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Rheumatic Disease Information

     There are over one hundred forms of arthritis. They afflict children, adults, and the elderly alike. Arthritis is distributed worldwide and afflicts men and women of all ethnic backgrounds. The presentation, progression, and severity may differ, but allmost all of them affect the joints. They can affect a single joint (monoarticular), a few joints (oligoarticular), or many joints (polyarticular). The progression may be rapid or slow and in some cases internal organs are involved. The spectrum of the clinical severity ranges from  mild to the very severe. Certain forms of arthritis affecting internal organs can  even be lethal.

Rheumatic Disease Information

Infections and Rheumatic Diseases

     The interrelationship between infections and rheumatic diseases has been discussed in the medical literature for decades. Microorganisms that cause bone and joint disease include bacteria, Mycoplasmas, viruses, fungi, and parasites.

Bacterial infections
Bacterial infections are most important in rheumatological diseases since they are known to cause septic arthritis (figure 1), reactive arthritis (figure 2), osteomyelitis (figure 3), and osteitis.

Figure 1

Bacteria Associated
with Septic Arthritis

Bacteroides fragilis
Enterococcus faecium
Enterococcus faecalis
Escherichia coli
Haemophilus influenzae
Klebsiella pneumoniae
Mycobacterium tuberculosis
Neisseria gonorrhoeae
Proteus mirabilis
Pseudomonas aeruginosa
Salmonella species
Staphylococcus aureus
Staphylococcus epidermidis
Streptococcus pneumoniae
Streptococcus pyogenes

Figure 2

Bacteria Most Commonly Found Triggering Reactive Arthritis

Borrelia burgdorferi
Campylobacter jejuni
Chlamydia trachomatis
Neisseria gonorrhoeae
Salmonella species
Shigella flexneri
Streptococcus pyogenes
Yersinia enterocolitica
Yersinia pseudotuberculosis

Figure 3

Bacteria Associated
with Osteomyelitis

Bacteroides fragilis
Enterobacteriaceae species 
     (Escherichia coli,
      Salmonella, Proteus,
      Klebsiella)
Mycobacterium tuberculosis
Non-group A streptococci
Peptostreptococcus anaerobius
Prevotella melaninogenica
     (formerly Bacteroides
     melaninogenicus)
Pseudomonas aeruginosa
Staphylococcus aureus

Viral infections
There are multiple viruses implicated in arthritis. There are some viruses that frequently cause arthritis (figure 4), such as rubella virus, human parvovirus B19, Hepatitis B virus, and others that less commonly affect the joints (figure 5).  

Figure 4

Figure 5

Viral Diseases Often Accompanied
by Arthritis

Virus/Disease Virus present
in Joint*
Alphaviruses
      Chikungunya
      Mayaro
      O'nyong-nyong
      Ibgo-Ora
      Ross River (epidemic polyarthritis)
      Sindbis
      Ockelbo (Pogosta and
Karelian fevers)
       Babanki
       Barmah Forest
Hepatitis B virus
Parvovirus B19
Rubella 
Mumps
Chickenpox

Yes
Yes

Yes

Viral Diseases Seldom Accompanied by Arthritis

Virus/Disease Virus present in Joint*

Adenovirus
Enteroviruses
   Echoviruses
   Coxsackieviruses
Hepatitis A virus
Herpesviruses
   Herpes simplex
   Varicella-zoster
   Epstein-Barr virus
   Cytomegalovirus        

Yes
Yes
Yes
Yes

* Demonstrated by culture, antigen detection of polymerase chain reaction in synovium/synovial fluid cells.

Fungal infections
Species of fungi (figure 6) are also known to be pathogens that can lead to arthritis, and include candida (figure 7).  

Figure 6

Fungi Associated with Joint and Bone Lesions
Actinomyces israelii
Actinomyces bovis
Aspergillus fumigatus
Blastomyces dermatidis
Candida albicans
Candida guillermondi
Candida tropicalis
Cephalosporium
Coccidiodes immitis
Cryptococcus neoformans
Histoplasma capsulatum
Petrilidium boydii
Sporothrix schenkii

Figure 7

Fungus
Underlying disease
Type of involvement
Location

Treatment
Candida Immunocompromised, i.v. drug abuser, broad spectrum antibiotics Osteomyelitis Chronic Monoarthritis Vertebrae,
Knee, hip, shoulder
Amphotericin B plus 5-flurocytosine plus arthrocentesis

Parasitic infections

Parasites (figure 8) have been associated with joint and bone lesions. These include protozoa, flat worms, and round worms.

Figure 8

Parasites Associated with Joint and Bone Lesions

Echinococcus granulosus
Giardia lamblia
Schistosoma mansoni
Strongyloides stercoralis
Taenia solium (larvae)
Taenia saginata (larvae)
Toxoplasma gondii
Trichinella spiralis
Trypanosoma cruzi (found in muscle)

 

Adjuvant Arthritis

It is interesting to note that microbial particles have been able to induce arthritis when injected into rats. This form of arthritis is called adjuvant arthritis. It was first described in 1956 by Pearson. It was induced by an intradermal injection of killed dried mycobacteria and mineral oil. Other bacteria have been used with the same response. After a latent period of 10-14 days following the injection, inflammation appears in the ankles, wrists, tarsals, and interphalangeal joints of rats. This disease is not limited to the joints, but has extra-articular manifestations, including tendonitis, iritis, nodular lesions in the visceral organs, urethritis, and diarrhea. The rheumatoid factor is not produced in this experimental form of arthritis. The symptoms peak about 15-25 days after the injections, followed by slow resolution. The synovial lesions when viewed under the microscope are similar to those observed in human rheumatoid arthritis. Here are some examples of microbe induced arthritis (figure 9).

Figure 9

Microbe-Induced Models of Arthritis

Microbe/microbial Component
Species
Natural Infections Caprine arthritis-encephalitis virus Goat

Erysipelothrix rhusiopathiae

Pig, dog, rabbit
Mycoplasma hyorhinis Pig
Mycoplasma synoviae Chicken
Mycoplasma arthritidis Rat
Chlamydia psittaci Cow, sheep
Experimental

Bifidobacterium cell-wall components

Rat
Escherichia coli Rabbit
Eubacterium cell-wall components Rat
Killed tubercle bacilli Rat
Lipopolysaccharide Rat
Mycoplasma arthritidis Mouse, rat
Mycoplasma gallisepticum Chicken
Mycoplasma pulmonis  Mouse, rat
Neisseria gonorrhoeae  Rabbit
Salmonella enteritidis  Rat
Staphylococcus aureus Rabbit
Streptococcal cell-wall components Rat
Streptococcus pyogenes  Rabbit
Yersinia enterocolitica O:8 Rat

 

Rheumatic Fever

   It is well accepted and understood that rheumatic fever is caused by Streptococcus pyogenes infection. After a latent period, symptoms related to the target organs ensue including arthritis, carditis, central nervous system involvement, and the occurrence of subcutaneous nodules. At times patients, following a streptococcal  infection, may develop kidney involvement (glomerulonephritis). This is due to a cross-reactivity (molecular mimicry), between the cell wall structure of the group A Streptococcus (Streptococcus pyogenes) and human tissue. Other times there is a cross-reactivity to the heart valves, heart muscles and pericardium.  The arthritis is is also thought to be due to cross-reactivity between bacterial cellular components  (peptidoglycans and carbohydrates), with human  structures containing glucosamine found in human cartilage, synovium, and tendons.

Reactive Arthritis

     Reactive arthritis has been associated with sexually transmitted diseases such as gonococcal urethritis. However, it is more frequently from Chlamydia infection. Chlamydia is a microorganism that grossly resembles Mycoplasmas. This illness will produce local (genital) and distant (joint, skin, eyes) damage. There are also multiple intestinal bacteria that can produce reactive arthritis, including Salmonella species, Shigella species, as well as Yersinia species. Other pathogens that reside in the intestine, including Klebsiella pneumoniae, have been associated with ankylosing spondylitis. More recently, Borrelia burgdorferi has been associated with Lyme's disease (figure 10). Patients with Lyme's disease not only have involvement of the joints (figure 11), but also skin (figure 12), brain (figure 13), and heart (figure 14). This disease is caused by a spirochete which is transmitted by a tick.

Figure 10

Lyme Disease Definition A tick-borne infection with the spirochete Borrelia burgdorferi, causing systemic inflammatory lesions of the skin, joints, nervous system and/or heart.
Clinical features

Typical peak incidence in summer and fall months in geographic areas endemic for infected tick vectors.  

First clinical feature usually expanding skin lesions, erythema migrans, occurring at sites of tick bites.  

Subsequent development of disseminated infection in most untreated patients resulting in a clinical picture which varies over time and, in some instances, chronic inflammation of joints, nervous system, heart or skin.  

Diagnosis based on clinical features, especially erythema migrans, and confirmatory serologic testing.  

Antibiotic treatment highly effective.

Syphilitic Arthritis Definition

Osteoarticular lesions occurring in congenital, secondary and tertiary forms of syphillis caused by infection with the spirochete Treponema pallidum.

Clinical features Diagnosis based on typical patterns of joint involvement, rash and lymphadenopathy, as well as serologic testing.

Figure 11

Late Manifestations

Musculoskeletal system
  • Recurrent, brief attacks (lasting weeks or months) of objective joint swelling in one or a few joints, sometimes followed by chronic arthritis in one or a few joints
  • Manifestations not considered to be criteria for diagnosis include chronic symmetric polyarthritis not preceded by brief attacks, chronic symmetric polyarthritis, or arthralgias, myalgias or fibromyalgia syndromes alone

Figure 12

Erythema migrans

  • Skin lesion typically beginning as a red macule/papule and expanding over days or weeks to form a large round lesion, often with partial central clearing
  • A solitary lesion must measure at least 5 cm; secondary lesions may also occur
  • An annular erythematous lesion developing within several hours of a tick bite represents a hypersensitivity reaction and does not qualify as erythema migrans
  • The expanding EM lesion is usually accompanied by other acute symptoms, particularly fatigue, fever, headache, mildly stiff neck, arthralgias and myalgias, which are typically intermittent
  • Diagnosis of EM must be made by a physician
  • Laboratory confirmation is recommended for patients with no known exposure

Figure 13

Late Manifestations

Nervous system
  • Lymphocytic meningitis, cranial neuritis, particularly facial palsy (may be bilateral), radiculoneuropathy or, rarely, encephalomyelitis alone or in combination
  • Encephalomyelitis must be confirmed by evidence of antibody production against Borrelia burgdorferi in cerebrospinal fluid (CSF), shown by a higher titer of antibody in the CSF than in serum
  • Headache, fatigue, paresthesias or mildly stiff neck alone are not accepted as criteria for neurologic involvement

Figure 14

Late Manifestations Cardiovascular system
  • Acute-onset, high-grade (2nd-or-3rd-degree) atrioventricular conduction defects that resolve in days to weeks and are sometimes associated with myocarditis
  • Palpitations, bradycardia, bundle-branch block or myocarditis alone are not accepted as criteria for cardiovascular involvement

 

Mycoplasma Infection

     Mycoplasma infections have for years been addressed in medical literature, but more recently have regained interest and with it the awareness of their role as trigger factors causing different forms of arthritis.

     The role of Mycoplasma in arthritis has been debated for years. Mycoplasma species differ from bacteria in that they are very small, and they lack a cell wall. Mycoplasmas are the smallest organisms that are able to survive outside of cells. They are a major cause of respiratory disease. They can remain in respiratory secretions for a long time after the signs of infections have disappeared. They can also be found in other organs causing disease. These organs include the genitals, the brain, and joints. They can also be found transiently in the blood and sometimes with the peripheral white blood cells, also called leukocytes. The organisms are then transported to different parts of the body. They enter the tissue in different areas and cause injury to the cell mucosa. Once this damage has occurred, the body frequently is unable to clear the Mycoplasma from the site of infection without antimicrobial treatment. They can reside for years in the tissue without being detected. Mycoplasmas have also been found in individuals who do not have apparent disease. Our research showed that 15% or less of healthy individuals have Mycoplasma infection. They can also be innocent bystanders (commensals). Since Mycoplasma is difficult to recover by routine culture once this has occurred, the laboratory must use other recovery methods. The two most common methods are ELISA, which detects antibodies of current and past infections, and PCR, which detects the genetic fingerprint of the Mycoplasma infection within the cells.

     The genus of Mycoplasma is comprised of 69 species of which 13 can be pathogenic. Some infect humans and others infect plants or animals.

     At the Arthritis Center of Riverside, we have conducted research for many years to determine the relationship between infectious microorganisms and different forms of arthritis. We have also published some of our results in scientific journals

      Our published studies have shown that approximately 50% of the patients who have rheumatoid arthritis, fibromyalgia, chronic fatigue syndrome, and Gulf War illness, have evidence of Mycoplasma infection. Mycoplasma infection can be difficult to treat. Sometimes it requires a combination of oral and parenteral antibiotics for prolonged periods.

Rheumatoid Arthritis (R.A.)

     Rheumatoid Arthritis is an inflammatory chronic disease that affects mostly joints and at times internal organs. Genetic predisposition and environmental factors play an important role. It is of worldwide distribution and affects all ethnic groups. It affects females twice as much as it does males. The peak incidence occurs between the fourth and the sixth decades. Although the cause of R.A. remains unclear in the mainstream literature, the possibility of bacterial, mycoplasma or viral infections is relevant, since all these pathogens can induce chronic arthritis in animal models or humans. Furthermore, the deposition of bacterial products in synovial tissue as well as chronic infections have been shown to be responsible for chronic synovial inflammation. Examples of these infections include those caused by such microorganisms as Borrelia burgdorferi that causes Lyme disease, Parvo virus causing inflammatory arthritis, and Rubella virus producing chronic polyarthritis.

     Several research groups as well as Dr. Franco have shown the association of mycoplasma infection with several inflammatory arthropathies.

     Although the clinical picture of R.A. is variable, usually patients present with a symmetrical polyarthritis affecting large, medium and small joints and occasionally the cervical spine. Extra-articular manifestations may involve the skin with the formation of nodules and or vasculitis. The respiratory tract may be involved with interstitial pulmonary  fibrosis that usually affects the bases of the lungs, lung nodules, and pleurisy. Likewise, the lining of the heart may be involved; the heart muscle itself and valves can also be affected. The salivary glands produce less secretion in Sjogren's associated with R.A. Neurological complications may affect the peripheral nerves or the spinal cord due to instability of the cervical spine caused by involvement of the cervical vertebrae. Anemia is not uncommon and correlates with disease activity. Elevated platelet counts are found in severe cases and they correlate with inflamtion. . Low white count is rarely encountered. Finally, renal involvement is very infrequent and usually caused as a toxic side effect of medications.

The following chart shows the diagnostic criteria for the classification of Rheumatoid Arthritis.

The American Rheumatism Association 1987 
Revised Criteria for the Classification of Rheumatoid Arthritis*

Criterion
Definition
1. Morning stiffness Morning stiffness in and around the joints, lasting at least 1 hour before maximal improvement
2. Arthritis of three or more joint areas At least three joint areas simultaneously have had soft tissue swelling or fluid (not bony overgrowth alone) observed by a physician. The 14 possible areas are right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints
3. Arthritis of hand joints At least one area swollen (as defined above) in a wrist, MCP, or PIP joint
4. Symmetric arthritis Simultaneous involvement of the same joint areas (as defined in 2) on both sides of the body (bilateral movement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry)
5. Rheumatoid nodules Subcutaneous nodules, over bony prominences, or extensor surfaces, or in juxtaarticular regions, observed by a physician.
6. Serum rheumatoid factor Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in <5% of normal control subjects
7. Radiographic changes Radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist radiographs, which must include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints (osteoarthritis changes alone do not qualify)
* For classification purposes, a patient shall be said to have rheumatoid arthritis if he/she has satisfied at least four of these seven criteria. Criteria 1 through 4 must have been present for at least 6 weeks. Patients with two clinical diagnoses are not excluded. Designation as classic, definite, or probable rheumatoid arthritis is not to be made.
Reprinted from Arnett FC, Edworthy, SM, Bloch DA, et all The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315-342, 1988, with permission of the American College of Rheumatology.

 

Antibiotics for Rheumatoid Arthritis — Our Experience

     Since January 1988 we have treated several thousand rheumatoid arthritis  patients with antibiotics. In order to determine the efficacy and safety of different antibiotic regimes and how they compare to our experience with disease-modifying antirheumatic drugs (DMARD), in treatment of rheumatoid arthritis, doctor Franco reviewed retrospectively, data on patients treated in a private practice setting at the Arthritis Center of Riverside in southern California.  Two hundred fifty five adults, whose age averaged 53 years at onset of treatment, and who had active rheumatoid arthritis, were selected from a larger number of patients on antibiotics with various rheumatic diseases (rheumatoid arthritis, juvenile rheumatoid arthritis, Reiter's syndrome, ankylosing spondylitis, systemic lupus erythematosus, scleroderma, etc.) The disease duration averaged 7 years prior to antibiotic treatment. The severity of illness was on average moderate, ranging from mild to severe. All patients had received the conventional and accepted treatment modalities for rheumatoid arthritis. The patients that were on disease-modifying antirheumatic drugs prior to antibiotic treatment, continued on them. Later some of these patients were able to decrease and even discontinue DMARD's. The antibiotics used included Clindamycin, Erythromycin, Tetracycline, the second generation Doxycycline, and the third generation Minocycline. A small number of patients were on other antibiotics. The patients were followed for an average of two years, ranging between six months and seven years. The results were based on patient assessment, examiner (doctor) assessment, laboratory and radiographic data.

     The results show that 78% of patients had a better than 20% improvement, and 53% had a better than 50% improvement. 22 % of the patients did not improve. Other findings were as follows:

  1. The earlier the treatment is started in the course of the illness, the better the results.
  2. The milder the disease, the better the response to the antibiotics.
  3. The longer the duration of treatment, the greater the improvement.
  4. The best responders were, on average, younger patients.
  5. Frequently patients worsen initially for a few weeks before noticing improvement due to Herxheimer reaction.
  6. The most effective antibiotics were the combination of oral Minocycline and intravenous Clindamycin.
  7. Tetracycline, especially at low doses, was not as effective.
  8. The incidence of side effects was minimal and usually mild, even in patients followed for several years.

     Dr. Franco concluded that the antibiotics tested were effective and safe for rheumatoid arthritis patients. These antibiotics should be a valuable addition to the armamentarium for the treatment of rheumatoid arthritis, especially in view of the fact that disease-modifying antirheumatic drugs were often not effective or tolerated for long periods of time.

      The treatment that Dr. Brown advocated for years, and that Dr. Franco continues to advocate now, is promising. It is based on a different perspective that the disease is potentially curable. So, there is hope for patients with rheumatoid arthritis and other rheumatic diseases. Most rheumatologists agree that the treatment of patients should be individualized, preferably using less toxic drugs. Because of our experience at the Arthritis Center of Riverside, we are refining treatment modalities based on a better understanding of how infections, especially chronic and hidden infections, trigger the immune system to partake in the ensuing damage of joints and other target organs. We find it is equally important to strengthen the immune system, to neutralize the inflammatory response, and to repair damaged tissue, preferably with non-toxic agents such as nutritional supplements.

Herxheimer Reaction

     We have noticed that initially patients may worsen. This is caused by a Herxheimer reaction. This is due to an increase in circulating bacterial particles and toxins, which promote an antigenic reaction that produces an intense inflammatory response. This can provoke flu like symptoms, increased arthralgias, myalgias, depression, fatigue, poor memory and concentration with increased reactive .

 

Scleroderma

     Although our experience with scleroderma is not nearly as extensive as our experience with rheumatoid arthritis patients, over the years we have seen several hundred patients who have had variable responses to antibiotics. Basically, we can group the responsive patients in three: those patients that will improve and reverse their disease, the patients that will stabilize and not worsen further, and the patients that will continue to worsen. The latter group is the one comprised of patients who come to the Arthritis Center of Riverside because they have terminal disease. These patients have pulmonary, cardiac, gastrointestinal, and renal involvement. Therefore, we find that the favorable responses occur when we are able to treat the patient earlier in the disease course. Some responses are very dramatic, with reversal of skin changes in a matter of 6-12 months. In some patients, we have also noticed that renal function tests have improved. Overall we have observed that we can stop or reverse the progress of scleroderma in 2/3 of our cases.

Systemic Lupus Erythematosus

     Our experience with systemic lupus erythematosus shows that some patients benefit from the antibiotic treatment. They can benefit significantly with improvement of their joints, skin, and pulmonary conditions. Lupus patients, nonetheless, may get worse at times with the administration of the tetracycline family antibiotics including Doxycycline and Minocycline. One should be cautious in administering this drug to systemic lupus patients since these antibiotics may, even in normal individuals,  promote drug-induced lupus The blood markers of drug induced lupus include the anti-histone and anti-chromtin antibodies. .We can monitor this very ??with specific laboratory tests. 

Fibromyalgia

     The fibromyalgia syndrome (FMS) is the most common rheumatic cause of chronic diffuse pain. The most important clinical features of FMS are symptoms of diffuse aching, stiffness, and fatigue coupled with a physical examination that demonstrates multiple tender points in specific areas. The pathophysiology has yet to be fully elucidated. Patients may have no underlying disease or may have concomitant chronic diseases such as RA, osteoarthritis, Lyme disease, or sleep apnea. In the absence of an underlying condition, FMS is characterized by a strong female predominance (>75% in most series) with a peak incidence ages 20-60 years old. FMS has been observed in up to 20% of rheumatology patients and about 5% of patients from a general medical practice. It was present in 2% of a random sample of Midwestern residents. It is estimated that there are 3-6 million Americans who suffer with it.

Location of the specific tender points in fibromyalgia.

 

     Dr. Franco's research has shown that 54% of patients with FMS have mycoplasma infection, (click here for more) compared to 15% of healthy controls.

     Fibromyalgia is now recognized as a chronic disorder that requires long-term treatment. Treatment is directed at education of patients regarding their illness, prescribing anti-depressant medications, preferably low doses, progressive aerobic conditioning, myofascial therapy in the form of stretching and psychological support. It is now recognized that patients can go from a regional myofascial pain syndrome (such as occurs in an injury) to a more characteristic generalized picture of fibromyalgia. In addition to aches and pains, multiple muscle tender points, fatigue and disturbed sleep pattern, these patients are also known to have increased incidence of headaches, irritable bowel syndrome, irritable urinary bladder syndrome, dysmenorrhea with premenstrual syndrome-like symptoms, cold sensitivity, restless legs, Raynaud's like phenomenon, atypical complaints of fleeting pain, burning and tingling in muscle groups, exercise intolerance and variable fatigue. Fatigue at times can be so severe that patients will require variable periods of rest including prolonged periods of bed rest.

     Conventional treatment is not always helpful, especially in patients with generalized and entrenched fibromyalgia. A multidisciplinary treatment approach is best including nutrients, appropriate physical therapy, acupuncture, trigger point injections, and psychological support.

 

 

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Arthritis Center of Riverside
11725 Slate Avenue
Riverside, CA  92505
Tel: 951.352.1700
Fax: 951.352.9117

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     *The information in this website is not intended to replace a rheumatology textbook nor be a complete update of the rheumatology scientific literature.  It should not be misconstrued as personal medical advice.  Rather, it portrays Dr. Al Robert Franco's interests in the field of rheumatology, namely, the interrelationship between infections and rheumatic diseases and how this applies to the treatment of arthritis.