Rheumatoid Arthritis

Question 1

Practice Essentials

Answer 1

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.

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 RA may include the following:

1. Persistent symmetric polyarthritis (synovitis) of hands and feet (hallmark feature)
2. Progressive articular deterioration
3. Extra-articular involvement
4. Difficulty performing activities of daily living (ADLs)
5. Constitutional symptoms

The physical examination should address the following:

• Upper extremities (metacarpophalangeal joints, wrists, elbows, shoulders)
• Lower extremities (ankles, feet, knees, hips)
• Cervical spine

Question 2

Background on Rheumatoid Arthritis

Answer 2

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.

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.

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.

Macrophage activation syndrome is a life-threatening complication of juvenile idiopathic arthritis (JIA) that necessitates immediate treatment with high-dose steroids and cyclosporine.

Question 3

Lab Tests for Rheumatoid Arthritis

Answer 3

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.

Question 4

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

Answer 4

1. 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.
2. While remission should be a clear target, low-disease activity may be an acceptable alternative therapeutic goal, particularly in long-standing disease.
3. The use of validated composite measures of disease activity, which include joint assessments, is needed in routine clinical practice to guide treatment decisions.
4. The choice of the (composite) measure of disease activity and the target value should be influenced by comorbidities, patient factors, and drug-related risks.
5. 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.
6. Structural changes and functional impairment and comorbidity should be considered when making clinical decisions, in addition to assessing composite measures of disease activity.
7. Until the desired treatment target is reached, drug therapy should be adjusted at least every 3 mo.
8. The desired treatment target should be maintained throughout the remaining course of the disease.
9. The rheumatologist should involve the patient in setting the treatment target and the strategy to reach this target.

Question 5

Pathophysiology of RA

Answer 5

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, rheumatoid factors).

Abnormal production of numerous cytokines, chemokines, and other inflammatory mediators has been demonstrated in patients with RA, including the following:

1. Tumor necrosis factor alpha (TNF-α)
2. Interleukin (IL)-1
3. IL-6
4. IL-8
5. Transforming growth factor beta (TGF-ß)
6. Fibroblast growth factor (FGF)
7. 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.

Question 6

Etiology

Answer 6

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.

Question 7

Genetic factors

Answer 7

Genetic factors account for 50% of the risk for developing RA. [10] 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. Results from sequencing genes of families with RA suggest the presence of several resistance and susceptibility genes, including PTPN22 and TRAF5.

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. [13] The IL2RA/CD25 gene has been implicated as a JIA susceptibility locus, as has the VTCN1 gene. [14]

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, which suggests that genomic imprinting from parents participates in its expression. 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.

Question 8

Infectious agents

Answer 8

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:
1. Occasional reports of flulike disorders preceding the start of arthritis

2. The inducibility of arthritis in experimental animals with different bacteria or bacterial products (eg, streptococcal cell walls)
3. The presence of bacterial products, including bacterial RNA, in patients’ joints
4. The disease-modifying activity of several agents that have antimicrobial effects (eg, gold salts, antimalarial agents, 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 antibodies to anaerobic bacteria that commonly cause periodontal infection, including Porphyromonas gingivalis.

Question 9

Hormonal factors

Answer 9

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.

Question 10

Immunologic factors

Answer 10

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.

Question 11

Epidemiology of RA

Answer 11

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, 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

Question 12

Prognosis

Answer 12

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.

Question 13

Prognostic factors

Answer 13

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:

1. HLA-DRB1*04/04 genotype
2. High serum titer of autoantibodies (eg, RF and ACPA)
3. Extra-articular manifestations
4. Large number of involved joints
5. Age younger than 30 years
6. Female sex
7. Systemic symptoms
8. Insidious onset

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. 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, [28] and the combined detection of these autoantibodies can increase the ability to predict erosive disease in RA patients. [29]

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.

Question 14

Morbidity and mortality

Answer 14

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.

Question 15

Discussing prognosis and treatment

Answer 15

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. [34] (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.

Question 16

Complication of RA

Answer 16

RA itself is not fatal, but complications of the disease may shorten survival by years in some individuals. In general, RA is progressive and cannot be cured, but in some patients, the disease gradually becomes less aggressive, and symptoms may even improve. However, if bone and ligament destruction and any deformities have occurred, the effects are permanent.

Joint disability and pain with daily life are common. Affected joints can become deformed, and the performance of even ordinary tasks may be very difficult or impossible; these factors can severely affect patients’ quality of life.

In addition, RA is a systemic disease that can affect other parts of the body in addition to joints. These effects include the following:
1. Anemia

2. Infections – Patients with RA are at greater risk for infections; immunosuppressive drugs further increase that risk
3. GI problems – Patients with RA may experience stomach and intestinal distress; however, lower rates of stomach and colorectal cancers have been reported in RA patients
4. Osteoporosis – This condition is more common than average in postmenopausal women with RA; the hip is particularly affected; the risk of osteoporosis appears to be higher than average in men with RA who are older than 60 years
5. Lung disease – A small study found a high prevalence of pulmonary inflammation and fibrosis in patients with newly diagnosed RA, but this finding may be associated with smoking
6. Heart disease – RA can affect blood vessels and increase the risk of coronary ischemic heart disease
7. Sjögren syndrome – Keratoconjunctivitis sicca is a common complication of RA; oral sicca and salivary gland enlargement are less common
8. Felty syndrome – This condition is characterized by splenomegaly, leukopenia, and recurrent bacterial infections; it may respond to disease-modifying antirheumatic drugs (DMARDs)
9. Lymphoma and other cancers – RA-associated immune system alterations may play a role; aggressive treatments for RA may help prevent such cancers

Question 17

Physical exam

Answer 17

Joint involvement is the characteristic feature of RA. In general, the small joints of the hands and feet are affected in a relatively symmetric distribution. In decreasing frequency, the metacarpophalangeal (MCP), wrist, proximal interphalangeal (PIP), knee, metatarsophalangeal (MTP), shoulder, ankle, cervical spine, hip, elbow, and temporomandibular joints are most commonly affected.

Affected joints show inflammation with swelling, tenderness, warmth, and decreased range of motion (ROM). Atrophy of the interosseous muscles of the hands is a typical early finding. Joint and tendon destruction may lead to deformities such as ulnar deviation, boutonniere and swan-neck deformities, hammer toes, and, occasionally, joint ankylosis.

Other commonly observed musculoskeletal manifestations include the following:
1. Tenosynovitis (defined as inflammation of the tendon and its enveloping tendon sheath) and associated tendon rupture due to tendon and ligament involvement, most commonly involving the fourth and fifth digital extensor tendons at the wrist

2. Periarticular osteoporosis due to localized inflammation
3. Generalized osteoporosis due to systemic chronic inflammation, immobilization-related changes, or corticosteroid therapy
4. Carpal tunnel syndrome

Question 18

Lab Studies

Answer 18

Routine viral screening by serologic testing does not significantly facilitate the diagnosis of RA in patients with early RA, nor is it helpful as a potential identifier of disease progression.

Potentially useful laboratory studies in suspected RA fall into 3 categories—markers of inflammation, hematologic parameters, and immunologic parameters—and include the following:
1. Erythrocyte sedimentation rate (ESR)

2. C-reactive protein (CRP) level
3. Complete blood count (CBC)
4. Rheumatoid factor (RF) assay
5. Antinuclear antibody (ANA) assay
6. Anti−cyclic citrullinated peptide (anti-CCP) and anti−mutated citrullinated vimentin (anti-MCV) assays (currently used in the 2010 American College of Rheumatology [ACR]

The ESR and the CRP level are associated with disease activity. The CRP value over time correlates with radiographic progression.

Question 19

Hematologic parameters

Answer 19

The CBC commonly demonstrates anemia of chronic disease and correlates with disease activity; it improves with successful therapy. Hypochromic anemia suggests blood loss, commonly from the gastrointestinal (GI) tract (associated with the use of nonsteroidal anti-inflammatory drugs [NSAIDs]). Anemia may also be related to disease-modifying antirheumatic drug (DMARD) therapy.
Thrombocytosis is common and is also associated with disease activity. Thrombocytopenia may be a rare adverse event of therapy and may occur in patients with Felty syndrome. Leukocytosis may occur but is usually mild. Leukopenia may be a consequence of therapy or a component of Felty syndrome, which may then respond to DMARD therapy.

Question 20

Immunologic parameters

Answer 20

Immunologic parameters include autoantibodies (eg, RF, anti-CCP antibodies, and ANAs). RF is an immunoglobulin (Ig) M antibody directed against the Fc fragment of IgG that is present in approximately 60-80% of patients with RA over the course of their disease (but in fewer than 40% of patients with early RA). RF values fluctuate somewhat with disease activity, though titers of RF generally remain high even in patients with drug-induced remissions.

RF is not specific for RA but is also present in other connective tissue diseases, infections, and autoimmune disorders, as well as in 1-5% of healthy people. The presence of RF predicts radiographic progression of bone erosions, independent of disease activity.

Although ANAs are present in approximately 40% of patients with RA, test results for antibodies to most nuclear antigen subsets are negative.

Assays for anti-citrullinated protein antibody (ACPA; often tested as anti-CCP) are now being used clinically for diagnosing RA. ACPA-positive and ACPA-negative RA may be 2 distinct disease subsets, with different underlying pathogeneses and risks for developing RA. ACPA-positive patients may have a more erosive RA disease course than ACPA-negative patients

Question 21

Treatment of RA

Answer 21

Optimal care of patients with rheumatoid arthritis (RA) consists of an integrated approach that includes both pharmacologic and nonpharmacologic therapies.

Many nonpharmacologic treatments are available for this disease, including exercise, diet, massage, counseling, stress reduction, physical therapy, and surgery. Active participation of the patient and family in the design and implementation of the therapeutic program helps boost morale and ensure compliance, as does explaining the rationale for the therapies used.

Medication-based therapies comprise several classes of agents, including nonsteroidal anti-inflammatory drugs (NSAIDs), nonbiologic and biologic disease-modifying antirheumatic drugs (DMARDs), immunosuppressants, and corticosteroids.

Early therapy with DMARDs has become the standard of care, in that it is capable not only of retarding disease progression more efficiently than later treatment but also, potentially, of inducing more remissions.

Surgical procedures used in the treatment of RA include the following:
-Synovectomy
-Tenosynovectomy
-Tendon realignment
-Reconstructive surgery or arthroplasty
Arthrodesis

Question 22

Treatment guidelines for RA

Answer 22

1. Patients with active disease should be monitored every 3 months, and treatment should be adjusted if there is no improvement at 6 months
2. Methotrexate (MTX) is recommended as first-line therapy; sulfasalazine (SSZ) or leflunomide can be substituted if there are contraindications to MTX
3. Tumor necrosis factor (TNF) inhibitors are no longer the only biologics recommended for patients with an insufficient response to MTX; all biologics are considered to be similarly effective
4. Biologics should be combined with disease-modifying antirheumatic drugs (DMARDs)

Question 23

Biologic DMARDs: TNF inhibitors

Answer 23

The TNF inhibitors that bind TNF and thus prevent its interaction with its receptors include etanercept, infliximab, adalimumab, certolizumab, and golimumab.

Precautions and adverse effects
Biologic agents are expensive. Consensus statements do not recommend their use until at least one nonbiologic DMARD, usually MTX, has been administered without sufficient success. In clinical trials, as many as 70% of patients achieve significant responses, but remissions are not usually observed.

Adverse effects associated with the biologic agents include the generation of antibodies against these compounds, emergence of antinuclear antibodies (ANAs), occasional drug-induced lupuslike syndromes, and infections (including tuberculosis). Rarely, demyelinating disorders and bone marrow suppression occur. Immunogenicity, such as the development of anti-drug antibodies, has been shown to occur in adalimumab and infliximab, potentially leading to decreased drug efficacy. Concomitant use of methotrexate may reduce the frequency of anti-drug antibodies.

Question 24

Medication Summary

Answer 24

Optimal care of patients with rheumatoid arthritis (RA) requires an integrated approach that includes both nonpharmacologic therapies and pharmacologic agents such as nonbiologic and biologic disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and corticosteroids.

DMARDs represent the most important measure in the successful treatment of rheumatoid arthritis. These agents can retard or prevent disease progression and, thus, joint destruction and subsequent loss of function. Successful DMARD therapy may eliminate the need for other anti-inflammatory or analgesic medications; however, until the full action of DMARDs takes effect, anti-inflammatory or analgesic medications may be required as bridging therapy to reduce pain and swelling.

MTX is a folic acid antagonist that is approved for the management of severe active RA in patients who have had an insufficient therapeutic response to or are intolerant of an adequate trial of first-line therapy, including full-dose NSAIDs. MTX is started at lower doses and increased to full doses within approximately 4-6 weeks. The initial dosage is 7.5 mg/wk PO in a single dose; alternatively, the weekly regimen may be administered in divided doses of 2.5 mg PO at 12-hour intervals for 3 doses. A self- administered subcutaneous injection is also available (Otrexup), and may improve bioavailability and avoid GI effects for patients who need higher doses.

DMARDs, TNF Inhibitors
Class Summary
The recognition of TNF-α and IL-1 as central proinflammatory cytokines has led to the development of agents that block either these cytokines or their effects. In addition to improving signs and symptoms and quality of life, all biologic agents significantly retard radiographic progression of joint erosions.

Question 25

DMARDs, TNF Inhibitors

Answer 25

Class Summary

The recognition of TNF-α and IL-1 as central proinflammatory cytokines has led to the development of agents that block either these cytokines or their effects. In addition to improving signs and symptoms and quality of life, all biologic agents significantly retard radiographic progression of joint erosions.
The TNF inhibitors, which bind TNF and thus prevent its interaction with its receptors, include etanercept, infliximab, golimumab, certolizumab, and adalimumab. Consensus statements do not recommend their use until at least one xenobiotic DMARD, usually MTX, has been administered without sufficient success.
Adverse effects associated with the biologic agents include the generation of antibodies against these compounds, the emergence of antinuclear antibodies (ANAs), occasional drug-induced lupuslike syndromes, and infections. Rarely, demyelinating disorders and bone marrow suppression occur.