NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.

Cover of StatPearls

StatPearls [Internet].

Show details

Rheumatoid Arthritis

; ; ; ; .

Author Information

Last Update: October 7, 2021.

Continuing Education Activity

Rheumatoid arthritis (RA) is an autoimmune disorder of the joints characterized by inflammatory arthritis as well as extra-articular involvement. It commonly involves multiple joints of both hands with morning stiffness that may last for several hours. This activity describes the evaluation and management of rheumatoid arthritis and reviews the role of the interprofessional team in improving care for patients with this condition.

Objectives:

  • Identify the comorbid conditions associated with rheumatoid arthritis.
  • Summarize the pathophysiology of rheumatoid arthritis.
  • Outline the use of rheumatoid factor and anti-citrullinated protein antibodies in the evaluation of rheumatoid arthritis.
  • Review the importance of improving care coordination among the interprofessional team to improve outcomes for those affected with rheumatoid arthritis.
Access free multiple choice questions on this topic.

Introduction

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammatory arthritis and extra-articular involvement. It is a chronic inflammatory disorder of unknown etiology that primarily involves synovial joints. It typically starts in small peripheral joints, is often symmetric, and progresses to involve proximal joints if left untreated.[1] Joint inflammation over time leads to the destruction of the joint with cartilage and bone erosion. RA with a symptom duration of fewer than six months is defined as early RA, and when the symptoms have been present for more than six months, it is defined as established RA.[1] 

There is no pathognomonic laboratory test for rheumatoid arthritis, which makes the diagnosis of this disease challenging. An astute and comprehensive clinical approach is required to make the diagnosis and prevent debilitating joint damage.[1] The treatment of patients with rheumatoid arthritis requires both pharmacological and non-pharmacological therapy. Today, the standard of care is early treatment with disease-modifying anti-rheumatic drugs. Despite treatment, many patients progress to disability and suffer significant morbidity over time. A comprehensive pharmacological and non-pharmacological support (physical therapy, counseling, and patient education) is required to improve clinical outcomes.

Etiology

The etiology of RA remains unknown.[2] It is thought to result from the interaction between patients' genotype and environment. In a nationwide study of 91 monozygotic (MZ) and 112 dizygotic (DZ) twin pairs in the United Kingdom, the overall MZ concordance rate was 15% and 5% among dizygotic twins.[3] The heritability of rheumatoid arthritis is approximately 40% to 65% for seropositive rheumatoid arthritis and 20% for seronegative rheumatoid arthritis.[2] The risk of developing rheumatoid arthritis has been associated with HLA-DRB1 alleles: HLA-DRB1*04, HLA-DRB1*01, and HLA-DRB1*10. These HLA-DRB1 alleles contain a stretch of conserved five amino acid sequences and the shared epitope (SE) in the third hypervariable region of their DRB1 chain, which has been associated with the risk of developing RA.[4][5]

It has been suggested that polymorphism in signal transducers and activators of transcription (STAT)-4 and interleukin (IL)-10 genes also confer susceptibility to RA. Single nucleotide polymorphism (SNP) in PSORS1C1, PTPN2, and MIR146A genes are associated with severe disease.[6]

The term epigenetics refers to heritable changes without altering the DNA sequence. These changes may be present in chromatin or the DNA. These include DNA methylation, histone modification, and non-coding RNA-mediated regulation. RA-FLS (fibroblast-like synoviocytes) overexpress tyrosine phosphatase SHP-2, coded by gene PTPN11 compared to synoviocytes from osteoarthritis (OA) patients, promoting the invasive nature of RA-FLS. The enhancer region of the PTPN11 intron contained two hypermethylated sites, resulting in abnormal epigenetic regulation of the gene and alteration of function of RA-FLS.[7]

Cigarette smoking is the strongest environmental risk factor associated with rheumatoid arthritis. Studies have shown in ACPA (anti-citrullinated protein antibody) positive individuals; there is an interaction between genes and smoking that increases the risk of RA.[8]

Changes in the composition and function of the intestinal microbiome have been related to rheumatoid arthritis as well. The composition of the gut microbiome becomes altered in patients with rheumatoid arthritis (dysbiosis), where rheumatoid arthritis patients have decreased gut microbiome diversity compared with healthy individuals. There is an increase in these genera: Actinobacteria, Collinsella, Eggerthalla, Faecalibacterium. Collinsella alters gut mucosal permeability and has been related to increased rheumatoid arthritis disease severity.[8]

Epidemiology

The worldwide prevalence of RA is about 0.24%.[9] The annual incidence of RA in the United States and other western nations of northern Europe is about 40 per 100,000 persons.[10] According to epidemiologic data, RA is more prevalent in women compared to men, with a lifetime risk of RA 3.6% in women compared to 1.7% in men.[11] RA risk also increases with age, with a peak incidence between age 65 to 80 years of age.[12]

As outlined above, there is a genetic disposition towards RA, which was demonstrated to be about 40% in a large study from Sweden in 2013.[13] The study also reported a higher heritability for seropositive RA and early-onset RA. According to their report, the risk of RA with a first-degree relative positive for RA is three-fold higher than a second-degree relative with RA giving a two-fold higher risk.[13] Multiple different genetic predispositions to explain this finding have now been identified. The strongest genetic predisposition for RA is from the HLA-DRB1 region.[14]

Among modifiable risk factors, cigarette smoking has the strongest association with RA.[15] Diet and nutrition have been shown to play a significant role as environmental triggers for RA. The typical 'western' diet that is rich, high in caloric content, and low in fiber increases the risk of RA.[16] Consumption of long-chain omega-3 polyunsaturated fatty acids is associated with a reduced risk of RA.[16]  

Obesity is another well-established risk factor for RA. There is a 30% increase in the risk of RA for patients with a body mass index (BMI) of greater than 30 kg/m^2 and a 15% increased risk for those with a BMI of 25 to 29.9 kg/m^2.[17]

There is significant literature regarding the association of RA in patients with chronic mucosal or periodontal disease. However, no clear, consistent link has been identified in well-established studies. There is evidence that mucosal injury from occupational exposures and environmental pollutants can increase the risk of RA.[18][19]

Pathophysiology

Rheumatoid arthritis patients contain antibodies to citrullinated proteins. Citrulline is an amino acid generated by post-translational modification of arginyl residues by peptidyl arginine deaminases. These antibodies are called anti-citrullinated protein antibodies (ACPA). ACPA can be IgG, IgM, or IgA isotypes. ACPA can bind citrullinated residues on self-proteins like vimentin, fibronectin, fibrinogen, histones, and type 2 collagen.[8] The binding of antibodies to proteins leads to complement activation. The presence of antibodies in rheumatoid arthritis is referred to as seropositive RA. ACPA can be present in the serum up to 10 years before the onset of clinical symptoms. With time the concentration of ACPA and serum cytokine level increases.[20][8]

The synovium in rheumatoid arthritis is infiltrated by immune cells, which include innate immune cells (monocytes, dendritic cells, mast cells) and adaptive immune cells (Th1 (T-helper 1), Th17 (T-helper 17), B cells, and plasma cells). Cytokines and chemokines like tumor necrosis factor (TNF), interleukin-6 (IL-6), and granulocyte-monocyte colony-stimulating factors activate endothelial cells and attract immune cells within the synovial compartment.[8] The fibroblast in the rheumatoid synovium changes to an invasive phenotype. Fibroblast and inflammatory cells lead to osteoclast generation resulting in bone erosion, the hallmark feature of rheumatoid arthritis.[21]

The mechanism behind environment-triggered RA is thought to be due to the repeated activation of innate immunity. Cigarette smoking induces peptidyl arginine deiminase (PAD) expression in alveolar macrophages, which leads to the conversion of arginine to citrulline in the airway.[22] This process creates a "neoantigen" that activates an immune response and leads to the formation of anti-citrullinated protein antibodies (ACPAs).[22]

Anti-carbamylated protein (anti-CarP) antibodies are anti-posttranslationally modified protein antibodies (AMPA) associated with RA.[8] Carbamylation is a cyanide-mediated chemical reaction in which lysine is converted into homocitrulline. The molecular structure of homocitrulline is similar to citrulline; however, anti-CarP antibodies are distinct antibodies that have been associated with RA in both ACPA-positive and ACPA-negative patients.[8]

Anti-acetylated protein antibodies have recently been associated with RA (in approximately 40% of RA patients), predominately in seropositive patients.[8] Acetylation is an enzymatic process thought to be mediated by bacteria, which may provide the link to RA and microbiome dysbiosis. The exact mechanism at this time remains unclear.[8]

It is important to note that synovial biopsies in seropositive patients with arthralgia were essentially unremarkable.[23] It is theorized that a second environmental trigger is needed to cause clinically apparent disease. When this is established, a destructive inflammatory process begins. Fibroblast-like synoviocytes (FLS) migrate from joint to joint, leading to progressive joint damage.[21]

Histopathology

One of the earliest histopathologic findings in RA is new synovial blood vessels growth; this leads to the transmigration of lymphocytes and polymorphonuclear leukocytes into the synovial fluid. Angiogenesis is required to support the highly catabolic synovium and is accomplished via proinflammatory cytokines such as tumor necrosis factor (TNF).[24] With angiogenesis, cytokines activate endothelial cells to produce adhesion molecules which in turn facilitate cell migration into the synovium. Despite angiogenesis, RA synovial fluid is a hypoxic environment, leading to increased production of cyclooxygenase (COX) 2-derived nociceptive eicosanoids and matrix metalloproteinases (MMPs).[25] This further stimulates an inflammatory response in the synovium. During the early phase of the disease, the influx of inflammatory cells into the synovial membrane leads to a proliferation of monocytes and thickening of the synovial membrane with small villous projections into the joint space.[24]

Rheumatoid nodules initially have a small vessel vasculitis phenomenon followed by a chronic inflammatory granulomatous phase. The development of rheumatoid nodules is frequent in rheumatoid arthritis, involving the dermis or subcutis in peri-articular areas. When multiple, this phenomenon can be related to methotrexate therapy and is called accelerated rheumatoid nodulosis.[26] The size is variable and can range from a few millimeters to centimeters. It appears grossly as a whitish fibrous lesion with yellowish areas, corresponding to collagenous necrobiosis. The histological appearance can be indistinguishable from granuloma annulare. There are areas of irregular geographic-like necrobiosis of the dermis and hypodermis surrounded by histiocytes arranged in a well-developed palisade, occasional lymphocytes, and neutrophils. Occasionally, giant cells and mast cells can be present. Fibrin and collagen are present in the center of the necrobiotic areas. The surrounding dermis and hypodermis have a perivascular infiltrate of plasma cells.[26] 

History and Physical

The most common and predominant symptoms include joint pain and stiffness, especially morning stiffness and swelling.[27] Usually, the onset of symptoms is slow and insidious; however, in some cases, an episodic pattern of symptoms can be seen and is defined as palindromic rheumatism.[28] Not all patients with palindromic rheumatism develop RA, and they symptomatically respond to hydroxychloroquine which supports the idea that palindromic rheumatism is a precursor of RA.[29] As discussed above, RA involves small peripheral joints, usually of the hands. Axial joint involvement, especially of the lumbar region, is not common.[30] However, cervical joint disease in long-standing RA can be present. Although multiple small joint involvements are a frequent feature, some patients may present with monoarticular and extraarticular involvement. 

On physical examination, the affected joint will be painful if pressure is applied to the joint or on movement with or without joint swelling. Synovial thickening with a "boggy" feel on palpation will be noted. Joint erythema and warmth are usually absent, and wrist involvement may present with typical signs and symptoms of carpal tunnel syndrome. With multiple joint involvements, reduced grip strength will be seen on physical testing. The classical physical findings of ulnar deviation, metacarpophalangeal joint subluxation, ulnar deviation, swan neck deformity, Boutonniere deformity, and the "bowstring" sign are seen on advanced chronic disease.

Rheumatoid nodules are the most common cutaneous manifestations of RA.[31] They are commonly found on pressure points such as the olecranon. RA patients can have ulcerative skin lesions as well and are thought to be due to venous stasis, arterial insufficiency, neutrophilic infiltration, and/or vasculitis.

Vasculitis involving both medium and small-sized blood vessels can also be seen as a presenting symptom of RA. However, the prevalence of vasculitis among patients with RA is low.[32] Patients with rheumatoid vasculitis may exhibit mononeuritis multiplex or asymmetric polyneuropathy. A secondary form of Sjögren disease is associated with rheumatoid arthritis. It comprises symptoms of ocular and/or oral dryness as the hallmark signs.[33]

Evaluation

Laboratory testing usually reveals anemia of chronic disease and thrombocytosis. Neutropenia may be present if Felty syndrome is present. About 75% to 85% of patients with RA will test positive for rheumatoid factor (RF), ACPA, or both.[8] These patients are designated as seropositive RA. About 45% to 75% of patients with rheumatoid arthritis test positive for rheumatoid factor. However, the presence of rheumatoid factor is not diagnostic of rheumatoid arthritis. It may be present in other connective tissue diseases, chronic infections, and healthy individuals, albeit in low titers. Anti-citrullinated protein antibodies (ACPA) are found in about 50% of patients with early arthritis, which are subsequently diagnosed with rheumatoid arthritis. If both RF and ACPA are positive, the sensitivity and specificity of the diagnosis increase substantially. Acute phase reactants, such as erythrocyte sedimentation rate (ESR) and levels of C-reactive protein (CRP), are usually elevated in patients with active disease and should be obtained. 

Synovial fluid examination usually reveals a leukocyte count between 1500 to 25,000/cubic mm and is predominantly polymorphonuclear cells. Cell counts higher than 25000/cubic mm are rare and can be seen with very active disease; however, they warrant workup to rule out underlying infection. The synovial fluid in RA will also reveal low C3 and C4 levels despite elevated serum levels.[34]

With advanced disease, joint involvement on plain radiographs will reveal periarticular osteopenia, joint space narrowing, and bony erosions. Erosions of cartilage and bone are considered pathognomonic findings for RA. However, these findings are consistent with advanced disease.[35] Magnetic resonance imaging (MRI) and ultrasonography are useful in early disease before radiographic evidence of bone erosion occurs.[36] A decreased signal from the bone marrow on T1-weighted images and gadolinium-enhanced images indicates bone marrow edema. MRI can also reveal synovial thickening, which has been shown to predict the future presence of bony erosions.[37] The clinical utility of MRI and its incorporation into the diagnostic criteria for RA remains to be determined. 

Due to the varied clinical presentation and lack of universal pathognomonic testing for RA, diagnosing the disease can be challenging. Traditionally the presence of at least four of the following criteria for at least six weeks would classify the patient as having RA. These criteria were: morning stiffness, arthritis of three or more joints, arthritis of the hands, symmetric arthritis, elevated acute phase reactants, elevated rheumatoid factor, and radiologic evidence of RA. These criteria separated inflammatory from non-inflammatory arthritis but were not very specific for RA. It was also not sensitive for early-stage RA, which was a significant drawback.[38] With the development of serologic markers, the diagnostic criteria were redefined. The 2010 American College of Rheumatology and the European League Against Rheumatism (ACR/EULAR) diagnostic criteria for RA are outlined below. It includes four different domains, which are as follows:

2010 ACR/EULAR Diagnostic Criteria for RA [39]

  • Number and site of involved joints
    • 2 to 10 large joints = 1 point (shoulders, elbows, hips, knees, and ankles)
    • 1 to 3 small joints = 2 points (metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists)
    • 4 to 10 small joints = 3 points
    • Greater than 10 joints (including at least 1 small joint) = 5 points
  • Serological testing for rheumatoid factor or anti-citrullinated peptide/protein antibody
    • Low positive = 2 points
    • High positive = 3 points
  • Elevated acute phase reactant (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]) = 1 point
  • Symptom duration at least six weeks = 1 point

A total score of greater than or equal to 6 classifies the patient as having RA. It is important to note that joint involvement refers to any swollen or tender joint on examination. Imaging studies may also be used to determine the presence of synovitis/joint involvement. The 2010 ACR/EALAR criteria excluded distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints from this criteria. Also, this criteria may only be applied to those patients where the joint involvement is not better explained by other inflammatory diseases, such as systemic lupus erythematosus or psoriasis. Specific testing must be obtained to rule out these diseases. The new criteria were noted to better predict the probability of RA, have the same sensitivity as the previous criteria for the diagnosis of RA and have a higher specificity as well as higher negative predictive value.[38]

Treatment / Management

The goal of treatment in patients with RA is early diagnosis and early initiation of treatment to prevent irreversible damage to the joints. The International Task Force Guidelines published in 2014 make the following recommendations regarding treatment of RA:[40] 

  • The primary goal of treatment is to achieve long-term clinical remission and optimize quality of life with the absence of signs and symptoms associated with inflammatory disease activity.
  • If clinical remission cannot be achieved, low disease activity is an acceptable alternative.
  • Disease activity should be assessed every month in patients with moderate to severe disease activity.
  • In patients with low disease activity or clinical remission, disease activity should be assessed every 3 to 6 months.

Multiple clinical assessment tools have been developed to assist clinicians in determining the disease activity of patients with RA. An updated recommendation from the American College of Rheumatology (ACR) in 2019 recommended using the following assessment tools because they met the minimum standard for evaluation per their recommendation:[41]

  • Clinical Disease Activity Index (CDAI) 
  • Disease Activity Score (DAS)
  • Disease Activity Score 28 Joints (DAS28-ESR/CRP)
  • Patient-Derived DAS28
  • Hospital Universitario La Princesa Index (HUPI)
  • Multi-Biomarker Disease Activity Score (MBDA score, VECTRA DA)
  • Rheumatoid Arthritis Disease Activity Index (RADAI)
  • Rheumatoid Arthritis Disease Activity Index 5 (RADAI-5)
  • Routine Assessment of Patient Index Data 3 (RAPID3)
  • Routine Assessment of Patient Index Data 5 (RAPID5)
  • Simplified Disease Activity Index (SDAI)

Disease-modifying antirheumatic drugs (DMARDs) typically used in treating RA include methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide. Anti-TNF-alpha agents include etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. Non-TNF biologic DMARDs include interleukin (IL) 6 receptor antagonists such as tocilizumab and sarilumab, T-cell blockers such as abatacept (CTLA4-Ig), and the anti-CD20 B-cell depleting monoclonal antibody such as rituximab. Other synthetic DMARDs include Janus kinases (JAK) inhibitors such as tofacitinib, baricitinib, and upadacitinib.

DMARD therapy, including biologic agents and targeted therapy agents (tofacitinib), should be temporarily held in patients with a serious active infection. They can be resumed after the infection has resolved and antimicrobial treatment has been completed.[42] It is essential to remember that all patients starting treatment for RA should be screened for hepatitis B and C and tuberculosis. Methotrexate should be avoided in patients with liver damage.[42] Patients with latent tuberculosis should complete treatment for at least one month before the initiation of biologic agents. If patients cannot take or complete treatment for latent tuberculosis, conventional DMARD therapy should be used.[42] In patients with underlying skin cancer and lymphoproliferative disorders, biologic agents should be avoided except for rituximab in patients with lymphoproliferative disorders as there is evidence of benefit from B-cell suppression in these cases.[42] The ACR also recommends that before starting therapy for RA, patients should receive vaccination for pneumococcus, hepatitis, influenza, human papillomavirus (HPV), and herpes zoster virus (HZV).

Nonbiologic DMARDs

This category includes hydroxychloroquine (HCQ), azathioprine (AZA), sulfasalazine, methotrexate, leflunomide, and cyclosporine. Methotrexate is the initial drug of choice for patients with RA. The recommended treatment plan recommends an initial dose of 15 mg/week of methotrexate with an escalation of 5 mg/month and a target dose of 25 to 30 mg/week.[43] In patients who do not have an adequate response to oral administration, subcutaneous administration can be tried. 

TNF inhibitors

The TNF inhibitors include etanercept, infliximab, adalimumab, certolizumab, and golimumab. The ACR does not recommend the use of TNF inhibitors until a nonbiologic DMARD has been tried.[42] However, studies have shown that the addition of TNF inhibitors in patients who have failed methotrexate therapy is better than adding another nonbiologic DMARD.[44] The most concerning adverse effect of these agents is opportunistic infections and reactivation of latent tuberculosis. There is some concern about the generation of antibodies against these agents, which may decrease their efficacy over time; however, the use of methotrexate in combination with these agents has been shown to decrease this complication.[45] Acute infection, advanced heart failure, and recent malignancies are a contraindication for using these agents.[42] 

Rituximab

Rituximab is a biologic non-TNF DMARD that can be added for the treatment of RA if patients have uncontrolled RA and who did not improve with TNF therapy.[46] Rituximab suppresses CD20+ B-cells and decreases the immune response to vaccines in patients receiving rituximab. As stated above, it is a preferred agent in patients with underlying lymphoproliferative disorders. 

Abatacept

Abatacept inhibits T-cell activation by binding to CD80 and CD86. It is administered as a monthly intravenous infusion or as a weekly subcutaneous injection. Patients with uncontrolled RA, who have shown an inadequate response to methotrexate and TNF inhibitor therapy, benefit from abatacept therapy with proven efficacy from 6 months to 5 years of therapy.[47] 

Interleukin 6 Inhibitors

Tocilizumab, an IL-6 receptor inhibitor, is indicated for moderate-to-severe active RA in adults who have had an inadequate response to TNF inhibitor therapy. These patients develop clinically meaningful improvement with the use of tocilizumab.[48] Sarilumab is another agent in this category that has been shown to improve clinical outcomes in patients with uncontrolled RA despite TNF inhibitor therapy.[49]

Janus kinase (JAK) Inhibitors

JAK is a group of tyrosine kinases that participate in intracellular signal transduction for hematopoiesis and immune cell function. JAK inhibitors (such as tofacitinib) reduce the production of cytokines and are approved as second-line agents for the treatment of RA.[50]

ACR and EULAR Treatment Guidelines [42]

  • According to the ACR treatment guidelines for early RA, patients who have not taken disease-modifying antirheumatic drug (DMARD) therapy should start DMARD therapy regardless of the activity level.
  • In patients with low disease activity and early disease, monotherapy with methotrexate is the preferred treatment.
  • Leflunomide or sulfasalazine are the first-line treatment in patients with a contraindication to methotrexate or intolerance to it.
  • If monotherapy with DMARD does not control disease activity (regardless of concomitant glucocorticoid use), therapy should be altered. Methotrexate can be continued or discontinued at this point. Additional therapy options after failed monotherapy with DMARD are recommended as either dual traditional/nonbiologic DMARD therapy, tumor necrosis factor (TNF) inhibitors, or non-tumor necrosis factor biologic agents.
  • In patients with established RA, who are DMARD naive, methotrexate is the preferred agent for initial monotherapy, regardless of the disease activity level.
  • If monotherapy with DMARD does not control disease activity in established RA (regardless of concomitant glucocorticoid use), dual DMARD therapy, a TNF inhibitor, a non-TNF biologic agent, or tofacitinib therapy can be added.
  • If disease activity remains high on TNF inhibitor monotherapy, DMARD therapy should be added in addition to the TNF inhibitor.
  • If disease activity remains high despite anti-TNF inhibitor switch to a non-TNF biologic agent with or without methotrexate
  • If disease activity remains high despite a trial of anti-TNF and non-TNF agents, use another non-TNF biologic agent before considering tofacitinib.
  • If still uncontrolled despite the above trials, use tofacitinib
  • If disease activity remains high despite the above combination therapies, short-term low-dose glucocorticoid therapy should be added.
  • TNF inhibitors should be avoided in patients with congestive heart failure.
  • Patients with hepatitis C who have not been treated or are currently not on treatment for it should receive nonbiologic DMARD therapy rather than TNF inhibitors.

Differential Diagnosis

  • Systemic lupus erythematosus
  • Chronic Lyme disease
  • Osteoarthritis
  • Septic arthritis
  • Psoriatic arthritis
  • Sjogren syndrome
  • Sarcoidosis

Staging

Stages of RA as Defined by the ACR: [42]

Stage 1: No destructive changes on x-rays

Stage 2: Presence of x-ray evidence of periarticular osteoporosis, subchondral bone destruction but no joint deformity

Stage 3: X-ray evidence of cartilage and bone destruction in addition to joint deformity and periarticular osteoporosis

Stage 4: Presence of bony or fibrous ankylosis along with stage 3 features

Prognosis

Rheumatoid arthritis has no cure and is a progressive disease. All individuals will experience multiple exacerbations, and without treatment tend to have poor outcomes with increased disability and mortality.[51] Early treatment (within six months of symptom onset) has shown improved functional capacity and decreased disease activity as measured by swollen joint count and tender joint count. However, the mortality rate was similar in patients receiving early treatment and late treatment (after six months of symptoms), and both were significantly improved from no treatment.[51] Approximately 40% of patients with RA will have a functional disability affecting their ability to work and complete activities of daily living within ten years of the diagnosis.[52] Patients with RA also develop other chronic medical conditions/complications which drastically affect their outcomes. The most notable of this correlation is the relationship between RA and atherosclerotic cardiovascular disease leading to accelerated coronary artery disease.[53] RA increases the risk of cardiovascular disease, lung diseases, and malignancies, which in turn increases the risk of premature mortality in these patients.[54]

Complications

Complications of RA span multiple organ systems and are known to worsen clinical outcomes in patients with RA. It is imperative to monitor patients for the development of these complications and quickly alter treatment plans if applicable. Frequent recurrent serious opportunistic infections occur in patients with RA, which warrant withholding DMARD therapy until they are treated. The increased frequency of infections in patients with RA is thought to be due to underlying immune dysfunction from the disease itself and the use of DMARD therapy.[55]

Osteopenia and osteoporosis are complications of the disease itself and can also be associated with drug therapies (glucocorticoids). Patients with RA have a 60% to 100% increased risk of fracture compared to the general population.[56] Patient factors that increase the risk of this complication in patients with RA are the same as those of osteoporosis, including postmenopausal state, low body mass index, and advanced age.

Pleuritis, bronchiolitis, and interstitial fibrosis are also associated with RA. Although rare, RA treatment with methotrexate and anti-TNF agents can lead to pulmonary injury as well. There is also an increased risk of pulmonary embolism in RA.

Coronary artery disease has a strong association with RA. RA is an independent risk factor for the development of coronary artery disease (CAD) and accelerates the development of CAD in these patients.[53] Accelerated atherosclerosis is the primary cause of morbidity and mortality in patients with RA leading to CAD and peripheral vascular disease.[57] There is increased insulin resistance and diabetes mellitus associated with RA and is thought to be due to chronic inflammation. When treated with specific DMARDs such as hydroxychloroquine, methotrexate, and TNF antagonists, there was a marked improvement in glucose control in these patients.[58]

Rheumatoid vasculitis is a rare phenomenon but can have severe complications if present. Clinical presentation ranges from focal digital involvement to severe systemic involvement resembling polyarteritis nodosa.[32]

There is an increased risk of venous thromboembolic disease in patients with RA, as stated above, even after adjusting for other risk factors for thromboembolic disease.[59] Multiple studies have reported a higher risk of thromboembolic disease in patients receiving TNF inhibitor therapy and JAK inhibitors.[60][61] however, the consensus regarding this association is not well established. Some studies suggest that higher thromboembolic disease with the use of these agents is secondary to higher disease activity rather than an adverse effect of the agents.[61] 

The secondary form of Sjögren syndrome is associated with RA and can have a prevalence of as high as 10% in patients with RA and pulmonary disease.[33] 

Depression is a significant complication of RA. It is present in patients with long-term active disease and debilitating physical dysfunction. A 2013 meta-analysis reported a 17% to 39% prevalence of depression in patients with RA.[62]

Anemia of chronic disease and Felty syndrome are well-documented complications of seropositive RA.[33] Patients with RA also have a greater risk of developing lymphoma with a higher incidence of non-Hodgkin lymphoma in these patients. The clinical course of RA in these patients is accelerated, and diffuse B-cell lymphoma is often the most common subtype.[63]

Deterrence and Patient Education

RA has a strong genetic component and cannot be entirely avoided; however, modifiable risk factors such as cigarette smoking and consuming a balanced diet should be addressed. Patients at risk for RA should be counseled to eat a well-balanced diet, exercise regularly, and maintain a healthy body weight. 

Enhancing Healthcare Team Outcomes

Rheumatoid arthritis is a chronic disorder that has no cure. It affects many other organs and is best managed with an interprofessional team to provide comprehensive care. The key is patient education by nurses, pharmacists, and primary care providers. The nurse should inform the patient about the signs and symptoms of different organ systems and when to seek medical care. The patient should enroll in an exercise program to recover joint function. An occupational therapy consult can help the patient manage daily living activities. The pharmacist should educate the patient on the types of drugs used to treat rheumatoid arthritis and their potential side effects. At each clinic visit, clinicians and nurses should provide patient education and encourage the individual to stop smoking, maintain a healthy body weight, get the recommended vaccinations and eat a healthy diet. The social worker should be involved in ensuring that the patient's home is liveable and the patient has ample support systems. The patient should be encouraged to join support groups. Due to progressive disability, chronic pain, and poor quality of life, many patients become depressed and need a mental health nurse and counselor to cope with their disease. A comprehensive interprofessional team can provide a multi-faceted approach to the treatment of RA and improve patient outcomes. [Level 5]

RA has frequent relapses and remissions. While some patients do have mild disease, others may have a disease that severely affects the quality of life. Worse outcomes are usually seen in patients with a high titer of autoantibodies, HLA-DRB1 genotypes, age younger than 30 years at onset, multiple joint involvements, female gender, and extra-articular involvement on presentation. In addition, the drugs used to treat rheumatoid arthritis also have potent side effects, which often are not well tolerated. As the disease progresses, many patients will develop adverse cardiac events leading to death. The overall mortality in patients with rheumatoid arthritis is three times higher than in the general population.[64][65] A comprehensive interprofessional approach to treatment and monitoring of patients with RA can help improve clinical outcomes for these patients. [Level 5]

Review Questions

Summary keynotes on Rheumatoid Arthritis

Figure

Summary keynotes on Rheumatoid Arthritis. Contributed by StatPearls

Ultrasound image of the thumb in a patient with a history of Rheumatoid Arthritis shows an abnormal amount of fluid within the flexor pollicus longus tendon sheath, consistent with an inflammatory tenosynovitis

Figure

Ultrasound image of the thumb in a patient with a history of Rheumatoid Arthritis shows an abnormal amount of fluid within the flexor pollicus longus tendon sheath, consistent with an inflammatory tenosynovitis. Contributed by Mike Tall, MD

Granuloma annulare, H/E 20x

Figure

Granuloma annulare, H/E 20x. Palizading histiocytes and lymphocytes surround an area of necrobiotic collagen. Contributed by Fabiola Farci, MD

References

1.
Bullock J, Rizvi SAA, Saleh AM, Ahmed SS, Do DP, Ansari RA, Ahmed J. Rheumatoid Arthritis: A Brief Overview of the Treatment. Med Princ Pract. 2018;27(6):501-507. [PMC free article: PMC6422329] [PubMed: 30173215]
2.
Kłodziński Ł, Wisłowska M. Comorbidities in rheumatic arthritis. Reumatologia. 2018;56(4):228-233. [PMC free article: PMC6142024] [PubMed: 30237627]
3.
Silman AJ, MacGregor AJ, Thomson W, Holligan S, Carthy D, Farhan A, Ollier WE. Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol. 1993 Oct;32(10):903-7. [PubMed: 8402000]
4.
du Teil Espina M, Gabarrini G, Harmsen HJM, Westra J, van Winkelhoff AJ, van Dijl JM. Talk to your gut: the oral-gut microbiome axis and its immunomodulatory role in the etiology of rheumatoid arthritis. FEMS Microbiol Rev. 2019 Jan 01;43(1):1-18. [PubMed: 30219863]
5.
Wu H, Liao W, Li Q, Long H, Yin H, Zhao M, Chan V, Lau CS, Lu Q. Pathogenic role of tissue-resident memory T cells in autoimmune diseases. Autoimmun Rev. 2018 Sep;17(9):906-911. [PubMed: 30005862]
6.
Ciccacci C, Conigliaro P, Perricone C, Rufini S, Triggianese P, Politi C, Novelli G, Perricone R, Borgiani P. Polymorphisms in STAT-4, IL-10, PSORS1C1, PTPN2 and MIR146A genes are associated differently with prognostic factors in Italian patients affected by rheumatoid arthritis. Clin Exp Immunol. 2016 Nov;186(2):157-163. [PMC free article: PMC5054570] [PubMed: 27342690]
7.
Stanford SM, Maestre MF, Campbell AM, Bartok B, Kiosses WB, Boyle DL, Arnett HA, Mustelin T, Firestein GS, Bottini N. Protein tyrosine phosphatase expression profile of rheumatoid arthritis fibroblast-like synoviocytes: a novel role of SH2 domain-containing phosphatase 2 as a modulator of invasion and survival. Arthritis Rheum. 2013 May;65(5):1171-80. [PMC free article: PMC3636201] [PubMed: 23335101]
8.
Derksen VFAM, Huizinga TWJ, van der Woude D. The role of autoantibodies in the pathophysiology of rheumatoid arthritis. Semin Immunopathol. 2017 Jun;39(4):437-446. [PMC free article: PMC5486798] [PubMed: 28451788]
9.
Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B, Gabriel S, Lassere M, Johns N, Buchbinder R, Woolf A, March L. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014 Jul;73(7):1316-22. [PubMed: 24550173]
10.
Myasoedova E, Crowson CS, Kremers HM, Therneau TM, Gabriel SE. Is the incidence of rheumatoid arthritis rising?: results from Olmsted County, Minnesota, 1955-2007. Arthritis Rheum. 2010 Jun;62(6):1576-82. [PMC free article: PMC2929692] [PubMed: 20191579]
11.
Crowson CS, Matteson EL, Myasoedova E, Michet CJ, Ernste FC, Warrington KJ, Davis JM, Hunder GG, Therneau TM, Gabriel SE. The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum. 2011 Mar;63(3):633-9. [PMC free article: PMC3078757] [PubMed: 21360492]
12.
Eriksson JK, Neovius M, Ernestam S, Lindblad S, Simard JF, Askling J. Incidence of rheumatoid arthritis in Sweden: a nationwide population-based assessment of incidence, its determinants, and treatment penetration. Arthritis Care Res (Hoboken). 2013 Jun;65(6):870-8. [PubMed: 23281173]
13.
Frisell T, Holmqvist M, Källberg H, Klareskog L, Alfredsson L, Askling J. Familial risks and heritability of rheumatoid arthritis: role of rheumatoid factor/anti-citrullinated protein antibody status, number and type of affected relatives, sex, and age. Arthritis Rheum. 2013 Nov;65(11):2773-82. [PubMed: 23897126]
14.
Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987 Nov;30(11):1205-13. [PubMed: 2446635]
15.
Sugiyama D, Nishimura K, Tamaki K, Tsuji G, Nakazawa T, Morinobu A, Kumagai S. Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis. 2010 Jan;69(1):70-81. [PubMed: 19174392]
16.
Philippou E, Nikiphorou E. Are we really what we eat? Nutrition and its role in the onset of rheumatoid arthritis. Autoimmun Rev. 2018 Nov;17(11):1074-1077. [PubMed: 30213695]
17.
Qin B, Yang M, Fu H, Ma N, Wei T, Tang Q, Hu Z, Liang Y, Yang Z, Zhong R. Body mass index and the risk of rheumatoid arthritis: a systematic review and dose-response meta-analysis. Arthritis Res Ther. 2015 Mar 29;17:86. [PMC free article: PMC4422605] [PubMed: 25890172]
18.
Li X, Sundquist J, Sundquist K. Socioeconomic and occupational risk factors for rheumatoid arthritis: a nationwide study based on hospitalizations in Sweden. J Rheumatol. 2008 Jun;35(6):986-91. [PubMed: 18464310]
19.
De Roos AJ, Koehoorn M, Tamburic L, Davies HW, Brauer M. Proximity to traffic, ambient air pollution, and community noise in relation to incident rheumatoid arthritis. Environ Health Perspect. 2014 Oct;122(10):1075-80. [PMC free article: PMC4181921] [PubMed: 24905961]
20.
Wegner N, Lundberg K, Kinloch A, Fisher B, Malmström V, Feldmann M, Venables PJ. Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. Immunol Rev. 2010 Jan;233(1):34-54. [PubMed: 20192991]
21.
López-Mejías R, Carmona FD, Genre F, Remuzgo-Martínez S, González-Juanatey C, Corrales A, Vicente EF, Pulito-Cueto V, Miranda-Filloy JA, Ramírez Huaranga MA, Blanco R, Robustillo-Villarino M, Rodríguez-Carrio J, Alperi-López M, Alegre-Sancho JJ, Mijares V, Lera-Gómez L, Pérez-Pampín E, González A, Ortega-Castro R, López-Pedrera C, García Vivar ML, Gómez-Arango C, Raya E, Narvaez J, Balsa A, López-Longo FJ, Carreira P, González-Álvaro I, Rodríguez-Rodríguez L, Fernández-Gutiérrez B, Ferraz-Amaro I, Gualillo O, Castañeda S, Martín J, Llorca J, González-Gay MA. Identification of a 3'-Untranslated Genetic Variant of RARB Associated With Carotid Intima-Media Thickness in Rheumatoid Arthritis: A Genome-Wide Association Study. Arthritis Rheumatol. 2019 Mar;71(3):351-360. [PMC free article: PMC6590191] [PubMed: 30251476]
22.
Makrygiannakis D, Hermansson M, Ulfgren AK, Nicholas AP, Zendman AJ, Eklund A, Grunewald J, Skold CM, Klareskog L, Catrina AI. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann Rheum Dis. 2008 Oct;67(10):1488-92. [PubMed: 18413445]
23.
de Hair MJ, van de Sande MG, Ramwadhdoebe TH, Hansson M, Landewé R, van der Leij C, Maas M, Serre G, van Schaardenburg D, Klareskog L, Gerlag DM, van Baarsen LG, Tak PP. Features of the synovium of individuals at risk of developing rheumatoid arthritis: implications for understanding preclinical rheumatoid arthritis. Arthritis Rheumatol. 2014 Mar;66(3):513-22. [PMC free article: PMC4034588] [PubMed: 24574210]
24.
Lally F, Smith E, Filer A, Stone MA, Shaw JS, Nash GB, Buckley CD, Rainger GE. A novel mechanism of neutrophil recruitment in a coculture model of the rheumatoid synovium. Arthritis Rheum. 2005 Nov;52(11):3460-9. [PMC free article: PMC3119436] [PubMed: 16255036]
25.
Demasi M, Cleland LG, Cook-Johnson RJ, James MJ. Effects of hypoxia on the expression and activity of cyclooxygenase 2 in fibroblast-like synoviocytes: interactions with monocyte-derived soluble mediators. Arthritis Rheum. 2004 Aug;50(8):2441-9. [PubMed: 15334456]
26.
Chua-Aguilera CJ, Möller B, Yawalkar N. Skin Manifestations of Rheumatoid Arthritis, Juvenile Idiopathic Arthritis, and Spondyloarthritides. Clin Rev Allergy Immunol. 2017 Dec;53(3):371-393. [PubMed: 28752373]
27.
Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet. 2001 Sep 15;358(9285):903-11. [PubMed: 11567728]
28.
Koskinen E, Hannonen P, Sokka T. Palindromic rheumatism: longterm outcomes of 60 patients diagnosed in 1967-84. J Rheumatol. 2009 Sep;36(9):1873-5. [PubMed: 19648311]
29.
Gonzalez-Lopez L, Gamez-Nava JI, Jhangri G, Russell AS, Suarez-Almazor ME. Decreased progression to rheumatoid arthritis or other connective tissue diseases in patients with palindromic rheumatism treated with antimalarials. J Rheumatol. 2000 Jan;27(1):41-6. [PubMed: 10648016]
30.
Lehtinen JT, Kaarela K, Belt EA, Kautiainen HJ, Kauppi MJ, Lehto MU. Incidence of acromioclavicular joint involvement in rheumatoid arthritis: a 15 year endpoint study. J Rheumatol. 1999 Jun;26(6):1239-41. [PubMed: 10381036]
31.
Sayah A, English JC. Rheumatoid arthritis: a review of the cutaneous manifestations. J Am Acad Dermatol. 2005 Aug;53(2):191-209; quiz 210-2. [PubMed: 16021111]
32.
Abdulqader Y, Al-Ani M, Parperis K. Rheumatoid vasculitis: early presentation of rheumatoid arthritis. BMJ Case Rep. 2016 Nov 08;2016 [PMC free article: PMC5129099] [PubMed: 27873751]
33.
Conforti A, Di Cola I, Pavlych V, Ruscitti P, Berardicurti O, Ursini F, Giacomelli R, Cipriani P. Beyond the joints, the extra-articular manifestations in rheumatoid arthritis. Autoimmun Rev. 2021 Feb;20(2):102735. [PubMed: 33346115]
34.
Kortekangas P, Aro HT, Tuominen J, Toivanen A. Synovial fluid leukocytosis in bacterial arthritis vs. reactive arthritis and rheumatoid arthritis in the adult knee. Scand J Rheumatol. 1992;21(6):283-8. [PubMed: 1475638]
35.
Fuchs HA, Kaye JJ, Callahan LF, Nance EP, Pincus T. Evidence of significant radiographic damage in rheumatoid arthritis within the first 2 years of disease. J Rheumatol. 1989 May;16(5):585-91. [PubMed: 2754663]
36.
McQueen FM. The use of MRI in early RA. Rheumatology (Oxford). 2008 Nov;47(11):1597-9. [PubMed: 18701537]
37.
McQueen FM, Stewart N, Crabbe J, Robinson E, Yeoman S, Tan PL, McLean L. Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals progression of erosions despite clinical improvement. Ann Rheum Dis. 1999 Mar;58(3):156-63. [PMC free article: PMC1752839] [PubMed: 10364913]
38.
Cornec D, Varache S, Morvan J, Devauchelle-Pensec V, Berthelot JM, Le Henaff-Bourhis C, Hoang S, Martin A, Chalès G, Jousse-Joulin S, Saraux A. Comparison of ACR 1987 and ACR/EULAR 2010 criteria for predicting a 10-year diagnosis of rheumatoid arthritis. Joint Bone Spine. 2012 Dec;79(6):581-5. [PubMed: 22405855]
39.
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovský J, Wolfe F, Hawker G. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010 Sep;62(9):2569-81. [PubMed: 20872595]
40.
Smolen JS, Breedveld FC, Burmester GR, Bykerk V, Dougados M, Emery P, Kvien TK, Navarro-Compán MV, Oliver S, Schoels M, Scholte-Voshaar M, Stamm T, Stoffer M, Takeuchi T, Aletaha D, Andreu JL, Aringer M, Bergman M, Betteridge N, Bijlsma H, Burkhardt H, Cardiel M, Combe B, Durez P, Fonseca JE, Gibofsky A, Gomez-Reino JJ, Graninger W, Hannonen P, Haraoui B, Kouloumas M, Landewe R, Martin-Mola E, Nash P, Ostergaard M, Östör A, Richards P, Sokka-Isler T, Thorne C, Tzioufas AG, van Vollenhoven R, de Wit M, van der Heijde D. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis. 2016 Jan;75(1):3-15. [PMC free article: PMC4717393] [PubMed: 25969430]
41.
England BR, Tiong BK, Bergman MJ, Curtis JR, Kazi S, Mikuls TR, O'Dell JR, Ranganath VK, Limanni A, Suter LG, Michaud K. 2019 Update of the American College of Rheumatology Recommended Rheumatoid Arthritis Disease Activity Measures. Arthritis Care Res (Hoboken). 2019 Dec;71(12):1540-1555. [PMC free article: PMC6884664] [PubMed: 31709779]
42.
Singh JA, Saag KG, Bridges SL, Akl EA, Bannuru RR, Sullivan MC, Vaysbrot E, McNaughton C, Osani M, Shmerling RH, Curtis JR, Furst DE, Parks D, Kavanaugh A, O'Dell J, King C, Leong A, Matteson EL, Schousboe JT, Drevlow B, Ginsberg S, Grober J, St Clair EW, Tindall E, Miller AS, McAlindon T. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2016 Jan;68(1):1-26. [PubMed: 26545940]
43.
Visser K, van der Heijde D. Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature. Ann Rheum Dis. 2009 Jul;68(7):1094-9. [PMC free article: PMC2689521] [PubMed: 19033290]
44.
Karlsson JA, Neovius M, Nilsson JÅ, Petersson IF, Bratt J, van Vollenhoven RF, Ernestam S, Geborek P. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in early rheumatoid arthritis: 2-year quality-of-life results of the randomised, controlled, SWEFOT trial. Ann Rheum Dis. 2013 Dec;72(12):1927-33. [PubMed: 23196701]
45.
Garcês S, Demengeot J, Benito-Garcia E. The immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis. Ann Rheum Dis. 2013 Dec;72(12):1947-55. [PubMed: 23223420]
46.
Porter D, van Melckebeke J, Dale J, Messow CM, McConnachie A, Walker A, Munro R, McLaren J, McRorie E, Packham J, Buckley CD, Harvie J, Taylor P, Choy E, Pitzalis C, McInnes IB. Tumour necrosis factor inhibition versus rituximab for patients with rheumatoid arthritis who require biological treatment (ORBIT): an open-label, randomised controlled, non-inferiority, trial. Lancet. 2016 Jul 16;388(10041):239-47. [PubMed: 27197690]
47.
Genovese MC, Pacheco-Tena C, Covarrubias A, Leon G, Mysler E, Keiserman M, Valente RM, Nash P, Simon-Campos JA, Box J, Legerton CW, Nasonov E, Durez P, Elegbe A, Wong R, Li X, Banerjee S, Alten R. Longterm Safety and Efficacy of Subcutaneous Abatacept in Patients with Rheumatoid Arthritis: 5-year Results from a Phase IIIb Trial. J Rheumatol. 2018 Aug;45(8):1085-1092. [PubMed: 29657147]
48.
Smolen JS, Schoels MM, Nishimoto N, Breedveld FC, Burmester GR, Dougados M, Emery P, Ferraccioli G, Gabay C, Gibofsky A, Gomez-Reino JJ, Jones G, Kvien TK, Murakami M, Betteridge N, Bingham CO, Bykerk V, Choy EH, Combe B, Cutolo M, Graninger W, Lanas A, Martin-Mola E, Montecucco C, Ostergaard M, Pavelka K, Rubbert-Roth A, Sattar N, Scholte-Voshaar M, Tanaka Y, Trauner M, Valentini G, Winthrop KL, de Wit M, van der Heijde D. Consensus statement on blocking the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions. Ann Rheum Dis. 2013 Apr;72(4):482-92. [PMC free article: PMC3595138] [PubMed: 23172750]
49.
Fleischmann R, van Adelsberg J, Lin Y, Castelar-Pinheiro GD, Brzezicki J, Hrycaj P, Graham NM, van Hoogstraten H, Bauer D, Burmester GR. Sarilumab and Nonbiologic Disease-Modifying Antirheumatic Drugs in Patients With Active Rheumatoid Arthritis and Inadequate Response or Intolerance to Tumor Necrosis Factor Inhibitors. Arthritis Rheumatol. 2017 Feb;69(2):277-290. [PMC free article: PMC6207906] [PubMed: 27860410]
50.
Wallenstein GV, Kanik KS, Wilkinson B, Cohen S, Cutolo M, Fleischmann RM, Genovese MC, Gomez Reino J, Gruben D, Kremer J, Krishnaswami S, Lee EB, Pascual-Ramos V, Strand V, Zwillich SH. Effects of the oral Janus kinase inhibitor tofacitinib on patient-reported outcomes in patients with active rheumatoid arthritis: results of two Phase 2 randomised controlled trials. Clin Exp Rheumatol. 2016 May-Jun;34(3):430-42. [PubMed: 27156561]
51.
Gwinnutt JM, Symmons DPM, MacGregor AJ, Chipping JR, Marshall T, Lunt M, Verstappen SMM. Twenty-Year Outcome and Association Between Early Treatment and Mortality and Disability in an Inception Cohort of Patients With Rheumatoid Arthritis: Results From the Norfolk Arthritis Register. Arthritis Rheumatol. 2017 Aug;69(8):1566-1575. [PMC free article: PMC5600136] [PubMed: 28425173]
52.
Paul BJ, Kandy HI, Krishnan V. Pre-rheumatoid arthritis and its prevention. Eur J Rheumatol. 2017 Jun;4(2):161-165. [PMC free article: PMC5473457] [PubMed: 28638695]
53.
Holmqvist M, Mantel Ä, Wållberg-Jonsson S, James S, Jernberg T, Askling J. Findings on Coronary Angiographies in Patients With Rheumatoid Arthritis and Ischemic Heart Disease: Are They Different From Patients Without Rheumatoid Arthritis? Arthritis Care Res (Hoboken). 2021 May;73(5):658-665. [PubMed: 33285616]
54.
Martin-Trujillo A, van Rietschoten JG, Timmer TC, Rodríguez FM, Huizinga TW, Tak PP, Marsal S, Ibrahim SM, Dijkmans BA, van der Pouw Kraan TC, Verweij CL. Loss of imprinting of IGF2 characterises high IGF2 mRNA-expressing type of fibroblast-like synoviocytes in rheumatoid arthritis. Ann Rheum Dis. 2010 Jun;69(6):1239-42. [PubMed: 19556211]
55.
Atzeni F, Masala IF, di Franco M, Sarzi-Puttini P. Infections in rheumatoid arthritis. Curr Opin Rheumatol. 2017 Jul;29(4):323-330. [PubMed: 28422773]
56.
Jin S, Hsieh E, Peng L, Yu C, Wang Y, Wu C, Wang Q, Li M, Zeng X. Incidence of fractures among patients with rheumatoid arthritis: a systematic review and meta-analysis. Osteoporos Int. 2018 Jun;29(6):1263-1275. [PubMed: 29546507]
57.
Carbone F, Bonaventura A, Liberale L, Paolino S, Torre F, Dallegri F, Montecucco F, Cutolo M. Atherosclerosis in Rheumatoid Arthritis: Promoters and Opponents. Clin Rev Allergy Immunol. 2020 Feb;58(1):1-14. [PubMed: 30259381]
58.
Nicolau J, Lequerré T, Bacquet H, Vittecoq O. Rheumatoid arthritis, insulin resistance, and diabetes. Joint Bone Spine. 2017 Jul;84(4):411-416. [PubMed: 27777170]
59.
Kim SC, Schneeweiss S, Liu J, Solomon DH. Risk of venous thromboembolism in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2013 Oct;65(10):1600-7. [PMC free article: PMC4090802] [PubMed: 23666917]
60.
Bacani AK, Gabriel SE, Crowson CS, Heit JA, Matteson EL. Noncardiac vascular disease in rheumatoid arthritis: increase in venous thromboembolic events? Arthritis Rheum. 2012 Jan;64(1):53-61. [PMC free article: PMC3474372] [PubMed: 21905005]
61.
Liang H, Danwada R, Guo D, Curtis JR, Kilpatrick RD, Hendrickson B, Islam SS. Incidence of inpatient venous thromboembolism in treated patients with rheumatoid arthritis and the association with switching biologic or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) in the real-world setting. RMD Open. 2019;5(2):e001013. [PMC free article: PMC6803007] [PubMed: 31673413]
62.
Matcham F, Rayner L, Steer S, Hotopf M. The prevalence of depression in rheumatoid arthritis: a systematic review and meta-analysis. Rheumatology (Oxford). 2013 Dec;52(12):2136-48. [PMC free article: PMC3828510] [PubMed: 24003249]
63.
Klein A, Polliack A, Gafter-Gvili A. Rheumatoid arthritis and lymphoma: Incidence, pathogenesis, biology, and outcome. Hematol Oncol. 2018 Dec;36(5):733-739. [PubMed: 29862535]
64.
Muñoz-Fernández S, Otón-Sánchez T, Carmona L, Calvo-Alén J, Escudero A, Narváez J, Rodríguez Heredia JM, Romero Yuste S, Vela P, Luján Valdés S, Royo García A, Baquero JL. Use of prognostic factors of rheumatoid arthritis in clinical practice and perception of their predictive capacity before and after exposure to evidence. Rheumatol Int. 2018 Dec;38(12):2289-2296. [PubMed: 30251128]
65.
Solomon DH, Yu Z, Katz JN, Bitton A, Corrigan C, Fraenkel L, Harrold LR, Smolen JS, Losina E, Lu B. Adverse Events and Resource Use Before and After Treat-to-Target in Rheumatoid Arthritis: A Post Hoc Analysis of a Randomized Controlled Trial. Arthritis Care Res (Hoboken). 2019 Sep;71(9):1243-1248. [PMC free article: PMC6421109] [PubMed: 30221841]
Copyright © 2022, StatPearls Publishing LLC.

This book is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, a link is provided to the Creative Commons license, and any changes made are indicated.

Bookshelf ID: NBK441999PMID: 28723028

Views

  • PubReader
  • Print View
  • Cite this Page

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...