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Basic Information ⬇

AUTHORS: Kenny Chang, BS and Manuel F. DaSilva, MD

Definition

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammatory polyarthritis that affects peripheral joints, especially the small joints of the hands and feet.1 It is a chronic, progressive disease in which untreated inflammation may lead to cartilage and bone erosions and joint destruction resulting in functional impairment.1

Synonym

RA

ICD-10CM CODES
M06.9Rheumatoid arthritis, unspecified
M05.10Rheumatoid lung disease with rheumatoid arthritis of unspecified site
M05.20Rheumatoid vasculitis with rheumatoid arthritis of unspecified site
M05.39Rheumatoid heart disease with rheumatoid arthritis of multiple sites
M05.49Rheumatoid myopathy with rheumatoid arthritis of multiple sites
M05.59Rheumatoid polyneuropathy with rheumatoid arthritis of multiple sites
M05.69Rheumatoid arthritis of multiple sites with involvement of other organs and systems
M05.79Rheumatoid arthritis with rheumatoid factor of multiple sites without organ or systems involvement
M05.80Other rheumatoid arthritis with rheumatoid factor of unspecified site
Epidemiology & Demographics
Incidence

Annual incidence of 12 to 1200 per 100,0002

Prevalence

0.5% to 1.0% of the worldwide population, with different rates in different ethnic groups2

Predominant Sex

Females are at higher risk of developing RA than males (2 to 3:1)3

Risk Factors

Female gender, age, tobacco use, silica exposure, and obesity, family history. Smoking has an additive detrimental effect in RA patients (twofold excess mortality risk).2

Typical Age at Diagnosis

Usually between age 30 and 50.4 Steadily increases with age until the mid-70s

Physical Findings & Clinical Presentation

Initial presentation:

  • Pain, swelling, warmth in one or more peripheral joints, frequently with symmetric small joint involvement, often associated with >1 hour of morning stiffness and constitutional symptoms such as fatigue, malaise, low-grade fevers, and weight loss occurring over a period of weeks to months.4 A subset of patients can also present with acute-onset polyarthritis instead of insidious symptoms.2
  • Most common joints involved include metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints (Fig. E1), and metatarsophalangeal (MTP) joints (Fig. E2), as well as wrists.4
  • Other affected joints involved include elbows, shoulders, hips, knees, and ankles.4
  • Distal interphalangeal (DIP) joints are spared.1
  • Sacroiliac and vertebral joints are spared, except for the C1 and C2 articulations.4

Chronic longstanding disease:

  • “Swan-neck” (DIP flexion and PIP hyperextension) (Fig. E3), “boutonniere” (DIP hyperextension and PIP flexion), and “Z-thumb” (MCP flexion and IP hyperextension) deformities (Fig. 4), ulnar deviation, and subluxation of the MCP joints as well as radial deviation of the wrists.
  • C1-C2 (atlantoaxial) inflammation can lead to odontoid erosion and transverse ligament laxity/rupture, resulting in atlantoaxial subluxation (Fig. E5) and cord compression.5
  • Joint damage of wrists, elbows, shoulders, hips, and knees can lead to severe secondary osteoarthritis, necessitating joint surgery and/or replacement.4

Figure 4 Characteristic hand deformities in rheumatoid arthritis.

MCP, Metacarpophalanges; PIPJs, proximal interphalangeal joints.

From Ballinger A: Kumar & Clark’s essentials of clinical medicine, ed 6, Edinburgh, 2012, Saunders.

Extraarticular manifestations:

  • Secondary Sjögren syndrome (∼35%): Immune-mediated inflammation of lacrimal and salivary glands, resulting in dry mouth (xerostomia) and eyes (keratoconjunctivitis sicca).6
  • Rheumatoid nodules (25%): Nontender, firm nodules on extensor surfaces and pressure points, usually in rheumatoid factor positive (RF+) disease.6 Histopathology demonstrates palisading histiocytes surrounding a central area of fibrinoid necrosis.7
  • Felty syndrome: RA with splenomegaly and leukopenia.4 Most patients are positive for HLA-DR4 and RF.

Figure E1 Rheumatoid arthritis.

(A) Initial x-ray shows early trabecular loss around the finger proximal interphalangeal joint with joint space preservation. (B) Subsequently there is erosive change with joint space narrowing.

From Sutton D: Textbook of radiology and imaging, ed 7, 1998, Churchill Livingstone. In Grant LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, 2019, Elsevier.

Figure E2 Rheumatoid Arthritis with the Earliest Feature of Erosive Change Seen Along the Radial Border of This Middle Metacarpal Head

There is localized osteopenia with a “dot-dash” pattern of deossification (white arrow). Note also the symmetric soft tissue swelling and frank erosion of the ulna border (black arrow).

From Adam A et al: Grainger and Allison’s diagnostic radiology, ed 6, 2015, Elsevier. In Grant LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, 2019, Elsevier.

Figure E3 Rheumatoid arthritis.

Bilateral symmetric changes with soft tissue swelling (especially over the ulnar styloids). Erosions are seen at the carpus, metacarpophalangeal joints, distal radius, and ulna with joint space narrowing and bone collapse. There is a swan neck deformity of the right 5th distal interphalangeal joint.

From Sutton D: Textbook of radiology and imaging, ed 7, 1998, Churchill Livingstone. In Grant LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, 2019, Elsevier.

Figure E5 Cervical Spine in Rheumatoid Arthritis (RA) (Radiography)

(A and B) Anterior Atlantoaxial Subluxation in RA. (A) Lateral Radiography in Flexion Shows Severe Anterior Atlantoaxial Subluxation with a Wide Anterior Atlantodental Interval (Asterisks) and a Decreased Posterior Atlantodental Interval (Arrow). (B) Almost Complete Reduction of Subluxation is Noted on the Lateral View in Extension. There Also is Subaxial Subluxation at the Level of C4-C5 (Arrowhead) with Erosive Changes in Various Facet Joints. O, Odontoid. (C) T2-Weighted Sagittal Magnetic Resonance (MR) Image in RA Shows Low Signal Periodontoid Pannus (P). The Odontoid Process Appears Irregular Secondary to Erosions (Arrow). The Atlantodental Distance Shows Mild Widening (Solid Line). There Also is Vertical Subluxation Without Signs of Cord Compression. The Anterior Subarachnoid Space is Compromised by Disk Protrusions at Multiple Levels. Small Erosions (Arrowheads) are Seen at the Vertebral End Plates at the C6-C7 Level.

From Firestein GS et al: Firestein & Kelley’s textbook of rheumatology, ed 11, Philadelphia 2021, Elsevier.

Pulmonary disease:

  • Pleural disease (exudative effusions, pleuritis)4
  • Interstitial lung disease (up to 10% clinically significant)4
  • Bronchiolitis obliterans4
  • Cryptogenic organizing pneumonia4
  • Pulmonary nodules: A combination of RA and pneumoconiosis is called Caplan syndrome4

Neuromuscular:

  • Entrapment neuropathy (carpal tunnel, tarsal tunnel, and cubital tunnel are most commonly involved)4,8,9
  • Mononeuritis multiplex4
  • Peripheral neuropathy9
  • Cervical myelopathy and cord compression secondary to atlantoaxial subluxation4
  • Pachymeningitis (rare)10
  • Vasculitis4

Cardiac disease:

  • Pericarditis (most common)4
  • Myocarditis11
  • Valvular nodules11
  • There is an increased risk of cardiovascular disease compared to the general population, thought to be secondary to accelerated atherosclerosis from systemic inflammation11

Ocular disease:

  • Keratoconjunctivitis sicca (dry eye, without dry mouth) (10%)4
  • Episcleritis, scleritis, scleral thinning, scleromalacia perforans, ulcerative keratitis4

Amyloidosis: Occurs in longstanding, poorly controlled RA. Usually presents as nephrotic syndrome. Organs affected include the heart, kidney, liver, spleen, intestines, and skin4

Osteoporosis12

Etiology

The exact cause of RA remains unknown despite extensive research. It is likely that a combination of genetic, hormonal, and environmental factors leads to aberrant immune activation and inflammatory response in the joint. A common genetic background plays a role in susceptibility to disease, as twins and first-degree relatives of RA patients are at an increased risk of developing the disease compared to the general population.13 Patients with HLA-DR4, DR1, and DR14 alleles have increased susceptibility to RA; in particular, one amino acid sequence in the DR β chain, known as the shared epitope, is overrepresented in these patients.13 Other identified genetic associations include polymorphisms in PTPN22, PADI4, CTLA4, TRAF1-C5, STAT4, TNFAIP3.13 Epigenetic factors are also likely to be involved.13 Multiple environmental factors have also been implicated as possible etiologic factors, including cigarette smoking, silica exposure, and low socioeconomic class.13 Infectious agents such as P. gingivalis, Epstein-Barr virus, and parvovirus B19 have also been reported as possible triggers.13

Stages of disease development presumably include:

  • Initiation of the innate immune response through toll-like receptor (TLR) activation by a stimulating signal.13 The preclinical stages of seropositive rheumatoid arthritis are characterized by disordered immunity, often associated with mucosal surfaces, including the oral cavity, lungs, and gastrointestinal tract, and by local and systemic generation of anti-citrullinated protein antibodies (ACPAs). These autoantibodies can be detected in the blood a median of 4.5 yr before the onset of arthritis.13a
  • Perpetuation of inflammatory response through activation of the adaptive immune system. There is migration of inflammatory cells (autoreactive B and T cells, monocytes) into the joint space, activation of macrophage-like and fibroblast-like synoviocytes, and development of a “synovial pannus,” a thickened synovial membrane.14
  • The pannus releases proinflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin [IL]-1, IL-6, IL-15, IL-17, IL-18) as well as proteases, which erode cartilage and bone.14 Bone erosions are caused mainly by osteoclasts, which express the receptor activator of NF-κB (RANK).13 TNF-α, IL-1, IL-6, and IL-17 promote the expression of RANK ligand (RANKL) on T cells and fibroblast-like synoviocytes, thus creating a positive feedback loop.13 IL-6 and TNF-α act synergistically to increase vascular endothelial growth factor levels, which in turn stimulate angiogenesis, thereby maintaining pannus formation. B-cell differentiation is also promoted by IL-6, leading to the production of autoantibodies.13
  • Many of the new “biologic” disease-modifying antirheumatic drugs (DMARDs) are engineered to target these cytokines (see “Treatment” section).15

Diagnosis ⬆ ⬇

The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) developed new classification criteria for RA in 2010 (Table 1). These are based on a point system where patients with score ≥6/10 are considered to have “definite RA.” Four variables constitute the new criteria:

TABLE 1 The 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritisa

CriteriaScore
Joint involvement
2-10 large joints1
1-3 small joints (with or without involvement of large joints)2
4-10 small joints (with or without involvement of large joints)3
>10 joints (with at least one small joint)5
Serology (at least one test result is needed for classification)
Negative RF and negative ACPA0
Low-positive RF or low-positive ACPA2
High-positive RF or high-positive ACPA3
Acute-phase reactants
Normal CRP and normal ESR0
Abnormal CRP or abnormal ESR1
Duration of symptoms
<6 wk0
≥6 wk1

A score of 6 or greater is needed for classification of a patient as having definite rheumatoid arthritis.

If incontrovertible radiographic evidence of rheumatoid arthritis exists, the diagnosis can be made even if the criteria provided are not fulfilled.

If a patient has previously fulfilled the criteria for rheumatoid arthritis, the diagnosis is maintained even if the criteria are not fulfilled on current reexamination.

ACPA, Anticitrullinated protein antibodies; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; RF, rheumatoid factor.

a Target population (patients who can be evaluated using these criteria): Those who have at least one joint with definite clinical synovitis (swelling), with the synovitis not better explained by another disease.

From Firestein GS et al: Firestein & Kelley’s textbook of rheumatology, ed 11, Philadelphia, 2021, Elsevier.

Differential Diagnosis

  • Infectious causes: Parvovirus B19, hepatitis B, hepatitis C, poststreptococcal reactive arthritis, acute rheumatic fever4
  • Connective tissue diseases: Systemic lupus erythematosus, scleroderma, mixed connective tissue disease, Sjögren syndrome4
  • Seronegative spondyloarthropathies4
  • Calcium pyrophosphate deposition (CPPD or “pseudo-RA”)4
  • Polyarticular gout4
  • Polymyalgia rheumatica4
  • Remitting seronegative symmetric synovitis with pitting edema (RS3PE) can resemble seronegative RA in elderly patients16
  • Hemochromatosis17
  • Paraneoplastic syndromes
  • Osteoarthritis, a degenerative arthritis that lacks prolonged morning stiffness and that usually lacks synovitis, should not be confused with RA (see Table 2)

TABLE 2 Factors Useful for Differentiating Early Rheumatoid Arthritis From Osteoarthritis

Rheumatoid ArthritisOsteoarthritis
Age at onsetAcross age spectrum, peak incidence in 50sIncreases with age
Predisposing factorsSusceptibility epitopes (HLA-DRB1∗01, HLA-DRB1∗04)Trauma, overuse
PTPN22, PADI4 polymorphisms; RF and ACPA positivityCongenital abnormalities (e.g., shallow acetabulum)
Smoking
Early symptomsMorning stiffness and gelling phenomenon, pain improves with activityPain increases through the day and with use
Joints involvedProximal interphalangeal joints, metacarpophalangeal joints, wrists most often; distal interphalangeal joints almost neverDistal interphalangeal joints (Heberden’s nodes), proximal interphalangeal joints (Bouchard’s nodes), knees, lumbar spine
Physical findingsSoft tissue swelling, warmthBony osteophytes, minimal soft tissue swelling early
Radiographic findingsPeriarticular osteopenia, marginal erosions, symmetric joint space narrowing in large jointsSubchondral sclerosis, osteophytes, asymmetric joint space loss in large joints
Laboratory findingsIncreased C-reactive protein, positive RF, positive ACPA, anemia, thrombocytosisNormal

ACPA, Anticitrullinated protein antibody; HLA, human leukocyte antigen; RF, rheumatoid factor.

From Firestein GS et al: Firestein & Kelley’s textbook of rheumatology, ed 11, Philadelphia, 2021, Elsevier.

Laboratory Tests

  • RF (sensitivity ∼60%; specificity ∼80%). False positives are seen with hepatitis C, subacute bacterial endocarditis, primary biliary cirrhosis, sarcoidosis, malignancy, Sjögren syndrome, systemic lupus erythematosus (SLE), and increasing age.4
  • Anti-CCP antibodies. Sensitivity is similar to RF, but it is more specific for RA than RF (up to 95% to 98%).18
  • The presence of either RF or anti-CCP (“seropositive RA”) is associated with more severe disease, more extraarticular manifestations, and worse prognosis.18
  • Elevated ESR and/or CRP. These markers decline with treatment; thus they can be used to monitor disease activity along with physical examination and clinical presentation.18
  • CBC with differential. RA may lead to anemia of chronic disease (through upregulation of the iron-regulating hormone, hepcidin) and thrombocytosis.18
  • Hypoalbuminemia and hypergammaglobulin-emia.
  • Antinuclear antibody (ANA) is present in 20% to 30% of patients. However, complement will usually be normal or increased, in contrast to patients with systemic lupus erythematosus. Many patients will have secondary Sjögren syndrome (positive ANA with negative SSA and SSB).18
  • Inflammatory synovial fluid with >2000 polymorphonuclear neutrophils (PMNs). Of note, patients with RA have an increased risk of developing septic arthritis.19 Hence, synovial fluid with white blood cells >50,000 cells/mm3 is concerning for an infectious process and must always be ruled out.19
Imaging Studies

Recommendations for the use of imaging in the clinical management of rheumatoid arthritis are summarized in Table 3.

TABLE 3 EULAR Recommendations for the Use of Imaging in the Clinical Management of Rheumatoid Arthritisa

When there is diagnostic doubt, conventional radiography, ultrasonography, or MRI can be used to improve the certainty of a diagnosis of RA in addition to clinical criteria alone.b
The presence of inflammation seen with ultrasonography or MRI can be used to predict the progression to clinical RA from undifferentiated inflammatory arthritis.
Ultrasonography and MRI are superior to clinical examination in the detection of joint inflammation; these techniques should be considered for more accurate assessment of inflammation. Conventional radiography of the hands and feet should be used as the initial imaging technique to detect damage. However, ultrasonography and/or MRI should be considered if conventional radiographs do not show damage and may be used to detect damage at an earlier time point (especially in early-stage RA).
MRI bone edema is a strong independent predictor of subsequent radiographic progression in early RA, and should be considered as a prognostic indicator. Joint inflammation (synovitis) detected by MRI or ultrasonography as well as joint damage detected by conventional radiographs, MRI, or ultrasonography can also be considered for the prediction of further joint damage.
Inflammation seen on imaging may be more predictive of a therapeutic response than clinical features of disease activity; imaging may be used to predict response to treatment.
Given the superior detection of inflammation by MRI and ultrasonography versus clinical examination, they may be useful in monitoring disease activity.
The periodic evaluation of joint damage, usually by radiographs of the hands and feet, should be considered. MRI (and possibly ultrasonography) is more responsive to change in joint damage and can be used to monitor disease progression.
Monitoring of functional instability of the cervical spine by lateral radiography obtained in flexion and neutral positions should be performed in patients with clinical suspicion of cervical involvement. When radiography is positive or specific neurologic symptoms and signs are present, MRI should be performed.
MRI and ultrasonography can detect inflammation that predicts subsequent joint damage, even when clinical remission is present and can be used to assess persistent inflammation.

EULAR, European League Against Rheumatism; MRI, magnetic resonance imaging; RA, rheumatoid arthritis.

a Recommendations are based on data from imaging studies that have mainly focused on the hands (particularly wrists, metacarpophalangeal, and proximal interphalangeal joints). There are few data with specific guidance on which joints to image.8

b In patients with at least one joint with definite clinical synovitis, which is not better explained by another disease.

From Firestein GS et al: Firestein & Kelley’s textbook of rheumatology, ed 11, Philadelphia, 2021, Elsevier.

Plain radiography (Table E4):

  • Early changes include soft tissue swelling, symmetric joint space narrowing, and periarticular osteopenia.
  • Later changes include periarticular erosions and deformities. This reflects cartilage and bone destruction secondary to pannus formation (Fig. E6).
  • Radiographs of hands and feet should be obtained at disease onset and repeated to monitor disease progression and to ensure that adequate treatment is achieved.

MRI and musculoskeletal US:

  • More sensitive for detecting erosive disease and joint effusions/synovitis.

Figure E6 Diagram showing the typical radiographic changes in rheumatoid arthritis.

From Grant LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, 2019, Elsevier.

TABLE E4 Plain Radiographic Findings in Rheumatoid Arthritis and Corresponding Pathophysiological Causes

Radiologic FindingsPathologic Cause
Periarticular osteoporosisThis reflects localized hyperemia and is most pronounced during the acute stages of the disease.
Soft tissue swellingThis represents synovial hypertrophy, joint effusion, and periarticular soft tissue edema; typically symmetric.
ErosionsThese are marginal in location caused by the inflammatory and erosive effect of the inflamed synovium on the “bare area” of the joint (the portion of the joint not covered by cartilage, adjacent to the synovium).
Joint space narrowingThis results from cartilage loss. Early uniform cartilage loss results from interruption of the flow of synovial fluid nutrients by the pannus. Later the hypertrophied synovium causes direct destruction with undermining of the cartilage and destruction of the subchondral bone. There may be joint widening in the early stages or ankylosis in the end stages of the disease.
Subchondral cystsThese result from destruction of the subchondral plate by pannus, allowing joint fluid to be forced into the subchondral bone under intraarticular pressure.
Joint subluxation and dislocationThese are due to damage or destruction to tendons and ligaments as a result of the inflammatory pannus. In the early stages the deformity may be reversible and therefore underestimated on plain films.
Generalized regional osteoporosisThis results from pain-induced disuse and may be exacerbated by the effects of therapy (e.g., steroids).

From Adam A et al: Grainger & Allison’s diagnostic radiology, ed 5, 2007, Churchill Livingstone. In Grant LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, 2019, Elsevier.

Treatment ⬆ ⬇

TABLE 5 Instruments Used to Measure Rheumatoid Arthritis Disease Activity

Thresholds of Disease Activity
InstrumentScore RangeRemissionLowModerateHigh
Disease Activity Score in 28 joints (DAS28)0-9.4≤2.6≤3.2>3.2 and ≤5.1>5.1
Simplified Disease Activity Index (SDAI)0.1-86.0≤3.3≤11>11 and ≤26>26
Clinical Disease Activity Index (CDAI)0-76.0≤2.8≤10>10 and ≤22>22
Rheumatoid Arthritis Disease Activity Index (RADAI)0-10≤1.4<2.22.2 and ≤4.9>4.9
Patient Activity Scale (PAS or PASII)0-10≤1.25<1.9≥1.9 and ≤5.3>5.3
Routine Assessment Patient Index Data (RAPID)0-30≤1<6≥6 and ≤12>12

From Firestein GS et al: Firestein & Kelley’s textbook of rheumatology, ed 11, Philadelphia, 2021, Elsevier.

Acute General Rx

  • NSAIDs: Can be used initially to relieve pain and mild inflammation or used later in the disease course for additional control of mild pain.4 NSAIDs are not disease modifying.
  • Corticosteroids: Oral or intraarticular, frequently used initially to reduce inflammation rapidly until oral DMARD treatments take effect.4 They may also be used during acute flares or in low doses for additional control of inflammation.4 The use of corticosteroids at the lowest dose possible and shortest duration is recommended.4 Corticosteroids have many side effects, including but not limited to weight gain, increased risk of diabetes, osteoporosis, cataract formation, peptic ulcer disease (especially when used in combination with NSAIDs), and avascular necrosis.
Chronic Rx

  • DMARDs: Can be classified into “nonbiologic” and “biologic” treatments (Table 6).
    1. Nonbiologic DMARDs: Most commonly used agents are methotrexate (MTX), hydroxychloroquine (HCQ), sulfasalazine (SSZ), and leflunomide (LEF).4 Most of these are associated with potential toxicity and require close monitoring. They are also slow-acting drugs that generally require >8 wk to start taking effect.
    2. MTX is the most commonly used DMARD worldwide for the treatment of RA.4 It is effective as monotherapy in about 30% of patients with RA.
    3. 3. “Triple therapy”-MTX, HCQ, and SSZ-has been shown to be superior to MTX alone.20
  • Biologic DMARDs: Newer biologically engineered therapies, which target cytokines and cells involved in the RA inflammatory response.4 Major side effects include an increased risk of infections, with potential reactivation of tuberculosis.4 A negative purified protein derivative (PPD) or interferon γ-release assay is a prerequisite to initiate therapy.4 Biologic DMARDs are most effective when used in combination with a nonbiologic DMARD, usually MTX.4
  • The five approved tumor necrosis factor α inhibitors (TNFI) include infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab.4
  • Abatacept (CTLA-4Ig) is a recombinant protein that prevents costimulatory binding of antigen presenting cell to T cell, preventing T-cell activation.4
  • Tocilizumab (anti-IL-6) is a monoclonal antibody against the IL-6 receptor.4
  • Sarilumab is another IL-6 inhibitor monoclonal antibody, approved by the FDA in 2017 for treatment of RA, and can be used as monotherapy or in combination with MTX or other conventional DMARDs.22
  • Tofacitinib (JAK1/2/3 inhibitor) inhibits the JAK-STAT intracellular signaling pathway, thus preventing the production of inflammatory mediators.13 The first oral biologic DMARD, it can be used as monotherapy or in combination with MTX. Baricitinib, an oral, once-daily Janus kinase (JAK1 and JAK2) inhibitor, was approved by the FDA in May 2018 for treatment of moderate to severe RA in patients who did not respond adequately to one or more TNFIs.23 A dose of 2 mg was approved, with concerns that higher doses had increased adverse events. Upadacitinib (JAK1 >JAK2/3 inhibitor) was approved in 2019 at 15 mg once daily for moderate to severely active RA resistant or intolerant to MTX, or in combination with MTX with other nonbiologic DMARDs.23
  • Rituximab (anti-CD20) is a monoclonal antibody against the CD20 antigen on B lymphocytes.4
  • Biosimilars are beginning to be available.24 These molecules are highly similar, but not identical, to the original drugs. Legal disputes have delayed the widespread adoption of these drugs in the U.S., but they are likely to be of increasing prevalence in the future.
  • Treatment recommendations in RA patient with high-risk comorbidities:
    1. TNFI should be avoided in patients with congestive heart failure, as it can worsen the condition.25
    2. In patients with hepatitis B, immunosuppressive therapy can be safely prescribed along with concomitant antiviral therapy.4
    3. Treatment of hepatitis C patients with RA should be done following standard guidelines in collaboration with gastroenterology/hepatology.4 Immunosuppressive therapy can be used safely in conjunction with antiviral therapy; avoidance of DMARDs such as MTX and LEF should be taken into consideration.15
    4. In patients with a history of skin cancer, DMARDs are recommended over the use of biologics.26 For patients with previously treated lymphoproliferative disorders, use of rituximab should be considered first, as well as combination DMARDs and non-TNF biologics.27 One should avoid TNFI, as there is an increased risk of lymphoma with these agents. Recommendations for treatment of patients with previously treated solid organ malignancy are the same as for patients without the condition.

TABLE 6 Disease-Modifying Drugs and Biologics for Rheumatoid Arthritis

DrugsUsual DoseSide Effects and Cautions
DMARDs
Methotrexate7.5-25 mg/wk in a single dose orally or SQ. Start low and increase by 5 mg every 1-2 mo until desired effects are achievedMyelosuppression, hepatotoxicity, hepatic fibrosis, cirrhosis, pulmonary infiltrates or fibrosis, mouth sores (daily folic acid can prevent this), nausea, hair loss
Sulfasalazine (Azulfidine, Azulfidine EC)500-3000 mg/day in 2-4 divided doses orallyMyelosuppression, hepatotoxicity, nausea
Hydroxychloroquine sulfate (Plaquenil)200-400 mg per day in 2 divided doses orally
Not to exceed 6.5 mg/kg of actual body weight		Retinal toxicity, rash
Leflunomide (Arava)10-20 mg per day in a single dose orallyMyelosuppression, hepatotoxicity, cirrhosis, diarrhea, hair loss
Azathioprine (Imuran)50-150 mg per day in 1-3 divided doses orallyMyelosuppression, hepatotoxicity, lymphoproliferative disorders, nausea, hair loss; check TPMT before initiation
BIOLOGICSMust check T-SPOT and hepatitis B and C serology before starting all biologics; discuss updating vaccinations before initiation
TNF blockers:
Adalimumab (Humira)
Etanercept (Enbrel)
Infliximab (Remicade)
Golimumab (Simponi)
Certolizumab (Cimzia)		40 mg SQ once a wk or every 2 wk
25 mg SQ twice a wk, or 50 mg SQ once a wk
3-10 mg/kg IV. Given at 0, 2, 6 wk then every 8 wk (usually taken with methotrexate)
50 mg SQ once a mo
400 mg SQ loading at 0, 2, 4 then 200 mg every 2 wk vs. 400 mg q 4 wk		Increased risk of infections, tuberculosis, histoplasmosis, or others
Injection site or infusion reaction
Congestive heart failure
T-cell costimulation blocker:
Abatacept (Orencia)		500-1000 mg IV 0, 2, 4 wk then every 4 wk or 500-1000 mg IV one time, then 125 mg SQ weeklyIncreased risk of infections; injection site or infusion reaction; COPD exacerbation
IL-6 blocker:
Tocilizumab (Actemra)		4-8 mg/kg IV every 4 wk; 162 mg SQ once every other wk or every wkIncreased risk of infections; myelosuppression; hepatotoxicity; hyperlipidemia
B-cell depletion:
Rituximab		1000 mg IV 0, 2 wk and again when arthritis becomes active; on average every 6 moIncreased risk of infection; progressive multifocal leukoencephalopathy (PML); tumor lysis syndrome
IL-1 blocker:
Anakinra		100 mg SQ daily, 100 mg SQ every other day in severe kidney diseaseIncreased risk of infections; injection site reaction

COPD, Chronic obstructive pulmonary disease; DMARDs, disease-modifying antirheumatic drugs; IL, interleukin; SQ, subcutaneously; TNF, tumor necrosis factor; TPMT, thiopurine S-methyltransferase.

From Warshaw G et al: Ham’s primary care geriatrics, ed 7, Philadelphia, 2022, Elsevier.

Rx in pregnancy:28

  • Patients with active rheumatoid arthritis should be tested for anti-Ro/SSA and anti-La/SSB antibodies once before or early in pregnancy, due to their associated increased in risk for neonatal lupus and congenital heart block.29
  • Fluorinated glucocorticoids (e.g., betamethasone and dexamethasone) cross the placenta at higher concentrations without significant metabolism and can hasten lung maturity. These should not be used routinely for the management of active RA during pregnancy.30 Glucocorticoids (e.g., prednisone, prednisolone, and methylprednisolone) should be maintained at the lowest dose possible.31
  • Hydroxychloroquine (HCQ) has been shown to cross the placenta. However, most studies have not described fetal toxicity with HCQ doses used for the treatment of rheumatic diseases.32
  • Methotrexate (MTX) should be stopped 1 to 3 mo before conception because of its teratogenic risks. If conception occurs while a woman is taking MTX, the medication should be stopped immediately and folic acid 5 mg/day taken for the remainder of the pregnancy.33
  • Leflunomide (LEF) should be avoided in pregnancy due to its teratogenic effects. Conception should be delayed until LEF is undetectable in the serum (<0.02 mg/L), typically 2 yr after discontinuation. An enhanced drug elimination procedure using cholestyramine can be used for faster results.32
  • TNF-α inhibitors, DMARDs, and other biologics can be continued throughout pregnancy. Most professional societies recommend discontinuing these medications in the third trimester. Noteworthy exception is certolizumab. It is pegylated and does not cross the placenta in significant amounts and can be continued throughout the pregnancy.34

Immunization, cardiovascular disease prevention (smoking cessation, blood pressure control, cholesterol control), and osteoporosis prevention (with calcium and vitamin D supplementation and bisphosphonate therapy) should be addressed in all RA patients.

Disposition

  • Remissions and exacerbations are common, but condition is chronically progressive in the majority of cases.
  • Joint degeneration and deformity often lead to disability. Joint replacement is indicated for patients with severe joint damage whose symptoms are poorly controlled by medical management. The ACR published guidelines in 2017 concerning the perioperative management of antirheumatic medications in patients undergoing elective total hip or total knee arthroplasty.35
  • Early and aggressive diagnosis and treatment are crucial in preventing or slowing joint destruction.
  • Factors associated with poorer prognosis in rheumatoid arthritis are summarized in Table 7.

TABLE 7 Factors Associated With Poorer Prognosis in Rheumatoid Arthritis

Presence of rheumatoid factor and titer
Presence of antibodies to CCP and titer
Presence of shared epitope and number of alleles
Presence of erosive disease at presentation
Disease activity at presentation
Magnitude of ESR or CRP elevations
Presence of nodules or extraarticular features
Female sex
Smoking currently and in the past
Obesity

CCP, Cyclic citrullinated peptide; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.

From Firestein GS et al: Firestein & Kelley’s textbook of rheumatology, ed 11, Philadelphia, 2021, Elsevier.

Referral

  • Early referral to rheumatologist
  • Orthopedic consultation for corrective surgery

Pearls & Considerations ⬆ ⬇

RA sometimes develops acutely in the postpartum patient; conversely, as high as 75% of pregnant RA patients will experience remission during pregnancy.

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Rheumatoid Arthritis (Patient Information)

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