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Our aim was to assess the linkage to care (LTC) and treatment for people newly diagnosed with HIV in Israel during 2011–2015. The Ministry of Health estimated the annual prevalence of undiagnosed HIV; new diagnoses were identified by the Central Virology Laboratory. Only adult Israeli citizens were included. LTC at HIV centers within 90 days of diagnosis was assessed. Demographic and clinical data were collected from patient files. A total of 1538 individuals were diagnosed in 2011–2015. A moderate improvement over time was observed in the calculated proportions of undiagnosed individuals (23.1–17.3%) but no change occurred in LTC rates (82.6–81%). The proportion of diagnosed patients initiating treatment within six months increased from 54.7% in 2011 to 89.7% in 2015, with a parallel increase in the viral suppression rate from 30.5% in 2011 to 59.9% in 2015. Of 1159 patients with detailed records, 79.4% were men, median age 36 years (16–92), median CD4 cell count 342 cells/µl. Younger age, intravenous drug use, and imprisonment were independent risk factors for loss to follow-up. HIV is diagnosed late in Israel and LTC rates remain stagnated; higher awareness is still needed. Once in care, however, treatment and outcomes were in line with international standards.

Background The cascade of HIV care indicates a country’s progress toward optimal diagnosis and care. In Israel national health insurance covers all citizens. Treatment and follow-up are provided in specialized HIV centers. We assessed the linkage to care and treatment of Israeli citizens, newly diagnosed during 2011–2015. Methods Annual estimates of new Israeli cases living with HIV was calculated by the Ministry of Health, and all newly diagnosed Israeli cases confirmed by the Central Virology Laboratory were included. Excluded were tourists, Israeli patients diagnosed abroad and non-Israeli migrants. Gender, age at diagnosis and linkage to care to HIV centers within 90 days was available for all adults (>16). Risk factors for infection, first CD4 and viral load, treatment start date, number of annual visits, last CD4 cell count and viral load (VL) in each year were available for 75% of the studied population (data from one center was missing). Results Included were1,538 newly diagnosed with HIV/AIDS in 2011–2015. No significant change was seen in proportions of unidentified people (~10%), link to care (~79%), or undetectability in those treated (~85% VL < 50). Proportion of patients starting treatment increased from 47.5% in 2011 to 89.9% in 2015, resulting in increase in undetectability (VL < 50) from 35% in 2011 to 71% in 2015 (figure). Median age at diagnosis was 36 (16–92); 15% were >50 years. 76.3% were men, 23.5% women and 0.2% transgender. Twenty-five patients (1.6%) died within 2 months of diagnosis, 62 (4%) were not linked to care for the entire follow-up period. Of 1,159 patients with detailed records, median CD4 at diagnosis was 342 cells/mL, (361 in men and 264 in women), CD4 below 200 cells/mL was found in 27.6%. CD4 at diagnosis did not improve over time (350, 362, 367,331, 283 in the years 2011–2015, respectively). By the end of 2015, 77.9% of the 1,159 patients were in care, 74% were treated and 67% had VL < 50 copies/mL. In multivariate analysis risk factors for lost to follow-up were: previous incarceration OR 4.56 (95% CI 1.8–11.5), and age OR 1.02 (95% CI 1.005–1.036). Conclusion This is the first country-wide individual-based data cascade of care in Israel. In a small country with national health coverage, linkage to care should be improved. The low CD4 levels at diagnosis might imply for a higher rate of undiagnosed individuals. Disclosures M. Chowers, GSK: Grant Investigator, Research grant.

Population HIV-1 sequencing is currently the method of choice for the identification and follow-up of HIV-1 antiretroviral drug resistance. It has limited sensitivity and results in a consensus sequence showing the most prevalent nucleotide per position. Moreover concomitant sequencing and interpretation of the results for several samples together is laborious and time consuming. In this study, the practical use of GS Junior and MiSeq bench-top next generation sequencing (NGS) platforms as an alternative to Trugene Sanger-based population sequencing in the clinical HIV laboratory was assessed. DeepChek(®)-HIV TherapyEdge software was used for processing all the protease and reverse transcriptase sequences and for resistance interpretation. Plasma samples from nine HIV-1 carriers, representing the major HIV-1 subtypes in Israel, were compared. The total number of amino acid substitutions identified in the nine samples by GS Junior (232 substitutions) and MiSeq (243 substitutions) was similar and higher than Trugene (181 substitutions), emphasizing the advantage of deep sequencing on population sequencing. More than 80% of the identified substitutions were identical between the GS Junior and MiSeq platforms, most of which (184 of 199) at similar frequency. Low abundance substitutions accounted for 20.9% of the MiSeq and 21.9% of the GS Junior output, the majority of which were not detected by Trugene. More drug resistance mutations were identified by both the NGS platforms, primarily, but not only, at low abundance. In conclusion, in combination with DeepChek, both GS Junior and MiSeq were found to be more sensitive than Trugene and adequate for HIV-1 resistance analysis in the clinical HIV laboratory.

Anti-BLyS treatment with the human belimumab monoclonal antibody was shown to be a safe and effective therapeutic modality in lupus patients with active disease (i.e., without significant neurological/renal involvement) despite standard treatment.To evaluate the "real-life" safety and efficacy of belimumab added to standard therapy in patents with active lupus in five Israeli medical centers.We conducted a retrospective open-labeled study of 36 lupus patients who received belimumab monthly for at least 1 year in addition to standard treatment. Laboratory tests (C3/C4, anti dsDNA autoantibodies, chemistry, urinalysis and complete blood count) were done every 3-4 months. Adverse events were obtained from patients' medical records. Efficacy assessment by the treating physicians was defined as excellent, good/partial, or no response.The study group comprised 36 lupus patients (8 males, 28 females) with a mean age of 41.6 } 12.2 years. Belimumab was given for a mean period of 2.3 } 1.7 years (range 1-7). None of the patients discontinued belimumab due to adverse events. Four patients (11.1%) had an infection related to belimumab. Only 5 patients (13.9%) stopped taking belimumab due to lack of efficacy. The response was excellent in 25 patients (69.5%) and good/partial in the other 6 (16.6%). Concomitantly, serological response (reduction of C3/C4 and anti-dsDNA autoantibodies) was also observed. Moreover, following belimumab treatment, there was a significant reduction in the usage of corticosteroids (from 100% to 27.7%) and immunosuppressive agents (from 83.3% to 8.3%).Belimumab, in addition to standard therapy, is a safe and effective treatment for active lupus patients.

The expression of psychological distress is culture-dependent. Ethiopian Jewish immigrants' expression of distress is anchored in their unique culture. The authors' aim in this study was to assess the psychological distress of HIV-positive (HIV+) Ethiopian Jewish immigrants in Israel, using a culture-based tool, and to examine the relations of psychological distress, psychosocial variables, and T lymphocyte subset counts and viral load. Participants were 56 HIV+ patients. The authors assessed psychological distress by the self-report questionnaire, which they adjusted for the Ethiopian immigrants (SRQ-E). The authors also assessed adherence to treatment regimen, number of life stressors, and degree of perceived social support, T lymphocyte subset counts, and viral load in plasma. The overall level of psychological distress was in the high range of the SRQ-E scale and was considerably higher in men than in women. Psychological distress was related to more life stressors and lower perceived social support. Women reported having more social support, had better T(CD4+) lymphocyte count and T(CD4+)/T(CD8+) ratio, and lower viral load than did men. Better HIV indicators were related to shorter duration of HIV+ since diagnosis, better adherence, and more social support, but not to psychological distress. The culture-based tool allowed identification of the high degree of psychological distress among the HIV+ Ethiopian immigrants. Researchers need to assess the adaptability of culture-based questionnaires to determine psychological distress in HIV+ patients.

Background HIV in Israel started with a subtype-B epidemic among men who have sex with men, followed in the 1980s and 1990s by introductions of subtype C from Ethiopia (predominantly acquired by heterosexual transmission) and subtype A from the former Soviet Union (FSU, most often acquired by intravenous drug use). The epidemic matured over the last 15 years without additional large influx of exogenous infections. Between 2005 and 2013 the number of infected men who have sex with men (MSM) increased 2.9-fold, compared to 1.6-fold and 1.3-fold for intravenous drug users (IVDU) and Ethiopian-origin residents. Understanding contemporary spread is essential for effective public health planning. Methods We analyzed demographic and virologic data from 1,427 HIV-infected individuals diagnosed with HIV-I during 1998–2012. HIV phylogenies were reconstructed with maximum-likelihood and Bayesian methods. Results Subtype-B viruses, but not A or C, demonstrated a striking number of large clusters with common ancestors having posterior probability ≥0.95, including some suggesting presence of transmission networks. Transmitted drug resistance was highest in subtype B (13%). MSM represented a frequent risk factor in cross-ethnic transmission, demonstrated by the presence of Israeli-born with non-B virus infections and FSU immigrants with non-A subtypes. Conclusions Reconstructed phylogenetic trees demonstrated substantial grouping in subtype B, but not in non-MSM subtype-A or in subtype-C, reflecting differences in transmission dynamics linked to HIV transmission categories. Cross-ethnic spread occurred through multiple independent introductions, with MSM playing a prevalent role in the transmission of the virus. Such data provide a baseline to track epidemic trends and will be useful in informing and quantifying efforts to reduce HIV transmission.

In facing global programs for treating HIV-infected patients in the developing countries, there is a real need for viral load assays that are accurate for the local subtypes. The present study was designed to evaluate viral load measurements using the newer version of the NASBA assay in subtype C-infected patients. The performances of this new version, a real-time nucleic acid sequence-based amplification HIV-1 assay (NucliSens EasyQ), were compared to Amplicor HIV-1 Monitor Assay version 1.5 in 79 samples of subtype C-infected patients originating from Ethiopia. Twenty HIV-1 subtype B-infected patients served as a control group. Blood samples from patients in both groups were tested by both assays. The results were compared by a paired, two-tailed Student's t-test. The disparity between the results of the two viral load assays was highly significant in subtype C samples (P = 0.005), such that in the vast majority, higher values of viral load were obtained by the Amplicor assay. However, no differences between the two assays were found in subtype B samples (P = 0.77). CD4 measurments were available for 78 samples of subtype C-infected patients. Of these, a CD4-to-viral load discrepancy (CD4 ≤ 200, viral load ≤5,000 IU/ml) was found in 11.5% of the samples when using the EasyQ assay, compared with 5.1% of the samples using the Amplicor assay. In conclusion, the performance of the NucliSens EasyQ assay was inferior to that of the Amplicor assay in assessing viral load levels in subtype C-infected patients. This difference may have a significant bearing on patient care. J. Med. Virol. 78:883–887, 2006. © 2006 Wiley-Liss, Inc.

Thrombocytopenia is frequently found in patients with the antiphospholipid syndrome (APS), yet data concerning clinical associations of thrombocytopenia in patients with APS are still scarce. We evaluated possible associations between thrombocytopenia and various APS-related manifestations in a large group of APS patients. Three hundred and seven APS patients were retrospectively evaluated, 259 women and 48 men. Most patients had primary APS (PAPS) ( n = 173 , 56.1%). APS was associated with systemic lupus erythematosus (SLE) in 104 patients (33.9%). All patients underwent detailed medical interview and routine physical examination. Further data were obtained from patients’ medical files regarding the expression of various clinical manifestations of the disease. There were 90 patients with thrombocytopenia (29.3%), the rate was significantly higher in SLE compared to PAPS patients (41.9% vs. 23.1%, p = 0.001 ). Similar rates of thrombocytopenia were found in male (29.2%) and female (29.3%) patients. Significant associations were found between thrombocytopenia and cardiac valves thickening and dysfunction, epilepsy, chorea, arthritis, livedo reticularis and skin ulcerations. In contrast, the rates of thrombotic episodes as well as obstetric complications were similar in patients with and without thrombocytopenia. Our data suggest the presence of thrombocytopenia may be a risk factor for cardiac, neurological, articular and cutaneous complications in APS.

Heart valves lesions and central nervous system involvement are among the most common manifestations of the antiphospholipid syndrome (APS).To evaluate possible interrelations between these manifestations in a large group of APS patients.284 APS patients were evaluated retrospectively, 159 of whom had primary APS. Cardiac-CNS associations were determined for the entire study population, and for subgroups of patients with primary APS or APS associated with systemic lupus erythematosus (SLE).Significant associations where found between cardiac vegetations and epilepsy (p0.02), and between cardiac valve thickening or dysfunction and migraine (p = 0.002). Borderline association was found between valvar vegetations and migraine (p = 0.09). A significant association was also found between all valvar lesions and stroke or transient ischaemic attacks. Subanalyses showed that patients with primary APS had significant associations between cardiac valve pathology and all CNS manifestations, while patients with APS associated with SLE had no such associations.The study suggests potential differences in biological behaviour between primary APS and APS associated with SLE. The presence of cardiac valve pathology may be a risk factor for several types of CNS involvement in PAPS.

In Israel,0.06% of the general population is infected with human immunodeficiency virus (HIV), with a much higher prevalence among specific groups. These groups are distinguished demographically by risk behavior category and by virus subtype. We investigated transmission of drug resistance within groups to assess the impact of these factors.Plasma samples from15% of all patients with new diagnoses of HIV infection were randomly collected between June 1999 and June 2003. Sequences from 176 drug-naive patients included 20 of subtype A, 20 of subtype AE, 2 of subtype AC, 29 of subtype B, 100 of subtype C, and 5 of subtype F.Major drug resistance mutations (protease: L90M; reverse transcriptase: M41L, K103N, V106M, M184V, Y181S, G190A, L210W, T215Y/F, and K219R) were detected in 1 subject with A subtype, 3 with subtype B, and 9 with subtype C. In addition, 1 subject with A subtypes, 2 with subtype B, and 10 with subtype C had secondary mutations (protease: M46I; reverse transcriptase: A98G, K101Q, and V108I). Only 1 patient had mutations associated with1 class of drugs. Among subjects who contracted HIV infection in Israel, 16 of 56 (1 of 7 with subtypes A or AE, 4 of 17 with subtype B, and 11 of 32 with subtype C; P=.7-1.0) carried resistant virus--a significantly higher proportion (P.001) than in subjects infected in other countries (10 of 120 infected).Drug-resistant virus was detected in 14.8% of patients with new diagnoses of HIV infection but in 28.6% of patients known to have been infected in Israel. The implications include a need for pretreatment resistance testing and for better programs aimed at prevention of transmission, directed particularly at patients. We did not find significant differences in transmission of resistant virus between those infected with subtypes B and C, despite the different demographic background. A conclusive analysis and interpretation should await a more extensive study.

Differences in baseline polymorphisms between subtypes may result in development of diverse mutational pathways during antiretroviral treatment. We compared drug resistance in patients with human immunodeficiency virus subtype C (referred to herein as “subtype-C-infected patients”) versus subtype-B-infected patients following protease inhibitor (PI) therapy. Genotype, phenotype, and replication capacity (Phenosense; Virologic) were determined. We evaluated 159 subtype-C- and 65 subtype-B-infected patients failing first PI treatment. Following nelfinavir treatment, the unique nelfinavir mutation D30N was substantially less frequent in C (7%) than in B (23%; P = 0.03) while L90M was similar ( P < 0.5). Significant differences were found in the rates of M36I (98 and 36%), L63P (35 and 59%), A71V (3 and 32%), V77I (0 and 36%), and I93L (91 and 32%) (0.0001 < P < 0.05) in C and B, respectively. Other mutations were L10I/V, K20R, M46I, V82A/I, I84V, N88D, and N88S. Subtype C samples with mutation D30N showed a 50% inhibitory concentration (IC 50 ) change in susceptibility to nelfinavir only. Other mutations increased IC 50 correlates to all PIs. Following accumulation of mutations, replication capacity of the C virus was reduced from 43% ± 22% to 22% ± 15% ( P = 0.04). We confirmed the selective nature of the D30N mutation in C, and the broader cross-resistance of other common protease inhibitor mutations. The rates at which these mutational pathways develop differ in C and subtype-B-infected patients failing therapy, possibly due to the differential impact of baseline polymorphisms. Because mutation D30N is not preferentially selected in nelfinavir-treated subtype-C-infected patients, as it is in those infected with subtype B, the consideration of using this drug initially to preserve future protease inhibitor options is less relevant for subtype-C-infected patients.

OBJECTIVE Genetic differences between subtypes of HIV-1, even when not associated with key resistance mutations, are known to affect baseline susceptibility to specific antiretroviral drugs and resistance-development pathways. We studied the prevalence and patterns of non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated mutations in HIV-1 subtype C-infected patients. METHOD We analysed the genetic variation at sites associated with NNRTI and nucleoside reverse transcriptase inhibitor resistance in subtype C- versus B-infected patients, both drug-naive and -experienced. We extended the comparison to subtype B records from the Stanford database. RESULTS A total of 150 subtype B and 341 subtype C-infected patients were studied. No significant differences were found in treatment and clinical parameters between the groups. In NNRTI-naive patients, changes in NNRTI positions were present in 9.3% of subtype B- versus 33.1% of subtype C-infected patients (P < 0.001). Differences were seen in both drug-naive (subtype B, 10.0% versus subtype C, 50.1%; P < 0.021) and drug-experienced NNRTI-naive patients (subtype B, 9.0% versus subtype C, 23.8%; P < 0.001). In NNRTI experienced patients, the number of A98G/S changes was significantly higher in subtype C patients treated with either efavirenz or nevirapine (P < 0.0001), and V106M was higher in efavirenz-treated subtype C-infected patients (P < 0.0001). The average mutation rates were 1.26 and 1.67 per patient for subtypes B and C, respectively (P = 0.036). The frequency of nucleoside associated mutations, but not M184V, in treated patients was significantly higher in subgroup B-infected patients (P = 0.028). CONCLUSION Collectively, these data indicate that genetic variation at NNRTI resistance-associated positions such as V106M and A98S is substantially greater in subtype C-infected patients than in subtype B-infected patients. The natural structure of each subtype probably affects the frequency and pattern of drug resistance mutations selected under treatment.

Quantitation assays of HIV-1 RNA used currently were designed and optimized for subtype B viruses. However, infection with non-B HIV viruses has become more common worldwide. Unfortunately, little information is available regarding the suitability of these assays for measurement of viral load in specific non-B subtypes. The performance of two commercial HIV-1 RNA quantitation assays was evaluated in 82 HIV subtype C-infected patients and in 43 HIV-1 subtype B-infected patients. Blood samples were tested by the Amplicor HIV-1 Monitor Assay, Version 1.5, and by the nucleic acid sequence-based amplification HIV-1 assay (NucliSens). The results were compared by using a paired, two-tailed Student's t-test; the difference between the assays was found to be significant only for subtype C. Discordant results (>0.5 log difference) between the two assays were detected in 39% of subtype C samples, compared to 23.2% of subtype B samples. In all cases in which a discordant result was detected, the lower results were obtained by the NucliSens assay. Discordant results between CD4 and viral load (CD4 < 200 cells/ml with a viral load

The benefit of combining quinacrine (Qn) with hydroxychloroquine (HCQ) in the treatment of systemic lupus erythematosus (SLE) was previously re-evaluated by us. In our current study we observed that, in 11 active SLE patients (SLEDAI score 5 - 12), the addition of Qn (100 mg=day) to their existing ongoing therapeutic regimens resulted in a significant attenuation of their previously persistent anticardiolipin antibody (aCL) response. This was in comparison with a matched non-Qn treated control group composed of 14 randomly chosen aCL-positive SLE patients with a similar SLEDAI score 6 - 10. Prior to Qn treatment the therapeutic regimens of 12 months’ duration, included in all cases HCQ (400 mg=day), in many cases prednisone (P, 10 - 20 mg=day) and in some additional cases immunosuppressive drugs. SLEDAI scores and aCL levels were monitored during the entire follow-up period which totaled 24 months in the study group and 15 - 18 months in the controls. Along with the beneficial effect of the added Qn on SLEDAI scores, aCL disappearance was documented in eight of 11 patients and remained negative during 8 - 12 months of follow-up (P = 0.004), compared with such a change in only three of 14 non-Qn treated aCL-positive patients (P = 0.18). We conclude that the added Qn treatment to former established therapeutic protocols may eliminate aCL response in SLE patients. Whether this agent’s effect is permanent needs further elucidation.

OBJECTIVE: To document the clinical association between the history of pregnancy loss in patients with the diagnosis of primary or secondary antiphospholipid syndrome (APS) and the presence of different antiprothrombin antibody subtypes [immunoglobulin G (IgG), IgM and IgA] in a cohort of patients with APS. METHODS: Records of 170 female patients with primary APS, or APS secondary to systemic lupus erythematosus (SLE) or secondary to other autoimmune diseases were studied. RESULTS: In female APS patients with IgG antiprothrombin antibodies (n = 105) significant associations to pregnancy loss (p

Two-hundred ninety five patients with the antiphospholipid syndrome (APS) were studied for the presence of antibodies against six anti-beta2GPI-related peptides Abs. The prevalence of a wide spectrum of clinical and laboratory parameters of APS was evaluated in all patients, and correlated with the presence of each anti-beta2GPI peptide antibody. The rates of the various antipeptides Abs ranged from 18.0 to 63.7%. Altogether, 87.1% of the patients had antibody reactivity against at least one of the six beta2GPI-related peptides. A high degree of simultaneous reactivity against several beta2GPI-peptides was found. Positive and negative correlations were found between several antipeptides Abs and the rates of thrombosis and fetal loss. Our results point to a heterogeneous activity of antiphospholipid Abs in APS patients, directed, often concurrently, against various epitopes of the beta2GPI molecule. Evaluation of APS patients for the presence of specific antipeptides Abs may be of a value in predicting the risk for future thrombotic and obstetrical complication, as well as for specific therapeutic purposes.

Background Today’s medical students are the future physicians of people living with HIV/AIDS (PLWHA). It is therefore essential that medical students possess the appropriate knowledge and attitudes regarding PLWHA. This study aims to evaluate knowledge and attitudes of pre-clinical Israeli medical students and to assess whether their knowledge and attitudes change throughout their pre-clinical studies. Methods A cross-sectional study was conducted among all pre-clinical medical students from the four medical schools in Israel during the academic year of 2010/2011 (a total of 1,470 students). A self-administered questionnaire was distributed. The questionnaire sought student responses pertaining to knowledge of HIV transmission and non-transmission routes, basic knowledge of HIV/AIDS treatment and attitudes towards HIV/AIDS. Results The study’s response rate was 62.24 percent. Knowledge among pre-clinical medical students was generally high and showed a statistically significant improvement as students progressed through their pre-clinical studies. However, there were some misconceptions, mostly regarding HIV transmission via breastfeeding and knowledge of HIV prevention after exposure to the virus. Students’ attitudes were found to include stigmatizing notions. Furthermore, the majority of medical students correlated HIV with shame and fear. In addition, students’ attitudes toward HIV testing and providing confidential medical information were contradictory to health laws, protocols and guidelines. Overall, no positive changes in students’ attitudes were observed during the pre-clinical years of medical school. Conclusion The knowledge of pre-clinical medical students in Israel is generally high, although there are some knowledge inadequacies that require more emphasis in the curricula of the medical schools. Contrary to HIV-related knowledge, medical students’ attitudes are unaffected by their progression through medical school. Therefore, medical schools in Israel should modify their curricula to include teaching methods aimed at improving HIV-related attitudes and adherence to medical professionalism.

Objective: To test the clinical response of systemic lupus erythematosus (SLE) patients to intravenous immunoglobulins (IVIg), and whether the clinical response of IVIg treatment in SLE is accompanied by modification of SLE-associated autoantibodies/antibodies (Abs) and complement levels.Methods: Twenty SLE patients were treated with high-dose (2 g/kg) IVIg monthly, in a 5-d schedule. Each patient received between 1-8 treatment courses. They were evaluated for the clinical response, Systemic Lupus Activity Measure (SLAM) score before and after IVIg, levels of antinuclear antibody (ANA), dsDNA (double-stranded DNA), SS-A or SS-B, ENA (extractable nuclear antigens), C3and C4levels before and after the treatment, and before and after each treatment course.Results: A beneficial clinical response following IVIg treatment was noted in 17 out of 20 patients (85%). Few clinical manifestations responded more to treatment: arthritis, fever, thrombocytopenia, and neuropsychiatric lupus. In 9 patients evaluated before and after IVIg, mean SLAM score decreased from 19.3 ± 4.7 to 4 ± 2.9 (P < 0.0001). There was a tendency towards abnormal levels of complement and Abs before IVIg courses among the treatment responders compared with the non-responders, and similarly the former tended to have normalization of their abnormal levels more than the latter. These differences were found statistically significant only with respect to C4and SS-A or SS-B levels before IVIg courses.Conclusion: IVIg has a high response rate among SLE patients. A combination of clinical manifestations, Abs and complement levels may aid in the future in predicting who among SLE patients will benefit more from IVIg treatment.

J. GEORGE, M. BLANK, M. HOJNIK, E. BAR-MEIR, T. KOIKE*, E. MATSUURA*, M. LORBER†,M. AVIRAM‡ & Y. SHOENFELDResearch Unit of Autoimmune Diseases, Department of Medicine ‘B’, Sheba Medical Centre,Tel Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Israel, *Department of Medicine II,Hokkaido University School of Medicine, Sapporo, Japan, and † Clinical Immunology Unit and ‡ Lipid Research Laboratories,Rambam Medical Centre and the Bruce Rappaport Faculty of Medicine, Technion, Israel(Accepted for publication 30 January 1997)SUMMARYOx-LDL is thought to play a major role in atherogenesis. The mechanisms mediating the deleteriousinfluences of Ox-LDL include foam cell formation and cell cytotoxicity. The production of anti-Ox-LDL antibodies results in the formation of immune complexes which are taken up at enhanced rate bymacrophages, leading to foam cell formation. APS is characterized by repeated venous and arterialthromboembolic phenomena, recurrent fetal loss and thrombocytopenia, associated with the presence ofantibodies to negatively charged phospholipids (aPL) (i.e. cardiolipin, phosphatidylserine). Phospho-lipids bear structural resemblance to LDL, and several studies have indeed proved that aPL displaycross-reactivity with anti-Ox-LDL antibodies. In this study we assessed the capacity of oxidized andnative forms of LDL to aggravate the clinical picture of experimentally induced APS in naive mice.Mice were actively immunized intradermally with anticardiolipin antibodies and developed a clinicalpicture resembling APS in humans. Subsequently, the mice were infused with either Ox-LDL, nativeLDL or PBS, and similar regimens were applied to controls. APS mice infused with Ox-LDL werefound to exhibit a significantly more severe form of the disease in comparison with native LDL- andPBS-infused mice, expressed by lower platelet counts (261000/mm

Serodiscordant couples live with the risk of HIV infection of the negative partner when attempting to become pregnant. Using density gradient centrifugation (DGC), spermatozoa can be separated from other seminal compartments. Isolated spermatozoa do not contain detectable HIV RNA. DGC followed by artificial insemination may significantly reduce the risk of infection. The Hadassah AIDS Center (HAC) has recently initiated a fertility center for serodiscordant couples.Our patient population includes serodiscordant couples in which the male is HIV positive. The male semen is washed using the DGC procedure. Washed semen is tested for HIV by standard PCR methods. Intrauterine insemination (IUI) is attempted using the washed semen.A total of 55 couples have registered for this procedure. This includes 16 men who have sex with men, 7 who have hemophilia and 8 couples of Ethiopian origin. The average female age is 33 years. Seven (12%) men had inadequate sperm counts and were referred for IVF. Overall, 34 semen samples were tested for HIV. Only one was found to be positive. During the procedure, 22 couples underwent at least one IUI attempt and 16 (72%) females became pregnant, 3 of them after the first IUI attempt. All women tested for HIV after IUI were found to be negative.The pregnancy success rate during the first year of operation was 72%, similar to that reported by other centers in Europe. There were no seroconversions of the female partner. Serodiscordant couples living with HIV in Israel today may consider starting a family, while significantly reducing the risk of infecting the negative female partner.

Recently, with the emergence of highly effective antiretroviral treatment (ART), chronic liver disease has become the leading cause of morbidity and mortality in co-infected HIV-HCV (Human immunodeficiency virus-Hepatitis C virus) patients. The overall SVR rate in this population remains unsatisfactory. The aim of this study was to evaluate the response to therapy in HIV-HCV co-infected patients in a single center.Consecutive HIV-HCV co-infected patients were evaluated in the liver clinic between 2003 -2010. Liver needle biopsy was conducted in 100% of the patients. The patients were treated by a multidisciplinary team consisting of immunologists, hepatologists, social workers and nurses and a close follow-up was conducted. The 48 weeks duration of peg-interferon and ribavirin combination was used for all genotypes according to recent guidelines. Weight-adjusted ribavirin doses were applied. Treatment was initiated after stabilization of HIV parameters and successful weaning from drug and alcohol addiction.A total of 86 out of 143 HIV- HCV co-infected patients, were evaluated; 39 completed treatment. Of those 31 (77%) achieved SVR. Out of 22 genotype 1 patients, 18 (82%) achieved SVR. Six patients had spontaneous viral clearance and 8 are still receiving treatment. In 17 non-one genotype patients, the SVR rate was 76.4% (13 of 17 patients); 6 patients were defined as relapsers and non-responders. Overall adherence to the treatment was high.Measures, such as the use of a multidisciplinary approach, high adherence of physicians to the guidelines, weight-based ribavirin dose, and selecting patients who are ready to start therapy, can significantly improve the SVR rate in this difficult-to-treat patient population.

The coexistence of systemic lupus erythematosus (SLE) and thymoma is rare. We describe 2 female patients with this combination. A 48-year-old woman presented with dyspnea due to a left pleural effusion. Her past history revealed over the previous 3 years the development of anemia, thrombocytopenia, alopecia, pericardial effusion and proteinuria. Four months prior to this hospitalization, the patient was first admitted due to purpura. At that time, laboratory tests revealed an elevated sedimentation rate, elevated titers of ANA and anti-DNA. Chest X-ray demonstrated a widened mediastinum, and upon operation an encapsulated thymoma was excised. Four months following the thymectomy, the patient is unresponsive despite high dose steroid therapy. Another patient, a 30-year-old woman, presented with SLE (cutaneous, arthritis, anemia, positive ANA and high titers of anti-DNA) and thymoma simultaneously. Six years after thymectomy the patient is in SLE remission. Thymectomy in mice prone to autoimmunity (NZB/W mice) has been shown to accelerate the autoimmune manifestations. Conversely, the opposite effect is seen in MRL/lpr mice. The immunological effect of adult thymectomy on the course of human SLE remains to be established, on a larger series of patients. It seems that the heterogenicity of human patients is exemplified by the contrasting effects of thymectomy for thymoma in SLE patients.

Patients with systemic lupus erythematosis (SLE) often manifest features of other autoimmune diseases. In this review, we provide a detailed compendium of features of SLE that overlap with other conditions. This compendium is important because a critical feature in our understanding of autoimmunity has been the clustering of coexisting/different autoimmune diseases both within an affected patient and within a pedigree. Indeed, autoimmune disorders share a variety of similar clinical and serological defects. For example, all autoimmune disorders are associated with the elaboration of autoantibodies and/or the production of self-reactive mononuclear cell populations; many have high levels of immune complexes and defects in cell-mediated immunity. Several diseases share similar genetic backgrounds, as reflected by study of loci within the major histocompatibility complex. In part the coassociation is due to common genetic tendencies with different environmental precipitating agents (trigger mechanisms). It is likely that many factors can modulate the immune system to autoimmunity in the presence of an appropriate genetic background, eg, drugs, viral infections, UV irradiation, and toxins, ie, toxic oil syndrome and l -tryptophan-induced eosinophilic myalgia. The coexistence of SLE with other autoimmune diseases is an excellent venue to understand these events, and we believe that the presence of other autoimmune diseases in patients with SLE can be called the kaleidoscope of autoimmunity.

The titers, isotypes and idiotypes of antiphospholipid and anti-dsDNA antibodies were determined in seven pairs of mothers with antiphospholipid syndrome (APLS) and their offspring, in 11 pairs of SLE mothers and their matched infants and in seven respective pairs of healthy subjects. In addition, maternal as well as fetal sera were evaluated for the presence of anti-SSA (Ro), anti-SSB (La) and anti-70 kd RNP autoantibodies. In the sera from APLS patients, as well as in the sera from their offspring, the mean antibody titer of IgG aCL was found to be significantly higher then the corresponding value in the control group (P < 0.01). Highly significant increased titers of IgG anti-DNA antibodies were found in the sera of SLE mothers and their matched offspring (P < 0.0008). The prevalance of anti-SSA, anti-SSA, and anti-7OKd RNP antibodies was lower then that of antiphospholipid and anti-dsDNA antibodies. Only one of the respective offspring had increased levels of these antibodies. The quantity of maternal antibodies transferd to the fetus was depended on their concentration in the maternal circulation, as well as on their type and specificity. Follow-up of newborn sera showed a progressive decrease in the antiphospholipid antibody titers during 3 months. After 6 months it was undetected. Our results point to a transplacental transfer of aCL and anti-DNA antibodies, a phenomenon which is not necessarily associated with respective clinical manifestations, in contrast to the classical humoral mediated autoimmune diseases (e.g. myasthenia gravis).

Henoch-Shoenlein Purpura (HSP) is a multisystem disorder of unknown etiology affecting predominantly the skin, joints, gastrointestinal tract, and the kidneys but other organs can be affected as well. It is one of the most common causes of vasculitic disorders in children. No specific autoantibodies have been detected in HSP, but the presence of IgA depositions in both skin and kidney biopsies and the presence of IgA-containing circulating immune complexes support the immunological pathogenesis. The natural history of the disease is cure in most cases, although recurrence and end-stage kidney disease are described. The treatment consists of corticosteroids and immunosuppressive drugs.

The effects of 2-week treatment with 20mg tenoxicam once daily, and 50mg diclofenac twice daily, in comparison with placebo, were investigated in 30 patients with rheumatoid arthritis (RA). Treatment efficacy was assessed by standard clinical parameters and by continuous actigraphic recordings of wrist movements.

Discordant couples, in which the man is HIV positive and the woman is HIV negative, face limited options when they wish to produce healthy children whilst practicing safe sex. In order to conceive they must abandon unprotected sex, which carries high risk of HIV infection to the woman.To develop a method for removing the HIV from semen and then perform intra uterine insemination, following verification of the HIV-negative spermatozoa fraction by PCR.Motile spermatozoa were isolated from semen samples by the gradient and "swim-up" techniques. HIV-RNA was tested before and after the procedure in both the semen and the purified spermatozoa fraction. Insemination was performed on ovulation day only when the absence of any viral particles was verified by PCR.Four couples underwent a total of 8 cycles of intra uterine insemination (IUI). Presently, two healthy babies were born. The two mothers and newborn were found to be HIV negative following the delivery.We report a safe procedure which enables biological parenthood for HIV-1 discordant couples without the risk of infecting the female partner. Our clinical data corroborate with the collaborative European data on this subject.

Background: Population-based epidemiological surveys in several countries have shown approximately 10- to 15-fold increased susceptibility to human immunodeficiency virus (HIV)–associated nephropathy (HIVAN) for populations of recent African ancestry. Accordingly, we sought to determine whether a similar or different pattern of susceptibility was evident among Ethiopians followed up in an HIV clinic in Israel. Methods: One hundred seventy-six consecutive patients (126 Ethiopians, 50 non-Ethiopian Israelis) followed up at the HIV clinic of Rambam Medical Center in northern Israel were examined for the presence of proteinuria and/or decreased glomerular filtration rate. HIV viral load, CD4 count, and treatment modality also were determined. Results: Overall, 73% of patients were treated with highly active antiretroviral therapy, and there was no difference between Ethiopians and non-Ethiopian Israelis in this regard. Mean CD4 count in Ethiopians was 288 ± 140/μL, significantly less than the corresponding CD4 count of 398 ± 190/μL for non-Ethiopian Israelis. Mean viral loads were greater in Ethiopians compared with non-Ethiopian Israelis. None of 176 HIV-infected patients fulfilled clinical criteria for HIVAN as delineated in this study. Conclusion: HIV-infected individuals of Ethiopian descent have a level of susceptibility to HIVAN similar to that of non-Ethiopian Israelis, which is strikingly less than that reported for other populations for recent African ancestry. This does not appear to be attributable to differences in HIV infection control or viral subtype and most likely represents population-based differences in host genetic factors. This finding emphasizes the importance of avoiding generalizations with respect to phylogeographic ancestry in disease-susceptibility studies.

The presence of antineuronal antibodies was compared in 43 patients with primary aPLS and 57 patients with neuropsychiatric SLE. Fifty-eight patients with Guillain-Barré syndrome and 72 normal healthy donors served as control groups. Seventeen patients in the study group had aPLS associated with CNS involvement. Antineuronal antibodies were studied in the sera employing a novel flow cytometric assay. The frequency of antineuronal antibodies in patients with aPLS and CNS involvement was not significantly different from that of patients with aPLS without CNS disease or from that found in the control groups (12%, 19% and 7%, respectively). However, it was significantly different from that found in SLE patients with CNS involvement (60%) (P < 0.001). Our results provide further evidence that unlike CNS-SLE, the major mechanism of CNS involvement in patients with primary aPLS might not be autoantibody (antineuronal) mediated, but rather 'thrombotic' in origin, or due to yet unknown factors.

A previous retrospective study has found an increased risk of uterine cervical atypia in women with systemic lupus erythematosus (SLE) who have been treated with cytotoxic drugs. Our objective was to prospectively reveal any increased incidence of cervical atypia in SLE patients and to evaluate the relationship to previous chemotherapy. A total of 39 SLE women were prospectively referred for cytologic PAP smears of the uterine cervix. A significantly higher incidence of cervical atypia was found in SLE women (35.9%) compared with non-SLE control groups (≤5%; P < 0.01). No significant difference was found between the incidence of atypia in patients previously treated by cytotoxic medications such as cyclophosphamide pulses or methotrexate (4 of 9) compared with SLE women not receiving cytotoxic drugs (10 of 30). Colposcopically directed biopsies revealed three cases of cervical intraepithelial neoplasia (CIN) I-III (23%) among the cases with atypia. We conclude that women with SLE should have regular cytologic cervical smears because of a significantly increased incidence of atypia, regardless of previous cytotoxic therapy.

Inflammation is considered to be a leading cause of morbidity in systemic lupus erythematosus (SLE), yet inflammatory periodontal involvement is rarely encountered. A young lady suffering from active SLE accompanied by severe periodontal loss, manifested by gingival recession of all her teeth, was referred to our clinic for treatment. The association between periodontal involvement and connective tissue diseases is unclear, and the literature dealing with periodontal involvement in patients suffering from Sjogren's syndrome and rheumatoid arthritis is comprised of studies showing both normal and pathological periodontal status. We discuss the possible underlying mechanisms.

Objective: To review the recent advances in clinical and experimental research in systemic lupus erythematosus (SLE). Methods: Review of the 5th International Congress of SLE that took place inCancun, Mexico, on April 20–25, 1998. Results: The main topics presented at the conference are summarized. These include new findings about the genetics of SLE due to fine mapping of the patients' genes and lupus mouse models, the nucleosome as a major autoantigen in SLE, serving as an immunogen for pathogenic T helper and B cells and contributing to the development of lupus nephritis, abnormalities of apoptosis as a cause of SLE, and apoptotic mechanisms as a cause of autoimmunization. Other topics included the pathophysiologic role of anti-endothelial cell antibodies in lupus with central nervous system involvement, vasculitis, the thrombotic diathesis associated with the antiphospholipid syndrome, induction of endothelial cell apoptosis and its regulation by the idiotypic network, the penetration of antinuclear antibodies to the cytoplasm and nucleus and the subsequent interaction with cellular organelles, and new aspects in the antiphospholipid syndrome, including animal models of the disease and the importance of antibodies to beta-2-glycoprotein-I and prothrombin. Advances in the clinical aspects of SLE included clinical manifestations, diagnosis, pregnancy and neonatal SLE, infections, hormones, and treatment. Additionally, four “Lectures of A Lifetime,” entitled (1) What causes lupus? (2) From natural autoimmunity to autoimmune disease; (3) The idiotypic network and SLE; and (4) Late-stage morbidity and mortality in SLE-the role of accelerated atherosclerosis were presented. Conclusions: Recent advances provide new insights into the pathogenesis of SLE, as well as hope for novel therapeutic modalities and diagnostic measures. These offer the possibility of improving life quality and decreasing mortality from the disease and its complications.

Objectives: Recent interest has been expressed in rheumatic manifestations inhepatitis C virus (HCV)-infected populations. The aim of this study was to determine the prevalence and characteristics of the musculoskeletal manifestations and serological markers of autoirnmunity in HCV-infected patients in Israel. Methods: Ninety anti- HCV-positive patients were consecutively interviewed and examined. The prevalence of autoantibodies and their association with rheumatologic symptoms were also determined. Results: Rheumatic manifestations were found in 28 subjects (31% ), andincluded arthralgias (9%), arthritis (4%), cryoglobulinemia (11%), sicca symptoms (8%), cutaneous vasculitis (2%), polymyositis (1%), and antiphospholipid syndrome (1%). Rheumatic complications were not associated with liver disease severity, or subjects' gender. In addition, myalgia was reported by 22 patients (24%), and fibromyalgia was diagnosed in 14 (16%). Sixty-nine percent of the patients had at least one autoantibody detected in their serum, the most prevalent being rheumatoid factor (RF), 44%; antinuclear antibody (ANA), 38%; and IgM and IgG anticardiolipin antibodies (acl), 28% and 22%, respectively. The frequency of autoantibodies was not associated with liver disease severity or rheumatic disorders. Conclusions: Musculoskeletal manifestations and autoimmune markers are common in HCV infection. An investigation of risk factors for HCV infection is pertinent in a patient presenting new rheumatic manifestations and should be included in the history of present illness. Future studies of these disorders may uncover the full spectrum of these associations and provide new insights into their operating mechanisms.

This study was undertaken to determine if there is an association between increased titers of five different antiphospholipid antibodies (aPLA) in young patients' sera and the occurrence of acute myocardial infarction (AMI). Antibodies to anticardiolipin (aCL), anti-phosphatidylserine (aPS), antiphosphatidylinositol (aPI), anti-phosphatidylcholine (aPC), and anti-phosphatidylethanol amine (aPEA) were measured in 214 patients (102 patients, 102 healthy controls and 10 patients with antiphospholipid syndrome). These antibodies were measured twice (within 4 h of onset of acute myocardial ischemic chest pain and 3 months after the myocardial infarction) by enzyme linked immunosorbent assay (ELISA). Elevated titers of four different aPLA were detected in 6.9% of all patients with AMI on hospitalization. Titers of aPLA in AMI were elevated in the younger age group Evidence of significantly elevated titers of different aPLA at the early stage of AMI suggests that these autoantibodies are present before the AMI and are not secondary to them. The disappearance of the elevated aPLA 3 months after AMI may be due to an absorption effect or possibly a cyclic phenomenon similarly found in other autoimmune diseases. aPLA may be an additional risk factor for AMI, and should especially be considered in a patient of the younger age group without apparent cardiovascular risk factors.

We surveyed the frequency of reported infections and target autoantigens in 56 Guillain Barré syndrome (GBS) patients by detecting antibodies to myelin and microbes. Sulfatide (43%), cardiolipin (48%), GD1a (15%), SGPG (11%), and GM3 (11%) antibodies were the most frequently detected heterogenous autoantibodies. A wide spectrum of antimicrobial IgG and IgM antibodies were also detected; mumps‐specific IgG (66%), adenovirus‐specific IgG (52%), varicella‐zoster virus‐specific IgG (46%), and S. pneumoniae serotype 7‐specific IgG (45%) were the most prevalent. Our results indicate that polyclonal expansion of physiologic and pathologic antibodies and/or molecular mimicry likely occurs following infection and is related to other autoimmune factors in the etiology of GBS. Although no single definitive myelin‐specific autoantibody was identified, our results suggest a unique pattern of reactivity against autoantigens.

SUMMARY IgG fractions were purified on Sepharosc anti-human IgG column from eight sera of healthy donors, having no anti-cardiolipin (aCL) activity as measured by anti-cardiolipin ELISA assay (aCL-ELISA). All the IgG fractions, after elution with 4.9 m MgCl2, reacted with CL. The antigen-binding characteristics of the IgG fractions purified from normal human serum (NHS) were similar to those of IgG fractions purified from sera of four patients with the anti-phospholipid syndrome (APLS). Competition assay confirmed the specificity of the binding of the purified IgG fractions to CL. The same results have been achieved with IgG fractions purified on Sepharose Protein-A column. The binding to CL was completely inhibited by either whole NHS and sera from various animal species, or by β2-glycoprotein I (β2-GPI). Our results support the notion of the existence of both natural anti-CL antibodies and serum inhibitor(s) in sera of healthy individuals. It is conceivable that in part the pathogenesis of APLS entails defects in the natural inhibitors of aCL antibodies.

OBJECTIVE: The purpose of this study was to compare the effectiveness of low-molecular-weight heparin with regular heparin in the prevention of fetal resorption in mice with the antiphospholipid syndrome. STUDY DESIGN: Antiphospholipid syndrome was passively induced in ICR mice by injecting them with anticardiolipin antibodies on the first day of pregnancy. Subsequently, these mice were treated with low-molecular-weight heparin in two different doses, with regular heparin, and with a placebo. On gestational day 17 the mice were killed by cervical dislocation, and the pregnancy outcome was evaluated. Statistical analysis was performed by means of a one-way analysis of variance using Bonferroni's t test. RESULTS: Treatment with low-molecular-weight heparin resulted in a resorption rate of 22.4% as opposed to 41.4% in mice with antiphospholipid syndrome that were given regular heparin and 51.7% in nontreated controls. CONCLUSION: We conclude that low-molecular-weight heparin can prevent fetal resorptions in mice with antiphospholipid syndrome.

Pregnancy in systemic lupus erythematosus (SLE) is at high risk to the mother and fetus. Impaired utero-placental perfusion may increase fetal loss and intrauterine growth retardation. We assessed the changes in impedance to blood flow in the umbilical and uterine arteries in five patients with SLE treated with low dose aspirin and corticosteroids, using Doppler ultrasound longitudinally throughout pregnancy. Blood flow velocity waveforms of the umbilical and uterine arteries were studied by transabdominal and transvaginal Doppler ultrasound, respectively. Resistance index (RI) was measured every two to four weeks from week 10 to term, and the values obtained were compared to those of normal pregnancies. All five patients delivered uneventfully. One neonate was delivered at 36 weeks (2550 g) and one neonate was growth retarded (1900 g at 38 weeks). Three women delivered at 39 weeks (3585 g, 2850 g, and 2800 g). Most umbilical artery RI values obtained throughout pregnancy were above the 95th percentile of normal pregnancies. The highest values of RI of the umbilical artery were assessed in the case of fetal growth retardation. However, most measurements of RI of the uterine artery were under the 95th percentile of normal. The improved pregnancy outcome in patients with SLE treated with aspirin and corticosteroids seems to correlate with their normal uterine artery flow velocity wave forms.

Twenty-six patients with Behcet's disease were studied for serum levels of anticardiolipin (ACL) antibody isotypes IgG and IgM. The frequency of elevated levels of ACL antibody isotype IgM was found to be significantly increased in these patients. This increased frequency, however, did not correlate statistically with a thrombotic tendency, colchicine intake, antinuclear antibodies, or a positive VDRL test.