The 1994 Kloppenburg Study (New Presentation)

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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 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 Anti Rheumatic 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. 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. "

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