|NEUROLOGICAL DISEASES - ORIGINAL ARTICLES
|Year : 2021 | Volume
| Issue : 3 | Page : 249-253
Relationship of Serum Cytokine Profile to Steroid Resistance in Demyelinating Neurologic Illnesses
Devaprasad Markandeyan1, Mabalirajan Ulaganathan2, Surajit Pathak3, Ramesh Ganesan Vengalathur4
1 Department of Neurology, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, India
2 CSIR-n Institute of Chemical Biology, Kolkata, India
3 Department of Biotechnology, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Chennai, India
4 Department of Neurosurgery, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, India
|Date of Submission||30-Apr-2021|
|Date of Decision||03-May-2021|
|Date of Acceptance||02-Jun-2021|
|Date of Web Publication||28-Jul-2021|
Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai 603103
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background and Purpose: Corticosteroids form main stay of treatment of autoimmune neurological diseases. Immunotherapy with Intravenous Immunoglobulin, Plasmapheresis, biological agents like Rituximab, Infliximab, etanarcept are also used for treatment of patients who are resistant to steroid treatment and in severe cases. This study was aimed to elicit the relationship between serum cytokine levels and steroid resistance which is important for early commencement of other medications. Methods: The serum samples of patients who presented with autoimmune neurological diseases were collected and cytokine levels were estimated. The cytokine profile of patients who responded well to steroid treatment was compared with that of steroid nonresponders. Results: The steroid unresponsive group had significantly higher serum Interferon gamma and IL-13 levels than steroid unresponsive group. Conclusion: when patients present with high serum levels of IL-13 and Interferon Gamma they should be considered for prompt escalation of immunomodulatory therapy.
Keywords: Autoimmune, central nervous system, cytokines, demyelinating, steroids
|How to cite this article:|
Markandeyan D, Ulaganathan M, Pathak S, Vengalathur RG. Relationship of Serum Cytokine Profile to Steroid Resistance in Demyelinating Neurologic Illnesses. Int J Nutr Pharmacol Neurol Dis 2021;11:249-53
|How to cite this URL:|
Markandeyan D, Ulaganathan M, Pathak S, Vengalathur RG. Relationship of Serum Cytokine Profile to Steroid Resistance in Demyelinating Neurologic Illnesses. Int J Nutr Pharmacol Neurol Dis [serial online] 2021 [cited 2022 Jul 4];11:249-53. Available from: https://www.ijnpnd.com/text.asp?2021/11/3/249/322482
| Introduction|| |
Immune system protects the body from various pathogens and cancer cells. Malfunctioning of this immune system results in recognition of normal body cells as foreign and damage the normal cells causing various diseases that are referred to as autoimmune diseases. Autoimmune diseases of the central nervous system (CNS), which include aquaporin-4-antibody seropositive neuromyelitis optica spectrum disorders, optic neuritis (ON), transverse myelitis (TM), and multiple sclerosis (MS), are distinguished by intricate interactions among the adaptive and innate immune system. Over the past decades, these noninfectious inflammatory disorders have been the aim of extensive analysis and research on etiopathogenic mechanisms and on diagnostic approaches. Myelin abnormalities that demonstrate impairment to the developing and mature brains are usually observed in neurologic illness with signs of microglial activation and inflammatory infiltration. Several cytokines are practically unrecognizable in the uninflamed CNS, so that their brisk induction and sustained deification in immune and glial cells contribute in the dysregulation of the inflammatory response and neural cell balance. This causes cytotoxicity, abnormal neural cell development, and loss of the primary myelin-producing cells of the CNS.
Based on site of damage in nervous system, the neurologic diseases are classified as acute inflammatory demyelinating polyradiculopathy (AIDP) and chronic inflammatory demyelinating polyradiculopathy (CIDP) when injury occurs to radicles and nerves. Similarly, TM is when injury occurs to spinal cord and ON to optic nerve. AIDP is otherwise called Guillain–Barré syndrome; it occurs at frequency of 2/100,000 per year and takes from few weeks or years for the recovery. It leaves people paralyzed and bedridden for life sometimes. Death occurs in 7.5% of patients.,, AIDP is treated with intravenous (IV) immunoglobulin and plasmapheresis and is poorly responsive to steroids.
The CIDP is an inflammatory disorder of nerve that sometimes presents with slowly progressive weakness, sensory loss, and areflexia. It is an illness that has chronic course of 8 weeks, and is more responsive to steroids. Asymmetric variant of CIDP is called Lewis–Sumner syndrome. CIDP generally grows deceptively over weeks to months, causing fairly symmetrical motor and sensory deficits in the limbs and is variable yet hugely handicapping. The disease may occur at any age, even in youth and the course might be either chronic progressive or relapsing with incremental residual deficits.,, During dynamic periods of their disease, patients frequently require helped ambulation and may become wheelchair or bed bound. In spite of the current treatment, the condition may lead to considerable chronic morbidity, inciting a continuous search for improved medicines. Humoral and cell-mediated responses against a range of myelin-derived autoantigens have been detected in some patients with CIDP.
The TM is a rare neurologic disorder of the spinal cord that is brought about by irritation and can have destroying neurologic impacts with up to 66% of patients having a moderate to extreme level of leftover incapacity. TM refers to a disorder in which there is autoimmune injury to spinal cord predominantly to the myelin sheath., TM is found in every 4.6 in 1 million, affecting men and women equally. It may leave one-third of patients paralyzed for life without any recovery. Mainly treated with steroids and some severe cases are treated with IV immunoglobulin or plasmapheresis. In the same way, ON is more responsive to steroids many times.
Additionally many new biologic agents, such as rituximab, infliximab, etanercept, etc., have revolutionized the treatment of autoimmune diseases. Hence, it is important to know the responsiveness and resistant patterns of various diseases to treatments like corticosteroids.
| Materials and methods|| |
The study was conducted in Chettinad Academy of Research and Education, a tertiary care medical college hospital in Tamil Nadu, India. Necessary ethical clearance was obtained from institutional ethical committee. The study was conducted during January 2017 to January 2019. Consecutive patients who were admitted for various autoimmune diseases such as AIDP, CIDP, TM, and ON who satisfied the respective diagnostic criteria such as Transverse Myelitis Consortium Working Group criteria, Asbury criteria for AIDP, Joint Task Force of the European Federation of Neurological Societies/Peripheral Nerve Society criteria for CIDP, clinically and Visual Evoked Potential confirmed for ON were selected and blood samples were collected on admission.
The samples were centrifuged, serum separated, and stored in ‒80°C for further processing. Most of the patients were treated with injecting methylprednisolone 1 g in 100 mL of normal saline intravenously over 1 hour. The patients were monitored regularly after treatment. The patients who had good response to treatment with methylprednisolone and patients who did not have response to the treatment, as well as patients having AIDP which is known for poor response to methylprednisolone were noted.
For this study, 17 patients were recruited of which 11 patients had good clinical response to methylprednisolone treatment and were included in steroid-responsive group. Among the group, two had idiopathic ON, one had Miller Fisher syndrome (a variant of AIDP), one had cervical TM, and rest had CIDP. Among the patients, six belonged to steroid nonresponsive group, of which four had the diagnosis of severe AIDP, one had TM which did not respond to methylprednisolone and was treated with IV immunoglobulin, and one had features of CIDP but had only insignificant improvement with methylprednisolone. The steroid-responsive group had five female and six male patients and the mean age was 44.7 years. On the other hand, the male and female distribution was equal among nonresponsive group and the mean age was 51.3 years. Among patients in steroid-responsive group, 45% were diabetics and 18% were hypertensives, whereas in steroid nonresponsive group, 50% were diabetics and 33% were hypertensives.
The serums of the two groups of patients were processed for levels of cytokines such as interferon-gamma (IFN-γ), interleukin-13 (IL-13), IL-8, IL-6, transforming growth factor-beta (TGF-β), and tumor necrosis factor-alpha (TNF-α). TGF-β kit Invitrogen 88-8350-22, IL-8 eBioscience, kit 88-8086, IL-13 Pipro tech kit 900-M23, IFN-gamma Pipro tech kit 900-M27, IL-17 Pipro tech kit 900-M84, IL-6 BD Pharmingen kit 555220, and TNF-α eBioscience kit 88‐7346 were kits used for the assays. The assays were performed using Synergy™ configurable multimode microplate reader and the results were recorded in pg/mL.
| Results|| |
On comparison between the groups by using Kruskal–Wallis test, the steroid unresponsive group had significantly higher IFN-γ levels than steroid responsive group ([Table 1]): steroid responsive (12.19 ± 13.77), unresponsive (89.88 ± 89.70), control (19.89 ± 29.92), KW-value = 7.082, P = 0.029 to 0.05.
|Table 1 Comparison of steroid sensitive and resistant groups by Kruskal–Wallis test|
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On comparison between the groups by using Kruskal‒Wallis test, the steroid unresponsive group had significantly higher IL-13 levels than steroid responsive group [Figure 1]: steroid responsive (137.67 ± 118.73), unresponsive (433.99 ± 544.44), control (53.30 ± 30.98), KW-value = 6.321, P = 0.042 to 0.05. There was no statistical difference between the other measured cytokine levels.
|Figure 1 Mean cytokine levels comparison steroid sensitive, resistant and control groups|
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On comparison between the groups by using Mann‒Whitney test, the steroid unresponsive group had significantly higher IFN-γ levels than steroid responsive and control groups: steroid responsive (12.19 ± 13.77), unresponsive (89.88 ± 89.70), Z-value = 2.513, P = 0.012 to 0.05. There was no statistical difference between the other measured cytokine levels which is evident from [Table 2] and [Figure 2], respectively.
|Table 2 Comparison of steroid sensitive and resistant groups by Mann–Whitney test|
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|Figure 2 Mean cytokine levels comparison steroid sensitive and resistant groups|
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| Discussion|| |
Evaluation of cytokine profiles has been suggested to detect the possibility to reflect distinct immunopathologic processes between antibody-associated conditions. They are not only important for an understanding of the pathophysiology, but may also prove as a useful biomarker to let the doctor and patients, choose an appropriate treatment. Our findings are strongly supported by various other studies such as Rajabally et al.; their work showed that patients with a higher mean-sensory-nerve action potential had poor response to steroids. Similarly, Rakusa et al. had shown that younger age and less severe disease are predictors of steroid responsiveness in TM and ON associated with MS. Significantly, lower serum TGF-β1 concentration was observed in CIDP which is usually sensitive to steroids when compared with AIDP in a study by Chang et al.
Hence, from this study, we have shown that patients with autoimmune demyelinating neurologic diseases who had higher levels of IFN-γ and IL-13 did not respond to steroids given in the form of high-dose methylprednisolone. Serum IFN-γ levels of more than 20 pg/mL was associated with the poor response. Clinical assessment also showed that such patients had greater morbidity and mortality compared to the steroid-sensitive patients.
| Conclusion|| |
The immunologic mechanisms are known to be associated in the pathogenesis of CIDP and AIDP. Molecular simulation between the myelin epitopes and the surface glycolipids of antigenic triggers may commence both humoral and cellular immune responses. The corollary autoantibodies interplay with the surface gangliosides of the Schwann cells, resulting in the activation of the complement pathways, and intrigue immune cells to destroy myelin. Patients with neurologic autoimmune demyelinating diseases, such as CIDP, TM, ON, and AIDP, when presenting with high serum levels of IL-13 and IFN-γ, should be considered for prompt immunomodulatory therapy with IV immunoglobulin or plasmapheresis instead of steroid trial as risk for steroid unresponsiveness is high in these patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]