If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Pathology Department, VU Medical Centre, VU University of Amsterdam, The NetherlandsNeuroimmunolgy Unit, Blizard Institute, Barts and the London School of Medicine & Dentistry Queen Mary University of London, United Kingdom
Evidence indicates that therapies targeting CD20+ B cells in MS also target T cells.
•
EAE is used to identify mechanisms and therapies for MS, a uniquely human disease.
•
B cells have many function in MS other than as a source of pathogenic antibodies.
•
B cell therapies in EAE do not reflect the efficacy in people with MS.
•
The efficacy of CD20 therapy may be removal of Epstein-Barr virus.
Abstract
MS is widely considered to be a T cell-mediated disease although T cell immunotherapy has consistently failed, demonstrating distinct differences with experimental autoimmune encephalomyelitis (EAE), an animal model of MS in which T cell therapies are effective. Accumulating evidence has highlighted that B cells also play key role in MS pathogenesis. The high frequency of oligoclonal antibodies in the CSF, the localization of immunoglobulin in brain lesions and pathogenicity of antibodies originally pointed to the pathogenic role of B cells as autoantibody producing plasma cells. However, emerging evidence reveal that B cells also act as antigen presenting cells, T cell activators and cytokine producers suggesting that the strong efficacy of anti-CD20 antibody therapy observed in people with MS may reduce disease progression by several different mechanisms. Here we review the evidence and mechanisms by which B cells contribute to disease in MS compared to findings in the EAE model.
Multiple sclerosis (MS) is a chronic immune-mediated neurodegenerative disease of the central nervous system (CNS) characterized by inflammation, demyelination and axonal loss. The most widely-used experimental animal model to study mechanisms of CNS damage, as well as for drug development for MS is experimental autoimmune encephalomyelitis (EAE) (
Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research.
), induced in many species. It is well known that the mode of induction, animal species and strains of rodents heavily influence the course of disease and observed immunological alterations and pathology in the CNS (
). Most of the current drugs available for MS are broad-spectrum immunomodulatory agents, although more recently specific therapies using cell-depleting antibodies such as those targeting B cells have been shown to be effective (
). Despite the apparent efficacy of B cell depletion there is much to be learned about how B cells contribute to the regulation and pathogenesis of MS, given the balance between regulatory and effector cell functions as shown both in EAE and MS. In addition, broad B cell-targeted depletion carries risks, notably associated infections. This indicates that despite being very effective, the depletion regimen could be better targeted to remove pathogenic B cells while leaving the protective and regulatory arm intact.
2. B cells and autoantibodies in EAE
Until the last decade MS has been widely considered a white matter disorder, and thus EAE has been commonly induced following immunization with myelin antigen such as myelin basic protein (MBP). However, clinical and pathological features of MS are usually better represented when EAE is induced using total CNS tissues (
) suggesting that autoimmunity to other myelin components may be essential to model chronic relapsing neurological disease, demyelination and axonal damage and secondary progressive disease. Currently, the most widely used autoantigen for induction of EAE is the minor protein myelin oligodendrocyte glycoprotein (MOG), present on the outer membrane of oligodendrocytes (
Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein.
Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encepahalomyelitis in SJL and Biozzi AB/H mice.
). Similar to EAE induced with other autoantigens, the clinical course and pathology of MOG-induced EAE is heavily dependent on the nature of the MOG antigen for example the presence of post translational modifications, as well as the mouse strain used for immunization (
Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encepahalomyelitis in SJL and Biozzi AB/H mice.
Importantly, the majority of studies, including those focusing on the role of B cells, make use of the C57BL/6 mice since most transgenic or mutant mice are bred on this background. Notably, the majority of EAE studies in this mouse strain uses mouse MOG35–55 peptide which induces a monophasic in which B cells and antibodies to MOG do not play a role (
The role of pathogenic autoantibodies was first indicated following the demonstration that circulating autoantibodies to myelin in EAE induce myelin damage in vitro and in vivo (
). This is supported by studies showing that titers of antibodies to myelin are high during chronic stages of EAE when demyelination was most pronounced, and that some MOG antibodies, notably those that fix complement, augment EAE (
Demyelinating antibodies to myelin oligodendrocyte glycoprotein and galactocerebroside induce degradation of myelin basic protein in isolated human myelin.
The complement system contributes to the pathology of experimental autoimmune encephalomyelitis by triggering demyelination and modifying the antigen-specific T and B cell response.
Tumor necrosis factor-alpha and alphaB-crystallin up-regulation during antibody-mediated demyelination in vitro: a putative protective mechanism in oligodendrocytes.
Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein.
). However, it appears that autoreactive T cells are necessary for the clinical disease to develop. It was shown in animals studies that T cells initiate the blood-brain barrier disturbances that facilitate entry of B cells and immunoglobulins into the CNS. Once in the CNS autoantibodies bind to oligodendrocytes and myelin, activate complement and induce demyelination that subsequently enhances inflammation and increases EAE severity.
3. B cell as immune modulators
Emerging evidence using B cell-deficient mice has revealed a complex role for B cells in antigen presentation, cytokine production and immune regulation during EAE (Fig. 1). While early studies showed that depletion of IgM from birth prevented B cell maturation and subsequent EAE induction (
), recent evidence for B cells in EAE comes from studies using the MOG EAE model in C57BL/6 following genetic ablation or B cell depletion using antibodies directed to CD20 (Table 1). These studies suggest that B cells are necessary for EAE induced with recombinant MOG protein but not MOG35–55 EAE, revealing the critical impact of the source and nature of immunogens (
). Next to the requirement of MHC class II the expression of T cell costimulatory molecules expressed by B cells, such as CD80/CD86 and CD40, plays a crucial role in EAE (
A case for regulatory B cells in controlling the severity of autoimmune-mediated inflammation in experimental autoimmune encephalomyelitis and multiple sclerosis.
). While mice (in this case B10. PL) in which B cells lack co-stimulatory CD80/CD86 molecules develop EAE, they fail to recover from acute disease due to a delay in IL-10 production and mobilization of Foxp3 regulatory T cells (
Fig. 1The multifunctional roles of B cells in EAE and MS. A) B cells act as antigen presenting cells that activate autoreactive T cells. B) B cells mature to plasma cells that produce antibodies including CNS reactive autoantigens. C) Mature B cells process antigens, and once activated produce pro- and anti-inflammatory cytokines important in D) the development of tertiary lymphoid tissue. B cells also harbor Epstein-Barr Virus (EBV) thought to a key etiological agent in MS.
Intracerebral expression of CXCL13 and BAFF is accompanied by formation of lymphoid follicle-like structures in the meninges of mice with relapsing experimental autoimmune encephalomyelitis.
B cells secrete lymphotoxin α1-β2 (LTα1β2) essential for lymph node expansion and development of tertiary lymphoid tissue, which are sometimes present in the CNS during EAE (
Epstein-Barr virus in the multiple sclerosis brain: a controversial issue – report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria.
Intracerebral expression of CXCL13 and BAFF is accompanied by formation of lymphoid follicle-like structures in the meninges of mice with relapsing experimental autoimmune encephalomyelitis.
Suppression of established experimental autoimmune encephalomyelitis and formation of meningeal lymphoid follicles by lymphotoxin β receptor-Ig fusion protein.
Suppression of established experimental autoimmune encephalomyelitis and formation of meningeal lymphoid follicles by lymphotoxin β receptor-Ig fusion protein.
). Another B cell-derived cytokine is interleukin-6 (IL-6) that is increased during EAE. That IL-6 production by B cells is key for EAE induction has been shown following B cell depletion studies in mice (
). A mechanism by which IL-6 may contribute to EAE is by regulating T cell infiltration into the CNS since expression of ICAM-1 and VCAM-1 are absent in IL-6 deficient mice (
). B cells also produce IL-10 as well as IL-35; cytokines that reduce EAE severity. This is supported by studies in which regulatory B cells (Bregs) extracted from mice during EAE remission, produce IL-10 in a CD40 dependent manner and, following transfer into mice with active EAE induce recovery (
). Thus, IL-10 producing Bregs are important for disease recovery. Furthermore, IL-10-producing B cells play an important role in EAE initiation by down-regulating the conditions leading to T cell CNS infiltration (
). Finally, IL-35 producing B cells also control EAE severity since mice lacking these B cells develop exacerbated EAE. IL-35 regulates APC functions of B cell that together with IL-10 induces differentiation of plasma cells. Mice in which B cells lack IL-35 have stronger antigen presentation capabilities, this is associated with stronger inflammatory responses and more severe EAE (
B cells, plasma cells, plasmablasts and antibodies directed to oligodendrocytes, myelin and neurons are detectable in peripheral blood and the cerebrospinal fluid (CSF) of people with MS (pwMS) (
). In the CSF oligoclonal IgG bands (OCBs), present in 95% pwMS, are an established diagnostic tool for MS. That immunoglobulins may play a role in disease is reflected by the close association of lesions to CSF flow such as ventricular and subpial lesions, and that OCB-negative patients are characterized by less global and regional brain atrophy (
). Further support comes from a study showing that clonally expanded plasma cells from the CSF of pwMS induce myelin damage in vitro, thus implicating intrathecal IgG in MS pathogenesis (
), indicating that like EAE CNS reactive antibodies mediate demyelination and neuronal damage (Fig. 2); findings that have been confirmed in vitro studies (
). In addition, the finding of B cell follicle-like structures as well as chemokines and cytokines that support B cell development all provide support for a key role of B cells, plasma cells and autoantibodies in MS pathogenesis. Like EAE, B cells extracted from pwMS and stimulation with CD40L and IL-4 have been shown to present myelin specific antigens to autoreactive T cells (
) indicating that B cells also have the capacity for antigen presentation in MS.
Fig. 2Antibody functions in MS and EAE. The primary effect of pathogenic antibodies is induction of tissue damage. Anti-myelin antibodies produced by plasma cells (1) attach to myelin leading to opsonisation (2). Macrophages bearing FcR bind to antibody on myelin (3). Alternatively, macrophages bind immunoglobulin via FcR receptors (4) that then bind to myelin inducing antibody dependent cell mediate cytotoxicity (ADCC). Antibodies on myelin (5) trigger complement activation leading to the formation of membrane attack complex (MAC) and cell death (6).
). In pwMS in which follicles are observed, the presence of the ectopic follicles were more pronounced in younger patients with more severe disease than the group in which follicles were not observed (
), were significantly higher in the CSF as compared to blood. Together with LT1α2β, CXCL13 has been found in the CSF and MS brain tissue in active lesions (
) and may thus contribute to disease severity by aiding inflammation. In support of this, B cell follicles and meningeal infiltrates have been associated with cortical grey matter lesions widely considered to contribute to cognitive decline in MS (
). How these follicles arise is as yet unknown, although several studies suggest strong association with EBV widely considered to be an etiological agent in MS.
There is also clinical evidence for regulatory B cell functions in MS (
Multiple sclerosis is associated with an imbalance between tumour necrosis factor-alpha (TNF-α)- and IL-10-secreting blood cells that is corrected by interferon-beta (IFN-β) treatment.
). As in rodents production of IL-10 in human B cells increases following treatment with CD40L, lipopolysaccharide (LPS) or CpG. Together the gathered data on the role for B cells in MS and EAE demonstrates its involvement in antigen presentation, cytokine production and T cell activation. This abundant evidence demonstrates that the role of B cells in MS pathology is not merely antibody production. Therefore targeting B cell in the treatment of MS has been a rational approach towards improving the MS pathology.
5. B cell therapies
Many current therapies for MS also inhibit or modify B cell function. For example the cytostatic agents mitoxantrone, cyclophosphamide preferentially kill B cells due to their high basal proliferation rate (Fox 2004), alemtuzumab depletes T and B cells (
). In contrast, natalizumab increases circulating B cells while IFN-β treatment increases CD19, CD24, CD38 B cells in peripheral blood, although whether B cells in the CNS are affected has not been reported. Cladribine is a highly effective depleting agent of peripheral B cells, compared to T cells (
). It is the only MS disease-modifying agent that is CNS penetrant, with an immunomodulatory action that is active in the CNS, which has the capacity to target plasma cells and can inhibit oligoclonal band protein formation (
). In summary, although studies clearly reveal the multifunctional roles of B cells in MS several therapeutic approaches can be applied to modulate B cell functions.
5.1 CD20 targeted therapy
Three anti-CD20 antibodies rituximab, a chimeric human/mouse IgG1 antibody; ocrelizumab, a humanized antibody, and ofatumumab, a full recombinant human IgG1 antibody have been used in clinical trials for MS (
). All antibodies deplete cells expressing CD20, a surface antigen present on maturating B cells, from pre-B cells to plasmablasts, precursors of plasma cells (Fig. 3), as well as a population of T cells. The first study of rituximab, conducted in 5 people with primary progressive MS (pwPPMS), showed that most peripheral blood B cells were depleted until 14 months (
). The depletion of CSF B cells was less efficient. A phase I open study, designed to assess the drug safety and tolerability in RRMS did not reveal serious adverse effects (
on behalf of the OPERA I and II clinical investigators
Efficacy and safety of ocrelizumab in relapsing multiple sclerosis - results of the interferon-beta-1a-controlled, doubleblind, phase III OPERA I and II studies.
Efficacy and safety of Ocrelizumab in primary progressive multiple sclerosis- results of the placebo-controlled, double blind, phase III ORATORIO study.
). Here, the study focused on younger people with active disease and closer to progressive onset of MS, based on the responder profile of an earlier trial in PPMS with rituximab (
). Lastly, ofatumumab, an approved drug for chronic lymphocytic leukemia is expected to be far less antigenic than rituximab. This was examined in RRMS, revealing over 99% reduction in newly formed lesions in RRMS compared to controls. No increase in adverse effects was noticed in treated compared to controls (
), not surprisingly since plasma cells do not express CD20 and are therefore not depleted. This suggests that CD20+ cell depletion interferes with antigen presentation, T cell activation or cytokine production (Fig. 4). The preclinical findings in EAE showing that B cells polarize T cell differentiation were confirmed in pwRRMS treated with anti-CD20 antibody treatment, emphasizing the APC function of B cells in RRMS (
Fig. 3B cell development. CD19 is highly expressed throughout B cell development but not on terminally differentiated plasma cells. CD20 is expressed on the majority of B cell subtypes but is down-regulated in plasmablasts. B cell activating factor receptor (BAFF-R) is expressed later in development from immature B cells to plasmablasts.
Fig. 4Effect of anti-CD20 antibody in MS. Anti-CD20 antibody binds to and depletes CD20+ cells, including CD20+ pro-inflammatory CD4 and CD8 cells, involved in CNS inflammation and demyelination. Breg – regulatory B cells, Mϕ – macrophage CTL: cytotoxic T cell.
In addition to the effect on B cell function and thereby indirectly affecting T cells, emerging evidence shows that anti-CD20 antibody therapies also directly affect CD20+ T cells. Interestingly, evidence for the direct T cell effect was suggested in early rituximab studies for treatment of rheumatoid arthritis (
). Since CD20 expression is lower on CSF T cells was less noticeable, they were characterized as CD20dim T cells that are both CD8+ and CD4+. Interestingly, CD20-specific antibodies predominantly depleted CD8+ CD20dim T cells although the overall CD4/CD8 ratio remained unchanged (
) suggesting that CD20-specific immunotherapy may thus modify disease by directly depleting inflammatory CD20high/dim T cells. Furthermore, it was demonstrated that rituximab was most effective in controlling EAE in human CD20 transgenic mice when antibody treatment induced marked T cell depletion (
Due to the broad B cell target, anti-CD20 antibodies also deplete B cells that regulate immune responses including those controlling viruses. Incidental cases of progressive multifocal leukoencephalopathy (PML) in people treated with rituximab with other immune disorders have been observed (
), which suggests a risk of PML development in MS. Furthermore, ocrelizumab development in rheumatoid arthritis and systemic lupus erythematosus was halted because it was linked to serious life-threatening infections (
Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to at least one tumor necrosis factor inhibitor: results of a forty-eight–week randomized, double-blind, placebo-controlled, parallel-group phase III trial.
). However, development of B cell depletion has a better risk: benefit profile in MS, because of the poor prognosis of MS. Whilst it has similar levels of efficacy to alemtuzumab in relapsing MS (
CARE-MS II investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial.
CARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.
CARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.
) thus making it an attractive new treatment for MS.
6. Novel B cell targeting therapies
Anti-CD19 therapy, under development for neuromyelitis optica has also been suggested as a new treatment for MS. This approach targets B cells including plasma blasts and short-lived plasma cells (
). MEDI-551, a humanized anti-CD19 IgG1 antibody has been reported to reduce lesions in RRMS (Aguis et al., 2015). The humanized antibody is able to bind and deplete a broader range of B cells but its method of action is similar to that of anti-CD20. In a humanized CD19 B cell animal model, anti-CD19 treatment could reduce antibody levels because of its ability to deplete plasma blasts (
Safety and tolerability of MEDI-551 in patients with relapsing forms of multiple sclerosis: results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study.
). However, such approaches might lead to more adverse events such as PML or opportunistic infections otherwise controlled by humoral immune responses in the CNS. In view of this VAY736, directed against the B-cell activating factor receptor (BAFF-R) has been designed to reduce the B cell fostering milieu in the CNS (Krumbholz et al., 2005,
Intracerebral expression of CXCL13 and BAFF is accompanied by formation of lymphoid follicle-like structures in the meninges of mice with relapsing experimental autoimmune encephalomyelitis.
). Upon binding to its receptor, BAFF aids B cell survival but it is also involved in B cell development and B cell mediated meningeal follicle formation (
Intracerebral expression of CXCL13 and BAFF is accompanied by formation of lymphoid follicle-like structures in the meninges of mice with relapsing experimental autoimmune encephalomyelitis.
). Since BAFF is elevated in MS, targeting the BAFF-R prevents its binding to take place thereby reducing B cell survival and lymphoid follicle-like structures. BAFF-R deficient mice with EAE had fewer mature B cells and increased EAE severity, suggesting a predominant effect on Breg (
). Similarly increased disease severity was also shown with atacicept, a BAFF-immunoglobulin fusion protein that targets BAFF receptor and A ProlifeRation-Inducing ligand (APRIL). However, the study was halted after increased inflammatory activity was observed in pwRRMS (
) demonstrating that B cell depletion is not universally a predictable and positive therapeutic effect, as was shown in initial studies in EAE, when B cell depletion inhibited, was ineffective or augmented disease (
Active RR- and PPMS is inhibited by peripheral B cell depletion with CD20-depleting antibodies, which may also be active in the CNS due to blood-brain barrier disturbances (
on behalf of the OPERA I and II clinical investigators
Efficacy and safety of ocrelizumab in relapsing multiple sclerosis - results of the interferon-beta-1a-controlled, doubleblind, phase III OPERA I and II studies.
Efficacy and safety of Ocrelizumab in primary progressive multiple sclerosis- results of the placebo-controlled, double blind, phase III ORATORIO study.
). Yet, intrathecal administration of B cell targeting therapies fails to induce marked B cell depletion within the CNS and simply drains from the natural flow of CSF into the circulation and depletes peripheral B cells (
). Therefore, it remains to be established whether intraventricular CD20 B cell depletion would have merit in targeting CNS-B cells or whether novel plasma cell depleting antibodies (
). With the knowledge that antibodies and B cells play a significant role in MS, B cell targeted therapies have been developed and have been found to have marked inhibitory activity on active MS although there are so far no surrogate markers to monitor efficacy. Success in treating relapsing and progressive MS by B cell therapy, has been hailed as the beginning of the end of the neurodegeneration of progressive MS (
Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis.
). Even though there has been much focus on T cell autoimmunity in MS, it is clear that the highly effective agents can target B cells. Although the etiology of MS is unknown, it is clear that genetics and environmental factors contribute to susceptibility to MS. One consistent feature of MS is the potential role of EBV as a trigger of disease activity (
). Given that EBV readily infects B cells another mechanism by which B cell depletion may operate removal of this etiological trigger of relapsing MS (
It is clear that broad B cell targeted depletion carries risks, notably associated with risks of infection. However, compared to drugs of similar efficacy such as natalizumab and alemtuzumab the adverse events may even be favorable. Yet, there is much to be learned about how B cells contribute to the regulation and pathogenesis of autoimmunity given the balance between B regulatory and B effector cell functions as shown EAE and MS. Irrespective of this it appears that depletion of CD20+ B cells offers promise as a disease modifying therapy of MS and it will probably gain approval for treatment of MS.
Conflict of interests
The authors declare no conflict of interest.
References
Agius M.
Klodowska-Duda G.
Maciejowski M.
Potemkowski A.
Sweeny S.
Li J.
Yao W.
Patra N.
Ratchford J.N.
Katz E.
Flor A.
Safety and tolerability of MEDI-551 in patients with relapsing forms of multiple sclerosis: results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study.
Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encepahalomyelitis in SJL and Biozzi AB/H mice.
Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis.
CARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.
CARE-MS II investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial.
Suppression of established experimental autoimmune encephalomyelitis and formation of meningeal lymphoid follicles by lymphotoxin β receptor-Ig fusion protein.
Tumor necrosis factor-alpha and alphaB-crystallin up-regulation during antibody-mediated demyelination in vitro: a putative protective mechanism in oligodendrocytes.
Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research.
on behalf of the OPERA I and II clinical investigators
Efficacy and safety of ocrelizumab in relapsing multiple sclerosis - results of the interferon-beta-1a-controlled, doubleblind, phase III OPERA I and II studies.
The complement system contributes to the pathology of experimental autoimmune encephalomyelitis by triggering demyelination and modifying the antigen-specific T and B cell response.
Epstein-Barr virus in the multiple sclerosis brain: a controversial issue – report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria.
Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein.
Intracerebral expression of CXCL13 and BAFF is accompanied by formation of lymphoid follicle-like structures in the meninges of mice with relapsing experimental autoimmune encephalomyelitis.
Demyelinating antibodies to myelin oligodendrocyte glycoprotein and galactocerebroside induce degradation of myelin basic protein in isolated human myelin.
Efficacy and safety of Ocrelizumab in primary progressive multiple sclerosis- results of the placebo-controlled, double blind, phase III ORATORIO study.
Multiple sclerosis is associated with an imbalance between tumour necrosis factor-alpha (TNF-α)- and IL-10-secreting blood cells that is corrected by interferon-beta (IFN-β) treatment.
A case for regulatory B cells in controlling the severity of autoimmune-mediated inflammation in experimental autoimmune encephalomyelitis and multiple sclerosis.
Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to at least one tumor necrosis factor inhibitor: results of a forty-eight–week randomized, double-blind, placebo-controlled, parallel-group phase III trial.
30120-1&id=gr1.jpg){kind=link}
30120-1&id=gr2.jpg){kind=link}
30120-1&id=gr3.jpg){kind=link}
30120-1&id=gr4.jpg){kind=link}