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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.
3. Why doesn’t my family doctor or rheumatologist know about AP as a treatment for rheumatic diseases?
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:
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, which provide an excellent foundation in understanding the rationale for this approach to treatment, are a good starting point. You will find these books and others listed in the Resource section of this site.
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.
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.
7. What are some of the common side-effects experienced while using long-term antibiotics and can these be averted?
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:
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"
10. Why is minocycline (U.S. brand name Minocin) the most commonly used antibiotic in AP? Are there others?
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:
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).
17. My rheumatologist has warned me that I could get a form of lupus from minocycline and this has scared me. What is this and what are the chances of this happening?
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"