Guest guest Posted May 30, 1999 Report Share Posted May 30, 1999 PROTOCOL FOR USING ANTIBIOTICS IN THE TREATMENT OF RHEUMATIC DISEASES As Presented at the 31st Annual Meeting of the American Academy of Environmental Medicine Boston, Massachusetts - October 1996 - by Dr. ph M. Mercola INTRODUCTION Rheumatoid arthritis affects about 1 percent of our population and at least two million Americans have definite or classical RA. It is a much more devastating illness than previously appreciated. Most patients with RA have a progressive disability. More than 50% of patients who were working at the start of their disease are disabled after five years of RA. The annual cost in the U.S. is estimated to be over $1 billion. There is also an increased mortality rate. The five year survival rate of patients with more than thirty joints involved is approximately 50%. This is similar to severe coronary artery disease or stage IV Hodgkins disease. Thirty years ago one researcher concluded that there was an average loss of eighteen years of life in patients who developed RA before the age of 50. Most authorities believe that remissions rarely occur. Some experts feel that the term " remission-inducing " should not be used to describe ANY current RA treatment. A review of contemporary treatment methods shows that medical science has not been able to significantly improve the long term outcome of this disease. INFECTIOUS CAUSE OF RHEUMATOID ARTHRITIS It is quite clear that autoimmunity plays a major role in the progression of RA. Most rheumatology investigators believe that an infectious agent causes RA. There is little agreement as to the involved organism. Investigators have proposed the following infectious agents: Human T-cell lymphotropic virus Type I, rubella virus, cytomegalovirus, herpesvirus, and mycoplasma. This review will focus on the evidence supporting the hypothesis that mycoplasma is a common etiologic agent of rheumatoid arthritis. Mycoplasmas are the smallest self-replicating prokaryotes. They differ from classical bacteria by lacking rigid cell wall structures and are the smallest known organisms capable of extracellular existence. They are considered to be parasites of humans, animals, and plants. In 1939 Dr. Sabin, the discoverer of the polio vaccine, first reported a chronic arthritis in mice caused by a mycoplasma. He suggested that human rheumatoid arthritis might be caused by this agent. Dr. Brown was a rheumatologist who worked with Dr. Sabin at the Rockerfeller Institute. Dr. Brown trained at Hopkins Hospital and then served as chief of medicine at Washington Medical School before serving as chairman of the Arthritis Institute in Arlington, Virginia. He was a strong advocate of the mycoplasma infectious theory over the past fifty years. CULTURING MYCOPLASMAS FROM JOINTS Mycoplasmas have limited biosynthetic capabilities and are very difficult to culture and grow from synovial tissues. They require complex growth media or a close parasitic relation with animal cells. This contributed to many investigators failure to isolate them from arthritic tissue. In reactive arthritis due to other microorganisms, immune complexes rather than viable organisms localize in the joints. The infectious agent is actually present at another site. Some investigators believe that the organism binding in an immune complex causes the difficulty in obtaining positive mycoplasma cultures. Despite this difficulty some researchers have successfully isolated mycoplasma from synovial tissues of patients with rheumatoid arthritis. A British group used a leucocyte-migration inhibition test and found two-thirds of their RA patients to be infected with Mycoplasma fermentens. These results are impressive since they did not include more prevalent Mycoplasma strains like M salivarium, M ovale, M hominis, and M pneumonia. One Finnish investigator reported a 100% incidence of isolation of mycoplasma from 27 rheumatoid synovia using a modified culture technique. None of the non- rheumatoid tissue yielded any mycoplasmas. The same investigator used an indirect hemagglutination technique and reported mycoplasma antibodies in 53% of patients with definite RA. Using similar techniques other investigators have cultured mycoplasma between 80- 100% of their RA test population. Some mycoplasma respiratory infections are followed by RA. One study of over 1000 patients was able to identify arthritis in nearly 1% of the patients. These infections can be associated with a positive rheumatoid factor. This provides additional support for mycoplasma as an etiologic agent for RA. Human genital mycoplasma infections have also caused septic arthritis. Harvard investigators were able to culture mycoplasma or a similar organism, ureaplasma urealyticum, from 63% of female patients with SLE and only 4% of patients with CFS. The researchers chose CFS as these patients shared similar symptoms as those with SLE, such as fatigue, arthralgias, and myalgias. ANIMAL EVIDENCE The full spectrum of human RA immune responses (lymphokine production, altered lymphocyte reactivity, immune complex deposition, cell-mediated immunity and development of autoimmune reactions) occurs in mycoplasma induced animal arthritis. Investigators have implicated at least 31 different mycoplasma species. Mycoplasma can produce experimental arthritis in animals from three days to months later. The time seems to depend on the dose given and the virulence of the organism. There is a close degree of similarity between these infections and those of human rheumatoid arthritis. Mycoplasmas cause arthritis in animals by several mechanisms. They either directly multiply within the joint or initiate an intense local immune response. Mycoplasma produces a chronic arthritis in animals that is remarkably similar to rheumatoid arthritis in humans. Arthritogenic mycoplasmas cause joint inflammation in animals by many mechanisms. They induce nonspecific lymphocyte cytotoxicity and antilymphocyte antibodies as well as rheumatoid factor. Mycoplasma clearly causes chronic arthritis in mice, rats, fowl, swine, sheep, goats, cattle and rabbits. The arthritis appears to be the direct result of joint infection with culturable mycoplasma organisms. Gorillas have tissue reactions closer to man than any other animal. Investigators have shown that mycoplasma can precipitate a rheumatic illness in gorillas. One study demonstrated mycoplasma antigens occur in immune complexes in great apes. The human and gorilla IgG are very similar and express nearly identical rheumatoid factors (IgM anti-IgG antibodies). The study showed that when mycoplasma binds to IgG it can cause a conformational change. This conformational change results in an anti-IgG antibody, which can then stimulate an autoimmune response. MINOCYCLINE If mycoplasma is a causative factor in RA, one would expect tetracycline type drugs to provide some sort of improvement in the disease. Additionally, collagenase activity increases in RA and probably has a role in its pathogenesis. Investigators demonstrated that tetracycline and minocycline inhibit leukocyte, macrophage, and synovial collagenase. There are several other aspects of tetracyclines that may play a role in RA. Investigators have shown minocycline and tetracycline to retard excessive connective tissue breakdown and bone resorption while doxycycline inhibits digestion of human cartilage. It is also possible that tetracycline treatment improves rheumatic illness by reducing delayed-type hypersensitivity response. Minocycline and doxycycline both inhibit phosolipases which are considered proinflammatory and capable of inducing synovitis. Minocycline is a more potent antibiotic than tetracycline and penetrates tissues better. These superior characteristics shifted the treatment of rheumatic illness away from tetracycline to minocycline. Minocycline may benefit RA patients through its immunomodulating and immunosuppressive properties. In vitro studies demonstrated a decreased neutrophil production of reactive oxygen intermediates along with diminished neutrophil chemotaxis and phagocytosis. Investigators showed that minocycline reduced the incidence of severity of synovitis in animal models of arthritis. The improvement was independent of minocycline's effect on collagenase. Minocycline has also been shown to increase intracellular calcium concentrations which inhibits T-cells. Individuals with the Class II major histocompatibility complex (MHC) DR4 allele seem to be predisposed to developing RA. The infectious agent probably interacts with this specific antigen in some way to precipitate RA. There is strong support for the role of T cells in this interaction. Minocycline may suppress RA by altering T cell calcium flux and the expression of T cell derived from collagen binding protein. Minocycline produced a suppression of the delayed hypersensitivity in patients with Reiter's syndrome. Investigators also successfully used minocycline to treat the arthritis and early morning stiffness of Reiter's syndrome. CLINICAL STUDIES In 1970 investigators at Boston University conducted a small randomized placebo-controlled trial to determine if tetracycline would treat RA. They used 250 mg of tetracycline a day. Their study showed no improvement after one year of tetracycline treatment. Several factors could explain their inability to demonstrate any benefits. Their study used only 27 patients for a one year trial, and only 12 received tetracycline. Noncompliance could have been a factor. Additionally, none of the patients had severe arthritis. Patients were excluded from the trial if they were on any anti-remittive therapy. Finnish investigators used lymecycline to treat the reactive arthritis in Chlamydia trachomatous infections. The study compared the effect of the medication in patients with two other reactive arthritis infections Yersinia and Campylobacter. Lymecyline produced a shorter course of illness in the Chlamydia induced arthritis patients, but did not affect the other enteric infections-associated reactive arthritis. The investigators later published findings that suggested lymecycline achieved its effect through non-antimicrobial actions. They speculated it worked by preventing the oxidative activation of collagenase. Breedveld published the first trial of minocycline for the treatment of animal and human rheumatoid arthritis. In the first published human trial, Breedveld treated ten patients in an open study for 16 weeks. He used a very high dose of 400 mg per day. Most patients had vestibular side effects resulting from this dose. However, all patients showed benefit from the treatment. All variables of efficacy were significantly improved at the end of the trial. Breedveld concluded an expansion of his initial study and observed similar impressive results. This was a 26 week double-blind placebo-controlled randomized trial with minocycline for 80 patients. They were given 200 mg twice a day. The Ritchie articular index and the number of swollen joints significantly improved (p < 0.05) more in the minocyline group than in the placebo group. Investigators in Israel studied 18 patients with severe RA for 48 weeks. These patients had failed two other DMARD. They were taken off all DMARD agents and given minocycline 100 mg twice a day. Six patients did not complete the study, three withdrew because of lack of improvement, and three had side effects of vertigo or leukopenia. All patients completing the study improved. Three had complete remission, three had substantial improvement of greater than 50% and six had moderate improvement of 25% in the number of active joints and morning stiffness. The MIRA trial in the United States was a double blind randomized placebo controlled trial done at six university centers involving 200 patients for nearly one year. The dosage they used (100 mg twice daily) was much higher and likely less effective than what most clinicians currently use. They also did not employ any additional antibiotics or nutritional regimens, yet 55% of the patients improved. This study finally provided the " proof " that many traditional clinicians demanded before seriously considering this treatment as an alternative regimen for RA. Dr. Brown's effort to treat the chronic mycoplasma infections believed to cause RA is the basis for this therapy. His book " The Road Back " , provides a basic framework upon which this article will expand. Other articles published since the book may also be helpful. Dr. Brown believed that most rheumatic illnesses responded to this treatment. He, and others used this therapy for SLE, ankylosing spondylitis, scleroderma, dermatomyositis and polymyositis. Dr. Osler was the preeminent figure of his time (1849- 1919). Many also regard him as the consummate physician of modern times. An excerpt from a commentary on Dr. Osler provides a useful perspective on application of alternative medical paradigms: " Osler would be receptive to the cautious exploration of nontraditional methods of treatment, particularly in situations in which our present science has little to offer. From his reading of medical history, he would know that many pharmacologic agents were originally derived from folk medicine. He would also remember that in the 19th century physicians no less intelligent than those in our own day initially ridiculed the unconventional practices of Semmelweis and Lister. Osler would caution us against the arrogance of believing that only our current medical practices can benefit the patient. He would realize that new scientific insights may emerge from as yet unproved beliefs. Although he would fight vigorously to protect the public against frauds and charlatans, he would encourage critical study of whatever therapeutic approaches were reliably reported to be beneficial to patients. " PRELIMINARY WORKUP FOR NON RHEUMATOLOGISTS It is important to evaluate patients to determine that they indeed have RA. Most patients will have received evaluations and treatment by one or more board certified rheumatologists. If this is the case, the diagnosis is rarely in question and one only needs to establish some baseline laboratory data. However, patients will frequently come in without having any appropriate workup done by a physician. Arthritic pain can be an early manifestation of 20-30 different clinical problems. These include not only rheumatic disease, but metabolic, infectious and malignant disorders. These patients will require a more extensive laboratory analysis. RA is a clinical diagnosis for which there is not a single test or group of laboratory tests which can be considered confirmatory. When a patient hasn't been properly diagnosed, then one needs to establish the diagnosis with the standard Rheumatism Association's criteria found in the table at the end of the article. One must also make certain that the first four symptoms listed in the table are present for six or more weeks. These criteria have a 91-94% sensitivity and 89% specificity for the diagnosis of rheumatoid arthritis. However, these criteria were designed for classification and not for diagnosis. One must make the diagnosis on clinical grounds. It is important to note that many patients with negative serologic tests can have a strong clinical picture for rheumatoid arthritis. The metacarpophalangeal joints, proximal interphalangeal and wrists joints are the first joints to become symptomatic. In a way the hands are the calling card of RA. If the patient completely lacks hand and wrist involvement, even by history, the diagnosis of RA is doubtful. RA rarely affects the hips and ankles early in its course. Fatigue may be present before the joint symptoms begin. Morning stiffness is a sensitive indicator of rheumatoid arthritis. An increase in fluid in and around the joint probably causes the stiffness. The joints are warm, but the skin is rarely red. When the joints develop effusions, the patients holds them flexed at 5 to 20 degrees as it is too painful to extend them fully. LABORATORY EVALUATION The general initial laboratory evaluation should include a baseline ESR, CBC, SMA, U/A, and an ASO titer. One can also draw RF and ANA titers to further objectively document improvement with the therapy. However, they seldom add much to the assessment. Follow-up visits can be every two months for patients who live within 50 miles, and every three to four months for those who live farther away. An ESR at every visit is an inexpensive and reliable objective parameter of the extent of the disease. However, one should run this test within several hours of the blood draw. Otherwise, one can not obtain reliable and reproducible results. This is nearly impossible with most clinical labs that pick up your specimen at the office. Inexpensive disposable ESR kits are a practical alternative to the commercial or hospital lab. One can then run them in the office, usually within one hour of the blood draw. One must be careful to not run the test on the same countertop as your centrifuge. This may cause a falsely elevated ESR due to the disturbance of the tube. ANTIBIOTIC THERAPY WITH MINOCIN There are three different tetracyclines available, simple tetracycline, doxycycline, or Minocin (minocycline). Minocin has a distinct and clear advantage over tetracycline and doxycycline in three important areas. 1. extended spectrum of activity 2. greater tissue penetrability 3. higher and more sustained serum levels Bacterial cell membranes contain a lipid layer. One mechanism of building up a resistance to an antibiotic is to produce a thicker lipid layer. This layer makes it difficult for an antibiotic to penetrate. Minocin's chemical structure makes it the most lipid soluble of all the tetracyclines. This difference can clearly be demonstrated when one compares the drugs in the treatment of two common clinical conditions. Minocin gives consistently superior clinical results in the treatment of chronic prostatitis. In other studies Minocin was used to improve between 75-85% of patients whose acne had become resistant to tetracycline., Strep is also believed to be a contributing cause to many patients with RA. Minocin has shown significant activity against treatment of this organism. There are several important factors to consider when using Minocin. Unlike the other tetracyclines, it tends not to cause yeast infections. Some infectious disease experts even believe that it even has a mild anti-yeast activity. Women can be on this medication for several years and not have any vaginal yeast infections. Nevertheless, it would probably be wise to have patients on prophylactic oral Lactobacillus acidophillus and bifidus powder. This will help to replace the normal intestinal flora that is killed with the Minocin. Another advantage of Minocin is that it tends not to sensitize patients to the sun. This minimizes the risk of sunburn and increased risk of skin cancer. One must incorporate several precautions with the use of Minocin. Like other tetracyclines, food impairs its absorption. However, the absorption is much less impaired than with simple tetracycline. This is fortunate because some patients can not tolerate Minocin on an empty stomach. They must take it with a meal to avoid GI side effects. If they need to take it with a meal they will still absorb 85% of the medication, whereas tetracycline is only 50% absorbed. In June of 1990 a pelletized version of Minocin became available. This improved absorption when taken with meals. This form is only available in the non-generic Lederele brand and is probably a reasonable justification to not substitute for the generic version. Many patients with RA have a hypochromic, microcytic CBC. This is probably due to the inflammation in the RA impairing optimal bone marrow utilization of iron. This type of anemia does NOT respond to iron. Patients who take iron can actually worsen if they don't need it as the iron serves as a potent oxidant stress. Ferritin levels are generally the most reliable indicator of total iron body stores. Unfortunately it is also an acute phase reactant protein and will be elevated anytime the ESR is elevated. This makes ferritin an unreliable test in patients with RA. However, many patients are on NSAID's which contribute to microulcerations of the stomach which cause chronic blood loss. It is certainly possible they can develop a peptic ulceration contributing to their blood loss. In either event, patients frequently receive iron supplements to correct their blood counts. IT IS IMPERATIVE THAT MINOCIN NOT BE GIVEN WITH IRON. Over 85% of the dose will bind to the iron and pass through the colon unabsorbed. If iron is taken, it should be at least one hour before the minocin and two hours after. One recent uncommon complication of Minocin is a cell-mediated hypersensitivity pneumonitis. Most patients can start on Minocin 100 mg. every Monday, Wednesday and Friday evening. Doxycycline can be substituted for patients who can not afford the more expensive Minocin. It is important to not give either medication daily as this does not seem to provide as great a clinical benefit. Tetracycline type drugs can cause a permanent yellow- grayish brown discoloration of the teeth. This can occur in the last half of pregnancy and in children up to eight years old. One should not routinely use tetracycline in children. If patients have severe disease, one can consider increasing the dose to as high as 200 mg three times a week. Aside from the cost of this approach, several problems result may result from the higher doses. Minocin can cause quite severe nausea and vertigo. Taking the dose at night does tend to decrease this problem considerably. However, if one takes the dose at bedtime, one must tell the patient to swallow the medication with TWO glasses of water. This is to insure that the capsule doesn't get stuck in the throat. If that occurs, a severe chemical esophagitis can result which can send the patient to the ER. For those physicians who elect to use tetracycline or doxycycline several methods may help lessen secondary yeast overgrowth. Lactobacillus acidophilus will help maintain normal bowel flora and decrease the risk of fungal overgrowth. Aggresive avoidance of all sugars, especially those found in non-diet sodas will also decrease the substrate for the yeast's growth. CLINDAMYCIN The other drug used to treat RA is clindamycin. Dr. Brown's book discusses the uses of intravenous clindamycin. It is important to use the IV form of treatment if the disease is severe. Nearly all scleroderma patients should take an aggressive stance and use IV treatment. Scleroderma is a particularly dangerous form of rheumatic illness that should receive aggressive intervention. A major problem with the IV form is the cost. The price ranges from $100 to $300 per dose if administered by a home health care agency. However, if purchased directly from Upjohn significant savings will be appreciated. A case of two dozen 900 mg prefilled IV bags can be purchased directly from Upjohn for about $100. For most patients the oral form is preferable. If the patient has a mild rheumatic illness (the minority of cases), it is even possible to exclude this from their regimen. Initial starting doses for an adult would be a 1200 mg. dose once a week. Patients do not seem to tolerate this medication as well as Minocin. The major complaint seems to be a bitter metallic type taste which lasts about 24 hours after the dose. Taking the dose after dinner does seem to help modify this complaint somewhat. One can gradually increase the dose over a few weeks if there is a problem with initial tolerance. Concern about the development of C. difficile pseudomembranous enterocolitis as a result of the clindamycin is appropriate. This complication is quite rare at this dosage regimen, but it certainly can occur. It is important to warn all patients about the possibility of developing a severe uncontrollable diarrhea. Administration of the acidophilus seems to limit this complication by promoting the growth of the healthy gut flora. If one encounters a resistant form of rheumatic illness, intravenous administration should be considered. Generally, weekly doses of 900 mg are administered until clinical improvement is observed. This generally occurs within the first ten doses. At that time, the regimen can be decreased to every two weeks with the oral form substituted on the weeks where the IV is not taken. AMOXICILLIN If the patient had a positive ASO titer one can initiate amoxicillin 250 mg tid. Repeat the ASO titer at the next visit. If it is still positive several options are available. One could increase the dose to 500 mg tid for another four weeks or use Augmentin 250 mg tid. However, one needs to warn the patients about diarrhea developing with this drug. OTHER ANTIBIOTICS Azulfidine is another drug that may be helpful as an alternative to amoxicillin. Typical doses would be 500 mg. bid. Sulfapyridine is the same drug without the ASA component and would be a safer choice for those patients on a salicylate anti-inflammatory. Investigators over the past 20 years have shown Rifampin to have immunosuppressive properties in both human and animal studies. It has a unique mechanism of action that is not shared by any other antibiotic. One small study investigated its use in RA but did not find it helpful. Investigators have also used Ceftriaxone to treat chronic inflammatory arthritis. However, this is a parenteral medication, but it has shown promise in resistant cases of RA. Cefuroxime axetail has recently been shown to be more effective than penicillin and tetracycline in the treatment of Lyme disease and may be another antibiotic to consider. Some of the newer macrolide antibiotics like Biaxin or Zithromax may be helpful, especially for patients with positive ASO titers. ANTI-INFLAMMATORIES I usually encourage patients to consider the use of non- acetylated salicylates such as salsalate, sodium salicylate, magnesium salicylate, and (i.e., Salflex, Disalcid, or Trilisate). They are the drugs of choice if there is renal insufficiency. They have minimal interference with anticyclooxygenase and other prostaglandins. Additionally, they will not impair platelet inhibition of those patients who are on every other day aspirin to decrease their risk for stroke or heart disease. Unlike aspirin, they do not increase the formation of products of lipoxygenase-mediated metabolism of arachidonic acid. For this reason they may be less likely to precipitate hypersensitivity reactions. These drugs have been safely used in patients with reversible obstructive airway disease and a history of aspirin sensitivity. They also are much gentler on the stomach then the other NSAIDs, and are the drug of choice if the patient has problems with peptic ulcer disease. Unfortunately, all these benefits are balanced by the fact they may not be as effective as the other agents and are less convenient to take. One needs to push them to 1.5-2 grams bid and tinnitus is a frequent complication. One should warn patients of this complication and can explain that if tinnitus does devleop they need to stop the drugs for a day and restart with a dose that is half a pill per day lower. They repeat this until they find a dose that relieves their pain and doesn't give them any ringing. The first non-aspirin NSAID, indomethacin, was introduced in 1963. Now more than 20 are available. Relafen is one of the better alternatives if the non-acetylated salicylates aren't working as it seems to cause list of an intestinal dysbiosis. If cost is a concern generic ibuprofen can be used. Unfortunately, recent studies suggest this drug is more damaging to the kidneys. One must be especially careful to monitor renal function studies periodically. It is important for the patient to understand and accept the risks associated with these more toxic drugs. Unfortunately, these drugs are not benign. Every year they do enough damage to the GI tract to kill 2,000 to 4,000 patients with rheumatoid arthritis alone. That is ten patients EVERY DAY. At any given time patients receiving NSAID therapy have gastric ulcers in the range of 10-20%. Duodenal ulcers are lower at 2- 5%. Patients on NSAIDs are at approximately three times greater relative risk for developing serious gastrointestinal side effects than are non users. Approximately 1.2% of patients taking NSAIDs are hospitalized for upper GI problems per year of exposure. One study of patients taking NSAIDs showed that a life-threatening complication was the first sign of ulcer in more than half of the subjects. Risk factor analysis helps to discriminate those that are at increased danger of developing these complications. Those associated with a higher frequency of adverse events are: 1. old age 2. peptic ulcer history 3. alcohol dependency 4. cigarette smoking 5. concurrent prednisone or corticosteroid use 6. disability 7. high dose of the NSAID 8. NSAID known to be more toxic Studies clearly show that the non-acetylated salicylates are the safest NSAIDs. They are followed by Relafen, Daypro, Voltaren, Motrin, and Naprosyn. Meclomen, Indocin, Orudis, and Tolectin are among the most toxic or likely to cause complications. They are much more dangerous than the antibiotics or non-acetylated salicylates. One should run an SMA at least once a year on patients who are on these medications . One must monitor the serum potassium levels if the patient is on an ACE inhibitor as these medications can cause hyperkalemia. One should also monitor their kidney function. The SMA will also show any liver impairment that the drugs might cause. These medications can also impair prostaglandin metabolism and cause papillary necrosis and chronic interstitial nephritis. The kidney needs vasodilatory prostaglandins (PGE2 and prostacycline) to counterbalance the effects of potent vasoconstrictor hormones such as angiotensin II and catecholamines. NSAIDs decrease prostaglandin synthesis by inhibiting cyclooxygenase, leading to unopposed constriction of the renal arterioles supplying the kidney. PREDNISONE One can give patients with severe disease a prescription for prednisone 5 mg. They can take one of them a day if they develop a severe flare-up as a result of going on the antibiotics. They can use an additional tablet at night if they are in really severe flare. Explain to all patients that the prednisone is very dangerous and every dose they take decreases their bone density. However, it is a trade-off. Since they will only be on it for a matter of months, it's use may be justifiable. This is the first medicine they should try to stop as soon as their symptoms permit. Blood levels of cortisol peak between 3 and 9 AM. It would therefore be safest to administer the prednisone in the morning. This will minimize the suppression on the hypothalamic-pituitary-adrenal axis. Patients often ask the dangers of these medications. The most significant one is osteoporosis. Other side effects that usually occur at higher doses include adrenal insufficiency, atherosclerosis acceleration, cataract formation, Cushing's syndrome, diabetes, ulcers, herpes simplex and tuberculosis reactivation, insomnia, hypertension, myopathy and renal stones. One also needs to be concerned about the increased risk of peptic ulcer disease when using this medicine with conventional nonsteroidal anti-inflammatories. Persons receiving both of these medicines may have a 15 times greater risk of developing an ulcer. FIBROMYALGIA One needs to be very sensitive to this clinical problem when treating patients with RA. It is frequently a complicating condition. Many times patients will confuse the pain from it with a flare-up of their arthritis. One needs to aggressively treat this problem. If this problem is ignored the likelihood of successfully treating the arthritis is significantly diminished. Fibromyalgia is a very common problem. Some experts believe that 5% of people are affected with it. Over 12% of the patients at the Mayo Clinic's Department of Physical Medicine and Rehabilitation have this problem. It is the third most common diagnosis by rheumatologists in the outpatient setting. Fibromyalgia affects women five times as frequently as men. SIGNS AND SYMPTOMS One of the main features of fibromyalgia is the morning stiffness, fatigue, and multiple areas of tenderness in typical locations. Most patients with fibromyalgia complain of pain over many areas of the body, with an average of six to nine locations. Although the pain is frequently described as being all over, it is most prominent in the neck, shoulders, elbows, hips, knees, and back. Tender points are generally symmetrical and on both sides of the body. The areas of tenderness are usually small ( inch in diameter) and deep within the muscle. They are often located in sites that are slightly tender in normal people. Patients with fibromyalgia, however, differ in being more tender at these sites than are normal persons. Firm palpation with the thumb (just past the point where the nail turns white) over the outside elbow will typically cause a vague sensation of discomfort. Patients with fibromyalgia will experience much more pain and will often withdraw the arm involuntarily. More than 70% of patients describe their pain as profound aching, and stiffness of the muscles. Often it is relatively constant from moment to moment, but certain positions or movements may momentarily worsen the pain. Other terms used to describe the pain are dull and numb. Sharp or intermittent pain is relatively uncommon. Patients with fibromyalgia often complain that sudden loud noises worsen their pain. The generalized stiffness of fibromyalgia does not diminish with activity, unlike the stiffness of rheumatoid arthritis which lessens as the day progresses. Despite the lack of abnormal lab tests, patients can suffer considerable discomfort. The fatigue is often severe enough to impair activities of work and recreation. Patients commonly experience fatigue on arising and complain of being more fatigued when they wake up then when they went to bed. Over 90% of patients believe the pain, stiffness, and fatigue are made worse by cold, damp weather. Overexertion, anxiety and stress are also factors. Many people find that local heat, such as hot baths, showers, or heating pads, give them some relief. There is also a tendency for pain to improve in the summer, with mild activity, or with rest. Some patients will date the onset of their symptoms to some initiating event. This is often an injury, such as a fall, a motor vehicle accident, or a vocational or sports injury. Others find that their symptoms began with a stressful or emotional event, such as a death in the family, a divorce, a job loss, or similar occurrence. PAIN LOCATION Patients with fibromyalgia have pain in at least 11 of the following 18 tender point sites (one on each side of the body): 1. Base of the skull where the suboccipital muscle inserts. 2. Back of the low neck (anterior intertransverse spaces of C5-C7). 3. Midpoint of the upper shoulders (trapezius). 4. On the back in the middle of the scapula. 5. On the chest where the second rib attaches to the breast bone (sternum). 6. One inch below the outside of each elbow (lateral epicondyle). 7. Upper outer quadrant of buttocks. 8. Just behind the swelling on the upper leg bone below the hip (trochanteric prominence). 9. The inside of both knees (medial fat pads proximal to the joint line). TREATMENT OF FIBROMYALGIA There is a persuasive body of emerging evidence that indicates that patients with fibromyalgia are physically unfit in terms of sustained endurance. Some studies show that cardiovascular fitness training programs can decrease fibromyalgia pain by 75%. Sleep is critical to the improvement. Many times, improved fitness will correct the sleep disturbance. Many environmental medicine physicians believe that allergies may be another significant factor contributing to this problem. This is especially likely if the patient has other allergic symptoms. Provocation neutralization techniques seem to be much more effective than the traditional allergy treatments and frequently accelerate clinical improvement in both fibromyalgia and RA. Unfortunately any prednisone dose precludes skin testing for three months. One might also consider food allergies as a possible etiology. Milk restriction, including ice cream and cheese, is sometimes helpful. Wheat, corn, egg and soy avoidance are also helpful. If one needs assistance in this area physicians trained in Environmental Medicine can be consulted for a modified form of provocation neutralization skin testing which is especially effective. Members in your area can be found by contacting the American Academy of Environmental Medicine at 913-642-6062. EXERCISE FOR RA It is very important to exercise or increase muscle tone of the non-weight bearing joints. Experts tell us that disuse results in muscle atrophy and weakness. Additionally, immobility may result in joint contractures and loss of range of motion. Active ROM exercises are preferred to passive. There is some evidence that passive ROM exercises increase the number of WBCs in the joint. If the joint is stiff one should stretch and apply heat before exercising. If the joint is swollen, application of ten minutes of ice before exercise would be helpful. The inflamed joint is very vulnerable to damage from improper exercise, so one must be cautious. People with arthritis must strike a delicate balance between rest and activity. They must avoid activities that aggravate joint pain. Patients should avoid any exercise that strains a significantly unstable joint. A good rule of thumb is that if the pain lasts longer than one hour after stopping exercise the patient should slow down or choose another form of exercise. Assistive devices are also helpful to decrease the pressure on affected joints. Many patients need to be urged to take advantage of these. The Arthritis Foundation has a book, Guide to Independent Living, which instructs patients about how to obtain them. Of course, it is important to maintain good cardiovascular fitness. Walking with appropriate supportive shoes is also another important consideration. NUTRITIONAL CONSIDERATIONS Implementing these suggestions seems to decrease the commonly associated flares typically seen with initiation of the antibiotic protocol. Limiting sugar is a critical element of the treatment program. Eating refined sugar weakens one's immune system and promotes yeast overgrowth. This of course includes ALL non-diet pops which generally have 8 teaspoons of sugar. In addition, natural sweeteners including honey, molasses, maple syrup, date sugar, cane sugar, corn sugar, beet sugar, corn syrup, and fructose, should also be avoided. Patients who are unable to decrease their sugar intake will not likely improve. However, one need not become obsessive about sugar. If it is the 4th or 5th ingredient in a food, that would probably be acceptable. However, many people are addicted to sugar and should avoid all types of sugars permanently for optimal health. This is not much different than someone who is addicted to alcohol and requires total abstinence. Stevia is an acceptable herbal sweetener that can be used, but Nutrasweet (aspartame) should be strictly avoided. Partially hydrogenated vegetable oils contain very dangerous fats called trans fatty acids. These are very damaging to one's health and should be avoided. They are present in all commercially made doughnuts, crackers, cookies, pastries, deep-fat fried foods including those from all major " fast-food " chains, potato and corn chips, imitation cheeses, and confectionery fats found in frosting and candies. Margarine should be avoided like the plague, butter is an acceptable alternative and should also be purchased organically to eliminate the pesticides, antibiotics and growth hormones that are in the commercial brands. It will be very important to stop all milk products. This includes not only skim milk, but ice cream, and cheese. Cultured dairy products like cottage cheese and plain (not vanilla) live culture yogurts are usually tolerated as the allergenic milk protein is usually predigested by the acidophillus in the yogurt. Lactaid milk is NOT acceptable. REMISSION The natural course of RA is quite remarkable. LESS THAN 1% of patients who are rheumatoid factor seropositive have a spontaneous remission. Some disability occurs in 50-70% of patients within five years after onset of the disease. Half of the patients will stop working within 10 years. This devastating natural prognosis is what makes the antibiotic therapy so exciting. The following criteria can help establish remission: * A decrease in duration of morning stiffness to no more than 15 minutes * No pain at rest * Little or no pain or tenderness on motion * Absence of joint swelling * A normal energy level * A decrease in the ESR to no more than 30 * A normalization of the patient's CBC. Generally the HGB, HCT, & MCV will increase to normal and their " pseudo " -iron deficiency will disappear * ANA, RF, & ASO titers returning to normal If patients discontinue their medications before all of the above criteria are met, there is a greater risk that the disease will recur. If the patient meets the above criteria, one can have them to try to stop their anti-inflammatory medication once they start to experience these improvements. If the improvements are stable for three months ask them to discontinue the clindamycin. If they are maintained for the next three months, one can then discontinue their Minocin and monitor for recurrences. If a patient's symptoms should recur, it would be wise to restart their previous antibiotic regimen. Overall nearly 80% of the patients do remarkably better. Approximately 5% of the patients continued to worsen and required conventional agents, like methotrexate, to relieve their symptoms. Approximately 15% of the patients who started the treatment dropped out of the program and were lost to follow-up. The longer and more severe the illness, the longer it takes to cure. Smokers tend not to do as well with this program. Age and competency of the person's immune system are also likely important factors. Dr. Brown's experience suggests that significant benefits from the treatment require on the average one to two years. The length of therapy can vary widely. In severe cases, it may take up to thirty months for the patients to gain sustained improvement. One requires patience because remissions may take up to 3 to 5 years. Dr. Brown's pioneering approach represents a safer less toxic alternative to many conventional regimens and results of the NIH trial have finally scientifically validated this treatment. The 1987 Revised Criteria for Classification of Rheumatoid Arthritis Morning Stiffness Morning stiffness in and around joints lasting at least one hour before maximal improvement is noted. Arthritis of three or more joint areas At least three joint areas have simultaneously had soft-tissue swelling or fluid (not bony overgrowth) observed by a physician. There are 14 possible joints: right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints. Arthritis of hand joints At least one joint area swollen as above in a wrist, MCP, or PIP joint Symmetric arthritis Simultaneous involvement of the same joint areas (as in criterion 2) on both sides of the body (bilateral involvement of PIPs, MCPs, or MTPs) is acceptable without absolute symmetry. Lack of symmetry is not sufficient to rule out the diagnosis of RA. Rheumatoid Nodules Subcutaneous nodules over bony prominences, or extensor surfaces, or in juxta-articular regions, observed by a physician. Only about 25% of patients with RA develop nodules, and usually as a later manifestation. Serum rheumatoid factor Demonstration of abnormal amounts of serum rheumatoid factor by any method that has been positive in less than 5% of normal control subjects. This test is positive only 30-40% of the time in the early months of RA. Radiological Changes Radiological changes typical of rheumatoid arthritis on PA hand and wrist X-rays, which must include erosions or unequivocal bony decalcification localized to or most marked adjacent to the involved joints (osteoarthritic changes alone do not count). Note: Patients must satisfy at least four of the seven criteria listed. Any of criteria 1-4 must have been present for at least 6 weeks. Patients with two clinical diagnoses are not excluded. Designations as classic, definite, or probable rheumatoid arthritis is not to be made. Key: MCP:metacarpophalangeal joint; MTP: metatarsophalangeal joint; PA posteroanterior; PIP: proximal interphalangeal joint. NOTES BY DR. JOSEPH MERCOLA ON THIS PROTOCOL I first became aware of Doctor Brown's protocol in 1989 when I saw him on 20/20 on ABC. This was shortly after the introduction of the first edition of the Road Back. By the end of 1996 I probably treated about 300 patients with rheumatic illnesses, including SLE, scleroderma, polymyositis and dermatomyositis. My application of the protocol has changed significantly since I first started implementing it. Initially I had followed Dr. Brown's work very rigidly with very little modification rather than shifting the tetracycline choice to Minocin. I believe I was one of the original people who recommended the shift to Minocin which seems to have been widely adopted. Around 1991-1992 I started to integrate the nutritional model into the program and noticed a significant improvement in the treatment response. I continued to modify the diet recommendations till the last several months through trial and error with many different strategies. I believe the diet therapy has reached an equilibrium and doubt it will change significantly in the future. It is important to know my changes with the protocol to understand the results of the treatment regimen prescribed in my office. Approximately one third of patients have been lost to followup for whatever reason and have not continued with treatment. The remaining patients seem to have a 60-90% likelihood of improvement on this treatment regimen. There are many variables associated with an increased chance of remission or improvement. The younger the patient is the better they seem to do. The closer they follow the diet the less likely they are to have a severe flareup and the more likely they are to improve. Smoking seems to be negatively associated with improvement. The longer the patient has had the illness and the more severe the illness the more difficult it seems to treat. I am significantly impressed with the power of the dietary changes within the last year. They have been so dramatic that I do not routinely start patients on the antibiotics until their second visit. I review the dietary regimens and have them shift their foods first. I have seen several patients go into complete and total remission with no symptoms and no medications on their second visit without the use of any antibiotics. It is most impressive. If, however, they are not doing better I will start the antibiotics on their second visit. I have also observed that many rheumatic illness patients have an associated fibromyalgia that does not respond well to the diet or Dr. Brown's protocol. They seem to respond to an advanced type of allergy treatment called Provocation Neutralization which is performed by physician members of the American Academy of Environmental Medicine. " Is This Your Child? " is a popular book that discusses this treatment for a different illness, ADD and is a good source of information about the technique and environmental medicine in general. My treatment is continually evolving and 1997 marks the progression of integration of emotional healing tools which are not yet in the protocol. I am convinced that this is a significant issue in many people with chronic illness. As an example, I had a patient visit me recently from Ohio who had joint deforming RA for the last ten years shortly after both his parents committed suicide. It was quite clear this was the precipitating issue for his RA. He currently is undergoing some advanced therapies to resolve these issues which should put the RA into remission. BIBLIOGRAPHY 1. Pincus T, Wolfe F: Treatment of Rheumatoid Arthritis: Challenges to Traditional Paradigms. AnnInternMed 115:825-6, Nov 15 1991. 2. Pincus T: Rheumatoid arthritis: disappointing long-term outcomes despite successful short-term clinical trials. J Clin Epidemiol 41:1037-41, 1988. 3. PM: Clinical management of rheumatoid arthritis. Lancet 341 :286-90, 1993. 4. 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