Hello everyone, good morning. My name is Rocio Vasquez. I'm an Associate Professor of Neurology at the University of Alabama at Birmingham. Welcome to this AEM session on Immunomediated Neuropathies. I'm accompanied today by two amazing colleagues and also friends, Dr. Divyanshu Dubey from Mayo Clinic and Dr. Surya Raja from Duke University. Each of us will give a 25, 30 minute talk. There won't be breaks between the talks but hopefully you can keep your questions and you can ask them at the end. We'll try to answer all the questions. I have to make an announcement. Dr. Dubey unfortunately won't be here to present in person but we have his talk recorded so hopefully you can enjoy it as well. So we're gonna start with the first talk on CIDP and its variants. I have nothing to disclose and these are the objectives of the talk. I wanna review with you recent updates in the CIDP spectrum, discuss typical CIDP and CIDP variants and I wanna spend some time as well reviewing other immunomediated neuropathies that are no longer considered in the spectrum of CIDP. However, they have multiple similarities and even some overlap particularly with some of the CIDP variants and these are anti-myelin-associated glycoprotein or anti-MAG neuropathy, multifocal motor neuropathy, autoimmune neuropathies and chronic immune sensory polyradiculopathy also known as CISP. One of the important messages of this talk really is that CIDP or chronic inflammatory demyelinating polyradicular neuropathy is not a single disease or a single entity but is rather a spectrum or a group of diseases, neuropathies, that share a common pathological substrate which is inflammatory demyelination. However, they present with a variety of different clinical phenotypes. For simplicity, I'm going to refer to this group of neuropathies as CIDP as a whole but as the talk advances, I will be able to break this concept down for you and talk about the different forms and variants. CIDP is a relatively rare disease. The prevalence ranges between one and nine per 100,000 individuals. It has its peak incidence between the fourth and sixth decades although other patients from other age ranges can also develop the disease. It has a male preponderance with a two to one male to female ratio. CIDP is a disease for which no specific diagnostic biomarker has been found yet, meaning there is no specific test or procedure that can tell us that a patient has the disease with a higher degree of certainty. There are no well-defined risk factors for CIDP either. It is unclear whether some genetic or environmental factors may play a role. CIDP is paradoxically over-diagnosed and under-diagnosed. So the over-diagnosis means that CIDP is diagnosed in a person that actually has another type of neuropathy and that happens more commonly with typical CIDP. And the under-diagnosis actually happens more often with the variants because they present a little bit different. They are more difficult to recognize and actually they can mimic other diseases that are far more common. In 2021, the European Academy of Neurology, Peripheral Neurosociety published new guidelines for the diagnosis and management of CIDP and they established a new categorization of the forms of CIDP into typical CIDP and the variants. The variants are now very well characterized and described in the new guidelines and they include distal, focal, multifocal, motor and sensory variants. And each of them has specific clinical and ectodiagnostic characteristics that are different from typical CIDP. Regardless, all forms of CIDP have common features. So CIDP, as the name implies, is a chronic neuropathy. So the temporal course extends beyond eight weeks. It's a demyelinated neuropathy, so large myelinated fibers are preferentially affected, which means that patients have more sensory loss and weakness than perhaps neuropathic pain or autonomic symptoms. The demyelination that we see in these patients is actually segmental or patchy and that gives a pattern in electrophysiological testing of non-uniform demyelination that distinguish CIDP from other demyelinated neuropathies that have more uniform demyelination on testing like Charcot-Marie-Tooth. It is an inflammatory or immune-mediated neuropathy, or that's what we suspect, and that can be seen also or observed on biopsy with T-cell infiltration and macrophage engulfing myelin on electron microscopy as well. And as an autoimmune disease, this CIDP spectrum of neuropathies have good response to immunotherapy. Remember that there are other immune-mediated neuropathies that for one reason or another don't feed or don't meet all these characteristics and they are no longer considered under the umbrella of CIDP. So let's move on to talk about typical CIDP. This is the most common form. It represents more than 50 to 60% of all the cases. The diagnosis of typical CIDP relies on a combination of both clinical and electrodiagnostic features. So the first step in the diagnostic process in these patients is asking yourself, does this patient meet clinical criteria? So patients with typical CIDP present with fairly symmetric and a diffuse pattern of weakness, proximal, very important, and distal weakness. And the pattern of sensory loss is actually more length-dependent, usually milder than the motor involvement and affects usually at least two limbs. Patients have globally reduced absent reflexes, which distinguish that from many other length-dependent neuropathies. And the temporal course, as I mentioned, extends beyond eight weeks and may be progressive or relapsing. The second step in the diagnostic process is asking yourself, does this patient meet electrodiagnostic criteria? So the new guidelines for CIDP establish that the patients have to have abnormalities on both motor and sensory and nerve conduction studies affecting at least two nerves for each. So on motor nerve conduction studies, you have to have features of demyelination that strongly support demyelination, including slowing of parameters of nerve conduction. These are the distal latencies, which represent conduction along distal segments, conduction velocity, which represents conduction along intermediate segments, and F waves, which actually represent conduction along the entire motor peripheral pathways, but this is the only parameter that also represents proximal nerve segment conduction. Patients have also segmental demyelination features, including conduction block or temporal dispersion. And even distal CMAP duration can be prolonged on these patients, and that also is a criteria that the guidelines established. The guidelines specify the degree of abnormality that you have to have in all these parameters to meet electrodiagnostic criteria. As far as the sensory nerve conduction studies, they don't specify how slow these nerve conductions or distal latencies have to be, but prolongation of the distal latency, slowing of conduction velocity, and low amplitudes in at least two nerves essentially are in the electrodiagnostic criteria as well. If the patient meets clinical and electrodiagnostic criteria the diagnosis of CIDP can be established. If they don't meet electrodiagnostic criteria, then they have to meet clinical criteria, and they have to have another supportive criteria or characteristic or feature to be able to establish the diagnosis. These include ancillary testing, including imaging studies, CSF analysis, or biopsy. One of the important things is that these patients that don't meet definitive criteria for CIDP have to have a response to immunotherapies. Remember that there is a number of red flags that should put the diagnosis in question, and these are some of them. For example, if the patient has prominent neuropathic pain, that is more common in small fiber neuropathies than demyelinated neuropathies, so that's a red flag. If the patient has a neuropathy with predominant distal involvement, that means that this patient or this neuropathy can actually be other type of length-dependent neuropathy that might be more common than CIDP. If patients fail to meet clinical criteria, that's a red flag, or if they have certain symptoms or signs that are not typical of demyelinated neuropathies, for example, severe muscle atrophy, or if they have high-arches hammer toes, which is more common in inherited neuropathies. If the diagnosis is based only on equivocal findings on nerve conduction studies, or just an elevated protein in CSF without meeting clinical criteria, that's another red flag. Patients that have diabetes or end-stage renal disease, these neuropathies can show slowing of parameters of nerve conduction on testing, so that's also something you have to keep in mind. If they have autonomic manifestations that are prominent, that's not typical for typical CIDP. If they have family history of neuropathy, you should take into consideration that you may need genetic testing to rule out first an inherited neuropathy, or if they don't have a clear response to treatment, that's another red flag. I'm not gonna go into this in detail, but just to remember that there are a number of exceptions and common pitfalls when you interpret electrodiagnostic studies in these patients. So you need to go to the guidelines and look at all the exceptions, read the small print, and make sure that you don't confuse these findings with evidence of primary demyelination. I also wanna emphasize that the electrodiagnostic criteria for CIDP are not 100% specific for CIDP, which means that there are other diseases that actually may meet electrodiagnostic criteria and mimic CIDP on nerve conduction studies, and these are some of them. I already mentioned diabetes, end-stage renal disease, polyneuropathies, but also inherited neuropathies, charcomery tooth, demyelinating variants, hereditary neuropathy with liability to pressure pulses, and others like POEMs, amyloidosis, vasculitis, so keep that in mind. I don't wanna miss the opportunity to also mention to the audience that the new guidelines on CIDP recommend that every suspected case of CIDP should actually, we should screen for monoclonal proteins in every case that we suspect it may be CIDP, with serum protein electrophoresis and immunofixation, and also with free light chains in serum and urine. This is just to screen these patients for hematologic dyscrasias like POEMs or the IgM monoclonal paraproteinemia associated with MAG antibodies, just remember that. So let's move now to the CIDP variants. There are a number of still unanswered questions about the CIDP variants. We don't know if these are difficult, different, sorry, clinical phenotypes of the same disease, meaning CIDP, whether they represent an early stage or a step in the disease process before these patients convert into CIDP, or whether they are completely separate clinical entities with different pathophysiology that we haven't figured out yet, and with different response to treatment. There are five well-recognized and well-characterized CIDP variants. These are three of them that differ from CIDP in the anatomical distribution of symptoms. So these are distal, focal, and multifocal, and two that differ from typical CIDP in that either motor or sensory fibers are purely or predominantly affected, and these are the pure motor and sensory variants and the predominantly motor and sensory variants. So the first variant I'm gonna talk about is distal CIDP. It's also known as distal-acquired demyelinating symmetric, or DATS neuropathy. This variant differs from typical CIDP in two main features. Number one, the involvement or the pattern of involvement is distal or length-dependent, and the second feature is that this is sort of like a predominantly sensory neuropathy, where typical CIDP is more motor than sensory. These patients actually presents with sensory loss and gait instability more than weakness. If they have weakness, the weakness is usually more distal and affects distal muscle groups in the lower limbs. Remember that half to two-thirds of these patients may have an IgG and monoclonal protein associated with MAG antibodies, and so these patients will be actually diagnosed with anti-MAG-associated neuropathy, which is different from CIDP. There are a number of red flags that should, actually you should think about, because there are certain neuropathies that may mimic distal CIDP. So some of the red flags are neuropathic pain or autonomic features. I mentioned already these are more common in small-fire neuropathies, diabetes, renal disease, or family history of neuropathies as well. The differences between distal CIDP and anti-MAG neuropathy, I already mentioned that anti-MAG has IgM, monoclonal protein in serum, and the antibodies are present. And then anti-MAG neuropathy is a little bit more chronic and protracted than distal CIDP. As far as the electrodiagnostic features, these patients have disproportionate slowing in distal nerve segments. Distal latency is that will be very prolonged. And they also do not respond as well to the standard immunotherapies like IVIG and corticosteroids. So these patients often need a trial of rituximab. Multifocal CIDP, the next variant I'm gonna talk about, is also known as Lewis-Zumner syndrome or MAD-ZUM. This variant differs from typical CIDP in the multifocal asymmetric pattern of involvement. So limbs are affected to different degrees and not necessarily symmetrically. Another important difference is that upper limbs are usually affected first and lower limbs are affected later. And this is one of the variants or the variant that oftentimes these patients may have cranial neuropathies which doesn't happen as frequently in other types. Red flags that should raise the possibility of alternative diagnosis is, for example, if the patients have asymmetric, just only motor features, this could be MMM. If they have family history of entrapment neuropathies, it could be HMPP. Or if they have predominant pain and systemic signs of vasculitis. Focal CIDP is the least common of the CIDP variants. The difference between typical and focal CIDP is the focal CIDP, there is only one limb that is affected in what we call a monomelic distribution or pattern. These neuropathies often present as a brachial or lumbosacral plexopathy. So nerves in the brachial and lumbosacral plexus are predominantly affected. However, there are some patients that may have involvement of just individual peripheral nerves or even just one single nerve. In the latter case, chronic inflammatory demyelinating mononeuropathy is a better term for these patients. The interesting thing about the focal CIDP as well, it's a little bit different from other variances. More often than not, you're gonna need ancillary testing like imaging or nerve biopsy to make the diagnosis because there will be a number of alternative diseases that could present in a very similar way. Remember, if these patients have neuropathic pain, they may have an inflammatory process. If they have, again, entrapment neuropathy in family members as systemic signs of vasculitis or if imaging suggests something different like a tumor or malignancy. These are the differential diagnosis for multifocal and focal CIDP. As I mentioned before, MMN, different types of plexopathies, peripheral nerve tumors, et cetera. Motor CIDP differs from typical CIDP in that only motor fibers are involved. It still is a symmetric and diffuse process affecting proximal and distal muscle groups. But sensory fibers are typically spared, both clinically and on electrodiagnostic studies. When they are affected, we don't talk about pure motor CIDP but rather motor predominant CIDP. The interesting thing about CIDP is that in case series published, there are some patients that actually deteriorate when treated with corticosteroids or plasma exchange, which is what happens in MMN as well. So they are authors that actually argue that maybe there is some overlap between motor CIDP and MMN and actually motor CIDP may be a sort of diffuse variant of MMN, but this is something that we still haven't figured out yet. So red flags that may suggest alternative diagnosis if patients have vulvar symptoms or hyperreflexia, this could be ALS. If they have elevated CK, maybe we're looking at a myopathy case. Asymmetric rather than symmetric onset, again, MMN is a possibility. These are, this is a table that actually shows the major differences between motor CADP and multifocal motor neuropathy. Well, in recent years, there has been increasing evidence that multifocal motor neuropathy actually is not necessarily a demyelinating neuropathy. It might actually be in the spectrum of autoimmune neuropathies, which I'll touch on that in a second. As I mentioned, MMN patients have antibodies present in serum, these are the GM1 type. MMN is more asymmetric and affect upper limbs, maybe predominantly. Sensory symptoms are completely absent. And as far as electrophysiological testing, patients with MMN has more multifocal conduction blocks, and maybe if we see temporal dispersion, that might actually be a little bit more typical for motor CADP. The protein in CSF in MMN is often normal. And MMN is a disease that does not respond very well to the standard immunotherapies either. As opposed to motor CIDP, really that those patients should respond as if they are CIDP patients. The last variant is sensory CIDP. Sensory CIDP differs from typical CIDP in that only sensory fibers are involved in the pure forms. So patients have sensory loss, they have gated instability and ataxia, and they also have impaired vibration and proprioception on examination that are quite prominent. So they don't have muscle weakness unless they have a sensory predominant CIDP in which they might have a little bit of weakness, but much less than the sensory loss, and their motor conduction studies might have mild abnormalities. One interesting point about sensory CIDP is that this is a variant that more often progresses into typical CIDP in up to 70% of the patients, as opposed to other variants that the progression rates are much lower. Red flags that may suggest other diagnosis, and this is really the entire group of sensory predominant neuropathies. Diabetic neuropathies, nutritional neuropathies associated with rheumatologic diseases such as Sjogren's syndrome, and remember the neuropathy associated with MAG antibodies as well. There is a disease that I want to mention here that has some similarities with sensory CIDP. This is the so-called chronic inflammatory demyelinating polyradiculopathy, or CISP. This is a disease that is currently sort of in a limbo. It was initially described as demyelinating neuropathy affecting selectively sensory nerve roots only. But this actually disease has not been included under the spectrum of CIDP in the most recent guidelines, and so we'll have to actually wait and see what happens, whether we can prove or disprove that it's a primary demyelinating neuropathy. There are some studies done these days with these patients, and some of them actually have positive contacting one antibodies, and if that's the case, these patients would better be classified in the autoimmune neuropathy category. So patients with CISP present with very prominent gait ataxia and limb ataxia. They also have prominent sensory loss, aryflexia. The particularity of CISP is that nerve conduction studies are typically normal because the pathological process affects the sensory nerve roots only, so the lesion is pre-ganglionic. However, some of the sensory evoked potentials will typically be abnormal in these patients, showing prolongation of the evoked responses at lumbar and cortical sites. The response of CISP to IVIG and corticosteroids is actually pretty good. Even years after the onset of the disease, these patients may respond quite well to these immunotherapies. Just mention also, a variant of CISP is called CISPlus. So in this disease, the pathological process affects predominantly the sensory nerve roots, but also post-ganglionic segments in the peripheral nerves can also be affected to a minor degree. So these patients may have mild abnormalities on nerve conduction studies, but they still have the abnormalities on some other sensory evoked potentials, and they also respond well to IVIG and corticosteroids. So just to finalize, I wanna touch a little bit on autoimmune neuropathies. This is a new category of diseases, a group of immune-mediated neuropathies, in which the immune attack is actually located at the nose of Ranvier, rather than the internose of the myelin, like we suspect in CIDP. These neuropathies are actually antibody-mediated. So the antibodies target proteins in the nodal and paranodal regions, including contactin-1, contactin-associated protein-1, or Casper-1, and neurofascin. These antibodies were initially found in a subset of patients that actually met diagnostic criteria for CIDP. This was more than a decade ago. And these neuropathies actually are now separated from CIDP because they have different pathophysiology, the clinical presentation is a little bit different with specific features that differ from typical CIDP, and they actually have different response to treatment. So autoimmune neuropathies might actually, some of them respond early on to IVIG, but as the disease progresses, they become quite refractory. So these patients will need to be treated with other drugs, including B-cell depleting therapies such as rituximab. And this is just a picture to show you where some of these target proteins are in the paranodes and even in the nodes. Just remember that, as I mentioned, these patients with autoimmune neuropathies may present very similar to CIDP, even electrophysiologically. They may have axonal and demyelinating features on nerve conductions. The presentation may be symmetric, sensory motor quite subacute or acute. So they can actually mimic CIDP. There are a number of typical features that these patients may have that would suggest that we're actually in front of a patient with autoimmune neuropathies rather than typical CIDP. So these are the following. Number one, refractoriness to IVIG or corticosteroids. If the patients have a very acute or subacute and aggressive onset, some of these patients actually may be diagnosed at the beginning with having GBS or acute onset CIDP. These patients may also have tremor. A taxa that is quite prominent and may be disproportionate from the sensory involvement. And they also have severe distal weakness. Some of them have respiratory failure, cranial neuropathies, even associated nephrotic syndrome in contacting one and pan-neurofascing as well. And they tend to have higher protein levels compared to typical CIDP. So the new guidelines actually recommend that in these cases with the typical features, these patients should actually be screened for nodal and paranodal proteins with antibody testing. And I don't have time for more, so these are some of the take-home points. Remember that CIDP represents a spectrum of immune-mediated neuropathies with the hallmark of demyelination on electrodiagnostic studies and biopsy. The CIDP variants differ from typical CIDP in certain clinical and electrodiagnostic features. There are other immune-mediated neuropathies outside of the umbrella of CIDP, including anti-MAG, MMN, CISP, or autoimmune neuropathies. And remember that screening for nodal and paranodal antibodies should be done in patients with suspected CIDP and atypical features. And screening for monoclonal proteins should be done in all suspected CIDP cases. So thank you so much. Share your feedback, claim your credits. Thank you. All right, so Dr. Dubé actually won't be able to present in person today, but we have his talk recorded, so I hope you enjoy the talk. Just a reminder for the audience, Dr. Dubé is an associate professor in neurology and laboratory medicine and pathology at Mayo Clinic. He's the co-director of Mayo Clinic Neuroimmunology Laboratory. His research focus in peripheral and central autoimmune neurological conditions. This includes search for novel biomarkers for these diseases. He has played an important role in the discovery of multiple antibody biomarkers, including CELCH1, LUZP4, IgG, SCORE2 IgG, and KAVIN4. So I'll leave you guys with his talk. Thank you for inviting me to present on this topic of antibody testing in peripheral neuropathies. These are some of my disclosures. We'll briefly touch on some of the antibodies that we have worked on or helped discover. I'm not gonna delve too much into clinical trials or immunotherapies in this particular talk. The focus of the talk is gonna be reviewing the clinical and electrodiagnostic features of seropositive neuropathies. And we'll also talk about diagnostic testing and specificities of certain antibodies associated with neuropathies. What things do we need to take care of when we are doing antibody testing or developing clinical assays? So we'll start by talking about a case that we had encountered in our inpatient practice a 66-year-old lady with metastatic mucosal cancer who received checkpoint inhibitors. Within one week of receiving these immune checkpoint inhibitors, she started developing numbness involving her hands along with dizziness. Went on to develop significant gait instability. MRIs were done, which were unremarkable. Symptoms continued to progress. And along with this peripheral neuropathy-like presentation also developed dysautonomia in the form of gastroparesis. EMG was consistent with sensory ganglionopathy as you can connect the gastroparesis angle. There was sort of not just the ganglionopathy affecting the hands and the feet, but there was sort of an autonomic component or autonomic ganglionopathy as well. Antibody testing was sent, which came back positive for ANA1 or anti-HU antibodies. Patient was started on high doses of steroids, continued to remain refractory, and then subsequently was initiated on cyclophosphamide. Unfortunately, this case, despite the cyclophosphamide, had a continued disease progression, especially the gastroparesis or GI dysmotility remained unresolved and then subsequently led to colonic perforation, sepsis, and patient became extremely sick and the patient's family elected to pursue palliative care and patient passed away. This is one of the few cases that I've come across lately of post-immune checkpoint inhibitor, perineoplastic autoimmunity. In many of these cases, if you ask the patients questions carefully, even before giving immune checkpoint inhibitors, sometimes they can report some early signs of neuropathy, neuronopathy, which can help prevent administration of these immune checkpoint inhibitors or could make it to help you talk to the oncologist about alternative therapies in these cases. These are the cases where testing for antibodies upfront before administering checkpoint inhibitors might be the way to go. And sensitive neuropathy is a classic neuropathy associated with perineoplastic syndromes. This entity has been around for a long, long time, was one of the first phenotypes associated with perineoplastic autoimmunity described by Derek Denny Brown. A lot of pathology studies have been done. This is an image from Dr. Amato's New England Journal Review article where he demonstrates infiltration of T lymphocytes in the DRG causing destruction. Oftentimes there is loss of neurons and changes in the dorsal column as well. So some of these patients, when you have obtained MRI, you see subtlety to flare hyperintensity in the dorsal column along with classic ganglionopathy, neuropathy, EMG findings. This is tissue immunofluorescence or including sort of dorsal root ganglia from mice showing anti-HU or ANA1 staining in the dorsal root ganglion neurons. It's one of the most common phenotypes that we encounter as far in association with ANA1 or anti-HU autoantibodies. And as I said, with checkpoint inhibitors, we are starting to see a pattern where patients who have neuroendocrine tumors such as Merkel cell cancer or small cell lung cancer, in those cases, we see a higher frequency of the classic perineoplastic phenotypes when these patients develop ICI-related neuropathies, sensory ganglionopathy, axonal peritoneal neuropathy. Oftentimes these are the cases who have underlying high-risk perineoplastic antibodies like anti-HU, CRMP5, PCA2 or MAP1B. Whereas the patients which have non-neuroendocrine tumors with renal cell cancer, melanoma, and these patients develop neuropathies, the phenotypes tend to be more cranial neuropathy, GBS-like presentations. And many of these cases actually respond much more favorably to treatment but stopping in the checkpoint inhibitors and giving them high-dose steroids does bring about more significant improvement, as you can see, based on this particular graph compared to those with the classic perineoplastic phenotype. So that's what I counsel my oncology colleagues is those are the cases, the ones with the perineoplastic phenotype, I strongly recommend avoiding checkpoint inhibitor re-challenge. So once these patients have developed these symptoms, we try our best to avoid giving them any more checkpoint inhibitors. And as I said, in the neuroendocrine tumor cases, we have to carefully evaluate the patient even before giving them checkpoint inhibitors to make sure they don't have those early signs to suggest they are already at risk. In addition to anti-HU, another antibody which has been associated with ganglionopathy is amfephysin. First described in association with perineoplastic stiff person syndrome, but now we know about 40 to 80% of cases actually have, I'm sorry, 40 to 60% of cases have neuropathy with sensory neuronopathy being one of the more common presenting phenotypes. The other phenotypes associated with amfephysin include perineoplastic polaritic neuropathy with exonal involvement. So I'll talk about another case. This case does not have amfephysin, but has a different antibody. Another case we presented to our hospital with history of significant smoking for many, many years, along with pain, asymmetric lower extremity weakness, but in addition to the lower extremity weakness, these protuberances involving his belly because of laxity or weakness of the abdominal wall. Patient was evaluated, underwent nerve biopsy, which showed lymphocytic cuffing and significant inflammation and subsequently the antibody panel came back positive for CRIM5. Given the CRIM5 positivity, the exonal polaritic neuropathy phenotype, a PET scan was performed, which showed a parietal lymph node sort of lit up, suggesting underlying malignancy, which on biopsy confirmed mixed small cell and non-small cell tumor. So CRIM5 polaritic neuropathy or CRIM5 neuropathy is one of the most common presentation associated with this perineoplastic antibody. And when we think about this syndrome or this antibody, most of these patients are not only positive by western blot, but also positive on tissue monofluorescence assay. So usually these are strongly positive cases with confirmation on two independent assays. In addition to exonal polaritic neuropathy phenotype, similar to our patient with painful lower, asymmetric lower extremity, sometimes thoracic, myotomal, dermatomal involvement, these patients can also have the ganglionopathy presentation similar to case one, where it's mostly sensitive predominant presentation, but that's less frequent compared to the polaritic neuropathy phenotype. Compared to ANA1, not only the ganglionopathy frequency is lower, the amount of pain with CRIM5 seems to be somewhat higher. Also the extent of dysautonomia with CRIM5 seems to be less, even though still up to one third of cases have evidence of dysautonomia. These are some thermoregulatory sweat test images showing patchy sweating loss, so just a diffuse multifocal patchy involvement, potentially some sort of polaritic neuropathy phenotype, as you can see in the figure down here. And then nerve biopsy, similar to our second case, there's lymphocytic cuffing, mostly lymphocytic infiltration in these cases. Another patient now moving on from sensitive dominant or sensory motor is only polaritic neuropathy to motor neuropathy. So these are cases who come to our clinic for second opinion for ALS or ALS with some other atypical features. This was a lady who was seen by one of my colleagues, Brian Crum, and then subsequently I got involved in the case as well. She had a history of some breathing difficulties more than two years prior to the presentation to our neuromuscular clinic. This was evaluated as she was found to have vocal cord immobility, subsequently underwent tracheostomy. In addition to these breathing difficulties, She also had bizarre dream enactment behavior and this progressive weakness involving her arms as well as the neck. No bulbar issues, but examination showed asymmetric upper extremity predominant weakness and some fasciculations with relatively preserved reflexes leading to that initial concern for motor neuron disease. And the neurogenic changes were also detected on EMG showing Fibs and Fasix raising concern for ALS meetings, potentially possible LS corneal criteria as well. But that dream enactment behavior story as well as the vocal cord immobility stories sort of raised red flags leading to serum and CSF antibody testing and which came back positive for Eglon 5. Since then, a few additional cases have been seen by neuromuscular clinic as well as our autoimmunology clinic, all of whom were referred for question of ALS, but all had features suggestive of more typical Eglon 5 autoimmunity. So again, REM behavioral disorder, early onset vocal cord dysfunction before the motor neuropathy becomes evident, and in some patients with sort of CNS manifestations with involuntary movements such as chorea, all being potential red flags to suggest this is not garden variety ALS. And there might be something more to the story. Others, including sort of colleagues from Europe, have reported patients with Eglon 5 autoimmunity with motor neuron disease presentation. And now, motor neuropathy or motor neuron involvement has also been described in pathological studies where Eglon 5 cases have power depositions potentially secondary to the initial autoimmunity in the motor neurons of some of these cases. Another motor neuropathy, which we sometimes encounter in our clinic, are in the setting of perineoplastic autoimmunity. So these are patients with very unique flail arm syndrome-like presentation. Nearly all of them have an underlying testicular cancer or have evidence of burnt-out germ cell tumor. This is one of the patients who had brain stem syndrome along with this bilateral upper extrope was required by one of the significant extreme. And as Dr. Eggers asks the patient, no anti-gravity strength, the patient is more relatively intact. You can see he's extremely weak. Approximately, there are some other cases with similar phenotype. And among these cases, two of the three had underlying testicular cancer in this image. And all of the patients were positive for an antibody called as leucine zipper 4, but some also having coexisting Calc 11 along with leucine zipper 4. So this is another sort of group of antibodies we should be concerned about when we are seeing patients with rapidly progressive motor neuropathy. So these are not your typical bibrachial ALS cases, which have a relatively slow progression over a few years. These are compared to the bibrachial ALS, faster progression, and often have a multifocal syndrome with some brain stem involvement as well to suggest something else is going on. Another patient seen in our outpatient neurology clinic who was referred to us for this question of refractory CIDP, or finally was suspected to have refractory CIDP. Initially, multiple other diagnoses were considered during his diagnostic journey. November 2017, bilateral hand numbness, was suspected to have carpal tunnel syndrome, underwent release, no improvement. Then the symptoms spread to involve his feet. He started noticing some gait imbalance. Mostly ankles kept turning as he walked. Started to, over time, develop autonomic dysfunction in the form of erectile dysfunction. And then CNS symptoms with speed changes along with some gait, along with the gait changes as well. Subsequently developed tremors. By the time he was examined at our center, he had distal more than proximal weakness, which was symmetric, had significant sensitivity ataxia, tremors, as well as the dysarthria I mentioned, which had already started before the examination. No conduction studies were performed, which showed evidence of demyelination, but no clear conduction block or significant temporal dispersion. And given the nerve conduction studies, which were having demyelinating features even at the outside facility, a concern for CIDP was raised, or refractory CIDP. And when the patient presented to us, we utilized some of the, some of the serum sent to us in a development assay, which was being developed at this, that stage of a live cell-based assay, and confirmed that the patient had neurofascian 155 antibodies. Neurofascian 155 IgG4 is one of the most common autoimmune neuropathy biomarkers we are encountering in our clinical practice. The frequency of these antibodies varies based on sort of where the patient is from. In European cohorts, the frequency has ranged from 1 to 8 percent, sort of falling in that 68 percent mark in patients suspected to have CIDP. Similar numbers have been reported by us evaluating our tertiary care hospital CIDP-like presentation or GBS-like presentation cohorts. And then the numbers seem to be quite, quite higher in patients from Japan or other East Asian countries, up to 20 percent in patients who are suspected to have CIDP. One of the possible sort of hypotheses that could potentially influence these frequencies is the HLA association, with HLA-DRB1 15 being much more common in Asian populations, which is strongly associated with neurofascian 155 IgG4. The majority of patients tend to be in their third or fourth decade. So some of these cases are somewhat younger than some of our other typical CIDP cases. And again, as demonstrated by the case we were talking about, they have significant sensitive ataxia presence or tremors, lack of response to IVIG, which all should make you concerned that this might be an autoimmune neuropathy case. In addition to some of these more classic features, which also includes marked enlargement of nerves and nerve roots on MRIs, some of the other subtle features that we identified on our analysis of a Mayo Clinic cohort were increased frequency of prenal neuropathies, some patients having evidence of papillodema, and then autonomic dysfunction, similar to our patient who presented erectile dysfunction. Other forms of autonomic dysfunction have also been reported. This entity has also been described in pediatrics. So one or two cases have been published so far. We recently went back and looked at our neuromanology lab database and identified nearly a dozen cases with pediatric onset autoimmune neuropathies or neurofascial autoimmune 155 autoimmune neuropathies. Interestingly, more commonly, the pediatric cases are suspected to have GBS that might be due to a more aggressive upfront disease progression, but the progression continues even beyond eight weeks. So technically, they won't meet the GBS criteria. Other features which were different compared to adults was the frequency of sensory ataxia was lower in pediatrics, but some of the other electrophysiologic MRI and CSF features were very similar to the adults. They are refracted IVIG, similar to the adult population, and they respond very well to ataxia, especially if initiated early in the disease course. This is a nerve biopsy from one of the pediatric neurofascial autoimmune 155 patients showing segmental demyelination, potentially, which is a sequel of initial paranodal splaying and paranodal injury from the antibody deposition. In addition to that, there's evidence of significant subperineural edema in this case as well. So neurofascial 155 IgG4 is a pathogenic antibody. Passive transfer experiment is done by some of the European groups have demonstrated direct pathogenicity of this antibody. This is an animal model of neurofascial 155 IgG4, where on the right side, we have an animal infused relatively continuously with neurofascial 155 IgG4, and this is the control side. You can clearly see that the neurofascial 155 administered mouse has hindering weakness, is unable to... And we think this happens because the neurofascial 155 antibodies go and bind to the neurofascial 155 protein expressed at the level of the paranodes and prevents its interaction with contact in Casper 1 complex, potentially leading to degradation of this paranode, subsequently leading to accumulation of fluids, inflammation at the level of the paranode, which over time can contribute to secondary segmental demyelination, as we saw in the pathology of that pediatric case, which is similar to what we've seen in adults as well. In terms of diagnostic features, I take into account when I'm thinking about autoimmune neuropathies, there are some things which are very common across the group. So distal predominant presentation, significant sensory ataxia, lack of response to IVIG. These are the things which I see commonly across the groups. But there are other features which can help us distinguish, is it a neurofascial case, is it a contactant case, even if it's a Casper 1 or a Casper 1 contactant complex case. Neurofascial patients tend to have sort of the tremor, dysarthria features in some reports of central and peripheral demyelination have also been reported, whereas contactant cases tend to have membranous glomerulonephropathy in addition to the autoimmune neuropathy presentation. So the Casper 1 cases that I've encountered have sort of asymmetric onset at times, but significant pain and sensory symptoms along with the other autoimmune neuropathy features. And there's an entity of anti-paneurofascial which has been described where antibodies are not only to neurofascial 155, but patients have antibodies also to neurofascial 140, 186. And these patients tend to have a much more severe presentation up front, sometimes requiring respiratory support with significant dysautonomia as well. The reason we check for IgG4 and not just pan-IgG against neurofascial is because some of the neurofascial 155 pan-IgG cases that didn't quite encounter in clinical practice looked like typical CIDP or did not have a specific autoimmune neuropathy phenotype. So this is one of the cases that was seen by me and Jim in our peripheral nerve clinic over a period of years, had a very typical presentation of proximal progressive weakness, which responded to some extent to IVIG following identification of this neurofascial pan-IgG and suspicion for autoimmune neuropathy. Rituximab was also tried, but the patient never showed any significant response. The nerve biopsy showed evidence of onion bulbs, as you can see here, which is typical for CIDP and not something which we see in autoimmune neuropathies. And the other presentation that we've come across now are also diverse with sort of multi-predominant poliogenic neuropathy, some LEN-dependent neuropathies, not something which we typically think about in terms of autoimmune neuropathy. Some patients also have sort of, autoimmune patients have small fiber involvement, with Casper-2 being one of the common antibodies, which can have asymmetric or non-LEN-dependent small fiber neuropathy or pain syndromes. These are some of the thermoregulatory sweat tests from our Casper-2 patients. Usually, these Casper-2 patients have high titers of Casper-2 with positivity at 1 to 100, and that's what this sort of, this is a typical CBA from a true positive case. Some of these Casper-2 patients can also have evidence of peripheral nerve hyperexcitability, as you can see in this video. This is a patient presented to us with LAS, evidence of muscle, when you consistently know mobility is one particular syndrome that we should consider, but the cases can also have a muscle origin. So, there's a, there's an entity called as immune times, similar to, once you see enough of these cases, you can display muscle disease. These patients have four antibodies, which we suspect are pathogenic, given the depletion of Cavin-4 from the muscle of these patients. I think one even relatively easy trick to distinguish, if you can't tell just by inspection, is checking for muscle bounding, which is another feature which we, which is associated with immediately muscle disease. And then, if you do an EMG in the nerve hyperexcitability cases, you'll see evidence of neuromyotonia, myokymia, whereas many of these muscle cases don't have an EMG correlate. So, dividing neuropathies based on phenotypes, these are sort of, this is a list of the antibodies that we should consider when we think about different neuropathy phenotypes. Ganglionopathy, example being ANA1, Ampifycin, CRIM5, demyelinating pulrodiculoneuropathy is where we need to think about all our autoimmune neuropathy antibodies. And even as physicians or neurologists, we have to have some idea about what techniques are being utilized for testing of these antibodies, especially as they're used become more and more common in our clinical practice. And the reason why it is important is what we're dealing with are extremely rare conditions. And if the conditions have very low disease prevalence, then a test which has 95% specificity versus 99% specificity, there's a significant chance of false positivity, even though it's only a 5% difference. So, we need to focus on tests with extremely high clinical specificity as far as testing and development of tests for these rare disorders are concerned. Good examples of such situations are doing just immunodots or perineoplastic antibodies can generate as high as 80% false positive results. So, therefore, for antibodies such as ANA1 or Ampifycin, our lab screens on tissue immunofluorescence assay. Those are thin sections of mouse brain where patient's serum or CSF is added and we look for patterns. And then if we see the right pattern, then we reflex off to immunodots or in some cases, western blots for confirmation. Then for some pathogenic antibodies which bind to cell surface antigens such as neurofascia, I think the antibody binding can be confirmationally dependent. So, using linear epitopes such as ELISA can sometimes generate not only false negative, but some cases false positive results as well. And this is something which we've seen comparing neurofascia 155 live flow-based assays to neurofascia 155 ELISA where we see quite a few false negatives as well as false positives. And then for certain antibodies, titers are relevant. A good example is alpha-3 ganglionic receptor antibody which is associated with autoimmune dysautonomia or autoimmune ganglionopathy where titers above 0.40 usually predict autonomic failure and to be associated with more severe disease and are truly suggestive of an autoimmune autonomic ganglionopathy. Lower titers can be seen non-specifically with wide variety of presentations, especially below 0.20 nanomoles per liter. The same thing occurs with MAG where that magic number that we're looking for where the specificity of detection of DADS phenotype is higher is the 10,000 BTU. And then there are certain antibodies where, at least in our experience, there's not a clear significant association with immune-mediated neuropathies, neither based on phenotype nor based on treatment response. And one of them is TSH-DSIGM, which we have sort of, at least in our practice, have produced utilizing this particular antibody in our evaluation of clinical care. So as we come towards the end of this talk, sort of some of the take-home points are, one, talked about the classic perineoplastic phenotypes, just sensory ganglionopathy, not only in the setting of perineoplastic syndrome, but some which occur in the setting of immune checkpoint inhibitor use, causing ICI-related neuropathies, especially those in association with neuroendocrine tumor, which can resemble perineoplastic syndrome, not only in terms of phenotype, but also in terms of outcome. We talked about axonal polar adicular neuropathy phenotypes with lymphocytic cuffing on nerve biopsies associated with crim-5 autoimmunity. Some motor neuropathy presentations, some with aglon-5 with REM behavioral disorder, or those with Flay-Lam syndrome in association with leucine zipper 4 or CELCH11 in patients with testicular cancer. Autoimmune demyelinating neuropathies, autoimmune neuropathies in association with neurofascial Nrm55, looking for those red flags, such as tremors, ataxias, and contacting, looking for evidence of miminus glomeruloneuropathy. And then testing specifically for IgG4 and neurofascial Nrm55 IgG4 instead of pan-IgG, that helps refine identification of autoimmune neuropathy cases. And then in some cases, the antibodies can cause hyper excitability, especially Casper-2 muscle versus assays. Even as clinicians, we need to have some idea about what assays are being utilized for detection of these antibodies, what are the titers, what do the titers mean, especially for certain antibodies where high titers seem to be associated with high disease specificity. And then finally, certain antibodies like striational or TSH-TSH IgM, where the specific clinical specificity of these antibodies is somewhat limited. So with that, I would like to end my presentation, thank our Mayo Clinic Neuromanology Lab, some of my sort of people who work with me on these research projects, as well as our Peripheral Nerve Lab. Thank you. So thank you to Dr. Dubey for his talk. The next speaker is Dr. Suri Raja. She's a member of the faculty in the Neuromuscular Division at Duke University Medical Center, and she's a member of the faculty in the Neuromuscular Division at Duke University Medical Center. She's heavily involved in clinical research implementation through her roles as faculty director of the Duke Early Phase Research Unit and co-medical director of the Duke Clinical Research. She has experience in clinical trials and neuromuscular outcomes research. She received a clinical research training fellowship grant in autoimmune neuromuscular disorders sponsored by the ANEM in 2017, and a clinician scientist development award sponsored by the MGFA and American Brain Foundation in 2019. Her research interests include autoimmune neuromuscular disorders and development of clinically relevant methodologies to assess therapeutic responses. So welcome to the stage Dr. Surya Raja. So good morning everybody. I will be quick that way I don't keep you separated from your lunch for too long. So today we're gonna have kind of a slightly different perspective on things. You know as we have learned there's a number of different types of autoimmune neuropathies and the challenge in all of them has long been to develop therapeutics that will actually be effective and be more strategic. So what we will do first is I will let you know that I don't actually have any disclosures that relate to neuropathy, they all relate to myasthenia. And so if we think about this, what is the current landscape of therapies for immune mediated neuropathies? We have our sort of traditional standby therapies of various immunoglobulins, plasma exchange, corticosteroids, but then there's also some newer therapies that are on the horizon. Particularly FCRN antagonism where there are numerous products that are either on the market or currently in development for immune mediated neuropathies. There are also specific therapies, monoclonals or other inhibitors that really are going to target lymphocytes and cell signaling. And then lastly the other area that is of increasing interest is actually complement inhibition because many of the pathogenic antibodies in immune mediated neuropathies do fix complement. As you heard earlier, we're talking about a very heterogeneous group of conditions and this is kind of demonstrating, this is a diagram sort of showing the variety, very similar to the one that Rossio showed earlier. And if you think about it, let's pull the nodopathies out of our typical CIDP category, but as you can see there's a lot of variety in the type of neuropathy based on phenotype as well as pathology. And so the challenge in this is that we're talking about a group of conditions where we may have 50 different antibodies that each have a slightly different configuration and that each will have a slightly different clinical phenotype. So then the question becomes, what are common mechanisms that we can target? And so to understand this, we have to think back to how exactly does the pathophysiology of immune mediated neuropathies occur? And there can be a number of different ways that they occur. In general, we are anticipating that you will have an autoreactive, you'll have an antigen that is ultimately going to trigger activation of a T cell and formation of antibodies. But at the same time, you're also going to have situations where this pro-inflammatory state actually causes destruction of the blood nerve barrier, which would then enable not only cytokines, chemokines, proteases, and also cellular components to enter the peripheral nerve compartment where they would typically not be expected to occur. And when these enter that system, that's when they start causing all kinds of damage. And there can be a number of different targets that can be affected. So if we think about this, essentially, you know, are we targeting the antibody? Are we targeting the production of complement? Are we targeting an antigen that's located on a Schwann cell? Are we targeting an axonal antigen? So to bring it in a little bit more closely to kind of look at the what actually might be happening at the level of the nodal region and the perinodal region, you know, we could have ganglicide antibodies that are binding to the Schwann cells. We could also have antibodies that are directly binding to epitopes on the axon. And the end result of all of these is that they trigger this immune activation that ultimately leads to destruction. And this is a process that is relatively conserved across many different types of immune-mediated neuropathy. In AMAN, you know, we're targeting, we have an antibody that is really targeting glycolipids and fixing complement. And so it's causing its damage at the axon. In AIDP, we're kind of attacking the Schwann cell. In CIDP, there's any number of different antigens. And then in multifocal motor neuropathy, we're talking more about something that's axonal. But the thing that all of these have in common, if you'll notice, is that in many cases, we're talking about IgG antibodies or we're talking about IgM antibodies. And all of those essentially have the ability to exert their effect through complement-mediated destruction. And so now, given this whole diversity of antibodies and clinical phenotypes, what are our therapeutic options that we actually have that we know are effective or that we need to be thinking about in more detail? And the first one is an oldie but a goodie, and that is immunoglobulin. You know, there's multiple different postulated mechanisms by which immunoglobulins serve their function. I have a diagram here that kind of shows some of the different effector mechanisms for IVIG, but this would also be applicable to the subcutaneous formulation. And this is an area of intensive research and an area where there's multiple products that are available, as well as multiple products that are currently in development. And the factors that really differentiate all of these have to do with how they are produced, their concentration in terms of the volume for administration, the osmolality, the different sodium and sugar content. Some of them are impacted by pH and then IgA content. And so there's a number of studies that are actually ongoing to look at different formulations of immunoglobulin for both subcutaneous as well as IV administration. There's also ongoing studies comparing IV versus subcutaneous. So I've posted here some of the active studies that are available on clinicaltrials.gov. And the whole idea here is you're trying to find out which...you want a level of efficacy, but at the same time you want to reduce potential for side effects. And so what you are really trying to do is craft a product that will maybe be more specific for a certain population. For example, it's been found that formulations that have a high sodium concentration can be associated with increased risk of thromboembolism. Likewise, those formulations that have high sugar contents can be associated with renal insufficiency or even renal failure, which we know is a big challenge with immunoglobulins in general and with the population that may be receiving them. So this is an area that's very active. And now we're going to move into areas that are more in development, if you will. So as a starter, we're talking about FCRN antagonism. So this is a recycling mechanism that essentially will result in destruction or preservation of immunoglobulin in circulation. And this is specific for IgG. Thus, you would not expect this to actually be as effective for a neuropathy that's mediated by IgG, which is an important consideration. And so the idea here is that basically you're promoting the degradation of IgG and removing it from circulation. So you're functioning in a way that's very similar to immunoglobulin, to immunoglobulins, or even to plasma exchange, which we know historically are effective. So in terms of what's actually available, what's out there, we're kind of in an exciting period for this particular mechanism. We do have one approved therapy for use in immunomediated neuropathies, particularly in CIDP, which is F-gartigiamod in its subcutaneous formulation. The study for rosinolixizumab assessing its effect in CIDP is completed, and there are some results available. And then there's ongoing trials looking at two other FCRN antagonists, nipocalumab and batoclumab. So I expect that we will ultimately see a lot of benefit in this area. And the nice part is that these are mechanisms that are relatively nonspecific. And the key thing that really will differentiate all of these is going to be partly their dosing regimen. Some of them will be cyclic. Others are based on an induction and maintenance protocol. The route of administration, we're seeing intravenous versus subcutaneous. One versus the other may result in easier access for patients and easier administration. And then the actual volume of medication that's needed for administration. Are we talking about something that's going to be a large volume infusion? Are we talking about a small volume infusion? Are we talking about something that can be done via an autoinjector? So these will all be factors that will likely long-term figure into the calculations and into the discussion for which agent is going to be most effective. So now we're going to kind of move into some more specific areas, but also some areas where there's still a lot of ongoing research. So one of the kind of hot areas right now in immune mediated neuropathies and really in immunology in general is the idea of B cell depletion through monoclonal antibodies that really target CD19 or CD20. And these have been shown to be particularly effective for the immune mediated neuropathies in which you have perinodal and nodal antigens that have an IgG4 construct. And so if we think about this, you know, what is the advantage of CD19 over CD20 as there are products currently available on the market that target both groups? So for CD20, you know, we're targeting a slightly narrower range of B cells. And most importantly, with CD19, we get the added benefit of being able to target both the plasmablasts and the plasma cells. So these are the antibodies that are, these are the cells that are actually going to be secreting the pathogenic antibodies. And so based on this mechanism, rituximab, which is an anti-CD20 monoclonal, has been shown, is used quite often in treatment of immune mediated neuropathies and particularly in ones that are mediated by IgG4. There are trials that are currently underway, and there's a lot of debate about what is the appropriate dosing regimen. You know, in some cases, it uses more of a, some studies will utilize more of an oncologic regimen, which would be a 375 milligrams per meter squared body surface area times four. Others prefer the slightly shorter regimen, which would be a thousand milligrams Q14 days, which in my experience is what patients generally prefer because it results in fewer visits to the clinic. And then the other question ultimately is when do you re-dose? How durable is the effect of the B-cell depletion? And so the other areas where I have not yet seen studies coming through, or at least not that are publicly available, but that I have a significant interest in, are for other agents that are really going to target these mechanisms. One would be ocrelizumab, which is the humanized version of rituximab. Rituximab, remember, is a chimeric antibody, so there's potential for significant hypersensitivity reactions. And then inobilizumab, which is an anti-CD19, which may give the effect of actually being able to long-term deplete a larger population of B-cells. And one other thing that I would kind of put out there to think about is that given the relationship between demyelination of the central nervous system and demyelination of the peripheral nervous system, there's actually a push to assess drugs that are effective in multiple sclerosis in immunomediated neuropathies, particularly in CIDP, because of that similar demyelinating mechanism and because of the same separation of the blood nerve or the blood-brain barrier. So again, this slide, what I am attempting to demonstrate is that we have gotten very, very good at engineering our antibodies to be extremely specific. And the advantage here is that given the wealth of different antibodies that can be associated with immunomediated neuropathies, we may actually have the ability to develop an antibody that could be specific for one flavor of immunomediated neuropathy. Likewise, we may also have the ability to develop antibodies that will help tag cells that are producing pathogenic antibodies for destruction. So, thoughts, things to think about. As a next step, you know, let's think about a lot of the damage is mediated by T-cells. So is there a way to reduce that T-cell response or to at least modulate it? And so this is a platform technology that is actually being developed right now for use that has been found to be effective in autoimmune diabetes. In this particular case, we have bispecific antibodies that are targeting both T-cells and B-cells. And what happens is you observe an early phase of effect and a late phase of effect. In the early phases, you're talking about more interactions directly with removal of the antibody with degradation of the antibody through either antigenic modulation, through induction of cellular apoptosis, or cellular energy. Long term, after the antibody has essentially been depleted, you're looking at a more modulatory effect that may involve modulation of the regulatory T-cell response with the ultimate goal of reducing the number of overall autoreactive T-cells and the number of pro-inflammatory cytokines. And the benefit here is that you may be able to selectively reduce the autoimmunity without impairing the overall immune response because of the way things are targeted. Other kind of therapy that's potentially attractive as a target would be inhibition of BAF. BAF is B-cell activating factor of the tumor necrosis factor family. And this is a key molecule that you need for maturation of B-cells following exposure to circulating antigens. And there's also some evidence that BAF can activate T-cells directly. And so the idea here is that BAF is kind of working as an on-off switch, if you will. It can either promote at a physiologic concentration, it can promote death, or it can promote life. And depending on what the immune balance is, you can push the selection towards removal of autoreactive cells versus preservation. And so by what has been found is that in many biopsies and also in analysis of sera from patients with immune-mediated neuropathies, they have been found to have high concentrations of BAF. So by reducing the BAF concentration through use of an antibody or antagonist targeting BAF, could you then shift things back into a more physiological concentration, which will then shift the cell towards death. So again, another mechanism for modulating the immune system. Lastly, we have the complement system. Now recall that, again, we have multiple antibody types that fix complement. We have our IgG1s, we have our IgG3s, and we have our IgMs, all of which are involved in the pathogenesis of immune-mediated neuropathies. And so in biopsies there has been significant demonstration of complement deposition and MAC formation, which ultimately leads to demyelination or axonal damage. And so if we think about this even more mechanistically, we have our autoreactive cells, antibodies, and cytokines kind of entering the peripheral nervous system compartment and then wreaking their havoc both directly and indirectly by calling other cells, macrophages, to do their destructive duty, if you will. And so this is attractive as a target because it would be a mechanism that would actually target multiple different types of neuropathy with one treatment. So in a sense, you're looking back to having something that might be a one-size-fits-all paradigm. And so within this realm, there are a number of targets that are currently under investigation. If we think back to our complement pathways, we have our classical pathway, we have our elected binding pathway, and then we have our alternative pathway. Currently under investigation is a C1S inhibitor, which is going to function only in the classical pathway, really a PruBart, which is currently under investigation in two clinical trials, one versus placebo and one versus IVIG. The other kind of hot target where we have products that are already available on the market would be C5 inhibitors, which are going to target here at the end as a common target. And so this is where we have our Eculizumab, our Raculizumab, our Zylucoplan. I was not able to specifically identify any Phase III studies with these agents. However, I suspect that they may still be undergoing proof-of-concept studies. And so with that, I will open it up for any questions, and feel free to reach out if there are any other concerns. If anyone has any questions, it's your time to do that. Yeah, so the question is about how to objectively quantify response to therapy in CIDP. Well the guidelines have several, you know, several tools to actually assess that in CAD or at ROS and all that. So you can use that in the clinic. I think like I personally find that a little bit, you know, time consuming and so what I tend to do honestly or what I would recommend is that people actually do a good exam. And those, you can use those tools as well to measure it. But if you don't have time in your clinic and you want to objectify, I would suggest, you know, to do muscle group examination, do your scale for motor strength and actually every three or six months repeat that as the patient is getting treated. Again the guidelines are a little bit more strict as far as how to measure that. But I realize that people might not have the time in the clinic to do it. And also like you can follow certain functions of the patient like the gait, functionality, daily activities, things like that. You can do either or. I personally in my clinic sometimes I don't have the time to do all the scales. So the question relates to why is the classical pathway under investigation versus the common pathway for C5? So the main idea here is that if you can selectively reduce activity partially, then you may have benefits for reducing the overall effect. C5 inhibition will carry a much higher risk of infection because you've essentially knocked out all of the potential innate immunity pathways as well. Whereas if you've only targeted the classical pathway, you are targeting one. You still have a functioning lectin pathway and a functioning alternative pathway. To that same end, there's also products I didn't mention that are in development that will target specifically the alternative pathway, leaving the other two intact. So it's a way to balance the benefit of the drug with the potential risk for infection. Thank you. You're welcome. Yes. About which one? Oh, CIS+. Oh. The variant of CIS+. Yeah. So, patients with CIS+, actually, what they have on nerve conduction studies is very mild findings. And, typically, you know, they may have a little reduced amplitudes, a little bit of slowing of parameters of nerve conduction, but, by definition, you know, their electrophysiological features are extremely mild, very mild. It's not like typical CIDP, when you have multiple nerves involved with multiple different features. They still latency prolongation, conduction velocity slowing, and, you know, prolongation. They have very, very minimal nerve conduction studies abnormalities. I do remember the paper that we published on CIS+. The majority of patients had just, you know, reduced or absent amplitudes in the lower limbs, actually. There were very few that had abnormalities in upper limbs. And they were extremely mild. Right, right, so, right, I, yeah, that's a really good question. You know, in my mind, and again, nerve conduction studies might not help you as much unless you see some slowing, maybe, perhaps. Correct, yeah, yeah, yeah, but if they are not completely gone. But I agree, I mean, it's extremely difficult to distinguish, you know, severe sensory neuropathy, sensory CIDP from sensory ganglionopathy. I tend to think about sensory ganglionopathies are being very severe, with sensory loss being very extensive, so extending up to thighs, up to pretty much above the elbows, very profound sensory loss, and very profound ataxia. Patients with sensory ganglionopathy are extremely ataxic, limbs, truncal, gait ataxia, and they have very extensive and profound sensory loss, so it's almost like more severe, their clinical presentation is more severe. Actually, you know, there's, sensory ganglionopathies may be associated with other syndromes like Sjogren's or peroneoplastic, and a one and a two, so sometimes if you look for SSA, SSB, you do lipopsis, you do peroneoplastic panels, and you find those markers, maybe that supports more a sensory ganglionopathy. I have to say also that in my experience, sensory ganglionopathies respond, regardless really of what is causing them, respond very poorly to treatment, particularly if their temporal course is very chronic, maybe the patients have been misdiagnosed or underdiagnosed for some time, they don't tend to respond very well, and I wonder if it's because the lesion is in the dorsal root ganglia, the drugs have a harder time getting there, yeah, it's a very difficult thing to treat. Perhaps sensory CLEP patients respond better to immunotherapies as well, at least in my experience. I have a question for Dr. Boudet, is he online? No he's not, unfortunately. He just recently had a baby, so he's doing other duties. to answer your question, and really the question comes down to how do you assess a patient and how do you determine therapeutic options for a patient who's not responding to rituximab? And I think it's really a bit up for debate. In some places you can look at B-cell suppression, but I have found that it doesn't really correlate very well. And then doing further genetic characterization is often prohibited actually by cost and availability. And so the new era of therapies, particularly agents like inibalizumab or even the FCRN antagonists may have their role in some of these patients who are specifically refractory to rituximab. I have given rituximab as frequently as every three months. Same. I was going to say the same thing. For patients who are not responding to a Q6 month regimen, the other consideration would be to consider the dose. Which regimen are you using? Are you using a regimen that is based on body surface area or are you using a dose-based regimen? What I have generally found is that the four-week regimens overall administer less rituximab than the standard regimen of one gram every 14 days. Pardon? Exactly. And then I think the other thing about, you know, regarding your question is also like is the lack of response, like no response whatsoever with the dosing or is it like a weighing off, right? Because I had patients that did respond, they did get better, but the rituximab wore off before the six months. And so that's when you'd give more often. It might be difficult for insurance companies, you know, to approve like a, you know, more restrictive regimen. But if you make a good point and, you know, you have to kind of work with them. But I've been lucky on getting patients. I wish Dr. Dubé was here. I think what I remember in terms of repeating testing is that if your suspicion of an underlying malignancy is high, and the patient has risk factors, smoking, if the patient has weight loss, certain other systemic manifestations that put that patient at high risk of being a potential cancer patient, my understanding is that screening at least every six months, it's a reasonable thing to do. Not only repeating peroneoplastic panel, but perhaps repeating a whole body CT, or a testicular ultrasound, or some other ultrasound, depending on whether it's a male or a female. But every six months. The question relates to results from the ADHEAR trial in CIDP looking at F-cartigemod and the effect on patients who are completely treatment-naive versus those who have been exposed to steroids. And I think ultimately this comes down to the fact that the disease itself is very clinically heterogeneous. When you have the, if you have a patient who's already receiving corticosteroids, they may already have some modulation of the immune response. They may have already reduced some of the T-cell activity. Unless you're not perpetuating the cycle, whereas in a patient who is naive to any kind of therapy, you are essentially starting from scratch. I think we are going to have to use it more in clinical practice to really see how it's going to pan out. I mean, the story, at least if we think to Myasthenia gravis, is that early use has been shown to be more effective than adding it in. However, in some cases, you also have a rebound effect when you introduce an FCR antagonist without having an immune modulator on board. All right, thank you so much, everyone. Enjoy the meeting.

Chronic Inflammatory Demyelinating Polyneuropathy

cidp

immunomediated neuropathies

inflammatory demyelination

diagnostic challenges

biomarkers

typical and atypical variants

immune system

T-cells

macrophages

therapeutic approaches

FCRN antagonists

monoclonal antibodies

cidp

Chronic Inflammatory Demyelinating Polyneuropathy