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Stem Cell Therapy for Rheumatoid Arthritis

Stem cell transplantation now offers a potentially useful treatment for rheumatoid arthritis.

At the Leiden University Medical Center in The Netherlands, researchers conducted a study in which a new type of treatment for patients with severe, refractory RA was formulated based upon high-dose chemotherapy (HDC) similar to that described above, and which was then followed by autologous hematopoietic stem cell transplantation (HSCT). The treatment was found to be safe, effective, and the patients improved. (From Arthritis & Rheumatism, Vol. 52, Issue 8, pp. 2272 - 2276: "Long-term follow-up of health status in patients with severe rheumatoid arthritis after high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation.")

A similar study was conducted by researchers in which hematopoietic stem cell transplantation (HSCT) was so successful that it was identified as "a possible cure for rheumatoid arthritis." (From Arthritis & Rheumatism, Dec. 12, 2005; Vol. 40, Issue 6, pp. 1005 - 1011: "Autologous hematopoietic stem cell transplantation. A possible cure for rheumatoid arthritis?") The research was funded by the Reid Charitable Trusts, and the Australian National Health and Medical Research Council.

In 2004, researchers in Australia conducted a study in which stem cells derived from bone marrow were administered to patients with RA; 2 of the patients experienced remission 11 and 13 years after the treatment, and the third patient with RA had a relapse 2 years after treatment, which then remitted, treatment-free, for 11 years. (From Arthritis & Rheumatism, May 28, 2004; Volume 41, Issue 3, pp. 453 - 459: "Long-term outcome of autoimmune disease following allogeneic bone marrow transplantation (BMT).")

In 2002, researchers in Australia again conducted a study in which stem cells were administered to patients with the most severe cases of RA. The researchers found that the treatment constituted a safe and effective therapy for a "treatment-resistant disease". The study was funded by the National Health and Medical Research Council of Australia, and by Amgen of Australia. (From Arthritis & Rheumatism, Sept. 27, 2002; Vol. 46, Issue 9, pp. 2301 - 2309: "A pilot randomized trial comparing CD34-selected versus unmanipulated hemopoietic stem cell transplantation (HSCT) for severe, refractory rheumatoid arthritis.")

In the United States, a recent segment on the daily television program, "Good Morning America", featured a young girl with juvenile rheumatoid arthritis who had been successfully treated with stem cells, and who is now free of the disease.

Researchers at Northwestern University Medical School, in collaboration with the Robert H. Lurie Comprehensive Cancer Center of Chicago, Illinois, and with researchers at the University of Wisconsin at Madison, conducted an early study in 2001 in which stem cell therapy was administered to a group of 4 patients afflicted with RA. (From Arthritis & Rheumatism, April 26, 2001; Vol. 42, Issue 11, pp. 2281 - 2285: "Autologous hematopoietic stem cell transplantation in refractory rheumatoid arthritis: Sustained response in two of four patients.") Even in this early study, the autologous HSCT treatment was found to be safe and effective in all of the patients to whom it was administered, with a strong positive response in half of the patients.

As stated on the website of the National Institute of Allergy and Infectious Diseases (NIAID), a division of the National Institutes of Health (NIH),

"Autoimmune diseases, including rheumatoid arthritis, type-I diabetes, and multiple sclerosis, afflict an estimated 5 percent of the U.S. population. The human and financial burden of these diseases is immense." (From the National Institute of Allergy and Infectious Diseases website).

As corroborated by the American College of Rheumatology,

"Rheumatoid arthritis (RA) is an autoimmune disorder of unknown etiology characterized by symmetric, erosive synovitis and, in some cases, extra-articular involvement. Most patients experience a chronic fluctuating course of disease that, despite therapy, may result in progressive joint destruction, deformity, disability, and even premature death. RA results in more than 9 million physician visits and more than 250,000 hospitalizations per year. Disability from RA causes major economic loss and can have a profound impact on families." (From the American College of Rheumatology, in a statement issued by the ACR Subcommittee on RA Guidelines).

Musculoskeletal diseases such as rheumatoid arthritis are recognized internationally not only as problems that impact individual lives, but also as problems that impact national economies. With an aging global population in which the number of people over the age of 50 is expected to double by the year 2020, the discovery of cures for diseases such as rheumatoid arthritis will become an economic, if not a medical, imperative. In an effort to address such growing international concerns, the United Nations, the World Health Organization and 37 countries have proclaimed 2000 to 2010 as the "Bone and Joint Decade". Additionally, individual countries have also proclaimed their own decades in which extra research would be dedicated to bone and joint health, and in the United States, 2002 to 2011 was declared to be the "National Bone and Joint Decade." As president George W. Bush stated in his proclamation,

"...In the U.S., musculoskeletal disorders are a leading cause of physical disability. Such conditions also affect hundreds of millions of people around the world. The National Bone and Joint Decade, 2002-2011, envisions a series of international initiatives among physicians, health professionals, patients, and communities, working together to raise awareness about musculoskeletal disorders and promoting research and development into therapies, preventative measures, and cures for these disorders. Advances in the prevention, diagnosis, treatment, and research of musculoskeletal conditions will greatly enhance the quality of life of our aging population."

(From the White House website).

In the treatment of all forms of arthritis, especially rheumatoid arthritis, stem cells offer a potentially useful therapy.

Rheumatoid Arthritis Overview

Although general symptoms of arthritis have been documented for thousands of years, rheumatoid arthritis was first described as a distinct syndrome by the early 19th century physicians Heberden and Haygarth, after whom the associated features known as "Heberden's nodes" and "Haygarth's nodes" are named. The disease then received its current name in 1859, which is derived from a combination of Greek words: "rheumatos", meaning "flowing", the suffix "-oid", meaning "in the shape of", "arthro" meaning "joint", and the suffix "-itis" which indicates inflammation.

Rheumatoid arthritis (RA) differs from other forms of arthritis in a number of significant ways. Most notably, it is categorized not simply as an inflammatory disease, but as an autoimmune disease. Although symptoms typically include the usual pain, swelling, stiffness and loss of function in the joints that characterize most forms of arthritis, in RA these symptoms are considered to be the result of the body's immunological attack upon itself. RA is ranked among the more than 100 types of rheumatic diseases, along with Crohn's Disease, Celiac Disease, rheumatic fever, and other related classifications. Rheumatic diseases in general share similarities in how the joints, tendons, ligaments, bones and muscles are affected, and RA is considered to be one of the more severe types of rheumatic disorders.

Another way in which RA differs from most forms of arthritis is that it is a systemic disease, unlike osteoarthritis and the other more commonly occurring forms of arthritis. In other words, not only are the joints of the body affected in RA, but "extra-articular tissues" throughout the body may also be affected, such as the skin, blood vessels, and organs such as the heart, the lungs, the kidneys or the eyes. Weight loss, fever and a general sense of malaise are also not uncommon in patients suffering from RA.

Rheumatoid arthritis is also known to be a symmetric disease, affecting the same joints equally on both sides of the body. Although initial symptoms usually appear to be asymmetrical, they develop a characteristic symmetry as the disease progresses. The most commonly affected joints are those of the fingers and wrists followed by those of the arms and legs. The surrounding muscles, tendons, ligaments and connective tissue associated with each joint are also commonly affected by this disease. The buildup of fluid within the joint capsule can cause pressure on the cartilage and may result in a "squishy" sensation when pressure is applied during motion. Unlike the characteristic pain of osteoarthritis, which progressively worsens toward the end of each day, the pain that is associated with RA is usually most pronounced in the morning.

Considered to be a chronic affliction, RA is typically observed by initial symptoms consisting simply of inflammation of the lining, or synovium, of the joints. Pain, stiffness, swelling and loss of function of the joints can also be accompanied by mild fever, tiredness, and small lumps under the skin. In its most advanced stages, however, bone deformity and irreversible joint damage may result.

RA is often difficult to diagnose. According to the American College of Rheumatology,

"RA affects 1% of the adult population. This low prevalence means that the average physician often develops little experience with its diagnosis or management." (From the American College of Rheumatology).

Approximately 2.1 million Americans currently suffer from rheumatoid arthritis, 35% of whom go untreated, due either to the difficulty involved in making a correct diagnosis, or to an unwillingness to seek treatment, both of which are common in the early stages of the disease. Three-quarters of all people who suffer from rheumatoid arthritis are women, indicating an important hormonal component to the disorder. The disease is 4 times more common in smokers than in nonsmokers, suggesting a strong environmental factor. Rheumatoid arthritis that develops after the age of 60 is often milder than when it develops earlier in life. It has been found that approximately half of all people with RA will experience a remission within 2 years of the initial onset of symptoms. However, the symptoms often return. (From the AllAboutArthritis.com).

The time of onset most typically strikes between the ages of 25 and 50, but in rare circumstances the disease has also been known to occur in children and senior citizens. Indeed, juvenile rheumatoid arthritis (JRA) is the most common form of arthritis in children. According to the website of the Arthritis Foundation,

"JRA may be a mild condition that causes few problems over time, but it can be much more persistent and cause joint and tissue damage in other children. JRA can produce serious complications in more severe cases. Arthritis is best described by the four major changes in the joints that may develop. The most common features of JRA are: joint inflammation, joint contracture (stiff, bent joint), joint damage and/or alteration or change in growth. Other symptoms include joint stiffness following rest or decreased activity level (also referred to as morning stiffness or gelling), and weakness in muscles and other soft tissues around the involved joints. ... The signs and symptoms of JRA vary from child to child, and even from day to day in the same child. ... There is no single test to diagnose JRA." (From the Arthritis Foundation website).

In cases in which JRA is suspected, an official diagnosis should be made by a pediatric rheumatologist.

Rheumatoid arthritis in adults is characterized by three distinct stages. In the first stage, swelling of the synovial lining is observed. The second stage is marked by a thickening of the synovium due to the rapid division and growth of cells. In the third stage, the inflamed cells release enzymes which may digest the bone and cartilage. These symptoms cause the joints to lose their shape and alignment, resulting in further pain, loss of movement, and structural damage which has heretofore been considered permanent. Clearly, identification and treatment of RA in the early stages is of critical importance in the successful treatment and management of the disease.

Symptoms may occasionally include the formation of subcutaneous rheumatoid nodules (lumps of inflamed cells), which are found in 20 - 30 % of RA cases. Such nodules may appear anywhere on the body, but are most commonly found over bony prominences and extensor surfaces such as the elbow, ankle and fingers. (From http://arthritis.about.com/od/nodules/g/nodule.htm).

As a systemic disease, RA can generate numerous complications. Many RA patients suffer from anemia, either chronically or as a consequence of gastrointestinal bleeding, which may be exacerbated by the use of NSAIDs (non-steroidal anti-inflammatory drugs), which are typically prescribed for RA. Additional secondary symptoms may also develop, such as Splenomegaly, Felty's Syndrome (leukopaenia), and Sjogren's Syndrome (lymphatic infiltration of the salivary and lacrimal glands), among other disorders. The lungs may be affected, and pleuritis or fibrosis may occur, or Caplan's nodules may develop as pulmonary effusions. Renal problems such as amyloidosis have been described in conjunction with RA, along with cardiac complications such as pericarditis, endocarditis, left ventricular failure, and cardiac valvulitis. Ocular problems such as episcleritis, scleromalacia, and keratoconjunctivitis sicca (dry eyes) have also been associated with RA. Neurological complications such as mononeuritis multiplex and atlanto-axial subluxation, though rare, have also developed as a result of RA.

As RA progresses, the inflammation and simultaneous soft-tissue swelling of many joints (polyarthritis) may lead to erosion, bony decalcification and irreversible destruction of the joint surface, which can result in permanent deformity. In the hands, the fingers follow a recognizable pattern of deviating towards the little finger (which is known as ulnar deviation), and other classic deformities have also been identified, such as "Boutonniere deformity", "swan neck finger deformity", and a "Z-thumb deformity". A "photo gallery" of arthritic deformities of the hand in patients with RA may be viewed at

http://arthritis.about.com/od/handandfingers/ig/Arthritis-Hand-Gallery/.

Vasculitis is another possible complication of RA, and one of the more serious complications that occur outside of the joints. As part of the autoimmune and systemic inflammatory reaction that characterizes RA, vasculitis is a severe inflammatory reaction to a blood vessel, such as an artery, a capillary, or a small or large vein. Such localized, acute inflammation results in damage to the tissue or organ which is served by the blood supply that is suddenly interrupted by the damaged vessel. Initial therapy for the onset of vasculitis in RA usually consists of systemic corticosteroids, which act as powerful anti-inflammatory agents, and which can work to salvage the blood supply to the associated tissue or organ by blocking the damage to the blood vessel. In cases in which the vasculitis proves to be controllable, methotrexate is often substituted for the low dose corticosteroids; if the vasculitis is not easily controllable, therapeutic options may include the use of immunosuppressive medications such as cyclophosphamide, Imuran&153;, or chlorambucil.

While most RA patients are able to cope with their symptoms, the overall life expectancy for anyone with RA is 5 to 10 years less than that of the general population. In the field of cellular aging, researchers are particularly interested in the physiological mechanisms at work in RA. The aging process is accelerated whenever damage at the molecular level occurs to such an extent that gross anatomical function is impaired, and this is precisely one of the distinguishing features of RA. In a study conducted at the Mayo Clinic, researchers calculated that RA patients age at approximately 1.25 times the rate of the general population; in other words, for each 10 years that elapse, people with RA have aged 12.5 years. "We've known for decades that the mortality rate among people with rheumatoid arthritis is higher, and that these patients are at increased risk for heart and lung disease," explains Sherine Gabriel, M.D., an epidemiologist who led the Mayo Clinic study. "With this study, we've now applied a mathematical model that shows consistency between our observed mortality rates and our understanding of the concept of accelerated aging." The research was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a division of the National Institutes of Health (NIH).

It has long been known that RA patients have twice the incidence of heart failure as does the rest of the population, and researchers may have now identified the cause. In March of 2005, Mayo Clinic epidemiologists found that the systemic inflammation characterizing RA may be to blame for the increased risk of cardiovascular death in patients with RA. Not only do people with RA have a higher risk of coronary heart disease than those in the general population, but they also have a more silent, insidious form of heart disease which often goes unrecognized and undiagnosed until resulting in heart attack or sudden cardiac death . (From the Feb. 9, 2005 issue of Arthritis & Rheumatism).

Although the exact causes of rheumatoid arthritis remain unknown, and the many abounding theories remain unproven, it is widely agreed that a complex combination of interacting factors must be involved in triggering the onset of rheumatoid arthritis. Among the prevailing theories which seem to merit the most consideration, there is some evidence to indicate that a virus or bacterium may be involved, although it may also be necessary for the individual to possess a genetic predisposition to the disease. Seventy percent of all people with rheumatoid arthritis test positive for an inherited chemical marker on their cells, indicating that a strong genetic component is necessary for the expression of the disease. The HLA-DR4 marker has been shown to be an especially accurate measure of the severity of RA in people of northern European ancestry. In June of 2006, researchers in Norway and the Netherlands collaborated in studying a gene known as the "protein tyrosine phosphatase N22 (PTPN22) gene", which they have now identified as being associated not only with susceptibility to the RA disease itself, but also to factors which determine the progression of the disease. Approximately 85 percent of people with RA also test positive for an antibody known as "rheumatoid factor", and testing for the presence of this antibody constitutes a routine part of the diagnostic process whenever a physician suspects RA in a patient. Clearly, along with multiple other risk factors, family history is an important consideration in the differential diagnosis.

In some cases, severe psychological and emotional stress have been found to play a role in the onset of RA, as the disease occasionally occurs after a person has experienced a major "life-changing" event, such as a divorce, the loss of a job or the death of a loved one. In 1949, the noted endocrinologist Hans Selye proposed that stress hormones released by the adrenal glands may cause adverse reactions in joint tissue and also in major organs, whenever these stress hormones are released either in excessive quantities or in abnormal ratios. Some experimental evidence supporting this hypothesis has been demonstrated by the fact that rheumatoid arthritis may be artificially induced in animals by injections of the hormone deoxycorticosterone. Certain nutritional deficiencies have also been proposed as triggering the onset of rheumatoid arthritis, and the unusually high incidence of RA in certain countries such as Jamaica and northern Thailand is believed to be attributable to low levels of boron.

A single test for diagnosing RA does not exist, and X-rays alone cannot detect the damage caused in the early stages of RA. Patients who have already suffered significant joint deterioration will often yield normal X-rays, as their "erosions" will be detectable only by ultrasound or MRI. Such damage has often progressed much farther than initially suspected, and by the time it is detectable by X-ray it will usually have become so extensive that it is irreversible. X-rays are useful in monitoring the progression of the disease in its advanced stages, but more sensitive imaging technologies should be employed when RA is first suspected.

Whatever the exact causes may be, there is no conventional medical cure for rheumatoid arthritis. Treatment therefore has focused on relieving pain, reducing inflammation, stopping or slowing damage to the joints, and improving the general well-being of the patient. In some cases, surgery may be prescribed for such procedures as joint replacement, reconstruction or fusion of the joint, or for the removal of diseased tissue from within the joint itself (known as a synovectomy).

The pharmacological treatment of RA may be divided into 3 general categories: disease-modifying anti-rheumatic drugs (DMARDs), anti-inflammatory agents, and analgesics. DMARDs are prescribed to prevent the bone and joint damage caused by RA, which is usually permanent once it has occurred. The anti-inflammatories and analgesics are known for improving pain and stiffness, but they do not prevent joint damage nor do they slow the progression of the disease.

DMARDs may be further subdivided into xenobiotic agents, which do not naturally occur in the body, and biological agents, which are less foreign to the body.

"Xenobiotics" include azathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, methotrexate (MTX), minocycline, and sulfaselazine (SSZ). Side effects are an important consideration, however, and may include liver and bone marrow toxicity, renal toxicity, allergic skin reactions and infections. Corticosteroids such as Prednisone may also be prescribed, which, while effective at reducing pain and stiffness, do not prevent bone damage and are still also known for their side effects. Biological agents include adalimumab (Humira), interleukin-1 blockers such as anakinra, an anti-B cell antibody such as rituximab (Rituxan), blockers of T cell activation such as abatacept (Orencia), and tumor tecrosis factor blockers such as etanercept (Enbrel) and infliximab (Remicade). Anti-inflammatory agents include glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs, most of which also act as analgesics). Analgesics include acetaminophen, opiates, and (topical) lidocaine.

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen are also commonly used to reduce short-term pain and swelling. Side effects, however, remain a serious consideration.

Whether or not surgery is recommended, conventional medical treatment for RA generally employs the use of NSAIDs (nonsteroidal anti-inflammatory drugs) such as aspirin and ibuprofen. In fact, half of all NSAID prescriptions in the U.S. are for various forms of arthritis. NSAIDs in general constitute a large class of medications that are used to treat both pain and inflammation, and are therefore frequently used in the treatment of all types of arthritis. A number of NSAIDs are available over the counter, such as ibuprofen (Advil, Motrin), naproxen sodium (Aleve) and ketoprofen (Orudis, and Oruvail). Additionally, there are more than a dozen others, including a subclass of NSAIDs known as COX-2 inhibitors, that are available only by prescription.

All NSAIDs work according to the same principle, which is by blocking prostaglandins, which contribute to inflammation and pain. However, since each NSAID is a different chemical, each NSAID therefore has a slightly different effect on the body; each NSAID also comes with its own particular list of warnings and contraindications. Most NSAIDs only cause gastrointestinal irritation, which can include ulcers, bleeding and perforation of the stomach or intestine; some NSAIDs can also damage kidney function, however, and may cause other long-term problems. The longer a person uses NSAIDs, the more likely he or she is to have side effects, ranging from mild to serious. One should also be cautious of interactions between medications, as many other drugs cannot be taken with NSAIDs, because the NSAIDs will alter the ways in which the body uses or eliminates these other drugs.

According to the website of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a division of the National Institutes of Health (NIH),

"The U.S Food and Drug Administration has warned that long-term use of NSAIDs, or use by people who have heart disease, may increase the chance of a heart attack or stroke. So it's important to work with your doctor to choose the one that's safest and most effective for you. Side effects can also include stomach upset and stomach ulcers, heartburn, diarrhea, and fluid retention. For unknown reasons, some people seem to respond better to one NSAID than another." (From NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases website).

Cytokines are known to play a role in RA, and ongoing studies are investigating various ways of blocking the particular cytokines that are involved in the chronic pain that is associated with RA. A "distinct profile of T cells, macrophage and stromal cells related to cytokines in synovial fluid" has been found to characterize RA, and researchers are working to understand these factors in greater detail. (From Arthritis Research & Therapy, April 22, 2005).

The conventional medical view holds that most types of arthritis, including RA, are incurable. As stated on the website of the American Academy of Orthopedic Surgeons,

"At present, most types of arthritis cannot be cured."

(From the American Academy of Orthopaedic Surgeons website).

As corroborated by the Arthritis Foundation,

"Right now, there is no cure for RA."

(From a brochure published in 2000, entitled "Practical Help from the Arthritis Foundation," available at www.arthritis.org).


 

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