cladribine reduces oligoclonal bands (OCB)

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cladribine reduces oligoclonal bands (OCB)

Post by frodo » Tue Jan 15, 2019 5:39 am

Cladribine reduces oligoclonal bands (OCB) in MS, and MS gets better without them. These are the conclusions of this study, which also points to a intrathecal reaction in MS.

Should our treatment target in MS include the intrathecal plasma cell response? ... via%3Dihub

In this issue, Rejdak and colleagues report the effect of parenteral cladribine on the intrathecal oligoclonal IgG response in patients with relapsing-remitting MS (RRMS). Remarkably 55% of 29 patients studied had lost their CSF oligoclonal IgG bands at least 10 years after treatment (Rejdak et al., 2018). Although this was an uncontrolled observational study at last follow-up the OCB-negative group had significantly lower EDSS scores compared to OCB-positive patients. These findings support an earlier study of low-dose subcutaneous cladribine that was shown to reduce the number of OCBs in MS but not eliminate them (Sipe et al., 1994). Overall this new study raises the possibility that the intrathecal oligoclonal IgG response in MS may be pathogenic, which clearly needs to be explored further with larger cohorts of patients. Whether this pathogenic response is antigen-specific, targeting MS-specific autoantigens (Winger and Zamvil, 2016), or non-specifically in response to tissue damage (Brändle et al., 2016) and/or simply activating microglia via their Fc receptors (Pryce and Baker, 2018), may be a moot point, but it is very important to our understanding of the pathogenesis of MS.

MS is invariably associated with an intrathecal oligoclonal IgG response or oligoclonal bands (OCBs) (Giovannoni, 2014). Although in some populations the rate of positive OCB is not as high as in European countries, positive OCBs indicate a worse clinical outcome (Lechner-Scott et al., 2012) Repeated CSF examination only shows a different outcome in a minority of patients and usually OCBs turn from negative to positive (Lechner-Scott et al., 2012, Zeman et al., 1996). OCBs are not specific to MS and occur with central nervous system (CNS) infections and other CNS-specific autoimmune diseases, in particular, paraneoplastic syndromes (McLean et al., 1990). Even when neuroinfectious diseases are successfully treated, OCBs can persist (van Eijk et al., 1987). In neurosyphilis, for example, OCBs are found a decade, or longer, after successful treatment with antibiotics (Thompson-E, 2005). The persistence of the OCBs has been ascribed to the longevity of long-lived plasma cells (Meinl et al., 2006). In the case of infections, these OCBs target the inciting pathogen and most bands can be removed using antigen-specific immunoadsorption (Luxton et al., 1995). In putative autoimmune diseases such as MS these OCBs may be targeting auto-antigens and therefore may be responsible for driving progressive MS pathology, which theoretically could become independent of autoimmune T-cell help (Giovannoni, 2014, Meinl et al., 2006). Another hypothesis, proposed by Pryce and Baker, is that the OCBs interact with microglia and astrocytes non-specifically to create a self-perpetuating activated phenotype, which creates an environment conducive to long-term plasma cell survival and the initiation and perpetuation of neurotoxicity that may contribute to disability worsening (Pryce and Baker, 2018).

Pathological studies have shown that B-cell-like follicles in the meninges of people with MS (pwMS) are associated with earlier onset age of progressive disease and bring forward the time of death (Magliozzi et al., 2007). Recent evidence has linked the subpial cortical MS lesion with antibody deposition and microglial activation (Lagumersindez-Denis et al., 2017). Patients with the so-called type 2 acute MS lesion, which is characterised by immunoglobulin deposition and complement activation (Lucchinetti et al., 1996), are more likely to respond to plasma exchange (Stork et al., 2018). CSF from pwMS is gliotoxic and neurotoxic in vitro (Ménard et al., 1998, Øren et al., 2001) and in vivo (Benjelloun et al., 2002). This toxicity may be antibody mediated. For example, a proportion of the OCBs react against neurofilaments (NFL) and the anti-NFL response has been shown to predict a worse outcome (Eikelenboom et al., 2003, Silber et al., 2002) and induce a progressive course in EAE, an animal model of MS (Puentes et al., 2017).

Based on Rejdak and colleagues data (Rejdak et al., 2018), and these other observations, we hypothesise that OCBs are likely to be pathogenic in MS. To the best of our knowledge, none of the currently licensed disease-modifying therapies have been shown to eliminate the intrathecal OCBs in pwMS, with the possible exception of natalizumab (von Glehn et al., 2012). A few small case series show loss of OCBs in a proportion of patients treated with natalizumab (Krasulová et al., 2007, Mancuso et al., 2014, von Glehn et al., 2012). This observation, however, was not confirmed in a larger German study (Harrer et al., 2013). It is noteworthy that in pwMS who are treated with alemtuzumab their intrathecal oligoclonal bands persist (Hill-Cawthorne et al., 2012), albeit it in the short-term.

We, therefore, propose that it may be important to target intrathecal plasma cells therapeutically to delay the onset, or slow down, the clinically-apparent progressive phase of MS. To varying degrees, most licensed DMTs are effective at suppressing relapses and focal MRI activity (new T2 or Gd-enhancing lesions), although none of the treatments has yet been shown to prevent the onset of non-relapsing progressive disease. If the non-relapsing progressive phase of the disease is driven by intrathecal OCBs and innate immune activation via Fc-receptors, the resistance of long-lived plasma cells to current therapeutic intervention may explain why this phase of the disease is so refractory to treatment. To treat successfully, or avert progressive MS, intrathecal plasma cells may need to be eliminated to prevent antibody-mediated mechanisms that underlie the progressive phase of MS.

Cladribine (2-chlorodeoxyadenosine) is a small molecule nucleoside analogue, which penetrates the blood-brain barrier (BBB) has been shown to have biological activity against myeloma cells, or malignant plasma cells, albeit in combination with a STAT3 inhibitor (Ma et al., 2011). This suggests cladribine has the potential for use as a treatment in progressive MS, targeting peripheral and central anti-inflammatory mechanisms as well as potential pathogenic intrathecal plasma cells.

The current study (Rejdak et al., 2018), needs confirmation but it provides tantalizing evidence that we may need to develop a range of new therapeutics that go beyond the usual T and B cell targets with the aim of ‘scrubbing clean’ the CNS of pathogenic long-lived plasma cells and their antibody products.

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