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10. Neuropsychiatric Manifestions in Patients with RA and AITD
Authors and Affiliations
Guided by :-Abjamilova Jazgul , Orcid
ID: [ https://orcid.org/0000-0001-8028-3343 ]
Submitted by :-
1. Dasu Sai Harsha
2. Veluguri Dishney Navaneetha
3. Syed Umar
4. Sumedha
Group 15
(Associate Professor , International Medical Faculty ,Osh State University ,Osh ,kyrgyztan)
(Students, International Medical Faculty , Osh State University ,Osh ,Kyrgyzstan)
Date : 13 December 2025
Abstract
Recent studies have demonstrated that immunological disease progression is closely related to abnormal function of the central nervous system (CNS). Rheumatoid arthritis (RA) is a chronic, inflammatory synovitis-based systemic immune disease of unknown etiology. In addition to joint pathological damage, RA has been linked to neuropsychiatric comorbidities, including depression, schizophrenia, and anxiety, increasing the risk of neurodegenerative diseases in life. Immune cells and their secreted immune factors will stimulate the peripheral and central neuronal systems that regulate innate and adaptive immunity. The understanding of autoimmune diseases has largely advanced insights into the molecular mechanisms of neuroimmune interaction. Here, we review our current understanding of CNS comorbidities and potential physiological mechanisms in patients with RA, with a focus on the complex and diverse regulation of mood and distinct patterns of peripheral immune activation in patients with rheumatoid arthritis. And in our review, we also discussed the role that has been played by peripheral neurons and CNS in terms of neuron mechanisms in RA immune challenges, and the related neuron-immune crosstalk.
Introduction
Rheumatoid arthritis (RA) and autoimmune thyroid diseases (AITD) are common autoimmune disorders characterized by chronic immune-mediated inflammation. Although these diseases primarily affect the joints and thyroid gland respectively, growing evidence indicates that they also involve the central nervous system (CNS). Patients with RA and AITD frequently experience a range of neuropsychiatric manifestations, including depression, anxiety, cognitive dysfunction, and, in some cases, severe psychiatric disorders.
The interaction between the immune system and the nervous system plays a crucial role in the development of these neuropsychiatric symptoms. Chronic inflammation, circulating autoantibodies, pro-inflammatory cytokines, and immune cell activation can influence brain function by altering neurotransmitter systems, neuroendocrine pathways, and neural plasticity. These immune-mediated changes may contribute to mood disturbances and cognitive impairment observed in patients with RA and AITD.
Furthermore, neuropsychiatric manifestations significantly affect quality of life, treatment adherence, and overall disease outcomes. Despite their high prevalence, these symptoms are often underrecognized and undertreated in clinical practice. Understanding the shared immunological and neurobiological mechanisms underlying RA- and AITD-associated neuropsychiatric disorders is essential for early diagnosis and integrated management.
This review focuses on the spectrum of neuropsychiatric manifestations in patients with RA and AITD and highlights the underlying neuroimmune mechanisms that link autoimmune inflammation with CNS dysfunction.
2.Rheumatoid Arthritis: Systemic and Neurological Implications
Rheumatoid arthritis is a chronic inflammatory disease marked by symmetric polyarthritis and progressive joint destruction. Genetic predisposition, environmental triggers, and immune dysregulation contribute to its pathogenesis. Activated T cells, B cells, macrophages, and synovial fibroblasts produce pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6), which drive both local and systemic inflammation.
Beyond musculoskeletal involvement, RA is associated with extra-articular manifestations affecting the cardiovascular, pulmonary, and nervous systems. Persistent systemic inflammation has been implicated in the development of mood disorders, cognitive decline, and increased risk of neurodegenerative diseases among RA patients.
3. Autoimmune Thyroid Diseases and CNS Function
Autoimmune thyroid diseases include Hashimoto’s thyroiditis, typically resulting in hypothyroidism, and Graves’ disease, which leads to hyperthyroidism. Both conditions are mediated by autoantibodies directed against thyroid antigens. Thyroid hormones play a crucial role in brain development, synaptic transmission, and emotional regulation.
Alterations in thyroid hormone levels can directly affect CNS function, leading to symptoms such as depression, anxiety, irritability, and cognitive slowing. In addition to hormonal effects, immune-mediated inflammation and circulating autoantibodies may further contribute to neuropsychiatric disturbances in AITD.
4. Spectrum of Neuropsychiatric Manifestations
Neuropsychiatric symptoms are common in both RA and AITD. Depression is the most frequently reported manifestation, followed by anxiety disorders. Cognitive impairment, often described as reduced attention, memory deficits, and mental fatigue, is increasingly recognized. Sleep disturbances and chronic fatigue further exacerbate psychological distress. In rare cases, severe psychiatric presentations such as psychosis and delirium have been reported, particularly during periods of active disease or significant hormonal imbalance.
5. Epidemiology and Clinical Impact
Epidemiological studies suggest that up to one-third of patients with RA experience clinically significant depression, while anxiety disorders are also highly prevalent. Similarly, patients with AITD demonstrate a higher incidence of mood and anxiety disorders compared to the general population. These neuropsychiatric manifestations negatively affect daily functioning, treatment compliance, and overall disease outcomes, underscoring their clinical relevance.
6. Neuroimmune Mechanisms Linking Autoimmunity and CNS Dysfunction
Several mechanisms have been proposed to explain CNS involvement in RA and AITD. Pro-inflammatory cytokines can influence brain function either by crossing the blood–brain barrier or by activating neural signaling pathways. Chronic inflammation may also alter neurotransmitter metabolism and neural plasticity.
Increased permeability of the blood–brain barrier during systemic inflammation allows immune mediators to access the CNS. Additionally, activation of microglial cells contributes to neuroinflammation and neuronal dysfunction. Dysregulation of the hypothalamic–pituitary–adrenal axis further affects stress responses and mood regulation.
7. Neuron–Immune Crosstalk
The nervous system actively modulates immune responses through neural pathways such as the vagus nerve, which exerts anti-inflammatory effects. Autonomic nervous system imbalance has been observed in autoimmune diseases and may contribute to both immune activation and psychiatric symptoms. This bidirectional communication highlights the integrated nature of neuroimmune regulation in RA and AITD.
8. Therapeutic and Research Implications
Recognition of neuropsychiatric manifestations in RA and AITD has important therapeutic implications. Effective disease control using immunomodulatory therapies may improve psychological outcomes. In addition, targeted psychiatric interventions and a multidisciplinary approach are essential for comprehensive patient care.
Future research should focus on identifying biomarkers of CNS involvement, exploring neuroimaging correlates, and elucidating the role of emerging pathways such as the gut–brain–immune axis
1. Mood Disorders
Depression and anxiety are the most frequently reported neuropsychiatric manifestations in both RA and AITD. Chronic inflammation, persistent pain, fatigue, and disability in RA contribute to depressive symptoms. In AITD, altered thyroid hormone levels directly affect neurotransmitter systems involved in mood regulation, increasing susceptibility to depression and anxiety disorders.
2. Cognitive Dysfunction
Patients with RA and AITD often report cognitive complaints such as impaired memory, reduced concentration, slowed thinking, and “brain fog.” These cognitive changes are thought to result from systemic inflammation, cytokine-mediated neuroinflammation, and, in AITD, thyroid hormone imbalance affecting cerebral metabolism and synaptic function.
3. Anxiety and Stress-Related Disorders
Anxiety disorders are particularly common in patients with Graves’ disease due to excess thyroid hormone activity, which enhances sympathetic nervous system stimulation. In RA, anxiety may arise from disease unpredictability, chronic pain, and immune-mediated effects on stress-regulating brain circuits.
4. Psychosis and Severe Psychiatric Symptoms
Although less common, severe psychiatric manifestations such as psychosis, delirium, and schizophrenia-like symptoms have been reported in both RA and AITD. These presentations are more likely during periods of active disease, severe systemic inflammation, or extreme thyroid dysfunction, suggesting a direct immune or hormonal influence on CNS function.
5. Fatigue and Sleep Disturbances
Chronic fatigue and sleep disorders are prominent neuropsychiatric features in RA and AITD. Pro-inflammatory cytokines disrupt normal sleep–wake cycles, while pain, anxiety, and hormonal imbalance further worsen sleep quality. Persistent fatigue contributes to reduced cognitive performance and emotional distress.
6. Impact on Quality of Life
Neuropsychiatric manifestations substantially impair daily functioning, social interactions, and treatment adherence. Patients with untreated depression or anxiety are less likely to comply with long-term immunosuppressive or hormone-based therapies, leading to poorer disease control and increased healthcare burden.
7. Clinical Relevance
Despite their high prevalence, neuropsychiatric manifestations in RA and AITD are frequently underdiagnosed. Early recognition and integrated management involving rheumatologists, endocrinologists, psychiatrists, and neurologists are essential to improve both mental health and overall disease outcomes.
Conclusion
Neuropsychiatric manifestations represent a significant but often underrecognized aspect of rheumatoid arthritis and autoimmune thyroid diseases. Accumulating evidence supports a central role for immune-mediated mechanisms in the development of CNS dysfunction in these conditions. Improved understanding of neuroimmune interactions will facilitate early identification and integrated management strategies, ultimately enhancing patient quality of life and long-term outcomes. Neuropsychiatric manifestations represent a significant but often underrecognized aspect of rheumatoid arthritis and autoimmune thyroid diseases. Accumulating evidence supports a central role for immune-mediated mechanisms in the development of CNS dysfunction in these conditions. Improved understanding of neuroimmune interactions will facilitate early identification and integrated management strategies, ultimately enhancing patient quality of life and long-term outcomes.
Acknowledgment
The author(s) would like to acknowledge the guidance and support provided by faculty members and colleagues during the preparation of this review. We also acknowledge the availability of previously published scientific literature that contributed to a better understanding of the neuroimmune mechanisms involved in rheumatoid arthritis and autoimmune thyroid diseases. No external funding was received for this work.
Keywords
Rheumatoid arthritis; Autoimmune thyroid disease; Neuropsychiatric manifestations; Depression; Anxiety; Neuroimmune interaction; Central nervous system; Autoimmunity.
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