2016-03-11

Kyle J. Norton (Scholar)

Health article writer and researcher; Over 10.000 articles and research papers have been written and published on line, including world wide health, ezine articles, article base, healthblogs, selfgrowth, best before it's news, the karate GB daily, etc.,.
Named TOP 50 MEDICAL ESSAYS FOR ARTISTS & AUTHORS TO READ by Disilgold.com Named 50 of the best health Tweeters Canada - Huffington Post
Nominated for shorty award over last 4 years
Some articles have been used as references in medical research, such as international journal Pharma and Bio science, ISSN 0975-6299.

Musculoskeletal disorders (MSDs) are  medical condition mostly caused by work related occupations and working environment, affecting patients’ muscles, joints, tendons, ligaments and nerves and developing over time. A community sample of 73 females and 32 males aged 85 and over underwent a standardised examination at home. Musculoskeletal pain was reported by 57% of those interviewed(1).

Types of Musculo-Skeletal disorders in elder(2)

1. Osteoarthritis
2. Gout
3. Rheumatoid Arthritis
4. Polymalagia Arthritis
5. Cervical myleopathy and spinal canal stenosis
6. Osteoporosis
7. Low back pain
8. Fibromyalgia

Rheumatoid Arthritis

Rheumatoid Arthritis is defined a chronic disorder as a result of inflammation, affecting mostly the flexible (synovial) joints and tissues and organs in the body. The disease affects more women than men and generally occurs after the ages of 40, causing diminished quality of life of many elders(1). According to CDC, Musculoskeletal disorders (MSDs)  affects over 52 millions of adults in the US alone, including 294,000 children under age 18 with some form of arthritis or rheumatic conditions(2). Rheumatoid Arthritis can induced bone loss through elevating bone resorption without increasing bone formation(4). A cross-sectional population-based study of 1042 patients with rheumatoid arthritis showed that RA patients had an increased risk of death from various causes(4a).

Signs and Symptoms

1. The feet and joints

Patient with rheumatoid arthritis (RA) often associate to valgus deformities of the feet and deformities of gait due to body function in effort to support the collapsing longitudinal arch of the foot(3). According to Dr. Brooks F and Dr. Hariharan K., feet demortities, effecting over 90% of the patient, behind only the hand, leading to painful callosities and dislocation of the metatarsophalangeal joints(5). Because of its severity, regardless to "....pharmacological management of rheumatoid arthritis and its impact upon disease progression, forefoot deformity and pain remain common manifestations requiring reconstruction from orthopadic surgeons" Dr. Amin A. and the reaserch team at the Royal National Orthopaedic Hospital, said(6).

In fact, the prevalence of deformations of hands, feet and gait can be seen among patient with rheumatoid arthritis among aging population may be depending to the severity and time factors which can lead to enormous pain and swelling of the ankle of which correlated weakly but statistically significantly with limitation and disability(7). The Jyväskylä Central Hospital, suggested that radiographic damage of hand and foot joints, and the number of tender and swollen joints are frequent found in patient with Rheumatoid Arthritis(8)(9).

2. The gait
Dr. Weiss RJ. and the research team at the Karolinska Institutet, showed that the kinematic and kinetic gait changes in rheumatoid arthritis (RA) patients are the result of a significant reduction in joint motions, joint moments, such as decreased hip flexion-extension range, hip abduction, knee flexion-extension range,...(9). The valgus deformities of the feet in patient withRA may be the main contribution to deformities of gait, including revealed decreases in velocity, stride length, and single-limb-support time(10). Used as characterise dysfunction of the lower limb and foot in people, gait also expressed its effects mainly in RA's patient with conditions of of a slower walk, longer double support time, and avoidance of extreme positions(11).

3. The hands
The affects of deformation of RA's hands can be described through the defects of bone ankylosis as a result of bone damage of the prolonged onset of the disease(12). These deformities of hand and wrist and small peripheral joints (such as fingers and wrist) due to chronic inflammation can be treated by transelectrical nerve stimulation, the University of Ottawa suggested(14).
According to the joint study lead by the University of Warwick, strengthening and stretching have been found effectively in reduced pain and dysfunction of the hands and/or wrists in RA patient with stable medication for at least 3 months(13)

4. The Muscle strength
The effects of muscle strength in patient with RA may contribute to the prevalence of functional limitations physically of that cdan effects daily living and quality of life. Dr. Häkkinen A and the research team at Jyväskylä Central Hospital, suggested that 2-year program of strength training showed a statistically significant improvement in clinical disease activity parameters, walking speed and physical function(15). Some researchers suggested that muscle strength was found inversely and independently associated with all-cause mortality, including the levels of physical activity or even cardiorespiratory fitness(16).
Dr. Brodin N and Dr. Swärdh said"... short-term land-based aerobic and strengthening exercise on moderate to high intensity results in positive effects on oxygen uptake and muscular strength, but not pain,..." (17).of that may be necessary for patient with RA.

5. Rheumatoid nodules
Rheumatoid nodules, lump on the skin, closed to the joint have been found to affect the joints of patients with rheumatoid nodules(18). Treatment of rheumatoid nodules are necessary in odd cases if the patient are experiencing pain or interference of mechanical function, according to Dr. Tilstra JS and Dr.Lienesch DW.(19). Use of methotrexate (MTX) in patient with RA may accelerate the occurance of nodulosis in the fingers. but nodules will be resolved after methotrexate was discontinued and recurred after methotrexate was reintroduced(20).

5. Conjunctival nodule
Although is rare in patients with rheumatoid arthritis, the appreance of the nodules may exhibit the
severity of the underlying disease, according to the Tehran University of Medical Sciences(21), including Pityriasis Lichenoides et Varioliformis Acuta(22), Epstein-Barr virus(23)

6. Morning stiffness
Morning stiffness, as a marker of inflammatory activity in reflecting functional disability and pain is a very common symptoms of patients in early rheumatoid arthritis(24). Use of glucocorticoid is found effectively in pain relief over 70 percent of patient with RA(25).
According to the Charité University Medicine, in a 12-week, multicentre, randomised, double-blind trial, 288 patients with active rheumatoid arthritis, treatment of modified-release prednisone exhibited a clinically relevant reduction of morningstiffness of the joint in comparison of immediate-release prednisone(26).

7. Quality of life
7.1. Physical disability
Although psychological distress and physical disability have been decreased with the cautious approach with respect to prescribing medication and physical exercise progressed toward RA patient(27), but tools necessary to measure RA disease activity are often incomplete, imprecise, or rely on a combination of physician and patient subjective evaluations(28)
Dr. Motl RW and Dr. McAuley E.said" The rationale and the associated onset of chronic disease conditions that influence function, disability, and quality of life (QOL) is embedded in the "Graying of America""(29), including patient with RA.

7.2. Concurrent psychiatric disorders
Concurrent psychiatric disorders, such as depression or anxiety in patient with Rheumatoid Arthritis is found to associate to poor quality of life, according to  Dr. Mok C, and the scientists at the Tuen
Mun Hospital(30). Patients with RA is found to associate to Neurologic (N) and psychiatric (P) syndromes including depression and anxiety and symptoms of cognitive dysfunction, etc.,....of that induced poorer quality of life, according to the Lby the SF-36 and fatigue by a 10 point Likert scale(32).
Dr. Arnold LM said" Chronic widespread pain is associated with several medical and psychiatric disorders,....,careful and comprehensive differential diagnosis must be performed to ensure a correct diagnosis before an appropriate treatment can be selected"(31).

The Causes

Rheumatoid arthritis is caused by immune dysfunction in attacking its own tissues, causing severe damage and inflammation of the joints, especially in the progresses to destruction of cartilage and bone. The causes of auto immune disorder is unknown, but some researchers expected the following.

1. Abnormal autoimmune response
Scientists in the study of Abnormal networks of immune response-related molecules in bone marrow cells from patients with rheumatoid arthritis suggested that  patients with abnormal gene expressions of interleukin (IL) -37,(32a), miR-573 on IL-6 production(33) and microRNA-203(34),... are associated to increased risk of rheumatoid arthritis.
Dr. Lee HM and the research team at the Osaka University said" Abnormal regulatory networks in the immune response and one marrow (BM) cells from RA patients, indicating that the BM is pathologically involved in RA"(35).

2. Abnormal lipid profile
Abnormal lipid profile in many cases is associated to the metabolic syndrome risk, especially in patient with type II diabetes(36). The University of California suggested that patient with rheumatoid arthritis are found to have a high expression of low-density lipoprotein (LDL) cholesterol driven by increases in cholesterol ester catabolism(37). Dr. Xue C and the research team at the People's Hospital of Peking University showed that the association of rheumatoid arthritis and an abnormal lipid profile may be contributed as a result of increased inflammation markers and autoimmune antibodies(38) or inflammatory changes in HDL-C and Lp(a) metabolisms(39).

3. Genetic susceptibility
Certain genetic variations inherited from a parent, may be involved in the expression of RA patient, some research insisted. The Immunochip custom SNP array of 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers found that people with certain gene of loci are found to have an increased risk of rheumatoid arthritis(40).

Genetic association of CCR5 promoter polymorphism also seems to play an important role in determining different forms of rheumatoid arthritis(41), according to the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. In fact, over expression of Aiolos polymorphisms(42), LRP3 rs35829419 polymorphism(43), Interleukin-6 promoter haplotypes(44),... are all found to induced certain human diseases, including rheumatoid arthritis.

4. Inflammatory and infectious connections
Chronic inflammation of the joint can result of thickens the synovium, of that affect the cartilage and bone within the joint. Dr. Liao F. and the the research team at the Wuhan University said" Rheumatoid arthritis (RA) is a common, systemic autoimmune disease which leads to destruction of the joint architecture and consequent disability"(46). According to Epidemiological studies, the prevalence of RA affects about 5% of the population are aged 50 years or older, involved the connection of infectious etiology with a complex inflammatory response(45).
T helper 17 cells (Th17), a major effector cells in several chronic inflammatory states, correlated with local and systemic parameters of inflammation may also be a causative link to the expression of patient with RA(47)

The Risk factors

1. Age
The prevalence of Rheumatoid arthritis is proportional with the progression of age. The University of Twente study suggests age is independently associated with the levels of both acute phase reactants in early RA.(48).
In a study of 950 RA patients, the median age at the time of onset of RA according to age of the young-onset RA (YORA) and late-onset RA (LORA) is 58(49).
According to the joint study lead by the Leiden University Medical Center, Zone, expression of gene IL7R gene expression associates with longevity and healthy ageing are also found to involved risk of immune-related disease, such as RA and reduced health(50).

2. Gender and body mass index
If you are women and overweight, you are at increased risk to develop Rheumatoid Arthritis(51)(52)(54), probably due to  the association between body composition BMI and inflammatory activity of in rheumatoid arthritis(55). The Korea study suggests, Middle- and old-aged women accounted for the majority of the Korean RA population, of which interfere with daily activity and employment rate(53).

3. Race
Genome-wide association studies and meta-analysis indicate that several genes/loci are consistently associated with rheumatoid arthritis (RA) in European and Asian populations(40). In treatment of RA, Dr. Constantinescu F and the research team at the Virginia Commonwealth University said " (there is) racial disparities in treatment preferences for rheumatoid arthritis(56). The University of Nebraska, Omaha suggests 52 percent of African American subjects were found to be risk averse compared with 12% of the white subjects. Race remained strongly associated with risk aversion in RA(57).

4. Smoking
Smoking is considered as one of the environment risk factor in involvement of Rheumatoid arthritis (RA) development and severity(58). The Danish study insisted that smoking exhibits other risk factors including IgM-rheumatoid factor, anti-CCP and shared epitopes in contribution to the early onset of rheumatoid arthritis(59). In fact, the medical literature was reviewed from 1985 to 2001 with the assistance of a MEDLINE showed that cigarette smoking has been increasingly shown in epidemiologic and case-control studies to be an important risk factor for both the incidence and severity of RA, especially in seropositive men. The poor habit also induce mutations or alterations in p53, a suppressor gene found in patients with RA(60).

5. Family history
Rheumatoid arthritis (RA) is associated to greater risk in the first degree relatives in familial clustering, mothers confer susceptibility to RA on their offspring more often than fathers(61). According to the data on patients with RA were ascertained through the nationwide Swedish Patient Register of 88,639, the clinical Swedish Rheumatology Quality Register of 11,519, risk of RA are same in both sex but Familial factors is found to be overlap between seropositive RA and seronegative RA(62).

6. Vaccines
Certain vaccines may cause Rheumatoid Arthritis(65). But there is no statistically significant association between exposure to vaccine and onset of RA, according to the Kaiser Permanente Vaccine Study Center(64).

7. Other risk factors
Dr. Oliver JE and Dr. Silman AJ. in the study risk factors are that lead to the development of rheumatoid arthritis (RA). suggest diets high in caffeine, low in antioxidants, high in red meat, changes in the female hormonal environment such as in pregnancy, breastfeeding and the use of the oral contraceptive (OC) pill, cigarette smoking and passive inhalation of smoke may also contribute to an increased risk of RA(63).

The Diagnosis

If you are experience certain subtle symptoms, such as achy joints or a morning stiffness, etc,....you may be at the early stage onset of rheumatoid arthritis. If your doctor suspect that have develop RA because of some RA symptoms such as such as warmth, swelling and pain in the joints, after physical exam, certain blood tests may be necessary, including
1. Erythrocyte sedimentation rate
ESR is a a common hematology test to calculate the rate of red blood cells sediment in a period of one hour. According to Dr. Wolfe F said " ESR is sensitive to immunoglobulins and rheumatoid factor (RF),... but a a poorer measure of inflammation"(64a) and may be effected by other factors. Other clinical findings, the individual's health history, and results from laboratory tests are necessary, such as C-reactive protein(64a) to rule out a suspected diagnosis for the confirmation of the result. Dr Sokka T and Dr. Pincus T. normal ESR and CRPC-reactive protein, are seen in a substantial proportion of patients with RA.(65a)

2.  C-reactive protein
A group of "acute phase reactants" protein produced by liver and found in patient with rheumatoid arthritis.,tends to elevate in case of inflammation. According to the Copenhagen University Hospital, oral nonsteroidal antiinflammatory drugs (NSAIDs) does not effects the levels of protein but may be constituted to the influence of NSAIDs on cardiovascular complications in patient with RA(66).

3. Test for Anemia
According to statistic, the prevalence of mild anemia characterized by low serum iron concentration ranged between 33% and 60% are found in patient with rheumatoid arthritis(67), such as aplastic anemia and iron deficiency anemia. In fact, patient with combination of RA and amenia are mostly experience severe forms of joint disease and improvement of anemia is found to contribute to over all quality of life (QOL) and response to RA therapy(67).

4. Anti-cyclic citrullinate d peptide (anti-CCP antibodies)
Cyclic citrullinated peptides (CCP) in most cases is ordered in conjunction with the test of rheumatoid factor in patient with RA. The positive find of anti-citrullinated peptide/protein antibodies may contribute to the presence of the early event in the disease(68). Dr van Venrooij WJ and the research team at the Radboud University said"...., the presence of these antibodies was highly predictive of and specific for RA, and illustrating the importance of ACPA"(69).

5. Rheumatoid factor
Rheumatoid factor test is a blood test to measure the antibody in patient with rheumatoid arthritis.
The study of 71 patients with rheumatoid arthritis and 25 control subjects. AIF-1 is found to associated with the pathogenesis of RA involved in the immunological process underlying RA(70).

Others such as elevation of interleukin-7 receptor (IL-7Ralpha)(71), interleukin-18(72),.... also involve in the presence of RA.
6. X ray

X ray may be important to determine the changes of bone mineral density. Patient with RA are found to have an lower BMD of that can lead to increased risk of major fracture and hip fracture(73). The family notebook suggested the relative change of  Rheumatoid Arthritis found in X ray according to Dr. Kirwan J and Dr. Byron M, Watt I. include soft tissue swelling, joint space narrowing and erosive damage(74).

Misdiagnosis and Delay diagnosis

1. Polyarticular gout

Polyarticular gout, a inflammatory condition with painful crystals forming in the joints has been found to be misdiagnosed as Rheumatoid Arthritis in elderly of that can constitute to poor treatment as well as failure to recognize underlying renal insufficiency, and increased cardiac risks(75), according to the Albert Einstein College of Medicine.

2. Hypercalcemia and Lytic Bone Lesions Masquerading Inflammatory Arthritis

According to the Mashhad University of Medical Sciences,  a 50-year-old woman with hypercalcemia, lytic bone lesions and inflammatory arthritis of both hands was misdiagnosed as rheumatoid arthritis due to the presence of perparathyroidism in rheumatologic manifestations(76).

3. Systemic sclerosis
Systemic sclerosis (SSc) is an autoimmune disease of the connective tissue may be misdiagnosed as rheumatoid arthritis. According to the Dr. Horimoto AM and Dr. Costa IP, arthritis, clinically observed, may be a feature often found in patient with Systemic sclerosis, often leading to early misdiagnosis with rheumatoid arthritis (RA)(77).

4. Jaccoud's arthropathy (JA)

Jaccoud's arthropathy (JA), a clinical situation foundt mostly in patient withsystemic lupus erythematosus (SLE) is found to be misdiagnosed as RA, due to swan neck," ulnar deviation and "Z-thumb which overlap with symptoms of patient with RA, according to the joint study lead by the Universidade Federal da Bahia, Salvador(78).

In fact, according to the joint study by the University of Texas Southwestern Medical Center and Victoria Hospital, the misdiagnosis of the atypical Infections versus Inflammatory Conditions of the Hand due to some similarity to inflammatory conditions regarding their clinical and imaging finding is rare but delay diagnosis can increase risk of severe bone and joint destruction, and higher morbidity(79).

The Complications

The progression of RA as of other chronic diseases in most cases induced complications constitute the expressions of other diseases, especially of the adverse effects of certain medication use.

1. Osteoporosis
The condition of gradually loss of bone mineral density due to aging has found to be associate to the complication of rheumatoid arthritis. It mat be result of bone weakening induced by the progression of the disease.
Dr Lee SG, and the research team at the Pusan National University School of Medicine, suggest, the prevalence of osteoporosis in the RA patients was 1.9 times higher than in healthy subjects. Glucocorticoid use for treatment of osteoporosis was a risk factor for generalized bone loss in female RA patients(80). In the study of  Italian Study Group on Bone Mass in patient with Rheumatoid Arthritis, Dr. Insignia L and his team concluded "... osteoporosis and its dramatic complications in RA the therapeutic challenge is to preserve functional capacity using the lowest possible dosage of corticosteroids"(81).

2.  Lymphoproliferative diseases
The use of Methotrexate (MTX) as a first choice of medicine for treatment of RA has been found to induced complication of MTX-related lymphoproliferative diseases (MTX-LPDs). The joint study by the Niigata Rheumatic Center suggests the cytological examinations of the synovial fluid followed by knee operation are important and effective for early diagnosis of MTX-LPD(82). The study 589 RA outpatients examined at the National Center for Global Health and Medicine in the period from January 1990 to October 2010 conducted by the Osaka University Graduate School of Medicine also supported of the above claim and expressed the concern of the therapeutic challenge is to preserve functional capacity using the lowest possible dosage of corticosteroids.(83).

3. Neurologic complications

According to Dr. Bhattacharyya S and Dr. Helfgott SM, insisted that patient with RA in many cases have found to associate to neurologic complications because of its inflammatory origins and affect on nervous system (84). Recent study of 2624 patients treated with rituximab for rheumatoid arthritis RA and other autoimmune diseases, the late-onset neutropenia was observed in 40 patients with 25 of RA  of which contributed to risk of 1.3% of patients(85). Other support of above includes the study by the
The Ipswich Hospital NHS Trust, of which insisted that Late-onset neutropenia (LON) occurs infrequently after treatment with RTX, but can present with infection(86).

4. Carpal tunnel syndrome
Carpal tunnel syndrome is defined as a condition of pressure on the nerve in the wrist that supplies Carpal tunnel syndrome caused by volar dislocation of the lunate, associated with median nerve neuropathy has found in a patient with rheumatoid arthritis(87).

5. Scabies
Scabies is highly contagious skin disease caused by an infestation by the itch mite Sarcoptes is found to be another complication of medication use cause of disease(89).

6. Dry eye syndrome and Sjogren’s syndrome
According to 61 patients with rheumatoid arthritis recruited at Siriraj Hospital during March 2009-September 2010. the prevalence of secondary Sjogren's syndrome and dry eye were found with astonished rate of 28%(90). The awareness and detection of dry eye syndrome and secondary Sjogren’s syndrome in rheumatoid arthritis may has constituted the importantevaluation of their severity and proper management(91), the Mahidol University suggested.

7. Cerebral vasculitis
Cerebral vasculitis is a condition of inflammation of blood vessel wall involving the nervous system.
The diseases also share some characteristics with RA such as elevated levels of white blood cells, erythrocyte sedimentation rate, C-reactive protein, IgG-rheumatoid factor and immune complex(92). Dr. Ohno T and the reaserch team at the Ohtsu Red Cross Hospital reported that methotrexate is found effectively in treatment of long lasting rheumatoid cerebral vasculitis(93).

8. Other complications
According to 10 relevant studies out of 2326 bibliographic citations found by the University of Palermo, complication associate to RA, include ericardial effusion (OR 10.7; 95% CI 5.0-23.0), valvular nodules (OR 12.5; 95% CI 2.8-55.4), tricuspidal valve insufficiency (OR 5.3; 95% CI 2.4-11.6), aortic valve stenosis (OR 5.2; 95% CI 1.1-24.1), mitral valve insufficiency (OR 3.4; 95% CI 1.7-6.7), aortic valve insufficiency (OR 1.7; 95% CI 1.0-2.7), combined valvular alterations (OR 4.3; 95% CI 2.3-8.0), mitral valve thickening and/or calcification (OR 5.0; 95% CI 2.0-12.7), aortic valve thickening and/or calcification (OR 4.4; 95% CI 1.1-17.4), valvular thickening and/or calcification (OR 4.8; 95% CI 2.2-10.5), and mitral valve prolapse (OR 2.2; 95% CI 1.2-4.0)(88).

The Diseases associated to Rheumatoid Arthritis(Comorbidities)

The simultaneous presence of chronic Rheumatoid Arthritis with other diseases or conditions, include cardiovascular diseases (CVD), cancer, osteoporosis, and depression  with often underrecognized in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or psoriasis (PsO)(94).according to the joint study lead by Notre-Dame Hospital.

1. Cardiovascular disease (CVD)
Cardiovascular disease (CVD), one the most leading cause of death in US, in particular Coronary artery disease, is found to associate to patient with RA(95). Dr.Goodson N said" Cardiovascular death is........ responsible for approximately half the deaths observed in RA(95).  The study of 54 patients with RA :87% were women, with a mean age of 51 and 92% with rheumatoid factor positive showed that high homocysteine concentration is correlate to highest risk of CVD in RA patient(96).
Recent study by Dr. Kumar N and Armstrong DJ. insisted that traditional risk factors such as homocysteine, oxidised low-density lipoprotein, high-sensitivity C-reactive protein and leptin may contribute to the growing rates CVD death in RA patient(97).

2. Infections
The chronic, debilitating, autoimmune nature of RA affected directly or indirectly in almost all organ systems of RA patient, have shown to induced risk of infection(98) which is found to be responsible for death of 25% of RA patients(99). According to the joint study lead by Tampere University, in total of 10,994 patient-years, 341 serious infections were found in patient with RA(100).
3. Mental health issues
According to the study by National Institute for Science and Technology high prevalence of anxiety and depression and even suicide ideation has been found to associated to patient with RA(101) probably due to inflict of medicine(101). Dr. Rouse PC and the research team at the joint study lead by the University of Birmingham, Birmingham, suggested that depression is one most concern and positive psychological well-being in RA patients(102).
Dr. Ryan and Dr. McGuire B insisted that chronic pain associated to PA may constitute to psychological symptoms of depression and anxiety in patients with RA(103).

4. Cancers
Use of TNF-alpha antagonists for treatment of inflammatory diseases may associate to risk of cancer, particular lung cancer(104). According Dr. Buchbinder R and the research team lead by the Monash University, "Malignancy incidence was low in this RA cohort and biologic exposure did not increase the risk of malignancy. Melanoma risk was increased in both TNFi-treated and biologic-naïve RA patients compared with the general population suggesting that RA status, and possibly methotrexate exposure, may be responsible"(105).

5. Gastrointestinal ulcer
Use of Non-steroidal anti-inflammatory drugs (NSAIDs) for treatment of RA is frequently associated to gastrointestinal (GI) ulcers and complications of ulcers(106). The Tokyo Women's Medical University study suggests the prevalence of upper gastrointestinal (UGI) ulcer in patient with RA is also related to Helicobacter pylori and the association of H. pylori infectionas well as the intake of nonsteroidal anti-inflammatory drug (NSAID), according to a cohort of Japanese patients with rheumatoid arthritis (RA)(107).

The Prevention and Management

The do’s and do not’s list

The aim of the do and do not list is to find the common strategy with the use of natural remedies to prevent the early onset of RA and protect against the progression and pregressive symptoms of rheumatoid arthritis. Dr. Combe B said in the study of early rheumatoid arthritis: strategies for prevention and management"... A very early use of effective disease-modifying anti-rheumatic drugs (DMARDs) is a key point in patients at risk of developing persistent and erosive arthritis" and " Information and education for patients, as well as some non-pharmacological interventions, can be proposed as treatment adjuncts. Finally, the reduction or stopping of smoking, which could prevent the development and progression of early RA, is the only prevention tool currently available"

In herbal medicine, disease-modifying anti-rheumatic drugs (DMARDs) may be replaced with the intake of anti inflammatory foods.

1. Reduce intake of saturated and trans fat and increase intake of omega 3 fatty acids
Omega-3 FAs imay protect against the development of RA-related autoimmunity in pre-clinical RA, according to a nested case-control study (109). But according to Dr. Devaraj S. and the research team at the UC Davis Medical Center, oonly limit study showed the effects of dietary fatty acids (ie, oleic acid and alpha-linolenic acid) reduce biomarkers of inflammation, null effects in fish oil(110).

According to  results of over 13 double-blind, placebo-controlled studies involving a total of more than 500 people suggest that omega-3 fatty acids may improve symptoms of rheumatoid arthritis.

Intake of high amount of saturated fat and trans fay can increase the production of inflammatory cytokines(111).

2. Increase intake of fruit and vegetable
Vegetables and fruit formed a important part of human nutrition with good sources of nutrients, dietary fibre, and phytochemicals have been found to reduce risk of chronic diseases, including rheimatoid arthritis RA(112)

In a cross-sectional study of  1200 Puerto Rican adults aged 45-75 y, intake variety of fruits and vegetable but not quantity appears to be important in reducing inflammation(113). The healthy  Mediterranean-type diet rich in fish, fruit and vegetables and low in saturated fats showed to contribute to over all health including complications of RA and RA itself(114).

3. Avoid high glycemic index diets
High glycemic index diets, which have low fiber content and are rich in trans fat cause the activation of the immune system, leading to excessive production of pro-inflammatory mediators(116). Dr. Kremer JM and Dr. Bigaouette J. of American diet in patients with RA said" Patients with RA ingest too much total fat and too little PUFA and fiber. Their diets are deficient in pyridoxine, zinc and magnesium vs the RDA and copper and folate vs the TAD"(115). Increase intake of  fruits, vegetables, and whole grain consumption seem to be associated with the improvement in subclinical inflammatory condition(116).

4. Maintaining body weight
According to the joint study lead by the Philadelphia VA Medical Center and University of Pennsylvania, a low body mass index (BMI) has been associated with accelerated mortality in patients with rheumatoid arthritis (RA) and obesity showed no support a biologically protective role in RA patients(117). Patients with high BMI have lower mortality than thinner patients(118).

5. Reduced intake of pro inflammatory foods
Foods sugar, dairy products, red meat and processed, meat, alcohol, artificial ingredients, refined products, etc. induced the production of pro inflammatory cytokine is associated to the expression and progression of  Rheumatoid Arthritis(120) as Dr. Seaman DR. said" Nearly all degenerative diseases have the same underlying biochemical etiology, that is, a diet-induced proinflammatory state" and "treatment program must also include nutritional protocols to reduce the proinflammatory state"(119).

6. Increase in take of anti inflammatory foods
such as fresh vegetables and fruits, seeds and sprouts whole grain, fish, turkey, chicken, legumes, etc.
A high vegetable diet and fish oil are found to associate to reduce inflammation and progression of RA. Dr. Adam O and the research team at the Medizinische Klinik Innenstadt der LMU suggested that auch diet improved tender and swollen joints decreased caused by expression of pro inflammatory cytokines(121). Others in the study of 49 patients with active rheumatoid arthritis completed a 24-week, showed the intake of fish oil with olive oil is also associated with certain changes in immune function, probably through the health benefits from the presence of omega-3 fatty acids in olive(122).

7. Stop smoking
Smoking are associated with increased of Rheumatoid Arthritis as it is considered as the most important extrinsic risk factors for the development and severity of Rheumatoid Arthritis, causing over expression of oxidative stress, inflammation, autoantibody formation and epigenetic changes(124).
According to the data of 2,800 adult patients included in the BARFOT early RA between 1992 and 2005study in Sweden. stop smoking after onset of RA did not change the poor prognosis of smokers with RA but reduced risk cardiovascular mortality and morbidity and the association of smoking with vasculitis and noduli in RA(123).

8. Occupations
If you are in occupation of increased risk of Rheumatoid Arthritis(RA), such as farmers, upholsterers, lacquerers, concrete workers, and hair-dressers, you should take all precaution if necessary(124).
According to the Department of Occupational Health, Karolinska Hospital, in a register based cohort study of a total of 375,035 men and 140,139 women concluded "there were rather small differences in the relative risk of RA in different exposure groups and different occupations"(125).

9. Moderate exercise
Moderate exercise such as yoga(127)(128), taichi(128), qi kong(128),.....enhances immune function in fighting against inflammatory and infectious disease outcomes(128).
In the study of habitual physical activity levels of 29 female patients with RA, researchers at the joint study lead by University of the Witwatersrand showed that the exercise improved bone density and induced protective effects on bone health(126).
In animal model,

The Diet

The Diet reduced risk of over expression of pro inflammatory cytokine is always important to prevent the early onset and patient with progression of the rheumatoid arthritis.
1. Organic Soy
Intake of soy protein can enhance the protective effect against Rheumatoid Arthritis(129). Genistein, an isoflavone derivative found in soy suppressed the proinflammatory cytokine production, through inhibiting the expression of accumulation of reactive oxygen species (ROS)(130).
In animal model with with collagen-induced arthritis (CIA),, genistein, daidzein, and soy protein found in organic soy, restore the paraoxonase and arylesterase activity as well as malondialdehyde (MDA) level fo that have a related improvement of patient with Rheumatoid Arthritis(131).

2. Green tea

Green tea uss as a precious drink in social activities in many culture has been found to prevent the onset of rheumatoid arthritis and protect against the progression of the diseases due tom aging, via its antioxidant property(132). In animal models, green tea aqueous extract improve over function of rat with rheumatoid arthritis through significantly decreasing and down-regulating the systemic production of pro-inflammatory cytokines and the expression of chemokine receptor-5 in synovial tissues(133). Dr. Ahmed S. said "Green tea's active ingredient, epigallocatechin 3-gallate (EGCG), ....one of the leading plant-derived molecules studied for its potential health benefits,........I summarize the findings from some of the most significant preclinical studies with EGCG in arthritic diseases(134).

3. Olive oil
Olive oil when used conjunction with fish oil is found to prevent the early development and protect against progression the diseases in patient with RA, in our earlier research(135). In other study of a total 145 RA patients and 188 control subjects, regular intake of of both cooked vegetables and olive oil was inversely and independently associated with risk of RA, probably through the consumption of n-3 fatty acids and nutrients effects(136). Dr. Rosillo MÁ and the research team lead by the University of Seville showed that phenolic compounds found in the extra virgin olive oil (EVOO) inhibited the levels of proinflammatory cytokines and prostaglandin E2 in the joint as well as down-regulation of the arthritic process(137).

4. Salmon
Salmon containing high amount Omega 3 fatty acid which is found to decrease the risk of RA(138).
Salmon cartilage proteoglycan (PG), in animal model is found effective in suppressed excess inflammation in different mouse inflammatory diseases, including rheumatoid arthritis, through attenuated collagen-induced arthritis (CIA) pathogenesis by modulating immune response and local production inflammatory cytokines and chemokines in the joints(139).Salmon calcitonin, a hormone found in salmon and used as spray for treatment of osteoporosis exhibited anti inappropriate inflammatory responses contribute to the pathogenesis of rheumatoid arthritis (RA), according to the School of Food Science and Environmental Health(140).

5. Ginger
Ginger (Zingiber officinale), one of traditional herbal medicine and spicy used in many Asian culture today, is being used as an anti-inflammatory in Chinese and Ayurvedic medicine. Crude dichloromethane extract from ginger, contained essential oils and more polar compounds, was found more efficacious in preventing both joint inflammation and destruction, according to Dr. Funk JL and scientists at the University of Arizona(141)).
Dr. Al-Nahain A and the research team at the University of Development Alternative said"..., phytochemicals( found in ginger) can form the basis of discovery of new drugs, which not only can provide symptomatic relief but also may provide total relief from RA by stopping RA-induced bone destruction"(142)

The Phytochemicals

1. Curcumin
Curcumin is a phytochemical found abundantly in Turmeric, principal curcuminoid of the popular Indian spice
1.1. Anti-inflammatory agent
Curcumin (diferuloyl methane) may be used as nonsteroidal anti-inflammatory drugs (NSAIDs for treatment of rheumatoid arthritis(143). Dr. Sarker MR and the research team at the University of North Texas Health Science Center in the study of animal model, suggested that dietary curcumin amy have a positive effects on improved anti-inflammatory or antioxidant actions(144).

1.1. Antioxidants

Curcumin, one of most powerful antioxidant found in foods was found epidemiologically as a proven antioxidant for its anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing effects(145).  The antioxidant is also considered as a novel promising therapeutics against chronic neuroinflammation and neurodegeneration in Alzheimer's disease by the Western Sydney University(146).
In rheumatoid arthritis patients, oral administration of curcumin sginificantly improved the American College of Rheumatology (ACR) DAS scores in reduction in tenderness and swelling of joint and and other arthritic conditions(147) such as dramatic amelioration of arthritis symptoms(148).

2. Gingerol
Gingerole, is also known as gingerol, a phytochemical of Flavonoids (polyphenols) found in fresh ginger.
2.1. Antioxidants and Anti-inflammatory effects
Crude ginger and rosemary extracts showed to inhibit the production of pro-inflammatory cytokines due ot its function as an inflammatory mediators with high antioxidant activity(149). The comparison of different ginger constituents, such as [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol, 6-Shogaol has found to be most potent antioxidant and anti-inflammatory phytochemical due the presence of alpha,beta-unsaturated ketone moiety(150).

Dr. Masuda Y. and the research team at the Osaka City University said" antioxidants isolated from the rhizomes of ginger,....the antioxidant activity might be due to not only radical scavenging activity of antioxidants but also their affinity of the antioxidants to the substrates"(151).

2.2. Rheumatoid arthritis

In rheumatoid arthritis, ginger-turmeric rhizomes mixture on animal model, may be effective against rheumatoid arthritis (RA) severity and complications, through the mediation of decreasing the systemic inflammation that occur at the appearance of polyarthritis, oxidative stress and dyslipidemia(152). According to DR. Ramadan G1 and the research team at the King Faisal University, the anti-inflammatory/anti-oxidant activity of ginger is less potent than turmeric but constitute to some beneficial effects against rheumatoid arthritis onset/progression(153).

3. Quercetin
Quercetin is a member of flavonoids, found in fruits, vegetables, leaves and grains with anti inflammatory and antioxidant property(154)(155). which have been found effectively in reduce the early onset and stop the progression of rheumatoid arthritis.
In rat adjuvant arthritis, an oral daily dose of 150 mg/kg b.w. of quercetin for 28 days,quercetin lowered levels of pro inflammatory cytokines, interleukin-1β, C-reactive protein, and monocyte chemotactic protein-1 and restored plasma antioxidant capacity(156), . Dr.Ji JJ and the research team at the Dalian Medical University, suggested that quecetin may be a potent agent for treatment of symptoms of RA such as disabling joint disease involved hands, wrists, feet and other small joints, through its anti inflammatory and antioxidant effects(157).

4. Epigallocatechin-3-gallate (EGCG)
Epigallocatechin-3-gallate (EGCG) found in green tea has been found to process antitumor,anti-Alzheimer, and anti-aging properties throguh epidemiological studies(158). According to the joint study lead by the Zhejiang University, Epigallocatechin-3-gallate (EGCG) improved anti-oxidant defense enzyme, reduced mitochondrial oxidative stress, through its antioxidants and inflammatory effects which may contribute to the treatment of rheumatoid arthritis(159).
In rheumatoid arthritis, Epigallocatechin-3-gallate (EGCG) may have a beneficiary effects for treatment of RA due to its suppressed autoimmune arthritis activity(160), also through vary antioxidant and anti inflammatory pathways.

The Antioxidant

Antioxidants found abundantly in fruits and vegetables can enhance the immune system fighting against forming of free radicals causes of irregular cell growth and foreign invasion of inflammation and infection.
1. Vitamin C
Vitamin C, one of most powerful free radical scavengers, played an important role in prevention of domino effects of imbalance of estrogen may be a potent antioxidant effectively in normalization of the impaired oxidant/antioxidant system and delayed complication of RA(161). Dr, Al-Okbi SY in the study of elevated oxidative stress and inflammatory biomarkers suggested that vitamin C can be used as as complementary medicine to manage rheumatoid arthritis due to its anti-inflammatory and antioxidant activities(162).
But Dr. Rosenbaum CC and the research team at the the Bethesda North Hospital Pharmacy iunsisted that more high quality research are necessary before supplements including vitamin C can be effectively and safely recommended to reduce nonsteroidal antiinflammatory drug or steroid usage"(163)

2. Vitamin E
Low intake of vitamin E and selenium have been found to the RA elder patient(166).Vitamin E, another free radical scavenger may also be  effective for patient with RA due to its positive effect on autoimmune disease by decreasing proinflammatory cytokines and lipid mediator(164). Dr. Aryaeian N. in the investigation of the effectiveness of supplements in RA, showed that the procession of property in promoted immunity and involvement of inflammatory parameters may put vitamin E in front of other rheumatoid arthritis (RA)management supplements(165).

3. Glucosamine
Glucosamine, a compound of the simple sugar glucose and the amino acid glutamine, is a precursor for glycosaminoglycans may be another antioxidant used for management of symptoms of patient with RA, according to the study of 25 patients in the glucosamine group and 26 patients in the placebo group(167). Dr. Matsuno H. and the research team at the Matsuno Clinic for Rheumatic Diseases, said" (oral administration of) glucosamine-chondroitin-quercetin glucoside (GCQG) for 3 months showed a significant improvement in pain symptoms, daily activities (walking and climbing up and down stairs), and visual analogue scale, and changes in the synovial fluid properties"(168) in patient of OA and RA. Further more, the supplement also found to consist the therapeutic potential for arthritis by exerting antioxidative and immunomodulatory effects(169).

4. Methylsulfonylmethane
Methylsulfonylmethane (MSM), an antioxidant with organosulfur compound has shown to involve in reduced the progression of inflammatory processes in RA patient(170). The Jazan University study in the comparison of the effectiveness of Echinacea extract and composite glucosamine, chondroitin and methyl sulfonyl methane supplements, showed that both ingredient exhibit anti inflammation, oedema and mild proliferation of synovial cells activities, through reduced cartilage damage and bone density of that may be a promising light on arthritis treatment(171)

The Treatment
A. In conventional medicine perspective
The aim of treatment is to stop the progression and relieve the symptoms of the diseases
1. Non Medication
1.1.  Physical therapy

Physical therapy with functions of  re mediated impairments and promoted mobility, used conjunction with others including education, medical treatment,and occupational therapy may play an essential role for management of RA(172). In the treatment of patient with RA using the Whole-body cryotherapy (WBC) in supplement to physical therapy, Dr. combination and the research team at the joint study lead by the University School of Physical Education in Poznań said" (The combined therapies showed )improvement in pain, disease activity, fatigue, time of walking, and the number of steps over a distance of 50 m,...... similar significant reduction in IL-6 and TNF-α level (the inflammatory cytokines),...regardless of the kind of the applied physical procedure in patient with RA(173).

1.2. Relaxation therapy and biofeedback training
Relaxation and temperature biofeedback training as an adjunctive therapy has showed to alleviate both pain and stress-related symptoms as well as improvement of pain, tension, and sleep patterns. In fact, the therapy are found to induced higher physical/functional indices in comparison to physical therapy(174). Dr. Astin JA. and the research team at the University of Maryland School of Medicine suggested that psychological interventions such as relaxation, biofeedback, cognitive-behavioral therapy, may form an important part in may be important adjunctive therapies in the medical management of RA, especially for patients who have had the illness for shorter duration(175).In fact, a systematic review and meta-analysis of randomized controlled trials, also showed that psychological intervention improved both depressive symptoms and anxiety among patients with RA(176).

1.3. Low level laser therapy
Low level laser therapy may be beneficiary in modulated inflammatory response both in early as well as in late progression stages of RA, through its effects in significantly improved mononuclear inflammatory cells(177) as well as modulating inflammatory mediators (IL-1β, IL-6)(178). The study of 132 patients at the age varying from 18 to 85 years presenting with rheumatoid arthritis by Dr.Kulova LA, and Dr. Burduli NM also found thatn the therapy showed an improvement of the endothelial function and the microcirculation indices in patient with rheumatoid arthritis(179). But according to a randomized double-blind controlled trial laser therapy using low-level aluminum gallium arsenide was not effective at the wavelength, dosage, and power studied for the treatment of hands among patients with rheumatoid arthritis(180).

1.4. Occupational therapy
According to the Canadian association of occupation therapy, it is form of treatment  to solve the problems that interfere with your ability to do the things that are important to you. It can also prevent a problem or minimize its effects(181). According to the Netherlands Institute for Health Services Research, in controlled (randomized and non-randomized) and other than controlled studies (OD) addressing OT for RA patients showed that occupation therapy improved outcome on functional ability, social participation and/or health related quality of life(182). Rheumatologically, occupation therapy in many cases has successfully improved and maintained functional capacity, prevented progression of deformities, ......... of that may require for the engagement of the individual in meaningful occupations, favoring autonomy and independence in self-care activities, employment, educational, social and leisure(183)

1.5. Prosorba column apheresis therapy (PCT)
Prosorba column apheresis therapy (PCT), a medical device containnig purified staphylococcal protein A covalently bound to a silica matrix has been used in many medical centers for treatment severerheumatoid arthritis (RA) since its approval in 1999(184) with some promising result(185).
The therapy showed a 52% improvement in joint tenderness, 40% improvement in swelling, 42% improvement in patient's pain, 38% improvement in patient's global response, and 48% improvement in physician's global scores 76% of responders, according to the study by Cypress Bioscience(184).

2. Medication
Medication or combined medication are used to stop the progression and relieve the symptoms of the diseases may include
2.1. Medication for reduced symptoms
Nonsteroidal anti-inflammatory drugs (NSAIDs)can be bought as over counter medicine for reduced pain and inflammation for patient with rheumatoid arthritis with an incidence of significant upper GI toxic effects, according to a total of 8059 patients (>/=18 years old) with osteoarthritis (OA) or rheumatoid arthritis (RA)(186). Dr. Wienecke T and Dr. Gøtzsche PC. in the comparison of NSAIDs and Paracetamol for treatment of RA said " There is a need for a large trial, with appropriate randomisation, double-blinding, test of the success of the blinding, and with explicit methods to measure and analyse pain and adverse effects"(187) due to favorable of onsteroidal anti-inflammatory drugs (NSAIDs) in general population.

2.2. Medication for interfering the disease progression
a. Corticosteroids

Corticosteroid, a class a class of chemicals including the steroid hormones medication prednisone, prednisolone and methyprednisolone have been used in conventional medicine for quick treatment of inflammatory diseases such as rheumatoid arthritis, through reduced in activity and expression as a result of oxidative/nitrative stress(188). The University de Montréal joint study of 838 patient indicated the effectiveness of corticosteroids for treatment of inflammation of RA may accompany with increased hazard of infection(189), risk for the development of secondary osteoporosis(190) and dyslipidemia and hypertension(192). adrenal suppression, bone loss, skin thinning, increased cataract formation, decreased linear growth in children, metabolic changes, and behavioral abnormalities(191).

b. DMARDs, (Disease-modifying antirheumatic drugs)

DMARDs,  a disease-modifying antirheumatic drug such as methotrexate, hydroxycholorquine, sulfasalazine, leflunomide used by conventional doctor to modify the course of the disease(RA in this case) by releasing 4 h later to coincide with the rise of nocturnal inflammatory cytokines associated with development of symptoms of RA(192). According to the report of Dr. Sitzia J and Dr. Huggins L. the adverse effects of DMARDs may include  alopecia, fatigue, weight gain with fatigue and nausea to be the "most troublesome" problems, followed by difficulty sleeping and sore eyes(193), as well as other incidences of gastrointestinal side effects(194).

c. Biologics

Biologics  including abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, infliximab, golimumab and rituximab works with similar effects as DMARDs but more quickly in blocking  a specific step in the inflammation process, such as blocking the activation of T cells(197), B cells(198), pro inflammatory cytokines(199),...... have found significantly improved outcomes for patients with rheumatoid arthritis(195), through reducing the signs and symptoms of RA, slowing radiographic progression of joint destruction, and improving physical function and quality of life in patients with RA(196).

d. JAK inhibitors
JAK inhibitors, the medication used in conventional doctors for inhibition of the activity of one or more of the Janus kinase family of enzymes, involving function in cytokine receptor signalling pathway, through interaction with signal transducers(transmission of molecularsignals from a cell's exterior to its interior) and activators of transcription proteins(a sequence-specific DNA-binding factor in controlling the rate of transcription of genetic information from DNA to messenger RNA)(200) is also known as a new subcategory of DMARDs. Dr. Norman P. said" JAK inhibitors differ in isoform specificity profiles, with good efficacy achievable by selective inhibition of either JAK1 (filgotinib or INCB-039110) or JAK3 (decernotinib)' of that contrite to the effective treatment of patient with rheumatoid arthritis)(201). According to the University of Occupational and Environmental Health, use of Tofacitinib, a new class of DMARDs orally available exhibited a strong clinical efficacy similar to biologic DMARDs through inhibited multiple cytokines and signaling pathways at clinical doses that are in contrast to biological DMARDs(202).

Here, we quoted the criteria of medication or combined medication is used to stop the progression and relieve the symptoms of RA by Dr. da Mota LM, and scientists at the Universidade de Brasília
1) The therapeutic decision should be shared with the patient;
2) Immediately after the diagnosis, a disease-modifying antirheumatic drug (DMARD) should be prescribed, and the treatment adjusted to achieve remission;
3) Treatment should be conducted by a rheumatologist;
4) The initial treatment includes synthetic DMARDs;
5) Methotrexate is the drug of choice;
6) Patients who fail to respond after two schedules of synthetic DMARDsshould be assessed for the use of biologic DMARDs;
7) Exceptionally, biologic DMARDs can be considered earlier;
8) Anti-TNF agents are preferentially recommended as the initial biologic therapy; 9) after therapeutic failure of a first biologic DMARD, other biologics can be used;
10) Cyclophosphamide and azathioprine can be used in severe extra-articular manifestations;
11) Oral corticoid is recommended at low doses and for short periods of time;
12) Non-steroidal anti-inflammatory drugs should always be prescribed in association with a DMARD; 13) clinical assessments should be performed on a monthly basis at the beginning of treatment;
14) Physical therapy, rehabilitation, and occupational therapy are indicated;
15) Surgical treatment is recommended to correct sequelae;
16) Alternative therapy does not replace traditional therapy;
17) Family planning is recommended;
18) The active search and management of comorbidities are recommended;
19) The patient’s vaccination status should be recorded and updated;
20) Endemic-epidemic transmissible diseases should be investigated and treated.

3. Surgery
Surgery in some cases may be necessary to relieve severe pain and extensive joint deformities and with patient do not response to non and medical treatment. According to the Wrightington Hospital NHS Trust, in the study of postoperative infection or surgical complications occurring within one year of surgery in patient with RA found that the surgical procedure induced 27% of infection and complication for patient with  different in the intake of Methotrexate(204), a synthetic compound used for treatment of some forms of cancers.

B. Treatment in herbal and traditional Chinese medicine

B.1. Life style modification according herbal and TCM medicine specialist
Life style modification has shown to be beneficiary for patients with Rheumatoid Arthritis to improve muscu

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