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Infections Related to Biologic Response Modifying Drug Therapy
Biologic response modifying drugs (BRMs) are substances that interact with the host immune system and modify it. BRMs include cytokines, chemokines, and antibodies that occur naturally in the body to protect against infections. Synthetic BRMs generally target or mimic natural cytokines or inhibitors—including tumor necrosis factor (TNF), interleukins (IL) 6, 12, and 23, and the receptors for IL 1 alpha (IL1α) and IL 1 beta (IL1β)—and are used to restore, boost, or dampen the host immune response. This chapter deals only with BRMs that are used to dampen the immune response in immune-mediated conditions. While very effective in reducing the underlying symptoms of the targeted condition and associated disability, BRMs also can lead to immunosuppression that persists for weeks to months following therapy. Consequently, many of these drugs have been associated with an increased risk of infection with certain viral and mycobacterial pathogens, as well as some fungal and other intracellular pathogens. Most of the data for BRMs come from adults, with recommendations for children primarily coming from small case series and cohort studies. , Table 107.1 summarizes the current US Food and Drug Administration (FDA)-approved BRMs, their mechanisms of action, route of administration, half-lives, and indications.
TABLE 107.1
FDA-Approved Biologic Response Modifying Drugs and Indications
| Generic Name (Year[s] FDA Approved for Indications) | Trade Name | Mechanism of Action | Usual Route, Half-Life | FDA-Approved Indication a |
|---|---|---|---|---|
| Infliximab (1999, 2009) | Remicade | TNF inhibitor (anti-TNF chimeric monoclonal IgG1κ antibody) | IV, 7.5–9.5 days | Crohn disease Rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis |
| Etanercept (1998) | Enbrel , , | TNF inhibitor (soluble TNF- receptor fusion protein) | SQ, 70–132 h | Juvenile idiopathic arthritis Rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis |
| Adalimumab (2002) | Humira , | TNF inhibitor (Anti-TNF humanized monoclonal IgG1 antibody) | SQ, 10–20 days | Juvenile idiopathic arthritis Rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn disease |
| Golimumab (2009) | Simponi | TNF inhibitor (Anti-TNF IgG1κ antibody) | SQ, 7–20 days | Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis |
| Certolizumab pegol (2009) | Cimzia | TNF inhibitor (PEGylated human Fab antigen binding) | SQ, 14 days | Rheumatoid arthritis, Crohn disease |
| Abatacept (2005, 2009) | Orencia | Anti-CTLA4 selective T-cell costimulation modulator protein, (blocks TNF-α , IL-2 and interferon–γ production) | IV or SQ, 8–25 days | Juvenile idiopathic arthritis Rheumatoid arthritis |
| Anakinra (2001) | Kineret | Recombinant Anti-IL1 receptor antagonist | SQ, 4–6 h | Rheumatoid arthritis |
| Rituximab (2006) | Rituxan | Anti-CD20 therapy | IV, 14–62 days | Rheumatoid arthritis, non-Hodgkin lymphoma |
| Tocilizumab (2010) | Actemra | Anti-IL6 humanized monoclonal antibody | IV, 8–14 days | Rheumatoid arthritis |
| Ustekinumab (2013) | Stelara | Anti-IL12 and IL23 humanized monoclonal antibody | SQ, 20–24 days | Psoriatic arthritis, plaque psoriasis |
| Canakinumab (2009, 2013) | Ilaris | Anti-IL1B human monoclonal antibody | SQ, 26 days | CAPS, juvenile idiopathic arthritis |
| Natalizumab (2008, 2013) | Tysabri | Humanized anti-integrin α 4 subunit monoclonal antibody (reduces leukocyte adhesion and transmigration) | IV, 11 days | Crohn disease, multiple sclerosis |
| Belimumab (2011) | Benlysta | Human IgG1λ monoclonal antibody against soluble human B lymphocyte stimulator protein | IV, 19 days | Systemic lupus erythematosus |
| Rilonacept (2008, Orphan Drug) | Arcalyst | IL1 receptor fusion protein | SQ, 8.6 days | CAPS |
| Tofacitinib (2012) | Xeljanz | Small molecule protein kinase inhibitor of JAK-3 and JAK 1 | Oral, 3 h | Rheumatoid arthritis |
CAPS, cryopyrin-associated periodic syndromes (consisting of familial cold autoinflammatory syndrome and Muckle-Wells syndrome); IV, intravenous.
a FDA approved indication: for conditions in italic, safety and efficacy have been established in children <18 years; for the remaining indications, safety and efficacy have only been shown in adults. Infliximab, etanercept, and adalimumab have been used off-label for scleritis, but none is FDA approved for this condition.
Infections Associated With use of BRMs
Overall Rate of Serious Infections
Use of BRMs has been associated with elevated risk of developing certain bacterial (mycobacterial), viral, and fungal infections. The increased risk of infection likely is also impacted by the concomitant use of other immunosuppressive agents, such as steroids and methotrexate, and the underlying inflammatory disease. ,
A Cochrane review involving >60,000 primarily adult participants receiving 9 different BRMs (adalimumab, certolizumab, etanercept, golimumab, infliximab, anakinra, tocilizumab, abatacept, and rituximab) for treatment of either rheumatoid arthritis (RA) or cancer showed an overall increased risk of serious infections (defined as associated with death, hospitalization, and/or use of intravenous antibiotics), with an odds ratio [OR] of 1.37 (95% confidence interval [CI], 1.04–1.82) compared with placebo recipients. The highest risks were seen with certolizumab (OR, 4.75, 95% CI, 1.52–18.5) and anakinra (OR, 4.05, 95% CI, 1.22–16.8). The risk of reactivation of tuberculosis (TB) among patients receiving BRMs also was elevated compared with those receiving a placebo. Other than mycobacterial infections, no other bacteria have been associated with clear evidence of elevated risk. Although BRMs increase the risk of serious infections on a temporary basis, this effect is counterbalanced by a strong positive effect on the underlying disease.
In pediatric studies, nonmycobacterial infections among patients receiving BRMs such as etanercept are similar to those receiving these BRMs, plus conventional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate. Infections seen while on these BRMs are primarily lower respiratory tract, gastrointestinal, sepsis, skin infections, and abscesses. Nonetheless, even though there is no clear evidence of increased risk of nonmycobacterial infections compared with patients on DMARDs alone, there have been case reports of sepsis and even death among patients receiving these drugs. This suggests a need for caution when using these drugs in patients who have active infections.
Rituximab-Associated Neutropenia
Rituximab-associated neutropenia (RAN) is a prolonged neutropenia lasting from 4 days to 1 year during or after completion of therapy with rituximab, primarily among adult patients being treated for lymphomas. It generally occurs in 0.02%–6% of treated patients, although was up to 25% in one series. In contrast to other BRMs in which the main risk is for mycobacterial infections, rituximab is often associated with fever and sepsis involving bacterial pathogens, especially Pseudomonas species. Circulating antibodies against neutrophils have been postulated but not proven as the cause. Among 55 children treated with rituximab for juvenile idiopathic arthritis (JIA) following failure to respond to infliximab and other DMARDs, 17 (31%) developed neutropenia between weeks 6 and 28 of treatment. During a 96-week follow up period among this cohort, 8 serious infections occurred, all of which were lower respiratory tract infections including Pneumocystis jirovecii and Mycoplasma pneumoniae ; however, there were no cases of sepsis or febrile neutropenia. Milder infections were also noted, including ear, nose, throat (14%), and skin (11%) infections, as well as four cases of herpetic infections. The neutrophil count was <1500/μL in 9 (16%) of the patients, <1000/μL in 5 (9%) of the patients, and <500/μL in 3 (6%) of the patients. The patients were all treated with granulocyte-macrophage colony-stimulating factor (5 μg/kg). Eighty percent of the patients had a complete depletion of their B lymphocytes (CD20 + cells), which remained low throughout the follow-up period. The serum immunoglobulin (IgM and IgG) levels also were reduced below the age-related lower limits of normal in 11 (20%) of patients.
Specific Pathogens
Mycobacterium tuberculosis
Risk of Active Infection
Use of TNF inhibitors has been associated with reactivation of infections caused by organisms in the Mycobacterium tuberculosis complex (Mtb). In mouse models, TNF has been shown to contribute to granuloma formation and to induce and maintain latency of Mtb infection, while blockage is associated with failure to control bacillary growth and form protective granulomata. In a Cochrane review of patients receiving BRMs compared with those receiving a placebo, the overall OR of Mtb reactivation was 4.7 (95% CI, 1.2–18.6), with an absolute risk of 20 cases per 10,000 compared with 4 per 10,000 patients receiving a placebo.
Studies in adults suggest that the risk of Mtb reactivation may be related to the class of TNF inhibitor, with TNF antibodies (e.g., infliximab and adalimumab) associated with the highest risk, while soluble TNF receptor antibodies (e.g., etanercept) appear to have the lowest risks. , Although risk appears lower with etanercept, the risk appears increased compared to the general population; when it occurs, disease tends to be localized, although disseminated infections have been reported. ,
Risk of Extrapulmonary and Disseminated Infection
In adults receiving BRMs, particularly TNF inhibitor agents, cases of TB (Mt disease) are associated with a significant increase in incidence of extrapulmonary and disseminated diseases that often require an invasive procedure for diagnosis. Reported frequency of extrapulmonary disease among active TB ranges from 56% to 62%, while 24%–28% have disseminated disease. This compares with a background rate of 18% and 2%, respectively, in patients with non-HIV-related TB. , Furthermore, because of the diminished host response against the Mtb, many patients do not develop granulomas. The median time to presentation varies from as early as 12 weeks with infliximab to 30 weeks (adalimumab), and as late as 46 weeks (etanercept). It should be noted that the risk of Mtb reactivation associated with the underlying autoimmune/inflammatory conditions alone without medications is estimated to be twice the baseline rate for the normal population.
While the data are much more sparse for children, there have been several case reports of Mtb reactivation with use of TNF inhibitor agents. , While data on screening and treating children for Mtb infection (formerly called latent tuberculosis infection [LTBI]) prior to initiating BRM therapy are limited, such practice appears to substantially reduce the risk of reactivation. Among 2210 adults treated worldwide with golimumab for a variety of rheumatologic conditions and followed for 52 weeks, none of 317 patients who were assessed and treated for Mtb infection with isoniazid developed Mtb disease, while 5 cases developed in patients not assessed and treated.
Nontuberculous Mycobacterium Species
Nontuberculous mycobacteria (NTM) infection has been reported to be twice as common as Mtb disease in adults receiving BRMs. , Pulmonary disease occurs most commonly (56%), but similar to patients developing Mtb disease, many cases (44%) are extrapulmonary infections. Mycobacterium avium is the most common NTM isolated. Unfortunately, there is no accurate (sensitive and specific) screening test on which to base screening recommendations.
Viruses
Varicella-Zoster Virus
Primary or reactivated varicella-zoster virus (VZV) infections are frequently reported as complications among patients receiving BRMs. , , , These data support the importance of appropriate varicella immunization and the recognition of exposures in patients taking all BRMs.
Data for increased risk of herpes zoster are almost exclusively from adults. Patients receiving monoclonal antibodies (infliximab or adalimumab), especially, appear to have increased risk of zoster compared with those receiving etanercept or DMARDs alone.
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