More cases of etanercept-induced SLE identified by FDA

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Aug 29, 2002

More cases of etanercept-induced SLE identified by FDA

Rockville, MD Systemic lupus erythematosus (SLE) " is probably associated

with etanercept treatment, " say staff at the US FDA's Center for Biologics

Evaluation and Research (CBER). In this week's Lancet [1], they report 16

cases of new-onset SLE during or soon after use of etanercept (Enbrel®,

Amgen/Wyeth) from November 1998 to February 2002.

" Clinicians managing patients with rheumatoid arthritis should be aware that

etanercept could cause drug-associated SLE, [which] generally improves when

the drug is stopped, " say Aparna K Mohan and colleagues in a letter to the

journal.

Mohan et al were prompted to identify new cases of SLE associated with

etanercept from the FDA's Adverse Event Reporting System, after reading a

paper by Shakoor et al in February about 4 female patients who developed

signs and symptoms of SLE during treatment with the drug, which resolved

promptly on discontinuation of therapy [2].

" Clinicians managing patients with rheumatoid arthritis should be aware that

etanercept could cause drug-associated SLE, which generally improves when

the drug is stopped. "

As reported by rheumawire, Shakoor and colleagues said that SLE was

unambiguous in 2 patients and " probable " in the other 2, and they suggested

that etanercept should be added to the list of agents associated with

drug-induced SLE.

Nine definitive cases, 4 possible

The CBER staff obtained follow-up information on 13 of the 16 patients

identified via the Adverse Event Reporting System (excluding the 4 cases

reported by Shakoor et al), and classified 9 patients as definitive cases of

SLE and the remaining 4 as possible cases.

The median period from starting etanercept treatment to diagnosis of SLE was

4 months. Discoid rash was reported in 8 cases, photosensitivity in 6, and

malar rash in 4 of the cases. Antinuclear antibody titers rose after

etanercept was started in 5 patients for whom baseline measurements of

antinuclear antibodies were available. In 12 of the cases, " symptoms

resolved completely within 1 to 4 months of withdrawal of etanercept, and 1

case showed incomplete improvement, " they note.

" Our findings affirm the assertion by Shakoor and colleagues that SLE is

probably associated with etanercept treatment because clinical features were

characteristic of SLE and due to the presence of temporal associations with

etanercept treatment, including rising concentrations of antinuclear

antibodies and symptom resolution after drug withdrawal, " Mohan et al

conclude.

Others doubt findings of Shakoor et al

However, in another letter in the same issue of the Lancet, Dr G F

Ferraccioli (University of Udine, Italy) and colleagues say they " do not

believe Shakoor and colleagues report drug-induced SLE [3]. " They add: " We

believe the title of . . . [their] report and the clinical laboratory

features may be misleading. "

They assert that 1 of the 4 patients described by Shakoor et al " already had

SLE " and that for another 2 of the patients, " arthritis cannot be taken into

account . . . as a criterion for SLE because they already had rheumatoid

arthritis. " Thus, only 1 patient " satisfies the possible diagnosis " of SLE.

Ferraccioli et al suggest that what was seen instead was " the possible

occurrence of a full-blown antiphospholipid-like disease. " They say that

during treatment with another TNF blocker, infliximab (Remicade®, Centocor),

they have noted " some patients who were negative at entry became positive

for antinuclear antibodies. " Also, in patients receiving etanercept,

especially those already positive for antinuclear antibodies, they have

reported antibodies to double-stranded DNA and cardiolipin during infections

of the upper respiratory tract. But " in no patient did we have to stop

treatment, " they say, adding that antibody titers rose and fell during the

recurrences of the infections " and could mostly be normalized with

antibiotics. "

In reply, Shakoor et al rebut the suggestion that their cases do not

sufficiently fulfill the diagnostic criteria for SLE [4]. They note that

formal diagnostic criteria for drug-induced SLE " have not been established, "

and they add, " Findings suggest that the diagnosis should be made if, after

sufficient duration of drug treatment, patients develop at least 1 clinical

feature of SLE and antinuclear antibodies, and, most importantly, symptoms

resolve after discontinuation of treatment. All 4 patients we described

fulfilled these criteria. "

Amgen: a step closer to tackling Enbrel supply problems

Meanwhile, Amgen is a step closer to resolving the supply problems with

etanercept, which have been widely reported. The company has filed a

supplemental biologics license application with the FDA for its new

etanercept manufacturing facility in Rhode Island.

This summer, rheumawire reported that supply problems with etanercept in the

US were continuing. Patients already established on etanercept were

experiencing delays in having their prescriptions refilled, while new

patients wanting to try the drug were facing a wait until the end of 2002,

when the new manufacturing facility was expected to open.

The application to the FDA means that the company is " on track " to meet the

goal of a timely approval of the Rhode Island facility, " so that we can, in

turn, increase the supply of Enbrel for patients in the future, " says

Fabrizio Bonanni (senior vice president for quality and compliance, Amgen).

Nainggolan

Cited sources

1. Mohan AK, ET, Cot? TR, et al. Drug-induced systemic lupus

erythematosus and TNF-alpha blockers. Correspondence. Lancet 2002; 360:646.

2. Shakoor N, Michalska M, CA, Block JA. Drug-induced systemic lupus

erythematosus associated with etanercept therapy. Lancet 2002 Feb 16;

359(9306):579-80.

3. Ferraccioli GF, Assaloni R, Perin A. Drug-induced systemic lupus

erythematosus and TNF-alpha blockers. Correspondence. Lancet 2002; 360:645.

4. Shakoor N, Block JA. Drug-induced systemic lupus erythematosus and

TNF-alpha blockers. Correspondence. Lancet 2002; 360:646.