Synergistic effects of immune checkpoints and checkpoint inhibitors in inflammatory neuropathies: Implications and mechanisms.

Immune checkpoint molecules play pivotal roles in the regulation of immune homeostasis. Disruption of the immune checkpoints causes autoimmune/inflammatory as well as malignant disorders. Over the past few years, the immune checkpoint molecules with inhibitory function emerged as potential therapeutic targets in oncological conditions. The inhibition of the function of these molecules by using immune checkpoint inhibitors (ICIs) has brought paradigmatic changes in cancer therapy due to their remarkable clinical benefits, not only in improving the quality of life but also in prolonging the survival time of cancer patients. Unfortunately, the ICIs soon turned out to be a "double-edged sword" as the use of ICIs caused multiple immune-related adverse effects (irAEs). The development of inflammatory neuropathies such as Guillain-Barré syndrome (GBS) and Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) as the secondary effects of immunotherapy appeared very challenging as these conditions result in significant and often permanent disability. The underlying mechanism(s) through which ICIs trigger inflammatory neuropathies are currently not known. Compelling evidence suggests autoimmune reaction and/or inflammation as the independent risk mechanism of inflammatory neuropathies. There is a lack of understanding as to whether prior exposure to the risk factors of inflammatory neuropathies, the presence of germline genetic variants in immune function-related genes, genetic variations within immune checkpoint molecules, the existence of autoantibodies, and activated/memory T cells act as determining factors for ICI-induced inflammatory neuropathies. Herein, we highlight the available pieces of evidence, discuss the mechanistic basis, and propose a few testable hypotheses on inflammatory neuropathies as irAEs of immunotherapy.

Safety and Tolerability of Intravenous Immunoglobulin in Chronic Inflammatory Demyelinating Polyneuropathy: Results of the ProCID Study.

BACKGROUND AND AIMS: The ProCID study evaluated the efficacy and safety of three doses of a 10% liquid intravenous immunoglobulin (IVIg) preparation (panzyga®) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). This report describes the safety findings. METHODS: Patients were randomised to receive a 2.0 g/kg induction dose followed by maintenance doses of either 0.5, 1.0 or 2.0 g/kg IVIg every 3 weeks over 24 weeks. RESULTS: All 142 enrolled patients were included in the safety analyses. In total, 286 treatment-emergent adverse events (TEAEs) were reported in 89 patients, of which 173 (60.5%) were considered treatment-related. Most TEAEs were of mild severity. Eleven serious TEAEs were reported in 6 patients. Two serious TEAEs in one patient (headache and vomiting) were considered related to treatment, which resolved without study discontinuation. No treatment-related thrombotic events, haemolytic transfusion reactions or deaths occurred. One patient discontinued the study due to a TEAE (allergic dermatitis) probably related to IVIg. Headache was the only dose-dependent TEAE, with incidences ranging from 2.9 to 23.7%, the incidence of all other TEAEs was similar across treatment groups. Most TEAEs were associated with the induction dose infusion, and the rate of TEAEs decreased thereafter. The median (IQR) daily IVIg dose was 78 (64-90) g, and 94.4% of patients tolerated the maximal infusion rate of 0.12 ml/kg/min without pre-medication. INTERPRETATION: Infusions of 10% IVIg at doses up to 2.0 g/kg with high infusion rates were safe and well tolerated in patients with CIDP. CLINICAL TRIAL NUMBERS: EudraCT 2015-005443-14, NCT02638207.

Chronic inflammatory demyelinating neuropathy after etanercept therapy in the course of juvenile idiopathic arthritis.

BACKGROUND: Chronic inflammatory demyelinating neuropathy has been reported after the use of tumor necrosis factor inhibitors. The mechanisms of nerve injury caused by tumor necrosis factor inhibitors are not yet well understood. CASE: In this paper, we report a 12 year and nine month old girl who developed chronic inflammatory demyelinating neuropathy in the course of juvenile idiopathic arthritis after etanercept withdrawal. She became non-ambulant with four-limb involvement. She received intravenous immunoglobulins, steroids, and plasma exchange, but had a limited response. Finally, rituximab was given and a slow, but progressive clinical improvement was seen. She was ambulant four months after rituximab treatment. We considered chronic inflammatory demyelinating neuropathy as a probable adverse effect of etanercept. CONCLUSIONS: Tumor necrosis factor inhibitors could elicit the demyelinating process, and chronic inflammatory demyelinating neuropathy might persist despite treatment discontinuation. First-line immunotherapy may be inefficient as in our case, and aggressive treatment may be necessary.

Extended surveillance to assess safety of 9-valent human papillomavirus vaccine.

The safety of 9-valent HPV vaccine (9vHPV) has been established with regard to common and uncommon adverse events. However, investigation of rare and severe adverse events requires extended study periods to capture rare outcomes. This observational cohort study investigated the occurrence of three rare and serious adverse events following 9-valent human papillomavirus (9vHPV) vaccination compared to other vaccinations, in US individuals 9-26 years old, using electronic health record data from the Vaccine Safety Datalink (VSD). We searched for occurrences of Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and stroke following 9vHPV vaccination from October 4, 2015, through January 2, 2021. We compared the risks of GBS, CIDP, and stroke following 9vHPV vaccination to risks of those outcomes following comparator vaccines commonly given to this age group (Td, Tdap, MenACWY, hepatitis A, and varicella vaccines) from January 1, 2007, through January 2, 2021. We observed 1.2 cases of stroke, 0.3 cases of GBS, and 0.1 cases of CIDP per 100,000 doses of 9vHPV vaccine. After observing more than 1.8 million doses of 9vHPV, we identified no statistically significant increase in risks associated with 9vHPV vaccination for any of these adverse events, either combined or stratified by age (9-17 years of age vs. 18-26 years of age) and sex (males vs. females). Our findings provide additional evidence supporting 9vHPV vaccine safety, over longer time frames and for more serious and rare adverse events.

Intravenouse immunoglobuline in dysautonomia.

Nowadays intravenous immunoglobulin (IVIg) treatment is considered to play a promising role in the autoimmune disease therapy. Despite its significant beneficial effects, the precise mechanism of action needs further studies, as well as recommended dosage in the treatment of autoimmune dysautonomia. In some diseases, like Guillain-Barre syndrome (GBS) and chronic inflammatory demyelinating neuropathy (CIDP), IVIg has a strong evidence that allows to recommend and prescribe the medication, while in other diseases only single case studies are available that requires further research. The review summarizes the currently available information on the effectiveness of IVIg in primary autoimmune neuropathies and neurological complications of systemic diseases, as well as side effects, features of clinical use with an emphasis on doses and treatment protocols in dysautonomia. Being safe and effective therapy, immunologic treatment is one of the most promising tools to achieve clinical remission of dysautonomia and good quality of life in autoimmune patients.

Posturography as a biomarker of intravenous immunoglobulin efficacy in chronic inflammatory demyelinating polyradiculoneuropathy.

INTRODUCTION/AIMS: Imbalance is a common feature of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Intravenous immunoglobulin (IVIg) exerts clinical benefit in CIDP, including improving balance, although objective markers of efficacy are lacking. Posturography is an established objective marker of balance; therefore, this study aimed to determine the utility of posturography as an objective marker of treatment efficacy in CIDP. METHODS: Posturography was performed on 18 CIDP patients, established on IVIg infusions, and results were compared to age-matched healthy controls. CIDP patients were assessed just prior to IVIg infusion and at the mid-point of the cycle. Center of pressure (CoP) was measured and the total path traveled by CoP (Sway Path, SP) was calculated for five different conditions: feet placed in parallel 16 cm apart at the medial border with eyes open (16cmEO) and eyes closed (16cmEC); medial borders of the feet touching with eyes open (0cmEO) and eyes closed (0cmEC); and tandem stance. RESULTS: The sway path (SP) was significantly increased in CIDP patients (mean SP 1191 ± 104 mm) when compared to healthy controls (mean SP 724 ± 26 mm, P < .001). The increase was most prominent during eyes closed and tandem stance conditions. Treatment with IVIg significantly reduced SP when assessing 0cmEC (1759 ± 324 mm vs. 1081 ± 134 mm, P = .019) and tandem stance (1775 ± 290 mm vs. 1152 ± 113 mm, P = .027). DISCUSSION: Posturography detected significant improvements in balance following IVIg in CIDP patients established on maintenance therapy. As such, posturography may be considered an objective marker of treatment response in clinical management and therapeutic trials.

Polirradiculoneuropatía desmielinizante inflamatoria crónica asociada al tratamiento con infusión intraduodenal de levodopa-carbidopa / Chronic inflammatory demyelinating polyradiculoneuropathy associated with treatment using intraduodenal infusion of levodopa-carbidopa

No disponible

[Chronic inflammatory demyelinating polyradiculoneuropathy associated with treatment using intraduodenal infusion of levodopa-carbidopa]. / Polirradiculoneuropatia desmielinizante inflamatoria cronica asociada al tratamiento con infusion intraduodenal de levodopa-carbidopa.

TITLE: Polirradiculoneuropatia desmielinizante inflamatoria cronica asociada al tratamiento con infusion intraduodenal de levodopa-carbidopa.

Chronic inflammatory demyelinating polyradiculoneuropathy secondary to immune checkpoint inhibitors in melanoma patients.

IMPORTANCE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune neurological disorder that is characterized by symmetrical progressive worsening or relapsing weakness and numbness of the limbs. There are no reliable diagnostic tests or definitive diagnostic criteria, and the diagnosis remains one of excluding other cases of polyneuropathy. Typical treatment for CIDP includes corticosteroids, intravenous immunoglobulin (IVIG), and plasma exchange. Little is known about CIDP as a treatment complication of immune checkpoint inhibitors (ipilimumab and nivolumab). This report will be helpful in increasing awareness and knowledge about this unique entity. OBSERVATIONS: We describe two cases of CIDP secondary to treatment with combined ipilimumab and nivolumab in patients with metastatic melanoma that were successfully treated with prednisone and IVIG. Conclusion and Relevance: This report illustrates that treatment with immune checkpoint inhibitors can lead to CIDP that can be successfully treated with complete resolution of symptoms. CIDP secondary to checkpoint inhibitors may have unique features such as low-grade lymphocytic pleocytosis on CSF evaluation as well as severe neuropathic pain as an early presenting symptom. Additionally, it is interesting to note that both patients presented in this report remained melanoma-free on follow-up more than 16 months later.

[Chronic inflammatory demyelinating polyneuropathy in a diabetic patient with syphilis]. / Polineuropatía desmielinizante inflamatoria crónica en paciente diabética con sífilis.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a disorder characterized by motor symptoms such as weakness in both proximal and distal muscles with globally diminished or absent reflexes. Insulin neuritis is referred as an acute pain in the extremities, due to the damage of peripheral nerves affecting mainly small fibers, in diabetic patients treated with insulin who achieved rapid glycemic control. Pain is unusual in classic CIDP. We report the case of a 54-year-old female patient with type II diabetes mellitus, and a recent onset of insulin therapy, who presented at the emergency room with a 2-month history of weakness and hyperalgesia of extremities. Physical examination showed marked pain and proximal and distal allodynia in the 4 limbs, with reduced muscle strength of the proximal muscles and patellar and achillear areflexia. Electrophysiological study showed sensory and motor polyneuropathy with a demyelinating predominance. Treatment with recombinant human immunoglobin was started, and the patient presented a total remission of the condition. Complementary studies confirmed weak serum positivity of GM1, GD1a, GD1b and anti-asialo GM1. Prior to hospital discharge, results of positive serum VDRL and FTA-Abs were received. VDRL in cerebrospinal fluid was negative, so neurosyphilis was ruled out, and treatment with benzathine penicillin was indicated.

Polineuropatía desmielinizante inflamatoria crónica en paciente diabética con sífilis / Chronic inflammatory demyelinating polyneuropathy in a diabetic patient with syphilis

La polineuropatía desmielinizante inflamatoria crónica (PDIC) se presenta generalmente con síntomas motores, debilidad tanto en los músculos proximales como en los distales con reflejos globalmente disminuidos o ausentes. La neuritis insulínica es un trastorno caracterizado por dolor agudo de las extremidades, y daño de los nervios periféricos con afectación predominante de las fibras pequeñas, en los pacientes diabéticos sometidos a un rápido control glucémico. El dolor es raro en la PDIC clásica. Describimos el caso de una mujer de 54 años con diabetes mellitus (DB) tipo II, en tratamiento reciente con insulina, que consultó por un cuadro de debilidad e hiperalgesia de los cuatro miembros de dos meses de evolución. Al examen físico presentaba dolor de intensidad 10/10 y alodinia en los cuatro miembros, a niveles proximal y distal, con fuerza muscular reducida de los músculos proximales y arreflexia patelar y aquilea bilateral. Se realizó un estudio electrofisiológico, el cual mostró una polineuropatía sensitiva y motora desmielinizante. Se indicó tratamiento con inmunoglobina humana recombinante, con total remisión del cuadro. Estudios realizados posteriormente demostraron positividad débil de los anticuerpos GM1, GD1a, GD1b y anti-asialo GM1. Previo al alta hospitalaria se recibieron los resultados de VDRL sérica positiva, y FTA-Abs. VDRL en líquido cefalorraquídeo fue negativa por lo que se descartó neurosífilis, indicándose tratamiento con penicilina benzatínica.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a disorder characterized by motor symptoms such as weakness in both proximal and distal muscles with globally diminished or absent reflexes. Insulin neuritis is referred as an acute pain in the extremities, due to the damage of peripheral nerves affecting mainly small fibers, in diabetic patients treated with insulin who achieved rapid glycemic control. Pain is unusual in classic CIDP. We report the case of a 54-year-old female patient with type II diabetes mellitus, and a recent onset of insulin therapy, who presented at the emergency room with a 2-month history of weakness and hyperalgesia of extremities. Physical examination showed marked pain and proximal and distal allodynia in the 4 limbs, with reduced muscle strength of the proximal muscles and patellar and achillear areflexia. Electrophysiological study showed sensory and motor polyneuropathy with a demyelinating predominance. Treatment with recombinant human immunoglobin was started, and the patient presented a total remission of the condition. Complementary studies confirmed weak serum positivity of GM1, GD1a, GD1b and anti-asialo GM1. Prior to hospital discharge, results of positive serum VDRL and FTA-Abs were received. VDRL in cerebrospinal fluid was negative, so neurosyphilis was ruled out, and treatment with benzathine penicillin was indicated.

Bilateral facial nerve palsies secondary to chronic inflammatory demyelinating polyneuropathy following adalimumab treatment.

PURPOSE: Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) presents uncommonly with cranial nerve involvement with ophthalmological implications. METHODS: We report the case of a 37year-old man who developed CIDP which manifested as progressive and relapsing bilateral facial nerve palsy with lagophthalmos and exposure keratopathy, in the setting of treatment of Crohn's disease with the anti-TNF-alpha agent adalimumab. RESULTS: Symptoms gradually improved over the course of several months following withdrawal of adalimumab and treatment with intravenous immunoglobulin (IVIg) and oral prednisolone. CONCLUSION: Bilateral facial nerve involvement occurs uncommonly as a feature of CIDP in its classic form. The prognosis is good for recovery of facial nerve function with discontinuation of anti-TNF-alpha therapy and concurrent use of steroid and intravenous immunoglobulin in this case.

Demyelinating Peripheral Neuropathy Due to Renal Cell Carcinoma.

Renal cell carcinoma (RCC) patients who develop a paraneoplastic syndrome may present with neuromuscular disorders. We herein report the case of a 50-year-old man who suffered from progressive gait disturbance and muscle weakness. The results of a nerve conduction study fulfilled the criteria of chronic inflammatory demyelinating polyneuropathy. An abdominal CT scan detected RCC, the pathological diagnosis of which was clear cell type. After tumor resection and a single course of intravenous immunoglobulin therapy, the patient's symptoms drastically improved over the course of one year. The patient's neurological symptoms preceded the detection of cancer. A proper diagnosis and the initiation of suitable therapies resulted in a favorable outcome.

Chronic inflammatory demyelinating polyradiculoneuropathy: A new animal model for new therapeutic targets.

Animal models are fundamental to advance knowledge of disease pathogenesis and to test/develop new therapeutic strategies. Most of the current knowledge about the pathogenic mechanisms underpinning autoimmune demyelination processes implicating autoantigens has been obtained using the Experimental Autoimmune Neuritis (EAN) animal model. The most widely used EAN model is obtained by active immunization of Lewis rats using a peptide, P0 (180-199), issuing from the major peripheral nervous system myelin protein. But this model mimics only the classical monophasic acute form of demyelinating polyradiculoneuropathy, i.e. Guillain-Barré syndrome (GBS). We developed a new model by immunizing Lewis rats using the same immunodominant neuritogenic peptide P0 (180-199) but this time with its S-palmitoyl derivative, S-palm P0 (180-199). All of the animals immunized with the S-palm P0 (180-199) peptide developed a chronic relapsing-remitting form of the disease corresponding to the electrophysiological criteria of demyelination (slow sensory nerve conduction velocity, prolonged motor nerve latency, partial motor nerve conduction blocks) with axon degeneration. These findings were confirmed by immunohistopathology study and thus, appear to mimic human chronic inflammatory demyelinating polyradiculopathy (CIDP). This new model opens up new avenues of research for testing new anti-inflammatory and neuroprotective therapeutic strategies.