derangement (34,37–40). Investigation should not preclude empiric therapy and should be
conducted as for coccidioidomycosis including assay for urine histoplasmin (39).
Opportunistic Mycoses and Parasites
Aspergillus sp. is a ubiquitous mycoses usually presenting as a mild allergic nuisance.
However, in immune-compromised populations, it is cause of concern for fatal invasive
disease. In the four years following FDA approval of anti-TNF therapy, 30 cases of aspergillosis
were identified (14). There have been serious and fatal cases reported with anti-TNF therapy
whereby diagnosis was revealed only after bronchoscopy or on autopsy thus making fluid
cultures possibly insufficient for diagnosis. High index of suspicion should be maintained (34).
Cryptococcus sp. may confer mortality and permanent neurological damage in the
immune-suppressed patients in whom disease is not recognized and treated early in disease
course. In the handful of years after FDA approval, 24 cases associated with anti-TNF agents
have been identified (14,41–45). Invasive disease has been reported to occur in absence of
positive CSF or serum serology in patients receiving anti-TNF therapy (42,43). Patients on
biologic therapy, who have a prior history of infection and have not been on suppressive
therapy with an anti-fungal agent, are at risk and should be treated empirically for
disseminated infection if serious infection is being considered.
Pneumocystis jirovecihad demonstrated cause for concern in RA patients receiving anti-
TNF therapy when there appeared to be more cases (15 cases) ofP. jirovecihaving been reported
in the first couple of years with anti-TNF therapy than in all the years with methotrexate since it
has been available (12 cases) (46,47). After five years, 84 cases ofP. jirovecihad been reported to
FDA in association with infliximab therapy alone with a fatality rate of 27% (48).
Candidasp. has been inconsistently described in the literature, though a statistically
significant increase of 2.3-fold with anti-TNF therapy has been calculated from cases reported
to the FDA with a fivefold increase in systemic infection with infliximab versus etanercept (14).
Viruses
TNF inhibition has variable effects on virus pathology. In some instances, as in certain stages of
hepatitis C and HIV, viral pathology may in fact be dependent on TNF-afor pathological
progression and anti-TNF therapy may interrupt viral pathology, whereby other viral entities,
such as influenza or hepatitis B in association with TNF-asuppression are opportunities for
potential devastation.
Influenzais the serious infection that is most likely to occur in patients receiving TNF
inhibition. Ideally, patients should have received influenza vaccine two weeks before initiation
of treatment and then annually while on therapy. However, history of vaccination does not
preclude the possibility of serious illness due to influenza.
Varicella zosteris not uncommonly seen in patients receiving biologic therapy (21).Herpes
simplesvirus pathology, as examined in animal models, may be inhibited by the presence of
TNF-ain both primary and reactivation phases (49,50). It is reasonable to pay close attention to
history of such lesions, specially to lesion recurrence.
JC virus,a virus that is latent in up to 80% of adults, and resultant progressive multifocal
leukoencephalopathy (PML) has been identified in one RA patient, two cases of SLE and
23 cases of non-Hodgkin’s lymphoma being treated with rituximab (34). There have been few
cases of PML in SLE patients receiving other immunosuppressant agents prior to these cases.
Whether these fatalities are a direct result of specific immunosuppression with rituximab is not
resolved. It is worth noting that off label use of rituximab for SLE is a fairly new treatment with
much fewer patients exposed. Similarly, natalizumab, for treatment of multiple sclerosis and
Crohn’s disease, was temporarily taken off the market with labeling now containing a black
box warning as its use “increases the risk of PML” after three patients with multiple sclerosis
developed PML (34). It is now administered only through a special program whereby prior to
initiation of treatment an MRI of the brain is recommended and treatment be stopped at signs
of neurological symptoms. Anti-TNF therapy has been associated with demyelinating disease
clinically similar to multiple sclerosis; however an association with the JC virus has not been
established (47).
382 Saketkoo and Espinoza