1997 O'Dell Study

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The 1997 O'Dell Study

O'Dell, JR, Haire, CE, Palmer, W, Drymalski, W, Wees, S, Blakely, K,

Churchill, M, Eckhoff, PJ, Weaver, A, Doud, D, son, N, Dietz, F,

Olson, R, Maloley, P, Klassen, LW, , GF, Treatment of early

Rheumatoid Arthritis with minocycline or placebo: Results of a

randomized, double-blind, placebo-controlled trial, Arthritis &

Rheumatism, 1997, 40:5, 842-848.

Objective:

To determine if minocycline is an effective therapy for Rheumatoid

Arthritis patients who are RF positive when used within the first year

of disease onset.

Results:

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

No patient withdrew from the study due to toxicity.

No patient reported dizziness that precluded continuation of the

protocol.

65% of the patients improved their symptoms by at least 50% within 3

months.

22% of the patients achieved a remission within 1 year and no longer

received any therapy.

Description:

Forty-six patients with active Rheumatoid Arthritis of more than 6

weeks and less than 1 year in duration were enrolled in this 6-month,

double-blind, randomized, controlled study. Each of the 46 patients was

randomly assigned to 1 of the 2 treatment groups: minocycline (n= 23)

or matching placebo (n= 23). There were no differences between the

groups at study entry. The dosage of minocycline was 100 mg twice per

day and was constant throughout the study. Patients in both groups

continued their pre-study NSAID treatment at stable doses. Patients who

had previously received DMARD or steroid therapy and women of

childbearing age who were not practicing contraception were not

eligible.

Experimental design. Three months after enrollment, physicians who were

unaware of the treatment groups evaluated the patients. If at that

time, patients did not meet criteria for 50% improvement, we considered

their treatment ineffective and they were dropped from the blinded

portion of the study. We again evaluated the patients after therapy had

been given for 6 months and recorded whether they had improved by 50%

over baseline; if so, we considered their treatment effective. The

blinded portion of the study ended after the 6-month evaluation.

Regardless of the response to therapy, the minocycline or placebo was

stopped in all patients at 6 months. All patients were then followed up

in the open portion of the study for an additional 6 months (9 months

for patients who were considered treatment failures in the 3-month time

point). Therefore, the total duration of the study was 1 year (3-6

months in the blinded portion and 6-9 months in the open portion).

During the open portion of the study, the treating physician was free

to prescribe whatever therapy he or she deemed most appropriate. If the

patient had been receiving minocycline during the blinded portion of

the study and had a disease flare during the open portion (11

patients), minocycline was restarted.

Toxicity. One patient in the placebo group stopped treatment because of

a gastrointestinal bleed. None of the minocycline-treated patients

withdrew due to toxicity. None of the patients reported dizziness that

precluded continuation of the protocol.

Concurrent therapy. During the blinded portion of the trial, patients

were allowed to take concurrent NSAIDs at stable doses, but were not

allowed to take systemic or intraarticular steroids. During the open

portion of the trial, physicians could prescribe any medication,

including changing NSAIDs, starting or restarting minocycline, or

initiating DMARDs and/or steroids.

Results of treatment. Eighteen patients had improved by 50% at 3 months

and maintained this improvement at the end of the 6-month treatment

period. This included 15 of 23 patients (65%) in the minocycline group

and 3 of 23 patients (13%) in the placebo group. Efficacy (50%

improvement) was not demonstrated in 8 patients in the minocycline

group and 19 in the placebo group. The remaining patient in the placebo

group withdrew because of toxicity.

One year after enrollment, in the open portion of the study, six

patients had achieved a remission and no longer received any therapy, 5

of the 23 patients (22%) originally in the minocycline group and 1 of

the 23 patients (4%) originally in the placebo group.

Observations during the open portion of the study. Table 3 compares the

minocycline group and the placebo group at 1 year. The number of

patients who had improved significantly (> 50% improvement or

remission) was greater in the minocycline group. Similarly, there were

fewer minocycline-treated patients who required DMARD therapy at 1

year.

Table 3 (page 845). Therapy at 1 year: minocycline versus placebo

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Patients originally in minocycline group (n= 23) vs.

Patients originally in placebo group (n= 20)

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No. in remission: 5 vs. 1

No. improved by 50%: 20 vs. 9

No. receiving DMARDs: 7 vs. 17

No. receiving minocycline: 11 vs. 3

No. receiving no therapy: 5 vs. 1

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At pages 845-846, the O'Dell study states:

" This double-blind, placebo-controlled study demonstrates the benefit

of minocycline when used to treat patients with seropositive RA within

the first year of disease onset. We believe that several key points

about our study design are worth emphasizing: we enrolled only patients

with early disease (these patients have been shown by many to have the

best response to therapy), we enrolled only patients who were RF

positive and thus we were studying a relatively homogeneous patient

population and a group of patients who were destined to have a low

spontaneous remission rate, and finally, we chose to define success as

50% improvement of symptoms instead of the 20% that is often used.

We believe our results are even more remarkable because our study

design almost certainly decreased the chances of finding a positive

effect. Since we were conducting a placebo-controlled trial, we

required 50% improvement at 3 months as a criterion for continuation in

the study. We did not want to continue placebo treatment for more than

3 months in patients with active RA. Data from our study and others

suggest that maximum benefit of minocycline does not occur until after

1 year of therapy. Therefore, we almost certainly lost patients before

they had a maximal response to minocycline.

The magnitude of improvement in our minocycline-treated patients was

dramatic compared with the modest but statistically significant benefit

in a study conducted in the Netherlands and in the Minocycline in

Rheumatoid Arthritis trials. Reconciliation of these seemingly

disparate results requires acknowledgment that our study group

consisted of an entirely different patient population. The most

significant difference was the disease duration, which averaged 8.6

years and 13 years in those other trials and <5 months in our trial.

The observed difference in magnitude of response may be explained by

the fact that patients with early disease respond better to most

therapies. Alternatively, there may be a window of opportunity early in

RA when minocycline can produce dramatic benefit. Additionally, we

observed fewer side effects in our trial compared with the Netherlands

trial, especially with regard to dizziness. The reasons for this are

unclear, but the young age of our patients is one possible explanation.

Minocycline has been shown to have antiinflammatory, immunomodulatory,

and chondroprotective effects in addition to its antibacterial

activity. Tetracyclines, particularly minocycline and doxycycline, are

potent inhibitors of metalloproteinases, including collagenase and

gelatinase. Metalloproteinases are almost certainly active in RA joint

destruction, and studies in animal models of arthritis (both RA and

osteoarthritis) have shown benefit with minocycline or doxycycline

treatment. Modified derivatives of minocycline that retain their

ability to inhibit metalloproteinases but do not have antibacterial

effects remain effective in some of these models. Finally, there has

been much recent enthusiasm for, and some evidence to support the use

of, agents with activity against tumor necrosis factor alpha in the

treatment of RA. Interestingly, tetracyclines, especially minocycline

and doxycycline, inhibit the production of tumor necrosis factor. "

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