INTRODUCTION
Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks the joints producing an inflammatory synovitis that often progresses to destruction of the articular cartilage and ankylosis of the joints. Rheumatoid arthritis can also produce diffuse inflammation in the lungs, pericardium, pleura, and sclera, and also nodular lesions, most common in subcutaneous tissue under the skin. Although the cause of rheumatoid arthritis is unknown, autoimmunity plays a pivotal role in its chronicity and progression.
About 1% of the world's population is afflicted by rheumatoid arthritis, women three times more often than men. Onset is most frequent between the ages of 40 and 50, but people of any age can be affected. It can be a disabling and painful condition, which can lead to substantial loss of functioning and mobility. It is diagnosed chiefly on symptoms and signs, but also 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.Various treatments are available. Non-pharmacological treatment includes physical therapy,orthoses and occupational therapy. Analgesia (painkillers) and anti-inflammatory drugs, including steroids, are used to suppress the symptoms, while disease-modifying antirheumatic drugs (DMARDs) are often required to inhibit or halt the underlying immune process and prevent long-term damage. In recent times, the newer group of biologics has increased treatment options.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.
Diagnosis
Imaging
X-ray of the hand in rheumatoid arthritis.
Appearance of synovial fluid from a joint with inflammatory arthritis.
Signs of destruction and inflammation on ultrasonography and magnetic resonance imaging in the second metacarpophalangeal joint in established rheumatoid arthritis. 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-rays of the hands and feet are generally performed in people with a polyarthritis. In rheumatoid arthritis, there may be no changes in the early stages of the disease, or the x-ray may demonstrate juxta-articular osteopenia, soft tissue swelling and loss of joint space. As the disease advances, there may be bony erosions and sublaxation. 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 and ultrasound are also used in rheumatoid arthritis.
Blood tests
When RA is clinically suspected, immunological studies are required, such as testing for the presence of rheumatoid factor (RF, a specific antibody).[9] A negative RF does not rule out RA; rather, the arthritis is called seronegative. This is the case in about 15% of patients. 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, and in approximately 10% of the healthy population, therefore the test is not very specific.Because of this low specificity, new serological test have been developed, which tests for the presence of so called anti-citrullinated protein antibodies (ACPAs). 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.The most common tests for ACPAs are the anti-CCP (cyclic citrullinated peptide) test and the Anti-MCV assay (antibodies against mutated citrullinated Vimentin). 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 rheumatoid arthritis 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, 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.
Etiology
Rheumatoid arthritis is a form of autoimmunity, the causes of which are still incompletely known. It is a systemic (whole body) disorder principally affecting synovial tissues.
Pathophysiology
The key pieces of evidence relating to pathogenesis are:
1. A genetic link with HLA-DR4 and related allotypes of MHC Class II and the T cell-associated protein PTPN22.
2. A link with cigarette smoking that appears to be causal.
3. A dramatic response in many cases to blockade of the cytokine TNF (alpha).
4. A similar dramatic response in many cases to depletion of B lymphocytes, but no comparable response to depletion of T lymphocytes.
5. A more or less random pattern of whether and when predisposed individuals are affected.
6. The presence of autoantibodies to IgGFc, known as rheumatoid factors (RF), and presentation of antigens by B cells to T cells via HLA-DR eliciting T cell help and
consequent production of RF and ACPA. Inflammation is then driven either by B cell or T cell products stimulating release of TNF and other cytokines. The process may be facilitated by an effect of smoking on citrullination but the stochastic (random) epidemiology suggests that the rate limiting step in genesis of disease in predisposed individuals may be an inherent stochastic process within the immune response such as immunoglobulin or T cell receptor gene recombination and mutation. 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.[15] [16] 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. 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 favour immune complexes (based on antibody synthesised elsewhere) as the initiators, even if not the sole perpetuators of inflammation. Moreover, work by Thurlings and others in Paul-Peter Tak's group and also by Arthur Kavanagh's group suggest that if any immune cells are relevant locally they are the plasma cells, which derive from B cells and produce in bulk the antibodies selected at the B cell stage.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 patients 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 in to
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.Possible infectious 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.
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 the Epstein-Barr virus. 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.
Psychological factors
There is no evidence that physical and emotional effects, 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, as suggested by Edwards et al. Alimentary antigens Several studies suspect food-derived antigenes to be involved within a scenario of a "leaky mucosa and that above all milk-products and cereals (wheat, corn etc.) can trigger the
autoimmune response.Dairy products & cerealsIn 1972, an "infectious agent" was hypothesized to be found in cow's milk]. RA can be exacerbated by dairy products (milk and cheese), resulting in an increase in synovitis,changes in immune complexes, IgE antibodies, and heat-damaged red cell clearance rates while exclusion of dairy products produced a considerable improvement. In RA, raised levels of IgA RF are associated with an increased IgG response to antigens which enter the body through the gastrointestinal tract.
Impact of raw food diets
In RA patients, an uncooked vegan diet rich in lactobacilli modifies the faecal microbial flora, associated with improvement in RA activity. An uncooked vegan diet rich in lactobacilli decreased subjective symptoms of rheumatoid arthritis.
AGEs
Raised AGE-levels have been detected in serum and synovial fluid of patients with RA. The Advanced glycation end product (AGE) pentosidine is raised in the articular cartilage, in the serum and synovial fluid of RA patients. In 2002, NE-carboxymethyllysine (CML), an AGE and marker of oxidative stress was detected for the first time in RA synovial tissue.
Continued abnormal immune response
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 rheumatoid arthritis, namely cigarExactly 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 triggers. 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 feedback mechanisms for certain antigens such as IgG Fc (bound by RF) and citrullinated fibrinogen (bound by ACPA) (see entry on autoimmunity).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 appear to activate macrophages through Fc receptor and perhaps complement binding. Thette 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.
is can contribute 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.
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 to which other medications and non-medical interventions can be added as needed.
Cortisone therapy has offered relief in the past, but its long-term effects have been deemed undesirable.. 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.
Pharmacological treatment of RA can be divided into disease-modifying antirheumatic drugs (DMARDs), anti-inflammatory agents and analgesics. Treatment also includes rest and physical activity.
Disease modifying anti-rheumatic drugs (DMARDs)
The term Disease modifying anti-rheumatic drug (DMARD) originally meant a drug that affects biological measures such as ESR and haemoglobin and autoantibody levels, but is now usually used to mean a drug that reduces the rate of damage to bone and cartilage.DMARDs have been found both to produce durable symptomatic remissions and to delay or halt progression. 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 among rheumatologists that permanent damage to the joints occurs at a very early stage in the disease. In the past it was common 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. 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. The aim now is to treat before damage occurs.
There may be other reasons why starting DMARDs early is beneficial as well as prevention of structural joint damage. From the earliest stages of the disease, the joints are infiltrated by cells of the immune system that signal to one another in ways that may involve a variety of positive feedback loops (it has long been observed that a single corticosteroid injection may abort synovitis in a particular joint for long periods). 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.
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.Methotrexate is considered by many rheumatologists 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.
Biological agents
Biological agents (biologics) are produced through genetic engineering, and include:
• tumor necrosis factor alpha (TNFα) blockers - etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi)
• Interleukin 1 (IL-1) blockers - anakinra (Kineret)
• monoclonal antibodies against B cells - rituximab (Rituxan)[47]
• T cell costimulation blocker - abatacept (Orencia)
• Interleukin 6 (IL-6) blockers - tocilizumab (an anti-IL-6 receptor antibody)(RoActemra, Actemra)
As of December 2007 Numerous biologics are in clinical trials (eg. Ocrelizumab,Ofatumumab).
Anti-inflammatory agents and analgesis
Anti-inflammatory agents include:
• glucocorticoids
• Non-steroidal anti-inflammatory drug (NSAIDs, most also act as analgesics)
Analgesics include:
• paracetamol (acetaminophen in US and Canada)
• opiates
• diproqualone
• lidocaine topical
Most of these have either had no effect at all, or their effects have been modest and transient, while not being generalizable.
Other therapiesOther therapies are weight loss, orthoses, occupational therapy, podiatry,physiotherapy, immunoadsorption therapy, 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.
Ayurveda, mostly in southern India, is another source of treatment, and while it is popular in India there are no studies to show that it benefits patients with RA.
A survey in the United Kingdom between 1998 and 2002 found that arthritis, in its various forms, was among the five most common reasons for the medicinal use of cannabis.
The effectiveness of treating RA with acupuncture is inconclusive, and "more rigorous research seems to be warranted" according to one study.
Severely affected joints may require joint replacement surgery, such as knee replacement.
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.
