FAQs

Antibiotic therapy—also known as AP—is an approach to treating rheumatic diseases with low-dose oral antibiotics, usually an antibiotic in the tetracycline class, but occasionally a tetracycline antibiotic in combination with oral antibiotics in other classes (e.g., a macrolide) and/or IV (intravenous) clindamycin. AP is based on the theory, pioneered by Dr. Thomas McPherson Brown, that rheumatic diseases have an infectious origin. This treatment approach is generally focused on slowly reducing the underlying infectious cause(s) in either a pulsed regimen (e.g., Monday, Wednesday and Friday, or M-W-F) or a daily regimen that is tailored to meet the patient’s needs.

It is the widely accepted view in the medical field today that rheumatic diseases are autoimmune (meaning that the immune system begins to attack one’s own tissues for no apparent reason) and also idiopathic (meaning that the disease is of unknown or uncertain origin). The standard treatment is prescription medications designed to control, mask, or suppress symptoms, such as fatigue and inflammatory joint pain. However, these conventional drugs can gradually fail to provide symptom relief over time and may produce a number of side effects, ranging from mild to severe. When a patient must discontinue the drugs, due either to lost effectiveness or to side effects, his/her overall health and physical condition may become considerably worse.

The rationale for using AP is based on the premise that there is an underlying infectious component to rheumatic diseases and the treatment is designed to target the cause(s). Rather than suppressing the immune system, tetracycline antibiotics have helpful immune-modulating properties as well as bacteriostatic actions that disable cell-wall-deficient microbes (bacteria without a cell wall). As the pathogen load is slowly reduced, the immune system gradually re-learns how to respond in a less reactive way to bacterial endotoxins. Endotoxins are the toxic antigenic substances that are bound to the pathogen’s cell wall and released when the cell wall ruptures or disintegrates. It is the protein component of these antigens that alerts the host’s immune system to the foreign nature of the bacteria, causing the production of antibodies, and sometimes fever and other symptoms, in response. Although AP is described as a “slow” therapy, the rheumatic patient can expect to improve with time as the root cause is addressed and symptoms begin to regress.

Rheumatic disease was originally believed to be caused by an infectious process. However, when cortisone, a steroid drug developed in the late 1940s, was found to have such a miraculous and immediate effect in alleviating painful inflammatory symptoms, a new assumption followed—that rheumatic disease was an inherited metabolic disorder. By the time the side effects and dependency created by the over-use of cortisone became evident and its promise of a “cure” was dispelled, a new medical paradigm and approach to treatment had become firmly established. As a result, treatment focus shifted in favor of using existing medications that could be prescribed for off-label purposes to suppress the immune system. Research into infectious causes for rheumatic diseases was thus sidelined as market forces began to drive the creation of novel, specifically targeted drugs to switch off or modulate a condition in which the immune system has gone mysteriously awry.

Medical doctors, including those in the field of rheumatology, adhere to standards of care that are created by various medical societies. These standards rely on evidence-based medicine and the conclusions drawn from large-scale clinical trials of various treatments. Herein lies the rub. There are many inherent difficulties in running clinical trials to test the efficacy of antibiotic treatment for rheumatic diseases. One such difficulty is that there is no profit to be made from studying inexpensive, generic antibiotics that are already approved by the U.S. Food and Drug Administration (FDA) and used for an assortment of off-label purposes. It is also difficult to obtain meaningful results within the usual clinical trial timeframe (e.g., 6 or 12 months), since measureable improvement with AP is not generally seen until at least the six-month mark or later.

In more entrenched and recalcitrant cases, it can take up to thirty months from the beginning of therapy until the patient clearly turns the corner toward improvement, and the achievement of lasting remission can take several years. —The New Arthritis Breakthrough by Henry Scammell, page 269

Placebo-controlled trials would also leave a portion of the patient study group untreated for extended periods of time and this would be unethical and inhumane. Taking into account these practical considerations, there have been some compelling results from modified studies, such as the MIRA (Minocycline in Rheumatoid Arthritis) trial, which have produced positive outcomes by American College of Rheumatology (ACR) standards.

The standard-of-care approach to rheumatic treatment is to follow pre-set guidelines in a stepped process of introducing various medications with specified dose increments in order to attain the desired treatment goals of efficacy (the reduction/remission of symptoms) and tolerability for patients (drug safety with acceptable/no side effects). An initial failure of treatment with one or two older, less expensive “gold standard” DMARDs (disease modifying anti-rheumatic drugs) may be required in order to then receive insurance approval for the newer, more expensive biologic agents. For clinicians who must adhere to pre-defined standards of care, AP presents an inherent challenge, because Dr. Brown’s approach was to tailor the treatment carefully to an individual’s needs. This approach includes taking into account disease type, severity and duration, other treatments being used, gastrointestinal health and varying degrees of sensitivity to the antibiotics being used to treat the infectious cause(s). Most managed-care practitioners do not have the time to titrate AP doses for each patient, taking a whole-body approach to all the variables. For example, the recommended ACR (American College of Rheumatology) minocycline dose for a rheumatoid arthritis (RA) patient is 100mg BID (BID is a medical term meaning twice daily) in a one-size-fits-all approach to dosing regimens in treatment. For a patient with a lot of inflammation, this can result in treatment failure within a short period of weeks or months when it is found that the patient experiences the paradoxical worsening in both symptoms and lab results due to a Jarisch-Herxheimer reaction (also called a “herx,” or “herxing,” and described in FAQ #20). The fact that this reaction is misunderstood by both doctor and patient to be an allergic reaction and/or worsening of disease may explain why many rheumatologists believe minocycline to be a weak, ineffective DMARD.

Although some rheumatologists are unaware of AP treatment or consider it to be ineffective, minocycline (the tetracycline drug most commonly used in AP) is approved by the ACR as a DMARD for rheumatoid arthritis and other rheumatic diseases due to its known immune-modulating effects. This approval should entitle rheumatic patients who reside in the United States to have the option of choosing to pursue AP, and minocycline’s ACR listing should also carry weight in many other western countries.

To learn more: American College of Rheumatology, Patient Fact Sheet for Minocycline (Minocin)

There is currently no cure for rheumatic diseases and treatment with AP is no exception. Patient experience over the course of many decades has, however, demonstrated that the treatment is safe and effective due to the many beneficial properties of tetracycline antibiotics. During Dr. Brown’s long tenure as a rheumatologist and in the decades since his death, the therapy has demonstrated positive effects in treating all forms of rheumatic disease, resulting in significant reversal of symptoms and/or remission. Response will be variable and affected by many factors, such as disease type, severity and duration, age, immune system strength, other treatments used in the past and present, complicating co-infections, hormone balance, other health conditions, gastrointestinal health, and sometimes the need to work with an experienced AP doctor to ensure an appropriately individualized protocol. Some people experience immediate improvement, but, in many cases, early worsening (due to herxing) occurs over a period of days, weeks, or even months before subtle, incremental improvements are noted.

Rheumatoid arthritis, scleroderma, juvenile rheumatoid arthritis (JRA, sometimes referred to as juvenile idiopathic arthritis or JIA), lupus, mixed and undifferentiated connective tissue diseases, the spondyloarthropathies, polymyositis and dermatomyositis, fibromyalgia, Reiter’s and associated syndromes such as Raynaud’s and secondary Sjögren’s have all responded well to AP treatment.

The patient stories that are shared on this site provide confirmation of Dr. Brown’s belief that all rheumatic diseases have an infectious component and would respond to AP.

To learn more: Although the following 2009 American College of Rheumatology Scientific Meeting presentation is currently unavailable in archived online form, hard copies (in full or abstract form) may still be available upon application to the author or Wiley Online Library by citing the following information:

American College of Rheumatology, “Tetracycline Antibiotics for Treating Rheumatoid Arthritis: A Systematic Review and Meta-Analysis” (Citation reference: Adwan, M. H. Q.; Tetracycline Antibiotics for Treating Rheumatoid Arthritis: A Systematic Review and Meta-Analysis [abstract]. Arthritis Rheum 2009;60 Suppl 10 :406 DOI: 10.1002/art.25489)

The following is an excerpted quote found in the original abstract describing the many properties of tetracycline antibiotics:

Background:

Tetracycline antibiotics have been used in Rheumatoid arthritis (RA) since the late 1940s. Animal and in vitro studies have shown them to modify the inflammatory process in various ways unrelated to their antimicrobial activities. These include effects on matrix metalloproteinases, Nitric oxide, phospholipase A2, inflammatory cytokines, immunomodulatory and anti-oxidant effect as well as effects on angiogenesis, apoptosis, MAP kinases, TGF beta and poly (ADP-ribose) polymerase-1.

Note: It is not uncommon for co-infections (additional infections) to be implicated in rheumatic disease and may be due, in part, to diminished immune system function. If other infections are suspected and found to be present through specific tests, these will also need to be addressed with appropriate treatment for an AP regimen to be fully effective.

For any patient wishing to learn about AP, the books by Henry Scammell provide an excellent foundation in understanding the rationale for this approach to treatment and are a good starting point. You will find these books in the Resources section of the site, as well as other useful books.

The Antibiotic Approach to Rheumatoid Arthritis is a video documentary created by Dr. Brown as a training tool for doctors, presenting the rationale for using AP to treat rheumatoid arthritis.

Click here to watch Dr. Brown’s video documentary, The Antibiotic Approach to Rheumatoid Arthritis. (Note: please allow time for video to buffer before playing)

Press Release: Harris Poll Results – Survey Reveals Common, Low Cost Antibiotic Therapy May Have Considerable Benefits for Rheumatoid Arthritis (RA). Survey shows substantial improvements in disease, reduction in pain, severity of condition and better quality of life as reported by rheumatoid arthritis and scleroderma patients. Key findings include the impact of antibiotic therapy versus traditional medication for RA in the overall management of the disease, as well as its effects on pain, quality of life and tolerability.

To review the entire survey, click here and file will download in PowerPoint (ppt) format. To read the Harris Poll press release, click here.

We suggest that you use FAQs 1-19 as a basis on which to talk with your Doctor as well as the information contained in the Protocols that you can find here.

Unless a person suffers from a genuine allergy to the tetracycline class of antibiotics, most doctors consider AP to be fairly benign when managed carefully. Side effects from low-dose tetracycline antibiotics are minimal when compared to the more powerful, palliative DMARDs, such as methotrexate, gold, hydroxychloroquinine (Plaquenil), penicillamine, prednisone, or the newer biologic drugs that are injected or infused. Side effects from tetracyclines may be averted with appropriate precautions. For example:

• Yeast infections may be averted with daily use of a good-quality probiotic and adherence to a sugar-free diet.
• Diarrhea is rarely experienced when tetracyclines are taken in low, pulsed doses, but should it occur, it is treatable with adequate probiotic intake.
• A heightened sensitivity to sunlight can be minimized with the use of a high-SPF sunscreen and by wearing clothing to cover exposed skin.
• In children whose permanent teeth have not erupted, tetracyclines can cause staining of the teeth. This may be averted by using a different class of antibiotic, such as a macrolide.
• Nausea, which can be a side effect of tetracyclines for some people, may be averted by taking the dose with a light snack or meal that does not contain any minerals that would bind to tetracyclines in the gut and diminish its bio-availability. Tetracycline has an absorption rate of 50% when taken with food. Minocycline’s absorption rate is 85% when taken with food, making it a better choice if food must be taken with the antibiotic to avoid nausea.
• Any woman who is planning to have a baby or is pregnant must avoid any antibiotic in the tetracycline class. Taking these antibiotics can cause harm to the fetus, including permanent discoloration of the teeth later in life. Antibiotics in this class will also reduce the effectiveness of birth control pills and alternative methods of birth control must be used to avoid unplanned pregnancy.
• Breast-feeding mothers must not take any tetracycline antibiotic as the drug passes into breast milk and can affect the bone and tooth development of a nursing baby.
• If the capsule of any antibiotic in the tetracycline class is not properly swallowed and becomes lodged in the esophagus, or if a person suffers from gastroesophageal reflux disease (GERD), serious irritation and painful ulceration of the esophagus can occur. This can be avoided by swallowing the capsule with a full glass of water, waiting an hour or two before lying down, and taking steps to control acid reflux.

Patients should be aware that most drugs, including antibiotics, may produce side effects (See FAQ# 7). Although the tetracyclines are considered quite safe and very benign relative to other more commonly prescribed NSAIDs (non-steroidal anti-inflammatory drugs), DMARDs and the newer biologic drugs, there may be early, transitory side effects, such as vestibular symptoms, including dizziness or nausea. As the body adjusts to the medication, these side effects commonly fade over time. However, patients should also be aware of the potential for other side effects, such as skin hyperpigmentation and eye sensitivity to sunlight.

Although rare, more serious events can also occur, such as antibiotic allergy, drug hypersensitivity reactions (e.g., pneumonitis), and minocycline-induced lupus or hepatitis. It is recommended that all patients choosing antibiotic therapy become familiar with potential side effects of any antibiotic being taken and these should also be discussed with the prescribing physician in order to be carefully monitored. While most U.S. pharmacies provide the patient with drug fact sheets when the prescription is filled, more detailed accounts of potential side effects and drug interactions can be researched at the following websites:

To Learn More:

• Drugs.com
• Physician’s Desk Reference (PDR)
• MedicineNet

Note: Pharmaceutical brand names may vary by country. Due to these variations, patients living outside the United States may need to find reliable drug information websites based on location.

Tetracycline antibiotics were first discovered as a natural product found in soil, in 1945, by American plant physiologist Benjamin Duggar. Three years later, the first tetracycline, called Aureomycin, was prescribed. Tetracyclines belong to a class of antibiotics that are bacteriostatic in action and have been used safely since this time, demonstrating a wide spectrum of activity against numerous pathogens and having additional immune-modulating effects. Today, they are commonly prescribed by dermatologists for extended periods of time to treat teenage acne. Tetracyclines are considered to be less subject to the promotion of disease-resistant strains of bacteria in terms of their mode of action and the types of bacteria they target. This has been evidenced by their continued efficacy over the past 70 years.

The prolonged use of most antibiotics can indeed give eventual rise to an immune strain of germ. Immunity is developed in a germ’s outer surface, which is the area affected by penicillin and other antibiotics. Tetracycline is different from all other antibiotics in that critical respect: it affects the core of the germ, not the outer surface, and therefore no immune strain of germs ever develops as a result of its use. Moreover, people who use tetracycline over a period of months or years tend to avoid colds, pneumonia, and other diseases. —The New Arthritis Breakthrough, by Henry Scammell, page 260

A May 2011JAMA and Archives Journals article documented a study that confirms Dr. Brown’s statement (above), finding no association between the long-term use of tetracycline antibiotics and bacterial resistance, and also found that their use lowered the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) infection.

To Learn More:

• Science Daily, Featured Research, “Long-term use of antibiotic to treat acne not associated with increased bacterial resistance, study finds“

Minocycline is a second-generation tetracycline, originally synthesized by Lederle Laboratories in 1967, approved by the FDA in 1971, became available for use and has been sold under the brand name, Minocin, in a pelleted capsule, since 1972. Minocin was last distributed through Onset Dermatologics, but its parent company, PreCision Dermatology Inc., was purchased by Valeant Pharmaceutical International, Inc.  in February 2014. Brand-name Minocin is costly, but a number of effective generic minocycline versions are available today. Although Dr. Brown used both tetracycline and doxycycline, minocycline later became the favored choice as a bacteriostatic antibiotic due to its greater lipid solubility (ability to cross cell walls) and hence superior absorption. Simply put, in many cases, it seems to work faster. Unlike bacteriocidal antibiotics, which target cell-walled pathogens, bacteriostatic antibiotics are intended for use against intracellular pathogens (those that parasitize host cells) and cell-wall-deficient bacteria (such as mycoplasma, that do not have a cell wall but rather just an outer lipid layer).

Minocycline’s spectrum of activity is broader than that of other tetracyclines within the same class; it has a longer half-life and is classified as long-acting. Serum levels may reach two to four times those of more water-soluble tetracyclines and so less is needed to achieve the same result. Absorption of minocycline is also less likely to be affected by food.

Tetracycline and doxycycline have also proven to be effective for the treatment of rheumatic disease. Doxycycline achieves much higher tissue concentrations than tetracycline, while minocycline penetrates tissue far more effectively than doxycycline. Tetracycline is the least expensive and oldest member of this family of antibiotics. It is more apt to react with foods and should be taken on an empty stomach with a full glass of water, three hours before or after consumption of food (especially foods high in mineral content, such as dairy products). Supplements and medications containing minerals, such as magnesium, calcium, zinc and iron, should also be avoided within this time frame. Doxycycline (the second drug to be developed in this family) is sold in the United States under the brand names Doryx and Vibramycin (brand names vary internationally) and is often given to patients who do not tolerate minocycline well and sometimes to those with lupus.

Dr. Brown found that when the tetracyclines cannot be used due to drug allergy, other classes of antibiotics could also be effective, including those with similar bacteriostatic properties, such as azithromycin or clarithromycin. Clindamycin may also be used and is most often administered intravenously as an adjunct to tetracycline therapy. When a patient has a high ASO (Antistreptolysin O titer) or has a strong history of streptococcal infection, even when the ASO test result is within range, penicillins such as amoxicillin or ampicillin may also be needed. While tetracycline therapy was most commonly used as the core therapy of AP, Dr. Brown used a variety of different classes of antibiotics, depending upon a patient’s pathogen load and individual needs.

To Learn More:

• Drugs.com, search tool (enter the name of the antibiotic in the search window on the home page)
• Drugs.com, Drug Interaction Checker (lets you check for interactions with other drugs you are taking)
• Wikipedia, Minocycline (provides further information on the properties, spectrum of activity, side effects, and potential drug and supplement interactions of minocycline)

Note: For more detailed information on alternative antibiotics that Dr. Brown used when patients experienced allergy or some other type of sensitivity to the tetracyclines, refer to The New Arthritis Breakthrough, by Henry Scammell (pages 250 to 251).

Minocycline is a second-generation tetracycline, originally synthesized by Lederle Laboratories in 1967, approved by the FDA in 1971, became available for use and has been sold under the brand name, Minocin, in a pelleted capsule, since 1972. Minocin was last distributed through Onset Dermatologics, but its parent company, PreCision Dermatology Inc., was purchased by Valeant Pharmaceutical International, Inc.  in February 2014. Brand-name Minocin is costly, but a number of effective generic minocycline versions are available today. Although Dr. Brown used both tetracycline and doxycycline, minocycline later became the favored choice as a bacteriostatic antibiotic due to its greater lipid solubility (ability to cross cell walls) and hence superior absorption. Simply put, in many cases, it seems to work faster. Unlike bacteriocidal antibiotics, which target cell-walled pathogens, bacteriostatic antibiotics are intended for use against intracellular pathogens (those that parasitize host cells) and cell-wall-deficient bacteria (such as mycoplasma, that do not have a cell wall but rather just an outer lipid layer).

Minocycline’s spectrum of activity is broader than that of other tetracyclines within the same class; it has a longer half-life and is classified as long-acting. Serum levels may reach two to four times those of more water-soluble tetracyclines and so less is needed to achieve the same result. Absorption of minocycline is also less likely to be affected by food.

Tetracycline and doxycycline have also proven to be effective for the treatment of rheumatic disease. Doxycycline achieves much higher tissue concentrations than tetracycline, while minocycline penetrates tissue far more effectively than doxycycline. Tetracycline is the least expensive and oldest member of this family of antibiotics. It is more apt to react with foods and should be taken on an empty stomach with a full glass of water, three hours before or after consumption of food (especially foods high in mineral content, such as dairy products). Supplements and medications containing minerals, such as magnesium, calcium, zinc and iron, should also be avoided within this time frame. Doxycycline (the second drug to be developed in this family) is sold in the United States under the brand names Doryx and Vibramycin (brand names vary internationally) and is often given to patients who do not tolerate minocycline well and sometimes to those with lupus.

Dr. Brown found that when the tetracyclines cannot be used due to drug allergy, other classes of antibiotics could also be effective, including those with similar bacteriostatic properties, such as azithromycin or clarithromycin. Clindamycin may also be used and is most often administered intravenously as an adjunct to tetracycline therapy. When a patient has a high ASO (Antistreptolysin O titer) or has a strong history of streptococcal infection, even when the ASO test result is within range, penicillins such as amoxicillin or ampicillin may also be needed. While tetracycline therapy was most commonly used as the core therapy of AP, Dr. Brown used a variety of different classes of antibiotics, depending upon a patient’s pathogen load and individual needs.

To Learn More:

• Drugs.com, search tool (enter the name of the antibiotic in the search window on the home page)
• Drugs.com, Drug Interaction Checker (lets you check for interactions with other drugs you are taking)
• Wikipedia, Minocycline (provides further information on the properties, spectrum of activity, side effects, and potential drug and supplement interactions of minocycline)

Note: For more detailed information on alternative antibiotics that Dr. Brown used when patients experienced allergy or some other type of sensitivity to the tetracyclines, refer to The New Arthritis Breakthrough, by Henry Scammell (pages 250 to 251).

After reading the educational materials on the Road Back Foundation website and the recommended books by Henry Scammell, which provide a foundation for understanding the rationale for using AP for treating rheumatic diseases, you will be equipped to consult with your family doctor or rheumatologist about the therapy. The benefits of doing this are discussed in The New Arthritis Breakthrough, by Henry Scammell, Chapter 28, “Rheumatoid Arthritis and Your Family Doctor,” pp 246-252.

RBF volunteers maintain AP provider lists by U.S. state, and for other countries. If you wish to pursue this treatment option and need an experienced AP doctor (travel may be necessary), or if you wish to locate a provider in your locale/state/country, you can request a listing here.

Choosing, or continuing to see, a rheumatologist is a personal decision for every patient that involves various considerations unique to each individual. These might include such factors as the degree of doctor-patient collaboration experienced and whether or not close oversight is needed for disease and treatment monitoring. Another consideration is whether or not a patient has already been using conventional medications to control disease symptoms and inflammation when starting AP or whether additional palliative medications, generally prescribed by a rheumatologist, are needed by the newly diagnosed patient. On occasion, a patient may find the rheumatologist unsupportive when the desire is expressed to try AP and the initiative must be taken to seek out a new doctor. In other cases, a rheumatologist may refuse to continue participating in the patient’s care after the treatment has been started with another doctor.

Patient experience in this matter has been widely variable and the decision or preference to either remain with one’s rheumatologist or not is usually easier to make when the patient has been on AP for some time and has begun noticing improvements in his/her condition.

The reasons for the reluctance of some doctors to allow their patients to try AP are discussed in The New Arthritis Breakthrough, by Henry Scammell, Chapter 26, pages 235-239.

When treating an acute infection, constant exposure to antibiotics to maintain optimal serum levels is required to reduce virulent pathogenic bacteria. However, in the case of mycoplasma, as with some other chronic infections (e.g., tuberculosis, brucellosis or rheumatic fever), only small amounts of medication are needed to control the infection. Dr. Brown’s contention was that although there were probably multiple infectious players in rheumatic diseases, various strains of mycoplasma that are pathogenic to humans are prime causative agents. He also stated that rheumatic tissues tend to be highly reactive to the antigenic substances released by these pathogens as they die. In his clinical experience, antibiotic dosing that was too high and led to excessive bacterial die-off in the rheumatic patient would defeat treatment goals by unnecessarily increasing the body’s natural inflammatory response to these antigenic substances.

Excessive inflammation, leading to a hypersensitive state that Dr. Brown called “bacterial allergy,” blocks treatment effectiveness, requiring patients to undertake a washout period from the medication for a few days to a week or more. Therefore, he started the therapy in low, pulsed, intermittent doses of 50mg or 100mg minocycline or doxycycline once a day, or 250mg tetracycline twice a day on M-W-F, and found that this was the most effective dosing schedule. In cases where rheumatic patients suffered with pre-existing, relatively high levels of inflammation, they also sometimes experienced extreme hypersensitivity; these patients would need to start with even lower doses of 50mg (or less) just once or twice a week. Treating patients in a carefully titrated, intermittent manner allowed inflamed, hypersensitive rheumatic tissues a chance to recover slowly, over time, without needlessly increasing the effects of a massive and disabling die-off reaction. (See FAQs #20-21 for more information on herxing, hypersensitivity and management of these)

Minocycline has been shown to have greater tissue penetration and is able to cross the blood-brain barrier more effectively than earlier tetracyclines. This may cause some patients to experience early, transitory vestibular side effects, including dizziness and nausea. These effects can be greatly reduced or avoided by starting in a “low and slow,” intermittent manner.

Note: In the case of scleroderma patients, if inflammation does not present a complicating factor, more aggressive, higher daily dosing of 100mg minocycline, given twice daily, is preferable.

In long-standing and/or severe disease, Dr. Brown would recommend preceding oral antibiotic therapy with a course of IV clindamycin, administered over the course of five days. The intended purpose of using clindamycin intravenously was to help eradicate long-standing microorganisms in the gut, respiratory tract and other areas of the body. Dr. Brown found the initial IV treatment to provide greater receptivity for the initiation of oral tetracycline therapy to follow. He would then continue IV therapy on a weekly, biweekly or monthly basis (one day only), or as a five-day series every six months, until disease markers and symptoms had returned to normal, after which oral clindamycin was used in a once-weekly, single dose pulse of 1200mg (or 600mg BID). Today, experienced AP doctors have adapted Dr. Brown’s protocols further and individual approaches may vary slightly.

Patients with early, less severe disease often do well on oral therapy alone. In many cases, they respond more swiftly than patients with long-standing rheumatic disease who may have additional health issues as a result of prior treatment with conventional drugs. For optimal results, the AP is best tailored to the individual patient’s needs.

When the Minocycline in Rheumatoid Arthritis (MIRA) trials were run in the early 1990s, the dosing schedule used (100mg minocycline, administered twice daily) became known as the “Harvard Protocol.” It was dubbed this because one of the lead authors, Dr. David Trentham, was based at Beth Israel Deaconess Medical Center, a Harvard Medical School teaching hospital.

Dr. Brown mostly used low-dose, pulsed, intermittent antibiotic therapy and his protocols are still valid and used as models for treatment today by experienced AP doctors. Sometimes the intermittent pulsing method would be used with just one class of antibiotic, such as the tetracyclines, on just three days a week (e.g., M-W-F). On these days, minocycline or doxycycline would be administered once daily (e.g., 50mg or 100mg) and tetracycline would be pulsed twice daily (e.g., 250mg BID). At times, other complementary antibiotics (to increase the spectrum of activity) would be added on an alternate day, although Dr. Brown also used IV clindamycin in a five-day series at various intervals on a case-by-case basis. Pulsed dosing was recommended as a means of allowing the patient’s inflamed tissues time to recover between doses in order to limit the effects of a herx reaction and to prevent excessive oxidative tissue damage.

To Learn More:

• “Minocycline in Rheumatoid Arthritis: a 48 week, Double Blind, Placebo-Controlled Trial”
• Review of Daily Antibiotic Protocol (‘Harvard Protocol’)
• Pulsed Antibiotic Protocol and Rationale

If the rheumatic disease patient has severe, long-standing disease, the optimal approach is to precede oral therapy with a five-day course of IV clindamycin, if possible. As described in FAQ #14, this can provide a boost to oral therapy by helping to clear organisms that may have taken up residence in the gut, respiratory tract and/or other parts of the body and provide for greater receptivity of oral therapy to follow. Patients with milder disease or shorter duration may also wish to try IV clindamycin when starting therapy to potentially speed recovery. Not all patients have easy access to physicians offering IV therapy, and this should not preclude beginning with oral therapy and seeking treatment with IV clindamycin later, if needed, or substituting IV clindamycin for its oral form (see FAQ #38 to understand the importance of probiotic supplementation).

Lupus erythematosus is a distinct rheumatic disease, and Dr. Brown found that the various forms of lupus may be treated with low-dose AP (including minocycline or doxycycline) with varying degrees of success. Distinction should be made, however, between the disease lupus (and its variants) and drug-induced lupus erythematosus (DILE), which manifests similarly in terms of symptoms, but is a different condition. DILE is not genuine lupus and may be caused by many different types of medications in individuals with certain genetic dispositions (see FDA article below). In addition to genetics, other factors may predispose some people to the development of DILE, including the elderly and in those who may be “poor acetylators” (unable to metabolize certain drugs in the intended way). This is a condition that may occur with chronic use of a drug that is known to cause it and is reversible upon discontinuation of the offending drug (see listing of drugs that may cause DILE below).

DILE may occur more commonly with some medications than others and, in rare instances, can occur with minocycline and others in the tetracycline class of antibiotics. It is important to note, however, that if a patient is prone to the development of DILE, then s/he is at risk from some of the other DMARDs and newer biologic drugs that have also been identified as causing this condition in varying degrees. These include sulphasalazine, penicillimine, hydroxychloroquinine, gold salts and the newer biologics drugs, called anti-tumor necrosis factor agents. (Drugs in this last category have warnings to this effect in their accompanying literature, in addition to a warning of possible drug-induced multiple sclerosis symptoms). Therefore, when a doctor warns a patient about the risk of DILE from the use of minocycline, it is appropriate that the patient should also be informed of the same risk from other commonly used rheumatic drugs. This is because a predisposition to one DILE-causing drug may also apply to other drugs. Patients should also be advised that monitoring for the development of DILE with blood tests (ANA, anti-single stranded DNA and, in some cases, anti-histone antibodies) can be done at intervals and, if clinical evidence in symptoms and/or lab results arises to suggest DILE, then the condition normally resolves within weeks of the offending medication being withdrawn. Abnormalities in lab results may take longer to normalize.

To put the risk of DILE caused by minocycline into broader perspective, according to the American College of Osteopathic Dermatology the risk of facial scarring from acne from this commonly used acne drug for teens and adults is considered to be a greater risk than that of DILE:

There are a few significant, but very rare side effects that develop in about 1 in 10:000 people. One is hypersensitivity lupus/hepatitis, which causes severe joint pains. The other is pseudotumorcerebri (an accumulation of fluid around the brain) that causes progressively worsening headaches and vision problems. Stop the medication if these occur. They resolve over time, but very slowly. These also occur with some other antibiotics. A form of lupus seems unique to minocycline. It appears after taking the pill for an average of 3 years. Remember that facial scarring and long lasting psychological harm are very real “side effects” of acne and are much more common than 1 in 10,000.

To learn more about DILE—what it is, what drugs cause it and how to get tested for it—please consult the following resources:

• Pharmaceutical Online, “FDA-led research team discovers an autoimmune mechanism for serious drug-induced adverse reactions”
• The Hospitalist (June 2008), “Stop Drug-Induced Lupus”
• Medscape, Drugs and Diseases, “Drug-Induced Lupus Erythematosus”
• DermNet NZ, “Drug-Induced Lupus Erythematosus”
• The Lupus Foundation of America, Get Answers / Understanding Lupus

Most patients who begin AP wish to eventually stop taking their immunosuppressive medications as one goal of the therapy. However, it is not necessary to stop using prescribed NSAIDs, DMARDs, or the biologic drugs when beginning AP, and this may actually be detrimental to the treatment’s success. Patients who abruptly stop any immunosuppressive medications in order to begin AP often report suffering from intolerable drug rebound in the weeks and months following. In some instances, symptoms that were previously masked by the withdrawn medications are more severe than first experienced and the discomfort may last for weeks or longer. This can lead to early AP treatment failure, because this is the period during which the patient also typically experiences a Jarisch-Herxheimer flare (herx). Patient experience has demonstrated that a successful outcome is more likely to be achieved when AP has been taken for several months and disease symptoms are stable enough to gradually taper from the other drugs, one at a time.

It is relevant to note that in the context of using tetracyclines alongside immunosuppressive medications that the antimicrobial effects of the antibiotic are diminished. Tetracyclines are classed as “bacteriostatic” drugs that target cell-wall-deficient microbes (bacteria without a cell wall) and slowly limit the growth of bacterial colonies. They do this by interfering with the microbes’ ability to synthesize proteins, by preventing replication of their DNA, and by impeding their metabolism. As tetracyclines do not kill bacteria outright, a fully functioning immune system is needed in order to dispose of disabled bacteria from the body. Therefore, although immune-suppressed AP patients can still enjoy the immune-modulating effects of the tetracyclines, they may not receive full antibacterial benefit until they begin to slowly wean themselves away from their other drugs and stop taking them altogether. Gradual cessation of any immune-suppressive medication should be done under a doctor’s close supervision to avoid excessive drug rebound and to be able to manage any breakthrough herxing effectively. Too much of either will defeat the object of using AP by creating an inflammatory barrier that will prevent penetration of the antibiotic to the affected tissues and the targeted microbes.

Patient experience has shown over time that those who start AP soon after diagnosis, without the use of other rheumatologic drugs, seem to respond more swiftly to the treatment than those who have more entrenched, longstanding disease and who must deal with gradually decreasing immunosuppressive medications. This withdrawal can be done successfully, but it can take much time and patience, and it helps to have a supportive physician to oversee the process.

For those concerned about the safety of using standard rheumatologic drugs alongside AP, scientific studies have demonstrated that methotrexate and doxycycline, taken in combination, are safe and efficacious for rheumatoid arthritis (see O’Dell study below). Various other conventional treatments can also be combined safely with the tetracyclines, as confirmed by rheumatologist, Dr. David Trentham, one of the lead researchers of the Minocycline in Rheumatoid Arthritis (MIRA) and Minocycline in Early Diffuse Scleroderma trials, provided that the patient has no contraindications for use (see Dr. Trentham’s article below).

To Learn More:

• Article by J.R. O’Dell and co-authors, “Treatment of early seropositive rheumatoid arthritis: doxycycline plus methotrexate versus methotrexate alone.”
• Article by David E. Trentham, M.D., “Antibiotic Therapy for Rheumatic Disease. You know where we have been; so where are we now?”
• Wikipedia article, “Bacteriostatic Agents”

Depending upon the rheumatic disease in question, all relevant disease markers should be evaluated at regular intervals to monitor progress while on AP. Further, a complete blood count, metabolic panel and liver and pancreatic enzyme tests should be run at the same time. Some doctors prefer to run all laboratory tests at various intervals (monthly, quarterly, half-yearly or annually). If testing is not requisitioned regularly, the patient may request more frequent monitoring (e.g., by requesting a standing order for lab tests on a monthly or bi-monthly basis) as this can sometimes provide further information on treatment progress.

It is not uncommon for lab markers to worsen during the early months of treatment, after which some improvement in these should be seen. Occasionally, improvements in symptoms are experienced before lab markers improve or vice versa.

During Dr. Brown’s tenure as a practicing rheumatologist, he would run baseline infection panels (e.g., mycoplasmas, Chlamydiae and streptococcal titers). These would be re-run at intervals to ensure that titers were decreasing as an indication that the patient was responding to treatment. When previously abnormal microbial titers and disease markers were found to be within expected reference ranges and all symptoms had regressed and stabilized, the patient was considered to be in remission. Today, due to the high cost of running laboratory testing, it may be impractical to re-test at frequent intervals. It does not require positive microbial lab findings in order to begin AP, though some patients and physicians prefer to see some evidence of infection prior to commencing therapy. Elevated microbial titers can also be helpful when the patient’s treatment plan involves IV clindamycin therapy, as they provide evidence to support infection for the purpose of applying to obtain an insurer’s approval to cover costs.

To learn more about commonly used lab markers:

• American Association for Clinical Chemistry, “Lab Tests Online“

Shortly after commencing AP, patients may experience a Jarisch-Herxheimer reaction, commonly referred to as a “herx.” This is the name given to the paradoxical worsening of disease symptoms, caused by increased levels of circulating endotoxins released by dying pathogens. This phenomenon was first described by dermatologists, Adolf Jarisch and Karl Herxheimer, when treating syphilis patients with mercury, Salvarsan, and antibiotics. A herx often presents with flu-like symptoms and can include fever, headache, chills, joint and muscle pain, exacerbation of skin rashes, skin flushing, increased heart rate, hyperventilation and low blood pressure. The herx response may begin within hours of starting AP or days/weeks later. The degree of intensity seems to correlate with pre-existing levels of inflammation, pathogen load, the body’s ability to eliminate (detoxify) the antigenic substances produced by dying microbes and antibiotic dosing levels. A herx may be transitory, lasting only hours or days or, in some instances, may continue for a longer period of time in waxing and waning cycles of weeks or even months. Although this reaction is certainly uncomfortable, it is a good sign that the antibiotic is reaching its intended target. Patient experience has demonstrated that there are various detoxification strategies that can help to relieve these symptoms (see FAQ #21) by flushing bacterial endotoxins more swiftly from the body.

To Learn More:

• Wikipedia article, “Jarisch-Herxheimer reaction”

First, it is reasonable to consider that the AP dose that is being taken is too high. The aim of AP is to kill pathogens while also keeping herxing at a bearable level. Excessive herxing may lead to a state of hypersensitivity (see FAQ #22) in which high levels of circulating endotoxins from bacterial die-off can result in increased swelling and intolerable levels of inflammation. This reaction is counterproductive and will block the antibiotic from reaching its intended target. In such instances, Dr. Brown would advise the patient to withdraw the medication for a brief “washout” period in order to allow the body time to recover and then to re-commence treatment, after several days to a week, at the same or a lower dose. As individual response to commencing AP can be unpredictable, it is critical to be aware that intolerable herxing can be circumvented largely by starting the therapy in a “low and slow” manner.

When pain and other discomfort arise from increased inflammation due to herxing, there are a number of detoxification strategies that can be used at home and with the help of a physician to counter these effects. Inflammation is the result of toxins (antigenic substances) released from dying pathogens, so the goal is to assist with the removal of these substances from the body as swiftly as possible. Inflammation causes oxidative free-radical damage to body tissues and this makes detoxification with anti-oxidative strategies a viable, helpful method for neutralizing and flushing these substances. Detoxification methods may include antioxidative supplements (see FAQ #40), using a far-infrared (FIR) sauna to sweat out toxins and/or taking warm epsoms/peroxide baths. Doctors skilled in integrative, alternative, naturopathic, holistic and functional medicine are usually very knowledgeable and can provide helpful advice to individualize appropriate detoxification strategies.

Delayed infectious hypersensitivity is the result of excessive amounts of antigens (endotoxins) released by dying pathogens, usually as a result of the AP dose being too high and causing excessive herxing. Sensitized RA tissues are highly reactive to any antigen and the result is similar to an allergic response, which is why Dr. Brown called this reaction a “bacterial allergy.” When extreme tissue reactivity occurs, the offending organisms hide from the host’s immune defenses, using cloaking mechanisms, and the body begins to react against the medication itself.

Delayed infectious hypersensitivity is described by Dr. Brown in a presentation he gave in the late 1970s, entitled, “Guidelines for Infectious Hypersensitivity: Approach to the Treatment of Rheumatoid Arthritis.” The following excerpt provides a description of the common clinical signs of this reaction in relation to RA (signs of which may also occur in other rheumatic conditions with an inflammatory component).

The signs of delayed sensitivity are those of slight loss of appetite, excessive fatigue (fatigue is a common feature of rheumatoid arthritis, and must be differentiated from excessive fatigue), increased pain in the areas where pain was being gradually reduced, and at times increased fluid retention, often expressed as puffiness of the feet and legs.

Dr. Brown’s recommendations for treatment of delayed infectious hypersensitivity were as follows:

When these signs of sensitivity are noted, the medication is interrupted and then resumed, usually at the same level that it was given before or else at a reduced frequency and amount. The tetracycline dosage* is generally given as 250 mg. every other night or possibly 500 mg. every other night. If the medication tends to aggravate the condition, it is spaced differently, maybe to once a week or twice a week and gradually worked up to the alternate night basis. Some patients are so highly sensitized to drugs that they can only tolerate one 250 mg. tetracycline tablet every two weeks or even once a month, but with continued titration of the dosage it is possible to work up to the dosage of alternate nights without flaring the disease.

*Tetracycline dosage (250 mg) described above is equivalent to 100 mg minocycline or doxycycline in this context.

To Learn More:
Transcript of a presentation given by Dr. Thomas McPherson Brown: “Guidelines for Infectious Hypersensitivity Approach to the Treatment of Rheumatoid Arthritis”

Patient experience has demonstrated that it can be challenging to distinguish between symptoms of herxing and flaring, because usually a herx will present as a worsening of existing symptoms and possibly some new ones. This can be particularly unnerving for the patient in the early stages of AP, who will inevitably wonder if the treatment isn’t working and the disease is progressing, or, on the other hand, if the treatment is indeed having an effect and what is being experienced is a herx. In rheumatic disease, a flare and a herx are both the result of inflammation creating tissue hypersensitivity due to the release of bacterial endotoxins. In the case of a herx, however, this could be viewed as a “controlled” flare, a temporary exacerbation of the “bacterial allergy,” as described by Dr. Brown. This reaction is caused by toxins released by dying pathogens and, although unpleasant, a good sign that the treatment is reaching the intended microbial target(s). Additionally, the AP patient should notice improvements after a herx has passed. A flare, in contrast, arises as a result of the natural life cycle of the offending organisms and heralds a worsening of the disease.

It is helpful to ask one’s doctor for copies of all lab results and to keep these in a file at home, so that trends in improvement, flaring or stalling out can be observed and discussed with the treating doctor. It is important to note that AP is not immunosuppressive and so flares may continue to occur during treatment and until remission is reached. Flares should, however, be diminishing in intensity, shorter in duration and less frequent as treatment proceeds. When plateaus in improvement occur, it may be time to re-assess one’s protocol and to look for anything that may be blocking progress (e.g. ensuring a therapeutic dose, a change in generic brands, untreated infections, poor diet or potential food offenders, hormone imbalances, poor detoxification, increased emotional stress, etc.). See FAQ #37 for additional information about diet.

Mayo Clinic, Diseases and Conditions / Drug Allergy

Rheumatic tissues tend to be hypersensitive already and a herx can sometimes present with symptoms similar to allergy as a result of what Dr. Brown termed “bacterial allergy.” Discerning whether one is truly allergic to a tetracycline antibiotic (or one in a different class of antibiotics) can be difficult. The only way to know for sure if an allergic reaction (not life-threatening anaphylaxis that would require emergency medical intervention) is being experienced is to discuss symptoms with the prescribing physician. It can be disappointing if an allergy is suspected and treatment with a particular antibiotic needs to be stopped and thus it can be very worthwhile to see an allergist/immunologist who can schedule an in-office re-challenge of the drug, perform skin testing (depending on the class of antibiotic being used), and/or have certain blood tests run (usually IgA, IgE and/or IgG). For example, if an allergic reaction has occurred with a tetracycline, there may be an increase (by about 30%) in eosinophils, a type of white blood cell that helps to control the mechanisms of allergy. It is very important to determine whether a patient has a true allergy to any drug, as this will preclude its future use. In the case of tetracyclines, if allergy is confirmed, this usually prevents the patient from using any antibiotic within the same family of antibiotics. However, in such cases, Dr. Brown did use other classes of antibiotics that had similar bacteriostatic actions.

Patient experience has demonstrated that flares typically will continue to occur while the patient is on AP. This may not be as evident for patients who are already using some form of immunosuppressive medication to control inflammation, such as DMARDs, biologic drugs or NSAIDs. This is because—unlike antibiotics, which do not suppress the immune system and will not mask symptoms—these other drugs are intended to do so. However, as time goes on and disease symptoms improve, a trend should begin to emerge whereby flares become less intense, less frequent and shorter in duration until remission is reached. Rheumatic patients report that flares occur with seasonal changes, switching to an ineffective generic antibiotic brand, when eating poorly and sometimes during periods of prolonged or acute stress, such as after a surgery, an accident, an emotional/psychological trauma or an acute infection. Renewed rounds of herxing may also occur if there have been any changes in the AP treatment—for example, adding a different antibiotic or changing the dosing schedule. During a herx or a flare, inflammation control is an important component of the treatment and helps to promote its effectiveness.

Early, objective signs of improvement are widely variable across the AP patient population and are not usually experienced in the first several months of treatment or until herxing has died down. After this period, incremental improvements usually begin to occur. At first, these improvements may be barely noticeable, lasting only for an hour or two per day. Fatigue and depression may be the first thing to decrease and morning stiffness may start to subside. Patients may then begin to have one or two “good days” and, over time, these should increase, with longer periods of feeling better between the “not so good” days. Patients have described this journey as being a bit like a dance—that is, taking a step or two forward and then one back. The goal of AP is to gradually retrain the immune system to enable rheumatic tissues to respond less violently to the “bacterial allergy.” With careful attention to individualizing the patient’s treatment, a balance can be achieved to slowly decrease the pathogen load while also ensuring gentle elimination of the inflammation-inducing toxic substances (antigens) released by the dying microorganisms.

Each patient’s path to wellness will be unique and progress is rarely linear, with ups and downs as treatment continues. Many diverse factors influence how quickly a person responds to treatment. Men, in general, seem to respond to treatment more swiftly than women. Age, severity, disease duration, use of other drugs, hormone imbalances and unaddressed infections (e.g., tick-borne diseases, streptococcus, chlamydiae or Candida) may all play a role. In some cases, it can take patience and self-advocacy to identify and correct lifestyle factors (e.g., smoking, poor nutrition, stress, lack of sleep) that may also be interfering with progress. Some patients may not experience any noticeable signs of improvement until after a year or more, while others may begin to feel better within weeks.

In the most entrenched and recalcitrant cases, it can take up to thirty months from the beginning of therapy until the patient clearly turns the corner toward improvement, and the achievement of lasting remission can take several years….In shorter-term cases – and short term doesn’t necessarily mean less severe – complete remission can be achieved in less than six months. —The New Arthritis Breakthrough, by Henry Scammell, pages 269-270

Patients have reported that they find it helpful to start keeping a journal when they begin AP. Keeping a journal from Day 1 of AP can be of tremendous value, as the treatment may take time to kick in and it can be easy to feel discouraged on the “not-so-good” days. Being able to compare one’s current condition to one’s state of health at the start of treatment can serve as a reminder that the therapy is actually working, albeit slowly. In journaling, patients may document information such as lab markers at baseline and over time, perhaps with a chart to watch for trends. A journal may also include notes on daily pain levels ranked on a scale from zero to 10, when and by how much doses have been modified, new antibiotics added to the protocol, supplements added or dropped, dietary changes, hormone rebalancing, detoxification methods tried, what has provided noticeable help in terms of pain relief, etc.

After commencing AP, by the six-to-eight month point, there should be some objective signs of improvement in either lab results or symptoms. At this stage, these changes may still be relatively minor, but if a person feels the same and either there are no changes in lab results or symptoms have worsened, then it is time to re-assess what may be impeding progress (see FAQs #16-18, 22-26 and 37-42) with the prescribing doctor.

As described in The New Arthritis Breakthrough, by Henry Scammell, Dr. Brown’s recommendations were that the therapy should be continued until all lab tests and symptoms had normalized for a reasonable length of time. However, even though in some cases drug-free, sustained remission is attainable, AP should not be considered a “cure” for rheumatic disease. Once remission is achieved, many patients will either need or choose to remain on a low-dose maintenance treatment indefinitely, preferring not to risk relapse. This is an important consideration, especially for patients who had experienced severe or long-standing disease at the point when AP was started.

Just as the cessation of any rheumatologic drug can result in rebound of symptoms, stopping AP abruptly can be detrimental to remission status. Working with an experienced AP doctor, who can provide guidance on how to taper the treatment to a maintenance dose or to cease treatment when sustained remission has been reached, can help to limit the risk of relapse. For example, if regular clindamycin IVs have been used in addition to oral therapy, tapering to a maintenance dose may begin by increasing the intervals between treatments. If symptoms remain stable during this time, IVs can be phased out completely. Oral antibiotic doses may also be slowly reduced to a level where remission can still be sustained on a lower “maintenance dose.” If symptoms return, it may be necessary to return to the previous therapeutic dose that was required to keep symptoms in check.

While it is the hope and goal of all AP patients to achieve complete and sustained remission from their rheumatic disease, whether a patient will in fact remain in remission when the treatment has been reduced or stopped altogether should be regarded as unpredictable. If treatment is resumed in order to re-establish remission after a relapse has occurred, response can be variable. Some patients may quickly return to a remissive state and others may find it more challenging.

There can be any number of reasons why a patient relapses after attaining remission and remaining on a maintenance dose of AP. Dr. Brown found that rotating the antibiotic(s) being used after four or five years, even within the same class of antibiotics (e.g., switching from doxycycline to minocycline), could prevent the patient from developing a tolerance to the drug. Rotation periods may vary, but if patients find they do just as well on a new antibiotic, then they may wish to remain on it indefinitely. If it is not as effective as the original antibiotic, they can then switch back after a period of months to re-establish remission. Additionally, Dr. Brown would treat a flare-up aggressively, if possible, adding in a round of IV clindamycin (see The New Arthritis Breakthrough, by Henry Scammell, page 295—Case study: management of Carol Lange’s flare).

If a rheumatic patient has a history of Lyme infection, has had past known exposure to ticks, has lived in or visited Lyme-endemic regions and/or has signs and symptoms indicative of Lyme disease, then testing for Lyme disease is a prudent measure to take. However, it is noteworthy that current CDC-approved tests, involving a two-tiered, staged method (first, the ELISA and, if positive, second, the Western Blot), lack sensitivity and specificity and may produce a false negative result. This type of “indirect” testing (tests that measure the patient’s response to an infection by looking for antibodies) can be a problem for patients with compromised immune systems, when unable to produce enough antibodies to be picked up by the tests. Factors that may influence the results might include immunosuppressive medications that block the ability to fight infections or the poor overall condition of the chronically ill patient who has a lowered immune response due to the infection(s). Standard two-tiered testing for Lyme in the United States may also fail to pick up strains of Lyme that are not included in these tests. Therefore, if Lyme is suspected, a clinical work-up by a Lyme-literate MD (LLMD) can help to form a more accurate diagnosis. This type of workup is very complex and is based upon additional whole-patient criteria. Such an assessment would include a comprehensive assessment of signs and symptoms, supporting lab tests, collecting of information on living in or visiting a Lyme-endemic region and past known tick exposures. If a diagnosis of Lyme (and/or other tick-borne diseases) has been confirmed by a LLMD, a protocol for treatment can then be individualized to address the infection(s).

Treatments for Lyme and associated tick-borne infections may require antimicrobial agents in various combinations that are prescribed in higher doses, with different dosing schedules and pulses, than are used in low-dose AP. Thus, it can be critical to determine if tick-borne infections are implicated, because inadequate or inappropriate treatments can, and often do, leave patients unwell. Ticks have been dubbed “nature’s dirty needles” and may transmit a number of other tick-borne co-infections to humans. In addition to the many (over 300 known) strains of Lyme found in the United States and worldwide, the more common tick-borne co-infections might include various strains of Babesia, Erhlichia, Anaplasma, Bartonella and Mycoplasma, as well as viruses (e.g., Powassan virus, phlebovirus, cytomegalovirus), micro-filarial nematodes and other insect-vector-transmitted pathogens. Additionally, some strains of Lyme disease, such as Borrelia miyamotoi or Rocky Mountain spotted fever (a rickettsia infection) will not show up on standard tests for Lyme.

Some experienced LLMDs are now referring to Lyme disease as “MSIDS,” meaning “mixed systemic infectious diseases syndrome,” recognizing that chronic Lyme patients are often afflicted with multiple co-infections. These patients can be so immune-compromised that latent infections (e.g., Chlamydia pneumoniae, Streptococcus, human herpes virus 6, known as HHV6) may also become re-activated.

To Learn More:

• International Lyme and Associated Diseases Society, a presentation by Richard Horowitz M.D.

Different laboratories use different tests and testing methods, and these have varying degrees of specificity and sensitivity.

Standard two-tiered testing (first an ELISA test and, if the result is positive, a Western Blot test to confirm) can be run initially and should be covered by insurance, but if results returned are negative and Lyme is still suspected, then more sensitive/specific testing can be run through a specialty laboratory, such as IGeneX, in California.

Although Lyme testing can confirm and support a clinical diagnosis of infection, Lyme-literate MDs agree that a negative reading cannot rule out Lyme disease and appropriate diagnosis should be based upon a complete patient history (which includes all potentials for recent/past exposure), signs/symptoms and additional laboratory findings (e.g., associated tick-borne co-infections and/or blood count anomalies) that support such a diagnosis.

The state of Virginia has now passed a bill into law requiring physicians to inform their patients in writing that negative results on standard Lyme two-tiered testing cannot be presumed to be conclusive evidence that a person does not have this infection. This new medical requirement speaks to the lack of reliability of current standard testing methods.

To Learn More:

• Lyme Diagnostic and Treatment Guidelines, “2014 Evidence-Based Guidelines For The Management of Lyme disease,” by the International Lyme And Associated Diseases Society (ILADs.org).
• Dr. Burrascano’s  Diagnostic and Treatment Guidelines, “Advanced Topics in Lyme Disease: Diagnostic Hints And Treatment Guidelines For Lyme And Other Tick-borne Illnesses,” by Joseph J. Burrascano Jr, MD.
• An Act to amend the Code of Virginia by adding a section numbered 54.1-2963.2, relating to Lyme disease; disclosure of information to patients  http://leg1.state.va.us/cgi-bin/legp504.exe?131+ful+CHAP0215

While the medical establishment recognizes that some type of infection is likely an initial trigger for rheumatic disease—and Lyme is no exception—rheumatologists and infectious disease doctors do not accept the theory that the chronic persistence of any organism in the body can drive rheumatic disease. Instead, the conventional belief is that autoimmunity is the result of some aberrant genetic switch or ongoing molecular mimicry and that the triggering pathogen has long gone. There is, however, an abundance of existing and emerging research indicating that Borrelia can persist in the mammalian host after short-term antibiotic treatment for the infection. Although this is still debated by many researchers, Lyme-literate Medical Doctors (LLMDs) and the patients who are experiencing persistent symptoms believe they are helped by long-term treatment with antibiotic therapy. Many rheumatic patients feel much worse on immunosuppressive medications and LLMDs are of the opinion that suppressing the immune system actually enables proliferation of the chronic infection(s) and causes worsening of disease.

There is also a growing body of evidence to suggest that Lyme disease can present as either seropositive or seronegative rheumatic disease (that is, symptoms of a rheumatic disease with or without definitive rheumatic disease markers). In this context, Lyme both causes and perpetuates an autoimmune response. Similarly, rheumatic disease may be caused and perpetuated by the presence of other chronic, persisting infections (sometimes in combination), such as Mycoplasma fermentens, Streptococcus, Chlamydia pneumoniae and others. Patient experience has demonstrated that once tick-borne infections (and any re-activated latent infections) are appropriately and adequately treated, the rheumatic disease symptoms subside and associated lab markers begin to return to normal.

To Learn More:

• Envita Medical Centers, Chronic Lyme Disease, video describing how Lyme may present as autoimmunity
• Article by H. Yrjanaienen and co-authors, “Anti–Tumor Necrosis Factor–a Treatment Activates Borrelia burgdorferi Spirochetes 4 Weeks after Ceftriaxone Treatment in C3H/He Mice”
• Article by M.E. Embers and co-authors, “Persistence of Borrelia burgdorferi in rhesus macaques following antibiotic treatment of disseminated infection”
• Article by E. Hodzic and co-authors, “Persistence of Borrelia burgdorferi following antibiotic treatment in mice”
• Article by E.N. Kologrivova and co-authors, [Intensity of the production of rheumatoid factor in patients with different degrees of sensitization to Borrelia garinii antigens]
• Article by J.S. Axford and co-authors, “Increased IgA rheumatoid factor and V(H)1 associated cross reactive idiotype expression in patients with Lyme arthritis and neuroborreliosis”
• Article by R.L. Wilder and co-author, “Do infectious agents cause rheumatoid arthritis?”
• Article by A. Czeczuga and co-author, [Usefulness of examinations of serum levels of matrix metalloproteinases 1, MMP-3, MMP-9, tissue inhibitor of metalloproteinases 1, hyaluronic acid and antibodies against cyclic citrullinated peptide in Lyme arthritis, rheumatoid arthritis and patients with arthritic complaints]
• Article by V. Goeb, “Clinical interest of autoantibodies directed against citrullinated peptides in Indian patients with rheumatoid arthritis”

If a patient is receiving treatment from a Lyme-literate MD (LLMD) who has had physician training through ILADS (International Lyme and Associated Diseases Society), then the doctor should be able to interpret the patient’s results accurately. The positive results of any test for Lyme disease are considered by LLMDs as confirmation of the infection, but one cannot rule out infection if results are negative or equivocal, especially if the patient is exhibiting typical signs/symptoms.

To Learn More:

• Lyme Diagnostic and Treatment Guidelines, “2014 Evidence-Based Guidelines For The Management of Lyme disease,” by the International Lyme And Associated Diseases Society (ILADs.org).
• Dr. Burrascano’s Diagnostic and Treatment Guidelines, “Advanced Topics in Lyme Disease: Diagnostic Hints And Treatment Guidelines For Lyme And Other Tick-borne Illnesses,” by Joseph J. Burrascano Jr, MD.
• To read patient-friendly information on how to interpret the IGeneX Western Blot test
• LymeNet, Dr C’s Western Blot Explanation
• Melissa Kaplan, Interpreting the IgG and IgM Western Blot for Lyme Disease

. . . too much of an antibiotic can create more problems than it cures. But conversely, as has been demonstrated in recent experience with Lyme disease, so can underprescribing either the dosage level or duration of therapy. Choosing the right drug is only part of the solution. Also important is the development of an appropriate protocol for its administration. —The New Arthritis Breakthrough, by Henry Scammell, page 295

In general, if a patient discovers s/he has Lyme disease and/or other associated tick-borne co-infections, then the ideal doctor to see would be a Lyme-literate medical doctor (LLMD). This is because diagnosing and treating tick-borne infections is a specialized field, requiring that a patient-specific protocol is designed with targeted antibiotic combinations that are prescribed in specific doses and pulses. Experienced LLMDs are highly skilled and have extensive knowledge about the complexities of multi-systemic illness caused by tick-borne infections and what might be needed to support the treatment. The antibiotic protocols designed by Dr. Brown involved using pulsed, low doses to treat chronic mycoplasma infections. This approach is inadequate for treating Lyme and associated tick-borne co-infections and may cause antibiotic resistance issues. In certain cases, however, rheumatic patients are so highly sensitive that the only alternative is to treat initially with low-dose monotherapy; this lighter approach should be discussed with the treating LLMD, because addressing hypersensitivity with complementary treatments and/or alternative antibiotics in various combinations/pulses may be a better solution.

To Learn More:

Professional information on Lyme disease and associated tick-borne co-infections can be found by reading the Diagnostic and Treatment Guidelines by ILADS and Dr. Joseph Burrascano:

• “2014 Evidence-Based Guidelines For The Management of Lyme disease,” by the International Lyme And Associated Diseases Society.”
• “Advanced Topics in Lyme Disease: Diagnostic Hints And Treatment Guidelines For Lyme And Other Tick-borne Illnesses,” by Joseph J. Burrascano Jr, MD.

There are numerous reliable Lyme Literate resources, including professional and patient advocacy organizations to learn about Lyme disease and other tick-borne co-infections.

To Learn More:

• International Lyme And Associated Diseases Society
• Tick-Borne Disease Alliance
• Lyme Disease Association, Inc.
• Lyme Info
• lymedisease.org
• Lyme Action Network video: What is Lyme disease?
• Documentary movie, Under Our Skin
• Cure Unknown—Inside the Lyme Epidemic, by Pamela Weintraub
• Why Can’t I Get Better? Solving the Mystery of Lyme and Chronic Disease, by Richard Horowitz M.D.

A growing body of research is producing evidence to suggest that following an anti-inflammatory diet and excluding certain dietary offenders (unique to an individual) may reduce the symptoms of rheumatic disease. Further, certain foods may either enhance gut dysbiosis (imbalances in gut microbiota) or correct it. In fact, in fasting studies, it has been found that intermittent fasting can also have an impact on a variety of inflammatory diseases, leading to the hypothesis that some foods may be driving inflammation and/or feeding unwanted microbes in the gut that perpetuate the inflammatory response.

Patient experience has demonstrated that foods laden with processed carbohydrates, containing gluten and sugar, starches, and in some cases, saturated and trans-fats (such as red meat and dairy products) can worsen inflammation. On the other hand, foods rich in omega-3 fatty acids, certain vitamins, antioxidants, bioflavonoids, fiber and certain spices (e.g., turmeric, ginger and capsaicin) may actually reduce CRP (cross-reacting protein, a measure of inflammation levels). Commonly used NSAIDs and DMARDs are also believed to compromise the gut lining and its permeability, leading to food proteins leaking into the body and setting the stage for food intolerances and allergies, which also exacerbate the inflammatory response. It just makes good sense that while the body is unwell and struggling to regain balance, a well-balanced, healthy diet, rich in foods known to promote a strong, functioning immune system, can contribute significantly in the healing process.

To Learn More:

• Article by L. Gonzalez Cernadas and co-authors, [Importance of nutritional treatment in the inflammatory process of rheumatoid arthritis patients; a review]
• Article by L.A. Macovei and co-author, “Clinical and epidemiological study on the prevalence of rheumatoid arthritis in some demographic structures”
• Article by A. Michalsen, “Fasting therapy for treating and preventing disease—current state of evidence”
• Article by D. Luckey et al., “Bugs & us: the role of the gut in autoimmunity”
• Article by D.R. Dawon et al., “Dietary modulation of the inflammatory cascade”
• Slide show by M.E. Ellis, “Anti-Inflammatory Diet for Rheumatoid Arthritis”

Whenever antibiotics are prescribed, for short- or long-term use, probiotics should be taken to replenish beneficial bacteria in the gut that have been lost as a result of the antimicrobial therapy. Current research has also demonstrated that specific strains of probiotics may actually modulate inflammation and lessen symptoms in rheumatic diseases. A growing number of doctors today are recognizing the importance of replacing beneficial bacteria in the gut during antibiotic treatment and that a balanced gut is a prerequisite for optimal digestive health. It is now understood that bacteria play pivotal roles in breaking down foods into readily absorbable nutrients, as well as reducing the risk of yeast (i.e., Candida) overgrowth in the gut that can lead to leaky gut syndrome.

Probiotics can be taken in various forms, including capsules, chewable tablets, liquid forms and even probiotic straws and gummies for children. Some people also prefer to purchase kefir grains (a fermented milk drink, rich in Lactobacillis bacteria and yeasts in a matrix of proteins, lipids and sugars) to make inexpensive, homemade probiotic yogurt, free of processing/fillers/sugar and rich in natural, fresh, beneficial microbes. In contrast, store-bought, processed/pasteurized yogurt alone will not be adequate to replace good bacteria in the gut and is contraindicated in those adhering to a dairy- and sugar-free diet.

To Learn More:

• Article by E. Vaghef-Mehrabany and co-authors, “Probiotic supplementation improves inflammatory status in patients with rheumatoid arthritis”
• M.A. Ghoneim and co-authors, “Antioxidant status and hormonal profile reflected by experimental feeding of probiotics”
• L. Galland, “Leaky gut syndromes: Breaking the vicious cycle”

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Supplements should always be discussed with the prescribing physician, as some may be detrimental to a particular patient, causing interactions with medications or potentially increasing disease symptoms. For example, Vitamin C helps to stimulate the production of collagen in the body and this may be beneficial to a rheumatoid arthritis patient by protecting cartilage. This vitamin is also helpful for its antimicrobial and anti-oxidative effects, which help to reduce inflammation. However, and although controversial, Vitamin C may not be good for a patient with scleroderma, a condition that produces an excess of collagen. Some supplements (e.g., vitamin E, garlic and ginko) have blood-thinning properties that may enhance or inhibit another medication. Others, such as MSM (Methylsulfonylmethane, an organosulfur compound), fish oil, systemic enzymes or curcumin (turmeric) may cause excessive blood thinning when taken alongside a pharmaceutical-grade blood thinner, such as heparin or Coumadin. Minerals in supplements and in some foods (e.g., such as calcium, magnesium, zinc or iron) will interfere with the absorption of tetracycline antibiotics, binding to them and rendering them useless in the gut, so these must be taken carefully, spaced well away from AP doses.

There are specific supplements that patient experience has shown to be helpful for certain conditions and also to help prevent complications of rheumatic disease. Such topics are discussed frequently in the Road Back Foundation (RBF) discussion forum, because some supplements are used universally by those using AP (e.g., probiotics) and some may provide specific support for certain rheumatic diseases. However, it cannot be overstated that each person must discuss any risk/benefit with his/her doctor before adding any supplements to the daily regimen. While some supplements have been studied extensively, others have not.

The Drug.com drug interactions checker provides some data on supplement interactions with various drugs, but does not provide complete information.

Road Back Foundation does not endorse any complementary therapy. However, patient experience has shown that there are a number of such therapies that may support AP. These types of complementary approaches are widely varied, and may include detoxification strategies such as Far Infrared (FIR) Sauna, IV nutritional therapies (e.g., intravenous vitamin C, Myer’s Cocktails or Glutathione IV pushes), colonic irrigation and enemas to help quell inflammation during flares and herx reactions, acupuncture for pain relief, chelation therapy to reduce heavy metal load and improve circulation, hyperbaric oxygen therapy, platelet-rich plasma, prolotherapy, prolozone and autologous adult stem cell therapy to enhance the body’s ability to heal cartilage and other tissues, and many others. While some therapies have been studied and there is research to support their efficacy, the value of others may be largely anecdotal. It is therefore suggested that all complementary therapies be researched thoroughly and discussed with the treating doctor to assess any potential risk/benefit in each individual’s case.

There are various types of anemia and it is important for the treating physician to assess which type a patient has, and its cause, in order to provide appropriate treatment. In Dr. Brown’s vast experience treating rheumatic disease with AP, he found that the type of anemia that is present in some rheumatic patients usually resolves as the patient improves on AP.

Once the blood begins to look good, the anemia is corrected, the rheumatoid factor is down, the sedimentation rate and hemoglobin are where they ought to be, and the mycoplasma antibodies are beginning to peter out, I know the patient is close to remission. —The New Arthritis Breakthrough, by Henry Scammell, page 269

This suggests that the type of anemia related to rheumatic disease responds directly to treating its infectious cause and will begin to correct itself as the patient starts to improve with individualized AP treatment. Patient experience has commonly confirmed this positive effect of AP (especially when no other rheumatologic drugs are being used).

Hormone imbalances are not unusual among rheumatic patients. There may be an overlap of autoimmune thyroid disease causing an imbalance in thyroid hormones, which can cause a constellation of metabolic symptoms, including joint and muscle pain. Adrenal fatigue is a common finding with chronic illness. Cortisol and dehydroepiandrosterone (DHEA) monitoring is helpful in determining if supportive measures for adrenals are needed. This may be especially important to patients with long-standing disease who have used prednisone for prolonged periods of time. Gender-specific hormone imbalances may occur at any time of life, but these are most common during the change of life and shortly after the birth of a baby. Age-appropriate correction of these imbalances may help patients with pain control and improving quality of life, as the symptoms sometimes overlap with those of rheumatic diseases. Discussing testing and treatment with the treating physician or a specialist may be needed to determine whether conventional hormone replacement (HRT) or bio-identical hormone replacement (BHRT) would be more effective.

To Learn More:

• Overcoming Arthritis, by Dr. David Brownstein
• STTM [Stop the Thyroid Madness]

AP = antibiotic protocols
ANA = antinuclear antibody (test)
Anti-CCP = anti-cyclic citrullinated peptide antibody (antibody test)
ABX = antibiotics
AS = ankylosing spondylitis
ASO = antistreptolysin O (antibody test)
bid = medical term for “bis in die,” meaning twice daily
CBC = complete blood count
CFIDs = chronic fatigue immune deficiency syndrome
CNS = central nervous system
CREST = acronym for the symptoms of a form of scleroderma that include: calcinosis, Raynaud’s phenomenon, esophageal motility disorders, sclerodactylyl and telangiectasia
CRP or cardio-CRP = cross-reacting protein or cardio cross-reacting protein (test for β-globulin)
DILE or DIL = drug-induced lupus erythematosus
DM = dermatomyositis
DMARD = disease-modifying anti-rheumatic drug
Doxy = doxycycline (medication)
ESR = erythrocyte sedimentation rate (test)
FM or FMS = fibromyalgia syndrome
IV = intravenous
JIA = juvenile idiopathic arthritis
JRA = juvenile rheumatoid arthritis
LLMD = Lyme Literate Medical Doctor
MCF = mycoplasma complement fixation (test)
MCTD = mixed connective tissue disease
mg = milligrams
ME = Myalgic encephalomyelitis
Mino = minocycline or Minocin (medication)
MSIDs = mixed systemic infectious diseases syndrome
M-W-F or MWF = antibiotic is pulse-dosed on Monday, Wednesday and Friday
MTX = methotrexate (medication)
NSAID = non-steroidal anti-inflammatory drug (medication)
PCR = polymerase chain reaction (test)
PsA or PA = psoriatic arthritis
Pred = prednisone (medication)
PM = polymyositis
qd = every day
qod = every other day
RA = rheumatoid arthritis
ReA = reactive arthritis
RF = rheumatoid factor (test)
RH = rheumatic
RS = Reiter’s syndrome
SD = scleroderma
SEID = systemic exertion intolerance disease
SSc = systemic scleroderma
SLE = systemic lupus erythematosus
SS = Sjögren’s syndrome
Tetra = tetracycline (medication)
UCTD = undifferentiated connective tissue disorder

In the United States, the original brand of minocycline (Minocin) is a pelleted capsule in 50 mg, 75 mg and 100 mg sizes that was last distributed by Onset Dermatologics as of February 2014. More information will be provided as it comes to hand.

It may be impossible to find the original trademarked, pelleted Minocin capsule in countries outside the United States. Comparable products are available, but brand names will vary. Click here for an international listing of these brands.

Generics may differ in how they are produced, with assorted fillers and dyes, and also in their active ingredients. As a result, not only may the experience of various generics be unique to the individual, these may also vary in bioavailability and/or bioequivalency. In the United States, patient experience has shown that the generic produced by Teva pharmaceutical company makes a reasonably good substitute for the original brand name, Minocin, and generics that are manufactured within the United States (and not outsourced to other countries for production) are most often preferred. Some trial and error may be necessary to find a suitable generic and appropriate dosing, depending upon an individual’s response to one generic over others. A similar approach to finding an effective generic will apply internationally.

Brand name Minocin in the United States is costly, if not covered by insurance, but some patients are able to have their prescribing doctor appeal to have it supplied on the grounds that they suffer from gastroesophageal reflux disease (GERD). Patient experience has shown that the original pelleted formulation allows for a delayed release of the medication that is less likely to cause gastric distress. If the original brand is not covered by insurance and is cost-prohibitive, it may be possible to find a suitable generic that is just as effective for treatment, although dosing may need to be adjusted on an individual basis. Local pharmacies are usually amenable to providing specific generic brands upon request, although these may need to be special-ordered.