Disease activity patterns in a monocentric cohort of SLE patients: a seven-year follow-up study.

OBJECTIVES: To evaluate disease activity patterns and flare occurrence in a cohort of systemic lupus erythematosus (SLE) patients. METHODS: Patients registered in our lupus Database, diagnosed with SLE between 1991 and 2004 and followed up quarterly from 2004 to 2010 were considered in the study. Disease activity patterns were defined using SLE Disease Activity Index-2000 (SLEDAI-2K), excluding serology, as follows: clinical quiescent disease (CQD), SLEDAI-2K=0 in the three annual visits; minimal disease activity (MDA), SLEDAI-2K=1 in one or more annual visits; chronic active disease (CAD), SLEDAI-2K≥2 in at least two annual visits; relapsing-remitting disease (RRD), SLEDAI-2K≥2 in one out of 3 annual visits. Flare was defined as an increase in SLEDAI-2K≥4 from the previous visit, according to SELENA-SLEDAI flare index. RESULTS: One hundred and sixty-five patients fulfilled the inclusion criteria. During the 7 year follow-up, 109 (66%) patients experienced at least one period of active disease (CAD, RRD and MDA), whereas 56 patients (34%) had a persistent CQD. The mean±SD number of patients in each pattern per year was: CAD 52.4±5.8 (31.7%), RRD 16.1±6.8 (9.7%), MDA 9.7±1.7, (5.9%), CQD 87±10.5 (52.6%). Annual flare-rate was 0.19 flare per patient/year and mean±SD number of flares was higher in CAD compared with RRD patients (p<0.01). At the multivariate analysis positive anti-dsDNA antibodies, low C3 or C4, male sex, longer lag time between SLE onset and diagnosis, higher number of flares, and use of immunosuppressant were independently associated with active disease including CAD and RRD patterns. CONCLUSIONS: Two-thirds of our patients developed at least one period of active disease during the 7-year follow-up despite tight monitoring and standard treatment.

Preventive strategies in systemic lupus erythematosus.

Despite the improvement of systemic lupus erythematosus (SLE) survival observed in the last decades, the long-term prognosis of these patients remains poor mainly due to complications of the disease and/or of its treatment. Therefore, in order to improve SLE prognosis, we should try to avoid long-term complications by adopting, early in the disease course, some strategies directed to prevent infections, atherosclerosis and cancer. Moreover, since it has been shown that autoantibodies appear before clinical manifestations in SLE, the question of whether or not asymptomatic individuals with a reliable positive serology should be treated arises. Other than advising these individuals to avoid sun exposure, drugs implicated in drug-induced lupus and cigarette smoking, the use of vitamin D and hydroxychloroquine could be considered. Finally, early SLE diagnosis has led to a modification of disease clinical spectrum at disease onset with an increased frequency of mild disease manifestations over severe ones. Thus great effort should be made in order to identify early in the disease course risk factors for the development of severe SLE manifestations. Finally patients with mild disease carrying factors predictive of severe manifestations should be treated more aggressively than we have done up to now.

Mycophenolate mofetil: what is its place in the treatment of autoimmune rheumatic diseases?

Mycophenolate mofetil (MMF) is a new immunosuppressant recently introduced in the treatment of autoimmune conditions. The greatest experience with the use of MMF has been achieved in the treatment of proliferative lupus glomerulonephritis. However, MMF has also been used to control SLE extra-renal manifestations as well as other autoimmune rheumatic diseases such as idiopathic inflammatory arthropathies, inflammatory myopathies, systemic sclerosis, and systemic vasculitis. MMF seems to be well tolerated and effective and could be considered a useful alternative to standard immunosuppressants for the treatment of autoimmune rheumatic disorders. However, further studies are needed in order to determine its real place in the treatment of these conditions. In this paper, the use of MMF in different autoimmune rheumatic diseases is reviewed and discussed.

Mycophenolate mofetil in lupus glomerulonephritis: effectiveness and tolerability.

Mycophenolate mofetil (MMF) is an immunosuppressive agent initially used in the treatment of transplant recipients. MMF has been used in renal, heart, and liver transplantation, where it seems more effective than other immunosuppressive regimens in reducing the incidence of acute rejection episodes. MMF has a variety of immunosuppressive effects, including selective suppression of T and B lymphocyte proliferation, and has been more recently used in many autoimmune inflammatory conditions. Systemic lupus erythematosus (SLE) is an autoimmune disease that can potentially involve any organ or system of the human body. Glomerulonephritis (GLN) has been recognized as the most frequent severe manifestation of SLE, leading to poor long-term prognosis. In the treatment of lupus GLN, several therapeutic approaches, all including immunosuppressive drugs, such as cyclophosphamide, azathioprine, or cyclosporine A, have been used. The short- and long-term toxicity of these drugs limits their use in a substantial number of patients. Over the last few years, MMF has emerged as an alternative therapeutic regimen in lupus GLN, mainly for patients refractory to other therapies. These studies have shown that it is highly effective and generally well tolerated.

Intravascular large B-cell lymphoma associated with silicone breast implant, HLA-DRB1*11:01, and HLA-DQB1*03:01 manifesting as macrophage activation syndrome and with severe neurological symptoms: a case report.

BACKGROUND: Silicone implants have been successfully used for breast augmentation and reconstruction in millions of women worldwide. The reaction to the silicone implant is highly variable; it can lead to local inflammatory symptoms, and sometimes to systemic symptoms and disease. Over 80 cases of anaplastic lymphoma kinase-negative anaplastic large cell lymphoma have been reported in patients with silicone breast implants and have been accepted as a new clinical entity. To the best of our knowledge, an intravascular large B-cell lymphoma associated with a silicone breast implant has not been reported previously. CASE PRESENTATION: A 48-year-old Caucasian woman who presented with high fever was found to have splenomegaly on physical examination. A laboratory diagnosis revealed pancytopenia, hypertriglyceridemia, and hyperferritinemia. She developed signs of altered sensorium, hemiparesis, aphasia, and cauda equina syndrome. On further evaluation, she fulfilled the necessary five out of eight criteria for diagnosis of macrophage activation syndrome/hemophagocytic lymphohistiocytosis. Dexamethasone administration was followed by prompt improvement; however, 3 days later she again manifested high fever, which persisted despite administration of immunoglobulin and cyclosporine A. Her silicone breast implant was considered a possible contributor to her macrophage activation syndrome and was therefore removed. A histological examination of the capsule tissue showed an extensive lymphohistiocytic/giant cell foreign body reaction suggestive of autoimmune/inflammatory syndrome induced by adjuvants. However, the histological examination unexpectedly also revealed an intravascular large B-cell lymphoma. CONCLUSIONS: The genetic background of our patient with silicone breast implants might have predisposed her to three rare and difficult to diagnose syndromes/diseases: macrophage activation syndrome/hemophagocytic lymphohistiocytosis, autoimmune/inflammatory syndrome induced by adjuvants, and intravascular large B-cell lymphoma. The simultaneous manifestation of all three syndromes suggests causal interrelationships. Human leukocyte antigen testing in all women who undergo silicon breast implantation could in the future enable us to better evaluate the risk of potential side effects.

Pregnancy and vasculitis: a systematic review of the literature.

Primary systemic vasculitis are uncommon diseases that may affect young women in their childbearing age. To date, patients affected with primary systemic vasculitis are often diagnosed and treated earlier than in the past, due to improvement in diagnostic skills and a larger availability of effective drugs. The progressive achievement of a longer life expectancy and a better quality of life have progressively led to an increased number of pregnancies observed during the course of such diseases. Here, we review 567 pregnancies among patients with primary systemic vasculitis, in order to define the relationship between pregnancy and these conditions and to suggest guidelines for their management. However, data on pregnancy outcomes are limited and knowledge about their gestational risk is mostly provided by single case reports or at best by retrospective studies which may result in intrinsic observational bias; unfortunately, long term prospective studies are still lacking. Analysis of the data highlighted a reciprocal influence between disease course and gestational outcome, although no definite effects can be outlined. Indeed, either improvement or worsening of the different vasculitis can occur, probably due to diverse genetic, clinical and immunological background of the patients. Since disease course may vary over time, careful management of systemic vasculitis during gestation is required. Furthermore, organ failure or damage must be carefully considered, since it can lead to adverse obstetrical and fetal outcomes.

The kaleidoscope of glucorticoid effects on immune system.

Glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressive agents which exert multiple effects on immune cell functions. Although their use dates back 60 years, their functions and mode of action have not been completely elucidated yet. GCs act through different genomic and non genomic mechanisms which are mediated by the binding to cytosolic glucocorticoid receptor as well as to cell membrane receptors, or by interacting directly with enzymes and other cell proteins. T cell subtypes have a different sensitivity and response to GCs; in fact, GCs have an immunosuppressive effect on pro-inflammatory T cells, while they stimulate regulatory T cell activity. The effect of GCs on B cells is less clear. Interestingly, treatment with GCs may determine apoptosis of autoreactive B cells by reducing the B cell activator factor (BAFF). Tolerogenic dendritic cells which express low levels of Major Histocompatibility Complex class II, co-stimulatory molecules and cytokines, such as IL-1ß, IL-6, and IL-12, can be induced by GCs. GCs at low levels stimulate and at high levels inhibit macrophage activity; moreover, they reduce the number of basophils, stimulate the transcription of inhibitors of leukocyte proteinases and the apoptosis of neutrophils and eosinophils. Finally, GCs inhibit the synthesis and function of some cytokines, particularly T helper type 1 cytokines, and to a lesser extent the secretion of chemokines and co-stimulatory molecules from immune and endothelial cells.

SLE diagnosis and treatment: when early is early.

Around 1980 antinuclear antibody testing became widely used in routine laboratory practice leading to a tapering in the lag time between SLE onset and diagnosis. Since then nothing relevant has been introduced which could help us in making the diagnosis of SLE earlier than now. Notably, there is increasing evidence that early diagnosis and treatment could increase SLE remission rate and improve patient prognosis. Although it has been shown that autoantibodies appear before clinical manifestations in SLE patients, currently we cannot predict which autoantibody positive subjects will eventually develop the disease. Thus, great effort should be made in order to identify new biomarkers able to improve our diagnostic potential. B lymphocyte stimulator (BLyS), anti-ribosomal P protein and anti-C1q antibodies are among the most promising. In recent years, some therapeutic options have emerged as appropriate interventions for early SLE treatment, including antimalarials, vitamin D, statins and vaccination with self-derived peptides. All these immune modulators seem to be particularly useful when introduced in an early stage of the disease.

Hormones, immune response, and pregnancy in healthy women and SLE patients.

During pregnancy the maternal immune system is modified in order to achieve immune tolerance toward paternal antigen expressed on foetal cells. These modifications, which occur both at the foeto-maternal interface and in the systemic circulation, are driven by oestrogens and progesterone whose blood concentrations increase during pregnancy. The cytokine profile is also modified. Th2 cytokines are enhanced while the Th1 response is inhibited. This could explain why Th1-mediated autoimmune diseases tend to improve and Th2-mediated diseases, such as systemic lupus erythematosus (SLE), tend to worsen during pregnancy. However, whether or not SLE relapses more frequently during pregnancy is still a matter of debate. Steroid hormone and cytokine profiles differ in SLE patients compared with healthy subjects during pregnancy leading to a dysregulation of the balance between cell-mediated and humoral immune response, which, in turn, could explain the variability of the SLE course during gestation. This review focuses on hormonal-related cytokine changes observed during pregnancy in healthy subjects and SLE patients.