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, and/or joint space narrowing on x-rays). There is no curative therapy for RA but early intervention with disease-modifying antirheumatic drugs ( ) using a treat-to-target strategy can prevent disease progression and RA-related disability.
- Idiopathic inflammatory autoimmune disorder of unknown etiology
- Risk factors include: 
- 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). 
- 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: 
- IL-4 production → B-cell proliferation and differentiation → production of anticitrullinated peptide antibodies → and
- 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.
Articular manifestations 
- Symmetrical pain and swelling of affected joints (also at rest)
- Frequently affected 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
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 
- Ulnar deviation of the fingers
- Piano key sign: dorsal subluxation of the ulna
- Hammer toe or claw toe
- (see “ ” below)
- Rheumatoid hand is characteristic and typically manifests with one or more of the following deformities:
- Physical examination: compression test (Gaenslen squeeze test)
Extraarticular manifestations 
- Constitutional symptoms
- Rheumatoid nodules
- Eye: keratoconjunctivitis sicca, scleritis, and episcleritis 
- Endocrine and exocrine glands: secondary
- 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 
- Synovial lining hyperplasia with mononuclear cell infiltrate
- Perivascular inflammatory infiltrates
- Fibrin deposition on synovial surfaces
- Rheumatoid nodules: central fibrinoid necrosis with palisading histiocytes (epithelioid cells)
Subtypes and variants
Rheumatoid arthritis of the cervical spine 
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.
- Definition: a potentially life-threatening complication caused by the inflammatory destruction of the ligaments affecting the atlantoaxial joint and the intervertebral joints
- Pain and stiffness of the neck (typically early-morning neck pain at rest)
- Head tilt
- Neurological deficits
- 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 
- Definition: a severe subtype of RA characterized by neutropenia and splenomegaly .
- Epidemiology: rare (1–3 % of patients with RA) 
- Clinical features
- Complications: Neutropenia increases risk of recurrent bacterial infections.
Adult-onset Still disease
- Epidemiology: 1.6:10,000 general population in France 
- Symptoms similar to juvenile idiopathic arthritis) (systemic onset
- Intermittent high fever
Salmon-pink maculopapular rash
- Affects the proximal limbs and torso
- Associated with pyrexial episodes (mostly evenings)
- Other symptoms: symmetrical polyarthritis, splenomegaly, polyserositis (pleura and pericardium)
- Laboratory studies
Undifferentiated arthritis 
- Definition: symptoms of inflammatory arthritis that are not attributable to trauma or acute inflammatory events; often a transitional state preceding a definitive diagnosis 
- Approach to management
- Spontaneous remission in approx. 50% of patients
- RA develops in approx. one-third of patients 
- The diagnosis of RA is clinical.
- Perform diagnostic studies to further support the diagnosis and help establish disease severity.
- Routine laboratory tests. 
- X-ray as the initial imaging study
- Consult rheumatology, particularly if the diagnosis is uncertain and when choosing a treatment regimen.
Laboratory studies 
- Nonspecific parameters
- Specific parameters (serological studies) 
|Serological testing in rheumatoid arthritis |
|ACPA|| || || |
|ANA|| || |
Additional studies should be considered on an individual basis.
- Synovial fluid analysis: not routinely recommended 
Imaging studies 
- X-ray: initial test
- 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)
- Further imaging studies: Perform if extraarticular manifestations are suspected (e.g., a CT scan for , an echocardiogram for ).
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: 
|Clinical Disease Activity Index (CDAI) |
|28-joint physical examination: swollen joints||0–28|
|28-joint physical examination: tender joints||0–28|
|Patient global assessment||0–10 on a visual analog scale|
|Evaluator global assessment||0– 10 on a visual analog scale|
Interpretation: add scores
- 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.
|Differential diagnoses of inflammatory arthritis|
|Condition||Rheumatoid arthritis (RA)|| |
|Risk factors|| |
Course of disease
| || || || |
|Symmetry of joint involvement|| || || || |
Pattern of disease
|Laboratory findings|| |
Other differential diagnoses
- Autoimmune-related arthritis (e.g., sarcoidosis, SLE, rheumatic fever, mixed connective tissue disease, polymyalgia rheumatica)
- Enteropathic arthritis
- Viral arthritis (e.g., parvovirus B19, hepatitis viruses)
- Lyme arthritis
- Reactive arthritis (post-urethritis, post-enteritis)
- CPPD disease
- Basic calcium phosphate crystal deposition diseases
- 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)
The differential diagnoses listed here are not exhaustive.
- 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 
- 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. 
- 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.
- Systemic prednisone
- NSAIDs and selective COX-2 inhibitors: relieve symptoms, but do not improve the prognosis
- 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). 
Long-term pharmacological treatment 
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). 
Early administration of DMARDs improves patients' outcomes.
Treat-to-target strategy 
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. 
Do not discontinue all DMARDs in patients who achieve disease remission, as this may trigger a disease flare. 
Disease-modifying antirheumatic drugs (DMARDs) 
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”). 
|Synthetic DMARDs for RA |
|Drug class||Agent||Important considerations|
|Conventional DMARDs|| |
|Targeted DMARDs ( )|
Biologic DMARDs 
- Indication: persistent moderate or severe disease activity after 3 months of conventional DMARD therapy
- Adverse effects include:
Prevention and monitoring of adverse effects 
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 “ ”): Perform baseline screening in patients who will receive biologic DMARDs or tofacitinib.
- Vaccinations for patients receiving biologic DMARDs
Nonpharmacological management 
- RA. measures are associated with improved outcomes in patients with
- Physical and occupational therapy can improve mobility.
- Heat or cold packs for pain management.
Surgical treatment 
- Total joint replacement (e.g., ): 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 
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. 
|2010 ACR/EULAR criteria for the classification of RA |
|Score||Joint involvement (pain or swelling)||Serology||Acute-phase reactants||Symptom duration|
|0||≤ 1 large joint||Negative RF and ACPA||Normal CRP and ESR||< 6 weeks|
|1||2–10 large joints||–||↑ CRP or ESR||≥ 6 weeks|
|2||1–3 small joints (with or without large joint involvement)||Low positive RF or ACPA||–||–|
|3||4–10 small joints (with or without large joint involvement)||High positive RF or ACPA||–||–|
Score: Obtained by adding together the points from each feature
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. 
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
- Other complications
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. 
- Male sex 
- Social factors (e.g., low socioeconomic status, low level of education)
- Presence of extraarticular disease
- Elevated laboratory values associated with poor prognosis