[15th Post-ECTRIMS Meeting: a review of the latest developments presented at the 2022 ECTRIMS Congress (Part II)]. / XV Reunión Post-ECTRIMS: revisión de las novedades presentadas en el Congreso ECTRIMS 2022 (II).

INTRODUCTION: On 4 and 5 November 2022, Madrid hosted the 15th edition of the Post-ECTRIMS Meeting, where neurologists specialised in multiple sclerosis outlined the latest developments presented at the 2022 ECTRIMS Congress, held in Amsterdam from 26 to 28 October. AIM: To synthesise the content presented at the 15th edition of the Post-ECTRIMS Meeting, in an article broken down into two parts. DEVELOPMENT: This second part describes the new developments in terms of therapeutic strategies for escalation and de-escalation of disease-modifying therapies (DMT), when and in whom to initiate or switch to highly effective DMT, the definition of therapeutic failure, the possibility of treating radiologically isolated syndrome and the future of personalised treatment and precision medicine. It also considers the efficacy and safety of autologous haematopoietic stem cell transplantation, different approaches in clinical trial design and outcome measures to assess DMT in progressive stages, challenges in the diagnosis and treatment of cognitive impairment, and treatment in special situations (pregnancy, comorbidity and the elderly). In addition, results from some of the latest studies with oral cladribine and evobrutinib presented at ECTRIMS 2022 are shown.

TITLE: XV Reunión Post-ECTRIMS: revisión de las novedades presentadas en el Congreso ECTRIMS 2022 (II).Introducción. El 4 y el 5 de noviembre se celebró en Madrid la Reunión Post-ECTRIMS, en la que neurólogos expertos en esclerosis múltiple resumieron las principales novedades presentadas en el congreso de ECTRIMS 2022, celebrado entre el 26 y el 28 de octubre en Ámsterdam. Objetivo. Sintetizar las ponencias que tuvieron lugar en la Reunión Post-ECTRIMS, en un artículo desglosado en dos partes. Desarrollo. En esta segunda parte, se presentan las novedades sobre las estrategias terapéuticas de escalado y desescalado de los tratamientos modificadores de la enfermedad (TME), cuándo y a quién iniciar o cambiar a TME de alta eficacia, la definición de fracaso terapéutico, la posibilidad de tratar el síndrome radiológico asilado, el futuro del tratamiento personalizado y la medicina de precisión, la eficacia y seguridad del autotrasplante de células madre hematopoyéticas, diferentes aproximaciones en el diseño de ensayos clínicos y en las medidas de resultados para evaluar TME en fases progresivas, retos en el diagnóstico y tratamiento del deterioro cognitivo, y tratamiento en situaciones especiales (embarazo, comorbilidad y personas mayores). Además, se muestran los resultados de algunos de los últimos estudios realizados con cladribina oral y evobrutinib presentados en el ECTRIMS 2022.

Similar biological effect of high-dose oral versus intravenous methylprednisolone in multiple sclerosis relapses.

UNLABELLED: Our aim was to investigate differences in immune mechanisms in multiple sclerosis (MS) relapse, after high-dose oral methylprednisolone (oMP) or intravenous methylprednisolone (ivMP). We measured serum cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α and IFN-γ) in 39 of 49 MS patients with moderate-severe relapse, whom were treated with ivMP or oMP in a placebo-controlled, non-inferiority clinical trial. We assessed these cytokine levels at baseline and at 1 and 4 weeks post-treatment. The cytokine levels between oMP and ivMP were similar at any time. Proinflammatory cytokines (IL-6 and IFN-γ) were significantly decreased in both groups at week 1 (p = 0.05 / p = 0.03) and at week 4 (p = 0.04 / p = 0.05). This study provides further confirmatory evidence that oMP is not inferior to ivMP. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00753792.

Primary Sjögren Syndrome with tumefactive central nervous system involvement.

Brain MR imaging abnormalities in primary Sjögren syndrome (pSS) are generally discrete white matter lesions. We describe a 50-year-old woman with recurrent neurologic deficits. MR imaging revealed a large brain lesion. A diagnosis of pSS was made on the basis of clinical features, positive anti-Ro and anti-La antibodies, abnormal Schirmer test findings, and salivary gland scintigraphy. The patient was treated with oral prednisone with good response. Large tumefactive brain lesions are a complication of pSS.

Induction of serum soluble tumor necrosis factor receptor II (sTNF-RII) and interleukin-1 receptor antagonist (IL-1ra) by interferon beta-1b in patients with progressive multiple sclerosis.

BACKGROUND: Cytokine inhibitors, such as soluble tumor necrosis factor receptor II (sTNFRII) and interleukin-1 receptor antagonist (IL-1ra) are possible regulators of proinflammatory cytokine activity. Although previous studies have shown induction of sTNF-RII and IL-1ra by interferon-beta (IFNbeta) in patients with relapse-onset forms of multiple sclerosis (MS), to date no studies of these cytokine inhibitors have been performed in patients with essentially progressive forms of MS. OBJECTIVE: To address the effects of IFNbeta on serum levels of sTNF-RII and IL-1ra in a cohort of progressive MS patients and to assess the relationship between levels and changes of sTNF-RII and IL-1ra and clinical and radiological variables. Methods Serial blood samples were obtained from a cohort of 73 patients with progressive MS who participated in a placebo-controlled clinical trial with IFNbeta-1b. Serum levels of sTNF-RII and IL-1ra were measured by multiplex enzyme-linked immunosorbent assay at baseline and after 3, 6, 12, and 24 months. EDSS and MSFC scores were recorded at the time of blood sampling, and MR scans were obtained at baseline and after 12 and 24 months. RESULTS: Treatment with IFNbeta was associated with significant increases of sTNF-RII and IL-1ra serum levels during the followup period. A strong correlation at 24 months was observed between levels of sTNF-RII and EDSS scores in the placebo group. Finally, a trend for negative association was found between changes in sTNFRII and percentage change in T2-weighted lesion load at 24 months in the IFNbeta treated group. CONCLUSIONS: sTNF-RII and IL-1ra levels are increased in the serum of progressive MS patients during IFNbeta therapy and may be one mechanism by which IFNbeta mediates its effects in the treatment of MS.

[Detection of silent peripheral arterial disease in stroke patients with a low ankle-arm index]. / Detección mediante el índice tobillo-brazo de enfermedad arterial periférica silente en pacientes con ictus isquémico.

INTRODUCTION: A low ankle-arm index (AAI) is a strong predictor of vascular events and stroke. Nevertheless few studies have prospectively determined AAI in stroke patients. We aimed to investigated the prevalence of low AAI in stroke patients and which variables are associated with abnormal AAI. METHODS: Clinical data and ultrasonographic findings were collected in 79 consecutive stroke patients (20 transient ischemic attacks and 59 cerebral < ischemic infarction). During admission, AAI was measured in all subjects with the Doppler. An AAI cutoff of 0.90 was used to categorize individuals (< or =0.90: abnormal). RESULTS: A low AAI was calculated in 16 (20.3%) patients. AAI < or = 0.90 was associated with hypertension, smoking, hypercholesterolemia, coronary disease, previous peripheral arterial disease, male gender, internal carotid stenosis>50% (p<0.10). The presence of peripheral artery disease varied between subtypes. The incidence was higher for large artery atherosclerosis, 25.0 % and small vessel disease (31.5%). Multivariate analyses (logistic regression) only identify the association of>3 risk factors as independent predictor of low AAI (odds ratio: 4.41; confidence interval 95%: 1.39-4.01; p=0.012). CONCLUSION: Stroke patients had higher incidence of low AAI. Abnormal AAI was associated with classical risk factors. Existence of silent peripheral arterial disease in these patients may be an indicator of cerebral atherosclerosis extension. The measurement of AAI may be useful in order to plan adequate prevention therapies.

IFN-beta treatment modulates the CD28/CTLA-4-mediated pathway for IL-2 production in patients with relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system probably mediated by Th1 lymphocytes. IFN-beta is an established therapy for relapsing MS patients, although the mechanisms underlying its efficacy are yet to be well characterized. We determined IL-2 production, CD25 expression and T-cell proliferation from relapsing-remitting MS patients before and three months after starting therapy. A decrease in the percentage of CD80-induced IL-2-producing cells was observed after in vivo IFN-beta treatment. These data support that one of the immunomodulatory effects of IFN-beta treatment in MS may be a limitation of the autoimmune response modifying the CD80:CD28/CTLA-4 pathway.

Myelopathy in seronegative Sjögren syndrome and/or primary progressive multiple sclerosis.

OBJECTIVE: The relationship between multiple sclerosis (MS) and Sjögren syndrome (SS) is controversial. Nine patients, previously diagnosed with primary progressive MS (PPMS) and who fulfilled the diagnostic criteria for SS, are described. METHODS: The European classification criteria for SS were used to study nine PPMS patients that complained of sicca complex symptoms. The following tests were performed: Schirmer test, rose bengal staining, salivary scintigraphy, minor salivary gland biopsy and serologic tests (antibodies Ro/SS-A, La/SS-B and antinuclear antibodies). RESULTS: The nine patients met criteria to be diagnosed with SS (at least four criteria). All patients were women with a mean age of 46.6 years at symptom onset. Spastic paraparesis was the presenting symptom in all patients, and spinal cord magnetic resonance imaging (MRI) showed abnormalities in most; anti-Ro and anti-La antibodies were mostly negative. CONCLUSIONS: Some MS patients, predominantly women over 45 years of age, with progressive spastic paraparesis, antiextractable nuclear antigen antibodies (Ro/SS-A or La/SS-B) negative and with abnormalities in spinal cord MRI, may have SS as an additional or alternative diagnosis.

Expression of chemokine receptors in the different clinical forms of multiple sclerosis.

Chemokines and their receptors are important in the trafficking of peripheral leukocytes into the central nervous system, a major event in the pathogenesis of multiple sderosis (MS). Evidence based on clinical, pathological and magnetic resonance imaging grounds supports some divergence between forms of MS with relapses [relapsing-remitting (RR) and secondary progressive (SP)] and the primary progressive (PP) form. To elucidate whether different pathogenic mechanisms are involved in PPMS, we compared membrane expression of a group of CC and CXC chemokine receptors (CCR1, CCR5, CXCR3, CXCR4) in peripheral blood of 68 MS patients (25 PPMS, 23 SPMS and 20 RRMS) and 26 healthy controls. We found a significant increase in surface expression of CCR5 in CD4+, CD8+, CD19+ and CD14+ cells as well as an increased percentage of CXCR3 and CXCR4 in CD14+ cells in MS patients compared to controls. Increased levels of CXCL10 (IP-10) and CCL5 (RANTES) in cerebrospinal fluid were also observed in a subgroup of MS patients. These results support that chemokines and their receptors are involved in the pathogenesis of MS However, a pattem of chemokine-chemokine receptor expression characteristic of each clinical form of the disease failed to be observed.

Similar pro- and anti-inflammatory cytokine production in the different clinical forms of multiple sclerosis.

Cytokines play an important role in the initiation and maintenance of the inflammatory reaction in multiple sclerosis, a chronic inflammatory demyelinating disease of the central nervous system. Magnetic resonance imaging evidence supports clinical divergence between forms of multiple sclerosis with relapses and the primary progressive form without relapses, which shows fewer and smaller inflammatory lesions. With the aim of understanding better the relative role of pro-inflammatory and/or anti-inflammatory cytokines in primary progressive multiple sclerosis in comparison to relapsing forms, we analysed in 65 patients (24 primary progressive, 20 relapsing-remitting and 21 secondary progressive) and 29 healthy controls, the production of cytokines (IFN-gamma, TNF-alpha, IL-6, IL-10 and IL-12) by peripheral blood mononuclear cells after in vitro stimulation. We found a similar percentage of cytokines producing cells between healthy controls and the different clinical forms of multiple sclerosis patients.

CD4(+)CD45RO(+)CD49d(high) cells are involved in the pathogenesis of relapsing-remitting multiple sclerosis.

In the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis, encephalitogenic T cells differ from the non-encephalitogenic ones in their expression of CD49d. The disease-inducing CD49d(high) and not the CD49d(low) cells enter the brain parenchyma. In this context, we characterized CD4(+)(CD45RO(+))CD49d(high) cells in relapsing-remitting multiple sclerosis (RR-MS) patients. These cells, showing characteristics of activated cells able to produce pro-inflammatory cytokines, were found to be increased in peripheral blood during relapses and present in high numbers in cerebrospinal fluid. These results suggest that the CD4(+)CD45RO(+)CD49d(high) subpopulation in RR-MS patients includes autoreactive cells and may be target for immunotherapy.

Population genetics of the Chilean frog Batrachyla leptopus (Leptodactylidae)

A variaçäo eletroforética de proteínas codificadas por 14 loci foi analisada em oito populaçöes (5 continentais e 3 insulares) da rä leptodactilídea chilena Batrachyla leptopus. A proporçäo geral de loci polimórficos foi estimada como sendo de 18,7 por cento e o número médio de alelos por loco, 1,2, enquanto que as heterozigosidades observada e esperada foram 1,7 e 5,1 por cento, respectivamente. O coeficiente esperado de identidade genética foi 0,940; o número correspondente para a distância genética foi 0,063. A análise estatística F mostrou um coeficiente de endogamia total (Fit) de 0,855 e altos níveis de subdivisäo genética (Fst=0,596), assim como de endogamia dentro das populaçöes (Fis=0,640). Contudo, houve apenas um nível moderado de diferenciaçäo genética (Fst=0,181) entre o grupo insular de populaçöes e o grupo continental.

[Exophthalmos and cranial neuropathy as a form of presentation of Wegener's granulomatosis]. / Exoftalmos y neuropatía craneal como forma de presentación de la granulomatosis de Wegener.

The cases of three patients with Wegener's granulomatosis presenting as exophthalmos and cranial neuropathy are reported. In the first patient's symptoms were secondary to the presence of a retro-orbital mass. In the second and third patients there was dissemination of neighboring granulomatous processes. Paranasal sinuses were involved in two patients, but clinical manifestations were evident in only one. Full remission was achieved in all three. Two patients had been received immunosuppressant therapy for inflammatory processes evaluated a posteriori in the context of Wegener's granulomatosis. The immunosuppressant treatment seems to have conditioned this unusual clinical presentation.