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FEATURE	DESCRIPTION
Risk Factors	Women (3:1 female-to-male ratio), age 30 to 60 years, HLA-DR4 positivity, smoking history, first-degree family history of RA
Etiology	Chronic systemic autoimmune disease driven by aberrant T-cell and B-cell activation against synovial tissue, with genetic susceptibility (HLA-DR4) and environmental triggers (smoking, infections)
Patient Presentation	Gradual onset of bilateral, symmetric joint pain and swelling involving the small joints of the hands (MCP and PIP joints) and wrists, accompanied by morning stiffness lasting more than 1 hour that improves with activity
Classic Physical Exam	Boggy synovial thickening of MCP/PIP joints with warmth and tenderness; ulnar deviation of fingers; swan neck deformity (PIP hyperextension + DIP flexion); boutonniere deformity (PIP flexion + DIP hyperextension); subcutaneous rheumatoid nodules on extensor surfaces (olecranon, forearms); Baker cyst (popliteal fossa)
Key Diagnostic Results	Anti-CCP antibody (most accurate serologic marker); Rheumatoid Factor (sensitive but not as discriminating); elevated ESR and CRP; X-ray of hands/wrists showing periarticular osteopenia, joint space narrowing, and marginal bony erosions
Management	Methotrexate is the cornerstone DMARD (first-line); TNF-alpha inhibitors (e.g., etanercept, adalimumab) added if inadequate response; NSAIDs and low-dose glucocorticoids for symptom bridging; folic acid supplementation with methotrexate
Keywords	"Morning stiffness more than 1 hour," "symmetric polyarthritis," "MCP and PIP joints," "ulnar deviation," "swan neck deformity," "boutonniere deformity," "rheumatoid nodules," "anti-CCP positive," "pannus formation"

1. Pathophysiology

Rheumatoid arthritis is a chronic, systemic autoimmune disorder in which the immune system mounts an inappropriate inflammatory attack against the synovial membrane of diarthrodial joints. The disease is initiated when genetically predisposed individuals (particularly those carrying HLA-DR4) encounter an environmental trigger such as cigarette smoke or microbial antigens, which promotes citrullination of self-proteins. Citrullination is a post-translational modification that converts arginine residues to citrulline, creating neoantigens that the immune system recognizes as foreign.

CD4+ T-helper cells are activated and recruit macrophages and B cells into the synovium. Macrophages release pro-inflammatory cytokines, most importantly TNF-alpha, IL-1, and IL-6, which amplify local inflammation and drive systemic features such as fatigue, anemia of chronic disease, and elevated acute-phase reactants. B cells produce rheumatoid factor (an IgM autoantibody directed against the Fc portion of IgG) and anti-citrullinated peptide antibodies (anti-CCP), both of which form immune complexes that deposit in the joint and perpetuate inflammation.

The sustained inflammatory milieu causes the synovial membrane to undergo hyperplasia, transforming into a thickened, invasive tissue called a pannus. The pannus behaves almost like a locally aggressive tissue, eroding into the articular cartilage and subchondral bone. This is why radiographs in established RA show marginal erosions and joint space narrowing. The erosive process is mediated by matrix metalloproteinases (MMPs) and osteoclast activation driven by RANKL signaling from the inflamed synovium.

The reason patients experience morning stiffness lasting more than one hour is directly tied to this pathophysiology. During prolonged rest at night, inflammatory cytokines and edema fluid accumulate in the joint space. Active movement gradually clears these mediators through the lymphatic system, which is why stiffness improves with use. This stands in contrast to osteoarthritis, where stiffness is brief (under 30 minutes) because the mechanism is mechanical friction, not inflammatory accumulation.

Extra-articular manifestations occur because RA is a systemic disease, not merely a joint disease. Rheumatoid nodules (granulomatous lesions on extensor surfaces) reflect the same immune-complex-mediated vasculitis that can affect the lungs (interstitial lung disease, pleuritis), the heart (pericarditis), the eyes (scleritis, keratoconjunctivitis sicca), and the blood vessels (rheumatoid vasculitis). Felty syndrome (RA + splenomegaly + neutropenia) and Caplan syndrome (RA + coal worker's pneumoconiosis with large lung nodules) are classic associations tested in vignettes. Chronic uncontrolled RA can also lead to secondary AA amyloidosis, presenting with nephrotic-range proteinuria.

2. Classification and Clinical Manifestation

The 2010 ACR/EULAR classification criteria use a point-based scoring system. A score of 6 or more out of 10 classifies the patient as having RA, provided there is at least one joint with definite clinical synovitis not better explained by another disease.

DOMAIN	CRITERIA	SCORE
Joint involvement	1 large joint	0
	2 to 10 large joints	1
	1 to 3 small joints (with or without large joints)	2
	4 to 10 small joints (with or without large joints)	3
	More than 10 joints (at least 1 small joint)	5
Serology	Negative RF and negative anti-CCP	0
	Low-positive RF or low-positive anti-CCP	2
	High-positive RF or high-positive anti-CCP	3
Acute-phase reactants	Normal CRP and normal ESR	0
	Abnormal CRP or abnormal ESR	1
Duration of symptoms	Less than 6 weeks	0
	6 weeks or more	1

The clinical manifestations can be organized into articular and extra-articular categories:

CATEGORY	MANIFESTATION	DETAILS
Articular	Symmetric polyarthritis	Involves MCP, PIP, wrists, and MTP joints; DIP joints are classically spared
	Morning stiffness	Lasts more than 1 hour, improves with activity
	Hand deformities	Ulnar deviation, swan neck (PIP hyperextension/DIP flexion), boutonniere (PIP flexion/DIP hyperextension), Z-thumb deformity
	Cervical spine	Atlantoaxial (C1-C2) subluxation; risk of spinal cord compression
	Baker cyst	Popliteal fossa cyst from posterior knee joint effusion; may rupture and mimic DVT
Extra-articular	Rheumatoid nodules	Firm, nontender subcutaneous nodules on extensor surfaces; histology shows central fibrinoid necrosis surrounded by palisading macrophages
	Pulmonary	Interstitial lung disease, pleural effusions (low glucose, high LDH), Caplan syndrome
	Cardiac	Pericarditis, accelerated atherosclerosis
	Ocular	Scleritis, episcleritis, keratoconjunctivitis sicca (secondary Sjogren syndrome overlap)
	Hematologic	Anemia of chronic disease, Felty syndrome (RA + splenomegaly + neutropenia)
	Neurologic	Carpal tunnel syndrome (median nerve compression from wrist synovitis), mononeuritis multiplex from vasculitis
	Renal	Secondary AA amyloidosis presenting with proteinuria (in long-standing uncontrolled disease)
	Vasculitis	Rheumatoid vasculitis affecting skin (digital infarcts, purpura), nerves, and other organs

3. Diagnostic Workup

TEST	ROLE	KEY FINDINGS
Anti-CCP antibody	Most accurate serologic test (high sensitivity and high specificity, approximately 95% specificity)	Positive result strongly favors RA over other causes of polyarthritis; also predicts more erosive disease
Rheumatoid Factor (RF)	Screening serologic test (sensitive but less discriminating)	IgM antibody against Fc portion of IgG; positive in ~80% of RA but also positive in hepatitis C, Sjogren syndrome, SLE, endocarditis, and even healthy elderly
ESR and CRP	Acute-phase reactants to gauge disease activity	Elevated in active RA; used for monitoring treatment response, not for diagnosis alone
CBC	Baseline evaluation	Normocytic, normochromic anemia of chronic disease; thrombocytosis (reactive); neutropenia if Felty syndrome
X-ray of hands and feet	Best initial imaging test	Early: soft tissue swelling, periarticular osteopenia. Late: symmetric joint space narrowing, marginal erosions
Ultrasound or MRI of joints	More sensitive than X-ray for early disease	Detects synovitis, early erosions, and tenosynovitis before they appear on plain films
Synovial fluid analysis	When monoarthritis or septic joint must be excluded	Inflammatory pattern: WBC 2,000 to 50,000/microL, predominantly neutrophils; no crystals; negative cultures

The best initial serologic test is the combination of RF and anti-CCP ordered together with acute-phase reactants (ESR, CRP). In a classic exam vignette, a middle-aged woman presents with symmetric polyarthritis of the MCP and PIP joints with morning stiffness lasting more than one hour. The next step is to order RF, anti-CCP, ESR/CRP, and X-rays of the hands and feet.

Anti-CCP is the most accurate serologic marker because of its superior specificity (~95%) compared to RF (~85%). RF is sensitive but can be positive in many other conditions (hepatitis C, Sjogren, SLE, infective endocarditis, and even normal aging). A patient who is RF-positive and anti-CCP-positive has a very high probability of RA. However, approximately 15 to 20% of RA patients are "seronegative" (both RF-negative and anti-CCP-negative), so negative serologies do not rule out the disease.

Plain radiographs remain the best initial imaging study and should include both hands and feet (the feet can show erosions even when the hands appear normal). In early disease, X-rays may be normal or show only soft tissue swelling and periarticular osteopenia. As the disease progresses, marginal erosions and uniform joint space narrowing develop. If X-rays are normal but clinical suspicion remains high, MRI or musculoskeletal ultrasound can detect subclinical synovitis and early bone edema.

Synovial fluid analysis is not routinely needed unless the presentation is atypical (acute monoarthritis raising concern for crystal disease or infection). The fluid shows an inflammatory pattern but is critical for excluding gout (needle-shaped, negatively birefringent crystals) and pseudogout (rhomboid-shaped, positively birefringent crystals).

4. Management and Treatment

PHASE	TREATMENT	DETAILS
Symptom bridging	NSAIDs	Ibuprofen 400 to 800 mg TID or naproxen 250 to 500 mg BID for pain relief; does not alter disease progression
Symptom bridging	Low-dose glucocorticoids	Prednisone 5 to 10 mg/day orally as a "bridge" while waiting for DMARDs to take effect (4 to 6 weeks); taper and discontinue as soon as possible
First-line DMARD	Methotrexate (MTX)	7.5 to 25 mg once weekly (oral or subcutaneous); cornerstone of RA treatment; takes 4 to 6 weeks for clinical effect
Adjunct to MTX	Folic acid 1 mg daily	Reduces methotrexate side effects (stomatitis, GI upset, cytopenias) without reducing efficacy
Second-line DMARD	Hydroxychloroquine, sulfasalazine, or leflunomide	Added to or substituted for MTX; hydroxychloroquine is the mildest (used in early, mild disease or combination therapy); leflunomide is an alternative when MTX is contraindicated
Biologic DMARDs	TNF-alpha inhibitors (etanercept, adalimumab, infliximab)	Added when MTX alone provides inadequate control after 3 to 6 months; always combine with MTX to reduce immunogenicity
Other biologics	Rituximab (anti-CD20), abatacept (CTLA-4-Ig), tocilizumab (anti-IL-6R), JAK inhibitors (tofacitinib, baricitinib)	Used when TNF inhibitors fail or are contraindicated
Intra-articular	Glucocorticoid injection	For acute flare in a single joint; provides rapid local relief

Acute stabilization begins with NSAIDs for pain and low-dose prednisone as a bridge to DMARD therapy. The key concept tested in vignettes is that NSAIDs and glucocorticoids do not prevent joint destruction. They are purely symptomatic. The patient must be started on a DMARD early ("treat-to-target" strategy within 3 months of symptom onset) to prevent irreversible erosive damage.

Methotrexate is the first-line DMARD and the anchor drug for RA. Its mechanism involves inhibition of dihydrofolate reductase and suppression of purine synthesis, resulting in immunosuppression. The dose begins at 7.5 mg once weekly and is titrated up to 25 mg weekly based on response. Patients must receive folic acid 1 mg daily to prevent the most common adverse effects: oral ulcers, nausea, hepatotoxicity, and bone marrow suppression. Monitoring includes a CBC and liver function tests every 4 to 8 weeks initially, then every 8 to 12 weeks once stable.

Critical contraindications for methotrexate include pregnancy (Category X, teratogenic: causes neural tube defects), significant hepatic disease, severe renal impairment ($CrCl < 30\ mL/min$, as MTX is renally cleared), active infection, and significant cytopenias. If methotrexate is contraindicated, leflunomide is the most commonly tested alternative (but leflunomide is also teratogenic). Hydroxychloroquine is the safest DMARD in pregnancy.

Biologic escalation is indicated when methotrexate at adequate doses for 3 to 6 months does not achieve disease remission or low disease activity. TNF-alpha inhibitors are the most commonly used first biologic. Before starting any TNF inhibitor, the patient must be screened for latent tuberculosis (PPD or interferon-gamma release assay) and hepatitis B, because TNF blockade can reactivate both.

Long-term management involves treating to a target of clinical remission or low disease activity, with regular monitoring of disease activity scores, inflammatory markers, and serial imaging to detect new erosions. Glucocorticoids should be tapered and discontinued as soon as the DMARD achieves its effect to avoid complications of chronic steroid use (osteoporosis, diabetes, adrenal suppression).

5. Differential Diagnosis and Distractors

DIFFERENTIAL	WHY IT IS SIMILAR	KEY DISCRIMINATOR
Osteoarthritis (OA)	Both cause joint pain and stiffness in the hands	OA affects DIP joints and first CMC joint (not MCP/PIP); morning stiffness is less than 30 minutes; Heberden (DIP) and Bouchard (PIP) nodes are hard and bony, not boggy; X-ray shows osteophytes and asymmetric joint space narrowing, not erosions
Systemic Lupus Erythematosus (SLE)	Both cause symmetric polyarthritis in young women with positive ANA and elevated ESR	SLE arthritis is non-erosive (Jaccoud arthropathy is reducible); look for malar rash, oral ulcers, serositis, renal disease, anti-dsDNA, and low complement levels
Psoriatic Arthritis (PsA)	Both cause inflammatory arthritis with morning stiffness and can cause joint erosions	PsA involves DIP joints (RA spares DIPs), has dactylitis ("sausage digits"), nail pitting, and enthesitis; often asymmetric; associated with psoriatic skin plaques; RF-negative
Gout	Both cause painful, swollen joints with inflammatory synovial fluid	Gout is typically acute monoarticular (first MTP joint "podagra"), not symmetric polyarticular; synovial fluid shows negatively birefringent needle-shaped crystals; tophi, not rheumatoid nodules
Reactive Arthritis	Both cause inflammatory arthritis with elevated ESR/CRP	Reactive arthritis is asymmetric oligoarthritis of large joints in a young man after urethritis or dysentery; associated triad of conjunctivitis, urethritis, arthritis; RF-negative; HLA-B27-positive
Viral Arthritis (Hepatitis C, Parvovirus B19)	Both can cause symmetric polyarthritis and RF positivity	Viral arthritis is self-limited (weeks to months); hepatitis C is a classic cause of false-positive RF; check hepatitis serologies and parvovirus IgM; no erosions on imaging
Adult-Onset Still Disease	Both cause polyarthritis with elevated inflammatory markers	Still disease presents with quotidian (daily spiking) fevers, salmon-colored evanescent rash, serositis, dramatically elevated ferritin (often >1,000 ng/mL), leukocytosis; RF and ANA are typically negative

6. Traps and High-Yield Pearls

The single most common trap with RA questions involves confusing RA with osteoarthritis based on joint distribution. Test-writers will describe hand pain and stiffness in an older patient to tempt you toward OA, but the key discriminators are the duration of morning stiffness (more than one hour favors RA, less than 30 minutes favors OA), the joints involved (MCP and PIP for RA, DIP and first CMC for OA), and the quality of joint swelling (boggy, warm, soft tissue swelling for RA versus hard, bony enlargement for OA). Never diagnose RA based solely on RF, because RF is positive in many other conditions and even in healthy elderly patients. Anti-CCP is the test that locks in the diagnosis when you need serologic confirmation.

Another common pitfall is the management sequence. A vignette will describe a patient already taking NSAIDs with persistent symptoms, and the question will ask for the "next best step." Students who answer "increase NSAIDs" or "add prednisone" are wrong. The answer is start methotrexate, because the core competency being tested is understanding that DMARDs, not symptomatic therapy, are the foundation of RA treatment. Similarly, if a patient is already on adequate methotrexate and still has active disease, the next step is to add a biologic (TNF inhibitor), not to switch to a different conventional DMARD alone.

Watch for the vignette that presents a woman with RA who is planning pregnancy. Methotrexate and leflunomide are both Category X teratogens. The tested answer is to stop methotrexate, switch to hydroxychloroquine (safe in pregnancy), and ensure the patient has been off methotrexate for at least 1 to 3 months before conception. If a patient on a TNF inhibitor needs TB screening before initiation and the PPD comes back positive, the tested step is to treat latent TB with isoniazid before starting biologic therapy.

Finally, be alert for extra-articular complications used as the clinical hook. A question may describe neck pain and upper extremity weakness in a long-standing RA patient, testing your recognition of atlantoaxial (C1-C2) subluxation, a potentially fatal complication. Another vignette may describe an RA patient with an enlarged spleen and recurrent infections, pointing toward Felty syndrome (RA + splenomegaly + neutropenia). The core competency across all RA questions is the ability to recognize the disease pattern, order the right confirmatory tests, initiate disease-modifying therapy early, and identify dangerous complications.

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