First World Congress report on Spondyloarthropathy
Date: Wednesday, November 04, 1998 7:39 PM

FIRST WORLD CONGRESS ON SPONDYLARTHROPATHY
Reported by Editor Andrei Calin

200 Delegates from around the world met in Ghent - an outstanding medieval city in the heart of Europe. Professors Eric Veys, Herman Mielants and an organising committee consisting of Elisabeth Marker-Hermann, Kaisa Granfors, Maxime Dougados and Andrei Calin planned the meeting over the last years.

RELATIONSHIP OF GI TRACT TO JOINT INFLAMMATION

The opening address came from Martin Kagnoff, La Jolla, California, who spoke on "Mucosal immunity: mechanisms and role in joint inflammation". He pointed out that the normal intestinal mucosa is in a state of "physiological chronic inflammation", and that the single layer of epithelial cells lining the mucosa plays an integral role in host immunity, encountering antigens of all types. Locally produced mediators serve to link host innate and acquired immunity, involved in so-called "cross-talk" with other cells. A variety of receptors and counter receptors down regulate the host inflammatory response, and allow the development of oral tolerance. In passing, it was noted that parasitic infestation - as seen in sub-Saharan Africa, may explain the Th2 response, which in turn suppresses immune disease and perhaps explains why rheumatoid arthritis is less aggressive in such a community.

RECENT GENETIC INFORMATION

Paul Wordsworth from Oxford, UK, reminded us that it is now 25 years since the link between HLA-B27 and spondylarthritis was first defined. In our own combined RNHRD, Bath/Oxford studies, 94% of our patients are HLA-B27 positive, compared to 9% of the background controls. HLA-B60 is present in 6% of healthy B27-positive subjects, compared to 12% of our patients, conferring a relative risk of 2 in both B27 positive and negative subjects. Monozygotic twins reveal a concordance rate of 75% for ankylosing spondylitis, compared to 12% of dizygotic twins and 27% where both of these twins are B27 positive. These figures, taken together with sib pair analyses, suggest that overall the HLA contribution is no more than 50%, and therefore a genome-wide linkage screening study has been carried out, identifying no less than 26 markers of interest. For example, there is a possible linkage with the TCRB locus, whereas a link with the TCRA locus has been excluded. Recruitment of a larger number of families is ongoing to explore this issue further. Jose Lopez de Castro from Madrid, Spain reviewed the polymorphism of HLA-B27, pointing out that we now recognise 13 sub-types. Certainly, B2702, 03, 04, 05 and 07 have all been associated with ankylosing spondylitis, whereas 06, and 09 appear to be protective. He reminded us that the arthritogenic peptide hypothesis postulates that autoreactive T cells activated upon external antigenic challenge would recognise endogenous peptides presented by HLA-B27. His data show that binding of a peptide epitope to a given subtype is not sufficient for presentation of that peptide to specific T cells, with B27 polymorphism playing a direct role in T > cell recognition, in addition to its effect on peptide binding. Tomas Hohler from Mainz, Germany explored the 6th chromosome further. Specifically, with knowledge that genetic polymorphisms of cytokine genes have a role in infectious and rheumatic diseases, a particularly interesting candidate gene is tumor necrosis factor alpha, encoded within the class III region of the MHC close to the HLA-B locus. TNF-a expression is controlled at the transcriptional and posttranscriptional level and two transitions within the promotor region are of interest - at position 308 and 238. For example, an increase of the wildtype TNF promotor allele, and a decrease of the promotor allele varient TNF-308.2 and TNF-238.2 among B27 positive patients with ankylosing spondylitis, compared to controls exists. He summarised by saying that TNF-308.2 and TNF-238.2 allele or haplotypes bearing these variants have a protective role against the development of ankylosing spondylitis in B27-positive subjects (in contrast to the situation with psoriatic arthropathy).

FAMILY AND GENDER STUDIES

Scofield and Harley from Oklahoma City carried out studies on two separate family cohorts, and showed that HLA-B27 and B40 transmitted to affected offspring more often than expected, while B35 tended to be transmitted to unaffected offspring more frequently than statistically anticipated. They concluded that there are both positive and negative contributions to the risk of AS at the HLA-B loci.

Hohler and colleagues from Mainz and Turku claim that gender is an important factor in determining disease concordance in MZ twins with AS - specifically, this was seen more frequently in male twins than female twins - a finding not present in our own series.

Maksymowich et al, from Edmonton, Alberta explored their model whereby B27 enters the class I antigen processing pathway followed by so-called ubiquitination and proteasomal-mediated proteolysis of the intact B27 molecule.

SPECULATIONS ON PATHOGENESIS

Toubert and colleagues from Paris studies antigenic peptides derived from triggering bacteria and autoantigens, presented by HLA-B27 positive cells to effector CD8+ T cells and suggested that alterations in the peptide presentation by B27 can occur during bacterial infection. This approach is being used to define cytotoxic T cell responses during the course of B27 associated arthropathy - attempting to unravel the molecular mechanisms of disease.

Breban from Paris, working with colleagues from Dallas, presented their work on the B27 transgenic rat, pointing out how high levels of B27 expression are needed in terms of disease pathogenesis, that CD4+ T cells play an important role and that normal resident bowel flora are required for disease. Their data suggest that human disease may relate to loss of tolerance to normal resident bowel flora. In this model, the tap gene status has no influence on the rat arthropathy, while pro-inflammatory TGF-b and Interleukin-6 cytokines are present in the joints. Interestingly, Metronidazole suppresses the development of disease in conventionalised B27 rats (i.e. those rats that were in a germ-free environment, returning now to normality). Thus, the role of anaerobic bacteroides vulgatus is suggested.

STUDIES IN MICE

David Chella, from Mayo Clinic, presented new material on the HLA-B27 transgenic mouse. In contrast to the rat, these animals are healthy, when B27 is expressed in the context of mouse b2 microglobulin. However, when the B27 gene is expressed either in the absence of mouse b2m or substitution of human b2m for mouse b2m has occurred, a spontaneous inflammatory disease develops. As with the rat, this only occurs out of the pathogen-free facility. Nail keratosis, arthritis and ankylosis of limb joints occur, and the disease is predominantly male (unlike the rat situation), but the bowel remains healthy.

When an antibody-specific against free heavy chains was injected into the mice, the disease was prevented. TAP knockout genes, introduced into the B27 transgenic mouse did not prevent disease. Type II collagen injected into pathogen-free mice resulted in disease. >>From San Diego, Kronenberg entertained us with a mouse model of colitis, developed by the transfer of syngeneic CD4+ T cells to immune deficient SCID mice. Features in common with Crohn's disease develop, and interestingly a few of the recipients develop eye and skin disease. Interleukin-10 knockout mice spontaneously develop colitis, while Interleukin-10 prevents the mouse model described by Kronenberg.

BACTERIAL PRODUCTS AND SPONDYLARTHRITIS

Three presentations focussed on the inter-relationship between bacterial products and B27. Granfors reminded us of the prolonged antibody response against infective agents in those with reactive arthropathy compared to controls, suggesting that components of the causative bacteria persist somewhere in the body. Recent detection of Salmonella DNA in synovial fluid contrasts with the > ease that Chlamydial bacterial DNA and RNA is frequently found.

Elisabeth Marker-Hermann described the oligoclonal peripheral blood T cell expansion, mainly of the CD8+ population in spondylarthropathy of the affected twin compared to the control healthy twin. The relative contribution of ab-TCR CD4+ and CD8+ cells and cdTCR+ cells remains unclear, but perhaps depends on the stage of disease.

David Yu from UCLA focussed on the HLA-B27 impact on gene products following infection. Here, as an example, c-fos is activated in B27 positive cells, but not the controls.

Paradela and colleagues from Madrid carried out a series of experiments looking at the different B27 subtypes and showed that cytotoxic T lymphocytes recognised an octamer on B*2705, 2702 and 2703, but not on 01, 04, 06 and 10. The authors concluded that the same peptide can be recognised by a single cytotoxic T lymphocyte clone in the context of multiple subtypes, but binding of the peptide is not sufficient for T cell recognition because polymorphic B27 residues contribute directly to the T cell epitope.

WHAT ABOUT CHLAMYDIA

Ralph Schumacher, Philadelphia, described in detail their extensive work on synovial membrane biopsies in the reactive arthritides. He described how originally electron microscopy was used to recognise Chlamydial antigenic determinants within the joint, followed by immunoelectron microscopy and molecular hybridization technology, followed in turn by PCR and finally immunoelectron microscopy staining for MOMP, heat shock protein and in situ hybridisation of DNA and RNA. Interestingly, two of 30 "normal" individuals were found to have evidence of Chlamydia on joint biopsy and, naturally, it would be fascinating to know what the situation would be if one would carry out the same experiment on 30 sexually active individuals with positive Chlamydia in terms of genitourinary infection. Does Chlamydia merely travel to joints, in terms of a natural tropism, or does Chlamydia cause damage once it arrives? This outstanding question remains to be answered. Schumacher reminded the audience that EB virus gets everywhere, frequently causing no problem.

THE T CELL ROLE

Hill Gaston from Cambridge reviewed the T cell story in reactive arthropathy, questioning why some individuals have self-limiting disease, whereas other chronic persistent arthropathy. In both situations there is dissemination of antigen to joint, a T cell response to the antigen, clearance of the antigen, down regulation of the T cell response and then resolution (in the self-limiting disease) whereas those with ongoing arthropathy, antigen persists as does the T cell response with presumably some form of aberrant immunity, ineffective clearance of the antigen and a lack of down regulation of immunity.

Sieper from Berlin spoke on the Th1/Th2 dichotomy in the spondylarthropathies. The balance of T helper cell subsets is known to be implicated in the regulation of many immune responses. Th1 cytokines include IFNg and TNFa while IL-4 and IL-5 are included in the Th2 grouping, while IL-11 down regulates Th1 responses. He showed how in HLA-B27 positive AS patients there was low TNFa production, and a low TNFa/IL-10 ratio, and that in B27 positive patients and controls TNFa and IFNg were lower than in B27 negative subjects. The possibility that this results in difficulty in handling relevant microbes was suggested, and it may well be that treatment against TNFa would be less helpful than in rheumatoid disease.

NEWS FOR THE CLINICIAN

Calin and Brophy from Bath, UK, compared 670 individuals with psoriatic spondylarthropathy with controls without this condition, and likewise enteropathic spondylitis (387 subjects) and those with and without arthritis, matched for disease duration, age and sex with individuals without the specified secondary disorder.

The conclusion was that patients with one concomitant disease were more likely to have additional disorders. That is to say, that if an individual had inflammatory bowel disease the relative risk of having psoriasis in addition was almost 2, and likewise psoriatic spondylitis was more likely to be associated with inflammatory bowel disease than by chance alone. Subjects with enteropathic spondylitis and psoriatic arthropathy had worse disease activity, function and well being than did individuals with primary ankylosing spondylitis.

Espinoza from New Orleans reviewed the inter-relationship between psoriasis, HIV and spondylarthropathy. There are now some 22 million individuals with HIV worldwide, 94% of whom are in the developing world, with 19 million in Africa or Asia. In the United States, approximately one million subjects have had HIV, with 400,000 deaths - 70% of whom are likely to have had disease because of unprotected sex. Psoriasis and the complicating psoriatic arthropathy appear to be somewhat less severe now than in the early l990's, perhaps because of more aggressive early treatment with Cyclosporin and perhaps Methotrexate. In the past, immunosuppressive therapy was avoided because of risk of enhancing the HIV disease, but in fact this appears not to be a concern. The striking and changing epidemic in sub-Saharan Africa was reviewed with, for example, the Zambian story whereby HIV positivity is prevalent to some 30% of the Lusaka population, 50% of those attending out-patient clinics and 70% of in-patients, while 84% of 418 patients with spondylarthropathy were HIV positive (J. Rheumatol l998, Vol 25; pp1553). By contrast, 30 cases with rheumatoid disease were all HIV negative, again stressing that low CD4 counts is associated with lower risk of rheumatoid disease, whereas spondylarthropathy occurs with ever increasing frequency. In HIV, psoriasis occurs in somewhere between 1-20%, and transgenic animals with HIV likewise experience psoriatic skin lesions supporting a direct effect of the viral infection.

Filip de Keyser from Gent, Belgium ended by focussing on the futuristic approach to therapy. If indeed gut inflammation is central to disease pathology, then treatment with Sulphasalazine, 5 amino salicylic acid, corticosteroids, antibiotics, antibody to tumor necrosis factor a and IL-11 may have a role to play. As an example, Budesonide, a very poorly absorbed 17a substituted steroid, is efficacious in Crohn's Disease and could be considered for the spondylarthropathies.

GENERAL COMMENT:

The extensive presentations at this first world congress indicates the widespread interest in this condition and the general belief that spondylarthropathies represent the real expression of infection in genetically susceptible individuals.