COMMENTS FROM DR. GABE MIRKIN

TREATMENT FOR SEVERE ARTHRITICS

Researchers at Long Island Jewish Medical Center showed that tetracycline antibiotics help to reduce the joint damage caused by osteoarthritis. Researchers at Indiana University showed that doxycycline, a type of tetracycline, prevents joint damage in dogs. The cells in the cartilage that lines joints are always changing. While some cells come out of cartilage, others go in. An enzyme called collagenase causes cells to come out of cartilage, and people with the most common type of arthritis called osteoarthritis have higher than normal joint fluid levels of collagenase. Tetracyclines prevent collagenase from breaking down cartilage. Recent research from Indiana University show that tetracyclines also stimulate cartilage to grow, so tetracyclines both inhibit cartilage breakdown and promote cartilage formation.

Another paper from Henry Ford Health Science Center in Detroit shows that tetracyclines help to relieve the swelling and symptoms of rheumatoid arthritis.

Since basic tetracycline does not get into joint fluid in high levels, doctors prescribe tetracycline derivatives called minocycline and doxycycline, which accumulate in high levels in joint fluid. Forty years ago, Dr. Thomas McPherson Brown of Washington, D.C. claimed that many cases of arthritis are caused by infection and he treated his patients with tetracyclines. Other doctors called him a quack. That's what often happens to prophets when they make new discoveries.

E COLI IN GUT CAUSES RHEUMATOID ARTHRITIS

When a germ gets into your body, you manufacture cells and proteins called antibodies that attach to and kill that germ. Sometimes, the germ has a surface protein that is exactly the same as the surface protein on your cells. Then, not only do the antibodies and cells attach to and kill the germ, they also attach to and kill your own cells that have the same surface membranes. In rheumatic fever, the surface protein of a beta strep bacteria is the same as that found in your heart muscle. So when a person with rheumatic fever is infected with beta strep, the body produces antibodies against the strep and the same antibodies also attach to and kill the heart muscle. Dr. Edward Keystone, of Wellesley Hospital in Toronto, has shown that heat shock protein from E coli, a bacteria found in everyone's intestines, has the same surface protein as many cells in your body. Normal intestines do not permit E. Coli to get into your bloodstream. The people who get rheumatoid arthritis are those whose intestines allow E. coli to pass into the bloodstream and cause the immune reaction that destroys muscles and joints.

Several recent papers show that the antibiotic minocycline helps to control the symptoms of rheumatoid arthritis and another recent study in the Journal of Rheumatology shows that protection is dependant on the dose. Many doctors now treat rheumatoid arthritis with 50 mg of minocycline four times a day.

REACTIVE ARTHRITIS

Usually one to four weeks after an illness, a person develops soreness and pains in many muscles and tendons and in one or more joints. It often occurs with burning on urination following an unfortunate sexual encounter, or a severe intestinal upset such as typhoid or shigella. Other associated symptoms include pain and burning in the eyes and small ulcers in the throat and mouth. The vast majority have a genetic predisposition for arthritis as evidenced by a positive blood test called HLA-B27. For some, the joint pains disappear after 6 month, but for most, the joint and muscle pains continue for many years.

Doctors do not know what causes the muscle and joint pains, but parts of dead, but not live, bacteria have been found in the fluid removed from painful joints. Most doctors treat this condition with antiinflammatory drugs such as aspirin and ibuprofin,/ and cortisone injections into the painful joints. Short term use of antibiotics has not been shown to help treat reactive arthritis, but long term use has resulted in aleviation of symptoms and cures. Therefore, many doctors treat sudden onset of pain primarily in one joint and aches in many muscles with the antibiotic minocycline 100 mg twice a day or clarithromycin 500 mg twice a day for many months.

1. Keystone E. et al. Nature Medicine. April, 1995.
2. (No relation to food) J Kjeldsenkragh, M Hvatum, M Haugen, O Forre, H Scott. Antibodies against dietary antigens in rheumatoid arthritis patients treated with fasting and a one-year vegetarian diet. Clinical and Experimental Rheumatology 13: 2(MAR-APR 1995):167-172.
3. Higher doses more effective. M Kloppenburg, H Mattie, N Douwes, BAC Dijkmans, FC Breedveld. Minocycline in the treatment of rheumatoid arthritis: Relationship of serum concentrations to efficacy. Journal of Rheumatology 22: 4 (APR 1995):611-616.
4. Lack of male hormones may increase susceptability. AT Masi. Sex hormones and rheumatoid arthritis: Cause or effect relationships in a complex pathophysiology? Clinical and Experimental Rheumatology 13: 2 (MAR-APR 1995):227-240.
5. Lancet July 11, 1992.
6. Lucino Yo, M.D. Indiana University.
7. Robert Greenwald, M.D. Long Island Jewish Medical Center.
8. AA Cole, S Chubinskaya, LJ Luchene, K Chlebek, MW Orth, RA Greenwald, KE Kuettner, TM Schmid: Doxycycline disrupts chondrocyte differentiation and inhibits cartilage matrix degradation. Arthritis and Rheumatism 37: 12 (DEC 1994):1727-1734.
9. Barbara Tilley, Henry Ford Health Science Center in Detroit. Annals of Internal Medicine. January 14, 1995.

ANTIBIOTICS AND ARTHRITIS

How do germs cause arthritis? When a germ gets into your body, you manufacture cells and proteins called antibodies that attach to and kill that germ. Sometimes, the germ has a surface protein that is similar to the surface protein on your cells. Then, not only do the antibodies and cells attach to and kill the germ, they also attach to and kill your own cells that have the same surface membranes. People with rheumatoid arthritis have high antibody titre to E. Coli, a bacteria that lives normally in everyone's intestines (1). It has the same surface protein as many cells in your body (3). Normal intestines do not permit E. Coli to get into your bloodstream. The people who get rheumatoid arthritis may be those whose intestines allow E. coli to pass into the bloodstream and cause the immune reaction that destroys muscles and joints. The same type of reaction applies to several other bacteria and viruses that can pass into your bloodstream. Venereal diseases, such as gonorrhea, chlamydia and ureaplasma have been found in the joint fluids of many people with arthritis (2). Antibiotics are effective in controlling the symptoms of rheumatoid arthritis (4,5,6,7) and higher doses are more effective (8). Short-term antibiotics are ineffective (9). Doxycycline may prevent joint destruction by stabilizing cartilage (10) in addition to clearing the germ from the body.

• 1) S Aoki, K Yoshikawa, T Yokoyama, T Nonogaki, S Iwasaki, T Mitsui, S Niwa. Role of enteric bacteria in the pathogenesis of rheumatoid arthritis: Evidence for antibodies to enterobacterial common antigens in rheumatoid sera and synovial fluids. Annals of the Rheumatic Diseases 55: 6 (JUN 1996):363-369.
• 2) F Li, R Bulbul, HR Schumacher, T Kieberemmons, PE Callegari, JM Vonfeldt, D Norden, B Freundlich, B Wang, V Imonitie, CP Chang, I Nachamkin, DB Weiner, WV Williams. Molecular detection of bacterial DNA in venereal-associated arthritis. Arthritis and Rheumatism 39: 6 (JUN 1996):950-958.
• 3) Keystone E. et al. Nature Medicine. April, 1995.
• 4) Kloppenburg et al. Minocycline double blind for RA. Arthritis and Rheumatism 1994;37:629-636.
• 5) Langevitz et al. RA with Minocycline. J.Rheumatology 1992;19:1502-1504.
• 6) Breedveld et al. J Rheumatology 1990;17:43-46.
• 7) Good summary in Lancet 1995(May 27);345:1319-1322.
• 8) Higher doses more effective. M Kloppenburg, H Mattie, N Douwes, BAC Dijkmans, FC Breedveld. Minocycline in the treatment of rheumatoid arthritis: Relationship of serum concentrations to efficacy. Journal of Rheumatology 22: 4 (APR 1995):611-616.
• 9) Short-term antibiotic treatment has no effect in manifest ReA, whereas a tendency to improvement has been seen with treatment over months, at least after chlamydia infection. B Svenungsson. International Journal of STD & AIDS 6: 3:(MAY-JUN 1995):156-160.
• 10) AA Cole, S Chubinskaya, LJ Luchene, K Chlebek, MW Orth, RA Greenwald, KE Kuettner, TM Schmid: Doxycycline disrupts chondrocyte differentiation and inhibits cartilage matrix degradation. Arthritis and Rheumatism 37: 12 (DEC 1994):1727-1734.

WHY ARTHRITIS MAY BE CAUSED BY INFECTION

Rheumatologists usually treat their arthritic patients with non-steroidal antiinflammatory drugs, such as ibuprofin and aspirin. These drugs do not slow down joint damage. Several studies show that they may even increase the rate that joint cartilage is damaged and that they can also cause bleeding in the stomach and kidney damage. Then, as joint pain and destruction increase, rheumatologists prescribe immune suppressants, such as methotrexate and imuran, which shorten life (2).

There are more than 100 different germs that are know to cause arthritis. (3) Lyme disease, from a tick bite, causes horrible arthritis which responds to antibiotics. (4) The most common causes of joint pains in people under 40 are bacteria called mycoplasma (5,6,7,8,9). Rheumatoid arthritis is felt to be tripped off by infection with a bacteria such as E. Coli (10). Rheumatoid spondylitis, arthritis of the spine may be caused by infection with a bacteria called klebsiella (11). All laboratory tests for arthritis are measures of immune reactions against invading germs. Antibiotics effectively treat rheumatoid arthritis (12,13,14,15,16,17,18,19,20) and even osteoarthritis, a type of arthritis that is not associated with infection (21,22,23). The antibiotics used most often to treat arthritis. minocycline and doxycycline (100 mg twice a day), are far safer than any of the drugs commonly used by rheumatologist, such as non-steroidals, aspirin and immune suppressants. It usually takes more than 6 weeks on antibiotics for the pain and swelling to lessen, and the pain usually returns within a few days after the medication is stopped.

• 1) V Goulden, D Glass, WJ Cunliffe. Safety of long-term high-dose minocycline in the treatment of acne. British Journal of Dermatology 134: 4 (APR 1996):693-695.
• 2) B Svenungsson. International Journal of STD & AIDS 6: 3:(MAY-JUN 1995):156-160.
• 2a) R Nanagara, F Li, A Beutler, A Hudson, HR Schumacher. Alteration of Chlamydia trachomatis biologic behavior in synovial membranes: Suppression of surface antigen production in reactive arthritis and Reiter's syndrome. Arthritis and Rheumatism 38: 10 (OCT 1995):1410-1417.

 
• 3) GS Alarcon, IC Tracey, GM Strand, K Singh, M Macaluso. Survival and drug discontinuation analyses in a large cohort of methotrexate treated rheumatoid arthritis patients. Annals of the Rheumatic Diseases 54: 9 (SEP 1995):708-712.

 
• 4) The persistence of B, burgdorferi sl. and clinical recurrences in patients despite seemingly adequate antibiotic treatment is described, The patients had clinical disease with or without diagnostic antibody titers to B, burgdorferi. VP Mursic, W Marget, U Busch, DP Rigler, S Hagl. Kill kinetics of Borrelia burgdorferi and bacterial findings in relation to the treatment of lyme borreliosis. Infection 24: 1 (JAN-FEB 1996):9-16.

 
• 5) JSH Gaston, KHO Deane, RM Jecock, JH Pearce. Identification of 2 Chlamydia trachomatis antigens recognized by synovial fluid T cells from patients with Chlamydia induced reactive arthritis. Journal of Rheumatology 23: 1 (JAN 1996):130-136. These are the first 2 chlamydial antigens to be identified as targets of the synovial T cell response in chlamydia induced ReA. Both have properties that are shared with target antigens identified in ReA induced by enteric infection and relevant to the pathogenesis of joint inflammation.

 
• 6) L Erlacher, W Wintersberger, M Menschik, A Benkestudnicka, K Machold, G Stanek, J Soltzszots, J Smolen, W Graninger. Reactive arthritis: Urogenital swab culture is the only useful diagnostic method for the detection of the arthritogenic infection in extra-articularly asymptomatic patients with undifferentiated oligoarthritis. British Journal of Rheumatology 34: 9 (SEP 1995):838-842.

 
• 7) B Svenungsson. International Journal of STD & AIDS 6: 3:(MAY-JUN 1995):156-160.

 
• 8) L Erlacher, W Wintersberger, M Menschik, A Benkestudnicka, K Machold, G Stanek, J Soltzszots, J Smolen, W Graninger. Reactive arthritis: Urogenital swab culture is the only useful diagnostic method for the detection of the arthritogenic infection in extra-articularly asymptomatic patients with undifferentiated oligoarthritis. British Journal of Rheumatology 34: 9 (SEP 1995):838-842.

 
• 9) J Wollenhaupt, F Kolbus, H Weissbrodt, C Schneider, T Krech, H Zeidler. Manifestations of Chlamydia induced arthritis in patients with silent versus symptomatic urogenital chlamydial infection. Clinical and Experimental Rheumatology 13: 4(JUL-AUG 1995):453-458.

 
• 10) Keystone E. et al. Nature Medicine. April, 1995.

 
• 11) Klebsiela Clinical Rheumatology 15: Suppl. 1 (JAN 1996):62-66. British Journal of Rheumatology 35: 2 (FEB,1996):125-128.

 
• 12) M Kloppenburg, FC Breedveld, BAC Dijkmans. Minocycline in rheumatoid arthritis: Rationale and trial results. Clinical Immunotherapeutics 1996(Jan):5(1):1-4.

 
• 13) Higher doses more effective. M Kloppenburg, H Mattie, N Douwes, BAC Dijkmans, FC Breedveld. Minocycline in the treatment of rheumatoid arthritis: Relationship of serum concentrations to efficacy. Journal of Rheumatology 22: 4 (APR 1995):611-616.

 
• 14) Lancet July 11, 1992.

 
• 15) Kloppenburg et al. Minocycline double blind for RA. Arthritis and Rheumatism 1994;37:629-636.

 
• 16) Langevitz et al. RA with Minocycline. J.Rheumatlogy 1992;19:1502-1504.

 
• 17) Breedveld et al. J Rheumatology 1990;17:43-46.

 
• 18) Good summary in Lancet 1995(May 27);345:1319-1322.

 
• 19) Short-term antibiotic treatment has no effect in manifest ReA, whereas a tendency to improvement has been seen with treatment over months, at least after chlamydia infection. B Svenungsson. International Journal of STD & AIDS 6: 3:(MAY-JUN 1995):156-160.

 
• 20) Higher doses more effective. M Kloppenburg, H Mattie, N Douwes, BAC Dijkmans, FC Breedveld. Minocycline in the treatment of rheumatoid arthritis: Relationship of serum concentrations to efficacy. Journal of Rheumatology 22: 4 (APR 1995):611-616.

 
• 21) AA Cole, S Chubinskaya, LJ Luchene, K Chlebek, MW Orth, RA Greenwald, KE Kuettner, TM Schmid: Doxycycline disrupts chondrocyte differentiation and inhibits cartilage matrix degradation. Arthritis and Rheumatism 37: 12 (DEC 1994):1727-1734.

 
• 22) Barbara Tilley, Henry Ford Health Science Center in Detroit. Annals of Internal Medicine. January 14, 1995.

 
• 23) LP Yu, DB Burr, KD Brandt, BL Oconnor, A Rubinow, M Albrecht. Effects of oral doxycycline administration on histomorphometry and dynamics of subchondral bone in a canine model of osteoarthritis. Journal of Rheumatology 23: 1 (JAN 1996):137-142. Doxycycline protects against joint breakdown in this OA model via inhibition of matrix metalloproteinases in articular cartilage, rather than through an effect on subchondral bone.

 
• 24) S Aoki, K Yoshikawa, T Yokoyama, T Nonogaki, S Iwasaki, T Mitsui, S Niwa. Role of enteric bacteria in the pathogenesis of rheumatoid arthritis: Evidence for antibodies to enterobacterial common antigens in rheumatoid sera and synovial fluids. Annals of the Rheumatic Diseases 55: 6 (JUN 1996):363-369.

 
• 25) F Li, R Bulbul, HR Schumacher, T Kieberemmons, PE Callegari, JM Vonfeldt, D Norden, B Freundlich, B Wang, V Imonitie, CP Chang, I Nachamkin, DB Weiner, WV Williams Molecular detection of bacterial DNA in venereal-associated arthritis. Arthritis and Rheumatism 39: 6 (JUN 1996):950-958.

 
• 26) MR Lovy, G Starkebaum, S Uberoi. Hepatitis C infection presenting with rheumatic manifestations: A mimic of rheumatoid arthritis. Journal of Rheumatology 23: 6 (JUN 1996):979-983.

 
• 27) M Ostensen, H Ostensen. Safety of nonsteroidal antiinflammatory drugs in pregnant patients with rheumatic disease. Journal of Rheumatology 23: 6 (JUN 1996):1045-1049.

 

ANKYLOSING SPONDYLITIS

Ankylosing spondylitis may be caused by an infection. Sufferers often have high blood levels of IGG antibodies that the body produces to kill germs. They also usually have a positive blood test for HLA-B27, a genetic marker for arthritis. Klebsiella is a bacteria that normally lives in the intestines of healthy people. The surface structure of Klebsiella contains 2 surface molecules similar to that of the HLA- B27 that is associated with arthritis. When the pain is severe, large amounts of Klebsiella are found in stool samples, and those with ankylosing spondylitis often have intestinal ulcers in the end of the small intestine. Patients with this condition from 10 different countries have high blood levels of antibodies against the Klebsiella bacteria. Therefore, Klebsiella bacteria, found in the normal intestine, might trigger the back pain. This germ grows luxuriously in intestines of people who eat a lot of refined starch. So, researchers arranged to place people with the severe back pain of ankylosing spondylitis on a diet that omits bread, spaghetti, macaroni, bagels, white rice, crackers, cookies, pastries and rolls. Blood levels of (IGA) antibodies dropped significantly, but more important, the back pain lessened significantly. Other doctors treat this condition with daily doses of the antibiotic, minocycline.

• A Ebringer, C Wilson. The use of a low-starch diet in the treatment of patients suffering from ankylosing spondylitis. Clinical Rheumatology 15: Suppl. 1 (JAN 1996):62-66

DOXYCYCLINE FOR ARTHRITIS

Arthritis means pain in the joints. Pain can be caused by trauma such as an accident, crystals in the joint fluid as in gout, and the two most common types called reactive arthritis and degenerative arthritis. The conventional treatment for arthritis is highly unsatisfactory. Doctors prescribe nonsteroidals such as ibuprofin which block pain, but also help to increase the rate that cartilage is destroyed. When a patient has severe joint damage, the doctor prescribes immunosuppressants, such as methotrexate, which inhibit immunity and shorten life.

The current theory is that the body's own immunity destroys the joints. Why should the immunity be so stupid that it destroys joints instead of attacking germs? All tests for arthritis are measures of an immunity that is too active. Rheumatoid factor is an antibody against your own antibodies. ASO and CRP and Lyme tests are antibodies against bacteria. There are more than 25 different germs that are known to cause arthritis. The most common cause of arthritis in people under 40 is chlamydia or mycoplasma, often a venereal disease. Several recent papers, including one from the current Journal of Rheumatology, show parts of chlamydia in the joint fluids of people with this type of arthritis (1).

People with arthritis and who have negative blood tests for arthritis ar often told that they have degenerative arthritis. Several recent papers show that the antibiotic doxycycline, helps to prevent joint breakdown in osteoarthritis (2)

So, it is reasonable to treat people with reactive or osteoarthritis with 100 mg of doxycycline per day. It usually takes more than 2 months for the joint pain to subside and the pain often returns when they stop taking the antibiotic. Doxycycline is safer than the other drugs used to treat arthritis.

• 1) JSH Gaston, KHO Deane, RM Jecock, JH Pearce. Identification of 2 Chlamydia trachomatis antigens recognized by synovial fluid T cells from patients with Chlamydia induced reactive arthritis. Journal of Rheumatology 23: 1 (JAN 1996):130-136. These are the first 2 chlamydial antigens to be identified as targets of the synovial T cell response in chlamydia induced ReA. Both have properties that are shared with target antigens identified in ReA induced by enteric infection and relevant to the pathogenesis of joint inflammation.

 
• 2) LP Yu, DB Burr, KD Brandt, BL Oconnor, A Rubinow, M Albrecht. Effects of oral doxycycline administration on histomorphometry and dynamics of subchondral bone in a canine model of osteoarthritis. Journal of Rheumatology 23: 1 (JAN 1996):137-142. Doxycycline protects against joint breakdown in this OA model via inhibition of matrix metalloproteinases in articular cartilage, rather than through an effect on subchondral bone.

TREAT RHEUMATOID ARTHRITIS EARLY WITH ANTIBIOTICS

Rheumatoid arthritis is characterized by pain in many muscles and joints and is thought to be caused by a person's own antibodies and cells attacking and destroying cartilage in joints. Several recent studies show that rheumatoid arthritis may actually be triggered by infection and that antibiotics may help to prevent and treat this joint destruction. (1 to 10) Most studies showing that antibiotics help to relieve the symptoms of rheumatoid arthritis were done on people who already had significant destruction of their joints.

All blood tests for rheumatoid arthritis are measures of increased immunity. Rheumatoid factor is an antibody against a person's own IGG antibody. Antistreptolysin O is an antibody against the strep bacteria. C reactive protein is an antibody against the pneumococcal bacteria, and the sed rate is a measure of immunity. The usual treatment for rheumatoid arthritis is to take aspirin-like medications called nonsteroidal anti-inflammatory drugs, such as Motrin, Tolectin and Indocin, which help to lessen pain, but do not stop joint destruction. After many years, the cartilages in the joints are destroyed and the doctor prescribes methotrexate, imuran and other toxic drugs that stop a person's immunity from continuing to destroy the joints. A recent report in The Annals of Rheumatic Diseases shows that these drugs are highly toxic and hasten death by destroying immunity. (11) In the future, people with suspected rheumatoid arthritis may be treated with doxycycline 100 mg twice day as soon as the disease is suspected.

• 1) Higher doses more effective. M Kloppenburg, H Mattie, N Douwes, BAC Dijkmans, FC Breedveld. Minocycline in the treatment of rheumatoid arthritis: Relationship of serum concentrations to efficacy. Journal of Rheumatology 22: 4 (APR 1995):611-616.

 
• 2) Lancet July 11, 1992.

 
• 3) AA Cole, S Chubinskaya, LJ Luchene, K Chlebek, MW Orth, RA Greenwald, KE Kuettner, TM Schmid: Doxycycline disrupts chondrocyte differentiation and inhibits cartilage matrix degradation. Arthritis and Rheumatism 37: 12 (DEC 1994):1727-1734.

 
• 4) Barbara Tilley, Henry Ford Health Science Center in Detroit. Annals of Internal Medicine. January 14, 1995.

 
• 5) Short-term antibiotic treatment has no effect in manifest ReA, whereas a tendency to improvement has been seen with treatment over months, at least after chlamydia infection. B Svenungsson. International Journal of STD & AIDS 6: 3:(MAY-JUN 1995):156-160.

 
• 6) Kloppenburg et al. Minocycline double blind for RA. Arthritis and Rheumatism 1994;37:629-636.

 
• 7) Langevitz et al. RA with Minocycline. J.Rheumatlogy 1992;19:1502-1504.

 
• 8) Breedveld et al. J Rheumatology 1990;17:43-46.

 
• 9) Good summary in Lancet 1995(May 27);345:1319-1322.

 
• 10) T Origuchi, K Eguchi, Y Kawabe, I Yamashita, A Mizokami, H Ida, S Nagataki. Increased levels of serum IgM antibody to staphylococcal enterotoxin B in patients with rheumatoid arthritis. Annals of the Rheumatic Diseases 54: 9 (SEP 1995):713-720.

 
• 11) GS Alarcon, IC Tracey, GM Strand, K Singh, M Macaluso. Survival and drug discontinuation analyses in a large cohort of methotrexate treated rheumatoid arthritis patients. Annals of the Rheumatic Diseases 54: 9 (SEP 1995):708-712