Abstract
8th International Congress on Autoimmunity
Granada, Spain, 9–13 March 2012
The 8th edition of the International Congress on Autoimmunity took place in the beautiful and historical city of Granada, Spain, from 9 to 13 March 2012. It gathered more than 2350 participants from 71 different countries, including internists, immunologists, rheumatologists, basic researchers and many other clinicians and laboratory people interested in autoimmune diseases who were updated with the latest available diagnostic tools and new therapeutic avenues. This top international autoimmunity meeting put together an international faculty of more than 100 experts to present a high-level scientific program under the leadership of Professor Yehuda Shoenfeld (Zabludowicz Center for Autoimmune Diseases, Tel-Hashomer, Israel) who chaired the congress together with Ricard Cervera (Hospital Clínic, Barcelona, Catalonia, Spain), Angela Tincani (University of Brescia, Italy) and Carlos Vasconcelos (Hospital S. António, Porto, Portugal) as co-chairpersons.
A wide range of topics were covered during the congress. Among them, several key issues and provocative aspects that were analyzed in depth included:
• Standardization of autoantibody testing
• The autoimmune epidemic
• Genetics, epigenetics and proteinomics of autoimmune diseases
• Gender, sex and autoimmunity
• Vaccines, adjuvants and autoimmunity – the ASIA syndrome
• Effects of helminths on host immunity and the control of autoimmune diseases
• Immunomodulation by natural immunoglobulins
• Biologic therapies: belimumab, rituximab, eculizumab, epratuzumab and tocilizumab
• Vitamin D as immune modulator
• Alzheimer as an autoimmune disease and immunomodulating its course
• Atherosclerosis and cardiovascular disease in autoimmune diseases.
Furthermore, the Consortium of Centres of Excellence for Autoimmune Diseases – a network of 12 international centers devoted to these conditions – was introduced.
This report will focus on the latest developments on the management of refractory cases of the catastrophic variant of the antiphospholipid syndrome (APS), one of the most challenging autoimmune conditions and a topic that was covered during the congress by this author. This variant is characterized by thrombosis in multiple organs, which develops over a short period of time, with the histopathological evidence of small-vessel occlusions Citation[1]. Due to the rarity of this syndrome, the European Forum on Antiphospholipid Antibodies created in 2000 an international registry of patients with catastrophic APS (CAPS) Registry that documents the clinical, laboratory and therapeutic data of the published cases with this condition as well as of many additional patients whose data have been submitted for registration Citation[2]. The term refractory refers to both patients who died despite the use of first-line therapies as well as to patients suffering recurrent episodes of CAPS Citation[3].
Data from the CAPS Registry provides information on the therapeutic regimen with higher survival rate. The combination of anticoagulants, glucocorticoids and plasma exchange shows higher recovery rate. Furthermore, the mortality rate decreased from 53% in the patients diagnosed before 2000 to 33.3% in those diagnosed from 2001 to 2005. This reduction in the mortality rate was related to the more frequent use of the combination of anticoagulants, glucocorticoids and plasma exchange and/or intravaneous immunoglobulins Citation[4].
Considering refractory CAPS patients also as those with recurrent episodes of CAPS (‘relapsing’ CAPS), in 2008 three patients with a total of seven episodes were documented Citation[5]. The median time between the episodes of CAPS was 12.5 months (range: 2.5–48) and the most significant manifestations were renal involvement (present in five episodes), followed by CNS and cardiac involvement (four episodes each). Laboratory features of definite microangiopathic hemolytic anemia were present in five episodes. More recently, nine additional cases have also been collected out of 282 (3%) patients from the CAPS Registry with a total of 35 episodes of CAPS (six patients presented two recurrences, two patients suffered three relapses and one patient developed 17 relapses). Notably, the laboratory features of microangiopathic hemolytic anemia were present in 72% of the episodes that were analyzed Citation[6].
Several additional treatments have been used in patients with refractory CAPS, including rituximab, defibrotide and eculizumab. Rituximab, a monoclonal antibody against CD20 B-cell surface antigens, has been approved for the management of refractory low-grade or follicular, CD20+, B-cell non-Hodgkin lymphoma and rheumatoid arthritis. In an off-label use, nine patients with CAPS have also been treated with this drug Citation[7–13]. It was used in different therapeutic protocols (including 375 mg/m2 once weekly for 4 weeks and two infusions of 500–1000 mg at 1 or 2 weeks apart) and in different combinations with anticoagulants, high doses of glucocorticoids, plasma exchange and intravenous immunoglobulins. The antiphospholipid antibodies became negative after the infusion of rituximab in three patients and only two patients died.
Defibrotide, a polydisperse mixture of 90% single-stranded and 10% double-stranded phosphodiester oligonucleotides derived from the controlled depolymerization of porcine intestinal mucosal DNA, has demonstrated several hemostatic properties (i.e., upregulates the release of prostacyclin and prostaglandin E2, reduces concentrations of leukotriene B4 and modulates platelet activity) and has shown beneficial effects in the management of hepatic veno-occlusive disease. Off-label, defibrotide has been used in two patients with CAPS Citation[14,15]. The first was a 55-year-old man who had shown intractable progression of multi-organ thrombosis during 1 week of full-dose intravenous heparin therapy, aspirin and dipyridamole. In the context of an investigational new drug protocol, a therapeutic trial with defibrotide was attempted while all antithrombotics and antiplatelets were stopped. The outcome of the patient was satisfactory Citation[14]. The second patient was a 53-year-old woman who presented with renal, intestinal and cutaneous thrombotic involvement. She was treated with anticoagulation and defibrotide but was unresponsive to treatment and died Citation[15].
Eculizumab, a humanized monoclonal antibody against complement protein C5, is currently approved for the treatment of paroxysmal nocturnal hemoglobinuria. Also off-label, eculizumab has been used in one patient with CAPS in order to achieve complement blockade at the level of end-organ parenchymal microvasculature. The patient was a 51-year-old man with end-stage renal disease due to CAPS who received a live-donor renal transplantation. The patient was enrolled in a protocol that included prophylactic administration of eculizumab together with anticoagulation and standard immunosuppression to prevent a recurrent episode of CAPS. The levels of antiphospholipid antibodies remained moderately elevated but without recurrence of thrombotic events Citation[16]. Currently, eculizumab is being tested in a clinical trial to prevent CAPS after kidney transplantation in patients with a history of this condition (NCT01029587).
In summary, the best first-line therapies for patients with CAPS are anticoagulants, glucocorticoids and plasma exchange and/or intravenous immunoglobulins. However, in refractory patients, new treatments, such as rituximab, defibrotide and eculizumab, have proven to be beneficial.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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