Pathogenesis Of Prurigo Nodularis Research Articles

Prurigo Nodularis: Pathogenesis and the Horizon of Potential Therapeutics.

Chronic pruritus that lasts for over 6 weeks can present in various forms, like papules, nodules, and plaque types, with prurigo nodularis (PN) being the most prevalent. The pathogenesis of PN involves the dysregulation of immune cell-neural circuits and is associated with peripheral neuropathies, possibly due to chronic scratching. PN is a persistent and challenging condition, involving complex interactions among the skin, immune system, and nervous system. Lesional skin in PN exhibits the infiltration of diverse immune cells like T cells, eosinophils, macrophages, and mast cells, leading to the release of inflammatory cytokines and itch-inducing substances. Activated sensory nerve fibers aggravate pruritus by releasing neurotransmitters, perpetuating a vicious cycle of itching and scratching. Traditional treatments often fail, but recent advancements in understanding the inflammatory and itch transmission mechanisms of PN have paved the way for innovative therapeutic approaches, which are explored in this review.

Prurigo nodularis: new insights into pathogenesis andnovel therapeutics.

Prurigo nodularis (PN) is an inflammatory skin condition characterized by intensely pruritic nodules on the skin. Patients with PN suffer from an intractable itch-scratch cycle leading to impaired sleep, psychosocial distress and a significant disruption in quality of life. The pathogenesis of PN is associated with immune and neural dysregulation, mediated by inflammatory cytokines [such as interleukin (IL)-4, -13, -17, -22 and -31] and neuropeptides (such as substance P and calcitonin gene-related peptide). There is a role for type 2 inflammation in PN in addition to T-helper (Th)17 and Th22-mediated inflammation. The neuroimmune feedback loop in PN involves neuropeptides released from nerve fibres that cause vasodilation and further recruitment of inflammatory cells. Inflammatory cells, particularly mast cells and eosinophils, degranulate and release neurotoxins, as well as nerve growth factor, which may contribute to the neuronal hyperplasia seen in the dermis of patients with PN and neural sensitization. Recent studies have also indicated underlying genetic susceptibility to PN in addition to environmental factors, the existence of various disease endotypes centred around degrees of type 2 inflammation or underlying myelopathy or spinal disc disease, and significant race and ethnicity-based differences, with African Americans having densely fibrotic skin lesions. Dupilumab became the first US Food and Drug Administration-approved therapeutic for PN, and there are several other agents currently in development. The anti-IL-31 receptor A inhibitor nemolizumab is in late-stage development with positive phase III data reported. In addition, the oral Janus kinase (JAK) 1 inhibitors, abrocitinib and povorcitinib, are in phase II trials while a topical JAK1/2 inhibitor, ruxolitinib, is in phase III studies.

New insight into prurigo nodularis: Proadrenomedullin N-terminal 20 peptide mediates mouse mast cell activation via Mrgprb2.

Prurigo nodularis (PN) is a chronic inflammatory skin disorder that is characterized by extremely itchy nodules. Proadrenomedullin N-terminal 20 (PAMP) activates mast cell degranulation via Mas-related G protein-coupled receptor X2 (MRGPRX2), which is associated with pruritus in allergic contact dermatitis. However, the mechanisms underlying the action of PAMP and MRGPRX2 in PN remain unclear. To determine the role of PAMP-induced mast cell activation via MRGPRX2 (mouse homologous Mrgprb2) in PN. The expression of PAMP and the number of MRGPRX2-expressing mast cells in the skin biopsies of patients with PN, atopic dermatitis (AD), and healthy participants were analyzed using immunohistochemistry and immunofluorescence, respectively. The biphasic response of PAMP9-20 mediated by Mrgprb2 in mouse peritoneal mast cells (PMC) was validated in vitro using qRT-PCR, ELISA, flow cytometry, and siRNA techniques. PAMP expression and the number of MRGPRX2+ mast cells in lesional PN skin, but not in AD, were elevated compared to healthy skin. PAMP9-20 mediates the immediate and delayed phase responses of PMC, such as degranulation, histamine and β-hexosaminidase release, and secretion of inflammatory factors such as CCL2, TNF-α, and GM-CSF. These effects were inhibited when Mrgprb2 expression was silenced. Silencing Mrgprb2 did not affect the biphasic response of PMC that was induced by IgE-FcεRI activation. The results show that PAMP mediates mouse mast cell activation via Mrgprb2, which may be involved in the pathogenesis of PN. The PAMP/ Mrgprb2 pathway, independent of classical IgE signaling, could be developed as a candidate drug target for treating PN.

Molecular mechanisms of pruritus in prurigo nodularis.

Pruritus is the most common symptom of dermatological disorders, and prurigo nodularis (PN) is notorious for intractable and severe itching. Conventional treatments often yield disappointing outcomes, significantly affecting patients' quality of life and psychological well-being. The pathogenesis of PN is associated with a self-sustained "itch-scratch" vicious cycle. Recent investigations of PN-related itch have partially revealed the intricate interactions within the cutaneous neuroimmune network; however, the underlying mechanism remains undetermined. Itch mediators play a key role in pruritus amplification in PN and understanding their action mechanism will undoubtedly lead to the development of novel targeted antipruritic agents. In this review, we describe a series of pruritogens and receptors involved in mediating itching in PN, including cytokines, neuropeptides, extracellular matrix proteins, vasculogenic substances, ion channels, and intracellular signaling pathways. Moreover, we provide a prospective outlook on potential therapies based on existing findings.

A case-control study addressing the population of epidermal and dermal inflammatory infiltrate including neural milieu in primary prurigo nodularis using S-100 and toluidine blue stain and its therapeutic implications.

The pathogenesis of prurigo nodularis (PN) is considered to be multifactorial, with numerous cells and cytokines confabulating to produce an aberrant immune response. A cross-sectional observational study was done in cases of untreated primary prurigo nodularis cases with histopathological assessment in 49 cases from lesional and nonlesional skin with assessment of epidermal and dermal changes, dermal infiltrate, S-100 andtoluidine blue staining to assess the expression of nerve and mast cells. The most common histological changes seen in lesional skin were hyperkeratosis (98%), irregular hyperplasia (69.4%), hypergranulosis (69.4%), subepidermal clefting (6%), vertical collagen bundles (51.0%), and dermal fibrosis (48.9%). Chronic inflammatory infiltrate was seen in all cases (100%) predominantly of lymphocytes (100%) followed by eosinophils (18.4%), plasma cells (8.2%), and neutrophils (2.0%). There was a marked increase in the expression of S-100 (6.92 ± 3.40 vs. 3.94 ± 2.15, P < 0.001) and toluidine blue (4.99 ± 4.47 vs. 1.22 ± 1.28, P < 0.001) in the lesional skin as compared to the nonlesional skin. We can infer that the epidermal and dermal pathology in PN is related to the infiltrate of lymphocytes, mast cells, and neural hyperplasia which perpetuate the pathogenesis by triggering the itch-inflammation cycle. Thus, apart from immunosuppressive agents that target lymphocytes and their cytokines, therapy targeted at mast cells and neural proliferation may be needed to treat prurigo nodularis.

Single-cell profiling of prurigo nodularis demonstrates immune-stromal crosstalk driving profibrotic responses and reversal with nemolizumab

Prurigo nodularis (PN) is a chronic neuroimmune skin disease characterized by bilaterally distributed pruritic hyperkeratotic nodules on extremities and trunk. Neuroimmune dysregulation and chronic scratching are believed to both induce and maintain the characteristic lesions. This study sought to provide a comprehensive view of the molecular pathogenesis of PN at the single-cell level to identify and outline key pathologic processes and the cell types involved. Features that distinguish PN skin from the skin of patients with atopic dermatitis were of particular interest. We further aimed to determine the impact of the IL31RA antagonist, nemolizumab, and its specificity at the single-cell level. Single-cell RNA-sequencing of skin from 15 healthy donors and nonlesional and lesional skin from 6 patients each with PN and atopic dermatitis, combined with spatial-sequencing using the 10x Visium platform. Integration with bulk RNA-sequencing data from patients treated with nemolizumab. This study demonstrates that PN is an inflammatory skin disease characterized by both keratinocyte proliferation and activation of profibrotic responses. This study also demonstrates that the COL11A1+ fibroblast subset is a major contributor to fibrosis and is predominantly found in the papillary dermis of PN skin. Activation of fibrotic responses is the main distinguishing feature between PN and atopic dermatitis skin. This study further shows the broad effect of nemolizumab on PN cell types, with a prominent effect driving COL11A1+ fibroblast and keratinocyte responses toward normal. This study provides a high-resolution characterization of the cell types and cellular processes activated in PN skin, establishing PN as a chronic fibrotic inflammatory skin disease. It further demonstrates the broad effect of nemolizumab on pathological processes in PN skin.

Dupilumab for Recurrent Prurigo Nodularis: A Case Report and Review of the Literature

Prurigo nodularis (PN) is a chronic inflammatory skin disease that affects the quality of life of patients and is classified in the ICD-10 as a group of chronic lichen simplex and itchy skin diseases (ICD-10/L28) with an incidence of approximately 36.7-148.53 per 100,000 people. The pathogenesis of PN is closely related to type 2 inflammatory response. There are no standardized treatment guidelines for this disease, and traditional anti-pruritic treatment regimens often fail to control the vicious pruritic-scratch cycle in PN and have a poor safety profile. Traditional treatment options for PN include oral antihistamines, thalidomide, and topical hormones, calcium phosphatase inhibitors, and other treatments. However, traditional treatment options often suffer from poor pruritus control and high side effects. A patient with prurigo nodularis was admitted to our hospital who responded poorly to routine topical glucocorticoids and other drug therapies and relapsed after discharge from treatment. After readmission, the patient was successfully treated with dupilumab, a biological agent targeting interleukin-4/13. The patient's rash was significantly flattened, and the pruritus NRS score was significantly decreased. In this case, successful treatment of refractory PN with dupilumab could provide new ideas for treatment.

Increased IL-31 expression in serum and tissue protein in prurigo nodularis.

Background:Prurigo nodularis (PN) is a chronic pruritic skin disease which can greatly impact patients’ quality of life. Moreover, the pathogenesis remains unclear, making it a difficult-to-treat condition.Aims:To investigate the expression of interleukin-31 (IL-31) in serum and skin biopsy specimens of PN patients and healthy subjects and identify its possible correlation to disease severity and itch intensity.Methods:Patients with PN and healthy volunteers were recruited for the study. Expression levels of IL-31 were measured by enzyme-linked immunosorbent assay and immunohistochemistry. Baseline characteristics, disease activity, itch intensity, and related laboratory results were collected.Results:Forty-three PN patients and 31 healthy subjects participated in our study. The PN patients had significantly higher mean serum IL-31 levels than the healthy subjects (52.9 ± 18.2 versus 36.3 ± 10.7 pg/ml, p < 0.001). Epidermal and dermal PN lesions also exhibited significantly higher IL-31 expression compared with the healthy skin (p < 0.001 and p = 0.01, respectively). However, there was no significant difference in serum or lesional expression of IL-31 by disease severity or itch intensity.Conclusion:Increased IL-31 expression in serum and PN lesions suggests that IL-31 has a potential role in the pathogenesis of PN.

A prospective study examining the expression of STAT 1, 3, 6 in prurigo nodularis lesions with its immunopathogenic and therapeutic implications

Prurigo nodularis (PN) is a chronic dermatologic condition manifesting as multiple papulonodular lesions occurring on the background of intense pruritus. PN could be primary or secondary. The exact immune pathogenesis of PN is not yet clear, and multiple pathways are proposed with the JAK-STAT pathway rarely being investigated. In this study, our aim was to assess the role of Th cells in PN by comparing the expression of STAT 1, 3, and 6 in involved and normal skin of primary prurigo nodularis. A total of 49 clinico-histopathologically proven cases of primary prurigo nodularis were included. Two skin biopsies for each patient from lesional and non-lesional skin were stained with STAT 1, 3, and 6, and the nuclear staining pattern in the epidermis was graded as strong, moderate, weak, or none. Statistically significant expression of STAT 3 and STAT 6 staining was seen in the epidermis of the lesional skin as compared to non-lesional skin. Our study showed a marked dominance of STAT 3 and STAT 6 staining in the epidermis which signifies that the keratinocytes play an important role in PN and suggest that Th2, Th17, and Th22 cytokines mediate the tissue response in PN.

Abnormal keratin expression pattern in prurigo nodularis epidermis.

BackgroundPrurigo nodularis (PN) is a highly pruritic, chronic dermatosis and difficult to treat. PN lesions are characterized by existence of many hyperkeratotic, erosive papules and nodules. However, the pathogenesis of PN still remains unelucidated.AimTo clarify the keratin role in the epidermis hyperproliferation, the keratin expression pattern in the PN lesional skin.MethodsIn this study, we enrolled 24 patients with PN and 9 healthy control volunteers. K1/K10, K5/K14, K6/K16/K17 expression pattern were investigated by using immunohistochemical staining.ResultsThe lesional skin consists of the thickened spinous layers, in which active cell division was found. K5/K14 were upregulated in PN lesional epidermis, the staining signal localized in the basal layer and lower suprabasal layers. Hyperproliferation‐associated K6 was found in all layers of epidermal lesional skin, especially in the spinous layers. In contrast, K16 was only detected in the basal and lower suprabasal layers, K17 was observed in the basal and spinous layers. Terminal differential keratins K1/K10 were upregulated, detected in the pan‐epidermis, but spared in the basal and low suprabasal layers.ConclusionThe keratinocytes enter an alternative differentiation pathway, which are responsible for the activated keratinocyte phenotype, abnormal keratins expression potentially contributes to the keratinocytes proliferation, subsequently lead to increased lesional skin epidermis thickness, hyperkeratiosis and alteration of skin barrier properties.

Transcriptomic characterization of prurigo nodularis and the therapeutic response to nemolizumab

Prurigo nodularis (PN) is a debilitating, difficult-to-treat, intensely pruritic, chronic inflammatory skin disease characterized by hyperkeratotic skin nodules. The pathogenesis of PN is not well understood but is believed to involve cross talk between sensory nerve fibers, immune cells, and the epidermis. It is centered around the neuroimmune cytokine IL-31, driving an intractable itch-scratch cycle. We sought to provide a comprehensive view of the transcriptomic changes in PN skin and characterize the mechanism of action of the anti-IL-31 receptor inhibitor nemolizumab. RNA sequencing of biopsy samples obtained from a cohort of patients treated with the anti-IL-31 receptor inhibitor nemolizumab and taken at baseline and week 12. Generation and integration of patient data with RNA-Seq data generated from reconstructed human epidermis stimulated with IL-31 and other proinflammatory cytokines. Our results demonstrate that nemolizumab effectively decreases IL-31 responses in PN skin, leading to effective suppression of downstream inflammatory responses including TH2/IL-13 and TH17/IL-17 responses. This is accompanied by decreased keratinocyte proliferation and normalization of epidermal differentiation and function. Furthermore, our results demonstrate how transcriptomic changes associated with nemolizumab treatment correlate with improvement in lesions, pruritus, stabilization of extracellular matrix remodeling, and processes associated with cutaneous nerve function. These data demonstrate a broad response to IL-31 receptor inhibition with nemolizumab and confirm the critical upstream role of IL-31 in PN pathogenesis.

LB817 Transcriptomic characterization of Prurigo Nodularis and the therapeutic response to Nemolizumab.

Prurigo Nodularis (PN) is a debilitating, difficult to treat, intensely pruritic, chronic inflammatory skin disease characterized by hyperkeratotic skin nodules. The pathogenesis of PN is not well understood but is believed to involve cross talk between itch-related neuronal cells, immune cells, and the epidermis, and centered around the pro-inflammatory cytokine IL-31, driving an intractable itch-scratch cycle. Here we provide a comprehensive view of the transcriptomic changes in PN skin and characterize the mechanism of action of the anti-IL-31 receptor inhibitor nemolizumab.

Treatment of Recalcitrant Prurigo Nodularis with Dupilumab

Objectives: Prurigo nodularis (PN) is a disease of aberrant and recalcitrant itching which is difficult to effectively manage. There are no current FDA-approved therapies for PN. The current topical and systemic medications used for this condition provide less than optimal efficacy for the majority of patients with this condition and often have unacceptable side effects. We report 4 patients who were effectively treated with dupilumab (Dupixent) for the treatment of recalcitrant PN.Methods: Four patients were treated successfully with dupilumab, a systemic biologic agent that is not immunosuppressive (Dupixent; Sanofi-Regeneron). Patients were treated with dupilumab monotherapy, without the use of other systemic immunosuppressing agents. The peak pruritus numerical rating scale (NRSi) was used to evaluate patients at weeks 0 and 4. Results: Dupilumab therapy results in a dramatic reduction in NRSi scores by week 4 and that result continues throughout the duration of therapy. This reduction in itch is seen with continuous therapy.Conclusion: Dupilumab therapy appears effective in reducing the overall itch severity in patients with PN. The usage of dupilumab as a monotherapy shows promise in the treatment of PN. The therapeutic response to dupilumab seen in PN suggests that the pathogenesis of PN may overlap with that of atopic dermatitis.

Association between Prurigo Nodularis and Etiologies of Peripheral Neuropathy: Suggesting a Role for Neural Dysregulation in Pathogenesis.

Background: Prurigo nodularis (PN) is an intensely pruritic skin condition of considerable morbidity. However, the pathogenesis of PN and its association with underlying neuropathy is unclear. Objective: We sought to investigate the association between PN and etiologies of peripheral neuropathy. Methods: A cross-sectional analysis of adult patients (≥18-year-old) with PN, AD, and Psoriasis at the Johns Hopkins Health System over a six-year period (January 2013–January 2019) was performed. The strength of association with etiologies of peripheral neuropathy were compared to a control cohort of individuals without PN, as well as those with AD or psoriasis. Results: A total of 1122 patients with PN were compared to 10,390 AD patients, 15,056 patients with psoriasis, and a control cohort of 4,949,017 individuals without PN, with respect to 25 comorbidities associated with peripheral neuropathies. Limitations: Comparisons between peripheral neuropathies and PN represent associations but are not causal relationships. Conclusion: Prurigo nodularis is strongly associated with peripheral neuropathies, suggesting a role for neural dysregulation in pathogenesis.

Diagnostic Workup and Evaluation of Patients with Prurigo Nodularis.

Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized oftentimes by symmetrically distributed, severely pruritic nodules. Currently, the pathophysiology of PN remains to be fully elucidated, but emerging evidence suggests that neuroimmune alterations play principal roles in the pathogenesis of PN. There are several associated etiologic factors thought to be associated with PN, including dermatoses, systemic, infectious, psychiatric, and neurologic conditions. We conducted a systematic literature review to evaluate the clinical presentation, diagnosis, and etiologic factors of PN. In this review, we discuss common differential diagnoses of PN and recommend an evidence-based, standardized diagnostic evaluation for those with suspected PN.

Prurigo nodularis as a sweat gland/duct-related disorder: resolution associated with restoration of sweating disturbance.

Little attention has been given to the involvement of sweat glands/ducts in the pathogenesis of prurigo nodularis (PN). According to recent studies, PN is likely to develop under conditions characterized by dry skin, such as atopic dermatitis (AD), suggesting a strong impact of skin dryness on PN development. No therapeutic modalities produced complete resolution of PN without exacerbations. We previously reported that increases in skin dryness by sweating disturbance could initiate the development of AD. We investigated whether sweating responses were impaired in refractory PN lesions; and, if so, we asked whether the PN lesions could resolve by restoring sweating disturbance. Using the impression mold technique, which allows an accurate quantification of individual sweat gland/duct activity, we examined basal sweating under quiescent conditions and inducible sweating responses to thermal stimulus in PN lesions and normal-appearing skin in the same patients before and after treatment with a moisturizer or topical corticosteroids. Sweating disturbance, either basal or inducible, was most profoundly detected in the "hub" structure corresponding to the center of PN papule before the treatment. This sweating disturbance was immunohistochemically associated with the leakage of sweat into the dermis. This disturbance was restored by treatment with a moisturizer. Our limitations include a relatively small patient cohort and lack of blinding. Sweating disturbance could be one of the aggravating factors of PN development. Refractory PN with low skin hydration may resolve by restoring sweating disturbance.

657 IL-17A upregulates endothelin-1 in keratinocytes in the pathogenesis of Prurigo nodularis

Prurigo nodularis is characterized by intensely itchy nodule and it can be a bothersome and debilitating disease. Histologically, the epidermis shows psoriasiform hyperplasia or pseudo-epitheliomatous hyperplasia. Despite the bothersome-to-debilitating disease course, the underlying mechanism, especially in the perspective of function of keratinocytes in mediating pruritus sensation, is not fully understood. It has been found that prurigo lesions shared the high expression levels of IL-17 and IL-22 with psoriasis. It has also found that epidermal keratinocytes proliferation in response to IL-17 and IL-22. Accordingly, Th17/Th22 may be responsible for the characteristics of prurigo, i.e. pruritus. Endothelin-1(ET-1) was originally characterized as a potent vasoconstrictor, but can also evoke itch sensations in humans. ET-1 is also involved in chronic itchy skin disorders such as atopic dermatitis {Nakahara, 2018 #35} and psoriasis. Here we hypothesized that IL-17A contributes to the development of pruritus in prurigo nodularis through increase of ET-1. To this end, we initially collected human prurigo samples and compared ET-1 levels in serum of the patients of prurigo and those from the normal people. The patients of prurigo showed higher ET-1 expression than that with normal human. We found a significant increase of endothelin-1 mRNA expression in prurigo patients compared to that of the control. Next, to reveal intracellular pathway involved in IL-17A-induced ET-1 expression, we then investigated whether IL-17A could activate MAPK pathways. These data deepen our understanding of the pathologenesis of prurigo nodularis.

Aberrant Expression of Histamine-independent Pruritogenic Mediators in Keratinocytes may be Involved in the Pathogenesis of Prurigo Nodularis.

Prurigo nodularis is a highly pruritic and hyperplastic chronic dermatosis with unknown pathogenesis. Many pruritogenic mediators, including nerve growth factor, interleukin (IL)-31, thymic stromal lymphopoietin, and endothelin-1, are implicated in chronic itch and inflammation. This study investigated the mRNA levels and immunoreactivity of the nerve growth factor, IL-31, thymic stromal lymphopoietin, and endothelin axes in both lesional and perilesional skin in prurigo nodularis by using quantitative real-time PCR and immunohistochemistry studies. The nerve growth factor high-affinity receptor tyrosine kinase receptor A was upregulated while the low affinity receptor p75 neurotrophin receptor was downregulated in prurigo nodularis lesions. Downregulated expression of IL-31/IL-31 receptor A and endothelin-3/endothelin receptor B and upregulation of thymic stromal lymphopoietin receptor were found in prurigo nodularis lesions. Aberrant expression of nerve growth factor, IL-31, thymic stromal lymphopoietin and endothelin axes was found in prurigo nodularis lesions, especially in the epidermis, indicating the importance of keratinocytes in prurigo nodularis pathogenesis.

Thalidomide for the treatment of chronic refractory prurigo nodularis

Prurigo nodularis (PN) is a highly pruritic skin condition that is caused by chronic scratching. It occurs in patients with chronic itch and is characterized by multiple hyperkeratotic papules and nodules. The pathogenesis of PN is unclear, but involves a complex interplay of numerous pathways including neurogenic and inflammatory factors. As such, PN is very difficult to treat and patients are often refractory to multiple medications before finding a treatment that is effective. We present a woman with a 20-year history of exuberant prurigo nodularis who failed multiple therapies, including dapsone, azathioprine, mycophenolic acid, prednisone, topical steroids, and phototherapy. She only obtained significant relief of chronic pruritus and lesion flattening with thalidomide 100mg daily. Thalidomide is an antipruritic and anti-inflammatory agent that has shown to be very effective in treating a variety of dermatologic conditions. However, its use today is limited by concerns for its teratogenic and neuropathic side effects. With strict adherence to medication protocols, these adverse effects can be minimized. As such, thalidomide should be considered for patients with refractory dermatologic conditions.

Prurigo Nodularis Management.

Characterized by the clinical presentation of individual to multiple symmetrically distributed, hyperkeratotic, and intensely itchy papules and nodules, prurigo nodularis (PN) is a rare disease that emerges in patients with chronic pruritus due to continuous scratching over a long period of time. The itching and scratching of the lesions contribute to the vicious cycle that makes this disease difficult to treat, thus reducing the quality of life of affected patients. The pathogenesis of PN is ambiguous, although immunoneuronal crosstalk is implicated. Its etiology was found to be heterogenous. It can emerge as the symptom of various dermatological, neurological, psychiatric, and systemic diseases. There is currently no approved therapy for PN. However, contemporary therapies consist of calcineurin inhibitors, capsaicin, topical steroids, UV therapy, and a systemic application of antihistamines, anticonvulsants, μ-opioid receptor antagonists, and immunosuppressants. Multimodal therapy should be utilized in order to achieve optimal results, including topical and systemic symptomatic therapies.