Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder that causes the immune system to attack the joints, where it causes inflammation (arthritis) and destruction, and some organs, such as the lungs and skin. It can be a disabling and painful condition, which can lead to substantial loss of functioning and mobility. It is diagnosed with blood tests (especially a test called rheumatoid factor) and X-rays. Diagnosis and long-term management are typically performed by a rheumatologist, an expert in the diseases of joints and connective tissues.[1]

Various treatments are available. Non-pharmacological treatment includes physical therapy and occupational therapy. Analgesia (painkillers) and anti-inflammatory drugs, as well as steroids, are used to suppress the symptoms, while disease-modifying antirheumatic drugs (DMARDs) are often required to reverse the disease process and prevent long-term damage. In recent times, the newer group of biologics has increased treatment options.[1]

The name is based on the term "rheumatic fever", an illness which includes joint pain and is derived from the Greek word rheumatos ("flowing"). The suffix -oid ("resembling") gives the translation as joint inflammation that resembles rheumatic fever. The first recognized description of rheumatoid arthritis was made in 1800 by Dr Augustin Jacob Landré-Beauvais (1772-1840) of Paris.[2]

Signs and symptoms

While rheumatoid arthritis primarily affects joints, problems involving all other organs of the body are known to occur. Extra-articular ("outside the joints") manifestations occur in about 15% of individuals with rheumatoid arthritis.[3] It can be difficult to determine whether disease manifestations are directly caused by the rheumatoid process itself, or from side effects of the medications commonly used to treat it - for example, lung fibrosis from methotrexate, or osteoporosis from corticosteroids.

[edit] Joints

The arthritis of rheumatoid arthritis is due to synovitis, which is inflammation of the synovial membrane that covers the joint. Joints become red, swollen, tender and warm, and stiffness prevents their use. By definition, RA affects multiple joints (it is a polyarthritis). Most commonly, small joints of the hands, feet and cervical spine are affected, but larger joints like the shoulder and knee can also be involved, differing per individual. Eventually, synovitis leads to erosion of the joint surface, causing deformity and loss of function.[1]

Inflammation in the joints manifests itself as a soft, "doughy" swelling, causing pain and tenderness to palpation and movement, a sensation of localized warmth, and restricted movement. Increased stiffness upon waking is often a prominent feature and may last for more than an hour. These signs help distinguish rheumatoid from non-inflammatory diseases of the joints such as osteoarthritis (sometimes referred to as the "wear-and-tear" of the joints). In RA, the joints are usually affected in a fairly symmetrical fashion although the initial presentation may be asymmetrical.

Hands affected by RA

As the pathology progresses the inflammatory activity leads to erosion and destruction of the joint surface, which impairs their range of movement and leads to deformity. The fingers are typically deviated towards the little finger (ulnar deviation) and can assume unnatural shapes. Common deformities in rheumatoid arthritis are the Boutonniere deformity (Hyperflexion at the proximal interphalangeal joint with hyperextension at the distal interphalangeal joint), swan neck deformity (Hyperextension at the proximal interphalangeal joint, hyperflexion at the distal interphalangeal joint). The thumb may develop a "Z-thumb" deformity with fixed flexion and subluxation at the metacarpophalangeal joint, and hyperextension at the IP joint.

[edit] Skin

The rheumatoid nodule is the cutaneous (strictly speaking subcutaneous) feature most characteristic of rheumatoid arthritis. The initial pathologic process in nodule formation is unknown but is thought to be related to small-vessel inflammation. The mature lesion(a part of an organ or tissue which has been damaged) is defined by an area of central necrosis surrounded by palisading macrophages and fibroblasts and a cuff of cellular connective tissue and chronic inflammatory cells. The typical rheumatoid nodule may be a few millimetres to a few centimetres in diameter and is usually found over bony prominences, such as the olecranon, the calcaneal tuberosity, the metacarpophalangeal joints, or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF titer and severe erosive arthritis. Rarely, they can occur in internal organs.

Several forms of vasculitis are also cutaneous manifestations associated with rheumatoid arthritis. A benign form occurs as microinfarcts around the nailfolds. More severe forms include livedo reticularis, which is a network (reticulum) of erythematous to purplish discoloration of the skin due to the presence of an obliterative cutaneous capillaropathy.

Other, rather rare, skin associated symtoms include:

pyoderma gangrenosum , a necrotizing, ulcerative, noninfectious neutrophilic dermatosis. Sweet's syndrome , a neutrophilic dermatosis usually associated with myeloproliferative

disorders drug reactions erythema nodosum lobular panniculitis atrophy of digital skin palmar erythema diffuse thinning (rice paper skin), and skin fragility (often worsened by corticosteroid

use).

[edit] Lungs

Fibrosis of the lungs is a recognised response to rheumatoid disease. It is also a rare but well recognised consequence of therapy (for example with methotrexate and leflunomide). Caplan's syndrome describes lung nodules in individuals with rheumatoid arthritis and additional exposure to coal dust. Pleural effusions are also associated with rheumatoid arthritis.

[edit] Kidneys

Renal amyloidosis can occur as a consequence of chronic inflammation. [4] Rheumatoid vasculitis is a rare cause of glomerular disease in the kidney. Treatment with Penicillamine and gold salts are recognized causes of membranous nephropathy.

[edit] Heart and blood vessels

People with rheumatoid arthritis are more prone to atherosclerosis, and risk of myocardial infarction (heart attack) and stroke is markedly increased.[5] Other possible complications that may arise include: pericarditis, endocarditis, left ventricular failure, valvulitis and fibrosis.[citation

needed]

[edit] Other

Ocular keratoconjunctivitis sicca (dry eyes), scleritis, episcleritis and scleromalacia.

Gastrointestinal and hematological Felty syndrome, anemia, thrombocytosis.

Neurological peripheral neuropathy and mononeuritis multiplex may occur. The most common problem is carpal tunnel syndrome due to 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's connection to the skull. Such an erosion (>3mm) can give rise to vertebrae slipping over one 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 rheumatoid arthritis.

Vasculitis Vasculitis in rheumatoid arthritis is common. It typically presents as vasculitic nailfold infarcts.

Osteoporosis Osteoporosis classically occurs in RA around inflamed joints. It is postulated to be partially caused by inflammatory cytokines.

Lymphoma

The incidence of lymphoma is increased in RA as it is in most autoimmune conditions.[citation needed]

[edit] Diagnosis

[edit] X-rays

X-rays of the hands and feet are generally performed in people with a polyarthritis. In rheumatoid arthritis, these may not show any changes in the early stages of the disease, but in more advanced cases demonstrates erosions and bone resorption. X-rays of other joints may be taken if symptoms of pain or swelling occur in those joints.[citation needed]

[edit] Blood tests

When RA is clinically suspected, immunological studies are required, such as testing for the presence of rheumatoid factor (RF, a specific antibody).[6] A negative RF does not rule out RA; rather, the arthritis is called seronegative. This is the case in 69% of patients.[7] During the first year of illness, rheumatoid factor is frequently negative. 80% of these individuals eventually convert to seropositive status. RF is also seen in other illnesses, for example Sjögren's syndrome, and in approximately 10% of the healthy population, therefore the test is not very specific.

Because of this low specificity, a new serological test has been developed, which tests for the presence of so called anti-citrullinated protein antibodies (ACPAs). Like RF, this test is positive in only a proportion (67%) of all RA cases, but is rarely positive if RA is not present, giving it a specificity of around 95%.[7] In addition, ACPAs can sometimes be detected in early stages of the disease, even before onset of clinical disease.[citation needed] Currently, the most common test for ACPAs is the anti-CCP (cyclic citrullinated peptide) test.

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, renal 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 RA, or be a sign of Still's disease a seronegative, usually juvenile, variant of rheumatoid.[citation needed]

[edit] Diagnostic criteria

The American College of Rheumatology has defined (1987) the following criteria for the classification of rheumatoid arthritis:[8]

Morning stiffness of >1 hour most mornings for at least 6 weeks. Arthritis and soft-tissue swelling of >3 of 14 joints/joint groups, present for at least 6

weeks Arthritis of hand joints, present for at least 6 weeks Symmetric arthritis, present for at least 6 weeks

Subcutaneous nodules in specific places Rheumatoid factor at a level above the 95th percentile Radiological changes suggestive of joint erosion

At least four criteria have to be met for classification as RA. These criteria are not intended for the diagnosis for routine clinical care; they were primarily intended to categorize research. For example: one of the criteria is the presence of bone erosion on X-Ray. Prevention of bone erosion is one of the main aims of treatment because it is generally irreversible. To wait until all of the ACR criteria for rheumatoid arthritis are met may sometimes result in a worse outcome. Most sufferers and rheumatologists would agree that it would be better to treat the condition as early as possible and prevent bone erosion from occurring, even if this means treating people who don't fulfill the ACR criteria. The ACR criteria are, however, very useful for categorising established rheumatoid arthritis, for example for epidemiological purposes.[citation needed]

[edit] Differential diagnosis

Several other medical conditions can resemble RA, and usually need to be distinguished from it at the time of diagnosis:[9]

Crystal induced arthritis (gout, and pseudogout) - usually involves particular joints and can be distinguished with aspiration of joint fluid if in doubt

Osteoarthritis - distinguished with X-rays of the affected joints and blood tests 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 and is usually diagnosed in males, although a RA-like symmetrical small-joint polyarthritis may occur in the context of this condition.

Rarer causes that usually behave differently but may cause joint pains:[9]

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. Bacterial arthritis (such as 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.

[edit] Pathophysiology

Joint abnormalities in rheumatoid arthritis

Rheumatoid arthritis is an autoimmune disease, the cause for which is still unknown. It is a systemic (whole body) disorder principally affecting synovial joints.

Cytokines (chemical mediators) give rise to inflammation of joint synovium. Constitutional symptoms such as fever, malaise, loss of appetite and weight loss are also due to cytokines released in to the blood stream. Blood vessel inflammation (vasculitis) affecting many other organ systems can give rise to systemic complications. [10]

As with most autoimmune disease, it is important to distinguish between the cause(s) that trigger the inflammatory process, and those that permit it to persist and progress.

It has long been suspected that certain infections could be triggers for this disease. The "mistaken identity" theory suggests that an infection triggers an immune response, leaving behind antibodies that should be specific to that organism. The antibodies are not sufficiently specific, though, and set off an immune attack against part of the host. Because the normal host molecule "looks like" a molecule on the offending organism that triggered the initial immune reaction - this phenomenon is called molecular mimicry. Some infectious organisms suspected of triggering rheumatoid arthritis include Mycoplasma, Erysipelothrix, parvovirus B19 and rubella, but these associations have never been supported in epidemiological studies. Nor has convincing evidence been presented for other types of triggers such as food allergies. There is also no clear evidence that physical and emotional effects, stress and improper diet 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, as suggested by Edwards et al [11].

Epidemiological studies have confirmed a potential association between RA and two herpesvirus infections: Epstein-Barr virus (EBV) and Human Herpes Virus 6 (HHV-6). [12] Individuals with RA are more likely to exhibit an abnormal immune response to the Epstein-Barr virus. [13][14] The allele HLA-DRB1*0404 is associated with low frequencies of T cells specific for the EBV glycoprotein 110 and predisposes one to develop RA.[15]

The factors that allow the inflammation, once initiated, to become permanent and chronic, are much more clearly understood. The genetic association with HLA-DR4 is believed to play a major role in this, as well as the newly discovered associations with the gene PTPN22 and with two additional genes [16], all involved in regulating immune responses. It has also become clear from recent studies that these genetic factors may interact with the most clearly defined environmental risk factor for rheumatoid arthritis, namely cigarette smoking [17] 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.

Autoimmune diseases require that the affected individual have a defect in the ability to distinguish foreign molecules from the body's own. There are markers on many cells that confer this self-identifying feature. However, some classes of markers allow for RA to happen. 90% of individuals with RA have the cluster of markers known as the HLA-DR4/DR1 cluster, whereas only 40% of unaffected controls do. Thus, in theory, RA requires susceptibility to the disease through genetic endowment with specific markers and an infectious event that triggers an autoimmune response.

Once triggered, B lymphocytes produce immunoglobins and rheumatoid factors of the IgG and IgM classes that are deposited in the tissue. This subsequently leads to the activation of the serum complement cascade and the recruitment of the phagocytic arm of the immune response, which further exacerbates the inflammation of the synovium, leading to edema, vasodilation and infiltration by activated T-cells (mainly CD4 in nodular aggregates and CD8 in diffuse infiltrates). Early and intermediate molecular mediators of inflammation include tumor necrosis factor alpha (TNF-α), interleukins IL-1, IL-6, IL-8 and IL-15, transforming growth factor beta, fibroblast growth factor and platelet-derived growth factor. 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.

[edit] Treatment

There is no known cure for rheumatoid arthritis, but many different types of treatment can alleviate symptoms and/or modify the disease process.

The goal of treatment is two-fold: alleviating the current symptoms, and preventing the future destruction of the joints with the resulting handicap if the disease is left unchecked. These two goals may not always coincide: while pain relievers may achieve the first goal, they do not have any impact on the long-term consequences. For these reasons, most authorities believe that most RA should be treated by at least one specific anti-rheumatic medication, also named DMARD (see below), to which other medications and non-medical interventions can be added as needed.[citation needed]

Cortisone therapy has offered relief in the past, but its long-term effects have been deemed undesirable.[18]. However, cortisone injections can be valuable adjuncts to a long-term treatment plan, and using low dosages of daily cortisone (e.g., prednisone or prednisolone, 5-7.5 mg daily) can also have an important benefit if added to a proper specific anti-rheumatic treatment.[citation

needed]

Pharmacological treatment of RA can be divided into disease-modifying antirheumatic drugs (DMARDs), anti-inflammatory agents and analgesics.[19][20] Treatment also includes rest and physical activity.

[edit] Disease modifying anti-rheumatic drugs (DMARDs)

Main article: Disease-modifying antirheumatic drug

This section does not cite any references or sources.Please help improve this section by adding citations to reliable sources. Unverifiable material may be challenged and removed. (August 2008)

Disease modifying anti-rheumatic drugs reduces the rate of damage to bone and cartilage. DMARDs have been found to produce durable remissions and delay or halt disease progression. In particular they prevent bone and joint damage from occurring secondary to the uncontrolled inflammation. This is important as such damage is usually irreversible. Anti-inflammatories and analgesics improve pain and stiffness but do not prevent joint damage or slow the disease progression.

There is an increasing recognition amongst rheumatologists that permanent damage to the joints occurs at a very early stage in the disease. In the past the strategy used was to start with just an anti-inflammatory drug, and assess progression clinically and using X-rays. If there was evidence that joint damage was starting to occur then a more potent DMARD would be prescribed. Tools such as ultrasound and MRI are more sensitive methods of imaging the joints and have demonstrated that joint damage occurs much earlier and in more sufferers than was previously thought. People with normal X-rays will often have erosions detectable by ultrasound that X ray could not demonstrate.

There may be other reasons why starting DMARDs early is beneficial as well as prevention of structural joint damage. In the early stage of the disease, the joints are increasingly infiltrated by

cells of the immune system that signal to one another and are thought to set up self-perpetuating chronic inflammation. Interrupting this process as early as possible with an effective DMARD (such as methotrexate) appears to improve the outcome from the RA for years afterwards. Delaying therapy for as little as a few months after the onset of symptoms can result in worse outcomes in the long term. There is therefore considerable interest in establishing the most effective therapy with early arthritis, when they are most responsive to therapy and have the most to gain.[21]

[edit] Traditional small molecular mass drugs

Chemically synthesised DMARDs:

azathioprine ciclosporin (cyclosporine A) D-penicillamine gold salts hydroxychloroquine leflunomide methotrexate (MTX) minocycline sulfasalazine (SSZ)

Cytotoxic drugs:

Cyclophosphamide

The most important and most common adverse events relate to liver and bone marrow toxicity (MTX, SSZ, leflunomide, azathioprine, gold compounds, D-penicillamine), renal toxicity (cyclosporine A, parenteral gold salts, D-penicillamine), pneumonitis (MTX), allergic skin reactions (gold compounds, SSZ), autoimmunity (D-penicillamine, SSZ, minocycline) and infections (azathioprine, cyclosporine A). Hydroxychloroquine may cause ocular toxicity, although this is rare, and because hydroxychloroquine does not affect the bone marrow or liver it is often considered to be the DMARD with the least toxicity. Unfortunately hydroxychloroquine is not very potent, and is usually insufficient to control symptoms on its own.

Many rheumatologists consider methotrexate to be the most important and useful DMARD, largely because of lower drop-out rates for reasons of toxicity. Nevertheless, methotrexate is often considered as a very 'toxic' drug. This reputation is not entirely justified, and at times can result in people being denied the most effective treatment for their arthritis. Although methotrexate does have the potential to suppress bone marrow or cause hepatitis, these effects can be monitored using regular blood tests, and the drug withdrawn at an early stage if the tests are abnormal before any serious harm is done (typically the blood tests return to normal after stopping the drug). In clinical trials, where one of a range of different DMARDs were used, people who were prescribed methotrexate stayed on their medication the longest (the others stopped because of either side-effects or failure of the drug to control the arthritis). Methotrexate is often preferred by rheumatologists because if it does not control arthritis on its own then it

works well in combination with many other drugs, especially the biological agents. Other DMARDs may not be as effective or as safe in combination with biological agents.

[edit] Biological agents

Biological agents (biologics) are produced through genetic engineering, and include:

tumor necrosis factor alpha (TNFα) blockers - etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira)

Interleukin 1 (IL-1) blockers - anakinra (Kineret) monoclonal antibodies against B cells - rituximab (Rituxan)[22] T cell activation blocker - abatacept (Orencia)

[edit] Anti-inflammatory agents and analgesics

Anti-inflammatory agents include:

glucocorticoids Non-steroidal anti-inflammatory drug (NSAIDs, most also act as analgesics)

Analgesics include:

acetaminophen (Paracetamol outside US) opiates diproqualone lidocaine topical

The Prosorba column blood filtering device was approved by the FDA for treatment of RA in 1999 [23] However, the results have been very modest.[citation needed]

Historic treatments for RA have also included: rest, ice , compression and elevation, acupuncture, apple diet, nutmeg, some light exercise every now and then, nettles, bee venom, copper bracelets, rhubarb diet, rest, extractions of teeth, fasting, honey, vitamins, insulin, magnets, and electroconvulsive therapy (ECT).[24]. Most of these have either had no effect at all, or their effects have been modest and transient, while not being generalizable.

[edit] Other therapies

Other therapies are weight loss, occupational therapy, podiatry, physiotherapy, joint injections, and special tools to improve hard movements (e.g. special tin-openers). Regular exercise is important for maintaining joint mobility and making the joint muscles stronger. Swimming is especially good, as it allows for exercise with a minimum of stress on the joints. Heat and cold applications are modalities that can ease symptoms before and after exercise. Pain in the joints is sometimes alleviated by oral ibuprofen or other anti-inflammatory. Other areas of the body, such as the eyes and lining of the heart, are treated individually. However, there is no diet that has

been shown to alleviate rheumatoid arthritis, although fish oil may have anti-inflammatory effects.

Radon therapy, popular in Germany and Eastern Europe, can induce beneficial long-term effects for rheumatoid arthritis.[25]

A survey in the United Kingdom between 1998 and 2002 found arthritis to be reported among the five most common reasons for the medicinal use of cannabis.[26]

Severely affected joints may require joint replacement surgery, such as knee replacement.

[edit] Prognosis

The course of the disease varies greatly. Some people 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.

[edit] Disability

Daily living activities are impaired in most individuals. After 5 years of disease, approximately 33% of sufferers will not be working.[citation needed] After 10 years, approximately half will have substantial functional disability.[citation needed]

[edit] 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]), and increased clinical severity.

[edit] Mortality

Estimates of the life-shortening effect of RA vary; most sources cite a lifespan reduction of 5 to 10 years. According to the UK's National Rheumatoid Arthritis Society, "Young age at onset, long disease duration, the concurrent presence of other health problems (called co-morbidity), and characteristics of severe RA – such as poor functional ability or overall health status, a lot of joint damage on x-rays, the need for hospitalisation or involvement of organs other than the joints – have been shown to associate with higher mortality".[27] 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,[28] 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.[29]

[edit] Epidemiology

The incidence of RA is in the region of 3 cases per 10,000 population per annum. Onset is uncommon under the age of 15 and from then on the incidence rises with age until the age of 80. The prevalence rate is 1%, with women affected three to five times as often as men. It is 4 times more common in smokers than non-smokers. Some Native American groups have higher prevalence rates (5-6%) and people from the Caribbean region have lower prevalence rates. First-degree relatives prevalence rate is 2-3% and disease genetic concordance in monozygotic twins is approximately 15-20%.[citation needed]

It is strongly associated with the inherited tissue type Major histocompatibility complex (MHC) antigen HLA-DR4 (most specifically DR0401 and 0404) — hence family history is an important risk factor.[citation needed]

Rheumatoid arthritis affects women three times more often than men, and it can first develop at any age. The risk of first developing the disease (the disease incidence) appears to be greatest for women between 40 and 50 years of age, and for men somewhat later.[30] 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.

[edit] History

The first known traces of arthritis date back at least as far as 4500 BC. A text dated 123 AD first describes symptoms very similar to rheumatoid arthritis. It was noted in skeletal remains of Native Americans found in Tennessee.[31] In the Old World the disease is vanishingly rare before the 1600s.[32] and on this basis investigators believe it spread across the Atlantic during the Age of Exploration. In 1859 the disease acquired its current name.

An anomaly has been noticed from investigation of Precolumbian bones. The bones from the Tennessee site show no signs of tuberculosis even though it was prevalent at the time throughout the Americas.[33] Jim Mobley, at Pfizer, has discovered a historical pattern of epidemics of tuberculosis followed by a surge in the number of rheumatoid arthritis cases a few generations later.[34] Mobley attributes the spikes in arthritis to selective pressure caused by tuberculosis. A hypervigilant immune system is protective against tuberculosis at the cost of an increased risk of autoimmune disease.

The art of Peter Paul Rubens may depict the effects of rheumatoid arthritis, for it is presumed that he used his own hands as a model. In his later paintings, his rendered hands show increasing deformity consistent with the symptoms of the disease.[35][36]

Rheumatoid arthritis appears to have been depicted in 16th century paintings.[37]

The first recognized description of rheumatoid arthritis was in 1800 by the French physician Dr Augustin Jacob Landré-Beauvais (1772-1840) who was based in the famed Salpêtrière Hospital

in Paris.[2] The name "rheumatoid arthritis" itself was coined in 1859 by British rheumatologist Dr Alfred Baring Garrod.[38]

ANTI CCP-IgGPENANDA RHEUMATOID ARTHRITIS

APA ITU RHEUMATOID ARTHRITIS (RA) ?

Rheumatoid Arthritis (RA) merupakan penyakit autoimun (penyakit yang terjadi pada saat tubuh diserang oleh sistem kekebalan tubuhnya sendiri) yang mengakibatkan peradangan dalam waktu lama pada sendi. Penyakit ini menyerang persendian, biasanya mengenai banyak sendi, yang ditandai dengan radang pada membran sinovial dan struktur-struktur sendi serta atrofi otot dan penipisan tulang. Pada Gambar 1, ditunjukkan bahwa RA dapat mengakibatkan nyeri, kemerahan, bengkok dan panas di sekitar sendi. Berdasarkan studi, RA lebih banyak terjadi pada wanita dibandingkan pria dengan rasio kejadian 3 : 1.

Umumnya penyakit ini menyerang pada sendi-sendi bagian jari, pergelangan tangan, bahu, lutut, dan kaki. Pada penderita stadium lanjut akan membuat si penderita tidak dapat melakukan aktivitas sehari-hari dan kualitas hidupnya menurun. Gejala yang lain yaitu berupa demam, nafsu makan menurun, berat badan menurun, lemah dan kurang darah. Namun kadang kala si penderita tidak merasakan gejalanya. Diperkirakan kasus Rheumatoid Arthritis diderita pada usia di atas 18 tahun dan berkisar 0,1% sampai dengan 0,3% dari jumlah penduduk Indonesia.

GEJALA RA RA umumnya ditandai dengan adanya beberapa gejala yang berlangsung selama minimal 6 minggu, yaitu :

1. Kekakuan pada dan sekitar sendi yang berlangsung sekitar 30-60 menit di pagi hari 2. Bengkak pada 3 atau lebih sendi pada saat yang bersamaan 3. Bengkak dan nyeri umumnya terjadi pada sendi-sendi tangan 4. Bengkak dan nyeri umumnya terjadi dengan pola yang simetris (nyeri pada sendi

yang sama di kedua sisi tubuh) dan umumnya menyerang sendi pergelangan tangan

Pada tahap yang lebih lanjut, RA dapat dikarakterisasi juga dengan adanya nodul-nodul rheumatoid, konsentrasi rheumatoid factor (RF) yang abnormal dan perubahan radiografi yang meliputi erosi tulang.

PENANDA RA YANG TERDAHULU

Rheumatoid Factor (RF) merupakan antibodi yang sering digunakan dalam diagnosis RA dan sekitar 75% individu yang mengalami RA juga memiliki nilai RF yang positif. Kelemahan RF antara lain karena nilai RF positif juga terdapat pada kondisi penyakit autoimun lainnya, infeksi kronik, dan bahkan terdapat pada 3-5% populasi sehat (terutama individu usia lanjut).

Oleh karena itu, adanya penanda spesifik dan sensitif yang timbul pada awal penyakit

sangat dibutuhkan. Anti-cyclic citrullinated antibody (anti-CCP antibodi) merupakan penanda baru yang berguna dalam diagnosis RA. Walaupun memiliki keterbatasan, RF tetap banyak digunakan sebagai penanda RA dan penggunaan RF bersama-sama anti-CCP antibodi sangat berguna dalam diagnosis RA.

ANTI-CCP IgG

Anti-CCP IgG merupakan penanda RA yang baru dan banyak digunakan dalam diagnosis kondisi RA. Beberapa kelebihan Anti-CCP IgG dalam kondisi RA antara lain :

1. Anti-CCP IgG dapat timbul jauh sebelum gejala klinik RA muncul. Dengan adanya pengertian bahwa pengobatan sedini mungkin sangat penting untuk mencegah kerusakan sendi, maka penggunaan Anti-CCP IgG untuk diagnosis RA sedini mungkin sangat bermanfaat untuk pengobatan sedini mungkin.

2. Anti-CCP IgG sangat spesifik untuk kondisi RA. Antibodi ini terdeteksi pada 80% individu RA dan memiliki spesifisitas 98%. Antibodi ini juga bersifat spesifik karena dapat membedakan kondisi RA dari penyakit artritis lainnya.

3. Anti-CCP IgG dapat menggambarkan risiko kerusakan sendi lebih lanjut. Individu dengan nilai anti-CCP IgG positif umumnya diperkirakan akan mengalami kerusakan radiologis yang lebih buruk bila dibandingkan individu tanpa anti-CCP IgG.

PENUTUP

Anti-CCP IgG merupakan penanda yang sangat berguna untuk diagnosis dan perkiraan keadaan akhir kondisi RA di mana pemeriksaan anti-CCP IgG memiliki nilai spesifisitas yang baik sehingga pemeriksaan ini merupakan alat diagnostik yang berharga.

DAFTAR PUSTAKA

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2. www.medicinenet.com/rheumatoid_arthritis/article.htm 3. www.arthritis.co/types%20of%20arthritis/ra/default.asp?s=1 4. Van Boekel MAM, Vossenaar ER, van Hoogen FHJ, van Venrooij WJ. Autoantibody

Systems in Rheumatoid Arthritis : Specificity, Sensitivity and Diagnostic Value. Arthritis Res 2002 ; 4 : 87-93

5. Vossenaar ER, van Venrooij WJ. Anti-CCP Antibodies. A Highly Specific Marker for (Early) Rheumatoid Arthritis. Clinical and Applied Immunology Reviews2004 ; 4 : 239-262

6. arthritis.about.com/od/radiagnosis/f/anticcp.htm 7. www.rheumatology.org/publications/hotline/1003anticcp 8. www.medterms.com/script/main/art.asp?articlekey=24647 9. rheumatoidarhritis.blogspot.com/

http://www.prodia.co.id/info_terkini/edukasi/2007_edu_rheumatoid.html

Definition

Rheumatoid arthritis is an inflammatory form of arthritis that causes joint pain and damage. Rheumatoid arthritis attacks the lining of your joints (synovium) causing swelling that can result in aching and throbbing and eventually deformity. Sometimes rheumatoid arthritis symptoms make even the simplest activities — such as opening a jar or taking a walk — difficult to manage.

Rheumatoid arthritis is two to three times more common in women than in men and generally occurs between the ages of 40 and 60. But rheumatoid arthritis can also affect young children and older adults.

There's no cure for rheumatoid arthritis. With proper treatment, a strategy for joint protection and changes in lifestyle, you can live a long, productive life with rheumatoid arthritis

Symptoms

Rheumatoid arthritis vs. osteoarthritis

Signs and symptoms of rheumatoid arthritis may include:

Joint pain

Joint swelling

Joints that are tender to the touch

Red and puffy hands

Firm bumps of tissue under the skin on your arms (rheumatoid nodules)

Fatigue

Morning stiffness that lasts at least 30 minutes

Fever

Weight loss

Signs and symptoms appear in smaller joints first Rheumatoid arthritis usually causes problems in several joints at the same time. Early rheumatoid arthritis tends to affect your smaller joints first — the joints in your wrists, hands, ankles and feet. As the disease progresses, your shoulders, elbows, knees, hips, jaw and neck can also become involved.

Signs and symptoms of a rheumatoid arthritis flare Rheumatoid arthritis signs and symptoms may vary in severity and may even come and go. Periods of increased disease activity — called flare-ups or flares — alternate with periods of relative remission, during which the swelling, pain, difficulty sleeping, and weakness fade or disappear.

Causes

Rheumatoid arthritis occurs when white blood cells — whose usual job is to attack unwanted invaders, such as bacteria and viruses — move from your bloodstream into the membranes that surround your joints (synovium). The blood cells appear to play a role in causing the synovium to become inflamed. The inflammation causes the release of proteins that, over months or years, cause the synovium to thicken. The proteins can also damage the cartilage, bone, tendons and ligaments near your joint. Gradually, the joint loses its shape and alignment. Eventually, it may be destroyed.

Doctors don't know what causes this process that leads to rheumatoid arthritis. It's likely that rheumatoid arthritis occurs as a result of a complex combination of factors, including your genes, your lifestyle choices, such as smoking, and things in your environment, such as viruses.

Risk factors

Factors that may increase your risk of rheumatoid arthritis include:

Sex. Women are more likely to develop rheumatoid arthritis than men are.

Age. Rheumatoid arthritis occurs most commonly between the ages of 40 and 60. However, it can also occur in older adults and in children (juvenile rheumatoid arthritis).

Family history. If a member of your family has rheumatoid arthritis, you may have an increased risk of the disease. Doctors don't believe you can directly inherit rheumatoid arthritis. Instead, it's believed that you can inherit a predisposition to rheumatoid arthritis.

Smoking. Smoking cigarettes increases your risk of rheumatoid arthritis. Quitting can reduce your risk.

When to seek medical advice Make an appointment with your doctor if you have persistent discomfort and swelling in multiple joints on both sides of your body.

If you've already been diagnosed with rheumatoid arthritis, contact your doctor if you experience side effects from your rheumatoid arthritis medications. Side effects may include nausea, abdominal discomfort, black or tarry stools, changes in bowel habits, constipation, and drowsiness.

Tests and diagnosis

Diagnosing rheumatoid arthritis usually begins with a physical exam. Your doctor will ask you about your signs and symptoms and examine your affected joints.

In addition, your doctor may recommend:

Blood tests. People with rheumatoid arthritis tend to have an elevated erythrocyte sedimentation rate (ESR, or sed rate), which indicates the presence of an inflammatory process in the body. Other common blood tests look for antibodies called rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies in the blood. While commonly found in the blood of people with rheumatoid arthritis, rheumatoid factor and anti-CCP antibodies aren't present in all cases.

In early rheumatoid arthritis, the presence of rheumatoid factor and anti-CCP antibodies in the blood may be associated with an increased risk of joint damage. Rheumatoid factor and anti-CCP antibodies can be present in people who have chronic infections, such as active tuberculosis, and other autoimmune rheumatic diseases, such as lupus and Sjogren's syndrome.

Joint fluid analysis. Your doctor may draw fluid from your joint using a needle. The fluid can be tested to help rule out other diseases and conditions.

X-rays. Your doctor may recommend X-rays to help track the progression of rheumatoid arthritis in your joint over time.

Complications Rheumatoid arthritis causes joint damage that can be both debilitating and disfiguring. Damage to your joints may make it difficult or

impossible to go about your daily activities. You may find at first that tasks take more energy to accomplish. With time you may find you are no longer able to do them at all. Newer treatments may stop joint damage or prevent it so you can continue the activities you enjoy.

Treatments and drugs

There is no cure for rheumatoid arthritis. Treatment for rheumatoid arthritis aims to reduce inflammation in your joints in order to relieve pain and prevent or slow joint damage. Early and aggressive rheumatoid arthritis treatments may slow joint damage and help reduce the risk of disability. Treatment typically involves medications, though surgery may be necessary in cases of severe joint damage.

MedicationsRheumatoid arthritis medications can relieve pain and slow or halt the progression of joint damage. What medications you can consider will depend on the severity of your rheumatoid arthritis. Options include:

NSAIDs. Nonsteroidal anti-inflammatory drugs (NSAIDs) can relieve pain and reduce inflammation. Over-the-counter NSAIDs include ibuprofen (Advil, Motrin, others) and naproxen sodium (Aleve). Stronger versions of these NSAIDs and others are available by prescription. NSAIDs have risks of side effects that increase when used at high dosages for long-term treatment. Side effects may include ringing in your ears, gastric ulcers, heart problems, stomach bleeding, and liver and kidney damage. Consuming alcohol or taking corticosteroids while using NSAIDs also increases your risk of gastrointestinal bleeding.

Steroids. Corticosteroid medications, such as prednisone and methylprednisolone (Medrol), reduce inflammation and pain, and slow joint damage. In the short term, corticosteroids can make you feel dramatically better. But when used for many months or years, they may become less effective and cause serious side effects. Side effects may include easy bruising, thinning of bones, cataracts, weight gain, a round face and diabetes. Doctors often prescribe a corticosteroid to relieve acute symptoms, with the goal of gradually tapering off the medication.

Disease-modifying antirheumatic drugs (DMARDs). Doctors prescribe DMARDs to limit the amount of joint damage that occurs in rheumatoid arthritis. These drugs are typically used in the early stages of rheumatoid arthritis in an effort to slow the disease and save the joints and other tissues from permanent damage. You may need to take DMARDs for weeks or months before you notice any benefit. For that reason, they may be combined with other medications that give you more immediate relief from signs and symptoms, such as NSAIDs or corticosteroids. Common DMARDs include hydroxychloroquine (Plaquenil), the gold compound auranofin (Ridaura), sulfasalazine (Azulfidine), minocycline (Dynacin, Minocin) and methotrexate (Rheumatrex).

Immunosuppressants. These medications act to tame your immune system, which is out of control in rheumatoid arthritis. In addition, some of these drugs attack and eliminate cells that are associated with the disease. Some of the commonly used immunosuppressants include leflunomide (Arava), azathioprine (Imuran), cyclosporine (Neoral, Sandimmune) and cyclophosphamide (Cytoxan). These medications can have potentially serious side effects such as increased susceptibility to infection.

TNF-alpha inhibitors. TNF-alpha is a cytokine, or cell protein, that acts as an inflammatory agent in rheumatoid arthritis. TNF inhibitors target or block this cytokine and can help reduce pain, morning stiffness, and tender or swollen joints — usually within one or two weeks after treatment begins. There is evidence that TNF inhibitors may stop progression of disease. These medications often are taken with methotrexate. TNF inhibitors approved for treatment of rheumatoid arthritis are etanercept (Enbrel), infliximab (Remicade) and adalimumab (Humira). Potential side effects include injection site irritation (adalimumab and etanercept), worsening congestive heart failure (infliximab), blood disorders, lymphoma, demyelinating diseases, and increased risk of infection. If you have an active infection, don't take these medications.

Anakinra (Kineret). Anakinra is similar to a naturally occurring chemical in your body — interleukin-1 receptor antagonist (IL-1Ra) — that stops a certain chemical signal from causing inflammation. You might consider anakinra if you have moderate to severe rheumatoid arthritis and haven't been helped by conventional DMARD therapy. Anakinra is given as a daily self-administered injection under the skin, and is sometimes combined with methotrexate. Potential side effects include injection site reactions, decreased white blood cell counts, headache and an

increase in upper respiratory infections. There may be a slightly higher rate of respiratory infections in people who have asthma or chronic obstructive pulmonary disease. If you have an active infection, don't use anakinra.

Abatacept (Orencia). Abatacept reduces the inflammation and joint damage caused by rheumatoid arthritis by inactivating T cells — a type of white blood cell. People who haven't been helped by TNF-alpha inhibitors might consider abatacept, which is administered monthly through a vein in your arm (intravenously). Side effects may include headache, nausea and mild infections, such as upper respiratory tract infections. Serious infections, such as pneumonia, can occur.

Rituximab (Rituxan). Rituximab reduces the number of B cells in your body. B cells are involved in inflammation. People who haven't found relief using TNF inhibitors might consider using rituximab, which is usually given along with methotrexate. Rituximab is administered as an infusion into a vein in your arm. Side effects include flu-like signs and symptoms, such as fever, chills and nausea. Some people experience extreme reactions to the infusion, such as difficulty breathing and heart problems.

SurgeryIf medications fail to prevent or slow joint damage, you and your doctor may consider surgery to repair damaged joints. Surgery may help restore your ability to use your joint. It can also reduce pain and correct deformities. Rheumatoid arthritis surgery may involve one or more of the following procedures:

Total joint replacement (arthroplasty). During joint replacement surgery, your surgeon removes the damaged parts of your joint and inserts a metal and plastic prosthesis.

Tendon repair. Inflammation and joint damage may cause tendons around your joint to loosen or tighten. Your surgeon may be able to repair the tendons around your joint.

Removal of the joint lining (synovectomy). If the lining around your joint (synovium) is inflamed and causing pain, your surgeon may recommend removing the lining of the joint.

Surgery carries a risk of bleeding, infection and pain. Discuss the benefits and risks with your doctor.

Lifestyle and home remedies

You can take steps to care for your body if you have rheumatoid arthritis. These self-care measures, when used along with your rheumatoid arthritis medications, can help you cope with your signs and symptoms. Consider trying to:

Exercise regularly. Gentle exercise can help strengthen the muscles around your joints, and it can help fight fatigue you might feel. Check with your doctor before you start exercising. If you're just getting started, begin by taking a walk. Try swimming or gentle water aerobics. Public pools and health clubs in your area may offer classes. Avoid exercising tender, injured or severely inflamed joints. If you feel new joint pain, stop. New pain that lasts more than two hours after you exercise probably means you've overdone it. If pain persists for more than a few days, call your doctor.

Eat a healthy diet. A healthy diet emphasizing fruit, vegetables and whole grains can help you control your weight and maintain your overall health. However, there's no special diet that can be used to treat rheumatoid arthritis. It hasn't been proved that eating any particular food will make your joint pain or inflammation better or worse.

Protect your joints. Find different ways to approach everyday tasks in order to take stress off your painful joints. For instance, if your fingers are sore, pick up an object using your forearms. Lean into a glass door to force it open, rather than pushing on the door with sore arms.

Use assistive devices. Assistive devices can make it easier to go about your day without stressing your painful joints. For instance, using specially designed gripping and grabbing tools may make it easier to work in the kitchen if you have pain in your fingers. Try a cane to help you get around. Your doctor or occupational therapist may have ideas about what sorts of assistive devices may be helpful to you. Catalogs and medical supply stores may also be places to look for ideas.

Apply heat. Heat can help ease your pain and relax tense, painful muscles. One of the easiest and most effective ways to apply heat is to take a hot shower or bath for 15 minutes. Other options include using a hot pack or an electric heat pad set on its lowest setting. If your skin has poor sensation or if you have poor circulation, don't use heat treatments.

Apply cold. Cold may dull the sensation of pain. Cold also has a numbing effect and decreases muscle spasms. Don't use cold treatments if you have poor circulation or numbness. Techniques may include using cold packs, soaking the affected joints in cold water and ice massage.

Relax. Find ways to cope with pain by reducing stress in your life. Techniques such as hypnosis, guided imagery, deep breathing and muscle relaxation can all be used to control pain.

Coping and support

The degree to which rheumatoid arthritis affects your daily activities depends in part on how well you cope with the disease. Talk to your doctor or nurse about strategies for coping. With time you'll find what strategies work best for you. In the meantime, try to:

Keep a positive attitude. With your doctor, make a plan for managing your arthritis. This will help you feel in charge of your disease. Studies show that people who take control of their treatment and actively manage their arthritis experience less pain and make fewer visits to the doctor.

Know your limits. Rest when you're tired. Rheumatoid arthritis can make you prone to fatigue and muscle weakness. A rest or short nap that doesn't interfere with nighttime sleep may help.

Connect with others. Keep your family aware of how you're feeling. They may be worried about you but might not feel comfortable asking about your pain. Find a family member or friend you can talk to when you're feeling especially overwhelmed. Also connect with other people who have rheumatoid arthritis — whether through a support group in your community or online. Contact the Arthritis Foundation for more information. Sometimes you'll feel like your friends and family can't understand what it's like to have rheumatoid arthritis, and other people with the disease can offer unique support during these times.

Take time for yourself. It's easy to get busy and not take time for yourself. Find time for what you like, whether it's time to write in a journal, go for a walk or listen to music. Use this time to relieve stress and reflect on your feelings.

Alternative medicine

People who are frustrated by conventional rheumatoid arthritis treatments sometimes turn to complementary and alternative medicine practices for relief. Mainstream doctors are becoming more open to discussing these options. But, since few of these treatments have been extensively studied in clinical trials, it's difficult to assess whether these treatments are helpful for rheumatoid arthritis pain. In some cases, the risks of these treatments aren't known.

If you're interested in trying complementary and alternative medicine therapies for your rheumatoid arthritis pain, discuss these treatments with your doctor first. Together you can weigh the benefits and risks and decide whether the treatments will interfere with your current rheumatoid arthritis medications.

Some common complementary and alternative treatments that have shown promise for rheumatoid arthritis include:

Plant oils that contain gamma-linolenic acid (GLA). GLA is a type of omega-6 fatty acid that comes from plant oils, such as evening primrose, borage and black currant. Some studies indicate GLA may help with rheumatoid arthritis pain and morning stiffness, though more research is needed. Side effects may include nausea, diarrhea and gas. Some plant oils can cause liver damage or interfere with medications, so check with your doctor first.

Fish oil that contains eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA). EPA and DHA are omegea-3 fatty acids commonly found in fish oil. Some preliminary studies have found that fish oil may reduce rheumatoid arthritis pain and stiffness, but more study is needed. Side effects can include nausea, belching and a fishy taste in the mouth. More serious side effects can include bleeding and mercury poisoning. Fish oil can interfere with medications, so check with your doctor first.

Tai chi. This movement therapy involves gentle exercises and stretches combined with deep breathing. Many people use tai chi to relieve stress in their lives. Small studies have found tai chi may reduce rheumatoid arthritis pain, though more study is needed. Talk to your doctor if you'd like to give tai chi a try. When led by a knowledgeable instructor, tai chi is safe. But don't do any moves that cause pain.

Be careful when considering alternative therapies. Many are expensive and some may be harmful. Before taking any complementary medications or dietary supplements, talk with your doctor to learn about potential dangers, particularly if you're taking other medications.