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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.
True anaphylaxis is a life-threatening situation, usually starting within minutes of taking the offending drug, and one should never wait to get medical assistance in these instances.
To learn more about the symptoms of drug allergy versus anaphylaxis:
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).