ARTHRITIS IN THE NEWS

       The topic of arthritis can be dizzyingly complex, with not only many different types of arthritis, but different treatment strategies based on different theories of the pathogenesis of the various types. Arthritis can be generally classified as degenerative, metabolic, and immune-mediated; but the definitive separation among these classifications is often blurred as the pathogenesis is explored in greater detail. Most subtypes of arthritis bear some autoimmune component, and most categories of autoimmune disease and inflammatory disease share comorbidity with arthritic disease of some type, positive rheumatoid factor, and other autoimmune diseases. Over a hundred different types of arthritis are described in the literature, but this general overview of a few manifestations may be helpful in staying informed on what is current.
      Ankylosing spondylitis (also Marie-Strumpell disease) is a spinal form of arthritis affecting the back and spine, but not infrequently involving the hips, shoulders, knees, or ankles as well. Joints and ligaments of the spine become inflamed and stiff and may eventually fuse to cause rigidity and inflexibility in addition to pain and swelling. Heredity seems to be a major risk factor, with one in five victims having a relative with ankylosing spondylitis. HLA-B27, a gene present in over 90% of victims, 8% of healthy white Americans, and 3% of healthy African Americans leads to expression of the disease in about 15% of all who inherit the gene (about 1% of the general population -- 300,000 Americans). Ankylosing spondylitis is seen three times as often in whites than in African Americans, and is more common in men.
     Inflammatory bowel disease (IBD – both Crohn's disease and ulcerative colitis) is considered an autoimmune disease and is characterized by chronic inflammation of the intestines that damages the bowel to permit entry of bacteria through the damaged bowel and into the bloodstream. Immune reaction to these bacteria may then cause problems in other areas of the body (skin sores, inflammation of the eyes, certain types of liver disease, and arthritic pain and swelling of the joints).
     Ulcerative colitis produces inflammation and breakdown along the lining of the colon, with inflammation commonly beginning in the rectum and extending up the colon to cause rectal bleeding, abdominal cramping, weight loss, and fever. Bowel symptoms generally precede the onset of arthritic symptoms (seen in about 25% of IBD patients); and joint symptoms usually appear between the ages of 25 and 45, most often when the large intestine is involved. Extent and severity of joint involvement typically mirrors that of bowel symptoms and may vary, correlating closely to flare-ups of bowel symptoms. Hips, knees, and ankles are affected most often, although any joint may be affected; one or more joints may be affected; and symptoms frequently migrate from one joint to another. Permanent joint damage is rare; but ulcerative colitis patients occasionally develop ankylosing spondylitis.
     Crohn's disease usually affects the lower small intestine, though it may involve any part of the digestive tract, from mouth to rectum, with inflammation of all layers of the intestinal wall. Fever, weight loss, loss of appetite, and scarring and narrowing of the bowel are common. Arthritic symptoms are seen before, after, concurrently with bowel symptoms, generally affecting the knees and ankles, though not necessarily bilaterally, and back pain can result from ankylosing spondylitis.
     Behcet's disease is rare affecting 15,000 to 20,000 people in the United States, mostly young adults between the ages of 20 and 30, and mostly women. It is characterized by classic symptoms of recurring mouth sores, uveitis, recurring genital sores, skin sores and/or a positive Behcetin Reaction; but it can involve arthritic pain and swelling of the knees, ankles, elbows, and wrists (usually without joint deformity); abdominal pain and tenderness and bloody stools (sometimes mistaken for Crohn's disease); fever, neck stiffness, and headaches (when the CNS in affected); phlebitis, usually in the legs, that may cause pain, swelling, and even cause thrombosis ; and lung or heart involvement that can be life-threatening.
     Osteoarthritis (OA), or degenerative joint disease (DJD), is the most common type of arthritis, victimizing 16 million people in the United States -- almost everyone over the age of 60 to some extent. Injuries, joint overuse, and genetic predisposition all seem to play a part in the disease process that involves progressive degeneration of the articular cartilage that provides a cushion between the bone surfaces of a joint and eventually degeneration of the bone itself. Collagen (hence the relationship with collagen diseases) and cartilage are produced by chondrocytes in a process that involves proteoglycans, chondroitin, and keraton sulfate or core proteins. The surface of the cartilage softens, becoming pitted and frayed as it breaks down, often altering the normal shape of the bones and joint. Articular ends of the bones thicken and form spurs at attachments.
     Such damage to the joint causes aching, stiffness, roughness on motion, and limited range of motion, particularly after heavy use. Since the cartilage has no sensory nerve endings, pain is generated by secondary effects of the disease that may not appear until substantial damage has been incurred.
     Rheumatoid Arthritis (RA) is the classic example of an autoimmune disease, and the overall pattern of the joint involvement generally differentiates it from other similar conditions. Rheumatoid factor is common but not always present; and joints tend to be involved in a bilateral symmetry not found as often in most other types of arthritis. It persists over prolonged periods of time, eventually causing deformity of affected joints. Some other forms of arthritis manifest shorter episodes and are less likely to cause permanent damage.
      Infectious arthritis is caused by infection with certain bacteria (gonococcus, certain Gram-positive bacteria, certain Gram-negative bacteria, spirochetes, and tuberculosis), viruses (infectious hepatitis, mumps, German measles, and infectious mononucleosis), or fungi (from in soil, bird droppings and certain plants). Infectious arthritis may occur without other infection (as in a trauma or surgical procedure that affords pathogen access to the joint directly), but it usually results from a previous infection of some other tissue, gaining access to the bloodstream and spreading to one or more joints. Typically, only one of the large joints (shoulders, hips, and knees) becomes infected, though involvement of two or three joints is occasionally seen.
     Since immunosuppression predisposes to infection, rheumatoid arthritis patients on immunosuppressive therapy can also get infectious arthritis that can be confused with a flare-up of the primary disease; so sudden exacerbations of symptoms should be carefully evaluated in such patients. AIDS patients are also at particular risk of infectious arthritis for obvious reasons; and particular jobs and environments can increase the risk (those who work with animals, plants, soil, or marine life -- farmers, gardeners, or fishermen), since animals and materials with which they come in constant contact can carry the infectious agents.
      Systemic lupus erythematosus (SLE) is a rheumatic autoimmune disease (and a collagen disease) that affects joints, muscles, skin, kidneys, nervous system, lungs, heart, and the blood-forming organs. It afflicts women about 10 times as frequently as men, generally between the ages of 18 and 45; but it is occasionally seen in children or older people. Blacks and some Asian and North American Indian groups are more prone to lupus than whites.
     Symptoms can be highly variable with fever, weakness, fatigue, and weight loss initially; skin rash on the face, neck, or arms (a characteristic “butterfly rash” on the nose and cheeks) that may appear or be exacerbated after exposure to the sun; Raynaud's phenomenon, where the fingers are unusually sensitive to cold and turn blue on exposure; joint pain of the hands, wrists, elbows, knees or ankles, usually without deformity; muscle aches, swollen glands, lack of appetite, low-grade temperature, hair loss, nausea and vomiting, increased susceptibility to infection and bleeding, and anemia. Other major organs my suffer the effects of inflammation, including heart, lung, and kidney are not uncommon and can be particularly problematic. Comorbidity with glomerular nephritis and rheumatoid arthritis is common.

It’s In The Genes
      Genetic analysis of synovial tissue from the joints of rheumatoid arthritis patients reveal mutations of the p53 gene, the same gene whose defects have been associated with certain cancers. P53 normally induces apoptosis (cellular suicide) in cells with severe mutagenic damage and facilitates repair in cells with only minimal genetic aberration. Loss of p53 function allows cells with genetic damage to proliferate unchecked to produce abnormal progeny and tumors. The analysis explains why synoviocytes of RA patients more closely resemble tumor cells than normal synoviocytes; but the abnormalities are probably the result of intense chronic inflammatory irritation rather than the cause of rheumatoid arthritis. It does help explain, though, how the faulty genes help to perpetuate the disease process, rendering the tissues unable to reverse the disease process, facilitating invasiveness and perpetuating the destruction of cartilage and bone tissue locally.

Source:
Doctor’s Guide to the Internet – http//www.pslgroup.com/dg/44862.htm

New Therapeutic Options
     The FDA has granted “Fast Track” status for Immunex Corp’s new Enbrel™ (TNFR: Fc) for the treatment of advanced rheumatoid arthritis (RA). The significance of the designation is that the FDA intends to expedite the development and review of the product. The soluble protein-based product composed of exclusively human amino acid sequences is a recombinant version of the soluble p75 TNF (tumor necrosis factor) receptor that is linked to the Fc portion of human IgG1 molecule that competitively inhibits the binding of TNF to receptors on the cell surface, thus impeding TNF activity. The inflammatory processes involved in RA are thought to be dependent on TNF activity, where it binds to cell-surface receptors to initiate the inflammatory cascade that causes joint damage.
     In a recent clinical trial, after six months of treatment with the injectable product, over 80% patients showed improvement in swollen or tender joints. Of those on Enbrel therapy for one year, 91% enjoyed a 20% improvement of symptoms. Improvements seem dose-related. Subjective results evaluated using the American College of Rheumatology criteria for changes in composite symptoms of arthritis; and results were corroborated by laboratory findings (CRP). Enbrel is generally well tolerated, with relatively mild injection site reactions compared with other biologicals, infections (including colds) during treatment in about 45% of patients (resolving without discontinuation of therapy), mild upper respiratory tract symptoms, and no detectable development of antibodies against the agent. . There were no dose-limiting toxic effects.

Sources: Immunex Press Release -- http://www.immunex.com/CORPORATE/HTML/PRESS/pr980317.html Doctor’s Guide to the Internet -- http://www.pslgroup.com/dg/2c4c6.htm http://www.pslgroup.com/dg/2f62a.htm

      In related research also conducted by Immunex, a converting enzyme for TNF-alpha (TACE) has been cloned and identified as another key element in the inflammatory processes involved in arthritis. The new metalloproteinase uses a bound metal ion to carry out its function. TACE lyses the TNF molecule from its attachment to an immune system cell to precipitate the chain of events leading to arthritic inflammation. The results of this research will enable the development of inhibitors to short-circuit the disease process more specifically with minimal effect on other aspects of immune function.
     Although levels of TNF, existing both as free-floating (soluble) and cell-bound forms, are essential in normal immune function to fight infection, higher levels are blamed for development of rheumatoid autoimmune disease. A TACE inhibitor could prevent the release of the soluble TNF. TNF binds to cell-surface receptors that stimulate the inflammatory cascade; but free-floating receptors can also serve as decoys to tie up circulating TNF and prevent activation of the cascade.

      Though arthritis other than infectious arthritis is typically not thought of as an infectious process, recent evidence indicates that infection may play a key role in many cases of rheumatoid arthritis and osteoarthritis. Doxycycline, minocycline, and tetracycline have been shown to provide improvement for many patients treated early in the disease process – within the first year of disease onset. One theory is that these antibiotics specifically inhibit metalloproteinase enzymes involved in the breakdown of cartilage, so characteristic of osteoarthritis.
     Another popular hypothesis is that infection with Chlamydia pneumoniae, mycoplasma and L-form variants can somehow elicit a hypersensitivity reaction that may be a closer look at the actual cause of rheumatoid disease. Yet another alternative theory of “molecular mimicry” suggests that Proteus or Klebsiella from the intestine enter the bloodstream to elicit an immune response, which via “mistaken identity”, mounts an attack the synovial tissues as well. If research currently underway by the NIH, among other entities, validates any of these theories, the whole idea of controlling the symptoms of rheumatoid diseases with anti-inflammatory steroids and NSAID’s may prove to be far more harmful than beneficial.

Source: The Road Back Foundation -- http://www.roadback.org/about.html MSNBC News -- http://www.msnbc.com/news/75600.asp Environmental and Preventive Health Center of Atlanta -- http://www.ephca.com/arth_syn.htm Doctor’s Guide to the Internet – http://www.pslgroup.com/dg/44866.htm and 41482.htm

     The treatment of rheumatoid/arthritic disease with anti-inflammatories and immunosuppressives is fraught with complications, and the line between more harm than good is a fine one. NSAID’s have proven a valuable tool in arthritis therapy, not only with their relatively mild anti-inflammatory properties, but in reducing the pain that tends to immobilize affected joints to promote atrophy. The dilemma has generated a first-line reliance upon NSAID’s, delaying use of the more potent disease-modifying antirheumatic drugs (DMARD’s). This conservative tactic has more recently come under attack, as the fact has come to light that a significant amount of joint damage occurs in the first year after the disease state is identified. At the same time, the recognition that potential NSAID side effects of GI and renal complications are in fact not significantly safer than the side effects of DMARD therapy has prompted earlier application of the latter.
     The anti-inflammatory mechanism of action of NSAID’s involves suppression of cyclooxygenase (COX), essential in the production of prostaglandins. Unfortunately prostaglandins are not only agents of inflammation in the joints (produced by COX-2), but important regulatory agents of cell division and mucous production in the GI system and sodium excretion and blood flow in the kidney (produced by COX-1). Since current NSAIDS inhibit both COX-1 and COX-2, GI side effects are inevitable with doses therapeutic for joint inflammation. Though higher levels of COX-1 are seen in joints later in the disease process, selective suppression of COX-2 in early disease would be highly advantageous with far fewer side-effect liabilities. Nabumetone and etodolac claim reduced COX-1 activity, but both Merck and Searle are working on COX-2 inhibitors with far greater specificity.

Source: Mediconsult.com: http://www.mediconsult.com/arthritis/jourtal/automation/960202003005.html New Drugs: http://www.ascp.com/public/pd/pubs/cp/1997/apr/newdrugs.html Searle Healthnet Press Release: http://www.searlehealthnet.com/pr/afcr.html

Sea Food and Arthritis
     According to findings discussed the British Society for Immunology Annual Congress, diets high in marine fish oils can benefit arthritis sufferers by “calming” neutrophil activity. Neutrophils, prolific in sites affected by inflammation in patients with rheumatoid arthritis and inflammatory bowel disease, promote inflammation by producing leukotriene BR (LTB4) from the polyunsaturated fatty acid, arachidonic acid, derived from fatty acids of land animals and plants. Substituting marine plants and animals in the diet replaces arachidonic acid with eicosapentaenoic acid and docosahexaenoic acid, which produces LTB4 with less inflammatory activity. It also reduces the rate of migration of neutrophils to inflammatory sites, further reducing inflammatory action.

Source: Doctor’s Guide to the Internet: http://www.pslgroup.com/dg/4b716.htm

Arthritis and Smoking
     Smoking is considered a risk factor affecting the severity of arthritis, according to research reported in the Annals of the Rheumatic Diseases. The longstanding assumption that smoking impairs normal functioning of the immune system is borne out by the project that assessed the severity of arthritic symptoms in just under 400 patients over a five-year period. Researchers assessed extent of joint erosion, deformity, subcutaneous nodules, tenderness, swelling, stiffness, and levels of rheumatoid factor. Results were adjusted for age, gender, and weight, then assessed the effect of smoking.
     Here are a number of important findings:
* Patients were considered smokers if they had ever smoked.
* Over half of such smokers no longer smoked at the time of the study.
* 75% of the smokers had quit smoking ten years before or five years after presentation of symptoms.
* Elevated rheumatoid factor was seen in three times as many smokers as non-smokers.
* Joint erosions were seen twice as often in smokers as non-smokers.
* Elevated rheumatoid factor and joint erosions were both seen three times more frequently in patients who had smoked for 25 years.
* The disease is more painful and progressive, and death comes sooner to patients with extensive joint erosion than those with less severe disease.

     From the findings, researchers conclude that smoking may be a more important risk in initiating erosive arthritis than in perpetuating the disease process.
      Other research has confirmed a relationship between rheumatoid arthritis and smoking, obesity, and blood transfusions. The caution remains, though, that association does not prove a cause-and-effect, but adds one more reason not to smoke, to lose weight, and to bank your own blood before surgery.

Source: Doctor’s Guide to the Internet – http://www.pslgroup.com/dg/366d2.htm and 36666.htm. http://www.obesity.com/news/news_971210a.htm