepatitis B virus (HBV) reactivation, cytomegalovirus (CMV) infection, and varicella-zoster virus (VZV) all well documented, with the median time from initiation of rituximab treatment to diagnosis of viral infection approximately 5 months. HBV reactivation occurring in the context of rituximab therapy has been specifically associated with significant morbidity and mortality. The median duration of time from rituximab administration to HBV reactivation is approximately 3 months, with 29% of cases occurring greater than 6 months after the last dose of rituximab. While the control of HBV infection is mediated by HBV-specific cytotoxic T lymphocytes, the profound and durable depletion of circulating B lymphocytes prevents adequate antigen presentation and is thought to be a major contributing factor involved in HBV viral replication and reactivation complicating rituximab therapy. Although the risk of HBV reactivation is greatest in hepatitis B surface antigen positive (HBsAg (+)) individuals, HBV core antibody positive patients (HBcAb (+)) are also at risk for serious complications. Moreover, in a meta-analysis of patients with NHL treated with rituximab therapy where 387 individuals were found to have HBV reactivation, 304 were HBcAb (+)/HBsAg (−) individuals while only 83 individuals were HBsAg (+). Thus, early identification of patients at risk for HBV reactivation – before they receive rituximab therapy – is critical for avoiding morbidity and mortality from HBV-related disease. In patients who will receive rituximab therapy, screening for chronic HBV infection with HBsAg, HBcAb, HBsAb, and serum HBV DNA testing is indicated. HBsAg (+) individuals – regardless of whether HBV DNA is detectable in the serum – should be initiated on antiviral therapy immediately to block viral replication and disease progression prior to administration of rituximab. While there have been differing opinions as to whether HBcAb (+)/HBsAg (−) individuals should be monitored by serial HBV DNA and liver function tests (LFTs) versus immediately placed on pre-emptive antiviral therapy, more recent recommendations are to use prophylactic antiviral therapy in these individuals as well. While the nucleoside analog lamivudine has been most extensively studied for antiviral prophylaxis of chronic HBV, high rates of lamivudine resistance have been reported. Therefore, newer nucleoside analogs including entecavir and tenofovir – either alone or in combination – are the preferred prophylactic therapy for chronic HBV infection in the setting of rituximab administration. Current guidelines suggest initiation of anti-HBV viral therapy 1 to 2 weeks prior to rituximab therapy with continuation of antiviral therapy for a minimum of 6 months after this biologic therapy is discontinued, and recommend concomitant close monitoring of HBV DNA and LFTs during the course of rituximab therapy.

Progressive multifocal leukoencephalopathy (PML), a severe and fatal central nervous system (CNS) demyelinating disease caused by reactivation of the polyomavirus John Cunningham (JC) virus, has also been reported in individuals with lymphoproliferative disorders treated with rituximab. For example, HIV-negative individuals with CLL treated with fludarabine and rituximab have been described to have clinical syndromes compatible with PML with JC virus detectable by PCR in the cerebrospinal fluid; these patients survived only months after the diagnosis of PML was made. It is not clear if PML from reactivated JC virus was a direct result of mature B-lymphocyte depletion caused by rituximab or a consequence of concurrent T-cell depleting therapies. Many patients with lymphoproliferative disorders who developed PML received multiple other chemotherapeutic agents, including purine analogs, corticosteroids, and alkylating agents in addition to rituximab, thus making it difficult to ascribe the presentation of PML to rituximab-related immunomodulatory effects alone. Nevertheless, given PML has been described in individuals receiving rituximab therapy, it remains important for clinicians to remain vigilant about any neuropsychiatric decline that may be attributable to JC virus-related disease.

While no firm guidelines exist regarding prophylaxis against Pneumocystis jirovecii (carinii) pneumonia (PCP) in non-HIV infected patients who are immunosuppressed, there is evolving evidence that PCP prophylaxis is warranted in individuals who receive rituximab as either mono or combination therapy, particularly in the setting of use in individuals for hematologic malignancies or underlying renal disease.

It is important to ensure vaccinations against polio (inactivated), influenza (inactivated), Haemophilus influenzae, pneumococcus, tetanus, diphtheria, pertussis, hepatitis A and B, and meningococcus (when indicated) are up to date in individuals who may receive lymphocyte-depleting biologic therapies. Administration of live viral vaccines during the course of or in the peri-administration period of rituximab is contraindicated. The United Kingdom Department of Health does provide some guidance on the timing of live vaccine administration in patients who receive biologic agents, suggesting that live vaccines should not be given 4 weeks before first administration of any biologic agent or 12 months after rituximab.

Tumor necrosis factor-α inhibiting therapies

Tumor necrosis factor-α (TNF-α

Related posts:

Peritonitis Diverticulitis Bordetella Syphilis and other treponematoses Hantavirus cardiopulmonary syndrome in the Americas Esophageal infections

Stay updated, free articles. Join our Telegram channel

Join