Protocol.pdf

Protocol for Using Antibiotics
in the Treatment of Rheumatoid Disease
It is important to read the entire protocol.
This use of antibiotics for rheumatoid disease is different from the traditional manner
in which antibiotics are prescribed.
____________________________________________
C) 1998, The Road Back Foundation____________________________________________
This protocol supersedes any previous Road Back Foundation protocols.
It remains based on the publications of Thomas McPherson Brown MD.
as well as current research and treatment experience covering over 50 years of clinical experience __________________________________________________________________________
________________________Table of Contents______________________
Background
Tetracycline Therapy
Disease Mechanism
An Important Note about Lupus and
The Hypersensitivity State
Minocycline
Treating the Microbial Cause
Increasing the Dose
Disease Characteristics
Injecting the Joint
Focal Infections
The Herxheimer Flare
Treatment
First Signs of Improvement
Treating Severe or Long-standing
Continuing Treatment During
Improvement
Treating Less Severe, Early Disease Drug Rotation A
Washout Period
Side Effects
Anti-inflammatories
Laboratory Tests
Beginning the Therapy
Medical Journal References
Clindamycin - TM, IV
Appendix A - Mycoplasma Drug Chart
Appendix B - Laboratory Tests
1. BACKGROUND (TOC)
Arthritis has been known to exist since prehistoric times. Over 37,000,000 people are currentlysuffering from some form of rheumatic disease resulting in tens of billions of dollars in healthcare costs and lost productivity. This protocol provides the means of returning these people to anactive, productive life through the safe and effective use of low dose antibiotics.
11. Disease Mechanism (TOC)
This protocol views inflammatory forms of arthritis as a persistent cell-mediated hypersensitivitycreated by long exposure to antigen derived from a hidden or invisible microbial source (i.e.
mycoplasma or closely related bacterial L forms).
It appears that mycoplasma produce their pathogenic effect in man, not by the classical methodof invasion and rapid tissue destruction as in lower animals, but by creating a cell-mediatedresponse resulting from long-standing cellular parasitism with gradual sensitization of the hostthrough intermittent antigen release from the cells.
Rheumatoid disease progression to its most advanced stage is the over-reactivity of the host
tissues with the development of the hyperimmune or autoimmune state, probably through cell or
molecular mimicry. This phase of the disease, characterized by the production of cellmediated
antibodies, macroglobulins and the rheumatoid factor appears to be an expression of a second
line of defense in the immune system, logically deterring the spread of microbial precursors. The
therapeutic focus must be on eliminating mycoplasma as the key antigenic source.
Virulence of disease may be determined by biological properties of mycoplasma and include: 1. Generation of hydrogen peroxide radicals by adhering mycoplasma causing host cell 2. Competition for and depletion of nutrients which disrupt host cell maintenance function3. Existence of capsule like, electron dense layers or structures which protect mycoplasma 4. Antigenic variation which causes possible avoidance of protective host immune defenses5. Secretion or introduction of mycoplasmal enzymes (ATHases, hemolysins, protease and nucleate) into host cell which leads to localized tissue disruption, disorganization andchromosomal aberration 6. Intracellular residence which protects mycoplasmas and establishes latent or chronic states and circumvents mycoplasmacidal immune mechanisms and selective drugtherapies.
It is suggested these agents enter the joint tissue perhaps early in life when the cellular immunityis weak and remain as parasites for many years. Over the years fixed tissue antibodies whichrepresent the defense mechanism of the cells, begin to increase in concentration in the tissues surrounding the cells that are infected. Finally, when the concentration of these antibodiesbecome sufficiently high, the stage is set for a reaction to occur between the two forces: theextra-cellular and the intracellular mycoplasma.
The beginning of the disease in the clinical sense is when the two forces are thrown together byinjury, stress, barometer alterations, or other environmental factors. The initial reaction is one ofinflammation in the spaces between the cells and this rapidly extends to produce hot, swollen,tender joints. A reaction is designed to keep the infectious process from spreading.
Unfortunately, this protective mechanism also becomes a barrier to the entry of the body'sdefense forces. Thus it is the nature of the disease to produce its own road block which accountsfor the chronic, unrelenting nature of the disease process.
The Hypersensitivity State (TOC)
The treatment approach in the microbial hypersensitivity state is determined to be altogetherdifferent from standard anti-microbial therapy. In rheumatoid disease, the hyperreactive stateitself suppresses microbial antigen replication and accounts for the high degree of localization ofmycoplasma foci of involvement. The primary objective of treatment is the suppression ofantigen production and at the same time avoiding the sudden release of excess antigen anddelayed drug sensitivity by over medication.
Effective treatment has evolved to be the converse of the treatment of standard infection.
The dosage of medication is relatively low instead of high, it is generally interrupted
instead of sustained, and the treatment is usually long-term.
In all microbial hypersensitivity states, the causative agent virtually goes underground as the
tissue reactivity becomes manifest. Thus, in the highly reactive state, very little anti-microbial
medication is needed to further control the disease. And if too much is given, the body begins
to react against the medicine itself and defeats the purpose of the treatment. This is the
main reason for the intermittent treatment. All bacterial hypersensitivity states require
intermittent antigen suppressing treatment as exemplified by tuberculosis, rheumatic fever and
brucellosis.
Treating the Microbial Cause (TOC)
The fundamental treatment goal in the induction of a sustained remission is to control andsuppress antigen production. The final objective has been the ultimate elimination of themicrobial antecedent.
In the primary objective, the suppression of antigen production, dosage needs to be tailored tothe individual patient to avoid the sudden release of excess antigen and delayed drug sensitivityby over- medication. The degree of anti-mycoplasmal medication may need to be reduced to theminimum, such as minocycline, 50 ma. once or twice a week, gradually increasing according topatient tolerance in these individuals.
An important guideline in successful treatment has been the avoidance of over- medication
with paradoxical worsening. Too much medication can cause a delayed hypersensitive
reaction to the drug itself and induce a flare of the arthritis with the development of
symptoms closely mimicking the disease (Herxheimer Reaction). A therapeutic balance can
be readily reestablished by the temporary interruption of the treatment for a week and
then restarting at the same low dose.
Disease Characteristics (TOC)
The toxic substances characteristically present in inflamed tissues as well as toxins fromorganism die-off escape into the blood stream and are transported to the liver where they aredestroyed. As they pass through the system, they react at the point of greatest antigenaccumulation and may affect the body in a devastating fashion because of their persistence: In the bone marrow, these toxic materials interfere with formation of blood and therefore
anemia is commonly observed in severe rheumatoid arthritis and cannot be corrected until the
disease has improved
•In the central nervous system these toxins promote depression, inability to concentrate, loss of
memory, loss of interest in one's vocational effort, mental irritability and epiloidal type seizures
•In the muscular system these toxins are responsible for excessive fatigue and persistent
weakness which is difficult to overcome by physical means
• Gland functions are also depressed
• There is an effect upon the digestive system and many other basic physiological processes
• Every organ system may be involved at one time or another
Those patients in whom arthritis has a severe onset but in whom it subsides rapidly withoutresidual change and who subsequently have recurrent, similar episodes, seem to be less likely todevelop destructive joint changes than patients in whom the onset is gradual with smolderinginvolvement. In the course of time, through the continuity of the anti-mycoplasma treatmentmethod, there is a gradual reduction in the many sites of joint inflammation and the toxicsubstances generally diminish.
Focal Infections (TOC)
It is imperative patients be examined for other sources of antigen in intra-vascular or extra-vascular fluids in various intercellular sites, or, more grossly, in various cysts, fibrotic cavitiesand other remote area (sinuses-allergies, genitourinary tract, gut, pelvic area, digestive tract,teeth, etc.). Each of these different locations for the antigenic source creates a new set ofvariables but the primary problem - bringing the anti-infectious drug into direct contact with themicroorganism - is common to all.
Focal infections are known to activate arthritis. It is possible that tissue invisible L-forms left
in the wake of an infection, can perpetrate the inflammatory reaction through continued antigen
releases rather than microbial invasion. The infectious tie-in becomes progressively more tenable
when bacterial variants (frequently streptococcus, L-forms) derived from focal infections arefound. Anti-streptococcal antibodies cross react with mycoplasma protein (heart myosin,tropomysin and mycoplasmal adhesions). These variants must be treated often simultaneouslywith the original mycoplasma infection, but using a different antibiotic to achieve effectiveness.
If the patient has an elevated ASO titre and/or strong history of streptococcal infection,
ampicillin, 250 ma. is prescribed to he taken once daily (preferably in the evenings and not at the
same time as the tetracycline). This is continued until the ASO titre becomes normal after which
the patient is monitored for recurrence.
III. Treatment (TOC)
Treating Patients with Severe or Long Standing Disease (TOC)
Treatment must be directed on two fronts: the hypersensitivity state and the microbial cause. Theinflammation is treated with a constant dosage of anti-inflammatory drugs and the suppression ofthe microbial infection with low dose, intermittent antibiotics. Since long-term treatment isrequired, continuous low dose, intermittent antibiotics are more viable for patient safety and canbe continued for years.
Washout period (TOC)
If the patient has been or is still on strong anti-rheumatic drugs (especially those which tend tobuild up in the liver like methotrexate or gold) or drugs which sensitize the digestive tract, awashout period of 4 to 6 weeks might be considered to avoid a reaction such as colitis. Low dose(<10 ma) prednisone can be used to maintain the patient during washout.
Anti-inflammatories (TOC)
'The first step is to reduce the inflammation with anti-inflammatory medications to prepare theway for the antibiotic action.
Enteric coated aspirin can be useful when given two to three tablets, three to four times a day.
Other anti-inflammatory drugs may be useful as well. Because of the individualized patient
response to NSAIDs, choice of drug will depend upon individual patient response.
People who have native allergies such as hay fever, asthma etc. often tolerate the phenylbutazone
derivatives rather than the other, non-steroidal anti-inflammatory drugs. In these highly allergic
individuals, antihistamines and even corticosteroids in very small doses (less than 5 ma. a day)
can be helpful.
Beginning the Therapy (TOC)
Patients must be advised that the treatment is extremely slow and gradual and may take sixmonths to a year before they can really see much improvement. In more severe or long-termpatients it can take much longer (25 years).
A proper chemotherapeutic approach must recognize that tetracyclines and erythromycins areeffective against many mycoplasma infections; some are resistant to one strain or the other.
Mycoplasma testing to isolate the strain may be necessary (See Appendix A).
Patients with severe or long-standing disease are started with a series of daily intravenous orintramuscular antibiotic treatments for a period ranging from one to three weeks. Clindamycin isgiven to eradicate long-standing L, forms of bacteria resident in the gut, respiratory tract,genitourinary tract and other areas to allow greater permeability of the tetracycline family ofantibiotics and diminish the variables of disease. Clindamycin is concentrated in the phagosomesof the neutrophils, and therefore accumulates at the site of inflammation.
Clindamycin IM - 300 ma. clindamycin can be administered intramuscularly (IM) once daily
for one to two weeks followed by 300 ma. weekly, monthly or at 6 week intervals as needed and
tolerated by the patient. Because it remains in the tissues longer, a lower dose is effective.
Clindamycin IV - The IVs should be started at a low dose (300 ma) and gradually increased as
needed to avoid the development of resistance in the bacterial L-forms that might be present. If
this resistance develops, the patient will not respond as well to the antibiotic therapy.
IV therapy is begun gradually at 300 ma. given in 250 cc 5% dextrose solution administered byIV drip over a 45 minute period for the first two days. The next two days, the dose is increased to600 ma. and finally to 900ma on subsequent days if no adverse reaction is observed.
IV or IM therapy with clindamycin is continued at spaced intervals according to the patient'sneed. It can be given once weekly or twice a month again titrated to patient need. If weekly ormonthly IVs are not possible for the patient, then a series can be administered at more widelyspaced intervals such as every six months and later on an annual basis until the laboratory valuesreturn to normal.
Oral Clindamycin - Some physicians have had success using clindamycin orally (i.e. 1200
mg.) in a single weekly dose instead of in IV or IM
Tetracycline Therapy (TOC)
Following the initial clindamycin IV or IM course, oral minocycline or doxycycline is mostcommonly prescribed, continuing the periodic clindamycin as an adjunct to therapy. Care shouldbe taken not to administer any antibiotic drug at too high a dosage too fast to avoid an allergicreaction by the patient.
Failure to achieve proper drug titration in either the continuous anti-inflammatory or
intermittent anti-microbial medications may result in disturbance of the rheumatoid state
of balance and promote clinical worsening (the Jarisch-Herxheimer Reaction).
Severe or Long-standing Disease
Patients with severe or long-standing disease are started on a low dose of oral minocycline ordoxycycline ranging, according to patient tolerance, from 50- l 00 mg or tetracycline 250 ma.
once daily one to two days per week. Titrated to patient tolerance the dose should be increased toa working standard dose of minocycline or doxycycline 100 mg once daily or tetracycline 250ma. twice daily Monday, Wednesday and Friday.
If the medication tends to aggravate the condition, it is spaced differently, maybe to once a week;or twice a week, and gradually increased to the M-W-F dosage. Some patients are so highlysensitized to drugs that they can only tolerate minocycline or doxycycline 25-50 ma. Once everytwo weeks or even once a month, but with continued titration of the dosage, it is possible to workup to the optimum standard dosage of minocycline or doxycycline 100 ma. once or twice daily,Monday. Wednesday and Friday without flaring the disease.
Less Severe, Early Disease (TOC)
For patients with less severe or early disease, the IV or IM treatment may not be required as they
experience the same result using oral medication exclusively. The optimum standard dosage
for these patients is minocycline or doxycycline 100 ma. once daily, Monday, Wednesday and
Friday or tetracycline 250 ma. twice daily Monday, Wednesday and Friday.
Unlike standard anti-microbial therapy, this method requires the application of new principles of
drug administration with low dosage properly spaced, clinically titrated and most often given
over a long period of time. Because absorption takes place from all levels of the alimentary
tract from the stomach onwards, but is never complete, the larger the dose the lower is the
proportion of it absorbed. The mechanism responsible for the decreased absorption appears to
be twofold:
1. Tetracycline solubility is better in the more acid solution of the stomach; less so in the 2. Tetracyclines also tend to combine with divalent metals, of which calcium is likely to be Important Note about Lupus & Minocycline (TOC)
Lupus patients may want to use another tetracycline other than minocycline. A few studies haveshown that minocycline can cause lupus like symptoms in some patients and the PDR states thatIV and oral minocycline can exacerbate the symptoms of lupus in some patients. This may be aHerxheimer expression.
IN ADDITION, an association has been shown between M. hominis and lupus. M. hominis isresistant to erythromycin so this also should be avoided when prescribing for lupus patients. 18Ginsburg, 19 Cassel1 M. hominis is susceptible to clindamycin in vitro, possibly making it aneffective adjunct to tetracyclines in patients testing positive for M. hominis. (See laboratoryinformation.) Increasing the Dosage (TOC)
Two basic methods of evaluation are considered as guides to the proper intervals for increasingthe antibiotic dosage.
I ) The patient should be watched and questioned carefully during the first months of treatmentfor subjective (invisible) and objective (visible) exacerbation of disease symptoms followingadministration of the medication. As long as a definite flare related to therapy (see section onHerxheimer) is noted, the dosage is not increased, regardless of laboratory findings. Usually thisassociation does not persist beyond four weeks to six months, at which time the dosage isincreased, if laboratory indications are present. In general, the initial dosage of antibiotic ismaintained for three to six months despite the frequent feeling that larger doses would speedrecovery.
2) Blood tests are followed at four to twelve week intervals until the patient stabilizes whenevery six months is often enough. As long as signs of improvement continue, the dosage ofantibiotic is not changed. If the laboratory evidence of improvement fails to occur or stabilizes atan abnormal level, an increase in dosage, in frequency or a change in route of administration isconsidered.
When an increase in dosage is indicated, it is accomplished either by decreasing the
interval between doses or the dosage itself is increased and administered at the same
intervals. In a converse manner, if it appears that the drug-induced flare is excessive,
dosage may be decreased by the same increments or by prolonging the interval between
doses. This process of adjustment or titration is continued until the patient reaches the optimum
standard dose of minocycline or doxycycline 100 ma. once or twice daily Monday, Wednesday
and Friday or tetracycline 250 ma. twice daily Monday, Wednesday and Friday.
Injecting the Joint (TOC)
Intra-articular injections of clindamycin have been very effective when the reactive state of the
joint is so intense that penetrance is not achieved by the oral or IV/IM route. The inflammation
must be reduced in most instances for maximum clindamycin effect - the usual treatment plan for
large joints, clindamycin 2 cc (300 mg.) plus dexamethasone I cc (4 mg). A reduced amount of
the same combination of these medications is used for smaller joints. A ratio that has been
found effective is either 2/3 to 1/3 or 1/2 to 1/2). This is one instance where the temporary
blocking effect of corticosteroids becomes important.
The Herxheimer (drug related flare) (TOC)
A general aggravation of symptoms is sometimes seen following onset of therapy and is morelikely to occur if the disease is severe. This flare may be subjective (invisible) or objective(visible), or both, and may occur several hours or even up to two to four weeks after themedication is started.
Those patients who test low in hematocrit and serum albumin levels and high globulin levelsprior to treatment have the most intense flare on a given dosage of antibiotic.
The Herxheimer flare is the first indication that the antibiotic is reaching its target, and
therefore considered a good sign.
When the severity of the arthritic condition begins to lessen, either from a spontaneousimprovement or as a result of the continued treatment with carefully measured doses ofantibiotic, a greater tolerance for the antibiotic, is noticed and larger doses are tolerated without areturn of the Herxheimer flare reaction. If however, the dose has been increased too rapidly atany time, the initial flare reaction may occur again.
In the evaluation of these exacerbations, the physicianmust remain aware of the frequent diseaseflares from other causes, and he should attempt to differentiate from those which may be druginduced.
In the evaluation of these exacerbations, the physician must remain aware of the frequent diseaseflares from other causes, and he should attempt to differentiate from those which may be druginduced.
Differentiating between a Herxheimer, an RA flare and an allergic reaction to the drug
Laboratory tests can help differentiate between a worsening of disease (RA flare), a Herxheimerreaction to microbial toxins, and an allergic reaction to medication.
1) WBC will elevate in a Herxheimer and lower in a flare.
2) A Herxheimer will also exhibit a coincidental elevation of SED rate, gamma globulin and
total globulin, and a fall in serum albumin and hematocrit. Patients who exhibit this flare
reaction accompanied by anemia, depression of serum albumin, elevated total globulin and
gamma globulin are probably reflecting a more intense reaction pattern to anti-L substances
than in hematologically mild cases.
3) A marked increase in eosinophils (for instance about 30%) is an indication of an allergic
reaction to the drug.
First signs of improvement (TOC)
There is usually little objective improvement in patients during the first three months of therapy.
In the ensuing three to nine months the improvement, when it occurs, is quite gradual. Thecourse of events is similar to, although sometimes slower than that noted with gold, methotrexateor chloroquine therapy.
The first sign of improvement is usually a lessening of duration of morning stiffness although theinitial onset may be as severe as usual. The patient notices a general feeling of well-being lastinginitially for perhaps an hour or two and gradually increasing to more good days and fewer baddays with a longer time span in between.
As anti-mycoplasma therapy continues, toxic substances are gradually reduced and normalfunctions begin to return. Strength increases, blood count rises to its normal level, mental acuity,ability to concentrate, a return in interest in work and a lessened sense of irritability all becomenoticeable dividends. All these symptoms may improve remarkably with rheumatoid remission,even after having been present for years.
It has been possible to measure clinical and laboratory parameters for the degree of disease
control over a five year period. During this period over 70 percent of patients treated showed
sustained improvement after five years. A major advantage of this approach has been the
freedom to treat early rheumatoid arthritis in a basic manner with success.
Continuing Treatment During: (TOC)
Improvement
Most patients need to continue treatment indefinitely. Medication should be continued until the
laboratory findings return to normal values for at least three months. Then gradually the IV
treatment is discontinued, and if no adverse effects are observed, the oral tetracycline derivative
is lowered. For some patients this treatment provides a permanent remission and no further
medication is needed. Still other patients need to stay on a maintenance dose to keep the disease
under control. If medication is discontinued too soon a rebound effect may occur which can be
more severe than the original disease. If symptoms should return, a short course of tetracycline
derivative may be sufficient to put the patient back in remission. Repeat courses at short intervals
may be needed and will usually reestablish the remission for an indefinite period. For some
patients, the hypersensitivity has probably cascaded into a form of molecular mimicry and
as such, the auto-immunity becomes the target. Antibiotics remain effective, although
rotation to other drugs with higher tissue concentration (such as azithromycin) may be
necessary to block receptor binding of the mimicry molecules.
Drug Rotation (TOC)
Thomas McPherson Brown, MD, originator of antibiotic therapy, found rotating the antibioticevery 4-5 years even within the same classification, decreased the possibility of developingpatient tolerance to the drug. After a rotation period, the original drug may be re-instituted.
Side Effects (TOC)
The tetracycline derivatives and crythromycin are both highly effective and safe anti-
mycoplasma substances. It is characteristic of microbial hypersensitivity states that the proper
use of anti-microbial agents is in general surprisingly free from drug complications unless the
medications possess sensitizing properties or innate toxicity’s. It is of additional interest that
mycoplasma, unlike bacteria, do not possess a cell wall, only a thin covering membrane. Thus,
long-term exposure to anti-mycoplasma substances would not be expected to create
mycoplasma resistance which is usually dependent upon cell wall enzymatic activity. In
over five decades of use, no ill effect from medication has been experienced, except the
emergence of delayed sensitivity as with all drugs in this field, but on a level that is very easy tomanage.
Candida is not usually a problem, but in some patients it can become severe. Acidophilus
should be prescribed as a preventive and testing should be done regularly to prevent an
overgrowth from occurring. The candida, if persistent, should also be treated concurrently with
the rheumatoid disease.
Laboratory Tests (TOC)
Patients stay on medication until all laboratory tests return to normal. Some patients indicatedthey began to feel better long before their laboratory results improved. The converse can also betrue. (See Appendix B) This protocol is compiled largely from the published works of Thomas McPherson Brown, M.D.,the physician who pioneered and developed this treatment over fifty years ago.
References (TOC)
1. 1992 Research Highlights, Arthritis' Rheumatic Diseases, and Related Disorders, a report bythe U.S. Department of Health and Human Services, The Public Health Service and NationalInstitutes of Health, 1-2.
2. Kloppenburg M, Breedveld FC, Terwiel J Ph, Mallee C, Dijkmans BAC, Minocycline inActive Arthritis, Arthritis & Rheumatism 1994; 17 5, 629-636.
3. Breedveld FC, Dijkmans BAC, Mattie H, Minocycline Treatment for Rheumatoid Arthritis: anOpen Dose Study, J of Rheum, 1994; 17:5, 629-636.
4. Langovitz P et al, (Israel) Treatment of Resistant Rheumatoid Arthritis with Minocycline: AnOpen Study, J of Rheum, 1992: 19:10, 1502-15()4.
5. Tilley BC, Alarcon AS, Heyse SP, Trentham DE, Neuner R, Kaplan DA, Clegg DO, LeisenJCC, Bucklcy L, Cooper SM, Duncan H, Pillemer SR. Tuttleman M, Fowler SE, Minocycline inRheumatoid Arthritis: A 48 Week, Double-Blind, Placobo-Controllcd Trial, Annals of InternalMedicine, 1995; 122:81 -Xt).
6. Sabin, AB, Johnson, D; Scarch for Microorganisms of the Pleuro Pncumoniae Group inRheumatic and Non- Rheumatic Children, Proc. Soc. Exp. Biol. Med., I 940, Vol. 44. 56')571.
7. Swift, HF, Brown TMcP. Pathogenic Pleuro-Pneumonia-like Microorganisms from AcuteRhcumatic Exudates and Tissues, Science, March 24, 1939, Vol. 89, No. 2308' 271-72.
8. Brown TMcP, Clark, HW, Bailcy JS; Rheumatoid Arthritis in the Gorilla: A Study of Mycoplasma-Host Interaction in Pathogenesis and Treatment, In Comparative Pathology of ZooAnimals, RJ Montali, G. Migaki (ed.) Smithsonian Institution Press, 1980, 259-266.
9. Brown T. McP, Bailey JS, Iden KI, Clark HW, Anti-mycoplasma Approach to the Mechanismand the Control of Rheumatoid Disease, BBCI from: Inflammatory Diseases and Copper, JRJSorenson (Ed.), The 1-Iumana Press, 1982, 391 -407.
10. Brown TMcP, Novak JW, Hockberg MC, et al; Antibiotic Therapy of Rheumatoid Arthritis:An Observational Cohort Study of '38 Patients with 451 Patient Years of Follow-up, XVIInternational Congress of Rheumatology, 1985.
11. Tan PLJ, Skinner MA. (New Zealand) Thc Microbial Cause of Rheumatoid Arthritis: Timeto Dump Koch's Postulates, Journal of Rheumotology, 1992: 19:8, 1] 7(~)- 1172.
12. Ford DK (Canada), The Microbiological Causes of Rheumatoid Arthritis; Journal ofRheumatology, 1991: 18: 10, 1441-1442.
13. Hakkarainen K, et al (Finland), Mycoplasmas and Arthritis, Annals of the RheumaticDiseases, 1992; 51: 1170- 1172.
14. Wirostko E, Johnson L, Wiroslko W (United States), Juvenile Rheumatoid ArthritisInflammatory Eye Disease, Parasitization of Ocular Leukocytes by Mollicute-like Organisms, J of Rheumatology, 1989; 16-21.
15. McCullough J, Lydyard PM, Rook GAW, (England) Rheumatoid Arthritis: How Well Do theTheories Fit the Evidence?, Clin Exp Immunol 1993; 92: 1-6.
16. Rook GAW, Lydyard PM, Stanford JL, (England) A Reappraisal of the Evidence thatRheumatoid Arthritis and Several Other Idiopathic Diseases Are Slow Bactcrial Infections,Annals of the Rheum Dis, 1993; 52: S30- S38.
17. Furr PM, Taylor-Robinson D, Webster ABD, (England) Mycoplasmas and Ureaplasmas inPatients with Hypogammaglobulinaemia and Their Role in Arthritis: MicrobiologicalObservations Over Twenty Years, Ann of Rheum Dis, 1994; 53: 1X3-187.
18. Ginsburg KS, Kundsin RB, Walter CW, Schur PH , Ureaplasma Urealyticum andMycoplasma Hominis in Women with Systemic Lupus Erythematosus, Arth & Rheum, 1992; 35:4, 429-433.
19. Cassell GH, Clough W, Septic Arthritis and Bacteremia Due to Mycoplasma Resistant toAntimicrobial Therapy in a Patient with Systemic I.upus Erythematosus, Clin Infect Dis, 1992;15: 402-407.
20. Brown TMcP, Bailey JS, Iden II, Clark HW, Antimycoplasma Approach to the Mechanismand the Control of Rheumatoid Disease, Inflammatory Diseases & Copper. paper presentation,1982; 391 -407.
21. Mattman Eida H, Cell Wall Deficient Forms: Stealth Pathogens, 2nd Edition. 1992, CRCPress.
22. Taylor-Robinson V, Davies HA, Sarathcvhandra P, Furr PM, Intracellular location ofmycoplasmas in cultured cells demonstrated by immunocytochemistry and electron microscopy,Int J Exp Path, 1991; 72: 705-714.
23. Palmer HM, Gilroy CB. Furr PM, Taylor-Robinson D. Development and Evaluation of thePolymerase Chain Reaction to Detect Mycoplasma genitalium, FEMS Microbial Letters, 1991;77: 199-204.
24. Brown, T McP, The Puzzling Problem of the Rheumatic Diseases, Maryland State MedicalJournal, 5: 2; 1956, 88-109.
25. Brown TMcP, Clark HW, Felts WR, Rheumatoid Disease and Gout, Longterm Illness,Chapt. 6, MG Wohl (Ed). WB Saunders Co. 195~3, 93- 125.
26. Brown TMcP, Clark HW, Bailey JS, Natural Occurrence of Rheumatoid Arthritis in GreatApes - a New Animal Model, Proc of the Centennial Symposium on Sci & Research, Zool Socof Phila., 1974, 49-79.
27. Brown, TMcP, Guidelines for Infectious Hypersensitivity Approach to the Treatment ofRheumatoid Disease, from a lecture by Dr. Brown.
28. Brown TMcP, The Antimycoplasma Treatment Program for Arthritis Should Be Investigatedby the NIH, Congr Record, Vol 129:E2561, 1983.
29. Waites, Cassell G, Canupp, Fernandes, In Vitro Susceptibilities of Mycoplasmas andUreaplasmas of New Macrolides and Aryl-Fluoroquinolones, Antimicrobial Agents andChemotherapy, 1988; 32:10.
Appendix A - Mycoplasma Response to Drugs (TOC)
Mycoplasma Strain
Susceptibility to
Resistant to
NIH 713-001-084found in urogenital tract & synovial fluid tetracycline, doxycyclineclindamycinzithromycin,clarithromycinofloxacin M. oralefound in the (mouth) & respiratory tract M. salivariumfound in the (mouth,) respiratory& urogenital tract later than 1981, minocyclinewould probably have been M. arthritidisfound in synovial fluid LIST FOUND: Cassell & Cole, NAME OF ARTICLE. NEJM ,304:2 1981
DRUGS FOUND): Waites, Cassell, Canupp, Fernandes, In Vitro Susceptibilities of
Mycoplasmas and Ureaplasmas of New Macrolides and Aryl-Fluoroquniolones, Antimicrobial
Agents and Chemotherapy 32: 10, Oct. 1988.
Baseman & Tully,, Mycoplasmas, Sophisticated, Reemerging and Burdened by Their Notoriety,
Emerging Infect Dis, 3:1
Poulin, Perkins,, Kundsin,, Antibiotic Susceptibilities of AIDS-Associated Mycoplasmas, J of
Clin Microbiol, 32:4, 1994
Appendix B - Laboratory Testing (TOC)
ESR, hemoglobin, platelet count, gamma globulin, C-reactive protein, rheumatoid factor, ANA,MCF, candida and ASO are some of those usually monitored in these patients. However, no testis perfect in all cases. Situations can change, interfering factors can change test results, as cansome drugs, and healthy people can have positive results and sick people can have negativeresults.
A major advantage of this approach has been the freedom to treat early rheumatoid arthritissuccessfully in a basic manner with antibiotics.
ESR - Erythrocyte Sedimentation Rate The ESR is a less reliable guide to the degree of basic
rheumatoid activity because of the frequent fluctuations associated with minor environmental
changes. The pattern formed by a series of ESR tests in a given individual is more useful in
interpreting the disease activity than in a single determination.
GAMMA GLOBULIN, Lymphocytes When the gamma globulin level is elevated it provides
an excellent index of the degree of rheumatoid activity.
Another index of the state of the rheumatoid process, which may be diagnostically useful insome patients, is an absolute increase in Lymphocytes.
RH - Rheumatoid Factor Rheumatoid factor, although frequently positive in arthritic patients,
has been negative in a number of patients diagnosed with severe disease (as high as 20%).
These patients have demonstrated improvement when treated with tetracycline derivatives.
PERCENTAGE OF PRESENCE OF RF IN
SOME RHEUMATIC DISEASES
Classic RA 50%Early or Atypical RA 50%Juvenile RA 20%Infectious Diseases 10%Elderly Persons 25%Healthy Adults 5% ANA - Antinuclear Antibody Abnormal ANA is considered an indication of rheumatic disease.
A negative ANA is sometimes interpreted as eliminating lupus or scleroderma as a possible
diagnosis. The higher the titer, the morespecific the test is to lupus.
There are many kinds of ANAs, some specific tocertain rheumatic diseases:Anti -SCL-70 - sclerodermaAnti-Centromere - CREST sclerodermaAnti-DNA - lupusAnti-RA33 - RA PERCENTAGE OF PRESENCE OF ANA
IN SOME RHEUMATIC DISEASES
Systemic Lupus Erythematosus 95-100%Diffuse Scleroderma 75-80%Sjogren's Syndrome 40-75%Rheumatoid Arthritis 25-60%Juvenile RA 15-30%Dermatomyositis, Polymyositis 10-30%Healthy Adults ~5% DISEASE ASSOCIATED WITH ANA PATTERNS
Peripheral exclusive to lupus
Homogenous, Diffuse lupus, related CT
Nucleolar scleroderma (SSc)
Speckled, Irregular mixed CTD (SLE & SSc)
MCF - Mycoplasma Complement Fixation Mycoplasma complement fixation test (MCF)
identifies antibodies to specific strains of mycoplasma. A positive test justifies using antibiotics
as a treatment, but can also be an aid in choosing the antibiotic prescribed. Low titers are
significant, and in humans, are seldom high. Often during treatment the MCF becomes strongly
positive sometimes showing as much as a fourfold increase before dropping again.
PCR - Polymerase Chain Reaction PCR is a highly specific test which identifies organisms,
such as mycoplasmas by their DNA.
ASO - Anti-streptolysin -O This test for the presence of streptococcus is elevated in many
patients with rheumatic disease. It has been noticed with some patients, that an elevated ASO
titer can mean response to treatment is compromised. Some patients cannot tolerate any titer
above negative. Treatment with ampicillin until a negative titer is achieved can speed treatment
response to antibiotic therapy, and failure to treat the strep concurrently can sometimes delay the
positive response to antibiotic therapy.

Source: http://www.okmicro.co.jp/Abt/protocol2.pdf