Hematologic Involvement Research Articles

Associated clinical factors for serious infections in patients with systemic lupus erythematosus

Infection occurs frequently in patients with systemic lupus erythematosus (SLE), and has been a major cause of morbidity and mortality. However, no large-scale comprehensive studies have estimated the effect of clinical characteristics on serious infection in actual clinical practice yet. We investigated the influence of clinical characteristics on serious infections using electronic medical records data. We conducted a nested case-control study. Patients with SLE who developed serious infection which needs hospitalization or intravenous antibiotics (n = 120) were matched to controls (n = 240) who didn’t. Odds ratios (OR) and 95% confidence intervals (CIs) for infection associated with clinical features were obtained by conditional logistic regression analyses. The conditional logistic regression analysis with adjustment showed that serositis (OR, 2.76; 95% CI, 1.33–5.74), hematologic involvement (OR, 2.53; 95% CI, 1.32–4.87), and use of higher than the low dose of glucocorticoids (GCs; >7.5 mg/d prednisolone-equivalent) (OR, 2.65; 95% CI, 1.31–5.34) were related to serious infections in SLE. Serositis, hematologic involvement, and use of higher than the low dose of GCs were associated with serious infections in patients with SLE.

PD-1+CXCR5−CD4+T cells are correlated with the severity of systemic lupus erythematosus

PD-1+CXCR5-CD4+T peripheral helper (Tph) cells, a recently identified T cell subset, are proven to promote B cell responses and antibody production in rheumatoid arthritis, but their role in the pathogenesis of SLE is unknown. We explored the role of Tph in lupus disease development. This cohort study included 68 patients with SLE and 41 age- and sex-matched healthy individuals. The frequency of PD-1+CXCR5-CD4+T cells was analysed in peripheral blood by flow cytometry. Inducible T-cell costimulator, CD38, MHC-II, IL-21, CXCR3 and CCR6 expression were measured in Tph cells. Comparisons between the two groups were performed, and correlations between Tph cells and other parameters were investigated. We revealed a markedly expanded population of Tph cells (8.31 ± 5.45 vs 2.86 ± 1.31%, P < 0.0001) in the circulation of patients with SLE (n = 68), compared with healthy controls (n = 41). Tph cells were much higher in the active group than in the inactive group (14.21 ± 5.21 vs 5.49 ± 2.52%, P < 0.0001). Tph cells were significantly associated with SLEDAI score (r = 0.802), ESR (r = 0.415), IgG (r = 0.434), C3 (r = -0.543), C4 (r = -0.518) and IL-21 level (r = 0.628), and ANA titre (r = 0.272). Furthermore, Tph cells were much higher in lupus patients with arthritis, nephritis, rash, alopecia, pleuritis, pericarditis and haematological involvement. Tph cells were associated with CD138+/CD19+ plasma cells (r = 0.518). Furthermore, MHC-II, inducible T-cell costimulator, CD38, and IL-21 expression were all higher in Tph cells from SLE patients compared with healthy controls. CXCR3+CCR6-Tph (Tph1) cells were expanded in the SLE patients. Our data show that relative number of Tph cells is correlated with disease measures in patients with SLE, suggesting an important role in lupus disease development.

PS1101 PERIOPERATIVE MANAGEMENT AND OUTCOMES IN CHILDREN WITH CONGENITAL BLEEDING DISORDERS: A RETROSPECTIVE REVIEW AT A SINGLE HEMOPHILIA TREATMENT CENTER

Background:Establishing hemostasis for surgical procedures in children with inherited bleeding disorders is challenging. Providers are often hesitant to undertake surgeries in children with bleeding disorders out of fear of bleeding complications. However, appropriate presurgery/preprocedure factor replacement can decrease pre‐, peri‐, and postoperative bleeding complications and allow almost any necessary surgical procedure to proceed.Aims:We review the results of surgical procedures in children with inherited bleeding disorders at our center and review the preoperative management and hemorrhagic complications.Methods:We conducted a retrospective electronic medical record review from October 2006 to November 2018. Primary focus was review of factor replacement strategies and bleeding complications. Data were collected from patients under 18 years of age.Results:In total, 152 procedures were performed in 99 children at our center. The distribution of bleeding disorders is as follows; hemophilia A 79, hemophilia B 15, Von Willebrand disease 3 and FVII deficiency 2. The median age of the patients was 13 years (range, 0∼18). Duration of hospitalization was median 8 days (range, 0∼44) and period from surgery to discharge was median 7 days (range, 0∼42). Nineteen procedures (12.5%) in 8 children were performed in the presence of high titer inhibitors to coagulation factor. Procedures included synovectomy (84/152, 55.3%), orthopaedic procedures except synovectomy (22/152, 14.5%), central venous catheter placement or revision (9/152, 5.9%), otolaryngology procedures (7/152, 4.6%), circumcision (6/152, 3.9%), laparoscopic appendectomy (5/152, 3.3%) and miscellaneous (19/152, 12.5%). All patients received preoperative factor replacement (100% in hemophilia patients) followed by various factor replacement regimens postoperatively. No deaths or life‐threatening bleeding occurred with any procedure. Seven of 152 procedures (4.6%) were complicated by bleeding. Tonsillectomy was the most common procedure complicated by hemorrhage 3 of 7 (42.9%).The complete list ofall 168 surgical procedures is shown in Table 2.All patients received preoperative factor replacement (100% in hemophilia patients) followed by various factor replacement regimens postoperatively. No deaths or life‐threatening bleeding occurred with any procedure. Seven of 152 procedures (4.6%) were complicated by bleeding. Tonsillectomy was the most common procedure complicated by hemorrhage 3 of 7 (42.9%).Summary/Conclusion:Surgical procedures are safe in children with bleeding disorders with adequate planning and factor replacement. Bleeding remains a problem in a subset of patients and requires ongoing hematological involvement and oversight. Delayed bleeding following tonsillectomy was especially common and suggests a need for close follow‐up and ongoing factor coverage for this group of patients.

Usefulness of Flow Cytometry for the Detection of Cutaneous Localization in Malignant Hematologic Disorders.

Histological evaluation of malignant hematologic involvement of the skin can be challenging and needs an extended immunohistochemistry panel. We assessed the ability of flow cytometry (FCM) to detect neoplastic cell subsets in skin biopsies as a useful tool that supplements the histological examination in a complementary way. Two hundred and forty-three consecutive skin biopsies were retrospectively analyzed between April 2012 and July 2017. Among them, 147 samples, corresponding to 128 patients, were analyzed at diagnosis. Eighty-seven patients had erythrodermic inflammatory dermatoses, and 41 patients had cutaneous hematologic neoplasms. Cutaneous T-cell lymphomas were the most frequent disorders, accounting for 70% of cases (29/41). Cutaneous B-cell lymphoma was found in only 17% of cases (7/41) and immature hematologic malignancies in 5% (2/41). Three patients had secondary skin involvement. The sensitivity of FCM skin biopsy analysis was 78.1% (32/41). Among the 243 samples, 27 patients had mycosis fungoides (MF) or Sezary syndrome (SS) with available FCM data. A loss of CD26 expression was identified in 92% of cases of transformed MF or SS versus 40% of cases of non-transformed MF (P = 0.0057 χ²). Among the 12 MF patients with negative CD26 expression, six progressed to SS versus none in the positive group (50% vs. 0% P = 0.0168 χ²). FCM analysis of the skin biopsies is a sensitive method and a useful tool for improving the sensitivity of diagnosis of hematologic skin neoplasms. Among the MF patients, a loss of CD26 expression could be a marker of higher risk of progression. © 2019 International Clinical Cytometry Society.

Indications for bone marrow examinations in rheumatology.

Hematologic involvement or hematologic malignancies are frequently encountered during the course of rheumatic diseases. Bone marrow (BM) aspiration and/or biopsy examinations may have a diagnostic role in explaining hematologic findings detected in rheumatology clinical practice. Our aim was to describe the indications for BM examinations and to share our BM aspiration/biopsy results. We analyzed 140 BM aspiration/biopsy results of patients conducted at the Department of Rheumatology from 2010 to 2018. Demographics, complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) values, serum biochemistry test results including lactate dehydrogenase (LDH), organomegaly, indications for BM examinations and BM examination results for each patient, and mortality rates were recorded. Out of the 140 patients, 63.6% were female, and the median (Q1-Q3) age was 53 (39.5-65) years. One hundred fifteen (82.1%) patients were diagnosed as having primary rheumatic disease, and 25 (17.8%) were admitted due to musculoskeletal symptoms. Rheumatoid arthritis (RA) (n = 34, [29.5%]), and systemic lupus erythematosus (SLE) (n = 21, [18.2%]) were the most common rheumatic diseases. Cytopenia was the most common indication for BM aspiration/biopsy (n = 83, [59.3%]). Thirty-nine (47%) of 83 patients had drug-induced cytopenia. A pathology was detected in 40 (28.5%) of the 140 BM examinations. Patients with pathologic BM results had either a hematologic malignancy (n = 38, [95%]) or metastasis to a solid organ (n = 2, [5%]). The group of patients with pathologic BM biopsy results had significantly higher rates of lymphadenopathy, splenomegaly, and monoclonal gammopathy compared with the group with non-pathologic results (p = 0.001, p = 0.011, and p = 0.023, respectively). Likewise, LDH concentrations of those with pathologic results were higher than in patients with non-pathologic results [737 (range 577-1420) IU/L vs. 541 (range 306-840) IU/L, p = 0.019]. In this study, cytopenia or CBC abnormalities accompanied by elevated LDH values or anemia along with increased ESR were the most common indications for BM aspiration/biopsy. Further prospective studies are needed to determine the indications of BM aspiration/biopsy and establish the parameters that predict abnormal BM results in rheumatology practice.

Epidural chloroma and spinal cord compression

Epidural chloroma and spinal cord compression

Predictors of Remission and Low Disease Activity State in Systemic Lupus Erythematosus: Data from a Multiethnic, Multinational Latin American Cohort.

To determine the predictors of remission and low disease activity state (LDAS) in patients with systemic lupus erythematosus (SLE). Three disease activity states were defined: Remission = SLE Disease Activity Index (SLEDAI) = 0 and prednisone ≤ 5 mg/day and/or immunosuppressants (maintenance dose); LDAS = SLEDAI ≤ 4, prednisone ≤ 7.5 mg/day and/or immunosuppressants (maintenance dose); and non-optimally controlled state = SLEDAI > 4 and/or prednisone > 7.5 mg/day and/or immunosuppressants (induction dose). Antimalarials were allowed in all groups. Patients with at least 2 SLEDAI reported and not optimally controlled at entry were included in these analyses. Outcomes were remission and LDAS. Multivariable Cox regression models (stepwise selection procedure) were performed for remission and for LDAS. Of 1480 patients, 902 were non-optimally controlled at entry; among them, 196 patients achieved remission (21.7%) and 314 achieved LDAS (34.8%). Variables predictive of a higher probability of remission were the absence of mucocutaneous manifestations (HR 1.571, 95% CI 1.064-2.320), absence of renal involvement (HR 1.487, 95% CI 1.067-2.073), and absence of hematologic involvement (HR 1.354, 95% CI 1.005-1.825); the use of immunosuppressive drugs before the baseline visit (HR 1.468, 95% CI 1.025-2.105); and a lower SLEDAI score at entry (HR 1.028, 95% CI 1.006-1.051 per 1-unit decrease). These variables were predictive of LDAS: older age at entry, per 5-year increase (HR 1.050, 95% CI 1.004-1.098); absence of mucocutaneous manifestations (HR 1.401, 95% CI 1.016-1.930) and renal involvement (HR 1.344, 95% CI 1.049-1.721); and lower SLEDAI score at entry (HR 1.025, 95% CI 1.009-1.042). Absence of mucocutaneous, renal, and hematologic involvement, use of immunosuppressive drugs, and lower disease activity early in the course of the disease were predictive of remission in patients with SLE; older age was predictive of LDAS.

High BAFF expression associated with active disease in systemic lupus erythematosus and relationship with rs9514828C&gt;T polymorphism in TNFSF13B gene

B cell-activating factor (BAFF) promotes the survival, proliferation and maturation of B lymphocytes, which are key elements in the pathogenesis of systemic lupus erythematosus (SLE). This cytokine is encoded on TNFSF13B gene, and diverse single-nucleotide polymorphisms have been associated with susceptibility in different autoimmune disorders. In this study, the relationship of TNFSF13B gene rs9514827T>C, rs1041567T>A and rs9514828C>T polymorphisms, mRNA expression and soluble BAFF levels was investigated in 175 SLE patients and 208 healthy controls (HC). The TNFSF13B polymorphisms were evaluated by PCR-RFLP technique. The TNFSF13B gene expression was quantified through the RT-PCR assays. The soluble BAFF (sBAFF) levels were measured with ELISA test. There were no differences in genotype and allele frequencies for the three TNFSF13B polymorphisms, between SLE patients and HC. SLE patients showed 3.15-fold more TNFSF13B gene expression than HC. The patients who displayed most mRNA expression were those with active disease and the carriers of rs9514828 T variant allele. The sBAFF serum levels were higher in SLE patients compared to HC (2.083 vs. 0.742ng/mL, p < 0.001). The SLE patients with active disease showed the higher sBAFF serum levels (2.403ng/mL), mainly patients with lupus nephritis and hematological manifestations. In addition, a correlation of sBAFF with disease activity was found (r = 0.32, p < 0.001). In conclusion, the TNFSF13B gene polymorphisms were not found to be associated with SLE susceptibility in Mexican mestizos. Nevertheless, rs9514828C>T polymorphism seems to increase TNFSF13B gene expression. High BAFF expression is related to active disease, renal and hematological involvement; therefore, it could be considered as follow-up biomarker in SLE patients.

Abstract TP423: Risk Factors for Intracranial Hemorrhage in Cerebral Venous Thrombosis

Cerebral venous thrombosis is associated with intracranial hemorrhage. The occurrence of brain bleeding complicates management and is associated with worse outcomes. We aimed to identify clinical and imaging risk factors for intracerebral hemorrhage. We hypothesized that higher clot burden would be associated with a higher risk of intracerebral hemorrhage. Methods: We performed a retrospective analysis of an international, multicenter cohort of patients with cerebral venous thrombosis who underwent CT within 2 weeks of symptom onset and who had a subsequent confirmed diagnosis of CVT on MRV, CTV or DSA. Clinical and imaging features were compared between patients with and without intracranial hemorrhage. Clot burden was assessed by counting the number of thrombosed venous sinuses and veins on confirmatory imaging. Results: We recruited 260 patients with cerebral venous thrombosis from 10 institutions in Europe and Mexico. The mean age was 42 and 74% were female. Intracranial hemorrhage was found in 102 (39%). Intracerebral hemorrhage occurred in 64 (63%), small juxtacortical hemorrhage in 30 (29%), subarachnoid hemorrhage in 24 (24%) and subdural hemorrhage in 11 (11%). Combinations of these types of hemorrhage occurred in 23 (23%). Intraparenchymal hemorrhages in multiple locations occurred in 6 (6%). Older age, presence of hematological disease and superior sagittal thrombosis involvement were significantly associated with presence of hemorrhage. The number of thrombosed venous sinuses was not associated with intracerebral hemorrhage (average number of sinuses/veins involved with hemorrhage 2.1 versus 1.9 without hemorrhage, p=0.4). Conclusion: The high rate of intracranial hemorrhage in cerebral venous thrombosis is not explained by widespread involvement of the venous sinuses. Superior sagittal sinus involvement is associated with the presence of intracranial hemorrhage.

Neurological Involvement in Systemic Lupus Erythematosus (SLE): Our Recent Experience

Introduction: The central, psychiatric and peripheral neurological manifestations of lupus are among the most severe visceral disorders and are grouped under the general term of “neuro-psychiatric systemic lupus erythematosus” (NPSLE). We conducted a cross-sectional observational study within our Department of Internal Medicine aimed at describing the clinical and evolutionary aspects of central neurological disorders of SLE, excluding lupus myelopathy. Patients and Methods: This was a retrospective and observational cross-sectional study carried out from 1 January 2015 to 31 October 2017, in the Department of Internal Medicine of Aristide le Dantec University Hospital in Dakar (Senegal). All patients hospitalized during this period who met the 1997 ACR classification criteria of SLE and who presented with a central neuropsychiatric syndrome attributable to SLE (as defined by ACR 1999) were included. Patients with isolated headache, acute myelitis or secondary neurological involvement attributable to a toxic, metabolic, infectious or tumour-related cause were excluded from our study. Results: During the study period, 10 patients with neuropsychiatric lupus involvement were treated at our institution, including 9 women and 1 man; the median age was 29 years (20 - 55 years). Neurological involvement occurred during the course of lupus evolution in 9/10 cases. The median time to SLE evolution was 18 months (0 - 60 months). Neuropsychiatric syndromes as defined by the 1999 ACR were commonly associated and more than half of our patients had multiple neuropsychiatric syndromes. There were 5 cases of confusion syndrome and coma, 4 cases of seizure, 3 cases of psychosis, 2 cases of acute cerebrovascular disease and 1 case of aseptic meningitis. Among the extra-neurological manifestations of SLE, haematological and dermatological involvements were common. Renal involvement affected half of the patients. The other manifestations were: polyarthritis in 3 patients, serositis in 2 patients, 5 cases of fever, 4 cases of deterioration of the general state, and one isolated case of ophthalmological involvement. Therapeutically, 8 patients received a bolus of methylprednisolone and 3 patients received a bolus of cyclophosphamide. Oral corticosteroids and hydroxychloroquine were administered to all patients, and azathioprine was administered in 2 patients. The evolution was favorable in 4 patients, other 2 patients maintained neurological sequelae and 2 patients were transferred to intensive care. Death was recorded in 4 patients. Conclusion: Neuropsychiatric manifestations of lupus are rare and sometimes severe, potentially life-threatening. In our patients, we have identified some of the most severe neurological syndromes according to the ACR nomenclature. The neurological involvement is exceptionally revealing, as these syndromes are often associated and integrated into a systemic context of lupus. The evolution is rapidly unfavorable and requires early diagnosis and optimal management.

Clinical Profile and Outcome of Dengue Fever in Multidisciplinary Intensive Care Unit of a Tertiary Level Hospital in India.

ABSTRACTBackgroundIndia is one of the seven identified countries in South-East Asia region regularly reporting dengue fever (DF)/dengue hemorrhagic fever (DHF) outbreaks. Even though the dengue prodrome and evolution of illness are most often similar in many patients, progress and outcome may differ significantly depending on the severity of illness as well as treatment instituted. We studied the clinical manifestations, outcome and factors predicting mortality of serology confirmed dengue fever cases admitted in Multidisciplinary Intensive Care Unit (MICU) of a high acuity healthcare facility in India.MethodologyAll patients with serology proven dengue fever admitted to MICU between 1st July 2015 and1st December 2015 were included in the study. Clinical presentation, laboratory findings, severity of illness scores and outcome were recorded.ResultsMajority of the patients (58.4%) belonged to 21–40 year age group. Hepatic (96.8%) followed by hematological (79.2%) involvement were the most common findings. CNS involvement observed among 27%. Survival to hospital discharge was 78.9%. Respiratory and gastrointestinal system involvement was associated with increased mortality. Acute respiratory distress syndrome (ARDS), acute kidney injury (AKI) and shock were the clinical syndromes associated with mortality. Serum lactate, aspartate transaminase (AST) and alanine transaminase (ALT) were significantly elevated among non survivors. Significant difference in sequential organ failure assessment (SOFA) and acute physiology and chronic health evaluation (APACHE) scores was also observed among survivors and non survivors.ConclusionOrgan system involvement and higher disease severity scores are strong predictors of mortality. High index of suspicion for atypical manifestations of dengue is warranted.How to cite this articlePadyana M, Karanth S, Vaidya S, Gopaldas JA. Clinical Profile and Outcome of Dengue Fever in Multidisciplinary Intensive Care Unit of a Tertiary Level Hospital in India. Indian J Crit Care Med 2019;23(6):270–273.

Life-threatening adverse reaction to a commonly used drug (drug reaction with eosinophilia and systemic symptoms syndrome)

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is one of the severe cutaneous adverse reactions with a mortality of 10% and is characterized by hematological abnormalities and organ involvement. Many drugs have been implicated in DRESS, and most often, it is related to aromatic anticonvulsants. We hereby report a case of DRESS syndrome precipitated due to allopurinol, the diagnostic challenge it presented, and the successful treatment with corticosteroids.

Prevalence and associations of anti-phosphatidylserine/prothrombin antibodies with clinical phenotypes in patients with primary antiphospholipid syndrome: aPS/PT antibodies in primary antiphospholipid syndrome

ObjectiveThe clinical significance of anti-phosphatidylserine/prothrombin (aPS/PT) in antiphospholipid syndrome (APS) is still controversial. We assessed the prevalence of aPS/PT antibodies, their association with other anti-phospholipid antibodies (aPL) and with different APS clinical phenotypes. MethodsWe included 95 primary APS patients according to the Sydney classification criteria, and patients with thrombocytopenia and/or hemolytic anemia who also fulfilled the serological APS criteria. We tested aCL, anti-β2GP-I and aPS/PT antibodies (both IgG and IgM isotypes) and lupus anticoagulant (LA). We used χ2 test, Spearman's correlation coefficient, Mann-Whitney U test and logistic regression. ResultsSeventy-seven percent of patients had thrombosis, 50% hematologic involvement and 25% obstetric events (non-exclusive groups). Twenty patients had only hematologic features. The prevalence of IgG and IgM aPS/PT antibodies was 61% and 60%, respectively. Patients with LA+ had a higher prevalence and higher titers of IgG and IgM aPS/PT antibodies. aPS/PT antibodies correlated with aPL antibodies including LA. IgG aPS/PT antibodies were associated with thrombosis (OR 8.6 [95% CI 2.13–33.8, p = 0.002]) and pure hematologic features (OR 0.2, CI 95% 0.05–0.97, p = 0.004). IgM anti-β2GP-I antibodies conferred high risk for both hematologic (OR 7.9, 95% CI 1.88–34.61, p = 0.006) and thrombotic involvement (OR 7.4, 95% CI 1.76–31.12, p = 0.006). ConclusionsaPS/PT antibodies were highly prevalent and correlated with other aPL antibodies. IgG aPTS/PT conferred a high risk for thrombosis, but not for pure hematologic involvement. aPS/PT antibodies may be a useful serological tool in the diagnosis and phenotypic characterization of APS patients.

Clinical Manifestations of Systemic Lupus Erythematous in Children at Dr. Hasan Sadikin General Hospital Bandung, Indonesia

Background : Systemic Lupus Erythematous (SLE) is an autoimmune disease, characterized by production of autoantibodies, leading to damage caused by inflammation, directed toward multiple organs in the body. It is difficult to diagnose due to its mimicry with other diseases. The differential diagnosis of SLE is broad, including infection, malignancy and other inflammatory disorders. It is important to recognize the clinical manifestation of SLE from other possible diseases. Methods : A descriptive study was conducted on 56 SLE patientsfrom the Department of Child Health in Dr. Hasan Sadikin General Hospital, Bandung, Indonesia, in which the medical records was collected from 2010 to 2014. A total sampling method was used and incomplete records were excluded. Results : Out of the 56 subjects, 82.1% were female, with female to male ratio was 4.6:1. Most of the subjects (52%) was in the age category of 11 to 15 years old. Hematologic involvement was the most common clinical manifestation based on the diagnostic criteria (83.9%), and fever was the most common chief complaint (41.1%). Conclusions : From this study, fever, rash, and joint pain are the common chief complaints among SLE patients in children with hematologic and renal disorders are also found to occur.

Electrocardiographic disturbances in children with systemic lupus erythematosus.

BackgroundConduction disturbances other than heart block related to neonatal lupus are rarely explored and reported in children with systemic lupus erythematosus (SLE).ObjectiveTo report the electrocardiographic (ECG) abnormalities in children with SLE and assess whether anti-Ro/SSA antibodies and hydroxychloroquine are associated with the rhythm disturbances.MethodsThis cross-sectional retrospective study comprised patients with SLE who had regular follow-up in the Pediatric Lupus Clinic at King Faisal Specialist Hospital and Research Center-Riyadh. All enrolled patients were evaluated with regard to demographics, age at disease onset, disease duration, clinical and laboratory variables including autoantibodies, disease activity using SLEDAI disease activity index, and medications. An expert pediatric cardiologist reviewed the ECG findings of all enrolled patients independently without knowing the clinical status of the patients.ResultsA total of 41 (35 females, 6 males) unselected patients with SLE with a mean age of 12.8 (2.5) years and mean follow-up duration of 4 (3) years completed the evaluation. The most frequent manifestations were renal disease (65.8%), followed by musculoskeletal (46.3%), hematological (41.5%), and cardiac involvement (19.5%). Thirty-two had active disease (SLEDAI >4), and the mean of SLEDAI was 9.2 (6.2). ECG abnormalities were seen in 12 patients (29.3%); these changes included ST-T changes (9.8%), right bundle branch block (7.3%), 4 prolonged QT interval (9.8%), and low QRS voltage (2.4%). Thirty-seven (90.3%) patients were on hydroxychloroquine, and 9 patients (22%) had positive anti-Ro/SSA antibodies. ECG abnormalities were associated significantly with anti-Ro/SSA antibodies (P < .05) and a low platelet count (P < .5) but had no association with other autoantibodies, hydroxychloroquine, or SLEDAI score.ConclusionChildren with SLE with anti-Ro/SSA antibodies are probably prone to heart conduction abnormalities. However, the heart rate and QT interval were affected by hydroxychloroquine. A larger prospective study is required to allow more definitive conclusions.

High-Risk Langerhans Cell Histiocytosis in Infants Exhibits Malignant Features in a Xenograft Model but Responds Durably to Targeted Therapy

Background: Langerhans cell histiocytosis (LCH) is a rare hematologic neoplasm primarily of childhood, characterized by a neoplastic proliferation of Langerhans-like cells. The clinical presentation of LCH is highly variable, and while some children are cured with combination chemotherapy, many will relapse and experience irreversible morbidity. Genomic profiling of LCH has identified recurrent somatic activating mutations in BRAF and MAP2K1, all of which culminate in activation of the mitogen-activated protein kinase pathway. However, key mechanistic and clinical questions such as the curative potential of targeted therapy and the cell of origin remain unanswered.Methods: Four infants with risk-organ positive (RO+) multisystem BRAF V600E-mutant LCH and secondary hemophagocytosis were treated at our institution with the BRAF V600E-inhibitor dabrafenib after failing chemotherapy, or up front at the discretion of the treating physician. Response assessment was performed as indicated for good clinical care. Excess bone marrow obtained during routine clinical evaluation was collected under an IRB-approved protocol, and transplanted into busulfan-conditioned NOD/LtSz-SCID interleukin-2(IL2)RG-/- (NSG) or NSG-SGM3 (NSGS) mice. Donor chimerism was assessed by flow cytometry for mouse and human CD45 and lineage reconstitution was determined with standard human markers. BRAF V600E detection was performed on extracted DNA from xenografts using a TaqMan Mutation Detection RTPCR assay.Results: At presentation, all patients exhibited features of HLH (hemophagocytic lymphohistiocytosis) with fever, splenomegaly, pancytopenia, elevated markers of inflammation, hypofibrinogenemia, and hemophagocytosis on bone marrow examination. All patients displayed marked and rapid improvement following initiation of dabrafenib. With a median follow up of 21 months, all patients remain in complete clinical remission, and are thriving. None of the patients experienced significant adverse effects classically associated with dabrafenib. In two patients, despite clinical disease resolution, BRAF V600E was still detectable in bone marrow by RTPCR at 23 and 26 months respectively post initiation of dabrafenib. Remarkably, the other two patients who were treated upfront with dabrafenib achieved molecular remissions (defined as undetectable BRAF V600E allele in a previously positive patient) after 11 and 12 months respectively of therapy.Among mice transplanted with patient bone marrow cells, the median survival was 9.6 weeks. A comparison arm consisting of mice transplanted with bone marrow from a low-risk LCH patient did not develop evidence of disease during the observation period. At necropsy, animals exhibited splenomegaly, thrombocytopenia and anemia. Flow cytometry of both bone marrow and spleens from mice demonstrated robust engraftment of human hematopoietic cells, and the BRAF V600E allele was detected from marrow and splenocytes in all mice. Frequent hemophagocytic forms were visible on bone marrow cytospins, and on histologic examination, bone marrow exhibited an abundance of CD1a-negative, CD163+ histiocytes, similar to findings observed in human disease.Bone marrow and splenocytes from primary NSG xenograft recipients were transplanted into secondary NSGS mice, and two out of three animals examined similarly became ill with comparable disease latency, and achieved engraftment of human cells with detectable BRAF V600E in bone marrow and splenocytes.Conclusions: For patients with LCH with hematologic involvement and secondary HLH, disease-initiating cells are present in the bone marrow and can engraft and recapitulate disease following primary and secondary transplant into immunodeficient mice. Targeted therapy with the BRAF V600E-specific inhibitor dabrafenib leads to durable, sustained remissions. Furthermore, we demonstrate that certain patients can achieve molecular remission with BRAF V600E-specific monotherapy alone. However, in at least a subset of patients with RO+ LCH, the persistence of mutated BRAF despite prolonged targeted therapy suggests that while quiescent, transformed disease-initiating cells are not eliminated by BRAF inhibition alone. Based on these results, we hypothesize that first-line therapy with BRAF inhibitors may be more likely to induce molecular remissions. DisclosuresNo relevant conflicts of interest to declare.

Twenty-Five Years Diagnosing Gaucher's Disease in Spain, What We Have Learned?

Gaucher disease (GD), has a pan-ethnic distribution with incidence in non-Ashkenazi Jewish population about 1/70-140 thousand inhabitants. The deficiency in lysosomal acid beta-glucosidase enzyme secondary to variants in the GBA gene with autosomal recessive inheritance gives rise to a variable clinical picture. It appears at any age with symptoms that include anemia, thrombocytopenia, pain and vascular bone lesions, visceral enlargement, persistent fatigue. It was the first EDL to have enzymatic replacement and substrate reduction therapy that impact in the awareness of the disease. In 1993, the Spanish Registry of Gaucher Disease was created (REsEG), within the Spanish Foundation for the Study and Therapeutics of EG (FEETEG), with the aim of providing support to all those involved in the management of patients with EG and summarize experience at the national level. This work review the characteristics at diagnosis of type 1 adult GD (GD1) patients, diagnosed outside active early diagnosis programs, along of twenty five years of REsEG existence focus on leading diagnostic symptoms in order to answer the current challenges in patients suspicions. Aim: To analyze the evolving profile of GD1 patients diagnosed before and after 2000 based on the principal manifestations including visceral, hematological involvement, bone pain, bleeding in order to define the current suspicious characteristics in our population. Methods: Patients 18+ years old included in the REsEG were selected. Demographic, genetic, clinical (hematological, visceral, bone, neurological) data, severity index, biomarkers and other relevant information were included in a database created for this purpose. Platelets <140x109/L were considered as thrombocytopenia and hemoglobin below 12 g/dL in females and 13 g/dL in males were considered as anemia. Ethic board of SpRGD and FEETEG approved the development of the present work. To analyze the evolution in the diagnostic features of adult GD1 patients, a cut-off settled according the year of diagnosis, <2000 or 2000+, was used. The use of this cut-off was made considering the awareness for diagnostic increased progressively since ERT availability in mid 90's in Spain. The statistical analysis were made using comparative methods with a level of 95% interval of confidence. Results: Since 1993 a total of 223 GD1 with 18+ years old patients were diagnosed and included in the registry. 50.7% (113) were females, mean age at diagnosis 38.5 (18-87). The symptoms that led to the diagnostic of GD1 were: splenomegaly 71.1%, (3 of them detected during pregnancy work out), thrombocytopenia 83.3%, isolated anemia 39.0%, pancytopenia 8.5%, hepatomegaly 22.5%, bone pain: 57.9%(bone crisis 48.8% pathological fractures 3 cases), hemorrhagic diathesis (ecchymosis, epistaxis): 20.6%, peripartum bleeding: 3 cases, family study: 19.3%, early Parkinson's study 3 cases, other reasons for referral were MGUS 4 cases, hyperferritinemia 7 cases. Also we have recorded that bone marrow aspiration or biopsy was the first test in the diagnosis process in about 80% of cases. According the year of diagnosis 131 (58.7%) patients were diagnosed before 2000 (group A), mean age at diagnosis 36 (18-87) y.o and 92 (41.3%) after 2000 (group B). mean age at diagnosis 41.8 (18-79) y.o. General characteristics and genotype distribution are detailed in tables 1 and 2. Concerning profile's patient diagnosed before 2000 showing a more clinical aggressive behavior, even the presence of thrombocytopenia was similar in both groups, the severity of thrombocytopenia were higher in group A (69.8; 16-129 x109/L) vs group B (83.4; 14-131 x109/L) (p=0.006), also anemia, bone pain and visceral enlargement show higher incidences. During this time there 7 cases have developed Parkinson's disease, 2 patients with de novo mutations, 21 neoplasms and other interesting findings. Conclusion: In our population we have found that the classical main characteristics of GD1 adult patients at diagnosis has evolved to a less severe phenotype in the present century. Features like bone pain, anemia, thrombocytopenia, visceral involvement are decreasing in percentage and severity; in parallel mild genetic variants were more prevalent. These data suggest that we need to continue the efforts on training in young hematologist to increase the awareness and visibility of disease, also among primary care providers in order to improve the early diagnosis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cutaneous manifestations and systemic correlation in patients with lupus erythematosus and its subsets: a study of 40 cases

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; The objective was to study various dermatological manifestations and clinical and laboratory features in patients of lupus erythematosus (LE) and its subsets.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; This is a cross sectional observational study done in a tertiary care hospital in a rural setup in Piparia, Ta. Waghodiya, Dist. Vadodara, Gujarat. All the patients with clinical features of LE and its subsets were included in the study over a period of 16 months and were subjected to detailed history taking, complete cutaneous and general examination and laboratory investigations.&lt;strong&gt;&lt;/strong&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; Out of the 40 cases, 22 cases were systemic lupus erythematosus (SLE), 13 cases were discoid lupus erythematosus (DLE), four cases were of Rowell’s syndrome and one case was of mixed connective tissue disorder (MCTD). 97.5% of cases had cutaneous involvement, i.e. photosensitivity (77.5%), oral ulcers, hair loss and malar rash. Systemic symptoms and abnormal laboratory parameters were present in the cases of SLE, Rowell’s syndrome and MCTD, with hematological involvement being the most common in both SLE (77%) and Rowell’s syndrome (100%) and positive anti-nuclear antibody (ANA) titer being the most common abnormal laboratory finding in both SLE (95.4%) and Rowell’s syndrome (100%). The most commonly found antibody was anti-dsDNA (64.3%) in SLE and anti SS-A (100%) in Rowell’s syndrome.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; Cutaneous features though occasionally subtle, are pointers to a diagnosis of SLE. Hair loss, malar rash and photosensitivity alone or in association with altered hematologic/ANA profile are the key markers of the disease activity.&lt;/p&gt;&lt;p&gt; &lt;/p&gt;

Increased CD4+CD25-Foxp3+ T cells in Chinese systemic lupus erythematosus: correlate with disease activity and organ involvement.

The increment of CD4+CD25-Foxp3+T cells has been reported in systemic lupus erythematosus (SLE) patients. However, the exact identity of this T cell subset is still unclear. Thus, we analyzed CD4+CD25-Foxp3+T cells and Treg cells (CD4+CD25+Foxp3+ T cells) in a large sample of Chinese SLE patients in different disease states. A total of 280 SLE patients and 38 healthy volunteers were enrolled, which included 21 patients with untreated new-onset lupus (UNOL), 13 patients with drug withdrawal more than 6 months and 246 patients with treatments. Phenotypic and functional analysis of peripheral blood CD4+CD25-Foxp3+ T cells and Treg cells were performed by flow cytometry. The correlation of CD4+CD25-Foxp3+T cells and Treg cells with disease activity, clinical indicators and organ involvement were analyzed. CD4+CD25-Foxp3+ T cells and Treg cells were significantly increased in SLE patients and showed significantly positive correlations with disease activity. CD4+CD25-Foxp3+ T cells were significantly increased in patients with skin and hematologic involvement as well as arthritis. Diverse changes between CD4+CD25-Foxp3+ T cells and Treg cells when faced with different medications, especially HCQ and MMF. CD4+CD25-Foxp3+ T cells expressed more IFN-γ and less CTLA-4 than CD4+CD25+Foxp3+ T cells, which were similar to CD4+CD25+Foxp3- T cells, and expressed similar IL-17, ICOS and Helios to CD4+CD25+Foxp3+ T cells. The synthesis capacity of IL-10 of CD4+CD25-Foxp3+ T cells and the expression of GITR on CD4+CD25-Foxp3+ T cells were between CD4+CD25+Foxp3+ and CD4+CD25+Foxp3- T cells. Our results indicate that increased CD4+CD25-Foxp3+ T cells in lupus patients, which combined the features of suppression and pro-inflammatory, may serve as a biomarker for disease activity and organ involvement in SLE.

Thrombotic Cutaneous Gangrene: A Rare Dermatologic and Hematologic Extraintestinal Manifestation of Ulcerative Colitis

Ulcerative colitis (UC) is associated with many extraintestinal manifestations, which can include dermatologic and hematologic involvement. Thrombotic cutaneous gangrene (TCG) is a rare dermatologic and hematologic complication with potentially poor prognosis, often needing colectomy in addition to anti-coagulation for complete resolution. A 33-year-old healthy female presented with chronic bloody diarrhea and was diagnosed with left sided UC. She was initiated on steroids and discharged on a prednisone taper. Three days after discharge, she presented with fever and progressive and extensive racemose and retiform purpura on her trunk and extremities. She continued to have bloody stool despite adherence to prednisone. Areas of purpura evolved to tense bullae which erupted. She had an elevated D-dimer, prolonged PT, and reduced anti-thrombin III activity. Complete antiphospholipid syndrome panel was negative. A skin punch biopsy showed thrombotic vasculopathy involving small dermal vasculature without vasculitis. No other end-organ complications of hypercoagulability were identified. MRE showed inflammatory changes limited to the descending colon, sigmoid colon, and rectum, with no involvement of the small bowel. Anti-thrombin III levels were replenished, high dose heparin drip was started, and her hypercoagulable state resolved. The patient's UC was refractory to steroids; she was subsequently started on Infliximab, which controlled her luminal symptoms. She was discharged on Lovenox, which significantly improved her skin manifestations. Our case underlines the importance of appreciating a hypercoagulable state in UC and suspecting TCG in UC cases presenting with rapidly progressing purpura. Immediate hypercoagulability work up, skin biopsy, and anticoagulation should be initiated to prevent further complications. Furthermore, we demonstrate that trial of biologic immunosuppressive therapy may prevent need for colectomy to treat TCG.2098_A Figure 1. Retiform purpura on shoulder and back2098_B Figure 2. Areas of purpura evolved to become tense bullae which eventually erupted.2098_C Figure 3. Mayo 3 UC