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  • Review Article
  • Published:

Elucidation of Lyme arthritis

Nature Reviews Immunology volume 4, pages 143–152 (2004)Cite this article

Key Points

  • Lyme arthritis was recognized as a separate entity from rheumatoid arthritis because of geographic clustering of children in Lyme, Connecticut, USA, who were thought to have juvenile rheumatoid arthritis.

  • The synovial histology in patients with chronic Lyme arthritis is typical of that found in all of the various forms of chronic inflammatory arthritis, including rheumatoid arthritis.

  • Lyme arthritis is now known to be a late manifestation of a tick-transmitted spirochetal infection, caused exclusively by Borrelia burgdorferi in the United States and mainly by Borrelia afzelii or Borrelia garinii in Europe and Asia. Of the three Borrelia species, B. burgdorferi is the most arthritogenic.

  • Studies in inbred strains of mice have delineated immune mechanisms that are important in susceptibility to and control of joint infection with B. burgdorferi.

  • Anti-inflammatory components of an innate immune response seem to protect some mouse strains from the development of severe arthritis despite infection of the joint.

  • Adaptive immune responses to B. burgdorferi control spirochetes and reduce the severity of arthritis in mice.

  • Lyme arthritis in human patients can usually be treated successfully with antibiotic therapy. However, in the United States, about 10% of patients develop persistent synovitis, which lasts for months or even several years after the apparent eradication of the spirochete from joints with antibiotic therapy.

  • Patients with antibiotic-treatment-resistant Lyme arthritis or rheumatoid arthritis share a similar immunogenetic susceptibility that mainly involves HLA-DRB1*0401, HLA-DRB1*0404 and HLA-DRB1*0101.

  • T-cell reactivity to an immunodominant epitope of B. burgdorferi outer-surface protein A (OspA) in genetically susceptible individuals is associated with treatment-resistant Lyme arthritis, but a relevant autoantigen has not been identified.

  • A crucial unresolved issue in Lyme arthritis is the nature of the stimulus that perpetuates synovial inflammation after the apparent eradication of live spirochetes from joints with antibiotic therapy.

Abstract

Before the first description of Lyme arthritis in 1976, patients with this disease were often thought to have juvenile or adult rheumatoid arthritis. It is now known that Lyme arthritis is caused by a tick-borne spirochete that disseminates to joints, where it induces marked pro-inflammatory responses. In most patients, the arthritis resolves with antibiotic treatment. However, in the United States, about 10% of patients with Lyme arthritis develop persistent synovitis, which lasts for months or even several years after the apparent eradication of the spirochete from the joint with antibiotic therapy. The elucidation of Lyme arthritis, from acute infection to chronic synovitis, might help in our understanding not only of this entity, but also of other forms of chronic inflammatory arthritis, including rheumatoid arthritis.

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Figure 1: The transmission of Borrelia burgdorferi to the mammalian host and the dissemination of the spirochete to the joint.
Figure 2: Immune responses to Borrelia burgdorferi in an inflamed joint.
Figure 3: Interactions of spirochetal proteins, including outer-surface lipoproteins, with immune mediators.
Figure 4: Synovial pathology in patients with chronic Lyme arthritis.

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Acknowledgements

This work was supported in part by the National Institutes of Health, the Mathers Foundation, the English, Bonter, Mitchell Foundation, the Lyme/Arthritis Reserach Fund and the Eshe Fund.

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Authors and Affiliations

  1. Division of Rheumatology, Center for Immunology and Inflammatory Diseases, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, Massachusetts, USA

    Allen C. Steere & Lisa Glickstein

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  1. Allen C. Steere
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Correspondence to Allen C. Steere.

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DATABASES

LocusLink

IFN-γ

IL-1β

IL-6

IL-10

IL-13

LFA1α

MMP1

MMP3

MMP8

MMP9

TNF

FURTHER INFORMATION

Rheumatology Division website

Glossary

ADULT RHEUMATOID ARTHRITIS

A form of chronic inflammatory arthritis that affects many large and small joints symmetrically. In early rheumatoid arthritis, only a few joints might be affected initially, and patients with Lyme arthritis were sometimes thought to have early seronegative (rheumatoid-factor negative) rheumatoid arthritis.

JUVENILE RHEUMATOID ARTHRITIS

(JRA). An inflammatory arthritis in children that lasts for at least six weeks, which is not caused by other known types of arthritis. In the pauciarticular form of the disease, which is most similar to Lyme arthritis, only one or a few joints are affected, most commonly the knee.

REACTIVE ARTHRITIS

A sterile joint inflammation that develops after a distant infection. The arthritis might affect only a few joints, including the knee, and might last for months to several years, as in Lyme arthritis.

SYNOVIAL TISSUE

A thin, highly vascular lining tissue that covers all intra-articular structures except for articular cartilage. It secretes small amounts of joint fluid, which might function as a lubricant and a source of nutrients for the relatively avascular cartilage in the joint.

LYME DISEASE

A complex, multi-system infection that is caused by a tick-transmitted spirochetal bacterium, Borrelia burgdorferi. After the initial infection of the skin (stage 1), the spirochete often disseminates to many sites (stage 2), particularly to other skin sites, the nervous system, heart or joints, where it might cause persistent infection (stage 3) for years.

ACRODERMATITIS CHRONICA ATROPHICANS

A late skin manifestation of Borrelia afzelii infection that mainly occurs in older patients, most often on distal surfaces of the extremities. The inflammatory phase is followed by thinning of the skin, a process that might continue for decades.

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Steere, A., Glickstein, L. Elucidation of Lyme arthritis. Nat Rev Immunol 4, 143–152 (2004). https://doi.org/10.1038/nri1267

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