Ocular and oropharyngeal manifestations of chronic graft versus host disease (cGVHD) represent the most frequent mucosal disorders characterized by inflammatory and fibrotic changes associated with xerophthalmia and xerostomia, impairment of quality of life and social functioning. Keratoconjunctivitis sicca (KCS) is the most frequent ocular manifestation of cGVHD causing intense ocular discomfort symptoms and impairment of visual function. A better understanding of pathogenic mechanisms and the availability of biomarkers of activity, severity and/or response to therapies of cGVHD will lead to improvement of GVHD management, quality of life and daily functioning and decrease costs. Neuromediators, including nerve growth factor (NGF), modulate ocular and oropharyngeal inflammation, improve would healing, maintain sensitivity and stimulate tear production. The aims of this prospective, non- interventional study are to: (i) characterize the role of local NGF pathway , neuropeptides and cytokines in cGVHD; (ii) to evaluate the potential use of NGF pathway assessment as biomarker of activity, severity and progression of cGVHD; (iii) to identify subpopulations of patients with cGVHD that could benefit from neuroimmune modulatory drugs. 15 patients with cGVHD and ocular involvement and 15 healthy subjects will be included. Complete ocular, nasal and oropharyngeal examination will be performed at baseline and after 6 and 12 months. Changes of tear, nasal secretion and salivary levels of NGF, pro-NGF, neuropeptides and cytokines and of conjunctival, nasal and oropharyngeal expression of NGF receptors, will be evaluated and related with clinical findings. The results of this study will allow to better understand the role of neuroinflammation in cGVHD with mucosal involvement and to identify potential biomarkers of clinical severity and activity, and novel therapeutic target.
This study represents the first attempt to characterize the role of NGF pathway in patients with cGVHD and ocular involvement in order to characterize the role of neuroinflammation and to identify biomarker of the disease and/or novel therapeutic target. Ocular and oropharyngeal involvement are the most frequent mucosal complications of cGVHD, severely impairing quality of life and functioning of the affected patients. Few data exist on the involvement of the nasal cavities during GVHD, but sinusitis and rhinitis has been describe leading to worsening of patients' quality of life. The primary pathogenic mechanism of dry eye and xerostomia in GVHD is lacrimal and salivary gland dysfunction, associated to fibrotic and immune reactions at the mucosal surface. However, the role of neuroimmunity in the development of cGVHD has not yet been evaluated and the relationship between ocular and oropharyngeal involvement have not been characterized. Dry eye associated with GVHD is known to be difficult to manage with conventional dry eye treatments. The NIH Consensus Working Group established guidelines for ancillary therapy and supportive care in chronic GVHD. However, most of available treatments aim solely at relieving the dry eye symptoms by means of lubrication (with lacrimal substitutes) and/or by decreasing tear drainage (by punctual occlusion) and ocular surface inflammation (by topical steroids or cyclosporine).
In addition, patients with cGVHD and KCS will be evaluated for other mucosal involvement including oropharyngeal and nasal evaluation with cytology assessment of the NGF pathway, to investigate the involvement of neuroinflammation in the pathogenesis of mucosal involvement during cGVHD.
This study will provide evidence on the role of NGF pathway in cGVHD. NGF is capable to provide trophic support to the ocular and oropharyngeal mucosae, to modulate the immune reaction, to promote corneal and oropharyngeal wound healing and sensitivity and to improve tear quality and quantity. Taken together, these functions make NGF a pleiotropic factor and a potential biomarker and therapeutic agent for several ocular and oropharyngeal inflammatory diseases, including GVHD.
The results of this study will allow to identify potential biomarkers of disease activity, severity and progression and/or response to treatments. In addition, the demonstration of a role of NGF in cGVHD will pave the way to a potential use of topical NGF as treatment for cGVHD patients.
The increasing understanding of the mechanisms underlying the development of cGVHD may lead to a better management of patients with improvements in clinical outcomes and quality of life and, as consequence to a cost saving for the National Health System (NHS).
In fact, the identification of novel biomarkers of the disease activity and progression would result in a better management of these patients with improvements in clinical outcomes and reduced need of medical and personal assistance, and to an improvement of the patients' quality of life and ability to perform daily activities including work.
At the same time, our results are expected to have a major impact on basic research, clinical knowledge, and pharmaceutical industry, since they will identify cGVHD patients population that could benefit by novel therapeutic interventions to be confirmed in subsequent clinical trials.
The results of the project will advance knowledge on clinical science in ocular, oropharyngeal and nasal physiopathology and disease treatment. Specifically, the study will define the involvement of NGF on tear and salivary production and function, ocular, oropharyngeal and nasal immune reaction, healing and innervation in patients with cGVHD, a challenging systemic disease in which ocular and oropharyngeal involvement represent a major burden decreasing quality of life and function of the affected patients.