Lyme document from the Lancet, TY bernadette!

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Chronic Lyme disease: the debate goes on

Lancet 2000; 355: 1437 - 1440Download PDF (104 Kb) </hub/pii=9213-00002148>

Mention of chronic Lyme disease raises temperatures, not only among

patients, but also among the experts who are trying to untangle exactly what

chronic Lyme disease is, why only some patients get chronic manifestations,

and how the disease should be treated. Lyme borreliosis is a complicated

disease in which both the specific disease-causing organism and host

responses seem to affect the course of disease. In Europe, Lyme borreliosis

is caused by any one of the three tick-borne spirochetes in the Borrelia

burgdorferi sensu lato complex--B burgdorferi sensu stricto, B afzelii, and

B garinii. In the USA, only the first species is involved. Everywhere, the

usual early sign is erythema migrans--a red bull's-eye rash. Stage II Lyme

disease--ie, early dissemination--can involve the skin, joints, muscles, or

the central and/or peripheral nervous system. In the USA, arthritis is the

most common late-stage sign, but in Europe, radiculomyelitis, peripheral

neuropathy, or chronic skin involvement (acrodermatitis chronica

atrophicans) is seen more often.

Lyme disease is treated with a course of antibiotics, and although most

patients will respond well, there is disagreement about how to treat late

cases, particularly with respect to the duration of antibiotic treatment.

Chronic Lyme disease or post-Lyme-disease syndrome are terms for the

clinical picture of patients who have chronic symptoms after what is thought

to be adequate antibiotic therapy. The underlying mechanism of these

symptoms is unknown, and the management of these patients is controversial.

The answer hinges on whether the disease-causing organism is still present

or whether these symptoms are a result of the host immune response against

the organism or even against tissue autoantigens.

The controversy is most intense in the USA. Roland (National

Institutes of Health, Bethesda, MD, USA)--a researcher from Germany--is

" amazed at how different the US nervous-system manifestations look. In

Europe, we assumed people would respond to treatment, with almost no

exceptions. If there was permanent organ damage, it would not be completely

cleared up, but at least it would not progress; but here, the signs are much

more subtle, for example the cerebrospinal fluid inflammatory findings.

Therefore, Lyme disease appears more complicated here than in Europe " .

The complex clinical picture is compounded by a history of inconsistent

laboratory tests and the lack of a standardised diagnostic definition.

Laboratory tests are improving all the time, but for now, the only

standardised way to measure the incidence of Lyme disease is the US Centers

for Disease Control and Prevention surveillance case definition. This,

however, may miss some cases of Lyme disease. It also does not include

chronic Lyme disease or post-Lyme-disease syndrome. Thus, says Leonard Sigal

of the University of Medicine and Dentistry of New Jersey (New Brunswick,

NJ, USA), " there is no way to know how common the chronic condition is.

There are definitely people with Lyme arthritis who do not respond to

antibiotic therapy. They have red, swollen, tender joints that just do not

resolve " .

But there are patients with non-specific complaints and no objective

findings who also do not respond to treatment. These patients, suggests

Sigal, may not actually have Lyme disease, a viewpoint unpopular with

patients who believe that doctors sometimes wrongly withhold antibiotics.

Sigal insists that " there is no documented example of B burgdorferi that did

not die when exposed to antimicrobials " , but he acknowledges that there is

no way of knowing whether unreachable organisms can survive in a treated

person. In an attempt to clear up this controversy, the US NIH are funding

placebo-controlled trials of long-term antibiotic therapies for patients

with chronic Lyme disease or post-Lyme-disease syndrome.

Meanwhile, and his colleagues are pursuing the hypothesis that

autoimmune responses to tissue antigens may play a role in these conditions.

By studying T-cell clones from patients with chronic disease, they have

identified several candidate autoantigens that could be involved in the

neurological and musculoskeletal symptoms at several stages of the disease.

" It has become clear that the deletion of autoreactive T cells in the thymus

is incomplete " , says . " We all carry autoreactive T cells for many

autoantigens, and, under circumstances such as up-regulation of HLA

molecules, co-stimulatory molecules, co-receptors, and adhesion molecules in

an affected tissue, these cells may be triggered to cause organ damage. "

The idea that Lyme disease complications may have an autoimmune origin began

with the finding that Borrelia-infected patients with the most severe and

prolonged arthritis have large numbers of antibodies against outer surface

protein A (OspA) of borrelia, and the subsequent discovery of a protein that

resembles OspA on human cells. But experience with the Lyme disease vaccine

(recombinant OspA) approved last year in the USA illustrates that, if

autoimmunity is indeed involved, it must take more than the mere presence of

a foreign protein that resembles a self-protein to trigger a pathological

attack on self-antigens. The vaccine has passed all its safety tests, and

the regulatory agencies (US Food and Drug Administration and US Centers for

Disease Control and Prevention) have found no evidence of an association

with arthritis.

So what does cause chronic Lyme disease? The question remains wide open.

Sigal argues that " molecular mimicry has not been proven to be a significant

issue in the genesis of Lyme arthritis; it may require seeding of the joint

with bacteria " . And Dennis Parenti of Kline Beecham (Collegeville, PA,

USA) notes that " although T-cell cross reactivity is common, it does not

imply molecular-mimicry-mediated pathology or autoimmunity " . Even

admits that, " one cannot easily distinguish between organ damage that will

not go back to normal, or persistence of the organism, or an ongoing immune

response that was initiated by the organism. Some damage could be bystander

damage from secretion of cytokines in vulnerable tissue and this damage can

look like autoimmunity " . More research is needed, conclude the scientists,

to determine what is going on in chronic Lyme disease and how to treat it.

M Rowe