Treating Rheumatic Diseases with Antibiotics

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http://www.mercola.com/2000/aug/27/Rheumatoid Arthritis.htm

Physicians' Protocol For Using Antibiotics in Rheumatic Disease

The following is a modified version of Dr. Brown's protocol.

Introduction

Rheumatoid arthritis affects about 1 percent of our population and at least two million Americans have definite or classical rheumatoid arthritis. It is a much more devastating illness than previously appreciated. Most patients with rheumatoid arthritis have a progressive disability. More than 50% of patients who were working at the start of their disease are disabled after five years of rheumatoid arthritis. The annual cost of this disease 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 Hodgkin's disease. Thirty years ago, one researcher concluded that there was an average loss of eighteen years of life in patients who developed rheumatoid arthritis 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 rheumatoid arthritis 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.

My Experience with the Dr. Brown's 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 his first edition of The Road Back.The newest version is The New Arthritis Breakthrough that is written by Henry Scammel. Unfortunately, Dr. Brown died from prostate cancer shortly after the 20/20 program so I never had a chance to meet him. By the year 2000, I will have treated over 1,500 patients with rheumatic illnesses, including SLE, scleroderma, polymyositis and dermatomyositis.

My application of Dr. Brown's protocol has changed significantly since I first started implementing it. Initially, I followed Dr. Brown's work rigidly with very little modification other than shifting the tetracycline choice to Minocin. I believe I was one of the first people who recommended the shift to Minocin, which seems to have been widely adopted at this time.

In the early 90s, I started to integrate the nutritional model into the program and noticed a significant improvement in the treatment response. I cannot emphasize strongly enough the importance of this aspect of the program. It is absolutely an essential component of the revised Dr. Brown protocol. One may achieve remission without it, but the chances are much improved with its implementation. The additional benefit of the dietary changes is that they severely reduce the risk of the two to six month worsening of symptoms that Dr. Brown described in his book.

In the late 80s, the common retort from other physicians was that there was "no scientific proof" that this treatment works. Well, that is certainly not true today. If one peeks ahead at the bibliography, one will find over 200 references in the peer-reviewed medical literature that supports the application of Minocin in the use of rheumatic illnesses.

The definitive scientific support for minocycline in the treatment of rheumatoid arthritis came with the MIRA trial in the United States. This 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 rheumatoid arthritis.

Dr. Brown's effort to treat the chronic mycoplasma infections believed to cause rheumatoid arthritis is the basis for this therapy. Dr. Brown believed that most rheumatic illnesses respond to this treatment. He and others used this therapy for SLE, ankylosing spondylitis, scleroderma, dermatomyositis and polymyositis.

Dr. Osler was also a preeminent figure of his time (1849- 1919). Many 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 might 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.

Nutritional Considerations

Limiting sugar is a critical element of the treatment program. Sugar has multiple significant negative influences on a person's biochemistry. Its major mode of action is through elevation of insulin levels. However, it has a similarly severe impairment of intestinal microflora. Patients who are unable to decrease their sugar intake are far less likely improve.

One of the major benefits of implementing the dietary changes is that one does not seem to develop worsening of symptoms the first three to six months that is described in Dr. Brown's book. Most of my patients tend to not worsen once they start the antibiotics. I believe this is due to the beneficial effects that the diet has on the immune response. I ask all new patients to read my 6-page handout on the dietary changes. Rather than repeat it here, one could obtain the current version on my web site at www.mercola.com under the tab heading on the left side of the page entitled Read This First.

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 rheumatoid arthritis. 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 be prudent to have patients on prophylactic oral Lactobacillus acidophilus and bifidus preparations. 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. However, 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 other tetracyclines. This is fortunate because some patients cannot 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 Lederle brand and is a more than reasonable justification to not substitute for the generic version. Clinical experience has shown that many patients will relapse when they switch from the brand name to the generic.

Clinically it has been documented that it is important to take Lederle brand Minocin. Most all generic minocycline is clearly not as effective. A large percentage of patients will not respond at all or not do as well with generic non-Lederle minocycline.

Traditionally it was recommended to only receive the brand name Lederle Minocin. However, there is one generic brand that is acceptable and that is the brand made by Lederle. The only difference between Lederle generic Minocin and brand name Minocin is the label and the price.

The problem is finding the Lederle brand generic. Some of my patients have been able to find it at Wal Mart. Since Wal Mart is one of the largest drug chains in the US, this should make the treatment more widely available for a reduced charge.

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 or 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 cannot 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 emergency room.

For those physicians who elect to use tetracycline or doxycycline for cost or sensitivity reasons, several methods may help lessen the inevitable secondary yeast overgrowth. Lactobacillus acidophilus will help maintain normal bowel flora and decrease the risk of fungal overgrowth.

Aggressive avoidance of all sugars, especially those found in non-diet sodas will also decrease the substrate for the yeast's growth. Macrolide antibiotics like Biaxin or Zithromax may be used if tetracyclines are contraindicated. They would also be used in the three pills a week regimen.

Clindamycin

The other drug used to treat rheumatoid arthritis 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.

For patients with milder illness, 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. If this is a problem, one can lower the dose and gradually increase the dose over a few weeks.

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.

What To Do If Severe Patients Fail To Respond

The most frequent reason for failure to respond to the protocol is lack of adherence to the dietary guidelines. Most patients will be eating too many grains and sugars, which disturb insulin physiology. It is important that patients adhere as strictly as possible to the guidelines.A small minority, generally under 15%, of patients will fail to respond to the protocol described above despite rigid adherence to the diet.These individuals should already be on the IV Clindamycin.

It appears that the hyaluronic acid, which is a potentiating agent commonly used in the treatment of cancer may be quite useful. It seems that hyaluronic acid has very little to no direct toxicity but works in a highly synergistic fashion when administered directly in the IV bag with the Clindamycin.

Hyaluronic acid is also used in orthopedic procedures. The dose is generally from 2 to 10 cc into the IV bag. Hyaluronic acid is not inexpensive as the cost may range up to $10 per cc.One does need to exert some caution with its use as it may precipitate a significant Herxheimer flare reaction.

Patients will frequently have emotional traumas that worsen their illness. Severe emotional traumas can seriously impair the immune response to this treatment.

Anti-Inflammatories

The first non-aspirin NSAID, indomethacin was introduced in 1963. Now more than 30 are available. Relafen is one of the better alternatives as it seems to cause less 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.

Researchers found that the drugs suppress production of prostacyclin, which is needed to dilate blood vessels and inhibit clotting. Earlier studies had found that mice genetically engineered to be unable to use prostacyclin properly were prone to clotting disorders.

Anyone who is at increased risk of cardiovascular disease should steer clear of these two new medications. Ulcer complications are certainly potentially life-threatening,but, heart attacks are a much more common and likely risk, especially in older individuals.

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. Celebrex and Vioxx likely cause the least risk for peptic ulcer. But as mentioned, they pose an increased risk for heart disease. Factoring these newer medications out would leave the following less toxic NSAIDs: 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.

One might consider the use of non-acetylated salicylates such as salsalate, sodium salicylate and magnesium salicylate (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 explain that if tinnitus does develop 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.

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, its 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 9am. 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 non-steroidal anti-inflammatories. Persons receiving both of these medicines may have a 15 times greater risk of developing an ulcer.

If a patient is already on prednisone, it is helpful to give them a prescription for 1 mg tablets so they can wean themselves off of the prednisone as soon as possible. Usually one lowers the dose by about 1 mg per week. If a relapse of the symptoms occurs, than further reduction of the prednisone is not indicated.

Remission

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

The natural course of rheumatoid arthritis 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.

Approximately one third of patients have been lost to follow-up 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. That is quite a stark contrast to the numbers quoted above.

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 more closely they follow the diet, the less likely they are to have a severe flare-up 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.

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 six months, then discontinue the clindamycin. If the improvements are maintained for the next six months, one can then discontinue their Minocin and monitor for recurrences. If symptoms should recur, it would be wise to restart the previous antibiotic regimen.

Overall, nearly 80% of the patients do remarkably better with this program. 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 successfully treated over 10,000 patients with this protocol. He found that significant benefits from the treatment require on the average one to two years. I have treated nearly over 1,500 patients and find that the dietary modification I advocate accelerates the response rate to several months. 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.

Preliminary Laboratory Evaluation For Non-Rheumatologists

It is important to evaluate patients to determine if indeed they have rheumatoid arthritis. 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 also metabolic, infectious and malignant disorders. These patients will require a more extensive laboratory analysis.

Rheumatoid arthritis 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 rheumatoid arthritis. If the patient completely lacks hand and wrist involvement, even by history, the diagnosis of rheumatoid arthritis is doubtful. Rheumatoid arthritis 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.

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 cannot 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 labs. 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 agitation of the ESR measuring tube.

Many patients with rheumatoid arthritis have a hypochromic, microcytic CBC. This is probably due to the inflammation in the rheumatoid arthritis 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 rheumatoid arthritis.

Fibromyalgia

One needs to be very sensitive to this clinical problem when treating patients with rheumatoid arthritis. 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 of Fibromyalgia

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 (less than an 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 having increased tenderness at these sites than 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 localized 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 breastbone (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.

My favorite, and most profoundly beneficial treatment for fibromyalgia is NST.

Allergies, especially to mold, seem to be another common cause of fibromyalgia. There are some simple interventions using techniques called Total Body Modification (TBM) 800-243-4826.

Exercise For Rheumatoid Arthritis

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 (ROM). 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 joints are stiff, one should stretch and apply heat before exercising. If the joints are 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.

The Infectious Cause Of Rheumatoid Arthritis

It is quite clear that autoimmunity plays a major role in the progression of rheumatoid arthritis. Most rheumatology investigators believe that an infectious agent causes rheumatoid arthritis. 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 this agent might cause that human rheumatoid arthritis. Dr. Brown was a rheumatologist who worked with Dr. Sabin at the Rockefeller 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 for over fifty years of his life.

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 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 the immune complex contributes to 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 rheumatoid arthritis 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 rheumatoid arthritis. Using similar techniques other investigators have cultured mycoplasma in 80- 100% of their rheumatoid arthritis test population.

Rheumatoid arthritis follows some mycoplasma respiratory infections. 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 rheumatoid arthritis. 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 for The Protocol

The full spectrum of human rheumatoid arthritis 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.

The Science of Why Minocycline Is Used

If mycoplasma were a causative factor in rheumatoid arthritis, one would expect tetracycline type drugs to provide some sort of improvement in the disease. Collagenase activity increases in rheumatoid arthritis and probably has a role in its cause. 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 rheumatoid arthritis. 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 characteristics shifted the treatment of rheumatic illness away from tetracycline to minocycline. Minocycline may benefit rheumatoid arthritis 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 that inhibit T-cells.

Individuals with the Class II major histocompatibility complex (MHC) DR4 allele seem to be predisposed to developing rheumatoid arthritis. The infectious agent probably interacts with this specific antigen in some way to precipitate rheumatoid arthritis. There is strong support for the role of T cells in this interaction.

Minocycline may suppress rheumatoid arthritis 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 rheumatoid arthritis. 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 rheumatoid arthritis 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.

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 rheumatoid arthritis.

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 rheumatoid arthritis 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 rheumatoid arthritis.

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.

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. Pincus T, Callahan LF: Remodeling the pyramid or remodeling the paradigms concerning rheumatoid arthritis - lessons learned from Hodgkin's Disease and coronary artery disease. JRheumatol 17:1582-5, 1990.

5. Reah TG: The prognosis of rheumatoid arthritis. Proc R Soc Med 56:813-17, 1963.

6. Wolfe F, Hawley DJ: Remission in rheumatoid arthritis. J Rheumatol 12:245-9, 1985.

7. Kushner I, Dawson NV: Changing perspectives in the treatment of rheumatoid arthritis. JRheumatol 19:1831-34, 1992.

8. Pinals RS: Drug therapy in rheumatoid arthritis a perspective. Br J Rheumatol 28:93-5, 1989.

9. Klippel JH: Winning the battle, losing the war? Another editorial about rheumatoid arthritis. JRheumatol 17:1118-22. 1990.

10. Healey LA, Wilske KR: Evaluating combination drug therapy in rheumatoid arthritis. J Rheumatol 18:641-2, 1991.

11. Wolfe F: 50 Years of antirheumatic therapy: the prognosis of rheumatoid arthritis. J Rheumatol 17:24-32, 1990.

12. SE, Luthra HS: Rheumatoid arthritis: Can the long term be altered? Mayo Clin Proc 63:58-68, 1988.

13. ED: Rheumatoid arthritis: Pathophysiology and implications for therapy. NEngl JMed 322:1277-1289, May 3, 1990.

14. Schwartz BD: Infectious agents, immunity and rheumatic diseases. Arthr Rheum 33 :457-465, April 1990.

15. Tan PLJ, Skinner MA: The microbial cause of rheumatoid arthritis: time to dump Koch's postulates. J Rheumatol 19:1170-71. 1992.

16. Ford DK: The microbiological causes of rheumatoid arthritis. JRheumatol 18:1441-2, 1991.

17. Burmester GR: Hit and run or permanent hit? Is there evidence for a microbiological cause of rheumatoid arthritis? J Rheumatol 18:1443-7, 1991.

18. PE: Evidence implications infectious agents in rheumatoid arthritis and juvenile rheumatoid arthritis. Clin EXD Rheumatol 1988 6:87-94.

19. Sabin AB: Experimental proliferative arthritis in mice produced by filtrable pleuropneumonia-like microorganisms. Science 89:228-29, 1939.

20. Swift HF, Brown TMcP: Pathogenic pleuropneumonia-like organisms from acute rheumatic exudates and tissues. Science 89:271-272. 1939.

21. HW, JS, Brown TMcP: Determination of mycoplasma antibodies in humans. Bacteriol Proc 64:59, 1964.

22. Brown Tmcp, Wichelausen RH, LB, et al: The in vivo action of aureomycin on pleuropneumonia-like organisms associated with various rheumatic diseases. J Lab Clin Med 34: 1404-1410. 1949.

23. Brown TMcP, Wichelhausen RH: A study of the antigen-antibody mechanism in rheumatic diseases. Amer JMed Sci 221:618, 1951.

24. Brown TMcP: The rheumatic crossroads. Postgrad Med 19:399-402, 1956.

25. Brown TMcP, HW, JS, et al: Relationship between mycoplasma antibodies and rheumatoid factors. ArthrRheum 13:309-310, 1970.

26. HW, Brown TMcP: Another look at mycoplasma. Arthr Rheum 19:649-50, 1976.

27. Hakkarainen K, et al: Mycoplasmas and arthritis. Ann Rheumat Dis 51: S70-72; l992.

28. Rook, GAW, et al: A reppraisal of the evidence that rheumatoid arthritis and several other idiopathic diseases are slow bacterial infections. Ann Rheum Dis 52:S30-S38; 1993.

29. HW, Coker-Vann MR, JS, et al: Detection of mycoplasma antigens in immune complexes from rheumatoid arthritis synovial fluids. Ann Allergy 60:394-98, May 1988.

30. Wilder RL: Etiologic considerations in rheumatoid arthritis. Ann Intern Med 101 :820-21, 1984.

31. Bartholomew LE: Isolations and characterization of mycoplasmas (PPLO) from patients with rheumatoid arthritis, systemic lupus erythematosus and Reiter's syndrome. Arthr Rheum 8:376-388. 1965.

32. Brown TMcP, et al: Mycoplasma antibodies in synovia. Arthritis Rheum 9:495, 1966.

33. LA, Urquhart GED, Dick WC: Mycoplasma pneumonia infection and arthritis in man. Br Med J 2: 14- 16. 1977.

34. Mc MI, JO, Harrelson JM, et al: Septic arthritis due to Mycoplasma hominis. Arth Rheum 26: 1044-47, 1983.

35. MH, Brostoff J, Roitt IM: Possible role of Mycoplasma fermenters in pathogenesis of rheumatoid arthritis. Lancet 2:277-280 1970

36. Jansson E, Makisara P, Vainio K, et al: An 8-year study on mycoplasma in rheumatoid arthritis. Ann Rheum Dis 30:506-508, 1971.

37. Jansson E, Makisara P, Tuuri S: Mycoplasma antibodies in rheumatoid arthritis. Scan J Rheumatol 4: 165-68, 1975.

38. Markham JG, Myers DB: Preliminary observations on an isolate from synovial fluid of patients with rheumatoid arthritis. Ann Rheum Dis, S 1-7 1976.

39. Tully JG, et al: Pathogenic mycoplasmas: cultivation and vertebrate pathogenicity of a new spiroplasma. Science 195:892-4, 1977.

40. Fahlberg WJ, et al: Isolation of mycoplasma from human synovial fluids and tissues. Bacteria Proceedings 66:48-9, 1966.

41. Ponka A: The occurrence and clinical picture of serologically verified Mycoplasma pneumonia infections with emphasis on central nervous system, cardiac and joint manifestations. Ann Clin Res II (suppl) 24, 1979.

42. LA, Urquhart GED, Dick WC: Mycoplasma pneumonia infections and arthritis in man. Br Med J2:14-16, 1977.

43. Ponka A: Arthritis associated with Mycoplasma pneumonia infection. Scand J Rheumatol 8:27-32, 1979.

44. Stuckey M, Quinn PA, Gelfand EW: Identification of T-Strain mycoplasma in a patient with polyarthritis. Lancet 2:917-920. 1978.

45. Webster ADB, - D, Furr PM, et al: Mycoplasmal septic arthritis in hypogammaglobuinemia. Br Med J 1 :478-79, 1978.

46. Ginsburg KS, Kundsin RB, Walter CW, et al: Ureaplasma urealyticum and Mycoplasma hominis in women with systemic lupus erythematosus. Arthritis Rheumatism 35 429-33, 1992.

47. Cole BC, Cassel GH: Mycoplasma infections as models of chronic joint inflammation. Arthr Rheum 22:1375-1381, Dec 1979.

48. Cassell GH, Cole BC: Mycoplasmas as agents of human disease. N Engl J Med 304: 80-89, Jan 8, 1981.

49. Jansson E, et al: Mycoplasmas and arthritis. Rheumatol 42:315-9, 1983.

50. Camon GW, Cole BCC, Ward JR, et al: Arthritogenic effects of Mycoplasma arthritides T cell mitogen in rats. JRheumatol 15:735-41, 1988.

51. Cedillo L, Gil C, Mayagoita G, et al: Experimental arthritis induced by Mycoplasma pneumonia in rabbits. JRheumatol 19:344-7, 1992.

52. Baccala R, LR, Vestberg M, et al: Mycoplasma arthritidis mitogen. Arthritis Rheumatism 35:43442, 1992.

53. Brown McP, HW, JS: Rheumatoid arthritis in the gorilla: a study of mycoplasma-host interaction in pathogenesis and treatment. In Comparative Pathology of Zoo Animals, RJ Montali, Gigaki (ed), sonian Institution Press. 1980. 259-266.

54. HW: The potential role of mycoplasmas as autoantigens and immune complexes in chronic vascular pathogenesis. Am J Primatol 24:235-243, 1991.

55. Greenwald, rheumatoid arthritis, Goulb LM, Lavietes B, et al: Tetracyclines imibit human synovial collagenase in vivo and in vitro. RhPn fol 14:28-32. 1987.

56. Goulb LM, Lee HM, Lehrer G, et al: Minocycline reduces gingival collagenolytic activity during diabetes. JPeridontRes 18:516-26, 1983.

57. Goulb LM, et al: Tetracyclines imibit comective tissue breakdown: new therapeutic implications for an old family of drugs. Crit Rev Oral Med Pathol 2:297-322, 1991.

58. Ingman T, Sorsa T, Suomalainen K, et al: Tetracycline inhibition and the cellular source of collagenase in gingival revicular fluid in different periodontal diseases. A review article. J Periodontol 64(2):82-8, 1993.

59. Greenwald rheumatoid arthritis, Moak SA, et al: Tetracyclines suppress metalloproteinase activity in adjuvant arthritis and, in combination with flurbiprofen, ameliorate bone damage. J Rheumatol 19:927-38, 1992.

60. Gomes BC, Golub LM, Ramammurthy NS: Tetracyclines inhibit parathyroid hormone induced bone resorption in organ culture. Experientia 40:1273-5, 1985.

61. Yu LP Jr, SMith GN, Hasty KA, et al: Doxycycline inhibits Type XI collagenolytic activity of extracts from human osteoarthritic cartilage and of gelantinase. JRheumatol 18:1450-2, 1991.

62. Thong YH, Ferrante A: Effect of tetracycline treatment of immunological responses in mice. Clin Exp Immunol 39:728-32, 1980.

63. Pruzanski W, Vadas P: Should tetracyclines be used in arthritis? J Rheumatol 19: 1495-6, 1992.

64. Editorial: Antibiotics as biological response modifiers. Lancet 337:400-1, 1991.

65. Van Barr HMJ, et al: Tetracyclines are potent scavengers of the superoxide radical. Br J Dermatol 117:131-4, 1987.

66. Wasil M, Halliwell B, Moorhouse CP: Scavenging of hypochlorous acid by tetracycline, rifampicin and some other antibiotics: a possible antioxidant action of rifampicin and tetracycline? Biochem Pharmacol 37:775-8, 1988.

67. Breedveld FC, Trentham DE: Suppression of collagen and adjuvant arthritis by a tetracycline. Arthritis Rheum 31(1 Supplement)R3, 1988.

68. Trentham, DE; Dynesium-Trentham rheumatoid arthritis: Antibiotic Therapy for Rheumatoid Arthritis: Scientific and Anecdotal Appraisals. Rheum Clin NA 21: 817-834, 1995.

69. Panayi GS, et al: The importance of the T cell in initiating and maintaining the chronic synovitis of rheumatoid arthritis. Arthritis Rheum 35:729-35, 1992.

70. Sewell KL, Trentham DE: Pathogenesis of rheumatoid arthritis. Lancet 341 :283-86, 1993.

71. Sewell KE, Furrie E, Trentham DE: The therapeutic effect of minocycline in experimental arthritis. Mechanism of action. JRheumatol 33(suppl):S106, 1991.

72. Panayi GS, B: Minocycline in the treatment of patients with Reiter's syndrome. Clin Erp Immunol 7: 100-1, 1989.

73. Pott H-G, Wittenborg A, Junge-Hulsing G: Long-term antibiotic treatment in reactive arthritis. Lancet i:245-6, Jan 30, 1988.

74. Skinner M, Cathcart ES, Mills JA, et al: Tetracycline in the Treatment of Rheumatoid Arthritis. Arthritis and Rheumatism 14:727-732, 1971.

75. Lauhio A, Leirisalo-Repo M, Lahdevirta J, et al: Double-blind placebo-controlled study of three-month treatment with Iymecycline in reactive arthritis, with special reference to Chlamydia arthritis. Arthritis Rheumatism 34:6-14, 1991.

76. Lauhio A, Sorsa T, Lindy O, et al: The anticollagenolytic potential of Iymecycline in the long-term treatment of reactive arthritis. Arthritis Rheumatism 35: 195-198, 1992.

77. Breedveld FC, Dijkmans BCA, Mattie H: Minocycline treatment for rheumatoid arthritis: an open dose finding study. JRheumatol 17:43-46, 1990.

78. Kloppenburg M, Breedveld FC, Miltenburg AMM, et al: Antibiotics as disease modifiers in arthritis. Clin Exper Rheumatol l l(suppl 8):S113-S115, 1993.

79. Langevitz P, et al: Treatment of resistant rheumatoid arthritis with minocycline: An open study. J Rheumatol 19: 1502-04, 1992.

80. Tilley, B, et al: Minocycline in Rheumatoid Arthritis: A 48 week double-blind placebo controlled trial. Ann Intern Med 122:81, 1995.

81. Mills, JA: Do Bacteria Cause Chronic Polyarthritis? N Enel J Med 320:245-246. January 26, 1989.

82. Rothschild BM, et al: Symmetrical Erosive Peripheral Polyarthritis in the Late Archaic Period of Alabama. Science 241:1498-1502, Sept 16, 1988.

83. , HW, et al: Detection of Mycoplasma Antigens in Immune Complexes From Rheumatoid Arthritis Synovial Fluids. Ann Allergy 60:394-398, May 1988.

84. Res PCM, et al: Synovial Fluid T Cell Reactivity Against 65kD Heat Shock Protein of Mycobacteria in Early Chronic Arthritis. Lancet ii:478-480, Aug 27, 1988.

85. Cassell GH, et al: Mycoplasmas as Agents of Human Disease. N Engl J Med 304:80-89, Jan 8, 1981.

86. Breedveld FC, et al: Minocycline Treatment for Rheumatoid Arthritis: An Open Dose Finding Study. J Rheumatol 17:43-46, January 1990.

87. PE: Evidence implicating infectious agents in rheumatoid arthritis and juvenile rheumatoid arthritis. Clin Exp Rheumatol 6:87-94. 1988.

88. ED: Rheumatoid Arthritis, Pathophysiology and Implications for Therapy. N Engl J Med 322:1277-1289, May 3, 1990.

89. HW: The Potential Role of Mycoplasmas as Autoantigens and Immune Complexes in Chronic Vascular Pathogenesis. Am Jof Primatology 24:235-243. 1991.

90. Silman AJ: Is Rheumatoid Arthritis an Infectious Disease? Br Med J 303:200 July 27, 1991.

91. HW: The Potential Role of Mycoplasmas as Autoantigens and Immune Complexes in Chronic Vascular Pathogenesis. Am J Primatol 24:235-243, 1991.

92. Wheeler HB: Shattuck Lecture Healing and Heroism. NEngl JMed 322:1540-1548, May 24, 1990.

93. Arnett FC: Revised Criteria for the Classification of Rheumatoid Arthritis. Bun Rheum Dis 38:1-6, 1989.

94. Braanan W: Treatment of Chronic Prostatitis. Comparison of Minocycline and Doxycycline. Urology 5:631-636, 1975.

95. Becker FT: Treatment of Tetracycline-Resistant Acne Vulgaris. Cutis 14:610-613. 1974.

96. Cullen, SI: Low-Dose Minocycline Therapy in Tetracycline-Recalcitrant Acne Vulgaris. Cutis 21:101-105, 1978.

97. Mattuccik, et al: Acute Bacterial Sinusitis. Minocycline vs.Amoxicillin. Arch Otolaryngol Head Neck Surgery 112:73-76, 1986.

98. Guillon JM, et al: Minocylcine-induced Cell-mediated Hypersensitivity Pneumonitis. Ann Intern Med 117:476-481, 1992.

99. SE, et al: Rifampin therapy in rheumatoid arthritis. J Rheumatol 17: 163-6, 1990.

100. Caperton EM, et al: Cefiriaxone therapy of chronic inflammatory arthritis. Arch Intern Med 150:1677-1682, 1990.

101. Ann Intern Med 117:273-280, 1992.

102. Clive DM, et al: Renal Syndromes Associated with Nonsteroidal Antiinflammatory drugs. NEngl JMed 310:563-572. March 1 l994.

103. Piper, et al: Corticosteroid Use and Peptic Ulcer Disease: Role of Non-Steroidal Anti-inflammatory Drugs. Ann Intern Med 114:735-740, May 1, 1991.

104. MC, et al: Gastrointestinal Damage Associated with the Use of Nonsteroidal Antiinflammatory Drugs. N Engl J Med 327:749-54, 1992.

105. Fries JF:Postmarketing Drug Surveillance: Are Our Priorities Right? JRheumatol 15:389-390, 1988.

106. PM, et al: Nonsteroidal Antiinflammatory Drugs Differences and Similarities. NEngl JMed 324:1716-1724, June 13, 1991.

107. Agrawal N: Risk Factors for Gastrointestinal Ulcers Caused by Nonsteroidal Anti-inflammatory Drugs (NSAIDs). J Fam Prac 32:619-624, June 1991.

108. Silverstein, F: Nonsteroidal Anti-Inflammatory Drugs and Peptic Ulcer Disease. Postgrad Med 89:33-30, May 15, 1991.

109. SE, et al: Risk for Serious Gastrointestinal Complications Related to Use of NSAIDs. Ann Intern Med 115:787-796 1991.

110. Fries JF, et al: Toward an Epidemiology of Gastropathy Associated With NSAID Use. Gastroent 96:647-55, 1989.

111. Armstrong CP, et al: NSAIDs and Life Threatening Complications of Peptic Ulceration. Gut 28:527-32, 1987.

112. Murray MD, et al: Adverse Effects of Nonsteroidal Anti-Inflammatory Drugs on Renal Function. AnnInternMed 112:559, April 15, 1990.

113. Cook DM: Safe Use of Glucocorticoids: How to Monitor Patients Taking These Potent Agents. Postgrad Med 91:145-154, Feb. 1992.

114. Piper JM, et al: Corticosteroid Use and Peptic Ulcer Disease: Role of Nonsteroidal Anti-inflammatory Drugs. Ann Intern Med 114:735-740, May 1, 1991.

115. JM: Tension Myalgia as a Diagnosis at the Mayo Clinic and Its Relationship to Fibrositis, Fibromyalgia, and Myofascial Pain Syndrome. Mayo Clin Proc 65:1237-1248, September 1990.

116. Semble EL, et al: Therapeutic Exercise for Rheumatoid Arthritis and Osteoarthritis. Seminars in Arthritis and Rheumatism 20:32-40, August 1990.

117. O'Dell, J, Haire, C, Palmer, W, Drymalski, W, Wees, S, Blakely, K, Churchill, M, Eckhoff, J, Weaver, A, Doud, D, kson, N, Dietz, F, Olson, R, Maloney, P, Klassen, L, , G, Treatment of Early Rheumatoid Arthritis with Minocycline or Placebo: Results of a Randomized, Double-Blind, Placebo-Controlled Trial, Arthritis & Rheumatism, 1997, 40:5, 842-848.

118. Tilley, BC, Alarcón, GS, Heyse, SP, Trentham, DE, Neuner, R, Kaplan, DA, Clegg, DO, Leisen, JCC, Buckley, L, , SM, Duncan, H, Pillemer, SR, Tuttleman, M, Fowler, SE, Minocycline in Rheumatoid Arthritis: A 48-Week, Double-Blind, Placebo-Controlled Trial, ls of Internal Medicine, 1995, 122:2, 81-89.

119. Bluhm, GB, Sharp, JT, Tilley, BC, Alarcon, GS, , SM, Pillemer, SR, Clegg, DO, Heyse, SP, Trentham, DE, Neuner, R, Kaplan, DA, Leisen, JC, Buckley, L, Duncan, H, Tuttleman, M, Shuhui, L, Fowler, SE, Radiographic Results from the Minocycline in Rheumatoid Arthritis (MIRA) Trial, Journal of Rheumatology, 1997, 24:7, 1295-1302.

120. Breedveld, FC, Editorial: Minocycline in Rheumatoid Arthritis, Arthritis & Rheumatism, 1997, 40:5, 794-796.

121. Breedveld, FC, Letters: Reply to Minocycline-Induced Autoimmune Disease, Arthritis & Rheumatism, 1998, 41:3, 563-564.

122. Fox, R, Sharp, D, Editorial: Antibiotics as Biological Response Modifiers, The Lancet, 1991, 337:8738, 400-401.

123. Greenwald, rheumatoid arthritis, Golub, LM, Lavietes, B, Ramamurthy, NS, Gruber, B, Laskin, RS, McNamara, TF, Tetracyclines Inhibit Human Synovial Collagenase In Vivo and In Vitro, Journal of Rheumatology, 1987, 14:1, 28-32.

124. Griffiths, B, Gough, A, Emery, P, Letters: Minocycline-Induced Autoimmune Disease: Comment on the Editorial by Breedveld, Arthritis & Rheumatism, 1998, 41:3, 563.

125. Kloppenburg, M, Breedveld, FC, Miltenburg, AMM, Dijkmans, BAC, Antibiotics as Disease Modifiers in Arthritis, Clinical and Experimental Rheumatology, 1993, 11: Suppl. 8, S113-S115.

126. Kloppenburg, M, Breedveld, FC, Terwiel, JPh, Mallee, C, Dijkmans, BAC, Minocycline in Active Rheumatoid Arthritis: A Double-Blind, Placebo-Controlled Trial, Arthritis & Rheumatism, 1994, 37:5, 629-636.

127. Kloppenburg, M, Mattie, H, Douwes, N, Dijkmans, BAC, Breedveld, FC, Minocycline in the Treatment of Rheumatoid Arthritis: Relationship of Serum Concentrations to Efficacy, Journal of Rheumatology, 1995, 22:4, 611-616.

128. Lauhio, A, Leirisalo-Repo, M, Lähdevirta, J, Saikku, P, Repo, H, Double-Blind, Placebo-Controlled Study of Three-Month Treatment with Lymecycline in Reactive Arthritis, with Special Reference to Chlamydia Arthritis, Arthritis & Rheumatism, 1991, 34:1, 6-14.

129. Lauhio, A, Sorsa, T, Lindy, O, Suomalainen, K, Saari, H, Golub, LM, Konttinen, YT, The Anticollagenolytic Potential of Lymecycline in the Long-Term Treatment of Reactive Arthritis, Arthritis & Rheumatism, 1992, 35:2, 195-198.

130. us, HE, Editorial: Minocycline Treatment of Rheumatoid Arthritis, ls of Internal Medicine, 1995, 122:2, 147-148.

131. Pruzanski, W, Vadas, P, Editorial: Should Tetracyclines be Used in Arthritis?, Journal of Rheumatology, 1992, 19:10, 1495-1497.

132. Sieper, J, Braun, J, Editorial: Treatment of Reactive Arthritis with Antibiotics, British Journal of Rheumatology, July 1998.

133. Baseman, JB, Tully, JG, Mycoplasmas: Sophisticated, Reemerging, and Burdened by Their Notoriety, CDC's Emerging Infectious Diseases, 1997, 3:1, 21-32.

134. Franz, A, Webster, ADB, Furr, PM, -, D, Mycoplasmal Arthritis in Patients with Primary Immunoglobulin Deficiency: Clinical Features and Outcome in 18 Patients, British Journal of Rheumatology, 1997, 36:6, 661-668.

135. Hakkarainen K, Turunen, H, Miettinen, A, Karppelin, M, Kaitila, K, Jansson, E, Mycoplasmas and Arthritis, ls of Rheumatic Diseases, 1992, 51, 1170-1172.

136. Hoffman, RH, Wise, KS, Letters: Reply to Mycoplasmas in the Joints of Patients with Rheumatoid Arthritis and Other Inflammatory Rheumatic Disorders, Arthritis & Rheumatism, 1998, 41:4, 756-757.

137. Schaeverbeke, T, Bébéar, C, Lequen, L, Dehais, J, Bébéar, C, Letters: Mycoplasmas in the Joints of Patients with Rheumatoid Arthritis and Other Inflammatory Rheumatic Disorders: Comment on the Article by Hoffman et al., Arthritis & Rheumatism, 1998, 41:4, 754-756.

138. Schaeverbeke, T, Gilroy, CB, Bébéar, C, Dehais, J, -, D, Mycoplasma fermentans, But Not M penetrans, Detected by PCR Assays in Synovium from Patients with Rheumatoid Arthritis and Other Rheumatic Disorders, Journal of Clinical Pathology, 1996, 49, 824-828.

139. Aoki, S, Yoshikawa, K, Yokoyama, T, Nonogaki, T, Iwasaki, S, Mitsui, T, Niwa, S, Role of Enteric Bacteria in the Pathogenesis of Rheumatoid Arthritis: Evidence for Antibodies to Enterobacterial Common Antigens in Rheumatoid Sera and Synovial Fluids, ls of Rheumatic Diseases, 1996, 55:6, 363-369.

140. Blankenberg-Sprenkels, SHD, Fielder, M, Feltkamp, TEW, Tiwana, H, , C, Ebringer, A, Antibodies to Klebsiella pneumoniae in Dutch Patients with Ankylosing Spondylitis and Acute Anterior Uveitis and to Proteus mirabilis in Rheumatoid Arthritis, Journal of Rheumatology, 1998, 25:4, 743-747.

141. Ebringer, A, Ankylosing Spondylitis is Caused by Klebsiella: Evidence from Immunogenetic, Microbiologic, and Serologic Studies, Rheumatic Disease Clinics of North America, 1992, 18:1, 105-121.

142. Erlacher, L, Wintersberger, W, Menschik, M, Benke-Studnicka, A, Machold, K, Stanek, G, Söltz-Szöts, J, Smolen, J, Graninger, W, Reactive Arthritis: Urogenital Swab Culture is the Only Useful Diagnostic Method for the Detection of the Arthritogenic Infection in Extra-Articularly Asymptomatic Patients with Undifferentiated Oligoarthritis, British Journal of Rheumatology, 1995, 34:9, 838-842.

143. Gaston, JSH, Deane, KHO, Jecock, RM, Pearce, JH, Identification of 2 Chlamydia trachomatis Antigens Recognized by Synovial Fluid T Cells from Patients with Chlamydia Induced Reactive Arthritis, Journal of Rheumatology, 1996, 23:1, 130-136.

144. Gerard, HC, Branigan, PJ, Schumacher Jr, HR, Hudson, AP, Synovial Chlamydia trachomatis in Patients with Reactive Arthritis/ Reiter's Syndrome Are Viable But Show Aberrant Gene Expression, Journal of Rheumatology, 1998, 25:4, 734-742.

145. Granfors, K, Do Bacterial Antigens Cause Reactive Arthritis?, Rheumatic Disease Clinics of North America, 1992, 18:1, 37-48.

146. Granfors, K, Merilahti-Palo, R, Luukkainen, R, Möttönen, T, Lahesmaa, R, Probst, P, Märker-Hermann, E, Toivanen, P, Persistence of Yersinia Antigens in Peripheral Blood Cells from Patients with Yersinia Enterocolitica 0:3 Infection with or without Reactive Arthritis, Arthritis & Rheumatism, 1998, 41:5, 855-862.

147. Inman, RD, The Role of Infection in Chronic Arthritis, Journal of Rheumatology, 1992, 19, Supplement 33, 98-104.

148. Layton, MA, Dziedzic, K, Dawes, PT, Letters to the Editor: Sacroiliitis in an HLA B27-negative Patient Following Giardiasis, British Journal of Rheumatology, 1998, 37:5, 581-583.

149. Mäki-Ikola, O, Lehtinen, K, Granfors, K, Similarly Increased Serum IgA1 and IgA2 Subclass Antibody Levels against Klebsiella pneumoniæ Bacteria in Ankylosing Spondylitis Patients With/Without Extra-Articular Features, British Journal of Rheumatology, 1996, 35:2, 125-128. 150. on, RP, Editorial: Persistent Chlamydia trachomatis Infection: In Vitro Phenomenon or in Vivo Trigger of Reactive Arthritis?, Journal of Rheumatology, 1998, 25:4, 610-612.

151. Mousavi-Jazi, M, Boström, L, Lövmark, C, Linde, A, Brytting, M, Sundqvist, V-A, Infrequent Detection of Cytomegalovirus and Epstein-Barr Virus DNA in Synovial Membrane of Patients with Rheumatoid Arthritis, Journal of Rheumatology, 1998, 25:4, 623-628.

152. Nissilä, M, Lahesmaa, R, Leirisalo-Repo, M, Lehtinen, K, Toivanen, P, Granfors, K, Antibodies to Klebsiella pneumoniæ, Escherichia coli, and Proteus mirabilis in Ankylosing Spondylitis: Effect of Sulfasalazine Treatment, Journal of Rheumatology, 1994, 21:11, 2082-2087.

153. Svenungsson, B, Editorial Review: Reactive Arthritis, International Journal of STD & AIDS, 1995, 6:3, 156-160.

154. Tani, Y, Tiwana, H, Hukuda, S, Nishioka, J, Fielder, M, , C, Bansal, S, Ebringer, A, Antibodies to Klebsiella, Proteus, and HLA-B27 Peptides in Japanese Patients with Ankylosing Spondylitis and Rheumatoid Arthritis, Journal of Rheumatology, 1997, 24:1, 109-114.

155. Tiwana, H, Walmsley, RS, , C, Yiannakou, JY, Ciclitira, PJ, Wakefield, AJ, Ebringer, A, Characterization of the Humoral Immune Response to Klebsiella Species in Inflammatory Bowel Disease and Ankylosing Spondylitis, British Journal of Rheumatology, 1998, 37:5, 525-531.

156. Wilkinson, NZ, Kingsley, GH, Sieper, J, Braun, J, Ward, ME, Lack of Correlation Between the Detection of Chlamydia trachomatis DNA in Synovial Fluid from Patients with a Range of Rheumatic Diseases and the Presence of an Antichlamydial Immune Response, Arthritis & Rheumatism, 1998, 41:5, 845-854.

157. Wollenhaupt, J, Kolbus, F, Weißbrodt, H, Schneider, C, Krech, T, Zeidler, H, Manifestations of Chlamydia Induced Arthritis in Patients with Silent Versus Symptomatic Urogenital Chlamydial Infection, Clinical and Experimental Rheumatology, 1995, 13:4, 453-458.

158. Alarcon, GS, Tilley, B, , S, Clegg, DO, Trentham, DE, Pillemer, SR, Neuner, R, Fowler, S, Letter: Another look at minocycline, Bulletin on the Rheumatic Diseases, 1996, 45(8), 6-7.

159. Amin, AR, Attur, MG, Thakker, GD, Patel, PD, Vyas, PR, Patel, RN, Patel, IR, Abramson, SB, A novel mechanism of action of tetracyclines: effects on nitric oxide synthases, Proceedings of the National Academy of Sciences of the United States of America, 1996, 93(24), 14014-14019.

160. Ayuzawa, S, Yano, H, Enomoto, T, Kobayashi, H, Nose, T, The Bi-Digital O-Ring Test used in the successful diagnosis & treatment (with antibiotic, anti-viral agents & oriental herbal medicine) of a patient suffering from pain & weakness of an upper extremity & Barre-Lieou syndrome appearing after whiplash injury: A case report, Acupuncture & Electro-Therapeutics Research, 1997, 22(3-4), 167-174.

161. Bitar, CN, Steele, RW, Use of prophylactic antibiotics in children, Advances in Pediatric Infectious Diseases, 1995, 10, 227-262.

162. Bluhm, GB, Sharp, JT, Tilley, BC, Alarcon, GS, , SM, Pillemer, SR, Clegg, DO, Heyse, SP, Trentham, DE, Neuner, R, Kaplan, DA, Leisen, JC, Buckley, L, Duncan, H, Tuttleman, M, Li, S, Fowler, SE, Radiographic Results from the Minocycline in Rheumatoid Arthritis (MIRA) Trial, Journal of Rheumatology, 1997, 24(7), 1295-1302.

163. Brandt, KD, Modification by oral doxycycline administration of articular cartilage breakdown in osteoarthritis, Journal of Rheumatology, 1995, Supplement 43, 149-151.

164. Breedveld, FC, Editorial: Minocycline in Rheumatoid Arthritis, Arthritis & Rheumatism, 1997, 40(5), 794-796.

165. Breedveld, FC, Letters: Reply to Minocycline- Induced Autoimmune Disease, Arthritis & Rheumatism, 1998, 41(3), 563-564.

166. Bullingham, R, Shah, J, Goldblum, R, Schiff, M, Effects of food and antacid on the pharmacokinetics of single doses of mycophenolate mofetil in rheumatoid arthritis patients, British Journal of Clinical Pharmacology, 1996, 41(6), 513-516.

167. Burton, IE, Moussa, KM, , PA, Agranulocytosis in rheumatoid arthritis associated with long-term flucloxacillin for staphylococcal osteomyelitis, Acta Haematologica, 1995, 94(4), 196-198.

168. Canvin, JM, Madhok, R, Letter: Minocycline in rheumatoid arthritis, ls of Internal Medicine, 1995, 123(5), 392.

169. Caruso, I, Twenty years of experience with intra-articular rifamycin for chronic arthritides, Journal of International Medical Research, 1997, 25(6), 307-317.

170. Currie, BJ, Are the currently recommended doses of benzathine penicillin G adequate for secondary prophylaxis of rheumatic fever?, Pediatrics, 1996, 97(6, Part 2), 989-991.

171. Ebell, MH, Minocycline for rheumatoid arthritis, Journal of Family Practice, 1995, 40(5), 497-498.

172. Elkayam, O, Yaron, M, Zhukovsky, G, Segal, R, Caspi, D, Toxicity profile of dual methotrexate combinations with gold, hydroxychloroquine, sulphasalazine and minocycline in rheumatoid arthritis patients, Rheumatology International, 1997, 17(2), 49-53.

173. Evdoridou, J, Roilides, E, Bibashi, E, Kremenopoulos, G, Multifocal osteoarthritis due to Candida albicans in a neonate: serum level monitoring of liposomal amphotericin B and literature review, Infection, 1997, 25(2), 112-116.

174. Galland, L, Letter: Minocycline and rheumatoid arthritis revisited, ls of Internal Medicine, 1995, 123(5), 392-393.

175. Griffiths, B, Gough, A, Emery, P, Letters: Minocycline- Induced Autoimmune Disease: Comment on the Editorial by Breedveld, Arthritis & Rheumatism, 1998, 41(3), 563.

176. Hanemaaijer, R, Sorsa, T, Konttinen, YT, Ding, Y, Sutinen, M, Visser, H, van Hinsbergh, VW, Helaakoski, T, Kainulainen, T, Ronka, H, Tschesche, H, Salo, T, Matrix metalloproteinase-8 is expressed in rheumatoid synovial fibroblasts and endothelial cells: Regulation by tumor necrosis factor-alpha and doxycycline, Journal of Biological Chemistry, 1997, 272(50), 31504-31509.

177. Herdy, GV, Editorial: The challenge of secondary prophylaxis in rheumatic fever [Portuguese, Original Title: Desafio da profilaxia secundaria na febre reumatica, Arquivos Brasileiros de Cardiologia, 1996, 67(5), 317.

178. Herdy, GV, Souza, DC, Barros, PB, Pinto, CA, Secondary prophylaxis in rheumatic fever: Oral antibiotic therapy versus benzathine penicillin [Portuguese, Original Title: Profilaxia secundaria na febre reumatica: Antibioticoterapia oral versus penicilina benzatina], Arquivos Brasileiros de Cardiologia, 1996, 67(5), 331-333.

179. Herrick, AL, Grennan, DM, Griffen, K, s, L, Gifford, LA, Lack of interaction between flucloxacillin and methotrexate in patients with rheumatoid arthritis, British Journal of Clinical Pharmacology, 1996, 41(3), 223-227.

180. Houck, HE, Kauffman, CL, Casey, DL, Minocycline treatment for leukocytoclastic vasculitis associated with rheumatoid arthritis, Archives of Dermatology, 1997, 133(1), 15-16.

181. Iwata, M, Ida, M, Oda, S, Takeuchi, E, Nakamura, Y, Horiguchi, T, Sato, A, Bronchiolitis obliterans preceding rheumatoid arthritis: effect of clarithromycin [Japanese], Nippon Kyobu Shikkan Gakkai Zasshi ^Ö Japanese Journal of Thoracic Diseases, 1996, 34(11), 1271-1276.

182. Kassem, AS, Zaher, SR, Abou Shleib, H, el-Kholy, AG, Madkour, AA, Kaplan, EL, Rheumatic fever prophylaxis using benzathine penicillin G (BPG): two- week versus four-week regimens: comparison of two brands of BPG, Pediatrics, 1996, 97(6, Part 2), 992-995.

183. Kim, NM, Freeman, CD, Minocycline for rheumatoid arthritis, ls of Pharmacotherapy, 1995, 29(2), 186-187.

184. Kloppenburg, M, Dijkmans, BA, Breedveld, FC, Antimicrobial therapy for rheumatoid arthritis, Baillieres Clinical Rheumatology, 1995, 9(4), 759-769.

185. Kloppenburg, M, Dijkmans, BA, Verweij, CL, Breedveld, FC, Inflammatory and immunological parameters of disease activity in rheumatoid arthritis patients treated with minocycline, Immunopharmacology, 1996, 31(2-3), 163-169.

186. Kloppenburg, M, Mattie, H, Douwes, N, Dijkmans, BA, Breedveld, FC, Minocycline in the treatment of rheumatoid arthritis: relationship of serum concentrations to efficacy, Journal of Rheumatology, 1995, 22(4), 611-616.

187. Kuznetsova, SM, Petrova, NK, Lecture: Antibiotics in the prevention of rheumatic fever [Russian, Original Title: Antibiotiki v profilaktike revmatizma (lektsiia)], Antibiotiki i Khimioterapiia, 1996, 41(2), 43-51.

188. Lai, NS, Lan, JL, Treatment of DMARDs-resistant rheumatoid arthritis with minocycline: a local experience among the Chinese, Rheumatology International, 1998, 17(6), 245-247.

189. Langevitz, P, Livneh, A, Bank, I, Pras, M, Minocycline in rheumatoid arthritis, Israel Journal of Medical Sciences, 1996, 32(5), 327-330.

190. Lauhio, A, Salo, T, Tjaderhane, L, Lahdevirta, J, Golub, LM, Sorsa, T, Letter: Tetracyclines in treatment of rheumatoid arthritis, The Lancet, 1995, 346(8975), 645-646.

191. McKendry, RJ, Is rheumatoid arthritis caused by an infection?, The Lancet, 1995, 345(8961), 1319-1320.

192. Meehan, R, Letter: Minocycline in rheumatoid arthritis, ls of Internal Medicine, 1995, 123(5), 391-392.

193. Nordstrom, D, Lindy, O, Lauhio, A, Sorsa, T, Santavirta, S, Konttinen, YT, Anti-collagenolytic mechanism of action of doxycycline treatment in rheumatoid arthritis, Rheumatology International, 1998, 17(5), 175-180.

194. O'Dell, JR, Haire, CE, Palmer, W, Drymalski, W, Wees, S, Blakely, K, Churchill, M, Eckhoff, PJ, Weaver, A, Doud, D, son, N, Dietz, F, Olson, R, Maloley, P, Klassen, LW, , GF, Treatment of Early Rheumatoid Arthritis with Minocycline or Placebo: Results of a Randomized, Double- Blind, Placebo- Controlled Trial, Arthritis & Rheumatism, 1997, 40(5), 842-848.

195. Panush, RS, Thoburn, R, Should minocycline be used to treat rheumatoid arthritis?, Bulletin on the Rheumatic Diseases, 1996, 45(2), 2-5.

196. Patmas, MA, Letter: Minocycline in rheumatoid arthritis, ls of Internal Medicine, 1995, 123(5), 391-392.

197. us, HE, Editorial: Minocycline treatment of rheumatoid arthritis, ls of Internal Medicine, 1995, 122(2), 147-148.

198. Pillemer, SR, Fowler, SE, Tilley, BC, Alarcon, GS, Heyse, SP, Trentham, DE, Neuner, R, Clegg, DO, Leisen, JC, , SM, Duncan, H, Tuttleman, M, Meaningful improvement criteria sets in a rheumatoid arthritis clinical trial: MIRA Trial Group, Minocycline in Rheumatoid Arthritis, Arthritis & Rheumatism, 1997, 40(3), 419-425.

199. , ME, Greenwald, rheumatoid arthritis, Golub, LM, Potential of tetracyclines to modify cartilage breakdown in osteoarthritis, Current Opinion in Rheumatology, 1996, 8(3), 238-247.

200. Sieper, J, Braun, J, Editorial: Treatment of Reactive Arthritis with Antibiotics, British Journal of Rheumatology, 1998, 37(7), 717-720.

201. , GN Jr, Yu, LP Jr, Brandt, KD, Capello, WN, Oral administration of doxycycline reduces collagenase and gelatinase activities in extracts of human osteoarthritic cartilage, Journal of Rheumatology, 1998, 25(3), 532-535.

202. Tilley, BC, Alarcon, GS, Heyse, SP, Trentham, DE, Neuner, R, Kaplan, DA, Clegg, DO, Leisen, JC, Buckley, L, , SM, Duncan, H, Pillemer, SR, Tuttleman, M, Fowler, SE, Minocycline in rheumatoid arthritis: A 48-week, double-blind, placebo-controlled trial, MIRA Trial Group, ls of Internal Medicine, 1995, 122(2), 81-89.

203. Trentham, DE, Dynesius-Trentham, rheumatoid arthritis, Antibiotic therapy for rheumatoid arthritis: Scientific and anecdotal appraisals, Rheumatic Diseases Clinics of North America, 1995, 21(3), 817-834.

204. , C, Senior, BW, Tiwana, H, Caparros-Wanderley, W, Ebringer, A, Antibiotic sensitivity and proticine typing of Proteus mirabilis strains associated with rheumatoid arthritis, Rheumatology International, 1998, 17(5), 203-205.

205. Yu, LP Jr, Burr, DB, Brandt, KD, O'Connor, BL, Rubinow, A, Albrecht, M, Effects of oral doxycycline administration on histomorphometry and dynamics of subchondral bone in a canine model of osteoarthritis, Journal of Rheumatology, 1996, 23(1), 137-142.

Presented at the 32nd International Congress of the Great Lakes College of Clinical Medicine. Baltimore, land, September 25, 1999

Dr. ph M. Mercola