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Rheumatoid Arthritis

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Rheumatoid Arthritis

Basics

Description

Annual incidence of 0.2/1,000 males and 0.4/1,000 females and increases with age

RA goes into remission during pregnancy approximately 75% of the time, but about 80% of women experience a flare postpartum.

New American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria recently developed in 2010 based on number of joints involved and laboratory findings (1)[A]

Referral to a rheumatologist is crucial so that proper diagnosis is made, and early DMARD therapy is initiated within 3 months after the onset of symptoms.

There are several surgical procedures for selected patients with severe RA.

1Scott D, Wolfe F, Huizinga T. Rheumatoid arthritis. Lancet. 2010;376:1094 " 1108. [View Abstract]2Rau R. Efficacy of methotrexate in comparison to biologics in rheumatoid arthritis. Clin Exp Rheumatol. 2010;28:S58 " S64. [View Abstract]3Nam JL, Winthrop KL, van Vollenhoven RF. Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: A systematic literature review informing the EULAR recommendations for the management of RA. Ann Rheum Dis. 2010;69:976 " 986. [View Abstract]4Khraishi M. Comparative overview of safety of the biologics in rheumatoid arthritis. J Rheumatol. 2009;36(Suppl 82):25 " 32.

  • Rheumatoid arthritis (RA) is a chronic, multisystem, inflammatory, autoimmune disease.
  • Inflammation of the joints can lead to cartilage destruction and inability to function.

Epidemiology

  • RA is a relatively common autoimmune disease.
  • Females > Males (4:1)Bimodal peak age of onset in women between 31 and 35, then after age 46
  • Bimodal peak age of onset in women between 31 and 35, then after age 46
  • Affects 1% of the US population
  • Worldwide: 0.8% of the adults

Risk Factors

  • The following are associated with a higher incidence of RA, but not necessarily linked to causation.
  • Hormonal influenceNulliparityBreastfeeding
  • Environmental factorsTobacco (main environmental risk)Coffee consumption
  • Nulliparity
  • Breastfeeding
  • Tobacco (main environmental risk)
  • Coffee consumption
  • 50% of the risk factors for RA are attributable to genetic factors and include:
  • HLA-DRB1 allelesTwin studies have heritability of 60%.Siblings have a 2- to 4-fold risk of developing RA.
  • Twin studies have heritability of 60%.
  • Siblings have a 2- to 4-fold risk of developing RA.

Pathophysiology

  • Immune-mediated diseaseCD4+ T cells induce an immune response from unknown endogenous or exogenous antigens.Monocytes, macrophages, and fibroblasts are recruited and produce TNF-alpha and IL-1 within synovium.Matrix metalloproteinases and osteoclasts are then triggered, which results in joint damage.
  • CD4+ T cells induce an immune response from unknown endogenous or exogenous antigens.
  • Monocytes, macrophages, and fibroblasts are recruited and produce TNF-alpha and IL-1 within synovium.
  • Matrix metalloproteinases and osteoclasts are then triggered, which results in joint damage.

Etiology

  • Unknown
  • RA is thought to be multifactorial with genetic and environmental factors playing a role.

Associated Conditions

  • There are multiple coexisting conditions associated with RA that impact prognosis. Some important ones to consider include:Infection: Incidence doubled in RAOsteoporosis: Incidence doubled in RACardiovascular disease: Accounts for most of the mortality in RAMalignancy: Increased 5 " “8 times over the rate of general population
  • Infection: Incidence doubled in RA
  • Osteoporosis: Incidence doubled in RA
  • Cardiovascular disease: Accounts for most of the mortality in RA
  • Malignancy: Increased 5 " “8 times over the rate of general population

Diagnosis

History

  • Gradual onset of joint pain and swellingMorning stiffness >1 hourFatigueInability to perform daily activities
  • Morning stiffness >1 hour
  • Fatigue
  • Inability to perform daily activities

Physical Exam

  • Tenderness, warmth, and swelling of joints
  • Joint effusions
  • Decreased range of motion of affected joints
  • Subcutaneous nodules

Tests

  • Rheumatoid factor (RF)Present in 60 " “85% of cases of RA, but specificity is lowHigh titer does have prognostic role and is associated with more severe diseases such as erosions, subcutaneous nodules, and extra-articular manifestations.
  • Antibodies to cyclic citrullinated antigens (CCP)Highest specificity of any antibody: 95%Sensitivity: 50 " “70%Already present in patients with very early RA and may be associated with more severe disease
  • Can also see anemia of chronic disease, elevated platelet count, ESR, and CRP
  • Present in 60 " “85% of cases of RA, but specificity is low
  • High titer does have prognostic role and is associated with more severe diseases such as erosions, subcutaneous nodules, and extra-articular manifestations.
  • Highest specificity of any antibody: 95%
  • Sensitivity: 50 " “70%
  • Already present in patients with very early RA and may be associated with more severe disease
  • There are some findings on plain x-ray that are suggestive of RA including:Fusiform soft tissue swellingPeriarticular osteoporosisJuxta-articular erosions and cystsLoss of joint space
  • MRI and ultrasound detect erosions, cysts, and effusions that may not be seen on plain x-ray.
  • Fusiform soft tissue swelling
  • Periarticular osteoporosis
  • Juxta-articular erosions and cysts
  • Loss of joint space

Differential Diagnosis

  • Differential diagnosis of a patient with polyarthritis
  • Inflammatory diseasePsoriatic arthritisReactive arthritisSpondyloarthropathyCrystal arthropathySystemic lupus erythematosusPolymyalgia rheumatica
  • Viral infectionParvovirus B19Hepatitis B
  • Psoriatic arthritis
  • Reactive arthritis
  • Spondyloarthropathy
  • Crystal arthropathy
  • Systemic lupus erythematosus
  • Polymyalgia rheumatica
  • Parvovirus B19
  • Hepatitis B

Treatment

  • Joint damage occurs early, and 30% of patients have radiographic evidence of bony erosions at time of diagnosis, so early intervention is key (2)[A].
  • Goals are remission of symptoms with no active joint inflammation and no erosive or functional deterioration.

Medication

  • 3 categories:NSAIDsCorticosteroidsDisease-modifying antirheumatic drugs (DMARDs)
  • NSAIDs
  • Corticosteroids
  • Disease-modifying antirheumatic drugs (DMARDs)
  • DMARDs (2)[A]
  • Reduce joint swelling and pain, decrease acute-phase markers, limit progressive joint damage, and improve function
  • Should be started within 3 months after onset of symptoms
  • Methotrexate (MTX) is considered the first line unless contraindicated (2)[A].Should not be used in patients with underlying liver disease or history of heavy alcohol useConcomitant use of folic acid (1 " “3 mg/day) significantly decreases side effects.Aminotransferase, albumin, and CBC should be monitored every 8 weeks.
  • Leflunomide: Similar to MTX; long half-lifeAdverse effects include myelosuppression and hepatic fibrosis.Should monitor CBC, AST, ALT, albumin every 8 weeks
  • Sulfasalazine: Safe to use in patients with liver diseaseAdverse effects include myelosuppression.CBC monitored every 2 weeks for first 3 months, then every 3 months
  • Hydroxychloroquine: Very well tolerated, effective in mild RA or in combination therapyAdverse effects include macular changes.Therefore, patients should have funduscopic examination every year.
  • Biologic response modifiers are extremely effective medications in inducing clinical and radiographic remission (all are injectable or IV infusions) (3)[A]Tumor necrosis factor (TNF) antagonists (3)[A]Etanercept: Soluble TNF-receptor fusion proteinInfliximab: Chimeric IgG anti-TNF-alpha antibodyAdalimumab: Recombinant human IgG monoclonal antibodyGolimumab: Recombinant human IgG monoclonal antibodyCertolizumab pegol: Pegylated TNF-alpha inhibitorAdverse effects of these drugs include increased rate of infections, reactivation of latent tuberculosis, lupus-like autoimmune disease, multiple sclerosis-like demyelinating disease, and worsening of heart failure.Other biologic response modifiers (4)[A]:Anakinra: IL-1 receptor antagonistTocilizumab: Humanized anti-IL-6 receptor antibodyRituximab: Chimeric monoclonal antibody that binds to CD20 B cellsAbatacept: CTLA4 linked to human IgG to decrease second signal activation of T cells
  • Should not be used in patients with underlying liver disease or history of heavy alcohol use
  • Concomitant use of folic acid (1 " “3 mg/day) significantly decreases side effects.
  • Aminotransferase, albumin, and CBC should be monitored every 8 weeks.
  • Adverse effects include myelosuppression and hepatic fibrosis.
  • Should monitor CBC, AST, ALT, albumin every 8 weeks
  • Adverse effects include myelosuppression.
  • CBC monitored every 2 weeks for first 3 months, then every 3 months
  • Adverse effects include macular changes.
  • Therefore, patients should have funduscopic examination every year.
  • Tumor necrosis factor (TNF) antagonists (3)[A]Etanercept: Soluble TNF-receptor fusion proteinInfliximab: Chimeric IgG anti-TNF-alpha antibodyAdalimumab: Recombinant human IgG monoclonal antibodyGolimumab: Recombinant human IgG monoclonal antibodyCertolizumab pegol: Pegylated TNF-alpha inhibitorAdverse effects of these drugs include increased rate of infections, reactivation of latent tuberculosis, lupus-like autoimmune disease, multiple sclerosis-like demyelinating disease, and worsening of heart failure.
  • Other biologic response modifiers (4)[A]:Anakinra: IL-1 receptor antagonistTocilizumab: Humanized anti-IL-6 receptor antibodyRituximab: Chimeric monoclonal antibody that binds to CD20 B cellsAbatacept: CTLA4 linked to human IgG to decrease second signal activation of T cells
  • Etanercept: Soluble TNF-receptor fusion protein
  • Infliximab: Chimeric IgG anti-TNF-alpha antibody
  • Adalimumab: Recombinant human IgG monoclonal antibody
  • Golimumab: Recombinant human IgG monoclonal antibody
  • Certolizumab pegol: Pegylated TNF-alpha inhibitor
  • Adverse effects of these drugs include increased rate of infections, reactivation of latent tuberculosis, lupus-like autoimmune disease, multiple sclerosis-like demyelinating disease, and worsening of heart failure.
  • Anakinra: IL-1 receptor antagonist
  • Tocilizumab: Humanized anti-IL-6 receptor antibody
  • Rituximab: Chimeric monoclonal antibody that binds to CD20 B cells
  • Abatacept: CTLA4 linked to human IgG to decrease second signal activation of T cells
  • MTX is contraindicated in pregnancy.Recommended to discontinue at least 3 months prior to conception
  • Leflunomide is contraindicated in pregnancy and should be discontinued 2 years prior to conception, because of its long half-life.The mother can undergo treatment with cholestyramine to bind the drug.
  • Biologic response modifiers are being studied in pregnancy and safety is not known.
  • Recommended to discontinue at least 3 months prior to conception
  • The mother can undergo treatment with cholestyramine to bind the drug.
  • NSAIDsUseful in the first few weeks of symptoms for relief of pain and stiffnessDo not slow progression of diseaseShould be used with DMARD in maintenance therapy
  • CorticosteroidsCan be used to bridge the effect of DMARD, but should not be used aloneAll patients should receive supplemental calcium (1 " “1.5 g/day) and vitamin D (800 IU/day) while receiving corticosteroids.
  • Useful in the first few weeks of symptoms for relief of pain and stiffness
  • Do not slow progression of disease
  • Should be used with DMARD in maintenance therapy
  • Can be used to bridge the effect of DMARD, but should not be used alone
  • All patients should receive supplemental calcium (1 " “1.5 g/day) and vitamin D (800 IU/day) while receiving corticosteroids.

Additional Treatment

  • There are several modalities that can provide relief.
  • Flexibility, range of motion, and aerobic exercise are all useful.Joint protection and energy conservationSplinting of hands or wrists or use of lower extremity orthotics can provide temporary pain relief.
  • Joint protection and energy conservation
  • Splinting of hands or wrists or use of lower extremity orthotics can provide temporary pain relief.

Complementary and Alternative Medicine

  • Patient education is a proven effective intervention in RA.
  • Local Arthritis Foundation chapter has information.

Surgery

  • Tenosynovectomy
  • Tendon reconstruction
  • Joint synovectomy
  • Peripheral nerve decompression
  • Joint fusion or replacement

Ongoing Care

Follow-Up Recommendations

  • Most patients with RA can participate in moderate-intensity aerobic exercise.
  • Patients with RA should be followed frequently to monitor toxicities of medical management and disease progression.

Prognosis

  • Prognosis has greatly improved with early therapy with DMARDs and newer biologic agents, but there is still significant morbidity associated with RA. Some poor prognostic indicators include:Early presence of bony erosionsExtra-articular featuresOlder age at onsetPositive RF and anti-CCP antibodiesGenetic factors such as presence of HLA-DR epitopes
  • The long-term prognosis and survival also depends on addressing the coexisting conditions as discussed.
  • Early presence of bony erosions
  • Extra-articular features
  • Older age at onset
  • Positive RF and anti-CCP antibodies
  • Genetic factors such as presence of HLA-DR epitopes

Complications

  • Tendon rupture
  • Synovial rupture of knee
  • Entrapment neuropathies
  • Septic arthritis
  • Instability of cervical spine
  • Osteoporosis

References

Codes

ICD9

ICD10

  • M05.9 Rheumatoid arthritis with rheumatoid factor, unspecified
  • M06.00 Rheumatoid arthritis without rheumatoid factor, unsp site
  • M06.9 Rheumatoid arthritis, unspecified

SNOMED

  • 69896004 rheumatoid arthritis (disorder)
  • 239792003 seronegative rheumatoid arthritis (disorder)
  • 239791005 seropositive rheumatoid arthritis (disorder)

Clinical Pearls

  • Multisystem autoimmune diseaseWomen in 4th and 5th decade
  • Symmetric inflammatory arthritisMorning stiffness >1 hour
  • Early treatment with DMARDs significantly improves quality of life, morbidity, and disease progression.
  • Women in 4th and 5th decade
  • Morning stiffness >1 hour