Krista Kuitwaard

Pharmacokinetics of intravenous immunoglobulin and outcome in Guillain-Barré syndrome.

Intravenous immunoglobulin (IVIg) is the first choice treatment for Guillain‐Barré syndrome (GBS). All patients initially receive the same arbitrary dose of 2g per kg body weight. Not all patients, however, show a good recovery after this standard dose. IVIg clearance may depend on disease severity and vary between individuals, implying that this dose is suboptimal for some patients. In this study, we determined whether the pharmacokinetics of IVIg is related to outcome in GBS.

Rasch-built Overall Disability Scale (R-ODS) for immune-mediated peripheral neuropathies

Objective: To develop a patient-based, linearly weighted scale that captures activity and social participation limitations in patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and gammopathy-related polyneuropathy (MGUSP). Methods: A preliminary Rasch-built Overall Disability Scale (R-ODS) containing 146 activity and participation items was constructed, based on the WHO International Classification of Functioning, Disability and Health, literature search, and patient interviews. The preliminary R-ODS was assessed twice (interval: 2–4 weeks; test-retest reliability studies) in 294 patients who experienced GBS in the past (n = 174) or currently have stable CIDP (n = 80) or MGUSP (n = 40). Data were analyzed using the Rasch unidimensional measurement model (RUMM2020). Results: The preliminary R-ODS did not meet the Rasch model expectations. Based on disordered thresholds, misfit statistics, item bias, and local dependency, items were systematically removed to improve the model fit, regularly controlling the class intervals and model statistics. Finally, we succeeded in constructing a 24-item scale that fulfilled all Rasch requirements. “Reading a newspaper/book” and “eating” were the 2 easiest items; “standing for hours” and “running” were the most difficult ones. Good validity and reliability were obtained. Conclusion: The R-ODS is a linearly weighted scale that specifically captures activity and social participation limitations in patients with GBS, CIDP, and MGUSP. Compared to the Overall Disability Sum Score, the R-ODS represents a wider range of item difficulties, thereby better targeting patients with different ability levels. If responsive, the R-ODS will be valuable for future clinical trials and follow-up studies in these conditions.

Recurrent Guillain–Barré syndrome

Background: Guillain–Barré syndrome (GBS) is generally considered to be monophasic, but recurrences do occur in a presently undefined subgroup of patients. Objectives: To determine which subgroup of patients develops a recurrence and to establish whether preceding infections and neurological symptoms are similar in subsequent episodes. Methods: A recurrence was defined as two or more episodes that fulfilled the NINCDS criteria for GBS, with a minimum time between episodes of 2 months (when fully recovered in between) or 4 months (when only partially recovered). Patients with a treatment-related fluctuation or chronic inflammatory demyelinating polyneuropathy with acute onset were excluded. The clinical characteristics of recurrent GBS patients were compared with those of 476 non-recurrent patients. Results: 32 recurrent GBS patients, who had a total of 81 episodes, were identified. The clinical symptoms in a first episode were similar to the following episodes in individual patients, being GBS or its variant Miller Fisher syndrome (MFS) but never both. While neurological symptoms in subsequent episodes were often similar, the severity of the symptoms and the nature of the preceding infections varied. Recurrent patients (mean age 34.2 years) were younger than non-recurrent patients (mean age 46.9; p = 0.001) and more often had MFS (p = 0.049) or milder symptoms (p = 0.011). Conclusions: Genetic or immunological host factors may play an important role in recurrent GBS, since these patients can develop similar symptoms after different preceding infections. Recurrences occur more frequently in patients under 30, with milder symptoms and in MFS.

Serum IgG levels in IV immunoglobulin treated chronic inflammatory demyelinating polyneuropathy

Objective To determine the variability of serum IgG in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Methods All 25 CIDP patients had active but stable disease and were treated with individually optimised fixed dose IVIg regimens. IgG was measured by turbidimetry and variability was defined as coefficient of variation (CV). Results The intra-patient variability of the pre-treatment IgG levels, post-treatment levels and increase in serum IgG shortly after IVIg (ΔIgG) was low (mean CV=3%, 4%, 10%). The inter-patient variability between patients treated with the same dose and interval was low in pre-treatment, post-treatment and ΔIgG level (mean CV=13%, 11%, 20%). The ΔIgG levels were associated with IVIg dosage (rs=0.78, p<0.001). Conclusions Clinically stable CIDP patients show a steady-state in serum IgG after serial IVIg infusions. The low intra- and inter-patient variability in IgG may indicate that constant levels are required to reach this stability.

Recurrences, vaccinations and long‐term symptoms in GBS and CIDP

Abstract We determined the frequency of recurrent Guillain–Barré syndrome (GBS), whether vaccinations led to recurrences of GBS or an increase of disability in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and we assessed the prevalence of pain, fatigue and the impact on quality of life after GBS and CIDP. Additionally, we assessed the presence of common auto‐immune disorders. Four hundred and sixty‐one members of the Dutch society of neuromuscular disorders received a questionnaire. Two hundred and forty‐five GBS and seventy‐six CIDP patients were included (response rate 70%). Nine patients had a confirmed recurrent GBS, and two patients had experienced both GBS and CIDP. Common auto‐immune diseases were reported in 9% of GBS and 5% of CIDP patients. None of the 106 GBS patients who received a flu vaccination (range 1–37 times, total 775 vaccinations) reported a recurrence thereafter. Five out of twenty‐four CIDP patients who received a flu vaccination (range 1–17 times) reported an increase in symptoms. Pain or severe fatigue was reported in about 70% of patients after the diagnosis of GBS (median 10 years) or after onset of CIDP (median 6 years), and quality of life was significantly reduced. Flu vaccinations seem relatively safe. GBS and CIDP patients often experience pain, fatigue and a reduced quality of life for many years after the diagnosis.

Newer Therapeutic Options for Chronic Inflammatory Demyelinating Polyradiculoneuropathy

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated disorder with variable symptoms and severity that can be difficult to diagnose. Intravenous immunoglobulin, plasma exchange and corticosteroids have all been proven to be beneficial in randomized controlled trials, although the proof for corticosteroids is less clear. Although these treatments are likely to be similar in efficacy, they differ in terms of their cost, availability and adverse effects. These characteristics should be taken into account when deciding which treatment to offer a patient. If there is no response to the first treatment option, one of the other treatments should be tried. Patients with a pure motor CIDP may deteriorate after corticosteroid treatment.Some patients do not respond or become refractory or intolerant to these conventional treatments. Those who become unresponsive to therapy should be checked again for the appearance of a monoclonal protein or other signs of malignancy. Over the years, small non-randomized studies have reported possible beneficial effects of various immunosuppressive agents. A Cochrane review concluded that currently there is insufficient evidence to decide whether these immunosuppressive drugs are beneficial in CIDP. When giving immunosuppressive drugs, one should be aware that some might even cause demyelinating disease. It is difficult to prove beneficial effects of these newer treatments since they have only been used in small groups of patients, who are refractory to other treatments, and often in combination with other treatments. CIDP patients can deteriorate during or after infections or improve spontaneously, making it more difficult to judge treatment efficacy. Various treatments for CIDP are described such as azathioprine, ciclosporin, cyclophosphamide, interferons, methotrexate, mycophenolate mofetil, rituximab and etanercept. An overview of these newer treatments, their mode of action, adverse effects and potential place in the spectrum of treatments for CIDP based on previous reports and their level of evidence is given.

IgG Fc N-Glycosylation in Guillain–Barré Syndrome Treated with Immunoglobulins

Intravenous immunoglobulin (IVIg) is the treatment of choice for Guillain-Barré syndrome (GBS), an immune-mediated peripheral neuropathy causing rapidly progressive limb weakness and respiratory failure. The working mechanism of IVIg in autoimmune diseases has not been elucidated, but previous studies indicate that some anti-inflammatory effects may be mediated by the N-glycosylation of the Fc-portion of IgG. GBS is a model disease to investigate these effects because GBS is an acute and monophasic disorder usually affecting healthy persons, which is treated with a standard course of IVIg, although the clinical response is highly variable. In the current study, the N-glycosylation of the Fc-portion of serum IgG was investigated in patients with GBS before and after treatment with IVIg in relation to clinical course and outcome. Glycoforms of serum IgG1 and IgG2 were determined separately by liquid chromatography mass spectrometry. These IgG subclasses were purified from the serum of 174 GBS patients before and in 150 patients 2 weeks after standard IVIg treatment regimen. Treatment-naive GBS patients compared with age- and sex-matched controls had lower levels of galactosylation of IgG1 and IgG2. IVIg preparations contained relatively high levels of galactosylated and sialylated IgG Fc glycoforms compared with serum IgG in patients. Treatment with IVIg resulted in an increase in serum of the Fc-galactosylation and -sialylation of both IgG1 and IgG2. The extent of normalization in serum IgG Fc glycosylation varied between patients. Multiple logistic regression analysis showed that patients with persistent low IgG galactosylation and sialylation despite IVIg treatment had the most severe forms of GBS and needed ventilator support more often. Kaplan-Meier analysis showed that these patients also needed more time to be able to walk again compared with patients with a normalized IgG Fc glycosylation profile. In conclusion, our results suggest that serum IgG Fc glycosylation in GBS is related to disease severity and clinical recovery after IVIg and may help to develop new measures to monitor the efficacy of treatment.

Serum IgG levels as biomarkers for optimizing IVIg therapy in CIDP.

Intravenous immunoglobulin (IVIg) is a proven effective treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Guillain‐Barré syndrome (GBS). In GBS, patients show a large variability in serum immunoglobulin G (IgG) levels after standard IVIg treatment and a large increase in serum IgG levels (ΔIgG) was associated with a better outcome. Whether this is also the case in CIDP is not known. In contrast to GBS, most patients with CIDP need regular IVIg treatment for a prolonged period of time but the speed and magnitude of clinical response varies considerably between patients. Some patients with CIDP may need at least two IVIg courses before clinical signs of improvement become clear. At present, this clinical response is the only indicator used to adjust the IVIg dose and interval during maintenance treatment. Biomarkers reflecting disease activity or IVIg pharmacokinetics might be helpful to monitor patients and find the optimal dosage and frequency of IVIg treatment for individual patients. A recent prospective study in CIDP indicated that the increased ΔIgG after standard IVIg dosage during maintenance treatment was relatively constant within individual patients, but differed considerably between patients who were treated with the same stable dosage and interval of IVIg. Further studies are required to determine whether this variation in pharmacokinetics of IVIg is related with clinical recovery and whether IgG levels can be used as biomarkers to monitor and to adjust the optimal IVIg dosage in individual patients with CIDP.

Intravenous immunoglobulin response in treatment-naïve chronic inflammatory demyelinating polyradiculoneuropathy

Objective There is no consensus on which treatment should be used preferentially in individual patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Patients unlikely to respond to intravenous immunoglobulin (IVIg) could be prescribed corticosteroids first to avoid high cost and a delayed treatment response. We investigated which factors determined a response to IVIg. Methods Treatment-naïve patients with CIDP initially treated with at least one full course of IVIg (2 g/kg) at one of two neuromuscular disease centres were included. Patients fulfilled the European Federation of Neurological Societies/Peripheral Nerve Society clinical criteria for CIDP. Significant improvement following IVIg was defined as an improvement (≥1 grade) on the modified Rankin scale. Difference in weakness between arms and legs was defined as ≥2 grades on the Medical Research Council scale between ankle dorsiflexion and wrist extension. Clinical predictors with a p value <0.15 in univariate analysis were analysed in multivariate logistic regression. Results Of a total of 281 patients, 214 patients (76%) improved. In univariate analysis, the presence of pain, other autoimmune disease, difference in weakness between arms and legs, and a myelin-associated glycoprotein negative IgM monoclonal gammopathy of undetermined significance were associated with no response to IVIg. In multivariate analysis no pain (p=0.018) and no difference in weakness between arms and legs (p=0.048) were independently associated with IVIg response. Of IVIg non-responders, 66% improved with plasma exchange and 58% with corticosteroids. Conclusions IVIg is a very effective first-line treatment. Patients with CIDP presenting with pain or a difference in weakness between arms and legs are less likely to respond to IVIg.

Association of Albumin Levels With Outcome in Intravenous Immunoglobulin–Treated Guillain-Barré Syndrome

Importance There is an urgent need for biomarkers to monitor treatment efficacy and anticipate outcome in patients with Guillain-Barré syndrome (GBS). Objective To assess whether there is an association between serum albumin levels, a widely used and relatively easily measurable biomarker of health and inflammation, and the clinical course and outcome of GBS in patients treated with intravenous immunoglobulin (IVIG). Design, Setting, and Participants We used serum samples derived from a cohort of patients with GBS admitted to hospitals across the Netherlands participating in national GBS studies from May 5, 1986, through August 2, 2000. Serum albumin was measured from January 13 to 20, 2011. Analysis was performed from February 25, 2013, to September 6, 2016. All patients fulfilled the criteria for GBS and had severe disease (defined as not being able to walk unaided >10 m). Patients misdiagnosed as having GBS were retrospectively excluded from the study. Serum samples were obtained before and after IVIG treatment at 4 standardized time points from 174 patients. Albumin levels were determined by routine diagnostic turbidimetry and related to demographics and clinical course during a follow-up of 6 months. Main Outcomes and Measures Serum albumin concentration was determined before and after treatment with IVIG and related to clinical outcome: muscle weakness (measured by Medical Research Council sum score), respiratory failure (measured by requirement and duration of mechanical ventilation), and ability to walk (measured by GBS disability score). Results Serum albumin levels were determined in 174 patients with GBS (mean [SD] age, 49.6 [20.1] years; 99 males [56.9%]). Before treatment, the median serum albumin level was 4.2 g/dL (interquartile range, 3.8-4.5 g/dL), with hypoalbuminemia (albumin, <3.5 g/dL) in 20 (12.8%) of 156 patients. Two weeks after commencing treatment with IVIG (2 g/kg), the median serum albumin level decreased to 3.7 g/dL (interquartile range, 3.2-4.1 g/dL) (P < .001), and the number with hypoalbuminemia increased to 60 (34.5%) of 174 (P < .001). Hypoalbuminemia was associated with an increased chance of respiratory failure before (16 [36.4%] of 44, P = .001) or after (29 [54.7%] of 53, P < .001) IVIG treatment, inability to walk unaided (21 [35.0%] of 60 vs 6 [5.3%] of 114, P < .001), and severe muscle weakness at 4 weeks (Medical Research Council sum score, 31.8 vs 52.9, P < .001) and 6 months (Medical Research Council sum score, 49.4 vs 58.4, P < .001). Conclusions and Relevance Patients with GBS may develop hypoalbuminemia after treatment with IVIG, which is related to a more severe clinical course and a poorer outcome. Further studies are required to confirm that serum albumin can be used as a biomarker to monitor disease activity and treatment response to IVIG in patients with GBS.