Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a protracted autoimmune disorder that primarily affects joints. It typically results in warm, swollen and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involved with typically the same joints involved on both sides of the body. The disease may also affect other parts of the body. This may result in low red blood cells, inflammation around the lungs and inflammation around the heart. Fever and low energy may also be present. Often symptoms come on gradually over weeks to months.

While the cause of rheumatoid arthritis is not clear, it is believed to involve a combination of genetic and environmental factors. The underlying mechanism involves the body’s immune system attacking the joints. This results in inflammation and thickening of the joint capsule. It also affects the underlying bone and cartilage. The diagnosis is made mostly on the basis of a person’s signs and symptoms. X-rays and laboratory testing may support a diagnosis or exclude other diseases with similar symptoms. Other diseases that may be present include systemic lupus erythematosus, psoriatic arthritis and fibromyalgia among others.

The goal of treatment is to improve pain, decrease inflammation and improve a person’s overall functioning. This may helped by balancing rest and exercise, the use of splints and braces or the use of assistive devices. Pain medications, steroids and NSAIDs are frequently used to combat the symptoms. A group of medications called disease-modifying antirheumatic drugs (DMARDs) may be used to try to slow the progress of the disease. They include the medications hydroxychloroquine and methotrexate. Biological DMARDs may be used when disease does not respond to other treatments. However, they may have a greater rate of adverse effects. Surgery to repair, replace or fusion joints may help in certain situations. Most alternative medicine treatments are not supported by evidence.

RA affects between 0.5 and 1% of adults in the developed world with between 5 and 50 per 100,000 patients newly developing the condition each year. Onset is most frequent on middle age and women are affected 2.5 times as often as men. In 2013, RA resulted in 38,000 deaths up from 28,000 deaths in 1990.

The first recognized description of RA was made in 1800 by Dr Augustin Jacob Landré-Beauvais (1772–1840) of Paris. The term rheumatoid arthritis is based on the Greek for watery and inflamed joints. RA primarily affects joints, however it also affects other organs in more than 15–25% of individuals.

Joints

A diagram showing how rheumatoid arthritis affects a joint

Arthritis of joints involves inflammation of the synovial membrane. Joints become swollen, tender and warm and stiffness limits their movement. With time, multiple joints are affected (it is a polyarthritis). Most commonly involved are the small joints of the hands, feet and cervical spine, but larger joints like the shoulder and may also be involved. Synovitis can lead to tethering of tissue with loss of movement and erosion of the joint surface causing deformity and loss of function.

RA typically manifests with signs of inflammation, with the affected joints being swollen, warm, painful and stiff, particularly early in the morning on waking up or following prolonged inactivity. Increased stiffness early in the morning is often a prominent feature of the disease and typically lasts for more than an hour. Gentle movements may relieve symptoms in early stages of the disease. These signs help distinguish rheumatoid from non-inflammatory problems of the joints, often referred to as osteoarthritis. In arthritis of non-inflammatory causes, signs of inflammation and early morning stiffness are less prominent with stiffness typically less than one hour and movements induce pain caused by mechanical arthritis. The pain associated with RA is induced at the site of inflammation and classified as nociceptive as opposed to neuropathic. The joints are often affected in a fairly symmetrical fashion although this is not specific and the initial presentation may be asymmetrical.

As the pathology progresses, the inflammatory activity leads to tendon tethering and erosion and destruction of the joint surface which impairs range of movement and leads to deformity. The fingers may suffer from almost any deformity depending on which joints are most involved. Specific deformities which also occur in osteoarthritis, include ulnar deviation, boutonniere deformity, swan neck deformity and “Z-thumb. ” “Z-thumb” or “Z-deformity” consists of hyperextension of the interphalangeal joint, fixed flexion and subluxation of the metacarpophalangeal joint and gives a “Z” appearance to the thumb. The hammer toe deformity may be seen. In the worst case, joints are known as arthritis mutilans due to the mutilating nature of the deformities.

Skin

The rheumatoid nodule which is sometimes in the skin is the most common non-joint feature. It occurs in 30% of patients. It is a type of inflammatory reaction known to pathologists as a “necrotizing granuloma”. The initial pathologic process in nodule formation is unknown but may be essentially the same as the synovitis, since similar structural features occur in both. The nodule has a central area of fibrinoid necrosis that may be fissured and which corresponds to the fibrin-rich necrotic material found in and around an affected synovial space. Surrounding the necrosis is a layer of palisading macrophages and fibroblasts, corresponding to the intimal layer in synovium and a cuff of connective tissue containing clusters of lymphocytes and plasma cells, corresponding to the subintimal zone in synovitis. The typical rheumatoid nodule may be a few mm to a few cm in diameter and is usually found over bony prominences such as the elbow, heel, knuckles or other areas subject to repeated mechanical stress. Nodules are associated with a positive RF (rheumatoid factor) titer and severe erosive arthritis. Rarely, these can occur in internal organs or at various sites on the body. Several forms of vasculitis occur in RA. A benign form occurs as microinfarcts around the nail folds. More severe forms include livedo reticularis which is a network (reticulum) of erythematous to purplish discoloration of the skin caused by the presence of an obliterative cutaneous capillaropathy.

Other, rather rare, skin associated symptoms include pyoderma gangrenosum, Sweet’s syndrome, drug reactions, erythema nodosum, lobe panniculitis, atrophy of finger skin, palmar erythema, diffuse thinning (rice paper skin) and skin fragility (often worsened by corticosteroid use).

Lungs

Fibrosis of the lungs is a recognized response to rheumatoid disease. It is also a rare but well recognized consequence of therapy (for example with methotrexate and leflunomide). Caplan’s syndrome describes lung nodules in individuals with RA and additional exposure to coal dust. Pleural effusions are also associated with RA. Another complication of RA is Rheumatoid Lung Disease. It is estimated that about one quarter of Americans with RA develop Rheumatoid Lung Disease.

Kidneys

Renal amyloidosis can occur as a consequence of chronic inflammation. RA may affect the kidney glomerulus directly through a vasculopathy or a mesangial infiltrate but this is less well documented (though this is not surprising, considering immune complex-mediated hypersensitivities are known for pathogenic deposition of immune complexes in organs where blood is filtered at high pressure to form other fluids such as urine and synovial fluid). Treatment with penicillamine and gold salts are recognizedcauses of membranous nephropathy.

Heart and Blood Vessels

People with RA are more prone to atherosclerosis and risk of myocardial infarction (heart attack) and the stroke risk is markedly increased. Other possible complications that may arise include: pericarditis, endocarditis, left ventricular failure, valvulitis and fibrosis. Many patients with RA do not experience the same chest pain that others feel when they have angina or myocardial infarction. To reduce cardiovascular risk, it is crucial to maintain optimal control of the inflammation caused by RA (which may be involved in causing the cardiovascular risk) and to use exercise and medications appropriately to reduce other cardiovascular risk factors such as blood lipids and blood pressure. Doctors who treat patients with RA should be sensitive to cardiovascular risk when prescribing anti-inflammatory medications and may want to consider prescribing routine use of low doses of aspirin if the gastrointestinal effects are tolerable.

Eyes

The eye is directly affected in the form of episcleritis which when severe can very rarely progress to perforating scleromalacia. Rather more common is the indirect effect of keratoconjunctivitis sicca which is a dryness of eyes and mouth, caused by lymphocyte infiltration of lacrimal and salivary glands. When severe, dryness of the cornea can lead to keratitis and loss of vision. Preventive treatment of severe dryness with measures such as against nasolacrimal duct blockage is important.

Liver

Liver problems in patients with rheumatoid arthritis may be due to the underlying disease process or as a result of the medications used to treat the disease. A coexisting autoimmune liver disease such as primary biliary cirrhosis or autoimmune hepatitis may also cause problems.

Blood

Anemia is by far the most common abnormality of the blood cells which may have a variety of causes. The chronic inflammation caused by RA leads to raised hepcidin levels, in turn leading to chronic anemia where iron is poorly absorbed and is also sequestered into macrophages. RA may also cause a warm autoimmune hemolytic anemia. The red cells are of normal size and colour (normocytic and normochromic). A low white blood cell count usually only occurs in patients with Felty’s syndrome with an enlarged liver and spleen. The mechanism of neutropenia is complex. An increased platelet count occurs when inflammation is uncontrolled.

Neurological

Peripheral neuropathy and mononeuritis multiplex may occur. The most common problem is carpal tunnel syndrome caused by compression of the median nerve by swelling around the wrist. Atlanto-axial subluxation can occur, owing to erosion of the odontoid process and/or transverse ligaments in the cervical spine connection to the skull. Such an erosion (>3mm) can give rise to vertebrae slipping one over another and compressing the spinal cord. Clumsiness is initially experienced but without due care this can progress to quadriplegia.

Constitutional Symptoms

Constitutional symptoms including fatigue, low grade fever, malaise, morning stiffness, loss of appetite and loss of weight are common systemic manifestations seen in patients with active RA.

Bones

Local osteoporosis occurs in RA around inflamed joints. It is postulated to be partially caused by inflammatory cytokines. More general osteoporosis is probably contributed to by immobility, systemic cytokine effects, local cytokine release in bone marrow and corticosteroid therapy.

Cancer

The incidence of lymphoma although uncommon is higher in RA.

Causes

RA is a chronic autoimmune disorder the causes of which are not completely understood. It is a systemic (i.e. whole-body) disorder principally affecting synovial tissues. There is no evidence that physical and emotional effects or stress could be a trigger for the disease. The many negative findings suggest that either the trigger varies or that it might in fact be a chance event inherent with the immune response.

Half of the risk for RA is believed to be genetic. It is strongly associated with the inherited tissue type major histocompatibility complex (MHC) antigen HLA-DRB1 (most specifically the shared epitope alleles, including *0401 and born 0404) and the genes PTPN22 and PADI4—hence family history is an important risk factor. Inheriting the PTPN22 gene has been shown to double a person’s susceptibility to RA. PADI4 has been identified as a major risk factor in patients of Asian descent, but not in those of European descent. The prevalence rate for first-degree relatives is 2–3% and disease genetic concordance in monozygotic twins is approximately 15–20%.

Smoking is the most significant non-genetic risk with RA being up to three times more common in smokers than non-smokers, particularly in men, heavy smokers and those who are rheumatoid factor positive. Modest alcohol consumption may be protective.

Epidemiological studies have confirmed a potential association between RA and two herpesvirus infections: Epstein-Barr virus (EBV) and Human Herpes Virus 6 (HHV-6). Individuals with RA are more likely to exhibit an abnormal immune response to EBV and have high levels of anti-EBV antibodies.

Vitamin D deficiency is more common in patients with rheumatoid arthritis than in the general population. However, whether vitamin D deficiency is a cause or a consequence of the disease remains unclear. 1?,25-dihydroxyvitamin D3 (1,25D), an active metabolite of vitamin D, affects bone metabolism indirectly through control of calcium and phosphate homeostasis. Interaction between 1,25D and the vitamin D receptor (VDR) affects the production of RANKL and delays osteoclastogenesis. Some trials have found a decreased risk for RA with vitamin D supplementation while others have not.

Pathophysiology

Both genetic as well as environmental factors are implicated in the pathophysiology of the disease. Smoking is the main environmental risk to RA. 50% of the risk of having RA is attributable to genetic factors. No infectious agent has been consistently linked with RA and there is no evidence of disease clustering to indicate its infectious etiology. HLA-DR4 is the major genetic factor implicated – but its relative importance varies across ethnic groups. Related allotypes of MHC Class II and the T cell-associated protein PTPN22 has also been found associated in many studies.

RA primarily starts as a state of persistent cellular activation leading to autoimmunity and immune complexes in both joints and other organs where it manifests. The initial site of disease is the synovial membrane, where swelling and congestion leads to infiltration by immune cells.

The various phases of progression of RA are:

• Initiation phase, due to non-specific inflammation.
• Amplification phase, due to T cell activation
• Chronic inflammatory phase with tissue injury, due to cytokinesIL–1, TNF-alpha and IL–6.

The factors that allow an abnormal immune response, once initiated, to become permanent and chronic, are becoming more clearly understood. The genetic association with HLA-DR4, as well as the newly discovered associations with the gene PTPN22 and with two additional genes all implicate altered thresholds in regulation of the adaptive immune response. It has also become clear from recent studies that these genetic factors may interact with the most clearly defined environmental risk factor for RA, namely cigarette smoking. Other environmental factors also appear to modulate the risk of acquiring RA and hormonal factors in the individual may explain some features of the disease such as the higher occurrence in women, the not-infrequent onset after child-birth and the (slight) modulation of disease risk by hormonal medications. Exactly how altered regulatory thresholds allow the triggering of a specific autoimmune response remains uncertain. However, one possibility is that negative feedback mechanisms that normally maintain tolerance of self are overtaken by aberrant positive feedback mechanisms for certain antigens such as IgG Fc (bound by RF) and citrullinated fibrinogen (bound by ACPA) (see entry on autoimmunity). The debate on the relative roles of immune complexes and T cell products in inflammation in RA has continued for 30 years. There is little doubt that both B and T cells are essential to the disease. However, there is good evidence for neither cell being necessary at the site of inflammation. This tends to favor immune complexes (based on antibody synthesized elsewhere) as the initiators, although not the sole perpetuators of inflammation. The presence of autoantibodies to IgGFc, known as rheumatoid factors (RF) and antibodies to citrullinated peptides (ACPA) is an integral part of RA disease process. As is the case with many other autoimmune diseases, patients with RA have abnormally glycosylated antibodies. It is believed that these glycan (oligosaccharide) alterations promote joint inflammation.

Once the abnormal immune response has become established (which may take several years before any symptoms occur), plasma cells derived from B lymphocytes produce rheumatoid factors and ACPA of the IgG and IgM classes in large quantities. These are not deposited in the way that they are in systemic lupus. Rather, they activate macrophages through Fc receptor and complement binding which seems to play an important role in the intense inflammatory response present in RA. Binding of an autoreactive antibody to the Fc receptors is mediated through the antibody’s N-glycans which are altered to promote inflammation in patients with RA. This contributes to inflammation of the synovium, in terms of edema, vasodilation and infiltration by activated T-cells (mainly CD4 in nodular aggregates and CD8 in diffuse infiltrates). Synovial macrophages and dendritic cells further function as antigen presenting cells by expressing MHC class II molecules, leading to an established local immune reaction in the tissue. The disease progresses in concert with formation of granulation tissue at the edges of the synovial lining (pannus) with extensive angiogenesis and production of enzymes that cause tissue damage. Modern pharmacological treatments of RA target these mediators. Once the inflammatory reaction is established, the synovium thickens, the cartilage and the underlying bone begins to disintegrate and evidence of joint destruction accrues.

TNF (alpha) plays a major role in the pathogenesis of RA. There are several theories on how TNF release happens in disease process. If TNF release is stimulated by B cell products in the form of RF or ACPA -containing immune complexes, through activation of immunoglobulin Fc receptors, then RA can be seen as a form of Type III hypersensitivity. If TNF release is stimulated by T cell products such as interleukin-17 it might be considered closer to type IV hypersensitivity although this terminology may be getting somewhat dated and unhelpful.

Although TNF appears to be the dominant, other cytokines (chemical mediators) are likely to be involved in inflammation in RA. Blockade of TNF does not benefit all persons or all tissues (lung disease and nodules may get worse). Blockade of IL-1, IL-15 and IL-6 also have beneficial effects and IL-17 may be important. Constitutional symptoms such as fever, malaise, loss of appetite and weight loss are also caused by cytokines released into the blood stream. As with most autoimmune diseases, it is important to distinguish between the cause(s) that trigger the process and those that may permit it to persist and progress.

Diagnosis

Imaging

Signs of destruction and inflammation on ultrasonography and magnetic resonance imaging in the second metacarpophalangeal joint in established RA. Thin arrows indicate an erosive change; thick arrows indicate synovitis. Ultrasonography (left side of image) in the (a) longitudinal and (b) the transverse planes shows both signs of destruction and inflammation. Axial T1-weighted magnetic resonance images were obtained (c) before and (d) after contrast administration, also demonstrating synovitis. Additionally, a coronal T1-weighted magnetic resonance image (e) before contrast administration visualizes the same bone erosion as shown in Panels c and d.

X-ray images of the hands and feet are generally performed on patients who have several joints affected. In RA, there may be no changes in the early stages of the disease or the X-ray image may demonstrate juxta-articular osteopenia, soft tissue swelling and loss of joint space. As the disease advances, there may be bony erosions and subluxation. X-rays of other joints may be taken if symptoms of pain or swelling occur in those joints.

Other medical imaging techniques such as magnetic resonance imaging (MRI) and ultrasound are also used in RA.

There have been technical advances in ultrasonography. High-frequency transducers (10 MHz or higher) have improved the spatial resolution of ultrasound images; these images can depict 20% more erosions than conventional radiography. Also, color Doppler and power Doppler ultrasound which show vascular signals of active synovitis depending on the degree of inflammation, are useful in assessing synovial inflammation. This is important, since in the early stages of RA, the synovium is primarily affected and synovitis seems to be the best predictive marker of future joint damage.

Blood tests

When RA is clinically suspected, testing for the presence of rheumatoid factor (RF, a non-specific antibody) and (ACPAs) may be required. A negative RF does not rule out RA; rather, the arthritis is called seronegative. This is the case in about 15% of patients with RA. During the first year of illness, rheumatoid factor is more likely to be negative with some individuals converting to seropositive status over time. RF is also seen in other illnesses, for example Sjögren’s syndrome, hepatitis C, systemic lupus erythematosus, chronic infections and in approximately 10% of the healthy population, therefore the test is not very specific. [14]

Because of this low specificity, new serological tests have been developed which test for the presence of the anti-citrullinated protein antibodies (ACPAs) or anti-CCP. Like RF, these tests are positive in only a proportion (67%) of all RA cases, but are rarely positive if RA is not present, giving it a specificity of around 95%. As with RF, there is evidence for ACPAs being present in many cases even before onset of clinical disease. [14]

The most common tests for ACPAs are the anti-CCP (cyclic citrullinated peptide) test and the Anti-MCV assay (antibodies against mutated citrullinatedVimentin). Recently a serological point-of-care test (POCT) for the early detection of RA has been developed. This assay combines the detection of rheumatoid factor and anti-MCV for diagnosis of RA and shows a sensitivity of 72% and specificity of 99. 7%.

Also, several other blood tests are usually done to allow for other causes of arthritis such as lupus erythematosus. The erythrocyte sedimentation rate (ESR), C-reactive protein, full blood count, kidney function, liver enzymes and other immunological tests (e. g. , antinuclear antibody/ANA) are all performed at this stage. Elevated ferritin levels can reveal hemochromatosis, a mimic of RA or be a sign of Still’s disease, a seronegative, usually juvenile, variant of rheumatoid arthritis.

Classification Criteria

In 2010 the 2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria were introduced. The new criterion is not a diagnostic criterion but a classification criterion to identify disease with a high likelihood of developing a chronic form. However a score of 6 or greater unequivocally classifies a person with a diagnosis of rheumatoid arthritis.

These new classification criteria overruled the “old” ACR criteria of 1987 and are adapted for early RA diagnosis. The “new” classification criteria, jointly published by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) establish a point value between 0 and 10.

Four areas are covered in the diagnosis:

• joint involvement, designating the metacarpophalangeal joints, proximal interphalangeal joints, the interphalangeal joint of the thumb, second through fifth metatarsophalangeal joint and wrist as small joints and shoulders, elbows, hip joints, knees and ankles as large joints:
  • Involvement of 1 large joint gives 0 points
  • Involvement of 2–10 large joints gives 1 point
  • Involvement of 1–3 small joints (with or without involvement of large joints) gives 2 points
  • Involvement of 4–10 small joints (with or without involvement of large joints) gives 3 points
  • Involvement of more than 10 joints (with involvement of at least 1 small joint) gives 5 points
• serological parameters – including the rheumatoid factor as well as ACPA – “ACPA” stands for “anti-citrullinated protein antibody”:
  • Negative RFand negative ACPA gives 0 points
  • Low-positive RFor low-positive ACPA gives 2 points
  • High-positive RFor high-positive ACPA gives 3 points
  • acute phase reactants: 1 point for elevated erythrocyte sedimentation rate, ESR or elevated CRP value (c-reactive protein)
  • duration of arthritis: 1 point for symptoms lasting six weeks or longer

The new criteria accommodate to the growing understanding of RA and the improvements in diagnosing RA and disease treatment. In the “new” criteria serology and autoimmune diagnostics carries major weight, as ACPA detection is appropriate to diagnose the disease in an early state, before joints destructions occur. Destruction of the joints viewed in radiological images was a significant point of the ACR criteria from 1987. This criterion no longer is regarded to be relevant, as this is just the type of damage that treatment is meant to avoid.

In clinical practice, the following criteria apply:

• two or more swollen joints
• morning stiffness lasting more than one hour for at least six weeks
• the detection of rheumatoid factors or autoantibodies against ACPA such as autoantibodies to mutated citrullinatedvimentin can confirm the suspicion of RA. A negative autoantibody result does not exclude a diagnosis of RA.

Differential diagnoses

Several other medical conditions can resemble RA and usually need to be distinguished from it at the time of diagnosis:

• Crystal induced arthritis (gout and pseudogout) – usually involves particular joints (knee, MTP1, heels) and can be distinguished with aspiration of joint fluid if in doubt. Redness, asymmetric distribution of affected joints, pain occurs at night and the starting pain is less than an hour with gout.
• Osteoarthritis – distinguished with X-rays of the affected joints and blood tests, age (mostly older persons), starting pain less than an hour, a-symmetric distribution of affected joints and pain worsens when using joint for longer periods.
• Systemic lupus erythematosus (SLE) – distinguished by specific clinical symptoms and blood tests (antibodies against double-stranded DNA)
• One of the several types of psoriatic arthritis resembles RA – nail changes and skin symptoms distinguish between them
• Lyme disease causes erosive arthritis and may closely resemble RA – it may be distinguished by blood test in endemic areas
• Reactive arthritis (previously Reiter’s disease) – asymmetrically involves heel, sacroiliac joints and large joints of the leg. It is usually associated with urethritis, conjunctivitis, iritis, painless buccal ulcers and keratoderma blennorrhagica.
• Ankylosing spondylitis – this involves the spine, although a RA-like symmetrical small-joint polyarthritis may occur in the context of this condition.
• Hepatitis C – RA-like symmetrical small-joint polyarthritis may occur in the context of this condition. Hepatitis C may also induce Rheumatoid Factor auto-antibodies

Rarer causes that usually behave differently but may cause joint pains:

• Sarcoidosis, amyloidosis and Whipple’s disease can also resemble RA.
• Hemochromatosis may cause hand joint arthritis.
• Acute rheumatic fever can be differentiated from RA by a migratory pattern of joint involvement and evidence of antecedent streptococcal infection. Acterial arthritis (such as by Streptococcus) is usually asymmetric while RA usually involves both sides of the body symmetrically.
• Gonococcal arthritis (another bacterial arthritis) is also initially migratory and can involve tendons around the wrists and ankles.

Monitoring Progression

There are many tools available for monitoring remission in rheumatoid arthritis. Disease Activity Score of 28 joints (DAS28) is widely used as an indicator of RA disease activity and response to treatment, but is not always a reliable indicator of treatment effect. The joints included in DAS28 are (bilaterally): proximal interphalangeal joints (10 joints), metacarpophalangeal joints (10), wrists (2), elbows (2), shoulders (2) and knees (2). When looking at these joints, both the number of joints with tenderness upon touching (TEN28) and swelling (SW28) are counted. In addition, the erythrocyte sedimentation rate (ESR) is measured. Also, the affected person makes a subjective assessment (SA) of disease activity during the preceding 7 days on a scale between 0 and 100, where 0 is “no activity” and 100 is “highest activity possible”.

Prevention

There is no known prevention for the condition other than the reduction of risk factors.

Management

There is no cure for RA, but treatments can improve symptoms and slow the progress of the disease. Disease-modifying treatment has the best results when it is started early and aggressively.

The goals of treatment are to minimize symptoms such as pain and swelling, to prevent bone deformity (for example, bone erosions visible in X-rays) and to maintain day-to-day functioning. This can often be achieved using two main classes of medications: analgesics such as NSAIDs and disease-modifying antirheumatic drugs (DMARDs). RA should generally be treated with at least one specific anti-rheumatic medication. The use of benzodiazepines (such as diazepam) to treat the pain is not recommended as it does not appear to help and is associated with risks. Analgesics, other than NSAIDs, offer lesser, but some benefit with respect to pain whilst not causing the same level of gastrointestinal irritation.

Lifestyle

Regular exercise is recommended as both safe and useful to maintain muscles strength and overall physical function. [67] It is uncertain if specific dietary measures have any effect. [68] Physical activity is beneficial for persons with rheumatoid arthritis complaining of fatigue. [69] Occupational therapy has a positive role to play in improving functional ability of persons with rheumatoid arthritis.

Disease-Modifying Agents

Disease-modifying antirheumatic drugs (DMARDs) are the primary treatment for RA. They are a diverse collection of drugs grouped by use and convention. They have been found to improve symptoms, decrease joint damage and improve overall functional abilities. DMARDs should be started early in the disease as they result in disease remission in approximately half of the patients and improved outcomes overall. The following drugs are considered as DMARDs: methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, TNF-alpha inhibitors, abatacept and anakinra. Rituximab and tocilizumab are monoclonal antibodies and are also DMARDs.

The most commonly used agent is methotrexate with other frequently used agents including sulfasalazine and leflunomide. Sodium aurothiomalate (Gold) and cyclosporin are less commonly used due to more common adverse effects. Agents may be used in combinations. [3] Methotrexate is the most important and useful DMARD and is usually the first treatment. Adverse effects should be monitored regularly with toxicity including gastrointestinal, hematologic, pulmonary and hepatic. Side effects such as nausea, vomiting or abdominal pain can be reduced by taking folic acid. The most common undesirable effect is that it increases liver enzymes in almost 15% of patients. It is thus recommended that those who consistently demonstrate abnormal levels of liver enzymes or have a history of liver disease or alcohol abuse undergo liver biopsies.

Bioagents should generally only be used if methotrexate and other conventional agents are not effective after a trial of three months. They are associated with a higher rate of serious infections as compared to other DMARDs. These agents used to treat rheumatoid arthritis include: tumor necrosis factor alpha (TNF?) blockers[3] such as infliximab; interleukin 1 blockers such as anakinra, monoclonal antibodies against B cells such as rituximab and tocilizumab, T cell costimulation blocker such as abatacept among others. They are often used in combination with either methotrexate or leflunomide. In those who are well controlled on TNF blockers decreasing the dose does not appear to affect overall function. Persons should be screened for latent tuberculosis before starting any TNF blockers therapy to avoid reactivation.

TNF blockers and methotrexate appear to have similar effectiveness when used alone and better results are obtained when used together. TNF blockers appear to have equivalent effectiveness with etanercept appearing to be the safest. [79] Abatacept appears effective for RA with 20% more patients improving with treatment than without but long term safety studies are yet unavailable. However, there is a lack of evidence to distinguish between the biologics available for RA. Issues with the biologics include their high cost and association with infections including tuberculosis.

Anti-Inflammatory Agents

NSAIDs reduce both pain and stiffness in those with RA. Generally they appear to have no effect on patients’s long term disease course and thus are no longer first line agents. NSAIDs should be used with caution in those with gastrointestinal, cardiovascular orkidney problems. Use of methotrexate together with NSAIDS is safe, if adequate monitoring is done.

COX-2 inhibitors such as celecoxib and NSAIDs are equally effective. They have a similar gastrointestinal risk as an NSAIDs plus a proton pump inhibitor. In the elderly there is less gastrointestinal intolerance to celecoxib than to NSAIDs alone. [89] There however is an increased risk of myocardial infarction with COX-2 inhibitors. Anti-ulcer medications are not recommended routinely but only in those high risks of gastrointestinal problems.

Glucocorticoids can be used in the short term for flare-ups while waiting for slow-onset drugs to take effect. Injection of glucocorticoids into individual joints is also effective. While long-term use reduces joint damage it also results in osteoporosis and susceptibility to infections and thus is not recommended.

Surgery

In early phases of the disease, an arthroscopic or open synovectomy may be performed. It consists of the removal of the inflamed synovia and prevents a quick destruction of the affected joints. Severely affected joints may require joint replacement surgery such as knee replacement. Postoperatively, physiotherapy is always necessary.

Alternative Medicine

In general, there is not enough evidence to support any complementary health approaches for RA, with safety concerns for some of them. Some mind and body practices and dietary supplements may help patients with symptoms and therefore may be beneficial additions to conventional treatments, but there is not enough evidence to draw conclusions. A systematic review of CAM modalities (excluding fish oil) found that ” The available evidence does not support their current use in the management of RA. “. Studies showing beneficial effects in RA on a wide variety of CAM modalities are often affected by publication bias and are generally not high quality evidence such as randomized controlled trials (RCTs).

Dietary Supplements

The American College of Rheumatology states that no herbal medicines have health claims supported by high quality evidence and thus they do not recommend their use. There is no scientific basis to suggest that herbal supplements advertised as “natural” are safer for use than conventional medications as both are chemicals. Herbal medications, although labeled “natural”, may be toxic or fatal if consumed. Some evidence supports omega-3 fatty acids and gamma-linolenic acid in RA. The benefit from omega-3 appears modest but consistent though the current evidence is not strong enough to determine that supplementation with omega-3 polyunsaturated fatty acids (found in fish oil) is an effective treatment for RA. Gamma-linolenic acid which may reduce pain, tender joint count and stiffness, is generally safe.

The following are under investigation for treatments for RA, based on preliminary promising results (not recommended for clinical use yet): boswellic acid, curcumin, Devil’s claw, Euonymus alatus and thunder god vine (Tripterygiumwilfordii). NCCIH has noted that, “In particular, thunder god vine (Tripterygiumwilfordii) can have serious side effects. ”

Due to the false belief that herbal supplements are always safe, there is sometimes a hesitancy to report their use which may increase the risk of adverse reaction. [5]

There is conflicting evidence on the role of Erythropoiesis-stimulating agents for treatment of anemia in persons with rheumatoid arthritis.

Pregnancy

More than 75% of patients with rheumatoid arthritis have symptoms improve during pregnancy but might have worsening after delivery. Methotrexate and leflunomide are teratogenic (harmful to fetus) and not used in pregnancy. It is recommended women of childbearing age should use contraceptives to avoid pregnancy and to discontinue its use if pregnancy is planned. Low dose of prednisolone, hydroxychloroquine and sulfasalazine are considered safe in pregnant persons with rheumatoid arthritis.

Vaccinations

People with RA have an increased risk of infections and mortality and recommended vaccinations can reduce these risks. Influenza vaccine should be received annually.

The pneumococcal vaccine should be administered twice for patients under the age 65 and once for those over 65. Lastly, the live-attenuated zoster vaccine should be administered once after the age 60, but is not recommended in patients on a tumor necrosis factor alpha blocker.

Prognosis

The course of the disease varies greatly. Some patients have mild short-term symptoms, but in most the disease is progressive for life. Around 20%–30% will have subcutaneous nodules (known as rheumatoid nodules); this is associated with a poor prognosis.

Prognostic Factors

Poor prognostic factors include

• Persistent synovitis
• Early erosive disease
• Extra-articular findings (including subcutaneous rheumatoid nodules)
• Positive serum RF findings
• Positive serum anti-CCP autoantibodies
• Carriership of HLA-DR4 “Shared Epitope” alleles
• Family history of RA
• Poor functional status
• Socioeconomic factors
• Elevated acute phase response (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP])
• Increased clinical severity.

Mortality

RA reduces lifespan on average from three to twelve years. Positive responses to treatment may indicate a better prognosis. A 2005 study by the Mayo Clinic noted that RA sufferers suffer a doubled risk of heart disease independent of other risk factors such as diabetes, alcohol abuse and elevated cholesterol, blood pressure and body mass index. The mechanism by which RA causes this increased risk remains unknown; the presence of chronic inflammation has been proposed as a contributing factor. It is possible that the use of new biodrug therapies extend the lifespan of patients with RA and reduce the risk and progression of atherosclerosis. This is based on cohort and registry studies and currently still remains hypothetical. It is still uncertain whether biologics improve vascular function in RA or not. There was increase in total cholesterol and HDLc levels and no improvement of the atherogenic index.

Epidemiology

RA is a chronic disease and although rarely, a spontaneous remission may occur, the natural course is almost invariably one of persistent symptoms, waxing and waning in intensity and a progressive deterioration of joint structures leading to deformations and disability.

Etymology

Rheumatoid arthritis is derived from the Greek word ῥεύμα-rheuma (nom.), ῥεύματος-rheumatos (gen. ) (“flow, current”). The suffix -oid (“resembling”) gives the translation as joint inflammation that resembles rheumatic fever. Rhuma which means watery discharge might refer to the fact that the joints or swollen or that the disease may be made worse by rainy weather.