Shaye Kivity

Hydroxychloroquine: From Malaria to Autoimmunity

Quinine was first recognized as a potent antimalarial agent hundreds of years ago. Since then, the beneficial effects of quinine and its more advanced synthetic forms, chloroquine and hydroxychloroquine, have been increasingly recognized in a myriad of other diseases in addition to malaria. In recent years, antimalarials were shown to have various immunomodulatory effects, and currently have an established role in the management of rheumatic diseases, such as systemic lupus erythematosus and rheumatoid arthritis, skin diseases, and in the treatment of chronic Q fever. Lately, additional metabolic, cardiovascular, antithrombotic, and antineoplastic effects of antimalarials were shown. In this review, we discuss the known various immunomodulatory mechanisms of antimalarials and the current evidence for their beneficial effects in various diseases and in potential novel applications.

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.

Evidence for the Use of Intravenous Immunoglobulins—A Review of the Literature

Intravenous immunoglobulins (IVIg) were first introduced in the middle of the twentieth century for the treatment of primary immunodeficiencies. In 1981, Paul Imbach noticed an improvement of immune-mediated thrombocytopenia, in patients receiving IVIg for immunodeficiencies. This opened a new era for the treatment of autoimmune conditions with IVIg. Since then, IVIg has become an important treatment option in a wide spectrum of diseases, including autoimmune and acute inflammatory conditions, most of them off-label (not included in the US Food and Drug Administration recommendation). A panel of immunologists and internists with experience in IVIg therapy reviewed the medical literature for published data concerning treatment with IVIg. The quality of evidence was assessed, and a summary of the available relevant literature in each disease was given. To our knowledge, this is the first all-inclusive comprehensive review, developed to assist the clinician when considering the use of IVIg in autoimmune diseases, immune deficiencies, and other conditions.

Myocardial Ischemic Preconditioning Preserves Postischemic Function of the 26S Proteasome Through Diminished Oxidative Damage to 19S Regulatory Particle Subunits

Rationale: The ubiquitin proteasome system (UPS) becomes dysfunctional as a result of ischemia/reperfusion (I/R), which may lead to dysregulation of signaling pathways. Ischemic preconditioning (IPC) may prevent dysregulation by preventing UPS dysfunction through inhibition of oxidative damage. Objective: Examine the hypothesis that early IPC preserves postischemic UPS function thus facilitating prosurvival signaling events. Methods and Results: I/R decreased proteasome chymotryptic activity by 50% in isolated rat heart and an in vivo murine left anterior descending coronary artery occlusion model. Following IPC, proteasome activity was decreased 25% (P<0.05) in isolated heart and not different from baseline in the murine model. Enriched 26S proteasome was prepared and analyzed for protein carbonyl content. Increased (P<0.05) carbonylation in a 53-kDa band following I/R was diminished by IPC. Immunoprecipitation studies indicated that the 53-kDa carbonylation signal was of proteasomal origin. Two-dimensional gel electrophoresis resolved the 53-kDa band into spots analyzed by liquid chromatography/tandem mass spectrometry containing Rpt3/Rpt5 both of which could be immunoprecipitated conjugated to dinitrophenylhydrazine (DNPH). Higher amounts of DNPH-tagged Rpt5 were immunoprecipitated from the I/R samples and less from the IPC samples. I/R increased Bax levels by 63% (P<0.05) which was decreased by IPC. Lactacystin (lac) pretreatment of preconditioned hearts increased Bax by 140% (P<0.05) and also increased ubiquitinated proteins. Pretreatment of hearts with a proteasome inhibitor reversed the effects of IPC on postischemic Rpt5 carbonylation, cardiac function, morphology and morphometry, and ubiquitinated and signaling proteins. Conclusions: These studies suggest that IPC protects function of the UPS by diminishing oxidative damage to 19S regulatory particle subunits allowing this complex to facilitate degradation of proapoptotic proteins.

Association of Serum Uric Acid and Cardiovascular Disease in Healthy Adults

Studies in different populations with high risk for cardiovascular disease (CVD) have shown an association between serum uric acid (SUA) and CVD. However, only a few studies have demonstrated such an association in healthy populations. The aim of this study was to investigate the association between SUA and CVD in a cohort of men and women without diabetes or CVD. A retrospective study was conducted, with a mean 4.8-year follow-up. The outcome was the occurrence of a cardiovascular event, defined as the diagnosis of ischemic heart disease, acute coronary syndrome, acute myocardial infarction, or ischemic stroke. Mean SUA levels were 6.2 ± 1.1 mg/dl for men (n = 6,580) and 4.4 ± 1.1 mg/dl for women (n = 2,559). For women, the rate of CVD occurrence was 11.6% for the highest quartile of SUA level, compared with 5.0% to 6.5% for the lower 3 quartiles. For men, the rate of CVD occurrence was 14.0% for the highest quartile of SUA level, compared with 10.8% for the lowest quartile. The hazard ratio for CVD, adjusted for age, serum creatinine level, body mass index, systolic blood pressure, low-density lipoprotein cholesterol level, triglyceride level, plasma fasting glucose, physical activity, cardiovascular family history, use of diuretics, and current smoking, was 1.24 (95% confidence interval 1.08 to 1.41) for women and 1.06 (95% confidence interval 1.00 to 1.13) for men (p for interaction = 0.04). In conclusion, the strong association of SUA levels with CVD in women, compared with the much lesser degree in men, highlights the necessity of stratifying by gender in investigations of cardiovascular risk factors and supports exploration of SUA as a marker of CVD risk in healthy populations.

A novel automated indirect immunofluorescence autoantibody evaluation

Autoantibodies (AAb), especially antinuclear (ANAs) and anticytoplasmatic antibodies (ACyA), are essential diagnosing markers for several autoimmune diseases. The current gold standard method for ANA detection is manual indirect immunofluorescence (IIF) on human epithelial-2 (HEp-2) cells. However, this technique is cost and time consuming, and characterized by considerable intra- and interlaboratory variability. Thus, an automated IIF-HEp-2 reader has been developed recently. In the current study, we compared the performance of the automated AAb IIF-HEp-2 interpretation to conventional detection methods. Autoantibody detection by IIF on HEp-2 cells was performed in a total of 260 sera of patients, including 34 with systemic lupus erythematosus, 111 with dermatomyositis or polymyositis, 74 with systemic sclerosis, 41 with rare AAb patterns, and 137 healthy individuals. Visual interpretation and routine immunoassays were compared with a novel automated IIF-HEp-2 system using Aklides pattern recognition algorithms. Positive AAbs were detected in 95–100% of rheumatic patients by automated interpretation, in 74–100% with manual reading, and in 64–100% by immunodot assay. Receiver operating characteristic curve analysis of fluorescent intensity revealed a high sensitivity and specificity for automated reading of AAb with an agreement ranging from 90% to 95% between manual and automated interpretation (kappa 0.554–0.69) for systemic sclerosis and myositis, respectively. This study demonstrates a good correlation between manual and automated interpretation of AAb including ANA and ACyA in patients with autoimmune diseases. Full automation of HEp-2 cell assay reading may minimize errors in ANA pattern interpretation and thus help in the standardization of ANA assessment.

Neuropsychiatric lupus: a mosaic of clinical presentations

Neuropsychiatric symptoms affect nearly half of the patients with systemic lupus erythematosus; however, the effect on disease severity, quality of life, and prognosis is tremendous. Symptoms of neuropsychiatric systemic lupus erythematosus may range from mild diffuse ones, to acute life threatening events. Although the underlying mechanisms are still largely unraveled, several pathogenic pathways are identified, such as antibody-mediated neurotoxicity, vasculopathy due to anti-phospholipid antibodies and other mechanisms, and cytokine-induced neurotoxicity. In the current review, we describe the old and the new regarding epidemiology, pathophysiology, diagnosis, and management of neuropsychiatric systemic lupus erythematosus. The possible link between neuropsychiatric symptoms and specific mechanisms may help to facilitate our understanding of the disease in the future, thus allowing for better treatment strategies.

Low levels of vitamin-D are associated with neuropathy and lymphoma among patients with Sjögren's syndrome.

BACKGROUND/PURPOSE Primary Sjögrens syndrome (SS) is a chronic autoimmune disease primarily involving the exocrine glands. The clinical picture of SS ranges from exocrinopathy to systemic disease affecting the lung, kidney, liver, skin, musculockeletal and nervous systems. The morbidity of SS is mainly determined by extraglandular disease and increased prevalence of lymphoma. Environmental and hormonal factors, such as vitamin-D may play a role in the pathogenic process and disease expression. Thus, we aimed to evaluate levels of vitamin-D and their association with manifestations of SS. METHODS Vitamin-D levels were determined in 176 primary SS patients and 163 matched healthy volunteers utilizing the LIAISON chemiluminescent immunoassays (DiaSorin-Italy). A correlation between vitamin-D levels and clinical and serological manifestations of SS was performed. RESULTS Mean vitamin-D levels were comparable between SS patients and control 21.2 ± 9.4 ng/ml and 22.4 ± 10 ng/ml, respectively. Peripheral neuropathy was diagnosed in 23% of SS patients and associated with lower vitamin-D levels (18.6 ± 5.5 ng/ml vs. 22.6±8 ng/ml (p = 0.04)). Lymphoma was diagnosed in 4.3% of SS patients, who had lower levels of vitamin-D (13.2 ± 6.25 ng/ml), compared to SS patients without lymphoma (22 ± 8 ng/ml), (p = 0.03). Other clinical and serological manifestations did not correlate with vitamin-D status. CONCLUSIONS In this study, low levels of vitamin-D correlated with the presence of peripheral neuropathy and lymphoma among SS patients. The link between vitamin-D and neuropathy or lymphoma was reported in other conditions, and may support a role for vitamin-D in the pathogenesis of these processes. Plausible beneficial effect for vitamin-D supplementation may thus be suggested.

Clinical characteristics and risk factors for low dose methotrexate toxicity: a cohort of 28 patients.

OBJECTIVE Low dose (10-25 mg/week) methotrexate is widely used for the management of systemic inflammatory diseases, and is considered to be relatively safe. Toxicity due to low dose MTX has been reported but is poorly characterized. We describe the clinical features, risk factors, and outcomes of low dose MTX toxicity in a large case series at our center. PATIENTS AND METHODS We conducted a retrospective case series of all adult (>18 years) patients hospitalized at Sheba Medical Center, between 2005 and 2012 for low dose MTX toxicity. RESULTS We identified 28 patients (age: 70.4±13.7 years, range: 33-88; 20 (71%) females) hospitalized for low dose MTX toxicity. Indications for MTX therapy included: rheumatoid arthritis (39.2%), psoriasis±arthritis (21.5%), polymyalgia rheumatica (10.8%) and other inflammatory conditions (28.5%). Pancytopenia was the most common manifestation of low dose MTX toxicity detected in 78.5% of the patients. Potential risk factors included acute renal failure, hypoalbuminemia, concurrent use of drugs known to interact with MTX, and dose errors. Serum MTX concentrations (n=20, mean 0.04±0.07 μg/mL range: 0-0.3) did not correlate with the degree of either neutropenia (r=-0.36; p=0.18) or thrombocytopenia (r=0.44; p=0.10). Seven (25%) patients died, all from pancytopenia followed by sepsis. Serum MTX concentrations did not differ between the patients who died from MTX toxicity (n=6; mean: 0.05±0.04 μg/mL) and those who survived the toxicity (n=14 mean 0.04±0.08; p=0.45). CONCLUSIONS Low-dose MTX toxicity can be life threatening, mainly due to myelosuppression. There is no rationale for MTX therapeutic drug monitoring in the setting of low-dose toxicity.

Passive transfer of narcolepsy: Anti-TRIB2 autoantibody positive patient IgG causes hypothalamic orexin neuron loss and sleep attacks in mice

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and cataplexy (a sudden weakening of posture muscle tone usually triggered by emotion) caused by the loss of orexin neurons in the hypothalamus. Autoimmune mechanisms are implicated in narcolepsy by increased frequency of specific HLA alleles and the presence of specific autoantibody (anti-Tribbles homolog 2 (TRIB2) antibodies) in the sera of patients with narcolepsy. Presently, we passively transferred narcolepsy to naïve mice by injecting intra-cerebra-ventricularly (ICV) pooled IgG positive for anti-TRIB2 antibodies. Narcolepsy-IgG-injected mice had a loss of the NeuN (neuronal marker), synaptophysin (synaptic marker) and orexin-positive neurons in the lateral hypothalamus area in narcolepsy compared to control-IgG-injected mice and these changes were associated with narcolepsy-like immobility attacks at four weeks post injection and with hyperactivity and long term memory deficits in the staircase and novel object recognition tests. Similar behavioral and cognitive deficits are observed in narcoleptic patients. This is the first report of passive transfer of experimental narcolepsy to naïve mice induced by autoantibodies and supports the autoimmune pathogenesis in narcolepsy.