Rheumatoid Arthritis, Gout, Pseudogout (CPPD) and Related Health Concerns

Paul L. Reller L.Ac. / Last Updated: August 03, 2017

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Understanding the disease mechanisms of Rheumatoid Arthritis so that all systemic health problems are addressed in therapy

Research is uncovering the pieces of the puzzle to understand the underlying mechanisms of disease that lead to Rheumatoid Arthritis. While the patient may be focused on the specific joints that flare with symptoms of swelling and pain, there is no doubt that RA is a systemic disease, and many of the mechanisms of this disease either go unnoticed, or are diagnosed as other health problems that the patient does not connect to the RA. Rheumatic disease in general is the realm of autoimmune reaction to a variety of antigens, and heat shock protein Bhsp65 is an antigen linked to B cell antibodies in RA. Underlying factors that initiate this autoimmune response are keys to the disease and successful treatment as well. As stated, there is a strong correlation between stiffening of arterial walls and RA, and a common underlying health problem shared between these disorders is the accumulation of advanced glycation endproducts (AGEs) and subsequent excess formation of receptors for AGEs, called RAGEs. This subject is explained in detail below. There is also a growing concern with hormonal imbalances, especially as we see a predominance of the disease in women in the years of premenopausal to postmenopausal states, and excess prolactin in a high percentage of patients, indicating an endocrine disorder. A growing science of the relationship between hormonal balance, inflammatory dysfunction, and even neurotransmitter imbalance seen in standard medicine and research is also revealing of the systemic problems associated with RA (e.g. psychoimmunoneurology and mind-body medicine).

The activity of key inflammatory mediators, or cytokines, is the subject of much research related to the pathophysiology of RA, especially concerning tumor necrosis factor alpha (TNF-alpha). For the last 20 years, we have known that TNF-alpha, Interleukin-1 and 6 (IL-1, IL-6), GM-CSF (a white blood cell growth factor) and IL-8 are proinflammatory cytokines found in excess in RA patients. The cytokines that are meant to temper these inflammatory signaling chemicals are often deficient, including IL-10, TGF-beta, IL-1ra, and TNF-R. This signifies that an immune imbalance related to T-helper cell types underlies the autoimmune mechanisms of RA. Deficiency or excess of growth factors also indicates that there may be a hormonal imbalance, and hyperprolactinemia has been highly associated with Rheumatoid Arthritis and other related autoimmune disorders, such as Lupus. Hyperprolactinemia is associated with hypothalamic dysfunction and hypothyroidism, as well as polycystic ovarian syndrome (PCOS). Bringing the immune system, as well as the endocrine system, back into homeostatic balance is thus very important in the holistic treatment scheme. The clear and direct causative link between these endocrine disorders and the pathology of Rheumatoid Arthritis is still unclear, but the clear association and comorbidity in numerous large studies is apparent. This implies that a more holistic imbalance is present, and the field of neurohormonal immunology is exploring these more complex pathological connections. Complementary Medicine has always had the goal of restoring homeostatic balance through natural therapeutic means, and such holistic restoration may be of great help to the patient with Rheumatoid Arthritis. The amount of research that now is underway revealing how herbal and nutrient medicine achieves this goal, and how acupuncture may play a key role in homeostatic modulation, as well as deep tissue physiotherapy, is very impressive. The modern physician that specializes in these areas may utilize this research data to improve the therapeutic results, both to relieve symptoms and inflammatory imbalance, and to restore a broader homeostatic balance to achieve remission of the disease.

The exact immune pathway in Rheumatoid Arthritis is the subject of much debate and research. Studies have revealed that an abundance of B-cells rather than T-cells, and an abundance of macrophages, exist in the synovial tissue of RA patients. Macrophages are also the predominant cells involved in creating atherosclerotic plaque lesions in atherosclerosis, which is highly correlated with RA. Macrophages play an important role in tissue regeneration, but appear to release different chemicals at different stages of tissue degradation and repair, due to the complexity of the complement immune system. While antirheumatic drugs have been created to inhibit TNF-alpha, more recent research indicates that other cytokines may be more important in the pathology of RA, and the creation of such immune specific drugs may be problematic in finding a cure or treatment for the disease. IL-18 has been implicated in RA pathology as a stimulator of excess VEGF and angiogenesis that is as effective as IL-1beta. IL-18 is a cytokine produced by macrophages and other cells that belong to the IL-1 superfamily. Studies (cited below) show that Curcumin, a chemical found in various Chinese herbs, inhibits the effects of IL-18 on VEGF. The Interleukin-1 (IL-1) family is a well studied group of immune cytokines and receptors, first found in leukocytes, but that express universally from the complement cells of the immune system, and are the core of the innate immune system and balanced effects related to inflammation, especially the regulation of function and differentiation of lymphocytes in both the innate and adaptive immune systems. Obviously, restoration of this balance and homeostasis would be optimal, rather than just an allopathic inhibition of one aspect of this complex system, and while CIM/TCM makes no claim of a miraculous assured restoration of such immune function and balance, research does show that a number of treatment protocols can help achieve this goal within a holistic protocol. To see an explanation of this IL-1 superfamily that lies at the heart of the RA pathology, by experts at the University of Colorado School of Medicine in the U.S. and the University degli Studi de Milano, in Italy, click here: http://www.ncbi.nlm.nih.gov/pubmed/24332029 . Such research benefits both standard pharmacology and integrative herbal medicine.

The advantage of utilizing Chinese herbal formulas in the treatment of Rheumatoid Arthritis is that the array of chemicals in the herbs affect a variety of mechanisms that are responsible for the disease pathology, and the array of chemicals in herbs are usually found to be modulatory because of complex evolution of these chemicals in plants. For example, Curcumin, mentioned above, found in E zhu and Yu jin, or Curcuma zedoaria and aromatica, are commonly used to treat inflammation and improve circulation. The herb Celastrus aculatus, or Guo shan feng, has been found to promote anti-Bhsp65 antibodies, as well as achieving specific anti-inflammatory and anti-oxidant effects useful in the treatment of RA. Analogous herbs in TCM herbal practice include Trypterygium wilfordii (Lei gong teng) and other Celastrus species, and a standardized extract of these herbs is called Celastrol, which a number of studies have shown to benefit patients safely in the treatment of a number of autoimmune disease, drug-resistant infections, and even the treatment of obesity as part of a holistic treatment protocol. Often these rheumatic herbs such as Celastrus/Trypterygium are combined in Chinese Herbal formulas as well. To see research from the University of Maryland 2007 for this herb, click here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2206370/ . These researchers stated in 2007 that: "The drugs commonly in use for the treatment of RA include glucocorticoids (for example, cortisone and prednisone), non-steroidal anti-inflammatory drugs (NSAIDS; for example, ibuprofen and naproxen), disease-modifying anti-rheumatic drugs (DMARDS; for example methotrexate (MTX) and leflunomide), and biological response modifiers (for example, humor necrosis factor-alpha-blocking agents). However, besides their high cost, the prolonged use of many of these drugs is associated with adverse reactions and toxicity, including some risk of infections in subsets of patients being treated with biological response modifiers (Biologics). As a result, alternative (complement) treatments based on natural plant products and herbal mixtures belonging to a realm of complementary and alternative (integrative) medicine (CAM) are becoming increasingly popular in the US and other countries." Obviously, it is well known that the standard pharmaceutical treatment of Rheumatoid Arthritis can be harsh and problematic over time for a percentage of patients. While there is an understandable reluctance to acknowledge this fact and to further research and guidelines for integration of herbal medicine and a holistic approach in standard medicine, patients are widely acknowledging that this is a more sensible approach to achieve better outcomes and quality of life, albeit a bit more complicated. With sound research we now have more and more assurance of effectiveness.

Not Only Immunotherapy but Health of the Gut Biota is Proving Essential in the Treatment of Rheumatoid Arthritis

Another theory of the underlying cause of RA and related autoimmune and collagen diseases is that a low grade infection related to amoebas, or protozoa, are responsible as the trigger for the autoimmune response. This is supported by the fact that drugs called pyrimidines, with anti-protozoal activity, are effective in the treatment of RA and other rheumatoid diseases. This also connects antibody responses and celiac disease to RA.

Restoring health to the gastrointestinal system is often helpful, as this removes excess physiological stress on the immune system and clears low grade protozoal infections of a chronic nature. Deep low grade infections often penetrate to blood cells, and then to tissues with poor blood circulation, where natural immune defenses are more difficult, and these small microbes grow in quantity. When these infections affect blood cells, this may translate to altered immune cytokines produced by these cells, and when the infection penetrates tissues such as the joint synovium, which normally has poor vascular circulation, but even in early stages of RA develops increased vascularity in response to immune needs, an autoimmune response may result. This may be the reason why antimalarials are also effective in the treatment of RA. In 2014, research at the University of Illinois at Chicago (cited in Additional Information) revealed that the protein CCL28 is overexpressed in all RA joints, resulting in over-expression of the CCL28 receptors on the synovial membranes, attracting increased cytokine responses and accommodating the many cells that migrate to RA membranes and cause sudden swelling. Research in France in 2014 also identified the overexpression of CCL28 in the intestinal membranes in response to overgrowth of bacteria, fungi and other parasitic microbes, linking again the gut health and health of the Biota to RA. CCL28 is known to express more rapidly in low oxygen conditions as well, or hypoxic states, which may be linked to overgrowth of anaerobic bacteria, fungi and protozoa. Such studies reveal the need for a more holistic approach in treatment and attention to the whole health of the RA patients, especially in early stages of the disease.

While the complex pathophysiology of Rheumatoid Arthritis is still too difficult to understand completely, research has shown us the progression of disease manifestation, and this points to key areas of emphasis in treatment and prevention. RA dramatically affects the jont synovium, or tissue that covers the entire joint complex, to which muscle tendons are attached. Normally, this synovial tissue is thin and poorly vascularized, and joint motion is responsible for much of the flow of blood nutrients to the tissues. In advanced stages of RA, the joint synovium goes from a very thin states, usually 1-3 cells thick, to a thickened state called hypertrophy, usually 8-10 cells thick. The density of the cell population in this synovium of advanced RA is also dramatically increased, and the primary cells are now macrophages and fibroblasts, with a high population of B-cells. B-cells are immune white blood cells, or lymphocytes, that are manufactured in bone marrow, retain an immune memory, and manufacture antibodies to foreign microbes, toxins, etc. These immune changes in the synovium stimulate much increase in the creation of small blood vessels (angiogenesis). While the early stages, or onset, of RA may be attributable to T-cells, which are white blood cells originating the thymus, and are key cells in the learned immune responses, there is an abscence of T-cells in more advanced synovial tissues in RA. The bridge between the B-cell, or innate immune response, and T-cell, or adaptive immune response, is the NK cell, called the Natural killer T cell. NK cells recognize antigens on the glycolipid membranes of cells. This has pointed scientists to heavily research altered glycolipids in the body, and hence advanced glycation endproducts (AGEs) are a subject of considerable interest in the research.

Tumor necrosis factor (TNF-alpha) is an immune cytokine that is one of the many cytokines in the complement system that may promote the excess inflammatory responses and systemic health problems in RA, such as endocrine dysfunction, appetite suppression, low grade fever, increased C-reactive protein, and insulin resistance. TNF is mainly produced by macrophages, but also by other lymphoid cells, mast cells, endothelial cells, fatty tissues, fibroblasts, and nerve tissues. Excess amounts of TNF are released in response to lipopolysaccharides, bacterial products, and the cytokine IL-1. Lipopolysaccharides are similar to advanced glycation endproducts, and cell receptors for advanced glycation endproducts (RAGES) may respond to lipopolysaccharides. It is theorized that AGEs may stimulate increased TNF responses as well, or at least act cooperatively with lipopolysaccharides to induce proinflammatory cytokine production (see study link below). Lipopolysaccharides compose the outer shell of bacteria, and when these bacteria are broken down by T-cells and cytokines, an excessive TNF response may result. Ultimately, the patient, in advanced stages of RA is prescribed TNF inhibitors. The problem is, since the TNF response is so integral to our normal healthy immune responses, which keep us alive, systemic inhibition of TNF with synthetic drugs is problematic. The problems presented by the therapy are dramatic. This leads many patients, and a growing number of MDs, to consider other approaches. Research has led us to the holistic approaches of Complementary and Integrative Medicine. While this approach is more complicated than simply taking one pill, a TNF inhibitor, the safety and overall benefits are dramatic, and worth the effort.

It is well known that chronic Rheumatoid Arthritis is often exacerbated by emotional and psychological stress. In recent years, the subject of an interrelationship between the immune, endocrine and nervous systems has been finally explored in more depth, usually referred to as Psychoimmunoneurology. This is a field now of standard medicine that admits to a holistic emphasis on scientific understanding of chronic disease mechanisms. For decades, research has unveiled the important relationship between hormones, inflammatory cytokines, and neurotransmitters, which often all stimulate the same cell receptors. Neurotransmitters may play an important role at times as hormonal triggers, hormones may stimulate nervous responses, and cytokines may modulate these effects dramatically. For this reason, holistic medicine is now becoming an important consideration for diseases such as RA. The complexity of these mechanisms requires a more holistic and comprehensive treatment strategy that must utilize Integrative and Complementary Medicine (CIM/TCM) to fulfill the goals of better outcomes.

Problems with Immunosuppressive Drugs and other Biologics in the Treatment of RA

While the development of new immunosuppressive drugs does increase the potential for control of symptoms in Rheumatoid Arthritis, the cozy picture of health and happiness presented in TV ads may not be real. Widespread problems with immunosuppression and infections, anemia, organ dysfunction affecting almost every organ, but especially the kidneys, lung and heart, and skin cancer risk make the considerations of risk versus benefit a serious concern. If a protocol without health risks can be initiated successfully, with the integration of Complementary Medicine (CIM/TCM), as well as benign treatments early in the disease course, this is obviously a better alternative. If the disease can be affected by Complementary therapy and a reduction in dosage, or even discontinuation of some of the drug protocol, can be achieved, this is obviously of great benefit to the patient with chronic use of these immunosuppressants and corticosteroids.

A wide array of adverse health effects are noted with immunosuppressive drugs, including anemia, arthralgia, bone marrow depletion, coronary artery disease, gastrointestinal irritation and dysfunction, liver toxicity, high cholesterol, hyperglycemia, mineral imbalance, hypertension, high triglycerides, high uric acid, kidney toxicity, cancer, pancreatitis, deficient blood platelets and easy bleeding, tremor, and osteoporosis/osteopenia. Cancerous malignancies are still one of the most substantial adverse effects with the use of immunosuppressant drugs in transplant therapies, and while the dosage is smaller with the treatment of autoimmune rheumatic diseases, these adverse health effects should be a serious consideration in treatment. While serious adverse effects are now relatively rare with standard therapeutic dose, the long-term depletion of health is obvious to a majority of patients. While standard medicine sticks to the recommendation that there is no effective treatment other than these drugs, many patients, and substantial scientific research, show that this is not the case. Complementary and Integrative Medicine (CIM/TCM) does offer integration of therapeutic protocols that are proven safe and effective, and should be administered professionally in a package of care, combining an array of therapies in treatment, and not depending upon single herbs on the unregulated market with unrealistic claims of success. Integration of TCM protocols could dramatically reduce the risk of adverse effects and improve outcomes and quality of life over time with use of immunosuppressant drugs and biologics. TCM therapies can also be used specifically to treat adverse effects of these medications when they occur, and the array of goals in CIM/TCM therapy are broad, allowing each patient to individualize their care as they choose.

An emerging health problem with long-term use of immunosuppressant drugs and other biologics is the onset of Interstitial Lung Disease, a class of serious chronic lung disease that includes pulmonary fibrosis. This category of disease includes more than 100 disease types that affect the interstitium, or tissues between the capillaries and the alveolar spaces in the lung, resulting in fibrosis and hypoxia, or the thickening and scarring of connective tissue and resultant deficiency of oxygen in the blood. It is now well known that pharmaceutical drugs are responsible for a growing percentage of cases of interstitial lung disease, especially immunosuppressant biologics, antibiotics, chemotherapy drugs, and antiarrhythmic agents. Often, these drugs will be prescribed together over a long period of time, dramatically increasing the risk. To see an assessment of this problem, by experts at the Ludwg-Maximillian University School of Medicine, in Munich, Germany, click here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3415629/ . Older patients are at most risk due to lowered function of the kidneys and liver, which CIM/TCM therapy could improve. The overuse of CT scans and other radiation could also increase risk. A 2014 study of 3017 RA patients, at the Nippon Medical School, in Tokyo, Japan showed that the best marker for this disease, KL-6 (Krebs von den Lungen-6) was elevated in 8.1 percent of RA patients treated with biologics (PMID: 25744479). There appears to be a small risk of interstitial lung disease in RA in general, but the increased use of immunosuppressant biologics in treatment has corresponded with a dramatic rise in incidence, and since the disease develops slowly over time in these cases, the incidence in the near future is expected to rise. Complementary and Integrative Medicine (CIM/TCM) could be utilized to improve lung health and prevent disease, as well as to treat this difficult disease. If not treated successfully, the result is a need for removal of the affected lung. Standard treatment for lung fibrosis induced by these drugs is the discontinuation of the drug and the introduction of corticosteroid therapy, which comes with alarming adverse health effects as well.

Virtually all medications used to treat rheumatic and autoimmune diseases come with serious risks for impaired fertility, problems with pregnancy and delivery, fetal effects, and potential problems with breastfed babies (see JAMA review link below in additional information). For instance, cytotoxic drugs used to treat rheumatoid arthritis and lupus, such as Revimmune (cyclophosphamide), cause amenorrhea in up to 45 percent, and ovarian failure in over 70 percent of patients with chronic use, as well as fetal defects. Imuran (azathioprine) is commonly prescribed for rheumatic disease in pregnancy, and while the fetal liver appears to lack the liver enzyme needed to convert the drug to its active form, there have been a variety of adverse effects reported, including retardation of fetal growth, depressed adrenal growth, and long-term consequences for immune function. Breastfeeding is discouraged as the drug may affect the baby's immune function and be carcinogenic. Methotrexate is now commonly prescribed for rheumatic autoimmune diseases, and causes severe folic acid deficiencies that may affect pregnancy, and fetal defects and health problems, with both the father and mother advised to discontinue use for months before trying to conceive. Even aspirin and NSAIDS pose potiential problems with fertility, conception, pregnancy, fetal health and the health of the breastfed baby with higher chronic dosage.

The most successful drug to date in the management of symptoms of Rheumatoid Arthritis is Enbrel (etanercept), a biologic TNF-alpha inhibitor that is administered in weekly intramuscular injections. Long-term studies were conducted for the first 8 years of treatment, showing that the overall safety profile was better than other immunosuppressive drugs, and that of the patients that did not drop out of long-term studies due to adverse health effects, 52 percent of long-standing Rheumatoid Arthritis patients achieved a score of 50 on the American College of Rheumatology test, or an improvement in the disease by 50 percent of the base value (ACR50), or the symptoms at the time the drug was started. Even with this benefit, many patients are realizing that integration of Complementary Medicine could achieve better than 50 percent improvement in RA symptoms. In these studies of Enbrel 75 percent of early rheumatoid arthritis patients achieved an improvement of only 20 percent over their initial presentation (ACR20). In a 9-year study, of long-standing Rheumatoid Arthritis patients, 22 percent achieved an improvement of symptoms of 70 percent over the initial symptoms, while 74 percent achieved only an improvement of 20 percent over baseline (ACR20). The majority of patients could use more help in their protocol. While these results are successful, obviously much more could be done to improve the symptoms, and the integration of Complementary Medicine could both achieve better ACR scores, as well as decrease the obvious long-term adverse health effects. Standard medicine will prescribe gastric acid inhibitors to counter the common problem of gastrointestinal dysfunction from the drugs, but these drugs lead to various essential malabsorptions over time, creating such problems as osteoporosis and anemia. Reactivation of tuberculosis, reactivation of hepatitis B virus infection, congestive heart failure, demyelinating neurologic disorders, hematologic disorders like aplastic anemia and pancytopenia, vasculitis, immunogenicity, and exacerbation or induction of psoriasis are class effects of all the anti-TNF drugs, pointing to a variety of cardiovascular, immunological and neurological effects that may be less dramatic and ignored, but are a concern nonetheless, and could be countered with Complementary Medicine. Since this TNF-alpha inhibiting biologic is so successful, herbal medicines that also exert proven TNF-alpha inhibition, as well as herbs that achieve overall improvement in immune health, could be a significant aid to better relief of symptoms, without the health risks and adverse side effects. The side effects of these herbal formulas are better overall health.