Clinical trials in CIDP and chronic autoimmune demyelinating polyneuropathies

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1 Journal of the Peripheral Nervous System 17(Supplement):34 39 (2012) REVIEW Clinical trials in CIDP and chronic autoimmune demyelinating polyneuropathies Marinos C. Dalakas Neuroimmunology Unit, University of Athens Medical School, Athens, Greece Abstract The main chronic autoimmune neuropathies include chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), and anti-myelinassociated glycoprotein (MAG) demyelinating neuropathy. On the basis of randomized controlled studies, corticosteroids, intravenous immunoglobulin (IVIg), and plasmapheresis provide short-term benefits in CIDP. MMN responds only to IVIg. Because in MMN and CIDP, IVIg infusions are required every 3 6 weeks to sustain benefits or long-term remissions, there is a need for IVIg-sparing agents. In CIDP, immunosuppressive drugs, such as azathioprine, cyclosporine, methotrexate, mycophenolate, and cyclophosphamide, are used, but controlled trials have not shown that they are effective. Controlled trials have also not shown benefit to any agents in anti-mag neuropathy. However, clinicians use many immunosuppressive drugs in both settings, but all have potentially serious side effects and are only effective in some patients. Thus, there is a need for new therapies in the inflammatory and paraproteinemic neuropathies. New agents targeting T cells, B cells, and transmigration and transduction molecules are discussed as potential treatment options for new trials. The need for biomarkers that predict therapeutic responses or identify patients with active disease is emphasized, and the search for better scoring tools that capture meaningful changes after response to therapies is highlighted. Key words: alemtuzumab, anti-mag neuropathy, chonic inflammatory demyelinating polyneuropathy, IVIg, multifocal motor neuropathy Introduction and Rationale for Immunotherapies in Autoimmune Neuropathies Autoimmune peripheral neuropathies occur when immunologic tolerance to peripheral nerve components (myelin, Schwann cell, axon, and motor or ganglionic neurons) is lost (Dalakas, 2008a). On the basis of immunopathologic similarities with Guillain Barré syndrome and experimental allergic neuritis, in most of these neuropathies, there is evidence that activated T cells, macrophages, complement, Address correspondence to: Prof. Marinos C. Dalakas, MD, FAAN, Neuroimmunology Unit, University of Athens Medical School, 75 Mikras Asias, Athens 11527, Greece. Tel: ; Fax: ; mdalakas@med.uoa.gr and autoantibodies work in concert with each other to induce an immune attack against heretofore unknown peripheral nerve antigens (Koller et al., 2005; Dalakas, 2008a; 2011a). Complement-fixing immunoglobulin (Ig)-G and IgM deposits are found on the patient s myelin sheath, while antibodies to various glycolipids or to myelin protein are more frequently detected than in controls. Except for the myelin-associated glycoprotein (MAG) antibodies in anti-mag/sulfoglucuronyl glycosphingolipid (SGPG) neuropathy, however, no pathogenic autoantibody or single triggering antigen have been so far identified. Generally, there are minimal signs of T-cell infiltrates. In CIDP, macrophages activated by T-cell-secreted cytokines constitute the final effector cells associated with the demyelinating process; they invade the myelin lamellae causing 2012 Peripheral Nerve Society 34

2 focal destruction of the myelin sheath (macrophagemediated demeylination) (Koller et al., 2005; Dalakas, 2008a; 2011a; Vallat et al., 2010). In MAG/SGPG, the myelin lamellae are split probably by IgM-anti MAG antibodies (Latov et al., 1988; Dalakas, 2008c). Accordingly, T cells, macrophages, cytokines, B cells, autoantibodies, and complement are the main molecules involved in the pathogenesis of autoimmune neuropathies and the main targets for specific therapy (Dalakas, 2008a; 2011a). Chronic Inflammatory Demyelinating Polyneuropathy Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common chronic autoimmune neuropathy with prevalence as high as 9/100,000 (Laughlin et al., 2009; Rajabally et al., 2009). It is treatable in the majority of the cases. First described as steroid-responding relapsing polyneuropathy, CIDP has emerged as a distinct entity. Because the demyelination is multifocal, affecting spinal roots, plexuses, and proximal nerve trunks, the clinicopathological picture may be at times atypical, accounting for a number of disease variants, according to the distribution of symptoms and signs (Koller et al., 2005; Dalakas 2008a; 2011a; Laughlin et al., 2009; Vallat et al., 2010). The most notable CIDP variants include the asymmetric, unifocal or multifocal motor-sensory (Lewis Sumner syndrome); the pure motor; the pure sensory; the sensory ataxic; and the pure distal forms (Koller et al., 2005; Dalakas, 2008a; 2011a). Although controlled trials have not been performed in the disease variants, it is assumed that the variants have the same response to immunotherapies as the typical CIDP. Treatment There is convincing data from randomized controlled trials that corticosteroids, intravenous immunoglobulin (IVIg), and plasma exchange exert short- or long-term meaningful clinical improvement in about 2/3 of the patients (Hughes et al., 2004; 2009; Dalakas, 2011a). Maintenance therapy is, however, needed for sustained benefits. Because up to one-third of patients achieve long periods of sustained improvement, there is a need to examine periodically the necessity for continuing long-term therapies to avoid overtreatment and reduce expenses or potential side effects, as recently discussed (Hughes et al., 2006; 2010; Dalakas, 2011a; Hartung et al., 2011). In CIDP, steroid efficacy was proven in a small controlled study (Dyck et al., 1982), albeit with inadequate blinding (Dalakas, 2011a), and reconfirmed with another parallel study (Hughes et al., 2001). Treatment may start with a high-dose regimen of mg oral daily prednisone for at least a month, followed by a taper to every other day. Improvement may begin as early as 2 weeks; the average time to induce a satisfactory response is about 2 months (Dalakas and Engel, 1980; Dalakas, 2011a). At least five small, randomized controlled studies have demonstrated the effectiveness of IVIg (reviewed in Dalakas, 2011a). The usual starting dose is 2 g/kg divided over 2 3 days. The IGIV-C CIDP Efficacy (ICE) trial, the most recent and the largest ever conducted, has not only confirmed the short-term efficacy of IVIg but also demonstrated that a maintenance dose of 1 g/kg every 3 weeks can sustain improvement, increase quality of life over 12 months, and prevent axonal degeneration (Hughes et al., 2008; Merkies et al., 2009; Bril et al., 2010). This study, which advocates IVIg as a first-line therapy, has led to Food and Drug Administration approval for one brand of IVIg. It has also shown that two rather than one infusions, over a 6-week period, are required to capture improvement in the majority of the patients (Latov et al., 2010). The schedule of maintenance therapy is generally individualized according to the duration of the improvement observed after each infusion. The most common regimen is 1 or 2 g/kg every 3 8 weeks, as needed. Because up to 55% of the responders to IVIg can discontinue treatment after 24 weeks without a relapse (Hughes et al., 2008), there is a need to periodically assess the necessity of continuing further infusions. The proposed subcutaneous immunoglobulin administration (Lee et al., 2008) may offer an easier and possibly less toxic means of administering immunoglobulin for maintenance therapy, especially in high-risk patients, provided efficacy is established with controlled trials. Plasmapheresis has been also effective in controlled studies (Dyck et al., 1986; 1994; Hahn et al., 1996). After a series of six plasma exchanges, maintenance therapy with one exchange at least every 8 weeks may be required, either solely or concomitantly with other immunmodulatory medications (Dalakas, 2011a). IVIg is generally preferred to plasmapheresis because it is more accessible and less invasive. It should be stressed, however, that some CIDP patients might benefit more from steroids, others more from IVIg, and still others more from plasmapheresis. Steroid- or IVIg-Sparing Agents: Failures and Future Prospects About one-third of CIDP patients are refractory or not sufficiently responsive to the aforementioned therapies (Hughes et al., 2004; Mahdi-Rodgers et al., 2010; Dalakas, 2011a), necessitating the need to search for alternate treatments. There is also a need for steroid 35

3 and IVIg-sparing agents to diminish the long-term steroid-related side effects and reduce the high cost of IVIg. Azathioprine up to 3 g/kg, cyclosporine 150 mg twice/day, mycophenolate up to 3 g daily, or intravenous cyclophosphamide 1 g monthly for 6 months are variably used, but their efficacy is highly variable and none have been shown effective in controlled trials. Adding β-interferon offers no benefit (Hughes et al., 2010). Methotrexate in a controlled trial was ineffective (RMC Trial Group, 2009). Better drugs are therefore needed. The involvement of activated lymphocytes, cytokines, complement, and adhesion or transmigration molecules in the pathogenesis of CIDP justifies pursuing new biological agents that target specific molecules connected with all the stages of immunopathology of the disease, from the early T- and B-cell activation process to the final induction of cytotoxicity (Dalakas, 2011a). These drugs are promising in other autoimmune diseases but remain formally untested in CIDP or other autoimmune neuropathies. Their experimental use should be pursued with controlled studies and with caution because of some rare but serious side effects, such as progressive multifocal leukoencephalopathy (PML) or bone marrow suppression (Dalakas, 2011a). T-cell intracellular signaling pathways Some of the main drugs in this family are (1) The monoclonal antibody alemtuzumab (CAM- PATH), directed against the CD52 molecule that causes long-lasting lymphocyte depletion via apoptosis. In a small study, 4/7 CIDP patients improved, 2 with complete remission (Marsh et al., 2010). (2) Inhibitors of the calcineurin phosphatase activity. This category includes tacrolimus and a similar drug rapamycin that acts downstream via a calcineurin-independent pathway to prevent the translation of mrna for key cytokines involved in T-cell signaling. B cells This family includes the monoclonal antibody directed against CD20, expressed on B cells (rituximab or the humanized version occrelizumab), and agents against B-cell growth factors, such as B-cell activating factor (BAFF) and a proliferating-inducing ligand (APRIL) (Dalakas, 2008a; 2008b). Rituximab, at a dose of 2 g given intravenously in two infusions, 15 days apart, or 375 mg/m 2 in 4 weekly infusions, is a promising agent; up to 50% of the treated CIDP patients seem to improve after 2 12 months (Münch et al., 2007; Briani et al., 2004; Kosmidis and Dalakas, 2010; Benedetti et al., 2011a; 2011b). Controlled studies are planned. Complement A monoclonal antibody against C 5 (eculizumab) inhibits C 5 and blocks the formation of membranolytic attack complex and subsequent generation of proinflammatory molecules. The drug was unsuccessful in a small series of patients with multifocal motor neuropathy (MMN), but in that disease, the role of complement is weak (Fitzpatrick et al., 2011). Eculizumab may be more applicable in CIDP. Cellular adhesion and T-cell migration Among these agents are natalizumab and fingolimod, two drugs approved for multiple sclerosis (MS). Natalizumab, directed against the α4β1 integrin (VLA4) on leukocytes, affects adhesion and transmigration of T cells; it is a reasonable drug to test in CIDP, even though in one case report, the drug was ineffective (Wolf et al., 2010). The same applies to fingolimod, an anti-t-cell migration agent that traps lymphocytes in the lymphoid organs. The drug, approved for multiple sclerosis, is now considered for acidptrial. Hematopoietic stem cell transplantation This procedure has been performed in a few patients with varying success (Vermeulen and Van Oers, 2002; Kazmi et al., 2008). A randomized study is, however, needed as this is a very risky method and the experience in CIDP very limited. Concerns With Clinical Trials in CIDP and Other Autoimmune Neuropathies Two main concerns have become apparent in the clinical trials of CIDP and other chronic autoimmune neuropathies: one is the need to use new objective scales to measure meaningful functional impairment or disability to assess long-term outcomes and evaluate treatment responses; the other is the need to identify and exclude patients with chronically stable or inactive disease because such patients are less likely to respond to new therapies (Gorson et al., 2010; Dalakas, 2011a; Hartung et al., 2011). The assumption that continuous therapy is needed to maintain stability is not often challenged in patient recruitment or in clinical practice; as a result, patients with burnt-out disease or those who may require lesser amounts of steroids or IVIg for maintenance therapy are routinely included. Periodically lowering the doses or skipping some monthly IVIg infusions used for maintenance will help us to assess disease activity before enrollment. Although this practice generates ethical challenges in trial designs and patient recruitment because it increases the chances for breakthrough of disease, it 36

4 is currently the best means to avoid overtreatment and conduct successful clinical trials with a smaller sample size and less placebo-responders, if proper safety guidelines are applied. A CIDP disease activity status (CDAS) score, a recently devised questionnaire, is a simple and reproducible tool that classifies patients according to disease activity and treatment status (Gorson et al., 2010). CDAS may be useful to identify those patients who are cured, chronically stable, or have a burnt-out disease and exclude them from entering into new clinical trials as they are less likely to respond to novel therapies (Gorson et al., 2010; Dalakas 2011a; Hartung et al., 2011). Biomarkers of Response to Therapies Biomarkers predicting the response to IVIg or other therapies from the outset are needed because some patients respond only to steroids, while others, especially with pure motor CIDP, not only fail to respond but may also even worsen with steroids (Dalakas, 2011a; 2011b). Although some clinical signs associated with a better response to IVIg have been proposed based on retrospective data (Chan et al., 2006), they are descriptive and do not provide a scientific basis that predicts a response. Among the potential biomarkers currently explored in CIDP (Dalakas, 2011b), the most promising ones are the transient axonal glycoprotein-1 (TAG-1), an adhesion molecule involved in axonal maintenance (Tackenberg et al., 2009), and the inhibitory Fcγ RIIB on B cells (Iijima et al., 2009). An analysis with single nucleotide polymorphisms and haplotype studies in 100 Japanese patients revealed an association between IVIg responsiveness and polymorphism in TAG-1, suggesting that the response to IVIg may be genetically determined. The inhibitory Fcγ RIIB on B cells, which transduce inhibitory signals preventing their transformation into IgG-producing plasma cells, were found to be lower on naïve B cells in CIDP patients. After clinically effective IVIg treatment, however, the Fcγ RIIB protein expression was upregulated on monocytes and B cells, suggesting that the effect on Fcγ RIIB may be a factor predicting patients more likely to respond to IVIg (Tackenberg et al., 2009). These interesting biomarkers are currently explored in more patients to solidify the noted assumptions. MMN With Conduction Block MMN is a distinct disease that should be recognized early because it is treatable. MMN presents with progressive weakness, atrophy, and areflexia that often begins in the hands and is prominent in distal muscle groups supplied by many individual peripheral nerves (multifocal). It differs from vasculitic neuropathy because it is slow and painless and by affecting only motor nerve fibers. It also differs from the motor variant of CIDP because it is multifocal and asymmetric (van Asseldonk et al., 2005; Dalakas, 2008a). This neuropathy responds well only to IVIg, based on a number of controlled trials, and IVIg is the treatment of choice. Frequent infusions, almost in a predictable fashion every 3 6 weeks, are required to sustain benefit however (van Asseldonk et al., 2005; Dalakas, 2008a). In difficult cases, cyclophosphamide or rituximab may help, but no controlled studies have been carried out. The need for new agents, as noted above, is essential not only for those cases insufficiently responding to IVIg but also to reduce the slowly evolving axonal degeneration and diminish the requirements for monthly IVIg infusions. IgM MGUS Polyneuropathies With Anti-MAG or Ganglioside Antibodies Most such patients present with a sensory, largefiber, demyelinating polyneuropathy that manifests as sensory ataxia. Other patients have a sensorimotor polyneuropathy with mixed features of demyelination and axonal loss (Latov et al., 1988; Dalakas and Quarles, 1996; Dalakas, 2008a). Nerve conduction studies demonstrate reduced conduction velocity and a rather characteristic prolonged distal motor latency. Sural nerve biopsy demonstrates a diminished number of myelinated axons. On electron microscopy there is splitting of the outer myelin lamellae, probably caused by the IgM deposits in the same area of the split myelin sheath. Sera from approximately 50% of patients with IgM monoclonal gammopathy of undetermined significance (MGUS) polyneuropathy react with MAG (Latov et al., 1988), as well as other glycoproteins or glycolipids that share antigenic determinants with MAG. The anti-mag IgM paraproteins co-react with an acidic glycolipid in the ganglioside fraction of the human peripheral nerve, identified as a SGPG (Ilyas et al., 1985). For the IgM anti-mag demyelinating polyneuropathies, treatments with prednisone plus chlorambucil, plasmapheresis, and IVIg have been disappointing (Dalakas et al., 1996; Dalakas, 2008a). Rituximab, a monoclonal antibody against CD20, failed to meet the primary endpoint in two controlled trials (Dalakas et al., 2009; Léger et al., 2011). There is clearly a need for more studies in these patients and experimentation with of one of the new agents mentioned above. 37

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