From its emergence in the 1960s, the rationale for antibiotic therapy was predicated on
the notion that RA was a chronic inflammatory disease caused by an infectious agent.
The most plausible candidate at that time was a mycoplasma organism based on early
animal studies. Limited successful clinical outcomes fostered its continued use and
culminated in two large scale placebo-controlled trials (the NIH sponsored MIRA and
that of the RA Investigative Network, i.e., RAIN) in the 1990s. The positive clinical
results in both studies provide the scientific foundation for use of minocycline today.
Unfortunately, the continued espousal of the mycoplasma etiology, despite numerous
negative searches for the organism, has enshrouded the approach in controversy.
Under-appreciated is the frequency with which anti-rheumatic agents are used in the
complete absence of knowledge of how they work. And that situation is pervasive in
medicine. How ether puts one to sleep is unknown. In rheumatology, the case applies
to hydroxychloroquine(Plaquenil), methotrexate, leuflunomide(Arava), as well as
minocycline. The mechanism by which minocycline improves acne also remains elusive.
 

Considerable time has now elapsed between the completion of those pivotal studies,
now almost two decades, and the present. A rule-of-thumb for the Food and Drug
Administration (FDA) approval for a medication in the treatment of a disease is at least
two positive placebo-controlled trials coupled with an adequate safety profile. By these
traditional criteria, minocycline should be approved for RA. The failure of the FDA
to act reflects the fact that no drug manufacturer has submitted an application for its
approval for its use in RA. The reason? : There is an insufficient profit margin for an
old generically available agent that has been supplanted by more effective antibiotic
therapies.

This time lag and the widespread availability of newer FDA-approved drugs
dampen physicians’ use of minocycline. Prescribing minocycline for RA is still on
a “compassionate use basis”. This tenet signifies that the prescription represents the
prescriber’s conclusion that it is the best approach for that individual patient. Although
a cardinal rule throughout medicine, using this justification to prescribe inflicts a degree additional medicolegal risk for the prescriber if things go awry.

Infrequent use also reflects practicing rheumatologists being bombarded by a plethora of new FDA-approved RA drugs by the pharmaceutical industry. These new drugs being
quite expensive are money-makers for their corporate sponsors. It’s not surprising that
specialists attend glamorous so-called continuing education sessions featuring their
products at sessions at major meetings. At home physicians are frequented at their
doorsteps by drug representatives bearing information and even incentives or reminders. Thus, they are overwhelmed by such a barrage of information and propaganda.

Both printed and visual media advertisements extend the pharmaceutical companies
opportunity to ‘educate’ the lay public about new drugs in the hope that they in turn can
request using them from their rheumatologist. Have you ever seen an advertisement for
minocycline?

As experience among practitioners has matured, so have additional insights.
Unfortunately all of this is highly anecdotal. Perhaps most importantly, the tetracycline
analogue, doxycycline can be considered for patients on minocycline developing
hyperpigmentation but otherwise doing well on it. Doxycycline appears to be devoid
of the cutaneous darkening phenomenon and may give the patient time to see if the
minocycline side effect slowly lessens. The usual dose for doxycycline is also 100 mg
twice a day. Overall I do not think that doxycycline is as effective as minocycline for
RA.*

Clearly minocycline can provide adjunctive therapy for RA. In other words, minocycline
can be combined with any other available agent. There are no exceptions! Examples
include Plaquenil, methotrexate, Arava, anti-TNF compounds like Enbrel & Humira
and the new intravenous drug, abetacept (Orencia). Decreased doses of one or both
agents may help to avoid gastrointestinal side effects. This regimen usually reflects
a desire to obtain additional improvement or to gradually convert to the safer drug,
minocycline. Examples include 1. Not having to increase the dose of methotrexate and
2. By increasing the dose of minocycline additional improvement and /or stability may
be gained. Perhaps use of two oral drugs might preclude the necessity for an injectable
and more expensive drug. Obviously judging the net effect of either drug is difficult or
impossible. The same impasse may arise if a clinical or laboratory side effect occurs.
 

Time and time again I have observed that patients have started minocycline in what I
consider a sub-optimal fashion. Internet citations and directions abound that describe less
well-studied antibiotics as well as varying ways to administer minocycline.** Personally
I have extrapolated the exact protocol of the MIRA and RAIN studies into my clinical
use. This involves 100 mg taken twice a day on an empty stomach. Similar to thyroid
replacement hormones, optimal absorption of minocycline appears to peak on an empty
stomach. For many patients, this is best accomplished by 1 tablet taken two hours after breakfast and another at bedtime.

Importantly I follow the study format of dosing (100 mg 2x/day) every single day. For
older or smaller patients, it may be best to start with only 100 mg or even 50 mg per day, since these patients may be more apt to experience dizziness or headaches if begun on the standard dose. Sufficient time must transpire before concluding that it is effective—or
non-effective. I cannot state what this precisely means for individual patients, but clearly
unacceptable arthritis activity after several months warrants rethinking.

Tolerability is, in general, excellent. After longer-term use darkening to portions of the
skin, particularly in those that are sun-exposed, may occur. This darkening is caused
by minocycline stimulating the skin cells that create a tan. Fortunately the problem is
infrequent and usually slowly reversible after drug discontinuation. Rarely, the gum
line next to teeth or even the whites of the eyes can darken. While it does not otherwise damage the skin, gum or eyes or lead to skin cancer, it can be cosmetically unacceptable. Laser removal is possible for the face but that procedure is difficult and expensive.

Both MIRA and RAIN studies used Minocin. For at least the MIRA effort, it was
intended to use the highest grade of product possible in the trial. Verbal opinions that the quality control of cheaper generic counterparts could be found accordingly, clinical use
of brand name Minocin continued thereafter. Increased purchases of Minocin led to price
escalations and subsequently the sale of manufacturing rights to other firms. Lack of
availability and refusal of payment by third party payers has occurred as well. Fortunately this reviewer now harbors the opinion that modern forms of minocycline (generic) are
just as effective as Minocin.

This reviewer thinks that the cutaneous and musculoskeletal aspects of early stage
scleroderma may benefit from this dose of minocycline as well. The caveat that the
concept remains a political “hot potato” should also be re-stated up front.

The author’s opinion stems from an extremely small 1-year uncontrolled trial published
in the Lancet in 1998. Both patients and investigators reported improvement. But was the
benefit truly drug-related or merely reflected the hope and optimism presented by any
therapeutic trial?

The clinical situation in scleroderma remains desperate! No consensus exists that
any approach works. The author’s prior experience with penicillamine and an array
of so-called immunosuppressive drugs has been dismal. This outcome applies to
cyclophosphamide as well where the intervention can be as bad as or even worse than the
disease itself. So why not consider the unproven and experimental but safe approach and
try using minocycline?

Currently patient testimonials appear to be the only tangible clue of whether minocycline
works in scleroderma. These experiences can be found on the Internet or in lay books
(‘Scleroderma’ by Henry Scammell). So far I trust implicitly those testimonials submitted
by patients under, at least in part, my care. Also persuasive for me are comments of
surprise and pleasure by co-involved physicians. The Hippocratic Oath I took exactly 40
years ago when graduating from medical school was a pledge to try to help and not to
harm. Except for research support provided by the NIH or the Road Back Foundation,
I’ve never made a nickel prescribing minocycline. So why do I and others continue doing
it?

If started in scleroderma, extreme patience is required. Raynaud’s, extreme hand
contractures, and perhaps internal organ involvement do not appear to respond.

The intent of this review is to provide patients with a currently up-to-date conclusion
of the role of minocycline in the treatment of RA and scleroderma. It cannot dismiss
potential criticism that it reflects bias on the part of the author. In defense, I would
point out that my conclusions are based on several science-based events. I was awarded
a research grant from the NIH to study minocycline in animal models of RA in the
1980s. Its purpose was to further assess claims of a few experienced antibiotic therapy
rheumatologists, chiefly Thomas McPherson Brown that this therapy worked. And this
proved to be the case in two animal models of arthritis. It also engendered the role of my
center in the MIRA study. For me extension of the use of minocycline into my day-to-
day practice then followed. In the last decade of the 20th century this evolutionary path
was a template that I had followed in the 1980s for methotrexate where involvement in
the placebo-controlled trial of methotrexate published in The New England Journal of
Medicine in 1985 led to its wide-spread clinical use. The contrast however, has been the
markedly more favorable safety profile of minocycline versus methotrexate.

Now approaching the “sunset” of my career, I hope that this retrospective review can be
useful for patients and their physicians—at least in the immediate future. Perhaps it can
be conveyed to your doctor along with the question: “Doctor, is it worth a try?”

Acknowledgements:

This author wishes to thank his patients, The Road Back Foundation for its informational
achievements and his supportive wife, Rosie.

RBF Editor’s Notes:

Patient experience reported to the foundation has demonstrated that:

*Doxycycline has proven to be successful for many patients who cannot tolerate
minocycline.

**Dose levels of antibiotics may need to be titrated to individual tolerance.