What is the differential diagnosis and treatment for a patient presenting with diffuse joint pain?

Differential Diagnosis and Treatment of Diffuse Joint Pain

Initial Clinical Assessment

Begin with a systematic history focusing on six key clinical factors: disease chronology (acute vs. chronic), presence of inflammation, joint distribution pattern, extra-articular manifestations, disease course, and patient demographics (age, gender, geographical location). 1, 2, 3

Critical History Elements

• Duration and timing of symptoms: Acute onset (<6 weeks) suggests viral infection, crystal-induced arthritis, or serum sickness; chronic presentation (≥6 weeks) indicates rheumatoid arthritis, systemic lupus erythematosus, or other chronic arthritides 1, 3
• Morning stiffness duration: Prolonged morning stiffness (>30-60 minutes) strongly suggests inflammatory arthritis 1, 2
• Number and pattern of affected joints: Document specific joints involved, symmetry, and whether small joints (metacarpophalangeal, proximal interphalangeal, metatarsophalangeal, wrists) or large joints (shoulders, elbows, hips, knees, ankles) predominate 1
• Functional status and disability: Assess impact on daily activities 1, 2
• Extra-articular features: Fever, weight loss, fatigue, rash, photosensitivity, Raynaud's phenomenon, dry eyes/mouth, pleuritis suggest systemic inflammatory disease 1, 2
• Family history: Joint hypermobility and autoimmune diseases are often familial 4

Physical Examination Priorities

• Complete rheumatologic examination of all peripheral joints for tenderness, swelling, warmth, and range of motion, plus spine and entheseal sites 2
• Distinguish inflammatory synovitis (palpable synovial thickening, warmth, effusion) from osteoarthritis (bony hypertrophy, crepitus) 3
• Assess for joint hypermobility using a 9-point scale (≥5 points indicates hypermobility), particularly in younger patients with diffuse pain 4
• Examine for clubbing (suggests idiopathic pulmonary fibrosis or other systemic disease) and skin changes 1

Differential Diagnosis by Clinical Pattern

Acute Diffuse Joint Pain (<6 weeks)

• Viral arthritis (parvovirus B19, hepatitis B/C, HIV, rubella) 3
• Crystal-induced arthritis (gout, pseudogout) 3
• Serum sickness or drug reaction 3
• Early presentation of chronic arthritides (rheumatoid arthritis, systemic lupus erythematosus) 3
• Reactive arthritis following infection 1

Chronic Diffuse Joint Pain (≥6 weeks)

• Rheumatoid arthritis: Symmetric small joint involvement, positive RF/ACPA, elevated inflammatory markers 1, 2
• Systemic lupus erythematosus: Non-erosive arthritis, ANA positive, multi-system involvement 1, 5
• Primary Sjögren's syndrome: Dry eyes/mouth, associated with fibromyalgia in 50% of cases 5
• Psoriatic arthritis: Asymmetric oligoarthritis or polyarthritis, psoriasis, nail changes 1
• Osteoarthritis: Bony enlargement, crepitus, age >50 years, statistically associated with joint hypermobility 1, 4
• Fibromyalgia syndrome: Widespread pain, ≥11/18 tender points, fatigue, sleep disturbance, coexists in 25% of RA, 30% of SLE, 50% of primary Sjögren's 5, 6
• Joint hypermobility syndrome: Familial, associated with osteoarthritis, affects 15% of adults referred to rheumatology 4
• Polymyalgia rheumatica: Age >50 years, shoulder and hip girdle pain, markedly elevated ESR 1

Pediatric Considerations

• Growing pains: Thighs, shins, calves; evening/night occurrence; relieved by massage 6
• Juvenile rheumatoid arthritis: Must be excluded before diagnosing benign syndromes 6
• Hypermobility syndrome: Pain in knees, ankles, hips; aggravated by exercise 6
• Fibromyalgia: Better prognosis in children than adults 6

First-Line Laboratory Investigations

Order the following tests at baseline to assess inflammation and guide diagnosis: 2

• Inflammatory markers: ESR and CRP to assess disease activity and prognosis 1, 2
• Complete blood count with differential: Evaluate for infection, inflammation, anemia, thrombocytopenia 2
• Comprehensive metabolic panel: More diagnostically useful than classic rheumatologic tests 3
• Urinalysis: Screen for renal involvement in systemic disease 3

Autoimmune and Serologic Testing

Perform targeted autoantibody testing based on clinical suspicion, not as a screening panel: 1, 2

• Rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA): Test when rheumatoid arthritis is suspected; both are predictive of RA diagnosis and prognosis, but negative tests do not exclude RA 1, 2
• Antinuclear antibody (ANA): Order only if connective tissue disease is suspected based on clinical features; 10-15% of fibromyalgia patients are ANA-positive without having lupus 1, 2, 5
• Additional autoantibodies: Consider anti-dsDNA, anti-Smith, anti-SSA/SSB only when specific connective tissue disease is suspected 1

Common pitfall: High-titer ANA (>1:160) suggests connective tissue disease, but low-titer positivity is nonspecific and found in healthy individuals and fibromyalgia patients 1, 5

Imaging Studies

Plain Radiographs

Obtain radiographs of affected joints as the initial imaging test in most cases to screen for structural damage, erosions, and exclude alternative diagnoses. 1, 2

• For hands and feet: Anteroposterior and oblique views detect early erosive changes in rheumatoid arthritis 1, 2
• For hips: Pelvis view plus additional proximal femur view is superior to isolated hip radiographs 1
• For knees: Include anteroposterior, lateral, and tangential patellar views 1
• Specialized views: False profile or Dunn view for femoroacetabular impingement; Rosenberg view for knee osteoarthritis 1

Advanced Imaging

MRI is the preferred advanced imaging modality when radiographs are negative, equivocal, or nondiagnostic and inflammatory arthritis is suspected. 1, 2

• MRI detects: Bone marrow edema (predictor of radiographic progression), synovitis (present in 96% of patients in clinical remission), erosions earlier than radiographs 2
• Ultrasound: Superior to clinical examination for detecting joint inflammation; useful for guiding injections and evaluating superficial structures 1, 2
• CT: Limited role; useful for evaluating soft tissue calcifications and bony detail when MRI contraindicated 1

Do not routinely obtain imaging in nonspecific low back pain without red flags. 1

Joint Fluid Analysis

Perform arthrocentesis when septic arthritis or crystal-induced arthritis is suspected, particularly with acute monoarticular or oligoarticular presentation. 2

Synovial Fluid Analysis Must Include:

• Cell count and differential: >50,000 WBC/mm³ suggests septic arthritis; 2,000-50,000 suggests inflammatory arthritis 2
• Crystal analysis: Polarized microscopy for monosodium urate (gout) or calcium pyrophosphate (pseudogout) 2
• Gram stain and culture: Essential to exclude infection 2

Diagnostic Algorithm for Inflammatory Arthritis

If ≥3 of the following are present, proceed with serologic testing and consider rheumatology referral: 1, 2

1. Morning stiffness >30 minutes
2. Symmetric small joint involvement
3. Palpable synovitis on examination
4. Elevated ESR or CRP
5. Positive provocative maneuvers (for specific joints)

For rheumatoid arthritis classification, use the 2010 ACR/EULAR criteria requiring ≥6/10 points: 1

• Joint involvement (0-5 points based on number and size)
• Serology: RF and/or ACPA (0-3 points)
• Acute phase reactants: ESR and/or CRP (0-1 point)
• Duration ≥6 weeks (1 point)

Treatment Approach

Rheumatoid Arthritis

Initiate disease-modifying antirheumatic drug (DMARD) therapy immediately upon diagnosis to prevent joint damage and achieve remission. 1

• Methotrexate is first-line DMARD; effects on articular swelling and tenderness seen at 3-6 weeks; does not induce remission or prevent radiologic progression alone but ameliorates symptoms 7
• Prednisone may be used as adjunctive therapy for short-term control during acute exacerbations; consider alternate-day dosing to minimize adrenal suppression 8
• Monitor disease activity with serial examinations and inflammatory markers every 4-6 weeks after treatment initiation 2

Fibromyalgia and Hypermobility

• Conservative symptomatic management: Physical therapy, graded exercise, sleep hygiene 5, 6
• Avoid misdiagnosis: DAS-28 and similar composite indices overestimate disease activity in RA patients with coexisting fibromyalgia 5
• Pediatric fibromyalgia has better prognosis than adult-onset disease 6

Infectious and Crystal-Induced Arthritis

• Blood cultures if fever, acute onset, or suspected bacteremia 2
• Test for viral hepatitis B, C, and tuberculosis before starting immunosuppressive therapy 2

Red Flags Requiring Urgent Evaluation

• Fever with joint pain: Septic arthritis until proven otherwise 2
• Severe or progressive neurologic deficits: Immediate imaging indicated 1
• Constitutional symptoms: Weight loss, night sweats, malaise suggest malignancy or systemic disease 1
• Monoarticular hot, swollen joint: Aspirate to exclude septic arthritis 2