Dirk Reske

Rituximab in a patient with multiple sclerosis – effect on B cells, plasma cells and intrathecal IgG synthesis

Objective –  To study the time course of immunoglobulin, B and plasma cells in the blood and cerebrospinal fluid (CSF) before and during rituximab treatment in a patient with severe relapsing–remitting multiple sclerosis (MS) in relation to clinical and MRI findings.

Difficulties in the differentiation of chronic inflammatory diseases of the central nervous system : value of cerebrospinal fluid analysis and immunological abnormalities in the diagnosis

Objectives –  A number of neurological syndromes may be evoked by involvement of the nervous system due to systemic diseases such as lupus erythematodes, sarcoidosis, Behçets disease and Sjögrens syndrome (SS) and may be confounded with another chronic inflammatory disease which is restricted to the central nervous system, e.g. multiple sclerosis (MS). Because of different treatment strategies, it is important to distinguish between these different autoimmune diseases.

Expansion of antibody reactivity in the cerebrospinal fluid of multiple sclerosis patients - follow-up and clinical implications.

BackgroundAn intrathecal polyspecific antibody response is a well known finding in multiple sclerosis. However, little is known about the evolution of intrathecal antibodies over time and their impact on the disease progress. Therefore, we focused in this study on the intrathecal polyspecific antibody response in multiple sclerosis.MethodsHere we present a follow-up study of 70 patients with multiple sclerosis over 1 to 106 months. Serum and cerebrospinal fluid sample pairs were obtained from 1 to 5 consecutive lumbar punctures. CSF cell count, the IgG index, local IgG synthesis, oligoclonal bands and the antibody index for measles, rubella or varicella zoster were calculated. Results were analysed with regard to clinical characteristics of the patients.ResultsOnce an intrathecal antibody response was established, it persisted. De novo antibody response against measles virus developed in 7% of the patients between the first and the second spinal tap. In two of seven patients where 5 consecutive CSF samples were available, the intrathecal antibody response expanded from one to three antigens. Furthermore, an intrathecal measles antibody production was associated with a rapid progression of the disease.ConclusionThese data stress the importance of activated B cells for the disease process and the clinical outcome in multiple sclerosis.

Long‐term persisting interferon beta‐1b neutralizing antibodies after discontinuation of treatment

Objectives – Neutralizing antibodies (NAB) against interferon beta (IFNB) with presumably negative impact on treatment outcome have been described in up to 42% of patients undergoing IFNB treatment. However, in most cases NAB decrease despite continuation of IFNB therapy. Observations on NAB after discontinuation of IFNB therapy are lacking. Here, we report for the first time on NAB which now persist for several years following discontinuation of IFNB treatment.

Impact of immunomodulatory treatment on leukocyte cytokine production in multiple sclerosis patients and healthy donors.

Objectives: Treatment with interferon(IFN) β, glatiramer acetate (GLAT) and intravenous immunoglobulins (IVIG) alters the cytokine production in multiple sclerosis (MS) patients. To date, it is not clear whether the effect on cytokines varies among these drugs. Therefore, we analyzed the effects of these drugs on the cytokine profiles of MS patients as well as healthy controls. Methods: The in vitro effects of IFNβ, GLAT and IVIG on leukocyte subsets producing the p40 subunit of interleukin 12 (IL12p40), IFNγ, tumor necrosis factor (TNF) and interleukin (IL) 10 were assessed in 21 MS patients and 11 healthy volunteers using flow cytometry. Results: In peripheral vein blood of healthy volunteers, IVIG reduced IL12p40-producing monocytes (p = 0.003) and IFNγ in CD4+ lymphocytes (p = 0.003). IFNβ treatment increased the proportion of IFNγ-producing CD4+ lymphocytes (p = 0.003) whereas GLAT reduced TNF production (p = 0.012). In MS patients, IVIG induced a suppression of leukocytes producing IL12p40 (p < 0.001) and IFNγ (p = 0.001). IFNβ decreased monocytes producing IL12p40 (p < 0.001) and increased IL10 (p = 0.005). GLAT reduced IL12p40 (p < 0.001), IFNγ (p = 0.001 in CD4+ and CD8+ lymphocytes) and TNF production of leukocytes (p < 0.001). In addition, the baseline cytokine patterns were inherently different between individual MS patients. Conclusions: IFNβ, GLAT and IVIG had different effects on cytokine patterns, which might point towards different mechanisms of action. Since the baseline cytokine patterns differed among MS patients, the evaluation of the cytokine pattern might serve as a surrogate marker before starting immunomodulatory treatments and might be helpful to tailor MS therapy effectively to the needs of each individual patient.

Gender change and its impact on the course of multiple sclerosis

We report the case of a 22‐years old genotypic women suffering from a relapsing‐remitting multiple sclerosis (MS) according to the Poser criteria. In this patient, a gender change had been performed by androgen‐supplementation and surgical intervention. During gender change, the patient experienced further relapses. Different immunomodulatory and immunosuppressive treatment strategies did not stabilise the course of MS in this patient. Actually, an escalating therapy with mitoxantrone has been initiated. During the observation period the patient received long‐term testosterone‐supplementation. Testosterone levels were elevated in the serum of this genotypic female MS patient under such a hormonal treatment compared to normal ranges before. The clinical course of the patient is presented in this case. As there are several studies investigating an immunomodulatory impact of hormones on the course of MS or experimental allergic encephalomyelitis, we discuss the presented case and a possible influence of androgens in this patient.

Use of rituximab in multiple sclerosis: current progress and future perspectives

In recent years, new insights into the immunological pathways in multiple sclerosis (MS) have been detected. This increasing knowledge has led to more distinct treatment options in modifying the disease course of MS. In 2006, natalizumab, an α4-integrin monoclonal antibody, introduced a new era of MS treatment. Another promising drug is the monoclonal CD20-antibody rituximab, which depletes CD20+ cells, pre-B cells and mature B cells. Rituximab is approved for the treatment of a number of autoimmune diseases other than MS, such as rheumatoid arthritis and non-Hodgkin’s lymphoma. Early-phase trials in the autoimmune-driven disorders Sjögren’s syndrome, vasculitis and thrombocytopenic purpura confirmed the use of rituximab in B-cell-mediated diseases. Another autoimmune disease affecting the CNS is neuromyelitis optica (NMO). NMO is characterized by having some similarities with MS and several studies demonstrated successful therapy of NMO using rituximab. In addition, numerous case reports in MS patients showed a stabilization of the course with a reduction of the relapse rate and MRI pathologies in MS patients. To date, one Phase II clinical trial in MS patients confirmed the results from these case reports. In this article, we will focus on the role of B cells in MS and the immunomodulatory pathways of rituximab. Recent data from experimental and clinical trials, as well as safety aspects, are discussed. A future perspective is given regarding the possible role of rituximab, as well as possible other candidates for treating MS.

Acknowledgement to the Reviewers

R. Ader, Rochester, N.Y., USA M. Anthracopoulos, Rio Patras, Greece E.G. Araujo, Rio de Janeiro, Brazil E. Arzt, Buenos Aires, Argentina A. Aubert, Tours, France L. Barbeito, Montevideo, Uruguay M. Bauer, Porto Alegre, Brazil I. Berczi, Winnipeg, Man., Canada H.O. Besedovsky, Marburg, Germany S. Bornstein, Dresden, Germany O. Bottasso, Santa Fe, Argentina S.D. Brain, London, UK A. Buske-Kirschbaum, Dresden, Germany M. Canal, Manchester, UK E. Charmandari, Athens, Greece D. Chiasserini, Perugia, Italy F.A. Costa-Pinto, São Paulo, Brazil M. Dardenne, Paris, France E.G. de Moura, Rio de Janeiro, Brazil K. Dornmair, Martinsried, Germany R.L. Doty, Philadelphia, Pa., USA J. Drouin, Montreal, Que., Canada G.E. Duffield, Notre Dame, Ind., USA A.J. Dunn, Honolulu, Hawaii, USA I. Elenkov, Rome, Italy G.G. Freund, Urbana, Ill., USA R. Furlan, Milan, Italy R.C. Gaillard, Lausanne, Switzerland Y. Gidron, Tilburg, The Netherlands N. Gilhus, Bergen, Norway F. Haour, Paris, France K. Hirata, Kyushu, Japan S.K. Jindal, Chandigarh, India J. Kasckow , Pittsburgh, Pa., USA T. Katafuchi, Fukuoka, Japan