Why Lyme Disease Tests Can Be Negative During Immune Suppression
Negative Lyme tests may not always exclude infection
Immune-modulating drugs can weaken antibody responses
Delayed diagnosis may occur when testing becomes less reliable
Welcome to another Inside Lyme Podcast. I am your host Dr. Daniel Cameron. In this episode, I discuss a case illustrating why Lyme disease tests can be negative when immune-modulating drugs alter normal antibody responses, delaying diagnosis in a young woman with multiple sclerosis (MS).
Listen to this Inside Lyme Podcast episode discussing delayed diagnosis, immune suppression, and false-negative Lyme testing.
Sjöwall and colleagues describe the case in an article entitled “Case Report: Borrelia-DNA Revealed the Cause of Arthritis and Dermatitis During Treatment With Rituximab,” published in Frontiers in Neurology.1
The case involves a 20-year-old woman diagnosed with multiple sclerosis (MS) at age 17. She was initially treated with tocilizumab to manage her MS. Tocilizumab, a biologic disease-modifying anti-rheumatic drug (DMARD), is marketed in the U.S. as Actemra.
Tocilizumab is a monoclonal antibody that blocks IL-6 receptor signaling. Because immune-modulating therapies can suppress normal immune responses, they may affect the body’s ability to generate antibodies used in Lyme disease testing.
The drug received significant attention during COVID-19 treatment studies. “Tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve survival,” writes Salama and colleagues.2
Common conventional DMARDs include methotrexate, sulfasalazine, hydroxychloroquine, azathioprine, and leflunomide.
Treatment with rituximab and delayed Lyme diagnosis
Eighteen months after receiving tocilizumab, the young woman was prescribed off-label treatment with Rituximab, a medication used for certain cancers and autoimmune diseases.
Rituximab targets CD20-positive B cells. Because Lyme disease testing frequently depends on antibody production, suppression of B cells may interfere with serologic testing.
Patients receiving B-cell therapies may therefore face challenges with Lyme disease testing accuracy, especially when antibody production is reduced.
Lyme-like symptoms emerge despite weak testing
Three years later, the young woman developed a 6-month history of knee arthritis and two circular erythematous rashes on her ankle.
“The right knee had typical signs of inflammation with rubor, tumor, and calor accompanied by a discretely reduced range of motion,” the authors explain.
Why Lyme disease tests can be negative during immune suppression
“Our case clearly illustrates that, during treatment with B-cell depleting therapies, infections may give rise to an atypical clinical picture as well as a weak serological response to specific pathogens.”
A dermatologist interpreted the skin findings as possible panniculitis with atypical erythema nodosum.
At symptom onset, Lyme disease testing was borderline. “The [test] results were interpreted to be of uncertain clinical significance,” the authors write. They add there was “an enduring clinical suspicion of Borrelia infection.”
False-negative testing remains one reason clinicians sometimes rely on clinical findings, exposure history, evolving symptoms, and additional testing strategies when evaluating why Lyme tests may miss infection or reviewing Lyme disease symptoms.
When serologic testing becomes difficult to interpret, clinicians may rely more heavily on clinical presentation, exposure history, tissue sampling, or alternative diagnostic strategies.
How accurate are Lyme disease tests during immune suppression?
Lyme disease testing accuracy may be reduced when immune-modulating drugs suppress antibody production. Because many Lyme tests depend on antibody responses, medications affecting B cells may increase the risk of false-negative or borderline results.
Biopsy confirmed Lyme disease
Clinicians ultimately diagnosed Lyme disease using a skin biopsy from the ankle lesions.
“Borrelia-DNA was detected in the biopsy analyzed by polymerase chain reaction (PCR),” the authors explain.
After a 3-week course of doxycycline, both the arthritis and rash resolved.
Risks of immune-modulating therapies
Immunomodulating treatments (IMTs) are widely used in MS and autoimmune diseases.
“B-cell depleting therapies are widely used in MS as well as in many other autoimmune diseases, often with a dramatic anti-inflammatory effect and symptom relief,” write the authors.
However, these therapies may increase infection risk and potentially alter diagnostic testing responses.
Doctors often screen for infections before beginning IMTs to reduce risk. In this case, Lyme disease appeared after immune-modulating therapy had already begun.
Delayed diagnosis may also contribute to persistent Lyme disease symptoms, particularly when treatment is postponed because testing appears inconclusive.
Conclusion: “This case highlights that Borrelia-specific antibody levels cannot be reliably interpreted in patients who have received B-cell depleting therapy,” the authors write.
Frequently Asked Questions
Can Lyme disease tests be negative even when infection is present?
Yes. Early infection, immune suppression, antibiotic exposure, and reduced antibody production may contribute to false-negative testing.
Can rituximab affect Lyme disease testing?
Rituximab suppresses B cells, which may reduce antibody production and weaken serologic responses used in Lyme disease testing.
Do autoimmune medications affect Lyme disease tests?
Some immune-modulating drugs may reduce immune responses and complicate interpretation of antibody-based testing.
How accurate are Lyme disease tests?
Lyme disease testing accuracy varies by disease stage, immune status, timing of testing, and the type of test performed. Immune suppression may further reduce test sensitivity.
What if Lyme disease tests are negative but symptoms continue?
Persistent symptoms, exposure history, medication effects, physical findings, and additional testing approaches may deserve reconsideration when suspicion remains high despite negative testing.
Clinical Takeaway
Immune suppression can complicate Lyme disease diagnosis by weakening antibody responses and altering testing performance.
When Lyme disease testing is negative despite ongoing suspicion, medication history, exposure risk, symptoms, and alternative diagnostic approaches may deserve additional consideration.
Related Articles
Why Lyme tests miss infection
Persistent Lyme disease symptoms
Undiagnosed Lyme disease
References
- Sjowall J, Xirotagaros G, Anderson CD, Sjowall C, Dahle C. Case Report: Borrelia-DNA Revealed the Cause of Arthritis and Dermatitis During Treatment With Rituximab. Front Neurol. 2021;12:645298.
- Salama C, Mohan SV. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. Reply. N Engl J Med. 2021;384(15):1473-1474. doi:10.1056/NEJMc2100217.
Dr. Daniel Cameron, MD, MPH
Lyme disease clinician with over 30 years of experience and past president of ILADS.
Symptoms • Testing • Coinfections • Recovery • Pediatric • Prevention
Thank you Dr. Cameron for all the case studies.
The above case study makes one think, how many Lyme patients may be mistreated or not treated at all. In my case after 10 years of suffering Lyme like symptoms, the doctor just wrote a note on my file ’Definately not an Infectious Disease’. He failed to comment, what is wrong eith me.
Would you kindly describe so called ACA? I suspect the infection from childhood, with aching knees and awakening from sleep with crying spells. My parents could not calm me down.
I can send you a picture os suspected ACA, purple color skin area with tissue damage, wrinkles, including sleep disorder, pain all over, including walking difficulty among other things.
I have not found a dermatologist or dermatopathologist to help me with a acrodermatitis chronica atrophicans (ACA) rash. I have had to make clinical decisions based on other factors including sleep issues and pain.
I was diagnosed with lyme disease. My blood work was sent to mayo clinic, it came back positive. I had the quintessential bullseye rash as well. I was on doxycycline for a week but developed a rash so my PCP switched my antibiotic to amoxicillin for another 10 days. I feel better but not 100%. Can lyme disease be eradicated? I did take oil of oregano the entire time I was on antibiotics as well as florastor. I read an article that taking oil of oregano with doxycycline will eradicate lyme disease. Do you believe that to be true?
I have some Lyme disease patients who have benefited from additional antibiotic. For example, amoxicillin is not effective for several tick borne illnesses including Babesia, Bartonella, and Anaplasmosis. I have also had to look for another cause of their illness. I do not have enough information to share whether oil of oregano is effective.