Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis

Sporadic inclusion-body myositis (sIBM) is the most common disabling, adult-onset, inflammatory myopathy histologically characterized by intense inflammation and vacuolar degeneration. In spite of T cell-mediated cytotoxicity and persistent, clonally expanded and antigen-driven endomysial T cells, the disease is resistant to immunotherapies. Alemtuzumab is a humanized monoclonal antibody that causes an immediate depletion or severe reduction of peripheral blood lymphocytes, lasting at least 6 months. We designed a proof-of-principle study to examine if one series of Alemtuzumab infusions in sIBM patients depletes not only peripheral blood lymphocytes but also endomysial T cells and alters the natural course of the disease. Thirteen sIBM patients with established 12-month natural history data received 0.3 mg/kg/day Alemtuzumab for 4 days. The study was powered to capture ≥10% increase strength 6 months after treatment. The primary end-point was disease stabilization compared to natural history, assessed by bi-monthly Quantitative Muscle Strength Testing and Medical Research Council strength measurements. Lymphocytes and T cell subsets were monitored concurrently in the blood and the repeated muscle biopsies. Alterations in the mRNA expression of inflammatory, stressor and degeneration-associated molecules were examined in the repeated biopsies. During a 12-month observation period, the patients’ total strength had declined by a mean of 14.9% based on Quantitative Muscle Strength Testing. Six months after therapy, the overall decline was only 1.9% (P < 0.002), corresponding to a 13% differential gain. Among those patients, four improved by a mean of 10% and six reported improved performance of daily activities. The benefit was more evident by the Medical Research Council scales, which demonstrated a decline in the total scores by 13.8% during the observation period but an improvement by 11.4% (P < 0.001) after 6 months, reaching the level of strength recorded 12 months earlier. Depletion of peripheral blood lymphocytes, including the naive and memory CD8+ cells, was noted 2 weeks after treatment and persisted up to 6 months. The effector CD45RA+CD62L­ cells, however, started to increase 2 months after therapy and peaked by the 4th month. Repeated muscle biopsies showed reduction of CD3 lymphocytes by a mean of 50% (P < 0.008), most prominent in the improved patients, and reduced mRNA expression of stressor molecules Fas, Mip-1a and αB-crystallin; the mRNA of desmin, a regeneration-associated molecule, increased. This proof-of-principle study provides insights into the pathogenesis of inclusion-body myositis and concludes that in sIBM one series of Alemtuzumab infusions can slow down disease progression up to 6 months, improve the strength of some patients, and reduce endomysial inflammation and stressor molecules. These encouraging results, the first in sIBM, warrant a future study with repeated infusions (Clinical Trials. Gov NCT00079768)

Stiff person syndrome presenting with sudden onset of shortness of breath and difficulty moving the right arm: a case report

<p>Abstract</p> <p>Introduction</p> <p>First described in 1956, stiff person syndrome is characterized by episodes of slowly progressive stiffness and rigidity in both the paraspinal and limb muscles. Although considered a rare disorder, stiff person syndrome is likely to be under-diagnosed due to a general lack of awareness of the disease in the medical community.</p> <p>Case presentation</p> <p>A 27-year-old Hispanic woman presented to our emergency department with a sudden onset of shortness of breath and difficulty moving her right arm. Her physical examination was remarkable in that her abdomen was firm to palpation and her right upper extremity was rigid on passive and active ranges of motion. Her right fingers were clenched in a fist. Her electromyography findings were consistent with stiff person syndrome in the right clinical setting. Stiff person syndrome is confirmed by testing for the anti-glutamic acid decarboxylase antibody. Her test for this was positive.</p> <p>Conclusion</p> <p>Stiff person syndrome may not be a common condition. However, if disregarded in the differential diagnosis, it can lead to several unnecessary tests being carried out causing a delay in treatment. This case report reveals some of the characteristic features of stiff person syndrome with an atypical presentation.</p

Fine specificity of antibodies against AQP4: Epitope mapping reveals intracellular epitopes

The autoantibody to aquaporin-4 (AQP4) is a marker and a pathogenetic factor in Neuromyelitis Optica (NMO) (Devic’s syndrome). Our aim was to identify B-cell antigenic linear epitopes of the AQP4 protein and investigate similarities with other molecules. To this end, we screened sera from 21 patients positive for anti-AQP4 antibodies (study group), from 23 SLE and 23 pSS patients without neurologic involvement (disease controls) and from 28 healthy individuals (normal controls). Eleven peptides, spanning the entire intracellular and extracellular domains of the AQP4 molecule, were synthesized, and all sera were screened for anti-peptide antibodies by ELISA. Specificity was evaluated by homologous inhibition assays. NMO positive sera exhibited reactivity against 3 different peptides spanning the sequences aa1e22 (AQPpep1) (42.9% of patients), aa88e113 (AQPpep4) (33%) and aa252e275 (AQPpep8) (23.8%). All epitopes were localized in the intracellular domains of AQP4. Homologous inhibition rates were ranging from 71.1% to 84.3%. A 73% sequence homology was observed between AQPpep80 aa257e271, a 15-mer peptide part of the AQPpep8 aa252e275, and the aa219e233 domain of the Tax1-HTLV-1 binding protein (TAX1BP1), a host protein associated with replication of the Human T-Lymphotropic Virus 1 (HTLV-1). Antibodies against the AQP4 and the TAX1BP1 15-mer peptides were detected in 26.3% (N ¼ 5) and 31.6% (N ¼ 6) of NMO positive sera (rs ¼ 0.81, P < 0.0001). Healthy controls did not react with these peptides, while homologous and cross-inhibition assays confirmed binding specificity. This first epitope mapping for AQP4 reveals that a significant proportion of anti-AQP4 antibodies target linear epitopes localized in the intracellular domains of the channel. One of the epitopes displays high similarity with a portion of TAX1BP1 protein

Reactivity to AQP4 epitopes in relapsing–remitting multiple sclerosis

Autoantibodies against the water channel AQP4, expressed predominately in central nervous system astrocytes, are markers and pathogenic factors in Devic's disease. In this study we examined whether Multiple Sclerosis (MS) patients recognize antigenic epitopes on AQP4 that may define distinct disease subsets. We screened sera from 45 patients with relapsing–remitting MS (RRMS) and 13 patients with primary progressive MS (PMS). 23 Neuromyelitis Optica (NMO) patients previously characterized were used as assay positive/negative controls. Sera from 23 patients with Systemic Lupus Erythematosus, 23 with primary Sjogren syndrome without neurological involvement and from 28 healthy individuals were also used as controls. NMO-positive sera exhibited reactivity against the intracellular epitope AQPaa252-275, confirming previous observations. All RRMS sera tested negative for anti-AQP4 antibodies using a cell-based assay, but surprisingly, 13% of them reacted with the epitope AQPaa252-275. PMS, healthy and disease controls showed no specific reactivity. Whether these antibodies define distinct MS subsets and have a pathogenic potential pointing to convergent pathogenetic mechanism with NMO, or are simply markers of astrocytic damage, remains to be determined

Incidence and prevalence of major central nervous system involvement in Systemic Lupus Erythematosus: A 3-year prospective study of 370 patients

Background: The incidence and prevalence of CNS involvement in SLE remains unclear owing to conflicting results in the published studies. The aim of the study was to evaluate the incidence and prevalence of major definite CNS events in SLE patients. Methods: 370 SLE patients with no previous history of CNS involvement were prospectively evaluated in a tertiary hospital referral center for 3 years. Major CNS manifestations were codified according to ACR definitions, including chorea, aseptic meningitis, psychosis, seizures, myelopathy, demyelinating syndrome, acute confusional state and strokes. Minor CNS events were excluded. ECLAM and SLEDAI-SELENA Modification scores were used to evaluate disease activity and SLICC/ACR Damage Index was used to assess accumulated damage. Results: 16/370 (4.3%) patients presented with a total of 23 major CNS events. These included seizures (35%), strokes (26%), myelopathy (22%), optic neuritis (8.7%), aseptic meningitis (4.3%) and acute psychosis (4.3%). Incidence was 7.8/100 person years. Among hospitalizations for SLE, 13% were due to CNS manifestations. Epileptic seizures were associated with high disease activity, while myelopathy correlated with lower disease activity and NMO-IgG antibodies (P#0.05). Stroke incidence correlated with APS coexistence (P = 0.06). Overall, CNS involvement correlated with high ECLAM and SLEDAI scores (P,0.001). Conclusions: Clinically severe CNS involvement is rare in SLE patients, accounting for 7.8/100 person years. CNS involvement correlates with high disease activity and coexistence of specific features that define the respective CNS syndromes

Exome sequencing identifies titin mutations causing hereditary myopathy with early respiratory failure (HMERF) in families of diverse ethnic origins

Background: Hereditary myopathy with early respiratory failure (HMERF) was described in several North European families and recently linked to a titin gene (TTN) mutation. We independently studied HMERF-like diseases with the purpose to identify the cause, refine diagnostic criteria, and estimate the frequency of this disease among myopathy patients of various ethnic origins. Methods: Whole exome sequencing analysis was carried out in a large U. S. family that included seven members suffering from skeletal muscle weakness and respiratory failure. Subsequent mutation screening was performed in further 45 unrelated probands with similar phenotypes. Studies included muscle strength evaluation, nerve conduction studies and concentric needle EMG, respiratory function test, cardiologic examination, and muscle biopsy. Results: A novel TTN p.Gly30150Asp mutation was identified in the highly conserved A-band of titin that co-segregated with the disease in the U. S. family. Screening of 45 probands initially diagnosed as myofibrillar myopathy (MFM) but excluded based on molecular screening for the known MFM genes led to the identification of a previously reported TTN p.Cys30071Arg mutation in one patient. This same mutation was also identified in a patient with suspected HMERF. The p.Gly30150Asp and p.Cys30071Arg mutations are localized to a side chain of fibronectin type III element A150 of the 10th C-zone super-repeat of titin. Conclusions: Missense mutations in TTN are the cause of HMERF in families of diverse origins. A comparison of phenotypic features of HMERF caused by the three known TTN mutations in various populations allowed to emphasize distinct clinical/pathological features that can serve as the basis for diagnosis. The newly identified p.Gly30150Asp and the p.Cys30071Arg mutation are localized to a side chain of fibronectin type III element A150 of the 10th C-zone super-repeat of titin

Polimiosite : investigação clínica em duas irmãs

We present an investigation of a case of polymyositis affecting two sisters of one same parenthood. Their cases have been documented for almost two decades, being investigated by means of a diagnostic protocol which combined clinical findings as well as laboratorial, histopathological and image tests. In both cases, clinical manifestations started in childhood, without signs of involvement of the central and peripheral nervous system. Both patients proved to respond to a therapeutics based on corticosteroids. The degree of relatedness between their parents corroborate the notion that genetic factors may contribute to the development of the disease. ___________________________________________________________________________________________________ RESUMOApresentamos a investigação de dois casos de polimiosite, ocorridos entre irmãs de uma mesma filiação. Seus casos foram documentados ao longo de quase duas décadas, tendo sido diagnosticados utilizando- se de protocolo diagnóstico que combinou achados clínicos, exames laboratoriais, histopatológicos e por imagem. Em ambos os casos, as manifestações clínicas se iniciaram ainda na infância, sendo constatada ausência de acometimento do sistema nervoso central ou periférico. Ambas as pacientes responderam satisfatoriamente a terapia baseada em corticosteróide. O grau de parentesco entre os genitores das pacientes sugere que fatores genéticos podem predispor ao desenvolvimento da doença