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BOTTOM LINE

Rheumatoid arthritis (RA) often presents as an insidious, additive, symmetrical polyarthritis frequently involving the small joints of hands and feet. Without treatment, it can become deforming and erosive. Extra-articular manifestations are protean, but include rheumatoid nodules, interstitial lung disease, osteopenia, and increased cardiovascular risk. Investigations often show elevated inflammatory markers. Rheumatoid factor (RF) and/or Anti-citrullinated protein antibodies (ACPA) can be positive in many patients, but not all, and less frequently in early disease. ACPA has a higher specificity for RA than RF. Flares of RA activity are treated with steroids and disease activity is maintained with disease modifying anti-rheumatic drugs (DMARDs), usually starting with methotrexate with additional conventional and biologic/targeted-synthetic DMARDs added if ongoing disease activity. [🕑 20 minute read ]

EPIDEMIOLOGY

—Population

• Prevalence
  • ~1.0/100 in Canada, 0.5-1.0/100 in Western countries
• Incidence
  • ~20–50/100,000 per year (0.2–0.5 per 1,000) in Western countries
• Ethnicity
  • All ethnicities affected
  • Indigenous peoples in Canada have 2-5X prevalence, younger onset, more seropositive, more large joint involvement, and worse prognosis

—Age, Sex

• Peak age
  • Peak onset 4th to 6th decade of life
  • Age at onset increasing with time due to aging population in Western World.
  • Age-specific incidence rates is 75-89 years-old in Canada.
• Sex:
  • Female > Male, 2-3:1

—Risk factors: Genetic (40-65% of risk)

Heritability estimated at 40–65% for seropositive RA, lower (~20%) for seronegative RA Disease concordance of 12-15% in twin studies A first degree relative with RA increases odds of RA 2-5x

• HLA Class II:
  • HLA-DRB1*01 (an allele that is part of the HLA-DR1 serotype)
    HLA-DRB1*04 (an allele that is part of the HLA-DR4 serotype)
    • “Shared epitope”: specific five amino acid motif commonly encoded by some alleles of the HLA-DR locus; strongly associated with risk of RA
• Non-HLA loci:
  • >100 risk loci across genome with weaker association for RA, including PTPN22, STAT4, TRAF1-C5, PADI4, and CTLA4
• Epigenetics:
  • DNA methylation patterns in HLA region

—Risk factors: Environmental (35-60% of risk)

• Smoking:
  • >20 pack-years doubles risk of RA, primarily through promoting citrullination of proteins in the lungs, with additional epigenetic modifications.
  • Effect is strongest for ACPA-positive/seropositive RA.
• Inhaled exposure:
  • Occupational dust exposure, e.g.: Silica dust, textile dust
• Microbiota:
  • Periodontal disease–oral microbiota may citrullinate proteins
  • Gut microbiota–lower biodiversity of gut microbiota in RA vs. general population
• Obesity
• EBV

CLINICAL MANIFESTATIONS

Joints

—Onset: Common

• Insidious symmetrical, additive over weeks-months (66%)
  Can start with one or a few joints before becoming polyarticular and symmetrical
• Subacute, with more systemic symptoms (33%)

—Onset: Less common

• Acute onset: rare
• Palindromic: intermittent self-limited mono/oligoarticular joint swelling lasting days. Some develop true RA with persistent disease activity. Approximately 40–60% of patients with palindromic rheumatism eventually develop persistent RA
• Arthritis robustus: marked inflammatory arthritis but minimal pain.
• Rheumatoid nodulosis: many rheumatoid nodules often subcutaneous, can appear in other organs (lung, liver, heart, central nervous system)

—General Features

Click for an approach to peripheral inflammatory arthritis

• History
  “Classic” features that may suggest “inflammatory joint pain”:
  • Morning stiffness ≥30 minutes (often ≥60 minutes)
  • Improvement with activity, stiffening up at rest
  • Symptoms wake patient up from sleep overnight
  • Visible swelling with decreased range of motion in joints
  • May have fatigue and constitutional symptoms (low-grade fever, weight loss, anorexia), particularly if high systemic inflammation
• Exam, joints:
  • LOOK bigger
  • FEEL boggy, soft, and warm
  • MOVE less than normal
  • Tender to palpation (squeeze test across MCPs/MTPs) is a useful screening maneuver

• Possible Joint Involvement in Rheumatoid versus Primary Osteoarthritis:

RA DEFORMITY	ANATOMICAL CHANGES
Boutonnière	PIP flexion, DIP hyperextension
Swan-neck	PIP hyperextension, DIP flexion
Ulnar Deviation	MCP subluxation and deviation to ulnar side  Due to MCP joint subluxation with extensor tendon dislocation Most common hand deformity in RA
Z-deformity	Thumb IP hyperextension, MCP adduction
Piano Key	Ulnar styloid floats above radius, reducible
Claw toe	MTP subluxation, PIP and DIP flexion
Hammer toe	MTP subluxation, PIP flexion, DIP extension

RA does not cause chronic lower back pain
In the cervical spine, RA most commonly affects the C1-C2 (atlantoaxial) joint but can also cause subaxial subluxation and cranial settling (basilar invagination). This instability can be dangerous during intubation of RA patients, thus RA patients need flexion/extension views of the C1-C2 joint prior to surgery

RA patients may have increased rates of secondary lumbar pathology (vertebral fractures, spondylolisthesis) related to osteoporosis and disease activity.

Extra-articular Manifestations

Rheumatoid arthritis is a systemic disease that can present with extra-articular manifestations. The list below is meant to be inclusive, though not all patients will have extra-articular manifestations on review. Extra-articular manifestations are more common in seropositive patients.

—Systemic:

• Fatigue, fever, anorexia, weight loss (particularly in patients with severe systemic inflammation)

—Ocular

• Keratoconjunctivitis sicca, episcleritis, scleritis, peripheral ulcerative keratitis
• Peripheral ulcerative keratitis can progress to corneal melt
• Scleritis can be anterior or posterior and may be the presenting feature of rheumatoid vasculitis; can lead to scleromalacia perforans in severe cases, which is a sight-threatening complication

—ENT

• Dry mouth, Sjogren’s-overlap. Secondary Sjögren syndrome occurs in approximately 10–30% of RA patients.
• Hoarseness (due to rare cricoarytenoid arthritis); cause stridor and upper airway obstruction in severe cases, which is an emergency

—Cardiac

• Pericardium:
  • Pericarditis, pericardial effusion, can get rare cardiac tamponade if large effusion
• Epicardium (coronary vessels):
  • Accelerated atherosclerosis, ↑MI risk.
    • RA confers cardiovascular risk that may be comparable to or exceed that of type 2 diabetes, depending on disease activity and duration
    • See Comorbidity Management below
  • Rare coronary vasculitis
• Myocardium:
  • Myocarditis (uncommon, but carries high mortality risk when it occurs
• Valvular:
  • Rheumatoid nodulosis (uncommon); can include nodular thickening and rarely regurgitation.

—Vascular

• Rheumatoid vasculitis:
  Rare, much less common with modern DMARD therapy; associated with high disease activity
  • Skin:
    Rheumatoid vasculitis — fingertip or nailfold petechiae, can progress to skin ulcers, necrosis.
  • Eye:
    Scleritis/peripheral ulcerative keratitis (see above)
  • Nerve:
    Sensory and/or motor polyneuropathy, mononeuritis multiplex
  • Cardiac:
    Coronary vasculitis, aortitis. pulmonary vasculitis (rare)
  • Pulmonary:
    Diffuse alveolar hemorrhage, pulmonary vasculitis (rare)

• DVT/PE
  • Higher risk of DVT/PE compared to matched controls
  • Meta-analysis OR 2.23 (95% CI: 2.02–2.47) for overall VTE, though individual study estimates range from HR 1.35 to 3.36.

—Respiratory

—Interstitial

Interstitial Lung Disease

• Prevalence:
  • Symptomatic ILD in ~10-15%; up to 58% asymptomatic interstitial changes
• Onset:
  • Most frequent: 1-5 years before or after onset of inflammatory arthritis
  • Timing: Incident ILD 5-15 years before/after onset of inflammatory arthritis; up to 15+ years before/after onset of inflammatory arthritis reported
• Risk factors:
  • Patient factors
    • Males, older age, smoking, obesity
  • Genetic factors
    • HLA-DR4
    • MUC5B promotor variant (strongest genetic risk factor, particularly for UIP pattern)
  • Disease factors
    • RF and/or CCP+
    • Disease duration >5 years
    • Persistent moderate-high disease activity
• Presentation:
  • Asymptomatic at early stages; symptoms can be masked if patient is sedentary
  • Symptoms/signs: insidious exertional dyspnea, cough, crackles, clubbing.
• CT pattern:
  • UIP >> NSIP > OP> LIP > DIP
  • Example CT scans: Radiopaedia.org
  • Note: X-rays are insensitive for detecting interstitial lung disease
• PFTs:
  • Restrictive physiology with reduced DLCO, often progressive
• Screening and Treatment:
  • See “Comorbidities” below
• Prognosis
  • Progressive fibrosis is common in RA-ILD: ~30–50% of patients demonstrating progression depending on the definition used and follow-up duration
    • Progression defined as:
      • Relative FVC decline ≥5% and <10% and worsened radiological appearance
      • Relative FVC decline ≥5% and <10% and worsened symptoms
      • Clinical worsening: lung transplant or oxygen therapy
      • Death
      • Relative FVC decline ≥10 % or relative DLCO decline ≥15%
      • Relative FVC decline ≥5% and <10% and worsened radiological appearance
    • Risk factors for progression include:
      • UIP pattern
      • Greater baseline ILD extent
      • Lower baseline DLCO
      • Higher disease activity
      • Elevated anti-CCP titers
    • Survival
      • HR of death of ~3X that of RA patients without ILD
      • 5-year mortality of 35–39%

Rheumatoid Nodules

• Risk:
  • Smoking, RF/CCP+, association with methotrexate, leflunomide in case series
• Presentation:
  • Subpleural asymptomatic nodules, can cavitate or rupture to cause empyema, abscess, pneumothorax, or rarely bronchopleural fistula

—Airways

• Small:
  • Follicular or obliterative bronchiolitis (obstructive physiology)
  • Bronchiectasis
• Large:
  • Cricoarytenoid arthritis (dysphonia, odynophagia, cough, hoarse, obstructive physiology; see ENT above)

—Pleura

• Pleuritis, pleural effusion, pleural thickening, empyema, trapped lung
• Pleural effusions can be asymptomatic and not correlated with inflammatory arthritis activity
• RA pleural effusions characteristically have low glucose (<60 mg/dL) and low pH,

—Pulmonary-vascular

• Pulmonary vasculitis (rare), pulmonary embolism (VTE more common than age/sex-matched general population)
• Pulmonary hypertension (Group II, III, IV; ?Group I),
  • ?Group I: Pulmonary arterial hypertension (ex: perhaps if overlap RA and limited scleroderma)
  • Group II: PH due to left heart disease (ex: from coronary artery disease and myocardial ischemia, more prevalent in RA patients)
  • Group III: PH due to hypoxia and lung disease (ex: from RA-ILD)
  • Group IV: PH due to chronic thromboembolic disease. RA patients at higher risk of VTE.

—Drugs

• Methotrexate pneumonitis:
  • Rarely causes acute/subacute pneumonitis within first years of use
  • See Methotrexate pneumonitis below

Nearly every DMARD has reported cases of pneumonitis; must be wary of confounding by indication. Drug-induced ILD may be more probable when organizing pneumonia is identified and when ILD develops within weeks to months following initiation of new medication. Presence of ILD should not necessarily limit treatment: controlling disease activity with DMARDs is crucial for improving lung outcomes.

—Skin

• Rheumatoid nodules
  • On pressure areas (extensor forearms/elbows sacrum, occiput, heel); can also be in heart, lung, sclera, liver
  • Risk: RF/CCP+, HLA-DR4, HLADRB1; can sometimes be paradoxically worsened with methotrexate therapy
  • Biopsy: central fibrinoid necrosis, palisading histiocytes/macrophages, outer layer of lymphocytes + fibroblasts
• Neutrophilic dermatoses, Sweet Syndrome
• Pyoderma gangrenosum
• Lower extremity skin ulcers (manifestation of rheumatoid vasculitis)

—Bone

• Osteopenia, osteoporosis (RA is risk factor in FRAX calculation for fracture risk): due to active RA, steroids
  • See Comorbidity Management below

—Hematological

• Normocytic anemia of chronic inflammation
  • Chronic inflammation: IL-6 induces hepatic hepcidin production via JAK-STAT3 signaling. Hepcidin binds ferroportin (the sole cellular iron exporter) on enterocytes, macrophages, and hepatocytes, causing its internalization and degradation. This reduces both dietary iron absorption and iron recycling from senescent erythrocytes, creating functional iron deficiency despite adequate iron stores.
• Thrombocytosis (acute inflammation)
• Felty’s syndrome
  • Classic triad: RA + neutropenia + splenomegaly.
    • Thrombocytopenia may occur (from splenic sequestration/hypersplenism neutropenia, splenomegaly + RF, thrombocytopenia from hepatic sequestration
  • Associated with active disease
  • Improves with treatment and disease remission
  • Felty syndrome and T-cell large granular lymphocyte (T-LGL) leukemia exist on a clinical spectrum, sharing HLA-DR4 association and frequent somatic STAT3 mutations. Distinguishing them requires T-cell clonality studies.
• Secondary amyloidosis (AA amyloidosis, rare)

—Neuro

• Central
  • ↑stroke risk (due to atherosclerosis, traditional vascular risk factors)
  • Cervical radiculopathy/myelopathy from C1-C2 instability

Consider cervical spine X-rays with flexion/extension views to screen for C1-C2 instability prior to surgical operations requiring intubation

• Peripheral
  • Entrapment neuropathies from peripheral joint swelling (ex: carpal tunnel)
  • Peripheral neuropathy (secondary amyloid, rare)
  • Mononeuritis multiplex (rheumatoid vasculitis, rare)

—Infection

• Increased infection risk (any infection) from disease activity or from medication exposure (in particular, from steroids)
• Biologic DMARDs (particularly TNF inhibitors) also increase infection risk, especially for tuberculosis reactivation and opportunistic infections.

—Cancer

• Increased prevalence: lung cancer, Hodgkin and non-Hodgkin lymphoma (especially due to active disease)
• Lymphoma risk is thought to be driven primarily by chronic immune stimulation/disease activity rather than treatment
• Ensure age-appropriate malignancy screening

INVESTIGATIONS: BLOODWORK

—Basic Bloodwork

• CBC
  • Hb: may have anemia of chronic inflammation (usually normocytic); microcytic from GI bleeding if on NSAIDs or corticosteroids
  • PTL: may have thrombocytosis with acute inflammation, thrombocytopenia if hypersplenism (associated with Felty’s syndrome) or drug-induced thrombocytopenia (e.g.: methotrexate, tocilizumab)
  • WBC: neutrophilia may reflect acute inflammation; neutropenia if Felty’s syndrome or hematologic malignancy or drug effect (ex: methotrexate)
• Chemistries:
  • Typically normal ALT and creatinine
  • Baseline ALT and creatinine are important to obtain before starting DMARDs
• ESR, CRP
  • Often (but not always) elevated
  • CRP >100 mg/L should prompt consideration of infection, though crystal arthritis and other causes of marked inflammation can also produce this degree of elevation.

—Serology

Seropostive RA patients get more severe and erosive disease and more extra-articular features

• Specificity
  • RF=rheumatoid factor, Specificity for RA 86%
    • Specificity per older meta-analyses, though in clinical practice the specificity of RF for RA appears to be lower.
  • ACPA=anti-citrullinated protein antibody
    • ACPA specificity for RA: 95% (95% CI 94–97%) per meta-analysis; individual studies report up to 98%
• Seropositivity in Established RA
  • RF: 70-80% prevalent
  • ACPA: 66-80% prevalent
• Seropositivity in Early RA
  • RF: 46-61% prevalent
  • ACPA: 43-53% prevalent
• ANA: positive in ≤30% of RA patients; ANA is non-specific and not generally considered in diagnosis of RA.

—RF+ Ddx

• Age:
  5% of young adults, up to 25% of those >85 years
• Infection:
  Bacterial endocarditis, hepatitis B or C, TB, Syphilis, EBV, CMV, other viral infection, leprosy, parasitic infections
• Respiratory:
  Sarcoid, IPF, Silicosis, Asbestosis
• Other:
  Primary biliary cirrhosis, malignancy
• Rheumatological:
  SLE, Sjogren’s, Scleroderma, myositis, cryoglobulinemia, mixed connective tissue disease

INVESTIGATIONS: IMAGING

• X-rays
  • Normal in early RA; can take months to develop changes
  • Early changes: may see juxta-articular osteopenia → diffuse osteopenia
  • Later changes:  joint space narrowing → juxta-articular/marginal erosions
    • Marginal erosions occur at ‘bare areas’ — marginal regions of intra-articular bone not covered by cartilage where inflamed synovium (pannus) directly contacts and erodes bone.
• Ultrasound
  • B-mode:
    • Shows structural abnormalities in soft tissue and bone: Joint effusions, erosions
  • Doppler:
    • Superimposed Doppler detects abnormal vascularity, which suggests active inflammation
  • Uncertain clinical importance:
    • Asymptomatic joint effusions without power-Doppler signal
  • Ultrasound is not required for RA diagnosis but may be used to detect subclinical synovitis and support clinical assessment
  • Quality of ultrasound is subject to technical expertise and inter-observer variability
  • Serial ultrasounds are not shown to improve rates of achieving remission in a treat-to-target approach

Musculoskeletal ultrasound assessment should include both B-mode (grayscale) and power Doppler evaluation.
Ultrasound must be performed and interpreted by trained, experienced, and properly equipped rheumatologist-sonographer or other specialist in MSK sonography.

• CT/MRI
  • Not routinely used to diagnosis or monitor rheumatoid arthritis.
  • CT can characterize erosive changes
  • MRI may have utility in diagnostically uncertain cases and can detect synovitis, tenosynovitis, and osteitis before radiographic changes appear

MRI can detect low-grade synovitis and bone marrow edema in healthy asymptomatic individuals, particularly at older ages, which limits its specificity for RA diagnosis and must be interpreted in clinical context.

• Nuclear Medicine Bone Scans
  • Bone scintigraphy is not recommended for routine RA diagnosis or monitoring; it lacks specificity and has been superseded by ultrasound and MRI, which provide superior characterization of synovitis and structural damage.

DIAGNOSIS

Rheumatoid arthritis is a clinical diagnosis; no formal diagnostic criteria exist. Early diagnosis and treatment within a 3–6 month window of opportunity from symptom onset is associated with less joint damage and higher rates of remission.

RA typically presents with insidious inflammatory joint pain that evolves into an additive, symmetrical polyarthritis involving the small joints of hands and feet, though early disease may be asymmetric or oligoarticular. Symptoms suggestive of inflammatory arthritis include morning stiffness ≥30 minutes (≥60 minutes is more specific), nocturnal joint pain waking from sleep, and improvement with activity. Exam should show objective evidence of joint swelling. Investigations often show elevated inflammatory markers (ESR, CRP). The RA diagnosis may be supported by positive serology for RF and ACPA in some patients, though serology (RF and/or ACPA) is negative in approximately 40–50% of patients with early RA. Approximately 20–30% of RA patients remain seronegative throughout their disease course; some may be re-diagnosed as another inflammatory arthritis as the clinical picture evolves. If performed, an ultrasound of an active joint would reveal synovial hypertrophy and/or joint effusion with power Doppler signal (when done by a trained and experienced sonographer); ultrasound may also detect tenosynovitis, which can precede clinically apparent synovitis. X-rays are often normal in early RA but early changes may include juxta-articular osteopenia.

A complete assessment requires exclusion of alternative diagnoses that better explain the synovitis. Screening for extra-articular manifestations should include respiratory symptom assessment and lung auscultation as part of routine care, but these alone are insufficient to detect ILD. For RA patients with ILD risk factors (male sex, older age, smoking, RF/ACPA positivity, obesity, high disease activity) consider screening with PFTs and HRCT chest. Chest X-ray is not recommended for ILD screening due to low sensitivity.

DIFFERENTIAL DIAGNOSIS

• Systemic Autoimmune Rheumatic Diseases
  • SLE
  • Sjögren Disease
  • Idiopathic inflammatory Myopathies
  • Antisynthetase syndrome (isolated polyarthritis can precede other features by years; consider in seronegative RA with ILD or Raynaud phenomenon; test anti-synthetase antibodies: anti-Jo-1, anti-PL7, anti-PL12)
  • Scleroderma
• Spondyloarthropathies
  • Psoriatic arthritis
  • Reactive arthritis (post-infectious trigger)
  • Ankylosing spondylitis
  • Inflammatory bowel disease–associated (enteropathic) arthritis
• Other inflammatory diagnoses
  • Polymyalgia rheumatica: especially in older adults; does not cause true synovitis of small joints of hands
  • Sarcoidosis: can present with acute polyarthritis, erythema nodosum, hilar lymphadenopathy, periarticular swelling
  • RS3PE: remitting seronegative symmetrical synovitis with pitting edema (acute bilateral hand synovitis with dorsal pitting edema; seronegative, steroid-responsive; screen for underlying malignancy, especially in older adults)
• Metabolic / Crystal
  • Calcium pyrophosphate deposition disease (can present as chronic polyarthritis “pseudo-RA” involving wrists and MCPs; 5–30% of seronegative RA patients may have radiographic chondrocalcinosis suggesting CPPD; synovial fluid crystal analysis can be definitive)
  • Polyarticular gout
  • Hemochromatosis arthropathy (characteristically affects 2nd–5th MCPs; hook-like osteophytes, chondrocalcinosis, elevated ferritin/transferrin saturation; absence of inflammatory markers)
• Infectious
  • Viral arthritis (parvovirus B19, hepatitis B/C, HIV, EBV, CMV, rubella, chikungunya, Zika)
  • Lyme disease (geography-dependent)
  • Bacterial endocarditis (can present with polyarthritis; RF often positive)
  • Septic arthritis (polyarticular involvement possible)
  • Whipple disease (underrecognized mimic of seronegative RA; median diagnostic delay ~7 years; episodic migratory polyarthritis with persistently elevated inflammatory markers despite DMARDs should prompt consideration; non-invasive PCR testing of saliva/stool available)
• Degenerative / Non-inflammatory
  • Osteoarthritis, inflammatory/erosive osteoarthritis
  • Fibromyalgia (does not cause synovitis but can coexist with or be confused for RA)
• Malignancy-associated
  • Paraneoplastic arthritis (consider in older adults with atypical or refractory inflammatory arthritis, disproportionate constitutional symptoms, or unexplained weight loss)
  • Immune-checkpoint Inhibitor related inflammatory arthritis
• Rare
  • Adult-onset Still’s disease
  • Relapsing polychondritis
  • Familial Mediterranean fever and other autoinflammatory disorders
  • Multicentric reticulohistiocytosis (symmetric erosive polyarthritis with papulonodular skin lesions; prominent DIP involvement; associated with malignancy in ~25–30%)
  • SAPHO syndrome

CLASSIFICATION CRITERIA

Rheumatoid arthritis is a clinical diagnosis.
Classification criteria are not meant as diagnostic criteria to diagnose disease in a single specific patient. Classification criteria are a standardized way of recruiting a well-defined homogenous population of patients in research studies in order to ensure comparability across studies of a heterogenous disease.

ACR 2010 CLASSIFICATION CRITERIA

TREATMENT

Evaluating Treatment Response

• Goal:
  • Treat early: Treatment should start immediately upon diagnosis; a window of opportunity exists early in disease to control inflammation. Diagnosis and treatment should ideally be started ≤3 months from symptom onset
  • Target: ≥50% improvement in disease activity within 3 months and achievement of remission or low disease activity by 6 months. Quantify disease using disease activity score (see table below).
  • Treat to target: If not at target at an appropriate time interval (ex: 3 months), change treatment until target achieved.
  • Tailored approach: Treatment should be tailored to the patient’s disease profile and comorbidities; guided by shared decision-making.
• Evaluation frequency:
  • Frequent in active disease (every 1-3 months) with clinical re-assessment (review, exam), quantification of disease score, and bloodwork.
  • Less frequent (ex: q6-12 months) when stable
  • Screen for comorbidities
• Rationale for treatment
  • Treatment improves quality of life; decreases likelihood of chronic deformity/disability/pain, extra-articular manifestations (particularly important for ILD), and risk of comorbidities (infection, lymphoma, MI, stroke, osteoporosis)
    
• Treatment targets: see table below

Treatment: Non-pharmacologic

• Patient Education
• Exercise
  • Incremental moderate/vigorous aerobic and strength training exercise at least several times weekly
• Diet:
  • No proven “anti-inflammatory diet”; however a diet high in vegetables and fruits such as a “Mediterranean diet” may reduce risk of cardiovascular disease. Vitamin D supplementation and 1,000–1,200 mg of calcium daily may be indicated depending on steroid use and bone density
• Obesity:
  • Weight loss recommended if obese — obesity predicts poor treatment response
• Smoking cessation
  • Smoking is a risk factor for development of and disease progression in RA
• Age appropriate cancer screening
• Routine vaccinations as indicated
• Allied health as needed:
  • Physiotherapy, occupational therapy, registered dietitian, pharmacist

Treatment: Pharmacologic

—Acute:

• Steroids: may consider concurrent short term glucocorticoid (<3 months) as a bridge while initiating DMARDs may be considered to control disease activity before DMARDs start working.
• Oral, intra-articular, intramuscular steroids (ex: prednisone 20-30mg/d tapering over 1-6 weeks)

—Maintenance

• Initial Therapy
  • Low disease activity:
    • May consider monotherapy hydroxychloroquine
  • Moderate-severe:
    • Start with Methotrexate alone or combined with other csDMARDs
    • Can consider combination methotrexate-csDMARD therapy at first visit depending on disease activity, clinical judgement, and shared decision with patient (ex: triple therapy = methotrexate, sulfasalazine, hydroxychloroquine)
  • Methotrexate:
    • Target 20-25mg/week oral or SC within ≤4-6 weeks
    • May consider splitting oral methotrexate as 2-doses over 24 hours for tolerance and increased absorption.
    • Add folic acid 5mg once/week; 5mg 6 days/week if mucositis or worsening macrocytic anemia.
    • If early intolerance to methotrexate, consider switching to sulfasalazine or leflunomide
• Monitoring
  • Should be frequent in active disease (every 1-3 months) with clinical re-assessment, quantification of disease score, and bloodwork
• Treat to target
  • If not at treatment target within reasonable time frame (target of remission within 3 months, less ideally low-disease activity): change treatment regimen until target is achieved
• Subsequent therapy, if not at treatment target within 3 months:
  • Combine csDMARDs if currently on monotherapy csDMARD, or
  • Add advanced DMARD (i.e. tsDMARD or bDMARD) to csDMARD.
  • If cannot tolerate csDMARD combination (ex: if intolerant to any dose of methotrexate), may favour IL-6 or JAK inhibitor for monotherapy
  • If failed an b/ts-DMARD, switch to different class of b/ts-DMARD.
• Terms
  • csDMARD:
    • conventional DMARD
  • Advanced DMARD:
    • tsDMARD (targeted synthetic DMARD), bDMARD (biologic DMARD)
  • csDMARD:
    • Methotrexate, sulfasalazine, hydroxychloroquine, leflunomide
  • tsDMARD
    • JAK inhibitors: Baricitinib, Filgotinib (not available in Canada), Tofacitinib, Upadacitinib
    • May consider avoiding JAKi (specifically, tofacitinib) in male patients >65 with a prior cardiovascular event and smoking history; or, patients with multiple high-risk cardiovascular risk factors due to possible signal for MACE with tofacitinib versus TNFi
  • bDMARD
    • TNF inhibitors: adalimumab, certolizumab, etanercept, golimumab
    • IL-6 inhibitors: sarilumab, tocilizumab, 
    • CD20 inhibitor: rituximab
    • CTLA-4 analogue: abatacept

—Special Populations

• Rheumatoid nodulosis:
  • Continue methotrexate, however if progressive subcutaneous nodules, could consider switching to non-methotrexate DMARD out of possible concern for methotrexate-accelerated nodulosis
• Interstitial lung disease:
  • See Comorbidities, below, for Interstitial Lung Disease screening and treatment
• Lymphoproliferative disease: 
  • Consider favouring rituximab over other DMARDs
• Metabolic dysfunction-associated fatty liver disease:
  • Consider using methotrexate only if normal liver enzymes, liver function, and no evidence of liver fibrosis. Consider baseline liver elastography and co-management with hepatology.
• Past serious infection:
  • Consider favouring combination or switching DMARDs over escalating glucocorticoid therapy. (Glucocorticoids should be minimized and not used long term anyways)
• Hepatitis B carrier:
  • Hepatitis B CORE antibody positive and starting rituximab:
    Prophylactic antiviral therapy regardless of hepatitis B surface antigen status
  • Hepatitis B CORE antibody positive and SURFACE ANTIGEN POSITIVE:
    Prophylactic antiviral therapy if starting a bDMARD or tsDMARD
  • Hepatitis B CORE antibody positive and SURFACE ANTIGEN NEGATIVE
    Frequent monitoring viral load and liver enzymes over prophylactic antiviral therapy
  • Co-manage with hepatology.
• Nontuberculous mycobacterial infection:
  • Consider minimizing glucocorticoids and favouring csDMARDs over bDMARD/tsDMARD if possible depending on disease activity. Consider favouring abatacept over TNF therapy if needed.

—Tapering DMARD

• Complete drug-free remission in RA is rare. Most patients will require continuation of full dose DMARDs
• For patients at treatment target for >6-12 months, could consider in select patients with careful shared decision:
  • Gradual discontinuation of csDMARD if on full dose b/tsDMARD, or
  • Dose-reduction of b/tsDMARD (ex: lowering dose, extending interval)
• If patients lack rapid access to care or if re-establishing medication access is challenging, consider avoiding DMARD tapers

COMORBIDITY MANAGEMENT

— Interstitial Lung disease

• Risk (see Clinical Manifestations above for ILD epidemiology and risk factors)
• Risk Assessment
  • If clinical evidence of ILD:
    (“velcro-like crackles” or chronic dyspnea/cough with abnormal PFTs):
    • High-resolution CT chest
    • Note: history and physical examination alone have poor diagnostic accuracy for ILD
  • If no clinical evidence of ILD:
    Evaluate risk factors, consider HRCT and PFT with ≥1 risk factor
    • Male sex
    • Age ≥60
    • Ever-smoker
    • RF/ACPA positivity especially >3× ULN
    • Moderate-high disease activity
    • Obesity

• Monitoring and Repeat screening
  • If no ILD diagnosis
    • Consider repeat PFTs once yearly in high risk patients
  • If ILD diagnosed:
    • PFTs q3-12 months then yearly once stable
    • Ambulatory desaturation testing q3-12 months then yearly once stable
    • High-resolution CT: repeat as needed
• Treatment of ILD (minimal evidence, driven by expert opinion, co-manage with respirology)
  • *FIRST TREAT UNDERLYING INFLAMMATORY ARTHRITIS WITH DMARDS UNTIL REMISSION IS ACHIEVED.*

Methotrexate in ILD

Is it necessary to stop methotrexate in known RA patients with new ILD diagnosis?
Not necessary to stop methotrexate
Most methotrexate alternatives also have case reports of pneumonitis

Does methotrexate benefit lung outcomes?
Methotrexate appears to benefit lung disease outcomes: improves overall disease activity, decreases odds, and delays incident ILD in RA patients

What about methotrexate pneumonitis?
Pneumonitis can occur within first 12 months of exposure
Presents present with progressive dyspnea, cough, fever, crackles on auscultation and abnormal lung imaging (including opacifications, ground glass, nodules). May have other features of methotrexate toxicity (ex: neutropenia, mucositis). May have eosinophilia on CBC or bronchoalveolar lavage.
Absolute risk is ~0.29% (prospective RCT, retrospective meta-analysis)

What about a treatment-naive patient with a new diagnosis of RA and severe RA-ILD at diagnosis with very low respiratory reserve?
Could avoid initiating new methotrexate treatment in patients with new RA and severe RA-ILD at diagnosis with very low respiratory reserve
Requires discussion and co-management with respirology.

• If active inflammatory arthritis and a b/ts-DMARD is required in context of comorbid ILD, some experts may favour the following (in no particular order, minimal evidence):
  • Abatacept
  • JAK inhibitors (upadactinib, tofacitinib, baricitinib, filgotinib)
  • Rituximab
  • Tocilizumab
• If severe or worsening ILD (ex: progressive decline in PFTs and CT) despite excellent control of inflammatory arthritis, may consider adding:
  • If active inflammatory changes on CT chest (ex: ground glass):
    • Adding an b/ts-DMARD listed above, if currently only on csDMARD.
      
      or, if already on an b/ts-DMARD with no desire to change b/ts-DMARDs:
    • Adding Mycophenolate (+/- nintendanib, particularly if progressive fibrosis) or cyclophosphamide
  • If progressive fibrotic changes on CT chest (ex: increasing honeycombing, reticulation, architectural distortion and lobar volume loss)
    • Nintendanib (+/- mycophenolate), or pirfenidone if not tolerated
    • Nerandomilast
    • Lung transplant referral if appropriate, comanaged by respirology

SARD-ILD requires multi-disciplinary management with rheumatology, respirology, and radiology

— Cardiovascular disease

• Risk:
  • RA confers degree of MI risk comparable to diabetes mellitus
• Risk assessment:
  • Estimate risk according to national guidelines (Canadian Cardiovascular Society, Framingham risk calculator)
  • Measure lipids (including total cholesterol, HDL, LDL) when disease activity is stable/in remission
  • Some experts apply a 1.5 multiplication factor to risk assessment for RA patients
  • Repeat screening at least every 5 years, more frequent in at-risk patients
• Treatment
  • Lifestyle modifications, including regular exercise, a healthy diet, and smoking cessation
  • Treat hypertension, dyslipidemia, and diabetes per national guidelines for general population

Controlling RA disease activity with DMARDs is itself a cardiovascular risk reduction strategy, as chronic inflammation drives atherogenesis

— Osteoporosis

• Risk:
  • RA patients have 2X risk of fracture compared with general population
• Risk Assessment
  • Estimate fracture risk and treat according to national guidelines (Osteoporosis Canada, FRAX calculator)
  • All patients ≥50 years: assess osteoporosis risk factors and signs of undiagnosed vertebral fracture
  • Patients on prednisone ≥2.5 mg/day for ≥3 months should be assessed for fracture risk and may require earlier pharmacotherapy initiation
  • Osteoporosis risk factors:
    • BMI < 20 kg/m2
    • Prior low trauma fracture after age 40 years
    • Falls ≥ 2 in the last year
    • Prednisone ≥5mg/d for ≥3 months
    • Current smoking or alcohol ≥3 units/day
    • Parent had hip fracture
    • Secondary Osteoporosis (includes RA, and SLE)
  • Signs of possible vertebral fracture
    • Prospective height loss > 2 cm or historical > 6 cm
    • Rib-to-pelvis distance ≤ 2 finger-breadths in midaxillary line
    • Occiput-to-wall distance > 5 cm
  • Obtain Bone Mineral density if:
    • Previous hip or spine fracture, or ≥2 fracture events
    • Age 50–64 yr with previous fracture or ≥ 2 risk factors
    • Age 65–69 yr with 1 risk factor
    • Age ≥ 70 yr with no risk factors
• Treatment
  • Exercise, Calcium 1200mg/d (preferably via diet), Vit D 1000IU/day
  • Pharmacotherapy: Bisphosphonates first line, further treatment (bisphosphonate holiday, denosumab, romosozumab and anabolic agents) per national guidelines.
  • Repeat BMD in 3 years if on pharmacotherapy, 3-5 years if not on pharmacotherapy

PROGNOSIS

• Poor prognostic factors
  • Treatment delay
  • Ongoing high disease activity
  • Functional limitation (HAQ ≥1.2)
  • RF or ACPA positivity (particularly high-titer)
  • Early radiographic erosions
  • Extra-articular disease (particularly ILD)
  • Smoking
  • Obesity
  • Comorbidities (≥2)
  • Older age at onset, male sex
  • Low socioeconomic status
  • Native aboriginal heritage (in Canada)
  • HLA-DR4 genotype (not routinely measured)
• Mortality
  • RA is associated with increased all-cause mortality (HR ~1.3–1.5 in contemporary cohorts)
    • Mortality gap has narrowed significantly in patients diagnosed in the modern treatment era likely due to earlier diagnosis, treat-to-target strategies, and wider bDMARD use.
  • Leading causes of death
    • Cardiovascular disease, neoplasm, and respiratory disease.
    • Respiratory causes (ILD, pneumonia) may be an increasingly important contributor to excess mortality as cardiovascular outcomes improve.
  • Persistent high disease activity is the strongest modifiable predictor of mortality.
    • Effective disease control with DMARDs (particularly bDMARDs) is associated with reduced mortality risk

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