1995 Kloppenburg Study

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The 1995 Kloppenburg Study

Kloppenburg, M, Mattie, H, Douwes, N, Dijkmans, BAC,

Breedveld, FC, Minocycline in the treatment of

Rheumatoid Arthritis: Relationship of serum

concentrations to efficacy, Journal of Rheumatology,

1995, 22:4, 611-616.

Objective:

To determine the relationship between blood serum

concentrations of minocycline and both the clinical

efficacy and the incidence of toxicity when

minocycline is used for the treatment of patients with

Rheumatoid Arthritis.

Results:

The patients took 100 mg of minocycline, twice a day,

every day.

72.5% of the patients completed the 26 weeks of the

trial with no dose reduction.

15% of the patients had a dose reduction to 100 mg

daily because of adverse effects.

12.5% of the patients withdrew from the trial during

the first 4 weeks due to adverse effects.

Higher blood concentrations of minocycline lead to

better results.

The blood concentrations of minocycline are different

for each person.

No individual difference can explain the variations in

the blood concentrations of minocycline, although this

is in contrast with earlier studies that have

described a correlation with body size or sex.

Description:

80 patients who had definite or classical Rheumatoid

Arthritis, according to the 1958 criteria of the

American Rheumatism Association, were admitted to the

26-week prospective, double blind, placebo controlled

trial if they had an active disease and were being or

had been treated with at least one disease modifying

antirheumatic drug (DMARD).

Minocycline (100 mg twice a day) or placebo was given

as adjuvant therapy. The concomitant dose of DMARD or

corticosteroids had to be stable for at least 3

months. No alteration was allowed in the use of

corticosteroids and DMARD during the trial. In case of

serious adverse effects, as judged by 2 physicians,

the daily dosage was reduced to 100 mg; if dosage

reduction did not lead to a decrease in severity of

the gastro-intestinal adverse effects, including

nausea, to a level that was tolerated by the patient

or did not lead to a total disappearance of the

vestibular adverse effects (dizziness, vertigo,

postural unsteadiness), the study medication was

discontinued.

40 patients with active RA were administered

minocycline. 29 patients (72.5%) completed the 26

weeks of the trial at a dose of 100 mg minocycline

twice a day. 6 patients (15%) had a dose reduction to

100 mg daily because of adverse effects; the dose

reduction led to a reduction in the adverse effects.

There were 5 premature discontinuations (12.5%) during

the first 4 weeks of the trial due to adverse effects.

At page 613, the Kloppenburg study states:

" Correlation between estimated concentrations and

patient characteristics: To analyse the possible

causes of the variations between the minocycline

concentrations explained by the patient effect, we

analysed several patient characteristics, including

sex, age, duration of RA, body weight, creatinine

clearance and the use of another DMARD simultaneously

with minocycline. In a multivariate ANOVA these

characteristics were analysed separately for each

characteristic. No statistically significant

contribution to the variation could be demonstrated

for any of these characteristics. "

At page 614, the Kloppenburg study adds:

" Moreover, as expected the variations in the serum

concentrations of minocycline between the patients

were significant, as were the effects of dose and

time. In our study there were no patient

characteristics that could explain the variation in

the serum concentrations. This is in contrast with

earlier studies that have described a correlation with

body size or sex. "

At page 615, the Kloppenburg study concludes:

" Our results suggest a relationship between the level

of serum concentrations of minocycline and the

clinical response, as expressed by the Ritchie

articular index and the number of swollen joints. No

relationship was found between the serum

concentrations of minocycline and the incidence of

toxicity. "