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转载 Rheumatoid arthritis

杜志峰 副主任医师 承德医学院附属医院 骨伤科
2013-09-26 374人已读
杜志峰 副主任医师
承德医学院附属医院
Rheumatoid arthritis
 
Causes[edit]
 
RA is a form of autoimmunity, the causes of which are still not completely known. It is a systemic (whole body) disorder principally affecting synovial tissues. There is no evidence that physical and emotional effects or stress could be a trigger for the disease. The many negative findings suggest that either the trigger varies, or that it might in fact be a chance event inherent with the immune response承德医学院附属医院骨伤科杜志峰
Half of the risk for RA is believed to be genetic. It is strongly associated with the inherited tissue type major histocompatibility complex (MHC) antigen HLA-DR4 (most specifically DR0401 and 0404), and the genes PTPN22 and PADI4—hence family history is an important risk factor Inheriting the PTPN22 gene has been shown to double a person's susceptibility to RA. PADI4 has been identified as a major risk factor in people of Asian descent, but not in those of European descent。 First-degree relatives prevalence rate is 2–3% and diseasegenetic concordance in monozygotic twins is approximately 15–20%.
Smoking is the most significant non-genetic risk with RA being up to three times more common in smokers than non-smokers, particularly in men, heavy smokers, and those who are rheumatoid factor positive. Modest alcohol consumption may be protective.
Epidemiological studies have confirmed a potential association between RA and two herpesvirus infections:Epstein-Barr virus (EBV) and Human Herpes Virus 6 (HHV-6). Individuals with RA are more likely to exhibit an abnormal immune response to EBV and have high levels of anti-EBV antibodies.
Vitamin D deficiency is common in those with RA and may be causally associated. Some trials have found a decreased risk for RA with vitamin D supplementation while others have not.
Pathophysiology[edit]
 
The key pieces of evidence relating to pathogenesis are:
A genetic link with HLA-DR4 and related allotypes of MHC Class II and the T cell-associated protein PTPN22.
An undeniable link to the pathogenesis of vascular disease of many types, including the possibility of a strong causal connection to rheumatoid vasculitis, a typical feature of this condition.
A remarkable deceleration of disease progression in many cases by blockade of the cytokine TNF (alpha).
A similar dramatic response in many cases to depletion of B lymphocytes, but no comparable response to depletion of T lymphocytes.
A more or less random pattern of whether and when predisposed individuals are affected.
The presence of autoantibodies to IgGFc, known as rheumatoid factors (RF), and antibodies to citrullinated peptides (ACPA).
These data suggest that the disease involves abnormal B cell–T cell interaction, with 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. (See entry under autoimmunity for general mechanisms.)
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 ofType III hypersensitivity. If TNF release is stimulated by T cell products such as interleukin-17 it might be considered closer to type IV hypersensitivity although this terminology may be getting somewhat dated and unhelpful. 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.[citation needed]
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 into the blood stream.
As with most autoimmune diseases, it is important to distinguish between the cause(s) that trigger the process, and those that may permit it to persist and progress.
Abnormal immune response[edit]
 
The factors that allow an abnormal immune response, once initiated, to become permanent and chronic, are becoming more clearly understood. The genetic association with HLA-DR4, as well as the newly discovered associations with the gene PTPN22 and with two additional genes, all implicate altered thresholds in regulation of the adaptive immune response. It has also become clear from recent studies that these genetic factors may interact with the most clearly defined environmental risk factor for RA, namely cigarette smoking Other environmental factors also appear to modulate the risk of acquiring RA, and hormonal factors in the individual may explain some features of the disease, such as the higher occurrence in women, the not-infrequent onset after child-birth, and the (slight) modulation of disease risk by hormonal medications. Exactly how altered regulatory thresholds allow the triggering of a specific autoimmune response remains uncertain. However, one possibility is that negative feedback mechanisms that normally maintain tolerance of self are overtaken by aberrant positive feedback mechanisms for certain antigens such as IgG Fc (bound by RF) and citrullinated fibrinogen (bound by ACPA) (see entry on autoimmunity).
Once the abnormal immune response has become established (which may take several years before any symptoms occur), plasma cells derived from B lymphocytes produce rheumatoid factors and ACPA of the IgG and IgM classes in large quantities. These are not deposited in the way that they are in systemic lupus. Rather, they activate macrophages through Fc receptor and complement binding, which seems to play an important role in the intense inflammatory response present in RA. This contributes to inflammation of the synovium, in terms of edema, vasodilation and infiltration by activated T-cells (mainly CD4 in nodular aggregates and CD8 in diffuse infiltrates). Synovial macrophages and dendritic cells further function as antigen presenting cells by expressing MHC class II molecules, leading to an established local immune reaction in the tissue. The disease progresses in concert with formation of granulation tissue at the edges of the synovial lining (pannus) with extensive angiogenesis and production of enzymes that cause tissue damage. Modern pharmacological treatments of RA target these mediators. Once the inflammatory reaction is established, the synovium thickens, the cartilage and the underlying bone begins to disintegrate and evidence of joint destruction accrues.
Diagnosis
 
 
 
 
 
Criteria[edit]
 
In 2010 the 2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria were introduced. These new classification criteria overruled the "old" ACR criteria of 1987 and are adapted for early RA diagnosis. The "new" classification criteria, jointly published by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) establish a point value between 0 and 10. Every patient with a point total of 6 or higher is unequivocally classified as an RA patient, provided he has synovitis in at least one joint and given that there is no other diagnosis better explaining the synovitis. Four areas are covered in the diagnosis:
joint involvement, designating the metacarpophalangeal joints, proximal interphalangeal joints, the interphalangeal joint of the thumb, second through fifth metatarsophalangeal joint and wrist as small joints, and shoulders, elbows, hip joints, knees, and ankles as large joints:
Involvement of 1 large joint gives 0 points
Involvement of 2–10 large joints gives 1 point
Involvement of 1–3 small joints (with or without involvement of large joints) gives 2 points
Involvement of 4–10 small joints (with or without involvement of large joints) gives 3 points
Involvement of more than 10 joints (with involvement of at least 1 small joint) gives 5 points
serological parameters – including the rheumatoid factor as well as ACPA – "ACPA" stands for "anti-citrullinated protein antibody":
Negative RF and negative ACPA gives 0 points
Low-positive RF or low-positive ACPA gives 2 points
High-positive RF or high-positive ACPA gives 3 points
acute phase reactants: 1 point for elevated erythrocyte sedimentation rate, ESR, or elevated CRP value (c-reactive protein)
duration of arthritis: 1 point for symptoms lasting six weeks or longer
The new criteria accommodate to the growing understanding of RA and the improvements in diagnosing RA and disease treatment. In the "new" criteria serology and autoimmune diagnostics carries major weight, as ACPA detection is appropriate to diagnose the disease in an early state, before joints destructions occur. Destruction of the joints viewed in radiological images was a significant point of the ACR criteria from 1987. This criterion no longer is regarded to be relevant, as this is just the type of damage that treatment is meant to avoid.
The criteria are not intended for the diagnosis for routine clinical care; they were primarily intended to categorize research (classificationcriteria). In clinical practice, the following criteria apply:[citation needed]
two or more swollen joints
morning stiffness lasting more than one hour for at least six weeks
the detection of rheumatoid factors or autoantibodies against ACPA such as autoantibodies to mutated citrullinated vimentin can confirm the suspicion of RA. A negative autoantibody result does not exclude a diagnosis of RA.
 around the wrists and ankles.
Monitoring progression[edit]
 
The progression of RA can be followed using scores such as Disease Activity Score of 28 joints (DAS28). It is widely used as an indicator of RA disease activity and response to treatment, but is not always a reliable indicator of treatment effect. The joints included in DAS28 are (bilaterally): proximal interphalangeal joints (10 joints), metacarpophalangeal joints(10), wrists (2), elbows (2), shoulders (2) and knees (2). When looking at these joints, both the number of joints with tenderness upon touching (TEN28) and swelling (SW28) are counted. In addition, the erythrocyte sedimentation rate (ESR) is measured. Also, the patient makes a subjective assessment (SA) of disease activity during the preceding 7 days on a scale between 0 and 100, where 0 is "no activity" and 100 is "highest activity possible". With these parameters, DAS28 is calculated as:[48] DAS28=0.56 \times \sqrt{TEN28} + 0.28 \times \sqrt{SW28} + 0.70 \times \ln(ESR) + 0.014 \times SA
From this, the disease activity of the patient can be classified as follows:
Current
DAS28 DAS28 decrease from initial value
> 1.2 > 0.6 but ≤ 1.2 ≤ 0.6
≤ 3.2 Inactive Good improvement Moderate improvement No improvement
> 3.2 but ≤ 5.1 Moderate Moderate improvement Moderate improvement No improvement
> 5.1 Very active Moderate improvement No improvement No improvement
Management[edit]
 
There is no cure for RA, but treatments can improve symptoms and slow the progress of the disease. Disease-modifying treatment has the best results when it is started early and aggressively.
The goals of treatment are to minimize symptoms such as pain and swelling, to prevent bone deformity (for example, bone erosions visible in X-rays), and to maintain day-to-day functioning. This can often be achieved using two main classes of medications: analgesics such as NSAIDS, and disease-modifying antirheumatic drugs (DMARDs). RA should generally be treated with at least one specific anti-rheumatic medication. The use of benzodiazepines (such as diazepam) to treat the pain is not recommended as it does not appear to help and is associated with risks. Analgesics, other than NSAIDS, offer lesser, but some benefit with respect to pain. whilst not causing the same level of gastrointestinal irritation.
Disease modifying agents[edit]
 
Disease-modifying antirheumatic drugs (DMARD) are the primary treatment for RA. They are a diverse collection of drugs, grouped by use and convention. They have been found to improve symptoms, decrease joint damage, and improve overall functional abilities. They should be started very early in the disease as when they result in disease remission in approximately half of people and improved outcomes overall.
The most commonly used agent is methotrexate with other frequently used agents including sulfasalazine and leflunomide. Sodium aurothiomalate (Gold) and cyclosporin are less commonly used due to more common adverse effects. Agents may be used in combinations.
Methotrexate is the most important and useful DMARD and is usually the first treatment. Adverse effects should be monitored regularly with toxicity including gastrointestinal, hematologic, pulmonary, and hepatic. Side effects such as nausea, vomiting or abdominal pain can be reduced by taking folic acid. The most common undesirable affect is that it increases liver enzymes in almost 15% of people. It is thus recommended that those who consistently demonstrate abnormal levels of liver enzymes or have a history of liver disease or alcohol use undergo liver biopsies. Methotrexate is also considered a teratogenic and as such, it is recommended women of childbearing age should use contraceptives to avoid pregnancy and to discontinue its use if pregnancy is planned.
Biological agents should generally only be used if methotrexate and other conventional agents are not effective after a trial of three months. These agents include: tumor necrosis factor alpha (TNFα) blockers such as infliximab; interleukin 1 blockers such as anakinra, monoclonal antibodies against B cells such as rituximab,T cell costimulation blocker such as abatacept among others. They are often used in combination with either methotrexate or leflunomide.
TNF blockers and methotrexate appear to have similar effectiveness when used alone and better results are obtained when used together. TNF blockers appear to have equivalent effectiveness with etanercept appearing to be the safest. Abatacept appears effective for RA with 20% more people improving with treatment than without. There however is a lack of evidence to distinguish between the biologics available for RA. Issues with the biologics include their high cost and association with infections including tuberculosis.
Anti-inflammatory agents[edit]
 
NSAIDS reduce both pain and stiffness in those with RA. Generally they appear to have no effect on people's long term disease course and thus are no longer first line agents.[20][64]NSAIDSshould be used with caution in those with gastrointestinal, cardiovascular, or kidney problems.
COX-2 inhibitors, such as celecoxib, and NSAIDSare equally effective. They have a similar gastrointestinal risk as an NSAIDSplus a proton pump inhibitor. In the elderly there is less gastrointestinal intolerance to celecoxib than to NSAIDSalone. There however is an increased risk of myocardial infarction with COX-2 inhibitors. Anti-ulcer medications are not recommended routinely but only in those high risk of gastrointestinal problems.
Glucocorticoids can be used in the short term for flare-ups, while waiting for slow-onset drugs to take effect. Injection of glucocorticoids into individual joints is also effective. While long-term use reduces joint damage it also results in osteoporosis and susceptibility to infections, and thus is not recommended.
Surgery[edit]
 
In early phases of the disease, an arthroscopic or open synovectomy may be performed. It consists of the removal of the inflamed synovia and prevents a quick destruction of the affected joints. Severely affected joints may require joint replacement surgery, such as knee replacement. Postoperatively, physiotherapy is always necessary.
Alternative medicine[edit]
 
There has been an increasing interest in the use of complementary and alternative medicine interventions for the treatment of pain in rheumatoid arthritis. While there have been multiple studies showing beneficial effects in RA on a wide variety of CAM modalities, these studies are often affected by publication bias and are generally not high quality evidence such asrandomized controlled trials (RCTs), making definitive conclusions difficult to reach.
The National Center for Complementary and Alternative Medicine has concluded, "In general, there is not enough scientific evidence to prove that any complementary health approaches are beneficial for RA, and there are safety concerns about some of them. Some mind and body practices and dietary supplements may help people with RA manage their symptoms and therefore may be beneficial additions to conventional RA treatments, but there is not enough evidence to draw conclusions." A systematic review of CAM modalities (excluding fish oil) found "The major limitation in reviewing the evidence for CAMs is the paucity of RCTs in the area. The available evidence does not support their current use in the management of RA." One review suggests that of the various alternative medicine treatments evaluated, only acupuncture, bee venom acupuncture, herbal remedies, dietary omega-3 fatty acids, and pulsed electromagnetic field therapy have been studied with RCTs and show promise in treating the pain of RA, though no definitive conclusions could be reached.
Dietary supplements[edit]
 
The American College of Rheumatology states that no herbal medicines have health claims supported by high quality evidence and thus they do not recommend their use. There is no scientific basis to suggest that herbal supplements advertised as "natural" are safer for use than conventional medications as both are chemicals. Herbal medications, although labelled "natural", may be toxic or fatal if consumed. Some evidence supports omega-3 fatty acids and gamma-linolenic acid in RA. The benefit from omega-3 appears modest but consistent,though the current evidence is not strong enough to determine that supplementation with omega-3 polyunsaturated fatty acids (found in fish oil) is an effective treatment for RA. Gamma-linolenic acid, which may reduce pain, tender joint count and stiffness, is generally safe.
The following show promise as treatments for RA, based on preliminary studies: boswellic acid, curcumin, Devil's claw, Euonymus alatus, and Thunder god vine (Tripterygium wilfordii).
Herbal supplements can often have significant side effects, and can interact with prescription medications being taken at the same time. These risks are often exacerbated by the false general belief by patients that herbal supplements are always safe and the hesitancy by patients in reporting the use of herbal supplements to physicians. NCCAM has noted that, "In particular, the herb thunder god vine (Tripterygium wilfordii) can have serious side effects."
Manual therapies[edit]
 
The evidence for acupuncture is inconclusive with it appearing to be equivalent to sham acupuncture.
 
 
 
Prognostic factors[edit]
 
 
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[edit]
 
RA is known to reduce the lifespan of patients by anywhere from three to 12 years. A new line of research does, however, show that the use of new biologic drug therapies extend the lifespan of patients with RA and reduce the risk and progression of atherosclerosis. 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 sufferers suffer a doubled risk of heart disease, independent of other risk factors such as diabetes, alcohol abuse, and elevated cholesterol, blood pressure and body mass index. The mechanism by which RA causes this increased risk remains unknown; the presence of chronic inflammation has been proposed as a contributing factor

 

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杜志峰 副主任医师

承德医学院附属医院 骨伤科

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