Mixed Topics

TOPLINE:

In patients with pulmonary oligometastases from colorectal cancer (CRC), both stereotactic body radiotherapy (SBRT) and surgery led to similar overall survival rates at 5 years. However, those who received surgery had significantly better progression-free and disease-free survival rates, as well as a longer time to intrathoracic progression.
 

METHODOLOGY:

• SBRT has been shown to provide effective local control and improve short-term survival for patients with pulmonary oligometastases from CRC and has become an alternative for these patients who are ineligible or reluctant to undergo surgery. It’s unclear, however, whether SBRT should be prioritized over surgery in patients with CRC pulmonary metastases, largely because of a lack of prospective data.
• In the current analysis, researchers compared outcomes among 335 patients (median age, 61 years) with lung metastases from CRC who underwent surgery or SBRT, using data from the Peking University Cancer Hospital and Institute between March 2011 and September 2022.
• A total of 251 patients were included in the final analysis after propensity score matching, 173 (68.9%) underwent surgery and 78 (31.1%) received SBRT. The median follow-up was 61.6 months in the surgery group and 54.4 months in the SBRT group.
• The study outcomes were freedom from intrathoracic progression, progression-free survival, and overall survival.

TAKEAWAY:

• At 5 years, rates of freedom from intrathoracic progression were more than twofold higher in the surgery group than in the SBRT group (53% vs 23.4%; hazard ratio [HR], 0.46; P < .001). Progression-free survival rates were also more than twofold higher in the surgery group vs the SBRT group (43.8% vs 18.5%; HR, 0.47; P < .001), respectively. In the SBRT group, a higher percentage of patients had a disease-free interval of less than 12 months compared with the surgery group, with rates of 48.7% and 32.9%, respectively (P = 0.025). 
• Overall survival, however, was not significantly different between the two groups at 5 years (72.5% in the surgery group vs 63.7% in the SBRT group; P = .260). The number of pulmonary metastases (HR, 1.87; 95% CI, 1.11-3.14, P = .019 and tumor size (HR, 1.03; 95% CI, 1.00-1.05, P = .023) were significant prognostic factors for overall survival.
• Local recurrence was more prevalent after SBRT (33.3%) than surgery (16.9%), while new intrathoracic tumors occurred more frequently after surgery than SBRT (71.8% vs 43.1%). Repeated local treatments were common among patients with intrathoracic progression, which might have contributed to favorable survival outcomes in both groups.
• Both treatments were well-tolerated with no treatment-related mortality or grade ≥ 3 toxicities. In the surgery group, 14 patients experienced complications, including atrial fibrillation (n = 4) and prolonged air leaks (n = 7). In the SBRT group, radiation pneumonitis was the most common adverse event (n = 21).

IN PRACTICE:

SBRT yielded overall survival benefits similar to surgery despite a “higher likelihood of prior extrapulmonary metastases, a shorter disease-free interval, and a greater number of metastatic lesions,” the authors wrote. Still, SBRT should be regarded as an “effective alternative in cases in which surgical intervention is either unviable or declined by the patient,” the authors concluded.
 

SOURCE:

The study was co-led by Yaqi Wang and Xin Dong, Peking University Cancer Hospital & Institute, Beijing, China, and was published online in the International Journal of Radiation Oncology, Biology, Physics.
 

LIMITATIONS:

This single-center retrospective study had an inherent selection bias. The lack of balanced sample sizes of the surgery and SBRT groups might have affected the robustness of the statistical analyses. Detailed data on adverse events were not available.
 

DISCLOSURES:

The study was supported by grants from the National Natural Science Foundation of China, Beijing Natural Science Foundation, and Beijing Municipal Administration of Hospital’s Ascent Plan. The authors did not declare any conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

In patients with pulmonary oligometastases from colorectal cancer (CRC), both stereotactic body radiotherapy (SBRT) and surgery led to similar overall survival rates at 5 years. However, those who received surgery had significantly better progression-free and disease-free survival rates, as well as a longer time to intrathoracic progression.
 

METHODOLOGY:

• SBRT has been shown to provide effective local control and improve short-term survival for patients with pulmonary oligometastases from CRC and has become an alternative for these patients who are ineligible or reluctant to undergo surgery. It’s unclear, however, whether SBRT should be prioritized over surgery in patients with CRC pulmonary metastases, largely because of a lack of prospective data.
• In the current analysis, researchers compared outcomes among 335 patients (median age, 61 years) with lung metastases from CRC who underwent surgery or SBRT, using data from the Peking University Cancer Hospital and Institute between March 2011 and September 2022.
• A total of 251 patients were included in the final analysis after propensity score matching, 173 (68.9%) underwent surgery and 78 (31.1%) received SBRT. The median follow-up was 61.6 months in the surgery group and 54.4 months in the SBRT group.
• The study outcomes were freedom from intrathoracic progression, progression-free survival, and overall survival.

TAKEAWAY:

• At 5 years, rates of freedom from intrathoracic progression were more than twofold higher in the surgery group than in the SBRT group (53% vs 23.4%; hazard ratio [HR], 0.46; P < .001). Progression-free survival rates were also more than twofold higher in the surgery group vs the SBRT group (43.8% vs 18.5%; HR, 0.47; P < .001), respectively. In the SBRT group, a higher percentage of patients had a disease-free interval of less than 12 months compared with the surgery group, with rates of 48.7% and 32.9%, respectively (P = 0.025). 
• Overall survival, however, was not significantly different between the two groups at 5 years (72.5% in the surgery group vs 63.7% in the SBRT group; P = .260). The number of pulmonary metastases (HR, 1.87; 95% CI, 1.11-3.14, P = .019 and tumor size (HR, 1.03; 95% CI, 1.00-1.05, P = .023) were significant prognostic factors for overall survival.
• Local recurrence was more prevalent after SBRT (33.3%) than surgery (16.9%), while new intrathoracic tumors occurred more frequently after surgery than SBRT (71.8% vs 43.1%). Repeated local treatments were common among patients with intrathoracic progression, which might have contributed to favorable survival outcomes in both groups.
• Both treatments were well-tolerated with no treatment-related mortality or grade ≥ 3 toxicities. In the surgery group, 14 patients experienced complications, including atrial fibrillation (n = 4) and prolonged air leaks (n = 7). In the SBRT group, radiation pneumonitis was the most common adverse event (n = 21).

IN PRACTICE:

SBRT yielded overall survival benefits similar to surgery despite a “higher likelihood of prior extrapulmonary metastases, a shorter disease-free interval, and a greater number of metastatic lesions,” the authors wrote. Still, SBRT should be regarded as an “effective alternative in cases in which surgical intervention is either unviable or declined by the patient,” the authors concluded.
 

SOURCE:

The study was co-led by Yaqi Wang and Xin Dong, Peking University Cancer Hospital & Institute, Beijing, China, and was published online in the International Journal of Radiation Oncology, Biology, Physics.
 

LIMITATIONS:

This single-center retrospective study had an inherent selection bias. The lack of balanced sample sizes of the surgery and SBRT groups might have affected the robustness of the statistical analyses. Detailed data on adverse events were not available.
 

DISCLOSURES:

The study was supported by grants from the National Natural Science Foundation of China, Beijing Natural Science Foundation, and Beijing Municipal Administration of Hospital’s Ascent Plan. The authors did not declare any conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

In patients with pulmonary oligometastases from colorectal cancer (CRC), both stereotactic body radiotherapy (SBRT) and surgery led to similar overall survival rates at 5 years. However, those who received surgery had significantly better progression-free and disease-free survival rates, as well as a longer time to intrathoracic progression.
 

METHODOLOGY:

• SBRT has been shown to provide effective local control and improve short-term survival for patients with pulmonary oligometastases from CRC and has become an alternative for these patients who are ineligible or reluctant to undergo surgery. It’s unclear, however, whether SBRT should be prioritized over surgery in patients with CRC pulmonary metastases, largely because of a lack of prospective data.
• In the current analysis, researchers compared outcomes among 335 patients (median age, 61 years) with lung metastases from CRC who underwent surgery or SBRT, using data from the Peking University Cancer Hospital and Institute between March 2011 and September 2022.
• A total of 251 patients were included in the final analysis after propensity score matching, 173 (68.9%) underwent surgery and 78 (31.1%) received SBRT. The median follow-up was 61.6 months in the surgery group and 54.4 months in the SBRT group.
• The study outcomes were freedom from intrathoracic progression, progression-free survival, and overall survival.

TAKEAWAY:

• At 5 years, rates of freedom from intrathoracic progression were more than twofold higher in the surgery group than in the SBRT group (53% vs 23.4%; hazard ratio [HR], 0.46; P < .001). Progression-free survival rates were also more than twofold higher in the surgery group vs the SBRT group (43.8% vs 18.5%; HR, 0.47; P < .001), respectively. In the SBRT group, a higher percentage of patients had a disease-free interval of less than 12 months compared with the surgery group, with rates of 48.7% and 32.9%, respectively (P = 0.025). 
• Overall survival, however, was not significantly different between the two groups at 5 years (72.5% in the surgery group vs 63.7% in the SBRT group; P = .260). The number of pulmonary metastases (HR, 1.87; 95% CI, 1.11-3.14, P = .019 and tumor size (HR, 1.03; 95% CI, 1.00-1.05, P = .023) were significant prognostic factors for overall survival.
• Local recurrence was more prevalent after SBRT (33.3%) than surgery (16.9%), while new intrathoracic tumors occurred more frequently after surgery than SBRT (71.8% vs 43.1%). Repeated local treatments were common among patients with intrathoracic progression, which might have contributed to favorable survival outcomes in both groups.
• Both treatments were well-tolerated with no treatment-related mortality or grade ≥ 3 toxicities. In the surgery group, 14 patients experienced complications, including atrial fibrillation (n = 4) and prolonged air leaks (n = 7). In the SBRT group, radiation pneumonitis was the most common adverse event (n = 21).

IN PRACTICE:

SBRT yielded overall survival benefits similar to surgery despite a “higher likelihood of prior extrapulmonary metastases, a shorter disease-free interval, and a greater number of metastatic lesions,” the authors wrote. Still, SBRT should be regarded as an “effective alternative in cases in which surgical intervention is either unviable or declined by the patient,” the authors concluded.
 

SOURCE:

The study was co-led by Yaqi Wang and Xin Dong, Peking University Cancer Hospital & Institute, Beijing, China, and was published online in the International Journal of Radiation Oncology, Biology, Physics.
 

LIMITATIONS:

This single-center retrospective study had an inherent selection bias. The lack of balanced sample sizes of the surgery and SBRT groups might have affected the robustness of the statistical analyses. Detailed data on adverse events were not available.
 

DISCLOSURES:

The study was supported by grants from the National Natural Science Foundation of China, Beijing Natural Science Foundation, and Beijing Municipal Administration of Hospital’s Ascent Plan. The authors did not declare any conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Prurigo nodularis (PN)(also called chronic nodular prurigo, prurigo nodularis of Hyde, or picker’s nodules) was first characterized by James Hyde in 1909.^1-3 Prurigo nodularis manifests with symmetrical, intensely pruritic, eroded, or hyperkeratotic nodules or papules on the extremities and trunk.^1,2,4,5 Studies have shown that individuals with PN experience pruritus, sleep loss, decreased social functioning from the appearance of the nodules, and a higher incidence of anxiety and depression, causing a negative impact on their quality of life.^2,6 In addition, the manifestation of PN has been linked to neurologic and psychiatric disorders; however, PN also can be idiopathic and manifest without underlying illnesses.^2,6,7

Prurigo nodularis has been associated with other dermatologic conditions such as atopic dermatitis (up to 50%), lichen planus, keratoacanthomas (KAs), and bullous pemphigoid.^7-9 It also has been linked to systemic diseases in 38% to 50% of cases, including chronic kidney disease, liver disease, type 2 diabetes mellitus, malignancies (hematopoietic, liver, and skin), and HIV infection.^6,8,10

The pathophysiology of PN is highly complex and has yet to be fully elucidated. It is thought to be due to dysregulation and interaction of the increase in neural and immunologic responses of proinflammatory and pruritogenic cytokines.^2,11 Treatments aim to break the itch-scratch cycle that perpetuates this disorder; however, this proves difficult, as PN is associated with a higher itch intensity than atopic dermatitis and psoriasis.¹⁰ Therefore, most patients attempt multiple forms of treatment for PN, ranging from topical therapies, oral immunosuppressants, and phototherapy to the newest and only medication approved by the US Food and Drug Administration for the treatment of PN—dupilumab.^1,7,11 Herein, we provide an updated review of PN with a focus on its epidemiology, histopathology and pathophysiology, comorbidities, clinical presentation, differential diagnosis, and current treatment options.

Epidemiology

There are few studies on the epidemiology of PN; however, middle-aged populations with underlying dermatologic or psychiatric disorders tend to be impacted most frequently.^2,12,13 In 2016, it was estimated that almost 88,000 individuals had PN in the United States, with the majority being female; however, this estimate only took into account those aged 18 to 64 years and utilized data from IBM MarketScan Commercial Claims and Encounters Database (IBM Watson Health) from October 2015 to December 2016.¹⁴ More recently, a retrospective database analysis estimated the prevalence of PN in the United States to be anywhere from 36.7 to 43.9 cases per 100,000 individuals. However, this retrospective review utilized the International Classification of Diseases, Tenth Revision code; PN has 2 codes associated with the diagnosis, and the coding accuracy is unknown.¹⁵ Sutaria et al¹⁶ looked at racial disparities in patients with PN utilizing data from TriNetX and found that patients who received a diagnosis of PN were more likely to be women, non-Hispanic, and Black compared with control patients. However, these estimates are restricted to the health care organizations within this database.

In 2018, Poland reported an annual prevalence of 6.52 cases per 100,000 individuals,¹⁷ while England reported a yearly prevalence of 3.27 cases per 100,000 individuals.¹⁸ Both countries reported most cases were female. However, these studies are not without limitations. Poland only uses the primary diagnosis code for medical billing to simplify clinical coding, thus underestimating the actual prevalence; furthermore, clinical codes more often than not are assigned by someone other than the diagnosing physician, leaving room for error.¹⁷ In addition, England’s PN estimate utilized diagnosis data from primary care and inpatient datasets, leaving out outpatient datasets in which patients with PN may have been referred and obtained the diagnosis, potentially underestimating the prevalence in this population.¹⁸

In contrast, Korea estimated the annual prevalence of PN to be 4.82 cases per 1000 dermatology outpatients, with the majority being men, based on results from a cross-sectional study among outpatients from the Catholic Medical Center. Although this is the largest health organization in Korea, the scope of this study is limited and lacks data from other medical centers in Korea.¹⁹

Histopathology and Pathophysiology

Almost all cells in the skin are involved in PN: keratinocytes, mast cells, dendritic cells, endothelial cells, lymphocytes, eosinophils, collagen fibers, and nerve fibers.^11,20 Classically, PN manifests as a dome-shaped lesion with hyperkeratosis, hypergranulosis, and psoriasiform epidermal hyperplasia with increased thickness of the papillary dermis consisting of coarse collagen with compact interstitial and circumvascular infiltration as well as increased lymphocytes and histocytes in the superficial dermis (Figure 1).²⁰ Hyperkeratosis is thought to be due to either the alteration of keratinocyte structures from scratching or keratinocyte abnormalities triggering PN.²¹ However, the increase in keratinocytes, which secrete nerve growth factor, allows for neuronal hyperplasia within the dermis.²² Nerve growth factor can stimulate keratinocyte proliferation²³ in addition to the upregulation of substance P (SP), a tachykinin that triggers vascular dilation and pruritus in the skin.²⁴ The density of SP nerve fibers in the dermis increases in PN, causing proinflammatory effects, upregulating the immune response to promote endothelial hyperplasia and increased vascularization.²⁵ The increase in these fibers may lead to pruritus associated with PN.^2,26

Many inflammatory cytokines and mediators also have been implicated in PN. Increased messenger RNA expression of IL-4, IL-17, IL-22, and IL-31 has been described in PN lesions.^3,27 Furthermore, studies also have reported increased helper T cell (T_H2) cytokines, including IL-4, IL-5, IL-10, and IL-13, in the dermis of PN lesions in patients without a history of atopy.^3,28 These pruritogenic cytokines in conjunction with the SP fibers may create an intractable itch for those with PN. The interaction and culmination of the neural and immune responses make PN a complex condition to treat with the multifactorial interaction of systems. 

Comorbidities

Prurigo nodularis has been associated with a wide array of comorbidities; however, the direction of the relationship between PN and these conditions makes it difficult to discern if PN is a primary or secondary condition.²⁹ Prurigo nodularis commonly has been connected to other inflammatory dermatoses, with a link to atopic dermatitis being the strongest.^5,29 However, PN also has been linked to other pruritic inflammatory cutaneous disorders, including psoriasis, cutaneous T-cell lymphoma, lichen planus, and dermatitis herpetiformis.^14,29

Huang et al¹⁴ found an increased likelihood of psychiatric illnesses in patients with PN, including eating disorders, nonsuicidal self-injury disorder, attention-deficit/hyperactivity disorder, schizophrenia, mood disorders, anxiety, and substance abuse disorders. Treatments directed at the neural aspect of PN have included selective serotonin reuptake inhibitors (SSRIs), which also are utilized to treat these mental health disorders.

Furthermore, systemic diseases also have been found to be associated with PN, including hypertension, type 2 diabetes mellitus, chronic kidney disease, heart failure, cerebrovascular disease, coronary heart disease, and chronic obstructive pulmonary disease.¹⁴ The relationship between PN and systemic conditions may be due to increased systemic inflammation and dysregulation of neural and metabolic functions implicated in these conditions from increased pruritic manifestations.^29,30 However, studies also have connected PN to infectious conditions such as HIV. One study found that patients with PN had 2.68 higher odds of infection with HIV compared to age- and sex-matched controls.¹⁴ It is unknown if these conditions contributed to the development of PN or PN contributed to the development of these disorders.

Clinical Presentations

Prurigo nodularis is a chronic inflammatory skin disease that typically manifests with multiple severely pruritic, dome-shaped, firm, hyperpigmented papulonodules with central scale or crust, often with erosion, due to chronic repetitive scratching and picking secondary to pruritic systemic or dermatologic diseases or psychological disorders (Figure 2).^1,2,4,5,8,31 Most often, diagnosis of PN is based on history and physical examination of the lesion; however, biopsies may be performed. These nodules commonly manifest with ulceration distributed symmetrically on extensor extremities in easy-to-reach places, sparing the mid back (called the butterfly sign).⁸ Lesions—either a few or hundreds—can range from a few millimeters to 2 to 3 cm.^8,32 The lesions differ in appearance depending on the pigment in the patient’s skin. In patients with darker skin tones, hyperpigmented or hypopigmented papulonodules are not uncommon, while those with fairer skin tones tend to present with erythema.³¹

Differential Diagnosis

Because of the variation in manifestation of PN, these lesions may resemble other cutaneous conditions. If the lesions are hyperkeratotic, they can mimic hypertrophic lichen planus, which mainfests with hyperkeratotic plaques or nodules on the lower extremities.^8,29 In addition, the histopathology of lichen planus resembles the appearance of PN, with epidermal hyperplasia, hypergranulosis, hyperkeratosis, and increased fibroblasts and capillaries.^8,29

Pemphigoid nodularis is a rare subtype of bullous pemphigoid that exhibits characteristics of PN with pruritic plaques and erosions.^8,29,33 The patient population for pemphigoid nodularis tends to be aged 50 to 60 years, and females are affected more frequently than males. However, pemphigoid nodularis may manifest with blistering and large plaques, which are not seen commonly with PN.²⁹ On histopathology, pemphigoid nodularis deposits IgG and C3 on the basement membrane and has subepidermal clefting, unlike PN.^7,29

Actinic prurigo manifests with pruritic papules or nodules post–UV exposure to unprotected skin.^8,29,33 This rare condition usually manifests with cheilitis and conjunctivitis. Unlike PN, which commonly affects elderly populations, actinic prurigo typically is found in young females.^8,29 Cytologic examination shows hyperkeratosis, spongiosis, and acanthosis of the epidermis with lymphocytic perivascular infiltration of the dermis.³⁴

Neurotic excoriations also tend to mimic PN with raised excoriated lesions; however, this disorder is due to neurotic picking of the skin without associated pruritus or true hyperkeratosis.^8,29,33 Histopathology shows epidermal crusting with inflammation of the upper dermis.³⁵

Infiltrative cutaneous squamous cell carcinoma (SCC) may imitate PN in appearance. It manifests as tender, ulcerated, scaly plaques or nodules. Histopathology shows cytologic atypia with an infiltrative architectural pattern and presence of collections of compact keratin and parakeratin (called keratin pearls).

Keratoacanthomas can resemble PN lesions. They usually manifest as nodules measuring 1 to 2 cm in diameter and 0.5 cm thick, resembling crateriform tumors.³⁶ On histopathology, KAs can resemble SCCs; however, KAs tend to manifest more frequently with a keratin-filled crater with a ground-glass appearance.³⁶

Inverted follicular keratosis commonly manifests on the face in elderly men as a single, flesh-colored, verrucous papule that may resemble PN. However, cytology of inverted follicular keratosis is characterized by proliferation and squamous eddies.³⁷ Consideration of the histologic findings and clinical appearance are important to differentiate between PN and cutaneous SCC.

Pseudoepitheliomatous hyperplasia is a benign condition that manifests as a plaque or nodule with crust, scale, or ulceration. Histologically, this condition presents with hyperplastic proliferation of the epidermis and adnexal epithelium.³⁸ The clinical and histologic appearance can mimic PN and other cutaneous eruptions with epidermal hyperplasia. 

In clinical cases that are resistant to treatment, biopsy is the best approach to diagnose the lesion. Due to similarities in physical appearance and superficial histologic presentation of PN, KAs from SCC, hypertrophic lichen planus, and other hyperkeratotic lesions, the biopsy should be taken at the base of the lesion to sample deeper layers of skin to differentiate these dermatologic disorders.

Management

Current treatments for PN yield varied results. Many patients with moderate to severe PN attempt multiple therapies before seeing improvement.³¹ Treatments include topical, oral, and injectable medications and are either directed at the neural or immune components of PN due to the interplay between increased nerve fibers in the lesions (neural axis) as well as increases in cytokines and other immunologic mediators (immune axis) of this condition. However, the FDA recently approved the first treatment for PN—dupilumab—which is an injectable IL-4 receptor antagonist directed at the immunologic interactions affiliated with PN.

Immune-Mediated Topical Therapies—Immunologic topical therapies include corticosteroids, calcipotriol, and calcineurin inhibitors. Studies that have analyzed these treatments are limited to case reports and small intraindividual and randomized controlled trials (Table 1). Topical therapies usually are first-line agents for most patients. Adverse effects include transient irritation of the skin.^40,42,43

Supplements—N-acetyl cysteine is an over-the-counter supplement that has been reported to improve symptoms in patients with skin-picking disorders.⁴⁸ The mechanism of action includes antioxidant effects such as decreasing reactive oxygen species, decreasing inflammatory markers, regulating neurotransmitters, and inhibiting hyperkeratosis.⁴⁹ N-acetyl cysteine has been poorly studied for its application in PN. A small study of 3 patients with subacute PN receiving 1200 mg of oral N-acetyl cysteine reported varying levels of improvement in skin appearance and reduction in skin picking.⁵⁰

Phototherapy—Phototherapy, a typical first- or second-line treatment modality for PN, targets both the neural- and immune-mediated aspects associated with pruritus in PN (Table 1).⁵¹ UV light can penetrate through the epidermal layer of the skin and reach the keratinocytes, which play a role in the immune-related response of PN. In addition, the cutaneous sensory nerves are located in the upper dermal layer, from which nerve fibers grow and penetrate into the epidermis, thereby interacting with the keratinocytes where pruritic signals are transmitted from the periphery up to the brain.⁵¹

Studies analyzing the effects of phototherapy on PN are limited to case series and a small randomized controlled trial. However, this trial has shown improvements in pruritus in the participants. Adverse effects include transient burning and erythema at the treated sites.^44,45

Immune-Mediated Oral Therapies—Immunologic-targeted oral therapies include bilastine, methotrexate, and cyclosporine (Table 2).^52,53 Bilastine efficacy was analyzed in a small phase 3, open-label, multicenter study in Japan; however, patients were allowed to use topical steroids in conjunction with the oral antihistamine.⁵⁴ Methotrexate and cyclosporine are immunosuppressive medications and were analyzed in small retrospective studies. Both treatments yielded notable relief for patients; however, 38.5% (15/39) of patients receiving methotrexate experienced adverse events, and 50.0% (4/8) experienced adverse events with cyclosporine.^52,53

Thalidomide was studied in a small retrospective case review that showed notable improvement in PN. Dosages of thalidomide varied, but on average the dose was 100 mg/d. However, greater than 50% of patients experienced at least 1 adverse effect with this treatment.⁶³

A study performed in Italy showed promising results for patients treated with pregabalin, with 70.0% (21/30) continuing to take pregabalin for almost 2 years following completion of the initial 3-month trial.⁵⁵ Naltrexone decreased pruritus in more than half of patients (9/17).⁵⁹ Amitriptyline yielded improvements in patients with PN; however, disease recurred in 5 patients (29%) after 7 months.⁶² A study performed in Germany reported promising results for paroxetine and fluvoxamine; however, some patients enrolled in the study had some form of psychiatric disorder.⁶¹

Serlopitant, aprepitant, and nalbuphine were studied in randomized controlled trials. The serlopitant trials were the largest of the neurally mediated oral medication studies; one showed substantial improvement in patients with PN,⁵⁶ while the most recent trial did not show significant improvement (ClinicalTrials.gov identifier NCT03546816).⁵⁷ On the other hand, aprepitant showed no major difference between the experimental and placebo groups.⁵⁸ Nalbuphine 162 mg twice daily showed greater improvement in PN than nalbuphine 81 mg twice daily.⁶⁰

Immune-Mediated Injectable Therapies—Immune-targeted injectables include nemolizumab and dupilumab (Table 2). Nemolizumab is an IL-31 antagonist that has been studied in a small randomized controlled trial that showed great success in decreasing pruritus associated with PN.⁶⁴ IL-31 has been implicated in PN, and inhibition of the IL-31 receptor has been shown to disrupt the itch-scratch cycle of PN. Dupilumab is a monoclonal antibody against the IL-4 and IL-13 receptors, and it is the only FDA-approved treatment for PN.⁶⁵ Blockage of these protein receptors decreases type 2 inflammation and chronic pruritus.^66,67 Dupilumab is FDA approved for the treatment of atopic dermatitis and recently was approved for adults with PN. Dupilumab acts to block the shared α-subunit of the pruritogenic cytokines IL-4 and IL-13 pathways,²⁹ thereby breaking the itch-scratch cycle associated with PN and allowing for the healing of these lesions. Results from 2 clinical trials showed substantially reduced itch in patients with PN.⁶⁵ Dupilumab also was approved by the European Medicines Agency for moderate to severe PN.⁶⁸

Conclusion

Prurigo nodularis is a chronic condition that affects patient quality of life and can mimic various dermatologic conditions. The epidemiology and pathophysiology of PN have not been fully expounded. More research should be conducted to determine the underpinnings of PN to help identify more consistently effective therapies for this complex condition.

Prurigo nodularis (PN)(also called chronic nodular prurigo, prurigo nodularis of Hyde, or picker’s nodules) was first characterized by James Hyde in 1909.^1-3 Prurigo nodularis manifests with symmetrical, intensely pruritic, eroded, or hyperkeratotic nodules or papules on the extremities and trunk.^1,2,4,5 Studies have shown that individuals with PN experience pruritus, sleep loss, decreased social functioning from the appearance of the nodules, and a higher incidence of anxiety and depression, causing a negative impact on their quality of life.^2,6 In addition, the manifestation of PN has been linked to neurologic and psychiatric disorders; however, PN also can be idiopathic and manifest without underlying illnesses.^2,6,7

Prurigo nodularis has been associated with other dermatologic conditions such as atopic dermatitis (up to 50%), lichen planus, keratoacanthomas (KAs), and bullous pemphigoid.^7-9 It also has been linked to systemic diseases in 38% to 50% of cases, including chronic kidney disease, liver disease, type 2 diabetes mellitus, malignancies (hematopoietic, liver, and skin), and HIV infection.^6,8,10

The pathophysiology of PN is highly complex and has yet to be fully elucidated. It is thought to be due to dysregulation and interaction of the increase in neural and immunologic responses of proinflammatory and pruritogenic cytokines.^2,11 Treatments aim to break the itch-scratch cycle that perpetuates this disorder; however, this proves difficult, as PN is associated with a higher itch intensity than atopic dermatitis and psoriasis.¹⁰ Therefore, most patients attempt multiple forms of treatment for PN, ranging from topical therapies, oral immunosuppressants, and phototherapy to the newest and only medication approved by the US Food and Drug Administration for the treatment of PN—dupilumab.^1,7,11 Herein, we provide an updated review of PN with a focus on its epidemiology, histopathology and pathophysiology, comorbidities, clinical presentation, differential diagnosis, and current treatment options.

Epidemiology

There are few studies on the epidemiology of PN; however, middle-aged populations with underlying dermatologic or psychiatric disorders tend to be impacted most frequently.^2,12,13 In 2016, it was estimated that almost 88,000 individuals had PN in the United States, with the majority being female; however, this estimate only took into account those aged 18 to 64 years and utilized data from IBM MarketScan Commercial Claims and Encounters Database (IBM Watson Health) from October 2015 to December 2016.¹⁴ More recently, a retrospective database analysis estimated the prevalence of PN in the United States to be anywhere from 36.7 to 43.9 cases per 100,000 individuals. However, this retrospective review utilized the International Classification of Diseases, Tenth Revision code; PN has 2 codes associated with the diagnosis, and the coding accuracy is unknown.¹⁵ Sutaria et al¹⁶ looked at racial disparities in patients with PN utilizing data from TriNetX and found that patients who received a diagnosis of PN were more likely to be women, non-Hispanic, and Black compared with control patients. However, these estimates are restricted to the health care organizations within this database.

In 2018, Poland reported an annual prevalence of 6.52 cases per 100,000 individuals,¹⁷ while England reported a yearly prevalence of 3.27 cases per 100,000 individuals.¹⁸ Both countries reported most cases were female. However, these studies are not without limitations. Poland only uses the primary diagnosis code for medical billing to simplify clinical coding, thus underestimating the actual prevalence; furthermore, clinical codes more often than not are assigned by someone other than the diagnosing physician, leaving room for error.¹⁷ In addition, England’s PN estimate utilized diagnosis data from primary care and inpatient datasets, leaving out outpatient datasets in which patients with PN may have been referred and obtained the diagnosis, potentially underestimating the prevalence in this population.¹⁸

In contrast, Korea estimated the annual prevalence of PN to be 4.82 cases per 1000 dermatology outpatients, with the majority being men, based on results from a cross-sectional study among outpatients from the Catholic Medical Center. Although this is the largest health organization in Korea, the scope of this study is limited and lacks data from other medical centers in Korea.¹⁹

Histopathology and Pathophysiology

Almost all cells in the skin are involved in PN: keratinocytes, mast cells, dendritic cells, endothelial cells, lymphocytes, eosinophils, collagen fibers, and nerve fibers.^11,20 Classically, PN manifests as a dome-shaped lesion with hyperkeratosis, hypergranulosis, and psoriasiform epidermal hyperplasia with increased thickness of the papillary dermis consisting of coarse collagen with compact interstitial and circumvascular infiltration as well as increased lymphocytes and histocytes in the superficial dermis (Figure 1).²⁰ Hyperkeratosis is thought to be due to either the alteration of keratinocyte structures from scratching or keratinocyte abnormalities triggering PN.²¹ However, the increase in keratinocytes, which secrete nerve growth factor, allows for neuronal hyperplasia within the dermis.²² Nerve growth factor can stimulate keratinocyte proliferation²³ in addition to the upregulation of substance P (SP), a tachykinin that triggers vascular dilation and pruritus in the skin.²⁴ The density of SP nerve fibers in the dermis increases in PN, causing proinflammatory effects, upregulating the immune response to promote endothelial hyperplasia and increased vascularization.²⁵ The increase in these fibers may lead to pruritus associated with PN.^2,26

Many inflammatory cytokines and mediators also have been implicated in PN. Increased messenger RNA expression of IL-4, IL-17, IL-22, and IL-31 has been described in PN lesions.^3,27 Furthermore, studies also have reported increased helper T cell (T_H2) cytokines, including IL-4, IL-5, IL-10, and IL-13, in the dermis of PN lesions in patients without a history of atopy.^3,28 These pruritogenic cytokines in conjunction with the SP fibers may create an intractable itch for those with PN. The interaction and culmination of the neural and immune responses make PN a complex condition to treat with the multifactorial interaction of systems. 

Comorbidities

Prurigo nodularis has been associated with a wide array of comorbidities; however, the direction of the relationship between PN and these conditions makes it difficult to discern if PN is a primary or secondary condition.²⁹ Prurigo nodularis commonly has been connected to other inflammatory dermatoses, with a link to atopic dermatitis being the strongest.^5,29 However, PN also has been linked to other pruritic inflammatory cutaneous disorders, including psoriasis, cutaneous T-cell lymphoma, lichen planus, and dermatitis herpetiformis.^14,29

Huang et al¹⁴ found an increased likelihood of psychiatric illnesses in patients with PN, including eating disorders, nonsuicidal self-injury disorder, attention-deficit/hyperactivity disorder, schizophrenia, mood disorders, anxiety, and substance abuse disorders. Treatments directed at the neural aspect of PN have included selective serotonin reuptake inhibitors (SSRIs), which also are utilized to treat these mental health disorders.

Furthermore, systemic diseases also have been found to be associated with PN, including hypertension, type 2 diabetes mellitus, chronic kidney disease, heart failure, cerebrovascular disease, coronary heart disease, and chronic obstructive pulmonary disease.¹⁴ The relationship between PN and systemic conditions may be due to increased systemic inflammation and dysregulation of neural and metabolic functions implicated in these conditions from increased pruritic manifestations.^29,30 However, studies also have connected PN to infectious conditions such as HIV. One study found that patients with PN had 2.68 higher odds of infection with HIV compared to age- and sex-matched controls.¹⁴ It is unknown if these conditions contributed to the development of PN or PN contributed to the development of these disorders.

Clinical Presentations

Prurigo nodularis is a chronic inflammatory skin disease that typically manifests with multiple severely pruritic, dome-shaped, firm, hyperpigmented papulonodules with central scale or crust, often with erosion, due to chronic repetitive scratching and picking secondary to pruritic systemic or dermatologic diseases or psychological disorders (Figure 2).^1,2,4,5,8,31 Most often, diagnosis of PN is based on history and physical examination of the lesion; however, biopsies may be performed. These nodules commonly manifest with ulceration distributed symmetrically on extensor extremities in easy-to-reach places, sparing the mid back (called the butterfly sign).⁸ Lesions—either a few or hundreds—can range from a few millimeters to 2 to 3 cm.^8,32 The lesions differ in appearance depending on the pigment in the patient’s skin. In patients with darker skin tones, hyperpigmented or hypopigmented papulonodules are not uncommon, while those with fairer skin tones tend to present with erythema.³¹

Differential Diagnosis

Because of the variation in manifestation of PN, these lesions may resemble other cutaneous conditions. If the lesions are hyperkeratotic, they can mimic hypertrophic lichen planus, which mainfests with hyperkeratotic plaques or nodules on the lower extremities.^8,29 In addition, the histopathology of lichen planus resembles the appearance of PN, with epidermal hyperplasia, hypergranulosis, hyperkeratosis, and increased fibroblasts and capillaries.^8,29

Pemphigoid nodularis is a rare subtype of bullous pemphigoid that exhibits characteristics of PN with pruritic plaques and erosions.^8,29,33 The patient population for pemphigoid nodularis tends to be aged 50 to 60 years, and females are affected more frequently than males. However, pemphigoid nodularis may manifest with blistering and large plaques, which are not seen commonly with PN.²⁹ On histopathology, pemphigoid nodularis deposits IgG and C3 on the basement membrane and has subepidermal clefting, unlike PN.^7,29

Actinic prurigo manifests with pruritic papules or nodules post–UV exposure to unprotected skin.^8,29,33 This rare condition usually manifests with cheilitis and conjunctivitis. Unlike PN, which commonly affects elderly populations, actinic prurigo typically is found in young females.^8,29 Cytologic examination shows hyperkeratosis, spongiosis, and acanthosis of the epidermis with lymphocytic perivascular infiltration of the dermis.³⁴

Neurotic excoriations also tend to mimic PN with raised excoriated lesions; however, this disorder is due to neurotic picking of the skin without associated pruritus or true hyperkeratosis.^8,29,33 Histopathology shows epidermal crusting with inflammation of the upper dermis.³⁵

Infiltrative cutaneous squamous cell carcinoma (SCC) may imitate PN in appearance. It manifests as tender, ulcerated, scaly plaques or nodules. Histopathology shows cytologic atypia with an infiltrative architectural pattern and presence of collections of compact keratin and parakeratin (called keratin pearls).

Keratoacanthomas can resemble PN lesions. They usually manifest as nodules measuring 1 to 2 cm in diameter and 0.5 cm thick, resembling crateriform tumors.³⁶ On histopathology, KAs can resemble SCCs; however, KAs tend to manifest more frequently with a keratin-filled crater with a ground-glass appearance.³⁶

Inverted follicular keratosis commonly manifests on the face in elderly men as a single, flesh-colored, verrucous papule that may resemble PN. However, cytology of inverted follicular keratosis is characterized by proliferation and squamous eddies.³⁷ Consideration of the histologic findings and clinical appearance are important to differentiate between PN and cutaneous SCC.

Pseudoepitheliomatous hyperplasia is a benign condition that manifests as a plaque or nodule with crust, scale, or ulceration. Histologically, this condition presents with hyperplastic proliferation of the epidermis and adnexal epithelium.³⁸ The clinical and histologic appearance can mimic PN and other cutaneous eruptions with epidermal hyperplasia. 

In clinical cases that are resistant to treatment, biopsy is the best approach to diagnose the lesion. Due to similarities in physical appearance and superficial histologic presentation of PN, KAs from SCC, hypertrophic lichen planus, and other hyperkeratotic lesions, the biopsy should be taken at the base of the lesion to sample deeper layers of skin to differentiate these dermatologic disorders.

Management

Current treatments for PN yield varied results. Many patients with moderate to severe PN attempt multiple therapies before seeing improvement.³¹ Treatments include topical, oral, and injectable medications and are either directed at the neural or immune components of PN due to the interplay between increased nerve fibers in the lesions (neural axis) as well as increases in cytokines and other immunologic mediators (immune axis) of this condition. However, the FDA recently approved the first treatment for PN—dupilumab—which is an injectable IL-4 receptor antagonist directed at the immunologic interactions affiliated with PN.

Immune-Mediated Topical Therapies—Immunologic topical therapies include corticosteroids, calcipotriol, and calcineurin inhibitors. Studies that have analyzed these treatments are limited to case reports and small intraindividual and randomized controlled trials (Table 1). Topical therapies usually are first-line agents for most patients. Adverse effects include transient irritation of the skin.^40,42,43

Supplements—N-acetyl cysteine is an over-the-counter supplement that has been reported to improve symptoms in patients with skin-picking disorders.⁴⁸ The mechanism of action includes antioxidant effects such as decreasing reactive oxygen species, decreasing inflammatory markers, regulating neurotransmitters, and inhibiting hyperkeratosis.⁴⁹ N-acetyl cysteine has been poorly studied for its application in PN. A small study of 3 patients with subacute PN receiving 1200 mg of oral N-acetyl cysteine reported varying levels of improvement in skin appearance and reduction in skin picking.⁵⁰

Phototherapy—Phototherapy, a typical first- or second-line treatment modality for PN, targets both the neural- and immune-mediated aspects associated with pruritus in PN (Table 1).⁵¹ UV light can penetrate through the epidermal layer of the skin and reach the keratinocytes, which play a role in the immune-related response of PN. In addition, the cutaneous sensory nerves are located in the upper dermal layer, from which nerve fibers grow and penetrate into the epidermis, thereby interacting with the keratinocytes where pruritic signals are transmitted from the periphery up to the brain.⁵¹

Studies analyzing the effects of phototherapy on PN are limited to case series and a small randomized controlled trial. However, this trial has shown improvements in pruritus in the participants. Adverse effects include transient burning and erythema at the treated sites.^44,45

Immune-Mediated Oral Therapies—Immunologic-targeted oral therapies include bilastine, methotrexate, and cyclosporine (Table 2).^52,53 Bilastine efficacy was analyzed in a small phase 3, open-label, multicenter study in Japan; however, patients were allowed to use topical steroids in conjunction with the oral antihistamine.⁵⁴ Methotrexate and cyclosporine are immunosuppressive medications and were analyzed in small retrospective studies. Both treatments yielded notable relief for patients; however, 38.5% (15/39) of patients receiving methotrexate experienced adverse events, and 50.0% (4/8) experienced adverse events with cyclosporine.^52,53

Thalidomide was studied in a small retrospective case review that showed notable improvement in PN. Dosages of thalidomide varied, but on average the dose was 100 mg/d. However, greater than 50% of patients experienced at least 1 adverse effect with this treatment.⁶³

A study performed in Italy showed promising results for patients treated with pregabalin, with 70.0% (21/30) continuing to take pregabalin for almost 2 years following completion of the initial 3-month trial.⁵⁵ Naltrexone decreased pruritus in more than half of patients (9/17).⁵⁹ Amitriptyline yielded improvements in patients with PN; however, disease recurred in 5 patients (29%) after 7 months.⁶² A study performed in Germany reported promising results for paroxetine and fluvoxamine; however, some patients enrolled in the study had some form of psychiatric disorder.⁶¹

Serlopitant, aprepitant, and nalbuphine were studied in randomized controlled trials. The serlopitant trials were the largest of the neurally mediated oral medication studies; one showed substantial improvement in patients with PN,⁵⁶ while the most recent trial did not show significant improvement (ClinicalTrials.gov identifier NCT03546816).⁵⁷ On the other hand, aprepitant showed no major difference between the experimental and placebo groups.⁵⁸ Nalbuphine 162 mg twice daily showed greater improvement in PN than nalbuphine 81 mg twice daily.⁶⁰

Immune-Mediated Injectable Therapies—Immune-targeted injectables include nemolizumab and dupilumab (Table 2). Nemolizumab is an IL-31 antagonist that has been studied in a small randomized controlled trial that showed great success in decreasing pruritus associated with PN.⁶⁴ IL-31 has been implicated in PN, and inhibition of the IL-31 receptor has been shown to disrupt the itch-scratch cycle of PN. Dupilumab is a monoclonal antibody against the IL-4 and IL-13 receptors, and it is the only FDA-approved treatment for PN.⁶⁵ Blockage of these protein receptors decreases type 2 inflammation and chronic pruritus.^66,67 Dupilumab is FDA approved for the treatment of atopic dermatitis and recently was approved for adults with PN. Dupilumab acts to block the shared α-subunit of the pruritogenic cytokines IL-4 and IL-13 pathways,²⁹ thereby breaking the itch-scratch cycle associated with PN and allowing for the healing of these lesions. Results from 2 clinical trials showed substantially reduced itch in patients with PN.⁶⁵ Dupilumab also was approved by the European Medicines Agency for moderate to severe PN.⁶⁸

Conclusion

Prurigo nodularis is a chronic condition that affects patient quality of life and can mimic various dermatologic conditions. The epidemiology and pathophysiology of PN have not been fully expounded. More research should be conducted to determine the underpinnings of PN to help identify more consistently effective therapies for this complex condition.

Prurigo nodularis (PN)(also called chronic nodular prurigo, prurigo nodularis of Hyde, or picker’s nodules) was first characterized by James Hyde in 1909.^1-3 Prurigo nodularis manifests with symmetrical, intensely pruritic, eroded, or hyperkeratotic nodules or papules on the extremities and trunk.^1,2,4,5 Studies have shown that individuals with PN experience pruritus, sleep loss, decreased social functioning from the appearance of the nodules, and a higher incidence of anxiety and depression, causing a negative impact on their quality of life.^2,6 In addition, the manifestation of PN has been linked to neurologic and psychiatric disorders; however, PN also can be idiopathic and manifest without underlying illnesses.^2,6,7

Prurigo nodularis has been associated with other dermatologic conditions such as atopic dermatitis (up to 50%), lichen planus, keratoacanthomas (KAs), and bullous pemphigoid.^7-9 It also has been linked to systemic diseases in 38% to 50% of cases, including chronic kidney disease, liver disease, type 2 diabetes mellitus, malignancies (hematopoietic, liver, and skin), and HIV infection.^6,8,10

The pathophysiology of PN is highly complex and has yet to be fully elucidated. It is thought to be due to dysregulation and interaction of the increase in neural and immunologic responses of proinflammatory and pruritogenic cytokines.^2,11 Treatments aim to break the itch-scratch cycle that perpetuates this disorder; however, this proves difficult, as PN is associated with a higher itch intensity than atopic dermatitis and psoriasis.¹⁰ Therefore, most patients attempt multiple forms of treatment for PN, ranging from topical therapies, oral immunosuppressants, and phototherapy to the newest and only medication approved by the US Food and Drug Administration for the treatment of PN—dupilumab.^1,7,11 Herein, we provide an updated review of PN with a focus on its epidemiology, histopathology and pathophysiology, comorbidities, clinical presentation, differential diagnosis, and current treatment options.

Epidemiology

There are few studies on the epidemiology of PN; however, middle-aged populations with underlying dermatologic or psychiatric disorders tend to be impacted most frequently.^2,12,13 In 2016, it was estimated that almost 88,000 individuals had PN in the United States, with the majority being female; however, this estimate only took into account those aged 18 to 64 years and utilized data from IBM MarketScan Commercial Claims and Encounters Database (IBM Watson Health) from October 2015 to December 2016.¹⁴ More recently, a retrospective database analysis estimated the prevalence of PN in the United States to be anywhere from 36.7 to 43.9 cases per 100,000 individuals. However, this retrospective review utilized the International Classification of Diseases, Tenth Revision code; PN has 2 codes associated with the diagnosis, and the coding accuracy is unknown.¹⁵ Sutaria et al¹⁶ looked at racial disparities in patients with PN utilizing data from TriNetX and found that patients who received a diagnosis of PN were more likely to be women, non-Hispanic, and Black compared with control patients. However, these estimates are restricted to the health care organizations within this database.

In 2018, Poland reported an annual prevalence of 6.52 cases per 100,000 individuals,¹⁷ while England reported a yearly prevalence of 3.27 cases per 100,000 individuals.¹⁸ Both countries reported most cases were female. However, these studies are not without limitations. Poland only uses the primary diagnosis code for medical billing to simplify clinical coding, thus underestimating the actual prevalence; furthermore, clinical codes more often than not are assigned by someone other than the diagnosing physician, leaving room for error.¹⁷ In addition, England’s PN estimate utilized diagnosis data from primary care and inpatient datasets, leaving out outpatient datasets in which patients with PN may have been referred and obtained the diagnosis, potentially underestimating the prevalence in this population.¹⁸

In contrast, Korea estimated the annual prevalence of PN to be 4.82 cases per 1000 dermatology outpatients, with the majority being men, based on results from a cross-sectional study among outpatients from the Catholic Medical Center. Although this is the largest health organization in Korea, the scope of this study is limited and lacks data from other medical centers in Korea.¹⁹

Histopathology and Pathophysiology

Almost all cells in the skin are involved in PN: keratinocytes, mast cells, dendritic cells, endothelial cells, lymphocytes, eosinophils, collagen fibers, and nerve fibers.^11,20 Classically, PN manifests as a dome-shaped lesion with hyperkeratosis, hypergranulosis, and psoriasiform epidermal hyperplasia with increased thickness of the papillary dermis consisting of coarse collagen with compact interstitial and circumvascular infiltration as well as increased lymphocytes and histocytes in the superficial dermis (Figure 1).²⁰ Hyperkeratosis is thought to be due to either the alteration of keratinocyte structures from scratching or keratinocyte abnormalities triggering PN.²¹ However, the increase in keratinocytes, which secrete nerve growth factor, allows for neuronal hyperplasia within the dermis.²² Nerve growth factor can stimulate keratinocyte proliferation²³ in addition to the upregulation of substance P (SP), a tachykinin that triggers vascular dilation and pruritus in the skin.²⁴ The density of SP nerve fibers in the dermis increases in PN, causing proinflammatory effects, upregulating the immune response to promote endothelial hyperplasia and increased vascularization.²⁵ The increase in these fibers may lead to pruritus associated with PN.^2,26

Many inflammatory cytokines and mediators also have been implicated in PN. Increased messenger RNA expression of IL-4, IL-17, IL-22, and IL-31 has been described in PN lesions.^3,27 Furthermore, studies also have reported increased helper T cell (T_H2) cytokines, including IL-4, IL-5, IL-10, and IL-13, in the dermis of PN lesions in patients without a history of atopy.^3,28 These pruritogenic cytokines in conjunction with the SP fibers may create an intractable itch for those with PN. The interaction and culmination of the neural and immune responses make PN a complex condition to treat with the multifactorial interaction of systems. 

Comorbidities

Prurigo nodularis has been associated with a wide array of comorbidities; however, the direction of the relationship between PN and these conditions makes it difficult to discern if PN is a primary or secondary condition.²⁹ Prurigo nodularis commonly has been connected to other inflammatory dermatoses, with a link to atopic dermatitis being the strongest.^5,29 However, PN also has been linked to other pruritic inflammatory cutaneous disorders, including psoriasis, cutaneous T-cell lymphoma, lichen planus, and dermatitis herpetiformis.^14,29

Huang et al¹⁴ found an increased likelihood of psychiatric illnesses in patients with PN, including eating disorders, nonsuicidal self-injury disorder, attention-deficit/hyperactivity disorder, schizophrenia, mood disorders, anxiety, and substance abuse disorders. Treatments directed at the neural aspect of PN have included selective serotonin reuptake inhibitors (SSRIs), which also are utilized to treat these mental health disorders.

Furthermore, systemic diseases also have been found to be associated with PN, including hypertension, type 2 diabetes mellitus, chronic kidney disease, heart failure, cerebrovascular disease, coronary heart disease, and chronic obstructive pulmonary disease.¹⁴ The relationship between PN and systemic conditions may be due to increased systemic inflammation and dysregulation of neural and metabolic functions implicated in these conditions from increased pruritic manifestations.^29,30 However, studies also have connected PN to infectious conditions such as HIV. One study found that patients with PN had 2.68 higher odds of infection with HIV compared to age- and sex-matched controls.¹⁴ It is unknown if these conditions contributed to the development of PN or PN contributed to the development of these disorders.

Clinical Presentations

Prurigo nodularis is a chronic inflammatory skin disease that typically manifests with multiple severely pruritic, dome-shaped, firm, hyperpigmented papulonodules with central scale or crust, often with erosion, due to chronic repetitive scratching and picking secondary to pruritic systemic or dermatologic diseases or psychological disorders (Figure 2).^1,2,4,5,8,31 Most often, diagnosis of PN is based on history and physical examination of the lesion; however, biopsies may be performed. These nodules commonly manifest with ulceration distributed symmetrically on extensor extremities in easy-to-reach places, sparing the mid back (called the butterfly sign).⁸ Lesions—either a few or hundreds—can range from a few millimeters to 2 to 3 cm.^8,32 The lesions differ in appearance depending on the pigment in the patient’s skin. In patients with darker skin tones, hyperpigmented or hypopigmented papulonodules are not uncommon, while those with fairer skin tones tend to present with erythema.³¹

Differential Diagnosis

Because of the variation in manifestation of PN, these lesions may resemble other cutaneous conditions. If the lesions are hyperkeratotic, they can mimic hypertrophic lichen planus, which mainfests with hyperkeratotic plaques or nodules on the lower extremities.^8,29 In addition, the histopathology of lichen planus resembles the appearance of PN, with epidermal hyperplasia, hypergranulosis, hyperkeratosis, and increased fibroblasts and capillaries.^8,29

Pemphigoid nodularis is a rare subtype of bullous pemphigoid that exhibits characteristics of PN with pruritic plaques and erosions.^8,29,33 The patient population for pemphigoid nodularis tends to be aged 50 to 60 years, and females are affected more frequently than males. However, pemphigoid nodularis may manifest with blistering and large plaques, which are not seen commonly with PN.²⁹ On histopathology, pemphigoid nodularis deposits IgG and C3 on the basement membrane and has subepidermal clefting, unlike PN.^7,29

Actinic prurigo manifests with pruritic papules or nodules post–UV exposure to unprotected skin.^8,29,33 This rare condition usually manifests with cheilitis and conjunctivitis. Unlike PN, which commonly affects elderly populations, actinic prurigo typically is found in young females.^8,29 Cytologic examination shows hyperkeratosis, spongiosis, and acanthosis of the epidermis with lymphocytic perivascular infiltration of the dermis.³⁴

Neurotic excoriations also tend to mimic PN with raised excoriated lesions; however, this disorder is due to neurotic picking of the skin without associated pruritus or true hyperkeratosis.^8,29,33 Histopathology shows epidermal crusting with inflammation of the upper dermis.³⁵

Infiltrative cutaneous squamous cell carcinoma (SCC) may imitate PN in appearance. It manifests as tender, ulcerated, scaly plaques or nodules. Histopathology shows cytologic atypia with an infiltrative architectural pattern and presence of collections of compact keratin and parakeratin (called keratin pearls).

Keratoacanthomas can resemble PN lesions. They usually manifest as nodules measuring 1 to 2 cm in diameter and 0.5 cm thick, resembling crateriform tumors.³⁶ On histopathology, KAs can resemble SCCs; however, KAs tend to manifest more frequently with a keratin-filled crater with a ground-glass appearance.³⁶

Inverted follicular keratosis commonly manifests on the face in elderly men as a single, flesh-colored, verrucous papule that may resemble PN. However, cytology of inverted follicular keratosis is characterized by proliferation and squamous eddies.³⁷ Consideration of the histologic findings and clinical appearance are important to differentiate between PN and cutaneous SCC.

Pseudoepitheliomatous hyperplasia is a benign condition that manifests as a plaque or nodule with crust, scale, or ulceration. Histologically, this condition presents with hyperplastic proliferation of the epidermis and adnexal epithelium.³⁸ The clinical and histologic appearance can mimic PN and other cutaneous eruptions with epidermal hyperplasia. 

In clinical cases that are resistant to treatment, biopsy is the best approach to diagnose the lesion. Due to similarities in physical appearance and superficial histologic presentation of PN, KAs from SCC, hypertrophic lichen planus, and other hyperkeratotic lesions, the biopsy should be taken at the base of the lesion to sample deeper layers of skin to differentiate these dermatologic disorders.

Management

Current treatments for PN yield varied results. Many patients with moderate to severe PN attempt multiple therapies before seeing improvement.³¹ Treatments include topical, oral, and injectable medications and are either directed at the neural or immune components of PN due to the interplay between increased nerve fibers in the lesions (neural axis) as well as increases in cytokines and other immunologic mediators (immune axis) of this condition. However, the FDA recently approved the first treatment for PN—dupilumab—which is an injectable IL-4 receptor antagonist directed at the immunologic interactions affiliated with PN.

Immune-Mediated Topical Therapies—Immunologic topical therapies include corticosteroids, calcipotriol, and calcineurin inhibitors. Studies that have analyzed these treatments are limited to case reports and small intraindividual and randomized controlled trials (Table 1). Topical therapies usually are first-line agents for most patients. Adverse effects include transient irritation of the skin.^40,42,43

Supplements—N-acetyl cysteine is an over-the-counter supplement that has been reported to improve symptoms in patients with skin-picking disorders.⁴⁸ The mechanism of action includes antioxidant effects such as decreasing reactive oxygen species, decreasing inflammatory markers, regulating neurotransmitters, and inhibiting hyperkeratosis.⁴⁹ N-acetyl cysteine has been poorly studied for its application in PN. A small study of 3 patients with subacute PN receiving 1200 mg of oral N-acetyl cysteine reported varying levels of improvement in skin appearance and reduction in skin picking.⁵⁰

Phototherapy—Phototherapy, a typical first- or second-line treatment modality for PN, targets both the neural- and immune-mediated aspects associated with pruritus in PN (Table 1).⁵¹ UV light can penetrate through the epidermal layer of the skin and reach the keratinocytes, which play a role in the immune-related response of PN. In addition, the cutaneous sensory nerves are located in the upper dermal layer, from which nerve fibers grow and penetrate into the epidermis, thereby interacting with the keratinocytes where pruritic signals are transmitted from the periphery up to the brain.⁵¹

Studies analyzing the effects of phototherapy on PN are limited to case series and a small randomized controlled trial. However, this trial has shown improvements in pruritus in the participants. Adverse effects include transient burning and erythema at the treated sites.^44,45

Immune-Mediated Oral Therapies—Immunologic-targeted oral therapies include bilastine, methotrexate, and cyclosporine (Table 2).^52,53 Bilastine efficacy was analyzed in a small phase 3, open-label, multicenter study in Japan; however, patients were allowed to use topical steroids in conjunction with the oral antihistamine.⁵⁴ Methotrexate and cyclosporine are immunosuppressive medications and were analyzed in small retrospective studies. Both treatments yielded notable relief for patients; however, 38.5% (15/39) of patients receiving methotrexate experienced adverse events, and 50.0% (4/8) experienced adverse events with cyclosporine.^52,53

Thalidomide was studied in a small retrospective case review that showed notable improvement in PN. Dosages of thalidomide varied, but on average the dose was 100 mg/d. However, greater than 50% of patients experienced at least 1 adverse effect with this treatment.⁶³

A study performed in Italy showed promising results for patients treated with pregabalin, with 70.0% (21/30) continuing to take pregabalin for almost 2 years following completion of the initial 3-month trial.⁵⁵ Naltrexone decreased pruritus in more than half of patients (9/17).⁵⁹ Amitriptyline yielded improvements in patients with PN; however, disease recurred in 5 patients (29%) after 7 months.⁶² A study performed in Germany reported promising results for paroxetine and fluvoxamine; however, some patients enrolled in the study had some form of psychiatric disorder.⁶¹

Serlopitant, aprepitant, and nalbuphine were studied in randomized controlled trials. The serlopitant trials were the largest of the neurally mediated oral medication studies; one showed substantial improvement in patients with PN,⁵⁶ while the most recent trial did not show significant improvement (ClinicalTrials.gov identifier NCT03546816).⁵⁷ On the other hand, aprepitant showed no major difference between the experimental and placebo groups.⁵⁸ Nalbuphine 162 mg twice daily showed greater improvement in PN than nalbuphine 81 mg twice daily.⁶⁰

Immune-Mediated Injectable Therapies—Immune-targeted injectables include nemolizumab and dupilumab (Table 2). Nemolizumab is an IL-31 antagonist that has been studied in a small randomized controlled trial that showed great success in decreasing pruritus associated with PN.⁶⁴ IL-31 has been implicated in PN, and inhibition of the IL-31 receptor has been shown to disrupt the itch-scratch cycle of PN. Dupilumab is a monoclonal antibody against the IL-4 and IL-13 receptors, and it is the only FDA-approved treatment for PN.⁶⁵ Blockage of these protein receptors decreases type 2 inflammation and chronic pruritus.^66,67 Dupilumab is FDA approved for the treatment of atopic dermatitis and recently was approved for adults with PN. Dupilumab acts to block the shared α-subunit of the pruritogenic cytokines IL-4 and IL-13 pathways,²⁹ thereby breaking the itch-scratch cycle associated with PN and allowing for the healing of these lesions. Results from 2 clinical trials showed substantially reduced itch in patients with PN.⁶⁵ Dupilumab also was approved by the European Medicines Agency for moderate to severe PN.⁶⁸

Conclusion

Prurigo nodularis is a chronic condition that affects patient quality of life and can mimic various dermatologic conditions. The epidemiology and pathophysiology of PN have not been fully expounded. More research should be conducted to determine the underpinnings of PN to help identify more consistently effective therapies for this complex condition.

Dermatology remains one of the most competitive specialties in the residency match, with successful applicants demonstrating a well-rounded application reflecting not only their academic excellence but also their dedication to research, community service, and hands-on clinical experience.¹ A growing emphasis on scholarly activities has made it crucial for applicants to stand out, with an increasing number opting to take gap years to engage in focused research endeavors.² In highly competitive specialties such as dermatology, successful applicants now report more than 20 research items on average.^3,4 This trend also is evident in primary care specialties, which have seen a 2- to 3-fold increase in reported research activities. The average unmatched applicant today lists more research items than the average matched applicant did a decade ago, underscoring the growing emphasis on scholarly activity.³

Ideally, graduate medical education should foster an environment of inquiry and scholarship, where residents develop new knowledge, evaluate research findings, and cultivate lifelong habits of inquiry. The Accreditation Council for Graduate Medical Education requires residents to engage in scholarship, such as case reports, research reviews, and original research.⁵ Research during residency has been linked to several benefits, including enhanced patient care through improved critical appraisal skills, clinical reasoning, and lifelong learning.^6,7 Additionally, students and residents who publish research are more likely to achieve higher rank during residency and pursue careers in academic medicine, potentially helping to address the decline in clinician investigators.^8,9 Publishing and presenting research also can enhance a residency program’s reputation, making it more attractive to competitive applicants, and may be beneficial for residents seeking jobs or fellowships.⁶

Dermatology residency programs vary in their structure and support for resident research. One survey revealed that many programs lack the necessary support, structure, and resources to effectively promote and maintain research training.¹ Additionally, residents have less exposure to researchers who could serve as mentors due to the growing demands placed on attending physicians in teaching hospitals.¹⁰

The Research Arms Race

The growing emphasis on scholarly activity for residency and fellowship applicants coupled with the use of research productivity to differentiate candidates has led some to declare a “research arms race” in residency selection.³ As one author stated, “We need less research, better research, and research done for the right reasons.”¹¹ Indeed, most articles authored by medical students are short reviews or case reports, with the majority (59% [207/350]) being cited zero times, according to one analysis.¹² Given the variable research infrastructure between programs and the decreasing availability of research mentors despite the growing emphasis on scholarly activity, applicants face an unfortunate dilemma. Until the system changes, those who protest this research arms race by not engaging in substantial scholarly activity are less likely to match into competitive specialties. Thus, the race continues.

The Value of Mentorship

Resident research success is impacted by having an effective faculty research mentor.¹³ Although all medical research at the student or resident levels should be conducted with a faculty mentor to oversee it, finding a mentor can be challenging. If a resident’s program boasts a strong research infrastructure or prolific faculty, building relationships with potential mentors is a logical first step for residents wishing to engage in research; however, if suitable mentors are lacking, efforts should be made by residents to establish these connections elsewhere, such as attending society meetings to network with potential mentors and applying to formal mentorship programs (eg, the American Society for Dermatologic Surgery’s Preceptor Program, the Women’s Dermatologic Society’s Mentorship Award). Unsolicited email inquiries asking, “Hi Dr. X, my name is Y, and I was wondering if you have any research projects I could help with?” often go unanswered. Instead, consider emailing or approaching potential mentors with a more developed proposition, such as the following example:

Hello Dr. X, my name is Y. I have enjoyed reading your publications on A, which inspired me to think about B. I reviewed the literature and noticed a potential to enhance our current understanding on the topic. My team and I conducted a systematic review of the available literature and drafted a manuscript summarizing our findings. Given your expertise in this field, would you be willing to collaborate on this paper? We would be grateful for your critical eye, suggestions for improvement, and overall thoughts.

This approach demonstrates initiative, provides a clear plan, and shows respect for the mentor’s expertise, increasing the likelihood of a positive response and fruitful collaboration. Assuming the resident’s working draft meets the potential mentor’s basic expectations, such a display of initiative is likely to impress them, and they may then offer opportunities to engage in meaningful research projects in the future. Everyone benefits! These efforts to establish connections with mentors can pave the way to further collaboration and meaningful research opportunities for dermatology residents.

The Systematic Review: An Attractive Option For Residents

There are several potential avenues for students or residents interested in pursuing research. Case reports and case series are relatively easy to compile, can be completed quickly, and often require minimal guidance from a faculty mentor; however, case reports rank low in the research hierarchy. Conversely, prospective blinded clinical trials provide some of the highest-quality evidence available but are challenging to conduct without a practicing faculty member to provide a patient cohort, often require extensive funding, and may involve complex statistical analyses beyond the expertise of most students or residents. Additionally, they may take years to complete, often extending beyond residency or fellowship application deadlines.

Most medical applicants likely hold at least some hesitation in churning out vast amounts of low-quality research merely to boost their publication count for the match process. Ideally, those who pursue scholarly activity should be driven by a genuine desire to contribute meaningfully to the medical literature. One particularly valuable avenue for trainees wishing to engage in research is the systematic review, which aims to identify, evaluate, and summarize the findings of all relevant individual studies regarding a research topic and answer a focused question. If performed thoughtfully, a systematic review can meaningfully contribute to the medical literature without requiring access to a prospectively followed cohort of patients or the constant supervision of a faculty mentor. Sure, systematic reviews may not be as robust as prospective cohort clinical trials, but they often provide comprehensive insights and are considered valuable contributions to evidence-based medicine. With the help of co-residents or medical students, a medical reference librarian, and a statistician—along with a working understanding of universally accepted quality measures—a resident physician and their team can produce a systematic review that ultimately may merit publication in a top-tier medical journal.

The remainder of this column will outline a streamlined approach to the systematic review writing process, specifically tailored for medical residents who may not have affiliations to a prolific research department or established relationships with faculty mentors in their field of interest. The aim is to offer a basic framework to help residents navigate the complexities of conducting and writing a high-quality, impactful systematic review. It is important to emphasize that resident research should always be conducted under the guidance of a faculty mentor, and this approach is not intended to encourage independent research and publication by residents. Instead, it provides steps that can be undertaken with a foundational understanding of accepted principles, allowing residents to compile a working draft of a manuscript in collaboration with a trusted faculty mentor.

The Systematic Review: A Simple Approach

Step 1: Choose a Topic—Once a resident has decided to embark on conducting a systematic review, the first step is to choose a topic, which requires consideration of several factors to ensure relevance, feasibility, and impact. Begin by identifying areas of clinical uncertainty or controversy in which a comprehensive synthesis of the literature could provide valuable insights. Often, such a topic can be gleaned from the conclusion section of other primary studies; statements such as “further study is needed to determine the efficacy of X” or “systematic reviews would be beneficial to ascertaining the impact of Y” may be a great place to start.

Next, ensure that sufficient primary studies exist to support a robust review or meta-analysis by conducting a preliminary literature search, which will confirm that the chosen topic is both researchable and relevant. A narrow, focused, well-defined topic likely will prove more feasible to review than a broad, ill-defined one. Once a topic is selected, it is advisable to discuss it with a faculty mentor before starting the literature search to ensure the topic’s feasibility and clinical relevance, helping to guide your research in a meaningful direction.

When deciding between a systematic review and a meta-analysis, the nature of the research question is an influential factor. A systematic review is particularly suitable for addressing broad questions or topics when the aim is to summarize and synthesize all relevant research studies; for example, a systematic review may investigate the various treatment options for atopic dermatitis and their efficacy, which allows for a comprehensive overview of the available treatments—both the interventions and the outcomes. In contrast, a meta-analysis is ideal for collecting and statistically combining quantitative data from multiple primary studies, provided there are enough relevant studies available in the literature.

Step 2: Build a Team—Recruiting a skilled librarian to assist with Medical Subject Headings (MeSH) terms and retrieving relevant papers is crucial for conducting a high-quality systematic review or meta-analysis. Medical librarians specializing in health sciences enhance the efficiency, comprehensiveness, and reliability of your literature search, substantially boosting your work’s credibility. These librarians are well versed in medical databases such as PubMed and Embase. Begin by contacting your institution’s library services, as there often are valuable resources and personnel available to assist you. Personally, I was surprised to find a librarian at my institution specifically dedicated to helping medical residents with such projects! These professionals are eager to help, and if provided with the scope and goal of your project, they can deliver literature search results in a digestible format. Similarly, seeking the expertise of a medical statistician is crucial to the accuracy and legitimacy of your study. In your final paper, it is important to recognize the contributions of the librarian and statistician, either as co-authors or in the acknowledgments section.

In addition, recruiting colleagues or medical students can be an effective strategy to make the project more feasible and offer collaborative benefits for all parties involved. Given the growing emphasis on research for residency and fellowship admissions, there usually is no shortage of motivated volunteers.

Next, identify the software tool you will use for your systematic review. Options range from simple spreadsheets such as Microsoft Excel to reference managers such as EndNote or Mendeley or dedicated systematic review tools. Academic institutions may subscribe to paid services such as Covidence (https://www.covidence.org), or you can utilize free alternatives such as Rayyan (https://www.rayyan.ai). Investing time in learning to navigate dedicated systematic review software can greatly enhance efficiency and reduce frustrations compared to more basic methods. Ultimately, staying organized, thorough, and committed is key.

Step 3: Conduct the Literature Review—At this point, your research topic has been decided, a medical reference librarian has provided the results of a comprehensive literature search, and a software tool has been chosen. The next task is to read hundreds or thousands of papers—easy, right? With your dedicated team assembled, the workload can be divided and conquered. The first step involves screening out duplicate and irrelevant studies based on titles and abstracts. Next, review the remaining papers in more detail. Those that pass this preliminary screen should be read in their entirety, and only the papers relevant to the research topic should be included in the final synthesis. If there are uncertainties about a study’s relevance, consulting a faculty mentor is advisable. To ensure the systematic review is as thorough as possible, pay special attention to the references section of each paper, as cited references can reveal relevant studies that may have been missed in the literature search.

Once all relevant papers are compiled and read, the relevant data points should be extracted and imputed into a data sheet. Collaborating with a medical statistician is crucial at this stage, as they can provide guidance on the most effective ways to structure and input data. After all studies are included, the relevant statistical analyses on the resultant dataset can be run.

Step 4: Write the Paper—In 2020, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was developed to ensure transparent and complete reporting of systematic reviews. A full discussion of PRISMA guidelines is beyond the scope of this paper; Page et al¹⁴ provided a summary, checklist, and flow diagram that is available online (https://www.prisma-statement.org). Following the PRISMA checklist and guidelines ensures a high-quality, transparent, and reliable systematic review. These guidelines not only help streamline and simplify the writing process but also enhance its efficiency and effectiveness. Discovering the PRISMA checklist can be transformative, providing a valuable roadmap that guides the author through each step of the reporting process, helping to avoid common pitfalls. This structured approach ultimately leads to a more comprehensive and trustworthy review.

Step 5: Make Finishing Touches—At this stage in the systematic review process, the studies have been compiled and thoroughly analyzed and the statistical analysis has been conducted. The results have been organized within a structured framework following the PRISMA checklist. With these steps completed, the next task is to finalize the manuscript and seek a final review from the senior author or faculty mentor. To streamline this process, it is beneficial to adhere to the formatting guidelines of the specific medical journal you intend to submit to. Check the author guidelines on the journal’s website and review recent systematic reviews published there as a reference. Even if you have not chosen a journal yet, formatting your manuscript according to a prestigious journal’s general style provides a strong foundation that can be easily adapted to fit another journal’s requirements if necessary.

Final Thoughts

Designing and conducting a systematic review is no easy task, but it can be a valuable skill for dermatology residents aiming to contribute meaningfully to the medical literature. The process of compiling a systematic review offers an opportunity for developing critical research skills, from formulating a research question to synthesizing evidence and presenting findings in a clear methodical way. Engaging in systematic review writing not only enhances the resident’s understanding of a particular topic but also demonstrates a commitment to scholarly activity—a key factor in an increasingly competitive residency and fellowship application environment.

The basic steps outlined in this article are just one way in which residents can begin to navigate the complexities of medical research, specifically the systematic review process. By assembling a supportive team, utilizing available resources, and adhering to established guidelines such as PRISMA, one can produce a high-quality, impactful review. Ultimately, the systematic review process is not just about publication—it is about fostering a habit of inquiry, improving patient care, and contributing to the ever-evolving field of medicine. With dedication and collaboration, even the most challenging aspects of research can be tackled, paving the way for future opportunities and professional growth. In this way, perhaps one day the spirit of the “research race” can shift from a frantic sprint to a graceful marathon, where each mile is run with heart and every step is filled with purpose.

Dermatology remains one of the most competitive specialties in the residency match, with successful applicants demonstrating a well-rounded application reflecting not only their academic excellence but also their dedication to research, community service, and hands-on clinical experience.¹ A growing emphasis on scholarly activities has made it crucial for applicants to stand out, with an increasing number opting to take gap years to engage in focused research endeavors.² In highly competitive specialties such as dermatology, successful applicants now report more than 20 research items on average.^3,4 This trend also is evident in primary care specialties, which have seen a 2- to 3-fold increase in reported research activities. The average unmatched applicant today lists more research items than the average matched applicant did a decade ago, underscoring the growing emphasis on scholarly activity.³

Ideally, graduate medical education should foster an environment of inquiry and scholarship, where residents develop new knowledge, evaluate research findings, and cultivate lifelong habits of inquiry. The Accreditation Council for Graduate Medical Education requires residents to engage in scholarship, such as case reports, research reviews, and original research.⁵ Research during residency has been linked to several benefits, including enhanced patient care through improved critical appraisal skills, clinical reasoning, and lifelong learning.^6,7 Additionally, students and residents who publish research are more likely to achieve higher rank during residency and pursue careers in academic medicine, potentially helping to address the decline in clinician investigators.^8,9 Publishing and presenting research also can enhance a residency program’s reputation, making it more attractive to competitive applicants, and may be beneficial for residents seeking jobs or fellowships.⁶

Dermatology residency programs vary in their structure and support for resident research. One survey revealed that many programs lack the necessary support, structure, and resources to effectively promote and maintain research training.¹ Additionally, residents have less exposure to researchers who could serve as mentors due to the growing demands placed on attending physicians in teaching hospitals.¹⁰

The Research Arms Race

The growing emphasis on scholarly activity for residency and fellowship applicants coupled with the use of research productivity to differentiate candidates has led some to declare a “research arms race” in residency selection.³ As one author stated, “We need less research, better research, and research done for the right reasons.”¹¹ Indeed, most articles authored by medical students are short reviews or case reports, with the majority (59% [207/350]) being cited zero times, according to one analysis.¹² Given the variable research infrastructure between programs and the decreasing availability of research mentors despite the growing emphasis on scholarly activity, applicants face an unfortunate dilemma. Until the system changes, those who protest this research arms race by not engaging in substantial scholarly activity are less likely to match into competitive specialties. Thus, the race continues.

The Value of Mentorship

Resident research success is impacted by having an effective faculty research mentor.¹³ Although all medical research at the student or resident levels should be conducted with a faculty mentor to oversee it, finding a mentor can be challenging. If a resident’s program boasts a strong research infrastructure or prolific faculty, building relationships with potential mentors is a logical first step for residents wishing to engage in research; however, if suitable mentors are lacking, efforts should be made by residents to establish these connections elsewhere, such as attending society meetings to network with potential mentors and applying to formal mentorship programs (eg, the American Society for Dermatologic Surgery’s Preceptor Program, the Women’s Dermatologic Society’s Mentorship Award). Unsolicited email inquiries asking, “Hi Dr. X, my name is Y, and I was wondering if you have any research projects I could help with?” often go unanswered. Instead, consider emailing or approaching potential mentors with a more developed proposition, such as the following example:

Hello Dr. X, my name is Y. I have enjoyed reading your publications on A, which inspired me to think about B. I reviewed the literature and noticed a potential to enhance our current understanding on the topic. My team and I conducted a systematic review of the available literature and drafted a manuscript summarizing our findings. Given your expertise in this field, would you be willing to collaborate on this paper? We would be grateful for your critical eye, suggestions for improvement, and overall thoughts.

This approach demonstrates initiative, provides a clear plan, and shows respect for the mentor’s expertise, increasing the likelihood of a positive response and fruitful collaboration. Assuming the resident’s working draft meets the potential mentor’s basic expectations, such a display of initiative is likely to impress them, and they may then offer opportunities to engage in meaningful research projects in the future. Everyone benefits! These efforts to establish connections with mentors can pave the way to further collaboration and meaningful research opportunities for dermatology residents.

The Systematic Review: An Attractive Option For Residents

There are several potential avenues for students or residents interested in pursuing research. Case reports and case series are relatively easy to compile, can be completed quickly, and often require minimal guidance from a faculty mentor; however, case reports rank low in the research hierarchy. Conversely, prospective blinded clinical trials provide some of the highest-quality evidence available but are challenging to conduct without a practicing faculty member to provide a patient cohort, often require extensive funding, and may involve complex statistical analyses beyond the expertise of most students or residents. Additionally, they may take years to complete, often extending beyond residency or fellowship application deadlines.

Most medical applicants likely hold at least some hesitation in churning out vast amounts of low-quality research merely to boost their publication count for the match process. Ideally, those who pursue scholarly activity should be driven by a genuine desire to contribute meaningfully to the medical literature. One particularly valuable avenue for trainees wishing to engage in research is the systematic review, which aims to identify, evaluate, and summarize the findings of all relevant individual studies regarding a research topic and answer a focused question. If performed thoughtfully, a systematic review can meaningfully contribute to the medical literature without requiring access to a prospectively followed cohort of patients or the constant supervision of a faculty mentor. Sure, systematic reviews may not be as robust as prospective cohort clinical trials, but they often provide comprehensive insights and are considered valuable contributions to evidence-based medicine. With the help of co-residents or medical students, a medical reference librarian, and a statistician—along with a working understanding of universally accepted quality measures—a resident physician and their team can produce a systematic review that ultimately may merit publication in a top-tier medical journal.

The remainder of this column will outline a streamlined approach to the systematic review writing process, specifically tailored for medical residents who may not have affiliations to a prolific research department or established relationships with faculty mentors in their field of interest. The aim is to offer a basic framework to help residents navigate the complexities of conducting and writing a high-quality, impactful systematic review. It is important to emphasize that resident research should always be conducted under the guidance of a faculty mentor, and this approach is not intended to encourage independent research and publication by residents. Instead, it provides steps that can be undertaken with a foundational understanding of accepted principles, allowing residents to compile a working draft of a manuscript in collaboration with a trusted faculty mentor.

The Systematic Review: A Simple Approach

Step 1: Choose a Topic—Once a resident has decided to embark on conducting a systematic review, the first step is to choose a topic, which requires consideration of several factors to ensure relevance, feasibility, and impact. Begin by identifying areas of clinical uncertainty or controversy in which a comprehensive synthesis of the literature could provide valuable insights. Often, such a topic can be gleaned from the conclusion section of other primary studies; statements such as “further study is needed to determine the efficacy of X” or “systematic reviews would be beneficial to ascertaining the impact of Y” may be a great place to start.

Next, ensure that sufficient primary studies exist to support a robust review or meta-analysis by conducting a preliminary literature search, which will confirm that the chosen topic is both researchable and relevant. A narrow, focused, well-defined topic likely will prove more feasible to review than a broad, ill-defined one. Once a topic is selected, it is advisable to discuss it with a faculty mentor before starting the literature search to ensure the topic’s feasibility and clinical relevance, helping to guide your research in a meaningful direction.

When deciding between a systematic review and a meta-analysis, the nature of the research question is an influential factor. A systematic review is particularly suitable for addressing broad questions or topics when the aim is to summarize and synthesize all relevant research studies; for example, a systematic review may investigate the various treatment options for atopic dermatitis and their efficacy, which allows for a comprehensive overview of the available treatments—both the interventions and the outcomes. In contrast, a meta-analysis is ideal for collecting and statistically combining quantitative data from multiple primary studies, provided there are enough relevant studies available in the literature.

Step 2: Build a Team—Recruiting a skilled librarian to assist with Medical Subject Headings (MeSH) terms and retrieving relevant papers is crucial for conducting a high-quality systematic review or meta-analysis. Medical librarians specializing in health sciences enhance the efficiency, comprehensiveness, and reliability of your literature search, substantially boosting your work’s credibility. These librarians are well versed in medical databases such as PubMed and Embase. Begin by contacting your institution’s library services, as there often are valuable resources and personnel available to assist you. Personally, I was surprised to find a librarian at my institution specifically dedicated to helping medical residents with such projects! These professionals are eager to help, and if provided with the scope and goal of your project, they can deliver literature search results in a digestible format. Similarly, seeking the expertise of a medical statistician is crucial to the accuracy and legitimacy of your study. In your final paper, it is important to recognize the contributions of the librarian and statistician, either as co-authors or in the acknowledgments section.

In addition, recruiting colleagues or medical students can be an effective strategy to make the project more feasible and offer collaborative benefits for all parties involved. Given the growing emphasis on research for residency and fellowship admissions, there usually is no shortage of motivated volunteers.

Next, identify the software tool you will use for your systematic review. Options range from simple spreadsheets such as Microsoft Excel to reference managers such as EndNote or Mendeley or dedicated systematic review tools. Academic institutions may subscribe to paid services such as Covidence (https://www.covidence.org), or you can utilize free alternatives such as Rayyan (https://www.rayyan.ai). Investing time in learning to navigate dedicated systematic review software can greatly enhance efficiency and reduce frustrations compared to more basic methods. Ultimately, staying organized, thorough, and committed is key.

Step 3: Conduct the Literature Review—At this point, your research topic has been decided, a medical reference librarian has provided the results of a comprehensive literature search, and a software tool has been chosen. The next task is to read hundreds or thousands of papers—easy, right? With your dedicated team assembled, the workload can be divided and conquered. The first step involves screening out duplicate and irrelevant studies based on titles and abstracts. Next, review the remaining papers in more detail. Those that pass this preliminary screen should be read in their entirety, and only the papers relevant to the research topic should be included in the final synthesis. If there are uncertainties about a study’s relevance, consulting a faculty mentor is advisable. To ensure the systematic review is as thorough as possible, pay special attention to the references section of each paper, as cited references can reveal relevant studies that may have been missed in the literature search.

Once all relevant papers are compiled and read, the relevant data points should be extracted and imputed into a data sheet. Collaborating with a medical statistician is crucial at this stage, as they can provide guidance on the most effective ways to structure and input data. After all studies are included, the relevant statistical analyses on the resultant dataset can be run.

Step 4: Write the Paper—In 2020, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was developed to ensure transparent and complete reporting of systematic reviews. A full discussion of PRISMA guidelines is beyond the scope of this paper; Page et al¹⁴ provided a summary, checklist, and flow diagram that is available online (https://www.prisma-statement.org). Following the PRISMA checklist and guidelines ensures a high-quality, transparent, and reliable systematic review. These guidelines not only help streamline and simplify the writing process but also enhance its efficiency and effectiveness. Discovering the PRISMA checklist can be transformative, providing a valuable roadmap that guides the author through each step of the reporting process, helping to avoid common pitfalls. This structured approach ultimately leads to a more comprehensive and trustworthy review.

Step 5: Make Finishing Touches—At this stage in the systematic review process, the studies have been compiled and thoroughly analyzed and the statistical analysis has been conducted. The results have been organized within a structured framework following the PRISMA checklist. With these steps completed, the next task is to finalize the manuscript and seek a final review from the senior author or faculty mentor. To streamline this process, it is beneficial to adhere to the formatting guidelines of the specific medical journal you intend to submit to. Check the author guidelines on the journal’s website and review recent systematic reviews published there as a reference. Even if you have not chosen a journal yet, formatting your manuscript according to a prestigious journal’s general style provides a strong foundation that can be easily adapted to fit another journal’s requirements if necessary.

Final Thoughts

Designing and conducting a systematic review is no easy task, but it can be a valuable skill for dermatology residents aiming to contribute meaningfully to the medical literature. The process of compiling a systematic review offers an opportunity for developing critical research skills, from formulating a research question to synthesizing evidence and presenting findings in a clear methodical way. Engaging in systematic review writing not only enhances the resident’s understanding of a particular topic but also demonstrates a commitment to scholarly activity—a key factor in an increasingly competitive residency and fellowship application environment.

The basic steps outlined in this article are just one way in which residents can begin to navigate the complexities of medical research, specifically the systematic review process. By assembling a supportive team, utilizing available resources, and adhering to established guidelines such as PRISMA, one can produce a high-quality, impactful review. Ultimately, the systematic review process is not just about publication—it is about fostering a habit of inquiry, improving patient care, and contributing to the ever-evolving field of medicine. With dedication and collaboration, even the most challenging aspects of research can be tackled, paving the way for future opportunities and professional growth. In this way, perhaps one day the spirit of the “research race” can shift from a frantic sprint to a graceful marathon, where each mile is run with heart and every step is filled with purpose.

Dermatology remains one of the most competitive specialties in the residency match, with successful applicants demonstrating a well-rounded application reflecting not only their academic excellence but also their dedication to research, community service, and hands-on clinical experience.¹ A growing emphasis on scholarly activities has made it crucial for applicants to stand out, with an increasing number opting to take gap years to engage in focused research endeavors.² In highly competitive specialties such as dermatology, successful applicants now report more than 20 research items on average.^3,4 This trend also is evident in primary care specialties, which have seen a 2- to 3-fold increase in reported research activities. The average unmatched applicant today lists more research items than the average matched applicant did a decade ago, underscoring the growing emphasis on scholarly activity.³

Ideally, graduate medical education should foster an environment of inquiry and scholarship, where residents develop new knowledge, evaluate research findings, and cultivate lifelong habits of inquiry. The Accreditation Council for Graduate Medical Education requires residents to engage in scholarship, such as case reports, research reviews, and original research.⁵ Research during residency has been linked to several benefits, including enhanced patient care through improved critical appraisal skills, clinical reasoning, and lifelong learning.^6,7 Additionally, students and residents who publish research are more likely to achieve higher rank during residency and pursue careers in academic medicine, potentially helping to address the decline in clinician investigators.^8,9 Publishing and presenting research also can enhance a residency program’s reputation, making it more attractive to competitive applicants, and may be beneficial for residents seeking jobs or fellowships.⁶

Dermatology residency programs vary in their structure and support for resident research. One survey revealed that many programs lack the necessary support, structure, and resources to effectively promote and maintain research training.¹ Additionally, residents have less exposure to researchers who could serve as mentors due to the growing demands placed on attending physicians in teaching hospitals.¹⁰

The Research Arms Race

The growing emphasis on scholarly activity for residency and fellowship applicants coupled with the use of research productivity to differentiate candidates has led some to declare a “research arms race” in residency selection.³ As one author stated, “We need less research, better research, and research done for the right reasons.”¹¹ Indeed, most articles authored by medical students are short reviews or case reports, with the majority (59% [207/350]) being cited zero times, according to one analysis.¹² Given the variable research infrastructure between programs and the decreasing availability of research mentors despite the growing emphasis on scholarly activity, applicants face an unfortunate dilemma. Until the system changes, those who protest this research arms race by not engaging in substantial scholarly activity are less likely to match into competitive specialties. Thus, the race continues.

The Value of Mentorship

Resident research success is impacted by having an effective faculty research mentor.¹³ Although all medical research at the student or resident levels should be conducted with a faculty mentor to oversee it, finding a mentor can be challenging. If a resident’s program boasts a strong research infrastructure or prolific faculty, building relationships with potential mentors is a logical first step for residents wishing to engage in research; however, if suitable mentors are lacking, efforts should be made by residents to establish these connections elsewhere, such as attending society meetings to network with potential mentors and applying to formal mentorship programs (eg, the American Society for Dermatologic Surgery’s Preceptor Program, the Women’s Dermatologic Society’s Mentorship Award). Unsolicited email inquiries asking, “Hi Dr. X, my name is Y, and I was wondering if you have any research projects I could help with?” often go unanswered. Instead, consider emailing or approaching potential mentors with a more developed proposition, such as the following example:

Hello Dr. X, my name is Y. I have enjoyed reading your publications on A, which inspired me to think about B. I reviewed the literature and noticed a potential to enhance our current understanding on the topic. My team and I conducted a systematic review of the available literature and drafted a manuscript summarizing our findings. Given your expertise in this field, would you be willing to collaborate on this paper? We would be grateful for your critical eye, suggestions for improvement, and overall thoughts.

This approach demonstrates initiative, provides a clear plan, and shows respect for the mentor’s expertise, increasing the likelihood of a positive response and fruitful collaboration. Assuming the resident’s working draft meets the potential mentor’s basic expectations, such a display of initiative is likely to impress them, and they may then offer opportunities to engage in meaningful research projects in the future. Everyone benefits! These efforts to establish connections with mentors can pave the way to further collaboration and meaningful research opportunities for dermatology residents.

The Systematic Review: An Attractive Option For Residents

There are several potential avenues for students or residents interested in pursuing research. Case reports and case series are relatively easy to compile, can be completed quickly, and often require minimal guidance from a faculty mentor; however, case reports rank low in the research hierarchy. Conversely, prospective blinded clinical trials provide some of the highest-quality evidence available but are challenging to conduct without a practicing faculty member to provide a patient cohort, often require extensive funding, and may involve complex statistical analyses beyond the expertise of most students or residents. Additionally, they may take years to complete, often extending beyond residency or fellowship application deadlines.

Most medical applicants likely hold at least some hesitation in churning out vast amounts of low-quality research merely to boost their publication count for the match process. Ideally, those who pursue scholarly activity should be driven by a genuine desire to contribute meaningfully to the medical literature. One particularly valuable avenue for trainees wishing to engage in research is the systematic review, which aims to identify, evaluate, and summarize the findings of all relevant individual studies regarding a research topic and answer a focused question. If performed thoughtfully, a systematic review can meaningfully contribute to the medical literature without requiring access to a prospectively followed cohort of patients or the constant supervision of a faculty mentor. Sure, systematic reviews may not be as robust as prospective cohort clinical trials, but they often provide comprehensive insights and are considered valuable contributions to evidence-based medicine. With the help of co-residents or medical students, a medical reference librarian, and a statistician—along with a working understanding of universally accepted quality measures—a resident physician and their team can produce a systematic review that ultimately may merit publication in a top-tier medical journal.

The remainder of this column will outline a streamlined approach to the systematic review writing process, specifically tailored for medical residents who may not have affiliations to a prolific research department or established relationships with faculty mentors in their field of interest. The aim is to offer a basic framework to help residents navigate the complexities of conducting and writing a high-quality, impactful systematic review. It is important to emphasize that resident research should always be conducted under the guidance of a faculty mentor, and this approach is not intended to encourage independent research and publication by residents. Instead, it provides steps that can be undertaken with a foundational understanding of accepted principles, allowing residents to compile a working draft of a manuscript in collaboration with a trusted faculty mentor.

The Systematic Review: A Simple Approach

Step 1: Choose a Topic—Once a resident has decided to embark on conducting a systematic review, the first step is to choose a topic, which requires consideration of several factors to ensure relevance, feasibility, and impact. Begin by identifying areas of clinical uncertainty or controversy in which a comprehensive synthesis of the literature could provide valuable insights. Often, such a topic can be gleaned from the conclusion section of other primary studies; statements such as “further study is needed to determine the efficacy of X” or “systematic reviews would be beneficial to ascertaining the impact of Y” may be a great place to start.

Next, ensure that sufficient primary studies exist to support a robust review or meta-analysis by conducting a preliminary literature search, which will confirm that the chosen topic is both researchable and relevant. A narrow, focused, well-defined topic likely will prove more feasible to review than a broad, ill-defined one. Once a topic is selected, it is advisable to discuss it with a faculty mentor before starting the literature search to ensure the topic’s feasibility and clinical relevance, helping to guide your research in a meaningful direction.

When deciding between a systematic review and a meta-analysis, the nature of the research question is an influential factor. A systematic review is particularly suitable for addressing broad questions or topics when the aim is to summarize and synthesize all relevant research studies; for example, a systematic review may investigate the various treatment options for atopic dermatitis and their efficacy, which allows for a comprehensive overview of the available treatments—both the interventions and the outcomes. In contrast, a meta-analysis is ideal for collecting and statistically combining quantitative data from multiple primary studies, provided there are enough relevant studies available in the literature.

Step 2: Build a Team—Recruiting a skilled librarian to assist with Medical Subject Headings (MeSH) terms and retrieving relevant papers is crucial for conducting a high-quality systematic review or meta-analysis. Medical librarians specializing in health sciences enhance the efficiency, comprehensiveness, and reliability of your literature search, substantially boosting your work’s credibility. These librarians are well versed in medical databases such as PubMed and Embase. Begin by contacting your institution’s library services, as there often are valuable resources and personnel available to assist you. Personally, I was surprised to find a librarian at my institution specifically dedicated to helping medical residents with such projects! These professionals are eager to help, and if provided with the scope and goal of your project, they can deliver literature search results in a digestible format. Similarly, seeking the expertise of a medical statistician is crucial to the accuracy and legitimacy of your study. In your final paper, it is important to recognize the contributions of the librarian and statistician, either as co-authors or in the acknowledgments section.

In addition, recruiting colleagues or medical students can be an effective strategy to make the project more feasible and offer collaborative benefits for all parties involved. Given the growing emphasis on research for residency and fellowship admissions, there usually is no shortage of motivated volunteers.

Next, identify the software tool you will use for your systematic review. Options range from simple spreadsheets such as Microsoft Excel to reference managers such as EndNote or Mendeley or dedicated systematic review tools. Academic institutions may subscribe to paid services such as Covidence (https://www.covidence.org), or you can utilize free alternatives such as Rayyan (https://www.rayyan.ai). Investing time in learning to navigate dedicated systematic review software can greatly enhance efficiency and reduce frustrations compared to more basic methods. Ultimately, staying organized, thorough, and committed is key.

Step 3: Conduct the Literature Review—At this point, your research topic has been decided, a medical reference librarian has provided the results of a comprehensive literature search, and a software tool has been chosen. The next task is to read hundreds or thousands of papers—easy, right? With your dedicated team assembled, the workload can be divided and conquered. The first step involves screening out duplicate and irrelevant studies based on titles and abstracts. Next, review the remaining papers in more detail. Those that pass this preliminary screen should be read in their entirety, and only the papers relevant to the research topic should be included in the final synthesis. If there are uncertainties about a study’s relevance, consulting a faculty mentor is advisable. To ensure the systematic review is as thorough as possible, pay special attention to the references section of each paper, as cited references can reveal relevant studies that may have been missed in the literature search.

Once all relevant papers are compiled and read, the relevant data points should be extracted and imputed into a data sheet. Collaborating with a medical statistician is crucial at this stage, as they can provide guidance on the most effective ways to structure and input data. After all studies are included, the relevant statistical analyses on the resultant dataset can be run.

Step 4: Write the Paper—In 2020, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was developed to ensure transparent and complete reporting of systematic reviews. A full discussion of PRISMA guidelines is beyond the scope of this paper; Page et al¹⁴ provided a summary, checklist, and flow diagram that is available online (https://www.prisma-statement.org). Following the PRISMA checklist and guidelines ensures a high-quality, transparent, and reliable systematic review. These guidelines not only help streamline and simplify the writing process but also enhance its efficiency and effectiveness. Discovering the PRISMA checklist can be transformative, providing a valuable roadmap that guides the author through each step of the reporting process, helping to avoid common pitfalls. This structured approach ultimately leads to a more comprehensive and trustworthy review.

Step 5: Make Finishing Touches—At this stage in the systematic review process, the studies have been compiled and thoroughly analyzed and the statistical analysis has been conducted. The results have been organized within a structured framework following the PRISMA checklist. With these steps completed, the next task is to finalize the manuscript and seek a final review from the senior author or faculty mentor. To streamline this process, it is beneficial to adhere to the formatting guidelines of the specific medical journal you intend to submit to. Check the author guidelines on the journal’s website and review recent systematic reviews published there as a reference. Even if you have not chosen a journal yet, formatting your manuscript according to a prestigious journal’s general style provides a strong foundation that can be easily adapted to fit another journal’s requirements if necessary.

Final Thoughts

Designing and conducting a systematic review is no easy task, but it can be a valuable skill for dermatology residents aiming to contribute meaningfully to the medical literature. The process of compiling a systematic review offers an opportunity for developing critical research skills, from formulating a research question to synthesizing evidence and presenting findings in a clear methodical way. Engaging in systematic review writing not only enhances the resident’s understanding of a particular topic but also demonstrates a commitment to scholarly activity—a key factor in an increasingly competitive residency and fellowship application environment.

The basic steps outlined in this article are just one way in which residents can begin to navigate the complexities of medical research, specifically the systematic review process. By assembling a supportive team, utilizing available resources, and adhering to established guidelines such as PRISMA, one can produce a high-quality, impactful review. Ultimately, the systematic review process is not just about publication—it is about fostering a habit of inquiry, improving patient care, and contributing to the ever-evolving field of medicine. With dedication and collaboration, even the most challenging aspects of research can be tackled, paving the way for future opportunities and professional growth. In this way, perhaps one day the spirit of the “research race” can shift from a frantic sprint to a graceful marathon, where each mile is run with heart and every step is filled with purpose.

To the Editor:

Chronic cutaneous lupus erythematosus (CCLE) is an inflammatory condition with myriad cutaneous manifestations. Most forms of CCLE have the potential to progress to systemic lupus erythematosus (SLE).¹

Blaschkolinear lupus erythematosus (BLE) is an exceedingly rare subtype of cutaneous lupus erythematosus that usually manifests during childhood as linear plaques along the lines of Blaschko.^2,3 Under normal conditions, Blaschko lines are not noticeable; they correspond to the direction of ectodermal cell migration during cutaneous embryogenesis.^4,5 The embryonic cells travel ventrolaterally, forming a V-shaped pattern on the back, an S-shaped pattern on the trunk, and an hourglass-shaped pattern on the face with several perpendicular intersections near the mouth and nose.⁶ During their migration, the cells are susceptible to somatic mutations and clonal expansion, resulting in a monoclonal population of genetically heterogenous cells. This phenomenon is known as somatic mosaicism and may lead to an increased susceptibility to an array of congenital and inflammatory dermatoses, such as cutaneous lupus erythematosus.⁴ Blaschkolinear entities tend to manifest in a unilateral distribution following exposure to a certain environmental trigger, such as trauma, viral illness, or UV radiation, although a trigger is not always present.⁷ We report a case of BLE manifesting on the head and neck in an adult patient.

A 46-year-old man presented with a pruritic rash of 3 months’ duration on the right cheek that extended inferiorly to the right upper chest. He had a medical history of well-controlled psoriasis, and he denied any antecedent trauma, fevers, chills, arthralgia, or night sweats. There had been no improvement with mometasone ointment 0.1% applied daily for 2 months as prescribed by his primary care provider. Physical examination revealed indurated, red-brown, atrophic plaques in a blaschkolinear distribution around the nose, right upper jaw, right side of the neck, and right upper chest (Figure, A).

To the Editor:

Chronic cutaneous lupus erythematosus (CCLE) is an inflammatory condition with myriad cutaneous manifestations. Most forms of CCLE have the potential to progress to systemic lupus erythematosus (SLE).¹

Blaschkolinear lupus erythematosus (BLE) is an exceedingly rare subtype of cutaneous lupus erythematosus that usually manifests during childhood as linear plaques along the lines of Blaschko.^2,3 Under normal conditions, Blaschko lines are not noticeable; they correspond to the direction of ectodermal cell migration during cutaneous embryogenesis.^4,5 The embryonic cells travel ventrolaterally, forming a V-shaped pattern on the back, an S-shaped pattern on the trunk, and an hourglass-shaped pattern on the face with several perpendicular intersections near the mouth and nose.⁶ During their migration, the cells are susceptible to somatic mutations and clonal expansion, resulting in a monoclonal population of genetically heterogenous cells. This phenomenon is known as somatic mosaicism and may lead to an increased susceptibility to an array of congenital and inflammatory dermatoses, such as cutaneous lupus erythematosus.⁴ Blaschkolinear entities tend to manifest in a unilateral distribution following exposure to a certain environmental trigger, such as trauma, viral illness, or UV radiation, although a trigger is not always present.⁷ We report a case of BLE manifesting on the head and neck in an adult patient.

A 46-year-old man presented with a pruritic rash of 3 months’ duration on the right cheek that extended inferiorly to the right upper chest. He had a medical history of well-controlled psoriasis, and he denied any antecedent trauma, fevers, chills, arthralgia, or night sweats. There had been no improvement with mometasone ointment 0.1% applied daily for 2 months as prescribed by his primary care provider. Physical examination revealed indurated, red-brown, atrophic plaques in a blaschkolinear distribution around the nose, right upper jaw, right side of the neck, and right upper chest (Figure, A).

To the Editor:

Chronic cutaneous lupus erythematosus (CCLE) is an inflammatory condition with myriad cutaneous manifestations. Most forms of CCLE have the potential to progress to systemic lupus erythematosus (SLE).¹

Blaschkolinear lupus erythematosus (BLE) is an exceedingly rare subtype of cutaneous lupus erythematosus that usually manifests during childhood as linear plaques along the lines of Blaschko.^2,3 Under normal conditions, Blaschko lines are not noticeable; they correspond to the direction of ectodermal cell migration during cutaneous embryogenesis.^4,5 The embryonic cells travel ventrolaterally, forming a V-shaped pattern on the back, an S-shaped pattern on the trunk, and an hourglass-shaped pattern on the face with several perpendicular intersections near the mouth and nose.⁶ During their migration, the cells are susceptible to somatic mutations and clonal expansion, resulting in a monoclonal population of genetically heterogenous cells. This phenomenon is known as somatic mosaicism and may lead to an increased susceptibility to an array of congenital and inflammatory dermatoses, such as cutaneous lupus erythematosus.⁴ Blaschkolinear entities tend to manifest in a unilateral distribution following exposure to a certain environmental trigger, such as trauma, viral illness, or UV radiation, although a trigger is not always present.⁷ We report a case of BLE manifesting on the head and neck in an adult patient.

A 46-year-old man presented with a pruritic rash of 3 months’ duration on the right cheek that extended inferiorly to the right upper chest. He had a medical history of well-controlled psoriasis, and he denied any antecedent trauma, fevers, chills, arthralgia, or night sweats. There had been no improvement with mometasone ointment 0.1% applied daily for 2 months as prescribed by his primary care provider. Physical examination revealed indurated, red-brown, atrophic plaques in a blaschkolinear distribution around the nose, right upper jaw, right side of the neck, and right upper chest (Figure, A).

New research provides more evidence that inflammation may contribute to the development of psychiatric disorders and suggests that measuring certain inflammatory biomarkers may aid in the early identification of individuals at high risk.

Using large-scale datasets, researchers found that elevated levels of certain inflammatory biomarkers, particularly leukocytes, haptoglobin, and C-reactive protein (CRP), and lower levels of anti-inflammatory immunoglobulin G (IgG) were associated with an increased risk for psychiatric disorders. 

Individuals with psychiatric disorders had persistently higher levels of leukocytes and haptoglobin, as well as persistently lower levels of IgG, than controls during the 30 years before diagnosis, which suggest “long-term processes and may aid in the identification of individuals at high risk,” the researchers wrote. 

In addition, a higher level of leukocytes was consistently associated with increased odds of depression across different methods of Mendelian randomization (MR) analysis, “indicating a possible causal relationship between leukocytes and depression,” they said. 

The study, with first author Yu Zeng, MSc, with the Mental Health Center and West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China, was published online on August 21 in JAMA Psychiatry. 
 

Inflammatory Phenotype

Individuals with psychiatric disorders have been found to have elevated levels of inflammatory biomarkers, but prospective evidence is limited regarding the association between inflammatory biomarkers and subsequent psychiatric disorders risk. 

To investigate further, the researchers employed a “triangulation” approach consisting of an exploration dataset of 585,279 adults in the Swedish AMORIS cohort with no prior psychiatric diagnoses and a measurement of at least one inflammatory biomarker, a validation dataset of 485,620 UK Biobank participants, and genetic and MR analyses using genome-wide association study summary statistics.

In the AMORIS cohort, individuals with a higher than median level of leukocytes (hazard ratio [HR], 1.11), haptoglobin (HR, 1.13), or CRP (HR, 1.02) had an elevated risk for any psychiatric disorder. In contrast, there was an inverse association for IgG level (HR, 0.92). 

“The estimates were comparable for depression, anxiety, and stress-related disorders, specifically, and these results were largely validated in the UK Biobank,” the authors reported. 

In trajectory analyses, compared with controls, individuals with psychiatric disorders had higher leukocyte and haptoglobin levels and lower IgG up to three decades before being diagnosed. 

The MR analysis suggested a possible causal relationship between leukocytes and depression. 

The underlying mechanisms for the associations of serum leukocytes, haptoglobin, CRP, and IgG with psychiatry disorders remain unclear.

“Possible explanations mainly include blood-brain barrier disruption, microglia activation, neurotransmission impairment, and other interactions between inflammations and neuropathology,” the researchers wrote. 

A related paper published online on August 21 in JAMA Psychiatry looked at trajectories of inflammation in childhood and risk for mental and cardiometabolic disorders in adulthood. 

This longitudinal cohort study found that having persistently raised levels of inflammation as measured by CRP throughout childhood and adolescence, peaking at age 9 years, were associated with an increased risk of developing psychosis disorder, severe depression, and higher levels of insulin resistance.
 

Support for Precision Psychiatry

This study is “another strong indication that inflammation plays a role in depression,” Andrew H. Miller, MD, professor of psychiatry and behavioral sciences and director of the behavioral immunology program, Emory University School of Medicine, Atlanta, Georgia, who wasn’t involved in the study, told this news organization. 

“The work adds to the mounting data that there exists an inflammatory phenotype of depression that may uniquely respond to treatment and may have a unique trajectory,” Dr. Miller said. 

“Eventually the field will want to embrace this novel phenotype and better understand how to recognize it and treat it. This is our entrée into precision psychiatry where we identify the right treatment for the right patient at the right time based on an understanding of the underlying cause of their illness,” Dr. Miller added. 

Also weighing in, Alexander B. Niculescu III, MD, PhD, professor of psychiatry and medical neuroscience, Indiana University School of Medicine, Indianapolis, cautioned that these biomarkers are “very nonspecific and are likely related to these subjects that go on to develop psychiatric disorders having more stressful, adverse life trajectories.”

“There are better, more specific blood biomarkers for psychiatric disorders already available,” Dr. Niculescu told this news organization.

His group recently reported that a panel of blood-based biomarkers can distinguish between depression and bipolar disorder, predict a person’s future risk for these disorders, and inform more tailored medication choices. 

Notably, they observed a strong circadian clock gene component to mood disorders, which helps explain why some patients’ conditions become worse with seasonal changes. It also explains the sleep alterations that occur among patients with mood disorders, they said.

This study had no commercial funding. Yu Zeng and Dr. Miller had no relevant disclosures. Dr. Niculescu is a cofounder of MindX Sciences and is listed as inventor on a patent application filed by Indiana University.
 

A version of this article first appeared on Medscape.com.

New research provides more evidence that inflammation may contribute to the development of psychiatric disorders and suggests that measuring certain inflammatory biomarkers may aid in the early identification of individuals at high risk.

Using large-scale datasets, researchers found that elevated levels of certain inflammatory biomarkers, particularly leukocytes, haptoglobin, and C-reactive protein (CRP), and lower levels of anti-inflammatory immunoglobulin G (IgG) were associated with an increased risk for psychiatric disorders. 

Individuals with psychiatric disorders had persistently higher levels of leukocytes and haptoglobin, as well as persistently lower levels of IgG, than controls during the 30 years before diagnosis, which suggest “long-term processes and may aid in the identification of individuals at high risk,” the researchers wrote. 

In addition, a higher level of leukocytes was consistently associated with increased odds of depression across different methods of Mendelian randomization (MR) analysis, “indicating a possible causal relationship between leukocytes and depression,” they said. 

The study, with first author Yu Zeng, MSc, with the Mental Health Center and West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China, was published online on August 21 in JAMA Psychiatry. 
 

Inflammatory Phenotype

Individuals with psychiatric disorders have been found to have elevated levels of inflammatory biomarkers, but prospective evidence is limited regarding the association between inflammatory biomarkers and subsequent psychiatric disorders risk. 

To investigate further, the researchers employed a “triangulation” approach consisting of an exploration dataset of 585,279 adults in the Swedish AMORIS cohort with no prior psychiatric diagnoses and a measurement of at least one inflammatory biomarker, a validation dataset of 485,620 UK Biobank participants, and genetic and MR analyses using genome-wide association study summary statistics.

In the AMORIS cohort, individuals with a higher than median level of leukocytes (hazard ratio [HR], 1.11), haptoglobin (HR, 1.13), or CRP (HR, 1.02) had an elevated risk for any psychiatric disorder. In contrast, there was an inverse association for IgG level (HR, 0.92). 

“The estimates were comparable for depression, anxiety, and stress-related disorders, specifically, and these results were largely validated in the UK Biobank,” the authors reported. 

In trajectory analyses, compared with controls, individuals with psychiatric disorders had higher leukocyte and haptoglobin levels and lower IgG up to three decades before being diagnosed. 

The MR analysis suggested a possible causal relationship between leukocytes and depression. 

The underlying mechanisms for the associations of serum leukocytes, haptoglobin, CRP, and IgG with psychiatry disorders remain unclear.

“Possible explanations mainly include blood-brain barrier disruption, microglia activation, neurotransmission impairment, and other interactions between inflammations and neuropathology,” the researchers wrote. 

A related paper published online on August 21 in JAMA Psychiatry looked at trajectories of inflammation in childhood and risk for mental and cardiometabolic disorders in adulthood. 

This longitudinal cohort study found that having persistently raised levels of inflammation as measured by CRP throughout childhood and adolescence, peaking at age 9 years, were associated with an increased risk of developing psychosis disorder, severe depression, and higher levels of insulin resistance.
 

Support for Precision Psychiatry

This study is “another strong indication that inflammation plays a role in depression,” Andrew H. Miller, MD, professor of psychiatry and behavioral sciences and director of the behavioral immunology program, Emory University School of Medicine, Atlanta, Georgia, who wasn’t involved in the study, told this news organization. 

“The work adds to the mounting data that there exists an inflammatory phenotype of depression that may uniquely respond to treatment and may have a unique trajectory,” Dr. Miller said. 

“Eventually the field will want to embrace this novel phenotype and better understand how to recognize it and treat it. This is our entrée into precision psychiatry where we identify the right treatment for the right patient at the right time based on an understanding of the underlying cause of their illness,” Dr. Miller added. 

Also weighing in, Alexander B. Niculescu III, MD, PhD, professor of psychiatry and medical neuroscience, Indiana University School of Medicine, Indianapolis, cautioned that these biomarkers are “very nonspecific and are likely related to these subjects that go on to develop psychiatric disorders having more stressful, adverse life trajectories.”

“There are better, more specific blood biomarkers for psychiatric disorders already available,” Dr. Niculescu told this news organization.

His group recently reported that a panel of blood-based biomarkers can distinguish between depression and bipolar disorder, predict a person’s future risk for these disorders, and inform more tailored medication choices. 

Notably, they observed a strong circadian clock gene component to mood disorders, which helps explain why some patients’ conditions become worse with seasonal changes. It also explains the sleep alterations that occur among patients with mood disorders, they said.

This study had no commercial funding. Yu Zeng and Dr. Miller had no relevant disclosures. Dr. Niculescu is a cofounder of MindX Sciences and is listed as inventor on a patent application filed by Indiana University.
 

A version of this article first appeared on Medscape.com.

New research provides more evidence that inflammation may contribute to the development of psychiatric disorders and suggests that measuring certain inflammatory biomarkers may aid in the early identification of individuals at high risk.

Using large-scale datasets, researchers found that elevated levels of certain inflammatory biomarkers, particularly leukocytes, haptoglobin, and C-reactive protein (CRP), and lower levels of anti-inflammatory immunoglobulin G (IgG) were associated with an increased risk for psychiatric disorders. 

Individuals with psychiatric disorders had persistently higher levels of leukocytes and haptoglobin, as well as persistently lower levels of IgG, than controls during the 30 years before diagnosis, which suggest “long-term processes and may aid in the identification of individuals at high risk,” the researchers wrote. 

In addition, a higher level of leukocytes was consistently associated with increased odds of depression across different methods of Mendelian randomization (MR) analysis, “indicating a possible causal relationship between leukocytes and depression,” they said. 

The study, with first author Yu Zeng, MSc, with the Mental Health Center and West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China, was published online on August 21 in JAMA Psychiatry. 
 

Inflammatory Phenotype

Individuals with psychiatric disorders have been found to have elevated levels of inflammatory biomarkers, but prospective evidence is limited regarding the association between inflammatory biomarkers and subsequent psychiatric disorders risk. 

To investigate further, the researchers employed a “triangulation” approach consisting of an exploration dataset of 585,279 adults in the Swedish AMORIS cohort with no prior psychiatric diagnoses and a measurement of at least one inflammatory biomarker, a validation dataset of 485,620 UK Biobank participants, and genetic and MR analyses using genome-wide association study summary statistics.

In the AMORIS cohort, individuals with a higher than median level of leukocytes (hazard ratio [HR], 1.11), haptoglobin (HR, 1.13), or CRP (HR, 1.02) had an elevated risk for any psychiatric disorder. In contrast, there was an inverse association for IgG level (HR, 0.92). 

“The estimates were comparable for depression, anxiety, and stress-related disorders, specifically, and these results were largely validated in the UK Biobank,” the authors reported. 

In trajectory analyses, compared with controls, individuals with psychiatric disorders had higher leukocyte and haptoglobin levels and lower IgG up to three decades before being diagnosed. 

The MR analysis suggested a possible causal relationship between leukocytes and depression. 

The underlying mechanisms for the associations of serum leukocytes, haptoglobin, CRP, and IgG with psychiatry disorders remain unclear.

“Possible explanations mainly include blood-brain barrier disruption, microglia activation, neurotransmission impairment, and other interactions between inflammations and neuropathology,” the researchers wrote. 

A related paper published online on August 21 in JAMA Psychiatry looked at trajectories of inflammation in childhood and risk for mental and cardiometabolic disorders in adulthood. 

This longitudinal cohort study found that having persistently raised levels of inflammation as measured by CRP throughout childhood and adolescence, peaking at age 9 years, were associated with an increased risk of developing psychosis disorder, severe depression, and higher levels of insulin resistance.
 

Support for Precision Psychiatry

This study is “another strong indication that inflammation plays a role in depression,” Andrew H. Miller, MD, professor of psychiatry and behavioral sciences and director of the behavioral immunology program, Emory University School of Medicine, Atlanta, Georgia, who wasn’t involved in the study, told this news organization. 

“The work adds to the mounting data that there exists an inflammatory phenotype of depression that may uniquely respond to treatment and may have a unique trajectory,” Dr. Miller said. 

“Eventually the field will want to embrace this novel phenotype and better understand how to recognize it and treat it. This is our entrée into precision psychiatry where we identify the right treatment for the right patient at the right time based on an understanding of the underlying cause of their illness,” Dr. Miller added. 

Also weighing in, Alexander B. Niculescu III, MD, PhD, professor of psychiatry and medical neuroscience, Indiana University School of Medicine, Indianapolis, cautioned that these biomarkers are “very nonspecific and are likely related to these subjects that go on to develop psychiatric disorders having more stressful, adverse life trajectories.”

“There are better, more specific blood biomarkers for psychiatric disorders already available,” Dr. Niculescu told this news organization.

His group recently reported that a panel of blood-based biomarkers can distinguish between depression and bipolar disorder, predict a person’s future risk for these disorders, and inform more tailored medication choices. 

Notably, they observed a strong circadian clock gene component to mood disorders, which helps explain why some patients’ conditions become worse with seasonal changes. It also explains the sleep alterations that occur among patients with mood disorders, they said.

This study had no commercial funding. Yu Zeng and Dr. Miller had no relevant disclosures. Dr. Niculescu is a cofounder of MindX Sciences and is listed as inventor on a patent application filed by Indiana University.
 

A version of this article first appeared on Medscape.com.

Each year in the United States, approximately 1.7 million Americans are diagnosed with a potentially lethal malignancy. Typical therapies of choice include surgery, radiation, and occasionally, toxic chemotherapy (chemo) — approaches that eliminate the cancer in about 1,000,000 of these cases. The remaining 700,000 or so often proceed to chemotherapy either immediately or upon cancer recurrence, spread, or newly recognized metastases. “Cures” after that point are rare.

I’m speaking in generalities, understanding that each cancer and each patient is unique.
 

Chemotherapy

Chemotherapy alone can cure a small number of cancer types. When added to radiation or surgery, chemotherapy can help to cure a wider range of cancer types. As an add-on, chemotherapy can extend the length and quality of life for many patients with cancer. Since chemotherapy is by definition “toxic,” it can also shorten the duration or harm the quality of life and provide false hope. The Table summarizes what chemotherapy can and cannot achieve in selected cancer types.

• Lack of response (the tumor failed to shrink).
• Progression (the cancer may have grown or spread further).
• Adverse side effects were too severe to continue.

The drugs used in second-line chemo will typically be different from those used in first line, sometimes because cancer cells can develop resistance to chemotherapy drugs over time. Moreover, the goal of second-line chemo may differ from that of first-line therapy. Rather than chiefly aiming for a cure, second-line treatment might focus on slowing cancer growth, managing symptoms, or improving quality of life. Unfortunately, not every type of cancer has a readily available second-line option.

Third-line treatment. Third-line options come into play when both the initial course of chemo (first line) and the subsequent treatment (second line) have failed to achieve remission or control the cancer’s spread. Owing to the progressive nature of advanced cancers, patients might not be eligible or healthy enough for third-line therapy. Depending on cancer type, the patient’s general health, and response to previous treatments, third-line options could include:

• New or different chemotherapy drugs compared with prior lines.
• Surgery to debulk the tumor.
• Radiation for symptom control.
• Targeted therapy: drugs designed to target specific vulnerabilities in cancer cells.
• Immunotherapy: agents that help the body’s immune system fight cancer cells.
• Clinical trials testing new or investigational treatments, which may be applicable at any time, depending on the questions being addressed.

The goals of third-line therapy may shift from aiming for a cure to managing symptoms, improving quality of life, and potentially slowing cancer growth. The decision to pursue third-line therapy involves careful consideration by the doctor and patient, weighing the potential benefits and risks of treatment considering the individual’s overall health and specific situation.

It’s important to have realistic expectations about the potential outcomes of third-line therapy. Although remission may be unlikely, third-line therapy can still play a role in managing the disease.

Navigating advanced cancer treatment is very complex. The patient and physician must together consider detailed explanations and clarifications to set expectations and make informed decisions about care.
 

Interventions to Consider Earlier

In traditional clinical oncology practice, other interventions are possible, but these may not be offered until treatment has reached the third line:

• Molecular testing.
• Palliation.
• Clinical trials.
• Innovative testing to guide targeted therapy by ascertaining which agents are most likely (or not likely at all) to be effective.

I would argue that the patient’s interests are better served by considering and offering these other interventions much earlier, even before starting first-line chemotherapy.

Molecular testing. The best time for molecular testing of a new malignant tumor is typically at the time of diagnosis. Here’s why:

• Molecular testing helps identify specific genetic mutations in the cancer cells. This information can be crucial for selecting targeted therapies that are most effective against those specific mutations. Early detection allows for the most treatment options. For example, for non–small cell lung cancer, early is best because treatment and outcomes may well be changed by test results.
• Knowing the tumor’s molecular makeup can help determine whether a patient qualifies for clinical trials of new drugs designed for specific mutations.
• Some molecular markers can offer information about the tumor’s aggressiveness and potential for metastasis so that prognosis can be informed.

Molecular testing can be a valuable tool throughout a cancer patient’s journey. With genetically diverse tumors, the initial biopsy might not capture the full picture. Molecular testing of circulating tumor DNA can be used to monitor a patient’s response to treatment and detect potential mutations that might arise during treatment resistance. Retesting after metastasis can provide additional information that can aid in treatment decisions.

Palliative care. The ideal time to discuss palliative care with a patient with cancer is early in the diagnosis and treatment process. Palliative care is not the same as hospice care; it isn’t just about end-of-life. Palliative care focuses on improving a patient’s quality of life throughout cancer treatment. Palliative care specialists can address a wide range of symptoms a patient might experience from cancer or its treatment, including pain, fatigue, nausea, and anxiety.

Early discussions allow for a more comprehensive care plan. Open communication about all treatment options, including palliative care, empowers patients to make informed decisions about their care goals and preferences.

Specific situations where discussing palliative care might be appropriate are:

• Soon after a cancer diagnosis.
• If the patient experiences significant side effects from cancer treatment.
• When considering different treatment options, palliative care can complement those treatments.
• In advanced stages of cancer, to focus on comfort and quality of life.

Clinical trials. Participation in a clinical trial to explore new or investigational treatments should always be considered.

In theory, clinical trials should be an option at any time in the patient’s course. But the organized clinical trial experience may not be available or appropriate. Then, the individual becomes a de facto “clinical trial with an n of 1.” Read this brief open-access blog post at Cancer Commons to learn more about that circumstance.

Innovative testing. The best choice of chemotherapeutic or targeted therapies is often unclear. The clinician is likely to follow published guidelines, often from the National Comprehensive Cancer Network.

These are evidence based and driven by consensus of experts. But guideline-recommended therapy is not always effective, and weeks or months can pass before this ineffectiveness becomes apparent. Thus, many researchers and companies are seeking methods of testing each patient’s specific cancer to determine in advance, or very quickly, whether a particular drug is likely to be effective.

Read more about these leading innovations:

SAGE Oncotest: Entering the Next Generation of Tailored Cancer Treatment

Alibrex: A New Blood Test to Reveal Whether a Cancer Treatment is Working

PARIS Test Uses Lab-Grown Mini-Tumors to Find a Patient’s Best Treatment

Using Live Cells from Patients to Find the Right Cancer Drug

Other innovative therapies under investigation could even be agnostic to cancer type:

Treating Pancreatic Cancer: Could Metabolism — Not Genomics — Be the Key?

High-Energy Blue Light Powers a Promising New Treatment to Destroy Cancer Cells

All-Clear Follow-Up: Hydrogen Peroxide Appears to Treat Oral and Skin Lesions

Cancer is a tough nut to crack. Many people and organizations are trying very hard. So much is being learned. Some approaches will be effective. We can all hope.

Dr. Lundberg, editor in chief, Cancer Commons, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Each year in the United States, approximately 1.7 million Americans are diagnosed with a potentially lethal malignancy. Typical therapies of choice include surgery, radiation, and occasionally, toxic chemotherapy (chemo) — approaches that eliminate the cancer in about 1,000,000 of these cases. The remaining 700,000 or so often proceed to chemotherapy either immediately or upon cancer recurrence, spread, or newly recognized metastases. “Cures” after that point are rare.

I’m speaking in generalities, understanding that each cancer and each patient is unique.
 

Chemotherapy

Chemotherapy alone can cure a small number of cancer types. When added to radiation or surgery, chemotherapy can help to cure a wider range of cancer types. As an add-on, chemotherapy can extend the length and quality of life for many patients with cancer. Since chemotherapy is by definition “toxic,” it can also shorten the duration or harm the quality of life and provide false hope. The Table summarizes what chemotherapy can and cannot achieve in selected cancer types.

• Lack of response (the tumor failed to shrink).
• Progression (the cancer may have grown or spread further).
• Adverse side effects were too severe to continue.

The drugs used in second-line chemo will typically be different from those used in first line, sometimes because cancer cells can develop resistance to chemotherapy drugs over time. Moreover, the goal of second-line chemo may differ from that of first-line therapy. Rather than chiefly aiming for a cure, second-line treatment might focus on slowing cancer growth, managing symptoms, or improving quality of life. Unfortunately, not every type of cancer has a readily available second-line option.

Third-line treatment. Third-line options come into play when both the initial course of chemo (first line) and the subsequent treatment (second line) have failed to achieve remission or control the cancer’s spread. Owing to the progressive nature of advanced cancers, patients might not be eligible or healthy enough for third-line therapy. Depending on cancer type, the patient’s general health, and response to previous treatments, third-line options could include:

• New or different chemotherapy drugs compared with prior lines.
• Surgery to debulk the tumor.
• Radiation for symptom control.
• Targeted therapy: drugs designed to target specific vulnerabilities in cancer cells.
• Immunotherapy: agents that help the body’s immune system fight cancer cells.
• Clinical trials testing new or investigational treatments, which may be applicable at any time, depending on the questions being addressed.

The goals of third-line therapy may shift from aiming for a cure to managing symptoms, improving quality of life, and potentially slowing cancer growth. The decision to pursue third-line therapy involves careful consideration by the doctor and patient, weighing the potential benefits and risks of treatment considering the individual’s overall health and specific situation.

It’s important to have realistic expectations about the potential outcomes of third-line therapy. Although remission may be unlikely, third-line therapy can still play a role in managing the disease.

Navigating advanced cancer treatment is very complex. The patient and physician must together consider detailed explanations and clarifications to set expectations and make informed decisions about care.
 

Interventions to Consider Earlier

In traditional clinical oncology practice, other interventions are possible, but these may not be offered until treatment has reached the third line:

• Molecular testing.
• Palliation.
• Clinical trials.
• Innovative testing to guide targeted therapy by ascertaining which agents are most likely (or not likely at all) to be effective.

I would argue that the patient’s interests are better served by considering and offering these other interventions much earlier, even before starting first-line chemotherapy.

Molecular testing. The best time for molecular testing of a new malignant tumor is typically at the time of diagnosis. Here’s why:

• Molecular testing helps identify specific genetic mutations in the cancer cells. This information can be crucial for selecting targeted therapies that are most effective against those specific mutations. Early detection allows for the most treatment options. For example, for non–small cell lung cancer, early is best because treatment and outcomes may well be changed by test results.
• Knowing the tumor’s molecular makeup can help determine whether a patient qualifies for clinical trials of new drugs designed for specific mutations.
• Some molecular markers can offer information about the tumor’s aggressiveness and potential for metastasis so that prognosis can be informed.

Molecular testing can be a valuable tool throughout a cancer patient’s journey. With genetically diverse tumors, the initial biopsy might not capture the full picture. Molecular testing of circulating tumor DNA can be used to monitor a patient’s response to treatment and detect potential mutations that might arise during treatment resistance. Retesting after metastasis can provide additional information that can aid in treatment decisions.

Palliative care. The ideal time to discuss palliative care with a patient with cancer is early in the diagnosis and treatment process. Palliative care is not the same as hospice care; it isn’t just about end-of-life. Palliative care focuses on improving a patient’s quality of life throughout cancer treatment. Palliative care specialists can address a wide range of symptoms a patient might experience from cancer or its treatment, including pain, fatigue, nausea, and anxiety.

Early discussions allow for a more comprehensive care plan. Open communication about all treatment options, including palliative care, empowers patients to make informed decisions about their care goals and preferences.

Specific situations where discussing palliative care might be appropriate are:

• Soon after a cancer diagnosis.
• If the patient experiences significant side effects from cancer treatment.
• When considering different treatment options, palliative care can complement those treatments.
• In advanced stages of cancer, to focus on comfort and quality of life.

Clinical trials. Participation in a clinical trial to explore new or investigational treatments should always be considered.

In theory, clinical trials should be an option at any time in the patient’s course. But the organized clinical trial experience may not be available or appropriate. Then, the individual becomes a de facto “clinical trial with an n of 1.” Read this brief open-access blog post at Cancer Commons to learn more about that circumstance.

Innovative testing. The best choice of chemotherapeutic or targeted therapies is often unclear. The clinician is likely to follow published guidelines, often from the National Comprehensive Cancer Network.

These are evidence based and driven by consensus of experts. But guideline-recommended therapy is not always effective, and weeks or months can pass before this ineffectiveness becomes apparent. Thus, many researchers and companies are seeking methods of testing each patient’s specific cancer to determine in advance, or very quickly, whether a particular drug is likely to be effective.

Read more about these leading innovations:

SAGE Oncotest: Entering the Next Generation of Tailored Cancer Treatment

Alibrex: A New Blood Test to Reveal Whether a Cancer Treatment is Working

PARIS Test Uses Lab-Grown Mini-Tumors to Find a Patient’s Best Treatment

Using Live Cells from Patients to Find the Right Cancer Drug

Other innovative therapies under investigation could even be agnostic to cancer type:

Treating Pancreatic Cancer: Could Metabolism — Not Genomics — Be the Key?

High-Energy Blue Light Powers a Promising New Treatment to Destroy Cancer Cells

All-Clear Follow-Up: Hydrogen Peroxide Appears to Treat Oral and Skin Lesions

Cancer is a tough nut to crack. Many people and organizations are trying very hard. So much is being learned. Some approaches will be effective. We can all hope.

Dr. Lundberg, editor in chief, Cancer Commons, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Each year in the United States, approximately 1.7 million Americans are diagnosed with a potentially lethal malignancy. Typical therapies of choice include surgery, radiation, and occasionally, toxic chemotherapy (chemo) — approaches that eliminate the cancer in about 1,000,000 of these cases. The remaining 700,000 or so often proceed to chemotherapy either immediately or upon cancer recurrence, spread, or newly recognized metastases. “Cures” after that point are rare.

I’m speaking in generalities, understanding that each cancer and each patient is unique.
 

Chemotherapy

Chemotherapy alone can cure a small number of cancer types. When added to radiation or surgery, chemotherapy can help to cure a wider range of cancer types. As an add-on, chemotherapy can extend the length and quality of life for many patients with cancer. Since chemotherapy is by definition “toxic,” it can also shorten the duration or harm the quality of life and provide false hope. The Table summarizes what chemotherapy can and cannot achieve in selected cancer types.

• Lack of response (the tumor failed to shrink).
• Progression (the cancer may have grown or spread further).
• Adverse side effects were too severe to continue.

The drugs used in second-line chemo will typically be different from those used in first line, sometimes because cancer cells can develop resistance to chemotherapy drugs over time. Moreover, the goal of second-line chemo may differ from that of first-line therapy. Rather than chiefly aiming for a cure, second-line treatment might focus on slowing cancer growth, managing symptoms, or improving quality of life. Unfortunately, not every type of cancer has a readily available second-line option.

Third-line treatment. Third-line options come into play when both the initial course of chemo (first line) and the subsequent treatment (second line) have failed to achieve remission or control the cancer’s spread. Owing to the progressive nature of advanced cancers, patients might not be eligible or healthy enough for third-line therapy. Depending on cancer type, the patient’s general health, and response to previous treatments, third-line options could include:

• New or different chemotherapy drugs compared with prior lines.
• Surgery to debulk the tumor.
• Radiation for symptom control.
• Targeted therapy: drugs designed to target specific vulnerabilities in cancer cells.
• Immunotherapy: agents that help the body’s immune system fight cancer cells.
• Clinical trials testing new or investigational treatments, which may be applicable at any time, depending on the questions being addressed.

The goals of third-line therapy may shift from aiming for a cure to managing symptoms, improving quality of life, and potentially slowing cancer growth. The decision to pursue third-line therapy involves careful consideration by the doctor and patient, weighing the potential benefits and risks of treatment considering the individual’s overall health and specific situation.

It’s important to have realistic expectations about the potential outcomes of third-line therapy. Although remission may be unlikely, third-line therapy can still play a role in managing the disease.

Navigating advanced cancer treatment is very complex. The patient and physician must together consider detailed explanations and clarifications to set expectations and make informed decisions about care.
 

Interventions to Consider Earlier

In traditional clinical oncology practice, other interventions are possible, but these may not be offered until treatment has reached the third line:

• Molecular testing.
• Palliation.
• Clinical trials.
• Innovative testing to guide targeted therapy by ascertaining which agents are most likely (or not likely at all) to be effective.

I would argue that the patient’s interests are better served by considering and offering these other interventions much earlier, even before starting first-line chemotherapy.

Molecular testing. The best time for molecular testing of a new malignant tumor is typically at the time of diagnosis. Here’s why:

• Molecular testing helps identify specific genetic mutations in the cancer cells. This information can be crucial for selecting targeted therapies that are most effective against those specific mutations. Early detection allows for the most treatment options. For example, for non–small cell lung cancer, early is best because treatment and outcomes may well be changed by test results.
• Knowing the tumor’s molecular makeup can help determine whether a patient qualifies for clinical trials of new drugs designed for specific mutations.
• Some molecular markers can offer information about the tumor’s aggressiveness and potential for metastasis so that prognosis can be informed.

Molecular testing can be a valuable tool throughout a cancer patient’s journey. With genetically diverse tumors, the initial biopsy might not capture the full picture. Molecular testing of circulating tumor DNA can be used to monitor a patient’s response to treatment and detect potential mutations that might arise during treatment resistance. Retesting after metastasis can provide additional information that can aid in treatment decisions.

Palliative care. The ideal time to discuss palliative care with a patient with cancer is early in the diagnosis and treatment process. Palliative care is not the same as hospice care; it isn’t just about end-of-life. Palliative care focuses on improving a patient’s quality of life throughout cancer treatment. Palliative care specialists can address a wide range of symptoms a patient might experience from cancer or its treatment, including pain, fatigue, nausea, and anxiety.

Early discussions allow for a more comprehensive care plan. Open communication about all treatment options, including palliative care, empowers patients to make informed decisions about their care goals and preferences.

Specific situations where discussing palliative care might be appropriate are:

• Soon after a cancer diagnosis.
• If the patient experiences significant side effects from cancer treatment.
• When considering different treatment options, palliative care can complement those treatments.
• In advanced stages of cancer, to focus on comfort and quality of life.

Clinical trials. Participation in a clinical trial to explore new or investigational treatments should always be considered.

In theory, clinical trials should be an option at any time in the patient’s course. But the organized clinical trial experience may not be available or appropriate. Then, the individual becomes a de facto “clinical trial with an n of 1.” Read this brief open-access blog post at Cancer Commons to learn more about that circumstance.

Innovative testing. The best choice of chemotherapeutic or targeted therapies is often unclear. The clinician is likely to follow published guidelines, often from the National Comprehensive Cancer Network.

These are evidence based and driven by consensus of experts. But guideline-recommended therapy is not always effective, and weeks or months can pass before this ineffectiveness becomes apparent. Thus, many researchers and companies are seeking methods of testing each patient’s specific cancer to determine in advance, or very quickly, whether a particular drug is likely to be effective.

Read more about these leading innovations:

SAGE Oncotest: Entering the Next Generation of Tailored Cancer Treatment

Alibrex: A New Blood Test to Reveal Whether a Cancer Treatment is Working

PARIS Test Uses Lab-Grown Mini-Tumors to Find a Patient’s Best Treatment

Using Live Cells from Patients to Find the Right Cancer Drug

Other innovative therapies under investigation could even be agnostic to cancer type:

Treating Pancreatic Cancer: Could Metabolism — Not Genomics — Be the Key?

High-Energy Blue Light Powers a Promising New Treatment to Destroy Cancer Cells

All-Clear Follow-Up: Hydrogen Peroxide Appears to Treat Oral and Skin Lesions

Cancer is a tough nut to crack. Many people and organizations are trying very hard. So much is being learned. Some approaches will be effective. We can all hope.

Dr. Lundberg, editor in chief, Cancer Commons, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Childhood cancers represent a diverse group of neoplasms, and thanks to advances in treatment, survival rates have improved significantly. Today, more than 80%-85% of children diagnosed with cancer in developed countries survive into adulthood.

This increase in survival has brought new challenges, however. Compared with the general population, childhood cancer survivors (CCS) are at a notably higher risk for early mortality, developing secondary cancers, and experiencing various long-term clinical and psychosocial issues stemming from their disease or its treatment.

Long-term follow-up care for CCS is a complex and evolving field. Despite ongoing efforts to establish global and national guidelines, current evidence indicates that the care and management of these patients remain suboptimal.

Sexual dysfunction is a common and significant late effect among CCS. The disruptions caused by cancer and its treatment can interfere with normal physiological and psychological development, leading to issues with sexual function. This aspect of health is critical as it influences not just physical well-being but also psychosocial, developmental, and emotional health.
 

Characteristics and Mechanisms

Sexual functioning encompasses the physiological and psychological aspects of sexual behavior, including desire, arousal, orgasm, sexual pleasure, and overall satisfaction.

As CCS reach adolescence or adulthood, they often face sexual and reproductive issues, particularly as they enter romantic relationships.

Sexual functioning is a complex process that relies on the interaction of various factors, including physiological health, psychosexual development, romantic relationships, body image, and desire.

Despite its importance, the impact of childhood cancer on sexual function is often overlooked, even though cancer and its treatments can have lifelong effects. 
 

Sexual Function in CCS

A recent review aimed to summarize the existing research on sexual function among CCS, highlighting assessment tools, key stages of psychosexual development, common sexual problems, and the prevalence of sexual dysfunction.

The review study included 22 studies published between 2000 and 2022, comprising two qualitative, six cohort, and 14 cross-sectional studies.

Most CCS reached all key stages of psychosexual development at an average age of 29.8 years. Although some milestones were achieved later than is typical, many survivors felt they reached these stages at the appropriate time. Sexual initiation was less common among those who had undergone intensive neurotoxic treatments, such as those diagnosed with brain tumors or leukemia in childhood.

In a cross-sectional study of CCS aged 17-39 years, about one third had never engaged in sexual intercourse, 41.4% reported never experiencing sexual attraction, 44.8% were dissatisfied with their sex lives, and many rarely felt sexually attractive to others. Another study found that common issues among CCS included a lack of interest in sex (30%), difficulty enjoying sex (24%), and difficulty becoming aroused (23%). However, comparing and analyzing these problems was challenging due to the lack of standardized assessment criteria.

The prevalence of sexual dysfunction among CCS ranged from 12.3% to 46.5%. For males, the prevalence ranged from 12.3% to 54.0%, while for females, it ranged from 19.9% to 57.0%.
 

Factors Influencing Sexual Function

The review identified the following four categories of factors influencing sexual function in CCS: Demographic, treatment-related, psychological, and physiological.

Demographic factors: Gender, age, education level, relationship status, income level, and race all play roles in sexual function.

Female survivors reported more severe sexual dysfunction and poorer sexual health than did male survivors. Age at cancer diagnosis, age at evaluation, and the time since diagnosis were closely linked to sexual experiences. Patients diagnosed with cancer during childhood tended to report better sexual function than those diagnosed during adolescence.

Treatment-related factors: The type of cancer and intensity of treatment, along with surgical history, were significant factors. Surgeries involving the spinal cord or sympathetic nerves, as well as a history of prostate or pelvic surgery, were strongly associated with erectile dysfunction in men. In women, pelvic surgeries and treatments to the pelvic area were commonly linked to sexual dysfunction.

The association between treatment intensity and sexual function was noted across several studies, although the results were not always consistent. For example, testicular radiation above 10 Gy was positively correlated with sexual dysfunction. Women who underwent more intensive treatments were more likely to report issues in multiple areas of sexual function, while men in this group were less likely to have children.

Among female CCS, certain types of cancer, such as germ cell tumors, renal tumors, and leukemia, present a higher risk for sexual dysfunction. Women who had CNS tumors in childhood frequently reported problems like difficulty in sexual arousal, low sexual satisfaction, infrequent sexual activity, and fewer sexual partners, compared with survivors of other cancers. Survivors of acute lymphoblastic leukemia and those who underwent hematopoietic stem cell transplantation (HSCT) also showed varying degrees of impaired sexual function, compared with the general population. The HSCT group showed significant testicular damage, including reduced testicular volumes, low testosterone levels, and low sperm counts.

Psychological factors: These factors, such as emotional distress, play a significant role in sexual dysfunction among CCS. Symptoms like anxiety, nervousness during sexual activity, and depression are commonly reported by those with sexual dysfunction. The connection between body image and sexual function is complex. Many CCS with sexual dysfunction express concern about how others, particularly their partners, perceived their altered body image due to cancer and its treatment.

Physiological factors: In male CCS, low serum testosterone levels and low lean muscle mass are linked to an increased risk for sexual dysfunction. Treatments involving alkylating agents or testicular radiation, and surgery or radiotherapy targeting the genitourinary organs or the hypothalamic-pituitary region, can lead to various physiological and endocrine disorders, contributing to sexual dysfunction. Despite these risks, there is a lack of research evaluating sexual function through the lens of the hypothalamic-pituitary-gonadal axis and neuroendocrine pathways.
 

This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Childhood cancers represent a diverse group of neoplasms, and thanks to advances in treatment, survival rates have improved significantly. Today, more than 80%-85% of children diagnosed with cancer in developed countries survive into adulthood.

This increase in survival has brought new challenges, however. Compared with the general population, childhood cancer survivors (CCS) are at a notably higher risk for early mortality, developing secondary cancers, and experiencing various long-term clinical and psychosocial issues stemming from their disease or its treatment.

Long-term follow-up care for CCS is a complex and evolving field. Despite ongoing efforts to establish global and national guidelines, current evidence indicates that the care and management of these patients remain suboptimal.

Sexual dysfunction is a common and significant late effect among CCS. The disruptions caused by cancer and its treatment can interfere with normal physiological and psychological development, leading to issues with sexual function. This aspect of health is critical as it influences not just physical well-being but also psychosocial, developmental, and emotional health.
 

Characteristics and Mechanisms

Sexual functioning encompasses the physiological and psychological aspects of sexual behavior, including desire, arousal, orgasm, sexual pleasure, and overall satisfaction.

As CCS reach adolescence or adulthood, they often face sexual and reproductive issues, particularly as they enter romantic relationships.

Sexual functioning is a complex process that relies on the interaction of various factors, including physiological health, psychosexual development, romantic relationships, body image, and desire.

Despite its importance, the impact of childhood cancer on sexual function is often overlooked, even though cancer and its treatments can have lifelong effects. 
 

Sexual Function in CCS

A recent review aimed to summarize the existing research on sexual function among CCS, highlighting assessment tools, key stages of psychosexual development, common sexual problems, and the prevalence of sexual dysfunction.

The review study included 22 studies published between 2000 and 2022, comprising two qualitative, six cohort, and 14 cross-sectional studies.

Most CCS reached all key stages of psychosexual development at an average age of 29.8 years. Although some milestones were achieved later than is typical, many survivors felt they reached these stages at the appropriate time. Sexual initiation was less common among those who had undergone intensive neurotoxic treatments, such as those diagnosed with brain tumors or leukemia in childhood.

In a cross-sectional study of CCS aged 17-39 years, about one third had never engaged in sexual intercourse, 41.4% reported never experiencing sexual attraction, 44.8% were dissatisfied with their sex lives, and many rarely felt sexually attractive to others. Another study found that common issues among CCS included a lack of interest in sex (30%), difficulty enjoying sex (24%), and difficulty becoming aroused (23%). However, comparing and analyzing these problems was challenging due to the lack of standardized assessment criteria.

The prevalence of sexual dysfunction among CCS ranged from 12.3% to 46.5%. For males, the prevalence ranged from 12.3% to 54.0%, while for females, it ranged from 19.9% to 57.0%.
 

Factors Influencing Sexual Function

The review identified the following four categories of factors influencing sexual function in CCS: Demographic, treatment-related, psychological, and physiological.

Demographic factors: Gender, age, education level, relationship status, income level, and race all play roles in sexual function.

Female survivors reported more severe sexual dysfunction and poorer sexual health than did male survivors. Age at cancer diagnosis, age at evaluation, and the time since diagnosis were closely linked to sexual experiences. Patients diagnosed with cancer during childhood tended to report better sexual function than those diagnosed during adolescence.

Treatment-related factors: The type of cancer and intensity of treatment, along with surgical history, were significant factors. Surgeries involving the spinal cord or sympathetic nerves, as well as a history of prostate or pelvic surgery, were strongly associated with erectile dysfunction in men. In women, pelvic surgeries and treatments to the pelvic area were commonly linked to sexual dysfunction.

The association between treatment intensity and sexual function was noted across several studies, although the results were not always consistent. For example, testicular radiation above 10 Gy was positively correlated with sexual dysfunction. Women who underwent more intensive treatments were more likely to report issues in multiple areas of sexual function, while men in this group were less likely to have children.

Among female CCS, certain types of cancer, such as germ cell tumors, renal tumors, and leukemia, present a higher risk for sexual dysfunction. Women who had CNS tumors in childhood frequently reported problems like difficulty in sexual arousal, low sexual satisfaction, infrequent sexual activity, and fewer sexual partners, compared with survivors of other cancers. Survivors of acute lymphoblastic leukemia and those who underwent hematopoietic stem cell transplantation (HSCT) also showed varying degrees of impaired sexual function, compared with the general population. The HSCT group showed significant testicular damage, including reduced testicular volumes, low testosterone levels, and low sperm counts.

Psychological factors: These factors, such as emotional distress, play a significant role in sexual dysfunction among CCS. Symptoms like anxiety, nervousness during sexual activity, and depression are commonly reported by those with sexual dysfunction. The connection between body image and sexual function is complex. Many CCS with sexual dysfunction express concern about how others, particularly their partners, perceived their altered body image due to cancer and its treatment.

Physiological factors: In male CCS, low serum testosterone levels and low lean muscle mass are linked to an increased risk for sexual dysfunction. Treatments involving alkylating agents or testicular radiation, and surgery or radiotherapy targeting the genitourinary organs or the hypothalamic-pituitary region, can lead to various physiological and endocrine disorders, contributing to sexual dysfunction. Despite these risks, there is a lack of research evaluating sexual function through the lens of the hypothalamic-pituitary-gonadal axis and neuroendocrine pathways.
 

This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Childhood cancers represent a diverse group of neoplasms, and thanks to advances in treatment, survival rates have improved significantly. Today, more than 80%-85% of children diagnosed with cancer in developed countries survive into adulthood.

This increase in survival has brought new challenges, however. Compared with the general population, childhood cancer survivors (CCS) are at a notably higher risk for early mortality, developing secondary cancers, and experiencing various long-term clinical and psychosocial issues stemming from their disease or its treatment.

Long-term follow-up care for CCS is a complex and evolving field. Despite ongoing efforts to establish global and national guidelines, current evidence indicates that the care and management of these patients remain suboptimal.

Sexual dysfunction is a common and significant late effect among CCS. The disruptions caused by cancer and its treatment can interfere with normal physiological and psychological development, leading to issues with sexual function. This aspect of health is critical as it influences not just physical well-being but also psychosocial, developmental, and emotional health.
 

Characteristics and Mechanisms

Sexual functioning encompasses the physiological and psychological aspects of sexual behavior, including desire, arousal, orgasm, sexual pleasure, and overall satisfaction.

As CCS reach adolescence or adulthood, they often face sexual and reproductive issues, particularly as they enter romantic relationships.

Sexual functioning is a complex process that relies on the interaction of various factors, including physiological health, psychosexual development, romantic relationships, body image, and desire.

Despite its importance, the impact of childhood cancer on sexual function is often overlooked, even though cancer and its treatments can have lifelong effects. 
 

Sexual Function in CCS

A recent review aimed to summarize the existing research on sexual function among CCS, highlighting assessment tools, key stages of psychosexual development, common sexual problems, and the prevalence of sexual dysfunction.

The review study included 22 studies published between 2000 and 2022, comprising two qualitative, six cohort, and 14 cross-sectional studies.

Most CCS reached all key stages of psychosexual development at an average age of 29.8 years. Although some milestones were achieved later than is typical, many survivors felt they reached these stages at the appropriate time. Sexual initiation was less common among those who had undergone intensive neurotoxic treatments, such as those diagnosed with brain tumors or leukemia in childhood.

In a cross-sectional study of CCS aged 17-39 years, about one third had never engaged in sexual intercourse, 41.4% reported never experiencing sexual attraction, 44.8% were dissatisfied with their sex lives, and many rarely felt sexually attractive to others. Another study found that common issues among CCS included a lack of interest in sex (30%), difficulty enjoying sex (24%), and difficulty becoming aroused (23%). However, comparing and analyzing these problems was challenging due to the lack of standardized assessment criteria.

The prevalence of sexual dysfunction among CCS ranged from 12.3% to 46.5%. For males, the prevalence ranged from 12.3% to 54.0%, while for females, it ranged from 19.9% to 57.0%.
 

Factors Influencing Sexual Function

The review identified the following four categories of factors influencing sexual function in CCS: Demographic, treatment-related, psychological, and physiological.

Demographic factors: Gender, age, education level, relationship status, income level, and race all play roles in sexual function.

Female survivors reported more severe sexual dysfunction and poorer sexual health than did male survivors. Age at cancer diagnosis, age at evaluation, and the time since diagnosis were closely linked to sexual experiences. Patients diagnosed with cancer during childhood tended to report better sexual function than those diagnosed during adolescence.

Treatment-related factors: The type of cancer and intensity of treatment, along with surgical history, were significant factors. Surgeries involving the spinal cord or sympathetic nerves, as well as a history of prostate or pelvic surgery, were strongly associated with erectile dysfunction in men. In women, pelvic surgeries and treatments to the pelvic area were commonly linked to sexual dysfunction.

The association between treatment intensity and sexual function was noted across several studies, although the results were not always consistent. For example, testicular radiation above 10 Gy was positively correlated with sexual dysfunction. Women who underwent more intensive treatments were more likely to report issues in multiple areas of sexual function, while men in this group were less likely to have children.

Among female CCS, certain types of cancer, such as germ cell tumors, renal tumors, and leukemia, present a higher risk for sexual dysfunction. Women who had CNS tumors in childhood frequently reported problems like difficulty in sexual arousal, low sexual satisfaction, infrequent sexual activity, and fewer sexual partners, compared with survivors of other cancers. Survivors of acute lymphoblastic leukemia and those who underwent hematopoietic stem cell transplantation (HSCT) also showed varying degrees of impaired sexual function, compared with the general population. The HSCT group showed significant testicular damage, including reduced testicular volumes, low testosterone levels, and low sperm counts.

Psychological factors: These factors, such as emotional distress, play a significant role in sexual dysfunction among CCS. Symptoms like anxiety, nervousness during sexual activity, and depression are commonly reported by those with sexual dysfunction. The connection between body image and sexual function is complex. Many CCS with sexual dysfunction express concern about how others, particularly their partners, perceived their altered body image due to cancer and its treatment.

Physiological factors: In male CCS, low serum testosterone levels and low lean muscle mass are linked to an increased risk for sexual dysfunction. Treatments involving alkylating agents or testicular radiation, and surgery or radiotherapy targeting the genitourinary organs or the hypothalamic-pituitary region, can lead to various physiological and endocrine disorders, contributing to sexual dysfunction. Despite these risks, there is a lack of research evaluating sexual function through the lens of the hypothalamic-pituitary-gonadal axis and neuroendocrine pathways.
 

This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Systemic amyloidosis is a rare and complex disease characterized by the extracellular deposition of misfolded proteins, known as amyloid fibrils, in various tissues and organs. This heterogeneous disorder can present with a wide range of clinical manifestations, including dermatological symptoms that may be the first or predominant feature. Systemic amyloidosis is characterized by macroglossia, periorbital purpura, and waxy skin plaques. Lateral scalloping of the tongue may be seen due to impingement of the teeth. Cutaneous amyloidosis occurs when amyloid is deposited in the skin, without internal organ involvement. Variants of cutaneous amyloidosis include macular, lichen, nodular and biphasic.

This condition requires a thorough diagnostic workup, including serum and urine protein electrophoresis and biopsy of the affected tissue. Biopsy of a cutaneous amyloidosis lesion will show fractured, amorphous, eosinophilic material in the dermis. Pigment and epidermal changes are often found with cutaneous amyloidosis, including hyperkeratosis, acanthosis, hypergranulosis, parakeratosis, and epidermal atrophy. Stains that may be used include Congo red showing apple-green birefringence, thioflavin T, and crystal violet.

If untreated, the prognosis is generally poor, related to the extent of organ involvement. Cardiac involvement, a common feature of systemic amyloidosis, can lead to restrictive cardiomyopathy, heart failure, and arrhythmias. Management strategies include steroids, chemotherapy, and stem cell transplantation. Medications include dexamethasone, cyclophosphamide, bortezomib, and melphalan.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Florida. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

1. Brunt EM, Tiniakos DG. Clin Liver Dis. 2004 Nov;8(4):915-30, x. doi: 10.1016/j.cld.2004.06.009.

2. Bolognia JL et al. (2017). Dermatology E-Book. Elsevier Health Sciences.

3. Mehrotra K et al. J Clin Diagn Res. 2017 Aug;11(8):WC01-WC05. doi: 10.7860/JCDR/2017/24273.10334.

4. Banypersad SM et al. J Am Heart Assoc. 2012 Apr;1(2):e000364. doi: 10.1161/JAHA.111.000364.

5. Bustamante JG, Zaidi SRH. Amyloidosis. [Updated 2023 Jul 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

Systemic amyloidosis is a rare and complex disease characterized by the extracellular deposition of misfolded proteins, known as amyloid fibrils, in various tissues and organs. This heterogeneous disorder can present with a wide range of clinical manifestations, including dermatological symptoms that may be the first or predominant feature. Systemic amyloidosis is characterized by macroglossia, periorbital purpura, and waxy skin plaques. Lateral scalloping of the tongue may be seen due to impingement of the teeth. Cutaneous amyloidosis occurs when amyloid is deposited in the skin, without internal organ involvement. Variants of cutaneous amyloidosis include macular, lichen, nodular and biphasic.

This condition requires a thorough diagnostic workup, including serum and urine protein electrophoresis and biopsy of the affected tissue. Biopsy of a cutaneous amyloidosis lesion will show fractured, amorphous, eosinophilic material in the dermis. Pigment and epidermal changes are often found with cutaneous amyloidosis, including hyperkeratosis, acanthosis, hypergranulosis, parakeratosis, and epidermal atrophy. Stains that may be used include Congo red showing apple-green birefringence, thioflavin T, and crystal violet.

If untreated, the prognosis is generally poor, related to the extent of organ involvement. Cardiac involvement, a common feature of systemic amyloidosis, can lead to restrictive cardiomyopathy, heart failure, and arrhythmias. Management strategies include steroids, chemotherapy, and stem cell transplantation. Medications include dexamethasone, cyclophosphamide, bortezomib, and melphalan.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Florida. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

1. Brunt EM, Tiniakos DG. Clin Liver Dis. 2004 Nov;8(4):915-30, x. doi: 10.1016/j.cld.2004.06.009.

2. Bolognia JL et al. (2017). Dermatology E-Book. Elsevier Health Sciences.

3. Mehrotra K et al. J Clin Diagn Res. 2017 Aug;11(8):WC01-WC05. doi: 10.7860/JCDR/2017/24273.10334.

4. Banypersad SM et al. J Am Heart Assoc. 2012 Apr;1(2):e000364. doi: 10.1161/JAHA.111.000364.

5. Bustamante JG, Zaidi SRH. Amyloidosis. [Updated 2023 Jul 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

Systemic amyloidosis is a rare and complex disease characterized by the extracellular deposition of misfolded proteins, known as amyloid fibrils, in various tissues and organs. This heterogeneous disorder can present with a wide range of clinical manifestations, including dermatological symptoms that may be the first or predominant feature. Systemic amyloidosis is characterized by macroglossia, periorbital purpura, and waxy skin plaques. Lateral scalloping of the tongue may be seen due to impingement of the teeth. Cutaneous amyloidosis occurs when amyloid is deposited in the skin, without internal organ involvement. Variants of cutaneous amyloidosis include macular, lichen, nodular and biphasic.

This condition requires a thorough diagnostic workup, including serum and urine protein electrophoresis and biopsy of the affected tissue. Biopsy of a cutaneous amyloidosis lesion will show fractured, amorphous, eosinophilic material in the dermis. Pigment and epidermal changes are often found with cutaneous amyloidosis, including hyperkeratosis, acanthosis, hypergranulosis, parakeratosis, and epidermal atrophy. Stains that may be used include Congo red showing apple-green birefringence, thioflavin T, and crystal violet.

If untreated, the prognosis is generally poor, related to the extent of organ involvement. Cardiac involvement, a common feature of systemic amyloidosis, can lead to restrictive cardiomyopathy, heart failure, and arrhythmias. Management strategies include steroids, chemotherapy, and stem cell transplantation. Medications include dexamethasone, cyclophosphamide, bortezomib, and melphalan.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Florida. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

1. Brunt EM, Tiniakos DG. Clin Liver Dis. 2004 Nov;8(4):915-30, x. doi: 10.1016/j.cld.2004.06.009.

2. Bolognia JL et al. (2017). Dermatology E-Book. Elsevier Health Sciences.

3. Mehrotra K et al. J Clin Diagn Res. 2017 Aug;11(8):WC01-WC05. doi: 10.7860/JCDR/2017/24273.10334.

4. Banypersad SM et al. J Am Heart Assoc. 2012 Apr;1(2):e000364. doi: 10.1161/JAHA.111.000364.

5. Bustamante JG, Zaidi SRH. Amyloidosis. [Updated 2023 Jul 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

WASHINGTON, DC — Cutaneous immune-related adverse events (cirAEs) in oncology patients receiving immune checkpoint inhibitors (ICIs) should be treated in as targeted a fashion as possible and with judicious usage and dosing of prednisone when deemed necessary, Blair Allais, MD, said during a session on supportive oncodermatology at the ElderDerm conference on dermatology in the older patient hosted by the George Washington University School of Medicine and Health Sciences, Washington, DC.

“It’s important when you see these patients to be as specific as possible” based on morphology and histopathology, and to treat the rashes in a similar way as in the non-ICI setting,” said Dr. Allais, a dermato-oncologist at the Inova Schar Cancer Institute, Fairfax, Virginia.

cirAEs are the most frequently reported and most visible adverse effects of checkpoint inhibition — a treatment that has emerged as a standard therapy for many malignancies since the first ICI was approved in 2011 for metastatic melanoma.

And contrary to what the phenomenon of immunosenescence might suggest, older patients are no less prone to cirAEs than younger patients. “You’d think you’d have fewer rashes and side effects as you age, but that’s not true,” said Dr. Allais, who completed a fellowship in cutaneous oncology after her dermatology residency.

A 2021 multicenter international cohort study of over 900 patients aged ≥ 80 years treated with single-agent ICIs for cancer did not find any significant differences in the development of immune-related adverse events among those younger than 85, those aged 85-89 years, and those 90 and older. Neither did the ELDERS study in the United Kingdom; this prospective observational study found similar rates of high-grade and low-grade immune toxicity in its two cohorts of patients ≥ 70 and < 70 years of age.

At the meeting, Dr. Allais, who coauthored a 2023 review of cirAEs from ICIs, reviewed recent developments and provided the following advice:
 

New diagnostic criteria: “Really exciting” news for more precise diagnosis and optimal therapy of cirAEs, Dr. Allais said, is a position paper published in the Journal for ImmunoTherapy of Cancer that offers consensus-based diagnostic criteria for the 10 most common types of dermatologic immune-related adverse events and an overall diagnostic framework. “Luckily, through the work of a Delphi consensus group, we can now have [more diagnostic specificity],” which is important for both clinical care and research, she said.

Most cirAEs have typically been reported nonspecifically as “rash,” but diagnosing a rash subtype is “critical in tailoring appropriate therapy that it is both effective and the least detrimental to the oncology treatment plan for patients with cancer,” the group’s coauthors wrote.

The 10 core diagnoses include psoriasis, eczematous dermatitis, vitiligo, Grover disease, eruptive atypical squamous proliferation, and bullous pemphigoid. Outside of the core diagnoses are other nonspecific presentations that require evaluation to arrive at a diagnosis, if possible, or to reveal data that can allow for targeted therapy and severity grading, the group explains in its paper.

“To prednisone or not to prednisone”: The development of cirAEs is associated with reduced mortality and improved cancer outcomes, making the use of immunosuppressants such as corticosteroids a therapeutic dilemma. “Patients who get these rashes usually do better with respect to their cancer, so the concern has been, if we affect how they respond to their immunotherapy, we may minimize that improvement in mortality,” said Dr. Allais, also assistant professor at the University of Virginia, Charlottesville, and clinical assistant professor of dermatology at George Washington University.

A widely discussed study published in 2015 reported on 254 patients with melanoma who developed an immune-related adverse event during treatment with ipilimumab — approximately one third of whom required systemic corticosteroids — and concluded that systemic corticosteroids did not affect overall survival or time to (cancer) treatment failure. This study from Memorial Sloan Kettering Cancer Center, New York City, “was the first large study looking at this question,” she said, and the subsequent message for several years in conferences and the literature was that steroids do not affect the efficacy of checkpoint inhibitors.

“But the study was not without limitations,” Dr. Allais said, “because the patients who got prednisone were mainly those with higher-grade toxicities,” while those not treated with corticosteroids had either no toxicities or low-grade toxicities. “If higher-grade toxicities were associated with better (antitumor) response, the steroids may have just [blunted] that benefit.”

The current totality of data available in the literature suggests that corticosteroids may indeed have an impact on the efficacy of ICI therapy. “Subsequent studies have come out in the community that have shown that we should probably think twice about giving prednisone to some patients, particularly within the first 50 days of ICI treatment, and that we should be mindful of the dose,” Dr. Allais said.

The takeaways from these studies — all published in the past few years — are to use prednisone early and liberally for life-threatening toxicity, to use it at the lowest dose and for the shortest course when there is not an appropriate alternative, to avoid it for diagnoses that are not treated with prednisone outside the ICI setting, and to “have a plan” for a steroid-sparing agent to use after prednisone, she said.

Dr. Allais recommends heightened consideration during the first 50 days of ICI treatment based on a multicenter retrospective study that found a significant association between use of high-dose glucocorticoids (≥ 60 mg prednisone equivalent once a day) within 8 weeks of anti–programmed cell death protein 1 (PD-1) monotherapy initiation and poorer progression-free and overall survival. The study covered a cohort of 947 patients with advanced melanoma treated with anti–PD-1 monotherapy between 2009 and 2019, 54% of whom developed immune-related adverse events.

This study and other recent studies addressing the association between steroids and survival outcomes in patients with immune-related adverse events during ICI therapy are described in Dr. Allais’ 2023 review of cirAEs from ICIs.

Approach to morbilliform eruptions: This rash is “super common” in patients on ICIs, occurring generally within 2-3 weeks of starting treatment. “It tends to be self-limited and can recur with future infusions,” Dr. Allais said.

Systemic steroids should be reserved for severe or refractory eruptions. “Usually, I treat the patients with topical steroids, and I manage their expectations (that the rash may recur with subsequent infusions), but I closely follow them up” within 2-3 weeks, she said. It’s important to rule out a severe cutaneous adverse drug eruption, of course, and to start high-dose systemic steroids immediately if necessary. “Antibiotics are a big culprit” and often can be discontinued.

Soak and smear: “I’m obsessed” with this technique of a 20-minute soak in plain water followed by application of steroid ointment, said Dr. Allais, referring to a small study published in 2005 that reported a complete response after 2 weeks in 60% of patients with psoriasis, atopic dermatitis, and other inflammatory skin conditions (none had cancer), who had failed prior systemic therapy. All patients had at least a 75% response.

The method offers a way to “avoid the systemic immunosuppression we’d get with prednisone,” she said. One just needs to make sure the older patient can get in and out of their tub safely.

ICI-induced bullous pemphigoid (BP): BP occurs more frequently in the ICI setting, compared with the general population, with a median time to development of 8.5 months after ICI initiation. It is associated in this setting with improved tumor response, but “many oncologists stop anticancer treatment because of this diagnosis,” she said.

In the supportive oncodermatology space, however, ICI-induced BP exemplifies the value of tailored treatment regimens, she said. A small multi-institutional retrospective cohort study published in 2023 identified 35 cases of ICI-BP among 5636 ICI-treated patients and found that 8 out of 11 patients who received biologic therapy (rituximab, omalizumab, or dupilumab) had a complete response to ICI-BP without flares following subsequent ICI cycles. And while statistical significance was not reached, the study showed that no cancer-related outcomes were worsened.

“If you see someone with ICI-induced BP and they have a lot of involvement, you could start them on steroids and get that steroid-sparing agent initiated for approval. ... And if IgE is elevated, you might reach for omalizumab,” said Dr. Allais, noting that her favored treatment overall is dupilumab.

Risk factors for the development of ICI-induced BP include age > 70, skin cancer, and having an initial response to ICI on first imaging, the latter of which “I find fascinating ... because imaging occurs within the first 12 weeks of treatment, but we don’t see BP popping up until 8.5 months into treatment,” she noted. “So maybe there’s a baseline risk factor that could predispose them.”

Caution with antibiotics: “I try to avoid antibiotics in the ICI setting,” Dr. Allais said, in deference to the “ever-important microbiome.” Studies have demonstrated that the microbiomes of responders to ICI treatment are different from those of nonresponders, she said.

And a “fascinating” study of patients with melanoma undergoing ICI therapy showed not only a higher abundance of Ruminococcaceae bacteria in responders vs nonresponders but a significant impact of dietary fiber. High dietary fiber was associated with significantly improved overall survival in the patients on ICI, with the most pronounced benefit in patients with good fiber intake and no probiotic use. “Even wilder, their T cells changed,” she said. “They had a high expression of genes related to T-cell activation ... so more tumor-infiltrating lymphocytes.”

A retrospective study of 568 patients with stages III and IV melanoma treated with ICI showed that those exposed to antibiotics prior to ICI had significantly worse overall survival than those not exposed to antibiotics. “Think before you give them,” Dr. Allais said. “And try to tell your older patients to eat beans and greens.”

Dr. Allais reported having no relevant disclosures.

A version of this article first appeared on Medscape.com.

WASHINGTON, DC — Cutaneous immune-related adverse events (cirAEs) in oncology patients receiving immune checkpoint inhibitors (ICIs) should be treated in as targeted a fashion as possible and with judicious usage and dosing of prednisone when deemed necessary, Blair Allais, MD, said during a session on supportive oncodermatology at the ElderDerm conference on dermatology in the older patient hosted by the George Washington University School of Medicine and Health Sciences, Washington, DC.

“It’s important when you see these patients to be as specific as possible” based on morphology and histopathology, and to treat the rashes in a similar way as in the non-ICI setting,” said Dr. Allais, a dermato-oncologist at the Inova Schar Cancer Institute, Fairfax, Virginia.

cirAEs are the most frequently reported and most visible adverse effects of checkpoint inhibition — a treatment that has emerged as a standard therapy for many malignancies since the first ICI was approved in 2011 for metastatic melanoma.

And contrary to what the phenomenon of immunosenescence might suggest, older patients are no less prone to cirAEs than younger patients. “You’d think you’d have fewer rashes and side effects as you age, but that’s not true,” said Dr. Allais, who completed a fellowship in cutaneous oncology after her dermatology residency.

A 2021 multicenter international cohort study of over 900 patients aged ≥ 80 years treated with single-agent ICIs for cancer did not find any significant differences in the development of immune-related adverse events among those younger than 85, those aged 85-89 years, and those 90 and older. Neither did the ELDERS study in the United Kingdom; this prospective observational study found similar rates of high-grade and low-grade immune toxicity in its two cohorts of patients ≥ 70 and < 70 years of age.

At the meeting, Dr. Allais, who coauthored a 2023 review of cirAEs from ICIs, reviewed recent developments and provided the following advice:
 

New diagnostic criteria: “Really exciting” news for more precise diagnosis and optimal therapy of cirAEs, Dr. Allais said, is a position paper published in the Journal for ImmunoTherapy of Cancer that offers consensus-based diagnostic criteria for the 10 most common types of dermatologic immune-related adverse events and an overall diagnostic framework. “Luckily, through the work of a Delphi consensus group, we can now have [more diagnostic specificity],” which is important for both clinical care and research, she said.

Most cirAEs have typically been reported nonspecifically as “rash,” but diagnosing a rash subtype is “critical in tailoring appropriate therapy that it is both effective and the least detrimental to the oncology treatment plan for patients with cancer,” the group’s coauthors wrote.

The 10 core diagnoses include psoriasis, eczematous dermatitis, vitiligo, Grover disease, eruptive atypical squamous proliferation, and bullous pemphigoid. Outside of the core diagnoses are other nonspecific presentations that require evaluation to arrive at a diagnosis, if possible, or to reveal data that can allow for targeted therapy and severity grading, the group explains in its paper.

“To prednisone or not to prednisone”: The development of cirAEs is associated with reduced mortality and improved cancer outcomes, making the use of immunosuppressants such as corticosteroids a therapeutic dilemma. “Patients who get these rashes usually do better with respect to their cancer, so the concern has been, if we affect how they respond to their immunotherapy, we may minimize that improvement in mortality,” said Dr. Allais, also assistant professor at the University of Virginia, Charlottesville, and clinical assistant professor of dermatology at George Washington University.

A widely discussed study published in 2015 reported on 254 patients with melanoma who developed an immune-related adverse event during treatment with ipilimumab — approximately one third of whom required systemic corticosteroids — and concluded that systemic corticosteroids did not affect overall survival or time to (cancer) treatment failure. This study from Memorial Sloan Kettering Cancer Center, New York City, “was the first large study looking at this question,” she said, and the subsequent message for several years in conferences and the literature was that steroids do not affect the efficacy of checkpoint inhibitors.

“But the study was not without limitations,” Dr. Allais said, “because the patients who got prednisone were mainly those with higher-grade toxicities,” while those not treated with corticosteroids had either no toxicities or low-grade toxicities. “If higher-grade toxicities were associated with better (antitumor) response, the steroids may have just [blunted] that benefit.”

The current totality of data available in the literature suggests that corticosteroids may indeed have an impact on the efficacy of ICI therapy. “Subsequent studies have come out in the community that have shown that we should probably think twice about giving prednisone to some patients, particularly within the first 50 days of ICI treatment, and that we should be mindful of the dose,” Dr. Allais said.

The takeaways from these studies — all published in the past few years — are to use prednisone early and liberally for life-threatening toxicity, to use it at the lowest dose and for the shortest course when there is not an appropriate alternative, to avoid it for diagnoses that are not treated with prednisone outside the ICI setting, and to “have a plan” for a steroid-sparing agent to use after prednisone, she said.

Dr. Allais recommends heightened consideration during the first 50 days of ICI treatment based on a multicenter retrospective study that found a significant association between use of high-dose glucocorticoids (≥ 60 mg prednisone equivalent once a day) within 8 weeks of anti–programmed cell death protein 1 (PD-1) monotherapy initiation and poorer progression-free and overall survival. The study covered a cohort of 947 patients with advanced melanoma treated with anti–PD-1 monotherapy between 2009 and 2019, 54% of whom developed immune-related adverse events.

This study and other recent studies addressing the association between steroids and survival outcomes in patients with immune-related adverse events during ICI therapy are described in Dr. Allais’ 2023 review of cirAEs from ICIs.

Approach to morbilliform eruptions: This rash is “super common” in patients on ICIs, occurring generally within 2-3 weeks of starting treatment. “It tends to be self-limited and can recur with future infusions,” Dr. Allais said.

Systemic steroids should be reserved for severe or refractory eruptions. “Usually, I treat the patients with topical steroids, and I manage their expectations (that the rash may recur with subsequent infusions), but I closely follow them up” within 2-3 weeks, she said. It’s important to rule out a severe cutaneous adverse drug eruption, of course, and to start high-dose systemic steroids immediately if necessary. “Antibiotics are a big culprit” and often can be discontinued.

Soak and smear: “I’m obsessed” with this technique of a 20-minute soak in plain water followed by application of steroid ointment, said Dr. Allais, referring to a small study published in 2005 that reported a complete response after 2 weeks in 60% of patients with psoriasis, atopic dermatitis, and other inflammatory skin conditions (none had cancer), who had failed prior systemic therapy. All patients had at least a 75% response.

The method offers a way to “avoid the systemic immunosuppression we’d get with prednisone,” she said. One just needs to make sure the older patient can get in and out of their tub safely.

ICI-induced bullous pemphigoid (BP): BP occurs more frequently in the ICI setting, compared with the general population, with a median time to development of 8.5 months after ICI initiation. It is associated in this setting with improved tumor response, but “many oncologists stop anticancer treatment because of this diagnosis,” she said.

In the supportive oncodermatology space, however, ICI-induced BP exemplifies the value of tailored treatment regimens, she said. A small multi-institutional retrospective cohort study published in 2023 identified 35 cases of ICI-BP among 5636 ICI-treated patients and found that 8 out of 11 patients who received biologic therapy (rituximab, omalizumab, or dupilumab) had a complete response to ICI-BP without flares following subsequent ICI cycles. And while statistical significance was not reached, the study showed that no cancer-related outcomes were worsened.

“If you see someone with ICI-induced BP and they have a lot of involvement, you could start them on steroids and get that steroid-sparing agent initiated for approval. ... And if IgE is elevated, you might reach for omalizumab,” said Dr. Allais, noting that her favored treatment overall is dupilumab.

Risk factors for the development of ICI-induced BP include age > 70, skin cancer, and having an initial response to ICI on first imaging, the latter of which “I find fascinating ... because imaging occurs within the first 12 weeks of treatment, but we don’t see BP popping up until 8.5 months into treatment,” she noted. “So maybe there’s a baseline risk factor that could predispose them.”

Caution with antibiotics: “I try to avoid antibiotics in the ICI setting,” Dr. Allais said, in deference to the “ever-important microbiome.” Studies have demonstrated that the microbiomes of responders to ICI treatment are different from those of nonresponders, she said.

And a “fascinating” study of patients with melanoma undergoing ICI therapy showed not only a higher abundance of Ruminococcaceae bacteria in responders vs nonresponders but a significant impact of dietary fiber. High dietary fiber was associated with significantly improved overall survival in the patients on ICI, with the most pronounced benefit in patients with good fiber intake and no probiotic use. “Even wilder, their T cells changed,” she said. “They had a high expression of genes related to T-cell activation ... so more tumor-infiltrating lymphocytes.”

A retrospective study of 568 patients with stages III and IV melanoma treated with ICI showed that those exposed to antibiotics prior to ICI had significantly worse overall survival than those not exposed to antibiotics. “Think before you give them,” Dr. Allais said. “And try to tell your older patients to eat beans and greens.”

Dr. Allais reported having no relevant disclosures.

A version of this article first appeared on Medscape.com.

WASHINGTON, DC — Cutaneous immune-related adverse events (cirAEs) in oncology patients receiving immune checkpoint inhibitors (ICIs) should be treated in as targeted a fashion as possible and with judicious usage and dosing of prednisone when deemed necessary, Blair Allais, MD, said during a session on supportive oncodermatology at the ElderDerm conference on dermatology in the older patient hosted by the George Washington University School of Medicine and Health Sciences, Washington, DC.

“It’s important when you see these patients to be as specific as possible” based on morphology and histopathology, and to treat the rashes in a similar way as in the non-ICI setting,” said Dr. Allais, a dermato-oncologist at the Inova Schar Cancer Institute, Fairfax, Virginia.

cirAEs are the most frequently reported and most visible adverse effects of checkpoint inhibition — a treatment that has emerged as a standard therapy for many malignancies since the first ICI was approved in 2011 for metastatic melanoma.

And contrary to what the phenomenon of immunosenescence might suggest, older patients are no less prone to cirAEs than younger patients. “You’d think you’d have fewer rashes and side effects as you age, but that’s not true,” said Dr. Allais, who completed a fellowship in cutaneous oncology after her dermatology residency.

A 2021 multicenter international cohort study of over 900 patients aged ≥ 80 years treated with single-agent ICIs for cancer did not find any significant differences in the development of immune-related adverse events among those younger than 85, those aged 85-89 years, and those 90 and older. Neither did the ELDERS study in the United Kingdom; this prospective observational study found similar rates of high-grade and low-grade immune toxicity in its two cohorts of patients ≥ 70 and < 70 years of age.

At the meeting, Dr. Allais, who coauthored a 2023 review of cirAEs from ICIs, reviewed recent developments and provided the following advice:
 

New diagnostic criteria: “Really exciting” news for more precise diagnosis and optimal therapy of cirAEs, Dr. Allais said, is a position paper published in the Journal for ImmunoTherapy of Cancer that offers consensus-based diagnostic criteria for the 10 most common types of dermatologic immune-related adverse events and an overall diagnostic framework. “Luckily, through the work of a Delphi consensus group, we can now have [more diagnostic specificity],” which is important for both clinical care and research, she said.

Most cirAEs have typically been reported nonspecifically as “rash,” but diagnosing a rash subtype is “critical in tailoring appropriate therapy that it is both effective and the least detrimental to the oncology treatment plan for patients with cancer,” the group’s coauthors wrote.

The 10 core diagnoses include psoriasis, eczematous dermatitis, vitiligo, Grover disease, eruptive atypical squamous proliferation, and bullous pemphigoid. Outside of the core diagnoses are other nonspecific presentations that require evaluation to arrive at a diagnosis, if possible, or to reveal data that can allow for targeted therapy and severity grading, the group explains in its paper.

“To prednisone or not to prednisone”: The development of cirAEs is associated with reduced mortality and improved cancer outcomes, making the use of immunosuppressants such as corticosteroids a therapeutic dilemma. “Patients who get these rashes usually do better with respect to their cancer, so the concern has been, if we affect how they respond to their immunotherapy, we may minimize that improvement in mortality,” said Dr. Allais, also assistant professor at the University of Virginia, Charlottesville, and clinical assistant professor of dermatology at George Washington University.

A widely discussed study published in 2015 reported on 254 patients with melanoma who developed an immune-related adverse event during treatment with ipilimumab — approximately one third of whom required systemic corticosteroids — and concluded that systemic corticosteroids did not affect overall survival or time to (cancer) treatment failure. This study from Memorial Sloan Kettering Cancer Center, New York City, “was the first large study looking at this question,” she said, and the subsequent message for several years in conferences and the literature was that steroids do not affect the efficacy of checkpoint inhibitors.

“But the study was not without limitations,” Dr. Allais said, “because the patients who got prednisone were mainly those with higher-grade toxicities,” while those not treated with corticosteroids had either no toxicities or low-grade toxicities. “If higher-grade toxicities were associated with better (antitumor) response, the steroids may have just [blunted] that benefit.”

The current totality of data available in the literature suggests that corticosteroids may indeed have an impact on the efficacy of ICI therapy. “Subsequent studies have come out in the community that have shown that we should probably think twice about giving prednisone to some patients, particularly within the first 50 days of ICI treatment, and that we should be mindful of the dose,” Dr. Allais said.

The takeaways from these studies — all published in the past few years — are to use prednisone early and liberally for life-threatening toxicity, to use it at the lowest dose and for the shortest course when there is not an appropriate alternative, to avoid it for diagnoses that are not treated with prednisone outside the ICI setting, and to “have a plan” for a steroid-sparing agent to use after prednisone, she said.

Dr. Allais recommends heightened consideration during the first 50 days of ICI treatment based on a multicenter retrospective study that found a significant association between use of high-dose glucocorticoids (≥ 60 mg prednisone equivalent once a day) within 8 weeks of anti–programmed cell death protein 1 (PD-1) monotherapy initiation and poorer progression-free and overall survival. The study covered a cohort of 947 patients with advanced melanoma treated with anti–PD-1 monotherapy between 2009 and 2019, 54% of whom developed immune-related adverse events.

This study and other recent studies addressing the association between steroids and survival outcomes in patients with immune-related adverse events during ICI therapy are described in Dr. Allais’ 2023 review of cirAEs from ICIs.

Approach to morbilliform eruptions: This rash is “super common” in patients on ICIs, occurring generally within 2-3 weeks of starting treatment. “It tends to be self-limited and can recur with future infusions,” Dr. Allais said.

Systemic steroids should be reserved for severe or refractory eruptions. “Usually, I treat the patients with topical steroids, and I manage their expectations (that the rash may recur with subsequent infusions), but I closely follow them up” within 2-3 weeks, she said. It’s important to rule out a severe cutaneous adverse drug eruption, of course, and to start high-dose systemic steroids immediately if necessary. “Antibiotics are a big culprit” and often can be discontinued.

Soak and smear: “I’m obsessed” with this technique of a 20-minute soak in plain water followed by application of steroid ointment, said Dr. Allais, referring to a small study published in 2005 that reported a complete response after 2 weeks in 60% of patients with psoriasis, atopic dermatitis, and other inflammatory skin conditions (none had cancer), who had failed prior systemic therapy. All patients had at least a 75% response.

The method offers a way to “avoid the systemic immunosuppression we’d get with prednisone,” she said. One just needs to make sure the older patient can get in and out of their tub safely.

ICI-induced bullous pemphigoid (BP): BP occurs more frequently in the ICI setting, compared with the general population, with a median time to development of 8.5 months after ICI initiation. It is associated in this setting with improved tumor response, but “many oncologists stop anticancer treatment because of this diagnosis,” she said.

In the supportive oncodermatology space, however, ICI-induced BP exemplifies the value of tailored treatment regimens, she said. A small multi-institutional retrospective cohort study published in 2023 identified 35 cases of ICI-BP among 5636 ICI-treated patients and found that 8 out of 11 patients who received biologic therapy (rituximab, omalizumab, or dupilumab) had a complete response to ICI-BP without flares following subsequent ICI cycles. And while statistical significance was not reached, the study showed that no cancer-related outcomes were worsened.

“If you see someone with ICI-induced BP and they have a lot of involvement, you could start them on steroids and get that steroid-sparing agent initiated for approval. ... And if IgE is elevated, you might reach for omalizumab,” said Dr. Allais, noting that her favored treatment overall is dupilumab.

Risk factors for the development of ICI-induced BP include age > 70, skin cancer, and having an initial response to ICI on first imaging, the latter of which “I find fascinating ... because imaging occurs within the first 12 weeks of treatment, but we don’t see BP popping up until 8.5 months into treatment,” she noted. “So maybe there’s a baseline risk factor that could predispose them.”

Caution with antibiotics: “I try to avoid antibiotics in the ICI setting,” Dr. Allais said, in deference to the “ever-important microbiome.” Studies have demonstrated that the microbiomes of responders to ICI treatment are different from those of nonresponders, she said.

And a “fascinating” study of patients with melanoma undergoing ICI therapy showed not only a higher abundance of Ruminococcaceae bacteria in responders vs nonresponders but a significant impact of dietary fiber. High dietary fiber was associated with significantly improved overall survival in the patients on ICI, with the most pronounced benefit in patients with good fiber intake and no probiotic use. “Even wilder, their T cells changed,” she said. “They had a high expression of genes related to T-cell activation ... so more tumor-infiltrating lymphocytes.”

A retrospective study of 568 patients with stages III and IV melanoma treated with ICI showed that those exposed to antibiotics prior to ICI had significantly worse overall survival than those not exposed to antibiotics. “Think before you give them,” Dr. Allais said. “And try to tell your older patients to eat beans and greens.”

Dr. Allais reported having no relevant disclosures.

A version of this article first appeared on Medscape.com.