- Author: Howard R Smith, MD; Chief Editor: Herbert S Diamond, MD more...
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown cause. An external trigger (eg, cigarette smoking, infection, or trauma) that triggers an autoimmune reaction, leading to synovial hypertrophy and chronic joint inflammation along with the potential for extra-articular manifestations, is theorized to occur in genetically susceptible individuals. See the image below.
See Rheumatoid Arthritis: In and Out of the Joint, a Critical Images slideshow, to help identify the distinguishing features of RA as well as the signs of extra-articular manifestations of this disfiguring disease.
Signs and symptoms
In most patients with RA, onset is insidious, often beginning with fever, malaise, arthralgias, and weakness before progressing to joint inflammation and swelling.
Signs and symptoms of rheumatoid arthritis may include the following:
Persistent symmetric polyarthritis (synovitis) of hands and feet (hallmark feature)
Progressive articular deterioration
Difficulty performing activities of daily living (ADLs)
The physical examination should address the following:
Upper extremities (metacarpophalangeal joints, wrists, elbows, shoulders)
Lower extremities (ankles, feet, knees, hips)
During the physical examination, it is important to assess the following:
Pain on motion
Limitation of motion
Guidelines for evaluation
2013 European League Against Rheumatism (EULAR) management guidelines
2010 American College of Rheumatology (ACR)/EULAR classification criteria 
2012 ACR disease activity measures 
2011 ACR/EULAR definitions of remission 
See Clinical Presentation for more detail.
No test results are pathognomonic; instead, the diagnosis is made by using a combination of clinical, laboratory, and imaging features. Potentially useful laboratory studies in suspected RA include the following:
Erythrocyte sedimentation rate
C-reactive protein level
Complete blood count
Rheumatoid factor assay
Antinuclear antibody assay
Anti−cyclic citrullinated peptide and anti−mutated citrullinated vimentin assays
Potentially useful imaging modalities include the following:
Radiography (first choice): Hands, wrists, knees, feet, elbows, shoulders, hips, cervical spine, and other joints as indicated
Magnetic resonance imaging: Primarily cervical spine
Ultrasonography of joints: Joints, as well as tendon sheaths, changes and degree of vascularization of the synovial membrane, and even erosions
Joint aspiration and analysis of synovial fluid may be considered, including the following:
Assessment of overall appearance
See Workup for more detail.
Nonpharmacologic, nonsurgical therapies include the following:
Heat and cold therapies
Orthotics and splints
Guidelines for pharmacologic therapy
2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis 
2013 EULAR management guidelines 
2007 Agency for Healthcare Research and Quality (AHRQ) recommendations
Nonbiologic DMARDS include the following:
Biologic TNF-inhibiting DMARDs include the following:
Biologic non-TNF DMARDs include the following:
Other drugs used therapeutically include the following:
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Surgical treatments include the following:
Reconstructive surgery or arthroplasty
See Treatment and Medication for more detail.
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown cause. The hallmark feature of this condition is persistent symmetric polyarthritis (synovitis) that affects the hands and feet, though any joint lined by a synovial membrane may be involved. Extra-articular involvement of organs such as the skin, heart, lungs, and eyes can be significant. (See Presentation.)
No laboratory test results are pathognomonic for RA, but the presence of anti-cyclic citrullinated protein antibody (ACPA) and rheumatoid factor (RF) is highly specific for this condition. (See Workup.)
Optimal care of patients with RA requires an integrated approach that includes nonpharmacologic therapies and pharmacologic agents such as nonbiologic and biologic disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and corticosteroids. (See Treatment and Medication.)
Early therapy with DMARDs has become the standard of care; it not only can more efficiently retard disease progression than later treatment but also may induce more remissions. (See Treatment.) Many of the newer DMARD therapies, however, are immunosuppressive in nature, leading to a higher risk for infections. (See Complications.)
Macrophage activation syndrome is a life-threatening complication of juvenile idiopathic arthritis (JIA) that necessitates immediate treatment with high-dose steroids and cyclosporine. (See Complications.)
The following guidelines on treating RA to therapeutic target were issued in 2015 by an international task force of rheumatologists, patient representatives, and a rheumatology nurse[6, 7] :
The primary target for treatment of RA should be a state of clinical remission. Clinical remission is defined as the absence of signs and symptoms of significant inflammatory disease activity.
While remission should be a clear target, low-disease activity may be an acceptable alternative therapeutic goal, particularly in long-standing disease.
The use of validated composite measures of disease activity, which include joint assessments, is needed in routine clinical practice to guide treatment decisions.
The choice of the (composite) measure of disease activity and the target value should be influenced by comorbidities, patient factors, and drug-related risks.
Measures of disease activity must be obtained and documented regularly: as frequently as monthly for patients with high/moderate disease activity or less frequently (such as every 6 mo) for patients in sustained low-disease activity or remission.
Structural changes and functional impairment and comorbidity should be considered when making clinical decisions, in addition to assessing composite measures of disease activity.
Until the desired treatment target is reached, drug therapy should be adjusted at least every 3 mo.
The desired treatment target should be maintained throughout the remaining course of the disease.
The rheumatologist should involve the patient in setting the treatment target and the strategy to reach this target.
The pathogenesis of RA is not completely understood. An external trigger (eg, cigarette smoking, infection, or trauma) that sets off an autoimmune reaction, leading to synovial hypertrophy and chronic joint inflammation along with the potential for extra-articular manifestations, is theorized to occur in genetically susceptible individuals.
Synovial cell hyperplasia and endothelial cell activation are early events in the pathologic process that progresses to uncontrolled inflammation and consequent cartilage and bone destruction. Genetic factors and immune system abnormalities contribute to disease propagation.
CD4 T cells, mononuclear phagocytes, fibroblasts, osteoclasts, and neutrophils play major cellular roles in the pathophysiology of RA, whereas B cells produce autoantibodies (ie, RFs). Abnormal production of numerous cytokines, chemokines, and other inflammatory mediators has been demonstrated in patients with RA, including the following:
Tumor necrosis factor alpha (TNF-α)
Transforming growth factor beta (TGF-ß)
Fibroblast growth factor (FGF)
Platelet-derived growth factor (PDGF)
Ultimately, inflammation and exuberant proliferation of the synovium (ie, pannus) leads to destruction of various tissues, including cartilage (see the image below), bone, tendons, ligaments, and blood vessels. Although the articular structures are the primary sites involved by RA, other tissues are also affected.
The cause of RA is unknown. Genetic, environmental, hormonal, immunologic, and infectious factors may play significant roles. Socioeconomic, psychological, and lifestyle factors (eg, tobacco use, the main environmental risk ) may influence disease development and outcome.
Genetic factors account for 50% of the risk for developing RA. About 60% of RA patients in the United States carry a shared epitope of the human leukocyte antigen (HLA)-DR4 cluster, which constitutes one of the peptide-binding sites of certain HLA-DR molecules associated with RA (eg, HLA-DR beta *0401, 0404, or 0405). HLA-DR1 (HLA-DR beta *0101) also carries this shared epitope and confers risk, particularly in certain southern European areas. Other HLA-DR4 molecules (eg, HLA-DR beta *0402) lack this epitope and do not confer this risk.
Genes other than those of the major histocompatibility complex (MHC) are also involved, and results from sequencing genes of families with RA suggest the presence of several resistance and susceptibility genes, including PTPN22 and TRAF5.[10, 11]
Juvenile idiopathic arthritis (JIA), also known as juvenile rheumatoid arthritis (JRA), is a heterogeneous group of diseases that differs markedly from adult RA. JIA is known to have genetically complex traits in which multiple genes are important for disease onset and manifestations, and it is characterized by arthritis that begins before the age of 16 years, persists for more than 6 weeks, and is of unknown origin. The IL2RA/CD25 gene has been implicated as a JIA susceptibility locus, as has the VTCN1 gene.
Some investigators suggest that the future of treatment and understanding of RA may be based on imprinting and epigenetics. RA is significantly more prevalent in women than in men,[14, 15] which suggests that genomic imprinting from parents participates in its expression.[16, 17] Imprinting is characterized by differential methylation of chromosomes by the parent of origin, resulting in differential expression of maternal over paternal genes.
Epigenetics is the change in DNA expression that is due to environmentally induced methylation and not to a change in DNA structure. Clearly, the research focus will be on environmental factors in combination with immune genetics.
For many decades, numerous infectious agents have been suggested as potential causes of RA, including Mycoplasma organisms, Epstein-Barr virus (EBV), and rubella virus. This suggestion is indirectly supported by the following evidence:
Occasional reports of flulike disorders preceding the start of arthritis
The inducibility of arthritis in experimental animals with different bacteria or bacterial products (eg, streptococcal cell walls)
The presence of bacterial products, including bacterial RNA, in patients’ joints
The activity of several agents that have antimicrobial effects as disease-modifying drugs (eg, gold salts, antimalarial agents, and minocycline)
Emerging evidence also points to an association between RA and periodontopathic bacteria. For example, the synovial fluid of RA patients has been found to contain high levels of oral anaerobic bacterial antibodies common in periodontal infection, including Porphyromonas gingivalis.[19, 20]
Sex hormones may play a role in RA, as evidenced by the disproportionate number of females with this disease, its amelioration during pregnancy, its recurrence in the early postpartum period, and its reduced incidence in women using oral contraceptives. Hyperprolactinemia may be a risk factor for RA.
All of the major immunologic elements play fundamental roles in initiating, propagating, and maintaining the autoimmune process of RA. The exact orchestration of the cellular and cytokine events that lead to pathologic consequences (eg, synovial proliferation and subsequent joint destruction) is complex, involving T and B cells, antigen-presenting cells (eg, B cells, macrophages, and dendritic cells), and various cytokines. Aberrant production and regulation of both proinflammatory and anti-inflammatory cytokines and cytokine pathways are found in RA.
T cells are assumed to play a pivotal role in the initiation of RA, and the key player in this respect is assumed to be the T helper 1 (Th1) CD4 cells. (Th1 cells produce IL-2 and interferon [IFN] gamma.) These cells may subsequently activate macrophages and other cell populations, including synovial fibroblasts. Macrophages and synovial fibroblasts are the main producers of TNF-a and IL-1. Experimental models suggest that synovial macrophages and fibroblasts may become autonomous and thus lose responsiveness to T-cell activities in the course of RA.
B cells are important in the pathologic process and may serve as antigen-presenting cells. B cells also produce numerous autoantibodies (eg, RF and ACPA) and secrete cytokines.
The hyperactive and hyperplastic synovial membrane is ultimately transformed into pannus tissue and invades cartilage and bone, with the latter being degraded by activated osteoclasts. The major difference between RA and other forms of inflammatory arthritis, such as psoriatic arthritis, lies not in their respective cytokine patterns but, rather, in the highly destructive potential of the RA synovial membrane and in the local and systemic autoimmunity.
Whether these 2 events are linked is unclear; however, the autoimmune response conceivably leads to the formation of immune complexes that activate the inflammatory process to a much higher degree than normal. This theory is supported by the much worse prognosis of RA among patients with positive RF results.
Worldwide, the annual incidence of RA is approximately 3 cases per 10,000 population, and the prevalence rate is approximately 1%, increasing with age and peaking between the ages of 35 and 50 years. RA affects all populations, though it is much more prevalent in some groups (eg, 5-6% in some Native American groups) and much less prevalent in others (eg, black persons from the Caribbean region).
First-degree relatives of individuals with RA are at 2- to 3-fold higher risk for the disease. Disease concordance in monozygotic twins is approximately 15-20%, suggesting that nongenetic factors play an important role. Because the worldwide frequency of RA is relatively constant, a ubiquitous infectious agent has been postulated to play an etiologic role.
Women are affected by RA approximately 3 times more often than men are,[14, 15] but sex differences diminish in older age groups. In investigating whether the higher rate of RA among women could be linked to certain reproductive risk factors, a study from Denmark found that the rate of RA was higher in women who had given birth to just 1 child than in women who had delivered 2 or 3 offspring. However, the rate was not increased in women who were nulliparous or who had a history of lost pregnancies.
Time elapsed since pregnancy is also significant. In the 1- to 5-year postpartum period, a decreased risk for RA has been recognized, even in those with higher-risk HLA markers.
The Danish study also found a higher risk of RA among women with a history of preeclampsia, hyperemesis during pregnancy, or gestational hypertension. In the authors’ view, this portion of the data suggested that a reduced immune adaptability to pregnancy may exist in women who are predisposed to the development of RA or that there may be a link between fetal microchimerism (in which fetal cells are present in the maternal circulation) and RA.
Outcome in RA is compromised when diagnosis and treatment are delayed. The clinical course of RA is generally one of exacerbations and remissions. Approximately 40% of patients with this disease become disabled after 10 years, but outcomes are highly variable. Some patients experience a relatively self-limited disease, whereas others have a chronic progressive illness.
Intervention with DMARDs in very early RA (symptom duration <12 weeks at the time of first treatment) provides the best opportunity for achieving disease remission. Better detection of early joint injury has provided a previously unappreciated view of the ubiquity and importance of early joint damage. Nonetheless, predicting the long-term course of an individual case of RA at the outset remains difficult, though the following all correlate with an unfavorable prognosis in terms of joint damage and disability:
High serum titer of autoantibodies (eg, RF and ACPA)
Large number of involved joints
Age younger than 30 years
In a retrospective study that used logistic regression to analyze clinical and laboratory assessments in patients with RA who took only methotrexate, the authors found that measures of C-reactive protein (CRP) and swollen joint count after 12 weeks of methotrexate administration were most associated with radiographic progression at week 52.
The prognosis of RA is generally much worse among patients with positive RF results. For example, the presence of RF in sera has been associated with severe erosive disease.[27, 28] However, the absence of RF does not necessarily portend a good prognosis.
Other laboratory markers of a poor prognosis include early radiologic evidence of bony injury, persistent anemia of chronic disease, elevated levels of the C1q component of complement, and the presence of ACPA (see Workup). In fact, the presence of ACPA and antikeratin antibodies (AKA) in sera has been linked with severe erosive disease, and the combined detection of these autoantibodies can increase the ability to predict erosive disease in RA patients.
RA that remains persistently active for longer than 1 year is likely to lead to joint deformities and disability. Periods of activity lasting only weeks or a few months followed by spontaneous remission portend a better prognosis.
Morbidity and mortality
Most data on RA disability rates derive from specialty units caring for referred patients with severe disease. Little information is available on patients cared for in primary care community settings. Estimates suggest that more than 50% of these patients remain fully employed, even after 10-15 years of disease, with one third having only intermittent low-grade disease and another one third experiencing spontaneous remission.
RA is associated with traditional and nontraditional cardiovascular risk factors. The leading cause of excess mortality in RA is cardiovascular disease, followed by infection, respiratory disease, and malignancies. The effects of concurrent therapy, which is often immunosuppressive, may contribute to mortality in RA. However, studies suggest that control of inflammation may improve mortality.
Nontraditional risk factors appear to play an important role in cardiovascular morbidity and mortality. Myocardial infarction, myocardial dysfunction, and asymptomatic pericardial effusions are common; symptomatic pericarditis and constrictive pericarditis are rare. Myocarditis, coronary vasculitis, valvular disease, and conduction defects are occasionally observed. A large Danish cohort study suggested the presence of an increased risk of atrial fibrillation and stroke in patients with RA.
The overall mortality in patients with RA is reportedly 2.5 times higher than that of the general age-matched population. In the 1980s, mortality among those with severe articular and extra-articular disease approached that among patients with 3-vessel coronary disease or stage IV Hodgkin disease. Much of the excess mortality derives from infection, vasculitis, and poor nutrition. With the exception of lymphoma, mortality from cancer is unchanged.
Patient education and counseling help to reduce pain, disability, and frequency of physician visits. These may represent the most cost-effective intervention for RA.[31, 32]
Informing patient of diagnosis
With a potentially disabling disease such as RA, the act of informing the patient of the diagnosis takes on major importance. The goal is to satisfy the patient’s informational needs regarding the diagnosis, prognosis, and treatment in appropriate detail. To understand the patient’s perspective, requests, and fears, the physician must employ careful questioning and empathic listening.
Telling patients more than they are intellectually or psychologically prepared to handle (a common practice) risks making the experience so intense as to trigger withdrawal. Conversely, failing to address issues of importance to the patient compromises the development of trust. The patient needs to know that the primary physician understands the situation and is available for support, advice, and therapy as the need arises. Encouraging the patient to ask questions helps to communicate interest and caring.
Discussing prognosis and treatment
Patients and families do best when they know what to expect and can view the illness realistically. Many patients fear crippling consequences and dependency. Accordingly, it is valuable to provide a clear description of the most common disease manifestations. Without encouraging false hopes, the physician can point out that spontaneous remissions can occur and that more than two thirds of patients live independently without major disability. In addition, emphasize that much can be done to minimize discomfort and to preserve function.
A review of available therapies and their efficacy helps patients to overcome feelings of depression stemming from an erroneous expectation of inevitable disability. (See Treatment). Even in those with severe disease, guarded optimism is now appropriate, given the host of effective and well-tolerated disease-modifying treatments that are emerging.
Dealing with misconceptions
Several common misconceptions regarding RA deserve attention. Explaining that no known controllable precipitants exist helps to eliminate much unnecessary guilt and self-recrimination. Dealing in an informative, evidence-based fashion with a patient who expresses interest in alternative and complementary forms of therapy can help limit expenditures on ineffective treatments.
Another misconception is that a medication must be expensive to be helpful. Generic NSAIDs, low-dose prednisone, and the first-line DMARDs are quite inexpensive yet remarkably effective for relieving symptoms, a point that bears emphasizing. The belief that one must be given the latest TNF inhibitor to be treated effectively can be addressed by a careful review of the overall treatment program and the proper role of such agents in the patient’s plan of care.
Active participation of the patient and family in the design and implementation of the therapeutic program helps boost morale and to ensure compliance, as does explaining the rationale for the therapies used.
The family also plays an important part in striking the proper balance between dependence and independence. Household members should avoid overprotecting the patient (eg, refraining from intercourse out of fear of hurting the patient) and should work to sustain the patient’s pride and ability to contribute to the family. Allowing the patient with RA to struggle with a task is sometimes constructive.
Supporting patient with debilitating disease
Abandonment is a major fear in these individuals. Patients are relieved to know that they will be closely observed by the primary physician and healthcare team, working in conjunction with a consulting rheumatologist and physical/occupational therapist, all of whom are committed to maximizing the patient’s comfort and independence and to preserving joint function. With the use of occupational therapy, the treatment effort is geared toward helping the patient maintain a meaningful work role within the limitations of the illness.
Persons with long-standing severe disease who have already sustained much irreversible joint destruction benefit from an emphasis on comfort measures, supportive counseling, and attention to minimizing further debility. Such patients need help in grieving for their disfigurement and loss of function.
An accepting, unhurried, empathic manner allows the patient to express feelings. The seemingly insignificant act of touching does much to restore a sense of self-acceptance. Attending to pain with increased social support, medication, and a refocusing of attention to function is useful. A trusting and strong patient-doctor relationship can do much to sustain a patient through times of discomfort and disability.
For more information, see the Arthritis Center and Pain Management Center, as well as Rheumatoid Arthritis, Juvenile Rheumatoid Arthritis, Rheumatoid Arthritis Medications, Chronic Fatigue Syndrome, and Chronic Pain.
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|Early RA (<6 months)||
|(Notable change from 2012 to 2015 guidelines: The 2015 guidelines do not recommend initial combination DMARD therapy in early RA with moderate to high disease activity)|
|Established RA (=6 month or meets 1987 ACR RA classification criteria)||If disease activity remains moderate or high despite DMARD monotherapy, ACR guidelines recommend one of the following:
|If disease activity remains moderate or high despite use of a single anti-TNF biologic:
|If disease activity remains moderate or high despite use of one anti-TNF biologic and one non-TNF biologic:
|(Notable change from 2012 to 2015 guidelines: Instead of switching from one anti-TNF biologic to another anti-TNF biologic because of continued activity, it is recommended to change first to a non-TNF biologic)|
|Result of Initial/Repeat TST or IGRA||Recommendation|
|Negative||In patients with RA but without risk factors or clinical suspicion for TB
|In patients with RA and immunosuppression plus LTBI risk factors
|ACR = American College of Rheumatology; IGRA = interferon gamma release assay; LBTI = latent tuberculosis infection; RA = rheumatoid arthritis; TB = tuberculosis; TST = tuberculin skin test.
Source: Singh JA, Saag KG, et al2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care and Research http://dx.doi.org/10.1002/art.39480 (2015).