Y Shoenfeld

Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines

The term ‘catastrophic’ antiphospholipid syndrome (APS) is used to define an accelerated form of APS resulting in multiorgan failure. Although catastrophicAPS patients represent less than 1% of all patients with APS, they are usually in a life-threatening medical situation that requires high clinical awareness. The careful and open discussion of several proposals by all participants in the pre-symposium workshop on APS consensus, held in Taormina on occasion of the 10th International Congress on aPL and chaired by Munther A Khamashta and Yehuda Shoenfeld (29 September 2002), has allowed the acceptation of a preliminary set of classification criteria. On the other hand, the optimal management of catastrophicAPS must have three clear aims: to treat any precipitating factors (prompt use of antibioticsif infection is suspected, amputation for any necrotic organ, high awareness in patients with APS who undergo an operation or an invasive procedure), to prevent and to treat the ongoing thrombotic events and to suppress the excessive cytokine ‘storm’. Anticoagulation (usually intravenous heparin followed by oral anticoagulants), corticosteroids, plasma exchange, intravenous gammaglobulins and, if associated with lupus flare, cyclophosphamide, are the most commonly used treatments for catastrophic APS patients.

Adjuvants and autoimmunity

Some adjuvants may exert adverse effects upon injection or, on the other hand, may not trigger a full immunological reaction. The mechanisms underlying adjuvant adverse effects are under renewed scrutiny because of the enormous implications for vaccine development. In the search for new and safer adjuvants, several new adjuvants were developed by pharmaceutical companies utilizing new immunological and chemical innovations. The ability of the immune system to recognize molecules that are broadly shared by pathogens is, in part, due to the presence of special immune receptors called toll-like receptors (TLRs) that are expressed on leukocyte membranes. The very fact that TLR activation leads to adaptive immune responses to foreign entities explains why so many adjuvants used today in vaccinations are developed to mimic TLR ligands. Alongside their supportive role, adjuvants were found to inflict by themselves an illness of autoimmune nature, defined as ‘the adjuvant diseases’. The debatable question of silicone as an adjuvant and connective tissue diseases, as well as the Gulf War syndrome and macrophagic myofaciitis which followed multiple injections of aluminium-based vaccines, are presented here. Owing to the adverse effects exerted by adjuvants, there is no doubt that safer adjuvants need to be developed and incorporated into future vaccines. Other needs in light of new vaccine technologies are adjuvants suitable for use with mucosally delivered vaccines, DNA vaccines, cancer and autoimmunity vaccines. In particular, there is demand for safe and non-toxic adjuvants able to stimulate cellular (Th1) immunity. More adjuvants were approved to date besides alum for human vaccines, including MF59 in some viral vaccines, MPL, AS04, AS01B and AS02A against viral and parasitic infections, virosomes for HBV, HPV and HAV, and cholera toxin for cholera. Perhaps future adjuvants occupying other putative receptors will be employed to bypass the TLR signaling pathway completely in order to circumvent common side effects of adjuvant-activated TLRs such as local inflammation and the general malaise felt because of the costly whole-body immune response to antigen. Lupus (2009) 18, 1217—1225.

Cancer and autoimmunity: autoimmune and rheumatic features in patients with malignancies

OBJECTIVES To review the autoimmune and rheumatic manifestations of patients with malignancy. METHODS A Medline search of all published papers using keywords related to malignancies, autoimmunity, rheumatic diseases, and paraneoplastic syndromes. RESULTS Patients with malignant diseases may develop autoimmune phenomena and rheumatic diseases as a result of (a) generation of autoantibodies against various autoantigens, including oncoproteins (P185, 1-myc, c-myc, c-myb), tumour suppression genes (P53), proliferation associated antigens (cyclin A, B1, D1, E; CENP-F; CDK, U3-RNP), onconeural antigens (Hu, Yo, Ri, Tr), cancer/testis antigens (MAGE, GAGE, BAGE, SSX, ESO, SCP, CT7), and rheumatic disease associated antigens (RNP, Sm). The clinical significance of the various autoantibodies is not clear. Anti-oncoprotein and anti-tumour suppression gene antigens are detected before the diagnosis of the cancer or in the early stages of the malignant disease, suggesting a potential diagnostic or prognostic role. Anti-onconeural antibodies are pathogenic and are associated with specific clinical neurological syndromes (anti-Hu syndrome and others). (b) Paraneoplastic syndromes, a wide range of clinical syndromes, including classic autoimmune rheumatic diseases that develop among patients with cancer. (c) Rheumatism after chemotherapy, a clinical entity characterised by the development of musculoskeletal symptoms after combination chemotherapy for malignancy. CONCLUSION Autoimmune and rheumatic features are not rare among patients with malignancies. They are the result of various diverse mechanisms and occasionally they may be associated with serious clinical entities.

Antiphospholipid syndrome infectious origin.

Antiphospholipid syndrome (APS) is characterized by the presence of pathogenic autoantibodies against β2-glycoprotein-I (β2GPI). The factors causing production of anti-β2GPI remain unidentified, but an association with infectious agents has been reported. Studies on experimental APS models proved that molecular mimicry between β2GPI-related synthetic peptides and structures within bacteria, viruses, tetanus toxoid, and CMV are a cause for experimental APS. Any explanation of how microbial infections might set off APS must take into account the observation that all individuals appear to harbor potentially autoreactive lymphocytes, as well as natural antiphospholipid antibodies, but that these cells or antibodies remain innocuous unless somehow activated. Herein, we discuss the association of antiphospholipid antibodies in the infectious state, molecular mimicry as a proposed cause for development of APS, and the contribution of the database to this topic.

Treatment of pregnant patients with antiphospholipid syndrome

Antiphospholipid Syndrome (APS) has been widely recognized as a risk factor for the recurrence of both thrombosis and pregnancy losses; however the optimal treatment of patients is debatable. The aim of this paper was to establish a consensus among experts on the treatment of APS in pregnancy. A questionnaire that described possible different clinical situations was sent to the International Advisory Board of the 10th International Congress on AntiphospholipidAntibodies. Sixteen experts from different medical branches and different geographic areas sent their replies. The consensus was that treatment for APS pregnant patients should be low molecular weight heparin (LMWH) and low dose aspirin (LDA). The dosage, and frequency of LMWH depends on different situations, including the body weight and past history. Patients with previous thromboses usually receive two injections per day. Warfarin can also be used from 14 to 34 weeks, for patients with previousstroke or severe arterial thromboses. The use of intravenous immunoglobulin (IVIG) seems to be restricted to patients with pregnancy losses despite conventional treatment. The experts usually advised barrier methods of contraception, intrauterine device (if the patient is not taking corticosteroids) or progestins. Oral contraception with oestrogens was usually avoided.

Prophylaxis of the antiphospholipid syndrome: a consensus report

Hypothetical circumstances that may require prophylaxis for a potential antiphospholipid syndrome (primary prophylaxis), or in some instances when there already had been some manifestations of the syndrome (secondary prophylaxis), were presented to a panel of experts for their consideration on potential prophylactic intervention. These were subsequently presented to the participants in the First InternationalConsensuson Treatment of the AntiphospholipidSyndrome. In most instances there was consensus in adding low dose aspirin, an exception being aspirin allergy when other antiaggregants could be used in nonpregnant subjects. General measures to prevent thrombosis and other vaso-protective actions should also be provided. Higher risk of fetal loss or thrombosis called for anticoagulation with coumadin in nonpregnant subjects or subcutaneous low molecular weight heparin in pregnant ones. When indicated, prophylaxis of the antiphospholipid syndrome should be provided in systemic lupus erythematosus patients who are being treated for their disease. In no instanceshould corticosteroidsor immunosuppresantsbe given as prophylacticof an antiphospholipid syndrome.

Autoimmunity following Hepatitis B vaccine as part of the spectrum of ‘Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants’ (ASIA): analysis of 93 cases:

Objectives: In this study we analyzed the clinical and demographic manifestations among patients diagnosed with immune/autoimmune-mediated diseases post-hepatitis B vaccination. We aimed to find common denominators for all patients, regardless of different diagnosed diseases, as well as the correlation to the criteria of Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants (ASIA). Patients and methods: We have retrospectively analyzed the medical records of 114 patients, from different centers in the USA, diagnosed with immune-mediated diseases following immunization with hepatitis-B vaccine (HBVv). All patients in this cohort sought legal consultation. Of these, 93/114 patients diagnosed with disease before applying for legal consultation were included in the study. All medical records were evaluated for demographics, medical history, number of vaccine doses, peri-immunization adverse events and clinical manifestations of diseases. In addition, available blood tests, imaging results, treatments and outcomes were recorded. Signs and symptoms of the different immune-mediated diseases were grouped according to the organ or system involved. ASIA criteria were applied to all patients. Results: The mean age of 93 patients was 26.5 ± 15 years; 69.2% were female and 21% were considered autoimmune susceptible. The mean latency period from the last dose of HBVv and onset of symptoms was 43.2 days. Of note, 47% of patients continued with the immunization program despite experiencing adverse events. Manifestations that were commonly reported included neuro-psychiatric (70%), fatigue (42%) mucocutaneous (30%), musculoskeletal (59%) and gastrointestinal (50%) complaints. Elevated titers of autoantibodies were documented in 80% of sera tested. In this cohort 80/93 patients (86%), comprising 57/59 (96%) adults and 23/34 (68%) children, fulfilled the required criteria for ASIA. Conclusions: Common clinical characteristics were observed among 93 patients diagnosed with immune-mediated conditions post-HBVv, suggesting a common denominator in these diseases. In addition, risk factors such as history of autoimmune diseases and the appearance of adverse event(s) during immunization may serve to predict the risk of post-immunization diseases. The ASIA criteria were found to be very useful among adults with post-vaccination events. The application of the ASIA criteria to pediatric populations requires further study.

Association of anti-cyclic citrullinated peptide antibodies with subclinical atherosclerosis in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is associated with increased mortality, predominantly due to accelerated atherosclerosis.1 Traditional cardiovascular disease (CVD) risk factors cannot fully account for this increased propensity and it seems that the sustained inflammatory state of RA represents a crucial element for enhanced atherosclerotic risk.1 2 In fact, CVD mortality in RA appears to be predicted by the level of disease activity and severity of joint damage and extra-articular manifestations.2 3 Some immunological markers, such as rheumatoid factor or antinuclear antibodies, are more often encountered in RA with extra-articular manifestations.4 Anti-cyclic citrullinated peptide (anti-CCP) antibodies have been shown to be highly specific for …

Environment and lupus-related diseases

Clinical manifestations of lupus are encountered in a variety of disease entities, including isolated cutaneous lupus, undifferentiated connective tissue disease, mixed connective tissue disease, drug-induced lupus, overlap syndrome, and systemic lupus erythematosus (SLE). While each entity has been recognized as a specific disease with its own diverse clinical and serological pattern, one could argue that many findings are common. Could it be that all of these entities actually represent a spectrum of one disease? Could it be that rather than the genetic predisposition and hence controlled factors that govern this spectrum of diseases, that environmental factors associated with SLE could also play a role in the different entities of this spectrum? The traditional environmental triggers in SLE include sunlight and ultraviolet (UV) light, infections, smoking, and medications including biologics such as tumor necrosis factor alpha (TNF-a) blockers. In this review, we update and further substantiate these traditional factors in the various lupus-related syndromes. We will also discuss the association with vaccine exposure, industrial estrogens, and other factors.

Intravenous immunoglobulins in systemic lupus erythematosus: from the bench to the bedside

This article is an update on the clinical and research data available on systemic lupus erythematosus (SLE) and intravenous immunoglobulin (IVIg) therapy that includes some studies performed under the umbrella of the European Working Party on SLE. Various mechanisms of IVIg may play a role, some synergistically, in the modulation of SLE. Recently it has been suggested that IVIg also suppresses the expansion of autoreactive B lymphocytes through signalling of the FcgRIIB, idiotype-mediated inhibition of B cell receptors and neutralisation of cytokines such as the B cell survival factors (B cell activation factor (BAFF and APRIL). In case reports and in open trials, high-dose IVIg (2 g/kg over a 5-day period) has consistently been shown to be a beneficial and safe adjunct therapeutic agent for over 20 manifestations in patients with SLE. It can be given as a first choice of therapy in some cases, for example, in neurological involvement and in those patients who refuse certain immunosuppressive agents such as cyclophosphamide, or in patients who have concomitant infections. Furthermore, IVIg may have a steroid-sparing effect although this characteristic needs further investigation. Specific IVIg (an anti-idiotype to anti-DNA, phosphorylcholine and antiphospholipids) has been shown to be effective in experimental murine models. Hence, extractable IVIg that is directed to the specific pathogenic immunoglobulins will enable the more specific therapy for patients with lupus.