Tacrolimus looks promising for DMARD-resistant RA

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Rheumawire

Feb 12, 2004

Tacrolimus looks promising for DMARD-resistant RA

Kanagawa, Japan - Tacrolimus (FK506, Prograf®, Fujisawa

Healthcare) was effective and safe in a placebo-controlled trial and

should be considered as an option for rheumatoid arthritis (RA) patients

resistant to methotrexate or other DMARDs, Dr Hirobumi Kondo reports in

the February 2004 issue of the Journal of Rheumatology [1]. Tacrolimus

is a macrolide that, like cyclosporine, is derived from a soil fungus,

inhibits helper T-cell activation, and is widely used to prevent graft

rejection. However, tacrolimus is 10 to 20 times more immunosuppressive

than cyclosporine.

" Our findings demonstrate excellent dose-dependent efficacy of

tacrolimus in patients with DMARD-resistant RA and strongly suggest the

usefulness of tacrolimus for treatment of RA. The optimal dosage appears

to be 3 mg/day in terms of efficacy and safety, " Kondo writes.

Patients in this double-blind study were randomized to placebo

(n=74), tacrolimus 1.5 mg/day po (n=68), or tacrolimus 3 mg/day po

(n=70) for 16 weeks. Patients switched from their current DMARD to their

assigned study medication with no washout period. Continuation of daily

fixed-dose prednisolone was allowed, not exceeding 5 mg/day, as was

continuation of 1 NSAID if it was being taken at study entry. DMARDs,

additional NSAIDs, and addition physiotherapy were prohibited.

Eligibility criteria included RA of more than 6 months' duration

meeting the American College of Rheumatology 1987 revised criteria,

resistance to at least 1 DMARD with at least 6-month administration,

active disease, and age between 20 and 64 years.

Renal toxicity is a known risk with tacrolimus, as it is with

cyclosporine, and patients with impaired renal function were excluded.

Of the patients, 179 were evaluable for response, including 64/74

placebo patients, 57/68 1.5-mg patients, and 58/70 3.0-mg patients.

ACR20 response rates were 14.1% with placebo, 24.6% with 1.5-mg

tacrolimus, and 48.3% with 3.0-mg tacrolimus. The 3.0-mg dose was

significantly better than placebo (p<0.001), but the 1.5-mg dose was

not. (The maintenance dose for preventing graft rejection is typically

between 2 and 5 mg bid).

Tacrolimus 3-mg treatment was associated with improvements in

physical function, C-reactive protein (CRP), erythrocyte sedimentation

rate (ESR), tender/swollen joint count, rheumatoid factor, and

immunological variables, including immunoglobulin (Ig) G, IgA, IgM,

circulating immune complexes, and complement.

Methotrexate had been used previously by 23/64 placebo patients,

21/57 1.5-mg tacrolimus patients, and 20/58 3-mg tacrolimus patients,

all of whom were considered to be methotrexate resistant at trial entry.

ACR20 response rates in these methotrexate patients were 4.3% with

placebo, 33.3% with 1.5-mg tacrolimus, and 40.0% with 3.0-mg tacrolimus.

The differences were statistically significant for both tacrolimus doses

vs placebo (p=0.024 and p=0.008, respectively).

Conversely, patients resistant to all DMARDs except methotrexate

had ACR20 response rates of 19.5% with placebo, 19.4% with 1.5-mg

tacrolimus, and 52.6% with 3.0-mg tacrolimus. This difference was

statistically significant only for the 3.0-mg tacrolimus dose vs placebo

(p<0.001).

Response to tacrolimus also occurred more rapidly than with

traditional DMARDs. " Compared with the placebo group, CRP and ESR were

significantly improved after 4 weeks of this study. Tender and swollen

joint counts were significantly improved after week 12, " Kondo reports.

The adverse effects of most concern with tacrolimus in the

posttransplant setting are kidney damage, seizures, tremors, headache,

and paresthesias, as well as the risk of infection associated with

long-term immune suppression. In this trial, there were no statistically

significant differences in adverse events for either of the tacrolimus

groups vs placebo. Two patients discontinued treatment due to elevated

serum creatinine, blood-urea-nitrogen, and uric-acid levels, but Kondo

says that those levels normalized within 3 weeks of discontinuing

treatment.

Average renal-function values were within normal ranges for all 3

groups, but Kondo notes, " The incidence of abnormal changes in

renal-function variables in the tacrolimus groups was higher than in the

placebo group. " For example, serum creatinine elevations of 0.5 mg/dL or

greater occurred in none of the placebo patients but in 3.3% of the

1.5-mg tacrolimus patients and in 16.1% of the 3.0-mg tacrolimus group.

No drug-related serious adverse events were observed in either

tacrolimus group.

" The results of this late phase 2 study strongly suggest a

significant role for tacrolimus in the treatment of RA, " Kondo

concludes.

Janis

Source

1. Kondo H, Abe T, Hashimoto H, et al. Efficacy and safety of

tacrolimus (FK506) in treatment of rheumatoid arthritis: a randomized,

double blind, placebo controlled dose-finding study. J Rheumatol 2004

Feb; 31(2):243.

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