Lyme disease is a complex infectious disease caused by Borrelia burgdorferi and transmitted through infected Ixodes ticks. Annually, more than 30,000 new cases of Lyme disease are reported to the Centers for Disease Control and Prevention (CDC); however, the true incidence is estimated at more than 450,000 cases each year.1 The incidence of Lyme disease and its distribution in the US and Canada are increasing.2

Early Lyme disease is sometimes characterized by fever, headache, fatigue, and erythema migrans. A second phase may include facial palsy or other neurologic symptoms. Many patients do not notice their symptoms or seek treatment in these phases. Untreated, late Lyme disease arthritis can develop months or years after infection. In addition, a spectrum of inflammatory or noninflammatory conditions can develop after Lyme disease treatment, including: postinfectious Lyme arthritis, post-treatment Lyme disease syndrome, and systemic autoimmune diseases.3

The American College of Rheumatology (ACR) Convergence 2021 featured a scientific session titled, Lyme Disease & Other Tick-Borne Illnesses: What Every Rheumatologist Must Know,3 that was aimed at informing rheumatologists about these conditions.  

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Robert Kalish, MD, director of Rheumatology Education at Tufts Medical Center moderated the session, and the presenters included John Aucott, MD, Johns Hopkins University School of Medicine, Baltimore and Sheila Arvikar, MD, Massachusetts General Hospital, Boston.

Late Lyme Disease Arthritis

Without treatment, approximately 60% of patients develop late Lyme disease monoarthritis or oligoarthritis.3 The primary site is the knee, with or without Baker’s cyst. Other locations include the shoulders, ankles, elbows, and wrists.

Diagnosis of Lyme disease uses 2-tiered testing that includes enzyme-linked immunoassay (ELISA) screening followed by Western blot testing.3 During the first 4 weeks after infection, a positive Western blot will show 2 of 3 IgM bands. After 4 weeks, 5 of 10 IgG bands indicate a positive result.

The sensitivity of 2-tiered testing for late Lyme disease arthritis is very high (97%).4 Polymerase chain reaction (PCR) testing of synovial fluid for the presence of B burgdorferi is also highly sensitive, but current guidelines only recommend this if needed for treatment decisions.5 However, antibody serology testing of synovial fluid is not recommended.

The initial treatment for late Lyme disease arthritis is a 30-day course of oral doxycycline or amoxicillin.6 Additional treatment depends on the patient’s response.

  • Complete response: No further treatment; refer to physical therapy.
  • Mild persistent arthritis: Treat with an additional 30 days of doxycycline.
  • Moderate or severe persistent arthritis: Treat with intravenous (IV) ceftriaxone for 30 days.

Testing by PCR can determine that patients who received at least 8 weeks of antibiotic therapy, including at least 2 weeks of IV ceftriaxone, and test negative for B burgdorferi may not need additional treatment with antibiotics.3

Treatment of late Lyme disease arthritis is 90% effective; however, 10% of patients develop postinfectious (antibiotic refractory) Lyme arthritis.

Postinfectious (Antibiotic Refractory) Lyme Arthritis

Postinfectious Lyme arthritis is thought to be caused by immune-mediated processes rather than persistent infection. Treatment is similar to autoimmune inflammatory arthritis6:

  • Disease-modifying antirheumatic drugs (DMARDs), such as methotrexate
  • Biologics, such as tumor necrosis factor inhibitors (TNFi)
  • Intra-articular steroids
  • Arthroscopic synovectomy

Post-Treatment Lyme Disease Syndrome

After Lyme disease treatment, 10% to 20% of patients develop arthralgia and other nonspecific symptoms without synovitis, arthritis, or systemic inflammation.5 This is called post-treatment Lyme disease syndrome (PTLDS) and is clinically defined as fatigue, widespread pain, and cognitive difficulties that lasts at least 6 months and begins within 6 months of Lyme diagnosis, though a definitive history of Lyme disease is not required. Risk factors for developing PTLDS include the female sex, severe disease, comorbidities, delay in diagnosis, and steroid use.7

Development of PTLDS is believed to be immune-mediated; therefore, additional antibiotic therapy is not recommended. There is no standard treatment for PTLDS. Treatment may include therapies used in fibromyalgia, such as duloxetine, tricyclic antidepressants, and milnacipran.7 Exercise, cognitive behavior therapy, and mind-body medicine may also be helpful. Rheumatologists should be cautious of treatments outside of purview of mainstream medicine, as some of them, such as urine ingestion, venom therapy, and laser therapy, may be harmful.8

Systemic Autoimmune Diseases After Lyme Disease

Autoimmune joint diseases, such as rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis, can emerge after Lyme disease. These conditions are distinguished from late Lyme arthritis by certain factors:

  • Clinical features: Systemic autoimmune diseases are characterized by psoriasis, polyarthritis, and axial involvement.
  • History: Patients may have a family history of autoimmune disease.
  • Laboratory results: Patients with autoimmune diseases will have disease-specific biomarkers, lower antibody titers to B burgdorferi, and lower frequency of Lyme disease-associated autoantibodies.

Patients with autoimmune joint diseases generally have a good response to standard treatments (eg, DMARDs).9

Other autoimmune and rheumatic conditions have been observed after Lyme disease, including lupus, polymyalgia rheumatica, thyroid disease, and autoimmune neuropathy. It is not clear whether Lyme disease triggers the onset of these conditions. Potential mechanisms include antigen-specific activation, adjuvant effects, changes in the microbiome from Lyme infection or antibiotics, autoantibody responses, and host factors or genetics.3

In patients presenting with new-onset autoimmune conditions following Lyme disease, rheumatologists should consider the possibility that the patient was misdiagnosed with Lyme disease. Other conditions can mimic Lyme disease and erythema migrans. In addition, serology testing can be misleading due the nonspecificity of IgM results and persistence of previous Lyme infections. Misdiagnosis may lead to the unnecessary use of antibiotics and delayed treatment of the underlying condition.

Diagnosing Post-Lyme Syndromes

Distinguishing characteristics of the spectrum of conditions that can occur after Lyme disease include the following:

  • Postinfectious Lyme arthritis: Limited autoimmunity, joint inflammation
  • Post-treatment Lyme disease syndrome: No overt inflammation
  • Systemic autoimmune diseases: Systemic inflammation, polyarthritis

Other Tick-Borne Illnesses

There are a number of other illnesses transmitted through Ixodes ticks. They are often febrile and some are associated with myalgia or arthralgias, but typically not frank arthritis or postinfectious syndromes.

  • Babesiosis: Symptoms are flu-like. Babesia parasites infect red blood cells and are visible with a blood smear. Laboratory findings include hemolytic anemia and thrombocytopenia. Babesiosis can persist or cause relapsing disease in patients who are immunocompromised.11
  • Borelia mayonii disease: Symptoms are similar to Lyme disease but may include nausea and vomiting. B mayonii may cause erythema migrans and arthritis. Diagnosis is by PCR, serologic tests, and blood smears.12
  • Borelia miyamotoi disease: Symptoms include fever, chills, fatigue, headache, arthralgia, and myalgia. Rash is uncommon. Laboratory findings include leukopenia, thrombocytopenia and elevated hepatic transaminase values. PCR and serologic tests are used to diagnose B miyamotoi.13
  • Ehrlichiosis and Anaplasmosis: Symptoms include fever, chills, headache, myalgia, and gastrointestinal symptoms. Untreated, severe illness can develop. Laboratory findings include leukopenia, thrombocytopenia, and elevated hepatic transaminase values. Diagnosis is by PCR and serologic tests.14,15
  • Powassan virus: This is a rare infection. Initial symptoms include fever, headache, vomiting, and weakness. Some patients develop encephalitis or meningitis, which can be fatal. Diagnosis is by serologic testing.16

Co-infection of B burgdorferi with other tick-borne illnesses is generally rare. However, there are some geographic areas, especially in the US northeast, where co-infection with Babesia or Anaplasma is relatively common.10 Clinicians should consider co-infection in patients with a fever that is not responding to doxycycline or unexpected laboratory abnormalities such as anemia or thrombocytopenia. 

Q&A Session After the Presentation

How do you distinguish between PTLDS and fibromyalgia?

Dr Arvikar acknowledged a significant overlap between PTLDS, fibromyalgia, and other similar syndromes. With PTLDS, it is helpful to have history and testing that support a previous Lyme disease diagnosis. In the absence of this, one can look at the clinical scenario and determine if a diagnosis seems reasonable. Dr Arvikar noted that clinicians are still learning about these syndromes.

Why do patients with late Lyme disease have persistent IgM activity?

Dr Aucott said that the traditional view that IgM levels peak shortly after infection and decrease afterward is not always accurate. In Lyme disease, a substantial percentage of patients continue to have high IgM levels even after many years, but this does not indicate acute infection.

In an endemic area, how often do you see repeat infections?

Dr Arvikar said that while repeat infections are common in early disease, repeat cases of Lyme arthritis or PTLDS are not commonly seen because patients have an expanded antibody response that protects them from reinfection.


  1. Centers for Disease Control and Prevention. Lyme disease: data and surveillance. Last updated April 29, 2021. Accessed November 21, 2021.
  2. Centers for Disease Control and Prevention. Lyme disease: recent surveillance data. Published online April 29, 2021. Accessed November 21, 2021.
  3. Aucott JN, Arvikar SL. Lyme disease and other tick-borne illnesses: what every rheumatologist must know. Presented at: ACR Convergence 2021; November 7, 2021. Session 7S419.
  4. Aguero-Rosenfeld ME, Wang G, Schwartz I, Wormser GP. Diagnosis of Lyme borreliosis. Clin Microbiol Rev. 2005;18(3):484-509. doi:10.1128/CMR.18.3.484-509.2005
  5. Lantos PM, Rumbaugh J, Bockenstedt LK, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 guidelines for the prevention, diagnosis and treatment of Lyme disease. Clin Infect Dis. 2021;72(1):e1-e48. doi:10.1093/cid/ciaa1215
  6. Arvikar SL, Steere AC. Diagnosis and treatment of Lyme arthritis. Infect Dis Clin N Am. 2015;29:269-280. doi:10.1016/j.idc.2015.02.004
  7. Rebman AW, Aucott JN. Post-treatment Lyme disease as a model for persistent symptoms in Lyme Disease. Front Med. 2020;7(57):1-16. doi:10.3389/fmed.2020.00057
  8. Lantos PM, Shapiro ED, Auwaerter PG, et al. Unorthodox alternative therapies marketed to treat Lyme disease. Clin Infect Dis. 2015;60(12):1776-1782. doi:10.1093/cid/civ186
  9. Arvikar SL, Crowley JT, Sulka KB, Steere AC. Autoimmune arthritides, rheumatoid arthritis, psoriatic arthritis, or peripheral spondyloarthritis following Lyme disease. Arthritis Rheum. 2017;69(1):194-202. doi:10.1002/art.39866
  10. Steere AC, MdHugh G, Suarez C, Hoitt J, Damle N, Sikand VK. Prospective study of coinfection in patients with erythema migrans. Clin Infect Dis. 2003;36(8):1078-1081. doi:10.1086/368187
  11. Centers for Disease Control and Prevention. Babesiosis. Last updated January 10, 2019. Accessed November 21, 2021.
  12. Centers for Disease Control and Prevention. What you need to know about Borrelia mayonii. Last updated September 12, 2021. Accessed November 21, 2021.
  13. Centers for Disease Control and Prevention. Borrelia miyamotoi disease. Last updated January 10, 2019. Accessed November 21, 2021.
  14. Centers for Disease Control and Prevention. Ehrlichiosis. Last updated January 17, 2019. Accessed November 21, 2021.
  15. Centers for Disease Control and Prevention. Anaplasmosis. Last updated January 11, 2019. Accessed November 21, 2021.
  16. Centers for Disease Control and Prevention. Powassan virus. Last updated June 23, 2021. Accessed November 21, 2021.

This article originally appeared on Rheumatology Advisor