Posterior reversible encephalopathy syndrome after liver transplantation in children: A rare complication related to calcineurin inhibitor effects

PRES is a neuroclinical and radiological syndrome that results from treatment with calcineurin inhibitor immunosuppressives. Severe hypertension is commonly present, but some patients may be normotensive. We report herein two children who received liver transplants, as treatment for biliary atresia in the first case and for Alagille`s syndrome in the second one. In the early postoperative, both patients presented hypertension and seizures. In both cases, the image findings suggested the diagnosis of PRES. The CT scan showed alterations in the posterior area of the brain, and brain MRI demonstrated parietal and occipital areas of high signal intensity. Both children were treated by switching the immunosuppressive regimen and controlling arterial blood pressure. They displayed full recuperation without any neurologic sequelae. Probably, the pathophysiology of PRES results from sparse sympathetic innervation of the vertebrobasilar circulation, which is responsible for supplying blood to the posterior areas of the brain. In conclusion, all liver-transplanted children who present with neurological symptoms PRES should be considered in the differential diagnosis, although this is a rare complication. As treatment, we recommend rigorous control of arterial blood pressure and switching the immunosuppressive regimen.

Systemic lupus erythematosus exhibits a dynamic and continuum spectrum of effector/regulatory T cells

Objective: The identification of regulatory T cells (Treg cells) as CD4(+)CD25(high) cells may be upset by the increased frequency of activated effector T cells (Teff cells) in inflammatory diseases such as systemic lupus erythematosus (SLE). This study aimed to evaluate the frequency of T-cell subsets according to the expression of CD25 and CD127 in active (A-SLE) and inactive SLE (I-SLE). Methods: Peripheral blood mononuclear cells (PBMCs) from 26 A-SLE patients (SLE Disease Activity Index (SLEDAI) = 10.17 +/- 3.7), 31 I-SLE patients (SLEDAI = 0), and 26 healthy controls (HC) were analysed by multicolour flow. cytometry. Results: CD25(high) cell frequency was increased in A-SLE (5.2 +/- 5.7%) compared to I-SLE (3.4 +/- 3.4%) and HC (1.73 +/- 0.8%) (p < 0.01). However, the percentage of FoxP3(+) cells in the CD25(high) subset was decreased in A-SLE (24.6 +/- 16.4%) compared to I-SLE (33.7 +/- 16) and HC (45 +/- 25.1%) (p < 0.01). This was partly due to the increased frequency of Teff cells (CD25(high)CD127(+)FoxP3(empty set)) in A-SLE (10.7 +/- 7.3%) compared to I-SLE (8.5 +/- 6.5) and HC (6.1 +/- 1.8%) (p = 0.02). Hence the frequency of Treg cells (CD25(+/high)CD127(low/empty set)FoxP3(+)) was equivalent in A-SLE (1.4 +/- 0.8%), I-SLE (1.37 +/- 1.0%), and HC (1.13 +/- 0.59%) (p = 0.42). A-SLE presented an increased frequency of CD25(+)CD127(+)FoxP3(+) and CD25(empty set)FoxP3(+)CD127(low/empty set) T cells, which may represent intermediate phenotypes between Treg and Teff cells. Conclusions: The present study has provided data supporting normal Treg cell frequency in A-SLE and I-SLE as well as increased frequency of Teff cells in A-SLE. This scenario reflects a Treg/Teff ratio imbalance that may favour the inflammatory phenotype of the disease. In addition, the increased frequency of T cells with putative intermediate phenotypes may be compatible with a highly dynamic immune system in SLE.

Irreversible blindness in juvenile systemic lupus erythematosus

Blindness caused by severe vasculitis or uveitis is rare in juvenile systemic lupus erythematosus (JSLE) patients. In a 27-year period, 5367 patients were followed at our Paediatric Rheumatology Division and 263 (4.9%) patients had JSLE (American College of Rheumatology criteria). Of note, two (0.8%) of them had irreversible blindness. One of them presented with cutaneous vasculitis and malar rash, associated with pain and redness in both eyes, impairment of visual acuity due to iridocyclitis and severe retinal vasculitis with haemorrhage. Another patient had peripheral polyneuropathy of the four limbs and received immunosuppressive drugs. Three weeks later, she developed diffuse herpes zoster associated with acute blindness due to bilateral retinal necrotizing vasculitis compatible with varicella zoster virus ocular infection. Despite prompt treatment, both patients suffered rapid irreversible blindness. In conclusion, irreversible blindness due to retinal vasculitis and/or uveitis is a rare and severe lupus manifestation, particularly associated with disease activity and viral infection. Lupus (2011) 20, 95-97.

Negative Anti-C1q Antibody Titers May Influence Therapeutic Decisions and Reduce the Number of Renal Biopsies in Systemic Lupus Erythematosus

In a cross-sectional study involving 62 patients with systemic lupus erythematosus (SLE), we found that patients with biopsy-proven lupus nephritis (LN) had higher titers of anti-C1q antibodies than active SLE without nephritis patients. Anti-C1q was associated with a negative predictive value of 94.59%, a positive predictive value of 52%, a sensitivity of 86.66% and a specificity of 74.47% for the diagnosis of LN. We conclude that high titers of anti-C1q antibodies are strongly associated with the presence of active LN, and the negative predictive value of this test for diagnosing LN is very high; therefore, it can influence therapeutic decisions and reduce the number of renal biopsies in patients with SLE. Copyright (C) 2011 S. Karger AG, Basel

Autoimmune hemolytic anemia in systemic lupus erythematosus: association with thrombocytopenia

Hematological disturbances are common in systemic lupus erythematous (SLE). Specifically, autoimmune hemolytic anemia (AHA) may manifest in SLE patients at the time of diagnosis or within the first year of the disease. AHA is often associated with thrombocytopenia, lupus nephritis, and central nervous system activity. In this study we investigated these associations in Brazilian patients with SLE. Forty-four consecutive SLE patients who had a history of AHA were age, gender, and disease duration matched with 318 SLE patients without AHA who formed the control group. All patients fulfilled the revised American College of Rheumatology criteria for SLE and were followed-up within our Service. Clinical and laboratorial manifestations were similar in both groups, except for the predominance of leukopenia, thrombocytopenia, and anti-dsDNA on univariate analysis in the AHA group. The multivariate logistic regression model revealed risk only for thrombocytopenia in the AHA group compared to the control group (odds ratio, 2.70; 95% confidence interval, 1.32-5.50). Our results corroborate previous data that AHA in SLE increases the risk of thrombocytopenia in individuals with SLE. This association suggests a common mechanism in AHA and SLE pathophysiologies.

Acute pancreatitis in juvenile systemic lupus erythematosus: a manifestation of macrophage activation syndrome?

Acute pancreatitis (AP) is a rare and life-threatening manifestation of juvenile systemic lupus erythematosus (JSLE). The objective of this study was to evaluate the prevalence and clinical features of AP in our JSLE population. AP was defined according to the presence of abdominal pain or vomiting associated to an increase of pancreatic enzymes and/or pancreatic radiological abnormalities. Of note, in the last 26 years, 5367 patients were followed up at our Pediatric Rheumatology Unit and 263 (4.9%) of them had JSLE diagnosis (ACR criteria). AP was observed in 4.2% (11/263) of JSLE patients. The median of age of the JSLE patients at AP diagnosis was 12.4 years (8.8-17.9). All of them had lupus disease activity at AP onset. Three patients were receiving corticosteroids before AP diagnosis. Interestingly, 10/11 JSLE patients fulfilled preliminary guidelines for macrophage activation syndrome, three of them with macrophage hemophagocytosis in bone marrow aspirate and hyperferritinemia. The hallmark of this syndrome is excessive activation and proliferation of T lymphocytes and macrophages with massive hypersecretion of proinflammatory cytokines and clinically it is characterized by the occurrence of unexplained fever, cytopenia and hyperferritinemia. AP treatment was mainly based on intravenous methylprednisolone. Four JSLE patients with AP died and two developed diabetes mellitus. In conclusion, AP was a rare and severe manifestation in active pediatric lupus. The association between AP and macrophage activation syndrome suggests that the pancreas could be a target organ of this syndrome and that pancreatic enzyme evaluation should also be carried out in all patients. Lupus (2010) 19, 1654 1658.

Oral lesions in lupus erythematosus-cytokines profiles of inflammatory infiltrate

Background: Lupus erythematosus (LE) is a chronic inflammatory disease. Presence of type 1 cytokines in cutaneous discoid lesions suggests that they may be critical for induction, development and maintenance of these manifestations. Type 2 cytokines in combination with local interferon gamma (INF-gamma) are thought to be related to the physiopathology of cutaneous LE. Cytokines profiles are still unknown in oral LE lesions. Materials and Methods: Expression of Th1 and Th2 cytokines (including IL-4, IL-5, IL-6, IL-10, IL-12, tumor necrosis factor alpha (TNF-alpha) and INF-gamma was investigated and compared in 29 biopsies of intra-oral (sun-protected) and labial lesions (sun-exposed) of LE using immunohistochemistry. Results: Inflammatory infiltrate of LE lesions was strongly positive for IFN-gamma (97%) and TNF-alpha (90%), both Th1 type cytokines. Interleukin-10, a Th2 cytokine was also strongly expressed. Other cytokines were only mildly positive. Cytokines patterns were similar in intra-oral (sun-covered) and labial (sun-exposed) LE lesions. Conclusions: Oral LE lesions are associated with both type 1 and type 2 cytokines, characterized by stronger expression of INF-gamma, TNF-alpha and IL-10. These findings suggest that although ultraviolet (UV) light is involved in the induction of LE lesions, mechanisms of lesions formation may be similar in sun-exposed as well as sun-covered areas.

Chronic polyarthritis as the first manifestation of juvenile systemic lupus erythematosus patients

Objective: To evaluate the prevalence of chronic polyarthritis in juvenile systemic lupus erythematosus (JSLE) and to describe the manifestations, treatments, and outcomes in these patients. Methods: From January 1983 to July 2010, 5419 patients were followed up at the Pediatric Rheumatology Unit of the University Hospital and 271 (5%) of them had JSLE (American College of Rheumatology [ACR] criteria). `Rhupus` was classified as the overlap of juvenile idiopathic arthritis (International League of Associations for Rheumatology [ILAR] criteria) and JSLE. We evaluated demographic data, polyarthritis and other clinical manifestations, disease activity and damage, laboratory exams, radiographic findings, treatments, and outcomes. Results: The prevalence of chronic polyarthritis in this JSLE population was 2.6% (7/271). This articular involvement was the initial manifestation in all seven JSLE patients. The median duration of chronic polyarthritis was 11 months (range 2-15 months). Interestingly, rhupus with chronic polyarthritis and limitation of movement, presence of rheumatoid factor, autoantibodies, and/or radiographic abnormalities (juxtaarticular osteopenia, joint-space narrowing, or erosions) was evidenced in three patients. No patient had deformities of hands and feet associated with Jaccoud`s arthropathy or osteonecrosis. All patients were treated with nonsteroidal anti-inflammatory drugs (NSAIDs, naproxen 10-15 mg/kg/day) when polyarthritis diagnosis was established. Prednisone and antimalarials were administered at JSLE diagnosis. The three non-responsive rhupus patients were treated in conjunction with immunosuppressive drugs (methotrexate, azathioprine, and/or cyclosporine). Conclusions: Chronic polyarthritis was a rare lupus manifestation in active pediatric patients. The interesting overlap between chronic arthritis and lupus, called rhupus suggests a new entity with a different clinical profile and a poor response to treatment with NSAIDs alone. In addition, the occurrence of this association in JSLE patients could be classified as a clinical sub-group of JSLE with possible specific genetic determinants. Lupus (2011) 20, 960-964.

Recovery of Renal Function in Heart Transplantation Patients After Conversion From a Calcineurin Inhibitor-Based Therapy to Sirolimus

Background. Renal failure is the most important comorbidity in patients with heart transplantation, it is associated with increased mortality. The major cause of renal dysfunction is the toxic effects of calcineurin inhibitors (CNI). Sirolimus, a proliferation signal inhibitor, is an imunossupressant recently introduced in cardiac transplantation. Its nonnephrotoxic properties make it an attractive immunosuppressive agent for patients with renal dysfunction. In this study, we evaluated the improvement in renal function after switching the CNI to sirolimus among patients with new-onset kidney dysfunction after heart transplantation. Methods. The study included orthotopic cardiac transplant (OHT) patients who required discontinuation of CNI due to worsening renal function (creatinine clearance <50 mL/min). We excluded subjects who had another indication for initiation of sirolimus, that is, rejection, malignancy, or allograft vasculopathy. The patients were followed for 6 months. The creatinine clearance (CrCl) was estimated according to the Cockcroft-Gault equation using the baseline weight and the serum creatinine at the time of introduction of sirolimus and 6 months there after. Nine patients were included, 7 (78%) were males and the overall mean age was 60.1 +/- 12.3 years and time since transplantation 8.7 +/- 6.1 years. The allograft was beyond 1 year in all patients. There was a significant improvement in the serum creatinine (2.98 +/- 0.9 to 1.69 +/- 0.5 mg/dL, P = .01) and CrCl (24.9 +/- 6.5 to 45.7 +/- 17.2 mL/min, P = .005) at 6 months follow-up. Conclusion. The replacement of CNI by sirolimus for imunosuppressive therapy for patients with renal failure after OHT was associated with a significant improvement in renal function after 6 months.

Prednisone monotherapy induced remission in a group of patients with membranous lupus nephritis

The treatment of membranous lupus nephritis (MLN) is still controversial in the literature. We conducted a retrospective analysis of patients in two medical centers of Sao Paulo-Brazil in order to evaluate the clinical response in patients submitted to either a regimen with prednisone alone or to a double immunosuppressive regimen (prednisone plus cyclophosphamide or prednisone plus azathioprine). Methods: MLN female patients were enrolled in this retrospective study conducted from February 1999 to June 2007. Data were collected from the patients` medical charts. Race distribution was similar in both groups: Caucasian (72.3%) and Afro-Latin-American (27.7%). The prednisone regimen consisted of 1 mg/kg/day for 8 weeks and tapering until 0.1 mg/kg/day (n = 29). The double immunosuppressive treatment consisted of the same doses of prednisone plus monthly intravenous cyclophosphamide or azathioprine for 6 months (n = 24). Criteria for remission (complete and partial) and renal function loss as well as flare criteria followed those used in the literature. Results: There was no difference between the prednisone group and the double immunosuppressive group regarding age (33.2 +/- 9.4 vs. 29.1 +/- 9.1 y), estimated GFR (76.5 +/- 26.6 vs. 74.1 +/- 39.6 ml/min/1.73 m(2)), serum albumin (2.8 +/- 0.7 vs. 2.6 +/- 0.3 g/dl), positive ANA (87.5 vs. 90.0%), positive anti-dsDNA (47.6 vs. 44.0%), renal SLEDAI indices (6.6 +/- 2.6 vs. 7.0 +/- 3.1), follow-up time (71 +/- 46 vs. 62 +/- 45 months), as well as proteinuria (3.1 +/- 1.9 vs. 4.8 +/- 2.4 g/day) and number of non-nephrotic patients (6 in the prednisone group vs. 3 in the double immunosuppressive group). The prednisone group presented higher C3 values (85.2 +/- 31.5 vs. 62.3 +/- 41.6 U/ml, p = 0.04). Clinical and laboratory characteristics at 6 months and at last follow-up did not reveal any differences between treatment regimens. Renal survival after an 8-year follow-up did not differ in both groups (prednisone group 86.2% vs. double immunosuppressive group 75%), and patients in both groups showed a high rate of renal flares (prednisone group 51.7% vs. double immunosuppressive group 62.5%). Univariate analysis showed that only patient age predicted flares (r = -0.048, p = 0.04). Borderline significance was obtained for proteinuria analysis (p = 0.07). Adverse effects did not differ between the groups. Conclusions: A regimen of corticosteroids in MLN induced a high remission rate after 6 months. Both treatment regimens showed a high flare rate and age was the only predictive parameter (r = -0.048, p = 0.04). Renal survival after 8 years did not differ between the groups.

Autoimmune hepatitis and juvenile systemic lupus erythematosus

Juvenile systemic lupus erythematosus (JSLE) and autoimmune hepatitis (AIH) are both autoimmune disorders that are rare in children and have a widespread clinical manifestation. A few case reports have shown a JSLE-AIH associated disorder. To our knowledge, this is the first study that simultaneously evaluated the prevalence of JSLE-AIH in a large JLSE and AIH population in groups of Hepatology and Rheumatology of a tertiary Paediatric University Hospital. In a 24-year period, 228 patients were diagnosed with JSLE (ACR criteria). In the same period, 252 patients were diagnosed with AIH according to the International Autoimmune Hepatitis Group. In this article, we present the demographic data, clinical features, laboratory exams and treatment of four children with both the diseases. The prevalence was 1.8% in JSLE population and was 1.6% in AIH population. The current median age was 15.5 years and three were females. In three of them, the diagnosis of AIH preceded JSLE. All of them had increased liver enzymes with a characteristic liver biopsy of AIH and responded to the combination of prednisone, azathioprine and antimalarial drugs. In conclusion, the presence of AIH-JSLE associated disorder was rarely observed. The liver biopsy could be necessary in patients with JLSE with a persistent increase of liver enzymes. Lupus (2009) 18, 747-751.

Apoptosis, cell proliferation and modulation of cyclin-dependent kinase inhibitor p21(cip1) in vascular remodelling during vein arterialization in the rat

Neo-intima development and atherosclerosis limit long-term vein graft use for revascularization of ischaemic tissues. Using a rat model, which is technically less challenging than smaller rodents, we provide evidence that the temporal morphological, cellular, and key molecular events during vein arterialization resemble the human vein graft adaptation. Right jugular vein was surgically connected to carotid artery and observed up to 90 days. Morphometry demonstrated gradual thickening of the medial layer and important formation of neo-intima with deposition of smooth muscle cells (SMC) in the subendothelial layer from day 7 onwards. Transmission electron microscopy showed that SMCs switch from the contractile to synthetic phenotype on day 3 and new elastic lamellae formation occurs from day 7 onwards. Apoptosis markedly increased on day 1, while alpha-actin immunostaining for SMC almost disappeared by day 3. On day 7, cell proliferation reached the highest level and cellular density gradually increased until day 90. The relative magnitude of cellular changes was higher in the intima vs. the media layer (100 vs. 2 times respectively). Cyclin-dependent kinase inhibitors (CDKIs) p27(Kip1) and p16(INKA) remained unchanged, whereas p21(Cip1) was gradually downregulated, reaching the lowest levels by day 7 until day 90. Taken together, these data indicate for the first time that p21(Cip1) is the main CDKI protein modulated during the arterialization process the rat model of vein arterialization that may be useful to identify and validate new targets and interventions to improve the long-term patency of vein grafts.

Systemic lupus erythematosus in the elderly: antimalarials in disease remission

To analyze the long-term antimalarials (AM) usage on elderly systemic lupus erythematosus (SLE) patients from 2002 to 2008. Fifty-seven consecutive SLE patients, a parts per thousand yen65 years, were enrolled. The patients were divided into groups A (disease remission) and B (disease activity: with clinical and/or laboratory alterations attributed to SLE activity, and/or using steroid and immunosuppressors). Forty-three patients (75.4%) were in group A. The mean age in groups A and B was, respectively, 69.8 +/- A 4.5 versus 67.8 +/- A 4.8 years (P = 0.210), with similar disease onset (46.9 +/- A 11.2 vs. 42.3 +/- A 11.6 years; P = 0.220). There was no difference in gender, ethnicity, and clinical previous manifestations. In 21 out of 57 cases (10 from group A and 11, group B, P < 0.001), AM had been suspended after 5.2 +/- A 1.3 years, because of its side effects (maculopathy). The disease remission was strongly associated to AM usage (OR 12.91; 95% CI 2.87-58.13). In summary, SLE remission was significantly associated with the long-term AM usage.

The frequency of anti-beta(2)-glycoprotein I antibodies is low and these antibodies are associated with pulmonary hypertension in mixed connective tissue disease

The objective of this study is to evaluate the prevalence of antiphospholipid antibodies, mainly anti-beta(2)-glycoprotein I (anti-beta(2)-GPI), and their possible clinical and laboratory relevance in mixed connective tissue disease (MCTD). This study included 39 consecutive patients with MCTD (Kasukawa`s criteria) from January, 2005, to March, 2007, and compared them with 21 age- and sex-matched healthy controls. IgG and IgM anticardiolipin (aCL) and anti-beta(2)-GPI were measured by ELISA. Lupus anticoagulant (LA) was detected by functional coagulation tests. Medium to high titres of aCL and anti-beta(2)-GPI antibodies were found in sera from four (10.2%) MCTD patients. One of these patients was found to be positive for IgM aCL, IgM anti-beta(2)-GPI and LA antibodies simultaneously. Additionally, this patient had a previous history of foetal loss in the second trimester and new-onset pulmonary arterial hypertension (PAH). The other three patients had none of the manifestations of antiphospholipid syndrome (APS) or PAH. The mean value of IgG anti-beta(2)-GPI was higher among those MCTD patients with PAH than in the group without PAH (34.2 +/- 46.8 vs 12.3 +/- 9.1, P = 0.018). None of the controls were positive for antiphospholipid antibodies. High to moderate titres of anti-beta(2)-GPI as well as APS were rare in MCTD, and these antibodies may be correlated with the development of PAH in these patients. Lupus (2009) 18, 618-621.

Influence of parecoxib (cox-2 inhibitor) in experimental pleurodesis

Background: The intrapleural instillation of a sclerosing agent produces an inflammatory process frequently followed by pain. The treatment can include the use of analgesics or anti-inflammatory drugs. Previously, it was demonstrated (experimental studies) that corticoids and nonsteroidal anti-inflammatory drugs (diclofenac) reduce the inflammation and fibrosis produced by talc but not by transforming growth factor-P or silver nitrate. The objective of this study was to determine whether parecoxib (COX-2 inhibitor) affects pleurodesis induced by talc or silver nitrate. Methods: 140 rabbits received intrapleural. injection (2 mL) of 400 mg/kg of talc or 0.5% silver nitrate. A subgroup of 70 animals received additional daily intramuscular parecoxib (1 mg/kg). They were sacrificed at 4, 24, 48, 72 h or 7, 14, or 28 days after the procedure. The pleural fluid was quantified; biochemical examinations (glucose, lactic dehydrogenase, and proteins) and immunologic dosages (interleukin-8, vascular endothelial growth factor, and transforming growth factor-beta(1)) were analyzed in pleural fluid and blood. Finally, macro- and microscopic pleura and lung studies were performed. Results: Evaluation after 28 days demonstrated that parecoxib reduced pleural and pulmonary inflammation but not pleural adhesions. The changes were observed precociously (72 h) and were more evident after silver nitrate injection. Conclusion: Systemic parecoxib injection does not interfere with talc or silver nitrate pleurodesis. These results suggest that use of COX-2 inhibitors can be considered and depending of the results of other studies, recommended in human pleurodesis. (c) 2008 Elsevier Ltd. All rights reserved.