Definition

N Engl J Med 2011;365:2205-19

  • Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammatory polyarthritis caused by chronic inflammation of the synovium (the membrane present in synovial joints that lines the joint capsules and produces synovial fluid).
  • Features include synovial inflammation and hyperplasia (which cause joint swelling), autoantibody production, cartilage and bone destruction (which cause deformity), and systemic features, including cardiovascular, pulmonary, and skeletal complications.

Criteria For Diagnosis

Arth Rheum 2010:62;2569–2581

Table 1: 2010 ACR/EULAR Criteria for RA

A. Joint involvement1 large joint

2-10 large joints

1_3 small joints (with or without involvement of large joints)#

4_10 small joints (with or without involvement of large joints)

>10 joints (at least 1 small joint)**

B. Serology

Negative RF and negative ACPA

Low-positive RF or low-positive ACPA

High-positive RF or high-positive ACPA

C. Acute-phase reactants

Normal CRP and normal ESR         0

Abnormal CRP or abnormal ESR    1

D. Duration of symptoms

<6 weeks

>/= 6 weeks

 0

1

2

3

5

 

0

2

3

 

0

1

 

0

1

Total   a score of 6/10 or greater is needed for a diagnosis of definite RA  

 “Large joints” refers to shoulders, elbows, hips, knees, and ankles.

“Small joints” refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists.

RF: rheumatoid factor

ACPA: anti-citrullinated peptide antibody

CRP: C-reactive protein

ESR: Erythrocyte sedimentation rate

  • There are no validated or accepted uniform criteria to classify individuals with early disease. This is an ongoing challenge in management of patients presenting with undifferentiated inflammatory arthritis.

Epidemiology

Hochberg: Rheumatoid Arthritis 1e, Ch 2

Am J Manag Care 2012;18(13 Suppl):s295-302.

  • RA affects approximately 1% of the world population.
  • The incidence varies by population. France has a low incidence rate o 8.8/100,000); rates in Scandinavian countries are higher at 24 to 36 per 100,000. The highest incidence rates (42–45/100,000) have been observed in the United States, but may be declining.
  • In most populations, the incidence of RA increases with age until the eighth decade, and then declines. RA is more common in women and is uncommon in young men (<35 years). The difference between genders is not consistent and changes with increasing age.

Etiology

Hochberg Rheumatology, 5e, Ch 81

N Engl J Med 2011;365:2205-19

Clinic Rev Allerg Immunol 2013: DOI 10.1007/s12016-012-8346-7

Kelley’s Textbook of Rheumatology, 9e, Ch 21

Ann Rheum Dis 2012;71:1984-1990

  • RA is considered to be an autoimmune disease. That is, the immunologic disturbance is found primarily in the adaptive immune system (see JIA chapter for more detail), and thus involves antibodies against self-antigens (“auto-antigens”). A degree of innate immune system dysfunction is also contributory.
    • Autoantibodies, such as rheumatoid factor (RF) and anti–citrullinated protein antibody (ACPA; tested as anti–cyclic citrullinated peptide [anti-CCP]) can precede the clinical manifestation of RA by many years. These are produced by B cells of the adaptive immune system.
  • RA arises from a complex interplay of genotype, environmental triggers, and chance.

Genetics

  • Twin studies have shown concordance rates of 15 to 30% among monozygotic twins and 5% among dizygotic twins. Siblings of individuals affected with RA have a two- to fourfold risk of developing RA. This increased risk could be genetic and/or related to factors in a shared family environment.
    • Large genome-wide association studies have identified over 30 loci involved in RA pathogenesis, involving both HLA and non-HLA genes (i.e. in the major histocompatibility complex [MHC]). Much of the risk is derived from 8 alleles that reside within the MHC region, with up to 5% of risk explained by 15 alleles outside the MHC.
  • The heritability of both ACPA positive and negative RA has been estimated to be about 60%.

 

Human Leukocyte Antigen

HLA is a cell-surface molecule that mediates the cell’s interaction with immune cells. It does this by presenting proteins from either inside or outside the cell (called epitopes) to T cells. It is coded by the Major Histocompatibility Complex, a large gene locus involving over 4 million base pairs on the short arm of chromosome 6.

MHC Class I includes HLA classes A, B, and C and is found on all cells. It functions to present peptides that have been degraded inside the cell to T cells. If cytotoxic (CD8+) T cells recognize the epitope as a foreign protein (whether truly foreign, as in an antigen from a bacterium, or interpreted as foreign, as in an self-protein), they will destroy the cell.

MHC Class II includes HLA classes DP, DM, DOA, DOB, DQ, and DR, and is present on antigen-presenting cells (e.g. dendritic cells). It presents peptides from outside the cell to T cells. If T-helper cells recognize the peptide to be an antigen, they will multiply and stimulate B-cells to produce antibodies to that specific antigen.

Immune activity against self-antigens is normally suppressed by suppressor T-cells.

The allelic variations among different HLA molecules significantly account for differences in the types of antigenic peptides an individual’s T cells will respond to, as well as the types of T cells called upon in an immune response. Certain mutations in HLA are implicated in autoimmune disease.

 

HLA genes

  • RA can be classified as ACPA-positive or ACPA-negative; this has implications for prognosis, as ACPAs have been shown to be strong predictors of more severe disease.
  • ACPA-positive RA: A number alleles of the HLA-DRB1 locus cause a predisposition to ACPA-positive RA. These alleles encode one of the several 5 amino acid sequences that are grouped under the term “shared epitope” (SE). As part of the HLA molecule, the SE produces particularly susceptibility to RA through an unknown mechanism. Examples of hypotheses include a role for the SE in T-cell repertoire selection or antigen presentation; molecular mimicry of the SE by microbial proteins; and a potential proinflammatory signaling function that is unrelated to the role of the SE in antigen recognition.
  • HLA-DRB1 SE alleles are quite common in the general population. In individuals of European ancestry, the collective allele frequency is ∼40%. The common HLA-DRB1 alleles are different in European and Asian populations.
  • The presence of a SE confers risk for more severe, destructive RA (e.g. development of bone erosion) as well as for the development of extraarticular manifestations. It may have an indirect bearing on outcome via ACPA production
  • ACPA-negative RA: Genetic risk factors for ACPA-negative disease are less well established, but seem to be different from ACPA-positive RA. HLA association with HLA-DR3 has been implicated, as have different immune-mediating proteins (e.g. interferon regulatory factors; lectin-binding proteins).
  • It has been thought that HLA-DRB1 SE alleles only influence the development of ACPA-positive RA, but recent studies have demonstrated an association with anti-CCP negative RA, at least in European Caucasians.
  • The contribution of HLA alleles to the genetic variance of ACPA-negative RA is much lower than for ACPA-positive disease (2% vs. 40%), even though they both have ~60% heritability.
  • It is currently a matter of debate as to whether ACPA-positive and ACPA-negative RA are two distinct entities or represent different subsets of the same disease.

Non-HLA genes

  • In the past few years, a number of non-HLA risk alleles have been identified for RA (at writing, 31 confirmed gene loci). The two most strongly associated genes will be presented here which confer risk regardless of serological status; the many others confer variable risk in different populations and range in the proteins affected, including receptors, ligands, and cytokines.
    • The gene PTPN22gene, which encodes the intracellular phosphatase protein tyrosine phosphatase non-receptor type 22, has the second strongest association with RA after HLA-DRB1. It has also been linked to other autoimmune diseases such as type I diabetes, Graves’ disease, myasthenia gravis, systemic sclerosis, lupus and Addison’s disease.
    • The gene TRAF1 (TNF receptor associated factor 1) may be the third most strongly RA- associated locus, associated primarily with ACPA positive RA. The protein coded by TRAF1 is an adaptor protein that links TNF family members, such as TNF-α, to downstream signaling networks. It has been implicated in cell growth, proliferation, apoptosis, bone turnover, and cytokine activation.
  • Apart from susceptibility to RA, some genes may have bearing on overall disease outcome and prognosis. Certain gene profiles have also been associated with response or nonresponse to therapy.

Epigenetics

J Autoimmun 2013 Jan 31.doi: 10.1016/j.jaut.2013.01.010.

  • The role of epigenetics in the mechanisms of autoimmunity pathogenesis have been of recent interest.
  • Epigenetics is defined as stable and heritable patterns of gene expression that do not involve alterations to the original DNA sequence. Epigenetic mechanisms primarily consist of DNA methylation, histone modifications and small non-coding RNA transcripts.
  • Epigenetic changes can be influenced by age and environmental triggers.
  • A number of complex epigenetic modifications have been linked to RA. One example is hypermethylation of the promoter region coding a death receptor on synoviocytes which leads to decreased apoptosis.

 Environment

  • Cigarette smoking: The strongest known environmental risk factor for RA, and most strongly associated with ACPA-positive and RF-positive RA. Risk increases with amount and duration of cigarette use, and can remain elevated for up to 20 years after cessation. Smoking and possibly other environmental and lifestyle-related factors may trigger ACPA production (smoking and HLA-DRB1 alleles synergistically increase risk of ACPA positivity). In addition to smoking, other forms of bronchial stress (e.g. exposure to silica) increase RA risk among individuals with susceptible HLA– DR4 alleles. Environmental stressors of barrier tissues (e.g. pulmonary epithelium) may promote posttranslational modifications that result in changes mucosal protein citrullination (see “Antibodies” section, below).
  • Infectious Agents: Epstein–Barr virus, cytomegalovirus, proteus species, and Escherichia coli and their products (e.g. heat-shock proteins) have been associated with RA, but a unifying mechanism is unknown. Molecular mimicry is suspected, supported by the existence of homology between the antigenic components of infectious organisms, synovium, and cartilage. The formation of immune complexes during infection may trigger the induction of RF. RA is also associated with periodontal disease with Porphyromonas gingivalis, a gram-negative anaerobe that is capable of promoting citrullination of proteins.The gastrointestinal microbiome is also recognized to influence the development of autoimmunity; specific bacterial signatures that are associated with autoantibody- positive RA are of emerging research interest. Interestingly, epidemiologic evidence has not strongly suggested an infectious etiology: incident cases of RA do not cluster in space or time, and patients with new-onset RA do not report an increased number of infections prior to onset.

Host Factors

  • Hormonal: RA has a greater incidence among pre-menopausal females. Pregnancy may influence the timing of disease onset. One study showed that the risk of new-onset RA is reduced during pregnancy but is increased in the 12 months after delivery (most apparent after the first pregnancy). Breastfeeding may also play a role in some women: studies have observed that more than 12 months of breastfeeding was associated with decreased risk, proportional to breastfeeding duration. Interestingly, among women who report a postpartum onset of RA, breastfeeding, especially after the first pregnancy, seems to actually increase the risk of RA fivefold. Further support for the contribution of hormonal factors to RA onset and severity is that women with RA have been found to have a relative androgen deficiency, with lower concentrations of testosterone and dehydroepiandrosterone. Males with RA have also been found to have low testosterone concentrations. The causal link between relative hypoandrogenism has yet to be confirmed in a larger study.
  • Stress: Adverse life events have been linked to the development of RA. Animal models of inflammation have demonstrated association between the hypothalamic–pituitary–adrenal axis and cytokine production. “Neuroimmunologic interactions” are of interest, and represent a role for central nervous system regulation of disease.

Antibodies                                                                       

Ann Rheum Dis. 2012 doi:10.1136/annrheumdis-2012-202349

Ann Rheum Dis2011;70:i55-i58

N Engl J Med 2011;365:2205-19

Rheumatol Int 2013: doi:10.1007/s00296-012-2635-6

  • Rheumatoid Factor (RF): Refers to a family of antibodies directed against the Fc portion of IgG (the Fc molecule is essential for complement fixation and interaction with the Fc receptor, and thus for uptake of immune complexes).
    • RF is present in 50% with early RA, and in 80% with established disease
    • It is not specific to RA: a transient increase of IgM-RF is part of the normal immunoregulatory process during a bacterial or viral infection, and therefore low-titer IgM-RF can be found in 10-15% of healthy individuals. Chronic persistence of high-titer and high-affinity IgM-RF as well as the presence of IgG and IgA subtypes is a characteristic feature of RA.
    • IgM-RF is also present in high titer in most patients with primary Sjögren’s syndrome or mixed cryoglobulinemia and can be found in lower titers in all other rheumatic autoimmune diseases.
    • High-titer IgM- and IgA-RF have prognostic value: they are associated with increased bone erosion, more rapid disease progression, worse outcome, and extra-articular manifestations

Table 2

  Sensitivity Specificity
Low titer (>20 U/mL) High titer (>50 U/mL) Low titer (>20 U/mL) High titer (>50 U/mL)
Early RA 56% 46% 89% 96%
Established RA 66% 46% 78% 88%

 

  • Anti-Citrullinated Protein Antibodies (ACPAs): (tested as anti–cyclic citrullinated peptide [anti- CCP]; a number of citrullinated self-proteins are recognized in anti-CCP assays).
    • Highly specific for RA – the newest anti-CCP assay yields a specificity of 98%, sensitivity of 80%.
    • Present in 70% of patients with established RA
    • Antibodies directed against post-translationally modified (i.e. chemically or enzymatically altered) proteins, especially proteins that have been “citrullinated” – modified to contain the amino acid citrulline, which was not encoded in the original protein. Citrulline is made by the conversion of the amino acid arginine by peptidyl arginine deiminase enyzmes. ACPAs are antibodies against such proteins.
    • ACPAs have been used as diagnostic markers of RA, but likely also have a functional role in pathogenesis. These antibodies can be seen years prior to RA onset and rarely develop after onset, suggesting that they are not just a consequence of inflammation
    • ACPA-positive RA is characterised by a more severe disease course, and carries a lower chance of drug-free remission.

Clinical features

Hochberg Rheumatology, 5e, Ch 82

Nat Rev Rheumatol. 2012 8(11):656-64.

Table 3

Feature Pathophysiology
Joint swelling and pain
  • Most cases of RA display a typical symmetrical pattern of joint involvement: the proximal interphalangeal joints (PIPs) and metacarpophalangeal joints (MCPs) are often the first to be affected, then wrists, elbows, shoulders, hips, knees, ankles, and metatarsophalangeal (MTP) joints. The axial skeleton is largely spared, except for the cervical spine in some cases.
  • Characteristic early finding: inability to “wring out a washcloth” or produce a strong grip
  • Caused by synovial inflammation, pannus, and effusion
Morning stiffness
  • Must last for at least one hour to be characterized as stiffness due to inflammatory arthritis
  • Stiffness after rest is often called “gelling”
Constitutional Symptoms
  • Fatigue
  • Anorexia
  • Mild weight loss
Deformity Signs of late disease with irreversible damage in the hands and wrist:

  • “swan-neck”: Hyperextension of the PIP and flexion of the DIP. The lateral bands of the central extensor tendon, which is damaged by tenosynovitis, sublux dorsally as the PIP herniates in a volar direction. Progressive shortening of the tendon maintains DIP flexion and PIP extension.
  • “boutonnière”: The opposite of swan-neck (flexion of the PIP and extension of the DIP), caused by rupture of the central extensor tendon at a different location. The lateral bands of the central extensor tendons displace to the volar aspect of the joint and begin to function as flexors of the PIP joint. With tendon shortening, hyperextension of the DIP develops.
  • Subluxation at the MCPswith ulnar deviation
  • Radial deviation of the wrist
Rheumatoid nodules
  • Occur in 20%; generally those with more severe disease and high-titer RF.
  • Uncommon for nodules to be present within the first year.
  • A rheumatoid nodule is a mass of inflammatory tissue with a central focus of necrosis, presumably the consequence of vascular inflammation, surrounded by chronic inflammatory cells.
  • Occur over extensor surfaces and joints, at sites of chronic mechanical irritation (elbow, toe, and heel), and in the subcutaneous tissues of the fingers.
Radiogaphic Findings
  • Soft-tissue swelling
  • Joint space narrowing from cartilage destruction
  • Erosion of periarticular cortical bone may occur early in the disease and results from excessive local bone resorption and inadequate bone formation
  • Subluxation

 

Pathophysiology

N Engl J Med 2011;365:2205-19

Nat Rev Rheumatol. 2012 8(11):656-64

Synovial inflammation and proliferation

  • The hallmark of RA is symmetric synovial proliferation and inflammation
  • The relationship between loss of self tolerance and synovial involvement is unclear
  • The normal synovial lining is only 1-2 cell layers thick. In RA, the synovium proliferates in an uncontrolled fashion.
  • The molecular mechanisms that sustain synovial hyperplasia are incompletely understood. One possible explanation is altered resistance to apoptosis of the synoviocytes.
  • Through migration rather than local proliferation, leukocytes infiltrate the synovial compartment and their activity results in synovitis. Their migration is enabled by endothelial activation in synovial microvessels, which increases the expression of adhesion molecules and chemokines.
  • Angioneogenesis takes place, induced by local hypoxic conditions and cytokines, and insufficient lymphangiogenesis limits cellular egress, further maintaining a hypercellular environment.
  • This process gives rise to profound synovial architectural reorganization and local fibroblast activation, contributing to the buildup of synovial inflammatory tissue.

Cartilage Damage

  • Damage to joint cartilage is primarily caused by the hyperplastic synovium.
  • Some of the normally protective properties of synovium are reduced (e.g. expression of lubricin), which alter the protein-bindingcharacteristics of the cartilage surface, promoting the adhesion and invasion of fibroblast-like synoviocytes (FLSs). FLSs are normally resident in the synovium, but those in RA are observed to have deranged function, and express high levels of disease-relevant cytokines and chemokines, adhesion molecules, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs). MMPs cause degradation of the type II collagen network, alter glycosaminoglycan content and lead directly to biomechanical dysfunction. FLSs participate in creating and maintaining a permissive environment for T-cell and B-cell survival.
  • Articular cartilage has limited regenerative potential; damage is therefore largely irreversible.

Bone Erosion

  • Periarticular bone erosion occurs rapidly, affecting 80% of patients within 1 year after diagnosis. It is a consequence of prolonged and increased inflammation.
  • Synovial cytokines (e.g. macrophage colony-stimulating factor, receptor activator of NF-κB ligand [RANKL], IL-6 and TNF-α) as well as ACPAs promote osteoclast differentiation, activation and invasion of the periosteal surface adjacent to articular cartilage. Osteoclasts are capable of destroying mineralized tissues, including mineralized cartilage and subchondral bone. Osteoclast destruction is not counterbalanced by bone formation.
  • Mechanical factors predispose particular sites to erosion, such as the second and third metacarpals.
  • Eroded periarticular bone shows little evidence of repair in RA, a contrast from what is observed in other inflammatory arthropathies. Bone formation is actively suppressed by proinflammatory cytokines. Cytokine- induced mediators potently inhibit the differentiation of mesenchymal precursors into chondroblasts and osteoblasts. Overall, however, the biologic characteristics of these synovial mesenchymal stem cells and the effect of local inflammation remain unknown.
  • Osteitis:Breach of cortical bone may allow synovial access to the bone marrow, leading to bone marrow inflammation, called osteitis. This can be seen with magnetic resonance imaging. Over time, T-cell and B-cell aggregates replace marrow fat.It is unclear whether osteitis occurs together with bone erosions or whether it necessarily or independently precedes erosion; RA may, possibly, start in the bone marrow and subsequently progress to the synovial membrane.

Table 4: Adaptive and innate mechanisms in the joint

Adaptive Innate
  • Genetics + autoantibodies clearly indicate that adaptive immunity is central to pathogenesis.

 

T Cells

  • Functional role of T cells, which are abundant in synovial inflammation, remains incompletely understood.

o   Autoreactive T cells against citrullinated self-proteins have been identified.

o   T-cell clones, and B-cell characteristics in the synovial environment suggest ongoing local, antigen-specific T-cell stimulation of B-cells.

  • RA is conventionally considered to be mediated by type 1 helper T cells (Th1), but recent study has focused on the role of type 17 helper T cells (Th17), a subset that produces interleukin-17A, 17F, 21, and 22 and TNF-α.
  • Regulatory T cells appear to have limited functional capability in RA, suggesting an imbalance between Th17 and regulatory T cells. TNF-α blocks the activity of regulatory T cells.

 

B Cells

  • Humoral adaptive immunity is integral to RA. Plasmablasts and plasma cells can be found in the synovium and in juxta-articular bone marrow.
  • There is evidence for a role of B cells beyond autoantibody production through rituximab, a monoclonal antibody against CD20 protein, which is effective against RA. Plasma cells are not targeted by rituximab and autoantibody levels are variably altered after treatment, therefore CD20+ B Cell are implicated in pathogenesis through other mechanisms, such as autoantigen presentation and cytokine production (IL-6, TNF-α, lymphotoxin-β).
  • Activation of the innate immune pathway is instrumental in perpetuating synovitis
  • A variety of innate effector cells, including macrophages, mast cells, and natural killer cells, are found in the synovial membrane. Neutrophils are found mainly in synovial fluid.
  • Macrophages are principal effectors of synovitis, evidenced by the effectiveness of biologic agents at reducing macrophage infiltration in the synovium.Macrophages, once activated, have several functions: phagocytosis; antigen presentation, and release of cytokines (e.g., TNF-α and interleukin-1, 6, 12, 15, 18, and 23), reactive oxygen intermediates, nitrogen intermediates; and production of prostanoids and matrix-degrading enzymes.
  • A number of pathways are involved in macrophage activation (e.g. toll-like receptors, cytokine, T-cell interaction, and immune complexes).
  • Neutrophils synthesize prostaglandins, proteases, and reactive oxygen intermediates
  • Mast cells produce high levels of vasoactive amines, cytokines, chemokines, and proteases

 

Joint-specific complications

  • A number of joint-specific complications can result from the arthritic process that destroys the joint and compromises surrounding architecture. The list below is certainly not exhaustive.
  • Spinal Complications:
    • RA involvement of the axial skeleton is mostly limited to the cervical spine, usually the upper portion. The most critical involvement occurs at the atlantoaxial joint, where the ring of C1 pivots on the odontoid process of C2:
      • Tenosynovitis can decrease the space available for the upper cervical cord, as it passes posterior to the odontoid in the spinal canal.
      • Inflammation can also cause laxity of the transverse ligament or erosion of the odontoid process, in which case atlantoaxial subluxation can result (i.e. the ring of C1 can move forward on neck flexion), which reduces the diameter of the spinal canal and compress the spinal cord.
      • Cranial settling refers to the caudal migration of the cranium on the spinal column. The odontoid, protruding into the foramen magnum, can compress vital structures.
    • Subaxial subluxation describes instability of a vertebral body on another below C1-C2. The vertebral arteries (segment II of which run within the transverse foramina of C5/C6 to C2) may be compromised by the structural changes occurring as a result of RA, increasing the risk of posterior circulation stroke.
  • Hip complications: The hip is frequently affected in RA, and many patients with progressive disease require total joint replacement, particularly as a consequence of secondary osteoarthritis or fracture. Avascular necrosis may occur in patients with a long history of steroid use, and is characterized by sudden hip pain that may radiate to the knee.
  • Knee complications: The posterior compartment of the knee capsule may distend produce outpouchings of synovium in the popliteal region, known as Baker’s cysts. Synovitis may eventually progress to secondary osteoarthritis, and total joint replacement may be required to maintain function.
  • Forefoot complications: As disease progresses, the metatarsals sublux on the plantar aspect of the proximal phalanges, displacing the soft tissue fat pads that normally underlie the metatarsal heads, eventually causing the patient’s metatarsal heads to directly bear the weight of the patient’s body. This causes calluses to develop and, in advanced cases, ulcerations may occur.
  • Peripheral nerve compression: Carpal tunnel syndrome commonly develops in patients with wrist involvement. At the ankle, the posterior tibial nerve can be compressed in the tarsal tunnel, producing paresthesias on the sole of the foot.

Long term consequences

  • The mortality rate is higher among patients with RA than among healthy persons, and systemic complications remain a major challenge:
  • Cardiovascular illness:
    • Myocardial infarction, cerebrovascular events, and heart failure
    • Increased rates are not explained by traditional risk factors, use of glucocorticoids, nonsteroidal antiinflammatory drugs, or shared genetic features.
    • Circulating components of the immune reaction have been implicated: cytokines (IL-6 and TNF-α), acute-phase reactants, immune complexes, and altered lipid particles that increase endothelial activation and potentially render atheromatous plaques unstable. Some cytokines alsocause insulin-resistance, resulting in an “inflammatory metabolic” syndrome. Changes to lipid biochemical features are produced by the body during inflammation to ensure metabolically efficient host defense, but participate in cardiovascular pathology. Active RA is paradoxically associated with reduced serum levels of total, HDL, and LDL cholesterol, which may rise with effective treatment.
  • CNS: fatigue and reduced cognitive function
  • Lungs: inflammatory and fibrotic disease
  • Exocrine glands: secondary Sjögren’s syndrome
  • Muscles: sarcopenia
  • Bones: osteoporosis
  • Cancer risk:
    • Lymphoma: risk is increased and strongly associated with disease activity; sustained inflammation confers the highest risk. Possible explanations includeclonal selection of B cells, disturbed immune surveillance due to impaired activity of regulatory T cells, and impaired function of natural killer cells.
    • Lung cancer: The association between smoking and RA may partly explain the increased risk of lung cancer among RA patients, but inflammation is known to increase lung cancer risk independently of smoking. This may be due to the effects of RA on lung parenchyma, namely fibrotic remodeling of interstitial lung tissue.

Treatment

N Engl J Med 2011;365:2205-19

Am J Manag Care. 2012 Nov;18(13 Suppl():s303-14.

Ann Rheum Dis. 2012 Jun;71(6):851-6.

  • In the past, treatment goals focused on reducing pain and joint symptoms with analgesics and NSAIDs; control of inflammation was a secondary goal. The current treatment strategy is to initiate aggressive therapy soon after diagnosis and to escalate it based on assessment of disease activity, with a view to clinical remission. Evidence has shown such early aggressive treatment can halt or slow progression of synovitis and bone erosions, ultimately decreasing disability and increasing the rate of remission.
  • “Disease modifying anti-rheumatic drugs,” or DMARDs, must be initiated within a few months of disease onset to optimize outcomes. DMARDs target elements of the underlying pathophysiology of RA, including suppression of immune activation, antigen presentation, and pro-inflammatory cytokine production
  • Unfortunately, sustained remission is rarely achieved and RA management requires ongoing pharmacologic therapy.

Table 5: DMARDs

DMARD Mechanism
Non-Biologics  
Cyclosporine T-cell activation inhibitor [IL-2]
Hydroxychloroquine interferes with antigen processing and immune function
Leflunomide Antimetabolite
Methotrexate Antimetabolite
Sulfasalazine Anti-inflammatory and anti-microbial properties
Biologics
Adalimumab TNF inhibitor
Certolizumab pegol TNF inhibitor
Etanercept TNF inhibitor
Golimumab TNF inhibitor
Infliximab TNF inhibitor
Abatercept Blocks T cell costimulation
Anakinra IL-1 receptor antagonist
Rituximab Monoclonal antibody against CD20 (B Cells)
Tocilizumab Monoclonal antibody against IL-6 receptor
Gold salts (Auronofin and Sodium Aurothiomalate), Azathioprine and Cyclosporine are not recommended in the 2012 American College of Rheumatology updated treatment recommendations due to infrequent use and lack of recently published evidence.

 

  • The ACR’s proposed algorithm for the management of early RA suggests (based on disease severity rating):
    • Low or moderate disease activity: non-biologic DMARD monotherapy may be sufficient if there are no features of poor prognosis.
    • Moderate disease activity with feature of poor prognosis: combination DMARD therapy (double or triple agent)
    • High disease activity without features of poor prognosis: DMARD monotherapy or hydroxychloroquine plus methotrexate.
    • Patients with high disease activity and features of poor prognosis: a TNF inhibitor with or without methotrexate, or double or triple non-biologic DMARD therapy.

Corticosteroids

  • Oral: The onset of DMARD effect has a delay of up to 6–8 weeks, therefore oral glucocorticoids may be used as a bridging treatment, as well as a supplement in periods of disease exacerbation. The addition of oral prednisone to any oral non-biologic DMARD has shown to result in less radiographic progression and fewer eroded joints than an oral DMARD alone.
  • While glucocorticoids improve symptoms, they are generally not considered disease-modifying agents when used as monotherapy. An exception lies in early disease management, however, where they may have disease-modifying effects.
  • Intra-articular injections: Locally injected steroids exhibit effective anti-inflammatory action in less than 2 weeks, markedly decrease the amount of corticosteroids required (compared with systemic doses), and can be injected in both large and small joints.

Alternative and complementary therapies

  • Occupational therapy, hydrotherapy, and dynamic exercise may be useful adjuncts to pharmacologic therapy, though overall, the use of alternative and complementary therapies has yielded inconsistent results.

Monitoring treatment outcomes and disease activity

  • Disease activity monitoring instruments
  • Radiographic assessment
  • Adverse effects of drug therapy
  • Quality-of-life tools
  • Assessment of pain, fatigue, and functional ability

Cardiovascular risk

  • Cardiovascular risk adjustment (e.g. to account for lower levels of serum cholesterol, and for ongoing inflammation) is recommended for RA patients, especially as it pertains to statin therapy. Statins decrease cardiovascular risk and favorably modify vascular physiology through reducing inflammatory factors.