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

___________________________________________________________

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

Patients originally in placebo group (n= 20)

___________________________________________________________

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. "