Tacrolimus safe and somewhat effective in active RA

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Tacrolimus safe and somewhat effective in active RA

Rheumawire

Aug 18, 2004

Mann

Tucson, AZ - Tacrolimus (Prograf, FK506, Fujisawa Healthcare Inc) is

safe and well tolerated and provides clinical benefit lasting at least

12 months in rheumatoid arthritis (RA), according to a new study in the

August 2004 issue of Rheumatology [1]. This T-cell suppressor may offer

an alternative to TNF inhibitors for patients who are unresponsive to or

unable to take them.

An accompanying editorial comments, " Tacrolimus may now be considered a

realistic therapeutic option in the treatment of active RA. Its efficacy

in monotherapy does, however, seem somewhat limited, and perhaps the

little evidence that we have regarding its use in combination with

methotrexate may suggest to us that it is more attractive as a component

for use in combination DMARD therapeutic strategies [2]. "

This open-label, long-term safety trial enrolled patients with active RA

who had discontinued all disease-modifying antirheumatic drugs (DMARDs)

for at least 2 weeks, had at least 5 tender/painful joints and 3 swollen

joints, and required DMARD treatment. In addition, 54 patients who had

completed at least 3 months of treatment with tacrolimus 2 mg/day,

tacrolimus 3 mg/day, or placebo in a phase 3 double-blind efficacy trial

rolled over into the new study.

All participants received 3 mg/day of tacrolimus in addition to their

current regimen of nonsteroidal anti-inflammatory drugs (NSAIDs) and

corticosteroids.

Of 896 patients who received at least 1 dose (3 mg) of tacrolimus, 489,

or 54.6%, completed the study. Median duration of treatment was 359

days. Of the patients, 145 (16.2%) withdrew from the study for adverse

events that were possibly or probably related to tacrolimus, 33 (3.7%)

withdrew for adverse events unrelated to tacrolimus, and 112 (12.5%)

withdrew for lack of efficacy.

No new adverse event with an incidence >0.7% appeared after the first 3

months of treatment with 3-mg tacrolimus. However, 529 patients (59%)

experienced an adverse event that was possibly or probably related to

tacrolimusmost commonly common diarrhea (14.6%), nausea (10.3%), tremor

(9.0%), headache (8.7%), abdominal pain (7.9%), dyspepsia (7.6%),

increased creatinine (6.8%), and hypertension (5.4%). Twenty-four

patients (2.7%) experienced serious adverse events possibly or probably

related to the study drug. Of these, the most common were pneumonia

(0.6%), hyperglycemia (0.3%), gastroenteritis (0.2%), pancreatitis

(0.2%), and diabetes mellitus (0.2%). One patient died of pneumonia and

renal failure, but study authors concluded that this was unrelated to

tacrolimus.

The mean creatinine level increased from 67+19 µmol/L at baseline to

75+26 µmol/L at the end of treatment. In 351 (40.3%) of the 872 patients

for whom creatinine levels were available at both baseline and during

treatment, there was a >30% increase from baseline in serum creatinine

during the study, either related or unrelated to tacrolimus. Of these,

73 patients (8.4%) had creatinine levels exceeding the normal range. At

the end of treatment, 177 patients (20.3%) had a >30% increase from

baseline in creatinine. Serum creatinine remained within the normal

range throughout the trial in approximately 90% of patients, study

authors report. These adverse effects are similar to those reported by

earlier trials of patients taking tacrolimus who underwent liver or

kidney transplants

At the end of treatment, the ACR20, ACR50, and ACR70 response rates were

38.4%, 18.6%, and 9.0%, respectively. More than 26% of patients had at

least a 70% improvement in both swollen and painful/tender joints. The

investigators also mention unpublished data showing that the percentages

of patients reaching >20%, >50%, and >70% improvement in most individual

ACR-responder components increased with time on treatment. However, only

45.3% of patients achieved an improvement of >20% in patient's

assessment of pain.

" ACR response rates were maintained for up to 18 months, the longest

time a patient could have been exposed to 3 mg/day in combined

tacrolimus studies, " conclude researchers, led by Dr Yocum

(University of Arizona, Tucson). " For patients who respond to

tacrolimus, tacrolimus is an effective and well-tolerated oral therapy

for RA. "

The Rheumatology editorialists note that trial data indicate that

tacrolimus is effective to a degree in treating active synovitis in RA,

but " the relative lack of a subjective benefit . . . will contribute to

problems with tolerability and compliance. "

Editorial coauthor Dr Rajan Madhok (Glasgow Royal Infirmary, UK) tells

rheumawire, " T-cell targeted therapies are of major interest since they

target the adaptive immune response. However, used alone, they have not

been effective. "

Madhok says that combinations with calcineurin inhibitors are an

attractive option, but their role in clinical practice still needs to be

defined. " Inhibiting the adaptive response does not provide the systemic

benefits that so many of the patients on TNF-alpha inhibitors report.

Tacrolimus may play a role in RA patients who do not respond

sufficiently to treatment with traditional DMARDS and are not good

candidates for TNF blockade. "

Madhok predicts that rheumatologists' lack of familiarity with

tacrolimus will be a major limiting factor.

Fujisawa filed for approval of tacrolimus for the treatment of RA in

Japan in November 2002 and is now conducting phase 3 trials in the US

and phase 2 trials in Europe, company spokesperson Hideo Shiba tells

rheumawire.

Sources

Yocum DE, Furst DE, Bensen WG, et al. Safety of

tacrolimus in patients with rheumatoid arthritis: long-term experience.

Rheumatology 2004; 43:992-999

McCarey DW, Capell HA, and Madhok R. Tacrolimus

therapy in rheumatoid arthritis. Rheumatology 2004; 43:946-948.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org