necessary for activation of T cells that directly impacts cytokine activation and B-cell
proliferation. Abatacept is used in the treatment of adult and juvenile RA.
Mycobacterium
Biologic agents, specifically, anti-TNF-ainhibitors, generated great concern when postmarket-
ing surveillance revealed a preponderance of tuberculosis (TB) infection associated with
infliximab use (12). Greater than 50% of these cases were disseminated extrapulmonary disease
with involvement of bone, bladder, meninges, and lymphoid tissue (12–14). With TNF-a
inhibition, the normal mechanisms of immunity are suppressed and unable to mount an
effective inflammatory response that would normally wall off the site of TB infection by
forming a granuloma, therefore predisposing the immune suppressed patient to disseminated
extrapulmonary disease (15). Patients often present atypically without the warning signs of
fever, night sweats, respiratory symptoms to which we are familiar (12,16,17). Non-TB
mycobacterium, such as Mycobacterium avium and M. leprae as well as disseminated
M. marinum,have been rarely described in association with anti-TNF therapy.
It now appears that TB cases associated with anti-TNF-atend to be reactivations of latent
tuberculosis infection (LTBI), occur in the first six months after initiation of therapy, and is
more likely to occur with infliximab (14,18–21). Also, 90% of new TB infections would normally
be contained; however, with anti-TNF use a high proportion of new infections progress to
active disease (20). Regardless of the results of screening tests, it is important to maintain a
high suspicion of disseminated mycobacterial infection in patients, receiving biologic agents
with collection of appropriate stains and cultures while maintaining a low threshold for
empiric treatment.
Bacterium
Adjusted risk of hospitalization for serious infection with an identified bacterial organism appears
to be two times greater overall and four times greater in the first three to six months in RA patients
on anti-TNF therapy than on methotrexate alone (22,23). Again, a high index of suspicion for both
the usual and unusual suspects should be maintained with signs of infection in patients receiving
biologic therapy especially in the early months of treatment. Inability to identify the bacterial
pathogen in serious infections is at least 15% with the most commonly unidentified infections
being pulmonary (23,24). Empiric antibiotic coverage for the organisms discussed subsequently is
appropriate in a patient on biologic agents who presents with signs of serious infection.
Listeria carries a general mortality rate as high as 25% (25) causing meningitis,
encephalitis, and sepsis in vulnerable populations such as newborns, elderly, and patients
with immune dysfunction. TNF-aappears to be an important cytokine in effecting macrophage
bactericidal ability againstListeria(6,7,26,27). Patients on biologic agents withListeriainfection
may present with severe flu-like, gastrointestinal, or neurological symptoms. Empiric therapy
in patients on biologic agents should include ampicillin forListeriacoverage.
Streptococcus pneumoniaehas been described as leading to sudden and severe pneumonia
and sepsis, meningitis, necrotizing fasciitis, and peritonitis in patients receiving biologics.
TNF-aprevents bacteremia and death in mouse models. TNF-alevels increase proportionally
to bacterial burden (28) with TNF-ainhibition conferring impaired clearance of bacteria and
early mortality (29) because of pneumococcal pneumonia and fatal peritonitis (30).
Legionellapneumonitis, contracted via inhalation from a humid source, usually manifests
in people who are elderly or immunosuppressed and has been described in case reports in
patients receiving anti-TNF therapy. Depletion of TNF-aimpairs pulmonary host immune
response toLegionellawith persistent pneumonitis in rats (31).
Salmonellahas been described as septicemia and septic arthritis in several case reports in
patients receiving anti-TNF therapy (32,33).Bartonella and Brucellahave been recorded in
patients receiving anti-TNF therapy withNocardiaoccurring 4.85-fold higher in infliximab than
etanercept (14).
Mycoses and Parasites
The Food and Drug Administration (FDA) has recently required stronger warnings for
invasive fungal infection, having declared patients receiving anti-TNF therapy as “at risk for
380 Saketkoo and Espinoza