Atopic dermatitis (AD) is a chronic, relapsing immunoinflammatory skin condition characterized by sensations such as pruritis, pain, and neuronal hypersensitivity. The mechanisms underlying these sensations are multifactorial and involve complex crosstalk among several cutaneous components. This review explores the role these components play in the pathophysiology of atopic dermatitis. In the skin intercellular spaces, sensory nerves interact with keratinocytes and immune cells via myriad mediators and receptors. These interactions generate action potentials that transmit pruritis and pain signals from the peripheral nervous system to the brain. Keratinocytes, the most abundant cell type in the epidermis, are key effector cells, triggering crosstalk with immune cells and sensory neurons to elicit pruritis, pain, and inflammation. Filaggrin expression by keratinocytes is reduced in atopic dermatitis, causing a weakened skin barrier and elevated skin pH. Fibroblasts are the main cell type in the dermis and, in atopic dermatitis, appear to reduce keratinocyte differentiation, further weakening the skin barrier. Fibroblasts and mast cells promote inflammation while dermal dendritic cells appear to attenuate inflammation. Inflammatory cytokines and chemokines play a major role in AD pathogenesis. Type 2 immune responses typically generate pruritis, and the type 1 and type 3 responses generate pain. Type 2 responses and increased skin pH contribute to barrier dysfunction and promote dysbiosis of the skin microbiome, causing the proliferation of Staphyloccocus aureus. In conclusion, understanding the dynamic interactions between cutaneous components in AD could drive the development of therapies to improve the quality of life for patients with AD.

Atopic dermatitis (AD) is predominantly characterized by intense itching, but concomitant skin pain is experienced by more than 40% of patients. Patients with AD display considerable somatosensory aberrations, including increased nerve sensitivity to itch stimuli (hyperknesis), perception of itch from innocuous stimuli (alloknesis), or perception of pain from innocuous stimuli (allodynia). This review summarizes the current understanding of the similarities and differences in the peripheral mechanisms underlying itch and pain in AD. These distinct yet reciprocal sensations share many similarities in the peripheral nervous system, including common mediators (such as serotonin, endothelin-1, IL-33, and thymic stromal lymphopoietin), receptors (such as members of the G protein-coupled receptor family and Toll-like receptors), and ion channels for signal transduction (such as certain members of the transient receptor potential [TRP] cation channels). Itch-responding neurons are also sensitive to pain stimuli. However, there are distinct differences between itch and pain signaling. For example, specific immune responses are associated with pain (type 1 and/or type 3 cytokines and certain chemokine C-C [CCL2, CCL5] and C-X-C [CXCL] motif ligands) and itch (type 2 cytokines, including IL-31, and periostin). The TRP melastatin channels TRPM2 and TRPM3 have a role in pain but no known role in itch. Activation of μ-opioid receptors is known to alleviate pain but exacerbate itch. Understanding the connection between itch and pain mechanisms may offer new insights into the treatment of chronic pain and itch in AD.

BACKGROUND: Skin pain in atopic dermatitis (AD) increases with disease severity and is associated with substantial quality of life (QoL) burden.
OBJECTIVE: The aim of the study was to evaluate abrocitinib efficacy on skin pain and QoL in adults and adolescents with moderate-to-severe AD.
METHODS: This post hoc analysis included data with abrocitinib administered as monotherapy (pooled phase 2b [NCT02780167] and phase 3 JADE MONO-1 [NCT03349060] and JADE MONO-2 [NCT03575871]) or in combination with topical therapy (phase 3 JADE COMPARE [NCT03720470] and JADE TEEN [NCT03796676]). Patients received oral, once-daily abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 or 16 weeks (JADE COMPARE). Skin pain was rated using the Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) skin pain Numerical Rating Scale (NRS) item (\"How painful was your skin over the past 24 h?\") on a scale from 0 (not painful) to 10 (extremely painful). Itch (Peak Pruritus NRS) and QoL (Dermatology Life Quality Index or Children\'s Dermatology Life Quality Index) were assessed. Least squares mean (LSM) change from baseline was analyzed using mixed-effects repeated measures modeling.
RESULTS: A total of 1,822 patients (monotherapy pool, n = 942; JADE COMPARE, n = 595; and JADE TEEN, n = 285) were analyzed. LSM change from baseline in PSAAD skin pain score was significantly greater with abrocitinib versus placebo from week 2 through week 12 or 16 across all 3 study populations and occurred in a dose-dependent manner. A greater proportion of patients achieved a ≥4-point improvement from baseline in PSAAD skin pain score with abrocitinib (200 mg and 100 mg) versus placebo in the monotherapy pool (56% and 38% vs. 12%; week 12), JADE COMPARE (72% and 52% vs. 26%; week 16), and JADE TEEN (51% and 60% vs. 31%; week 12). Additionally, a greater proportion of patients achieved a stringent threshold of skin pain improvement (PSAAD skin pain score <2) with abrocitinib versus placebo. Adults and adolescents who achieved a ≥4-point improvement in skin pain reported greater QoL improvement than those who did not achieve a ≥4-point improvement. A positive correlation (≥0.3) was observed between skin pain and QoL and separately between skin pain and itch across the 3 study populations.
CONCLUSIONS: Abrocitinib as monotherapy or in combination with topical therapy improved skin pain and was associated with improved QoL in both adults and adolescents with moderate-to-severe AD across all evaluated studies.

BACKGROUND: Janus kinase 1 inhibition may alleviate hidradenitis suppurativa (HS)-associated inflammation and improve symptoms.
OBJECTIVE: To assess efficacy and safety of povorcitinib (selective oral Janus kinase 1 inhibitor) in HS.
METHODS: This placebo-controlled phase 2 study randomized patients with HS 1:1:1:1 to receive povorcitinib 15, 45, or 75 mg or placebo for 16 weeks. Primary and key secondary end points were mean change from baseline in abscess and inflammatory nodule count and percentage of patients achieving HS Clinical Response at week 16.
RESULTS: Of 209 patients randomized (15 mg, n = 52; 45 mg, n = 52; 75 mg, n = 53; placebo, n = 52), 83.3% completed the 16-week treatment. At week 16, povorcitinib significantly reduced abscess and inflammatory nodule count from baseline (least squares mean [SE] change: 15 mg, -5.2 [0.9], P = .0277; 45 mg, -6.9 [0.9], P = .0006; 75 mg, -6.3 [0.9], P = .0021) versus placebo (-2.5 [0.9]). More povorcitinib-treated patients achieved HS Clinical Response at week 16 (15 mg, 48.1%, P = .0445; 45 mg, 44.2%, P = .0998; 75 mg, 45.3%, P = .0829) versus placebo (28.8%). A total of 60.0% and 65.4% of povorcitinib- and placebo-treated patients had adverse events.
CONCLUSIONS: Baseline lesion counts were mildly imbalanced between groups.
CONCLUSIONS: Povorcitinib demonstrated efficacy in HS, with no evidence of increased incidence of adverse events among doses.

BACKGROUND: Three patient-reported outcome (PRO) questionnaires-Worst Pruritus Numerical Rating Scale (WP-NRS), Atopic Dermatitis Symptom Scale (ADerm-SS), and Atopic Dermatitis Impact Scale (ADerm-IS)-were developed to assess the symptoms and impacts of atopic dermatitis (AD). Severity strata for these PROs are needed to aid in their interpretation.
METHODS: Using data from a global, randomized, double-blind, placebo-controlled, phase 3 clinical trial (NCT03568318) of patients with moderate-severe AD (age ≥ 12 years), equipercentile linking analyses were conducted to define severity strata applying the Patient Global Impression of Severity as an anchor. Analyses were conducted separately for adults and adolescents, and then harmonized between the two age groups.
RESULTS: The sample included 769 adults and 113 adolescents. For the WP-NRS, 0 was associated with absent, 1-2 with minimal, 3 with mild, 4-7 with moderate, and 8-10 with severe. For the ADerm-SS Skin Pain, 0 was associated with absent, 1 with minimal, 2 with mild, 3-6 with moderate, and 7-10 with severe. For ADerm-SS 7-Item Total Symptom Score (TSS-7), 0-1 was associated with absent, 2-11 with minimal, 12-22 with mild, 23-47 with moderate, and 48-70 with severe. For ADerm-IS Sleep, 0 was associated with absent, 1-3 with minimal, 4-6 with mild, 7-20 with moderate, and 21-30 with severe. For ADerm-IS Daily Activities, 0 was associated with absent, 1-2 with minimal, 3-7 with mild, 8-25 with moderate, and 26-40 with severe. For ADerm-IS Emotional State, 0 was associated with absent, 1-2 with minimal, 3-8 with mild, 9-22 with moderate, and 23-30 with severe.
CONCLUSIONS: These severity strata provide score interpretations of the WP-NRS, ADerm-SS, and ADerm-IS, translating these scores to simple and intuitive outcomes, which can inform clinical studies and clinical practice.
BACKGROUND: NCT03568318.

Itch is a common symptom of atopic dermatitis (AD), however, there is limited evidence of the frequency and association of skin pain alongside itch. This study assessed the incremental dual burden and impact of itch and skin pain on satisfaction, quality of life and work productivity in patients with AD in Japan.
Data were drawn from the 2020 Adelphi AD Disease Specific Programme, a point-in-time survey of dermatologists (n = 56) and their patients with history of moderate/severe AD (n = 265). Patients were grouped accordingly: no itch/skin pain (No I/SP, reference group, n = 89), itch/no skin pain (I-only, n = 71), and itch and skin pain (I + SP, n = 26). Descriptive analyses were performed alongside a range of regression models, dependent on outcome variables.
I + SP patients had a 4.97-point worse POEM score (p = .005) and 14.5% more overall work impairment (p = .034) versus the reference group. I-only and I + SP patients were 8.92 and 23.5 times more likely, respectively, to experience sleep disruption on a day-to-day basis (both p < .001). I + SP patients were 4.6 times more likely to be bothered by their symptoms (p = .034), had a mean EASI score 6.7 points higher (p = .008) and had 1.39 more areas affected (p = .001). I + SP patients were 7.26 times more likely to express dissatisfaction with lack of improvement in their condition and 8 times more likely to be dissatisfied with convenience of treatment (both p < .05).
This dissatisfaction, alongside variations in reported symptomatic burdens, suggests that physicians could consider alternative and/or novel therapeutic approaches for the management of both itch and skin pain.
Patients with atopic dermatitis experience a broad range of symptoms, including both itch and skin pain, however it is not clear how these symptoms combine to impact patients in everyday life. This survey of 56 dermatologists and 265 patients with a history of moderate or severe atopic dermatitis investigated the impact of both itch and skin pain on quality of life and treatment satisfaction in Japan. Patients were categorised into three groups depending on the presence of these symptoms; patients with either no itch or skin pain, patients with itch but no skin pain, or patients with both itch and skin pain. These three groups were then compared. Patients with both itch and skin pain reported this combination of symptoms together impacted on their daily lives more than patients with itch but no skin pain, or no itch or skin pain. In particular, patients with both itch and skin pain had more areas of their body affected and reported being more bothered by their symptoms compared to those who did not experience these symptoms, with daily work impairment, sleep disruption and quality of life all worse. Importantly, patients with both itch and skin pain were more likely to be dissatisfied with the lack of improvement in their condition and with the convenience of their treatment. These results suggest that physicians should take into consideration the presence of both itch and skin pain when making treatment decisions in atopic dermatitis, and the need to consider treatments to target both symptoms.

BACKGROUND: Skin pain (discomfort/soreness) is a common symptom associated with atopic dermatitis (AD).
OBJECTIVE: To evaluate rapid changes in skin pain severity with baricitinib, and its impact on patient quality of life (QoL) in adults with moderate-to-severe AD who were inadequate responders to topical therapy.
METHODS: Adult patients with moderate-to-severe AD who were inadequate responders to topical therapies (N = 440, BREEZE-AD5 [NCT03435081]) were randomized to once-daily placebo, baricitinib 1 mg, or baricitinib 2 mg for 16 weeks. Change in Skin Pain Numeric Rating Scale (NRS) scores were assessed for the randomized population. Skin Pain NRS and Dermatology Life Quality Index (DLQI) scores were assessed for Skin Pain Response groups and patients with Body Surface Area (BSA) 10% to 50%.
RESULTS: Skin Pain NRS improvement was significant versus placebo by day 1 baricitinib 2 mg (least squares mean [LSM] difference -4.4%, P = .048) and by day 2 for baricitinib 1 mg (-6.7%, P = .011). As measured weekly, improvement was significant starting at Week 1 and remained significant through Week 16 for both doses. At Week 16, 70.9% of Skin Pain NRS responders vs 10.4% of nonresponders had a clinically meaningful improvement in DLQI (P < .0001). At week 16, LSM DLQI change from baseline was -11.1 for all Skin Pain NRS responders versus -3.5 for nonresponders (P < .0001). Patients with BSA 10% to 50% showed similar trends.
CONCLUSIONS: Patients with moderate-to-severe AD, treated with baricitinib, reported rapid improvements in skin pain severity by day 1 for baricitinib 2 mg and day 2 for baricitinib 1 mg and remained effective through 16 weeks of treatment, which positively impacted patient QoL.

Topical opioid formulations offer a potential solution to manage pain and decrease the use of systemic opioids. Synthesis of use and efficacy of topical opioids in dermatological conditions has not been well characterized. We conducted a systematic search of the PubMed, Embase, and Cochrane databases from 1980 to February 2021. This study analyzed data from 14 articles and 263 patients on the use of topical opioids for pain related to chronic ulcers, burns, oral lichen planus, photodynamic therapy, and split-thickness skin grafts. Topical opioids included in this review were topical morphine and diamorphine. Common formulations consisted of 0.2-10 mg of opioid compounded with hydrogel or IntraSite gel. Topical opioids were variably effective in the use for pain control related to chronic ulcers and other dermatologic conditions. For example, the use of topical opioids appears to be effective in the reduction of pain related to pressure ulcers. Topical opioids were generally well tolerated. Insufficient data exist to adequately evaluate the efficacy and safety of topical opioid use in the context of nonpressure ulcers, burns, oral lichen planus, photodynamic therapy, and split-thickness skin grafts.

BACKGROUND: Skin pain (described as discomfort or soreness) is increasingly recognized as a symptom of atopic dermatitis which impacts patient quality of life. This analysis examined the effect of baricitinib on skin pain in atopic dermatitis in three phase 3 studies (BREEZE-AD1, -AD2, and -AD7).
METHODS: Patients were randomly assigned 2:1:1:1 to receive once-daily placebo, baricitinib 1 mg, 2 mg, or 4 mg in BREEZE-AD1 (N = 624) and -AD2 (N = 615) and 1:1:1 to receive once-daily placebo, baricitinib 2 mg, or 4 mg, with topical corticosteroids, in BREEZE-AD7 (N = 329) for 16 weeks. Patients recorded their skin pain severity using the Skin Pain Numerical Rating Scale (NRS) via an electronic daily diary. Data were analyzed by study as least squares mean change from baseline in daily scores for the randomly assigned patients using mixed model repeated measures analysis. Analysis of Skin Pain NRS response was done using logistic regression using non-responder imputation.
RESULTS: Baricitinib produced significant percentage change from baseline compared with placebo in patient-reported skin pain severity by day 2 in BREEZE-AD1 (baricitinib 4 mg - 11.9%, p < 0.001; baricitinib 2 mg - 6.4%, p = 0.016; baricitinib 1 mg - 6.2%, p = 0.016), -AD2 (baricitinib 4 mg - 12.6%, p < 0.001; baricitinib 2 mg - 5.6%, p = 0.036; baricitinib 1 mg - 6.9%, p = 0.011), and -AD7 (baricitinib 4 mg - 6.9%, p = 0.04; baricitinib 2 mg - 7.9%, p = 0.018). A greater proportion of patients treated with baricitinib reported at least a 4-point reduction in Skin Pain NRS score at week 16 (Skin Pain NRS responders) in BREEZE-AD1 (baricitinib 4 mg 25.3%, p < 0.001), -AD2 (baricitinib 4 mg 20.0%, p < 0.001; baricitinib 2 mg 19.0%, p < 0.001), and -AD7 (baricitinib 4 mg 48.8%, p < 0.001; baricitinib 2 mg 45.2%, p = 0.004) compared to placebo. A significantly higher proportion of Skin Pain NRS responders also achieved at least a 4-point improvement in Dermatology Life Quality Index at week 16 when compared with Skin Pain NRS non-responders in BREEZE-AD1 (89.2%, p < 0.0001), -AD2 (92.5%, p < 0.0001), and -AD7 (88.3%, p < 0.0001).
CONCLUSIONS: Baricitinib improved patient-reported skin pain severity as early as day 2. CLINICALTRIALS.
UNASSIGNED: BREEZE-AD1, NCT03334396; BREEZE-AD2, NCT03334422; BREEZE-AD7, NCT03733301.

BACKGROUND: Baricitinib, an oral selective Janus kinase 1/Janus kinase 2 inhibitor, is being studied for moderate-to-severe atopic dermatitis (AD) in adults.
OBJECTIVE: To evaluate the efficacy and safety of baricitinib monotherapy in a North American phase 3 trial (BREEZE-AD5/NCT03435081) of adults with moderate-to-severe AD who responded inadequately or were intolerant to topical therapy.
METHODS: Patients (N = 440) were randomized 1:1:1 to once-daily placebo or baricitinib (1 mg or 2 mg). The primary endpoint was the proportion of patients achieving ≥75% reduction in the Eczema Area and Severity Index at week 16. A key secondary endpoint was the proportion of patients achieving a validated Investigator Global Assessment for AD score of 0 (clear)/1(almost clear) with ≥2-point improvement.
RESULTS: At week 16, the proportion of patients achieving Eczema Area and Severity Index was 8%, 13%, and 30% (P < .001, 2 mg vs placebo) and those with a validated Investigator Global Assessment for AD score of 0/1 were 5%, 13%, and 24% (P < .001, 2 mg vs placebo) for placebo, baricitinib 1 mg, and baricitinib 2 mg, respectively. Safety findings were similar to those of other baricitinib AD studies.
CONCLUSIONS: Short-term clinical trial results may not be generalizable to real-world settings.
CONCLUSIONS: Baricitinib was efficacious for patients with moderate-to-severe AD with no new safety findings over 16 weeks.