Case 27

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 22/04/2025

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CASE 27

Arnold, a 28-year-old man, recently returned from a camping trip in Massachusetts and has noticed several large, itchy, erythematous (red) patches (that seem to “move around”) on his arms. He remembers being bitten by some “bugs” while camping, but otherwise there is no significant medical history of note and no drug history. You recall reading about Lyme disease while you were at medical school and order a serum test for antibodies to Borrelia burgdorferi. The test comes back positive, confirming your suspicions (and the recognition of a classic “erythema migrans” picture).

You treat Arnold with a 28-day course of doxycycline with complete resolution of the symptoms. Several months later, Arnold reappears in your office with severe arthritic symptoms of several weeks’ duration, predominantly in the large joints (knees). He has been taking over-the-counter anti-inflammatory medication with no relief. An aunt suffers from rheumatoid arthritis, and he is concerned that he is developing the same disease.

You are concerned instead that this represents a persistent manifestation of the Lyme disease. In fact, titers to B. burgdorferi are even higher than when you first saw him. Despite further rounds of antibiotic therapy there is no obvious resolution of the arthritic picture, and indeed over the next 3 years his disease is marked by frequent exacerbations. What are some current thoughts regarding this picture? What is known about the pathophysiology?

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Implications/Analysis of Family History

A major genetic risk factor for therapy failure in patients with Lyme disease is HLA-DR4. Interestingly, Arnold’s aunt has rheumatoid arthritis, which is not linked to Lyme disease, but about 70% of patients with RA express the HLA-DR4 allele (control, 28%).

Implications/Analysis of Clinical History

There is no significant history of note and no drug history. Arnold’s “bug” bites were, in fact, tick bites. Ticks are arthropods that belong to the same class as mites. Life stages of ticks include egg, larvae, nymph, and adult. The larvae, nymph, and adult tick obtain their blood meal from mammals and humans. During the blood meal, nymph and adult ticks that are infected with B. burgdorferi (in saliva) transmit these bacteria to the host. Because the nymph form is so tiny, it can attach to the host unnoticed and feed for days.

Sixty to 80 percent of patients infected with B. burgdorferi initially develop a red spot that expands to form the characteristic ring shape with an outer red shape with a clear center, often described as “bull’s-eye” in appearance. Doxycycline is the treatment of choice for men and nonpregnant women and appeared to be effective for Arnold. However, the later presentation of arthritis and the fact that there was no obvious resolution of the arthritic picture suggests that bacterial persistence is not likely the cause of the arthritis. Patients who fail therapy continue to have reactivity to B. burgdorferi outer surface lipoprotein A (OspA), suggesting that this antigen cross reacts with a host protein.

Implications/Analysis of Laboratory Investigation

Laboratory testing plays an important role in diagnosis. Serum tests for antibodies to B. burgdorferi include enzyme immunoassay (EIA) and indirect immunofluorescence test. Depending on the laboratory, diagnosis is confirmed with a Western blot. Arnold’s EIA results came back positive. In fact, the EIA antibody titers to B. burgdorferi were even higher than they were at the initial diagnosis.

Additional Laboratory Tests

A polymerase chain reaction (PCR) test might be considered; however, given the many rounds of antibiotics it is unlikely that B. burgdorferi persists in serum. Furthermore, in most patients resistant to drug therapy, PCR technology has generally failed to detect spirochetes.

DIAGNOSIS

Arnold is diagnosed with persistent synovitis, which is seen in about 10% of individuals with so-called antibiotic-resistant Lyme disease.

THERAPY

Patients who do not respond to antibiotic therapy are treated with anti-inflammatory drugs or synovectomy (removal of joint tissue that is inflamed).

ETIOLOGY: LYME DISEASE

Immunologic Response

B. burgdorferi stimulates both innate immune responses (via toll-like receptors), causing release of inflammatory cytokines and other mediators from neutrophils and macrophages, as well as adaptive immune responses. In general, it is thought that Th1-type immunity is engaged as part of the protective immune response.

The final synovial pathology in both rheumatoid arthritis and Lyme arthritis is quite similar. Synovial inflammation and hypertrophy are noted, as are vascular proliferation, mononuclear cell infiltration, and increased expression of adhesion molecules. Multiple nodular aggregates of T cells and B cells with follicular dendritic cells and even germinal center B cells are consistent with ongoing antigen-driven activation, as expected from an autoimmune process. Inflammatory cells express mRNAs for proinflammatory cytokines and a few anti-inflammatory cytokines (e.g., IL-10). Abundant matrix metalloproteinases (MMPs) predominate in the joint fluid (e.g., MMP8), which probably contribute to joint erosion. This picture has led to the idea that understanding the cause of this infectious arthritis may hold key information to the study and understanding of RA.

Persistent Synovitis

The persistent synovitis seen in about 10% of individuals, often in the absence of evidence for persistent infection (so-called antibiotic treatment resistant Lyme disease) has been explained as potentially representing one, or a combination of, the following.

Spirochete Survival?

One hypothesis suggests the spirochetes are protected from host immunity by virtue of modulation of outer surface (immunogenic) epitopes, or following coating by host proteins. Consequently, they are not targeted by B cells, macrophages, or complement. However, in general, even sensitive PCR technology has failed to detect spirochetes in most patients. A “rescue” position for this hypothesis is that there is some long-term retention of spirochete antigens (without viable organisms), which leads to continued stimulation of an arthritogenic response.

Another hypothesis put forth is that the spirochetes survive in a niche (e.g., the cytosol of synoviocytes) where they are not accessible to B cells, phagocytes, or complement. Antigens present in the cytosol are generally processed by the proteasome and displayed on the cell surface of the infected cell where they are recognized by cytotoxic T cells. In this scenario, synoviocytes would be destroyed and B. burgdorferi released from the infected cell. To comment on the fate of the bacteria released from these cells would be mere speculation.

Molecular Mimicry?

More interesting is the hypothesis of Borrelia-induced autoimmunity, following epitope mimicry. In this model, antigenic determinants on B. burgdorferi are similar or identical to a series of amino acids in a host protein (e.g., OspA and LFA-1). Therefore, B cell and T cell activation in response to OspA would generate immune cells and antibodies that would target LFA-1.

Dominant Antigenic Epitope?

The dominant epitope in the B. burgdorferi protein, OspA, in the North American form of disease is distinct in sequence from that of the European variant, where treatment-resistant disease is rare. T cells from a susceptible North American population show a higher frequency of responses to this epitope than a North American population with simple Lyme disease. Finally, there is some (albeit weak) evidence that this T cell epitope in OspA shows some relatedness with a sequence in the LFA-1 molecule.

Loss of Tolerance: Autoimmunity?

General inflammation, associated with large-scale tumor necrosis factor-α/interleukin-1β release after B. burgdorferi infection, triggers autoimmunity in a bystander fashion (e.g., perhaps potentiated by loss of regulatory T cells). This general mechanism may hold true for several autoimmune-type disorders but has yet to be shown unequivocally for any one particular disorder.

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