Mariele Gatto

Autophagy in human health and disease.

From the Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston (A.M.K.C., S.W.R.); and the Howard Hughes Medical Institute and Department of Internal Medicine, Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas (B.L.). Address reprint requests to Dr. Choi at the Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, or at amchoi@rics.bwh.harvard.edu.

Emerging and critical issues in the pathogenesis of lupus.

Systemic lupus erythematosus (SLE) is a multisystemic, autoimmune disease, encompassing either mild or severe manifestations. SLE was originally labeled as being an immune complex-mediated disease, but further knowledge suggested its pathogenesis is motlier than that, involving complex interactions between predisposed individuals and their environment. People affected with SLE have their immune system skewed toward aberrant self-recognition usually after encountering a triggering agent. Defeats in early and late immune checkpoints contribute to tolerance breakdown and further generation and expansion of autoreactive cell-clones. B and T cells play a master role in SLE, however clues are emerging about other cell types and new light is being shed on SLE autoantibodies, since some of them display really harmful potential (pathogenic antibodies), while others are just connected with disease development (pathological antibodies) and may even be protective. Autoantibody generation is elicited by abnormal apoptosis and inefficient clearance of cellular debris causing intracellular autoantigens (e.g. nucleosomes) to persist in the extracellular environment, being further recognized by autoreactive cells. Here we explore the complexity of SLE pathogenesis through five core issues, i.e. genetic predisposition, B and T cell abnormalities, abnormal autoantigen availability, autoantibody generation and organ damage, relying on current knowledge and recent insights into SLE development.

Overlap connective tissue disease syndromes.

Overlap Syndromes (OSs) have been defined as entities satisfying classification criteria of at least two connective tissue diseases (CTDs) occurring at the same or at different times in the same patient. CTDs include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), polymyositis/dermatomyositis (PDM), and Sjögren syndrome (SS). Every combination between these disorders has been reported. In some OS a specific autoantibody has been indentified, supporting the hypothesis that these syndromes are not a mere association of two or more CTD in the same patient, but a well defined clinical entity with specific clinical characteristics. As an example, anti-t-RNA synthetase syndrome is characterized by the presence of anti-t-RNA synthetase antibodies. Notably, clinical manifestations observed in OS may be different from those observed in the single CTD. The treatment of OS is mainly based on the use of corticosteroids and immunosuppressants. Biologic drugs, i.e. anti-TNFα or anti-CD20 monoclonal antibodies, have been recently introduced as alternative treatments in refractory cases. Moreover, there are some concerns with the use of anti-TNF agents in patients with systemic autoimmune diseases due to the risk of triggering disease exacerbations. In this paper the most frequent OS are described with a special focus on the specific immunologic and clinical aspects. Furthermore, some personal data on anti-t-RNA synthetase syndrome and rhupus syndrome are reported.

The clinical features, diagnosis and classification of dermatomyositis

Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by an inflammatory infiltrate primarily affecting the skeletal muscle and skin. Most common and peculiar cutaneous lesions include Gottrons papules, Gottrons sign and heliotrope rash. Different DM subsets have been identified until now encompassing classic DM, amyopathic DM, hypomyopathic DM, post-myopathic DM, and DM sine dermatitis. Patients with DM have a higher incidence rate of malignancy than the normal population. In these patients cancer occurs in about 30% of cases with higher occurrence in men and in elderly people. Bohan and Peters diagnostic criteria, proposed in 1975, have been widely accepted and used until now. In the last ten years muscle immunopathology, myositis specific autoantibodies testing, and the use of new techniques of muscle imaging such as contrast-enhanced ultrasound or Magnetic Resonance Imaging have been introduced in the diagnostic work-up of patients with DM leading to the development of new diagnostic criteria.

Human papillomavirus vaccine and systemic lupus erythematosus

To investigate the association between human papillomavirus (HPV) vaccination and autoimmune manifestations compatible with systemic lupus erythematosus (SLE) or SLE-like disease, the medical history of six women who presented with SLE or SLE-like disease following HPV immunization was collected. Data regarding type of vaccine, number of immunization, family and personal, clinical and serological features, as well as response to treatments were analyzed. In the reported cases, several common features were observed, such as personal or familial susceptibility to autoimmunity or adverse response to a prior dose of the vaccine, both of which may be associated with a higher risk of post-vaccination autoimmunity. Favorable response to immunosuppressant was observed in all patients. In the current study, a temporal association between immunization with HPV vaccine and the appearance of a spectrum of SLE-like conditions is reported. Additionally, among the patients described, several common features were observed that may enable better identification of subjects at risk. Further studies are required to assess the safety of immunization with the HPV vaccine in patients with autoimmune-rheumatic diseases or in subject at risk of autoimmunity as well as the potential beneficial effect of preventive immunosuppressants.

Optimizing outcome in SLE: treating-to-target and definition of treatment goals.

Patients affected with systemic lupus erythematosus (SLE) display poor-long term prognosis and increased mortality in respect of general population. This may be due to continuous organ damage accrual which is fostered both by persistent disease activity (mainly in the short term) and prolonged corticosteroid exposure (mainly in the long term). The effort of defining novel therapeutic goals to which patients should be treated in order to have their prognosis improved is named treat-to-target. Remission in SLE was shown to be associated with better outcome and prolonged survival; in clinical practice, patients may experience either complete or clinical remission, which are defined as complete clinical/serological healing or no clinical signs of lupus with active serology, respectively. The main treat-to-target in SLE is complete remission, however since longitudinal observations suggest that clinical remission or low disease activity even with minimal corticosteroid intake do improve patients prognosis and survival as well, they may be assumed as acceptable alternative targets. Suitable therapeutic strategies have to be defined in order for these goals to be achieved including early diagnosis, effective treatment and proper corticosteroid tapering which in turn require development of more reliable serum biomarkers for early disease detection and less toxic targeted therapies with a steroid-sparing potential.

Prolonged remission in Caucasian patients with SLE: prevalence and outcomes

Aim To assess the prevalence of prolonged remission in Caucasian patients affected with systemic lupus erythematosus (SLE) and its relationship with damage accrual. Methods Caucasian patients diagnosed with SLE between 1990 and 2009 and quarterly seen from 2009 to 2013 were included in the study. We defined remission as prolonged when lasting ≥5 consecutive years. Three levels of remission were defined using the SLE Disease Activity Index-2000 (SLEDAI-2K): complete remission: no disease activity in corticosteroid-free and immunosuppressant-free patients; clinical remission off corticosteroids: serologically active clinical quiescent (SACQ) disease in corticosteroid-free patients and clinical remission on corticosteroids: SACQ disease in patients taking prednisone 1–5 mg/day. Damage was measured by the SLICC/American College of Rheumatology Damage Index (SDI). Results 224 patients fulfilled inclusion criteria: 196 (87.5%) were women, mean±SD disease duration 11.2±6.8 years. During the 5-year follow-up, 16 patients (7.1%) achieved prolonged complete remission, 33 (14.7%) prolonged clinical remission off corticosteroids and 35 (15.6%) prolonged clinical remission on corticosteroids. At the multivariate analysis, vasculitis (OR 4.95), glomerulonephritis (OR 2.38) and haematological manifestations (OR 2.19) over the patients’ disease course were associated with an unremitted disease. SDI increased more frequently in unremitted (72/140, 51.4%) than in remitted patients (22/84, 26.2%; p=0.001); SDI median increase was higher in unremitted than in remitted patients: 1 (0–3) vs 0 (0–2), respectively (p<0.001). At multivariate analysis, unremitted disease (OR 2.52) and high-dose corticosteroid intake (OR 2.35) were risk factors for damage accrual. Conclusions Thirty-seven percent of our Caucasian patients achieved a prolonged remission, which was associated with a better outcome in terms of damage accrual.

Serpins, Immunity and Autoimmunity: Old Molecules, New Functions

Serine protease inhibitors (serpins) are evolutionary old, structurally conserved molecules which encompass nearly all branches of life. More than 1,000 serpins were characterized to date which are subdivided into 16 subgroups (A–P) according to their common ancestry; among them, 37 are found in humans. Serpins were termed after their capability to inhibit serine proteases, but mounting evidence suggests that they may achieve a greater deal of functions, ranging from embryological growth to synaptic plasticity, development of both myeloid and lymphoid immune cells, and modulation of apoptosis. Serpins are mainly extracellular molecules, although some of them (namely, ov-serpins or clade B serpins) mostly act inside the cells, being either ubiquitously or tissue-specifically expressed. Among newly characterized serpin functions, regulation of cellular proliferation through apoptosis modulation and proteasome disturbance seems to play a major role. Accordingly, several serpins were found to be hyperexpressed in tumor cells. Indeed, apoptosis dysregulation is likely to be a cornerstone in both tumorigenesis and autoimmunity, since uncontrolled cellular viability results in tumor proliferation, while inefficient disposal of apoptotic debris may favor the rescue of autoreactive immune cells. Such a process was widely documented in systemic lupus erythematosus (SLE). Interestingly, alterations in the expression of some serpins, e.g., the ov-serpin SERPINB3, are being unraveled in patients affected with SLE and other autoimmune disorders, suggesting that a failure in serpin function might affect immune homeostasis and self-tolerance, thereby contributing to autoimmunity. Here, we provide an overview of serpin origin, function, and dysfunction, focusing on human serpins and ov-serpins, with a hub on SERPINB3.

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.

Vaccination of patients with auto-immune inflammatory rheumatic diseases requires careful benefit-risk assessment

Will vaccination raise the incidence of autoimmune diseases, what is the impact of increasingly crowded vaccination schedules, the vaccination in age groups and the risk of coincidental temporal association? All these issues are still under debate. However, for the time being, to avoid confusion in the medical community and the media, we have to adhere to guidelines established consensually by experts while ensuring a strict surveillance and reporting possible side effects. Recommendation for vaccination in patients with autoimmune inflammatory rheumatic diseases (AIIRD) based on the currently available evidence and expert opinion were recently formulated by an EULAR task force. Major recommendations for AIIRD include: i) vaccination should ideally be administered during stable disease; ii) influenza vaccination and pneumococcal vaccination should be strongly considered; iii) vaccination can be administered during the use of DMARDs and TNF-inhibitors, but before starting rituximab; iv) live attenuated vaccines should be avoided whenever possible in immunosuppressed patients; v) BCG vaccination is not recommended.