rheumatoid arthritis (RA)

Introduction

See diagnostic criteria for rheumatoid arthritis (RA), cervical spine involvement in rheumatoid arthritis (RA) & articular deformities of rheumatoid arthritis (RA).

Etiology

unknown
infectious agent suspected
- urogenital infections & gastroenteritis within 2 years may be modestly protective (RR=0.7-0.8)^[65]
- cross-reactivity between RA-relevant autoantigens & intestinal bacteria in the closely related families Lachnospiraceae & Ruminococcaceae
  - bacteria of the genus Subdoligranulum in the family Ruminococcaceae implicated specifically implicated in the pathology of RA^[128]
- Prevotella copri also implicated in the pathology of RA^[128]
paraneoplastic syndrome (common in the elderly)^[7]
smoking is a risk factor for rheumatoid arthritis^[3]
- smoking cessation might blunt risk for developing RA^[119]
occupational exposure may play a role^[104]
- electrical & electronics workers, bricklayers & concrete workers, material handling operators (RR > 2)^[104]
- occupational inhalation of synthetic fiber dust to fungicides, insecticides, asbestos, silica dust (RR > 2)^[130]
- volatile organic chemicals
  - gasoline engine exhaust, welding fumes, organic solvents, carbon monoxide (RR > 1.5)^[130]
  - automobile mechanics
increased risk in first year after 1st pregnancy^[3]

Epidemiology

occurs in 1% of adults
overall, women affected 3 fold more than men
- 6 fold in the 4th decade of life
- female:male ratio declines to 1:1 after 6th decade of life
age of onset peaks in 5th decade for both sexes
pleuro-pulmonary involvement is more common in men
seronegative rheumatoid arthritis more likely in men^[3]
among women with rheumatoid arthritis, 2/3 will improve during pregnancy^[3]

Pathology

(see pathology of rheumatoid arthritis)

Genetics

(60% of risk, see genetics of rheumatoid arthritis)

Clinical manifestations

time course of disease
- onset generally insidious
- course generally progressive, but may be exacerbations & remissions
- patients generally present with pain & swelling in > 3 small joints of the hands &/or feet & morning stiffness^[3]
- symptoms present for > 6 weeks
musculoskeletal manifestations
- symmetric polyarthritis^[3]
  - initially involves small joints of the hands, wrist & feet
    - wrist, MCP joint, PIP joint, MTP joint^[3]
    - DIP joints generally spared^[88]
  - progresses proximally to involve larger joints
  - not all symmetric arthritis is RA
  - involvement of a single joint is unusual for presentation or a flare of RA^[3]
- joint pain & tenderness, local warmth^[3]
- joint swelling: fusiform-shaped swelling of PIP joint
- palpable joint effusion^[3]
- decreased range of motion
  - pain on active & passive range of motion^[3]
- morning stiffness
  - lasts more than 1 hour
  - improves with activity
- manifestations of joint destruction/deformities
- joint contractures
  - ulnar deviation
- joints usually involved in RA
  - proximal interphalangeal (PIP) joint
  - metacarpophalangeal (MCP) joint
  - metatarsophalageal (MTP) joint
  - wrist
- joints commonly involved in RA
  - ankle
  - knee
  - elbow
  - cervical spine (50% of seropositive patients)
    - high posterior neck pain (50%)
      - occipital headaches
      - cervical spine instability^[3]; C1, C2 subluxation
- joints not commonly involved
  - hip
  - shoulder
  - temporomandibular joint (TMJ)
- joints generally not involved
- periarticular manifestations^[3]
  - popliteal (Baker's) cyst, ganglion cyst
  - tenosynovitis, tendonitis & bursitis
    - olecronon bursitis common
    - rotator cuff tendonitis common
    - tenosynovitis may cause trigger finger
  - swan neck deformity, boutonniere deformity
  - flexion contractures
  - periarticular osteopenia
- subcutaneous rheumatoid nodules over bony prominences or extensor surfaces^[80] (images)
- carpal tunnel syndrome may be presenting symptom^[3]^[36]
constitutional symptoms
- malaise
- easy fatigability
- muscle weakness
- anorexia
- weight loss
- low-grade fever
extra-articular manifestations
- pulmonary
  - obstructive airway disease
    - bronchiolitis obliterans (34%)
    - cough, fever, pulmonary infiltrates
  - bronchiectasis 14%^[123]
  - pleural effusion - exudative, pleurisy 10%, rheumatoid pleuritis
    - lymphocytic predominance
    - low pleural fluid glucose
    - spindle-shaped cells (macrophages)
  - pulmonary rheumatoid nodules, pleural based
    - multiple basilar pulmonary nodules (Caplan's syndrome)
    - occur with active disease
    - bronchopleural fistula is a complication
  - interstitial lung disease (especially in smokers) 16%^[126]
    - pulmonary interstitial fibrosis
    - interstitial pneumonia
  - acute lung injury
  - pulmonary hypertension due to pulmonary vasculitis
  - arytenoid arthritis
    - upper airway obstruction (rare)
    - hoarseness from cricoarytenoid joint involvement
  - increased risk for pulmonary infections^[3]
- cardiovascular
  - pericarditis (50% of RA autopsies)
    - generally serous & asymptomatic
    - pericardial effusion (30-40%)
    - recurrent serous pericarditis may evolve into constrictive pericarditis (70% 1 year mortality if untreated)
  - coronary artery disease (independent risk factor)
  - valvular heart disease: leaflet fibrosis (30%)
  - cardiomyopathy, LV diastolic dysfunction (15%)
- vasculitis (mediated by immune complex deposition)^[80]
  - rheumatoid nodules^[80] (images)
  - palpable purpura
  - pyoderma gangrenosum, ulcerations
  - polyarteritis with mononeuritis multiplex
  - nailfold infarcts^[80]
  - systemic vasculitis is rare
- neurological manifestations
  - entrapment neuropathies
    - especially carpal tunnel syndrome
  - mononeuritis multiplex
    - foot drop or wrist drop (vasculitis)
  - myelopathy from cervical vertebral subluxation
    - occipital headache from C1-C2 subluxation
    - arm paresthesia, hyperreflexia
    - increased risk of intubation
- diffuse muscular atrophy
  - drug-induced myopathy: steroid myopathy^[3]
- bone: periarticular osteopenia, osteoporosis, increased risk of fractures
- ocular manifestations:
  - xerophthalmia^[3]
  - scleritis may progress to scleromalacia perforans & blindness
  - episcleritis, keratitis
  - keratoconjunctivitis sicca (Sjogren's syndrome)
- skin:
  - rheumatoid nodules over extensor surfaces & juxta-articular regions, almost exclusively in patients with rheumatoid factor positive RA
    - rheumatoid nodule commonly over olecranon^[3]
  - periungual purpura is a result of nailfold thrombosis
- Felty's syndrome
- xerostomia^[3]
- secondary amyloidosis: cardiac amyloidosis, renal amyloidosis
- anemia of chronic inflammation^[3]
- seronegative RA is not associated with extra-articular manifestations*

* ref^[3] states seronegative RA identical to seropositive RA

Laboratory

serology^[68]
- rheumatoid factor
  - single most useful laboratory test
  - positive in 80% of RA patients, sensitivity 70%, specificity 85%
    - often negative in early phases of disease
    - seronegative RA may convert to seropositive RA^[3]
  - false positives occur
    - other systemic diseases
    - 1% of normal population, especially women
  - not useful for assessing disease activity^[3]
- antinuclear antibodies (ANA)
  - high titers in 30% of RA patients
  - generally diffuse immunofluorescence pattern
- anti-cyclic citrullinated peptide antibody (anti-CCP)*
  - sensitivity 70%, specificity 95%^[3]
- anti keratin antibodies (AKA)
- anti perinuclear factor
- anti RA33
- anti RA-associated nuclear antigen (RANA)
- anti synovial stimulatory protein p205
- anti-GOLGB1
synovial fluid analysis
- WBC 2000-50,000/mm3
- 40-75% neutrophils
pleural fluid analysis (pleural effusion, pleuritis)
- mixed inflammatory cells (exudative)
- low pleural fluid glucose (< 30 mg/dL)
erythrocyte sedimentation rate (ESR) or serum CRP (C-reactive protein in serum)
- non-specific
- generally elevated
- may be helpful in following course of disease
protein electrophoresis
- polyclonal gammopathy
anemia workup
- complete blood count (CBC)
  - normocytic normochromic anemia
  - leukocytosis
  - may be granulocytopenia with Felty's syndrome
  - thrombocytosis
  - pancytopenia may occur with Felty's syndrome
- peripheral smear
  - large granular lymphocyte syndrome (Felty's syndrome)
- iron studies:
  - low serum iron with transferrin saturation (serum iron/TIBC) > 15%, consistent with anemia of chronic disease
liver function tests may be mildly abnormal, especially serum alkaline phosphatase
- may be related to treatment
- may be due to nodular hyperplasia of the liver
serum chemistries recommended for baseline workup^[3]
- serum creatinine
- serum electrolytes
- serum 25-hydroxyvitamin D
  - patients on glucocorticoids
urinalysis recommended for baseline workup^[3]
stool guaiac for occult blood^[3]
genetic testing
- PTPN22 gene mutation
Vectra DA panel 12 different unspecified biomarkers of unknown clinical significance
troponin I in serum predicts excess cardiovascular mortality^[107]
see ARUP consult^[29]

* most specific diagnostic laboratory test

Diagnostic procedures

cardiac stress test if
- epigastric pain &/or LUQ abdominal pain
  - nausea, vomiting, diaphoresis
  - normal abdominal CT
  - long-term glucocorticoids^[133]
- even if
  - normal electrocardiogram
  - 2 sets of cardiac enzyme levels 6 hours apart are normal
upper GI endoscopy unlikely to be helpful if
- normal abdominal examination
- normal abdominal CT^[133]

Radiology

radiographs of joints (hand & wrists &/or feet)*
periarticular soft tissue swelling
juxta-articular osteoporosis (osteopenia)
juxta-articular bony erosions
symmetric narrowing of joint space
subluxations^[3]
ankylosis^[88]
involvement of the metacarpophalangeal joints & proximal interphalageal joints
useful for initial diagnosis & for monitoring disease progression^[3]
- radiographic changes even in the absence of symptoms suggest a need to change treatment^[3]
radiographs of hands may show no deformities or erosions in early RA^[133]
radiograph of cervical spine
- C1,C2 most commonly involved
- erosive disease in 20%
- lateral views in flexion & extension
- preoperative cervical spine films in flexion & extension
- cervical spine vulnerable during endotracheal intubation^[95]
MRI of the cervical spine to assess spinal cord compression
MRI & ultrasound are more sensitive imaging modalities for synovitis & early erosive rheumatoid arthritis than radiography^[40]
- ultrasound not useful in guiding treatment^[86]
MRI is not indicated for routine monitoring of disease activity
- asymptomatic individuals frequently with abnormalities on MRI^[3]^[91]^[117] (see arthritis Radiology section)
bone-density (DEXA) for patients on glucocorticoids
- bone mineral density may underestimate risk of fracture^[3]

* radiograph images^[120]

Complications

Felty's syndrome (splenomegaly, granulocytopenia)
amyloidosis occurs rarely
- generally AA amyloidosis (amyloid protein AA)
- manifested by proteinuria +/- nephrotic syndrome, +/- hematuria
- treatment unsatisfactory; prognosis is poor
osteoporosis, increased risk of fracture^[16]
spinal cord compression due to cervical spine disease
- C1, C2 subluxation
- 50% mortality in 1 year without surgery
mortality
- greatest 3-10 years after diagnosis
- correlates with disease severity factors, older age, radiologic progression, RF titer, anti-CCP, resistance to therapy & extra-articular manifestations^[3]
- biologic agents may be protective relative to conventional DMARDs from sepsis or mortality following serious infection^[89]
increased risk of cardiovascular disease^[22]^[64]
- major cause of death in RA^[3]
  - smoking doubles this risk^[105]
- coronary artery disease
- increased risk of atrial fibrillation (HR=1.3)^[27]
- increased risk of stroke (HR=3.0 in patients < 50)^[27]
- pericardial effusion (30-40%)
- valvular heart disease
  - leaflet fibrosis (< 30%)
  - increased risk of aortic stenosis^[135]
- heart failure, left ventricular diastolic dysfunction^[3]
  - subclinical myocardial inflammation correlates with RA disease activity^[118]
  - TNF inhibitor toxicity
- coronary artery calcification scoring is more likely than cardiovascular risk calculators to place RA patients in a high-risk category^[66]
  - the implications are unknown
- patients with severe extra-articular manifestations of RA at highest risk for cardiovascular events^[3]
increased risk of thromboembolism^[31] (RR=2)
pulmonary complications
- drug-related lung disease (methotrexate)
- bronchiolitis
- interstitial pneumonia, organizing pneumonia
- rheumatoid nodules
- pulmonary embolism
muscle atrophy due to disuse & glucocorticoid myopathy, especially interosseous muscles & quadriceps^[3]
risk of cancer similar for DMARDs vs biologic agents^[99]
infectious arthritis (acute monoarthritis)
- synovial fluid cultures, blood cultures if signs of systemic infection
- empiric antibiotics awaiting cultures^[131]^[132]
increased risk of Parkinson's disease (RR=1.74)^[134]

Differential diagnosis

osteoarthritis
spondyloarthropathies
systemic lupus erythematosus (SLE) (skin rash & leukopenia)
systemic sclerosis (Raynaud's phenomenon)
Lyme disease
crystal-induced arthritis
- gout
- pseudogout
paraneoplastic syndrome (especially in the elderly)^[7]
parvovirus B19 infection (daycare worker or mother of small children)
- symmetric polyarthritis present for > 6 weeks suggests RA
hemochromatosis (2nd MCP & PIP joints)
polymyositis, dermatomyositis (proximal muscle weakness)
post-rubella immunization arthritis^[3]

Management

general
- physical therapy
  - hand therapy cost-effective^[60]
- occupational therapy
- cardiovascular risk reduction
- early, agrressive therapy with multiple agents^[32]
- treat to target of remission or low disease activity^[3]
  - reduces joint damage & cardiovascular risk, & increases productivity

pharmacologic agents

disease-modifying anti-rheumatic drugs (DMARDs)
- methotrexate, start with 7.5 mg PO weekly
  - improves long-term survival^[10]^[12] by reducing cardiac deaths
  - adjunctive prednisone 10 mg QD for 1st 2 years may be of benefit^[28]
    - taper & discontinue prednisone after 2 years^[28]
  - probably best initial DMARD^[3]
    - relatively low cost, good efficacy, generally well-tolerated, good long-term compliance
  - gold-standard DMARD for treatment of RA^[3]
  - monotherapy for initial treatment of rapidly progressive or erosive RA^[3]^[56]
  - in combination with sulfasalazine & hydroxychloroquine^[18]^[32]^[55]
  - subcutaneous methotrexate is more effective than once-weekly oral dosing^[98] & should be tried before resorting to a biologic agent
  - maximize use of methotrexate prior to resorting to other agents^[125]
  - contraindicated in pregnancy^[3]
- hydroxychloroquine, start with 400 mg PO QD
  - used to treat early, mild & non-erosive disease & in combination with methotrexate & sulfasalazine^[3]
  - safe during pregnancy^[3]
- sulfasalazine, start with 500 mg PO QD
  - safe during pregnancy^[3]
- leflunomide (Arava) may be alternative to methotrexate
- cyclophosphamide (Cytoxan)
- azathioprine (Imuran)
- penicillamine
- dapsone
- minocycline or doxycycline 100 mg PO BID^[4]
  - within the 1st year of diagnosis
  - may delay use of steroids or other DMARDs
  - allow at least 3 months for therapeutic effect
- use of multiple DMARDs concurrently may be more effective than a single agent at a cost of increased adverse effects
- starting DMARD within 3 months of diagnosis may be the new standard of care^[3]^[9]
initial therapy with multiple DMARDs^[18]
- methotrexate, sulfasalazine & hydroxychloroquine is standard (triple therapy)^[32] & may be more durable than treatment with biologics^[100]
- methotrexate, sulfasalazine, prednisone 60 mg QD, tapered to 7.5 mg QD over 7 weeks
- methotrexate plus TNF-alpha inhibitor
  - more effective than triple therapy^[124]
- recommended as initial therapy for early aggressive rheumatoid arthritis^[55]
  - ref^[56] challenges this recommendation, noting that methotrexate alone is effective in 30% of these patients with no cost to coverting to multiple DMARDs at 6 months for methotrexate monotherapy failure^[56]
- DMARDs in combination result in non-inferior outcomes to treatment with TNF inhibitors at substantially lower costs^[67]
- 73% of patients on triple therapy vs 63% of those on methotrexate/etanercept remain on treatment at 1 year^[100]
- more patients change from methotrexate/etanercept to triple therapy than from triple therapy to methotrexate/etanercept^[100]
prednisone or prednisolone in addition to DMARDs or biologics
- intra-articular injection for acutely inflamed joints
- low-dose oral therapy (prednisone 10 mg QD)^[8]
  - prednisolone 7.5 mg QD^[19] may retard progression of RA
  - 5 mg of prednisolone PO QD confers moderate benefit^[127]
    - does not increase cardiovascular risk^[136]
  - risk of serious infection is 14%/year vs 9%/year without prednisone^[122]
- long-term use of prednisone-equivalent dose 10 mg QD, cumulative dose > 1800 mg associated with increased risk of adverse effects (RR=1.2)^[106]
- <= 5 mg prednisone/day considered safe for long-term use^[101]
  - absence of RA flares without adrenal insufficiency in 77% of patients continuing prednisone 5 mg/day vs 65% of patients tapering prednisone^[121]
  - risk of serious infection is 11%/year vs 9%/year without prednisone^[122]
- screen for & treat osteoporosis
  - calcium, vitamin D, bisphosphonate
- glucocorticoids do not alter course of disease
biologic agents
- TNF-alpha inhibitors (all of similar benefit)^[3]
  - etanercept (Enbrel) 25 mg SC twice weekly^[13]
    - may be superior to methotrexate
    - in combination with methotrexate superior to either alone^[15]^[32]
    - after 36 weeks of stable disease, cutting the dose of etanercept by 1/2 results in minimal loss of effectiveness^[33]
    - stopping etanercept results in disease flares in 57% of patients^[33]
    - patients who achieve remission with etanercept plus methotrexate
    - 23% & 40% of patients are able to complete taper of etanercept with or without methotrextate^[61]
    - remission sustained after taper^[61]
    - study funded by Pfizer
    - addition of etanercept to methotrexate 25 mg/week (50 mg/week max dose) preferred over maximizing dose of methotrexate^[3]
    - patients who fail treatment with a TNF-alpha inhibitor are more likely to respond to another biologic agent that is not a TNF-alpha inhibitor than another TNF-alpha inhibitor (69% vs 52%)^[90]
    - TNF-alpha inhibitors diminish cardiovascular risk by controlling disease activity & presumably inflammation^[93]
  - infliximab (Remicade) in combination with methotrexate^[26]
  - adalimumab (Humira)* in combination with methotrexate^[57]
  - certolizumab
  - golimumab
  - TNF-alpha inhibitor + methotrexate is the most effective treatment of rheumatoid arthritis^[3]
  - standard practice is to add TNF-alpha inhibitor to methotrexate^[83]
  - rheumatoid arthritis more likely to flair when patients in remission stappe TNF-alpha inhibitor (51 vs 18%)^[87]
- anakinra (Kineret) 1-2 mg/kg SC^[11] in combination with methotrexate
- tofacitinib (Janus kinase inhibitor)
  - as effective as TNF-alpha inhibitor
  - in combination with methotrexate for TNF inhibitor failure: effective in 40% of patients^[34]
  - monotherapy with tofacitinib is superior to methotrexate monotherapy at the cost of increased adverse effects^[59]
  - initial therapy with tocilizumab +/- methotrexate increases likelihood of rapid remission vs methotrexate alone (84-86% vs 44%)^[84]
  - initial treatment with methotrexate with addition of tocilizumab after 2 years results in similar outcomes as initiating therapy with tocilizumab^[84]
- rituximab (Rituxan) FDA approved 2005
  - as effective as a TNF-inhibitor & more cost-effective^[83]
  - standard practice is to add rituximab to methotrexate^[83]
- abatacept (Orencia) FDA approved 2005
- combination therapy with two biologic agents (TNF inhibitor, anakinra, rituximab, abatacept) is contraindicated^[3]^[55]
- after symptom control is achieved, biologic agent can be discontinued in some patients^[57]
- infection risks highest with infliximab, etanercept, & rituximab^[81]
- adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab & abatacept, all in combination with methotrexate, are recommended as options for treating rheumatoid arthritis, only if:
  - disease is severe, disease activity score (DAS28) > 5.1 &
  - disease has not responded to intensive therapy with a combination of conventional DMARDs (NICE) [NGC]
- sarilumab (IL-6 receptor inhibitor) superior as monotherapy to adalimumab (TNF-alpha inhibitor)^[92]
- upadacitinib (Rinvoq) a JAK-1 inhibitor with benefits of > 1 year duration for treatment of refractory RA^[103]
- screening for tuberculosis prior to intitiating biologic & periodically during therapy^[3]
statin in combination with DMARDs^[16]
intensive therapy may improve outcome (see TICORA study)^[16]
methotrexate, sulfasalazine & hydroxychloroquine as effective as etanercept for patients with methotrexate failure^[35] & more cost-effective^[97]
patients more likely to comply with methotrexate+biologic agent than with methotrexate, sulfasalazine & hydroxychloroquine^[96]
non-steroidal anti-inflammatory agents (NSAIDs)
- symptomatic relief but do not alter course of disease^[3]
Tripterygium wilfordii Hook F may be of benefit

surgery & other procedures

all patients with RA undergoing general anesthesia should have cervical spine X-rays to assess atlantoaxial subluxation
- identify RA-related cervical spine disease prior to elective surgery (risk of spinal cord injury during intubation & extubation)^[3]^[39]
- cervical spine radiography with flexion & extension views
indications for surgery:
- incapacitating pain & disability due to joint damage or tendon rupture
- nerve entrapment syndromes unresponsive to local injection, rest & casting
- septic joint unresponsive to needle drainage & antibiotics
- cervical spinal cord compression
surgical procedures
- synovectomy, bursectomy, bunionectomy, nodulectomy
- joint fusion & joint replacement
- arthroplasty (hip & knee)
- tendon repairs & transfers
electrotherapy, thermotherapy
vagus nerve stimulation
- reduces proinflammatory cytokine production
- diminishes disease severity^[85]

other considerations

activity
- aerobic exercise
- adequate rest
diet, nutrition
- fish oils may augment DMARD therapy^[62]
- eating fish at least twice a week is associated with lower disease activity^[102]
- calcium & vitamin D for all patients^[3]
patient education
- smoking associated with 2-fold increase in mortality^[105]
prevention:
- long-term, moderate alcohol consumption associated with diminished risk for rheumatoid arthritis (RR=0.5)^[30]
- smoking is a risk factor; smoking cessation reduces risk^[3]^[44]
- bisphosphates for osteoporosis
vaccination
- routine immunizations including Covid-19 vaccine, annual influenza vaccine, pneumococal vaccine
- treatment may influence immunogenicity of vaccines
- methotrexate discontinuation for 2 weeks after influenza vaccination improves immunogenicity of the vaccine without increasing RA disease activity^[108]
adjuvant physical therapy & occupational therapy^[3]
prognosis
- increasing longevity in rheumatoid arthritis patients, possibly because of earlier & more fequent use of biologic agents & conventional DMARDs^[94]
complications:
- acute monoarthritis:
  - empiric antibiotics for infectious arthritis awaiting cultures^[131]^[132]

* Veteran's Administration VISN 21 preferred agent in this class

More general terms

More specific terms

Additional terms

References

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Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
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↑ Journal Watch 21(2):1, 2001 Bathon JM et al A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 343:1586,2001 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11096165
Lipsky PE et al Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 343:1594, 2000 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11096166 Kipple JH Biologic therapy for rheumatoid arthritis. N Engl J Med 343:1640, 2000 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11096174
↑ ^7.0 ^7.1 ^7.2 Weiner, S in: Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
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↑ ^13.0 ^13.1 Journal Watch 22(15):116, 2002 Genovese MC et al Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum 46:1443, 2002 PMID: https://www.ncbi.nlm.nih.gov/pubmed/12115173
↑ Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004
↑ ^15.0 ^15.1 Journal Watch 24(7):58, 2004 Klareskog L et al Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 363:675, 2004 PMID: https://www.ncbi.nlm.nih.gov/pubmed/15001324
↑ ^16.0 ^16.1 ^16.2 ^16.3 Journal Watch 24(15):119, 2004 McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakov O, Ford I, Capell HA, Sattar N. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet. 2004 Jun 19;363(9426):2015-21. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15207950
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↑ Prescriber's Letter 16(2): 2008 PATIENT HANDOUT: What I Need to Know About My Rheumatoid Arthritis Medication COMMENTARY: Rheumatoid Arthritis: The Role of DMARDs Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=250210&pb=PRL (subscription needed) http://www.prescribersletter.com
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↑ ^101.0 ^101.1 Roubille C, Rincheval N, Dougados M et al. Seven-year tolerability profile of glucocorticoids use in early rheumatoid arthritis: Data from the ESPOIR cohort. Ann Rheum Dis 2017 Nov; 76:1797 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28213564 <Internet> http://ard.bmj.com/content/76/11/1797
↑ ^102.0 ^102.1 Kelly JC Eating Fish May Reduce Rheumatoid Arthritis Symptoms Medscape - Jun 23, 2017. https://www.medscape.com/viewarticle/882026
Tedeschi SK, Bathon JM, Giles JT et al The relationship between fish consumption and disease activity in rheumatoid arthritis. Arthritis Care Res (Hoboken). 2018 Mar;70(3):327-332. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28635117 <Internet> http://onlinelibrary.wiley.com/doi/10.1002/acr.23295/abstract
↑ ^103.0 ^103.1 McNamara D JAK-1 Inhibitor Effective for RA, but Safety Signal Troubles. Medscape - Nov 13, 2017. https://www.medscape.com/viewarticle/888522
Walsh N Rinvoq for RA: Benefits Persist Beyond 1 Year - Manufacturer's extension study shows no loss of clinical response. MedPage Today November 6, 2020 https://www.medpagetoday.com/meetingcoverage/acr/89523
van Vollenhoven R, et al Upadacitinib monotherapy in methotrexate-naive patients with rheumatoid arthritis: results at 72 weeks. American College of Rheumatology (ACR) 2020; Abstract 0207
↑ ^104.0 ^104.1 ^104.2 Pullen LC Occupational Exposures Increase Rheumatoid Arthritis Risk. Medscape - Aug 10, 2017. https://www.medscape.com/viewarticle/884103
Ilar A, Alfredsson L, Wiebert P, Klareskog L, Bengtsson C. Occupation and Risk of Developing Rheumatoid Arthritis: Results From a Population-Based Case-Control Study. Arthritis Care Res (Hoboken). 2017 Aug 10. PMID: https://www.ncbi.nlm.nih.gov/pubmed/28795508
↑ ^105.0 ^105.1 ^105.2 Sparks JA, Chang SC, Nguyen UDT et al. Smoking behavior changes in the early rheumatoid arthritis period and risk of mortality during thirty-six years of prospective followup. Arthritis Care Res (Hoboken) 2018 Jan; 70:19. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28464477 <Internet> http://onlinelibrary.wiley.com/doi/10.1002/acr.23269/abstract
↑ ^106.0 ^106.1 Best JH, Kong AM, Lenhart GM et al. Association between glucocorticoid exposure and healthcare expenditures for potential glucocorticoid-related adverse events in patients with rheumatoid arthritis. J Rheumatol 2018 Mar; 45:320. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/29335343 <Internet> http://www.jrheum.org/content/45/3/320
↑ ^107.0 ^107.1 Walsh N. Troponin Predicts Mortality in Inflammatory Arthritis. High levels associated with all-cause and cardiovascular death. MedPage Today. May 01, 2018 https://www.medpagetoday.com/meetingcoverage/bsr/72632
Skeoch S, et al The association of high sensitivity troponin levels with subsequent cardiovascular mortality in an inflammatory arthritis cohort: Results from the Norfolk arthritis register. British Society for Rheumatology (BSR) 2018; Abstract O10.
↑ ^108.0 ^108.1 Park JK, Lee YJ, Shin K et al. Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis: A randomised clinical trial. Ann Rheum Dis 2018 Jun; 77:898 PMID: https://www.ncbi.nlm.nih.gov/pubmed/29572291 Free PMC Article
↑ National Institute of Arthritis and Muscluloskeletal and Skin Diseases (NIAMS) Rheumatoid Arthritis https://www.niams.nih.gov/health-topics/rheumatoid-arthritis
↑ Crowson CS, Liao KP, Davis JM 3rd Rheumatoid arthritis and cardiovascular disease. Am Heart J. 2013 Oct;166(4):622-628.e1. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/24093840 Free PMC Article
↑ Di Giuseppe D, Orsini N, Alfredsson L, Askling J, Wolk A. Cigarette smoking and smoking cessation in relation to risk of rheumatoid arthritis in women. Arthritis Res Ther. 2013 Apr 22;15(2):R56. PMID: https://www.ncbi.nlm.nih.gov/pubmed/23607815 Free PMC Article
↑ Artifoni M, Rothschild PR, Brezin A et al Ocular inflammatory diseases associated with rheumatoid arthritis. Nat Rev Rheumatol. 2014 Feb;10(2):108-16. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/24323074
↑ Chang PY, Yang CT, Cheng CH, Yu KH. Diagnostic performance of anti-cyclic citrullinated peptide and rheumatoid factor in patients with rheumatoid arthritis. Int J Rheum Dis. 2016 Sep;19(9):880-6. PMID: https://www.ncbi.nlm.nih.gov/pubmed/25940989
↑ Ince-Askan H, Dolhain RJ. Pregnancy and rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2015 Aug-Dec;29(4-5):580-96. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/26697768
↑ Del Grande M, Del Grande F, Carrino J et al Cervical spine involvement early in the course of rheumatoid arthritis. Semin Arthritis Rheum. 2014 Jun;43(6):738-44. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/24444595
↑ Singh JA, Saag KG, Bridges SL Jr et al 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2016 Jan;68(1):1-26. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/26545940 Free Article
↑ ^117.0 ^117.1 Moller-Bisgaard S, Horslev-Petersen K, Ejbjerg B et al. Effect of magnetic resonance imaging vs conventional treat-to-target strategies on disease activity remission and radiographic progression in rheumatoid arthritis: The IMAGINE-RA randomized clinical trial. JAMA 2019 Feb 5; 321:461. PMID: https://www.ncbi.nlm.nih.gov/pubmed/30721294 https://jamanetwork.com/journals/jama/fullarticle/2724024
Aletaha D, Smolen JS. Achieving clinical remission for patients with rheumatoid arthritis. JAMA 2019 Feb 5; 321:457. PMID: https://www.ncbi.nlm.nih.gov/pubmed/30721278 https://jamanetwork.com/journals/jama/fullarticle/2724006
↑ ^118.0 ^118.1 Amigues I, Tugcu A, Russo C et al. Myocardial inflammation, measured using 18-fluorodeoxyglucose positron emission tomography with computed tomography, is associated with disease activity in rheumatoid arthritis. Arthritis Rheumatol 2019 Apr; 71:496. PMID: https://www.ncbi.nlm.nih.gov/pubmed/30407745 https://onlinelibrary.wiley.com/doi/abs/10.1002/art.40771
↑ ^119.0 ^119.1 Liu X, Tedeschi SK, Barbhaiya M et al. Impact and timing of smoking cessation on reducing risk of rheumatoid arthritis among women in the Nurses' Health Studies. Arthritis Care Res (Hoboken) 2019 Jul; 71:914. PMID: https://www.ncbi.nlm.nih.gov/pubmed/30790475 https://onlinelibrary.wiley.com/doi/abs/10.1002/acr.23837
↑ ^120.0 ^120.1 Satis H, Tufan A. Images in Clinical Medicine. Telescoping Fingers in Rheumatoid Arthritis. N Engl J Med 2019; 381:e41. Dec 12, PMID: https://www.ncbi.nlm.nih.gov/pubmed/31826343 https://www.nejm.org/doi/full/10.1056/NEJMicm1905982
↑ ^121.0 ^121.1 Burmester GR et al. Continuing versus tapering glucocorticoids after achievement of low disease activity or remission in rheumatoid arthritis (SEMIRA): A double-blind, multicentre, randomised controlled trial. Lancet 2020 Jul 25; 396:267 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32711802 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30636-X/fulltext
↑ ^122.0 ^122.1 ^122.2 George MD, Baker JF, Winthrop K et al Risk for Serious Infection With Low-Dose Glucocorticoids in Patients With Rheumatoid Arthritis. A Cohort Study. Ann Intern Med. Sept 22, 2020 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32956604 https://www.acpjournals.org/doi/10.7326/M20-1594
Orange DE, Mehta B. Rethinking the Balance of Risks and Rewards of Chronic Low-Dose Glucocorticoids in Rheumatoid Arthritis. Ann Intern Med. Sept 22, 2020 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32956596 https://www.acpjournals.org/doi/10.7326/M20-6010
↑ ^123.0 ^123.1 Huang S et al. Rheumatoid arthritis-related lung disease detected on clinical chest computed tomography imaging: Prevalence, risk factors, and impact on mortality. Semin Arthritis Rheum 2020 Dec; 50:1216 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33059295 https://www.sciencedirect.com/science/article/abs/pii/S0049017220302596
↑ ^124.0 ^124.1 Curtis JR, Palmer JL, Reed GW Real-World Outcomes Associated with Triple Therapy versus TNFi/MTX Therapy. Arthritis Care Res (Hoboken). 2020 May 6 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32374918
↑ ^125.0 ^125.1 Walsh N New ACR Rheumatoid Arthritis Guideline: Emphasis on Methotrexate. Many RA patients succeed with optimized use of the DMARD before adding another medication. https://www.medpagetoday.com/rheumatology/arthritis/93323
Fraenkel L, Bathon JM, England BR et al 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res 2021 Jul;73(7):924-939. Online June 8. PMID: https://www.ncbi.nlm.nih.gov/pubmed/34101387 https://onlinelibrary.wiley.com/doi/10.1002/acr.24596
↑ ^126.0 ^126.1 Zamora-Legoff JA, Krause ML, Crowson CS et al. Progressive decline of lung function in rheumatoid arthritis-associated interstitial lung disease. Arthritis Rheumatol. 2017;69(3):542-549 PMID: https://www.ncbi.nlm.nih.gov/pubmed/27788297 PMCID: PMC5328843 Free PMC article https://onlinelibrary.wiley.com/doi/epdf/10.1002/art.39971
↑ ^127.0 ^127.1 Boers M, Hartman L, Opris-Belinski D et al. Low dose, add-on prednisolone in patients with rheumatoid arthritis aged 65+: The pragmatic randomised, double-blind placebo-controlled GLORIA trial. Ann Rheum Dis 2022 Jul; 81:925 PMID: https://www.ncbi.nlm.nih.gov/pubmed/35641125 PMCID: PMC9209692 Free PMC article https://ard.bmj.com/content/81/7/925
↑ ^128.0 ^128.1 ^128.2 Gever J Momentum Builds for Microbiome as RA Trigger. Second study published in a week's time to implicate intestinal bacteria in joint pathology. MedPage Today October 26, 2022 https://www.medpagetoday.com/rheumatology/arthritis/101435
Chriswell ME Lefferts AR, Clay MR et al Clonal IgA and IgG autoantibodies from individuals at risk for rheumatoid arthritis identify an arthritogenic strain of Subdoligranulum. Science Translational Medicine. 2022. 14(688):eabn5166. Oct 26 PMID: https://www.ncbi.nlm.nih.gov/pubmed/36288282 https://www.science.org/doi/10.1126/scitranslmed.abn5166
↑ Gever J Does Rheumatoid Arthritis Get Its Start in the Gut? Patients and at-risk individuals show antibodies to common intestinal bacterium. MedPage Today October 20, 2022 https://www.medpagetoday.com/rheumatology/arthritis/101321
Seifert JA, Bemis EA, Ramsden K et al Association of antibodies to Prevotella copri in anti-CCP-positive individuals at-risk for developing rheumatoid arthritis and in those with early or established rheumatoid arthritis. Arthritis & Rheumatology. 2022. Oct 19 PMID: https://www.ncbi.nlm.nih.gov/pubmed/36259174 https://onlinelibrary.wiley.com/doi/abs/10.1002/art.42370
↑ ^130.0 ^130.1 ^130.2 Gever J Not Just a Miner's Problem: Workplace Fumes, Dust Tied to RA. Swedish study expands range of airborne toxics associated with rheumatic disease. MedPage Today December 6, 2022 https://www.medpagetoday.com/rheumatology/arthritis/102083
Tang B, Liu Q, Ilar A et al Occupational inhalable agents constitute major risk factors for rheumatoid arthritis, particularly in the context of genetic predisposition and smoking. Annals of Rheumatic Diseases. 2022. Dec 6 https://ard.bmj.com/content/early/2022/11/28/ard-2022-223134
↑ ^131.0 ^131.1 ^131.2 Galloway JB, Hyrich KL, Mercer LK et al Risk of septic arthritis in patients with rheumatoid arthritis and the effect of anti-TNF therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2011 Oct;70(10):1810-4. PMID: https://www.ncbi.nlm.nih.gov/pubmed/21784730 PMCID: PMC3168332 Free PMC article
↑ ^132.0 ^132.1 ^132.2 Edwards CJ, Cooper C, Fisher D, Field M, van Staa TP, Arden NK. The importance of the disease process and disease-modifying antirheumatic drug treatment in the development of septic arthritis in patients with rheumatoid arthritis. Arthritis Rheum. 2007 Oct 15;57(7):1151-7 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17907232 Free article.
↑ ^133.0 ^133.1 ^133.2 ^133.3 NEJM Knowledge+ Rheumatology
Fraenkel L, Bathon JM, England BR et al 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2021 Jul;73(7):1108-1123. PMID: https://www.ncbi.nlm.nih.gov/pubmed/34101376
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↑ ^136.0 ^136.1 So H, Lam TO, Meng H, Lam SHM, Tam LS. Time and dose-dependent effect of systemic glucocorticoids on major adverse cardiovascular event in patients with rheumatoid arthritis: a population-based study. Ann Rheum Dis. 2023 Nov;82(11):1387-1393. Epub 2023 Jul 24. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37487608

Patient information

rheumatoid arthritis patient information

Database

OMIM: https://mirror.omim.org/entry/180300

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[ref2-2] Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 821-828, 786-87

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Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022

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Lipsky PE et al Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 343:1594, 2000 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11096166 Kipple JH Biologic therapy for rheumatoid arthritis. N Engl J Med 343:1640, 2000 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11096174

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[ref9-9] 9.0 ^9.1 Prescriber's Letter 9(3):13 2002 (subscription needed) http://www.prescribersletter.com

[ref10-10] 10.0 ^10.1 Prescriber's Letter 9(5):26 2002 (subscription needed) http://www.prescribersletter.com

[ref11-11] 11.0 ^11.1 Journal Watch 22(9):70, 2002 Dayer J-M & Bresniban R Targeting interleukin-1 in the treatment of rheumatoid arthritis. Arthritis Rheum 46:574, 2002 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11920390

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[ref14-14] Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004

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[ref20-20] Turesson C & Matteson EL, Genetics of rheumatoid arthritis Mayo Clin Proc 2006; 81:94 PMID: https://www.ncbi.nlm.nih.gov/pubmed/16438485

[ref21-21] Breedveld FC et al, The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 2006, 54:26 PMID: https://www.ncbi.nlm.nih.gov/pubmed/16385520

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[ref24-24] Choosing Medications for Adults With Rheumatoid Arthritis Clinician Summary Guide published 9 Apr 2008 Agency for Healthcare Research and Quality (AHRQ) http://effectivehealthcare.ahrq.gov/healthInfo.cfm?infotype=sg&DocID=85&ProcessID=14

[ref25-25] Prescriber's Letter 16(2): 2008 PATIENT HANDOUT: What I Need to Know About My Rheumatoid Arthritis Medication COMMENTARY: Rheumatoid Arthritis: The Role of DMARDs Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=250210&pb=PRL (subscription needed) http://www.prescribersletter.com
GUIDELINES: Use of Disease-Modifying Antirheumatic Drugs (DMARDs) in Rheumatoid Arthritis http://www.rheumatology.org/publications/guidelines/recommendations.pdf

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rheumatoid arthritis (RA)

Contents

Introduction

Etiology

Epidemiology

Pathology

Genetics

Clinical manifestations

Laboratory

Diagnostic procedures

Radiology

Complications

Differential diagnosis

Management

pharmacologic agents

surgery & other procedures

other considerations

More general terms

More specific terms

Additional terms

References

Patient information

Database

Navigation menu

rheumatoid arthritis (RA)

Introduction

Etiology

Epidemiology

Pathology

Genetics

Clinical manifestations

Laboratory

Diagnostic procedures

Radiology

Complications

Differential diagnosis

Management

pharmacologic agents

surgery & other procedures

other considerations

More general terms

More specific terms

Additional terms

References

Patient information

Database

Navigation menu

Search