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Minocycline in Early Diffuse Scleroderma SSc - The Next Step
David E. Trentham, MD, is a rheu-matologist at Beth Israel Deaconess Medical Center in Boston, MA, an associate professor at Harvard Medical School, and has published numerous papers on varying aspects of rheumatic disease. He was an investigator in the Minocycline in Rheumatoid Arthritis study (MIRA) in 1995.
Background
No universally effective treatment for scleroderma exists and many drugs used for this disease can, on occasion, produce toxic side effects. In an uncontrolled trial involving 11 patients with early but severe diffuse scleroderma, oral minocycline was well tolerated and appeared to improve the skin manifestations in 4 of 6 patients that completed a year of treatment. Expanded studies are in order.
Criteria
Eleven patients with symptom duration <3 years and no serious internal organ involvement were enrolled. For those on interventional treatment, a 1-month washout occurred. Patients were started on oral minocycline and evaluated at 3-month intervals for the subsequent year.
Three patients washed off penicillamine and 1 methotrexate. Four of the six patients that completed 1 year of treatment had complete normal-ization in their skin score; three in the patient and physician assessment of global status normalized as well. Yeast infection developed in two patients and transient nausea and dizziness in another.
Results
Patients were begun on 50 mg. bid Minocin® taken with water on an empty stomach. The dose was increased to 100 mg. bid after 1 month. This protocol was used to avoid the dizziness and/or headache occasionally encountered by RA patients when starting on minocycline.
After the initial evaluation, patients returned at three month intervals for total skin score assessment (maximum of 51, normal = 0) and both patient and physician global visual analogue scale (VAS) (10 = could not be worse, 0 = could not be better). A 35% improvement in TSS was considered clinically significant and >25% in VAS score at 12 months was clinically significant.
Although this is a preliminary trial, and small in numbers, the results correlate with much larger numbers of anecdotal cases. This study was funded with the expectation that the results would be significant and would stimulate interest in more research in this area.
In an interview, Dr. Trentham was asked his impression of the results of the study. "(The results) were highly, highly significant. . . we had hoped to see remissions, and we did see them. What surprised us was that we also saw a reversal of symptoms. We had not expected to see that."
"The evidence that minocycline is a safe and effective treatment for RA led us to believe it might also be helpful in related diseases such as scleroderma. This study shows that premise was correct."
The announcement of the results of the Minocycline in Scleroderma study at the 6th Biennial Congress of the International Society for Rheumatic Therapies on May 8, 1998 has created quite a stir.
Following the pattern set by the first minocycline in RA study by FC Breedveld of The Netherlands in 1990, this first study in scleroderma was small and not blinded. The Breedveld study followed 10 patients for 16 weeks; the scleroderma study followed 11 patients for 1 year.
These preliminary results are promising and the treatment non-toxic in a form of a disease which has no effective treatment and can be fatal in 50% of cases within 10 years. Notification will be made when the paper is published. A larger, multi-center trial will follow.
Rheumatoid arthritis and scleroderma are not the only diseases found to respond to antibiotics. It seems that several diseases, ulcers and athero-sclerosis among them, show indications of a possible microbial component. We hope that future research will investigate this area as well and we intend to be participants in some of those investigations. New DNA technologies may enable scientists to determine, once and for all, if a microbe is involved in rheumatic disease or not. The mechanism of action of antibiotics in RA and scleroderma will most likely not be determined until an organism is either proven or eliminated as a participant in the disease process.
"The true aim of peer review in biomedical science must be to improve the quality of patient care... To further the cause of improving patient care, it is the duty of editors to encourage innovation as well as to insure quality control. (JAMA 1990; 263:10, p 1441)
Combination Therapy - Why Two Might Be Better than One "The major impediment in controlling RA is delay - between disease onset, instituting effective drugs, and achieving disease control.1
"The last decade has seen significant advances in our ability to treat RA. . . It is our responsibility as rheumatologists to make sure our patients benefit from them."2 Among those advances are the seven minocycline studies, all of which showed the antibiotic to be safe and effective, making minocycline an increasingly popular and effective treatment for both recent onset, and surprisingly, also for long-term disease.
The Hypersensitivity Theory
According to Thomas McP Brown, MD, a Washington DC area rheumatologist who pioneered antibiotic therapy, RA represents a form of bacterial hypersensitivity with the responsible antigen derived primarily from mycoplasma and/or bacterial L-forms. Mycoplasma have a great affinity for joint tissue and are the primary sensitizers in the rheumatoid complex.4
Even if you are not convinced that arthritis has an infectious component, consider for a moment these facts:
1) The symptomatic therapies used for decades have not proven effective (DL Scott, Lancet)
2) Minocycline has proved effective in every study since 1990, and it is, among other things, antimicrobial. (7 RA studies)
3) Most standard remedies eventually become toxic to the patient or lose their effectiveness (JM Cash3)
4) Although difficult to culture because of their intercellular nature, mycoplasma have been found in RA patients (Schaeverbeke) as well as a number of other rheumatic diseases such as lupus (Ginsburg) and JRA (Oen).
5) Patients using minocycline long-term, are usually able to discontinue other medications except for an occasional NSAID and continue to see improvement.
6) Remissions are not uncommon on antibiotics, and have been shown, anecdotally, to continue for decades with little or no side effects from the medication.
7) In asthma, TB, and brucellosis the organism responsible for the disease is often not present when the hypersensitivity state is active; because this form of bacterial hypersensitivity is antimicrobial.
Which Drugs and How Much?
NSAIDs - Minocycline by itself is most often ineffective without first preparing the way for its action to be fulfilled. (Brown). In inflammatory forms of arthritis such as RA, JRA, SLE, and fibromyalgia, one of the anti-inflammatory drugs (NSAID) needs to be used to reduce inflammation and as a result, pain.
Antibiotic - Tetracyclines have been found to be the most effective and have the fewest side effects, with minocycline or doxycycline being the antibiotic of choice. Brand names (Minocin by Lederle; Vibramycin by Pfizer) are preferred as some generics are ineffective.
Low doses are more effective than higher dose due to the highly reactive state of the patient. If too much is given, the body can begin to react against the medication, defeating the purpose of the treatment. All bacterial hypersensitivity states require intermittent antigen suppressing treatment. Many dosing regimens have been used, but the most common is M-W-F.
Improvement will be gradual, sometimes subtle, but usually steady. Treatment needs to be pursued long enough to suppress antigen formation. The treatment can be carried on virtually indefinitely without ill effects as evidenced in the long-term safe treatment used by dermatologists for acne with minocycline.
Antihistamine - Dr. Brown used an antihistamine such as Benedril (25 mg) with the evening antibiotic dose. The antihistamine serves to potentiate the action of the antibiotic.
Why Two Are Better Than One
"We must treat all patients with the clear goal of remission. This approach must start as early as possible and continue for the duration."2
When to Use Combination Therapy
"Possible ways to maximize the long-term efficacy of second-line drugs include introducing them earlier and giving them in combinations. . . Presumably, the benefits of combination therapy would be improved efficacy due to drug synergism and, as a consequence, the use of lower doses to minimize toxicity."3
The practice of combining 2, 3, and even 4 drugs to increase the response in the rheumatic patient is a common practice, especially in the rheumatology community. In the case of antibiotic therapy, a combination of antibiotics can also increase response and speed improvement time.
In the case of scleroderma, especially in advanced and/or severe disease, combining an oral tetracycline (usually minocycline or doxycycline) with IV clindamycin has been shown, anecdotally, to be a better choice of treatment than oral alone.
The clindamycin dose should be intermittent and titrated to patient tolerance and need. An initial 5 day course of IV clindamycin, administered once a day starting at 300 mg, increasing to 600 and ending with 900 mg can provide significant benefit. IVs can be continued once a week, twice a month, or once a month as needed or the 5 day course can be repeated every 4-6 months as needed. As the dose is increased, the space between doses is generally increased. When symptoms have improved sufficiently, oral treatment will become effective and adequate to maintain control.
Caution: Starting IV therapy at lower doses, gradually increasing, helps prevent adverse gut reactions such as colitis. Using the clindamycin in higher dilutions such as 200 cc D5W makes it less caustic to the veins than the smaller, but more convenient bags. A limited number of patients find the smaller concentration causes a burning sensation during administration of the IV.
References
1 WG Bensen et al, Back to the Future: The Pyramids of Rheumatoid Arthritis, editorial, J Rhu, 1997; 24:6, 1023-1027.
2 JR O'Dell, The Therapeutic Pyramid: A Work in Progress, editorial,
J Rhu, 1997; 24:6, 1029-1030.
3 JM Cash, JH Klippel, Second-Line Drug Therapy for Rheumatoid Arthritis, NEJM, May 12, 1994; 330:19, 1368-1375.
4 TMcP Brown, Guidelines for Infectious Hypersensitivity Approach to the Treatment of rheumatoid Disease
5 TMcP Brown, JS Bailey, II Iden, HW Clark, Antimycoplasma Approach to the Mechanism and the Control of Rheumatoid Disease, Inflammatory Diseases and Copper, JRJ Sorenson, ed, Humana Press, 1982. 391-407.
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