Differentials of RA with correct points of differentiation

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Differentials of Rheumatoid Arthritis (RA) with Points of Differentiation

RA is a clinical diagnosis with no single pathognomonic test. A broad differential must be considered, especially early in disease when the presentation overlaps with many other conditions. Below is a systematic breakdown by category.

1. Other Connective Tissue / Idiopathic Arthritides

Systemic Lupus Erythematosus (SLE)

Feature	RA	SLE
Arthritis type	Erosive, deforming	Non-erosive; reducible deformities (Jaccoud's arthropathy)
Serology	RF+, ACPA+ (high specificity)	ANA+, anti-dsDNA+; ACPA usually negative
Organ involvement	Primarily joints + extra-articular RA features	Kidney (nephritis), skin (malar rash, discoid), CNS, serositis
Complement	Normal	Low (hypocomplementemia)

Spondyloarthropathy (SpA) - includes Ankylosing Spondylitis, Psoriatic, Reactive, Enteropathic

Feature	RA	SpA
Sex	Female predominance	Male predominance
Joint pattern	Symmetric small joints (MCPs, PIPs, wrists)	Often oligoarticular; large joints; lower extremity predominant
Spine	Cervical involvement only (late)	Sacroiliac + axial spine involvement (hallmark)
Serology	RF+, ACPA+	RF-, ACPA-; HLA-B27+
Extra-articular	Nodules, vasculitis, scleritis	Uveitis, psoriasis, IBD, urethritis

Polymyalgia Rheumatica (PMR)

Feature	RA	PMR
Distribution	Hands, feet, wrists (distal)	Shoulder and hip girdle (proximal); no true synovitis of small joints
Serology	RF+/ACPA+ possible	RF-, ACPA-
ESR/CRP	Elevated	Markedly elevated
Response to steroids	Partial	Dramatic response to low-dose prednisolone
Association	-	Giant cell arteritis (temporal arteritis)
Age	Any adult	Typically >60 years

Adult-onset Still's Disease (AOSD)

Feature	RA	AOSD
Fever	Low-grade or absent	High spiking fever >39°C for >1 week
Rash	Absent	Evanescent salmon-colored rash
WBC	Normal or mildly elevated	Leukocytosis >10,000/mm³ with >80% PMNs
Ferritin	Mildly elevated	Markedly elevated (often >5x normal)
Serology	RF+, ACPA+	RF-, ACPA-; ANA usually negative
Lymphadenopathy/splenomegaly	Absent	Common

Sjögren's Syndrome (Primary)

Feature	RA	Primary Sjögren's
Arthritis	Erosive synovitis	Non-erosive arthritis
Serology	RF+, ACPA+	RF+, ANA+; anti-Ro/SS-A, anti-La/SS-B positive; ACPA-
Glandular features	Absent	Keratoconjunctivitis sicca (dry eyes), xerostomia (dry mouth), salivary gland enlargement

Note: Secondary Sjögren's can occur alongside RA.

Fibromyalgia

Feature	RA	Fibromyalgia
Inflammation	Present (swollen joints, elevated CRP/ESR)	Absent - no true synovitis
Serology	RF+, ACPA+ possible	RF-, ACPA-; normal ESR, CRP
Joint exam	Warm, swollen, tender joints	Tender points/pressure points; no swelling

Relapsing Seronegative Symmetric Synovitis with Pitting Edema (RS3PE)

Feature	RA	RS3PE
Serology	RF+/ACPA+	RF-, ACPA-
Edema	Absent	Marked pitting edema of the hands
Age/Sex	Any age, female > male	Elderly men
Response	Requires DMARDs	Very responsive to low-dose glucocorticoids
Association	-	Malignancy/paraneoplastic association

Sarcoidosis

Feature	RA	Sarcoidosis
Joint distribution	Small joints of hands/feet	Large joints, predilection for ankles
Serology	RF+, ACPA+	Often RF+, but ACPA-
Erosions	Yes	Non-erosive
Systemic features	Extra-articular RA features	Hilar lymphadenopathy, erythema nodosum (Löfgren's syndrome), noncaseating granulomas on biopsy

2. Infection-Related

Viral Arthritis (Parvovirus B19, Hepatitis B/C, Rubella, EBV, Chikungunya)

Feature	RA	Viral Arthritis
Onset	Gradual	Acute
Fever/Rash	Absent (unless systemic RA)	Often present (especially Chikungunya, Rubella)
Duration	Chronic/progressive	Usually self-limiting (<6 weeks); Chikungunya can persist for months
Serology	RF+, ACPA+	RF± (Hep B/C may be RF+); ACPA-
Specific tests	-	HBsAg, anti-HCV, parvovirus IgM, CHIKV antibodies
Erosions	Yes (late)	No (non-erosive)

Chikungunya is a notable exception - can cause seronegative chronic arthritis mimicking RA for months/years, but lacks ACPA positivity.

Bacterial Endocarditis

Feature	RA	Bacterial Endocarditis
Fever	Low-grade (if present)	High fever, septic picture
Joints	Symmetric small joints	Predominantly large joints
Serology	RF+, ACPA+	RF+ (in ~50%), ACPA-
Cardiac	Absent	Audible murmur, peripheral emboli (Osler's nodes, Janeway lesions)
Cultures	Sterile	Positive blood cultures

Reactive Arthritis (formerly Reiter's Syndrome)

Feature	RA	Reactive Arthritis
Preceding infection	Absent	Urethritis or gastroenteritis (Chlamydia, Salmonella, Shigella, Campylobacter)
Serology	RF+, ACPA+	RF-, ACPA-
Pattern	Symmetric polyarthritis	Asymmetric oligoarthritis; lower extremities
Extra-articular	-	"Can't see, can't pee, can't climb a tree" - uveitis, urethritis, circinate balanitis, keratoderma blennorrhagica
Genetics	HLA-DR4	HLA-B27+

HIV-Associated Arthritis

Feature	RA	HIV Arthritis
Pattern	Symmetric small joint	Oligoarticular; brief acute pain with initial viremia
Serology	RF+, ACPA+	RF-, ACPA-; HIV serology positive
Fever	Absent unless systemic	Present

3. Crystal Arthropathies

Polyarticular Gout (Chronic Tophaceous Gout)

Feature	RA	Gout
Serology	RF+, ACPA+	RF-, ACPA-
Nodules	Rheumatoid nodules (firm, non-tender, extensor surfaces)	Tophi (chalky deposits; can ulcerate)
Uric acid	Normal	Elevated (hyperuricemia)
Erosions	Marginal erosions, periarticular osteopenia	"Overhanging edge" (punched-out erosions away from joint margin)
DIP involvement	Rare (RA spares DIPs)	Can involve DIP and first MTP
Synovial fluid	Inflammatory; no crystals	Monosodium urate crystals (needle-shaped, negatively birefringent)

Calcium Pyrophosphate Deposition Disease (CPPD / Pseudogout)

Feature	RA	CPPD
Age	Any	Predominantly elderly women
Serology	RF+, ACPA+	RF-, ACPA-
Radiograph	Marginal erosions, periarticular osteopenia	Chondrocalcinosis (cartilage calcification)
Crystal	None	CPPD crystals (rhomboid, weakly positive birefringent)
Associations	-	Hemochromatosis, hyperparathyroidism, hypothyroidism, hypomagnesemia
Pseudo-RA form	-	5% present in a chronic symmetric polyarthritis pattern mimicking RA

Osteoarthritis (Erosive OA)

Feature	RA	Erosive OA
Joints	MCPs, PIPs, wrists (spares DIPs)	DIPs and PIPs (Heberden's/Bouchard's nodes); spares MCPs
Inflammation	Warm, swollen synovitis	Bony enlargement; minimal synovial inflammation
Serology	RF+, ACPA+	RF-, ACPA-
Systemic features	Present	Absent
Radiograph	Erosions, osteopenia	Joint space narrowing, subchondral sclerosis, osteophytes

4. Systemic Manifestations of Other Conditions

Rheumatic Fever

Feature	RA	Rheumatic Fever
Preceding infection	No	Group A Streptococcal pharyngitis
Pattern	Symmetric, additive	Migratory polyarthritis
Cardiac	Extra-articular RA-associated pericarditis/effusion	Carditis with valvular disease
Serology	RF+, ACPA+	RF-, ACPA-; ASO titre elevated
Skin	Rheumatoid nodules	Erythema marginatum; subcutaneous nodules
Criteria	2010 ACR/EULAR	Jones criteria

Thyroid Disease (Hypothyroidism)

Feature	RA	Hypothyroidism
Joints	True synovitis	Polyarthralgias and myalgias
Carpal tunnel	Can occur	Common
Serology	RF+, ACPA+	RF-, ACPA-; TSH elevated
Response	DMARDs	Resolves with thyroid replacement

Malignancy / Paraneoplastic Arthritis

Feature	RA	Paraneoplastic
Serology	ACPA+ (highly specific for RA)	RF+ possible, ACPA usually negative
Onset	Gradual	Often acute/fulminant
Constitutional	Variable	Weight loss, marked fatigue, prominent B symptoms
Association	-	Lymphoma particularly can present like RA

Hypertrophic Osteoarthropathy (HOA)

Feature	RA	HOA
Distribution	MCPs, PIPs, wrists	Knees, ankles, wrists predominate
Bone involvement	Juxtaarticular erosions	Periostitis on X-ray
Association	-	Chronic lung disease, intrathoracic malignancy
Clubbing	Absent	Present

Key Serological Points to Remember

Test	RA	Important Caveat
ACPA (anti-CCP)	Positive in ~70% (specificity >95%)	Most specific test for RA; rarely positive in other diseases
RF	Positive in ~70-80%	Non-specific; also positive in Hep B/C, bacterial endocarditis, Sjögren's, SLE, sarcoidosis
ANA	Low titer positive in ~30%	Without subserologies (anti-dsDNA, anti-Sm, etc.)
ESR/CRP	Elevated	Normal in fibromyalgia; very high in PMR/bacterial endocarditis

A practical rule: ACPA positivity in the right clinical context is strongly diagnostic of RA. The combination of symmetric small joint arthritis + morning stiffness >1 hour + RF + ACPA in an adult >18 years makes RA highly likely.

Sources: Firestein & Kelley's Textbook of Rheumatology (Table 72.2); Goldman-Cecil Medicine (Table 243-2); Rheumatology 2-Volume Set (Elsevier, 2022, Table 90.2)

Clinical points of dd of RA

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I have all the clinical data needed. Here is a focused, purely clinical differentiation guide:

Clinical Points of Differentiation of RA

The focus here is purely on history, symptoms, and physical examination findings - what you find at the bedside, not in the lab.

1. RA vs. Systemic Lupus Erythematosus (SLE)

Clinical Point	RA	SLE
Joint deformity	True erosive deformity - fixed, non-reducible (swan neck, boutonniere, ulnar drift)	Jaccoud's arthropathy - deformities are reducible (passively correctable) due to ligament laxity, not bone erosion
Skin	Rheumatoid nodules (extensor surfaces, firm, non-tender)	Malar rash (butterfly, spares nasolabial folds), discoid rash, photosensitivity
Mucous membranes	Absent	Painless oral ulcers
Hair	Normal	Alopecia (diffuse or frontal)
Kidneys	No nephritis	Lupus nephritis - edema, hypertension
Serositis	Pleuritis/pericarditis rare	Pleuritis, pericarditis common
Raynaud's	Uncommon	Common
Fever	Low-grade if present	More prominent constitutional fever

Key bedside clue: If you can passively reduce the finger deformity - think SLE, not RA.

2. RA vs. Spondyloarthropathy (SpA)

Clinical Point	RA	SpA (AS, PsA, ReA, IBD-related)
Sex	Female predominance (3:1)	Male predominance
Joint pattern	Symmetric, small joints (MCPs, PIPs, wrists) - additive	Asymmetric, large joints, lower limb predominant; axial spine
Back pain	Cervical spine only (late, atlantoaxial subluxation)	Inflammatory low back pain (worse at rest, better with movement); sacroiliitis
Enthesitis	Absent	Present - tender Achilles tendon insertion, plantar fascia, iliac crests
Dactylitis ("sausage digit")	Absent	Present - entire digit swells (distinguishes from RA where only the joint swells)
Eyes	Scleritis, episcleritis	Anterior uveitis (acute, painful, red eye)
Skin	Rheumatoid nodules	Psoriatic plaques (check scalp, umbilicus, natal cleft), keratoderma blennorrhagica (ReA)
Nails	Normal	Pitting, onycholysis (PsA)
DIP joints	Spared	Involved (PsA especially)

Key bedside clue: Dactylitis (whole sausage finger/toe) = SpA until proven otherwise. RA never causes dactylitis.

3. RA vs. Polymyalgia Rheumatica (PMR)

Clinical Point	RA	PMR
Distribution	Distal small joints - hands, wrists, feet	Proximal girdle - shoulder and hip girdle, neck
Stiffness	Morning stiffness of hands/feet	Profound morning stiffness - "can't lift arms to comb hair," "can't rise from a chair"
True synovitis	Present on examination (warm, swollen joints)	Minimal synovitis on examination; pain predominantly from periarticular structures
Muscle strength	Preserved	Preserved (no true myopathy, distinguishes from polymyositis)
Age	Any adult	>60 years; rare before 50
Associated vascular	Absent	Giant cell arteritis - jaw claudication, temporal artery tenderness, visual disturbance

Key bedside clue: PMR has stiffness out of proportion to clinical synovitis. RA has both stiffness AND objective swollen joints.

4. RA vs. Adult-onset Still's Disease (AOSD)

Clinical Point	RA	AOSD
Fever	Low-grade or absent	High spiking fever >39°C, typically once or twice daily (quotidian), returns to normal between spikes
Rash	Absent	Evanescent salmon-pink maculopapular rash - appears with the fever spike, disappears when afebrile (pathognomonic)
Sore throat	Absent	Prominent sore throat at onset
Lymphadenopathy	Absent (or mild)	Prominent generalized lymphadenopathy
Splenomegaly	Rare (Felty's syndrome - late)	Common, early
Joint involvement	Small symmetric joints	Wrist arthritis prominent; also larger joints

Key bedside clue: The evanescent rash that comes and goes with fever spikes is characteristic of AOSD - examine the patient during the fever.

5. RA vs. Reactive Arthritis

Clinical Point	RA	Reactive Arthritis
Preceding history	None relevant	Urethritis/cervicitis (Chlamydia) 1-4 weeks prior, OR acute gastroenteritis (Salmonella, Campylobacter, Shigella)
Pattern	Symmetric polyarthritis	Asymmetric oligoarthritis, lower limbs (knees, ankles)
Classic triad	Absent	"Can't see, can't pee, can't climb a tree" - conjunctivitis, urethritis, arthritis
Skin	Rheumatoid nodules	Keratoderma blennorrhagica (hyperkeratotic rash on soles/palms, resembles pustular psoriasis)
Genitalia	Normal	Circinate balanitis (painless penile lesion)
Mouth	Absent	Painless oral ulcers
Achilles/plantar	Not typically	Enthesitis common

Key bedside clue: Always ask about urethral discharge or diarrhea in the weeks preceding the arthritis.

6. RA vs. Psoriatic Arthritis (PsA)

Clinical Point	RA	PsA
Skin	Rheumatoid nodules (extensor)	Psoriatic plaques - check scalp hairline, elbows, knees, umbilicus, natal cleft (often missed)
Nails	Normal	Pitting, onycholysis, subungual hyperkeratosis, transverse ridging
DIP joints	Spared	Characteristically involved (with nail changes on same digit)
Dactylitis	Absent	Present in ~40%
Symmetry	Symmetric	Variable - can be symmetric polyarthritis (mimics RA closely), or asymmetric, or DIP-only, or axial
Arthritis mutilans	Rare	Classic severe form - "opera glass" deformity, telescoping digits
Nodules	Present	Absent

Key bedside clue: Inspect every nail carefully. Nail pitting + arthritis = PsA until proven otherwise.

7. RA vs. Gout (Chronic Tophaceous)

Clinical Point	RA	Gout
Nodules	Rheumatoid nodules - firm, over extensor surfaces, non-tender, no chalky discharge	Tophi - chalky/white material, may ulcerate with white paste discharge, over ear helix, Achilles, finger pads
DIP joints	Spared	Can involve DIP + first MTP (RA spares first MTP)
Pattern	Symmetric	Asymmetric; episodic acute attacks initially
First MTP	Spared	First MTP involvement (podagra) is classic
Skin over joints	Normal	Tense, shiny, erythematous skin over affected joint during acute attack
Tophi locations	N/A	Ear helix (pinna), Achilles, olecranon bursa, finger pads

Key bedside clue: White chalky discharge from a nodule = tophus (gout). Firm non-tender nodule over olecranon = rheumatoid nodule.

8. RA vs. Osteoarthritis (OA)

Clinical Point	RA	OA
Morning stiffness	Prolonged - >1 hour, may last most of morning	Brief - <30 minutes ("gelling")
Joints involved	MCPs, PIPs, wrists (spare DIP and CMC)	DIPs (Heberden's nodes), PIPs (Bouchard's nodes), 1st CMC thumb; spares MCPs
Joint feel	Soft, boggy, warm synovitis	Bony hard enlargement; crepitus on movement
Pain pattern	Worse at rest/morning; improves with movement	Worse with use/activity; improves with rest
Systemic features	Present (fatigue, weight loss, anemia)	Absent
Nodules	Rheumatoid nodules (soft tissue)	Heberden's (DIP bony) and Bouchard's (PIP bony) nodes - hard, bony

Key bedside clue: Warm, boggy swelling = synovitis (inflammatory) = RA. Hard, bony enlargement = OA.

9. RA vs. Fibromyalgia

Clinical Point	RA	Fibromyalgia
Joint exam	Warm, swollen, tender joints with synovitis	No joint swelling; diffuse tender points (bilateral, above + below waist)
Morning stiffness	True prolonged stiffness with synovitis	Generalized stiffness but no objective swelling
Fatigue	Present	Prominent
Sleep	Disrupted	Non-restorative sleep (characteristic)
Mood	Variable	Depression/anxiety often co-existing
Constitutional	Anemia, weight loss possible	Normal

Key bedside clue: In fibromyalgia, you cannot find a swollen joint - the entire exam is normal except diffuse tenderness.

10. RA vs. RS3PE (Remitting Seronegative Symmetric Synovitis with Pitting Edema)

Clinical Point	RA	RS3PE
Edema	Absent	Dramatic pitting edema of both hands (hallmark)
Onset	Gradual	Often abrupt
Patient profile	Any adult; female predominance	Elderly men (>60 years)
Response to steroids	Partial	Dramatic - almost complete resolution with low-dose prednisolone
Remission	Chronic/progressive	Often remits spontaneously
Associated	-	Consider occult malignancy (paraneoplastic)

11. RA vs. Viral Arthritis

Clinical Point	RA	Viral Arthritis
Onset	Gradual, insidious	Acute
Fever/constitutional	Absent or low-grade	Present, often prominent
Rash	Absent	Common (rubella - maculopapular; Hep B - urticarial; parvovirus - "slapped cheek")
Duration	Persistent, progressive	Self-limiting, usually resolves in <6 weeks
History	-	Travel history (Chikungunya), contact with children (parvovirus), vaccination history (rubella)

Practical Bedside Summary

Feature on Exam	Think of
Reducible deformities	SLE (Jaccoud's)
Sausage digit (dactylitis)	Spondyloarthropathy
Nail pitting + arthritis	Psoriatic arthritis
White chalky nodule discharge	Gout (tophi)
Evanescent rash with fever spike	Adult Still's disease
Pitting hand edema + elderly man	RS3PE
Proximal girdle stiffness, minimal swelling	PMR
Bony hard DIP/PIP enlargement	OA (not RA)
Urethritis + conjunctivitis + arthritis	Reactive arthritis
Warm boggy symmetric MCP/PIP/wrist swelling	RA until proven otherwise

Sources: Firestein & Kelley's Textbook of Rheumatology (Table 72.2); Rheumatology 2-Volume Set, Elsevier 2022; Goldman-Cecil Medicine (Table 243-2); Harrison's Principles of Internal Medicine 22E

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