Macrophage activation syndrome in adult systemic lupus erythematosus: report of seven adult cases from a single Italian rheumatology center.

The aim was to describe the macrophage activation syndrome (MAS), a life-threatening syndrome characterized by excessive immune activation that can be triggered by conditions affecting immune homeostasis, in a cohort of adult Italian patients with systemic lupus erythematosus (SLE). This was a monocentric retrospective evaluation. The utility of the H-score, developed to estimate the individual risk of having reactive MAS in adult patients, was assessed. Among 511 patients with SLE, 7 cases (1.4%) of MAS (all females) were identified and their medical records reviewed. In all cases, MAS was simultaneous to the onset of SLE. All patients had fever, lymphadenopathy, hematological involvement, and high titer of anti-dsDNA antibodies. Workup for infections and malignancies was negative. In all cases, the H-score was higher than the cut-off suggested for the classification of reactive MAS. All cases required hospital admission, and 2 patients were admitted to the intensive care unit. Most patients were treated successfully with high doses of corticosteroids and with immunosuppressive drugs, whereas the full therapeutic regimen developed for primary hemophagocytic lymphohistiocytosis HLH was used only in one case. No death from MAS was observed. MAS is a rare and severe disorder that complicated the onset of SLE in our cohort. The H-score may be useful in the classification of these patients.

Effector T-cells are expanded in systemic lupus erythematosus patients with high disease activity and damage indexes.

Background and objectives T-cell activation may be one of the pathogenic mechanisms of systemic lupus erythematosus (SLE). After repeated antigenic stimulation, T-cells undergo different modifications, leading to the differentiation into effector memory T-cells (CCR7-CD45RA-) and terminally differentiated effector memory (TDEM) T-cells (CCR7-CD45RA+). Similarly, down-modulation of CD28 may lead to the expansion of the CD28- T-cells, a subpopulation with peculiar effector activities. The aim of this study was the characterization of T-cell phenotype in a cohort of patients with SLE according to disease activity and damage index. Materials and methods Phenotypic analysis of peripheral blood T lymphocytes of 51 SLE patients and 21 healthy controls was done by flow-cytometry. SLE disease activity was evaluated by SLE Disease Activity Index-2000 (SLEDAI-2K) and damage by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI). The variations between different groups were evaluated by Mann-Whitney test. Bonferroni correction was applied to adjust for multiple comparisons ( padj). Spearman rank test was used to evaluate the correlations between quantitative variables. Results CD4+ lymphopenia was found among SLE patients. Patients showed a trend for a higher percentage of TDEM among the CD4+ T-cell subpopulation in comparison with healthy controls ( p = .04). SLE patients were divided into two groups according to disease activity: patients with SLEDAI-2K ≥ 6 ( n = 13) had a higher percentage of circulating CD4+ T-cells with CD28- phenotype ( padj = .005) as well as those with an effector memory ( padj = .004) and TDEM ( padj = .002) phenotype and a trend of decrease of regulatory T-cells (TREGs) ( p = .02), in comparison with patients with low disease activity ( n = 38). Patients with damage (SDI ≥ 1) tended to show an expansion of TDEM among CD4+ T-cells as compared with patients with no damage ( p = .01). In SLE patients an inverse correlation was found between the percentages of TREGs and those of TDEM ( p < .01) or CD4 + CD28- ( p < .01) T-cells. Conclusions CD4+ T-cell subpopulations displaying phenotype characteristics of effector lymphocytes are proportionally expanded in patients with active SLE and a higher damage index. These findings may suggest a role of effector T-cells in the pathogenesis of the disease and in the mechanisms of damage in SLE.

Pregnancy in patients with autoimmune disease: A reality in 2016.

Autoimmune rheumatic diseases are chronic systemic conditions often affecting young women during their reproductive years, so that pregnancy is a major issue in their management. For a long time pregnancy has been discouraged in these women, mainly for two reasons: gestation could aggravate maternal disease and, vice versa, the disease could negatively influence the gestational outcome. The great improvement in the approach to pregnancy done in the past few decades has allowed a progressively increasing number of affected women to fulfill their family plan. Women should be informed about potential risks related to their disease, but they should also be reassured that a good pregnancy outcome is possible if conception occurs in a stable remission state, teratogenic medications have been properly withdrawn and "safe" drugs have been mantained to prevent disease flare. A brief excursus regarding the main issues regarding SLE/APS, Systemic Sclerosis and Systemic Vasculitis is provided, in the attempt to delineate the main risk factors for adverse pregnancy outcome, the onset of maternal complications and the role played by a close multi-specialistic monitoring.

Phenotype modifications of T-cells and their shift toward a Th2 response in patients with systemic lupus erythematosus supplemented with different monthly regimens of vitamin D.

BACKGROUND: Vitamin D receptor is constitutively expressed on the lymphocyte surface. Recent studies highlight that vitamin D may exert actions on T-cells, inhibiting Th1 and Th17 response and enhancing Th2 and T-regulatory (T-reg) function. METHODS: Thirty-four patients with systemic lupus erythematosus (SLE) were randomly enrolled in a two-year prospective study. In the first year, 16 patients were supplemented with an intensive regimen of cholecalciferol (IR) (300.000 UI of cholecalciferol at baseline and 50.000 UI/monthly as maintenance, 850.000 UI annually), whereas 18 with a standard regimen (SR) (25.000 UI of cholecalciferol monthly, 300.000 UI annually). During the second year, patients were switched to the other arm of treatment. Phenotypic analysis of peripheral T lymphocyte and the quantification of cytokine production from peripheral blood mononuclear cells (PBMCs) were evaluated by flow cytometry. RESULTS: At baseline, no significant difference between the two groups emerged among main T-cell subtypes. Over two years of treatment, we saw an increase in the number of T-reg cells, in the total amount of CD4+CD45RA+CCR7- T-cells, whereas a significant reduction of CD8+CD28- T-cells was observed. In addition, the analysis of PBMCs from eight patients following the IR showed the reduction of the IFN-γ/IL-4 ratio (p = 0.01) among CD8+ T-cells after 12 months. CONCLUSIONS: After a long-term of monthly treatment with vitamin D in SLE patients, an enhancement of T-reg cells and the production of Th2 cytokines should be expected.

A 24-month prospective study on the efficacy and safety of two different monthly regimens of vitamin D supplementation in pre-menopausal women with systemic lupus erythematosus.

BACKGROUND: Low vitamin D (vit.D) serum levels are common in patients with systemic lupus erythematosus (SLE) and seem to correlate with higher disease activity. We investigated the effects of different regimens of vit.D supplementation in SLE patients with inactive disease. METHODS: This 24-month prospective study included 34 SLE women who were randomized to receive, together with their ongoing treatment, a standard regimen (SR) of cholecalcipherol (25,000 UI monthly) or an intensive regimen (IR) (300,000 UI initial bolus followed by 50,000 UI monthly) for one year and then were switched to the other regimen in the second year. Patients were seen quarterly for assessment of 25-OH vit.D levels, disease activity, SLE serology and bone metabolism markers. RESULTS: By intra-patient comparison, only the IR was found able to significantly raise vit.D serum levels. After 12 months, values above 30 ng/ml were found in 75% of patients in IR while in only 28% in SR. No significant differences in disease activity and SLE serology were found at any time point between SR and IR. No changes in the mineral metabolism were observed. CONCLUSIONS: The IR was safe and effective in obtaining sufficient levels of vit.D in most SLE patients. However, both regimens of supplementation did not differently affect disease activity nor SLE serology.

Patients with longstanding primary antiphospholipid syndrome: retrospective analysis of organ damage and mortality.

OBJECTIVE: To assess the prevalence of disease- and therapy-related complications and of the organ damage after a follow-up of 15 years or more in patients with primary antiphospholipid syndrome (PAPS). METHODS: Medical records of patients prospectively followed in our centre for at least 15 years were retrospectively reviewed. RESULTS: Thirty-five Caucasian patients (33 female, two male) with diagnosis of PAPS followed from 1984 to 2013 with a mean age at onset of 32 years (SD 8.17) and a median follow-up of 20.5 years (range 15-30) were included. The occurrence of systemic autoimmune disease was observed in 14% of patients. Haemorrhagic, infective and neoplastic events were recorded in 34%, 6% and 9% respectively. Organ damage was present in 20% of patients at the end of the follow-up (17% neurological and 3% renal) and was significantly associated with the occurrence of thrombotic events (p: 0.027), particularly arterial (p<0.001). A 48-year-old patient died from sepsis. CONCLUSION: During long-term follow-up of PAPS systemic autoimmunity is not unexpected. Organ damage progresses in a significant proportion of patients especially if they have suffered previous arterial events. Our study clearly shows the possible evolution of the disease and of organ damage, suggesting that optimal therapy and optimal prophylaxis of each PAPS patient should be carefully identified and strictly applied.

Vitamin D and antiphospholipid syndrome.

Vitamin D (vitD) has been shown to have multiple immunomodulatory properties. Hypovitaminosis D has been described in many systemic autoimmune diseases. Antiphospholipid syndrome (APS), an autoimmune disease characterized by immune-mediated thrombosis and pregnancy loss, is a peculiar model for studying vitD, since these patients do not usually have a full-blown autoimmune disease, nor do they have particular restrictions regarding sun exposure. We assessed 25-OH vitD levels in 115 APS and 128 normal healthy donors (NHD) with the LIAISON® chemiluminescent immunoassay by DiaSorin (Italy). Median values were lower in APS patients than in NHD, with the greatest difference occurring during summertime (p < 0.01), suggesting that APS patients may be somehow prevented from vitD generation upon sun exposure. In our cohort, APS patients may have been instructed to use sunscreens in the presence of positive antinuclear antibodies (ANA). Comparing patients with positive and negative ANA, we found comparable vitD levels during the summer. By subdividing APS patients according to clinical features, thrombotic APS patients showed significantly lower levels than did pure obstetric APS patients (p < 0.01). In conclusion, our study confirms previous reports of hypovitaminosis D in APS patients, making them more similar to patients with other systemic autoimmune diseases than NHD. Hypovitaminosis D may be part of the mosaic of factors that determine autoimmunity, rather than a consequence of chronic disease and its treatment. The observation that patients with thrombotic APS, an aggressive phenotype, may be more deficient than those with exclusive obstetric manifestations fits well with the beneficial effects of vitD on thrombosis described both in vitro and in vivo. Therefore, there may be a rationale to assess the efficacy of vitD supplementation in APS patients.

Phytoestrogen intake and cardiovascular risk markers in Bangladeshi postmenopausal women.

Menopause is the transitional event of female life creating a considerable degree of clinical and psychological as well as social problem and it is known to affect the risk markers of cardiovascular diseases. Hormone replacement therapy (HRT) was though to be a cornerstone in the management of menopause, but evidences accumulated in the recent past have raised serious questions regarding its safety and usability. In this context, phytoestrogens are getting increasingly more attention for therapeutic (as an alternate of HRT) and dietary interventions. Menopause is a special problem for women in developing countries and intake of phytoestrogens can be highly useful also from the economic point of views. The nutraceuticals of specific vitamins, minerals and especially phytoestrogens supplementations are a vital component of the strategy to reduce health problem. The present study was aimed to assess the association of phytoestrogens and risk markers of cardiovascular diseases in postmenopausal women. A total of 111 postmenopausal subjects [age, (years, M±SD) 52±5.35] were studied. The dietary intake of phytoestrogens by study subjects was calculated by a specific food frequency questionnaire (FFQ). Serum fasting homocysteine was measured by AxSYM system. Serum glucose was estimated by glucose-oxidase method. Serum total cholesterol, triglyceride and HDL-C were estimated by enzymatic-colorimetric method LDL-C was estimated by the Friedewald's formula. The intake of total phytoestrogens, isoflavones and lignans (mean±SD, mg/day) were 7.65±3.33, 0.32±0.16, 7.32±3.28 respectively in postmenopausal women. The intake of diadzein, genistein, formononetin, biochanin A (mean±SD, mg/day) were 0.085±0.035, 0.168±0.101, 0.074±0.052 and 0.001±0.0008 respectively. The intake of matairesinol and secoisolaiciresinol (SILR) (mean±SD, mg/day) were 0.022±0.006 and 7.30±3.28 respectively. The total phytoestrogens (r=-0.19, p=0.03) and SILR, one specific type of lignans (r=-0.19, p=0.04) consumption in this study were inversely significantly associated with serum glucose level. The dietary formononetin, one specific type of isoflavones was negatively significantly associated with LDL-cholesterol (r=-0.18, p=0.04). There was no significant relationship found between phytoestrogen intake and serum homocysteine level (r=-0.11, p=0.23). Phytoestrogens containing food intake should be encouraged for reducing risk markers of cardiovascular disease in postmenopausal women.

Ceguera tras cirugía discal lumbar. Aspectos asistenciales y médico-legales. Presentación de un caso y revisión de la Literatura / Blindness afer limbar diskectomy. Clinical and medico-legal aspects. Case report and literature review

Entre las complicaciones de la cirugía discal lumbar, una, poco frecuente pero especialmente incapacitante es la ceguera. Presentamos un caso de ceguera cortical transitoria tras una microcirugía discal convencional L5-S1 en una paciente sana. Se discuten las posibles causas propuestas por la literatura, y se propone el embolismo gaseoso como origen probable de la ceguera cortical experimentada por la paciente. Al tratarse de una complicación de diagnóstico difícil, pero con cierto grado de posibilidad de prevención, y de tratamiento eficaz, se analizan también los principales problemas médico-legales tanto relativos al análisis de mala praxis como a cuestiones relacionadas con el consentimiento informado (AU)

Between the complications of lumbar disc surgery, one with small frequency but very incapacitating consequences is blindness. We communicate a case of transitory cortical blindness after L5-S1 conventional microdiskectomy. Possible causes described by literature are discussed, proposing the air embolism as a probable origin of cortical blindness in this case. Considering that perioperative blindness it is a complication with difficult diagnosis, but potential preventive measures and treatment can be adopted, medico-legal problems are also analyzed, mainly in negligence expert assessment and informed consent (AU)

Vascular adrenal pseudocyst: cytologic and immunohistochemical study.

Adrenal vascular cysts are rare lesions that might be considered in the differential diagnosis of adrenal tumors. Their origin is not clear. We report the clinicopathological findings of a large adrenal hemorrhagic pseudocyst (AHP) in a 73-yr-old man who complained of abdominal pain. An abdominal CT showed a 9 cm tumor in the left adrenal. A fine-needle aspiration biopsy (FNAB) was hemorrhagic and inconclusive. The tumor was excised and touch imprints were taken showing groups of spindled and fusiform cells with elongated nuclei, without atypia. Histologically, the tumor was well delimited by a fibrous capsule and contained numerous cystic spaces lined by endothelial cells and filled with erythrocytes, fibrin thrombus, and necrotic debris. Immunohistochemical study showed strong positivity for factor VIII-RA, CD31, and CD34. Also, the remaining adrenal showed a prominent frame of thin and medium caliber vessels, supporting a vascular origin for this entity. This case illustrates the difficulty in making a diagnosis by FNA and to keep in mind AHP when hematic aspirates are obtained from an adrenal tumor mass.

High frequency of mitochondrial ND4 gene mutation in Japanese pedigrees with Leber hereditary optic neuropathy.

The association of the ND4 gene mutation (mutation) at nucleotide position 11778 of mitochondrial DNA (mtDNA) was investigated in 14 definitive Japanese pedigrees with Leber hereditary optic neuropathy (LHON). The mutation was detected by SfaNI and MaeIII restriction fragment length polymorphisms of mtDNA amplified by polymerase chain reaction. All 14 LHON pedigrees exhibited the mutation, whereas 10 controls did not. The association of this mutation with LHON was revealed to be significantly higher in Japanese (91.7%) than in 27 reported Caucasian (51.9%) LHON pedigrees, implying genetic heterogeneity. In the tested 14 pedigrees, 28 cases with the mutation comprised 19 affected (17 male and 2 female) and 9 asymptomatic (all female except for one) individuals. Such a predominance of males in the incidence of LHON suggested probable participation of additional pathogenetic factor(s) in the development of optic atrophy in LHON patients.

[A trial of molecular diagnosis in Leber's optic neuropathy].

The high frequency of mitochondrial DNA mutation at the nucleotide position (nt) 11,778 was reported in cases of Leber's hereditary optic neuropathy (LHON) after the first report by Wallace et al.. We already reported that it provided a simple diagnostic test by means of PCR (polymerase chain determined the diagnosis of LHON in a case. No nt 11,778 mutation was found in patients with the other optic nerve diseases and in normal controls. This shows the usefulness of molecular diagnosis in LHON. Problems of genetic counselling for patients and female carriers and the possibilities to clarify the cause of LHON were discussed.

A mutation of mitochondrial DNA in Japanese families with Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease characterized by optic nerve degeneration associated with severe bilateral visual loss in young men and occasionally in women. A mitochondrial DNA (mtDNA) replacement mutation in LHON patient, G to A transition at nucleotide position (nt) 11778 converting the 340th arginine to histidine in the NADH dehydrogenase subunit 4, was detected as SfaNI site polymorphism (Wallace et al., Science, 242: 1427-1430, 1988). To evaluate if the SfaNI site loss can be used to diagnose LHON patients, mtDNAs from peripheral blood of six affected males including five probands from five unrelated Japanese families with LHON, a pair of parents and a normal sister of one of the probands and 4 control persons were analyzed using PCR amplification method. The mutation of leukocyte mtDNA at nt 11778 was identified in all of the affected patients, the normal mother and the sister examined, while the father who is normal and 4 control persons did not show the change. These findings support that the mutation at nt 11778 is also associated with LHON in the Japanese and the test of the SfaNI site loss described here is useful for confirming the clinical diagnosis of LHON patients with the mutation at nt 11778.

Outbreak of gastroenteritis in different areas of Pakistan.

Outbreak of acute gastroenteritis occurred during July to August, 1988 in districts of Mansehra, Swat and Muzaffarabad. Thirty cases, clinically diagnosed as cholera, were investigated. On examination, 22 (73.3%) cases were bacteriologically confirmed as cholera due to V. cholerae Eltor, ogawa. All strains were sensitive to chloramphenicol.

Ultrasonography in the diagnosis of obstructive jaundice.

Ultrasonography was employed in the diagnosis of obstructive jaundice. In a group of 38 patients who were studied, Ultrasonography was found to be reliable in confirming the diagnosis. In majority of the cases it was also found to be reliable in revealing the cause of obstruction. Nineteen of these patients were examined by percutaneous transhepatic cholangiography (PTC) and there were 100 per cent correlation with Ultrasonography. Twelve of these patients underwent operation and the findings were in good agreement with those of Ultrasonography.

Study of thyroid functions in protein energy malnutrition.

Thyroid functions were studied in eight children suffering from PEM. The assessment of thyroid functions were done by measuring serum T3 and T4 levels by radioimmunoassay. Both T3 and T4 levels in serum were significantly (P less than 0.001) reduced in PEM as compared to normal healthy children. These results suggest that thyroid functions are affected in PEM. The impairment of such functions may possibly be due to a deficiency of protein or to a blockade in the incorporation of iodine into thyroid hormone at some stage after iodide transport into the gland. The possibility of alteration of some biochemical or metabolic changes induced by PEM during biosynthesis of thyroid hormones cannot be excluded.