Infections Associated with Anti Tumor Necrosis Factor (TNF) Medications
Authors: David Saunders, Steven Burdette
BACKGROUND
Cytokines are proteins that regulate a variety of cell processes, including cell growth and differentiation, inflammation, repair, and immunity. Tumor necrosis factor alpha (TNF-a) is a cytokine that plays an important role in the inflammatory response. It is produced primarily by macrophages, B cells, and Th1 cells. It functions to regulate the expression of vascular adhesion molecules, migration and maturation of inflammatory cells, antibody production by B cells, phagocytosis, production of reactive oxygen intermediates, cytokines, chemokines, nitric oxide and prostaglandins by neutrophils, and apoptosis. TNF-a regulates the immune response to tuberculosis (TB) through macrophage activation, cell recruitment, granuloma formation and maintenance, and the production of interferon gamma (IFN-γ). TNF-a also regulates tumor surveillance and tissue repair. Target tissues for TNF-a include blood vessel endothelial cells, synovial cells, neuronal tissue, and bone.
Serum and tissue levels of TNF-a are elevated with chronic inflammatory diseases such as rheumatoid arthritis. This leads to articular and soft tissue damage by stimulating metalloproteinase production by synovial fibroblasts, osteoclasts, and chondrocytes and by blocking metalloproteinase-inhibitor production. To counteract the adverse effects of TNF-a in patients with chronic inflammatory diseases, medications that bind TNF-a were introduced: infliximab and etanercept in 1998, adalimumab and certolizumab in 2008, and golimumab in 2009 (Table 1). TNF inhibitors are used to treat rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, juvenile rheumatoid arthritis, Crohn’s disease, and ulcerative colitis. Conditions that do not respond to TNF inhibitors include Wegener’s granulomatosis, multiple sclerosis, sarcoidosis, and Sjogren’s disease. TNF inhibitors act through complement-mediated lysis, antibody-dependent cytotoxicity, and intracellular signaling which results in hastened cell cycle arrest, apoptosis, and suppression of cytokine production.
Immunogenic differences between the TNF inhibitors have been observed. Infliximab stimulates apoptosis of monocytes and T-cells, and lysis of TNF-a-expressing cells. Etanercept is an antiapoptotic drug that does not lyse TNF-a-expressing cells. Infliximab binds the TNF receptor p75 more avidly than etanercept. The p75 receptor, which binds both soluble and transmembrane TNF-a, plays a more important role in immune function than TNF receptor p55, which etanercept binds most avidly. Infliximab is associated with decreased levels of IFN-γ and TNF-a in CD4 and CD8 cells, while etanercept is associated with increased levels. Adalimumab stimulates monocyte apoptosis and lysis of TNF-a-expressing cells.
Blockade of TNF-a is associated with an increased risk of infection with opportunistic organisms (Table 2). In June 2007, members of the Emerging Infections Network (EIN) were asked to report cases of tuberculosis and nontuberculous mycobacteria (NTM) during the previous six months. A total of 1,876 mycobacterial infections were reported; 54 percent were NTM infections (most frequently Mycobacterium avium complex) and 45 percent were tuberculosis. Of these patients, 2.6 percent received anti-TNF therapy and 43 percent received corticosteroid and/or methotrexate therapy.
ANTI-TNF-a MEDICATIONS (Table 1)
Etanercept (Enbrel)
Etanercept is a recombinant human fusion protein composed of two human TNF receptors bound to the Fc portion of human IgG1. It acts by competitively inhibiting the binding of soluble TNF-a and lymphotoxin-a to receptors on inflammatory cells. It is approved for the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, and ankylosing spondylitis. It is not effective in treating granulomatous inflammatory conditions such as Crohn's disease or sarcoidosis. It is administered subcutaneously once or twice weekly.
Infliximab (Remicade)
Infliximab is a chimeric monoclonal antibody composed of a human IgG Fc fragment bound to murine antigen-binding regions. It binds both soluble and cell-bound TNF-a. It is approved for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and Crohn's disease. It is administered by intravenous infusion at four to six week intervals.
Adalimumab (Humara)
Adalimumab is a fully humanized IgG1 monoclonal antibody that binds both soluble and transmembrane TNF-a. It is approved for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and Crohn's disease. It is administered by subcutaneous injection every other week.
Certolizumab (Cimzia)
Certolizumab is a pegylated humanized monoclonal anti-TNF Fab manufactured through microbial fermentation withEscherichia coli. It is approved for the treatment of Crohn's disease. It is administered by subcutaneous injection every other week.
Golimumab (Simponi)
Golimumab is a fully humanized anti-TNF-a IgG1 monoclonal antibody that binds both soluble and transmembrane TNF-a. It is approved for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. It is administered by subcutaneous injection once monthly.
Patients with rheumatoid arthritis are at increased risk of infection independent of treatment with disease-modifying anti-rheumatic drugs. A population-based study reported a hazard ratio (HR) for infections requiring hospitalization of 1.83 in patients with rheumatoid arthritis A compared to matched controls. A cohort study reported 19.64 bacterial infections (most commonly septic arthritis and osteomyelitis) per 100 patient-years in patients with rheumatoid arthritis compared to 12.87 per 100 patient-years in controls. Another study reported a two-fold increased incidence of serious infections (defined as infections requiring hospitalization and intravenous antibiotics; most commonly pneumonia and skin infections) in patients with rheumatoid arthritis compared to controls. Mortality is increased in patients with rheumatoid arthritis who have infectious diseases compared to the general population. For instance, mortality due to pneumonia is five times higher in patients with rheumatoid arthritis compared to the general population.
Anti-TNF therapy may increase the risk of infection in patients with rheumatoid arthritis independent of disease severity. However, patients with poorly-controlled disease often receive TNF inhibitors and/or other disease-modifying anti-rheumatic drugs, and many patients with rheumatoid arthritis have other comorbidities that predispose to infection.
SERIOUS INFECTIONS AND ANTI-TNF THERAPY
Several studies evaluated whether anti-TNF therapy predisposes rheumatoid arthritis patients to infection. During phase III trials and post-marketing surveillance of infliximab, etanercept and adalimumab, no increased risk of infection was observed in patients with rheumatoid arthritis who received TNF inhibitors compared to placebo controls. However, several subsequent studies contradicted these results. A meta-analysis of nine randomized, placebo-controlled trials reported an odds ratio (OR) of 2.0 for serious infections in patients with rheumatoid arthritis who received either infliximab or adalimumab for twelve weeks or more. Adalimumab monotherapy was associated with an increased incidence of serious infections compared to placebo controls in another study.
Several randomized, placebo-controlled trials studied the risk of serious infections in patients with RA who received anti-TNF therapy compared to patients with rheumatoid arthritis who received other disease-modifying anti-rheumatic drugs. One study reported that patients who received infliximab plus methotrexate were more than twice as likely to develop serious infections compared to patients who received methotrexate alone. Two studies reported an increased incidence of serious infections in patients who received adalimumab plus methotrexate compared to patients who received either drug alone. However, no increased incidence of serious infections was observed in patients who received etanercept plus methotrexate compared to patients who received either drug alone in two other studies.
Results from several observational studies showed an incidence of three to six infections per 100 patient-years in patients who received anti-TNF therapy, which is similar to infection rates in the pre-biologic era. However, the relative risk of infection was 2.2-fold in these patients. Several factors such as differences in mean age, comorbidities, duration of disease, glucocorticoid use, and case identification for infections may explain discordant results.
PERIOPERATIVE INFECTIONS
Rheumatoid arthritis is an independent risk factor for postoperative orthopedic infections. A two-to-four fold increased risk of postoperative infections has been reported in patients with rheumatoid arthritis. A retrospective review of patients with rheumatoid arthritis who underwent at least one orthopedic surgical procedure while receiving anti-TNF therapy reported an OR of 4.4 for postoperative infections within 30 days of surgery. Another study reported a two-fold increased risk of postoperative infections in patients who received anti-TNF therapy within 28 days of surgery.
The American College of Rheumatology recommends against administering TNF inhibitors within one week prior to and one week after surgery. The Dutch Society for Rheumatology recommends discontinuing TNF inhibitors 39 days, twelve days, and 56 days prior to surgery for patients receiving infliximab, etanercept, and adalimumab, respectively (Table 3). The timing of these recommendations is based on the half-life of the TNF inhibitor utilized (Table 1).
DURATION OF ANTI-TNF THERAPY AND RISK OF INFECTION
The risk of infection in patients with rheumatoid arthritis who receive anti-TNF therapy changes over time. One observational study reported that the risk of infection (most commonly respiratory tract infections) decreased as the duration of anti-TNF therapy increased. An RR (relative risk) of 1.4, 1.2 and 0.8 was observed during the first, second, and beyond two years of anti-TNF therapy, respectively. Large induction doses of infliximab and better control of inflammation with anti-TNF therapy over time may predispose to early infections in these patients.
SPECIFIC PATHOGENS
Tuberculosis (TB)
TNF inhibitors prevent the body from containing M. tuberculosis in the initial phase of infection. They also inhibit TNF-a-dependent granuloma formation later in the disease process. Granuloma formation occurs after chemokines and adhesion molecules attract inflammatory cells to the site of infection. Infections with M. tuberculosis in this setting represent reactivation of latent tuberculosis rather than primary tuberculosis.
Mycobacterial infections are the most common opportunistic infections in patients receiving TNF inhibitors reported to the Federal Drug Administration (FDA) MedWatch database. Two-hundred ninety five and thirty-six cases of tuberculosis (TB) in patients who received infliximab and etanercept, respectively, were reported through June 2002. Patients with infliximab-associated tuberculosis had a higher percentage of extrapulmonary and disseminated disease. Thirteen cases of TB were reported during the clinical development program of adalimumab. By 2004, 82, 633, and 15 cases of TB were reported in patients who received etanercept, infliximab, and adalimumab, respectively. The US National Databank for Rheumatic Diseases registry reported an incidence rate of TB of 52.5 cases per 100,000 patient-years in patients with rheumatoid arthritis who received infliximab compared to 6.2 cases per 100,000 patient-years in patients with rheumatoid arthritis who did not receive anti-TNF therapy. A cohort study reported that patients with rheumatoid arthritis who received anti-TNF therapy had a four-fold increased risk of tuberculosis compared to controls. Two phase III placebo-controlled trials of patients with rheumatoid arthritis who received certolizumab reported five cases of active TB in each trial, with 6.9 and 12.5 cases per 1,000 patient-years of exposure reported.
Innfliximab has a higher risk of TB than etanercept, possibly due to infliximab’s longer half-life and higher affinity for TNF-a. The OR for TB for adalimumab and infliximab was 14.6, compared to 5.9 for etanercept in one case control study. Other smaller studies confirmed the reduced risk and delayed onset of TB with etanercept compared to other TNF inhibitors. One retrospective study reported no cases of active TB in patients with positive purified protein derivative (PPD) who received etanercept, most of whom received TB prophylaxis prior to anti-TNF therapy. Small clinical trials of patients who developed TB after initiation of anti-TNF therapy suggest that adjunctive etanercept therapy may accelerate microbiological and clinical response. This data suggests that etanercept does not hinder successful treatment of TB.
Nontuberculous Mycobacterial Infections
The risk of nontuberculous mycobacterial infections in patients who receive anti-TNF therapy is not clear. Nine cases of nontuberculous mycobacterial infections were reported in patients with chronic inflammatory diseases who received anti-TNF therapy. Three cases involved Mycobacterium marinum, two involved Mycobacterium xenopi, and two involved Mycobacterium abscessus. Three cases were complicated by pulmonary infections and death.
When anti-TNF therapy may be resumed in patients with nontuberculous mycobacterial infections is unknown. A case report was published of a 64 year-old male who was diagnosed with cutaneous Mycobacterium marinum infection after receiving etanercept for ankylosing spondylitis. Etanercept was resumed after five weeks of antibiotic therapy due to a flare-up of ankylosing spondylitis. No evidence of recurrence was observed on follow-up eighteen months after starting antibiotic therapy. Another case report of a patient with Mycobacterium xenopi infection of the hip joint and thoracic spine also reported no evidence of recurrence with resumption of etanercept therapy.
Fungal Infections
Histoplasmosis
Granuloma formation plays a critical role in the immune response to fungal infections. Alveolar macrophages release TNF-a and IFN-g upon phagocytosis of Histoplasma capsulatum yeast forms, which generates reactive nitrogen species as the primary immune response to infection. Secondary granuloma formation contains the infection.
In the appropriate geographic setting, Histoplasmosis occurs three times more commonly than tuberculosis in patients who receive anti-TNF therapy, and is the most common invasive fungal infection in these patients. By September 2008, 240 cases of histoplasmosis were reported in patients who received anti-TNF therapy. Most cases occurred in the Ohio and Mississippi River valleys.
Histoplasmosis should be suspected in patients who present with a prolonged febrile illness or an undiagnosed pneumonia, especially if travel to an endemic area has occurred. Other clinical findings include hepatosplenomegaly, extrapulmonary lymphadenopathy, oral or skin lesions, adrenal or intestinal masses, and gastrointestinal obstruction or bleeding. Suggestive radiographic findings include diffuse reticulonodular or miliary infiltrates, focal or patchy infiltrates, noncalcified pulmonary nodules, and/or hilar or mediastinal lymphadenopathy.
Coccidioidomycosis
By February 2003, thirteen cases of coccidioidomycosis were reported in patients who received anti-TNF therapy. All cases occurred in endemic areas, such as Arizona and southern California. Most cases represented primary infection (five patients had negative coccidioides serologies prior to anti-TNF therapy). A retrospective review of patients from the southwestern US who received infliximab for chronic inflammatory diseases reported a RR for coccidioidomycosis of 5.23. All patients presented with pneumonia and 30 percent had disseminated disease. Eighty-five percent of patients received concomitant methotrexate therapy. Another literature review reported that all patients with coccidioidomycosis while receiving anti-TNF therapy received concomitant methotrexate or corticosteroid therapy. All patients presented with pneumonia and four patients had disseminated infection.
Other Fungal Infections
Granulomatous infections due to fungi reported to the FDA Adverse Event Reporting System (AERS) occurred 3.25 times more commonly during infliximab administration compared to etanercept. A literature review of invasive fungal infections complicating anti-TNF therapy was performed. The organisms most commonly identified were histoplasmosis (30 percent),candidiasis (23 percent), and aspergillosis (23 percent). Most cases of histoplasmosis occurred in endemic areas and patients presented most commonly with pulmonary infections. Pneumocystis jiroveci pneumonia is rarely reported in association with anti-TNF therapy. Ten and five cases were reported in patients who received infliximab and etanercept, respectively.
A cohort study reported no increase in bacterial infections requiring hospitalization in patients with RA who received anti-TNF therapy compared to patients who received methotrexate. Patients with malignancy (except non-melanoma skin cancer) or human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) were excluded. Twenty-nine cases of listeriosis in association with anti-TNF therapy were reported to FDA MedWatch through June 2002. However, no cases of listeriosis were reported in several randomized controlled trials that followed.
Viral Infections
Herpes Zoster
The annual incidence of herpes zoster infection in patients with RA is 2.8 per 100 patient- years. The risk of infection increases with the administration of prednisone, cyclophosphamide, and combinations of disease-modifying anti-rheumatic drugs and anti-TNF medications. However, the risk of herpes zoster infection is not increased in patients who receive anti-TNF therapy alone.
Hepatitis C (HCV)
TNF-a levels are elevated in patients with hepatitis C, and TNF-a levels correlate with alanine aminotransferase (ALT) levels. Several case reports of patients with chronic hepatitis C who received infliximab or etanercept for chronic inflammatory conditions were reported. No flares of hepatitis C were reported during treatment with infliximab or etanercept, as evidenced by stable liver function tests and hepatitis C viral loads. A prospective analysis of patients with chronic hepatitis C who received etanercept for rheumatoid arthritis reported no statistically significant increases in serum aminotransferases or mean viral loads. A randomized, double-blind, placebo-controlled trial studied patients with chronic hepatitis C who received either interferon, ribavirin and placebo or interferon, ribavirin and etanercept. Patients in the etanercept arm had a higher frequency of disappearance of HCV ribonucleic acid (RNA) at 24 weeks, and more patients had ALT normalization at 24 weeks compared to placebo. The literature does not suggest that anti-TNF therapy worsens hepatitis C. Therefore, it may be reasonable to continue anti-TNF therapy while closely monitoring ALT and HCV RNA levels in these patients.
Hepatitis B (HBV) Reactivation
TNF-a plays an important role in the immune response to hepatitis B. Anti-TNF therapy is associated with hepatitis B reactivation and often occurs two to three months after initiation of anti-TNF therapy. Several case reports of patients with chronic hepatitis B who received infliximab for chronic inflammatory conditions were published. Reactivation of chronic hepatitis B occurred on several occasions, as evidenced by increasing serum aminotransferases and serum HBV deoxyribonucleic acid (DNA) levels above baseline. Several case reports reported no reactivation of hepatitis B when lamivudine was administered with infliximab.
Clinicians should avoid administering TNF inhibitors to patients with hepatitis B whenever possible. If anti-TNF therapy must be given, lamivudine (or other antiviral medication active against hepatitis B) should be administered to prevent hepatitis B reactivation. Antiviral therapy should be administered two to four weeks prior to initiating anti-TNF therapy in patients with inactive hepatitis B.
gressive Multifocal Leukoencephalopathy (PML)
PML is a demyelinating disease that occurs due to reactivation of the JC virus. A case report documented subacute neurologic and cognitive deficits in a patient with RA after three years of infliximab, methotrexate, and prednisone. Brain biopsy confirmed PML and symptoms improved after discontinuation of infliximab and methotrexate.
OTHER MEDICATION RELATED ADVERSE EVENTS AND CONTRAINDICATIONS
Noninfectious adverse events associated with infliximab include infusion reactions (immediate or delayed), autoimmune phenomena (e.g., drug-induced lupus, hemolytic anemia, glomerulonephritis, and antineutrophil cytoplasmic antibody associated systemic vasculitis), dermatological symptoms (e.g., psoriasiform dermatitis, eczema, psoriasis, parakeratosis), neurological events (e.g., peripheral neuropathy, retrobulbar optic neuritis, demyelinating syndrome), malignancy, lymphoma, and hepatosplenic T-cell lymphoma. Permanent renal loss associated with TNF inhibitor-induced glomerulonephritis has been reported.
Contraindications to anti-TNF therapy include active bacterial infection, active TB (or latent TB infection prior to starting preventative therapy), active herpes zoster infection, active life-threatening fungal infections, severe upper respiratory tract infections (bacterial or viral), or nonhealed infected skin ulcers. TNF inhibitors may be given after successful treatment or full resolution of bacterial infections. Other contraindications to anti-TNF therapy include lymphoproliferative diseases (diagnosed and/or treated within five years), moderate or severe heart failure (New York Heart Association class III-IV with reduced ejection fraction), acute hepatitis B or C, chronic hepatitis B or C with significant liver injury (Child-Pugh classes B or C), and multiple sclerosis or demyelinating disorders.
TNF inhibitors are rated pregnancy category B. A review of the FDA database of reported adverse events for etanercept, infliximab, and adalimumab was performed. Sixty-one congenital anomalies in 41 children born to mothers who received anti-TNF therapy were reported. A form of heart defect was the most commonly reported abnormality. Fifty-nine percent of children had one or more anomalies associated with the VACTERL spectrum (vertebral abnormalities, anal atresia, cardiac defect, and tracheoesophageal, renal and limb abnormalities). Forty-seven percent of VACTERL anomalies were significantly more common compared to controls. Until more definitive safety data is available, clinicians should avoid administering anti-TNF drugs to pregnant patients.
Immune Reconstitution Inflammatory Syndrome (IRIS)
Withdrawal of TNF inhibitors is associated with paradoxical worsening of certain active infections, such as TB or histoplasmosis. IRIS occurs due to an exaggerated recovery of Th1 cell function, including IFN-γ and TNF-α production, after discontinuation of TNF inhibitors. IRIS presents similarly in patients with HIV, but in this situation it occurs after initiation of antiretroviral therapy (versus with TNF inhibitors where it occurs after discontinuation of therapy). Increased lymphocyte proliferation with recovery of immune function leads to inflammatory reactions at sites of previous infection.
The presentation of IRIS varies with the site of infection and whether localized or systemic disease is present. Signs and symptoms may include fever, pulmonary infiltrates, hypoxic respiratory failure, enlargement and necrosis of mediastinal lymph nodes, liver dysfunction, splenic lesions, and evolution of intracranial tuberculomas.
IRIS should be suspected in patients with histoplasmosis who clinically deteriorate after initial improvement with antifungal therapy if the following are present (in order of significance): decreasing urine antigen concentrations, failure to improve despite effective antifungal therapy, and sustained improvement after initiation of corticosteroid therapy.
Case reports of the successful treatment of refractory central nervous system-related IRIS with TNF inhibitors have been published. Tuberculosis-associated IRIS of the brain was successfully treated with infliximab in a case that was refractory to high-dose corticosteroids and cyclophosphamide. A case of HIV-related inflammatory cerebral cryptococcoma was successfully treated with adalimumab when neurological deterioration occurred with tapering of corticosteroids.
PREVENTING INFECTION
Overview
Pre-treatment vaccination and screening for latent infections decreases the risk of infection in patients receiving anti-TNF therapy (Tables 4a, Table 4b and 5 )
Vaccinations
The pneumococcal vaccine should be administered to patients prior to initiating anti-TNF therapy. TNF inhibitors do not appear to antagonize optimal antibody responses after pneumococcal vaccination, as occurs with methotrexate. Pneumococcal vaccination should be administered two weeks prior to initiating anti-TNF therapy. However, vaccination is beneficial even after anti-TNF therapy has been initiated. A second dose should be administered five years after the first dose.
The trivalent inactivated influenza vaccine should be administered yearly. Antibody responses after influenza vaccination are diminished in patients with RA. However, disease-modifying anti-rheumatic drugs do not appear to exacerbate this phenomenon.
The hepatitis B vaccination series should be administered to patients with risk factors (patients with multiple sexual partners, homosexual and bisexual males, household contacts of patients with hepatitis B, intravenous drug users, healthcare workers, patients receiving chronic hemodialysis, patients requiring frequent blood or blood product transfusion, and patients with chronic liver disease) prior to anti-TNF therapy.
Live vaccinations that are contraindicated during anti-TNF therapy include influenza (nasal administration), oral polio,measles/mumps/rubella, yellow fever, and smallpox. If zoster vaccine is administered, it should be given fourteen days prior to the initiation of anti-TNF therapy, or deferred until one month after discontinuation of anti-TNF therapy. Live vaccinations should not be administered until three months after discontinuation of anti-TNF therapy.
Prevention of TB
Prior to initiating anti-TNF therapy, a detailed history should be performed to evaluate patients for latent TB (LTBI). Risk factors include living in or arriving from high risk areas, institutionalization, malnourishment, chronic renal failure, history of transplantation, and receipt of immunosuppressants. TST (Tuberculosis skin test) should be performed prior to initiating anti-TNF therapy. TST measures delayed-type hypersensitivity reactions to PPD; a PPD with 5 mm or more of induration is considered positive. TST responses are reduced in patients with rheumatoid arthritis; therefore, repeat testing (boosting) should be considered after seven to ten days if TST is negative in these patients. Consideration for treatment of patients with a history of TB exposure should occur regardless of TB testing results. A chest x-ray should be obtained for all patients with a positive TB test or a history of TB exposure. Patients with LTBI should receive a minimum of one month of isoniazid before initiating anti-TNF therapy with preference for completing as much therapy as possible prior to anti-TNF treatment. Total duration of treatment for LTBI is 9 months with INH or 4 months with rifampin.
The QuantiFERON-TB Gold (QFT-G) test is an interferon-γ release assay (IGRA) that measures antigen-specific IFN-γ secretion by CD4+ T lymphocytes, which may be more specific for TB than TST. The performance of TST and QFT-G was studied prospectively in patients with immunomediated inflammatory diseases (IMID). The concordance between TST and QFT-G was good (87.7 percent). A history of previous Bacillus Calmette-Guerin (BCG) vaccination was associated with discordant QFT-G-negative/TST-positive results, and the use of TNF inhibitors was associated with discordant QFT-G-positive/TST-negative results. On multivariate analysis, corticosteroid administration affected the results of both TST and QFT-G. Another study compared TST and QFT-G in patients with chronic inflammatory diseases, most of whom received immunosuppressive drugs. QFT-G was more strongly associated with risk factors for latent TB compared to TST. False positive QFT-G results have been reported following TST. Therefore, it is recommended that if both TST and QFT-G are utilized, that QFT-G be tested the day that TST is read.
The T-SPOT.TB test is an IGRA that was studied retrospectively in patients with psoriasis who received anti-TNF therapy. Twelve patients had a positive TST/negative T-SPOT.TB, 10 of whom were not treated for latent TB. No cases of tuberculosis occurred in untreated patients after a median of 64 weeks of either etanercept, infliximab, or adalimumab and a mean of 76 weeks of follow-up. However, further studies are needed before IGRAs can be strongly recommended as a routine screening test for latent TB in patients receiving anti-TNF therapy.
Other Pre-treatment Screening
There is no consensus regarding screening for latent fungal infections prior to initiating anti-TNF therapy. A chest x-ray and serologic testing for Coccidioides should be considered for patients who live in endemic areas (southwestern US and parts of Central and South America). No reliable skin or serologic test is available to screen for latent histoplasmosis. Patients should be questioned about possible exposure to Histoplasma from old buildings (demolition, remodeling, cleaning), chicken coops (demolition, cleaning, fertilizer), bird roosts (excavation, camping, cutting wood), and caves (spelunking). A chest x-ray should be obtained if patients have traveled to endemic areas (parts of the Midwestern US, Mexico, Central and South America, Africa, and Asia), if histoplasmosis or pneumonia was diagnosed within two years, or if symptoms suggestive of histoplasmosis occurred within three months. Calcified nodules, lymph nodes, or splenic lesions suggest past histoplasmosis and may not predispose to reactivation.
There is no consensus regarding screening for hepatitis B prior to initiation of anti-TNF therapy. Testing for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) should be considered. Hepatitis B viral load (HBV DNA) should be measured if HBsAg is positive. Active carriers (HBV DNA >20,000 IU/ml or >2,000 IU/ml in anti-HBe positive patients) should be treated with antiviral medications active against hepatitis B. Antiviral therapy should be completed prior to initiating anti-TNF therapy. Inactive carriers (HBV DNA <20,000 IU/ml) should receive prophylaxis with antiviral medications active against hepatitis B. Patients who are HBsAg negative, anti-HBs positive or negative, and anti-HBc positive are considered occult hepatitis B carriers. These patients should be closely monitored for reactivation or seroconversion.
CONCLUSIONS
TNF inhibitors have revolutionized the management of chronic inflammatory diseases through their ability to reverse the destructive effects of TNF-a. Reduced activity of TNF-a is associated with an increased risk of infections during anti-TNF therapy. Pre-treatment vaccination and screening for latent infections prior to initiating anti-TNF therapy decreases the risk of infection in these patients.
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Tables
Table 1: Properties of TNF-a Inhibitors
Elimination half-life (days) |
Fixes complement; antibody-mediated cell lysis |
|
|---|---|---|
Etanercept (Embrel) |
4.2 |
No |
Infliximab (Remicade) |
9.5 |
Yes |
Adalimumab (Humara) |
14 |
Yes |
Certolizumab (Cimzia) |
14 |
No |
Golimumab (Simponi) |
7 to 20 |
Unknown |
- Smith JA, Kauffman CA. Endemic fungal infections in patients receiving tumor necrosis factor-a inhibitor therapy. Drugs 2009;69:1403. [PubMed]
- Taylor PC. Pharmacology of TNF blockade in rheumatoid arthritis and other chronic inflammatory diseases. Curr Opin Pharmacol 2010;10:308. [PubMed]
Table 2: Infections Associated with TNF-a Inhibitors
Viral
Bacterial
Fungal
Adapted from Pappa A, et al. Use of infliximab in particular clinical settings: management based on current evidence. Am J Gastroenterol. 2009;104(6):1575-86. Epub 2009 Apr 28. [PubMed] |
Table 3: Dutch Society for Rheumatology: Recommendations for Perioperative Management of TNF-a Inhibitors
| nfliximab | Discontinue 39 days prior to surgery |
| Etanercept | Discontinue 12 days prior to surgery |
| Adalimumab | Discontinue 56 days prior to surgery |
Table 4a: Recommended vaccinations prior to administration of TNF-a Inhibitors
|
Table 4b: Live Vaccinations that are Contraindicated During Anti-TNF Therapy
|
Table 5: Screening Recommendations Prior to Administration of TNF-a Inhibitors
Screening for latent TB
Screening for latent fungal infections
Screening for hepatitis B
|
What's New
Solovic I, et al. The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement. Eur Respir J 2010;36:1185-1206.
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History
Table of Contents
- Background
- Anti-TNF-a Medications
- Risk of Infection in Patients with Rheumatoid Arthritis
- Serious Infections and Anti-TNF Therapy
- Perioperative Infections
- Duration of Anti-TNF Therapy and Risk of Infection
- Specific Pathogens
- Other Medication Related Adverse Events and Contraindications
- Preventing Infection
- Conclusions