Rheumatoid arthritis

Rheumatoid arthritis (RA) is traditionally considered a chronic, inflammatory autoimmune disorder that causes the immune system to attack the joints. It is a disabling and painful inflammatory condition, which can lead to substantial loss of mobility due to pain and joint destruction. RA is a systemic disease, often affecting extra-articular tissues throughout the body including the skin, blood vessels, heart, lungs, and muscles. About 60% of RA patients are unable to work 10 years after the onset of their disease.

Rheumatoid arthritis appears to have been described in paintings more than a century before the first detailed medical description of the condition in 1800 by Landre-Beauvais.

Etymology

The name is derived from the Greek. Rheumatos means "flowing", and this initially gave rise to the term 'rheumatic fever', an illness that can follow throat infections and which includes joint pain. The suffix -oid means "resembling", i.e. resembling rheumatic fever. Arthr means "joint" and the suffix -itis, a "condition involving inflammation". Thus rheumatoid arthritis was a form of joint inflammation that resembled rheumatic fever.

Features

Articular (joints)

The inflammatory activity leads to erosion and destruction of the joint surface as the pathology progresses, 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. Classical 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.

Cutaneous manifestations

The most prominent cutaneous manifestations of rheumatoid arthritis are rheumatoid nodules and vasculitis.

Vasculitis

Rheumatoid arthritis is associated with a variety of forms of vasculitis. 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. (This rash is also otherwise associated with the antiphospholipid-antibody syndrome, a hypercoagulable state linked to antiphospholipid antibodies and characterized by recurrent vascular thrombosis and second trimester miscarriages.

Other cutaneous manifestations

Rheumatoid arthritis is rarely associated with pyoderma gangrenosum, a necrotizing, ulcerative, noninfectious neutrophilic dermatosis. Other complications include erythema nodosum, lobular panniculitis, atrophy of digital skin, palmar erythema, diffuse thinning of the skin (rice paper skin), and skin fragility.

Rheumatoid nodules

The cutaneous (strictly speaking subcutaneous) feature most characteristic of rheumatoid arthritis is the rheumatoid nodule. The initial pathologic process in nodule formation is unknown but is thought to be related to small-vessel inflammation. The mature lesion is defined by an area of central necrosis surrounded by palisading macrophages and fibroblasts and a cuff of cellular connective tissue and chronic inflamed 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 calcaneum at the Achilles tendon insertion, the metacarpophalangeal joints, or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF titer and severe erosive arthritis. They can rarely occur throughout the body in internal organs.

Others

Pulmonary

The lungs may become involved as a part of the primary disease process or as a consequence of therapy. If such is the case, fibrosis may occur spontaneously or as a consequence of therapy (for example methotrexate). In addition, Caplan's nodules are found as are pulmonary effusions.

Renal

Amyloidosis in the kidney can occur.

Cardiovascular

Possible complications that may arise include: pericarditis, endocarditis, left ventricular failure, valvulitis and fibrosis. The risk of cardiovascular, specifically myocardial infarction (heart attack) or congestive heart failure are greater in individuals with RA. Over 1/3 of deaths of people with RA are directly attributable to cardiovascular death.

Ocular

Keratoconjunctivitis sicca (dry eyes), scleritis, episcleritis and scleromalacia are possible complications of rheumatoid arthritis.

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. At first the patient experiences clumsiness but without due care this can progress to quadriplegia.

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.

Rheumatoid arthritis and osteoarthritis

Rheumatoid arthritis is in many aspects similar to osteoarthritis. However, the differences are the following:

In contrast to osteoarthritis, rheumatoid arthritis is a chronic, inflammatory, multisystem, autoimmune disorder. It is commonly polyarticular, i.e. it affects many joints. The symptoms that distinguish rheumatoid arthritis from other forms of arthritis are inflammation and soft-tissue swelling of many joints at the same time (polyarthritis). The joints are usually affected initially asymmetrically and then in a symmetrical fashion as the disease progresses. The pain generally improves with use of the affected joints, and there is usually stiffness of all joints in the morning that lasts over 1 hour. Thus, the pain of rheumatoid arthritis is usually worse in the morning compared to the classic pain of osteoarthritis where the pain worsens over the day as the joints are used.

Extra-articular manifestations also distinguish this disease from osteoarthritis (hence it is a multisystemic disease). For example, most patients also suffer with anemia, either as a consequence of the disease itself (anaemia of chronic disease) or as a consequence of gastrointestinal bleeding as a side effect of drugs used in treatment, especially NSAIDs (non-steroidal anti-inflammatory drugs) used for analgesia. Hepatosplenomegaly may occur with concurrent leukopaenia (Felty's syndrome), and lymphocytic infiltration may affect the salivary and lacrimal glands (Sjögren's syndrome). Pericarditis, pleurisy, alveolitis, scleritis and subcutaneous nodules are other features associated with rheumatoid arthritis.

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 black persons from the Caribbean region have lower prevalence rates. First-degree relatives prevalence rate is 2-3% and disease concordance in monozygotic twins is approximately 15-20%.

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.

Diagnosis

Diagnostic criteria

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

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

It is important to note that these criteria are not intended for the diagnosis of patients for routine clinical care. They were primarily intended to categorise patients, for 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 is therefore likely to result in a worse outcome for the patient. Most patients and rheumatologists would agree that it would be better to treat the patient as early as possible and prevent bone erosion from occurring, even if this means treating patients who don't fulfill the ACR criteria. The ACR criteria are, however, very useful for categorising patients with established rheumatoid arthritis, for example for epidemiological purposes.

Blood tests

When RA is suspected, immunological blood studies are required.

Rheumatoid factor

The rheumatoid factor (RF) blood test may help diagnose RA. A meta-analysis of the accuracy of the rheumatoid factor found:

• sensitivity 69%
• specificity 85%

Thus, a negative RF does not rule out RA.

Anti-cyclic citrullinated peptide (anti-CCP) antibody

Because of the low specificity of the RF, a new test is for the presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies. A meta-analysis of the accuracy of the anti-CCP found:

• sensitivity 67%
• specificity 95%

Pathophysiology

Causes

The cause of RA is not known. Once triggered, the immune response causes 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 dentritic cells function as antigen presenting cells by expressing MHC class II molecules, leading to the production of immunoglobins, rheumatoid factors of the IgG and IgM class and complement components by B-Lymphocytes. 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. Once the inflammatory reaction is established, the synovium thickens, the cartilage and the underlying bone begins to disintegrate and evidence of joint destruction accrues.

Environmental factors

The risk decreased as the consumption of alcohol increased from light to moderate levels.

Inheritance and molecular basis

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. The major histocompatibility complex encodes the cell-surface proteins known as the human leukocyte antigens (HLAs) that are responsible for self-identification. In some populations, some HLA genotypes are associated with RA. Among anglo patients with RA, 70% express HLA-DR4, compared to 28% of patients without RA. In Native Americans, a similar association occurs with HLA-DR9.

Genes outside of the HLA region are also associated with RA. A single-nucleotide polymorphism (SNP) of the STAT4 gene is associated with both rheumatoid arthritis and systemic lupus erythematosus (SLE).

The role of infections

Various infections have been suspected of contributing to RA. Examples are Mycoplasma, Erysipelothrix, Epstein-Barr virus, Parvovirus B19 and rubella have been suspected but never supported in epidemiological studies. Although tetracycline antibiotics have been used to treat RA, these antibiotics may have nonspecific immunomodulator effects.

Treatment

There is no known cure for rheumatoid arthritis. However, many different types of treatment can be used to alleviate symptoms.

Historic treatments for this condition have included: gold salts, RICE, acupuncture, apple diet, nutmeg, some light exercise every now and then, nettles, bee venom, prayer, copper bracelets, rhubarb diet, rest, extractions of teeth, fasting, honey, vitamins, insulin, magnets, and electric convulsion therapy (ECT). Cortisone therapy has offered relief to many patients in the past, but its long-term effects have been deemed undesirable.

Pharmacological treatment of RA can be divided into disease-modifying antirheumatic drugs (DMARDs), anti-inflammatory agents and analgesics. 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 patients than was previously thought. Patients with normal X-rays will often have erosions detectable by ultrasound that X ray could not demonstrate.

Light exercise may be beneficial for improving blood circulation to joints and thereby allowing white blood cells to get to the area requiring treatment.

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 in patients with early arthritis, when they are most responsive to therapy and have the most to gain.

For certain patients shown to be unresponsive to or intolerant of DMARDs, the Prosorba column blood filtering device appeared promising after the FDA approved it for treatment of RA in 1999 . The Prosorba column employs protein A covalently bound to an inert silica matrix. The protein A binds immunoglobulin G (IgG) and circulating immune complexes (CIC). This blocks antigens responsible for autoimmune joint deterioration. [2]

Treatment also includes rest and physical activity. 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 acetaminophen (paracetamol). 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.

Disease modifying anti-rheumatic drugs (DMARDs)

The term Disease Modifying Anti-Rheumatic Agent was originally introduced to indicate a drug that reduced evidence of processes thought to underly the disease, such as a raised erythrocyte sedimentation rate, reduced haemoglobin level, raised rheumatoid factor level and more recently, raised C-reactive protein level. More recently, the term has been used to indicate a drug that reduces the rate of damage to bone and cartilage. DMARDs can be further subdivided into traditional small molecular mass drugs synthesised chemically and newer 'biological' agents produced through genetic engineering.

Traditional small molecular mass drugs:

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

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 for most patients hydroxychloroquine alone is insufficient to control symptoms.

Many rheumatologists consider methotrexate to be the most important and useful DMARD, largely because of lower rates of stopping the drug through toxicity. Nevertheless, methotrexate is often considered by patients and even other doctors as a very "toxic" drug. This reputation is not entirely justified, and at times can result in patients being denied the most effective treatment for their arthritis. Although methotrexate does indeed have the potential to suppress the 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 in which patients with RA were treated with one of a range of different DMARDs, patients who were prescribed methotrexate were those who stayed on their medication the longest (the others stopped theirs because of either side-effects or failure of the drug to control the arthritis). Lastly, 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 safe in combination with biological agents.

Biological agents

Biological agents include:

• tumor necrosis factor alpha (TNFα) blockers - etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira)
• interleukin-1 blockers - anakinra
• anti-B cell (CD20) antibody - rituximab (Rituxan)
• blockers of T cell activation - abatacept (Orencia)

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

Research

Pain relief

Recent research indicates that cytokines, a group of chemicals that are produced by various cells in the body, may be responsible for generating the response of chronic pain associated with Rheumatoid Arthritis. Medications that affect the release of cytokines or block the action of cytokines may reduce the response of chronic pain. Various anti-cytokine medications are now being used to treat painful disease states such as Rheumatoid Arthritis, and Crohn's Disease. In addition, research using the anti-cytokine medication, Thalidomide, is being evaluated for its effect in treating chronic pain associated with Arachnoiditis. Food (vegetables) with higher water content should be avoided.

Specific desensitization

An experimental treatment known as enzyme potentiated desensitization (EPD) is now under development for the treatment of rheumatoid arthritis and other autoimmune diseases. EPD uses dilutions of allergen (in this case type 2 collagen) and an enzyme, β-glucuronidase, to which T-regulatory lymphocytes respond by favouring desensitization, rather than sensitization. Initial results are encouraging but the treatment is still at an early stage of development.

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).

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

Prognosis

The course of the disease varies greatly from patient to patient. 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.

Disability

• Daily living activities are impaired in most patients.
• After 5 years of disease, approximately 33% of patients will not be working
• After 10 years, approximately half will have substantial functional disability.

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.

Mortality

Estimates of the life-shortening effect of RA vary; most sources cite a lifespan reduction of 5 to 10 years; the National Institutes of Health has estimated a lifespan reduction of 10 to 20 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". Positive responses to treatment may indicate a better prognosis. A 2005 study by the Mayo Clinic noted that RA patients 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.

History

To delineate the history of rheumatoid arthritis a researcher must rely on scanty and ambiguous data from old medical literature and buried skeletons. The current consensus is too speculative for the taste of some scholars. Nevertheless a tentative best guess has emerged.

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. In the Old World the disease is vanishingly rare before the 1600s. and on this basis investigators believe it spread across the Atlantic during the Age of Exploration. In 1859 the disease acquired its current name.

A fascinating 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.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. 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.

List of notable people with rheumatoid arthritis

• Kathleen Turner
• Aida Turturro
• Peter Paul Rubens
• Barry Gibb
• Lucille Ball
• Christiaan Barnard
• Pierre-Auguste Renoir
• Billy Bowden
• Max Clifford
• Hitesh Dhalawat

External links

• Use of Jellyfish Collagen (Type II) in the Treatment of Rheumatoid Arthritis
• Rheumatoid Arthritis. Arthritis Foundation.
• Rheumatoid Arthritis. Arthritis Research Campaign.
• Charles Weber. History of rheumatoid arthritis.
• ANA
• Living with Rheumatoid Arthritis. NLM. Retrieved on 2007-04-01. video
• The Vector Theory
• BioMedCode Animal Models for Rheumatoid Arthritis (TNF^ΔARE)