Borrelia Arthritis - a Hidden Cause of Arthritis in Danish Patients?

Introduction Borrelia arthritis is, despite being a painful and debilitating disease, barely studied in Europe. The investigating research group has discovered an alarming number of cases in the last few years, and believe Borrelia arthritis is underdiagnosed in Denmark. This project therefore aims to systematically investigate the prevalence and trajectory of Borrelia arthritis in Denmark, in order to enhance the diagnostic capabilities, to improve outcomes for future patients, as well as reduce the costs for the Danish health care system.

Background Clinical aspect \& outcome of Borrelia arthritis. Borrelia arthritis is a joint infection caused by the Borrelia burgdorferi bacteria group. Patients with Borrelia arthritis typically present months after tick exposure, most commonly with monoarthritis of the knee, although oligoarthritis can occur. Diagnosing Borrelia arthritis has been a challenge, based solely on patient history and the presence of Borrelia IgG antibodies in plasma. Tools like polymerase chain reaction (PCR) analysis of synovial fluid provide better diagnostic accuracy, but are not readily available. Though antibiotic therapy relieves symptoms in most cases, Borrelia bacteria within the joint can activate the immune system leading to persistent synovial inflammation. In these patients, disease-modifying anti-rheumatic drugs are required, and recovery may take months to years, with risk of lasting pain and disability.

Distribution \& prevalence. In North America, Borrelia arthritis is found in 30% of Lyme borreliosis cases, whereas in Europe, it is considered rare. This discrepancy is attributed to differences in Borrelia species and their tissue tropism: European species tend to primarily affect the skin and nervous system, while American species more commonly target the joints. Current knowledge on European Borrelia arthritis epidemiology and outcomes is limited, but it is thought to present with subtler symptoms than in North America, potentially leading to overlooked cases. A French cohort study reported a median delay of 5 months from symptom onset to diagnosis, and found several Borrelia-species involved. Few studies have been conducted in Scandinavia. In Southern Norway a study found the Borrelia arthritis incidence to be 2.7/100,000 adults, while it was 2.3% in a high-endemic area of Sweden. In Denmark, a registry study in the Capital Region found that 4 of 146 patients with Borrelia antibodies had a possible Borrelia arthritis.

Current status in Denmark. Since 2021, the investigators research group has identified multiple patients with Borrelia arthritis from a specific area (Marbæk plantage) near Esbjerg. This indicates an emerging Borrelia-hotspot in this area, possibly an effect of climatic changes on the distribution of Borrelia host animals and tick abundance. Initially, Borrelia arthritis was not suspected in these cases, but as awareness of the disease increased, the diagnostic delay was reduced: from 38 months in the first patient to six weeks in the most recent one. With heightened attention on the condition and with the availability of improved diagnostic tools, more than 50 additional cases of Borrelia arthritis from other regions of Denmark have been identified since 2023. The high positive sample rate of 49% (25 of 51 patients tested so far in 2025) suggests undertesting and overlooked cases.

Aim. More knowledge regarding the incidence and clinical features of Borrelia arthritis in Denmark is needed, to ensure a timely and appropriate diagnosis and treatment, thereby reducing risk of complications for affected patients in the future. With this project, the aim is to determine the incidence of Borrelia arthritis in patients with mono/oligoarthritis across all Danish regions, to characterize the clinical presentation of Borrelia Arthritis in Northern European patients, and to determine if the Borrelia-species involved belong to genotypes associated with Borrelia arthritis in North America or the more common European types.

Hypotheses. The investigators hypothesise that Borrelia arthritis is an underrecognised infection in Denmark, and that Borrelia arthritis has a favourable prognosis compared with other causes of mono/oligoarthritis, that Borrelia arthritis is an emerging infection in Northern Europe due to climate changes favoring tick survival, and that the Borrelia genotypes responsible for Northern European Borrelia arthritis differ from Northern American strains.

Methods Sub-study 1 - Borrelia arthritis incidence \& outcome study: To establish the number of Borrelia arthritis cases, all patients presenting with mono/oligoarthritis at the Departments of Rheumatology at eight hospitals across Denmark will be tested prospectively with a serum-Borrelia IgG antibody test from 1.1.26 until 31.12.27. All patients will have their synovial fluid tested for B.burgdorferi DNA by PCR and sampled blood and synovial fluid tested for intrasynovial synthesis of B.burgdorferi antibodies. A biobank will be established at the Department of Clinical Microbiology, OUH, containing blood and synovial fluid. Around 25 patients from each of the eight sites are expected to be included yearly, in all 350-400 patients in two years. A RedCap database will be established including data on 1-year arthritis outcomes where the patients with Borrelia arthritis and patients with arthritis of other origin will be compared.

Sub-study 2 - Borrelia arthritis characterisation study: A questionnaire for all patients included in Study 1 will be designed. The RedCap database will include data from the questionnaire and from patient charts; demographic information, clinical history (symptom debut, affected joints), course of disease (fluctuating, stable or progressing arthritis, pain, fever, other symptoms, and comorbidities), tick exposure history, diagnostic pathway (health professionals involved), diagnostic test results (joint fluid (WBC count, direct microscopy, culture, PCR), blood tests (Borrelia antibody status, hematology, inflammatory markers, uric acid, autoantibodies), final diagnosis and treatment (pain medicine, anti-inflammatory drugs and antibiotics). The investigators will compare the Borrelia arthritis patients (cases) with the arthritis patients without Borrelia (control group) in terms of tick-bite history and exposure, symptoms and paraclinical data through statistical analyses.

Expected impact. The primary expected outcome is an improved understanding of the occurence, clinical characteristics, and microbiological profile of Borrelia arthritis. By collecting comprehensive data on diagnostic pathways and outcomes, the research will provide insights into the challenges faced by Borrelia arthritis patients, especially in the context of delayed diagnoses. The study's findings will inform targeted interventions, including the development of more efficient diagnostic protocols and increased awareness among healthcare providers regarding symptoms and diagnostic markers of Borrelia arthritis. Additionally, the establishment of a biobank will facilitate future research into the disease's pathophysiology and guide the development of tailored treatment strategies. Ultimately, the study could lead to the establishment of public health initiatives aimed at better prevention, early detection, and management of Borrelia arthritis in Denmark.