Peripheral Involvement Research Articles

Refractory case of myelin oligodendrocyte glycoprotein antibody‐associated encephalomyelitis with lumbosacral radiculitis

AbstractBackgroundMyelin oligodendrocyte glycoprotein antibody (MOG‐IgG) has been identified in demyelinating diseases of the central nervous system, including neuromyelitis optica spectrum disorders (NMOSD) without the presence of anti‐aquaporin‐4 antibody. Patients with MOG‐IgG present with clinical symptoms distinct from those of multiple sclerosis or NMOSD, so MOG‐IgG‐associated encephalomyelitis (MOG‐EM) is regarded as an entity distinct from multiple sclerosis and NMOSD. In contrast to NMOSD with anti‐aquaporin‐4 antibody, MOG‐EM has been reported to respond well to steroid therapy, and the functional prognosis of this disease is good. However, here we report a patient with MOG‐EM and lumbosacral radiculitis who showed little response to various immune therapies.Case presentationA 40‐year‐old man presented with acute paraplegia and sensory disturbance in the lower body. MOG‐IgG was positive both in serum and cerebrospinal fluid. Steroid pulse therapy, plasma exchange, intravenous immunoglobulin and cyclophosphamide pulse therapy were ineffective. In nerve conduction studies, compound muscle action potentials and F‐waves were not evoked in bilateral lower limb nerves, suggesting severe damage of peripheral nerves and lower motor neurons. Gadolinium enhancement was observed in the cauda equina.ConclusionsThe mechanisms of peripheral nerve system involvement in MOG‐EM are unknown, but the present case suggests that MOG‐EM might occasionally combine with peripheral nerve system disturbance. Lumbosacral radiculitis combined with MOG‐IgG can be refractory, and serious sequela might be observed.

Mucopolysaccharidoses : quand y penser ?

Mucopolysaccharidosis are lysosomal storage diseases, secondary to the accumulation of mucopolysaccharides. Type 1 mucopolysaccharidosis is the most common form and affects between 0.69 and 1.66 newborns per 100,000. The severity of mucopolysaccharidosis is variable with lethal forms in utero and attenuated forms diagnosed in adults. The most common symptoms are short stature, facial dysmorphism, chronic articular pains that can mimic chronic inflammatory rheumatism, axial and peripheral bone involvement, hepatosplenomegaly and an early carpal tunnel. Depending on the type of mucopolysaccharidosis, corneal, cerebral or cardiac involvements are possible. Screening is based on the analysis of urinary glycosaminoglycans. The deficient enzyme assay and the gene analysis confirm the diagnosis. Mucopolysaccharidosis recognition is important for patient management and family screening. In addition, specific enzyme replacement therapy exists for certain types of mucopolysaccharidosis. Role of clinician is important to evoke and diagnose mucopolysaccharidosis.

The Lag Time of Diagnosis of Axial Spondyloarthritis: A Bangladesh Perspective

Background & Objective: The lag time of diagnosis of axial spondyloarthrits varies from country to country. The aim of this study was to find out the lag time of diagnosis of axial spondyloarthritis in Bangladesh based on the patients visiting the morning Rheumatology OPD of a tertiary-care hospital. Materials & Methods: This study was conducted in the Department of Rheumatology of Enam Medical College & Hospital, Savar, Dhaka, Bangladesh from October, 2018 to December, 2019. Ninety six patients with axial spondyloarthritis were recruited and they were enquired about their ages, places of residence, educational qualifications and duration of axial pain as well as peripheral pain. The participants also underwent estimation of ESR by Westergren method. Results: Mean age of the participants was 39.98 years. The mean and median lag times of diagnosis were 58.17 and 36 months respectively. The lag time of diagnosis followed a nonnormal (right-skewed) distribution. There was no significant difference between males and females (p≈0.921), between rural and urban participants (p≈0.221), between those with and without peripheral involvement (p≈0.387) as well as between those with and without elevated ESR according to Mann-Whitney U test. But the median lag time in those who were highly educated, ie. those who completed at least a bachelor degree was significantly (p≈0.016) shorter than that in those who were not highly educated. Conclusion: There is a considerable median delay in the diagnosis of axial spondyloarthritis in Bangladesh. Further research is required to identify the factors contributing to the delay so that those can be addressed to shorten the lag time.

Plasma and salivary irisin levels in lepramatous leprosy patients

Aim: We aimed to investigate the plasma and salivary irisin levels in leprosy patients, as well as to evaluate the role of the irisin in the leprosy pathogenesis. Leprosy is a granulomatous disease with the peripheral nerves, mucous membrane, and skin involvement primarily. Irisin, a novel protein, has been associated with several inflammatory diseases and demonstrated in the peripheral nerve cells, deep sebaceous glands, and saliva excessively. To our knowledge, there is no study investigating the irisin levels in patients with leprosy. Material and Methods: We conducted a case-control study on 20 patients with lepromatous leprosy and 20 healthy controls between January 2016 and January 2017. Of the participants, the demographic data and disease history including duration of the disease, any current treatments, and presence of any other family members with leprosy were recorded. The plasma and salivary irisin levels of the participants were measured by enzyme-linked immunosorbent assay (ELISA). Additionally, the serum levels of C-reactive protein (CRP), glucose, hemoglobin A1c (HbA1C), triglyceride, cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) were evaluated in both groups.Results: The plasma and salivary irisin levels were significantly lower in the patient group than those in the control group (P = 0.001 and P = 0.03, respectively). In patients with leprosy, the serum and salivary irisin levels had a positive correlation (r: 576, p: 0.008). In addition, there was a negative correlation between the plasma irisin and CRP levels (r: −468, p: 0.037).Conclusion: The irisin may act an immunomodulatory role in leprosy. The irisin production is probably suppressed by the increased inflammatory markers in leprosy or the bacillus to reach the temperature for its reproduction. Further studies are needed to clarify the role and prognostic value of the irisin in leprosy with a large number of patients examined before and after the treatments.

Imaging of Pancreatic Carcinoma on Multidetector Computed Tomography, A Tertiary Care Experience at Liaquat National Hospital, Karachi

Introduction: Pancreatic cancer is a lethal disease. The mortality rate for pancreatic tumor has changed over the last 20 years. Early diagnosis of pancreatic carcinoma is very important for therapeutic decisions and surgical planning. Contrast enhance CT facilitated the detection of primary tumor and staging. Objective: This study is to evaluate various presentations of pancreatic carcinomas on their initial MDCT (Multidetector Computed Tomography) and to evaluate its resectability and to compare CT features among resectable and non-resectable tumors. Methodology: All the patients underwent multi-phasic CT scan on a 16-slice MDCT. CT findings were analyzed included tumor location, size, enhancement pattern, nodal disease, duct dilatations, vascular involvement and evidence of metastatic disease. Results: Total 63 records of patients examined during 2017 and 2019 meeting the inclusion criteria were reviewed. The average age at time of MDCT examination was 62.51 ± 13.17 years. The disease was more common in males (n=36, 57.1%). Out of 63 pancreatic tumors, 14 (22.22%) tumors were identified as resectable tumors on MDCT examination. Tumor size (p<0.001), peripancreatic nodes (p=0.006), contrast enhancement (p=0.018), vessel involvement (p<0.001), ascites (p=0.006), hepatic metastases (p=0.001) and peripheral organ involvement (p<0.001) were significantly different among resectable and non-resectable tumors. Conclusion: MDCT is an excellent and most commonly used modality for diagnosis and staging of pancreatic carcinoma particularly with a high sensitivity for detection of vascular invasion and metastatic disease.

Клинические особенности псориатического артрита в детском возрасте

Study Objective: to present literature review of clinical parameters and course of psoriatic arthritis (PsA) in children, and results of PsA patients examination in University Clinical Children Hospital of I.M. Sechenov First Moscow State Medical University. Study Design: open prospective study. Materials and Methods. We analysed medical records of 83 children with PsA aged 3 to 17 years who were examined and managed in University Clinical Children Hospital of I.M. Sechenov First Moscow State Medical University in 1989 – 2019. Study Results. Confirmed PsA was diagnosed in 59 (71%) children, suspected PsA — in 24 (29%) children; 44 (53%) children got ill before they were 6.5 years old. In 24 (29%) patients, disease started with skin involvement; in 59 (71%) patients, articular syndrome was the first manifestation of disease. In the group of patients with confirmed psoriasis, the most common was plaque psoriasis: it was diagnosed in 45 (76.3%) out of 59 children; guttate psoriasis was found in 8 (13.5%) children, isolated nail plaque psoriasis — in 3 (5.1%) patients, and palm and foot psoriasis — in 3 (5.1%) children. Psoriasis of the scalp was diagnosed in 23 (39%) subjects. In 8 (13.5%) patients, skin syndrome was associated with mild infiltration and scant desquamation. 18 (21.7%) out of 83 children had skin involvement together with nail bed involvement. Psoriasic onychodystrophy was diagnosed in 19 (23%) children (onycholysis, “oil patches” on fingers and toes); 15 (18.1%) children had “thimble syndrome”. On disease onset, 68.7% of children had oligoarticular, sometimes asymmetric articular syndrome; 18.1% had symmetric rheumatoid-like disease, 13.2% — psoriasic spondylitis. After 5 years of follow-up, articular syndrome transformed: 41.2% of patients had symmetric rheumatoid-like disease, 24.1% — asymmetric oligoarthritis, 24.1% — spondylarthritis with peripheral joint involvement, and 10.8% — arthritis mutilans. Most commonly PsA affected knee, talocrural joints, small hand joints – 41%, 31.3%, 29%, respectively. Conclusion. Clinical manifestations of PsA varied a lot. Our patients did not have a second peak. Almost one third of children had skin changes prior to arthritis development. Onset of disease was associated with asymmetric oligoarthritis prevalence. Later, articular syndrome changed, and symmetric rheumatoid-like disease prevailed. Keywords: children, psoriatic arthritis, psoriasis, juvenile idiopathic arthritis, Vancouver diagnostic criteria.

The relationship of serum vitamin D receptor levels with disease activity and clinical parameters in patients with ankylosing spondylitis.

The aim of this study was to investigate the relationship between serum vitamin D receptor (SVDR) levels and disease activity parameters in patients with ankylosing spondylitis (AS). Between July 2016 and January 2017, a total of 62 patients (51 males, 11 females; mean age 36.5±12.8 years; range, 23 to 49 years) with AS and 32 healthy volunteers (25 males, 7 females; mean age 41.57±13.6 years; range, 26 to 48 years) were included in the study. The SVDR levels were measured using the enzyme-linked immunosorbent assay. Erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) levels were recorded. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores were used to assess disease activity. Although there was no significant difference between the patient and control groups (p=0.66), SVDR levels were significantly elevated in patients with active AS (BASDAI score ≥4) (p=0.01). The SVDR levels significantly increased in AS patients with peripheral joint involvement and enthesitis (p=0.01, p=0.05, respectively). The SVDR levels significantly elevated in patients treated with non-steroidal anti- inflammatory drugs, compared to those treated with biological agents and control group (p=0.01, p=0.03, respectively). The SVDR levels were positively correlated with the BASDAI, CRP and ESR in the patient group (p=0.01, r=0.751; p=0.01, r=0.75; p=0.01, r=0.81, respectively). Our study results suggest that serum SVDR levels are associated with the disease activity and clinical parameters in patients with AS. Based on these findings, SVDR level may be used as a marker of disease activity in AS.

Retinal hemangioblastomas in Von Hippel‐Lindau germline mutation carriers: progression, complications and treatment outcome

AbstractPurposeEvaluating the phenotype, complications and treatment outcome of retinal hemangioblastomas (RH) and correlating this features with the genotype of Von Hippel‐Lindau (VHL) germline mutation carriers.MethodsRetrospective analysis of the medical and genetic records of 21 individuals with a VHL germline mutation and a diagnosis of RH. Germline mutation status was correlated to phenotype, complications, treatment methods and outcomes. Mutations were categorized in two genotypic categories: the truncating mutation (TM) group and the missense mutation (MM) group.ResultsFrom the 36 VHL germline mutation carriers, 21 VHL patients developed RH. Prevalence of RH in VHL disease was higher in TM carriers (15 of 21, 68.2%) vs. 40% of the MM carriers (6 of 15). The mean age of diagnosis of RH was 25.7 years. There was no significant difference in age of diagnosis of RH between genotypic categories (P = 0.931). Mean follow‐up duration was 16.3 years and did not differ significantly between the mutation groups (P = 0.383). Bilateral involvement was observed in 66.7% of the patients. Missense mutation (MM) carriers (n = 6) developed more RH (more than 5 RH: 50.0% vs. 38.5%), had a larger extent of peripheral retinal involvement of ocular VHL disease (66.7% vs. 35.7% all quadrants involved) and developed more progression‐related complications compared to TM carriers (n = 15) (100% vs. 46.7%). Complete tumor regression at last recorded visit was achieved in fifteen patients (71.4%). Moderate (VA 20/80 to 20/200) to severe (less than VA 20/200) visual impairment was observed in 53.3% of the eyes of MM carriers and 28.1% of the eyes of TM carriers at last recorded visit.ConclusionsGermline mutation status might play a role in the course of progression of RH in VHL disease. In our observational study, VHL missense mutation carriers had a more complicated progression of RH than carriers of a truncating mutation.

A 8-year retrospective clinical analysis of 272 patients of epidemic Keratoconjunctivitis in Beijing, China

BackgroundEpidemic keratoconjunctivitis (EKC) is one of the most common eye infections worldwide. The analysis of clinical manifestations in different age groups help better know the disease. This study aims to provide more detailed analysis of 272 cases of EKC in 8 years, describe the differences of the clinical features among different age groups, and establish new clinical grading criteria.Methods272 individuals were reviewed (2011–2019) in Beijing China. All the patients were classified into 3 grades according to the new grading criteria. The typical clinical signs of EKC and the photographs of the multiple subepithelial corneal infiltrates (MSI) were collected and analyzed. The number of 3 grades among and within different age groups were compared. The incidence of the typical signs among and within different age groups were compared. The proportion of each region of the cornea involved by MSI were compared.ResultsNo significant differences were detected among the 4 groups in terms of the number of mild, moderate and severe cases, no matter in all-patients analysis (P = 0.271) nor in acute-phase-patients analysis (P = 0.203). The proportion of the severe cases was the highest among all patients (P = 0.000). Among the incidence of the typical signs, corneal involvement was the most common accounting for 69.8% (P<0.05). The probability of central region involvement was significantly higher than that of pericentral region involvement (P = 0.015) and peripheral region involvement (P = 0.000).ConclusionsAppropriate attention should be paid on EKC, because of the considerable proportion of severe cases, the high incidence of corneal lesion, and the high incidence of central region involvement of MSI.

The Neuropathic Pain Features in Psoriatic Arthritis: A Cross-sectional Evaluation of Prevalence and Associated Factors.

To evaluate the prevalence and factors associated with the neuropathic pain features in a cohort of patients with psoriatic arthritis (PsA). A cross-sectional evaluation was conducted in consecutive patients having PsA with prevalent peripheral joint involvement, referred to 3 rheumatological centers. For each patient, a comprehensive assessment of disease activity, physical function, and disease effect was carried out. The presence of comorbid fibromyalgia syndrome (FMS) was evaluated. Acute-phase reactants were also recorded. The neuropathic pain features were investigated through the PainDETECT Questionnaire (PDQ). A logistic regression analysis was therefore conducted using the PDQ as the dependent variable. The final evaluation included 118 patients. A comorbid FMS was detectable in 30 of the 118 patients with PsA (25.4%). Probable characteristics of neuropathic pain (PDQ ≥ 19) were found in 30 (25.4%) patients overall, ambiguous (PDQ > 12 and < 19) in 21 (17.8%) patients, and unlikely (PDQ ≤ 12) in 67 (56.8%) patients. Using logistic regression analysis, the only independent variable among those investigated that could explain the neuropathic pain features was the presence of a comorbid FMS (p = 0.0127). Excluding patients with comorbid FMS, an association with disability (measured by Health Assessment Questionnaire-Disability Index) emerges (p = 0.0489). In patients with PsA and comorbid FMS, PDQ scores were significantly higher than in patients without comorbid FMS. Neuropathic pain features are common in patients with PsA, and the presence of pain sensitization (comorbid FMS) seems to be its main predictor.

Collagen fibrils and proteoglycans of peripheral and central stroma of the keratoconus cornea - Ultrastructure and 3D transmission electron tomography

Keratoconus (KC) is a progressive corneal disorder in which vision gradually deteriorates as a result of continuous conical protrusion and the consequent altered corneal curvature. While the majority of the literature focus on assessing the center of this diseased cornea, there is growing evidence of peripheral involvement in the disease process. Thus, we investigated the organization of collagen fibrils (CFs) and proteoglycans (PGs) in the periphery and center of KC corneal stroma. Three-dimensional transmission electron tomography on four KC corneas showed the degeneration of microfibrils within the CFs and disturbance in the attachment of the PGs. Within the KC corneas, the mean CF diameter of the central-anterior stroma was significantly (p ˂ 0.001) larger than the peripheral-anterior stroma. The interfibrillar distance of CF was significantly (p ˂ 0.001) smaller in the central stroma than in the peripheral stroma. PGs area and the density in the central KC stroma were larger than those in the peripheral stroma. Results of the current study revealed that in the pre- Descemet’s membrane stroma of the periphery, the degenerated CFs and PGs constitute biomechanically weak lamellae which are prone to disorganization and this suggests that the peripheral stroma plays an important role in the pathogenicity of the KC cornea.

Childhood-onset autosomal recessive ataxias: a cross-sectional study from Turkey.

Autosomal recessive ataxias (ARAs) are a heterogeneous group of inherited neurodegenerative disorders that affect the cerebellum, the spinocerebellar tract, and/or the sensory tracts of the spinal cord. This study is aimed at establishing molecular classification and phenotypic correlation of childhood-onset ARAs in Southeast Anatolia of Turkey. Sixty-five children (aged 0 to 18) from 40 unrelated families who were analyzed through hereditary ataxia NGS panel between the years of 2015-2018 were selected for the study. Seventeen different, clinically significant ARA-related pathogenic variants were detected in 33 of 40 families (82.5%), 12 of which were noted to be unreported variants. Among these 33 families, 24 had ATM-related (72.72%), four had SACS-related (12.12%), three had COQ8A-related (9.09%), and two had APTX-related (6.06%) pathogenic variants. The c.3576G>A (p.K1192=) was the most common homozygous pathogenic ATM variant (33.33%) that was associated with milder phenotype of ataxia telangiectasia (AT) with the onset of age of 3. Patients with SACS variants demonstrated developmental delay and progressive ataxia before the age of 3. Slowly progressive ataxia and intellectual disability were the common clinical manifestations of the patients with homozygous c.1396delG (p. E466Rfs*11) pathogenic variant in COQ8A. Homozygous APTX c.689T>G (p.V230G) pathogenic variant was identified in two patients who had chief complaint of ataxic gait onset after puberty. The most common types of ARAs in this region are AT- and Charlevoix-Saguenay-type spastic ataxia. ATM gene analysis should be performed foremost on children presenting early-onset ataxia from Southeastern Anatolia. If there is a concomitant peripheral neuron involvement, SACS gene analysis should be preferred. This valuable data will be a guide for the first step molecular diagnostic approach before requesting the NGS panel for ARA.

Peripheral Blood Involvement By Flow Cytometry As a Prognostic Factor in Aggressive T Cell Lymphomas Following Autologous Stem Cell Transplantation

Introduction: Aggressive T cell lymphomas (TCL) are a heterogenous group of lymphomas that are frequently associated with poor outcomes. Autologous stem cell transplantation (ASCT) is recommended according to the NCCN guidelines and by practice standards for most subtypes as a consolidation for patients in first remission. A large prospective study of up-front ASCT by the Nordic Lymphoma group identified age, ECOG performance status &lt;2, and bone marrow involvement as important prognostic factors. We have identified peripheral blood involvement by flow cytometry at diagnosis in up to one third of patients with aggressive TCL and analyzed whether this was a prognostic factor for outcomes after ASCT. Methods: We retrospectively analyzed data from consecutively treated patients (pts) with aggressive T-cell lymphomas who underwent ASCT at our institution from July 2009 to February 2019. Patient and disease characteristics were summarized using descriptive statistics. Kaplan-Meier analysis was used to estimate progression free survival (PFS) that was defined as the time from SCT to the first evidence of recurrence, and overall survival (OS) that was defined as the time from SCT to death or last institutional follow up with a hematologist. We collected data on age, co-morbidities, disease subtype, stage, response to therapy and treatment both pre and post SCT. Flow cytometry was obtained at diagnosis and phenotype of atypical circulating cells was compared with immunophenotype from tumor biopsy specimens. Results: 50 pts with TCL who received ASCT were identified for this analysis. Of this population, 41 (80%) of pts had peripheral blood flow available at the time of initial diagnosis. T-cell lymphoma types included peripheral T cell lymphoma not otherwise specified (PTCL NOS, 17 pts), angioimmunoblastic T cell lymphoma (AITCL, 15pts), ALK negative anaplastic large cell lymphoma (ALCL, 1pt), enteropathy-type T-cell lymphoma (EATL, 2pts), extranodal natural killer T-cell lymphoma (NKTCL, 2pts) and panniculitis like T cell lymphoma (2 pts) (Table 1). Median age of the cohort was 62 years (range 20-75 years) and all patients included had an ECOG PS 0-1 at the time of diagnosis. The majority had stage 4 disease (36/41, 87.8%), but analysis included a small number of patients with stage 2 (1/41, 2.4%) and stage 3 (4/41,9.7%) disease. Bone marrow involvement by morphologic criteria was noted on bone marrow biopsy in 8/41 (19.5%) pts; bone marrow was negative in 28/41 or 61% pts and not evaluated in 8/41 or 19.5% pts. Flow cytometry of peripheral blood performed as part of initial staging was positive for circulating malignant cells in 13/41 pts (31.7%) at the time of diagnosis. All patients underwent ASCT in first remission. The median PFS and OS were 15.2 and 29.9 months respectively in the flow positive group, while neither median PFS nor OS were reached in the flow negative group (Figures 1 and 2). Flow cytometry results from time of diagnosis was not strongly associated with PFS (log rank, p = 0.39), however, it was associated with overall survival (log rank, p = 0.012). There were 11 deaths in the cohort- 4 in the flow negative group and 7 in the flow positive group. Further, when bone marrow involvement was evaluated, 7 of 13 pts with positive flow cytometry (53.8%) and 5 of 28 (17.8%) pts with negative flow cytometry had BM involvement, suggesting a correlation between positive bone marrow and detection of lymphoma cells in the peripheral blood at the time of diagnosis. Conclusions: We demonstrate in our cohort of patients that detection of circulating lymphoma cells at diagnosis by flow cytometry was associated with a worse outcome in patients with aggressive T cell lymphomas undergoing ASCT as a consolidation in first remission. Larger cohorts will be needed to validate these findings, but these results suggest peripheral blood involvement by sensitive flow cytometry may identify patients with worse outcomes who might benefit from a more aggressive strategy such as allogeneic stem cell transplantation or alternative consolidation strategies. Disclosures Huntington: Bayer: Consultancy, Honoraria; Pharmacyclics: Honoraria; Celgene: Consultancy, Research Funding; DTRM Biopharm: Research Funding; Genentech: Consultancy; AbbVie: Consultancy. Isufi:Celgene: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy. Foss:Seattle Genetics: Consultancy, Other: fees for non-CME/CE services ; Mallinckrodt: Consultancy; miRagen: Consultancy; Spectrum: Other: fees for non-CME/CE services ; Eisai: Consultancy; Acrotech: Consultancy.

Recurrent Chromosomal Abnormalities in Tumoral Lesions of Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia: A Large-Scale Fluorescent in-Situ Hybridization Study on Tissue Biopsy Sections

Background: Small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) is a lymphoproliferative disorder of small mature B-cells, most commonly presenting with peripheral blood and bone marrow involvement. Tumoral lesions are variably encountered, resulting from either lymph node involvement or, less commonly, infiltration into virtually any extramedullary site. The prognostic assessment of patients with SLL/CLL relies strongly on the identification of recurrent chromosomal abnormalities, which are routinely tested by fluorescence in situ hybridization (FISH) on peripheral blood or bone marrow specimens. However, the incidence of such recurrent chromosomal abnormalities on tumoral lesions has only been studied on small series, and its concordance with peripheral blood and/or bone marrow testing remains unknown. We hereby report a large series of chromosomal abnormalities detected on tumoral SLL/CLL lesions, based on a validated FISH panel for formalin-fixed/paraffin-embedded (FFPE) biopsy sections. Methods: FISH was performed at Mayo Clinic on FFPE tissue sections from biopsies obtained from May 2014 to November 2018, as clinically indicated. Pathology reports and H&amp;E-stained sections were reviewed and were consistent with a diagnosis of SLL/CLL in all cases. Probes were validated to detect previously described chromosomal abnormalities in SLL/CLL, including trisomy 12 (+12) and deletions of 6q23 (6q-), 11q22.3 (11q-), 13q14.3 (13q-) and 17p13.1 (17p-). Available FISH results performed on peripheral blood or bone marrow samples from these patients were also reviewed for comparison. Results: Tissue biopsies involved by SLL/CLL from 346 patients were evaluated by FISH. The majority of specimens were either lymph nodes (65%) or soft tissue masses (29%). The median age was 66.9 years (range: 36 to 91), and the male to female ratio was 2.1:1. FISH abnormalities were identified in 60% of evaluated tissue sections. The most frequently detected aberration was +12 (35%), followed by 13q- (24%), 11q- (15%), 17p- (6%) and 6q- (2%) (Figure A). In particular, the incidence of +12 was significantly higher, and the incidence of 13q- significantly lower compared to frequencies previously reported on peripheral blood or bone marrow specimens (p&lt;0.01 for both abnormalities, in comparison to a recently published cohort of 1585 patients: Br J Haematol 2016;173:105). Most cases had 1 abnormality (55%), with fewer patients having 2 abnormalities (13%), and only 1 case showing 3 abnormalities. Of 47 patients with 2 or more chromosomal aberrations, most (72%) had 13q- in combination with either 11q- (7 cases), +12 (10 cases) or 17p- (7 cases) (Figure 1B). Of 29 patients with positive blood or bone marrow FISH results within 12 months of tissue biopsy, 7 patients (24%) had discrepant results, all of which were limited to discordant +12 and/or 13q- detection. In 14 additional patients with positive blood or bone marrow FISH results more than 12 months before or after tissue biopsy, discordant results were found in 3 cases (21%), all of which indicated gains of 17p- (2 cases) or 11q- (1 case) on the follow-up analysis. Conclusions: We hereby report the largest documented series (to the best of our knowledge) of FISH results performed on tumoral lesions of SLL/CLL. Trisomy 12 was overrepresented in tumoral lesions, as compared to the reported predominance of 13q- in leukemic involvement. Discrepant results between concurrent tumoral and leukemic FISH testing were limited to differences in +12 and 13q- in our series. We also document the acquisition of aberrancies of unfavorable prognosis (17p- and 11q-) on follow up FISH analysis in a small subset of patients, which should be taken into account when considering repeat FISH studies. Figure Disclosures Horna: MorphoSys AG: Research Funding.

Characteristics and burden of disease in patients with radiographic and non-radiographic axial Spondyloarthritis: a comparison by systematic literature review and meta-analysis

ObjectivesTo compare the clinical characteristics, burden of disease (eg, disease activity, function, quality of life), treatment modalities and treatment effect in patients with radiographic and non-radiographic axial Spondyloarthritis (r-axSpA and...

The Lag Time of Diagnosis of Axial Spondyloarthritis: A Bangladesh Perspective

Background &amp; Objective: The lag time of diagnosis of axial spondyloarthrits varies from country to country. The aim of this study was to find out the lag time of diagnosis of axial spondyloarthritis in Bangladesh based on the patients visiting the morning Rheumatology OPD of a tertiary-care hospital. Materials &amp; Methods: This study was conducted in the Department of Rheumatology of Enam Medical College &amp; Hospital, Savar, Dhaka, Bangladesh from October, 2018 to December, 2019. Ninety six patients with axial spondyloarthritis were recruited and they were enquired about their ages, places of residence, educational qualifications and duration of axial pain as well as peripheral pain. The participants also underwent estimation of ESR by Westergren method. Results: Mean age of the participants was 39.98 years. The mean and median lag times of diagnosis were 58.17 and 36 months respectively. The lag time of diagnosis followed a nonnormal (right-skewed) distribution. There was no significant difference between males and females (p≈0.921), between rural and urban participants (p≈0.221), between those with and without peripheral involvement (p≈0.387) as well as between those with and without elevated ESR according to Mann-Whitney U test. But the median lag time in those who were highly educated, ie. those who completed at least a bachelor degree was significantly (p≈0.016) shorter than that in those who were not highly educated. Conclusion: There is a considerable median delay in the diagnosis of axial spondyloarthritis in Bangladesh. Further research is required to identify the factors contributing to the delay so that those can be addressed to shorten the lag time.

The assessment of sensory pathway in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune polyneuropathy, predominately affecting motor, less sensory fibers, sometimes with the central nervous system involvement. The aim of the study was the assessment of the prevalence of peripheral and central sensory impairment, and their reciprocal reliance in patients with CIDP. 24 patients (mean 60.7 years old) diagnosed with CIDP, and 35 healthy controls, age and sex-matched. Multimodal (visual- VEP, brainstem auditory - BAEP, somatosensory SEP) evoked potentials (EPs) were studied. The results were compared to neurographic parameters of sensory responses in peripheral nerves. Neurological examination, cerebro-spinal fluid analysis, and brain CT/MRI were done in all participants. Statistically significant negative correlations were obtained between BAEP and SEP responses (amplitude, latencies, interlatencies) and the amplitude and sensory conduction velocity of peripheral nerves. There were no correlations between the P100 VEP latency and the peripheral sensory parameters. There were no structural changes of the central nervous system in neuroimages, and central symptoms in the neurological examination. The authors confirmed the presence of peripheral and central sensory involvement in patients with CIDP. The severity of central damage correlates with the degree of peripheral nerve impairment. Subclinical lesion of the central sensory pathways is possible.

Reactive Vasodilation Predicts Mortality in Primary Systemic Light-Chain Amyloidosis.

Rationale: Cardiac involvement and hypotension dominate the prognosis of light-chain amyloidosis (AL). Evidence suggests that there is also peripheral vascular involvement in AL but its prognostic significance is unknown. Objective: To evaluate vascular dysfunction in patients with AL as a potential future area of intervention, we assessed the prognostic utility of flow-mediated dilatation (FMD), a marker of vascular reactivity, which is augmented under conditions of hypotension and autonomic dysfunction. Methods and Results: We prospectively evaluated 115 newly diagnosed untreated AL patients in whom FMD was measured. FMD in AL patients was significantly higher than age-, sex- and risk factors-matched controls (4.0% versus 2.32%; P=0.006) and comparable with control groups at lower cardiovascular risk (P>0.1). Amyloidosis patients presented increased plasma and exhaled markers of the NO pathway while their FMD significantly correlated with augmented sustained vasodilatation after sympathetic stimulation. Increased FMD (≥4.5%) was associated with early mortality (hazard ratio, 4.36; 95% CI, 1.41-13.5; P=0.010) and worse survival (hazard ratio, 2.11; 95% CI, 1.17-3.82; P=0.013), even after adjustment for Mayo stage, nerve involvement and low systolic blood pressure. This finding was confirmed in a temporal validation AL cohort (n=55; hazard ratio, 4.2; 95% CI, 1.45-12.3; P=0.008). FMD provided significant reclassification value over the best prognostic model (continuous Net Reclassification Index, 0.61; P=0.001). Finally, better hematologic response was associated with lower posttreatment FMD. Conclusions: FMD is relatively increased in AL and independently associated with inferior survival with substantial reclassification value. Reactive vasodilation merits further investigation as a novel risk biomarker in AL.Visual Overview: An online visual overview is available for this article.

CLINICAL AND LABORATORY FEATURES OF ANTICENTROMERE ANTIBODY-POSITIVE SJö GREN’S SYNDROME

Objective: to study the clinical and laboratory features of patients with anticentromere antibody (ACA) positive Sjö gren’s syndrome (SjS); to assess the spectrum of autoantibodies in patients of this group; to determine the frequency with which the SjS patients who are highly positive for ACA, meet the international classification criteria for SjS and systemic sclerosis (SS); to reveal the incidence of MALT lymphomas in this patient group; to estimate the incidence of primary biliary cirrhosis (PBC)/biliary lesions as part of autoimmune epithelitis in SjS in this patient group.Material and methods. A total of 83 patients with ACA positive SjS were comprehensively examined at the V.A. Nasonova Research Institute of Rheumatology during the period 2012 to 2018. The inclusion criteria were con formity to the 2001 Russian SjS criteria and a high ACA level. MALT lymphomas were diagnosed on the basis of histological and immunohistochemical studies and polymerase chain reaction-based determination of B-cell clonality in the biopsy samples of affected organs according to the World Health Organization classification of Hematopoietic Tumors. The diagnosis of PBC/biliary lesions was made on the basis of histological and immunohistochemical studies of liver biopsy specimens.Results and discussion. The investigation revealed low detection rates for anti-Ro antibodies (32.5%), anti-La antibodies (7.2%) and rheumatoid factor (RF) (21.7%), which were typical for the classical SjS immunophenotype), increased ESR (14%), leukopenia (7%), hypergammaglobulinemia (17.6%), elevated levels of IgG (9.5%) and IgA (18.7%), and hypocomplementemia (16.1%) in the ACA positive SjS patients. Despite the low detection rate of RF, 15 (18%) patients in this group developed MALT lymphomas: 14 patients had salivary gland MALT lymphoma and one patient had tonsil MALT lymphoma with peripheral lymph node involvement (generalized marginal zone lymphoma). Also, the patients of this group showed high detection rates for AMA antibodies (34.6%), increased IgM level (29.7%) and a higher risk for PBC/biliary lesions as a manifestation of autoimmune epithelitis in SjS (14.5%). AMA-antibodies were absent in only two patients who were diagnosed with liver disease according to biopsy specimens. Nervous system and renal lesions, antiphospholipid syndrome, rheumatoid arthritis, hypergammaglobulinemic purpura, and cryoglobulinemic vasculitis were much less common and sporadic. Also ACA-positive SjS patients often have Raynaud’s phenomenon (54.9%) with scleroderma-type capillaroscopic changes (68%) and a limited form of SS (24%) according to the 2013 ACR criteria.Conclusion. ACA-positive SjS is a subtype of the disease, which is significantly different from the classic one in a number of clinical and laboratory signs and characterized by an increased risk for SS, MALT lymphomas, and PBC/biliary lesions as a manifestation of autoimmune epithelitis in SjS which in some cases leads to the underdiagnosis of SjS. ACA should be considered as pathogenetically related to SjS autoantibodies; and all patients who are seropositive for ACA should be examined for SjS and PBC/biliary lesions as a manifestation of autoimmune epithelitis in SjS regardless of whether they have SS or not, as well as complaints of dry mouth and eyes. Patients with significantly enlarged salivary glands should undergo biopsy to rule out or confirm MALT lymphoma before initiating hormonal, antilymphoproliferative, and anti-B-cell therapy.

Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination.

Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function.