Doctors should be aware of histoplasmosis with infliximab

[Guest guest]

Oct 23, 2002

Doctors should be aware of histoplasmosis with infliximab

Rockville, MD Doctors should be alert to the possibility of histoplasmosis

as a potentially life-threatening complication of treatment with the

TNF-alpha antagonists infliximab (Remicade®; Centocor) and etanercept

(Enbrel®; Amgen Pharmaceuticals), say officials from the FDA's Center for

Biologics Evaluation and Research. The side effect, although rare, seems to

be particularly associated with infliximab use, they note.

Through May 31, 2002, there have been 22 of cases histoplasmosis in the US

associated with TNF-alpha therapy, 19 of which were linked to infliximab and

3 to etanercept. Five of these patients have died, Dr Jong-Hoon Lee (CBER,

FDA, Rockville, MD) and colleagues report this month in Arthritis &

Rheumatism [1]. There have also been 2 cases of infliximab-associated

histoplasmosis from outside the US 1 from Canada and 1 from Switzerland,

they add.

" Histoplasmosis should be considered early in the evaluation of patients who

reside in Histoplasma capsulatum (HC)-endemic areas in whom infectious

complications develop during treatment with infliximab or etanercept. "

" Histoplasmosis should be considered early in the evaluation of patients who

reside in Histoplasma capsulatum (HC)-endemic areas in whom infectious

complications develop during treatment with infliximab or etanercept, " they

comment. The presenting signs or symptoms of histoplasmosis include fever,

malaise, cough, dyspnea, and interstitial pneumonia on chest radiographs.

24 cases around the world

In their paper, Lee et al report on 10 patients who developed histoplasmosis

up to July 2001; in an addendum they note that there have been 12 additional

cases reported in the US through May 31, 2002, as well as the 2 overseas

cases.

Of the 10 original patients, symptoms of histoplasmosis occurred in 9 taking

infliximab 5 with rheumatoid arthritis and 4 with Crohn's diseasefrom

within 1 week to 6 months after receiving the first dose. The 1 patient who

developed the infection after etanercept did so after 11 months of therapy.

All 10 of these patents were also receiving at least 1 other

immunosuppressive medication, such as azathioprine, prednisone, or

methotrexate in addition to the TNF-alpha antagonists, the FDA staff notes.

These 10 cases produce a histoplasmosis rate of 6 patients in every 100 000

for infliximab and 1 in 100 000 for etanercept.

All of those affected in the US resided in states known to be endemic for

histoplasmosis. For the total of 22 patients who developed histoplasmosis

and were reported to the FDA through May 2002, the total number in each

state was as follows: 3 patients each in Ohio, Tennessee, Kentucky, and

Indiana; 2 patients in Minnesota; and 1 patient each in Alabama, Iowa,

Louisiana, Wisconsin, land, Michigan, Missouri, and Texas. The

researchers note that the most highly endemic areas for HC in the US are the

Ohio and Mississippi river valleys.

" A discussion regarding avoidance of activities related to risks of HC

exposure, such as frequent exposure to soil . . . and exploring caves,

should be considered in patients receiving TNF-alpha antagonists who reside

in HC-endemic areas. "

HC is transmitted by inhalation of mycelial fragments and microconidia of

the organism after disturbance of contaminated soil. HC infection is

frequently asymptomatic and generally self-limited in the normal host, but

immunocompromised individuals exposed to HC are at high risk for developing

symptomatic histoplasmosis. " A discussion regarding avoidance of activities

related to risks of HC exposure, such as frequent exposure to soil (eg,

cleaning chicken coops, disturbing soil beneath bird-roosting sites) and

exploring caves, should be considered in patients receiving TNF-alpha

antagonists who reside in HC-endemic areas, " they suggest.

Different mechanisms of action may explain why HC infection more prevalent

with infliximab

Because infliximab and etanercept inhibit TNF-alpha through different

mechanisms, this may explain why the infection seems to be particularly

associated with infliximab, Lee et al say. However, it may also be possible

that other factors are responsible for this observationfor example, the fact

that methotrexate is used concurrently with infliximab when the latter is

prescribed to rheumatoid arthritis patients (multiple cases of

histoplasmosis have been reported in patients taking methotrexate, they

note).

Lee and colleagues also point out that they were unable to determine the

proportion of patients in whom histoplasmosis represented reactivation of

latent infection, acute primary infection, or reinfection. They also caution

that, as with all passive surveillance systems, " use of the adverse event

reporting system (AERS) database to detect drug-associated risks is limited

by underreporting, the possible presence of unrecognized confounding

factors, and the potential for inclusion of coincidental events. " It is also

not known whether RA or Crohn's disease may be independent risk factors for

histoplasmosis, they add.

They note that a warning has been added to the package insert of infliximab

in the US, indicating that for patients who have resided in HC-endemic

areas, " the risks and benefits of infliximab treatment should be carefully

evaluated before beginning treatment. " As reported by rheumawire, this

warning was added to the label in August 2001.

Nainggolan

Cited source

1. Lee JH, Slifman NR, Gershon SK, et al. Life-threatening histoplasmosis

complicating immunotherapy with tumor necrosis factor alpha antagonists

infliximab and etanercept. Arthritis Rheum 2002 Oct;