Paraneoplastic itch

Paraneoplastic itch | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Equine Veterinary Education This is a preprint and has not been peer reviewed. Data may be preliminary. 25 March 2025 V1 Latest version Share on Paraneoplastic itch Author : Philip Johnson 0000-0002-8180-7601 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174293281.15467293/v1 Published Equine Veterinary Education Version of record Peer review timeline 345 views 286 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract not-yet-known not-yet-known not-yet-known unknown This commentary presents information about paraneoplastic phenomena, with emphasis on paraneoplastic pruritus and its pathophysiology in the equine species. Pruritus that results from the development of underlying malignancy is often overlooked during the diagnostic and therapeutic management of affected equids. Unexplained pruritus should warrant consideration of a cancer diagnosis and, when appropriate, lead to expanded diagnostic testing in candidate patients. Earlier recognition of underlying cancer may lead to improved treatment outcomes or, in some cases, better welfare outcomes (euthanasia). The emerging role of interleukin-31 as a principal mediator of itchiness (regardless of underlying aetiology) is leading to new research, with an eye to the availability of novel treatment approaches. [1]¿p1 [1]¿m1 CLINICAL COMMENTARY Paraneoplastic itch Philip J. Johnson Veterinary Health Center, University of Missouri, Columbia, Missouri, USA Correspondence : Philip J. Johnson Email: [email protected] [1]¿p1 [1]¿m1 Summary This commentary presents information about paraneoplastic phenomena, with emphasis on paraneoplastic pruritus and its pathophysiology in the equine species. Pruritus that results from the development of underlying malignancy is often overlooked during the diagnostic and therapeutic management of affected equids. Unexplained pruritus should warrant consideration of a cancer diagnosis and, when appropriate, lead to expanded diagnostic testing in candidate patients. Earlier recognition of underlying cancer may lead to improved treatment outcomes or, in some cases, better welfare outcomes (euthanasia). The emerging role of interleukin-31 as a principal mediator of itchiness (regardless of underlying aetiology) is leading to new research, with an eye to the availability of novel treatment approaches. Paraneoplastic phenomena are broadly defined as clinical signs or bloodwork abnormalities that arise in association with malignant neoplasia, especially lymphoproliferative malignancies, but are not directly caused by the tumour’s physical presence, local effects on surrounding tissues, or metastasis. The Special Interest Group of the International Forum on the Study of Itch defines paraneoplastic itch as ”the sensation of itch as a systemic (not local) reaction to the presence of a tumour or haematological malignancy, neither induced by the local presence of cancer cells nor by tumour therapy” (Weisshaar et al ., 2015). Alternatively, Yosipovitch (2010) characterises paraneoplastic itch as pruritus that occurs during the natural progression of malignancy or precedes evidence of an underlying malignancy. This type of itch typically subsides following the resolution of the malignancy. While many paraneoplastic abnormalities result from the action of circulating hormones, hormone-like substances, cytokines, or antibodies targeting cancer cells, confident pathophysiological explanations cannot always be established. In numerous cases, the onset of paraneoplastic signs serves as the earliest clinical indicator—or even the sole sign—of an underlying malignancy. Importantly, paraneoplastic clinical signs often differ from those anticipated due to disease in the organ or tissue affected by the primary tumour. Furthermore, the impact of paraneoplastic disease can be more debilitating and potentially life-threatening than the primary neoplastic condition itself, especially in its early stages. In some instances, the severity of paraneoplastic disease may even hinder further diagnostic testing or treatment of the underlying cancer. Paraneoplastic signs or abnormalities typically resolve when the underlying primary tumour is successfully treated. Recurrence of paraneoplastic signs after successful or palliative treatment of a primary tumour often indicates the reemergence of the primary disease, either at the original site or at novel, remote locations. While certain tumour types are known to cause specific paraneoplastic effects, paraneoplastic syndromes are generally not reliably predictive of the nature of the underlying cancer. This is because any given paraneoplastic sign can result from a variety of different tumour types. Consequently, the specific diagnosis of an underlying cancer cannot be determined solely based on the presence of a particular paraneoplastic syndrome. Paraneoplastic phenomena are frequently overlooked, under-recognised, or misinterpreted in equine veterinary practice, often resulting in delays in both diagnosis and, when applicable, the initiation of treatment for underlying cancer. The identification of paraneoplastic abnormalities often precedes the recognition of the underlying malignancy, leading to misdirected treatments and further delays in addressing the primary disease. By including paraneoplastic syndromes in the differential diagnosis for relevant clinical presentations, veterinarians can potentially identify cancer earlier in its course, enabling earlier interventions and improving clinical outcomes—to the extent possible in equine oncology. Additionally, measurable aspects of paraneoplastic phenomena can serve as helpful markers to assess clinical progress and treatment efficacy, enhancing the impact of therapeutic interventions and potentially improving prognosis. Paraneoplastic conditions are somewhat uncommonly encountered (or reported) in equine veterinary practice. Among the clinical paraneoplastic syndromes more frequently reported in horses are cachexia/anorexia, fever, vasculitis, protein-losing enteropathy, hypertrophic pulmonary osteopathy (Marie syndrome), and pruritus. Hypercalcaemia and hypoglycaemia are also among the more commonly observed paraneoplastic endocrinopathies. Haematological abnormalities linked to paraneoplastic influences in horses include anaemia, hyperfibrinogenaemia, thrombocytopenia, and neutrophilia. As illustrated in the accompanying clinical report (Rovňanová et al., 2025), dermatological conditions, often stemming from autoimmunity, can also arise as paraneoplastic disease. Examples in horses include pemphigus, ulcerative coronitis, and pruritus. For a broader and more detailed exploration of paraneoplastic syndromes in horses, readers may consult comprehensive reviews (Ogilvie 1998; Axiak & Johnson 2012; Knottenbelt et al ., 2015; Johns 2024). Pruritus (or itchiness) is a common clinical sign resulting from an abnormal skin sensation that triggers the urge to scratch or rub the affected area. It is a significant source of morbidity in human cancer patients, who describe the severity of PP as ranging from mild to unbearable, often severely compromising their quality of life. In human oncology, pruritus is particularly associated with cancers of the skin, liver, hematopoietic system, gallbladder, and biliary tract (Larson et al ., 2019). Paraneoplastic pruritus (PP) is typically generalized and, in its early stages, is not accompanied by visible dermatological changes. However, prolonged PP can lead to excoriation, alopecia, bruising, pigmentary changes, and scarring. In horses, PP has been documented as a complication of lymphosarcoma (Finley et al ., 1998), renal carcinoma (Curnow 2020), mast cell tumour (Combarros et al ., 2020), and poorly differentiated round-cell neoplasia (possibly aggressive lymphoma or a histiocytic sarcoma) (Rovňanová et al ., 2025). The severity of PP does not necessarily correlate with the extent of the underlying cancer, and it may precede other signs of malignancy by several years. Paraneoplastic pruritus should be suspected when itchiness arises in patients undergoing treatment for malignant disease or in those with chronic pruritus that lacks a satisfactory explanation, particularly after a thorough physical examination and diagnostic workup. Underlying malignancy must also be considered in patients experiencing chronic pruritus without evidence of primary skin disease. Gross physical and histopathological examination of biopsied skin affected by PP often reveals minimal and nonspecific changes. In certain cases, findings may include vasculitis or secondary lesions resulting from self-inflicted trauma due to excessive scratching (Knottenbelt et al , 2015). Additionally, as highlighted in the accompanying report (Rovňanová et al ., 2025), commonly used treatments for equine pruritus, such as corticosteroids and other anti-inflammatory therapies, are often disappointing for the treatment of PP. Paraneoplastic pruritus should be distinguished from skin cancer-associated pruritus, in which itching results from a localized reaction to malignancy. Skin cancer pruritus is frequently observed in human patients with cutaneous T-cell lymphoma. In contrast, PP is commonly associated with Hodgkin’s lymphoma (25% prevalence), non-Hodgkin’s lymphoma (15% prevalence), and multiple myeloma. Among these, Hodgkin’s lymphoma is the most frequently reported malignancy linked to PP (Cohen, 1994). Approximately 30% of Hodgkin’s lymphoma patients develop PP, and in 10% of these cases, it serves as the initial clinical sign of the disease. Although little research has been conducted PP in equids, pathophysiological mechanisms observed in other species provide valuable insights. These mechanisms include the invasion of skin by cancer cells, intraepidermal T-cell destruction mediated by cancer-derived cytokines, direct nerve stimulation or compression, cholestasis due to bile duct obstruction, histamine release from mast cells, and the secretion of inflammatory cytokines—particularly interleukin-31—that provoke itching (Knottenbelt et al ., 2015; Rowe and Yosipovitch, 2016a). Notably, PP can sometimes emerge following the initiation of cancer treatment, suggesting that pruritus may sometimes be triggered either by drug-related factors or by mediators released from dying cancer cells. Interleukin-31 (IL-31), a cytokine within the IL-6 family, has emerged as a key player in both immune/inflammatory pruritus and PP. Often referred to as the ’itchy cytokine,’ IL-31 is a potent trigger of pruritus in various dermatological and inflammatory conditions (Furue et al ., 2018). Primarily secreted by CD4+ type 2 (TH 2 ) helper T cells, IL-31 binds to either the IL-31 receptor A (IL-31RA) or the oncostatin M receptor (OSMR) (Dillon et al ., 2004). IL-31RA is highly expressed in sensory dorsal root ganglion neurons, where the sensation of itch originates (Zhang et al ., 2008). Binding of IL-31 to its receptor on these sensory neurons triggers nerve stimulation, leading to pruritus. While the role of IL-31 as a primary mediator of itch in inflammatory diseases such as atopic dermatitis, psoriasis, and other allergic conditions has been well-established, its contribution to PP is less clearly defined (Borgia et al ., 2022), especially in the equine species. Some (human) studies suggest a correlation between IL-31 levels, itching severity, and the stage of underlying cancer (Borgia et al ., 2022; Akhtar et al ., 2024). Elevated expression of IL-31 appears to be a significant and emerging factor driving the severity of PP. Activation of the IL-31/IL-31RA axis plays a significant role in the development of pruritus across multiple species. The relationship between activation of the IL-31/IL-31RA axis and pruritus is increasingly being explored in horses affected by insect bite hypersensitivity (IBH), particularly Culicoides hypersensitivity (commonly known as ”sweet itch”). In a study of four horses with chronic pruritus of unknown origin, upregulated transcription of IL-31 was observed in lesioned skin but not in unaffected skin (Fettelschoss et al ., 2021). Another transcriptomics study compared lesioned and normal skin from 10 IBH-affected horses and 9 healthy controls, revealing that both IL-31RA and OSMR transcription were upregulated in IBH-affected horses, regardless of whether the skin was lesioned or normal (Cvitas et al ., 2020). However, differences in IL-31 expression were not detected in that study. Further supporting the role of IL-31, Olomski et al . (2020) demonstrated that IL-31 transcription was upregulated in peripheral blood mononuclear cells from IBH-affected horses following treatment with an allergen extract derived from Culicoides nubeculosus , but not in mononuclear cells from unaffected horses. These findings contributed to the development of a vaccine targeting equine IL-31, which showed promising clinical outcomes in IBH-affected horses (Olomski et al ., 2020; Fettelschoss et al ., 2021; Fettelschoss-Gabriel et al ., 2021). However, more recent work by Craig et al . (2024) found no evidence of upregulated IL-31 transcription in a cohort of IBH-affected horses. Those authors proposed that dysregulated IL-31 signaling might occur downstream or in localised tissues, or that unidentified receptor splice variants could be involved. These conflicting findings highlight the need for further research to clarify the role of the IL-31/IL-31RA axis in the pathogenesis of pruritus in IBH-affected horses—and, by extension, in horses with PP. Novel therapeutic agents targeting inhibition of the IL-31/IL-31RA axis are currently being developed to alleviate pruritus associated with cutaneous (immune) hypersensitivity. However, additional studies are needed to determine whether these treatments could also effectively mitigate PP. For instance, activation of the IL-31/IL-31RA axis stimulates the Janus kinase (JAK)/STAT pathway, and JAK inhibitors have shown promise as effective treatments for pruritus in conditions such as atopic dermatitis and psoriasis. Despite that potential, the employment of JAK inhibitors for immune-mediated pruritus is attended by significant caveats, including warnings about potential increases in malignancy risk. As a result, this class of drugs may not be safe for the management of PP, as a result of risk of worsening underlying cancer (Han et al ., 2023). Nemolizumab, an experimental humanised monoclonal antibody developed by Chugai Pharma, blocks IL-31RA and inhibits IL-31 signaling. This treatment has proven effective in managing pruritus in humans with conditions such as prurigo nodularis and atopic dermatitis (Kabashima and Irie, 2021). Similarly, lokivetmab (Cytopoint™, Zoetis™), a monoclonal antibody that binds and neutralizes canine IL-31, has been successful in suppressing pruritus in dogs with allergic dermatitis (Fleck et al ., 2021). However, for equine patients, the practicality of daily JAK inhibitor treatments or monthly monoclonal antibody treatments is limited due to patient size. Moreover, the efficacy of these treatments for managing PP in horses remains unknown. The use of vaccines to provoke anti-IL-31 antibodies could offer a practical and effective solution for managing IL-31-associated pruritus in horses, making it a particularly promising avenue for further exploration (Olomski et al . 2022). The most effective approach to managing PP is to effectively treat the underlying malignancy. In cases in which human malignancies are unresponsive to treatment, alternative therapies such as selective serotonin reuptake inhibitors, mirtazapine, gabapentin, thalidomide, opioids, aprepitant, and histone deacetylase inhibitors have shown potential in alleviating PP (Rowe and Yosipovitch, 2016a). Additionally, orally administered corticosteroids have demonstrated effective anti-pruritic effects, correlating with reduced serum levels of IL-31 in patients with malignancy-associated pruritus (Rowe and Yosipovitch, 2016b). Although lacking efficacy when used in the accompanying case (Rovňanová et al ., 2025), corticosteroids may yet represent a practical treatment option for some horses affected by PP. The combination of clinical signs such as loss of bodily condition, unexplained pruritus, and the development of characteristic alopecia with a ’moth-eaten’ appearance should prompt veterinary diagnosticians to consider PP and the potential presence of underlying malignancy. In such cases, a comprehensive diagnostic approach is warranted, including cavitary imaging (e.g., ultrasonography), analysis of pleural or peritoneal fluid, haematological and plasma biochemical profiling, bone marrow evaluation, and assessment of cancer-related biomarkers such as parathyroid hormone-related protein and thymidine kinase. As highlighted in this case, a deeper and more nuanced understanding of the clinical signs, pathophysiology, and treatment efficacy of paraneoplastic syndromes in horses can be achieved through meticulous veterinary examinations, thorough postmortem investigations, and the dissemination of findings in published literature. AUTHOR CONTRIBUTIONS P. Johnson prepared the manuscript. CONFLICT OF INTEREST STATEMENT No conflicts of interest have been declared ETHICS STATEMENT None ORCID Philip J. 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Cytokine Growth Factor Rev . 19 , 347–56. doi:10.1016/j.cytogfr.2008.08.003. Information & Authors Information Version history V1 Version 1 25 March 2025 Peer review timeline Published Equine Veterinary Education Version of Record 22 Apr 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Equine Veterinary Education Authors Affiliations Philip Johnson 0000-0002-8180-7601 [email protected] University of Missouri View all articles by this author Metrics & Citations Metrics Article Usage 345 views 286 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Philip Johnson. Paraneoplastic itch. Authorea . 25 March 2025. DOI: https://doi.org/10.22541/au.174293281.15467293/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. 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