Lyme Disease - Musculoskeletal Manifestations

Lyme disease is a multisystem infectious disease caused by the spirochete Borrelia burgdorferi (and related species B. afzelii and B. garinii in Europe). It is the most common vector-borne disease in North America and Europe, transmitted by Ixodes species ticks (deer tick/black-legged tick).

Epidemiology:

• Burden: insurance-claims data estimate approximately 476,000 patients diagnosed and treated for Lyme disease annually in the USA (Kugeler 2021); reported European cases exceed 200,000 per year with marked under-reporting
• Endemic areas: Northeastern USA, Upper Midwest, Northern California, temperate Europe, temperate Asia
• Peak transmission: late spring to early autumn (nymphal Ixodes activity)
• Musculoskeletal involvement: in the pre-antibiotic-era natural history, around 60% of untreated patients developed intermittent arthritis
• Knee involvement: roughly 90% of Lyme arthritis episodes involve the knee

Risk Factors:

• Geographic exposure: Residence or travel to endemic areas
• Outdoor activities: Hiking, camping, gardening in wooded/grassy areas
• Tick exposure: Tick attachment greater than 36-48 hours required for transmission
• Season: Late spring to early autumn (peak tick activity)

Understanding the pathophysiology of Lyme disease explains its clinical stages and the rationale for treatment.

The Causative Organism

Borrelia burgdorferi sensu lato complex:

• B. burgdorferi sensu stricto: North America and Europe - arthritis predominant
• B. afzelii: Europe - skin manifestations (acrodermatitis chronica atrophicans)
• B. garinii: Europe - neurological predominant

Spirochete characteristics:

• Gram-negative spirochete with outer surface proteins (Osp)
• OspA: Expressed in tick gut, target for vaccines
• OspC: Upregulated during transmission to host
• VlsE: Variable surface protein enabling immune evasion

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Transmission and Dissemination

Tick bite to disease:

1. Ixodes tick attaches and feeds (nymph or adult)
2. Spirochetes migrate from tick midgut to salivary glands
3. Transmission requires greater than 36-48 hours of attachment
4. Local infection at bite site causes erythema migrans
5. Haematogenous and lymphatic dissemination to distant sites

Joint involvement mechanism:

• Spirochetes have tropism for synovial tissue
• Bind to decorin and glycosaminoglycans in extracellular matrix
• Induce Th1 inflammatory response
• IL-17 and IFN-gamma drive synovial inflammation
• Persistent inflammation despite spirochete clearance in some patients

Immune Response

• Early infection: Innate immune response, neutrophil infiltration
• Adaptive response: T-cell and B-cell activation, antibody production
• IgM antibodies: Detectable 1-2 weeks after infection
• IgG antibodies: Detectable 4-6 weeks, persist long-term
• Molecular mimicry: OspA shares epitopes with human LFA-1 (implicated in refractory arthritis)

Stage 1: Early Localised Disease (3-30 days)

Erythema migrans (EM):

• Occurs in 70-80% of infected individuals
• Expanding annular erythematous patch at bite site
• "Bull's-eye" or target lesion appearance (central clearing)
• Minimum size greater than 5cm for diagnosis
• Usually painless, may have mild burning
• Resolves spontaneously but indicates active infection

Associated symptoms:

• Fatigue, malaise, low-grade fever
• Headache, myalgia
• Regional lymphadenopathy
• Mild arthralgia (not true arthritis)

Stage 2: Early Disseminated Disease (Weeks to Months)

Musculoskeletal features:

• Migratory polyarthralgia: Fleeting joint pains, multiple joints
• Migratory myalgia: Muscle pain without weakness
• Brief swelling episodes (days), then resolution
• Moves from joint to joint
• No permanent joint damage at this stage

Other manifestations:

• Multiple EM lesions: Secondary skin lesions distant from bite
• Carditis: AV block (first to complete), myocarditis (4-10%)
• Early neuroborreliosis: Facial palsy (bilateral in 25%), meningitis, radiculopathy (Bannwarth syndrome)

Stage 3: Late Disseminated Disease (Months to Years)

Lyme Arthritis:

• Develops in approximately 60% of untreated patients
• Intermittent oligoarthritis progressing to chronic monoarthritis
• Knee affected in 90% of cases
• Large effusion, often out of proportion to pain
• Episodes last weeks to months
• Can cause erosive joint damage if untreated

Examination findings:

• Large, cool effusion (less inflammatory than septic)
• Mild synovial thickening
• Range of motion often preserved
• Less pain than degree of swelling suggests
• Baker's cyst may develop

Other late manifestations:

• Late neuroborreliosis: Encephalopathy, polyneuropathy
• Acrodermatitis chronica atrophicans (European species)

Post-Treatment Lyme Disease Syndrome (PTLDS)

• Persistent symptoms after adequate antibiotic treatment
• Fatigue, musculoskeletal pain, cognitive difficulties
• Duration greater than 6 months post-treatment
• NO evidence of ongoing infection
• Further antibiotics NOT beneficial
• Management is supportive

Laboratory Studies

Two-Tier Serological Testing (CDC Recommended):

Step 1 - ELISA or IFA (Screening):

• High sensitivity (greater than 90% in late disease)
• Lower sensitivity in early disease (40-60%)
• If NEGATIVE and early disease suspected, treat clinically and repeat in 2-4 weeks
• If POSITIVE or EQUIVOCAL, proceed to Step 2

Step 2 - Western Blot (Confirmation):

• Detects antibodies to specific Borrelia proteins
• IgM criteria: 2 of 3 bands (23, 39, 41 kDa) - valid only in first 4 weeks
• IgG criteria: 5 of 10 bands - use after 4 weeks of symptoms
• More specific than ELISA alone
• Do NOT perform Western blot without positive/equivocal ELISA

Other laboratory tests:

• ESR/CRP: Mildly elevated in active disease
• RF and anti-CCP: Negative (distinguishes from RA)
• ANA: Usually negative
• PCR: Can detect Borrelia DNA in synovial fluid (60-85% sensitivity)

Synovial Fluid Analysis

Joint aspiration is essential to exclude septic arthritis:

• WBC count: 10,000-100,000/microL (typically 25,000-50,000)
• Predominance: Neutrophils (may shift to lymphocytes in chronic)
• Gram stain: NEGATIVE
• Culture: NEGATIVE (routine culture does not grow Borrelia)
• Crystals: NEGATIVE
• PCR for Borrelia DNA: Positive in 60-85% of untreated cases

Distinguishing from septic arthritis:

• Lower WBC count (usually less than 50,000 in Lyme)
• Patient less systemically unwell
• Less pain relative to swelling
• PCR positive for Borrelia, culture negative

Differential Diagnosis of Chronic Knee Monoarthritis

Imaging

Plain radiographs:

• Usually normal in early Lyme arthritis
• Soft tissue swelling
• Effusion
• May show erosions in chronic untreated disease

MRI:

• Synovial thickening and enhancement
• Joint effusion
• May show Baker's cyst
• Bone marrow oedema in severe cases
• Useful to assess cartilage damage

Ultrasound:

• Effusion quantification
• Synovial hypertrophy
• Guides aspiration

Indications for Orthopaedic Intervention

Surgical intervention in Lyme disease is limited to refractory cases:

1. Antibiotic-refractory Lyme arthritis: Persistent synovitis after two courses of antibiotics
2. Diagnostic arthroscopy: When diagnosis uncertain
3. Joint damage: Rare end-stage arthropathy requiring arthroplasty

Disease Complications

Musculoskeletal:

• Chronic arthritis: Persistent joint inflammation
• Erosive joint damage: In prolonged untreated cases
• Post-infectious autoimmune arthritis: Antibiotic-refractory disease
• Baker's cyst: Popliteal cyst from chronic effusion
• Tendinopathy: Achilles, patellar tendon involvement

Cardiac:

• Lyme carditis: AV block (1st, 2nd, 3rd degree) in 4-10%
• Myocarditis: Rare, may require temporary pacing
• Usually resolves with antibiotics

Neurological:

• Facial palsy: Unilateral or bilateral (25% bilateral)
• Meningitis: Lymphocytic meningitis
• Radiculopathy: Bannwarth syndrome (painful radiculoneuritis)
• Late encephalopathy: Cognitive impairment

Treatment Complications

• Jarisch-Herxheimer reaction: Fever, chills within 24 hours of antibiotic initiation (spirochete lysis)
• Antibiotic-related: C. difficile colitis, photosensitivity (doxycycline)
• PICC line complications: Infection, thrombosis (IV therapy)

Prognosis

• Early treatment: Excellent prognosis, complete resolution expected
• Late disease: 80-90% respond to oral or IV antibiotics
• Antibiotic-refractory: 10-20%, responds to immunomodulation/synovectomy
• PTLDS: May persist for months but eventually improves
• Erosive arthritis: Rare with modern treatment

• Post-treatment Lyme disease syndrome (PTLDS): persistent fatigue, pain and cognitive symptoms after adequate treatment. Multiple randomized trials show no durable benefit from prolonged antibiotics, yet the underlying mechanism (immune dysregulation vs residual antigen vs unrelated) remains unresolved.
• "Chronic Lyme disease": a term used outside evidence-based guidelines for ill-defined symptom complexes, often without serologic confirmation. Guideline bodies do not endorse long-course or repeated antibiotic regimens for it given harm without benefit.
• Antibiotic-refractory arthritis - infection vs autoimmunity: despite negative synovial PCR, debate continues over whether residual peptidoglycan/antigen drives persistent synovitis versus a purely autoimmune (OspA/LFA-1 mimicry, HLA-DRB1*04) process. This determines whether escalation is immunomodulatory rather than antimicrobial.
• DSCATT / locally acquired tick illness in non-endemic regions: whether a Lyme-like syndrome can be acquired where no enzootic B. burgdorferi cycle is demonstrated remains scientifically unsettled.
• Optimal antibiotic duration: trends favour shorter courses (e.g. comparative data supporting shorter doxycycline regimens for early disease), but the precise minimum effective duration for arthritis is not firmly established.
• Synovial PCR interpretation: a positive synovial PCR does not always equate to viable organisms, complicating decisions on re-treatment versus immunomodulation.

Global epidemiology

• Northern-hemisphere disease following the Ixodes enzootic cycle; highest incidence in the Northeastern/Upper Midwest USA and temperate Central Europe (Slovenia, Germany, Austria show some of the highest reported rates)
• US diagnosed-and-treated burden estimated at approximately 476,000 patients annually; surveillance under-counts substantially (Kugeler 2021)
• Late manifestation differs by genospecies and region: arthritis predominates in North America (B. burgdorferi); neuroborreliosis and acrodermatitis chronica atrophicans are more common in Europe/Asia (B. garinii, B. afzelii)
• In regions with no demonstrated enzootic cycle (e.g. Australia), classic B. burgdorferi Lyme disease is acquired only abroad; locally acquired tick-symptom complexes (DSCATT) are a distinct, unresolved entity and should prompt consideration of other tick-borne illness (e.g. rickettsioses)

Side-by-side society guidance

Registry and practice variation

• No dedicated Lyme arthritis implant registry exists; surgical evidence rests on case series (e.g. Schoen 1991). End-stage destructive arthropathy requiring arthroplasty is rare with modern antibiotic therapy.
• High-resource settings: ready access to two-tier serology, synovial PCR, MRI and arthroscopic synovectomy.
• Limited-resource or non-endemic settings: diagnosis hinges on exposure history and clinical erythema migrans; serology may be sent to reference laboratories with delay, and empirical doxycycline for a compatible clinical picture is reasonable.