Intravenous immunoglobulin modulates lymphocyte CD54 and monocyte FcgammaRII expression in patients with chronic inflammatory neuropathies

We studied the expression of different lymphocyte and monocyte cellular determinants involved in leukodiapedesis and antigen presentation in 10 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) with persistent conduction blocks before intravenous immunoglobulin (IVIg), immediately after infusion of IVIg and 1 week after infusion. We observed a decrease of T lymphocytes expressing ICAM-1 (CD54) immediately after infusion in 8 out of 10 patients (p<0.04) with a return to pretreatment values after 1 week. The monocytes showed an increase in CD14(+) cells and CD14(+) FcgammaRII inhibitory receptor positive cells, no change in the number of CD14(+) FcgammaRIII activation receptor cells, and an increase in the FcgammaRII/FcgammaRIII ratio on monocytes 1 week after IVIg. Thus, the mechanism of action of IVIg in both CIDP and MMN may involve inhibition of T cell transmigration and modulation of antigen presentation capacities through FcgammaR expression.     

CD16+CD57- natural killer cells in multifocal motor neuropathy

We analyzed the CD16+CD57- lymphocyte subset, which is considered to have strong natural killer (NK) cell activity, in peripheral blood from patients with chronic immune-mediated neuropathies and patients with other neurological diseases. We found that the ratio of CD16+CD57- NK cells to total lymphocytes was increased in 4 of 6 patients with multifocal motor neuropathy (MMN) with persistent conduction block. Since the CD16 molecule is an Fc receptor for immunoglobulin G (IgG), high-dose intravenous immunoglobulin (IVIg) may interfere with CD16+CD57- NK cells via Fc receptor blockade. In addition, cyclophosphamide (Cy) is often used to suppress NK cells. Therefore, our findings may partly account for the effectiveness of IVIg or Cy, which is the current treatment of choice for MMN.     

Efficacy and tolerability of different brands of intravenous immunoglobulin in the maintenance treatment of chronic immune‐mediated neuropathies

High‐dose intravenous immunoglobulin (IVIg) is effective in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN). Not all brands of IVIg are however licensed for these neuropathies. We reviewed six patients with CIDP and seven with MMN treated with maintenance therapy with IVIg from 2009 to 2013. In all patients, we measured the Medical Research Council (MRC) and Overall Neuropathy Limitation Scale (ONLS) scores before each infusion, registered the monthly dose and brand of IVIg, and recorded adverse events. Patients were treated for 25–60 months (mean 49 months) alternating different brands of IVIg including IgVena, Gammagard, Kiovig, and Flebogamma. Minor and transient side effects were equally observed with each brand. No difference in the MRC or ONLS scores was observed in relation to the brand of IVIg used. Chronic maintenance treatment with IVIg in patients with MMN and CIDP was not associated with a different tolerability or efficacy despite the use of different brands of IVIg.     

What’s new in chronic inflammatory demyelinating polyradiculoneuropathy in 2007–2008?

Abstract Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)–related research has made progress in the field of pathogenesis, genetics, and treatment. The number of circulating CD4⁺ CD25⁺ T‐regulatory cells was shown to be reduced in CIDP patients. Increased frequency of genotype GA13‐16 of the SH2D2A gene encoding for a T‐cell‐specific adapter protein in CIDP patients may result in a defective control and elimination of autoreactive T cells. IVIg treatment has been shown to increase numbers and function of peripheral CD4⁺ CD25⁺ T‐regulatory cell in a mouse model. These findings shed new light on the understanding of why peripheral tolerance is breached in CIDP patients and why the disease becomes chronic and adds another possible mechanism of action of intravenous immunoglobulin to the already long list. Long‐term effectiveness of IVIg has now been proven. Subcutaneous immunoglobulin could be an alternative for IVIg, but this has to be explored further in well‐designed trials. Autologous stem cell transplantation has been tried in refractory patients, but larger trials are necessary to assess safety and effect of this treatment.     

Protocol of a dose response trial of IV immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy (DRIP study)

High peak levels of serum IgG may not be needed for maintenance treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with intravenous immunoglobulin (IVIg). More frequent dosing of IVIg leads to more stable IgG levels and higher trough levels which may be related with improved clinical efficacy. More frequent lower dosing leads to lower peak levels and may induce less systemic side‐effects. The DRIP study is a double‐blind randomized controlled cross‐over intervention study. CIDP patients ≥18 years old, proven IVIg dependent and receiving an individually established but stable maintenance dose and interval of IVIg (Kiovig) can be included. One group (A) will be treated with their normal dosage and interval of IVIg and receive a placebo (albumin 0.5%) infusion in between their regular IVIg infusions, for a total of four infusions. The other group (B) will be treated with half their normal IVIg dosage (with the same volume of placebo to maintain the total volume) at half their interval (double their frequency) for four infusions. After a wash‐out phase (2 infusions), patients will cross‐over to the other treatment group. During the study the total dose of IVIg administered will remain unchanged as before start of the trial. The main objective is to investigate whether high frequent low dosage IVIg treatment is more effective than low frequent high dosage IVIg treatment as maintenance treatment for CIDP. Hand grip strength, as measured by the Martin Vigorimeter, will be used as the primary outcome measure. Secondary objective is to investigate whether high frequent low dosage of IVIg results in less adverse events compared to low frequent high dosage treatment. The DRIP study is currently ongoing and the protocol is presented.     

Expression and function of the inhibitory Fcγ-receptor in CIDP

The inhibitory Fc-gamma receptor (FcγR) IIB, expressed on myeloid and B cells, has a critical role in the balance of tolerance and auto-immunity, and is required for the anti-inflammatory activity of intravenous immunoglobulin (IVIg) in various murine disease models. We found that treatment-na?ve patients with chronic inflammatory demyelinating polyneuropathy (CIDP) showed an impaired expression of FcγIIB levels on na?ve B cells, and failed to upregulate or to maintain upregulation of FcγIIB, as B cells progressed from the na?ve to the memory compartment. The impaired expression of FcγRIIB was, at least partially, restored by clinically effective IVIg treatment. It remains to be determined whether FcγRIIB expression is a candidate for pre-treatment assessment and might thus be used as a prognostic marker of treatment response to IVIg. Nonetheless, our data suggest that new strategies specifically targeting FcγRIIB expression might have therapeutic merit in CIDP.     

Inhibition of peripheral blood natural killer cell cytotoxicity in patients with myasthenia gravis treated with plasmapheresis

Background and purpose: Myasthenia gravis (MG) is an autoimmune disorder that may involve natural killer (NK) cells. Although NK cells are part of the innate immune system, they also influence adaptive immune responses. Double‐filtration plasmapheresis (DFP) is an effective therapy for MG crisis. Thus, we examined the effects of DFP on the cytotoxicity of NK cells. Methods: A total of 20 patients with MG and 16 healthy controls were recruited for the study. Ficoll‐Paque‐isolated peripheral blood mononuclear cells (PBMCs) and K562 cells were used as the effector and target cells, respectively. NK cell cytotoxicity was analyzed using flow cytometry immediately before and after DFP and upon course completion. Results: Double‐filtration plasmapheresis treatment decreased significantly the NK cell cytotoxicity in patients with MG, especially in good responders, those who were positive for acetylcholine receptor (AChR) antibodies, and those receiving immunosuppressants. Conclusions: The decrease in NK cell cytotoxicity after DFP and the decline of AChR antibody titer were observed in good responders indicating that this could benefit patients with MG.     

Changes in serum macrophage-related factors in patients with chronic inflammatory demyelinating polyneuropathy caused by intravenous immunoglobulin therapy

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a slowly progressive or recurrent neuropathy accompanied by infiltration of macrophages in the peripheral nerves. Macrophage colony-stimulating factor (M-CSF) and monocyte chemoattractant protein-1 (MCP-1) are a macrophage-related cytokine and chemokine, respectively. Although, intravenous immunoglobulin (IVIg) infusion therapy has been used for treating CIDP patients, not all CIDP patients have responded to IVIg infusion therapy. To determine the mechanisms of the action of IVIg, we examined serum M-CSF and MCP-1 levels during and after IVIg infusion therapy in 19 CIDP patients treated with IVIg (0.4 g/kg/day for 5 days). Ten of the 19 patients (52.6%) responded to IVIg therapy. Both M-CSF and MCP-1 concentrations in IVIg responders were significantly higher on day 1 postinfusion than those in nonresponders, but decreased to their pretreatment values on day 5 postinfusion. The results suggest that immunomodulation through M-CSF and MCP-1 is involved in the mechanisms underlying the effect of IVIg infusion therapy in CIDP patients.     

Subcutaneous versus intravenous immunoglobulin for chronic autoimmune neuropathies: A meta‐analysis

Introduction: High‐dose intravenous immunoglobulin (IVIg) is an evidence‐based treatment for multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyneuropathy (CIDP). Recently, subcutaneous immunoglobulin (SC‐Ig) has received increasing attention. Methods: We performed a meta‐analysis of reports of efficacy and safety of SC‐Ig versus IVIg for inflammatory demyelinating polyneuropathies. Results: A total of 8 studies comprising 138 patients (50 with MMN and 88 with chronic CIDP) were included in the meta‐analysis. There were no significant differences in muscle strength outcomes in MMN and CIDP with Sc‐Ig (MMN: effect size [ES] = 0.65, 95% confidence interval [CI] = ‐0.31‐1.61; CIDP: ES = 0.84, 95% CI = ‐0.01‐1.69). Additionally SC‐Ig had a 28% reduction in relative risk (RR) of moderate and/or systemic adverse effects (95% CI = 0.11‐0.76). Conclusions: The efficacy of SC‐Ig is similar to IVIg for CIDP and MMN and has a significant safety profile. Muscle Nerve 55 : 802–809, 2017     

A randomised,multi‐centre phase III study of 3 different doses of intravenous immunoglobulin 10% in patients with chronic inflammatory demyelinating polyradiculoneuropathy (ProCID trial): Study design and protocol

Patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) show varying degrees of response to intravenous immunoglobulin (IVIg) therapy. This randomised phase III study in patients with CIDP (ProCID trial) will compare the efficacy and safety of 3 different doses (0.5, 1.0, and 2.0 g/kg) of IVIg 10% (panzyga) administered every 3 weeks for 24 weeks. The primary efficacy endpoint is the rate of treatment response, defined as a decrease in adjusted inflammatory neuropathy cause and treatment disability score of ≥1 point, in the IVIg 1.0 g/kg arm at week 24. Patients with definite or probable CIDP according to European Federation of Neurological Sciences/Peripheral Nerve Society criteria with IVIg or corticosteroid dependency and active disease are eligible. All potentially eligible patients will undergo IVIg or corticosteroid dose reduction (washout phase) over ≤12 weeks or until deterioration of CIDP (active disease). Patients with deterioration during the washout phase will be randomised to receive study treatment during a dose‐evaluation phase starting with a loading dose of IVIg 2.0 g/kg followed by maintenance treatment with IVIg 0.5, 1.0, or 2.0 g/kg every 3 weeks. Rescue medication (2 doses of IVIg 2.0 g/kg given 3 weeks apart) will be administered to patients in the IVIg 0.5 and 1.0 g/kg groups who deteriorate after week 3 and before week 18 or who do not improve at week 6. Safety, tolerability and quality of life will be assessed. The ProCID study will provide new information on the best maintenance dose of IVIg for patients with CIDP.     

Home monitoring of maintenance intravenous immunoglobulin therapy in patients with chronic inflammatory neuropathy

To evaluate the utility of different outcome measures to monitor dose adjustment of intravenous immunoglobulin (IVIg) therapy in patients with chronic inflammatory neuropathy (CIN). We assessed the adjustment of IVIg maintenance therapy in 20 patients (10 CIDP and 10 MMN) by regularly monitoring grip strength (GS) using a Martin Vigorimeter, RODS, and quality of life using the SF‐36 questionnaire. These measures were regularly performed by the patient at home. We also assessed the extended MRC sumscore (eMRC sumscore) at each outpatient visit for IVIg infusion. We also enrolled 30 healthy controls to measure any possible training effect of GS with time and to analyze random fluctuation of GS. Clinically relevant change was detected by eMRC sumscore in 14 (93%) patients, by RODS in 11 (73%) patients, and by GS in 8 (53%) patients. Early sensitivity was greatest for RODS (73%), followed by GS (53%), and eMRC sumscore (27%). This differed from CIDP, with an early change in RODS in 100% of patients, and MMN with an early change in GS in 75%. None of the outcome measures alone was sufficient to detect clinically significant changes in all patients. Home monitoring of outcome measures objectively assisted clinical decision during individualization of IVIg treatment. We recommend a multimodal approach using different outcome measures to monitor the individual patient with CIN.     

Subcutaneous immunoglobulin infusion: a new therapeutic option in chronic inflammatory demyelinating polyneuropathy

Intravenous application of immunoglobulins (IVIg) is an effective and usually well tolerated yet costly therapeutic regimen in chronic inflammatory demyelinating polyneuropathy (CIDP). We report two CIDP patients treated with subcutaneous infusion of immunoglobulins (SCIg) after IVIg therapy was shown to be effective. Application of SCIg was well tolerated, easy to manage, and led to stabilization of the disease course. SCIg may represent an effective new therapeutic option in CIDP and is associated with a cost reduction of at least 50% compared to IVIg therapy.     

Intermittent intravenous immunoglobulin infusion prevented relapses in patients with remission-exacerbation type chronic inflammatory demyelinating polyradiculoneuropathy]

The intravenous immunoglobulin infusion therapy (IVIg) has recently acquired an important role in the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Some patients, however, require repetitive infusions to maintain the improvement. We planned a one-day therapy with 0.4 g/kg of IVIg in every 7 or 10 days for two CIDP patients who had required a 5-day course of IVIg in every month because of frequent exacerbations. Serum levels of IgG in both patients were kept as high as 2,000 mg/dl resulting in maintaining the improvement without any side effects.     

Maintenance IV immunoglobulin treatment in chronic inflammatory demyelinating polyradiculoneuropathy

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients treated with intravenous immunoglobulin (IVIg) usually start with a standard dosage of 2 g/kg bodyweight. Only a minority of patients has a sustained improvement, and most require ongoing maintenance treatment. Preferred IVIg regimens, however, vary considerably between doctors and at present it is unknown which is optimal. As there are also large differences in IVIg dosage and interval requirements between patients, optimal IVIg maintenance treatment of CIDP is even more complex. The lack of evidence‐based guidelines on how IVIg maintenance treatment should be administered may potentially lead to under‐ or overtreatment of this expensive therapy. We provide an overview of published practical IVIg maintenance treatment regimens, IVIg maintenance schedules used in randomized controlled trials and one based upon our own long‐term experience on how this treatment could be given in CIDP.     

Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyradiculoneuropathy,a time to start and a time to stop

Intravenous immunoglobulin (IVIg) is often used as preferred treatment in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Several studies highlighted the short‐term efficacy of IVIg for CIDP yet many patients need maintenance therapy. Notwithstanding the fact IVIg has been used for over 30 years in CIDP, there is only limited evidence to guide dosage and interval during maintenance treatment. The variation in disease course, lack of biomarkers, and fear of deterioration after stopping IVIg makes long‐term treatment challenging. Recent studies suggest a proportion of patients receive unnecessary IVIg maintenance treatment. This review provides an overview of the use of IVIg for CIDP treatment, focusing on evidence for long‐term IVIg use.     

Long-term effects of intravenous immunoglobulin in CIDP.

OBJECTIVE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired demyelinating disease of the peripheral nervous system characterized by muscle weakness, areflexia or hyporeflexia, and sensory disturbances. Although short-term efficacy of intravenous immunoglobulin (IVIg) has been demonstrated in randomized-controlled trials, the data pertaining to long-term outcome in CIDP are limited. Consequently, the aim of the present study was to assess the long-term effects of IVIg on neurophysiological parameters in CIDP. METHODS: Neurophysiological records from 11 CIDP patients, treated with IVIg for 12 months, were reviewed. Nerve conduction studies were assessed at baseline, 1-year, and last follow-up. RESULTS: There was a significant reduction in the frequency of conduction blocks (pre-treatment nerve segments affected 61%; last follow-up 39%, P<0.01) and a reduction in ongoing axonal loss (pre-treatment regions with spontaneous activity, 47%; post-treatment 29%, P<0.01) with IVIg treatment. Further, there was significant improvement in sensory nerve conduction studies with IVIg treatment (sensory amplitudes reduced pre-treatment, 90% nerves tested; post-treatment, 62%, P<0.01). CONCLUSIONS: The present study suggests that long-term IVIg maintenance therapy improves neurophysiological parameters in CIDP. However, CIDP patients remain IVIg dependent and new conduction blocks may develop. SIGNIFICANCE: The present study suggests that long-term IVIg maintenance therapy improves neurophysiological parameters in CIDP, possibly by reducing the immune response and thereby fostering nerve healing.     

Mechanism of norepinephrine-mediated inhibition of human NK cytotoxic functions: inhibition of cytokine secretion,target binding,and programming for cytotoxicity

Norepinephrine (NE) has been shown to inhibit human peripheral blood-derived natural-killer (NK) cell cytotoxicity (NKCC) in vitro. We demonstrate in this study that NE not only inhibits IL-2-activated NKCC but antibody-dependent cellular cytotoxicity (ADCC) as well. NK cytotoxicity by purified NK cells against K562 (NKCC) and against Raji cells (ADCC) were inhibited by NE (1-100 microM) by more than 50% in a 4-h (51)Cr release assay. The mechanism underlying the inhibition has been examined. NK cytotoxicity is dependent on target recognition and formation of NK-target conjugates, and activation by IL-2 is dependent on the secretion of cytokines (such as TNF-alpha) by NK cells. We hypothesized that the inhibition of NK functions by NE may be due to disruption of NK-target conjugation, blocking programming for lysis, and/or inhibition of cytokine secretion. Pretreatment of human peripheral blood mononuclear cells (PBMC) with NE for 15 min significantly reduced the binding to K562 cells by CD16(+) NK lymphocytes. In the presence of K562 cells, NE down-regulated the expression of CD16 (FcgammaRIII) by human PBMC, an NK cell receptor responsible and necessary for ADCC and cytokine secretion. We also demonstrate that NE inhibited the IL-2-mediated up-regulation of the activation marker CD69. At concentrations of 10(-6) to 10(-5) M, NE inhibited TNF-alpha, IFN-gamma, and GM-CSF secretion by NK cells, which are essential for IL-2-driven NK maturation and functions. In addition, using single-cell analysis, NE pretreatment of lymphocytes reduced the frequency of killer cells in the NK-K562 conjugate population in a concentration-dependent manner, indicating an inhibition of the programming for lysis by NK cells. In summary, these data demonstrate that NE-induced inhibition of NK cytotoxicity is manifested at multiple levels, including a modification of NK cell receptor ligation to target cells, blockade of NK cytokine secretion necessary for NK maturation and differentiation, and inhibition of the target-induced activation of the cytotoxic mechanism(s) in NK cells. Thus, sympathetic activation, as often induced experimentally, may profoundly impair natural cellular immunity through varied measurable pathways.     

Motor chronic inflammatory demyelinating polyneuropathy (CIDP) in 17 patients: Clinical characteristics,electrophysiological study,and response to treatment

Motor chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare and poorly described subtype of CIDP. We aimed to study their clinical and electrophysiological characteristics and response to treatment. From a prospective database of CIDP patients, we included patients with definite or probable CIDP with motor signs and without sensory signs/symptoms at diagnosis. Patients were considered to have pure motor CIDP (PM‐CIDP) if sensory conductions were normal or to have motor predominant CIDP (MPred‐CIDP) if ≥2 sensory nerve action potential amplitudes were abnormal. Among the 700 patients with CIDP, 17 (2%) were included (PM‐CIDP n = 7, MPred‐CIDP n = 10); 71% were male, median age at onset was 48 years (range: 13‐76 years), 47% had an associated inflammatory or infectious disease or neoplasia. At the more severe disease stage, 94% of patients had upper and lower limb weakness, with distal and proximal weakness in 4 limbs for 56% of them. Three‐quarters (75%) responded to intravenous immunoglobulins (IVIg) and four of five patients to corticosteroids including three of three patients with MPred‐CIDP. The most frequent conduction abnormalities were conduction blocks (CB, 82%) and F‐wave abnormalities (88%). During follow up, 4 of 10 MPred‐CIDP patients developed mild sensory symptoms; none with PM‐CIDP did so. Patients with PM‐CIDP had poorer outcome (median ONLS: 4; range: 22‐5) compared to MPred‐CIDP (2, range: 0‐4; P = .03) at last follow up. This study found a progressive clinical course in the majority of patients with motor CIDP as well as frequent associated diseases, CB, and F‐wave abnormalities. Corticosteroids might be considered as a therapeutic option in resistant IVIg patients with MPred‐CIDP.     

Dose of intravenous immunoglobulins in chronic inflammatory demyelinating polyneuropathy

The usual initiating dose of intravenous immunoglobulins (IVIg) in the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) is 2 g/kg/course. Although not evidence based, subsequent reductions are advised to the lowest possible level for maintenance. In practice, the achievable levels of such reductions and their impact on treatment frequency have not been studied. Factors determining maximal dosage reduction are unknown. We retrospectively reviewed data concerning IVIg therapy for 15 patients with CIDP, from their medical records between 1997 and 2005. Lowest effective dose and treatment frequency were determined. The following correlations were ascertained: dose to frequency, dose to weight, dose to disease duration, amplitude of dose reduction to disease duration, and dose to pre-therapeutic disease severity. Dose reductions were possible in all (mean: 63.3%, range: 42.4-88%). The lowest effective dose of IVIg per course and treatment frequency were both very variable (18-108 g and 2-17 weeks, respectively). Lowest dose per course did not correlate to weight, frequency of administration, disease duration, or pre-therapeutic degree of disability. Amplitude of dose reduction achieved was independent of disease duration. Treatment frequency could not be lowered in any patient. Our findings show that IVIg target doses should be titrated individually but suggest that infusion frequencies are fixed in each case in relapsing CIDP. Importantly, lower dose treatment is not associated with shorter intervals between courses, and lowest effective dose is independent of weight and disease duration. Initial level of disability does not appear to influence dose required. These results suggest considerably lower, standardized, initiating, and maintenance doses might be effective and highlight the need for prospective dose comparative trials.     

Motor-dominant chronic inflammatory demyelinating polyneuropathy

We reviewed the clinical, electrophysiological an laboratory findings, plus the therapeutics and evolution of patients with motor-dominant Chronic inflammatory demyelinating polyneuropathy (CIDP) and compared them with those of other CIDP patients. Among 12 consecutive CIDP patients, we identified five patients with motor-dominant CIDP. The five patients with motor-dominant CIDP initially presented with weakness of the upper limbs. Cervical magnetic resonance imaging (MRI) examinations of the patients with motor-dominant CIDP showed that the most affected lesions are the cervical nerve roots and brachial plexus. The clinical course of these patients was relapsing-remitting, and they improved markedly after treatment by intravenous immunoglobulin (IVIg) infusion or plasmapheresis. However, they did not improve in response to corticosteroid therapy during the acute phase of relapses. The relapses frequently occurred within 2 years, but rarely occurred after that. The score in the modified Rankin disability scale (mRDS) at the last follow-up period was statistically lower for the patients with motor-dominant CIDP than for the other CIDP patients (P < 0.002). The characteristic clinical features, responsiveness to treatment, and prognosis suggest that motor-dominant CIDP is a distinct subtype of CIDP, with a specific immunological background. Repeated IVIg therapy is required to maintain the motor functions of patients with motor-dominant CIDP. We consider that treatment for recurrence prevention as an alternative to IVIg therapy is very important for patients with motor-dominant CIDP.