When MS Treatment Masks Lyme Disease

Welcome to another Inside Lyme Podcast. I am your host Dr. Daniel Cameron. I find that the best way to get to know Lyme disease is through reviewing actual cases. In this episode, I will be discussing the case of a young woman with multiple sclerosis (MS), who had a delay in diagnosis of Lyme disease due to immune modulating drug effects.

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.

The case involves a 20-year-old woman who was diagnosed with multiple sclerosis at age 17. She was initially treated with tocilizumab to manage her MS. Tocilizumab, a biological disease-modifying anti-rheumatic drug (DMARD), is used to treat rheumatoid arthritis. It’s marketed in the U.S. as Actemra.

Tocilizumab is a monoclonal antibody which blocks signals from IL-6 receptors. The drug can lower the immune system’s ability to fight infections.

Treatment with Rituximab

Eighteen months after receiving tocilizumab, the young woman was prescribed off-label treatment with Rituximab, a medication used to treat certain types of cancer and autoimmune diseases. In the U.S., it is sold under the brand name Rituxan.

Rituximab is a monoclonal antibody directed against the B-cell lineage specific CD20. The drug, which suppresses B cell production, can weaken the immune system, making patients more susceptible to infections.

More importantly for Lyme disease diagnosis, rituximab depletes the B cells that produce antibodies—the very antibodies that Lyme disease tests detect.

Lyme-Like Symptoms Emerge

Three years later the young woman was evaluated for a 6-month history of arthritis in her knee and the presence of 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.

“A dermatologist interpreted the skin symptoms as possible panniculitis with atypical erythema nodosum as a potential alternative diagnosis.”

At the onset of symptoms, Lyme disease tests were borderline. “The results were interpreted to be of uncertain clinical significance,” the authors write. They add, “there were an enduring clinical suspicion of Borrelia infection.”

Despite the clinical picture strongly suggesting Lyme disease—arthritis and circular rashes in a patient with potential tick exposure—the antibody tests could not confirm the diagnosis because rituximab had depleted the B cells needed to produce detectable antibodies.

Biopsy Confirms Lyme Disease

Clinicians diagnosed Lyme disease based on a skin biopsy of the lesions on her ankle. “Borrelia-DNA was detected in the biopsy analyzed by polymerase chain reaction (PCR),” the authors explain.

After a 3-week course of treatment with doxycycline, both the arthritis and rash resolved.

This case demonstrates a critical principle: when antibody testing is unreliable due to immune suppression, direct detection methods like PCR or tissue biopsy become essential.

Risks of Immune-Modulating Therapies

A number of immunomodulating treatments are widely used in patients with MS and other 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, there are risks associated with these therapies, particularly with B-cell depleting drugs, including an increased risk of infections.

Doctors typically screen for infections prior to starting patients on immunomodulating therapies. In this case, the patient appeared to contract Lyme disease after starting rituximab.

The challenge is that B-cell depleting therapies don’t just prevent new antibody production—they eliminate the cells that would normally respond to new infections. This creates a diagnostic blind spot where patients can have active infection without producing detectable antibodies.

Why This Matters for Lyme Disease Testing

Standard Lyme disease testing relies entirely on antibody detection. ELISA and Western blot tests measure IgM and IgG antibodies produced by B cells in response to Borrelia burgdorferi infection.

When B cells are depleted by medications like rituximab, patients cannot mount a normal antibody response. This means:

Standard two-tier testing will likely be negative or borderline despite active infection. Antibody tests cannot be reliably interpreted in patients on B-cell depleting therapy. Clinical diagnosis and alternative testing methods become essential. Direct detection methods like PCR or tissue biopsy may be the only way to confirm infection.

This case illustrates that Borrelia-specific antibody levels cannot be reliably interpreted in patients who have received B-cell depleting therapy. As the authors note, “an ongoing infection can easily be overlooked or misinterpreted due to a weak serological response during treatment with a B-cell depleting drug.”

Frequently Asked Questions

Do immune-modulating drugs affect Lyme disease test accuracy?
Yes. B-cell depleting therapies like rituximab suppress antibody production, causing false negative or borderline Lyme disease tests despite active infection.

Which medications affect Lyme disease testing?
B-cell depleting therapies including rituximab (Rituxan), ocrelizumab, and other monoclonal antibodies targeting CD20 can prevent normal antibody responses. Corticosteroids and other immunosuppressants may also affect test accuracy.

How should Lyme disease be diagnosed in immunosuppressed patients?
Direct detection methods like PCR testing or tissue biopsy should be used when antibody testing is unreliable. Clinical diagnosis based on symptoms and exposure history becomes especially important.

Can patients on immunosuppressive therapy still get Lyme disease?
Yes. Immunosuppressive medications increase susceptibility to infections, including Lyme disease and other tick-borne illnesses.

What should doctors do if they suspect Lyme disease in a patient on rituximab?
Don’t rely on antibody testing alone. Consider PCR testing, tissue biopsy of skin lesions, or empirical treatment based on clinical presentation. Standard serologic testing may remain negative despite active infection.

Clinical Takeaway

This case highlights a critical gap in Lyme disease diagnosis: standard antibody testing fails precisely when patients need it most—during immune suppression. The young woman presented with classic Lyme disease manifestations: arthritis and circular erythematous rashes. But because rituximab had depleted her B cells, antibody tests remained borderline and “of uncertain clinical significance” for six months. Only tissue biopsy and PCR detection of Borrelia DNA confirmed what was clinically apparent. For clinicians, this case provides an essential reminder: B-cell depleting therapies create a diagnostic blind spot. Patients on rituximab, ocrelizumab, or other CD20-targeting medications cannot mount normal antibody responses to new infections. In these patients, negative or borderline Lyme serologies should never exclude the diagnosis when clinical suspicion is high. Alternative testing methods—PCR, tissue biopsy, or empirical treatment trials—become essential diagnostic tools when antibody testing is unreliable.