Presentation made by Thomas McPherson Brown, M.D.
(exact date unknown – probably mid to late 1970’s)
Because of the tissue hypersensitivity aspect of the human as well as gorilla host, where the reactive level is particularly intense, delayed sensitivity to drugs, especially those with allergic potentials, is very marked; and when it emerges, it blocks treatment effectiveness. Drugs in current use, such as gold salts and the antimalarial compounds plaquenil and chloroquine, possess sensitizing qualities even when not given to a sensitized host such as a rheumatoid arthritic. As a result, a large number of patients on these two most important standard remedies eventually become completely refractory or else develop severe toxicity associated with the hypersensitivity component. Over the years we have published considerable evidence that mycoplasma are the primary sensitizers in the rheumatoid complex. Synovial biopsies reveal mycoplasma antibodies as well as antigens often in high concentration. Direct isolates have been attempted for years from rheumatic joints with minimal success. A number of reports have appeared in the literature of isolates of mycoplasma from joint fluid; but, unfortunately, these strains have died out in the artificial environment and have been, therefore, unavailable for definitive studies. Recently, we have isolated a strain directly from the joint fluid of a rheumatoid arthritic which is surviving and lends itself well for proper studies. The past evidence in animal models and through indirect findings as well as the therapeutic probe has justified the assumption that mycoplasma are truly the microbial antecedent to the rheumatoid complex reaction. It would appear that the burden of proof is on the side of those who say that mycoplasma have no role in the rheumatoid complex.
Because of the toxicity of gold and antimalarial compounds and their obviously limited effectiveness because of the emergence of delayed sensitivity from continued use of these drugs, it becomes essential to find substitutes for their effect. We have found that tetracycline not only has a much stronger effect in vitro on these organisms in terms of suppressing growth as well as suppressing DNAse production which is a characteristic of mycoplasma. Thus, from a theoretical standpoint tetracycline is a far better drug to use than anything that has been developed heretofore. Tetracyclines are not accumulative, as is the case with gold salts and, to some extent, antimalarials. Their sensitizing effect, as judged by their long-term use in the treatment of acne and bronchiectasis, is virtually nil, and the emergence of bacterial resistance is not a problem due to the fact that tetracycline’s effect, the soma of the microbe rather than the cell wall where bacterial resistance develops.
We have employed tetracyclines in place of gold salts and antimalarial drugs to suppress mycoplasma antigen formation for more than thirty years. In no instance have we found an ill effect from the medication except the emergence of delayed sensitivity as with all d rugs in this field but on a level that is very easy to handle. When delayed sensitivity develops from gold salts it can’t be undone because of the cumulative action of this drug. It is well-known that a single injection of gold remains in the system for at l east a year. Delayed sensitivity to tetracycline is easily reversed by simply omitting treatment for a few days or a week and then resuming the program once again as usual. The signs of delayed sensitivity are those of slight loss of appetite, excessive fatigue, (fatigue is a common feature of rheumatoid arthritis, and must be differentiated from excessive fatigue), increased pain in the areas where pain was being gradually reduced, and at times increased fluid retention, often expressed as puffiness of the feet and legs. When these signs of sensitivity are noted, the medication is interrupted and then resumed, usually at the same level that it was given before or else at a reduced frequency and amount. The tetracycline dosage is generally given as 250 mg. every other night or possibly 500 mg. every other night. If the medication tends to aggravate the condition, it is spaced differently, maybe to once a week or twice a week and gradually worked up to the alternate night basis. Some patients are so highly sensitized to drugs that they can only tolerate one 250 mg. tetracycline tablet every two weeks or even once a month, but with continued titration of the dosage it is possible to work up to the dosage of alternate nights without flaring the disease.
At the time of initiation of any antimycoplasma remedy, such as gold salts, plaquenil, chloroquine, or tetracycline, there is often a flare reaction akin to the Herxheimer phenomenon. All anti-mycoplasma drugs can produce this at the initiation of treatment, and we have not seen this in non-anti-mycoplasma medication, such as penicillin or any of its derivatives or sulfa drugs, or other compounds known to be ineffective against mycoplasma. This Herxheimer type of reaction is strongly in support of mycoplasma being the common denominator for the rheumatoid process.
The antimicrobial approach is not complete without anti-inflammatory medication paving the way for its effectiveness. Aspirin or ascriptin, when acceptable, can be useful drugs when given two to three tablets, three to four times a day. Naprosyn is also particularly useful given as 250 mg. twice daily. Motrin, Endocin, Telectin, Clinoril, and other anti-inflammatory drugs are all quite useful. It is of interest that people who have native allergies such as hay fever, asthma, etc. often tolerate the Phenylbutazone derivatives rather than the newer, non-steroidal, anti-inflammatory drugs. In these highly allergic individuals, the degree of anti-mycoplasmal medication must also be reduced to the minimum, such as 250 mg. of tetracycline once or twice a week and gradually increased.
There is an aspect of the hypersensitivity state, whether it be in the standard allergies or the rheumatoid complex, which is extremely important and seldom realized to be a factor. For example, the sputum of the asthmatic is generally sterile with few if any bacteria and asthmatics rarely contract pneumonia. Children who have had rheumatic fever and develop streptococcal pharyngitis, the streptococcus suddenly disappears at the moment of recurrent rheumatic fever. Thus, this form of bacterial hypersensitivity is also antimicrobial, and cultures for brucella become completely negative soon after the disease develops. Furthermore, brucellosis has never been transmitted from one human to another, though it is easily transmitted from an animal to man or animal to animal. The pleural fluid in tuberculous pleurisy with effusion is most often devoid of culturable tubercle bacilli.
Therefore, all these examples of bacterial hypersensitivity point out that this particular condition is an anti-microbial state. In rheumatoid disease, the hyper-reactive state is therefore designed, we believe, to suppress microbial antigen replication and accounts for the high degree of localization of mycoplasma foci of involvement. Thus, in the highly reactive state very little antimicrobial medication is needed to further control of 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 of tuberculosis with streptomycin, the use of tetracycline intermittently for the treatment of chronic brucellosis, and the use of penicillin intermittently for treatment of chronic rheumatic fever. In other words, all bacterial hypersensitivity states require intermittent antigen suppressing treatment.
In summary, it appears that one must not only program the medication to meet the patient’s needs and pursue the treatment long enough to eventually suppress antigen formation and to give the antimicrobial medicine in conjunction with anti-inflammatory medication in order to reach the source of antigen production. The tetracycline by itself is most often ineffective without preparing the way for its action to be fulfilled.
A fairly standard approach to treatment then would be one of the anti-inflammatory drugs as often as necessary to reduce pain through the reduction of inflammation. This may be as little as Clinoril or Naprosyn twice daily or Motrin three or four times a day, or Ascriptin, three tablets four times a day. If pain is not subdued with this approach, then Tylenol #3 or Empirin #3 or other pain relievers can be added. We generally employ tetracycline in 250 mg. amounts every other evening at bedtime combined with an antihistamine which seems to potentiate its action such as Ateldrinspansule, 8 mg., or Benadryl, 25 mg. As time goes on, often 500 mg. every other night is well-accepted and helps to promote improvement. Very often fluid retention is noted due to release of antigen from the antimicrobial medications in stirring up the hypersensitivity reactions, and this can be treated with a diuretic in the morning such as Diazide or any other acceptable form of diuretic.
The fatigue of rheumatoid arthritis is often a very severe problem, and the only medication I have ever found to be highly effective against it is Dexamil in extremely small doses, maybe ½ or ¼ of a tablet each morning until fatigue dissipates. Iron is ineffective in the rheumatoid complex when anemia is present until the disease itself is subdued which accounts for the lack of improvement of the fatigue of arthritis by the use of iron in many instances. Vitamin B12 for a non-specific reason as yet not completely understood often does help the fatigue of arthritis when given perhaps as often as once a week. Many patients feel that vitamins are helpful for this same depressing group of symptoms, and, if so, we suggest their use, avoiding large doses of Vitamin D or Vitamin A. Vitamin E. 400 units given at least once a day with or without calcium gluconate or other forms of calcium often seems to affect favorably the leg cramps commonly noted in rheumatoid arthritis.
If one follows this program and interrupts the use of tetracycline occasionally if there seems to be a build-up of delayed sensitivity, the treatment can be carried on virtually indefinitely. In the course of thirty years, we have never found an ill effect from this particular program which is in absolute contradistinction to the usual standard remedies which continually threaten the physician and the patient with the possibility of the sudden emergence of toxic reactions.
It is of interest that we have a number of patients who have had repetitive attacks of pneumonia and, on the tetracycline long-term therapy, have never had another attack. Were the drug to promote bacterial resistance, certainly attacks would not only recur but would be more serious than ever, and this has not been the case in a single instance. Patients must be advised that the treatment is extremely slow and may take six months to a year before they can really see much improvement. Once improvement has been established, it can be maintained indefinitely, except for certain seasonal flares, flares associated with trauma or infection, or other environmental factors.
This long-term sustained improvement is completely different from that we have experienced with other forms of treatment. It should be recognized that it is not possible to do double blind controls after a year of treatment of any sort, thus new methods of measurement must be devised. Studies that tend to discredit this type of approach do not take into account the
long-term problem of gradually reducing antigen production, nor are those in opposition to these views familiar with the likelihood that mycoplasma are truly the basic antigenic precursor. Thus, the great need in the field today is final agreement regarding the basic mechanism of the disease production. We have found that those who are vehemently opposed to any new views are generally completely unaware of the mechanistic studies such as those we have made, and once they see how all the features of this puzzling problem fit together, through a proper mechanistic approach, they may show signs of awakening to the importance of new thinking in a field devoid of basic therapeutic progress over a period of many decades.