Speaker: Ulrike RAAP
Acute itch serves a biological purpose by prompting us to remove irritants like parasites, insects, or toxic plants from our skin. For example, if we don't scratch away parasites like those causing scabies, they can lay eggs, leading to severe consequences. On the other hand, chronic itch is a symptom of an underlying disease and acts as an alarm signal from the skin or internal organs. Unlike acute itch, it is not caused by external parasites. Historical figures like Jean-Paul Marat, who suffered from a severe skin disease and chronic itch in the 18th century, highlight the enduring struggle with this condition. Marat, who spent three years in cold baths to alleviate his itch, was ultimately assassinated, making him the first known person to describe chronic itch. The prevalence of itch ranges from 3% to 17% in adults, with a lifetime prevalence of up to 21%. Patients with chronic itch experience significant burdens, including social limitations, sleep disorders, impaired quality of life, and psychological issues. Diagnosing the underlying causes of chronic itch and providing effective therapy is challenging. Diagnosis consider whether the skin is inflamed, non-lesional, or shows chronic scratch lesions. Causes can be dermatologic, systemic, neurologic, psychiatric, multifactorial, or unknown, making tailored treatment essential for effective management.
Several skin diseases are associated with chronic and severe itch, including chronic prurigo, chronic spontaneous urticaria, and atopic dermatitis, each exhibiting different scratching behaviors: chronic prurigo patients use metal objects or knives, chronic spontaneous urticaria patients rub their skin, and atopic dermatitis patients scratch until they bleed. Other diseases like cutaneous lymphoma, conditions requiring hemodialysis, notalgia paresthetica, and somatoform pruritus also manifest diverse clinical outcomes related to itch. Additionally, systemic diseases such as cholestatic liver disease, end-stage renal disease, and haematological conditions like lymphoma, diabetes, and hyperthyroidism can cause itch. Understanding the mechanisms of itch requires knowledge of skin innervation and the functions of afferent and efferent nerve fibers. Recent research highlights that different nerve fibers, including large, afferent small, and efferent autonomic fibers, play roles in itch regulation, with afferent small fibers being particularly significant. These neurons, belonging to various classes and possessing both sensory and efferent functions, respond to different microenvironments, which may explain the varied aspects of itch.
Cutaneous nerves, such as Merkel cells, interact with neuronal encoding. Keratinocytes, along with Schwann cells and inflammatory cells, promote immunomodulation, illustrating neuroimmune interactions. Skin nociceptors signal immune cells, initiating neurogenic inflamation and establishing bidirectional communication between immune cells and peripheral nerves. It is evident in conditions like itch, where neural sensitization occurs. For instance, nerve fibre numbers decrease in skin inflammation and atopic dermatitis. Neurogenic itch involves inflammation, inflammatory response, mast cell activation, increased receptor and neuropeptide levels in the spinal cord, and activation of astrocytes. It leads to reduced descending inhibition, changes in gray matter volume, and higher brain region activation. Interestingly, the same brain regions activated during itch are also activated by rewards, which may explain why scratching is persistent and pleasurable. The classical itch pathway involves histamine, as shown in Brian Kim's work, and is effective in treating chronic spontaneous urticaria with antihistamines. However, this approach does not work for atopic dermatitis, indicating that different diseases require different treatments. The neuroimmune axis of itch involves an inflammatory response with ILC2 cells, Th2 cells, basophils, and mast cells, which release mediators like histamine and IL31RA. These mediators activate receptors on neurons, causing neuronal activation through channels influenced by factors such as pH changes during inflammation.
Basophils play a crucial role in the early phase of the inflammatory response, being among the first cells to invade the skin. Though not abundant, they release various mediators, including IL-4, IL-13, TSLP, LTC, neuropeptides, nerve growth factors, IL-31, S1PR1, and histamine, activating peripheral neurons through their receptors. In chronic itch, neuroimmune interactions involve basophils and eosinophil granulocytes, which release IL-4, IL-31, and IL-13, similarly activating peripheral nerves. T-cells contribute to these interactions by releasing cytokines like IL-4 and IL-31, while keratinocytes release TSRP. Neuronal channels such as TRPA1 and TRPV1 are also activated in these processes. Understanding the mechanisms of itch can also be approached through therapeutic responses. A recent review by Martin Metz's group from Berlin's Charité highlights therapeutic options for atopic dermatitis and explains the signaling pathways of itch in this disease. Treatments such as Nemolizumab for IL-31 regulation, dupilumab for IL-4 and IL-13, and other medications like lebrikizumab, tralokinumab, and JAK inhibitors provide relief from itch and offer insights into the underlying mechanisms of this condition.
A recent review by Garovich and colleagues presented that specific cytokine profiles and itch levels may elucidate pruritus-related pathways. The review focuses on the burden of pruritus in different dermatological diseases. For instance, Th1-classified diseases like lichen planus, regulated by interferon-gamma and TNF alpha, exhibit moderate itch. Psoriasis, regulated by IL-17, IL-22, and TNF alpha, shows a very low level of itch. Conversely, conditions with a high burden of itch, such as scabies, atopic dermatitis, prurigo nodularis, chronic urticaria, and bullous pemphigoid, show cytokine patterns of IL-4, IL-13, and IL-31. Bullous pemphigoid, traditionally seen as a classical autoimmune disease, is interestingly classified here as a type 2 inflammation, which raises questions about the nature of inflammation in this disease. Patients with bullous pemphigoid experience significant pruritus but do not scratch as intensely as those with prurigo nodularis or atopic dermatitis.
A study utilizing the TriNetX platform, which includes data from over 100 million patients in the US healthcare system, conducted a propensity-matched retrospective cohort analysis of over 1.7 million cases and a similar number of controls. The study found that pruritus significantly increases the risk of being diagnosed with autoimmune blistering skin diseases, such as bullous pemphigoid. The hazard ratio for developing bullous pemphigoid in pruritus is 6.9, indicating a strong association. Bullous pemphigoid is characterized by tense blisters, erythema, and severe itching. The study emphasizes the connection between the skin and brain in bullous pemphigoid and focuses on the eosinophil granulocyte and IL-31 axis. In patients with bullous pemphigoid, high levels of eosinophils were found in the blisters. For instance, one million eosinophils can be isolated from one million blisters, requiring 60 ml of blood to obtain the same amount from a healthy patient. The eosinophils were stained with EG1, and the IL-31 overlay resulted in a yellow expression, indicating IL-31 positivity. Blister fluid showed increased levels of IL-31, similar to levels found in patients with mastocytosis, but IL-31 was absent in the serum of controls. Eosinophils isolated from the blister fluid and cultured produced levels of IL-31 in the supernatants comparable to those found in the blister fluid.The study by Bernard Homa demonstrated that neurons express the IL31 receptor (IL31 RA) prominently. When neurons are stimulated with IL31, there is a significant outgrowth of nerve fibers, illustrating the pathway of itch sensation from the skin to the brain. Various approaches are used to understand better this complex sensation, including examining therapeutic responses to anti-itch drugs and immunological perspectives. Immune cells, such as keratinocytes, mast cells, eosinophils, basophils, and T cells, are crucial in activating neuronal and neuroimmune interactions in the skin, leading to the sensation of itch.
European Academy of Allergy and Clinical Immunology (EAACI), 2024 31st May-3rd June, Valencia
