Lyme Disease - Musculoskeletal Manifestations

Lyme disease is a multisystem infection caused by the spirochaete Borrelia burgdorferi and, in Europe, by the related species B. afzelii and B. garinii. It is the most common vector-borne disease in North America and Europe, and it is transmitted by Ixodes ticks, the deer or black-legged tick.

Burden. Insurance-claims data estimate that about 476,000 patients are diagnosed and treated for Lyme disease in the USA each year (Kugeler 2021). Reported European cases exceed 200,000 a year, with marked under-reporting.

Where and when. The endemic areas are the north-eastern USA, the Upper Midwest and Northern California, temperate Europe and temperate Asia. Transmission peaks from late spring to early autumn, when nymphal Ixodes ticks are active. In a non-endemic region such as Australia, where no enzootic B. burgdorferi cycle has been demonstrated, a travel history to an endemic area is essential.

Who. Risk follows exposure: living in or travelling to an endemic area, and hiking, camping or gardening in wooded or grassy country during the tick season.

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The organism. Borrelia burgdorferi sensu lato is a complex of genospecies that differ in geography and in the disease they cause:

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

Surface proteins. Borrelia is a Gram-negative spirochaete carrying outer surface proteins (Osp). OspA is expressed in the tick gut and is the target for vaccines, OspC is upregulated during transmission to the host, and VlsE is a variable surface protein that enables immune evasion.

From bite to disease. The sequence runs:

1. An Ixodes tick, nymph or adult, attaches and feeds
2. Spirochaetes migrate from the tick midgut to the salivary glands
3. Transmission requires more than 36-48 hours of attachment
4. Local infection at the bite site causes erythema migrans
5. Haematogenous and lymphatic dissemination carries the organism to distant sites

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Into the joint. Spirochaetes have a tropism for synovial tissue, binding decorin and glycosaminoglycans in the extracellular matrix. They induce a Th1 inflammatory response in which IL-17 and IFN-gamma drive the synovitis. In some patients the inflammation persists after the spirochaetes have been cleared.

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The immune response. Early infection provokes an innate response with neutrophil infiltration, followed by T-cell and B-cell activation and antibody production. IgM is detectable 1-2 weeks after infection; IgG appears at 4-6 weeks and persists long-term.

Stage 1: early localised disease (3-30 days). Erythema migrans occurs in 70-80% of infected individuals and is pathognomonic. It is an expanding annular erythematous patch at the bite site, with central clearing that gives the bull's-eye or target appearance, and it must measure more than 5 cm for the diagnosis. It is usually painless, though it may burn mildly, and it resolves spontaneously, but it still indicates active infection.

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The rash may come with fatigue, malaise and low-grade fever, headache and myalgia, and regional lymphadenopathy. Any joint symptoms are mild arthralgia rather than true arthritis.

Stage 2: early disseminated disease (weeks to months). Migratory polyarthralgia gives fleeting pains that move from joint to joint, with brief episodes of swelling lasting days before they resolve. Migratory myalgia causes muscle pain without weakness. There is no permanent joint damage at this stage. Beyond the joints:

• Multiple EM lesions - secondary skin lesions distant from the bite
• Lyme carditis in 4-10% - AV block, from first-degree to complete; myocarditis is rare and may require temporary pacing. Carditis usually resolves with antibiotics
• Early neuroborreliosis - facial palsy (bilateral in 25%), lymphocytic meningitis, and painful radiculoneuritis (Bannwarth syndrome)

Stage 3: late disseminated disease (months to years). This is Lyme arthritis, and in the pre-antibiotic-era natural history about 60% of untreated patients developed it. An intermittent oligoarthritis progresses to a chronic monoarthritis, affecting the knee in 90%. Episodes last weeks to months, and untreated disease can cause erosive joint damage.

The knee on examination. The effusion is large and cool, less inflammatory than a septic joint, and out of proportion to the pain. Synovial thickening is mild, range of motion is often preserved, and a Baker's cyst may develop.

Other late manifestations are late neuroborreliosis, with encephalopathy and cognitive impairment or polyneuropathy, and acrodermatitis chronica atrophicans from the European species.

Post-treatment Lyme disease syndrome (PTLDS). Fatigue, musculoskeletal pain and cognitive difficulties persist for more than 6 months after adequate antibiotic treatment, with no evidence of ongoing infection. Further antibiotics are not beneficial and management is supportive.

The stages side by side, with the serology and first-line treatment expected at each (treatment is set out in Management):

Aspirate the joint. Joint aspiration is essential in acute presentations to exclude septic arthritis, and the fluid shows:

• White cell count 10,000-100,000/microL, typically 25,000-50,000
• Neutrophil predominance, which may shift to lymphocytes in chronic disease
• Gram stain and culture negative - routine culture does not grow Borrelia
• No crystals
• PCR for Borrelia DNA positive in 60-85% of untreated cases

Lyme or septic? Lyme arthritis is inflammatory, not septic. The synovial white count is usually below 50,000, against more than 50,000 in septic arthritis; the patient is less systemically unwell and has less pain relative to the swelling; and Borrelia PCR is positive while culture is negative.

Two-tier serology. The CDC-recommended standard two-tier test (STTT) screens first and confirms second. The first step is an ELISA or IFA, with a sensitivity above 90% in late disease but only 40-60% in early disease. A negative screen with early disease suspected means treating clinically and repeating in 2-4 weeks; a positive or equivocal screen goes to the second step.

The Western blot detects antibodies to specific Borrelia proteins and is more specific than ELISA alone. Never perform it without a positive or equivocal ELISA: on its own it has a high false-positive rate. The band criteria depend on the duration of symptoms:

• IgM - 2 of 3 bands (23, 39, 41 kDa), valid only in the first 4 weeks
• IgG - 5 of 10 bands, used after 4 weeks of symptoms

Other blood tests. ESR and CRP are mildly elevated in active disease. Rheumatoid factor and anti-CCP are negative, which distinguishes Lyme arthritis from rheumatoid arthritis, and ANA is usually negative.

Radiographs are usually normal in early Lyme arthritis beyond soft-tissue swelling and an effusion, and may show erosions in chronic untreated disease.

MRI shows synovial thickening and enhancement, the effusion and bone marrow oedema in severe cases, and may show a Baker's cyst. It is useful to assess cartilage damage.

Ultrasound quantifies the effusion, shows synovial hypertrophy and guides aspiration.

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The two-tier algorithm described above is the standard two-tier test (STTT): an EIA/IFA screen followed by an IgM/IgG immunoblot (Western blot). The modified two-tier test (MTTT) replaces the subjective immunoblot with a second, different EIA. It is endorsed alongside STTT by the 2020 IDSA/AAN/ACR guideline and underpinned by several assay combinations cleared by the US FDA in 2019.

How it works. Both tiers are enzyme immunoassays:

• Tier 1 - a first EIA, commonly a whole-cell sonicate EIA
• Tier 2 - if tier 1 is positive or equivocal, a second EIA (typically the C6 peptide EIA) rather than an immunoblot
• A result is called positive only if both EIAs are reactive; the order of the two may be reversed depending on the cleared combination

Why it matters. MTTT removes the operator-dependent, band-counting interpretation of the Western blot, and it is fully automatable, faster and cheaper to run at scale. In early disease it has higher sensitivity than STTT with comparable specificity; in a European erythema-migrans cohort the best algorithm reached about 78% sensitivity and about 96% specificity.

The same caveat. Neither algorithm reliably detects early localised disease. Seronegativity is common in the first two weeks, and a compatible erythema migrans is still treated clinically whichever algorithm is used.

Children are a major Lyme-arthritis demographic, and in Lyme-endemic areas most acute knee monoarthritis in a child is inflammatory rather than septic. In one large series of children presenting with knee monoarthritis, roughly half had Lyme arthritis and only about 3% had true septic arthritis (Deanehan 2013). The challenge is to avoid an unnecessary washout while never missing a septic joint.

What favours Lyme in a child. Knee involvement and a history of tick exposure point towards Lyme. So do an absent or only low-grade fever, a child often well enough to bear weight, and peripheral inflammatory markers (ESR, CRP, neutrophil count) and a synovial white count lower than in septic arthritis.

The prediction rule. In endemic paediatric knee monoarthritis, two predictors mark high risk of septic arthritis:

• A peripheral absolute neutrophil count of 10,000 cells/mm3 or greater
• An ESR of 40 mm/h or greater

Children below both thresholds are low-risk and may reasonably be observed with serology rather than immediate arthrocentesis. Deanehan derived the rule and it was externally validated in a multicentre Pedi Lyme Net cohort with 100% sensitivity for septic arthritis, but it is a rule-out aid, not a substitute for aspiration when septic arthritis is genuinely suspected. The evidence card below sets out how few septic children Deanehan's own validation contained.

Doxycycline at any age. The historical avoidance of doxycycline in children under 8 was driven by concern over dental staining with tetracyclines. Short courses, 21 days or fewer, do not cause clinically significant tooth discolouration, and current IDSA/AAN/ACR guidance supports doxycycline for Lyme disease at any age. Amoxicillin or cefuroxime remain effective alternatives, but the older under-8 contraindication should no longer automatically exclude a short Lyme course of doxycycline.

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 the diagnosis is uncertain
3. Joint damage - rare end-stage arthropathy requiring arthroplasty

Musculoskeletal complications. The joint and its surroundings can be left with:

• Chronic arthritis - persistent joint inflammation
• Erosive joint damage - in prolonged untreated cases
• Post-infectious autoimmune arthritis - antibiotic-refractory disease
• Baker's cyst - a popliteal cyst from the chronic effusion
• Tendinopathy - Achilles and patellar tendon involvement

The cardiac and neurological complications are described with the stages in Clinical Presentation.

Complications of treatment. Treatment brings its own problems:

• Jarisch-Herxheimer reaction - fever and chills within 24 hours of starting antibiotics (spirochaete lysis)
• Antibiotic-related - C. difficile colitis; photosensitivity with doxycycline
• PICC line - infection and thrombosis during IV therapy

Prognosis. Treated early, the prognosis is excellent and complete resolution is expected. Late disease responds to oral or IV antibiotics in 80-90%, and the antibiotic-refractory remainder responds to immunomodulation or synovectomy. PTLDS may persist for months but eventually improves, and erosive arthritis is rare with modern treatment.

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.

• 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.