Tali Czarnowicki, MD, MSc

Pruritus, which is defined as an itching sensation that elicits a desire to scratch, is the most common cutaneous condition. Pruritus is considered chronic when it lasts for more than 6 weeks.¹ Etiologies implicated in chronic pruritus include but are not limited to primary skin diseases such as atopic dermatitis, systemic causes, neuropathic disorders, and psychogenic reasons.² In approximately 8% to 35% of patients, the cause of pruritus remains elusive despite intensive investigation.³ The mechanisms of itch are multifaceted and include complex neural pathways.⁴ Although itch and pain share many similarities, they have distinct pathways based on their spinal connections.⁵ Nevertheless, both conditions show a wide overlap of receptors on peripheral nerve endings and activated brain parts.^6,7 Fibromyalgia, the third most common musculoskeletal condition, affects 2% to 3% of the population worldwide and is at least 7 times more common in females.^8,9 Its pathogenesis is not entirely clear but is thought to involve neurogenic inflammation, aberrations in peripheral nerves, and central pain mechanisms. Fibromyalgia is characterized by a plethora of symptoms including chronic widespread pain, autonomic disturbances, persistent fatigue and sleep disturbances, and hyperalgesia, as well as somatic and psychiatric symptoms.¹⁰

Fibromyalgia is accompanied by altered skin features including increased counts of mast cells and excessive degranulation,¹¹ neurogenic inflammation with elevated cytokine expression,¹² disrupted collagen metabolism,¹³ and microcirculation abnormalities.¹⁴ There has been limited research exploring the dermatologic manifestations of fibromyalgia. One retrospective study that included 845 patients with fibromyalgia reported increased occurrence of “neurodermatoses,” including pruritus, neurotic excoriations, prurigo nodules, and lichen simplex chronicus (LSC), among other cutaneous comorbidities.¹⁵ Another small study demonstrated an increased incidence of xerosis and neurotic excoriations in females with fibromyalgia.¹⁶ A paucity of large epidemiologic studies demonstrating the fibromyalgia-pruritus connection may lead to misdiagnosis, misinterpretation, and undertreatment of these patients.

Up to 49% of fibromyalgia patients experience small-fiber neuropathy.¹⁷ Electrophysiologic measurements, quantitative sensory testing, pain-related evoked potentials, and skin biopsies showed that patients with fibromyalgia have compromised small-fiber function, impaired pathways carrying fiber pain signals, and reduced skin innervation and regenerating fibers.^18,19 Accordingly, pruritus that has been reported in fibromyalgia is believed to be of neuropathic origin.¹⁵ Overall, it is suspected that the same mechanism that causes hypersensitivity and pain in fibromyalgia patients also predisposes them to pruritus. Similar systemic treatments (eg, analgesics, antidepressants, anticonvulsants) prescribed for both conditions support this theory.^20-25

Our large cross-sectional study sought to establish the association between fibromyalgia and pruritus as well as related pruritic conditions.

Methods

Study Design and Setting—We conducted a cross-­sectional retrospective study using data-mining techniques to access information from the Clalit Health Services (CHS) database. Clalit Health Services is the largest health maintenance organization in Israel. It encompasses an extensive database with continuous real-time input from medical, administrative, and pharmaceutical computerized operating systems, which helps facilitate data collection for epidemiologic studies. A chronic disease register is gathered from these data sources and continuously updated and validated through logistic checks. The current study was approved by the institutional review board of the CHS (approval #0212-17-com2). Informed consent was not required because the data were de-identified and this was a noninterventional observational study.

Study Population and Covariates—Medical records of CHS enrollees were screened for the diagnosis of fibromyalgia, and data on prevalent cases of fibromyalgia were retrieved. The diagnosis of fibromyalgia was based on the documentation of a fibromyalgia-specific diagnostic code registered by a board-certified rheumatologist. A control group of individuals without fibromyalgia was selected through 1:2 matching based on age, sex, and primary care clinic. The control group was randomly selected from the list of CHS members frequency-matched to cases, excluding case patients with fibromyalgia. Age matching was grounded on the exact year of birth (1-year strata).

Other covariates in the analysis included pruritus-related skin disorders, including prurigo nodularis, neurotic excoriations, and LSC. There were 3 socioeconomic status categories according to patients' poverty index: low, intermediate, and high.²⁶

Statistical Analysis—The distribution of sociodemographic and clinical features was compared between patients with fibromyalgia and controls using the χ² test for sex and socioeconomic status and the t test for age. Conditional logistic regression then was used to calculate adjusted odds ratio (OR) and 95% CI to compare patients with fibromyalgia and controls with respect to the presence of pruritic comorbidities. All statistical analyses were performed using SPSS software (version 26). P<.05 was considered statistically significant in all tests.

Results

Our study population comprised 4971 patients with fibromyalgia and 9896 age- and sex-matched controls. Proportional to the reported female predominance among patients with fibromyalgia,²⁷ 4479 (90.1%) patients with fibromyalgia were females and a similar proportion was documented among controls (P=.99). There was a slightly higher proportion of unmarried patients among those with fibromyalgia compared with controls (41.9% vs 39.4%; P=.004). Socioeconomic status was matched between patients and controls (P=.99). Descriptive characteristics of the study population are presented in Table 1.

We assessed the presence of pruritus as well as 3 other pruritus-related skin disorders—prurigo nodularis, neurotic excoriations, and LSC—among patients with fibromyalgia and controls. Logistic regression was used to evaluate the independent association between fibromyalgia and pruritus. Table 2 presents the results of multivariate logistic regression models and summarizes the adjusted ORs for pruritic conditions in patients with fibromyalgia and different demographic features across the entire study sample. Fibromyalgia demonstrated strong independent associations with pruritus (OR, 1.8; 95% CI, 1.8-2.4; P<.001), prurigo nodularis (OR, 2.9; 95% CI, 1.1-8.4; P=.038), and LSC (OR, 1.5; 95% CI, 1.1-2.1; P=.01); the association with neurotic excoriations was not significant. Female sex significantly increased the risk for pruritus (OR 1.3; 95% CI, 1.0-1.6; P=.039), while age slightly increased the odds for pruritus (OR, 1.0; 95% CI, 1.0-1.04; P<.001), neurotic excoriations (OR, 1.0; 95% CI, 1.0-1.1; P=.046), and LSC (OR, 1.0; 95% CI, 1.01-1.04; P=.006). Finally, socioeconomic status was inversely correlated with pruritus (OR, 1.1; 95% CI, 1.1-1.5; P=.002).

Comment

A wide range of skin manifestations have been associated with fibromyalgia, but the exact mechanisms remain unclear. Nevertheless, it is conceivable that autonomic nervous system dysfunction,^28-31 amplified cutaneous opioid receptor activity,³² and an elevated presence of cutaneous mast cells with excessive degranulation may partially explain the frequent occurrence of pruritus and related skin disorders such as neurotic excoriations, prurigo nodularis, and LSC in individuals with fibromyalgia.^15,16 In line with these findings, our study—which was based on data from the largest health maintenance organization in Israel—demonstrated an increased prevalence of pruritus and related pruritic disorders among individuals diagnosed with fibromyalgia.

This cross-sectional study links pruritus with fibromyalgia. Few preliminary epidemiologic studies have shown an increased occurrence of cutaneous manifestations in patients with fibromyalgia. One chart review that looked at skin findings in patients with fibromyalgia revealed 32 distinct cutaneous manifestations, and pruritus was the major concern in 3.3% of 845 patients.¹⁵

A focused cross-sectional study involving only women (66 with fibromyalgia and 79 healthy controls) discovered 14 skin conditions that were more common in those with fibromyalgia. Notably, xerosis and neurotic excoriations were more prevalent compared to the control group.¹⁶

The brain and the skin—both derivatives of the embryonic ectoderm^33,34—are linked by pruritus. Although itch has its dedicated neurons, there is a wide-ranging overlap of brain-activated areas between pain and itch,⁶ and the neural anatomy of pain and itch are closely related in both the peripheral and central nervous systems^35-37; for example, diseases of the central nervous system are accompanied by pruritus in as many as 15% of cases, while postherpetic neuralgia can result in chronic pain, itching, or a combination of both.^38,39 Other instances include notalgia paresthetica and brachioradial pruritus.³⁸ Additionally, there is a noteworthy psychologic impact associated with both itch and pain,^40,41 with both psychosomatic and psychologic factors implicated in chronic pruritus and in fibromyalgia.⁴² Lastly, the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system are altered in both fibromyalgia and pruritus.^43-45

Tey et al⁴⁵ characterized the itch experienced in fibromyalgia as functional, which is described as pruritus associated with a somatoform disorder. In our study, we found a higher prevalence of pruritus among patients with fibromyalgia, and this association remained significant (P<.05) even when excluding other pruritic skin conditions and systemic diseases that can trigger itching. In addition, our logistic regression analyses revealed independent associations between fibromyalgia and pruritus, prurigo nodularis, and LSC.

According to Twycross et al,⁴⁶ there are 4 clinical categories of itch, which may coexist⁷: pruritoceptive (originating in the skin), neuropathic (originating in pathology located along the afferent pathway), neurogenic (central origin but lacks a neural pathology), and psychogenic.⁴⁷ Skin biopsy findings in patients with fibromyalgia include increased mast cell counts¹¹ and degranulation,⁴⁸ increased expression of δ and κ opioid receptors,³² vasoconstriction within tender points,⁴⁹ and elevated IL-1β, IL-6, or tumor necrosis factor α by reverse transcriptase-polymerase chain reaction.¹² A case recently was presented by Görg et al⁵⁰ involving a female patient with fibromyalgia who had been experiencing chronic pruritus, which the authors attributed to small-fiber neuropathy based on evidence from a skin biopsy indicating a reduced number of intraepidermal nerves and the fact that the itching originated around tender points. Altogether, the observed alterations may work together to make patients with fibromyalgia more susceptible to various skin-related comorbidities in general, especially those related to pruritus. Eventually, it might be the case that several itch categories and related pathomechanisms are involved in the pruritus phenotype of patients with fibromyalgia.

Age-related alterations in nerve fibers, lower immune function, xerosis, polypharmacy, and increased frequency of systemic diseases with age are just a few of the factors that may predispose older individuals to pruritus.^51,52 Indeed, our logistic regression model showed that age was significantly and independently associated with ­pruritus (P<.001), neurotic excoriations (P=.046), and LSC (P=.006). Female sex also was significantly linked with pruritus (P=.039). Intriguingly, high socioeconomic status was significantly associated with the diagnosis of ­pruritus (P=.002), possibly due to easier access to medical care.

There is a considerable overlap between the therapeutic approaches used in pruritus, pruritus-related skin disorders, and fibromyalgia. Antidepressants, anxiolytics, analgesics, and antiepileptics have been used to address both conditions.⁴⁵ The association between these conditions advocates for a multidisciplinary approach in patients with fibromyalgia and potentially supports the rationale for unified therapeutics for both conditions.

Conclusion

Our findings indicate an association between fibromyalgia and pruritus as well as associated pruritic skin disorders. Given the convoluted and largely undiscovered mechanisms underlying fibromyalgia, managing patients with this condition may present substantial challenges.⁵³ The data presented here support the implementation of a multidisciplinary treatment approach for patients with fibromyalgia. This approach should focus on managing fibromyalgia pain as well as addressing its concurrent skin-related conditions. It is advisable to consider treatments such as antiepileptics (eg, pregabalin, gabapentin) that specifically target neuropathic disorders in affected patients. These treatments may hold promise for alleviating fibromyalgia-related pain⁵⁴ and mitigating its related cutaneous comorbidities, especially pruritus.

Pruritus, which is defined as an itching sensation that elicits a desire to scratch, is the most common cutaneous condition. Pruritus is considered chronic when it lasts for more than 6 weeks.¹ Etiologies implicated in chronic pruritus include but are not limited to primary skin diseases such as atopic dermatitis, systemic causes, neuropathic disorders, and psychogenic reasons.² In approximately 8% to 35% of patients, the cause of pruritus remains elusive despite intensive investigation.³ The mechanisms of itch are multifaceted and include complex neural pathways.⁴ Although itch and pain share many similarities, they have distinct pathways based on their spinal connections.⁵ Nevertheless, both conditions show a wide overlap of receptors on peripheral nerve endings and activated brain parts.^6,7 Fibromyalgia, the third most common musculoskeletal condition, affects 2% to 3% of the population worldwide and is at least 7 times more common in females.^8,9 Its pathogenesis is not entirely clear but is thought to involve neurogenic inflammation, aberrations in peripheral nerves, and central pain mechanisms. Fibromyalgia is characterized by a plethora of symptoms including chronic widespread pain, autonomic disturbances, persistent fatigue and sleep disturbances, and hyperalgesia, as well as somatic and psychiatric symptoms.¹⁰

Fibromyalgia is accompanied by altered skin features including increased counts of mast cells and excessive degranulation,¹¹ neurogenic inflammation with elevated cytokine expression,¹² disrupted collagen metabolism,¹³ and microcirculation abnormalities.¹⁴ There has been limited research exploring the dermatologic manifestations of fibromyalgia. One retrospective study that included 845 patients with fibromyalgia reported increased occurrence of “neurodermatoses,” including pruritus, neurotic excoriations, prurigo nodules, and lichen simplex chronicus (LSC), among other cutaneous comorbidities.¹⁵ Another small study demonstrated an increased incidence of xerosis and neurotic excoriations in females with fibromyalgia.¹⁶ A paucity of large epidemiologic studies demonstrating the fibromyalgia-pruritus connection may lead to misdiagnosis, misinterpretation, and undertreatment of these patients.

Up to 49% of fibromyalgia patients experience small-fiber neuropathy.¹⁷ Electrophysiologic measurements, quantitative sensory testing, pain-related evoked potentials, and skin biopsies showed that patients with fibromyalgia have compromised small-fiber function, impaired pathways carrying fiber pain signals, and reduced skin innervation and regenerating fibers.^18,19 Accordingly, pruritus that has been reported in fibromyalgia is believed to be of neuropathic origin.¹⁵ Overall, it is suspected that the same mechanism that causes hypersensitivity and pain in fibromyalgia patients also predisposes them to pruritus. Similar systemic treatments (eg, analgesics, antidepressants, anticonvulsants) prescribed for both conditions support this theory.^20-25

Our large cross-sectional study sought to establish the association between fibromyalgia and pruritus as well as related pruritic conditions.

Methods

Study Design and Setting—We conducted a cross-­sectional retrospective study using data-mining techniques to access information from the Clalit Health Services (CHS) database. Clalit Health Services is the largest health maintenance organization in Israel. It encompasses an extensive database with continuous real-time input from medical, administrative, and pharmaceutical computerized operating systems, which helps facilitate data collection for epidemiologic studies. A chronic disease register is gathered from these data sources and continuously updated and validated through logistic checks. The current study was approved by the institutional review board of the CHS (approval #0212-17-com2). Informed consent was not required because the data were de-identified and this was a noninterventional observational study.

Study Population and Covariates—Medical records of CHS enrollees were screened for the diagnosis of fibromyalgia, and data on prevalent cases of fibromyalgia were retrieved. The diagnosis of fibromyalgia was based on the documentation of a fibromyalgia-specific diagnostic code registered by a board-certified rheumatologist. A control group of individuals without fibromyalgia was selected through 1:2 matching based on age, sex, and primary care clinic. The control group was randomly selected from the list of CHS members frequency-matched to cases, excluding case patients with fibromyalgia. Age matching was grounded on the exact year of birth (1-year strata).

Other covariates in the analysis included pruritus-related skin disorders, including prurigo nodularis, neurotic excoriations, and LSC. There were 3 socioeconomic status categories according to patients' poverty index: low, intermediate, and high.²⁶

Statistical Analysis—The distribution of sociodemographic and clinical features was compared between patients with fibromyalgia and controls using the χ² test for sex and socioeconomic status and the t test for age. Conditional logistic regression then was used to calculate adjusted odds ratio (OR) and 95% CI to compare patients with fibromyalgia and controls with respect to the presence of pruritic comorbidities. All statistical analyses were performed using SPSS software (version 26). P<.05 was considered statistically significant in all tests.

Results

Our study population comprised 4971 patients with fibromyalgia and 9896 age- and sex-matched controls. Proportional to the reported female predominance among patients with fibromyalgia,²⁷ 4479 (90.1%) patients with fibromyalgia were females and a similar proportion was documented among controls (P=.99). There was a slightly higher proportion of unmarried patients among those with fibromyalgia compared with controls (41.9% vs 39.4%; P=.004). Socioeconomic status was matched between patients and controls (P=.99). Descriptive characteristics of the study population are presented in Table 1.

We assessed the presence of pruritus as well as 3 other pruritus-related skin disorders—prurigo nodularis, neurotic excoriations, and LSC—among patients with fibromyalgia and controls. Logistic regression was used to evaluate the independent association between fibromyalgia and pruritus. Table 2 presents the results of multivariate logistic regression models and summarizes the adjusted ORs for pruritic conditions in patients with fibromyalgia and different demographic features across the entire study sample. Fibromyalgia demonstrated strong independent associations with pruritus (OR, 1.8; 95% CI, 1.8-2.4; P<.001), prurigo nodularis (OR, 2.9; 95% CI, 1.1-8.4; P=.038), and LSC (OR, 1.5; 95% CI, 1.1-2.1; P=.01); the association with neurotic excoriations was not significant. Female sex significantly increased the risk for pruritus (OR 1.3; 95% CI, 1.0-1.6; P=.039), while age slightly increased the odds for pruritus (OR, 1.0; 95% CI, 1.0-1.04; P<.001), neurotic excoriations (OR, 1.0; 95% CI, 1.0-1.1; P=.046), and LSC (OR, 1.0; 95% CI, 1.01-1.04; P=.006). Finally, socioeconomic status was inversely correlated with pruritus (OR, 1.1; 95% CI, 1.1-1.5; P=.002).

Comment

A wide range of skin manifestations have been associated with fibromyalgia, but the exact mechanisms remain unclear. Nevertheless, it is conceivable that autonomic nervous system dysfunction,^28-31 amplified cutaneous opioid receptor activity,³² and an elevated presence of cutaneous mast cells with excessive degranulation may partially explain the frequent occurrence of pruritus and related skin disorders such as neurotic excoriations, prurigo nodularis, and LSC in individuals with fibromyalgia.^15,16 In line with these findings, our study—which was based on data from the largest health maintenance organization in Israel—demonstrated an increased prevalence of pruritus and related pruritic disorders among individuals diagnosed with fibromyalgia.

This cross-sectional study links pruritus with fibromyalgia. Few preliminary epidemiologic studies have shown an increased occurrence of cutaneous manifestations in patients with fibromyalgia. One chart review that looked at skin findings in patients with fibromyalgia revealed 32 distinct cutaneous manifestations, and pruritus was the major concern in 3.3% of 845 patients.¹⁵

A focused cross-sectional study involving only women (66 with fibromyalgia and 79 healthy controls) discovered 14 skin conditions that were more common in those with fibromyalgia. Notably, xerosis and neurotic excoriations were more prevalent compared to the control group.¹⁶

The brain and the skin—both derivatives of the embryonic ectoderm^33,34—are linked by pruritus. Although itch has its dedicated neurons, there is a wide-ranging overlap of brain-activated areas between pain and itch,⁶ and the neural anatomy of pain and itch are closely related in both the peripheral and central nervous systems^35-37; for example, diseases of the central nervous system are accompanied by pruritus in as many as 15% of cases, while postherpetic neuralgia can result in chronic pain, itching, or a combination of both.^38,39 Other instances include notalgia paresthetica and brachioradial pruritus.³⁸ Additionally, there is a noteworthy psychologic impact associated with both itch and pain,^40,41 with both psychosomatic and psychologic factors implicated in chronic pruritus and in fibromyalgia.⁴² Lastly, the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system are altered in both fibromyalgia and pruritus.^43-45

Tey et al⁴⁵ characterized the itch experienced in fibromyalgia as functional, which is described as pruritus associated with a somatoform disorder. In our study, we found a higher prevalence of pruritus among patients with fibromyalgia, and this association remained significant (P<.05) even when excluding other pruritic skin conditions and systemic diseases that can trigger itching. In addition, our logistic regression analyses revealed independent associations between fibromyalgia and pruritus, prurigo nodularis, and LSC.

According to Twycross et al,⁴⁶ there are 4 clinical categories of itch, which may coexist⁷: pruritoceptive (originating in the skin), neuropathic (originating in pathology located along the afferent pathway), neurogenic (central origin but lacks a neural pathology), and psychogenic.⁴⁷ Skin biopsy findings in patients with fibromyalgia include increased mast cell counts¹¹ and degranulation,⁴⁸ increased expression of δ and κ opioid receptors,³² vasoconstriction within tender points,⁴⁹ and elevated IL-1β, IL-6, or tumor necrosis factor α by reverse transcriptase-polymerase chain reaction.¹² A case recently was presented by Görg et al⁵⁰ involving a female patient with fibromyalgia who had been experiencing chronic pruritus, which the authors attributed to small-fiber neuropathy based on evidence from a skin biopsy indicating a reduced number of intraepidermal nerves and the fact that the itching originated around tender points. Altogether, the observed alterations may work together to make patients with fibromyalgia more susceptible to various skin-related comorbidities in general, especially those related to pruritus. Eventually, it might be the case that several itch categories and related pathomechanisms are involved in the pruritus phenotype of patients with fibromyalgia.

Age-related alterations in nerve fibers, lower immune function, xerosis, polypharmacy, and increased frequency of systemic diseases with age are just a few of the factors that may predispose older individuals to pruritus.^51,52 Indeed, our logistic regression model showed that age was significantly and independently associated with ­pruritus (P<.001), neurotic excoriations (P=.046), and LSC (P=.006). Female sex also was significantly linked with pruritus (P=.039). Intriguingly, high socioeconomic status was significantly associated with the diagnosis of ­pruritus (P=.002), possibly due to easier access to medical care.

There is a considerable overlap between the therapeutic approaches used in pruritus, pruritus-related skin disorders, and fibromyalgia. Antidepressants, anxiolytics, analgesics, and antiepileptics have been used to address both conditions.⁴⁵ The association between these conditions advocates for a multidisciplinary approach in patients with fibromyalgia and potentially supports the rationale for unified therapeutics for both conditions.

Conclusion

Our findings indicate an association between fibromyalgia and pruritus as well as associated pruritic skin disorders. Given the convoluted and largely undiscovered mechanisms underlying fibromyalgia, managing patients with this condition may present substantial challenges.⁵³ The data presented here support the implementation of a multidisciplinary treatment approach for patients with fibromyalgia. This approach should focus on managing fibromyalgia pain as well as addressing its concurrent skin-related conditions. It is advisable to consider treatments such as antiepileptics (eg, pregabalin, gabapentin) that specifically target neuropathic disorders in affected patients. These treatments may hold promise for alleviating fibromyalgia-related pain⁵⁴ and mitigating its related cutaneous comorbidities, especially pruritus.

Pruritus, which is defined as an itching sensation that elicits a desire to scratch, is the most common cutaneous condition. Pruritus is considered chronic when it lasts for more than 6 weeks.¹ Etiologies implicated in chronic pruritus include but are not limited to primary skin diseases such as atopic dermatitis, systemic causes, neuropathic disorders, and psychogenic reasons.² In approximately 8% to 35% of patients, the cause of pruritus remains elusive despite intensive investigation.³ The mechanisms of itch are multifaceted and include complex neural pathways.⁴ Although itch and pain share many similarities, they have distinct pathways based on their spinal connections.⁵ Nevertheless, both conditions show a wide overlap of receptors on peripheral nerve endings and activated brain parts.^6,7 Fibromyalgia, the third most common musculoskeletal condition, affects 2% to 3% of the population worldwide and is at least 7 times more common in females.^8,9 Its pathogenesis is not entirely clear but is thought to involve neurogenic inflammation, aberrations in peripheral nerves, and central pain mechanisms. Fibromyalgia is characterized by a plethora of symptoms including chronic widespread pain, autonomic disturbances, persistent fatigue and sleep disturbances, and hyperalgesia, as well as somatic and psychiatric symptoms.¹⁰

Fibromyalgia is accompanied by altered skin features including increased counts of mast cells and excessive degranulation,¹¹ neurogenic inflammation with elevated cytokine expression,¹² disrupted collagen metabolism,¹³ and microcirculation abnormalities.¹⁴ There has been limited research exploring the dermatologic manifestations of fibromyalgia. One retrospective study that included 845 patients with fibromyalgia reported increased occurrence of “neurodermatoses,” including pruritus, neurotic excoriations, prurigo nodules, and lichen simplex chronicus (LSC), among other cutaneous comorbidities.¹⁵ Another small study demonstrated an increased incidence of xerosis and neurotic excoriations in females with fibromyalgia.¹⁶ A paucity of large epidemiologic studies demonstrating the fibromyalgia-pruritus connection may lead to misdiagnosis, misinterpretation, and undertreatment of these patients.

Up to 49% of fibromyalgia patients experience small-fiber neuropathy.¹⁷ Electrophysiologic measurements, quantitative sensory testing, pain-related evoked potentials, and skin biopsies showed that patients with fibromyalgia have compromised small-fiber function, impaired pathways carrying fiber pain signals, and reduced skin innervation and regenerating fibers.^18,19 Accordingly, pruritus that has been reported in fibromyalgia is believed to be of neuropathic origin.¹⁵ Overall, it is suspected that the same mechanism that causes hypersensitivity and pain in fibromyalgia patients also predisposes them to pruritus. Similar systemic treatments (eg, analgesics, antidepressants, anticonvulsants) prescribed for both conditions support this theory.^20-25

Our large cross-sectional study sought to establish the association between fibromyalgia and pruritus as well as related pruritic conditions.

Methods

Study Design and Setting—We conducted a cross-­sectional retrospective study using data-mining techniques to access information from the Clalit Health Services (CHS) database. Clalit Health Services is the largest health maintenance organization in Israel. It encompasses an extensive database with continuous real-time input from medical, administrative, and pharmaceutical computerized operating systems, which helps facilitate data collection for epidemiologic studies. A chronic disease register is gathered from these data sources and continuously updated and validated through logistic checks. The current study was approved by the institutional review board of the CHS (approval #0212-17-com2). Informed consent was not required because the data were de-identified and this was a noninterventional observational study.

Study Population and Covariates—Medical records of CHS enrollees were screened for the diagnosis of fibromyalgia, and data on prevalent cases of fibromyalgia were retrieved. The diagnosis of fibromyalgia was based on the documentation of a fibromyalgia-specific diagnostic code registered by a board-certified rheumatologist. A control group of individuals without fibromyalgia was selected through 1:2 matching based on age, sex, and primary care clinic. The control group was randomly selected from the list of CHS members frequency-matched to cases, excluding case patients with fibromyalgia. Age matching was grounded on the exact year of birth (1-year strata).

Other covariates in the analysis included pruritus-related skin disorders, including prurigo nodularis, neurotic excoriations, and LSC. There were 3 socioeconomic status categories according to patients' poverty index: low, intermediate, and high.²⁶

Statistical Analysis—The distribution of sociodemographic and clinical features was compared between patients with fibromyalgia and controls using the χ² test for sex and socioeconomic status and the t test for age. Conditional logistic regression then was used to calculate adjusted odds ratio (OR) and 95% CI to compare patients with fibromyalgia and controls with respect to the presence of pruritic comorbidities. All statistical analyses were performed using SPSS software (version 26). P<.05 was considered statistically significant in all tests.

Results

Our study population comprised 4971 patients with fibromyalgia and 9896 age- and sex-matched controls. Proportional to the reported female predominance among patients with fibromyalgia,²⁷ 4479 (90.1%) patients with fibromyalgia were females and a similar proportion was documented among controls (P=.99). There was a slightly higher proportion of unmarried patients among those with fibromyalgia compared with controls (41.9% vs 39.4%; P=.004). Socioeconomic status was matched between patients and controls (P=.99). Descriptive characteristics of the study population are presented in Table 1.

We assessed the presence of pruritus as well as 3 other pruritus-related skin disorders—prurigo nodularis, neurotic excoriations, and LSC—among patients with fibromyalgia and controls. Logistic regression was used to evaluate the independent association between fibromyalgia and pruritus. Table 2 presents the results of multivariate logistic regression models and summarizes the adjusted ORs for pruritic conditions in patients with fibromyalgia and different demographic features across the entire study sample. Fibromyalgia demonstrated strong independent associations with pruritus (OR, 1.8; 95% CI, 1.8-2.4; P<.001), prurigo nodularis (OR, 2.9; 95% CI, 1.1-8.4; P=.038), and LSC (OR, 1.5; 95% CI, 1.1-2.1; P=.01); the association with neurotic excoriations was not significant. Female sex significantly increased the risk for pruritus (OR 1.3; 95% CI, 1.0-1.6; P=.039), while age slightly increased the odds for pruritus (OR, 1.0; 95% CI, 1.0-1.04; P<.001), neurotic excoriations (OR, 1.0; 95% CI, 1.0-1.1; P=.046), and LSC (OR, 1.0; 95% CI, 1.01-1.04; P=.006). Finally, socioeconomic status was inversely correlated with pruritus (OR, 1.1; 95% CI, 1.1-1.5; P=.002).

Comment

A wide range of skin manifestations have been associated with fibromyalgia, but the exact mechanisms remain unclear. Nevertheless, it is conceivable that autonomic nervous system dysfunction,^28-31 amplified cutaneous opioid receptor activity,³² and an elevated presence of cutaneous mast cells with excessive degranulation may partially explain the frequent occurrence of pruritus and related skin disorders such as neurotic excoriations, prurigo nodularis, and LSC in individuals with fibromyalgia.^15,16 In line with these findings, our study—which was based on data from the largest health maintenance organization in Israel—demonstrated an increased prevalence of pruritus and related pruritic disorders among individuals diagnosed with fibromyalgia.

This cross-sectional study links pruritus with fibromyalgia. Few preliminary epidemiologic studies have shown an increased occurrence of cutaneous manifestations in patients with fibromyalgia. One chart review that looked at skin findings in patients with fibromyalgia revealed 32 distinct cutaneous manifestations, and pruritus was the major concern in 3.3% of 845 patients.¹⁵

A focused cross-sectional study involving only women (66 with fibromyalgia and 79 healthy controls) discovered 14 skin conditions that were more common in those with fibromyalgia. Notably, xerosis and neurotic excoriations were more prevalent compared to the control group.¹⁶

The brain and the skin—both derivatives of the embryonic ectoderm^33,34—are linked by pruritus. Although itch has its dedicated neurons, there is a wide-ranging overlap of brain-activated areas between pain and itch,⁶ and the neural anatomy of pain and itch are closely related in both the peripheral and central nervous systems^35-37; for example, diseases of the central nervous system are accompanied by pruritus in as many as 15% of cases, while postherpetic neuralgia can result in chronic pain, itching, or a combination of both.^38,39 Other instances include notalgia paresthetica and brachioradial pruritus.³⁸ Additionally, there is a noteworthy psychologic impact associated with both itch and pain,^40,41 with both psychosomatic and psychologic factors implicated in chronic pruritus and in fibromyalgia.⁴² Lastly, the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system are altered in both fibromyalgia and pruritus.^43-45

Tey et al⁴⁵ characterized the itch experienced in fibromyalgia as functional, which is described as pruritus associated with a somatoform disorder. In our study, we found a higher prevalence of pruritus among patients with fibromyalgia, and this association remained significant (P<.05) even when excluding other pruritic skin conditions and systemic diseases that can trigger itching. In addition, our logistic regression analyses revealed independent associations between fibromyalgia and pruritus, prurigo nodularis, and LSC.

According to Twycross et al,⁴⁶ there are 4 clinical categories of itch, which may coexist⁷: pruritoceptive (originating in the skin), neuropathic (originating in pathology located along the afferent pathway), neurogenic (central origin but lacks a neural pathology), and psychogenic.⁴⁷ Skin biopsy findings in patients with fibromyalgia include increased mast cell counts¹¹ and degranulation,⁴⁸ increased expression of δ and κ opioid receptors,³² vasoconstriction within tender points,⁴⁹ and elevated IL-1β, IL-6, or tumor necrosis factor α by reverse transcriptase-polymerase chain reaction.¹² A case recently was presented by Görg et al⁵⁰ involving a female patient with fibromyalgia who had been experiencing chronic pruritus, which the authors attributed to small-fiber neuropathy based on evidence from a skin biopsy indicating a reduced number of intraepidermal nerves and the fact that the itching originated around tender points. Altogether, the observed alterations may work together to make patients with fibromyalgia more susceptible to various skin-related comorbidities in general, especially those related to pruritus. Eventually, it might be the case that several itch categories and related pathomechanisms are involved in the pruritus phenotype of patients with fibromyalgia.

Age-related alterations in nerve fibers, lower immune function, xerosis, polypharmacy, and increased frequency of systemic diseases with age are just a few of the factors that may predispose older individuals to pruritus.^51,52 Indeed, our logistic regression model showed that age was significantly and independently associated with ­pruritus (P<.001), neurotic excoriations (P=.046), and LSC (P=.006). Female sex also was significantly linked with pruritus (P=.039). Intriguingly, high socioeconomic status was significantly associated with the diagnosis of ­pruritus (P=.002), possibly due to easier access to medical care.

There is a considerable overlap between the therapeutic approaches used in pruritus, pruritus-related skin disorders, and fibromyalgia. Antidepressants, anxiolytics, analgesics, and antiepileptics have been used to address both conditions.⁴⁵ The association between these conditions advocates for a multidisciplinary approach in patients with fibromyalgia and potentially supports the rationale for unified therapeutics for both conditions.

Conclusion

Our findings indicate an association between fibromyalgia and pruritus as well as associated pruritic skin disorders. Given the convoluted and largely undiscovered mechanisms underlying fibromyalgia, managing patients with this condition may present substantial challenges.⁵³ The data presented here support the implementation of a multidisciplinary treatment approach for patients with fibromyalgia. This approach should focus on managing fibromyalgia pain as well as addressing its concurrent skin-related conditions. It is advisable to consider treatments such as antiepileptics (eg, pregabalin, gabapentin) that specifically target neuropathic disorders in affected patients. These treatments may hold promise for alleviating fibromyalgia-related pain⁵⁴ and mitigating its related cutaneous comorbidities, especially pruritus.

To the Editor:

Psoriasis is a chronic inflammatory papulosquamous skin disease affecting 2% to 3% of the population.¹ Its pathogenesis is multifactorial, consisting of a disrupted skin barrier and dysregulated immune activation.²

A wide armamentarium of topical and systemic treatments targeting different aspects of the disease pathogenesis have been developed over the years.^3,4 Psoriasis was once considered a skin disease exclusively, but accumulating evidence suggests that it is accompanied by a multitude of systemic inflammatory comorbidities.⁵ This insight supports the concept of systemic treatment for patients with moderate to severe psoriasis. As a chronic disease, psoriasis requires continuous therapy. The treatment approach should focus on achieving efficacy and minimizing side effects. These goals can be achieved by combination, rotational, and sequential treatment approaches.⁶ Many therapeutic combinations have proven effective, using beneficially different mechanisms of action (MOAs) and toxicity profiles.⁷ We present a patient with moderate to severe recalcitrant palmoplantar psoriasis who demonstrated improvement with combination therapy.

A 50-year-old man presented with palmoplantar psoriasis of 7 years’ duration. His medical history included mild hyperlipidemia treated with atorvastatin. Prior topical treatments including calcipotriene, betamethasone dipropionate, and tacrolimus ointment did not result in improvement. Persistent acral involvement required further intervention, and the excimer laser was added to the therapeutic regimen with a minor additive therapeutic value. Acitretin (25 mg/d) was initiated; however, the disease flared up soon after. Acitretin was discontinued, and the patient was treated with apremilast (30 mg twice daily) for 9 months with a slight improvement. Physical examination revealed erythematous, fissured, scaly plaques involving both the palms and soles. Acitretin (25 mg/d) was reintroduced to the therapeutic regimen, and the acitretin-apremilast combination was used for 2 months. With this regimen, the patient experienced 90% improvement (Figures 1 and 2).

Acitretin, the active metabolite of etretinate, modulates epidermal differentiation and has immunomodulating activities.¹⁷ It commonly is used for treating palmoplantar psoriasis.⁸ Until recently, it was the only nonimmunosuppressive systemic treatment for psoriasis, and its combination with other systemic treatments, particularly biologics, has been advocated.¹⁸ Prior reports showed remarkable disease improvement when combining acitretin with alefacept, etanercept, infliximab, adalimumab, and ustekinumab.¹⁹ The optimal combination should include modalities with different MOAs without overlapping toxicities.¹⁹ Apremilast and acitretin have different MOAs and side-effect profiles, but another theoretical advantage is that they both interfere with intracellular signaling on the transcription level rather than affecting extracellular targets.¹³

Our patient with moderate to severe recalcitrant palmoplantar psoriasis demonstrated approximately 90% improvement following apremilast and acitretin combination therapy. This treatment regimen should be considered in cases of persistent acral disease resistant to other therapeutic efforts.

To the Editor:

Psoriasis is a chronic inflammatory papulosquamous skin disease affecting 2% to 3% of the population.¹ Its pathogenesis is multifactorial, consisting of a disrupted skin barrier and dysregulated immune activation.²

A wide armamentarium of topical and systemic treatments targeting different aspects of the disease pathogenesis have been developed over the years.^3,4 Psoriasis was once considered a skin disease exclusively, but accumulating evidence suggests that it is accompanied by a multitude of systemic inflammatory comorbidities.⁵ This insight supports the concept of systemic treatment for patients with moderate to severe psoriasis. As a chronic disease, psoriasis requires continuous therapy. The treatment approach should focus on achieving efficacy and minimizing side effects. These goals can be achieved by combination, rotational, and sequential treatment approaches.⁶ Many therapeutic combinations have proven effective, using beneficially different mechanisms of action (MOAs) and toxicity profiles.⁷ We present a patient with moderate to severe recalcitrant palmoplantar psoriasis who demonstrated improvement with combination therapy.

A 50-year-old man presented with palmoplantar psoriasis of 7 years’ duration. His medical history included mild hyperlipidemia treated with atorvastatin. Prior topical treatments including calcipotriene, betamethasone dipropionate, and tacrolimus ointment did not result in improvement. Persistent acral involvement required further intervention, and the excimer laser was added to the therapeutic regimen with a minor additive therapeutic value. Acitretin (25 mg/d) was initiated; however, the disease flared up soon after. Acitretin was discontinued, and the patient was treated with apremilast (30 mg twice daily) for 9 months with a slight improvement. Physical examination revealed erythematous, fissured, scaly plaques involving both the palms and soles. Acitretin (25 mg/d) was reintroduced to the therapeutic regimen, and the acitretin-apremilast combination was used for 2 months. With this regimen, the patient experienced 90% improvement (Figures 1 and 2).

Acitretin, the active metabolite of etretinate, modulates epidermal differentiation and has immunomodulating activities.¹⁷ It commonly is used for treating palmoplantar psoriasis.⁸ Until recently, it was the only nonimmunosuppressive systemic treatment for psoriasis, and its combination with other systemic treatments, particularly biologics, has been advocated.¹⁸ Prior reports showed remarkable disease improvement when combining acitretin with alefacept, etanercept, infliximab, adalimumab, and ustekinumab.¹⁹ The optimal combination should include modalities with different MOAs without overlapping toxicities.¹⁹ Apremilast and acitretin have different MOAs and side-effect profiles, but another theoretical advantage is that they both interfere with intracellular signaling on the transcription level rather than affecting extracellular targets.¹³

Our patient with moderate to severe recalcitrant palmoplantar psoriasis demonstrated approximately 90% improvement following apremilast and acitretin combination therapy. This treatment regimen should be considered in cases of persistent acral disease resistant to other therapeutic efforts.

To the Editor:

Psoriasis is a chronic inflammatory papulosquamous skin disease affecting 2% to 3% of the population.¹ Its pathogenesis is multifactorial, consisting of a disrupted skin barrier and dysregulated immune activation.²

A wide armamentarium of topical and systemic treatments targeting different aspects of the disease pathogenesis have been developed over the years.^3,4 Psoriasis was once considered a skin disease exclusively, but accumulating evidence suggests that it is accompanied by a multitude of systemic inflammatory comorbidities.⁵ This insight supports the concept of systemic treatment for patients with moderate to severe psoriasis. As a chronic disease, psoriasis requires continuous therapy. The treatment approach should focus on achieving efficacy and minimizing side effects. These goals can be achieved by combination, rotational, and sequential treatment approaches.⁶ Many therapeutic combinations have proven effective, using beneficially different mechanisms of action (MOAs) and toxicity profiles.⁷ We present a patient with moderate to severe recalcitrant palmoplantar psoriasis who demonstrated improvement with combination therapy.

A 50-year-old man presented with palmoplantar psoriasis of 7 years’ duration. His medical history included mild hyperlipidemia treated with atorvastatin. Prior topical treatments including calcipotriene, betamethasone dipropionate, and tacrolimus ointment did not result in improvement. Persistent acral involvement required further intervention, and the excimer laser was added to the therapeutic regimen with a minor additive therapeutic value. Acitretin (25 mg/d) was initiated; however, the disease flared up soon after. Acitretin was discontinued, and the patient was treated with apremilast (30 mg twice daily) for 9 months with a slight improvement. Physical examination revealed erythematous, fissured, scaly plaques involving both the palms and soles. Acitretin (25 mg/d) was reintroduced to the therapeutic regimen, and the acitretin-apremilast combination was used for 2 months. With this regimen, the patient experienced 90% improvement (Figures 1 and 2).

Acitretin, the active metabolite of etretinate, modulates epidermal differentiation and has immunomodulating activities.¹⁷ It commonly is used for treating palmoplantar psoriasis.⁸ Until recently, it was the only nonimmunosuppressive systemic treatment for psoriasis, and its combination with other systemic treatments, particularly biologics, has been advocated.¹⁸ Prior reports showed remarkable disease improvement when combining acitretin with alefacept, etanercept, infliximab, adalimumab, and ustekinumab.¹⁹ The optimal combination should include modalities with different MOAs without overlapping toxicities.¹⁹ Apremilast and acitretin have different MOAs and side-effect profiles, but another theoretical advantage is that they both interfere with intracellular signaling on the transcription level rather than affecting extracellular targets.¹³

Our patient with moderate to severe recalcitrant palmoplantar psoriasis demonstrated approximately 90% improvement following apremilast and acitretin combination therapy. This treatment regimen should be considered in cases of persistent acral disease resistant to other therapeutic efforts.

Atopic dermatitis (AD) is the most common inflammatory skin disease in both adults and children.¹ Unfortunately, the current treatment armamentarium is largely confined to topical calcineurin inhibitors, topical and systemic steroids, phototherapy, cyclosporine (not approved by the US Food and Drug Administration for AD), and other oral immunosuppressants.² The availability of partially helpful and highly toxic treatments creates a huge unmet need for more effective and safer treatments, particularly for patients with moderate to severe AD who often require systemic approaches.

Recent extensive translational (bench top to bedside and back) investigations in skin of AD patients has shown that skin phenotype is characterized by increased T-cell infiltration and related inflammatory cytokines as well as epidermal abnormalities (eg, hyperplasia, aberrant differentiation).³ Clinical improvement of AD has been demonstrated with broad T-cell targeted therapeutics, such as cyclosporine and narrowband UVB, coupled with decreases of T-cell infiltrates and inflammatory gene products as well as improvement of the pathologic epidermal phenotype.^4,5

In the past, AD was conceptualized as a T helper cell T_H2 (acute disease)/T_H1 (chronic disease) bipolar cytokine disorder.⁶ Acute lesions are characterized by high T_H2, T_H22, and some T_H17 signals, with intensification of these axes and T_H1 augmentation orchestrating the chronic phenotype.⁷ The identification of the inflammatory pathways underlying AD has led to the development and testing of more than 10 broad or targeted therapeutics (Table).⁸ Phase 1 and phase 2 studies of dupilumab (targeting IL-4Rα) have shown not only tremendous AD improvement (~70%) but also tissue reversal of the immune and barrier abnormalities, including inflammatory cytokines and epidermal hyperplasia.^9-11 As a result, other T_H2 axis inhibitors (anti–IL-13/tralokinumab, anti–IL-31RA/CIM 331) are now in clinical trials. The identification of IL-22 in AD lesions has prompted trials with an anti–IL-22 (ILV 094) and an IL-12/IL-23p40 (ustekinumab) inhibitor.¹² For psoriasis, ustekinumab showed 75% improvement in approximately 70% of patients,¹³ but for AD, despite clear clinical and molecular effects, differences compared to placebo were not statistically significant,¹² probably due to underdosing of the drug in an excessively immune-activated disease¹⁴ as well as allowing topical steroids in patients, which may minimize the differences in treatment effect between drug and placebo.

The developments seen in AD are now moving into other inflammatory skin diseases, particularly alopecia areata (AA), a T-cell–mediated disease that shares phenotypic similarities with AD and often is associated with it.¹⁵ There is a paucity of effective, remission-sustaining treatments of AA, particularly for patients with severe disease who rarely experience spontaneous hair regrowth and who have a limited response to topical interventions.^16,17 Our clinical experience showed that successfully treating patients with concurrent AD and AA has led to hair regrowth. Inspired by these clinical observations and by results obtained in AD,^9-12 studying AA skin showed an upregulation of not only the traditionally suspected culprit T_H1 but also T_H2 and T_H9 axes, IL-23 cytokines, and phosphodiesterase 4.¹⁸ Subsequently, a pilot study of 3 patients with extensive AA treated with ustekinumab showed that all 3 patients not only experienced hair regrowth but also had a reduction in inflammatory markers in scalp lesions.¹⁹ Although these results are promising, AA is an immunologically complex disease and it is yet to be determined if therapeutically targeting 1 (eg, IL-4) rather than a wide array of cytokines can reverse disease phenotype. There are ongoing clinical trials directed at different pathogenic targets (eg, Jak inhibitors, IL-13 antagonist, IL-17 antagonist, phosphodiesterase 4 antagonist); some showed some efficacy in small studies.^20,21

The finding of a commonly upregulated T_H2 pathway in both AD and AA will pave the way for studies with T_H2 antagonists in AA patients. Future targeted therapeutic studies will shed light on the pathogenic pathways of this devastating skin disease and answer the extensive unmet therapeutic need it presents.

Atopic dermatitis (AD) is the most common inflammatory skin disease in both adults and children.¹ Unfortunately, the current treatment armamentarium is largely confined to topical calcineurin inhibitors, topical and systemic steroids, phototherapy, cyclosporine (not approved by the US Food and Drug Administration for AD), and other oral immunosuppressants.² The availability of partially helpful and highly toxic treatments creates a huge unmet need for more effective and safer treatments, particularly for patients with moderate to severe AD who often require systemic approaches.

Recent extensive translational (bench top to bedside and back) investigations in skin of AD patients has shown that skin phenotype is characterized by increased T-cell infiltration and related inflammatory cytokines as well as epidermal abnormalities (eg, hyperplasia, aberrant differentiation).³ Clinical improvement of AD has been demonstrated with broad T-cell targeted therapeutics, such as cyclosporine and narrowband UVB, coupled with decreases of T-cell infiltrates and inflammatory gene products as well as improvement of the pathologic epidermal phenotype.^4,5

In the past, AD was conceptualized as a T helper cell T_H2 (acute disease)/T_H1 (chronic disease) bipolar cytokine disorder.⁶ Acute lesions are characterized by high T_H2, T_H22, and some T_H17 signals, with intensification of these axes and T_H1 augmentation orchestrating the chronic phenotype.⁷ The identification of the inflammatory pathways underlying AD has led to the development and testing of more than 10 broad or targeted therapeutics (Table).⁸ Phase 1 and phase 2 studies of dupilumab (targeting IL-4Rα) have shown not only tremendous AD improvement (~70%) but also tissue reversal of the immune and barrier abnormalities, including inflammatory cytokines and epidermal hyperplasia.^9-11 As a result, other T_H2 axis inhibitors (anti–IL-13/tralokinumab, anti–IL-31RA/CIM 331) are now in clinical trials. The identification of IL-22 in AD lesions has prompted trials with an anti–IL-22 (ILV 094) and an IL-12/IL-23p40 (ustekinumab) inhibitor.¹² For psoriasis, ustekinumab showed 75% improvement in approximately 70% of patients,¹³ but for AD, despite clear clinical and molecular effects, differences compared to placebo were not statistically significant,¹² probably due to underdosing of the drug in an excessively immune-activated disease¹⁴ as well as allowing topical steroids in patients, which may minimize the differences in treatment effect between drug and placebo.

The developments seen in AD are now moving into other inflammatory skin diseases, particularly alopecia areata (AA), a T-cell–mediated disease that shares phenotypic similarities with AD and often is associated with it.¹⁵ There is a paucity of effective, remission-sustaining treatments of AA, particularly for patients with severe disease who rarely experience spontaneous hair regrowth and who have a limited response to topical interventions.^16,17 Our clinical experience showed that successfully treating patients with concurrent AD and AA has led to hair regrowth. Inspired by these clinical observations and by results obtained in AD,^9-12 studying AA skin showed an upregulation of not only the traditionally suspected culprit T_H1 but also T_H2 and T_H9 axes, IL-23 cytokines, and phosphodiesterase 4.¹⁸ Subsequently, a pilot study of 3 patients with extensive AA treated with ustekinumab showed that all 3 patients not only experienced hair regrowth but also had a reduction in inflammatory markers in scalp lesions.¹⁹ Although these results are promising, AA is an immunologically complex disease and it is yet to be determined if therapeutically targeting 1 (eg, IL-4) rather than a wide array of cytokines can reverse disease phenotype. There are ongoing clinical trials directed at different pathogenic targets (eg, Jak inhibitors, IL-13 antagonist, IL-17 antagonist, phosphodiesterase 4 antagonist); some showed some efficacy in small studies.^20,21

The finding of a commonly upregulated T_H2 pathway in both AD and AA will pave the way for studies with T_H2 antagonists in AA patients. Future targeted therapeutic studies will shed light on the pathogenic pathways of this devastating skin disease and answer the extensive unmet therapeutic need it presents.

Atopic dermatitis (AD) is the most common inflammatory skin disease in both adults and children.¹ Unfortunately, the current treatment armamentarium is largely confined to topical calcineurin inhibitors, topical and systemic steroids, phototherapy, cyclosporine (not approved by the US Food and Drug Administration for AD), and other oral immunosuppressants.² The availability of partially helpful and highly toxic treatments creates a huge unmet need for more effective and safer treatments, particularly for patients with moderate to severe AD who often require systemic approaches.

Recent extensive translational (bench top to bedside and back) investigations in skin of AD patients has shown that skin phenotype is characterized by increased T-cell infiltration and related inflammatory cytokines as well as epidermal abnormalities (eg, hyperplasia, aberrant differentiation).³ Clinical improvement of AD has been demonstrated with broad T-cell targeted therapeutics, such as cyclosporine and narrowband UVB, coupled with decreases of T-cell infiltrates and inflammatory gene products as well as improvement of the pathologic epidermal phenotype.^4,5

In the past, AD was conceptualized as a T helper cell T_H2 (acute disease)/T_H1 (chronic disease) bipolar cytokine disorder.⁶ Acute lesions are characterized by high T_H2, T_H22, and some T_H17 signals, with intensification of these axes and T_H1 augmentation orchestrating the chronic phenotype.⁷ The identification of the inflammatory pathways underlying AD has led to the development and testing of more than 10 broad or targeted therapeutics (Table).⁸ Phase 1 and phase 2 studies of dupilumab (targeting IL-4Rα) have shown not only tremendous AD improvement (~70%) but also tissue reversal of the immune and barrier abnormalities, including inflammatory cytokines and epidermal hyperplasia.^9-11 As a result, other T_H2 axis inhibitors (anti–IL-13/tralokinumab, anti–IL-31RA/CIM 331) are now in clinical trials. The identification of IL-22 in AD lesions has prompted trials with an anti–IL-22 (ILV 094) and an IL-12/IL-23p40 (ustekinumab) inhibitor.¹² For psoriasis, ustekinumab showed 75% improvement in approximately 70% of patients,¹³ but for AD, despite clear clinical and molecular effects, differences compared to placebo were not statistically significant,¹² probably due to underdosing of the drug in an excessively immune-activated disease¹⁴ as well as allowing topical steroids in patients, which may minimize the differences in treatment effect between drug and placebo.

The developments seen in AD are now moving into other inflammatory skin diseases, particularly alopecia areata (AA), a T-cell–mediated disease that shares phenotypic similarities with AD and often is associated with it.¹⁵ There is a paucity of effective, remission-sustaining treatments of AA, particularly for patients with severe disease who rarely experience spontaneous hair regrowth and who have a limited response to topical interventions.^16,17 Our clinical experience showed that successfully treating patients with concurrent AD and AA has led to hair regrowth. Inspired by these clinical observations and by results obtained in AD,^9-12 studying AA skin showed an upregulation of not only the traditionally suspected culprit T_H1 but also T_H2 and T_H9 axes, IL-23 cytokines, and phosphodiesterase 4.¹⁸ Subsequently, a pilot study of 3 patients with extensive AA treated with ustekinumab showed that all 3 patients not only experienced hair regrowth but also had a reduction in inflammatory markers in scalp lesions.¹⁹ Although these results are promising, AA is an immunologically complex disease and it is yet to be determined if therapeutically targeting 1 (eg, IL-4) rather than a wide array of cytokines can reverse disease phenotype. There are ongoing clinical trials directed at different pathogenic targets (eg, Jak inhibitors, IL-13 antagonist, IL-17 antagonist, phosphodiesterase 4 antagonist); some showed some efficacy in small studies.^20,21

The finding of a commonly upregulated T_H2 pathway in both AD and AA will pave the way for studies with T_H2 antagonists in AA patients. Future targeted therapeutic studies will shed light on the pathogenic pathways of this devastating skin disease and answer the extensive unmet therapeutic need it presents.