David E. Trentham, M.D.
Beth Israel Deaconess Medical Center/Harvard Medical School
Factors Influencing the Use of Minocycline in Rheumatoid arthritis (RA)
Mycoplasma Theory
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.
Lack of Physician Awareness
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?
Recent Nuances
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.
Poorly Informed Use
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.
Are Generic Minocycline Preparations as Effective as the brand name Minocin product?
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.
Thoughts about Scleroderma and Minocycline
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.
Patient Recommendations
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.