1994 Kloppenburg Study

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The 1994 Kloppenburg Study

Kloppenburg, M, Breedveld, FC, Terwiel, JPh, Mallee,

C, Dijkmans, BAC, Minocycline in active Rheumatoid

Arthritis: A double-blind, placebo-controlled trial,

Arthritis & Rheumatism, 1994, 37:5, 629-636.

Objective:

To determine the efficacy of minocycline for the

treatment of patients with active Rheumatoid

Arthritis.

Methods:

Minocycline (maximal oral daily dose 200 mg) or

placebo was administered in a 26-week, randomized,

double-blind study to 80 patients with active RA, who

were treated or had previously been treated with at

least one disease modifying antirheumatic drug

(DMARD).

Results:

There were 15 premature discontinuations: 6 (5 taking

minocycline) because of adverse effects, 8 (all taking

placebo) because of lack of efficacy, and 1 (taking

placebo) because of intercurrent illness. There was a

statistically significant improvement in the

minocycline group over the placebo group. There was a

pronounced improvement in laboratory parameters of

disease activity; however, improvement in clinical

parameters was less impressive. The observed adverse

effects attributable to minocycline were mainly

gastrointestinal symptoms and dizziness.

The results of the present study suggest that

minocycline is beneficial and relatively safe in RA

patients.

Description:

80 patients who had definite or classical Rheumatoid

Arthritis, according to the 1958 criteria of the

American College of Rheumatology (formerly, 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).

At pages 633-634, the Kloppenburg study states:

" Adverse effects and toxicity. During the trial, the

frequency of adverse effects was considerable in both

groups (Table 5), but was significantly higher in the

minocycline than in the placebo group. Thirty-seven

patients (26 in the minocycline group versus 11 in the

placebo group; P <0.005) reported adverse effects;

such effects led to dose reduction in 7 patients (6

taking minocycline and 1 taking placebo) and to

premature discontinuation of the trial medication in 6

patients (5 taking minocycline and 1 taking placebo).

All adverse effects resolved after the study

medication was discontinued.

Table 5 (page 634). Type and frequency of adverse

effects in 80 rheumatoid arthritis patients, by

treatment group

___________________________________________________________

Adverse /

Minocycline / Placebo

effects / (40

patients) / (40 patients)

___________________________________________________________

Gastrointestinal 23

(4/4) 6 (0/0)

Nausea 20

(4/4) 5 (0/0)

Vomiting 1

(0/1) 1 (0/0)

Increased appetite 10 (2/0)

0

Change of taste 7

(2/0) 0

Dizziness 16

(6/4) 6 (0/1)

Leading to a

major event (+) 2

(1/0) 0

Skin eruption 0

1 (1/0)

Allergic pneumonitis 1 (0/1)

0

Headache 1

(0/0) 0

Miscellaneous 0

3 (0/0)

Candida esophagitis 0

1 (0/0)

Herpes zoster 0

2 (0/0)

___________________________________________________________

Values are the number of patients with adverse effects

leading

to (dose reduction/premature discontinuation).

Several patients had more than one adverse effect.

(+) One patient had a fracture of the elbow, another a

fracture of the humerus.

___________________________________________________________

Continued from pages 633-634:

Women experienced roughly the same number of adverse

effects as men, whereas the percentage of women whose

dose was reduced and who withdrew early because of

adverse effects was higher (38%) than that for men

(7%). Fifty percent of the women experienced

dizziness, compared with 21% of the men.

Minocycline showed no effect on serum values of

creatinine and albumin. The hepathic enzymes, except

GGT, showed a slight but significant increase in the

minocycline-treated group. The WBC count decreased

slightly but significantly in the minocycline-treated

group. The increase in hepathic enzymes and the

decrease in the WBC counts were within the normal

range and did not lead to premature discontinuation of

the study medication. "

At page 635, the Kloppenburg study adds:

" The counterpart of efficacy is toxicity. In a

metaanalysis of the toxicity of second-line drugs used

in clinical trials in RA patients, 15% of the patients

dropped out because of drug toxicity. The percentage

of premature discontinuations due to adverse effects

in the present study (12.5%) was therefore relatively

low compared with the established DMARDs. In the

present study, GI intolerance and dizziness were the

most frequently seen adverse effects. In terms of

severity, there was a life-threatening allergic

pneumonitis in 1 patient. However, such an allergic

pneumonitis caused by minocycline or another

tetracycline is extremely rare. Discontinuation of the

therapy, if needed, combined with the administration

of corticosteroids, results in prompt and complete

recovery, as in our patient.

Dizziness, which occured in almost half of the

patients, was completely reversible upon

dose-reduction or discontinuation of the drug. Despite

strict monitoring, this adverse effect led to a bone

fracture in 2 patients. Dizziness, a notorious adverse

effect of minocycline, is vestibular in origin and

more frequent in females than males. The present study

confirms this prevalence in women, and this might be

the cause of a higher percentage of dose reduction and

of withdrawals among women. Since the majority of RA

patients are female, this vestibular adverse effect

needs serious consideration. Since dizziness is

thought to be dose-related, further research into

other dose regimens would be warranted to minimize the

adverse vestibular effects, while maintaining the

beneficial effect of the drug for the arthritis. "

At page 635, the Kloppenburg study finally concludes:

" There is no unanimity about the mode of action of

tetracyclines in patients with arthritis. Besides the

antibacterial effect, tetracyclines have a variety of

characteristics that may be responsible for the

anti-arthritic effect. Tetracyclines have the ability

to inactivate enzymes, such as metalloproteinase and

phospholipase A2, that are thought to play a role in

arthritis. Moreover, tetracyclines suppress cells of

several types, for instance, neutrophils and T

lymphocytes. The latter are thought to play a crucial

role in the pathogenesis of RA. One unproven

hypothesis implicates a microbial cause in the

pathogenesis and the ongoing process of RA, and

consistent with that, tetracyclines may exert their

effect by influencing tetracycline-sensitive

microorganisms. All these characteristics, perhaps in

combination, might play a role in the anti-arthritic

effect.

The conclusion drawn from the present study is that

minocycline appears to have beneficial properties in

RA, especially when laboratory parameters of disease

activity are considered. The effect of minocycline on

clinical parameters of disease activity is not

unequivocal. Since the trial was performed in patients

with advanced, or even intractable, RA, the drug might

not have had an optimal chance to prove efficacious.

The adverse effects should not be disregarded, but may

be considered rather mild in relation to other

established DMARDs. The results of the present study

are such that further investigations comparing

minocycline with an established DMARD in RA patients

in earlier stages of disease promise to be worthwile. "