rheumatoid arthritis

The name is derived from the Greek rheumatos meaning "flowing", the suffix -oid meaning "in the shape of", arthr meaning "joint" and the suffix -itis, a "condition involving inflammation".

Features

Rheumatoid arthritis is a chronic, inflammatory, multisystem, autoimmune disorder. It commonly affects the joints in a polyarticular manner. 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.

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. 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, leading to a "squared" appearance in the hand.

Extra-articular manifestations also distinguish this disease from osteoarthritis (hence it is a multisystemic disease). For example, most patients also suffer of 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. Splenomegaly may occur with concurrent leukopaenia (Felty's syndrome), and lymphocytic infiltration may affect the salivary and lacrimal glands (Sjögren's syndrome).

Dermatological: Subcutaneous nodules on extensor surfaces, such as the elbows, are often present.

Pulmonary: The lungs may become involved as a part of the primary disease process or as a consequence of therapy. Fibrosis may occur spontaneously or as a consequence of therapy (for example methotrexate). Caplan's nodules are found as are pulmonary effusions.

Autoimmune: Vasculitic disorders, resulting in nail fold infarcts, neuropathies and nephropathies.

Renal: Amyloidosis, which can also result in muscular pseudohypertrophy.

Cardiovascular: Pericarditis, endoscarditis, left ventricular failure, valvulitis and fibrosis.

Ocular: Keratoconjunctivitis sicca (dry eyes), episcleritis and scleromalacia, which can lead to fissure and leaking of eye contents.

Neurological: There can be signs of mononeuritis multiplex and atlanto-axial subluxation. The latter is due 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 quadraplegia.

Epidemiology

Rheumatoid arthritis occurs most frequently in the 20-40 age group, although can start at any age. It is strongly associated with the HLA marker DR4 (W4, W14 & W15 are associated with the disease and W10 & W13 are protective) - hence family history is an important risk factor. The disease is 3 times more common in women than men and up to 4 times more common in smokers than non-smokers.

Diagnosis

Diagnostic criteria

The American College of Rheumatology has defined (1987) the following criteria for the diagnosis of rheumatoid arthritis [1].

• Morning stiffness of >1 hour.
• 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 to establish the diagnosis, although many patients are treated despite not meeting the criteria. This is because these criteria are relatively insensitive for early disease. They were primarily intended to categorise patients, especially for research, rather than to help rheumatologists to reach a diagnosis. 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 being clinically suspected, immunological studies are required, such as rheumatoid factor [2] (RF, a specific antibody). A negative RF does not rule out RA; rather, the arthritis is called seronegative. During the first year of illness, rheumatoid factor is frequently negative. 80% of patients eventually convert to seropositive status. RF is also seen in other illnesses, like 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 in recent years, which tests for the presence of so called anti-citrullinated protein (ACP) antibodies. Like RF, this test can detect approximately 80% of all RA patients, but is rarely positive in non-RA patients, giving it a specificity of around 98%. In addition, ACP antibodies can be often detected in early stages of the disease, or even before disease onset. Currently, most common test for ACP antibodies is the anti-CCP[3] (cyclic citrulinated 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[4], full blood count, renal function, liver enzymes and immunological tests (e.g. antinuclear antibody/ANA)[5] are all performed at this stage. Ferritin can reveal hemochromatosis, which can mimic RA.

Pathophysiology

The cause of RA is still unknown to this day, but has long been suspected to be infectious. It could be due to food allergies or external organisms. Mycoplasma, Erysipelothrix, Epstein-Barr virus, parvovirus B19 and rubella have been suspected but never supported in epidemiological studies. As in other autoimmune diseases, the "mistaken identity" theory suggests that an offending organism causes an immune response that leaves behind antibodies that are specific to that organism. The antibodies are not specific enough, though. They begin an immune attack against, in this case, the synovium, because some molecule in the synovium "looks like" a molecule on the offending organism that created the initial immune reaction - this phenomenon is called molecular mimicry.

But physical and emotional effects, stress and improper diet could play a role in the disease.

Autoimmune diseases require that the affected individual have a defect in the ability to distinguish self from foreign molecules. There are markers on many cells that confer this self-identifying feature. However, some classes of markers allow for RA to happen. 90% of patients 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, the immune response causes inflammation of the synovium. 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. 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.

Bacteria/antibiotic hypothesis

Thomas McPherson Brown along with other researchers and patient groups believe that it can be demonstrated that RA is caused by a bacterial infection, in particular mycoplasma that localizes to joints.^[1] There are a number of important features of rheumatoid arthritis that this hypothesis fails to account for however. Thomas McPherson Brown used tetracycline antibiotics to treat rheumatoid arthritis, and concluded that improvement in symptoms was evidence that the antibiotic must be killing a bacteria that caused the arthritis. The tetracycline antibiotics that he used, however also "exhibit immunomodulatory properties, which may contribute significantly to their beneficial effects in rheumatoid arthritis".^[2]. In other words, the same drug can both kill bacteria and suppress the immune system, and the latter may be responsible for its benefits in rheumatoid arthritis. If active bacterial infection were the cause of the arthritis, then we would expect sufficient antibiotic treatment to completely cure the disease by killing all bacteria. In fact, the benefits of antibiotics are fairly modest and the disease almost always persists. If rheumatoid arthritis was caused by a bacterial infection then we would expect that a treatment that lowered a patient's resistance to infection would make the disease much worse. Tumor necrosis factor inhibitors are a class of drugs that markedly reduce resistance to bacterial infection but are very effective in treating RA. In fact, they are the most effective treatment for rheumatoid arthritis in widespread use. The bacteria/antibiotic hypothesis therefore has very little support amongst modern rheumatologists and researchers.

Treatment

Pharmacological treatment of RA can be divided into disease-modifying antirheumatic drugs (DMARDs), anti-inflammatory agents and analgesics ^[3][4]. 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 damge 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. For this reason, it is logical to start a DMARD as soon as the diagnosis of RA is certain, before joint damage has occurred, in order to prevent damage.

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.^[5]

Disease modifying anti-rheumatic drugs (DMARDs)

DMARDs can be further subdivided into xenobiotic agents and biological agents. Xenobiotic agents are those DMARDs that do not occur naturally in the body, as opposed to biologicals.

Xenobiotics

Xenobiotics include:

• 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. This is because it is the most effective not only in controlling the pain and stiffness of arthritis, but also in preventing the bone damage that can result from uncontrolled inflammation. Other drugs, such as corticosteroids, whilst effective at reducing pain and stiffness, are less effective at retarding bone damage. Methotrexate 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 (TNFα) blockers - etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira)
• interleukin-1 blockers - anakinra
• anti-B cell (CD20) antibody - rituximab (Rituxan)^[6]
• 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
• opiates
• 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.

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.

Epidemiology

The incidence of RA is 30 cases per 10,000 population. The peak incidence is between the ages of 40 and 60. The prevalence rate is 1%, with women affected three to five times as often as men. 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%.

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

• Life expectancy for patients with RA is shortened by 5-10 years, although those who respond to therapy may have lower mortality rates.

Prevention

Regular exercise and carefully controlled diet can usually help lessen the pain and stiffness associated with arthritic flare-ups.

Cold can increase the pain and stiffness.

Also see Eastern and Naturopathic Approaches in this article.

History

The first known traces of arthritis date back as far as 4500 BC. It was noted in skeletal remains of Indians found in Tennessee. A text dated 123 AD first describes symptoms very similar to rheumatoid arthritis. In 1859 the disease got its current name.

References

1. ^ www.roadback.org - patient group
2. ^ Reeta K, Mediratta P, Mahajan P, Sharma K (2002). "Effect of minocycline and tetracycline on immunological responses in experimental animals.". Indian J Med Sci 56 (11): 553-9. PMID 14510338.
3. ^ O'Dell JR. Therapeutic strategies for rheumatoid arthritis. N Engl J Med. 2004;350(25):2591-602 PMID 15201416
4. ^ Hasler P. Biological therapies directed against cells in autoimmune disease. Springer Semin Immunopathol. 2006 Jun;27(4):443-56. PMID 16738955
5. ^ Vital EM, Emery P. Advances in the treatment of early rheumatoid arthritis. Am Fam Physician. 2005 Sep 15;72(6):1002, 1004
6. ^ Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572-2581. PMID 15201414

See also

• Arthritis

External links

• Rheumatoid Arthritis (RA) What is it ? ...
• Online Mendelian Inheritance in Man (OMIM) entry #180300
• History of rheumatoid arthritis