1999 O'Dell Study

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The 1999 O'Dell Study

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

Eckhoff, PJ, Klassen, LW, Churchill, M, Doud, D, Weaver, A, , GF,

Treatment of early seropositive Rheumatoid Arthritis with minocycline:

Four-Year followup of a double-blind, placebo-controlled trial,

Arthritis & Rheumatism, 1999, 42:8, 1691-1695.

Objective:

To compare patients treated with conventional therapy in the early

phase of Rheumatoid Arthritis and those treated with minocycline after

4 years of followup.

Methods:

Forty-six patients with seropositive Rheumatoid Arthritis of more than

6 weeks and less than 1 year in duration were enrolled in a

double-blind study of minocycline (100 mg, twice daily) versus placebo.

After the blinded portion of the study (3-6 months, depending upon

response), all patients were treated with conventional therapy. If a

patient had been receiving minocycline during the blinded portion of

the study, but had a disease flare during the open portion, minocycline

was restarted in most cases.

Twenty of the 23 original minocycline-treated patients and 18 of the 23

original placebo-treated patients were available for followup (mean 4

years). This report compares the patients randomized to receive placebo

for 3 months and then conventional therapy for the duration of 4 years

versus those originally randomized to receive minocycline.

Results of the minocycline-treated group after 4 years:

65% of the patients improved their symptoms by at least 75%, some

achieving a remission.

40% of the patients fulfilled remission criteria without DMARDs or

steroids.

50% of the patients never required any DMARD or steroids.

20% of the patients reported skin hyperpigmentation.

15% of the patients discontinued minocycline because of

hyperpigmentation.

Introduction:

Currently, rheumatologists are emphasizing the importance of early

control of RA and studies have shown that patients respond best when

treated early with disease-modifying therapy. In a double-blind,

controlled trial of minocycline compared with placebo in patients with

early seropositive RA, we have previously shown that the

minocycline-treated patients were significantly better at 6 months and

continued to show excellent responses after 1 year. In this

communication, we extend those observations and report superior (and,

in some cases, dramatic) results after a median followup of 4 years in

the minocycline-treated patients compared with controls treated in a

conventional manner.

Patients and methods:

Experimental design. We enrolled 46 patients in the original 6-month,

double-blind, controlled study. Twenty-three of the patients were

randomized to receive minocycline (100 mg, twice daily) and 23 to

receive placebo. Three months after enrollment, patients were

evaluated; if a patient did not meet 50% improvement criteria, he or

she was withdrawn from the blinded portion of the study. All patients

remaining in the blinded portion were again evaluated for 50%

improvement after a further 3 months of therapy. The blinded portion of

the study ended after the 6-month evaluation and, regardless of the

response to therapy, the minocycline or placebo was stopped in all

patients at 6 months.

Once the blinded portion ended and the data were recorded, the

physician was informed of the randomization and was then free to

prescribe whatever therapy he or she deemed most appropriate, including

DMARDs alone or in combination, prednisone and minocycline. If the

patient had been receiving minocycline during the blinded portion of

the study and had a good response (15 patients) but had a disease flare

during the open portion (all 15 patients), minocycline was restarted in

most cases.

Concurrent therapy. During the open portion of the study, physicians

could prescribe any medication, including changing NSAIDs, starting or

restarting minocycline, using DMARDs alone or in combination, and/or

initiating steroids.

Results:

In the original protocol we randomly assigned each of the 46 patients

to 1 of the 2 treatment groups (23 patients in each). There were no

significant differences between the groups at entry. Results of the

blinded portion of the study have been published previously; 65% of the

minocycline-treated group and 13% of the placebo-treated group met 50%

improvement criteria at the end of the blinded portion of the study.

Toxicity (pages 1692-1693). None of the minocycline-treated patients

withdrew due to toxicity during the blinded portion of the study. One

patient in the placebo group withdrew because of a gastrointestinal

bleed. Subsequent to the blinded phase, 3 of the minocycline-treated

patients discontinued minocycline because of hyperpigmentation and 1

patient reported mild hyperpigmentation but elected to continue

therapy. This occured at 1, 2.5, 3, and 3.5 years of therapy. In the 3

patients who stopped minocycline, the hyperpigmentation decreased

slowly over time. None of the patients reported dizziness that

precluded continuation of the treatment.

Table 1 (page 1693).

Long-term results in patients with early rheumatoid arthritis treated

with minocycline versus placebo

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No. of patients available for followup: 20 vs. 18

Years of followup, mean (range): 3.8 (1.5-6.3) vs. 4 (2.0-6.1)

No. in remission *: 8 (40%) vs. 3 (17%) **

No. in remission without DMARDs: 8 (40%) vs. 1 (6%) ***

No. with ACR 75% response ****: 13 (65%) vs. 4 (22%) *****

No. with DMARD therapy: 10 (50%) vs. 16 (89%)

No. with prednisone therapy: 9 (45%) vs. 11 (65%)

No. with current minocycline therapy: 11 (55%) vs. 4 (24%)

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Notes:

* Remissions according to American College of Rheumatology (ACR)

criteria, but measured at only a single time point.

** One of these 3 patients was treated with minocycline during the open

phase.

*** Minocycline is not considered a disease-modifying antirheumatic

drug (DMARD) in this analysis.

**** All patients with > 75% response, including those in remission.

***** Two of these 4 patients were treated with minocycline during the

open phase.

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Results of long-term treatment with minocycline (page 1693). Of the 23

patients who were originally treated with minocycline, 20 have had

followup past 1 year (median 4.25 years, mean 3.8 years), as have 18 of

the 23 placebo-treated patients. The current status of these patients

is shown in Table 1. The difference between the number of patients in

the minocycline group and the number in the placebo group whose RA was

in remission without DMARDs (minocycline not considered a DMARD) or

steroids was significant, 1 of 18 (6%) in the placebo group versus 8 of

20 (40%) in the minocycline group, as was the number of patients

requiring DMARD therapy, 16 of 18 (89%) of the placebo-treated patients

compared with 10 of 20 (50%) of the minocycline-treated patients. One

of the 3 patients originally in the placebo group whose RA was in

remission at followup was receiving minocycline at the time of the

followup evaluation. Importantly, 50% of the patients (10 of 20)

originally treated with minocycline never required treatment with

DMARDs or steroids, and 40% (8 of 20) fulfilled remission criteria

without DMARDs or steroids.

Time course of response to minocycline (page 1693). Figure 1 plots the

total joint counts (sum of tender and swollen joints) versus months of

minocycline treatment for the 15 patients who were responders to

minocycline. Although significant response had been seen by 3 months

(at which time the mean total joint count of 31.1 had decreased to

13.5), maximal response did not occur until at least 9 months [mean

total joint count of 5 at 9 months, and 1 at 18 months].

Discussion (pages 1693-1694):

" With currently available DMARD therapy, complete remissions of RA are

disappointingly rare. This realization has fueled a surge of interest

in alternate forms of therapy for RA, including a significant increase

in the use of combination DMARD therapy and of minocycline. Our

double-blind, placebo-controlled study has demonstrated the benefit of

minocycline when used to treat patients with seropositive RA within the

first year of disease, and the present report confirms that these

patients continue to do well for up to 4 years (mean followup). We

believe that several key points about our study design are worth

emphasizing: all of the patients studied had early disease (these

patients have been shown by many to be most responsive to therapy); all

were rheumatoid factor positive (and thus we studied a relatively

homogeneous patient population and a group of patients who were

destined to have a low rate of spontaneous remission and who could be

predicted to have ongoing, aggressive disease); and, finally, we chose

to define success as a 50% improvement in composite criteria instead of

the 20% that is often used.

Our findings and those of other investigators suggest that the maximum

benefit of minocycline does not occur until after 1 year of therapy.

Therefore, the results of the original study are even more remarkable.

We did not want to continue placebo treatment for more than 3 months in

patients with active RA; therefore, the double-blind portion of the

trial was continued for only 6 months, and some patients may have been

dropped from the minocycline treatment arm before they had an

opportunity to have a maximal response.

The magnitude of improvement in our minocycline-treated patients was

dramatic compared with the modest but statistically significant benefit

in the Netherlands and Minocycline in Rheumatoid Arthritis trials.

Reconciliation of these seemingly disparate results requires

acknowledgment that our study used 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, in which minocycline can produce dramatic

benefit. Additionally, we observed fewer side effects, especially

dizziness, in our trial compared with the Netherlands trial. The

reasons for this are unclear, but the young age of our patients is one

possible explanation. Like all other treatments for RA, minocycline may

need to be continued indefinitely to remain effective; therefore, the

localized hyperpigmentation that appears to increase with duration of

minocycline therapy is problematic. Recently, we have switched some of

our patients to doxycycline, which is similar to minocycline in most of

its known activities, but appears to be associated with less

hyperpigmentation.

Tetracyclines, particularly minocycline and doxycycline, are 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. In patients with RA, minocycline or

doxycycline treatment has been shown to result in decreased synovial

collagenase production, decreased levels of metalloproteinase breakdown

products in the urine, and decreased collagenase activity in the

saliva. In this latter open-label study, clinical features of RA also

improved significantly.

Early advocates for the use of tetracyclines in the treatment of RA

based their choice on the antibacterial effect, believing that RA was

initiated and perpetuated by an infectious agent. Two currently

well-accepted disease-modifying drugs, gold and sulfasalazine, were

initially used for similar reasons. Recent experiences with Lyme

disease, human immunodeficiency virus, and hepatitis C are vivid

reminders of how much we have to learn about infectious triggers of

diseases with immunologic and rheumatic manifestations. Therefore, it

is clearly possible that an infectious agent will be shown to play a

role in the pathogenesis of RA. Recent data on evidence of organisms

demonstrated by polymerase chain reaction in the joints of some RA

patients, differences in the bowel flora of RA patients with and those

without erosive disease, and the ability of one of the most commonly

used and effective DMARDs, sulfasalazine, to alter bowel flora are

intriguing.

In addition to their antimicrobial and antimetalloproteinase effects,

the tetracyclines have been shown to have antiinflammatory effects,

immunomodulating effects, and the ability to inhibit angiogenesis. With

regard to the immunomodulating effects of tetracyclines, the recent

reports of apparent drug-induced lupus in acne patients treated with

minocycline are of interest. Finally, there has been much recent

enthusiasm for, and some evidence to support the use of, agents with

activity against tumor necrosis factor alpha (TNFa) in the treatment of

RA. Metalloproteinases are involved in the processing of TNF and may be

affected by matrix metalloproteinase inhibitors.

Our study does not address the critically important question of the

mechanisms of action of minocycline. Based on the observed benefit in

animal models of arthritis when tetracyclines are used, we postulate

that part of the efficacy is due to inhibition of matrix

metalloproteinases. We believe that metalloproteinase inhibition will

be a key part of combination therapy for the future treatment of RA.

Whether antibacterial effects are important is unclear, but we

certainly cannot rule out this possibility. Interestingly, in the

majority of our patients who had favorable responses to minocycline,

the RA flared when this treatment was stopped. Whether this reaction

favors one of the proposed mechanisms over another is unclear.

We believe that minocycline is effective for treating seropositive RA

within the first year of disease. Further studies are needed to define

the optimal duration of treatment, mechanism(s) of action, and to

compare minocycline with other DMARDs given alone and in combination

early in the disease. "

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