Pathogenesis of Pruritic Disorders and Mechanisms of Phototherapy

Soham Chaudhari, BA,* Argentina Leon, MD,** Ethan Levin, MD,** Om Chaudhari,*** John Koo, MD****

*Osteopathic Medical Student, 4th year, Touro University Nevada, Osteopathic College of Medicine, Henderson, NV **Research Fellow, Department of Dermatology, University of California, San Francisco, CA ***University of Nevada Las Vegas, College of Sciences, Honors College, Las Vegas, NV ****Professor and Vice Chairman, Department of Dermatology; Director, Psoriasis Treatment Center, University of California, San Francisco, CA

Abstract Phototherapy is an efficacious method for managing many cutaneous conditions. Although psoriasis is the most commonly treated condition, phototherapy also has a role in the management of pruritic disorders, including atopic (AD), nodularis (PN), and (UP). We have reviewed the pathogenesis of pruritus and the mechanism of action of phototherapy in treating pruritic disorders. AD is an inflammatory with an induction of pruritus due to cytokines released by CD4-positive-T helper (Th) 2 cells. Langerhans cells, T cells, proinflammatory cytokines, and keratinocytes are decreased in AD patients treated with phototherapy. PN has an increase in mast cells and neuropeptides that mediate pruritus. UV light decreases the release of these neuropeptides and alleviates pruritus in PN. Finally, UP causes a microinflammatory state with changes in cutaneous nociceptive endings. A circulating substance responsible for pruritus in UP is annihilated through the apoptotic actions of phototherapy.

Introduction their entire spectrum. Narrowband UVB (NB- Discussion Pruritus is the number one symptom presented UVB) uses 311-313 nm, and UVA1 uses 340- Pathogenesis of : Localized itch involves to any dermatology practice.1 The physical 400 nm with a peak at 365 nm. UVA1 can be alpha-delta fibers, whereas diffuse, generalized and psychological distress caused by chronic administered at high dose (HD-UVA1) (130 J/ itch is transmitted through dermal unmyelinated cm2), medium dose (MD-UVA1) (50 J/cm2), and pruritus has a significant impact on quality 2 c-fibers. Both of these nociceptive fibers travel of life for patients. Because topical therapy is low dose (LD-UVA1) (20 J/cm ). Monochromic to the dorsal horn of the spinal cord, which is often inadequate in controlling pruritus, other excimer laser (MEL) (308nm) is a more targeted then processed by the cerebral cortex through treatments are needed. Phototherapy can alleviate phototherapy device that delivers 308 nm UVB to the spinothalamic tract.3 They have a slow the constant sensation of itch without many of a localized area and can expand treatment options conduction velocity and innervate large areas the adverse effects of systemic medications. In by sparing unaffected areas. Both cutaneous and of the skin.4 Dry skin and disruption of the addition, it is safe and can be utilized in all age systemic diseases can present with pruritus as skin barrier can induce keratinocytes to release categories.2 UVB (290-320 nm) and UVA (320- the primary symptom. This article summarizes pruritogenic substances.5 Nerve fibers typically 400 nm) are implemented in UV-based therapy. the pathogenesis of pruritic disorders including end at the dermal-epidermal junction, although Broadband UVB (BB-UVB) and broadband AD, PN, and UP and the mechanism of action of some project into the epidermis.6 Itch receptors, UVA (BB-UVA) use a light source covering phototherapy in each of these (Table 1). formed mostly by keratinocytes, respond to

Figure 1. Pruritus

CHAUDHARI, LEON, LEVIN, CHAUDHARI, KOO Page 29 pruritogens such as histamine, proteases, growth of eczematous lesions is a Th2-driven response, interfere with ceramide metabolism, as cytolytic factors, neuropeptides, cytokines, and opioids chronic lesions demonstrate a greater level of Th1 alpha toxin causes keratinocyte damage and (Figure 1).7,8 They are found only in skin, mucus activity.18 Acute and chronic AD lesions contain superantigenic toxin causes release of TNF- membranes, and cornea.9 Substance P (SubP) more mRNA expression for IL-4, IL-5, and alpha and Beta-hemolysin, which interfere with and calcitonin gene-related peptide (CGRP) are IL-13 than normal skin. The mRNA expression ceramide metabolism.34 These toxins also prevent the most studied neurotransmitters and have both of IFN-gamma, however, is similar to that of keratinocytes from producing antimicrobial central and peripheral activity.10,11 Allokinesis, normal skin.20,30 Chronic lesions express more peptides to kill S. aureus.35 the perception of non-pruritic stimuli as pruritic, IL-5, IL-12 and anti-eosinophil cationic protein Mechanism of Action for Phototherapy in AD: is due to central sensitization. This explains the (ECP) antibody eosinophils than acute lesions. Many studies have demonstrated the beneficial intense pruritus AD patients experience in Thus, IL-12 may be important in the transition effects of phototherapy in treating AD.36 The response to sweat or sudden changes in ambient from acute to chronic lesions. The predominance intralesional mRNA expression of IFN-gamma temperature. of Th2 cytokines in the acute phase, such as was successfully downregulated during the course Mast cells produce two proteinases, tryptase and IL-4 and IL-5, stimulates eosinophils, which of UVA1 therapy, whereas IL-4 mRNA expression chymase. Tryptase activates C fibers and thus produce IL-12, thereby activating Th1 cells and remained relatively unchanged even after those stimulates the sensation of itch. It also triggers the undifferentiated T cells to produce IFN-gamma, with chronic AD improved under treatment.37,38 release of SubP, which not only causes pruritus causing a negative feedback on Th2 responses The high efficacy of UVA1 phototherapy in and maintaining the AD lesion over an extended but also evokes further mast-cell activation. 19 the treatment of AD can be attributed to the Increased levels of tryptase have been observed in period (Figure 2). patients with UP.12 The sensations of pain and itch are carried by different C-fibers. Frequency of the stimulus can modulate the magnitude of itch but does not change the quality of itch into pain. Histamine- induced itch activates some motor areas, suggesting a neuronal association between itch and scratching.13 Scratching and vibration are transmitted by larger A-beta fibers that inhibit itch signals on the slower C-fibers.14 While pain causes one to avoid a motor response, itch causes a stimulatory motor response. Painful stimuli can inhibit itch, as observed in pruritic patients who only stop scratching once skin lesions begin bleeding and become painful. Itch and pain share the same cortical brain areas but have different patterns of activation: Itch has a weaker activation of somatosensory cortices and a stronger activation of ipsilateral motor areas as compared with pain processing.15,16

ATOPIC DERMATITIS (AD) Pathogenesis of AD: The pathogenesis of AD is a complex interplay between several different cell types and factors. CD-4 positive Th2 cells have been found to play a major role in pruritus induction by producing and releasing cytokines and chemokines.17 Localization Figure 2. to the skin in AD is due to the presence of a skin-homing receptor on memory effector T lymphocytes, called “cutaneous lymphocyte- The stratum corneum is the permeability barrier combination of UV-light induced apoptosis associated antigen,” which interacts with the between the body and the external environment, of T lymphocytes as well as the reduction of vascular endothelial cell-surface antigens to direct and thus when it is impaired, increased Langerhans cells and mast cells in the dermis.39 circulating T lymphocytes to the reactive skin transepidermal water loss causes xerosis and Preventing Langerhans cells and mast cells 18 site. Th1 cells initiated by IL-12 predominantly intense pruritus.31 The barrier is compromised from exiting the epidermis results in a decreased secrete IL-2 and interferon-gamma (IFN- due to an overexpression of an enzyme that number of Ig-E binding cells in the dermis.40 gamma), whereas Th2 cells are activated by IL- hydrolyzes sphingomyelin, producing free fatty Phototherapy induces the immunosuppressive 19- 10 to produce mainly IL-4, IL-5, and IL-13. acid and sphingosylphosphorylcholine, an mechanisms of the body, such as suppressing the 24 Atopic disorders such as eczema have been inducer of keratinocyte proliferation and up- antigen-presenting function of Langerhans cells, associated with a hyper Th2 response, as they regulator of plasminogen activator, resulting in inducing apoptosis in infiltrating T cells, causing signal B lymphocytes to produce IgE, stimulate decreased ceramides.32 Additionally, scratching DNA damage, and halting the rapid accumulation eosinophils and mast cells, and cause type 1 from pruritus induces trauma and further of epidermal keratinocytes.41-43 Colonization by 25-27 hypersensitivity reactions. Environmental insult to an already compromised stratum Staphylococcus aureus and Pityrosporum orbiculare 28 factors may enhance Th2 allergic response. AD corneum, which triggers keratinocytes to release is decreased through the use of UV radiation.44,45 patients commonly have a higher Staphylococcus proinflammatory cytokines. It is also because UV light also increases the thickness of the aureus burden than the general population, and of this defective barrier that microorganisms stratum corneum and therefore results in the Th2 cytokines of AD augment the toxicity such as S. aureus enter and colonize eczematous smaller eczematous reactions due to a decreased 29 of the lytic staphylococcal protein alpha toxin. skin.33 Toxins released by microbes further penetration of antigens.46 Thus, UV light exerts It has been shown that, although the initiation Page 30 PATHOGENESIS OF PRURITIC DISORDERS AND MECHANISMS OF PHOTOTHERAPY Figure 4. Uremic pruritus

UREMIC PRURITUS (UP) Pathogenesis of UP and Mechanism of Action for Phototherapy in UP: Although the pathogenesis of UP is not completely understood, it is known to present with dystrophic neurotrophic changes in cutaneous nociceptor nerve endings, with a “microinflammatory” state Figure 3. of increased Th1 markers, chemokines, and interleukin-6 (IL-6).71,72 It also causes calcium- its beneficial effects through a multitude of release NGF and contribute to neurohyperplasia 53 phosphate imbalance, hyperparathyroidism, mechanisms. Although AD is the primary disease of PN. Dermal Langerhans cells are increased anemia, increased serum histamine levels, and explained above, a similar mechanism of action in PN, suggesting their involvement in the peripheral neuropathy.73,74 for UV-based therapy can be applied to PN and development or persistence of PN.57 In addition, LSC owing to their similar inflammatory nature. the numbers of Merkel cells are increased in PN at the basal cell layer, explaining the abnormal UVB therapy is beneficial for patients with PRURIGO NODULARIS (PN) sensitivity to touch from these slowly adapting UP. Possible mechanisms include reduction in 58 Pathogenesis of PN: A background of atopic sensory touch receptors. skin divalent-ion content, reduction in Vitamin diathesis has been suggested for PN after Mechanism of Action for Phototherapy in A and retinol content, stabilization of or examining the history of AD, allergic rhinitis, PN: UV light hinders rapid epidermal cell reduction in number of mast cells, detoxification and bronchial asthma.47,48 Tanaka et al. found turnover and thereby leads to a reduction in of undetermined pruritogenic substances, PN patients with an atopic background to pseudoepitheliomatous hyperplasia of the photoactivation of antipruritogenic substances, develop the disease at a younger age and display epidermis.59 PN patients have an increase in the and changes in the excitability of epidermal nerve a hypersensitivity reaction pattern similar to that number of nerve fibers in the papillary dermis.60 endings. Mast-cell proliferation, degranulation, and subsequent histamine release plays a role in observed in AD, suggesting a close pathological These nerve fibers demonstrate immunoreactivity 49 uremic pruritus (Figure 4). Histamine secretion link between the two disorders. The typical for SubP and CGRP and thus mediate the 76 PN nodule is secondary to traumatization. cutaneous neurogenic inflammation and pruritus is evoked by an increased release of SubP. NB- Histopathologically, PN has an increased in PN. It is postulated that MEL modulates UVB induces apoptosis of dermal mast cells 61-63 and reduces the release of neuropeptides such as downward projection of the epidermis, suggesting the release of these neuropeptides. The 66,77 pseudoepitheliomatous hyperplasia. Skin biopsies long remission noted for MEL could be due SubP by decreasing epidermal nerve fibers. of PN reveal an increase in the number of mast to inhibition of neuropeptide releases, which Nitric oxide and IL-2 have also been implicated in the pathogenesis of uremic pruritus, both of cells in both the epidermis and the dermis, with cause pruritus and can consequently perpetuate 76,78-80 some invasion into the cutaneous nerve-fiber the rubbing, scratching, and picking cycle. which are decreased by NB-UVB. Schultz bundles.50,51 Mast cells are known to release MEL treatment causes a depletion of T cells et al. suggest the response to UVB indicates a nerve growth factor (NGF) and are seen in and alterations of apoptosis-related molecules, deposition of some substance in the skin that proximity to nerves expressing increased levels along with a decreased proliferation index of is degraded or inactivated by the light. Because of NGF receptor (NGFr) (Figure 3).52,53 Thus, keratinocytes.64 PUVA downregulates CGRP uremic patients respond to cholestyramine, and the overexpression of NGF in PN explains the and Th2 cytokines and depletes epidermal phototherapy serves to clear bilirubin in jaundiced 65-67 premature infants, bile salts were considered to be neurohyperplasia, which subsequently explains the dendritic cells. The longer wavelengths used 81 strong itch secondary to increased axon firing.54 in PUVA penetrate the acanthotic thick epidermis involved in UP pathogenesis. Individuals with The mast cells in PN lesions also demonstrate more fully than classical NB-UVB.63,67-69 UVB advanced CRF had higher levels of serum total morphological changes, such as enlarged cell irradiation inhibits mast-cell granule release.70 bile acids when compared to controls, and those bodies with a dendritic shape as compared to Thus, phototherapy is successful in combating with pruritus had higher levels of bile acids than 52,55,56 those without pruritus. Thus, the intensity of the round shape seen in normal skin. Thus, itch in PN because it reduces the number of 82 neuropeptides and histamine from mast cells epidermal nerve fibers.66 pruritus correlated with bile acid concentration. Certain bile acids also cause cytotoxicity to cooperatively generate neurogenic inflammation 83 to induce and transmit itch. Eosinophils can also mastocytes, thereby releasing histamine.

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