Conference Scene: Report on the Second International Congress on Controversies in Rheumatology & Autoimmunity

The second Controversies in Rheumatology & Autoimmunity meeting, which was organized by five well-known experts in rheumatology and autoimmunity, took place in Budapest at the beginning of April, and was attended by specialists from all over Europe. The presentations covered a wide range of topics from genes to the side effects of biological agents, rare autoimmune diseases, the role of infections in autoimmunity, and bone alterations.

The meeting started early in the morning of Thursday, 4 April, with a lecture on morning and night glucocorticoids by the incoming President of the European League Against Rheumatism, Maurizio Cutolo of the University of Genoa (Italy), and continued until Saturday, 6 April.

There were many good and well-updated presentations, but undoubtedly the most interesting was that made by Yaakon Naparstek of Hadassah University Hospital (Jerusalem, Israel) concerning the role of autoreactive B cells in systemic lupus erythematosus (SLE) and the unresolved question as to whether they are the right therapeutic target. He explained that the demonstration of a close association between anti-DNA antibodies and SLE has theoretically made B cells the ideal candidate for targeted therapies, including the induction of B-cell tolerance, B-cell depletion and the suppression of B-cell stimulating factors, and the costimulatory molecules that activate B cells. However, as most of the trials were completed without reaching their end points or terminated because of serious adverse events, and even the successful trials (the BLISS trials) revealed only a slight effect, Naparstek pointed out that B cells may not really be the most appropriate target for immunotherapy in SLE and their role in the pathogenesis of the disease should be reanalyzed.

The second most important talk was given by Yehuda Shoenfeld from the Zabludowitcz Center for Autoimmune Diseases at Sheba Medical Center (affiliated with the Sackler Faculty of Medicine, Tel Aviv, Israel) concerning the complex pathogenetic/protective role of infections in autoimmune diseases. He explained that everything used to be considered “autoimmune until proven the opposite” but the last decade has induced us to believe that “everything is infectious until proven the opposite”. He reminded us that some pathogens, such as HBV, Helicobacter pylori, EBV andSaccharomyces cerevisiae, in association with some genes, are involved in the pathogenesis of a number of autoimmune diseases, and others only in one. On the contrary, other pathogens in association with some genes can be protective in some diseases. On the basis of these major points, he asked whether it is useful to vaccinate the population or more useful to use natural therapies, and enthusiastically explained the relationships between pathogens and autoimmunity, and the relevance of several genes.

Zoltàn Szekanec, the chairperson of the Congress on Controversies in Rheumatology and Autoimmunity from the University of Debrecen Medical and Health Sciences Center (Hungary) spoke about the controversy concerning the use of biological drugs to treat rheumatoid arthritis (RA). It is well known that biological drugs can control synovial inflammation and joint damage, and improve the quality of the life of RA patients. However, it is also well known that patients with RA suffer from cardiovascular disease and, although biological agents improve endothelial dysfunction and atherosclerosis in the short term, they may also alter lipid profiles. Furthermore, RA patients are more likely to develop cancer as a result of sustained disease activity and, although it has been found that biological drugs may decrease the risk of malignancies, a number of registry and observational studies have shown that their use may actually be associated with an increased risk.

The most intriguing talk on Saturday was given by Eiji Matsuura of the Department of Cell Chemistry at Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences (Japan), who explained all of the possible mechanisms involved in the process of early atherogenesis. He pointed out that β2GPI influences fibrinolysis, angiogenesis, apoptosis and atherogenesis, and binds oxidized low-density lipoprotein (oxLDL) to generate oxLDL–β2GPI complexes, which induce an adaptive autoimmune response. This process may upregulate the macrophage expression of FcγRI and scavenger CD36 receptors, thus accelerating the uptake of oxLDL. In mouse models, higher levels of oxLDL–β2GPI complexes correlate with the size of atherosclerotic lesions and, in patients with cardiovascular disease, they correlate with disease severity and adverse outcomes. Matsuura also showed that oxLDL–β2GPI complexes are rapidly incorporated into macrophage lysosomes where proinflammatory inflammasome/IL-1 responses are generated and play a role in innate immunity and chronic inflammation. The accumulation of cellular cholesteryl esters or oxLDL in macrophages can elicit an inflammatory reaction by triggering macrophage IL-1β secretion. As the mechanism of NLRP3 inflammasome activation by cholesterol crystals involves both potassium efflux and cathepsin B leakage into the cytoplasm, inflammasome-induced IL-1β dysregulation may represent an early mechanism that initiates atherosclerosis. Finally, oxLDL and oxLDL–β2GPI complexes are not only involved in early atherogenesis via the innate inflammasome–IL-1 pathway, but can also perpetuate atherogenesis via an adaptive autoimmune response, a subject that was covered in more detail by Fabiola Atzeni of Luigi Sacco University Hospital (Milan, Italy).

The challenging and generally undiscussed subject of balneotherapy was presented by Pàl Geher and Tamàs Bender of Hospitaller Brothers of St John of God (Budapest, Hungary). Bender described its efficacy in treating various conditions such as pain, muscle tone and joint mobility, but Geher underlined the lack of scientific evidence concerning its efficacy and the fact that, as it can only be offered by spa resorts, it is rather expensive. Another problem is that little is known about how it works and it is not clear why different mineral waters have the same clinical effect under the same conditions. On the basis of their findings, they believe that balneotherapy should remain a palliative treatment for diseases for which there is no adequate treatment, however, its cost–effectiveness remains an issue.

Laboratory aspects were covered by two Italian speakers, Nicola Bizzaro of the Laboratory of Clinical Pathology (Tolmezzo, Italy) and Pierluigi Meroni from the University of Milan’s Department of Clinical Sciences and Community Health (Italy). They confirmed the importance of measuring autoantibody levels when diagnosing autoimmune diseases and the value of detecting antinuclear antibodies (ANAs), and the role of HEp-2 cells in indirect immunofluorescence tests. Although it has a number of pitfalls, this is the standard method of ANA detection and has led to the proposal of developing automated ANA readers. However, as none of these have yet been validated, they suggested that this should be done in the near future.

Two posters were awarded during the Closing and Awards Ceremony on Saturday: two by Alessia Alunno of the University of Perugia (Italy), concerning the ability of galactomannans to rebalance the Treg:Th17 cell ratio in RA and one by Luigi Gianturco of the University of Milan concerning cardiovascular involvement in Sjögren’s syndrome. Furthermore, two oral presentations were awarded. The first was made by Leendert Trow from the Rheumatology Department, Leiden University Medical Center (The Netherlands), who presented a comparative study of the presence of anti-CCP and anti-CARP antibodies in early RA, and the second by Alessandra Soriano of the Periodic Fever Research Centre of Rome’s Catholic University of the Sacred Heart (Rome, Italy), who described the clinical features of familial Mediterranean fever without MEFV mutations in a large cohort of Italian patients.

Finally, we must not forget the other experts who presented some interesting data concerning controversies about new and old drugs arising from clinical trials and registry studies.

Fabiola Atzeni

Piercarlo Sarzi-Puttini