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 can be positive in many patients, but not all, and less frequently in early disease. 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.
[🕑 14 minute read ]

EPIDEMIOLOGY

—Population

• Prevalence
  • ~1.0/100 in Canada, 0.5-1.0/100 in Western countries
• Incidence
  • 0.5-1.0 per 1000 individuals per year
• Ethnicity
  • All ethnicities affected
  • Native aboriginals in Canada have 2-5X prevalence, younger onset, more seropositive, more large joint involvement, and worse prognosis

—Age, Sex

• Peak age
  • At onset 40-60 years, younger in women than men
  • Peak age at onset increasing with time due to aging population in Western World.
  • Highest Incidence is 75-89 years-old in Canada.
• Sex:
  • Female > Male, 2-3:1

—Risk factors: Genetic (60% of risk)

Disease concordance of 12-15% in twin studies A first degree relative with RA increases odds of RA 3x

• 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 (40% of risk)

• Smoking:
  • 20-pack-year current smoker has 2X risk of RA, due to epigenetic modifications (hypomethylating certain DNA regions) and citrullination of proteins 
• Inhaled exposure:
  • Silica dust, textile dust
• Microbiota:
  • Periodontal disease–oral microbiota may citrullinate proteins
  • Gut microbiota–lower biodiversity of gut microbiota in RA vs. general population

CLINICAL MANIFESTATIONS

Joints

—Onset: Common

• Insidious symmetrical, additive over weeks-months (66%)
• 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
• 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 >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
• Exam, joints:
  • LOOK bigger
  • FEEL boggy and warm
  • MOVE less than normal

• Possible Joint Involvement in Rheumatoid versus Primary Osteoarthritis:

RA DEFORMITY	ANATOMICAL CHANGES
Boutonniere’s	PIP flexion, DIP hyperextension
Swan-neck	MCP flexion, PIP hyperextension, DIP flexion
Ulnar Deviation	MCP subluxation and deviation to ulnar side
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 spine, RA only affects C1-C2 joint; can cause C1-C2 instability affecting spinal cord. 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

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, weight loss

—Ocular

• Keratoconjunctivitis sicca, episcleritis, scleritis, peripheral ulcerative keratitis
• Peripheral ulcerative keratitis can progress to corneal melt

—ENT

• Dry mouth, Sjogren’s-overlap
• Hoarseness (due to rare cricoarytenoid arthritis)

—Cardiac

• Pericardium:
  • Pericarditis, pericardial effusion, can get rare cardiac tamponade if large effusion
• Epicardium (coronary vessels):
  • Accelerated atherosclerosis, ↑MI risk.
    • RA confers a degree of cardiovascular risk similar to diabetes mellitus, driven by disease activity
    • See Comorbidity Management below
  • Rare coronary vasculitis
• Myocardium:
  • Myocarditis (uncommon)
• Valvular:
  • Rheumatoid nodulosis (uncommon)

—Vascular

• Rheumatoid vasculitis:
  Rare, 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 (OR 2.23 [95% CI: 2.02, 2.47])

—Respiratory

—Interstitial

Interstitial Lung Disease

• Prevalence:
  • Symptomatic ILD in ~5-15%; 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
  • Genetic factors
    • HLA variants (HLA-B54, HLA-DQB1*0601, HLA-B40 and HLA-DR4)
    • MUC5B promotor variant
  • Disease factors
    • RF and/or CCP+
    • Disease duration >5 years
    • Persistent moderate-high disease activity
    • Erosions
• Presentation:
  • Asymptomatic at early stages; symptoms can be masked if patient is sedentary
  • Symptoms/signs: insidious exertional dyspnea, cough, crackles, clubbing.
• CT pattern:
  • UIP >> OP> NSIP > 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
  • 24 months after diagnosis of RA-ILD, 52% of RA-ILD patients develop progressive fibrosis
    • 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%
  • Median survival: 6.6 years [95% CI 5.6 to 8.6 years]
  • Increased mortality: HR 2.86 [95% CI 1.98–4.12]

Rheumatoid Nodules (“Caplan Syndrome”, rheumatoid pneumoconiosis)

• 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)

—Pleura

• Pleuritis, pleural effusion, pleural thickening, empyema, trapped lung
  Pleural effusions can be asymptomatic and not correlated with inflammatory arthritis activity

—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. 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
• 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: high circulating IL-6 induces hepcidin production, which reduces ferroportin expression in the GI tract and thus decreases iron absorption in the GI tract
• Thrombocytosis (acute inflammation)
• Felty’s syndrome: neutropenia, splenomegaly + RF, thrombocytopenia from hepatic sequestration
  • Associated with active disease
  • Improves with treatment and disease remission
  • Felty’s can progress to large granular lymphocytic leukemia.
• 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)

—Cancer

• Increased prevalence: lung cancer, breast cancer, Hodgkin and non-Hodgkin lymphoma (especially due to active disease)
• Ensure age-appropriate malignancy screening

INVESTIGATIONS: BLOODWORK

—Basic Bloodwork

• CBC
  • Hb: may have anemia of chronic inflammation (usually normocytic)
  • PTL: may have thrombocytosis with acute inflammation, thrombocytopenia if Felty’s syndrome
  • 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
• ESR, CRP
  • Often (but not always) elevated
  • If CRP >100 always consider infection on differential

—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, Specificity for RA 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:
  Positive in 10-25% age >70
• Infection:
  Bacterial endocarditis, hepatitis, TB, Syphilis, 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: the margins of the MCPs/PIP joints have thin or no cartilage (i.e.: the synovium touches bone directly) and is therefore more affected by active synovitis. Thus, rheumatoid erosions are typically marginal
• 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 used routinely for diagnosis of RA.
  • 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 ultrasounds should be done with power Doppler.
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 can show synovitis, tenosynovitis, and bone marrow edema.

MRI can detect synovitis in healthy controls and asymptomatic patients without joint pain

• Nuclear Medicine Bone Scans
  • Don’t order bone scans; neither sensitive nor specific for inflammatory arthritis

DIAGNOSIS

Rheumatoid arthritis is a clinical diagnosis, made in a patient typically presenting with insidious, additive, and symmetrical inflammatory joint pain including the small joints of hands and feet with symptoms like morning stiffness >30min, nocturnal joint pain waking from sleep, and some improvement with use. Exam should show objective evidence of joint swelling. Investigations often show elevated inflammatory markers. If performed, an ultrasound of an active joint would reveal a joint effusion with power Doppler signal (when done by an trained and experience sonographer); X-rays will sometimes show early juxta-articular osteopenia. The RA diagnosis may be supported by positive serology for RF and ACPA in some patients, though serology is negative in many with early RA. A complete assessment includes an evaluation to detect features suggesting alternate causes of inflammatory arthritis (see differential below, also see Approach to Inflammatory Arthritis). Screening for extra-articular manifestations should include questions about dyspnea and auscultation of the chest for interstitial lung disease; PFTs and a CT chest should be pursued in patients at higher risk of RA-related ILD.

DIFFERENTIAL DIAGNOSIS

• Autoimmune
  • Seronegative spondyloarthropathies (ex: psoriatic arthritis, reactive arthritis)
  • SLE, myositis, scleroderma
  • Small-vessel vasculitis
  • Polymyalgia rheumatica
• Metabolic
  • Calcium pyrophosphate deposition disease
  • Polyarticular gout
• Infectious-related
  • Viral arthritis (EBV, HIV, Hep B,/C, parvovirus, chikungunya, Zika)
  • Reactive arthritis
• Other:
  • Osteoarthritis, inflammatory/erosive osteoarthritis, Fibromyalgia
• Rare:
  • Relapsing polychondritis, familial Mediterranean fever, Adult-onset Stills Disease, other autoinflammatory disorders, remitting seronegative symmetrical synovitis with pitting edema (RS3PE). SAPHO, multicentric recticulohistiocytosis

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 ideally be started ≤3 months from symptom onset
  • Target: Aim for remission within ≤3 months (less ideal target is low disease activity) as a shared decision with the patient. 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 3-servings of daily calcium 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: concurrent short term glucocorticoid (<3 months) 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 or sulfasalazine
  • 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 (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
  • If no clinical evidence of ILD:
    Evaluate risk factors
    • Risk calculator per expert opinion (Narvaez et al, table below):
      • 4 points: clinical monitoring
      • 5-6 points: PFTs, high-resolution CT chest if abnormal PFTs
      • ≥7 points: high resolution CT chest

RISK FACTOR	SCORE
Age ≥ 60 years	2 points
Male sex	1 point
Smoking (active or ex)	≤ 20packs/year: 2 points > 20packs/year: 3 points
Disease duration >5 years	1 point
Persistent high disease activity for >6 months	1 point
Serology	RF+ >3x ULN: 1 point ACPA+ ≤3x ULN: 2 points ACPA+ >3x ULN: 3 points
Family history ILD	1 point

• Monitoring and Repeat screening
  • If no ILD diagnosis, but score ≥5:
    • Repeat PFTs once yearly
  • 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
    • Lung transplant referral if appropriate, comanaged by respirology

— 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
• Treatment
  • Lifestyle modifications, including regular exercise, a healthy diet, and smoking cessation
  • Treat hypertension, dyslipidemia, and diabetes per national guidelines for general population

— 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
  • 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 disease activity
  • Functional limitation
  • RF or ACPA positivity
  • Extra-articular disease
  • Interstitial lung disease
  • Low socioeconomic status
  • Native aboriginal heritage
  • Obesity
  • HLA-DR4 genotype (not routinely measured)
• Mortality
  • May have slightly increased all-cause mortality (HR 1.45 [CI: 1.41, 1.48)
  • Leading causes: cardiovascular disease, neoplasm, and respiratory disease.

REFERENCES

Agca R, Heslinga SC, Rollefstad S, Heslinga M, McInnes IB, Peters MJ, Kvien TK, Dougados M, Radner H, Atzeni F, Primdahl J, Södergren A, Wallberg Jonsson S, van Rompay J, Zabalan C, Pedersen TR, Jacobsson L, de Vlam K, Gonzalez-Gay MA, Semb AG, Kitas GD, Smulders YM, Szekanecz Z, Sattar N, Symmons DP, Nurmohamed MT. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis. 2017 Jan;76(1):17-28. doi: 10.1136/annrheumdis-2016-209775. Epub 2016 Oct 3. PMID: 27697765.

Bongartz T, Nannini C, Medina-Velasquez YF, Achenbach SJ, Crowson CS, Ryu JH, Vassallo R, Gabriel SE, Matteson EL. Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study. Arthritis Rheum. 2010 Jun;62(6):1583-91. doi: 10.1002/art.27405. PMID: 20155830; PMCID: PMC4028137.

Conforti, A., Di Cola, I., Pavlych, V., Ruscitti, P., Berardicurti, O., Ursini, F., Giacomelli, R., & Cipriani, P. (2021). Beyond the joints, the extra-articular manifestations in rheumatoid arthritis. Autoimmunity reviews, 20(2), 102735. https://doi.org/10.1016/j.autrev.2020.102735

Conway R, Low C, Coughlan RJ, O’Donnell MJ, Carey JJ. Methotrexate and lung disease in rheumatoid arthritis: a meta-analysis of randomized controlled trials. Arthritis Rheumatol. 2014 Apr;66(4):803-12. doi: 10.1002/art.38322. PMID: 24757133.

Cush J. J. (2021). Rheumatoid Arthritis: Early Diagnosis and Treatment. The Medical clinics of North America, 105(2), 355–365. https://doi.org/10.1016/j.mcna.2020.10.006

Farquhar, H., Vassallo, R., Edwards, A. L., & Matteson, E. L. (2019). Pulmonary Complications of Rheumatoid Arthritis. Seminars in respiratory and critical care medicine, 40(2), 194–207. https://doi.org/10.1055/s-0039-1683995

Fraenkel, L., Bathon, J. M., England, B. R., St Clair, E. W., Arayssi, T., Carandang, K., Deane, K. D., Genovese, M., Huston, K. K., Kerr, G., Kremer, J., Nakamura, M. C., Russell, L. A., Singh, J. A., Smith, B. J., Sparks, J. A., Venkatachalam, S., Weinblatt, M. E., Al-Gibbawi, M., Baker, J. F., … Akl, E. A. (2021). 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis & rheumatology (Hoboken, N.J.), 73(7), 1108–1123. https://doi.org/10.1002/art.41752

Frisell, T., Holmqvist, M., Källberg, H., Klareskog, L., Alfredsson, L., & Askling, J. (2013). Familial risks and heritability of rheumatoid arthritis: role of rheumatoid factor/anti-citrullinated protein antibody status, number and type of affected relatives, sex, and age. Arthritis and rheumatism, 65(11), 2773–2782. https://doi.org/10.1002/art.38097

Fragoulis, G. E., Nikiphorou, E., Larsen, J., Korsten, P., & Conway, R. (2019). Methotrexate-Associated Pneumonitis and Rheumatoid Arthritis-Interstitial Lung Disease: Current Concepts for the Diagnosis and Treatment. Frontiers in medicine, 6, 238. https://doi.org/10.3389/fmed.2019.00238

Haavardsholm, E. A., Aga, A. B., Olsen, I. C., Lillegraven, S., Hammer, H. B., Uhlig, T., Fremstad, H., Madland, T. M., Lexberg, Å. S., Haukeland, H., Rødevand, E., Høili, C., Stray, H., Noraas, A., Hansen, I. J., Bakland, G., Nordberg, L. B., van der Heijde, D., & Kvien, T. K. (2016). Ultrasound in management of rheumatoid arthritis: ARCTIC randomised controlled strategy trial. BMJ (Clinical research ed.), 354, i4205. https://doi.org/10.1136/bmj.i4205

Hazlewood GS, Pardo JP, Barnabe C, Schieir O, Barber CEH, Proulx L, Richards DP, Tugwell P, Bansback N, Akhavan P, Bombardier C, Bykerk V, Jamal S, Khraishi M, Taylor-Gjevre R, Thorne JC, Agarwal A, Pope JE. Canadian Rheumatology Association Living Guidelines for the Pharmacological Management of Rheumatoid Arthritis With Disease-Modifying Antirheumatic Drugs. J Rheumatol. 2022 Oct;49(10):1092-1099. doi: 10.3899/jrheum.220209. Epub 2022 Jul 15. PMID: 35840155.

Hyldgaard C, Hilberg O, Pedersen AB, Ulrichsen SP, Løkke A, Bendstrup E, Ellingsen T. A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease: comorbidity and mortality. Ann Rheum Dis. 2017 Oct;76(10):1700-1706. doi: 10.1136/annrheumdis-2017-211138. Epub 2017 Jun 13. PMID: 28611082.

Johnson SR, Bernstein EJ, Bolster MB, Chung JH, Danoff SK, George MD, Khanna D, Guyatt G, Mirza RD, Aggarwal R, Allen A Jr, Assassi S, Buckley L, Chami HA, Corwin DS, Dellaripa PF, Domsic RT, Doyle TJ, Falardeau CM, Frech TM, Gibbons FK, Hinchcliff M, Johnson C, Kanne JP, Kim JS, Lim SY, Matson S, McMahan ZH, Merck SJ, Nesbitt K, Scholand MB, Shapiro L, Sharkey CD, Summer R, Varga J, Warrier A, Agarwal SK, Antin-Ozerkis D, Bemiss B, Chowdhary V, Dematte D’Amico JE, Hallowell R, Hinze AM, Injean PA, Jiwrajka N, Joerns EK, Lee JS, Makol A, McDermott GC, Natalini JG, Oldham JM, Saygin D, Lakin KS, Singh N, Solomon JJ, Sparks JA, Turgunbaev M, Vaseer S, Turner A, Uhl S, Ivlev I. 2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) Guideline for the Treatment of Interstitial Lung Disease in People with Systemic Autoimmune Rheumatic Diseases. Arthritis Rheumatol. 2024 Aug;76(8):1182-1200. doi: 10.1002/art.42861. Epub 2024 Jul 8. PMID: 38978310.

Johnson SR, Bernstein EJ, Bolster MB, Chung JH, Danoff SK, George MD, Khanna D, Guyatt G, Mirza RD, Aggarwal R, Allen A Jr, Assassi S, Buckley L, Chami HA, Corwin DS, Dellaripa PF, Domsic RT, Doyle TJ, Falardeau CM, Frech TM, Gibbons FK, Hinchcliff M, Johnson C, Kanne JP, Kim JS, Lim SY, Matson S, McMahan ZH, Merck SJ, Nesbitt K, Scholand MB, Shapiro L, Sharkey CD, Summer R, Varga J, Warrier A, Agarwal SK, Antin-Ozerkis D, Bemiss B, Chowdhary V, Dematte D’Amico JE, Hallowell R, Hinze AM, Injean PA, Jiwrajka N, Joerns EK, Lee JS, Makol A, McDermott GC, Natalini JG, Oldham JM, Saygin D, Lakin KS, Singh N, Solomon JJ, Sparks JA, Turgunbaev M, Vaseer S, Turner A, Uhl S, Ivlev I. 2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) Guideline for the Screening and Monitoring of Interstitial Lung Disease in People with Systemic Autoimmune Rheumatic Diseases. Arthritis Rheumatol. 2024 Aug;76(8):1201-1213. doi: 10.1002/art.42860. Epub 2024 Jul 8. PMID: 38973714.

Juge PA, Lee JS, Lau J, Kawano-Dourado L, Rojas Serrano J, Sebastiani M, Koduri G, Matteson E, Bonfiglioli K, Sawamura M, Kairalla R, Cavagna L, Bozzalla Cassione E, Manfredi A, Mejia M, Rodríguez-Henriquez P, González-Pérez MI, Falfán-Valencia R, Buendia-Roldán I, Pérez-Rubio G, Ebstein E, Gazal S, Borie R, Ottaviani S, Kannengiesser C, Wallaert B, Uzunhan Y, Nunes H, Valeyre D, Saidenberg-Kermanac’h N, Boissier MC, Wemeau-Stervinou L, Flipo RM, Marchand-Adam S, Richette P, Allanore Y, Dromer C, Truchetet ME, Richez C, Schaeverbeke T, Lioté H, Thabut G, Deane KD, Solomon JJ, Doyle T, Ryu JH, Rosas I, Holers VM, Boileau C, Debray MP, Porcher R, Schwartz DA, Vassallo R, Crestani B, Dieudé P. Methotrexate and rheumatoid arthritis associated interstitial lung disease. Eur Respir J. 2021 Feb 11;57(2):2000337. doi: 10.1183/13993003.00337-2020. PMID: 32646919; PMCID: PMC8212188.

Kay, J., & Upchurch, K. S. (2012). ACR/EULAR 2010 rheumatoid arthritis classification criteria. Rheumatology (Oxford, England), 51 Suppl 6, vi5–vi9. https://doi.org/10.1093/rheumatology/kes279

Kerola, A. M., Kazemi, A., Rollefstad, S., Lillegraven, S., Sexton, J., Wibetoe, G., Haavardsholm, E. A., Kvien, T. K., & Semb, A. G. (2022). All-cause and cause-specific mortality in rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis: a nationwide registry study. Rheumatology (Oxford, England), 61(12), 4656–4666. https://doi.org/10.1093/rheumatology/keac210

Kiely P, Busby AD, Nikiphorou E, Sullivan K, Walsh DA, Creamer P, Dixey J, Young A. Is incident rheumatoid arthritis interstitial lung disease associated with methotrexate treatment? Results from a multivariate analysis in the ERAS and ERAN inception cohorts. BMJ Open. 2019 May 5;9(5):e028466. doi: 10.1136/bmjopen-2018-028466. PMID: 31061059; PMCID: PMC6501950.

Kishore, S., Maher, L., & Majithia, V. (2017). Rheumatoid Vasculitis: A Diminishing Yet Devastating Menace. Current rheumatology reports, 19(7), 39. https://doi.org/10.1007/s11926-017-0667-3

Koduri G, Solomon JJ. Identification, Monitoring, and Management of Rheumatoid Arthritis-Associated Interstitial Lung Disease. Arthritis Rheumatol. 2023 Dec;75(12):2067-2077. doi: 10.1002/art.42640. Epub 2023 Oct 4. PMID: 37395725.

Mouterde, G., Rincheval, N., Lukas, C., Daien, C., Saraux, A., Dieudé, P., Morel, J., & Combe, B. (2019). Outcome of patients with early arthritis without rheumatoid factor and ACPA and predictors of rheumatoid arthritis in the ESPOIR cohort. Arthritis research & therapy, 21(1), 140. https://doi.org/10.1186/s13075-019-1909-8

Morin, S. N., Feldman, S., Funnell, L., Giangregorio, L., Kim, S., McDonald-Blumer, H., Santesso, N., Ridout, R., Ward, W., Ashe, M. C., Bardai, Z., Bartley, J., Binkley, N., Burrell, S., Butt, D., Cadarette, S. M., Cheung, A. M., Chilibeck, P., Dunn, S., … Wark, J. D. (2023). Clinical practice guideline for management of osteoporosis and fracture prevention in Canada: 2023 update. Canadian Medical Association Journal, 195(39), E1333-E1348. https://doi.org/10.1503/cmaj.221647

Narváez J, Aburto M, Seoane-Mato D, Bonilla G, Acosta O, Candelas G, Cano-Jiménez E, Castellví I, González-Ruiz JM, Corominas H, López-Muñiz B, Martín-López M, Robles-Pérez A, Mena-Vázquez N, Rodríguez-Portal JA, Ortiz AM, Sabater-Abad C, Castrejón I, Dos Santos R, Garrote-Corral S, Maese J, Silva-Fernández L, Castañeda S, Valenzuela C. Screening criteria for interstitial lung disease associated to rheumatoid arthritis: Expert proposal based on Delphi methodology. Reumatol Clin (Engl Ed). 2023 Feb;19(2):74-81. doi: 10.1016/j.reumae.2021.12.003. Epub 2022 Jun 23. PMID: 35753951.

Nishimura, K., Sugiyama, D., Kogata, Y., Tsuji, G., Nakazawa, T., Kawano, S., Saigo, K., Morinobu, A., Koshiba, M., Kuntz, K. M., Kamae, I., & Kumagai, S. (2007). Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Annals of internal medicine, 146(11), 797–808. https://doi.org/10.7326/0003-4819-146-11-200706050-00008

Peschken, C. A., Hitchon, C. A., Robinson, D. B., Smolik, I., Barnabe, C. R., Prematilake, S., & El-Gabalawy, H. S. (2010). Rheumatoid arthritis in a north american native population: longitudinal followup and comparison with a white population. The Journal of rheumatology, 37(8), 1589–1595. https://doi.org/10.3899/jrheum.091452

Public Health Agency of Canada (PHAC). Rheumatoid arthritis in Canada. Ottawa (ON): PHAC; 2020 [cited 2023 June 4]. Available from: https://www.canada.ca/content/dam/phac-aspc/documents/services/publications/diseases-conditions/rheumatoid-arthritis/rheumatoid-arthritis-factsheet.pdf

Sathi N, Chikura B, Kaushik VV, Wiswell R, Dawson JK. How common is methotrexate pneumonitis? A large prospective study investigates. Clin Rheumatol. 2012 Jan;31(1):79-83. doi: 10.1007/s10067-011-1758-6. Epub 2011 Jun 3. PMID: 21638023.

Shmerling, R. H., & Delbanco, T. L. (1991). The rheumatoid factor: an analysis of clinical utility. The American journal of medicine, 91(5), 528–534. https://doi.org/10.1016/0002-9343(91)90190-9

Smolen, J. S., Aletaha, D., Barton, A., Burmester, G. R., Emery, P., Firestein, G. S., Kavanaugh, A., McInnes, I. B., Solomon, D. H., Strand, V., & Yamamoto, K. (2018). Rheumatoid arthritis. Nature reviews. Disease primers, 4, 18001. https://doi.org/10.1038/nrdp.2018.1

Smolen, J. S., Landewé, R. B. M., Bergstra, S. A., Kerschbaumer, A., Sepriano, A., Aletaha, D., Caporali, R., Edwards, C. J., Hyrich, K. L., Pope, J. E., de Souza, S., Stamm, T. A., Takeuchi, T., Verschueren, P., Winthrop, K. L., Balsa, A., Bathon, J. M., Buch, M. H., Burmester, G. R., Buttgereit, F., … van der Heijde, D. (2023). EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Annals of the rheumatic diseases, 82(1), 3–18. https://doi.org/10.1136/ard-2022-223356

Solomon DH, Glynn RJ, Karlson EW, Lu F, Corrigan C, Colls J, Xu C, MacFadyen J, Barbhaiya M, Berliner N, Dellaripa PF, Everett BM, Pradhan AD, Hammond SP, Murray M, Rao DA, Ritter SY, Rutherford A, Sparks JA, Stratton J, Suh DH, Tedeschi SK, Vanni KMM, Paynter NP, Ridker PM. Adverse Effects of Low-Dose Methotrexate: A Randomized Trial. Ann Intern Med. 2020 Mar 17;172(6):369-380. doi: 10.7326/M19-3369. Epub 2020 Feb 18. PMID: 32066146; PMCID: PMC7229518.

Sparks JA, Barbhaiya M, Karlson EW, Ritter SY, Raychaudhuri S, Corrigan CC, Lu F, Selhub J, Chasman DI, Paynter NP, Ridker PM, Solomon DH. Investigating methotrexate toxicity within a randomized double-blinded, placebo-controlled trial: Rationale and design of the Cardiovascular Inflammation Reduction Trial-Adverse Events (CIRT-AE) Study. Semin Arthritis Rheum. 2017 Aug;47(1):133-142. doi: 10.1016/j.semarthrit.2017.02.003. Epub 2017 Feb 10. PMID: 28284844; PMCID: PMC5765986.

Widdifield, J., Paterson, J. M., Bernatsky, S., Tu, K., Tomlinson, G., Kuriya, B., Thorne, J. C., & Bombardier, C. (2014). The epidemiology of rheumatoid arthritis in Ontario, Canada. Arthritis & rheumatology (Hoboken, N.J.), 66(4), 786–793. https://doi.org/10.1002/art.38306

Wysham, K. D., Baker, J. F., & Narla, R. (2022). Osteoporosis evaluation and treatment recommendations in rheumatoid arthritis. Best Practice &Amp; Research Clinical Rheumatology, 36(3), 101757. https://doi.org/10.1016/j.berh.2022.101757

.