Symptomatic Management of Lyme Arthritis
Phase: PHASE3
Conditions: Lyme Arthritis, Lyme Disease, Arthritis
Sponsor: Desiree Neville, MD

Symptomatic Management of Lyme Arthritis 
NCT04038346 
Version: 4/3/2024  
 
Protocol: 
 
Short Title: Symptomatic Management of Lyme Arthritis 
 
Full Title: Symptomatic Management of Lyme Arthritis: Feasibility and preliminary data 
study to compare symptomatic outcomes and side effects of adjunct scheduled NSAID 
therapy for Lyme arthritis versus scheduled acetaminophen or standard care 
 
Brief description: 
Lyme arthritis resolves with appropriate antimicrobial treatment in a majority of patients, 
but 10-20% of patients develop antibiotic-refractory Lyme arthritis with prolonged 
arthritis symptoms and treatment courses. Excessive up-regulation of the inflammatory 
process has been shown in patients with antibiotic-refractory Lyme arthritis. The over 
expressed proinflammatory cell mediators are downstream of NSAID inhibition, which 
would suggest initial inflammatory inhibition may be beneficial in these patients. While 
NSAIDs are known to reduce pro-inflammatory cell mediators early in the course of 
inflammation, research has shown that there are other cytokines that play a role in the 
healing after inflammation that are also inhibited by NSAIDs, and that NSAID use can 
delay healing. 
It is not known if scheduled NSAID therapy will reduce, increase, or have no effect on 
the occurrence of refractory Lyme arthritis cases. The hypothesis of the study is that 
prescribing scheduled NSAIDs at the time of diagnosis of Lyme arthritis can prevent the 
development of the excessive inflammatory phase and decrease the number of patients 
with antibiotic refractory Lyme arthritis, or at least decrease the duration of persistent 
Lyme arthritis symptoms. 
The pilot study design randomizes patients to scheduled NSAIDs, scheduled 
acetaminophen, or scheduled NSAIDs x 1 week than acetaminophen. Primary 
outcomes are duration of arthritis symptoms, number of refractory cases, side effects 
and compliance. 
 

 
Specific Aims: 
1. Demonstrate feasibility to ensure adequate patient enrollment and symptomatic 
follow-up of patients with Lyme arthritis. 
2. Develop pilot data necessary for sample size and power calculations: 
a. Quantification of antibiotic-refractory Lyme arthritis in our population 
b. Symptomatic outcomes of patients with Lyme arthritis on scheduled NSAIDs 
versus those not placed on scheduled NSAIDs (duration to resolution and 
number of patients with resistant arthritis) 
c. Assess side effects of patients with Lyme arthritis placed on scheduled 
NSAIDs versus those not placed on scheduled NSAIDs 
d. Assess changes in resources (follow-up visits, further prescriptions) required 
for patients taking scheduled NSAIDs versus not taking scheduled NSAIDs 
 
Background: 
Lyme disease is the systemic tick-borne disease caused by Borrelia burgdorferi 
infection, and is endemic to an expanding portion of the United States. Lyme arthritis is 
a common presentation of Lyme disease. While Lyme arthritis resolves with appropriate 
antimicrobial treatment in most patients, 10-20% of patients develop antibiotic-refractory 
Lyme arthritis with prolonged inflammatory arthritis. Research suggests excessive up-
regulation of the inflammatory process in patients with prolonged symptoms. The over-
expressed proinflammatory cell mediators are downstream of NSAID inhibition, which 
would suggest NSAIDs may be beneficial in these patients. In fact, there is data that 
NSAIDs and/or disease-modifying anti-rheumatic drugs (DMARDs) may be beneficial in 
refractory Lyme arthritis cases, once diagnosed as refractory. 
There are studies that show that NSAIDs in addition to inhibition of pro-inflammatory cell 
mediators, also inhibit prostaglandins that active during the healing phase of 
inflammation. Those studies have questioned whether NSAIDs can delay healing. This 
question has not been evaluated in acute joint inflammation, particularly in Lyme arthritis 
patients. It is possible that scheduled NSAID therapy would reduce inflammation early, 
but delay overall time to resolution of inflammation. 
The hypothesis of the study is that prescribing scheduled NSAIDs at the time of 
diagnosis can prevent the development of the excessive inflammatory phase and 
decrease the number of patients with antibiotic-refractory Lyme arthritis, or at least 
decrease the duration of persistent Lyme arthritis symptoms. There are no known 
methods to identify patients at the time of diagnosis who will go on to develop antibiotic-
refractory Lyme arthritis. 

While antibiotic-refractory Lyme arthritis has been studied at a microbiologic/cytokine 
level as well as evaluated in terms of treatment once patients have been deemed 
antibiotic refractory, to our knowledge there are no published studies evaluating 
prevention. With no literature looking at the question of NSAIDs for the prevention of 
antibiotic refractory Lyme arthritis, this pilot study is needed to adequately calculate 
sample size and power calculations for a large-scale multicenter study. There is 
anecdotal data from the Rheumatology and Infectious Disease departments at our 
institution that early scheduled NSAIDs may decrease refractory cases, but there has 
been no formal evaluation into this question. Retrospective evaluation is challenging 
since the medications in question (NSAIDs) are over the counter, and clinicians may or 
may not recommend scheduled or intermittent NSAID therapy at the time of initial 
diagnosis without documentation, and certainly without prescriptions in the medical 
record. Many patients with REFRACTORY Lyme arthritis are placed on NSAIDs but 
given the question of delayed healing with inhibition of prostaglandins during the healing 
phase of inflammation, the question of whether NSAIDs are beneficial in patients to 
prevent refractory arthritis is worthwhile rather than the current process of variable 
NSAID prescription. This work is important to delineate optimal timing and duration of 
NSAIDs given the research that shows the anti-inflammatory effects during healing can 
potentially delay recovery in other inflammatory conditions. 
 
Study Design: 
300 patients will be enrolled in a randomized active treatment-controlled trial.  
Inclusion criteria: 
Study patients are eligible for inclusion is they are >or= to 3 years and <18 years of age 
with arthritis and the clinical team is ordering a Lyme test. Patients will remain eligible 
for analysis if their Lyme test is positive.  
Exclusion criteria: 
Patients will be secondarily withdrawn from analysis and instructed to stop study 
medication if their Lyme test is negative. 
Underlying diagnosis of rheumatoid or recurrent arthritis 
Already on scheduled NSAIDs 
Anything that restricts the prescription of naproxen or acetaminophen: 
• Hypersensitivity to naproxen (for example: anaphylactic reactions, serious skin 
reactions) or any component of the formulation; history of aspirin induced asthma, 
urticaria, or allergic-type reactions after taking aspirin or other NSAIDs, underlying 
kidney or liver impairment 
• Already taking daily NSAIDs (naproxen or ibuprofen) or daily acetaminophen 

• Hypersensitivity to acetaminophen or any component of the formulation; severe liver 
impairment or severe active liver disease 
Research activities 
Patients 3-17 years of age suspected to have Lyme arthritis (physician diagnosed 
arthritis and evaluation with a Lyme EIA with reflex western blot) will be enrolled in the 
study and receive randomization to adjunct treatment arms in addition to their standard 
of care antibiotic treatment. 
Patients will be enrolled in the emergency department, primary care center, or infectious 
disease clinic where they have their initial point of contact for the diagnosis of Lyme 
arthritis. 
Adjunct Treatment arms: Children will be randomized 1:1:1 to three treatment groups 
1. Group 1 - Scheduled naproxen bid x 28 days or until symptom resolution. 
Dose of naproxen will be 5-7.5 mg/kg/dose. (per prescription table) doses by 
weight in prescription table in attached documents- maximum prescribed: 1000 
mg/day of naproxen. 
2. Group 2 - Scheduled acetaminophen qid x 28 days or until symptom 
resolution. Dose of acetaminophen will be 15 mg/kg/dose. (per prescription table) 
doses by weight in prescription table in attached documents- maximum 
prescribed: 2600 mg/day of acetaminophen. 
3. Group 3 -Scheduled naproxen bid x 7days, then acetaminophen qid x 21 days 
or until symptom resolution. (at the same doses and maximums as above) 
4. Patients who refuse enrollment for randomization will be offered consent to 
follow-up only arm (current standard of care treatment) 
 
Prescriptions given to the families for symptomatic medications (naproxen and/or 
acetaminophen) can be filled in any pharmacy the family chooses. 
Outcomes: 
1. Feasibility of enrollment and data collection 
2. Number of patients with antibiotic-refractory arthritis 
3. Days until joint symptom resolution 
4. Compliance with medication (and other medications taken) 
5. Side effects 
6. Days until return to baseline function 
7. Need for repeated medical appointments/care seeking 
 
 

Methods: 
Enrollment visit - obtain written informed consent then randomize to one of three 
treatment arms. 
- collect standardized physical examination 
- symptom assessment Day 0 
Outcomes 2-5 to be collected by text surveys at days from enrollment: 1, 3, 7, 10, 
14, 21, 28, 60: 
o Joint redness/swelling 
o Joint function 
o Joint pain 
o Compliance with medication 
o Side effects 
o Overall function versus baseline 
 
A phone call may be made if the text survey is not filled out within 24 hours of 
sending. 
Outcome 6 and 7 to be evaluated through electronic medical record follow-up at 
30, 60, 180 days (and every 30 days as needed in antibiotic-refractory cases, 
until symptoms resolve up to 1 year)