Chronic Inflammatory Demyelinating Polyneuropathy Patients Research Articles

Trends in Outcome and Cost of Hospitalization in Chronic Inflammatory Demyelinating Polyneuropathy Patients Treated with IVIG, Versus Steroid or Other Treatments (2009-2013). A New York Statewide Planning and Research Cooperation System (SPARCS) Database Report (P2.270)

Trends in Outcome and Cost of Hospitalization in Chronic Inflammatory Demyelinating Polyneuropathy Patients Treated with IVIG, Versus Steroid or Other Treatments (2009-2013). A New York Statewide Planning and Research Cooperation System (SPARCS) Database Report (P2.270)

Contactin-1 IgG4 antibodies cause paranode dismantling and conduction defects.

Paranodal axoglial junctions formed by the association of contactin-1, contactin-associated protein 1, and neurofascin-155, play important functions in nerve impulse propagation along myelinated axons. Autoantibodies to contactin-1 and neurofascin-155 define chronic inflammatory demyelinating polyradiculoneuropathy subsets of patients with specific clinical features. These autoantibodies are mostly of the IgG4 isotype, but their pathogenicity has not been proven. Here, we investigated the mechanisms how IgG subclasses to contactin-1 affect conduction. We show that purified anti-contactin-1 IgG1 and IgG4 bind to paranodes. To determine whether these isotypes can pass the paranodal barrier, we incubated isolated sciatic nerves with the purified antibody or performed intraneural injections. We found that IgG4 diffused into the paranodal regions in vitro or after intraneural injections. IgG4 infiltration was slow and progressive. In 24 h, IgG4 accessed the paranode borders near the nodal lumen, and completely fill the paranodal segments by 3 days. By contrast, control IgG, anti-contactin-1 IgG1, or even anti-contactin-associated-protein-2 IgG4 did not pass the paranodal barrier. To determine whether chronic exposure to these antibodies is pathogenic, we passively transferred anti-contactin-1 IgG1 and IgG4 into Lewis rats immunized with P2 peptide. IgG4 to contactin-1, but not IgG1, induced progressive clinical deteriorations combined with gait ataxia. No demyelination, axonal degeneration, or immune infiltration were observed. Instead, these animals presented a selective loss of the paranodal specialization in motor neurons characterized by the disappearance of the contactin-associated protein 1/contactin-1/neurofascin-155 complex at paranodes. Paranode destruction did not affect nodal specialization, but resulted in a moderate node lengthening. The sensory nerves and dorsal root ganglion were not affected in these animals. Electrophysiological examination further supported these results and revealed strong nerve activity loss affecting predominantly small diameter or slow conducting motor axons. These deficits partly matched with those found in patients: proximal motor involvement, gait ataxia, and a demyelinating neuropathy that showed early axonal features. The animal model thus seemed to replicate the early deteriorations in these patients and pointed out that paranodal loss in mature fibres results in conduction defects, but not conduction slowing. Our findings indicate that IgG4 directed against contactin-1 are pathogenic and are reliable biomarkers of a specific subset of chronic inflammatory demyelinating polyneuropathy patients. These antibodies appear to loosen the paranodal barrier, thereby favouring antibody progression and causing paranodal collapse.

Novel Therapeutic Avenues for Chronic Inflammatory Demyelinating Polyneuropathy: The Difficulties of Disease Diversity

Novel Therapeutic Avenues for Chronic Inflammatory Demyelinating Polyneuropathy: The Difficulties of Disease Diversity

NADPH oxidase 2 (NOX2) enzyme activation in patients with chronic inflammatory demyelinating polyneuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immunomediated condition affecting the peripheral nervous system where probably macrophages are the primary effector cells for demyelination. Reactive oxygen species (ROS), catalyzed by the NOX family of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzymes, can induce peroxidation and are potentially injurious to myelin. Our aim was to assess the activity of NOX2, an isoform of NOX, in a series of CIDP patients and to analyze the effect of intravenous immunoglobulin (IVIg) on NOX2. Thirty CIDP patients treated with IVIg and 30 control subjects were enrolled. To evaluate NOX2 activity, neutrophil and monocyte oxidative burst was measured directly in fresh whole blood using the Phagoburst™ assay, a fluorescence-activated cell sorting method. The mean fluorescence intensity, emitted in response to different stimuli, leads to the production of ROS and corresponds to the percentage of oxidizing cells and their enzymatic activity. Mean fluorescence intensity values for granulocyte and monocyte burst in patients (mean 633.3, SD 191; mean 111.8, SD 28.5) were different from those measured in healthy controls (granulocytes, mean 436.6, SD 137.0, P = 0.0003; monocytes, mean 78.2, SD 17.3, P = 0.000001). Moreover, IVIg administration increased both granulocyte (P = 0.005) and monocyte (P = 0.0009) burst. Our findings demonstrate that oxidative burst is significantly increased in CIDP patients and that treatment with IVIg enhances oxidative values, thus representing a possible IVIg therapeutic effect linked to a regulatory effect of ROS. Based on this, the development of treatments targeting the specific activation of NOX may be beneficial in autoimmune disorders.

Sural sensory nerve conduction studies in demyelinating polyneuropathies

Objective To examine the pathophysiological state of sensory nerve conduction studies in different types of demyelinating polyneuropathies. Methods A total 16 Acute Inflammatory Demyelinating Polyneuropathy (AIDP), 12 Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) and 7 Hereditary Motor Sensory Neuropathy (HMSN) Type 1 patients were included prospectively. In all patients, bilateral sural nerves were examined with near nerve technique. The pathophysiological states of the sensory nerves were described as normal, demyelinating, axonal or neuropathic using ESTEEM criteria (Tankisi et al., 2005). Result In 16 AIDP patients, sural nerve was normal in 8, demyelinating in 2 and axonal in 6 while, in 12 CIDP patients sural nerve was normal in 4, demyelinating in 2, axonal in 5 and neuropathic in 1. In AIDP and CIDP patients with demyelinating sensory nerves, an atypical disease course with poor response to therapy was observed. In all 7 HMSN Type 1 patients, sural nerves were demyelinating. Conclusion In inflammatory demyelinating polyneuropathies sural nerve is mostly axonal, however demyelinating sensory sural nerves may indicate subtypes. Sensory nerves are always demyelinating in HSMN Type 1 which may help in differential diagnosis. Key message Sensory sural nerve conduction studies may contribute to differential diagnosis of inflammatory and hereditary polyneuropathies.

Chronic inflammatory demyelinating polyneuropathy: A case report

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a treatable autoimmune neuropathic condition, which characterize progressive and relapsing stages. Major clinical presentations are gradatory increasing sensory loss and weakness interrelated with loss of reflexes. Relapse can occur at any time for CIDP patients. Diagnosis is based on cerebrospinal fluid protein, electromyography, nerve conduction velocity (NCV) test, peripheral nerve biopsy and electron micrograph of peripheral nerve. Standard treatments for CIDP are corticosteroids, Intravenous Immune Globulin (IVIG), plasma exchange or plasmapheresis. Second line drugs commonly used are immunosuppressant and immune modulatory agents, there are usually chemotherapy drugs which should be only given in special circumstances by specialist in their use. A 55 year old female encountered in the department of neurology, old case of Guillain-Barre Syndrome (GBS) was treated with steroids, later developed CIDP and was on reduced dose of prednisolone. Now presented with complaints of numbness and difficulty in walking, diagnosed to have CIDP relapse. Started treatment with corticosteroid [Tab. Wysolone (prednisolone) 50mg 1-0-0] and immunosuppressant [Tab. Cellcept (mycophenolate mofetil) 500mg 1-0-1]. Patient had significant improvement in symptoms. This case of CIDP relapse is effectively treated with corticosteroid and immunosuppressant with tapering of steroid dose.

Characterization of IgG4 anti-neurofascin 155 antibody-positive polyneuropathy.

ObjectiveTo investigate anti-neurofascin 155 (NF155) antibody-positive chronic inflammatory demyelinating polyneuropathy (CIDP).MethodsSera from 50 consecutive CIDP patients diagnosed in our clinic, 32 patients with multiple sclerosis, 40 patients with other neuropathies including 26 with Guillain–Barré syndrome (GBS)/Fisher syndrome, and 30 healthy controls were measured for anti-NF antibodies by flow cytometry using HEK293 cell lines stably expressing human NF155 or NF186. Four additional CIDP patients with anti-NF155 antibodies referred from other clinics were enrolled for clinical characterization.ResultsThe positivity rate for anti-NF155 antibodies in CIDP patients was 18% (9/50), who all showed a predominance of IgG4 subclass. No other subjects were positive, except one GBS patient harboring IgG1 anti-NF155 antibodies. No anti-NF155 antibody carriers had anti-NF186 antibodies. Anti-NF155 antibody-positive CIDP patients had a significantly younger onset age, higher frequency of drop foot, gait disturbance, tremor and distal acquired demyelinating symmetric phenotype, greater cervical root diameter on magnetic resonance imaging neurography, higher cerebrospinal fluid protein levels, and longer distal and F-wave latencies than anti-NF155 antibody-negative patients. Marked symmetric hypertrophy of cervical and lumbosacral roots/plexuses was present in all anti-NF155 antibody-positive CIDP patients examined by neurography. Biopsied sural nerves from two patients with anti-NF155 antibodies demonstrated subperineurial edema and occasional paranodal demyelination, but no vasculitis, inflammatory cell infiltrates, or onion bulbs. Among anti-NF155 antibody-positive patients, treatment responders more frequently had daily oral corticosteroids and/or immunosuppressants in addition to intravenous immunoglobulins than nonresponders did.InterpretationAnti-NF155 antibodies occur in a subset of CIDP patients with distal-dominant involvement and symmetric nerve hypertrophy.

Chronic inflammatory demyelinating polyneuropathy (CIDP): change of serum IgG dimer levels during treatment with intravenous immunoglobulins.

BackgroundIntravenous immunoglobulin (IVIg) is an effective treatment in chronic inflammatory demyelinating polyneuropathy (CIDP). In most patients, the optimal IVIg dose and regime is unknown. Polyvalent immunoglobulin (Ig) G form idiotypic/anti-idiotypic antibody pairs in serum and IVIg preparations. We determined IgG dimer levels before and after IVIg treatment in CIDP patients with the aim to explore their utility to serve as a surrogate marker for treatment response.MethodsIgG was purified from serum of five controls without treatment, as well as from serum of 16 CIDP patients, two patients with Miller Fisher syndrome (MFS), and one patient with myasthenia gravis before and after treatment with IVIg. IgG dimer levels were determined by size exclusion chromatography. IgG dimer formation was correlated with clinical response to IVIg treatment in CIDP. Re-monomerized IgG dimer fractions were analyzed for immunoreactivity against peripheral nerve tissue.ResultsIgG dimer levels were significantly higher in post- compared to pre-IVIg infusion samples. Low post-treatment IgG dimer levels in CIDP patients were associated with clinical worsening during IVIg treatment. Re-monomerized IgG dimer fractions from CIDP patients showed immunoreactivity against peripheral nerve tissue, whereas similarly treated samples from MFS patients showed immunoreactivity against GQ1b.ConclusionAssessment of IgG dimer levels could be a novel approach to monitor CIDP patients during IVIg treatment, but further studies in larger cohorts are warranted to explore their utility to serve as a potential therapeutic biomarker for IVIg treatment response in CIDP.

Nerve Ultrasound and Electrophysiology for Therapy Monitoring in Chronic Inflammatory Demyelinating Polyneuropathy.

We evaluated prospectively nerve ultrasound and electrophysiology as monitoring methods of intravenous immunoglobulin (IVIG) therapy in chronic inflammatory demyelinating polyneuropathy (CIDP). Overall 15 healthy subjects and 11 CIDP patients undergoing IVIG therapy were recruited in the study. All patients underwent clinical, ultrasound, and electrophysiological evaluation at the time point of first onset of symptoms (<6 weeks of symptoms) and 4, 8, and 12 months after onset. The intranerve cross-sectional area (CSA) variability of each nerve, but not the CSA alone, correlated with the MRC Scale score during 12-month follow-up. On the other hand, none of the electrophysiological parameters correlated with the MRC Scale Score in each of the peripheral nerves. Interestingly, in ¾ of the CIDP patients, the resolution of the conduction block correlated with the improvement in the MRC Sum score. Nerve ultrasound and in particular the intranerve CSA variability seems to be a useful method in monitoring CIDP patients. Although the sample size is small, the intranerve CSA variability seems to be more promising than neurophysiology.

Autoantibodies against vinculin in patients with chronic inflammatory demyelinating polyneuropathy

To identify the target molecules of chronic inflammatory demyelinating polyneuropathy (CIDP), we used proteomic-based approach in the extracted proteins from porcine cauda equina. Two of 31 CIDP patients had markedly elevated serum autoantibodies against vinculin, a cell adhesion protein. Both of the patients with anti-vinculin antibodies had similar clinical manifestation, which are compatible with those of “typical” CIDP. Immunocytochemistry showed that vinculin was stained at the myelin sheath of the sciatic nerves by serum samples. Our results suggest that vinculin is a possible immunological target molecule in a subpopulation of typical CIDP patients.

Comparison of clinical, electrophysiological, sonographic and MRI features in CIDP

IntroductionWe investigated the applicability of nerve ultrasound and magnetic resonance imaging (MRI) in chronic inflammatory demyelinating polyneuropathy (CIDP). MethodsWe systematically examined several nerves with ultrasound and the lumbar roots and tibial nerve in the popliteal fossa of nine CIDP patients with MRI additionally to the nerve conduction studies. ResultsPatients with overall disability sum score (ODSS) 2–3 were characterised by normal fascicular structure in MRI and ultrasound. Patients with higher ODSS showed isolated enlarged fascicles and increased cross sectional area (CSA) of the peripheral nerves and of the diameter of the cauda equina and L5 root, whereas two of them showed atrophic fascicles in both imaging techniques. ConclusionsNerve ultrasound and MRI findings show the same morphological fascicle alterations in peripheral nerves in correlation to ODSS. Nerve ultrasound as an affordable tool, easy and quick to perform, could replace MRI in daily routine for monitoring peripheral nerve morphology.

Subcutaneous immunoglobulin in treating inflammatory neuromuscular disorders.

Intravenous immunoglobulin administration has long been used in the treatment of autoimmune neuromuscular disorders. Immunoglobulins may be administered by intramuscular, intravenous or subcutaneous routes. This is a report on the long-term clinical follow up of six patients with inflammatory neuromuscular disorders, that is, three chronic inflammatory demyelinating polyneuropathy (CIDP), one multifocal motor neuropathy (MMN), one inclusion body myositis (IBM) and one myasthenia gravis (MG), treated with subcutaneous immunoglobulins for a mean of 3.25 years. One MMN and two CIDP patients received a weekly dose of subcutaneous immunoglobulins equivalent to intravenous immunoglobulin. One CIDP patient received a 50% dose reduction, the IBM patient received a 30% reduction and the MG patient a 20% reduction. The lower dose chosen in the majority of patients was based not only on clinical effects, but also on studies of primary immunodeficiency syndromes. One patient with CIDP showed clinical fluctuation, which was successfully treated with an adaptation of the dose of subcutaneous immunoglobulins, while the remaining patients with neuromuscular disorders had a stable clinical course for 2 years. No serious side effects were observed. Our results suggest that subcutaneous immunoglobulins can be an attractive alternative therapy in autoimmune neuromuscular disorders.

Contactin 1 IgG4 associates to chronic inflammatory demyelinating polyneuropathy with sensory ataxia.

A Spanish group recently reported that four patients with chronic inflammatory demyelinating polyneuropathy carrying IgG4 autoantibodies against contactin 1 showed aggressive symptom onset and poor response to intravenous immunoglobulin. We aimed to describe the clinical and serological features of Japanese chronic inflammatory demyelinating polyneuropathy patients displaying the anti-contactin 1 antibodies. Thirteen of 533 (2.4%) patients with chronic inflammatory demyelinating polyneuropathy had anti-contactin 1 IgG4 whereas neither patients from disease or normal control subjects did (P = 0.02). Three of 13 (23%) patients showed subacute symptom onset, but all of the patients presented with sensory ataxia. Six of 10 (60%) anti-contactin 1 antibody-positive patients had poor response to intravenous immunoglobulin, whereas 8 of 11 (73%) antibody-positive patients had good response to corticosteroids. Anti-contactin 1 IgG4 antibodies are a possible biomarker to guide treatment option.

Chronic Inflammatory Demyelinating Polyneuropathy in Diabetes Patients

Diabetes mellitus (DM) is pandemic, and is the leading global cause of polyneuropathy, most commonly, a distal symmetric sensorimotor polyneuropathy (DSP). By contrast, chronic inflammatory demyelinating polyneuropathy (CIDP) is rare, and characterized mainly by symmetrical proximal and distal muscles weakness. There are currently 15 sets of criteria using a variable combination of clinical, electrophysiologic, laboratory, and biopsy features to identify CIDP, but it is unclear if these criteria are the same in patients with and without DM. Slowed conduction velocity, a feature of demyelination, is observed in patients with type 1 DM with poor control, and the clinical characteristics of these patients differ from those who have CIDP and DM, suggesting a different pathophysiology. Treatment response rates in CIDP patients, with and without DM, are as high as 80 %, and it is recommended that treatment be started early to prevent secondary axonal loss. However, patients with type 1 DM with CIDP are far less likely to be treated than CIDP patients who do not have DM. In patients with type 1 DM with polyneuropathy who have prominent weakness or demyelination in electrophysiologic studies, a diagnosis of CIDP and a trial of therapy should be considered.

Serum cytokine and chemokine profiles in patients with chronic inflammatory demyelinating polyneuropathy

To identify serum cytokine networks specific to chronic inflammatory demyelinating polyneuropathy (CIDP), serum samples of two subgroups (18 patients with typical CIDP and 12 patients with multifocal acquired demyelinating sensory and motor neuropathy [MADSAM]) were analyzed with multiplex magnetic bead-based cytokine assay. TNF-α, HGF, MIP-1β and IL-1β levels were significantly higher in total CIDP patients than in normal controls. Of these, HGF levels were elevated in typical CIDP patients, but not in MADSAM patients. Patients with high HGF levels showed good responses to steroid treatment. Different cytokine profiles among the CIDP subtypes presumably reflect differences in pathophysiology.

Reconstruction magnetic resonance neurography in chronic inflammatory demyelinating polyneuropathy.

To study distribution and patterns of nerve hypertrophy in chronic inflammatory demyelinating polyneuropathy (CIDP), magnetic resonance neurography with 3-dimensional reconstruction of short tau inversion recovery images was performed in 33 patients. This technique clearly showed longitudinal morphological changes from the cervical roots to the nerve trunks in the proximal arm. Nerve enlargement was detected in 88% of the patients. According to the clinical subtype of CIDP, typical CIDP patients showed symmetric and root-dominant hypertrophy, whereas Lewis-Sumner syndrome patients had multifocal fusiform hypertrophy in the nerve trunks. The patterns of nerve hypertrophy presumably reflect the different pathophysiology of each CIDP subtype.

Use of immunoglobulin (Ig) in peripheral neuropathies. Impact of Ig on remission rates: comparison of intravenous immunoglobulin and subcutaneous immunoglobulin.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a progressive or relapsing disease with a worldwide prevalence of up to nine individuals per 100 000 1. Randomized trials suggest that corticosteroids, plasma exchange and intravenous immunoglobulin (IVIg) can temporarily reduce impairment and disability. Although approximately 60–70% of the patients respond to the initial therapy, reports on long-term experience of IVIg use in CIDP are rare. Corticosteroids, plasma exchange and IVIg are first-line treatment options in CIDP; however, a risk of long-term adverse effects is the main disadvantage of corticosteroids. Long-term plasma exchange may be less tolerated, and expense can be a concern with IVIg. Two Phase III clinical trials proved the efficacy of IVIg for long-term treatment in CIDP. The IVIg CIDP Efficacy (ICE) trial was a large study that evaluated for the first time the long-term efficacy of IVIg in 117 patients with CIDP 2. Of the 57 patients who received IVIg and were first-period or cross-over-period responders, as assessed with the adjusted inflammatory neuropathy cause and treatment (INCAT) scale, 31 were reassigned randomly to IVIg and 26 were assigned randomly to placebo. IVIg-treated patients (13%) showed a significantly lower relapse rate compared to placebo-treated patients (45%), meaning that 55% of those who were re-randomized to placebo in the extension trial did not deteriorate in a time-frame of approximately 24 weeks 2. In the Privigen Impact on Mobility and Autonomy (PRIMA) study, IVIg-pretreated and IVIg-naive CIDP patients were enrolled and treated for 21 weeks 3. Approximately 61% of the patients showed a significant improvement according to the INCAT scale. Fifty per cent of patients responded to IVIg within the first 4 weeks and 88% of patients within 10 weeks. Of the 31 screened patients, only one CIDP patient (9%) failed the IVIg dependency test and did not deteriorate in the wash-out phase 3. Recently, a retrospective study aimed to evaluate the long-term outcomes in 86 CIDP patients treated with IVIg 4. Data were collected at four time-points: baseline (prior to the start of IVIg treatment); at short-term visit (approximately 6 weeks after IVIg initiation); at mid-term visit (approximately 24 weeks after IVIg); and at last follow-up visit (more than 48 weeks after initiating IVIg treatment). At the mid-term visit, 31 patients had only one IVIg course throughout the entire observation period. Twenty CIDP patients did not receive IVIg at all. Of these 20 patients, 12 were stable. At the long-term visit, 22 patients (25·6%) showed no signs of deterioration 4. There are limited data available on the long-term treatment of CIDP and multifocal motor neuropathy (MMN) with subcutaneous immunoglobulin (SCIg). In a recent report, two patients with atypical CIDP (multifocal acquired demyelinating sensory and motor neuropathy – MADSAM), were treated with SCIg over a time-period of 46 months 5. The Medical Research Council (MRC) sum score remained stable during the entire time-period. In a randomized Phase II study, 30 CIDP patients were enrolled and randomized to placebo and SCIg 6. The treatment period was 12 weeks, with twice- or thrice-weekly SCIg injections (30–300 ml/week; 4·8–48 g/week). After 12 weeks, significant increases (P > 0·05) in isokinetic muscle strength were observed in SCIg-treated patients (5·5 ± 9·5%) compared to the decline observed in the placebo group (14·4 ± 20·3%) 6. Two small case series investigated the effect of SCIg in MMN 7,8. SCIg proved its effectiveness in MMN in short- 7 and long-term use 8. It should be noted that the initial SCIg dose should be 100% equivalent to the monthly IVIg dose 7. A Phase III study proving the efficacy of SCIg in treating CIDP (PATH-Study) is still ongoing (ClinicalTrials.gov identifier: NCT01545076). More recently, a cost-effectiveness study comparing IVIg and SCIg was performed in Italy. Assuming that approximately 2100 CIDP patients exist in Italy, and 50% of those patients were prescribed SCIg, the estimated cost-saving in their model was approximately €1·4 million for the health-care sector 9. However, it should be noted that the cost of SCIg differs within Europe. In conclusion, both IVIg and SCIg are safe and well tolerated for long-term treatment in CIDP and MMN. The most common side effects are headaches (IVIg) and local skin reactions (SCIg). Although not very common, haemolysis is a severe side effect seen with IVIg that can potentially lead to hospitalization, especially when higher doses are administered (2 g/kg body weight).

Efficiency of long-term treatment with intravenous immunoglobulins correlates with reduced autoreactive T cell responses in chronic inflammatory demyelinating polyneuropathy patients.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare disease of the peripheral nervous system, characterized by gradual increasing weakness of the limbs, with more than 50% of patients experiencing marked disability 1. The underlying pathophysiological mechanism of CIDP remains unknown; however, studies have shown activated T cells in the circulation of CIDP patients 2–4. In addition, patient studies suggest a key role for autoreactive T cell responses against peripheral myelin antigens such as P0, P1, P2 and peripheral myelin protein PMP-22 5,6. Mechanism-of-action studies in other chronic autoimmune diseases have shown that the T cell memory compartment influences antigen responses by showing up-regulation of CD4+ or CD8+ T effector memory (TEM) cells 7,8. Recently, published data from a randomized, placebo-controlled clinical trial demonstrated the long-term efficacy and safety of intravenous immunoglobulin (IVIg) treatment in CIDP patients 9. However, the underlying mechanism of action of IVIg in the treatment of CIDP remains unclear 10,11. The aim of this study was to investigate the course of autoreactive T cell responses against the two peripheral myelin antigens P2 and PMP-22 in addition to the frequency of memory T cell subsets during IVIg treatment in CIDP patients 12.

Optimizing immunoglobulin G therapy in chronic autoimmune neuropathies.

Prolonged intravenous immunoglobulin (IVIg) therapy is frequently used for the treatment of chronic autoimmune neuropathies, such as chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). Recent studies of the electrophysiology and immunology of various neurological diseases, including CIDP, suggest that antibody-induced reversible dysfunction of nodes of Ranvier plays an important role in conduction block and morbidity 1. This may be more important, at least in the short term, than demyelination or axon destruction. The IVIg doses and dosing intervals are usually chosen empirically due to a paucity of data from dose-response and pharmacodynamic studies. The use of 2 g/kg as loading dose and maintenance doses of 1 g/kg every 3–4 weeks are common. European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) guidelines suggest that the dose and frequency of IVIg should be tailored to an individual patient's needs 2. However, there are no recommendations as to how this can be achieved or the outcomes upon which adjustments in therapy should be based. Clinical observations suggest that with currently used immunoglobulin (Ig) regimens the beneficial effects of each dose of IVIg may be transient, wearing off before the next cycle of treatment is required. These observations have been confirmed by case reports. A patient with CIDP repeatedly showed improvement in ankle dorsiflexion over the first 5–9 days following the administration of IVIg. The improvement was sustained for approximately 10 days but then declined, reaching pretreatment levels by the end of the month 3. These periodic fluctuations in strength were also reported in a patient with MMN on monthly IVIg therapy 4. However, this patient was switched to subcutaneous immunoglobulin (SCIg) therapy and, with a 25% increase in total monthly dose, his disease stabilized. Weekly SCIg has been investigated as a means of continuously maintaining high serum IgG levels, resulting in stabilization of neuromuscular function in CIDP and MMN patients 5–8. Significant variations in IgG metabolism have been reported among patients with CIDP 9. These differences were unrelated to the administered dose, weight, body mass index or degree of functional improvement. However, the patient-specific post-infusion rise in IgG levels, which may be dependent upon the individual rate of IgG metabolism, may explain the interpatient differences in infusion frequency requirements. The optimum dosage and frequency of IVIg infusions appears to be patient-specific 9. It has been shown that actual doses and dosing intervals vary from conventional empirical dosing, suggesting that physicians may already be adjusting doses based on the individual patient's clinical condition and treatment response 10. A prospective study has shown that CIDP patients maintain strength optimally when their IgG levels reach a plateau supported by infusions as frequent as once every 10 days. The intra- and interpatient variability in IgG may indicate that individualized constant levels of IgG facilitate achieving clinical stability 11. Overall, these studies show that many patients with CIDP have increased benefit when IVIg is administered at more frequent intervals, with 30–60% of patients showing improvement when IVIg is administered at intervals of 10–14 days or less 9–11. An ongoing study supported by CSL Behring in collaboration with AxelaCare has demonstrated that grip strength and disability measurements performed frequently by the patient at home can be reported wirelessly, collected by a database service, and reported to the physician 12. This information can prove useful for assessing the extent and duration of responses to individual IgG doses. In addition, this type of frequent data collection can be used to identify patients who would benefit from weekly SCIg rather than IVIg every 3−4 weeks and those in whom IgG therapy is ineffective. Currently, Ig replacement therapy is widely used in the treatment of chronic autoimmune neuropathies. Individualization of IgG treatment regimens may optimize efficacy and minimize disability. Further studies are needed to determine whether patient-specific regimens result in improved long-term outcomes.

7(th) International Immunoglobulin Conference: Poster presentations.

Immunoglobulin (Ig) therapy is the mainstay of treatment for primary antibody deficiency disorders and has proved to be efficacious in specific autoimmune and inflammatory diseases. Additionally, due to the role of Ig in complement activation, it is being used increasingly in solid organ transplantation. Furthermore, Ig is the primary or secondary treatment in some immune-mediated neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP) or multifocal motor neuropathy (MMN). This session discusses trends of Ig use in Europe, proposed mechanisms of action, adverse effects and the potential role of Ig therapy in transplantation. Dr Šedivá reported that Ig therapy is available in all European countries, although dosing is not always optimal, due partly to reimbursement plans. Subcutaneous immunoglobulin (SCIg) has become increasingly accessible in recent years; however, the chosen route of administration still varies widely between countries. Dr Berger's presentation on optimization of Ig therapy in neuropathies, and Dr Rojavin's report on a pharmacometric model to determine the serum IgG levels achieved by different dosing regimens in primary antibody deficiency (PAD) patients, led to the challenging concept of using individualized dosing strategies. Dr Klehmet reported on the potential benefit of using antigen-specific T cell responses as a biomarker of IVIg responsiveness in CIDP patients, while Dr von Gunten provided an insight into the mechanisms of action of Ig preparations, suggesting that the immunoregulatory effects of IgG may be mediated by IgG antibodies against glycans. Dr Basta reported on the potential thrombogenic adverse effects associated with Ig therapy. Although these adverse events are rare, further studies are needed to clarify the relationship between Ig replacement and immunomodulatory therapy and these adverse reactions. In transplantation, Dr Carbone described that prophylactic IVIg treatment was found to decrease the incidence of severe infection in IgG hypogammaglobulinaemia patients undergoing heart transplantations. Furthermore, Dr Clatworthy reported that inactivating polymorphisms in the inhibitory receptor FcγRIIB do not impact upon kidney allograft survival.