Rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disorder that primarily affects the joints (e.g., causes pain, swelling, synovial destruction, deformities), but may also manifest with extraarticular features (e.g., rheumatoid nodules, pulmonary fibrosis). The risk of RA increases with age, and the disease predominantly affects women. The diagnosis is clinical and may be supported by laboratory tests (e.g., rheumatoid factor, anticitrullinated peptide antibodies) and imaging studies (e.g., the presence of synovitis on ultrasound and, later in the disease course, bone erosions and/or joint space narrowing on x-rays). There is no curative therapy for RA but early intervention with disease-modifying antirheumatic drugs (DMARDs) using a treat-to-target strategy can prevent disease progression and RA-related disability.

• Prevalence
  • ∼ 0.24% worldwide [1]
  • 1% in northern Europe and US [2]
• Sex: : ♀ > ♂ (3:1) [3]
• Peak incidence: : 30–50 years [4]

Epidemiological data refers to the US, unless otherwise specified.

• Idiopathic inflammatory autoimmune disorder of unknown etiology
• Risk factors include: [5]
  • Genetic disposition: associated with HLA-DR4 and HLA-DR1 [6]
  • Environmental factors (e.g., smoking)
  • Female sex hormones: Risk of RA is increased in premenopausal individuals and in the first year postpartum.
  • Infection (e.g., periodontitis) [7]
  • Obesity
  • Family history of RA

“A DRone with 4 propellers and 1 camera:” rheumatoid arthritis is associated with HLA-DR4 and HLA-DR1.

• Certain interstitial tissue proteins (e.g. intracellular filament protein vimentin, filaggrin, type II collagen) undergo a posttranslational modification that involves the conversion of arginine to citrulline (citrullination). [8]
• Citrullinated proteins are recognized as foreign by the antigen-presenting cells that present them to CD4⁺ T cells.
• Activation of CD4⁺ T cells leads to the following sequences of events: [9]
  • IL-4 production → B-cell proliferation and differentiation → production of anticitrullinated peptide antibodies → type II hypersensitivity reaction and type III hypersensitivity reaction
  • Migration of CD4⁺ T cells to synovial joints → secretion of cytokines (IFN-γ, IL-17) → recruitment of macrophages → secretion of cytokines (TNF-α, IL-1, IL-6) → inflammation and proliferation
• Bouts of inflammation, angiogenesis, and proliferation → proliferative granulation tissue with mononuclear inflammatory cells → pannus and synovial hypertrophy → invasion, progressive destruction, and deterioration of cartilage and bone
• Antibodies against Fc portion of IgG (rheumatoid factor, RF) are produced to aid in removing autoantibodies and immune complexes.
  • RF excess triggers formation of new immune complexes and type III HSR
  • Individuals with positive RF are more likely to develop extraarticular manifestations. [10]

Articular manifestations [11]

• Polyarthralgia
  • Symmetrical pain and swelling of affected joints (also at rest)
  • Frequently affected joints ; [12]
    • Metacarpophalangeal joints (MCP joints)
    • Proximal interphalangeal joints (PIP joints)
    • Wrist joints
    • Knee joints
    • Metatarsophalangeal joints (MTP joints)
  • Rarely affected: distal interphalangeal joints (DIP joints), first carpometacarpal (CMC) joint, and the axial skeleton (except for the cervical spine)
• Morning stiffness (often > 30 min) that usually improves with activity
• Joint deformities
  • Rheumatoid hand is characteristic and typically manifests with one or more of the following deformities:
    • Deepening of the interosseous spaces of the dorsum of hand
    • Swan neck deformity: PIP hyperextension and DIP flexion
    • Boutonniere deformity: PIP flexion and DIP hyperextension.
    • Hitchhiker thumb deformity (Z deformity of the thumb): hyperextension of the interphalangeal joint with fixed flexion of the MCP joint [13]
    • Ulnar deviation of the fingers
    • Piano key sign: dorsal subluxation of the ulna
  • Hammer toe or claw toe
  • Atlantoaxial subluxation (see “Rheumatoid arthritis of the cervical spine” below)
• Physical examination: compression test (Gaenslen squeeze test)
  • Painful compression of hands (or feet) at the level of the MCP joint (metatarsophalangeal joint)
  • Painful handshake is an early sign of arthritis

DIP joints are not typically affected in RA.

Extraarticular manifestations [14]

• Constitutional symptoms
  • Low-grade fever
  • Myalgia
  • Malaise
  • Fatigue
  • Weight loss
  • Night sweats
• Rheumatoid nodules
  • Skin
    • Nontender, firm, subcutaneous swellings (2 mm–5 cm)
    • Commonly occur in areas exposed to higher pressure, e.g., extensor side of the forearm, bony prominences
  • Lungs
    • Typically bilateral and peripheral
    • Rheumatoid pulmonary nodules may be accompanied by fibrosis and pneumoconiosis (Caplan syndrome).
• Lungs
  • Pleuritis, pleural effusions
  • Interstitial lung disease (e.g., organizing pneumonia) [15]
• Eye: keratoconjunctivitis sicca, scleritis, and episcleritis [16]
• Endocrine and exocrine glands: secondary Sjogren syndrome
• Hematological
  • Anemia
    • Anemia of chronic disease (normocytic anemia)
    • NSAIDs and/or steroids → increased risk of GI bleeding → iron deficiency anemia (microcytic anemia)
    • Methotrexate → decreased folate level → macrocytic anemia
  • Neutropenia
  • Splenomegaly
  • Large granular lymphocyte leukemia
  • Lymphoma
• Musculoskeletal
  • Tenosynovitis and bursitis
  • Carpal tunnel syndrome
    • Typical nocturnal paresthesia of volar hand, thumb, index and middle fingers
    • Atrophy of thenar muscles → difficulty making a fist and inability to oppose the thumb
  • Tarsal tunnel syndrome
• Heart
  • Pericarditis and myocarditis
  • Increased risk of myocardial infarction, stroke, CHF, and atrial fibrillation [17]
• Vascular
  • Peripheral vasculitis, manifests as livedo reticularis
  • Raynaud phenomenon
  • Purpura
  • Vasculitic ulcers
  • Necrosing fingertips
  • Peripheral neuropathy

• Synovial pannus formation and bone invasion: pathological layer of proliferative granulation tissue, mononuclear inflammatory cells, and fibroblast-like mesenchymal cells, releasing cytokines and enzymes, which, in turn, damage and invade the surrounding connective tissue [18]
• Synovial lining hyperplasia with mononuclear cell infiltrate
• Perivascular inflammatory infiltrates
• Angiogenesis
• Fibrin deposition on synovial surfaces
• Rheumatoid nodules: central fibrinoid necrosis with palisading histiocytes (epithelioid cells)

Rheumatoid arthritis of the cervical spine [12]

RA typically affects the cervical spine early in the course of the disease, while normally sparing the thoracic and lumbar spine. RA of the cervical spine most commonly manifests with atlantoaxial subluxation. Other patterns of instability are atlantoaxial impaction and subaxial subluxation.

Atlantoaxial subluxation

• Definition: a potentially life-threatening complication caused by the inflammatory destruction of the ligaments affecting the atlantoaxial joint and the intervertebral joints
• Clinical features
  • Pain and stiffness of the neck (typically early-morning neck pain at rest)
  • Head tilt
  • Neurological deficits
    • Cervical radiculopathy with peripheral paresthesias of the upper limb
    • In some cases, symptoms of high spinal cord compression (see also “Incomplete spinal cord injury”)
      • Slowly progressive spastic quadriparesis
      • Hyperreflexia or positive Babinski reflex
      • Respiratory insufficiency
• Diagnostics
  • Extension and flexion x-rays of the cervical spine
  • MRI
• Treatment: surgery if instability or myelopathy are present

Before undergoing general anesthesia, an airway and neck assessment is crucial in patients with RA, as atlantoaxial subluxation may be present, which increases the risk for spinal cord injury. Preoperative flexion-extension radiographs can help to evaluate the position of the cervical vertebra atlas (C1) with regard to the axis (C2).

Felty syndrome [12]

• Definition: a severe subtype of RA characterized by neutropenia and splenomegaly .
• Epidemiology: rare (1–3 % of patients with RA) [19]
• Clinical features
  • Clinical triad consisting of arthritis, splenomegaly, and neutropenia
  • Other features
    • Skin ulcers of the lower limbs (indicating vasculitis)
    • Hepatomegaly
    • Fever
    • Chest pain (indicating pleuritis or pericarditis)
  • Associated with increased risk of non-Hodgkin lymphoma
• Diagnostics
  • Leukopenia with selective neutropenia
  • ↑ RF
  • ↑ ACPA
• Treatment
  • DMARD: methotrexate
  • Alternative: rituximab [20]
  • Prompt and aggressive antibiotic treatment for suspected infections
  • Consider splenectomy to treat leukopenia and improve the disease course.
  • G-CSF (granulocyte-colony stimulating factor) in cases of severe granulocytopenia
• Complications: Neutropenia increases risk of recurrent bacterial infections.

Arthritis, splenomegaly, and neutropenia may suggest Felty syndrome.

Undifferentiated arthritis [7][21][22]

• Definition: symptoms of inflammatory arthritis that are not attributable to trauma or acute inflammatory events; often a transitional state preceding a definitive diagnosis [7][22]
• Approach to management
  • Refer to a rheumatologist for periodical follow-up.
  • Management strategies are aimed at preventing progression and can be:
    • Nonpharmacological: e.g., smoking cessation, oral health programs [7]
    • Pharmacological: DMARDs [23]
• Prognosis [23]
  • Spontaneous remission in approx. 50% of patients
  • RA develops in approx. one-third of patients [21]

Approach [7][24][25]

• The diagnosis of RA is clinical.
  • Consider RA in patients with arthralgia, joint stiffness, and synovitis lasting ≥ 6 weeks (see “Clinical features”).
  • Consider alternative diagnoses in patients with atypical presentations (see “Differential diagnoses”).
• Perform diagnostic studies to further support the diagnosis and help establish disease severity.
  • Routine laboratory tests. [7][25]
  • X-ray as the initial imaging study
• Consult rheumatology, particularly if the diagnosis is uncertain and when choosing a treatment regimen.

RA is a clinical diagnosis. The 2010 ACR/EULAR classification criteria for RA can help identify RA, but the criteria do not need to be fulfilled in order to establish a diagnosis. [24]

Laboratory studies [7][25]

Routine studies

• Nonspecific parameters
  • ↑ Inflammatory markers
    • ↑ CRP and ↑ ESR
    • Other acute phase reactants may also be elevated (e.g., ferritin).
  • CBC: anemia of chronic disease, thrombocytosis
  • TFTs: to rule out an autoimmune thyroid disease, which is common in patients with RA
  • Serology: ↑ ANAs in 30–50% of patients with RA [21]
• Specific parameters (serological studies) [7][26]
  • Anticitrullinated peptide antibodies; (ACPA), e.g., anticyclic citrullinated peptide (anti-CCP) [27]
  • Rheumatoid factor; (RF): IgM autoantibodies against the Fc region of IgG antibodies [21]
  • Serological studies may be negative (i.e., seronegative RA)

Approx. 30% of patients with RA are negative for ACPA and RF. [25]

Additional studies

Additional studies should be considered on an individual basis.

• Synovial fluid analysis: not routinely recommended [25]
  • Indications
    • Suspicion of septic arthritis
    • Atypical presentation, to rule out differential diagnoses (e.g., gout)
  • Findings are nonspecific [21]
    • Cloudy, yellow appearance
    • Sterile specimen with leukocytosis (WBC count 5,000–50,000/μL)
    • ↑ Neutrophils, granulocytes, and ragocytes
    • ↑ Protein level
    • Possibly RF
• ASCVD risk assessment [7][25]
  • Recommended in all patients with RA, as RA is an ASCVD risk-enhancing factor
  • Includes diabetes mellitus screening, screening for lipid disorders, and a risk calculation using the 2013 ACC/AHA pooled cohort equation

ASCVD is the most common cause of premature death in patients with RA; therefore, an ASCVD risk assessment is recommended in all patients with RA.

Imaging studies [25][29][30]

While x-ray is recommended as the initial test, ultrasound and MRI might additionally be necessary to assess joint disease severity.

• X-ray: initial test
  • Studies
    • Baseline radiographs of both hands (dorsopalmar view) and feet
    • Radiographs of symptomatic joints
  • Findings
    • Early: soft tissue swelling, osteopenia (juxtaarticular)
    • Late: joint space narrowing, marginal erosions of cartilage and bone, osteopenia (generalized), subchondral cysts
• Ultrasound [31]
  • Indication: If available, perform on affected joints to detect clinical or subclinical synovitis.
  • Supportive findings
    • Early signs of inflammation: e.g., subclinical synovitis (synovial hyperemia)
    • Synovial proliferation (pannus formation)
    • Joint effusion: increased fluid (e.g., pus, blood, inflammatory infiltrate) within the synovial compartment of a joint
    • Using contrast can increase the sensitivity of detecting inflammation.
• MRI of the affected joints (with or without contrast)
  • Can help detect early changes in large joints (e.g., subclinical synovitis)
  • Consider especially if cervical spine involvement is suspected (see “Atlantoaxial subluxation”).
• Further imaging studies: Perform if extraarticular manifestations are suspected (e.g., a CT scan for interstitial lung disease, an echocardiogram for pericarditis).

Typical RA findings on x-rays may be subtle or absent upon diagnosis in many patients with early RA; therefore, ultrasound or MRI may be more informative, as they have higher sensitivity for detecting early signs of inflammation and erosion.

Disease activity can be estimated by evaluating a combination of clinical and laboratory features. Disease activity scores may be used to assess RA activity and help guide a treat-to-target strategy (see “Treatment”). The ACR has recommended numerous disease activity scores for clinical practice, including the following: [32]

• Clinical Disease Activity Index

• Simplified Disease Activity Index (SDAI) : includes CDAI parameters plus CRP
• Disease Activity Score with 28-joint count (DAS28) : includes CDAI parameters plus ESR or CRP , but does not include the evaluator global assessment

Consider the influence of concomitant conditions such as fibromyalgia or depression on subjective parameters (i.e., tender joint count and patient or evaluator global assessment) to help prevent patient misclassification.

• Other differential diagnoses
  • Autoimmune-related arthritis (e.g., sarcoidosis, SLE, rheumatic fever, mixed connective tissue disease, polymyalgia rheumatica)
  • Enteropathic arthritis
  • Vasculitides
  • Hemochromatosis
  • Viral arthritis (e.g., parvovirus B19, hepatitis viruses)
  • Lyme arthritis
  • Reactive arthritis (post-urethritis, post-enteritis)
  • Juvenile idiopathic arthritis
  • CPPD disease
  • Basic calcium phosphate crystal deposition diseases
  • Fibromyalgia
  • Soft tissue rheumatic disorders: a group of common nonsystemic focal syndromes characterized by nonarticular pain
  • Hypertrophic osteoarthropathy: typically characterized by periosteal reaction in the metaphyses and diaphyses of long bones and associated with lung disease (e.g., lung cancer)
  • Palindromic rheumatism: autoinflammatory and autoimmune disorder [34]
    • Characterized by relapsing episodes of joint pain, swelling, and stiffness that typically last 12–72 hours followed by asymptomatic periods lasting days to months
    • May progress to RA or other autoimmune conditions (e.g., SLE)

The differential diagnoses listed here are not exhaustive.

Approach [7][25][35]

• Initiate acute antiinflammatory treatment with glucocorticoids and NSAIDs for disease flares.
• Long-term treatment
  • Initiate treatment with conventional DMARD monotherapy.
  • Consider short-term concomitant antiinflammatory treatment.
• Initiate nonpharmacological management.
• Consider surgical treatment in specific cases (e.g., patients with severe joint deformities).

Consult a rheumatologist before initiating treatment.

Acute antiinflammatory treatment [7][25][35]

Temporary (< 3 months) symptomatic treatment with glucocorticoids and/or NSAIDs is indicated for disease flares (i.e., episodes of increased disease activity and symptom worsening). [36]

• Glucocorticoids
  • Systemic prednisone
    • Short-term (i.e., < 3 months) therapy at the lowest effective dose is preferred.
    • Longer-term therapy: Only use in patients with highly active RA who do not respond to maximum doses of DMARDs. [7][35]
    • See also “Side effects of glucocorticoid therapy” and “Preventing complications of long-term glucocorticoid therapy” in “Glucocorticoids.”
  • Intraarticular injections (e.g., with triamcinolone acetonide) can be considered by specialists alongside treatment with DMARDs in patients with predominant symptoms in ≥ 1 medium or large joint.
• NSAIDs and selective COX-2 inhibitors: : relieve symptoms, but do not improve the prognosis
  • Ibuprofen
  • Diclofenac
  • Celecoxib
• Other measures: If a flare occurs due to medication tapering, restart the previous effective treatment regimen.

Glucocorticoids should be used at the lowest effective dose and only for short periods of time to reduce the risk of their many adverse effects (e.g., hypertension, osteoporosis, infections). [25][35]

Long-term pharmacological treatment [7][25][30][35]

Initiation of treatment

• All patients (regardless of baseline disease activity or disease duration): monotherapy with a conventional DMARD
• Consider short-term concomitant use of acute antiinflammatory therapy (i.e., glucocorticoids and/or NSAIDs) for symptom control until the onset of action of DMARDs (e.g., ≥ 6 weeks). [35]

Early administration of DMARDs improves patients' outcomes.

Treat-to-target strategy [30][35]

Long-term treatment is guided by disease activity scoring systems for RA involving clinical and laboratory features, e.g., CDAI. The 2021 ACR guideline does not provide definitions for different stages of disease activity.

• Target at 3 months: ≥ 50% improvement in the disease activity index
• Target at 6 months: low disease activity (or remission)
• Targets not reached: Consult rheumatology to adjust treatment.

A treat-to-target strategy can prevent RA-related disability. [7][30][35]

Do not discontinue all DMARDs in patients who achieve disease remission, as this may trigger a disease flare. [35]

Disease-modifying antirheumatic drugs (DMARDs) [25][30][35]

DMARDs are used as long-term therapy; . They interfere with the inflammatory mechanisms of RA, which can potentially lead to remission. DMARD therapy reduces RA mortality and morbidity by up to 30%. Prevention and monitoring of potential adverse effects are required (see also “Adverse effects” in “Immunosuppressants”). [12]

Synthetic DMARDs

Methotrexate monotherapy is strongly recommended over all other synthetic and biologic DMARDs in patients with moderate to high disease activity. [35]

Biologic DMARDs [30]

• Indication: : persistent moderate or severe disease activity after 3 months of conventional DMARD therapy
• Agents
  • TNF-α inhibitors: e.g., adalimumab , infliximab , etanercept (see also “Contraindications to anti-TNF-α treatment”)
  • Others: rituximab, anakinra, tocilizumab
• Adverse effects include:
  • Infections
  • TB reactivation
  • Hepatitis B reactivation

All biologic DMARDs have similar efficacy when combined with MTX. When choosing a biologic DMARD, consider patient preferences, comorbidities, potential adverse effects, and drug availability. [7]

Prevention and monitoring of adverse effects [25][35][37][38]

Perform studies and vaccinations before the initiation of therapy based on the patient's individual risk and potential adverse effects of the prospective agent.

• CBC, liver transaminases, and serum creatinine at baseline
• HCV and HBV serology at baseline
• TB screening (see “Diagnosis of latent TB”): Perform baseline screening in patients who will receive biologic DMARDs or tofacitinib.
• Vaccinations for patients receiving biologic DMARDs
  • Influenza, pneumococcus, and hepatitis B
  • Herpes zoster
• Offer contraception counseling, family planning, and information on teratogenicity of pharmacological treatment to all patients. See also “RA in pregnancy.”

Nonpharmacological management [25]

• ASCVD prevention measures are associated with improved outcomes in patients with RA.
• Physical and occupational therapy can improve mobility.
• Heat or cold packs for pain management.

Surgical treatment [25][39]

• Indications
  • Consider in patients with extensive joint deformity.
  • Rarely, surgery may be used for symptom control in patients who do not respond to or cannot tolerate the recommended pharmacological regimen.
• Procedures
  • Total joint replacement (e.g., hip joint replacement): Consider in patients with severe joint damage or concomitant osteoarthritis.
  • Synovectomy: surgical removal of the synovial tissue
  • Radiation synovectomy: ablation of inflamed synovia via injection of radioactive agents (beta particles) into the synovial cavity of affected joints [40]
    • Inhibits synovial growth and fibrosis of the synovia
    • May reduce inflammatory activity and pain
    • Also indicated in patients with other chronic inflammatory joint diseases (e.g., active arthrosis, psoriatic arthritis) who do not respond to pharmacological treatment

The ACR/EULAR classification criteria were developed for research purposes and should not be used as diagnostic criteria. These criteria are for targeted use in patients who have at least one joint with clinical synovitis that is not better explained by another cause, e.g. trauma or degenerative joint conditions. [24]

The ACR/EULAR classification criteria have high specificity but low sensitivity. Therefore, the purpose of these criteria is to standardize case definitions for enrollment in clinical studies, not to guide practice. [7][24][41]

Untreated and/or severe cases can result in permanent damage to the joints with stiffening and deformity.

• Complications in the upper limbs: rheumatoid hand deformities (see “Clinical features” above)
• Complications in the lower limbs
  • Baker cyst due to inflammatory joint effusion
  • Foot impairment: pes plano‑valgus (flat feet) [42]
• Other complications
  • Muscle weakness
  • Vasculitis involving the kidneys
  • Amyloid A amyloidosis (AA amyloidosis)
  • Septic arthritis [43]
  • Osteopenia, osteoporosis, and bone fractures [44]
  • Caplan syndrome

We list the most important complications. The selection is not exhaustive.

• Factors associated with poor prognosis
  • Cardiovascular disease and infections are the most common causes of death. [12]
  • Male sex [45]
  • Smoking
  • Social factors (e.g., low socioeconomic status, low level of education)
  • Presence of extraarticular disease
• Elevated laboratory values associated with poor prognosis
  • CRP
  • ESR
  • ACPA
  • RF

Rheumatoid arthritis in pregnancy [46][47]

• General principles
  • Pharmacological treatment for patients desiring pregnancy should be adjusted to avoid teratogenicity.
  • Advise patients with moderate to high disease activity against pregnancy until they reach disease remission or low activity. See “RA activity assessment.”
  • Consider LactMed^® and other trusted databases to provide information for patients (see “Tips and Links”).
• Pharmacological treatment
  • Preferred agents: acetaminophen, NSAIDs, glucocorticoids, sulfasalazine
  • Alternative agents: TNF-α inhibitors, azathioprine [47]
  • Contraindicated agents: methotrexate, leflunomide
  • See also “Pharmacological treatment during pregnancy.”
• Disease course [46]
  • Pain decreases in ∼ 60% of patients during pregnancy, and some patients experience remission even in the absence of DMARD therapy.
  • Flares may increase in the postpartum period.

Discontinue methotrexate ≥ 3 months before patients attempt conception. [46][47]

Management of RA in patients planning pregnancy involves a multidisciplinary team of specialists (e.g., an obstetrician specializing in high-risk pregnancies, and a rheumatologist).