Familial Mediterranean Fever treatment for attacks, prevention and cause, use of supplements, herbal remedy, by Ray Sahelian, M.D.
Use of colchicine to prevent amyloidosis, natural and alternative therapy, the role of diet and food
July 12 2015

Familial Mediterranean fever is a hereditary syndrome -- an autosomal recessive disease -- characterized by recurrent episodes of fever and serositis, resulting in pain in the abdomen, chest, joints and muscles. It is primarily diagnosed in people of Jewish, Arabic, Turkish or Armenian ancestry and is caused by mutations in the gene encoding for pyrin. Abdominal familial Mediterranean fever attacks resemble the clinical presentation of 'acute abdomen', with severe abdominal pain and rigidity, but familial Mediterranean fever symptoms always resolve spontaneously. It is important to distinguish these regular pain episodes from small bowel obstruction due to adhesions to prevent life-threatening bowel strangulation.

Symptoms
FMF symptoms and signs are due to recurrent crises of fever and serosal inflammation, leading to abdominal, thoracic or articular pain. Erysipela like erythema affecting mainly feet and legs and effort-induced myalgia are less frequently encountered symptoms. The major complication of familial Mediterranean fever is the development of renal amyloidosis.
   Sometimes symptoms can be trigger by emotional or work-related stress.

Diagnosis
Standard laboratory tests of patients are non-informative, except for the high sedimentation rate and white blood cell count, but during and immediately after crises, diminished albumin concentrations and elevated fibrinogen, C-reactive protein, beta2 and alpha2 M globulins, haptoglobin and lipoprotein concentrations are noted. Studies have measured immunoglobulin (Ig) levels in the sera of familial Mediterranean fever patients and found elevated levels of IgA, IgM, IgG, and IgD. Familial Mediterranean fever crises are characterised by a massive influx of polymorphonuclear leukocytes into the inflamed regions. Moreover, the peritoneal fluid of familial Mediterranean fever patients contains abnormally low levels of the inhibitor of complement fragment C5a and interleukin 8. Failure to suppress inflammatory response to C5a may explain the typical inflammatory Familial Mediterranean fever crises.

Autoimmun Rev. 2014 Jan 11. Diagnostic criteria of familial Mediterranean fever. FMF is the most prevalent monogenic autoinflammatory disease, mainly affecting ethnic groups living at Mediterranean basin. FMF is characterized by recurrent, self-limited episodes of fever and serositis. The diagnosis is difficult in the presence of atypical signs, which may result in significant delay in initiating treatment. As autoinflammatory diseases may have overlapping symptoms, strict diagnostic criteria are essential. Since the discovery that mutations in the gene MEFV underlie FMF, molecular genetic testing has been used as a diagnostic adjunct, especially in atypical cases. However, despite progress in the understanding of FMF disease mechanisms during the past 15years; the diagnosis is still based on clinical criteria.

Familial Mediterranean fever treatment
Continuous treatment with colchicine, at a daily dose of 1 to 2 mg, reduces attack frequency, duration and intensity in the majority of patients, and also prevents the development of secondary amyloidosis, the most dreaded complication of the disease. In most cases, colchicine will prevent new painful attacks. There are suggestions that one should consume less milk while taking cochicine due to lactose intolerance but I have not seen studies to know if this is true. Rilonacept reduces the frequency of FMF attacks and seems to be a treatment option for patients with colchicine-resistant or -intolerant FMF. Children with FMF are able to use colchine if needed. This website is focused on natural treatment remedies as discussed below.

After a 5-year monopoly on the sale of colchicine put the gout medication out of reach for many patients, a federal judge in January 2015 denied an injunction request by Takeda Pharmaceuticals U.S.A. to halt the distribution of colchicine products by Hikma Pharmaceuticals PLC. Thus, the price of colchicine will drop back down to a more reasonable cost.

Familial Mediterranean fever treatment with herbs and natural supplements, alternative and natural therapy, diet, food
Very little human research has been done with alternative medicine or natural supplements for FMF, hence no definite answers or treatment regimens can be provided.

Food and diet
Is it possible that consuming an anti-inflammatory diet with high amounts of fish and vegetables and low amounts of sugar, sweets, pies, pastries, white bread and junk foods helps reduce attacks? Are some people gluten sensitive yet misdiagnosed with this disorder? Would the use of fish oils or salmon eggs help? I don't have the answers yet.
   Some websites claim that a low fat diet is helpful but I am not yet sure if this is true.

Supplements and herbs, vitamin therapy
The following herbs have been evaluated with some positive responses, but more research is needed before we know the ideal dosages, frequency of use and long term side effects. Echinacea angustifolia and purpurea, Astragalus membranaceus, and Eleutherococcus senticosus (Siberian Ginseng herb), Andrographis paniculata, Schizandra chinensis, and Glycyrrhiza glabra (licorice). I am not sure if vitamin D is of benefit.

Int J Rheum Dis. 2014 Jan 11. Decreased vitamin D levels in children with familial Mediterranean fever. Our results suggest that serum 25-hydroxyvitamin D levels are decreased in children with FMF. Cumulative colchicine dose appears to negatively affect vitamin D levels.

Ren Fail. 2015. Association between colchicine resistance and vitamin D in familial Mediterranean fever. Although colchicines are the only effective treatment of familial Mediterranean fever (FMF), resistance to colchicines (CR) which is observed in up to 30% of the patients is still a problem. Plasma vitamin D levels were significantly lower in colchicine resistant patients.

FMF research studies

Medicine (Baltimore). 2012. Familial Mediterranean fever: risk factors, causes of death, and prognosis in the colchicine era. We assessed the risk factors and causes of death in patients with FMF in an era when colchicine is the standard therapy for all patients.The overall patient survival rate was not significantly different from the age- and sex-matched Turkish general population. Our findings suggest that although the survival of FMF patients in the colchicine era is comparable to that of the general population, renal involvement still predicts mortality.

Plasma nitric oxide level in familial Mediterranean fever and its modulations by Immuno-Guard.
Nitric Oxide. 2003. Panossian A, Hambartsumyan M, Panosyan L, Abrahamyan H, Mamikonyan G, Gabrielyan E, Amaryan G, Astvatsatryan V. Pharmaceuticals and Nutraceuticals Expertise Research Institute, Yerevan, Armenia.
Familial Mediterranean fever is a recessively inherited inflammatory disorder, characterised by recurrent attacks of fever and serositis. Since nitric oxide (NO) is an important mediator of inflammation, the production of NO (assessed as the accumulation of nitrate and nitrite and measured by capillary electrophoresis) in blood plasma of Familial Mediterranean fever patients during acute attacks (active) and attack-free periods (inactive) of the disease has been determined and compared with NO levels found in healthy volunteers (control group C). Thirty-six Familial Mediterranean fever patients were involved in a placebo-controlled double-blind study (group A received the drug, group B the placebo) of the effects of Immuno-Guard, a novel herbal preparation which relieves the severity and longevity of Familial Mediterranean fever attacks on NO blood levels. Thirty-two Familial Mediterranean fever patients (group D) being permanently treated with colchicine were also examined with respect to their NO blood level. No significant differences were found between the NO levels in blood of inactive Familial Mediterranean fever patients and those of control group C, or between inactive colchicine-treated group D patients and inactive patients of groups A and B, a finding which is atypical for chronic inflammatory disorders. Significantly lower plasma NO levels were found in active Familial Mediterranean fever patients in groups A and B compared with inactive patients in those groups and with patients of group D and the control group C. The decrease of NO in blood of Familial Mediterranean fever patients may trigger the generation of fever by initiating the production of pro-inflammatory IL-6. Plasma NO levels in inactive Familial Mediterranean fever patients were significantly increased during attack-free periods following treatment with Immuno-Guard. The preparation has a normalising effect both on NO and IL-6 blood levels in Familial Mediterranean fever patients during attacks, demonstrating a relationship between the beneficial effect of Immuno-Guard in reducing the severity of inflammatory attacks in Familial Mediterranean fever patients and the increase in NO blood levels. Herbs found in Immuno-Guard: Echinacea angustifolia and purpurea, Astragalus membranaceus, and Eleutherococcus senticosus (Siberian Ginseng)

Double-blind, placebo-controlled, randomized, pilot clinical trial of ImmunoGuard -- a standardized fixed combination of Andrographis paniculata Nees, with Eleutherococcus senticosus Maxim, Schizandra chinensis Bail. and Glycyrrhiza glabra extracts in patients with Familial Mediterranean Fever.
Phytomedicine. 2003. Amaryan G, Astvatsatryan V, Gabrielyan E, Panossian A, Panosyan V. Republican Children's Familial Mediterranean fever Center, Yerevan State Medical University, Yerevan, Armenia.
Double blind, randomized, placebo controlled pilot study of ImmunoGuard -- a standardized fixed combination of Andrographis paniculata, Eleutherococcus senticosus, Schizandra chinensis, and Glycyrrhiza glabra (licorice) , was carried out in two parallel groups of patients. The study was conducted in 24 (3-15 years of both genders) patients with Familial Mediterranean Fever (Familial Mediterranean fever), 14 were treated with tablets of series A (verum) and 10 patients received series B product (placebo). The study medication was taken three times of four tablets daily for 1 month. Daily dose of the andrographolide--48 mg. The primary outcome measures in physician's evaluation were related to duration, frequency and severity of attacks in Familial Mediterranean fever patients (attacks characteristics score). The patient's self-evaluation was based mainly on symptoms--abdominal, chest pains, temperature, arthritis, myalgia, erysipelas-like erythema. All of 3 features (duration, frequency, severity of attacks) showed significant improvement in the verum group as compared with the placebo. In both clinical and self evaluation the severity of attacks was found to show the most significant improvement in the verum group. Both the clinical and laboratory results of the present phase II (pilot) clinical study suggest that ImmunoGuard is a safe and efficacious herbal drug for the management of patients with Familial Mediterranean fever.

Q. Can you tell me where I can buy Immuno-Guard?
   A. We search online for the formula used in the studies but cannot seem to find this product for sale. However, the individual ingredients, andrographis and others are available for sale individually. See the links above.

Emails
My children and I suffer from severe pains of Familial Mediterranean Fever. On colchicine, my son is stable, however, off colchicine and trying different alternatives, I suffer from a lot of attacks. I had read an article on your web-site years ago regarding ImmunoGuard, an herbal blend prepared in Armenia for FMF, resulting in significant improvement of the duration, frequency and severity of attacks. At the time, you had told me there is not enough research right now but to check back. Could you please instruct me on how to do so and/or please let me if there is any new research on the subject.
   As of 2011, I have not seen any additional studies using natural supplements for this condition.

I have spoken to an Armenian doctor at Arabkir Center (Republic Children’s FMF Center) and he advised me that ImmunoGuard works well for FMF in conjunction with colchicine for the treatment of Familial Mediterranean Fever, a condition I have as well as my children. I would like to try the combination of herbs. On your web-site, you mention specifically that the ImmunoGuard herbs can be purchased through individually as opposed to the combination formula, however, I do not know the amounts of each herb to use.
    I am not sure what the ideal dosage would be. Perhaps one capsule of each each day? A good option is to begin with half a capsule a day of each for a week before increasing or decreasing the dosage.

I currently reside in Australia. I have been a sufferer of Familiar Mediterranean Fever for forty five years. I was very interested to read about Immuno-guard on your website as I desperate for relief. I have not been able to purchase this product on line or able to get the right combination of Immuno guard for FMF sufferers here in Australia. I have seen many doctors and have been on many opiods for the pain to no avail. Could you please help.
    We did a search for this product on google in March 2011 and could not find any vendors, perhaps the product is discontinued. However, each of the ingredients is available as single herbs and perhaps one can buy 2, 3 or all four of the herbs and use a quarter or half of each pill, or perhaps one capsule of each if the smaller amounts are tolerated without side effects.

Q. I have familial Mediterranean fever and it appears my 4 year-old son has it too though he most likely has only one mutation (M694V) causing his symptoms. My son’s osteopath referred me to your web-site so that I may find a safe alternative to taking colchicine. I would like to ask the history and known side effects of ImmunoGuard / the herbal remedies that comprise it, indicated for FMF treatment, and if there is any research comparing its use, side effects and benefits to colchicine in FMF patients. I have been in contact with a research doctor at National Institutes of Health in Bethesda, Maryland since 1989 regarding my condition and have been on colchicine almost continuously since then. I have also directed my doctor to your web-site in the hopes that he may contact you with any questions.
   A. All the information we have on these topics is on our website and we try to update it as soon as we find more research on familial Mediterranean fever.

Q. My daughter is five years old and had been suffering from periodic fevers from April through September 2007. These fevers began with joint pain and 11 days of 102-104. As the months passed the duration of the fevers lessened and the joint pain became more severe. Within that period of time, I had made appointments with rheumatologists. One wanted to medicate and the other wanted to wait. I decided to wait and observe. In the meantime, after some discussion with people who had positive results in general with vitamin D, I did some research and began supplementing my daughters diet with vitamin D (at the beginning of September). The fevers did not recur until this month, January 2008 ( I thought viral, but there were no other symptoms so the doctor thinks it could be familial Mediterranean fever. We have done no other testing other than blood work ups. I realized that I had stopped giving her the vitamin D in the beginning of December and the fevers recurred mid January. Her bloods were tests in October of 2007 and I requested her levels of D be tested. the results were optimum (from what I am reading on the internet. Her level of 25 hydroxy... was 52. I am concerned with toxicity as well. This episode of fever and blood work, the idea of vitamin D did not enter my mind until 3 days after the blood was drawn to have the D levels tested again. I have been reading a lot about vitamin D deficiencies and auto immune diseases and I was wondering if there was any specific research in regard to familial Mediterranean fever and vitamin D deficiencies. I was impressed with your article due to the attention paid to the natural remedies. I'm sure like all mothers I am exploring all natural options before pharmaceuticals. I have began the supplementation of Vitamin D again and will wait at least two months to see if the fevers cease again before administering the medication. Of course I am not abandoning science altogether and I am certainly not pretending to be a doctor, but I want the most natural "cure" or "treatment" for this disease (if it is familial Mediterranean fever) possible. Genetic testing is in the near future. The doctors were not quick to test because of the short history of fevers and lack of data.
   A. Familial Mediterranean fever, the most frequent of the periodic fever syndromes, is an autosomal recessive disease, predominantly affecting people of Mediterranean descent. The disease is caused by mutations in the MEFV gene, encoding the pyrin protein thought to be associated with the interleukin-1 related inflammation cascade. We are not aware of any research regarding the use of vitamin D as a treatment for familial Mediterranean fever. This condition is more common in the Middle East where people are exposed to a lot of sun and hence are not deficient in vitamin D.

Q. I am 60 years old and have had familial Mediterranean fever since infancy. I take colchicine which UCLA's familial Mediterranean fever clinic prescribed when I was 16 years old. It's when my familial Mediterranean fever was diagnosed after years of confusion! Doctors believe my sister died of the disease due to a bowel obstruction. This occurred before my birth. It was in 1945 and she was only 17 years old. Since familial Mediterranean fever is an "inflammation response" disease, do you know of any other medications or treatments for this condition?
   A. Certain herbs have been tried for this condition as discussed above. As a general rule, fish and vegetables reduce inflammation and you may consider increasing your intake of these foods while decreasing the ingestion of foods that have sugar.

Q. In your web-page regarding Familial Mediterranean Fever, you mention a product called Immuno-Guard, which may be used instead of colchecine. Where would I locate Immuno-Guard? I'd also like to know if Immuno-Guard may prevent the development of amyloidosis as does colchecine? Please provide me with any information that would be helpful for someone considering replacing colchecine with an alternative treatment.
   A. The study with Immuno-Guard was done in Armenia, and we are not sure if this product is available in the US. Immunoguard has the following herbs that are available individually: Echinacea angustifolia and purpurea, Astragalus membranaceus, and Eleutherococcus senticosus (Siberian Ginseng).

Q. Does the use of saw palmetto for prostate gland health influence FMF attacks? For sexual enhancement I take herbs such as lj100 which is an extract of tongkat ali and was wondering if this herb had any influence on this condition, good or bad.
    A. I have not seen such studies so I don't know.

I stumbled across your website and I was hoping that you might be able to answer a question. My FMF doctor passed away last year and I have been unable to find anyone on the entire East coast who knows anything about FMF, except for Dr. Kastner in MD who does the government study (I want a practicing doctor to go to for checkups, problems, etc.). I live in the Philadlephia area and since Dr. Sahelian went to school here, I was wondering if he knew of a doctor OR if can just recommend a way for me to find another FMF doctor. I know you said that you don't have a referral system in place, but I'm desperate and thought I'd just give it a try.
    Sorry, I do not know of doctors in the Philadelphia area who focus on this medical condition.

My daughter is 14 years old and was diagnosed with Familial Mediterranean fever back in 2005 when she was only 9 year old, since then she has been taking colchicine to prevent having those painful attacks. But somehow as older she gets as more number of colchicine she needs to take on daily bases to avoid any attacks. Now she is taking two, but some how I have been noticing her attacks are coming back much faster, even every week. I know that FMF attacks are mainly abdominal pain and fever, but her attacks are really bad, she will have short breath, abdominal pain, fever, joint pains, shoulder pain…etc…I cry every time she has those attacks, wishing it was me and not her. I would really wish if I could bring my daughter to your office or what specialist is the best for this disease. Or what other options I have to prevent her taking too much medicine. Please HELP, HELP.
    I don't have a good solution for this medical condition at this time but I hope further research will reveal dietary advice or supplements that may be of benefit.

I am writing to you as an Armenian mother with the hope that you can guide us through these tough times our family is going through. Less then a week ago, I received the copy of my daughter's blood test. It states: homozygous positive for the M694V mutation in the Mefv gene. My daughter's pediatrician has limited knowledge about FMF. My daughter is 3 years old. She had an attack episode twice, she is not on any medication now, until I find a specialist who can confirm her condition. I find all the information in you site very useful. My parents live in Yerevan. I will ask them to find the herbs you referred to and send it to me. Hopefully that will help my daughter. In the meantime, a huge thank you for all your accomplishments and for giving hope to me as I read your articles.

My daughter is 8 years old and has FMF. recently the SAA test shows very elevated number 16000. The same test was in January was 2800. The doctor wants to use biological drugs such as Ilaris or Kineret. Is there any way we can reduce the amyloid without going with biological injections?
   A. I don't have any good answers at this time, this is a complicated issue.




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