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Refractory Lyme Arthritis May Be Autoimmune

In most patients Lyme arthritis is treated successfully but, in a small subset, proliferative arthritis persists despite apparent spirochetal killing with antibiotics, so-called antibiotic-refractory arthritis

http://www.medpagetoday.com/Rheumatology/Arthritis/36694






Refractory Lyme Arthritis May Be Autoimmune

Activated T- and B-cell responses to an autoantigen in synovial tissue may explain the development of resistant arthritis among a small number of patients with Lyme disease, researchers suggested.
Robust T-cell responses to an antigen known as endothelial cell growth factor (ECGF) were seen in 38% of peripheral blood mononuclear cells from patients with Lyme arthritis that had not cleared with antibiotic therapy, according to Allen C. Steere, MD, of Harvard Medical School, and colleagues.
In addition, B-cell-produced antibodies to ECGF were observed in 17% of patients with antibiotic refractory Lyme arthritis, but in no healthy controls (P<0.0001), the researchers reported in the January issue of Arthritis & Rheumatism.
"We have shown definitively that T- and B-cell responses to ECGF occur in a subset of patients with Lyme disease, thereby identifying the first autoantigen that is a target of autoimmune T- and B-cell responses in this illness," they stated.
Other autoantigens are likely to be involved as well, they noted.
The majority of patients with Lyme disease, even those with the late development of arthritis, recover with appropriate antibiotic treatment to eliminate the causative spirochete Borrelia burgdorferi.
But a subset of patients continues to have symptoms of arthritis long after treatment, and the management of these patients has remained controversial, with many patient groups demanding long-term antibiotics.
Steere and colleagues have previously suggested that this persistence reflects infection-induced autoimmunity rather than ongoing infection.
The concept that autoimmunity is involved is supported by the observation that certain genetic HLA-DR alleles are common in patients with resistant Lyme disease.
These HLA molecules are capable of presenting autoantigens to T cells, which is thought to be an important event in autoimmunity.
To explore this autoimmune hypothesis, Steere and colleagues first performed a proteomic exploration to identify possible antigens.
Initially, they identified 120 HLA-DR-presented peptides in the synovium of a patient with refractory Lyme-associated arthritis, one of which was capable of causing proliferation of the patient's peripheral blood mononuclear cells.
They then tested this reactive antigen and its various peptides in a broader population of patients and controls using several molecular assays, and found that only peptides from the chemotactic factor ECGF could induce the antigenic proliferative responses.
In addition, the T-cell reactivity to the ECGF peptides occurred primarily in patients with the HLA-DR alleles known to confer risk for the antibiotic-resistant arthritis.
The B-cell production of ECGF autoantibodies also was seen twice as often in patients with the antibiotic-resistant arthritis than in those with antibiotic-responsive disease (17% versus 8%,P=0.09).
To confirm the role of ECGF as an antigen involved in the infection-induced autoimmunity, the researchers then quantified the level of ECGF in patients' synovial fluid, and found that those whose Lyme-associated arthritis had not responded to antibiotic therapy had notably high levels, with a mean of 448 ng/mL.
"For ECGF to have pathogenic relevance as an autoantigen in antibiotic-refractory Lyme arthritis, one would predict that this protein would be present in high concentrations in patients' inflamed synovial fluid and tissue," they observed.
In contrast, the mean level in patients with antibiotic-responsive Lyme arthritis was considerably lower, at 154 ng/mL (P<0.0001), while the level in patients with osteoarthritis is only 8.7 ng/mL.
These analyses suggested that autoreactivity to at least one ECGF peptide is involved in the persistence of arthritis in patients with Lyme disease, with the abnormal T- and B-cell responses being seen in 10% to 30% of patients.
However, an explanation as to why the specific spirochetal infection should cause this autoreactivity has been uncertain.
So Steere and colleagues now have postulated that the pathogenesis and resolution of antibiotic-resistant Lyme arthritis is a three-step process that occurs in a minority of patients following the acute infectious disease.
The first step involves the development of an autoimmune response to ECGF in up to 20% of patients with Lyme disease, which probably results from both host and pathogen factors.
For example, the HLA-DR allele of an individual patient is likely to contribute, and certain strains ofB. burgdorferi have been shown to be far more inflammatory than others.
The second step of the pathogenic process occurs in patients who have marked accumulation of the antigen in their joints, which leads to inflammation and T-cell activation.
The T-cell response in the joint then can provoke the upregulation of various inflammatory cytokines such as tumor necrosis factor-α and interleukin-1β, a process which some patients seem unable to turn off.
The final step in the proposed pathogenic model is the later resolution of synovitis, usually after treatment with immunomodulators such as methotrexate that can interrupt the T-cell activation.
"In these patients, we postulate that the innate immune 'danger' signals provided by live spirochetes are no longer present, and without these signals, the adaptive immune response to autoantigens eventually regains homeostasis," the researchers concluded.
The study was supported by the National Institutes of Health, the Dana Foundation, the Materns Foundation, the English, Bonter, Mitchell Foundation, the Eshe fund, and the Lyme-Arthritis Research Fund at Massachusetts General Hospital.
Four of the co-authors have an application pending for an antibody test for endothelial cell growth factor.
Steere has received fees and honoraria from Merck and Alere.