It has been an impressive year in the field of dermatology. This annual article highlights some of the advances, discoveries, and recommendations in 2017.
Psoriasis
Cardiovascular Event Risk Assessment in Psoriasis Patients Treated With TNF-α Inhibitors vs Methotrexate
A recent study in the Journal of the American Academy of Dermatology sought to determine whether treatment of psoriasis with biologics vs methotrexate would lead to a decreased risk of cardiovascular (CV) events in patients on biologic therapy.1 Through a retrospective study using the Truven MarketScan databases from 2000 to 2011, the authors included adult psoriasis patients who were prescribed either a tumor necrosis factor-α (TNF-α) inhibitor or methotrexate. To determine major CV events, ICD-9 codes associated with myocardial infarction (MI), strokes, or transient ischemic attacks (TIA) recorded for an insurance inpatient stay claim were used. Over the observation period, the risk of CV events was statistically significantly decreased in all 3 metrics (MI, TIA, and stroke) for those taking TNF-α inhibitor compared with methotrexate, and the adjusted hazard ratio for all CV events was 0.55 (P<.0001). Furthermore, with cumulative exposure to TNF-α inhibitor, an 11% reduction in CV events was observed every 6 months in patients treated with TNF-α (P=.020). The results of this study demonstrate that strong control of psoriatic disease can have a more profound impact on these patients’ morbidity than originally thought; however, the retrospective nature of the study makes it difficult to draw definitive conclusions.
Malignancy Rates in a Large Cohort of Patients With Systemically Treated Psoriasis in a Managed Care Population
While treating psoriasis with systemic medications can lead to an overall improvement in CV disease, these medications also pose certain risks due to their immunosuppressive nature, which can potentially predispose them to an increased risk of malignancy, infection, or reactivation of latent infections. In a retrospective observation study by Asgari and colleagues, the authors sought to determine the overall risk of malignancy including nonmelanoma skin cancer in psoriasis patients treated with systemic immunosuppressants.2 They utilized the Kaiser Permanente Northern California health delivery system along with a cancer registry and a pathology database to investigate the rate of malignancy in psoriasis patients treated with both biologics (more than 97% of whom were treated with TNF-α inhibitors) and nonbiologic systemic medications such as methotrexate.
Although there was no statistically significant difference in overall nonmelanoma skin cancer associated malignancy, patients exposed to biologics had a statistically significant 80% increased risk of cutaneous squamous cell carcinoma (SCC), and a 42% increased risk of overall nonmelanoma skin cancer when adjusted for the confounding variables of age, gender, race, and comorbidity. Though there was a slight increased risk for basal cell carcinoma (BCC) in the biologic group, the results were not statistically significant. It is important to note that there was a higher percentage of biologic patients who were exposed to phototherapy compared with the nonbiologic group (22% vs 17%, P<.01), though the specific type or duration was not specified.
Adalimumab Is a Safe Option for Patients With Psoriasis and Concomitant HBV or HCV
Due to the concerns of immunosuppression, TNF-α medications have been used with extreme caution in patients infected with either hepatitis B virus (HBV) or hepatitis C virus (HCV). The underlying concern is that blocking TNF-α would lead to reactivation of patients with chronic HBV or HCV. Piaserico and colleagues sought to determine the validity of these concerns in a prospective observation study of 37 patients with psoriasis and concomitant HBV or HCV treated with adalimumab (Humira).3 In this study, the authors monitored these patients’ viral load as well as their liver fibrosis scores. Not only did they not note any incidences of reactivation of HBV or HCV over a follow-up period of 40 months, but patients with HCV infections had lower liver fibrosis scores at the end of the study.
Brodalumab Approved to Treat Adults With Moderate to Severe Plaque Psoriasis
Brodalumab (Siliq), an anti-interleukin (IL)-17 biologic, was FDA approved in February 2017 for treatment of adults with moderate to severe plaque psoriasis. Brodalumab had a tenuous journey toward FDA approval as there were a total of 3 completed suicides during clinical trials in patients treated with the medication. Although experts have casted doubts as to whether the medication played a role in the suicide completions,4 FDA approval was granted with the following contingencies: placement of a black box warning and restricted drug availability under a Risk Evaluation and Mitigation Strategy (REMS) Program.
Risankizumab vs Ustekinumab for Moderate to Severe Plaque Psoriasis
A recent head-to-head phase 2 clinical trial comparing risankizumab, an IL-23 inhibitor, and ustekinumab (Stelara), an IL-12/IL-23 inhibitor, showed promising results for risankizumab.5 In this study, a total of 166 patients received either risankizumab (18 mg, 90 mg, or 180 mg at weeks 0, 4, and 16) or ustekinumab at weeks 0, 4, and 16 (45 mg or 90 mg depending on weight). The patients were randomized 3:1 to rizankizumab (in the 3 aforementioned dosages) or ustekinumab. The study’s primary endpoint was achievement of Psoriasis Area and Severity Index (PASI) reduction of 90% from baseline.
For the pooled 90- and 180-mg group treated with risankizumab, PASI 90 was 77% at week 16 vs 40% in the ustekinumab group (P<.001). In addition, the onset of improvement was quicker and the durability of response following discontinuation was longer with risankizumab as decreases in PASI scores were maintained for 20 weeks vs 8 weeks with ustekinumab. Skin biopsy samples in the risankizumab group showed overall superior improvement and downregulation of certain genes associated with the IL-23 pathway, and psoriatic disease process were observed only in the risankizumab group. While this study demonstrates the efficacy of risankizumab, further studies, with larger sample sizes and placebo groups, are needed.
Guselkumab Shows Benefit in Psoriasis Patients With Inadequate Response to Ustekinumab
A similar head-to-head study compared guselkumab (Tremfya), another IL-23 inhibitor, to ustekinumab in a phase 3, randomized, double-blinded clinical trial.6 All patients in the study were initially treated with ustekinumab (weight-based dose of either 45 mg or 90 mg at weeks 0 and 4), and after 16 weeks patients with an inadequate response to ustekinumab determined by an Investigator’s Global Assessment (IGA) score of 2 or more were randomized to guselkumab or to continue ustekinumab through 40 to 44 weeks, respectively. The primary endpoint was an IGA of 0 or 1 and a total decrease in IGA of 2 or more from week 28 to week 40 (compared to week 16). Patients were followed for a maximum of 4 visits over that period.
The mean number of visits at which patients achieved IGA of 0 or 1 and at least a 2-point improvement from week 28 to week 40 was significantly higher in guselkumab group compared with the ustekinumab group (1.5 vs 0.7; P<.001). Furthermore, the mean number of visits during that same time for patients who had achieved PASI 90 was also significantly higher in the guselkumab group (2.2 vs 1.1; P<.001). At week 28, the proportion of patients with an IGA score of 0 or 1 compared to week 16 was 31.1% for the guselkumab group and 14.3% for the ustekinumab group (P=.001).
Acne and Rosacea
Isotretinoin Treatment for Acne and Relation to Depression
Isotretinoin has long been associated with depression, suicidal ideation, and suicide, with the FDA releasing a warning regarding these associations in 1998. Huang and Cheng performed at systematic review and meta-analysis of the literature from inception to September 30, 2016 to evaluate the relationship between isotretinoin and depression.7 Thirty-one studies met inclusion criteria, including acne treated with isotretinoin, at least 15 patients, and depression data (prevalence or depression scores). The meta-analysis showed there was no increased risk of depression in patients treated with isotretinoin for acne, and there was an improvement in depression scores following treatment of acne with isotretinoin.7 Acne alone may be associated with depression;8 therefore, clinicians should consider depression in all acne patients, regardless of treatment.
Rosacea, Demodex, and Ivermectin
Although a common disease, the complete pathophysiology of rosacea has not been elucidated, particularly given the different clinical variants (erythematotelangiectatic, papulopustular, phymatous, and ocular). It has been suggested that Demodex mites may play a role in the pathogenesis of the papulopustular variant. A meta-analysis by Chang and Huang was performed to further evaluate the association of Demodex mites in both papulopustular and erythematotelangiectatic rosacea.9 Inclusion criteria for articles included English publications from inception to November 16, 2016, case-controlled studies with at least 15 patients, and prevalence, count, and density of Demodex mites in both affected and control patients. Twenty-three studies were included, with a total of 1513 patients. Patients with rosacea had a significantly higher prevalence (odds ratio [OR], 9.039; 95% CI, 4.827-16.925) and density (standard mean difference [SMD] 1.617; CI 1.090-2.145) of Demodex mites compared with the control group. Demodex density was higher in both erythrotelangiectatic and papulopustular rosacea than control groups and density in papulopustular variant was higher than erythrotelangiectatic variant, although not statistically significant.9
Given high prevalence and density of Demodex mites in patients with rosacea,9 antiparasitic agents have been employed in the treatment. A small retrospective case series investigated oral or topical ivermectin (Soolantra) for treatment of papulopustular rosacea (n=8) and periorificial dermatitis (n=7) in children.10 Patients were treated with a single dose of oral ivermectin, 200 to 250 g/kg (6 children with papulopustular rosacea and 3 with perioral dermatitis) or topical 1% ivermectin daily for 3 months (2 children with papulopustular rosacea and 4 with perioral dermatitis). Treatment choice was based on severity of condition. Fourteen of 15 patients achieved complete or almost complete clearance based on IGA. One child treated with oral ivermectin did not improve. Mild transient desquamation of the affected skin, occurring in 3 patients treated systemically and 2 treated topically, was noted as the only adverse effect. Topical ivermectin 1% is FDA approved only for treatment of rosacea in adults and oral ivermectin is licensed just for filariasis in the pediatric group.
Expert Consensus on Acne Fulminans
Acne fulminans is a variant of acne that has remained poorly defined and understood. To address this issue, 12 experts reviewed the literature and convened to further define, discuss treatment options, and recommend further areas of research for acne fulminans.11 Terminology used to describe acne fulminans and related variants are: acne fulminans with systemic symptoms (AF-SS), acne fulminans without systemic symptoms (AF-WOSS), isotretinoin-induced acne fulminans with systemic symptoms (IIAF-SS), and isotretinoin-induced acne fulminans without systemic symptoms (IIAF-WOSS). Consistent throughout all types is the characteristic inflammatory papules often with erosions, crust, and ulcers. Systemic symptoms that may be present in AF-SS and IIAF-WOSS include constitutional symptoms (fever and malaise), arthralgias, and bone pain (potentially related to osteolytic bone lesions). Isotretinoin, and rarely testosterone and anabolic steroids, are a known trigger for acne fulminans when started in patients with severe acne, necessitating the separate terminology for the drug-induced form of acne fulminans. The pathogenesis behind acne fulminans and isotretinoin as causing acne fulminans remains unknown with several theories suggested. Unfortunately, large, randomized controlled trials have not been performed evaluating treatment options for acne fulminans. Based on case reports and series, systemic corticosteroids combined with low-dose isotretinoin is the recommended treatment.
Greywal and colleagues recommend starting prednisone monotherapy at 0.5 to 1 mg/kg/day for at least 4 weeks for AF-SS and 2 weeks for AF-WOSS and continued until crusted lesions heal. Then low-dose isotretinoin (0.1 mg/kg/day) may be added. Corticosteroids and isotretinoin should overlap for at least 4 weeks, then corticosteroids can slowly be tapered as isotretinoin is slowly increased. Many patients with acne fulminans will require a prolonged course and may require a higher cumulative dose than the typical 120 to 150 mg/kg for isotretinoin. To minimize the risk of IIAF in patients with severe inflammatory acne, overlapping prednisone for several weeks with low-dose isotretinoin or starting prednisone monotherapy for 2 weeks prior to starting isotretinoin should be considered.11
Atopic Dermatitis
Atopic Dermatitis Associated With Several Autoimmune Skin Conditions
Atopic dermatitis (AD) has previously been linked with several autoimmune skin conditions including inflammatory bowel disease, rheumatoid arthritis (RA), and type 1 diabetes. A recent Danish study looked at 8112 adults diagnosed with AD between 1997 and 2012 and compared them to 40,560 age- and sex-matched controls.12 They found AD to be significantly associated with alopecia areata (AA), vitiligo, chronic urticaria, celiac disease, chronic glomerulonephritis, Sjögren syndrome, systemic lupus erythematosus, ankylosing spondylitis, Crohn disease, ulcerative colitis, and RA. No significant associations were found between AD, autoimmune thyroid diseases, multiple sclerosis, type 1 diabetes, autoimmune hematologic disease, or pulmonary fibrosis.12
Nemolizumab: Emerging Biologic for Pruritus in AD Patients
Pruritus plays a significant role in perpetuating AD and has a profound impact on quality of life. IL-31 is believed to play a role in pruritus in AD through an uncertain mechanism.13 In a phase 2, 12-week clinical trial, 216 patients with uncontrolled pruritus and AD were randomly assigned to receive subcutaneous nemolizumab, a fully human monoclonal antibody against IL-31, or placebo. The dosing was 0.1 mg/kg, 0.5 mg/kg, or 2.0 mg/kg body weight every 4 weeks for subcutaneous nemolizumab. A significant improvement in pruritus was seen in all dosing groups for nemolizumab. The most common side effects were worsening of AD and peripheral edema.13
Safety of Crisaborole 2% Ointment for Children and Adults With AD
Topical steroids and calcineurin inhibitors have been the mainstay topical treatments for children and adults with AD. No new topical agents had been approved for 15 years until crisaborole (Eucrisa) in 2016. A recent phase 3 clinical trial looked at the long-term safety of crisaborole ointment in 517 patients aged 2 years and older with AD over 48 weeks.14 The most common side effects were upper respiratory tract infection (10.3%), flaring of AD (11.2%), nasopharyngitis (97.7%), cough (6.8%), and pyrexia (5.6%). Most adverse effects were mild (51.2%) to moderate (44.6%) and did not require discontinuation of the product. Based on these findings, crisaborole is a safe, long-term treatment for AD in children and adults.14
Infectious Disease
Topical Timolol for Classic and HIV-Related Kaposi Sarcoma
While previous case series have demonstrated the efficacy of topical timolol 0.05% for classical and HIV-related Kaposi sarcoma, a recent case series suggests lower doses of topical timolol may be just as successful.15 Four patients with localized, cutaneous Kaposi sarcoma were successfully treated with topical timolol 0.01% gel twice daily until resolution. The average treatment duration until complete resolution was 4 to 6 weeks. No adverse effects related to the topical timolol were reported. One patient terminated treatment at week 6 after being hospitalized with an active tuberculosis. These findings support the use lower dose timolol for classical and HIV-related Kaposi sarcoma.15
Pneumocystis Pneumonia Prophylaxis in Patients With Bullous Dermatosis on Long- term Immunosuppression
Patients with autoimmune blistering disease (AIBD) generally require treatment with long-term immunosuppression. As a result, they are at an increased risk for opportunistic infection. Pneumocystis pneumonia (PCP) rates among dermatologic patients on immunosuppression vary from 0.5% to 2%.16 Experts have differing opinions as to whether these patients need PCP prophylaxis. In general, PCP incidence of 3.5% is recommended before starting prophylaxis. A retrospective study of patients with AIBD was conducted at 6 tertiary referral centers for AIBD in Germany, Netherlands, Italy, and Singapore.16 Among the 801 patients with AIBD identified, only one (0.1%) developed PCP in the 3-year follow- up period. This patient, however, was 40 years old and had recalcitrant mucocutaneous pemphigus vulgaris requiring high-dose oral prednisolone in combination with rituximab. Further analysis of only patients with pemphigus vulgaris showed that 1 of 411 patients (0.02%) had PCP. Based on the findings in this large retrospective study, PCP prophylaxis is not indicated in patients with AIBD on systemic immunosuppresants.16
Improving Diagnostic Accuracy for Lower Extremity Cellulitis
Reported misdiagnosis rates for lower extremity cellulitis range from 30% to 90%.17 Common mimickers include venous stasis dermatitis, lymphedema, deep venous thrombosis, gout, and contact dermatitis. A recent cross-sectional study of 259 patients admitted to a large urban hospital between June 2010 and December 2012 found that 30% of patients admitted with a diagnosis of lower extremity cellulitis were misdiagnosed.17 Among the 79 misdiagnosed patients, 52 of 79 (66%) were admitted for inpatient treatment of cellulitis, and 42 of the 52 (85%) did not need admission based on their final diagnosis.
Based on these findings, the study authors developed a risk prediction model for diagnosing lower extremity cellulitis called ALT-70.18 ALT-70 includes 4 variables: unilateral leg involvement, heart rate 90 beats per minute, white blood cell count 10,000, and age 70. Three points were assigned to asymmetric leg involvement, 2 points for age 70, and 1 point for white cell count 10,000 and heart rate 90. Empiric treatment for cellulitis was recommended if patients had 5 or more points. A dermatology consultation was advised for patients with 3 to 4 points. Reassessment was recommended for patients with 2 or fewer points.
Using the cohort of patients from the original study, patients with ALT-70 score of 3 or lower had 83% likelihood of having pseudocellulitis while those with a score above 4 had an 82% likelihood of having true cellulitis. Interestingly, an increased risk of cellulitis among patients with a history of cellulitis, tinea pedis, lymphedema, venous insufficiency, dermatitis, and malignancy was not found. This scoring system is the first step to providing clinicians with a tool to aid in the diagnosis of lower extremity cellulitis.18
Autoimmune and Systemic Disease
Potential Future Treatment for Keratin Disorders
Topical broccoli sprout extract (BSE) is being studied as a potential treatment for disorders of keratinization.19 Sulforaphane, an isothiocyante and key ingredient in BSE, has been shown to increase expression of healing keratins 16 and 17 in mice. A recent study looked at whether these effects are seen in humans.19 Five healthy individuals were recruited to apply topical BSE to the inner aspect of 1 arm and vehicle only to the other arm daily for 1 week.19 Both BSE and vehicle treated skin sites were biopsied after 1 week. While 1 patient had to be excluded for poor tissue quality, the remaining 4 patients showed 3.6 higher levels of keratin-17 messenger RNA (P=.0022). Indirect immunofluorescence also showed increased induction of keratin-17 in BSE-treated skin. Keratin-16 expression was increased 10 to 14 times in the 2 female individuals and 4 times in 1 male individual. There was no difference in keratin-16 expression in the other male individual. Indirect immunofluorescence showed elevated keratin-16 in the suprabasal layer of BSE-treated skin in 3 patients. No statistical difference was found in keratin 5, 6, and 15 RNA expression levels. Further studies are needed including patients with epidermolysis bullosa simplex to determine whether topical BSE is a potential treatment option.19
Treatment of Cutaneous Manifestations of Tuberous Sclerosis With Topical Sirolimus
Cutaneous manifestations of tuberous sclerosis include angiofibromas, shagreen patches, hypomelanotic macules, and periungual fibromas. Since 2010, several studies have been published on the efficacy of topical sirolimus for treating facial angiofibromas, but none on other cutaneous manifestations.20 In a recent study on topical sirolimus for facial angiofibromas, cephalic plaques, shagreen patches, hypomelanotic macules, and periungual fibromas, 25 patients used topical sirolimus daily and were followed for 18 months.20 Half of the patients had clinical clearance of their facial angiofibromas after 9 months of treatment. Among 7 of the 12 patients who agreed to use a maintenance regimen of 3 times weekly application, 6 had recurrence of facial angiofibromas within 2 months. No significant response was seen with topical tacrolimus for fibrous cephalic plaques, shagreen patches, hypomelanotic patches, and periungual fibromas. No series adverse effects were seen over 18 months. There was mild aggravation of facial acne in 3 patients, aseptic folliculitis at the site of application in 1 patient, and mild irritation in 8 patients. Topical sirolimus is an effective and safe treatment for angiofibromas but must be used regularly to maintain clearance. It is not effective for other cutaneous manifestations of tuberous sclerosis.20
Cyclosporine May Provide Mortality Benefit in SJS
To date, the role of corticosteroids, intravenous immunoglobulin, cyclosporine, and other immunomodulators in the treatment of Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) remains unclear. Lee and colleagues evaluated the effect of cyclosporine for SJS/TEN patients at a large academic hospital by comparing SCORTEN predicted mortality to actual mortality.21 Twenty-four patients were randomized to receive cyclosporine 3 mg/kg for 10 days, 10 mg/kg for the next 10 days, and then 1 mg/kg/day for 10 days. Twenty patients received only supportive care. Patients who received cyclosporine were younger (50 years of age; P=.009) and had a lower incidence of cardiac disease (P=.035). There was no difference in terms of disease classification, SCORTEN scores on admission, or maximum body surface area.
In the cyclosporine group, SCORTEN predicted 7.2 deaths, and 3 actual deaths occurred. In the supportive care only group, SCORTEN predicted 5.9 deaths, and 6 deaths occurred. Among the 19 patients who only received cyclosporine and no other immunomodulatory therapies (intravenous immunoglobulin or systemic steroids), 2 deaths were observed while 5.3 were predicted. Nine patients did have to stop cyclosporine during the study due to worsening renal function. This study is the first trial to show survival benefit with the use of cyclosporine in SJS/TEN.21
Bullous Pemphigoid and Malignancy
The association with bullous pemphigoid (BP) and malignancy is controversial. While some studies have demonstrated an association, others have not. A recent systemic review of all studies on BP and malignancy found an association between BP and hematologic malignancies, including Hodgkin lymphoma, non-Hodgkin lymphoma, mature natural killer/T-cell lymphoma, myeloid leukemia, and leukemia unspecified.22 Hematological malignancy preceded the diagnosis of BP in half of the patients. There were no other malignancies with significant associations with BP. These findings are limited due to the retrospective and observational nature of all available studies on BP and malignancy. It is important to ensure all newly diagnosed patients with BP are up-to-date on age-appropriate cancer screening, but further investigational workup is not recommended.22
Vitiligo
Repigmentation With Phototherapy
Treatment options for vitiligo include phototherapy such as psoralen–UV-A (PUVA) and narrowband UV-B, laser therapy, and various topical agents. Phototherapy, a popular treatment option, has varying rates for repigmentation and duration of treatment. A database review examined all prospective trials on phototherapy for vitiligo.23 Regimentation with narrowband UV-B was mild (>25% repigmentation) in 75% of 512 patients and marked (>75% response) in 35.7% of 540 patients. The face and neck responded best with 44% of 153 patients showing a marked repigmentation response. No repigmentation was seen on the hands and feet in 172 patients. PUVA phototherapy had lower rates of repigmentation with mild response in 61.6% of 72 patients at 12 months and marked response in 13.6% of 72 patients. Based on these findings, 1 year is needed to see the maximal response from phototherapy for vitiligo lesions.23
Oral Simvastatin and Vitiligo
Vitiligo is thought to be a Th1-cell-mediated autoimmune disease with high levels of interferon (IFN)-γ and chemokines CXCL0 and CXCL10 promoting depigmentation. In mouse models, simvastatin has been shown to inhibit the activation of STAT1, which prevents IFN-γ induced signaling of CXCL10. Repigmentation in a patient with vitiligo on simvastatin has been described in the literature. A recent double-blind, placebo-controlled, phase 2 clinical trial failed to show repigmentation in any of the patients.24 Fifteen patients with vitiligo were randomly assigned to simvastatin 40 mg daily for 1 month followed by 90 mg daily for another 5 months or placebo. All other treatments were discontinued prior to the study with washout periods. Worsening of vitiligo was seen in 26% of patients in the oral simvastatin group (P=.094), and no effect was seen on serum levels of CXCL10. These results do not support the use of oral simvastatin in the treatment of vitiligo.24
Janus Kinase Inhibitors for Treating Vitiligo
Janus kinase (JAK) inhibitors, specifically JAK 1/2, have been shown to inhibit IFN-γ signaling and are potential treatments for vitiligo. Two studies on JAK inhibitors for vitiligo have been recently published. In a phase 2 clinical trial, 11 patients with vitiligo used topical ruxolitinib 1.5% cream (Jakafi), a JAK 1/2 inhibitor, twice daily for more than 20 weeks.25 Application of topical ruxolitinib was restricted to 10% body surface area or 3.75 g of topical ruxolitinib per exposure. Based on Vitiligo Area Scoring Index scores, four of 11 patients with facial vitiligo experienced 75% improvement at week 20 (P=.001). Repigmentation was minor and not significant at other body sites. Erythema at the application site occurred in 8 of 11 patients and was the most common adverse effect. Two patients experienced a transient, mild papular eruption on the face that resolved. No laboratory monitoring was performed during this study.25
Ten patients with vitiligo took oral tofacitinib (Xeljanz), a JAK 1/3 inhibitor, for an average of 10 months in another study.26 Baseline laboratory analysis was obtained. Patients received either 5 to 10 mg oral tofacitinib daily or twice daily. While 5 of 10 patients did experience repigmentation, repigmentation occurred only in sun-exposed areas in 3 of the 5 patients. The other 2 patients with repigmentation were also being treated concurrently with narrowband UV-B. Of the five patients with no repigmentation, only 1 reported sun exposure while the remaining 4 practiced sun avoidance. Four patients had mild elevated lipid levels. Two patients experienced an upper respiratory tract infection. JAK inhibitors may require light exposure to achieve repigmentation based on data from both of these studies.25,26
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Hair
Systemic Tofacitinib as a Treatment for Alopecia Areata and its Variants
Use of tofacitinib as a treatment for AA and its variants was discussed in last year’s Year in Review article27; however, further data regarding safety and efficacy in a variety of age groups and use of topical formulations have been added to the literature this year. Multiple single-site, retrospective studies have been performed evaluating tofacitinib in the treatment of AA and its variants.28,29
The study by Ibrahim and colleagues evaluated 13 adult patients (7 had alopecia universalis (AU), 2 had alopecia totalis (AT), and 4 had AA treated with tofacitinib. Mean pretreatment scalp hair loss was 93%. Patients were treated with tofacitinib 5 mg twice a day, monotherapy, with other treatments for AA ceased prior to initiation of tofacitinib. The tofacitinib was increased by 5 mg monthly until hair regrowth was noted by provider. The average duration of disease and current episode was 18 years (standard deviation [SD]: 14) and 3.3 years (SD: 2.3), respectively. Mean regrowth rate was 44.3% (SD: 31.9%). Range of regrowth was from 2% to 90%, 7 had regrowth of at least 50%. Response time ranged from 1 to 9 months, with a mean of 4.2 (SD: 2.6). Two of the 13 patients stopped the medication due to lack of insurance coverage and experienced re-shedding of the hair. Side effects were minimal with 1 patient developing a morbilliform eruption and peripheral edema necessitating medication withdrawal and 2 patients experiencing lipid and liver abnormalities that resolved with a dose decrease.28
The retrospective review by Liu and colleagues was a larger study of 90 adult patients that assessed longer-term efficacy of tofacitinib in the treatment of AA and its variants. It was noted in the study that patients with a current AA flare greater than 10 years were significantly less likely to respond to treatment with tofacitinib than those whose duration of current flare was less than 10 years. Therefore, a “potential responders to therapy” group was defined as patients with current AA flare of less than 10 years, for a total of 65 patients. Of the potential responders to the therapy group, median duration of disease was 15 years (range: 2-45 years) and median duration of current episode was 2.5 years (range: 0-10 years). The majority were treated with tofacitinib 5 mg twice daily monotherapy for the first 2 to 3 months (3 patients were treated initially with standard monotherapy and pulsed prednisone). At 2 to 3 months, hair growth was assessed and based on presence, absence, or plateau of hair growth adjuvant treatment was added with pulsed prednisone (300 mg once monthly for 3 doses). Of the potential responders, 43% received standard monotherapy and 57% received adjuvant treatment. Response was measured in change in Severity in Alopecia Tool (SALT score), which estimates the percent of total hair loss.30
Twenty percent of the potential responders had a greater than 90% change in SALT score, 38.4% had a 51% to 90% change in SALT score, 18.5% had 6% to 50% change in SALT score, and 23.1% had no response, defined by less than 5% change in SALT score. As in the study by Ibrahim and colleagues,28 no serious events were reported. Mild adverse events included upper respiratory infections (28.9%), urinary tract infections (3.3%), tonsillitis (2.2%), headache (14.4%), acne (7.8%), fatigue (6.7%), and lab abnormalities (1 patient each with abnormal liver function tests and leukopenia), which returned to normal without stopping tofacitinib. Fifteen patients had elevated low-density lipoprotein levels, which resolved in 3 patients and remained stable and minimally elevated in the other 12. Eight patients experienced relapse, 3 had a tapered dose after response, and 5 remained on the same initial dose. The median duration of treatment was 12 months, and no serious adverse events had been noted.29 Malignancy and serious infections had been seen in patients treated with tofacitinib for RA, however, these patients may be at increased risk based on their underlying disease.31
Craiglow and colleagues studied tofacitinib in an adolescent population with AA in a retrospective study.32 Thirteen patients, aged 12 to 17 years old, were included. Six had AA, 1 had AT, and 6 had AU. Mean duration of disease was 7.6 years (SD: 1.5-15 years). All were treated with tofacitinib monotherapy with 5 mg twice daily, except one whose dose was increased to a total daily dose of 15 mg after relapse, with subsequent regrowth. Nine patients experienced clinical regrowth, with a median change in SALT score of 100% and mean of 88% (SD: 20%-100%). An additional patient experienced regrowth then subsequent loss while still on treatment and was considered a nonresponder. Adverse effects were mild and included headaches, upper respiratory infections, and mild elevations in liver transaminase levels.32
Topical JAK Inhibitors as AA Treatment
Several studies have discussed systemic JAK inhibitors as an effective treatment for AA.28,29,32 To ameliorate systemic side effects associated with JAK inhibitors, topical formulations have been investigated for the treatment of AA.33,34 Bayart and colleagues investigated the use of topical tofacitinib 2%, ruxolitinib 1%, and ruxolitinib 2% in 6 pediatric patients with AA. Four patients experienced regrowth (patient 1: 20% of eyebrows, patient 2: 75% of eyelashes, patient 3: 95% of scalp, and patient 4: 80% of scalp). Treatment was well tolerated without serious adverse effects. Liu and colleagues studied 10 adult patients with AA treated with topical tofacitinib 2% ointment twice daily to half of affected scalp. Three of 10 patients experienced regrowth, characterized as excellent regrowth in 1 patient and partial regrowth in 2 patients. Adverse effects were mild and included skin irritation and folliculitis.34 Further studies are needed to assess topical JAK inhibitors as treatment option for AA.
Platelet-Rich Plasma and Androgenic Alopecia
Platelet-rich plasma (PRP) has been used for several years for dermatologic and nondermatologic indications. PRP contains bioactive molecules and aids in tissue regeneration owing to its use in a variety of procedures for healing and rejuvenation, including androgenic hair loss. Jhu and colleagues studied 20 men with androgenic alopecia not responding to traditional treatment (topical minoxidil and/or oral finasteride). Patients received PRP injections and microneedling every 3 weeks for 3 months. Improvement was measured by dermoscopy appearance of hair follicles and shafts and patients’ subjective hair growth assessment scale. Eighteen of the 20 patients had a patient satisfaction of greater than 75%. Dermoscopy demonstrated an increase in vellus and total hairs, increased hair diameter, and fewer black/yellow dots.35
PRP in androgenic alopecia in women was studied by Tawfik and Osman.36 Thirty patients (20-45 years old) with androgenic alopecia ranging from Ludwig grade 1 to Ludwig grade 3 were included. Each patient’s scalp was randomly treated with intralesional PRP to a selected area and intralesional normal saline to another selected area. Patients were treated weekly for 4 treatments and followed for 6 months. Assessment included photography, hair pull test, patient’s satisfaction scale, and standardized phototrichograms. Hair pull test was initially positive in all 30 patients, but was negative at 6-month follow up in 83% of patients in PRP injected site. Areas treated with PRP had a statistically significant increase in hair density and thickness. Mean patient satisfaction score was 7.0 on a scale of 1 to 10.36
Anitua and colleagues studied PRP in 19 patients, 13 men and 6 women, with androgenic alopecia. Patients underwent monthly treatment for 3 months, then 2 additional treatments at months 4 and 7. Treatment response was measured by macrophotographs, scalp biopsies (for 6 patients), phototrichograms, and patient self-assessment and satisfaction scores. Hair density increased significantly (from 117 ± 29 follicles/cm2 to 156 + 36 follicles/cm2), hair diameter increased (from 37 ± 10 to 55 ± 9 μm), and number of terminal hairs increased following treatment. Thirteen of the 19 patients rated their satisfaction as satisfied and very satisfied. On histomorphometic evaluation there was a statically significant increase in epidermal layer thickness, proliferative basal keratinocytes, follicular proliferation, terminal/miniaturized hair follicle ratio, and an increase in new blood vessels.37 Reports from 2017 suggest PRP improves androgenic alopecia both subjectively and objectively.35-37
Cutaneous Malignancy
Analysis of Trends in US Melanoma Incidence and Mortality
Despite efforts in secondary prevention of melanoma and nonmelanoma skin cancers, a recent research letter published in JAMA Dermatology using data from the National Cancer Institute (Surveillance, Epidemiology, and End Results [SEER] Program) indicates that in 2016 the incidence of melanoma is estimated to climb from 22.2 to 23.6 per 100,000 people when compared with 2009 data.38 The lifetime risk of melanoma will have increased from 1 in 78 to 1 in 58, with the estimated lifetime risk of melanoma in situ (MIS) being 1 in 28. The compounded annual growth rate of melanoma is 0.9% for melanoma and 1.5% for MIS from 2009 to 2016. It is also estimated that melanoma deaths will have risen from 8650 in 2009 to 10,130 in 2016.
Ugly Duckling Sign Improves Performance in Melanoma Detection
The failure of practitioners in decreasing the overall melanoma mortality highlights the importance of establishing effective screening tools for practitioners examining pigmented lesions. It is understood that 2 strategies are likely employed by dermatologists examining pigmented lesions: (1) intrapatient comparative analysis (IPCA), ie, identifying pigmented lesions that are morphologically different than the patient’s other lesions (lesions with the so-called ugly duckling sign), and (2) lesion-focused analysis (LFA) that focuses on examining a solitary lesion for suspicious characteristics.39
A recent experimental study aimed at identifying the effectiveness of using the ugly duckling sign in identifying melanomas when compared with LFA.40 The authors assessed this by presenting 9 senior dermatologists with 2089 digital images of a nevi from 80 patients, and 766 dermascopic images in a random fashion. The participants were then asked to identify ugly duckling nevi after presenting the patient’s nevi on a dual-monitor display. Alternatively, to assess LFA, these same images were shown individually in a random order to the same participants and asked to identify those that were suspicious appearing. The authors then determined the specificity of each approach for identifying melanoma. The authors noted that the specificity of IPCA was 0.96 for clinical images and 0.95 for demascopic images compared with 0.88 and 0.85, respectively, for LFA. They also noted that by combining the 2 techniques, unnecessary biopsies were reduced by a factor of 6.9 when compared with LFA alone.
Variation in the Cost of Managing Actinic Keratosis
Health expenditures related to the treatment of actinic keratosis (AK) comprise roughly $920 million per year, which comprises a significant portion of health care costs in the United States.41,42 As efforts to curtail the ever-expanding cost of health care delivery evolve, Kirby and colleagues sought to evaluate the variation in costs in managing AKs in the United States using a retrospective analysis of Truven Health MarketScan Commercial Claims and Encounters Database from 2008 to 2012.43 The authors used a ratio of mean cost of the highest quintile compared to the that of the lowest quintile (Q5:Q1 ratios) to exhibit the variation in cost. Cryotherapy was the treatment that was associated with the highest variability, with a Q5:Q1 ratio of 1.92, while the smallest was topical therapies with a Q5:Q1 ratio of 1.66. However, procedure visits where cryotherapy are performed are not billed for a physician visit, which may skew the results. The mean total annual cost for the management of AKs was 82% to 89% higher for the group of patients in the top quintile when compared with that of the bottom quintile.
Outpatient vs Operating Room Setting for Surgical Treatment of Skin Cancer
A separate study by Johnson and colleagues, published in Dermatologic Surgery, evaluated the differences in costs between cutaneous surgeries done in an outpatient setting vs those done in an operating room setting.44 They performed a retrospective study of hospital records from 2010 to 2014, searching for procedure codes associated with excisions of BCC, SCC, or melanoma. The authors then used patients data including age, gender, and skin characteristics to match cases of patients treated with Mohs micographic surgery (MSS) or traditional excision in an operating room setting compared with those treated in an outpatient setting. A total of 18 matched pairs were included in the study, and there was no statistically significant difference in the age or American Association of Anesthesiology scores of the 2 groups. The median cost for outpatient cases was $1773 vs $11,589 for operating room cases (P<.001).
FDA Approves Avelumab for Merkel Cell Carcinoma
Although Merkel cell carcinoma is often responsive to conventional chemotherapies, these medications have displayed a poor durability of response, leading to relapses and poor survival rates.45,46 This past March, the FDA approved its first medication for the treatment of Merkel cell carcinoma, avelumab (Bavencio), which is a monoclonal antibody that blocks the PD-1/PD-L1 pathway. The medication gained accelerated approval and orphan drug status after promising results from a multicenter, single-arm, phase 2 clinical trial in patients with metastatic Merkel cell carcinoma who have failed chemotherapy.47 The study enrolled a total 88 patients aged 18 years and older, and noted that during a median follow-up of 10.4 months, an objective response was noted in 28 patients (31.8%), 92% of whom experienced a durable response into 6 months of treatment.
Cutaneous Surgery
FDA Bans Powdered Medical Gloves
After significant evidence demonstrating the dangers of cornstarch in latex gloves over the past 30 years, and a citizen’s petition pleading for the ban the substance,48 the FDA has issued a ban of powdered medical gloves. The cornstarch powder promotes not only an irritant dermatitis, but also types I and IV hypersensitivity reactions to latex.49 It is understood that the cornstarch acts as a nidus for bacterial colonization and can carry bacterial endotoxin.50 This ban of powdered surgical gloves by the FDA was long awaited, and lags roughly 20 years behind a similar ban in Germany and about 17 years after a United Kingdom ban.48
Surgery vs 5% Imiquimod for Nodular and Superficial BCC: 5-Year Results From the SINS Trial
A recently published randomized controlled study in the Journal of Investigative Dermatology compared the efficacy of once-daily topical 5% imiquimod for both superficial and nodular BCCs to the gold standard treatment: surgical excision with 4 mm margins.51 Patients with superficial BCCs were treated with imiquimod once daily for 6 weeks, while those with nodular BCCs were treated for 12 weeks. Patients were closely monitored for possible signs of recurrence at 1-, 3-, and 5-year intervals. The combined cure rate for the imiquimod group was 82.5% in 5 years, with the majority of recurrences occurring in the first year. Conversely, the group receiving surgical excision had a 97.7% cure rate overall. While topical imiquimod may be promising for certain, high-risk patient populations for which surgery is not an option, it was still noted to be significantly inferior to surgical excision with a relative risk of 0.84 (P<.001).
Long-Term Outcomes of Melanoma In Situ Treated With Topical 5% Imiquimod Cream
Topical 5% imiquimod was also studied in the treatment of MIS. A retrospective chart review of 12 patients treated with imiquimod 5% daily or on weekdays only for 6 to 12 weeks noted that 2 patients (17%) had recurrence of their MIS over a median time of 5.5 years.52
Outcomes Comparable Between Mohs and Wide Local Excision for Melanoma Treatment
While topical imiquimod has been used for successfully for MIS, the expert recommendations for MIS is wide local excision (WLE),53 with margins of 1 cm.54 While approximately 90% of MIS are treated with this surgical modality,55 the challenge in attaining clear surgical margins in MIS has led some to favor MMS, which enables surgeons to examine margins intraoperatively via frozen sections of tissue.55 In a retrospective review comparing patients with MIS treated with either MMS (without utilization of immunohistochemistry stains) or WLE, Nosrati and colleagues examined whether appreciable differences exist between the groups regarding recurrence and melanoma associated mortality.56 They noted that despite MMS had more favorable outcomes, with a lower recurrence rate (5-year recurrence rates of 1.8% with MMS vs 5.7% with WLE) and fewer melanoma associated mortalities (2 patients with MMS vs 13 patients with WLE), neither was statistically significant. The authors noted that there was a degree of heterogeneity in the patient populations, as certain anatomically sensitive areas, would benefit more from MMS to preserve healthy tissue and minimize disfigurement. Interestingly, WLE-treated tumors that recurred had larger surgical margins taken than those that did not recur.
Other Advances
Burden of Skin Disease
The Global Burden of Skin Disease is a source of health information compiled from numerous experts from several databases to attempt to quantify health information, including epidemiologic data on numerous diseases. Specific to dermatology Karimkhani and colleagues evaluated global morbidity and mortality of skin diseases. Fifteen categories were included: dermatitis (including eczema, seborrheic dermatitis, and contact dermatitis), psoriasis, cellulitis, pyoderma, scabies, fungal skin diseases, viral skin diseases, acne vulgaris, AA, pruritus, urticarial, decubitus ulcer, malignant skin melanoma, keratinocyte carcinoma (including BBCs and SCCs), and other skin and subcutaneous diseases. Epidemiologic data (incidence and prevalence) and applicable clinical data (remission, duration, severity, and mortality risk) were compiled via PubMed and Google Scholar searches in English and Spanish from 1980 to 2013.
Disability-adjusted life years (DALY; one DALY equals 1 year of healthy life lost), years lived with disease (YLD), and years of life lost to disease (YLL) were used to compare skin conditions. Overall in 2013, 41.6 million DALYs and 39.0 million YLDs were related to skin conditions. Dermatitis was the largest global burden of DALYs and YLDs. DALYs for diseases varied based on age group and geographic location. The 15 to 19 age group had the most DALYs related to acne vulgaris. Australia had the highest amount of DALYs related to melanoma compared with other regions studied. 57
The burden of skin disease specific to the United States was discussed by Lim and colleagues.58 Data was extracted from several databases to assess disease prevalence, health care costs, indirect costs, and mortality from skin disease for 24 categories of skin disease (acne, actinic damage, AD, noncancerous skin growths, bullous diseases, congenital abnormalities, connective tissue disorders, contact dermatitis, cutaneous infections, cutaneous lymphoma, drug eruptions, hair and nail disorders, HPV/warts/molluscum, melanoma, nonmelanoma skin cancer, pruritus, psoriasis, rosacea, seborrheic dermatitis, ulcers, urticarial, viral and fungal diseases, vitiligo, and wounds and burns). About 85 million of the US population (27%) was seen by a physician for one of the above skin conditions in 2013. The estimated direct cost of skin disease in the United States in 2013 was $75 billion, and an estimated opportunity cost of $11 billion.
The health care costs related to skin disease increased roughly 1.7-fold from 2004 to 2013, in part due to the cost of new medications and increasing costs of older medications. Skin disease directly caused 0.9% of the total deaths in 2013. The statistics cited by Lim and colleagues are underestimated due to the data collected was only on patients who sought treatment.58 By quantifying the burden of skin disease it has prompted specific implications to the field of dermatology, discussed by Edison and Brod.59 To decrease morbidity and mortality, disease prevention should be a research focus. Access to dermatology care is a barrier; therefore, working on dermatologists’ role in health care models, telemedicine, and high-risk groups is suggested as a place for improvement. Finally, data registry of skin diseases can be improved to advance accuracy of epidemiologic information and to monitor burden of skin disease in the future.
PRP for Skin Rejuvenation
As noted above, PRP was studied widely in 2017 for androgenic alopecia.35-37 It was also further studied in facial and skin rejuvenation. Heresant and colleagues60 evaluated PRP combined with hyaluronic acid on skin facial rejuvenation in 31 patients. Equal parts of hyaluronic acid and PRP, 2 mL of each, was injected into each cheek and an additional 1 mL of the mixture spread on each cheek following microneedling, repeated monthly for 3 months. Outcomes were assessed at 1, 3, and 6 months after the last injection. FACE-Q scores (patient evaluation of outcomes) and skin elasticity showed a statistically significant improvement.60
Gawdat and colleagues61 performed a split face study comparing PRP to readymade growth factors for skin rejuvenation in 20 adult women. Treatment was assigned randomly to each half of the face. Patients were blinded to treatment. On one side, 3 mL of mesotherapy (a commercial mixture of epidermal growth factor, insulin-like growth, basic fibroblast growth factor, thioredoxin, copper tripeptide-1, multivitamins, amino acids, and minerals) was injected intradermally at 1 cm intervals. The other side was treated with 3 mL of intradermal activated PRP at 1 cm intervals. Treatment was repeated at 2-week intervals for 3 months. Evaluation was performed via blinded physician assessment, optical coherence tomography (examining epidermal and dermal thickness), and patient satisfaction level. At 1 month following the final treatment, no statistically significant difference was found between the sides for skin turgor, smoothness, hydration, and overall vitality of the skin. Both sides showed a significant increase in epidermal and dermal thickness. Patients had a higher level of satisfaction in the area treated with PRP compared with the area treated with mesotherapy. At 6 months following the last treatment, the area treated with PRP showed a more sustained improvement based on both clinical evaluation and optical coherence tomography.61
Dr Anderson is a PGY-2 dermatology resident at Wake Forest Baptist Health Department of Dermatology in Winston-Salem, NC.
Dr Bomar is a PGY-2 dermatology resident at Wake Forest Baptist Health Department of Dermatology in Winston-Salem, NC.
Dr Farhangian graduated from SUNY Downstate Medical College. In between his third and fourth year of medical school, he elected to perform dedicated research at Wake Forest University School of Medicine in Winston-Salem, NC, and started his first year of dermatology residency there this past July.
Disclosure: The authors report no relevant financial relationships.
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<p><em>It has been an impressive year in the field of dermatology. This annual article highlights some of the advances, discoveries, and recommendations in 2017.</em></p>
<div class="small-image left-image"><strong><img alt="psoriasis behind ear" data-align="left" data-entity-type="file" data-entity-uuid="27e9335d-7113-48ba-8523-7c94d2fc8618" src="/sites/default/files/inline-images/Screen%20Shot%202017-12-27%20at%208.24.42%20AM.png" />Psoriasis</strong></div>
<div class="small-image left-image"> </div>
<p><i>Cardiovascular Event Risk Assessment in Psoriasis Patients Treated With TNF-</i>α<i> Inhibitors vs Methotrexate</i></p>
<p>A recent study in the <i>Journal of the American Academy of Dermatology</i> sought to determine whether treatment of psoriasis with biologics vs methotrexate would lead to a decreased risk of cardiovascular (CV) events in patients on biologic therapy.<sup>1</sup> Through a retrospective study using the Truven MarketScan databases from 2000 to 2011, the authors included adult psoriasis patients who were prescribed either a tumor necrosis factor-α (TNF-α) inhibitor or methotrexate. To determine major CV events, ICD-9 codes associated with myocardial infarction (MI), strokes, or transient ischemic attacks (TIA) recorded for an insurance inpatient stay claim were used. Over the observation period, the risk of CV events was statistically significantly decreased in all 3 metrics (MI, TIA, and stroke) for those taking TNF-α inhibitor compared with methotrexate, and the adjusted hazard ratio for all CV events was 0.55 (<i>P</i><.0001). Furthermore, with cumulative exposure to TNF-α inhibitor, an 11% reduction in CV events was observed every 6 months in patients treated with TNF-α (<i>P</i>=.020). The results of this study demonstrate that strong control of psoriatic disease can have a more profound impact on these patients’ morbidity than originally thought; however, the retrospective nature of the study makes it difficult to draw definitive conclusions.</p>
<p><i>Malignancy Rates in a Large Cohort of Patients With Systemically Treated Psoriasis in a Managed Care Population</i></p>
<p>While treating psoriasis with systemic medications can lead to an overall improvement in CV disease, these medications also pose certain risks due to their immunosuppressive nature, which can potentially predispose them to an increased risk of malignancy, infection, or reactivation of latent infections. In a retrospective observation study by Asgari and colleagues, the authors sought to determine the overall risk of malignancy including nonmelanoma skin cancer in psoriasis patients treated with systemic immunosuppressants.<sup>2</sup> They utilized the Kaiser Permanente Northern California health delivery system along with a cancer registry and a pathology database to investigate the rate of malignancy in psoriasis patients treated with both biologics (more than 97% of whom were treated with TNF-α inhibitors) and nonbiologic systemic medications such as methotrexate. </p>
<p>Although there was no statistically significant difference in overall nonmelanoma skin cancer associated malignancy, patients exposed to biologics had a statistically significant 80% increased risk of cutaneous squamous cell carcinoma (SCC), and a 42% increased risk of overall nonmelanoma skin cancer when adjusted for the confounding variables of age, gender, race, and comorbidity. Though there was a slight increased risk for basal cell carcinoma (BCC) in the biologic group, the results were not statistically significant. It is important to note that there was a higher percentage of biologic patients who were exposed to phototherapy compared with the nonbiologic group (22% vs 17%, <i>P</i><.01), though the specific type or duration was not specified. </p>
<p><i>Adalimumab Is a Safe Option for Patients With Psoriasis and Concomitant HBV or HCV</i></p>
<p>Due to the concerns of immunosuppression, TNF-α medications have been used with extreme caution in patients infected with either hepatitis B virus (HBV) or hepatitis C virus (HCV). The underlying concern is that blocking TNF-α would lead to reactivation of patients with chronic HBV or HCV. Piaserico and colleagues sought to determine the validity of these concerns in a prospective observation study of 37 patients with psoriasis and concomitant HBV or HCV treated with adalimumab (Humira).<sup>3</sup> In this study, the authors monitored these patients’ viral load as well as their liver fibrosis scores. Not only did they not note any incidences of reactivation of HBV or HCV over a follow-up period of 40 months, but patients with HCV infections had lower liver fibrosis scores at the end of the study.</p>
<p><i>Brodalumab Approved to Treat Adults With Moderate to Severe Plaque Psoriasis</i></p>
<p>Brodalumab (Siliq), an anti-interleukin (IL)-17 biologic, was FDA approved in February 2017 for treatment of adults with moderate to severe plaque psoriasis. Brodalumab had a tenuous journey toward FDA approval as there were a total of 3 completed suicides during clinical trials in patients treated with the medication. Although experts have casted doubts as to whether the medication played a role in the suicide completions,<sup>4</sup> FDA approval was granted with the following contingencies: placement of a black box warning and restricted drug availability under a Risk Evaluation and Mitigation Strategy (REMS) Program. </p>
<p><i>Risankizumab vs Ustekinumab for Moderate to Severe Plaque Psoriasis</i></p>
<p>A recent head-to-head phase 2 clinical trial comparing risankizumab, an IL-23 inhibitor, and ustekinumab (Stelara), an IL-12/IL-23 inhibitor, showed promising results for risankizumab.<sup>5</sup> In this study, a total of 166 patients received either risankizumab (18 mg, 90 mg, or 180 mg at weeks 0, 4, and 16) or ustekinumab at weeks 0, 4, and 16 (45 mg or 90 mg depending on weight). The patients were randomized 3:1 to rizankizumab (in the 3 aforementioned dosages) or ustekinumab. The study’s primary endpoint was achievement of Psoriasis Area and Severity Index (PASI) reduction of 90% from baseline. </p>
<p>For the pooled 90- and 180-mg group treated with risankizumab, PASI 90 was 77% at week 16 vs 40% in the ustekinumab group (<i>P</i><.001). In addition, the onset of improvement was quicker and the durability of response following discontinuation was longer with risankizumab as decreases in PASI scores were maintained for 20 weeks vs 8 weeks with ustekinumab. Skin biopsy samples in the risankizumab group showed overall superior improvement and downregulation of certain genes associated with the IL-23 pathway, and psoriatic disease process were observed only in the risankizumab group. While this study demonstrates the efficacy of risankizumab, further studies, with larger sample sizes and placebo groups, are needed.</p>
<p><i>Guselkumab Shows Benefit in Psoriasis Patients With Inadequate Response to Ustekinumab</i></p>
<p>A similar head-to-head study compared guselkumab (Tremfya), another IL-23 inhibitor, to ustekinumab in a phase 3, randomized, double-blinded clinical trial.<sup>6</sup> All patients in the study were initially treated with ustekinumab (weight-based dose of either 45 mg or 90 mg at weeks 0 and 4), and after 16 weeks patients with an inadequate response to ustekinumab determined by an Investigator’s Global Assessment (IGA) score of 2 or more were randomized to guselkumab or to continue ustekinumab through 40 to 44 weeks, respectively. The primary endpoint was an IGA of 0 or 1 and a total decrease in IGA of 2 or more from week 28 to week 40 (compared to week 16). Patients were followed for a maximum of 4 visits over that period. </p>
<p>The mean number of visits at which patients achieved IGA of 0 or 1 and at least a 2-point improvement from week 28 to week 40 was significantly higher in guselkumab group compared with the ustekinumab group (1.5 vs 0.7; <i>P</i><.001). Furthermore, the mean number of visits during that same time for patients who had achieved PASI 90 was also significantly higher in the guselkumab group (2.2 vs 1.1; <i>P</i><.001). At week 28, the proportion of patients with an IGA score of 0 or 1 compared to week 16 was 31.1% for the guselkumab group and 14.3% for the ustekinumab group (<i>P</i>=.001). </p>
<div class="small-image left-image"><strong><img alt="acne_rosacea" data-align="left" data-entity-type="file" data-entity-uuid="3ee9af98-d0f9-4304-b837-7ee37145bb46" src="/sites/default/files/inline-images/Screen%20Shot%202017-12-27%20at%208.25.05%20AM.png" />Acne and Rosacea</strong></div>
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<p><i>Isotretinoin Treatment for Acne and Relation to Depression</i></p>
<p>Isotretinoin has long been associated with depression, suicidal ideation, and suicide, with the FDA releasing a warning regarding these associations in 1998. Huang and Cheng performed at systematic review and meta-analysis of the literature from inception to September 30, 2016 to evaluate the relationship between isotretinoin and depression.<sup>7</sup> Thirty-one studies met inclusion criteria, including acne treated with isotretinoin, at least 15 patients, and depression data (prevalence or depression scores). The meta-analysis showed there was no increased risk of depression in patients treated with isotretinoin for acne, and there was an improvement in depression scores following treatment of acne with isotretinoin.<sup>7</sup> Acne alone may be associated with depression;<sup>8</sup> therefore, clinicians should consider depression in all acne patients, regardless of treatment.</p>
<p><i>Rosacea, Demodex, and Ivermectin</i></p>
<p>Although a common disease, the complete pathophysiology of rosacea has not been elucidated, particularly given the different clinical variants (erythematotelangiectatic, papulopustular, phymatous, and ocular). It has been suggested that <i>Demodex</i> mites may play a role in the pathogenesis of the papulopustular variant. A meta-analysis by Chang and Huang was performed to further evaluate the association of <i>Demodex</i> mites in both papulopustular and erythematotelangiectatic rosacea.<sup>9</sup> Inclusion criteria for articles included English publications from inception to November 16, 2016, case-controlled studies with at least 15 patients, and prevalence, count, and density of <i>Demodex</i> mites in both affected and control patients. Twenty-three studies were included, with a total of 1513 patients. Patients with rosacea had a significantly higher prevalence (odds ratio [OR], 9.039; 95% CI, 4.827-16.925) and density (standard mean difference [SMD] 1.617; CI 1.090-2.145) of <i>Demodex</i> mites compared with the control group. <i>Demodex</i> density was higher in both erythrotelangiectatic and papulopustular rosacea than control groups and density in papulopustular variant was higher than erythrotelangiectatic variant, although not statistically significant.<sup>9</sup></p>
<p>Given high prevalence and density of <i>Demodex</i> mites in patients with rosacea,<sup>9</sup> antiparasitic agents have been employed in the treatment. A small retrospective case series investigated oral or topical ivermectin (Soolantra) for treatment of papulopustular rosacea (n=8) and periorificial dermatitis (n=7) in children.<sup>10 </sup>Patients were treated with a single dose of oral ivermectin, 200 to 250 g/kg (6 children with papulopustular rosacea and 3 with perioral dermatitis) or topical 1% ivermectin daily for 3 months (2 children with papulopustular rosacea and 4 with perioral dermatitis). Treatment choice was based on severity of condition. Fourteen of 15 patients achieved complete or almost complete clearance based on IGA. One child treated with oral ivermectin did not improve. Mild transient desquamation of the affected skin, occurring in 3 patients treated systemically and 2 treated topically, was noted as the only adverse effect. Topical ivermectin 1% is FDA approved only for treatment of rosacea in adults and oral ivermectin is licensed just for filariasis in the pediatric group.</p>
<p><i>Expert Consensus on Acne Fulminans</i></p>
<p>Acne fulminans is a variant of acne that has remained poorly defined and understood. To address this issue, 12 experts reviewed the literature and convened to further define, discuss treatment options, and recommend further areas of research for acne fulminans.<sup>11</sup> Terminology used to describe acne fulminans and related variants are: acne fulminans with systemic symptoms (AF-SS), acne fulminans without systemic symptoms (AF-WOSS), isotretinoin-induced acne fulminans with systemic symptoms (IIAF-SS), and isotretinoin-induced acne fulminans without systemic symptoms (IIAF-WOSS). Consistent throughout all types is the characteristic inflammatory papules often with erosions, crust, and ulcers. Systemic symptoms that may be present in AF-SS and IIAF-WOSS include constitutional symptoms (fever and malaise), arthralgias, and bone pain (potentially related to osteolytic bone lesions). Isotretinoin, and rarely testosterone and anabolic steroids, are a known trigger for acne fulminans when started in patients with severe acne, necessitating the separate terminology for the drug-induced form of acne fulminans. The pathogenesis behind acne fulminans and isotretinoin as causing acne fulminans remains unknown with several theories suggested. Unfortunately, large, randomized controlled trials have not been performed evaluating treatment options for acne fulminans. Based on case reports and series, systemic corticosteroids combined with low-dose isotretinoin is the recommended treatment. </p>
<p>Greywal and colleagues recommend starting prednisone monotherapy at 0.5 to 1 mg/kg/day for at least 4 weeks for AF-SS and 2 weeks for AF-WOSS and continued until crusted lesions heal. Then low-dose isotretinoin (0.1 mg/kg/day) may be added. Corticosteroids and isotretinoin should overlap for at least 4 weeks, then corticosteroids can slowly be tapered as isotretinoin is slowly increased. Many patients with acne fulminans will require a prolonged course and may require a higher cumulative dose than the typical 120 to 150 mg/kg for isotretinoin. To minimize the risk of IIAF in patients with severe inflammatory acne, overlapping prednisone for several weeks with low-dose isotretinoin or starting prednisone monotherapy for 2 weeks prior to starting isotretinoin should be considered.<sup>11</sup> </p>
<div class="small-image left-image"><strong><img alt="atopic dermatitis " data-align="left" data-entity-type="file" data-entity-uuid="12f16866-eceb-4026-8cd5-feccc135212c" src="/sites/default/files/inline-images/Screen%20Shot%202017-12-27%20at%208.25.13%20AM.png" />Atopic Dermatitis </strong></div>
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<p><i>Atopic Dermatitis Associated With Several Autoimmune Skin Conditions</i></p>
<p>Atopic dermatitis (AD) has previously been linked with several autoimmune skin conditions including inflammatory bowel disease, rheumatoid arthritis (RA), and type 1 diabetes. A recent Danish study looked at 8112 adults diagnosed with AD between 1997 and 2012 and compared them to 40,560 age- and sex-matched controls.<sup>12</sup> They found AD to be significantly associated with alopecia areata (AA), vitiligo, chronic urticaria, celiac disease, chronic glomerulonephritis, Sjögren syndrome, systemic lupus erythematosus, ankylosing spondylitis, Crohn disease, ulcerative colitis, and RA. No significant associations were found between AD, autoimmune thyroid diseases, multiple sclerosis, type 1 diabetes, autoimmune hematologic disease, or pulmonary fibrosis.<sup>12</sup></p>
<p><i>Nemolizumab: Emerging Biologic for Pruritus in AD Patients </i></p>
<p>Pruritus plays a significant role in perpetuating AD and has a profound impact on quality of life. IL-31 is believed to play a role in pruritus in AD through an uncertain mechanism.<sup>13</sup> In a phase 2, 12-week clinical trial, 216 patients with uncontrolled pruritus and AD were randomly assigned to receive subcutaneous nemolizumab, a fully human monoclonal antibody against IL-31, or placebo. The dosing was 0.1 mg/kg, 0.5 mg/kg, or 2.0 mg/kg body weight every 4 weeks for subcutaneous nemolizumab. A significant improvement in pruritus was seen in all dosing groups for nemolizumab. The most common side effects were worsening of AD and peripheral edema.<sup>13</sup></p>
<p><i>Safety of Crisaborole 2% Ointment for Children and Adults With AD </i></p>
<p>Topical steroids and calcineurin inhibitors have been the mainstay topical treatments for children and adults with AD. No new topical agents had been approved for 15 years until crisaborole (Eucrisa) in 2016. A recent phase 3 clinical trial looked at the long-term safety of crisaborole ointment in 517 patients aged 2 years and older with AD over 48 weeks.<sup>14</sup> The most common side effects were upper respiratory tract infection (10.3%), flaring of AD (11.2%), nasopharyngitis (97.7%), cough (6.8%), and pyrexia (5.6%). Most adverse effects were mild (51.2%) to moderate (44.6%) and did not require discontinuation of the product. Based on these findings, crisaborole is a safe, long-term treatment for AD in children and adults.<sup>14</sup> </p>
<p><strong>Infectious Disease </strong></p>
<p><i>Topical Timolol for Classic and HIV-Related Kaposi Sarcoma </i></p>
<p>While previous case series have demonstrated the efficacy of topical timolol 0.05% for classical and HIV-related Kaposi sarcoma, a recent case series suggests lower doses of topical timolol may be just as successful.<sup>15</sup> Four patients with localized, cutaneous Kaposi sarcoma were successfully treated with topical timolol 0.01% gel twice daily until resolution. The average treatment duration until complete resolution was 4 to 6 weeks. No adverse effects related to the topical timolol were reported. One patient terminated treatment at week 6 after being hospitalized with an active tuberculosis. These findings support the use lower dose timolol for classical and HIV-related Kaposi sarcoma.<sup>15</sup> </p>
<p><i>Pneumocystis Pneumonia Prophylaxis in Patients With Bullous Dermatosis on Long- term Immunosuppression </i></p>
<p>Patients with autoimmune blistering disease (AIBD) generally require treatment with long-term immunosuppression. As a result, they are at an increased risk for opportunistic infection. Pneumocystis pneumonia (PCP) rates among dermatologic patients on immunosuppression vary from 0.5% to 2%.<sup>16</sup> Experts have differing opinions as to whether these patients need PCP prophylaxis. In general, PCP incidence of 3.5% is recommended before starting prophylaxis. A retrospective study of patients with AIBD was conducted at 6 tertiary referral centers for AIBD in Germany, Netherlands, Italy, and Singapore.<sup>16</sup> Among the 801 patients with AIBD identified, only one (0.1%) developed PCP in the 3-year follow- up period. This patient, however, was 40 years old and had recalcitrant mucocutaneous pemphigus vulgaris requiring high-dose oral prednisolone in combination with rituximab. Further analysis of only patients with pemphigus vulgaris showed that 1 of 411 patients (0.02%) had PCP. Based on the findings in this large retrospective study, PCP prophylaxis is not indicated in patients with AIBD on systemic immunosuppresants.<sup>16</sup> </p>
<p><i>Improving Diagnostic Accuracy for Lower Extremity Cellulitis</i></p>
<p>Reported misdiagnosis rates for lower extremity cellulitis range from 30% to 90%.<sup>17</sup> Common mimickers include venous stasis dermatitis, lymphedema, deep venous thrombosis, gout, and contact dermatitis. A recent cross-sectional study of 259 patients admitted to a large urban hospital between June 2010 and December 2012 found that 30% of patients admitted with a diagnosis of lower extremity cellulitis were misdiagnosed.<sup>17</sup> Among the 79 misdiagnosed patients, 52 of 79 (66%) were admitted for inpatient treatment of cellulitis, and 42 of the 52 (85%) did not need admission based on their final diagnosis. </p>
<p>Based on these findings, the study authors developed a risk prediction model for diagnosing lower extremity cellulitis called ALT-70.<sup>18</sup> ALT-70 includes 4 variables: unilateral leg involvement, heart rate 90 beats per minute, white blood cell count 10,000, and age 70. Three points were assigned to asymmetric leg involvement, 2 points for age 70, and 1 point for white cell count 10,000 and heart rate 90. Empiric treatment for cellulitis was recommended if patients had 5 or more points. A dermatology consultation was advised for patients with 3 to 4 points. Reassessment was recommended for patients with 2 or fewer points. </p>
<p>Using the cohort of patients from the original study, patients with ALT-70 score of 3 or lower had 83% likelihood of having pseudocellulitis while those with a score above 4 had an 82% likelihood of having true cellulitis. Interestingly, an increased risk of cellulitis among patients with a history of cellulitis, tinea pedis, lymphedema, venous insufficiency, dermatitis, and malignancy was not found. This scoring system is the first step to providing clinicians with a tool to aid in the diagnosis of lower extremity cellulitis.<sup>18</sup> </p>
<div class="small-image left-image"><strong><img alt="autoimmune diseases" data-align="left" data-entity-type="file" data-entity-uuid="58c4d0b1-df71-4623-9ba6-ae4cd0b04bf0" src="/sites/default/files/inline-images/Screen%20Shot%202017-12-27%20at%208.25.19%20AM.png" />Autoimmune and Systemic Disease </strong></div>
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<p><i>Potential Future Treatment for Keratin Disorders </i></p>
<p>Topical broccoli sprout extract (BSE) is being studied as a potential treatment for disorders of keratinization.<sup>19</sup> Sulforaphane, an isothiocyante and key ingredient in BSE, has been shown to increase expression of healing keratins 16 and 17 in mice. A recent study looked at whether these effects are seen in humans.<sup>19</sup> Five healthy individuals were recruited to apply topical BSE to the inner aspect of 1 arm and vehicle only to the other arm daily for 1 week.<sup>19</sup> Both BSE and vehicle treated skin sites were biopsied after 1 week. While 1 patient had to be excluded for poor tissue quality, the remaining 4 patients showed 3.6 higher levels of keratin-17 messenger RNA (<i>P</i>=.0022). Indirect immunofluorescence also showed increased induction of keratin-17 in BSE-treated skin. Keratin-16 expression was increased 10 to 14 times in the 2 female individuals and 4 times in 1 male individual. There was no difference in keratin-16 expression in the other male individual. Indirect immunofluorescence showed elevated keratin-16 in the suprabasal layer of BSE-treated skin in 3 patients. No statistical difference was found in keratin 5, 6, and 15 RNA expression levels. Further studies are needed including patients with epidermolysis bullosa simplex to determine whether topical BSE is a potential treatment option.<sup>19</sup></p>
<p><i>Treatment of Cutaneous Manifestations of Tuberous Sclerosis With Topical Sirolimus </i></p>
<p>Cutaneous manifestations of tuberous sclerosis include angiofibromas, shagreen patches, hypomelanotic macules, and periungual fibromas. Since 2010, several studies have been published on the efficacy of topical sirolimus for treating facial angiofibromas, but none on other cutaneous manifestations.<sup>20</sup> In a recent study on topical sirolimus for facial angiofibromas, cephalic plaques, shagreen patches, hypomelanotic macules, and periungual fibromas, 25 patients used topical sirolimus daily and were followed for 18 months.<sup>20</sup> Half of the patients had clinical clearance of their facial angiofibromas after 9 months of treatment. Among 7 of the 12 patients who agreed to use a maintenance regimen of 3 times weekly application, 6 had recurrence of facial angiofibromas within 2 months. No significant response was seen with topical tacrolimus for fibrous cephalic plaques, shagreen patches, hypomelanotic patches, and periungual fibromas. No series adverse effects were seen over 18 months. There was mild aggravation of facial acne in 3 patients, aseptic folliculitis at the site of application in 1 patient, and mild irritation in 8 patients. Topical sirolimus is an effective and safe treatment for angiofibromas but must be used regularly to maintain clearance. It is not effective for other cutaneous manifestations of tuberous sclerosis.<sup>20</sup> </p>
<p><i>Cyclosporine May Provide Mortality Benefit in SJS</i></p>
<p>To date, the role of corticosteroids, intravenous immunoglobulin, cyclosporine, and other immunomodulators in the treatment of Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) remains unclear. Lee and colleagues evaluated the effect of cyclosporine for SJS/TEN patients at a large academic hospital by comparing SCORTEN predicted mortality to actual mortality.<sup>21</sup> Twenty-four patients were randomized to receive cyclosporine 3 mg/kg for 10 days, 10 mg/kg for the next 10 days, and then 1 mg/kg/day for 10 days. Twenty patients received only supportive care. Patients who received cyclosporine were younger (50 years of age; <i>P</i>=.009) and had a lower incidence of cardiac disease (<i>P</i>=.035). There was no difference in terms of disease classification, SCORTEN scores on admission, or maximum body surface area. </p>
<p>In the cyclosporine group, SCORTEN predicted 7.2 deaths, and 3 actual deaths occurred. In the supportive care only group, SCORTEN predicted 5.9 deaths, and 6 deaths occurred. Among the 19 patients who only received cyclosporine and no other immunomodulatory therapies (intravenous immunoglobulin or systemic steroids), 2 deaths were observed while 5.3 were predicted. Nine patients did have to stop cyclosporine during the study due to worsening renal function. This study is the first trial to show survival benefit with the use of cyclosporine in SJS/TEN.<sup>21</sup></p>
<p><i>Bullous Pemphigoid and Malignancy </i></p>
<p>The association with bullous pemphigoid (BP) and malignancy is controversial. While some studies have demonstrated an association, others have not. A recent systemic review of all studies on BP and malignancy found an association between BP and hematologic malignancies, including Hodgkin lymphoma, non-Hodgkin lymphoma, mature natural killer/T-cell lymphoma, myeloid leukemia, and leukemia unspecified.<sup>22</sup> Hematological malignancy preceded the diagnosis of BP in half of the patients. There were no other malignancies with significant associations with BP. These findings are limited due to the retrospective and observational nature of all available studies on BP and malignancy. It is important to ensure all newly diagnosed patients with BP are up-to-date on age-appropriate cancer screening, but further investigational workup is not recommended.<sup>22</sup></p>
<div class="small-image left-image"><strong><img alt="vitiligo on fingers" data-align="left" data-entity-type="file" data-entity-uuid="e923eae0-40d1-4175-9c1c-df0e10ba2ae0" src="/sites/default/files/inline-images/Screen%20Shot%202017-12-27%20at%208.25.32%20AM.png" />Vitiligo</strong></div>
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<p><i>Repigmentation With Phototherapy </i></p>
<p>Treatment options for vitiligo include phototherapy such as psoralen–UV-A (PUVA) and narrowband UV-B, laser therapy, and various topical agents. Phototherapy, a popular treatment option, has varying rates for repigmentation and duration of treatment. A database review examined all prospective trials on phototherapy for vitiligo.<sup>23</sup> Regimentation with narrowband UV-B was mild (>25% repigmentation) in 75% of 512 patients and marked (>75% response) in 35.7% of 540 patients. The face and neck responded best with 44% of 153 patients showing a marked repigmentation response. No repigmentation was seen on the hands and feet in 172 patients. PUVA phototherapy had lower rates of repigmentation with mild response in 61.6% of 72 patients at 12 months and marked response in 13.6% of 72 patients. Based on these findings, 1 year is needed to see the maximal response from phototherapy for vitiligo lesions.<sup>23</sup></p>
<p><i>Oral Simvastatin and Vitiligo</i></p>
<p>Vitiligo is thought to be a T<sub>h</sub>1-cell-mediated autoimmune disease with high levels of interferon (IFN)-γ and chemokines CXCL0 and CXCL10 promoting depigmentation. In mouse models, simvastatin has been shown to inhibit the activation of STAT1, which prevents IFN-γ induced signaling of CXCL10. Repigmentation in a patient with vitiligo on simvastatin has been described in the literature. A recent double-blind, placebo-controlled, phase 2 clinical trial failed to show repigmentation in any of the patients.<sup>24</sup> Fifteen patients with vitiligo were randomly assigned to simvastatin 40 mg daily for 1 month followed by 90 mg daily for another 5 months or placebo. All other treatments were discontinued prior to the study with washout periods. Worsening of vitiligo was seen in 26% of patients in the oral simvastatin group (<i>P</i>=.094), and no effect was seen on serum levels of CXCL10. These results do not support the use of oral simvastatin in the treatment of vitiligo.<sup>24</sup> </p>
<p><i>Janus Kinase Inhibitors for Treating Vitiligo </i></p>
<p>Janus kinase (JAK) inhibitors, specifically JAK 1/2, have been shown to inhibit IFN-γ signaling and are potential treatments for vitiligo. Two studies on JAK inhibitors for vitiligo have been recently published. In a phase 2 clinical trial, 11 patients with vitiligo used topical ruxolitinib 1.5% cream (Jakafi), a JAK 1/2 inhibitor, twice daily for more than 20 weeks.<sup>25</sup> Application of topical ruxolitinib was restricted to 10% body surface area or 3.75 g of topical ruxolitinib per exposure. Based on Vitiligo Area Scoring Index scores, four of 11 patients with facial vitiligo experienced 75% improvement at week 20 (<i>P</i>=.001). Repigmentation was minor and not significant at other body sites. Erythema at the application site occurred in 8 of 11 patients and was the most common adverse effect. Two patients experienced a transient, mild papular eruption on the face that resolved. No laboratory monitoring was performed during this study.<sup>25</sup> </p>
<p>Ten patients with vitiligo took oral tofacitinib (Xeljanz), a JAK 1/3 inhibitor, for an average of 10 months in another study.<sup>26</sup> Baseline laboratory analysis was obtained. Patients received either 5 to 10 mg oral tofacitinib daily or twice daily. While 5 of 10 patients did experience repigmentation, repigmentation occurred only in sun-exposed areas in 3 of the 5 patients. The other 2 patients with repigmentation were also being treated concurrently with narrowband UV-B. Of the five patients with no repigmentation, only 1 reported sun exposure while the remaining 4 practiced sun avoidance. Four patients had mild elevated lipid levels. Two patients experienced an upper respiratory tract infection. JAK inhibitors may require light exposure to achieve repigmentation based on data from both of these studies.<sup>25,26</sup></p>
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<p><strong>Hair</strong></p>
<p><i>Systemic Tofacitinib as a Treatment for Alopecia Areata and its Variants</i></p>
<p>Use of tofacitinib as a treatment for AA and its variants was discussed in last year’s Year in Review article<sup>27</sup>; however, further data regarding safety and efficacy in a variety of age groups and use of topical formulations have been added to the literature this year. Multiple single-site, retrospective studies have been performed evaluating tofacitinib in the treatment of AA and its variants.<sup>28,29</sup> </p>
<p>The study by Ibrahim and colleagues evaluated 13 adult patients (7 had alopecia universalis (AU), 2 had alopecia totalis (AT), and 4 had AA treated with tofacitinib. Mean pretreatment scalp hair loss was 93%. Patients were treated with tofacitinib 5 mg twice a day, monotherapy, with other treatments for AA ceased prior to initiation of tofacitinib. The tofacitinib was
<p><em>It has been an impressive year in the field of dermatology. This annual article highlights some of the advances, discoveries, and recommendations in 2017.</em></p>
<div class="small-image left-image"><strong><img alt="psoriasis behind ear" data-align="left" data-entity-type="file" data-entity-uuid="27e9335d-7113-48ba-8523-7c94d2fc8618" src="/sites/default/files/inline-images/Screen%20Shot%202017-12-27%20at%208.24.42%20AM.png" />Psoriasis</strong></div>
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<p><i>Cardiovascular Event Risk Assessment in Psoriasis Patients Treated With TNF-</i>α<i> Inhibitors vs Methotrexate</i></p>
<p>A recent study in the <i>Journal of the American Academy of Dermatology</i> sought to determine whether treatment of psoriasis with biologics vs methotrexate would lead to a decreased risk of cardiovascular (CV) events in patients on biologic therapy.<sup>1</sup> Through a retrospective study using the Truven MarketScan databases from 2000 to 2011, the authors included adult psoriasis patients who were prescribed either a tumor necrosis factor-α (TNF-α) inhibitor or methotrexate. To determine major CV events, ICD-9 codes associated with myocardial infarction (MI), strokes, or transient ischemic attacks (TIA) recorded for an insurance inpatient stay claim were used. Over the observation period, the risk of CV events was statistically significantly decreased in all 3 metrics (MI, TIA, and stroke) for those taking TNF-α inhibitor compared with methotrexate, and the adjusted hazard ratio for all CV events was 0.55 (<i>P</i><.0001). Furthermore, with cumulative exposure to TNF-α inhibitor, an 11% reduction in CV events was observed every 6 months in patients treated with TNF-α (<i>P</i>=.020). The results of this study demonstrate that strong control of psoriatic disease can have a more profound impact on these patients’ morbidity than originally thought; however, the retrospective nature of the study makes it difficult to draw definitive conclusions.</p>
<p><i>Malignancy Rates in a Large Cohort of Patients With Systemically Treated Psoriasis in a Managed Care Population</i></p>
<p>While treating psoriasis with systemic medications can lead to an overall improvement in CV disease, these medications also pose certain risks due to their immunosuppressive nature, which can potentially predispose them to an increased risk of malignancy, infection, or reactivation of latent infections. In a retrospective observation study by Asgari and colleagues, the authors sought to determine the overall risk of malignancy including nonmelanoma skin cancer in psoriasis patients treated with systemic immunosuppressants.<sup>2</sup> They utilized the Kaiser Permanente Northern California health delivery system along with a cancer registry and a pathology database to investigate the rate of malignancy in psoriasis patients treated with both biologics (more than 97% of whom were treated with TNF-α inhibitors) and nonbiologic systemic medications such as methotrexate. </p>
<p>Although there was no statistically significant difference in overall nonmelanoma skin cancer associated malignancy, patients exposed to biologics had a statistically significant 80% increased risk of cutaneous squamous cell carcinoma (SCC), and a 42% increased risk of overall nonmelanoma skin cancer when adjusted for the confounding variables of age, gender, race, and comorbidity. Though there was a slight increased risk for basal cell carcinoma (BCC) in the biologic group, the results were not statistically significant. It is important to note that there was a higher percentage of biologic patients who were exposed to phototherapy compared with the nonbiologic group (22% vs 17%, <i>P</i><.01), though the specific type or duration was not specified. </p>
<p><i>Adalimumab Is a Safe Option for Patients With Psoriasis and Concomitant HBV or HCV</i></p>
<p>Due to the concerns of immunosuppression, TNF-α medications have been used with extreme caution in patients infected with either hepatitis B virus (HBV) or hepatitis C virus (HCV). The underlying concern is that blocking TNF-α would lead to reactivation of patients with chronic HBV or HCV. Piaserico and colleagues sought to determine the validity of these concerns in a prospective observation study of 37 patients with psoriasis and concomitant HBV or HCV treated with adalimumab (Humira).<sup>3</sup> In this study, the authors monitored these patients’ viral load as well as their liver fibrosis scores. Not only did they not note any incidences of reactivation of HBV or HCV over a follow-up period of 40 months, but patients with HCV infections had lower liver fibrosis scores at the end of the study.</p>
<p><i>Brodalumab Approved to Treat Adults With Moderate to Severe Plaque Psoriasis</i></p>
<p>Brodalumab (Siliq), an anti-interleukin (IL)-17 biologic, was FDA approved in February 2017 for treatment of adults with moderate to severe plaque psoriasis. Brodalumab had a tenuous journey toward FDA approval as there were a total of 3 completed suicides during clinical trials in patients treated with the medication. Although experts have casted doubts as to whether the medication played a role in the suicide completions,<sup>4</sup> FDA approval was granted with the following contingencies: placement of a black box warning and restricted drug availability under a Risk Evaluation and Mitigation Strategy (REMS) Program. </p>
<p><i>Risankizumab vs Ustekinumab for Moderate to Severe Plaque Psoriasis</i></p>
<p>A recent head-to-head phase 2 clinical trial comparing risankizumab, an IL-23 inhibitor, and ustekinumab (Stelara), an IL-12/IL-23 inhibitor, showed promising results for risankizumab.<sup>5</sup> In this study, a total of 166 patients received either risankizumab (18 mg, 90 mg, or 180 mg at weeks 0, 4, and 16) or ustekinumab at weeks 0, 4, and 16 (45 mg or 90 mg depending on weight). The patients were randomized 3:1 to rizankizumab (in the 3 aforementioned dosages) or ustekinumab. The study’s primary endpoint was achievement of Psoriasis Area and Severity Index (PASI) reduction of 90% from baseline. </p>
<p>For the pooled 90- and 180-mg group treated with risankizumab, PASI 90 was 77% at week 16 vs 40% in the ustekinumab group (<i>P</i><.001). In addition, the onset of improvement was quicker and the durability of response following discontinuation was longer with risankizumab as decreases in PASI scores were maintained for 20 weeks vs 8 weeks with ustekinumab. Skin biopsy samples in the risankizumab group showed overall superior improvement and downregulation of certain genes associated with the IL-23 pathway, and psoriatic disease process were observed only in the risankizumab group. While this study demonstrates the efficacy of risankizumab, further studies, with larger sample sizes and placebo groups, are needed.</p>
<p><i>Guselkumab Shows Benefit in Psoriasis Patients With Inadequate Response to Ustekinumab</i></p>
<p>A similar head-to-head study compared guselkumab (Tremfya), another IL-23 inhibitor, to ustekinumab in a phase 3, randomized, double-blinded clinical trial.<sup>6</sup> All patients in the study were initially treated with ustekinumab (weight-based dose of either 45 mg or 90 mg at weeks 0 and 4), and after 16 weeks patients with an inadequate response to ustekinumab determined by an Investigator’s Global Assessment (IGA) score of 2 or more were randomized to guselkumab or to continue ustekinumab through 40 to 44 weeks, respectively. The primary endpoint was an IGA of 0 or 1 and a total decrease in IGA of 2 or more from week 28 to week 40 (compared to week 16). Patients were followed for a maximum of 4 visits over that period. </p>
<p>The mean number of visits at which patients achieved IGA of 0 or 1 and at least a 2-point improvement from week 28 to week 40 was significantly higher in guselkumab group compared with the ustekinumab group (1.5 vs 0.7; <i>P</i><.001). Furthermore, the mean number of visits during that same time for patients who had achieved PASI 90 was also significantly higher in the guselkumab group (2.2 vs 1.1; <i>P</i><.001). At week 28, the proportion of patients with an IGA score of 0 or 1 compared to week 16 was 31.1% for the guselkumab group and 14.3% for the ustekinumab group (<i>P</i>=.001). </p>
<div class="small-image left-image"><strong><img alt="acne_rosacea" data-align="left" data-entity-type="file" data-entity-uuid="3ee9af98-d0f9-4304-b837-7ee37145bb46" src="/sites/default/files/inline-images/Screen%20Shot%202017-12-27%20at%208.25.05%20AM.png" />Acne and Rosacea</strong></div>
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<p><i>Isotretinoin Treatment for Acne and Relation to Depression</i></p>
<p>Isotretinoin has long been associated with depression, suicidal ideation, and suicide, with the FDA releasing a warning regarding these associations in 1998. Huang and Cheng performed at systematic review and meta-analysis of the literature from inception to September 30, 2016 to evaluate the relationship between isotretinoin and depression.<sup>7</sup> Thirty-one studies met inclusion criteria, including acne treated with isotretinoin, at least 15 patients, and depression data (prevalence or depression scores). The meta-analysis showed there was no increased risk of depression in patients treated with isotretinoin for acne, and there was an improvement in depression scores following treatment of acne with isotretinoin.<sup>7</sup> Acne alone may be associated with depression;<sup>8</sup> therefore, clinicians should consider depression in all acne patients, regardless of treatment.</p>
<p><i>Rosacea, Demodex, and Ivermectin</i></p>
<p>Although a common disease, the complete pathophysiology of rosacea has not been elucidated, particularly given the different clinical variants (erythematotelangiectatic, papulopustular, phymatous, and ocular). It has been suggested that <i>Demodex</i> mites may play a role in the pathogenesis of the papulopustular variant. A meta-analysis by Chang and Huang was performed to further evaluate the association of <i>Demodex</i> mites in both papulopustular and erythematotelangiectatic rosacea.<sup>9</sup> Inclusion criteria for articles included English publications from inception to November 16, 2016, case-controlled studies with at least 15 patients, and prevalence, count, and density of <i>Demodex</i> mites in both affected and control patients. Twenty-three studies were included, with a total of 1513 patients. Patients with rosacea had a significantly higher prevalence (odds ratio [OR], 9.039; 95% CI, 4.827-16.925) and density (standard mean difference [SMD] 1.617; CI 1.090-2.145) of <i>Demodex</i> mites compared with the control group. <i>Demodex</i> density was higher in both erythrotelangiectatic and papulopustular rosacea than control groups and density in papulopustular variant was higher than erythrotelangiectatic variant, although not statistically significant.<sup>9</sup></p>
<p>Given high prevalence and density of <i>Demodex</i> mites in patients with rosacea,<sup>9</sup> antiparasitic agents have been employed in the treatment. A small retrospective case series investigated oral or topical ivermectin (Soolantra) for treatment of papulopustular rosacea (n=8) and periorificial dermatitis (n=7) in children.<sup>10 </sup>Patients were treated with a single dose of oral ivermectin, 200 to 250 g/kg (6 children with papulopustular rosacea and 3 with perioral dermatitis) or topical 1% ivermectin daily for 3 months (2 children with papulopustular rosacea and 4 with perioral dermatitis). Treatment choice was based on severity of condition. Fourteen of 15 patients achieved complete or almost complete clearance based on IGA. One child treated with oral ivermectin did not improve. Mild transient desquamation of the affected skin, occurring in 3 patients treated systemically and 2 treated topically, was noted as the only adverse effect. Topical ivermectin 1% is FDA approved only for treatment of rosacea in adults and oral ivermectin is licensed just for filariasis in the pediatric group.</p>
<p><i>Expert Consensus on Acne Fulminans</i></p>
<p>Acne fulminans is a variant of acne that has remained poorly defined and understood. To address this issue, 12 experts reviewed the literature and convened to further define, discuss treatment options, and recommend further areas of research for acne fulminans.<sup>11</sup> Terminology used to describe acne fulminans and related variants are: acne fulminans with systemic symptoms (AF-SS), acne fulminans without systemic symptoms (AF-WOSS), isotretinoin-induced acne fulminans with systemic symptoms (IIAF-SS), and isotretinoin-induced acne fulminans without systemic symptoms (IIAF-WOSS). Consistent throughout all types is the characteristic inflammatory papules often with erosions, crust, and ulcers. Systemic symptoms that may be present in AF-SS and IIAF-WOSS include constitutional symptoms (fever and malaise), arthralgias, and bone pain (potentially related to osteolytic bone lesions). Isotretinoin, and rarely testosterone and anabolic steroids, are a known trigger for acne fulminans when started in patients with severe acne, necessitating the separate terminology for the drug-induced form of acne fulminans. The pathogenesis behind acne fulminans and isotretinoin as causing acne fulminans remains unknown with several theories suggested. Unfortunately, large, randomized controlled trials have not been performed evaluating treatment options for acne fulminans. Based on case reports and series, systemic corticosteroids combined with low-dose isotretinoin is the recommended treatment. </p>
<p>Greywal and colleagues recommend starting prednisone monotherapy at 0.5 to 1 mg/kg/day for at least 4 weeks for AF-SS and 2 weeks for AF-WOSS and continued until crusted lesions heal. Then low-dose isotretinoin (0.1 mg/kg/day) may be added. Corticosteroids and isotretinoin should overlap for at least 4 weeks, then corticosteroids can slowly be tapered as isotretinoin is slowly increased. Many patients with acne fulminans will require a prolonged course and may require a higher cumulative dose than the typical 120 to 150 mg/kg for isotretinoin. To minimize the risk of IIAF in patients with severe inflammatory acne, overlapping prednisone for several weeks with low-dose isotretinoin or starting prednisone monotherapy for 2 weeks prior to starting isotretinoin should be considered.<sup>11</sup> </p>
<div class="small-image left-image"><strong><img alt="atopic dermatitis " data-align="left" data-entity-type="file" data-entity-uuid="12f16866-eceb-4026-8cd5-feccc135212c" src="/sites/default/files/inline-images/Screen%20Shot%202017-12-27%20at%208.25.13%20AM.png" />Atopic Dermatitis </strong></div>
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<p><i>Atopic Dermatitis Associated With Several Autoimmune Skin Conditions</i></p>
<p>Atopic dermatitis (AD) has previously been linked with several autoimmune skin conditions including inflammatory bowel disease, rheumatoid arthritis (RA), and type 1 diabetes. A recent Danish study looked at 8112 adults diagnosed with AD between 1997 and 2012 and compared them to 40,560 age- and sex-matched controls.<sup>12</sup> They found AD to be significantly associated with alopecia areata (AA), vitiligo, chronic urticaria, celiac disease, chronic glomerulonephritis, Sjögren syndrome, systemic lupus erythematosus, ankylosing spondylitis, Crohn disease, ulcerative colitis, and RA. No significant associations were found between AD, autoimmune thyroid diseases, multiple sclerosis, type 1 diabetes, autoimmune hematologic disease, or pulmonary fibrosis.<sup>12</sup></p>
<p><i>Nemolizumab: Emerging Biologic for Pruritus in AD Patients </i></p>
<p>Pruritus plays a significant role in perpetuating AD and has a profound impact on quality of life. IL-31 is believed to play a role in pruritus in AD through an uncertain mechanism.<sup>13</sup> In a phase 2, 12-week clinical trial, 216 patients with uncontrolled pruritus and AD were randomly assigned to receive subcutaneous nemolizumab, a fully human monoclonal antibody against IL-31, or placebo. The dosing was 0.1 mg/kg, 0.5 mg/kg, or 2.0 mg/kg body weight every 4 weeks for subcutaneous nemolizumab. A significant improvement in pruritus was seen in all dosing groups for nemolizumab. The most common side effects were worsening of AD and peripheral edema.<sup>13</sup></p>
<p><i>Safety of Crisaborole 2% Ointment for Children and Adults With AD </i></p>
<p>Topical steroids and calcineurin inhibitors have been the mainstay topical treatments for children and adults with AD. No new topical agents had been approved for 15 years until crisaborole (Eucrisa) in 2016. A recent phase 3 clinical trial looked at the long-term safety of crisaborole ointment in 517 patients aged 2 years and older with AD over 48 weeks.<sup>14</sup> The most common side effects were upper respiratory tract infection (10.3%), flaring of AD (11.2%), nasopharyngitis (97.7%), cough (6.8%), and pyrexia (5.6%). Most adverse effects were mild (51.2%) to moderate (44.6%) and did not require discontinuation of the product. Based on these findings, crisaborole is a safe, long-term treatment for AD in children and adults.<sup>14</sup> </p>
<p><strong>Infectious Disease </strong></p>
<p><i>Topical Timolol for Classic and HIV-Related Kaposi Sarcoma </i></p>
<p>While previous case series have demonstrated the efficacy of topical timolol 0.05% for classical and HIV-related Kaposi sarcoma, a recent case series suggests lower doses of topical timolol may be just as successful.<sup>15</sup> Four patients with localized, cutaneous Kaposi sarcoma were successfully treated with topical timolol 0.01% gel twice daily until resolution. The average treatment duration until complete resolution was 4 to 6 weeks. No adverse effects related to the topical timolol were reported. One patient terminated treatment at week 6 after being hospitalized with an active tuberculosis. These findings support the use lower dose timolol for classical and HIV-related Kaposi sarcoma.<sup>15</sup> </p>
<p><i>Pneumocystis Pneumonia Prophylaxis in Patients With Bullous Dermatosis on Long- term Immunosuppression </i></p>
<p>Patients with autoimmune blistering disease (AIBD) generally require treatment with long-term immunosuppression. As a result, they are at an increased risk for opportunistic infection. Pneumocystis pneumonia (PCP) rates among dermatologic patients on immunosuppression vary from 0.5% to 2%.<sup>16</sup> Experts have differing opinions as to whether these patients need PCP prophylaxis. In general, PCP incidence of 3.5% is recommended before starting prophylaxis. A retrospective study of patients with AIBD was conducted at 6 tertiary referral centers for AIBD in Germany, Netherlands, Italy, and Singapore.<sup>16</sup> Among the 801 patients with AIBD identified, only one (0.1%) developed PCP in the 3-year follow- up period. This patient, however, was 40 years old and had recalcitrant mucocutaneous pemphigus vulgaris requiring high-dose oral prednisolone in combination with rituximab. Further analysis of only patients with pemphigus vulgaris showed that 1 of 411 patients (0.02%) had PCP. Based on the findings in this large retrospective study, PCP prophylaxis is not indicated in patients with AIBD on systemic immunosuppresants.<sup>16</sup> </p>
<p><i>Improving Diagnostic Accuracy for Lower Extremity Cellulitis</i></p>
<p>Reported misdiagnosis rates for lower extremity cellulitis range from 30% to 90%.<sup>17</sup> Common mimickers include venous stasis dermatitis, lymphedema, deep venous thrombosis, gout, and contact dermatitis. A recent cross-sectional study of 259 patients admitted to a large urban hospital between June 2010 and December 2012 found that 30% of patients admitted with a diagnosis of lower extremity cellulitis were misdiagnosed.<sup>17</sup> Among the 79 misdiagnosed patients, 52 of 79 (66%) were admitted for inpatient treatment of cellulitis, and 42 of the 52 (85%) did not need admission based on their final diagnosis. </p>
<p>Based on these findings, the study authors developed a risk prediction model for diagnosing lower extremity cellulitis called ALT-70.<sup>18</sup> ALT-70 includes 4 variables: unilateral leg involvement, heart rate 90 beats per minute, white blood cell count 10,000, and age 70. Three points were assigned to asymmetric leg involvement, 2 points for age 70, and 1 point for white cell count 10,000 and heart rate 90. Empiric treatment for cellulitis was recommended if patients had 5 or more points. A dermatology consultation was advised for patients with 3 to 4 points. Reassessment was recommended for patients with 2 or fewer points. </p>
<p>Using the cohort of patients from the original study, patients with ALT-70 score of 3 or lower had 83% likelihood of having pseudocellulitis while those with a score above 4 had an 82% likelihood of having true cellulitis. Interestingly, an increased risk of cellulitis among patients with a history of cellulitis, tinea pedis, lymphedema, venous insufficiency, dermatitis, and malignancy was not found. This scoring system is the first step to providing clinicians with a tool to aid in the diagnosis of lower extremity cellulitis.<sup>18</sup> </p>
<div class="small-image left-image"><strong><img alt="autoimmune diseases" data-align="left" data-entity-type="file" data-entity-uuid="58c4d0b1-df71-4623-9ba6-ae4cd0b04bf0" src="/sites/default/files/inline-images/Screen%20Shot%202017-12-27%20at%208.25.19%20AM.png" />Autoimmune and Systemic Disease </strong></div>
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<p><i>Potential Future Treatment for Keratin Disorders </i></p>
<p>Topical broccoli sprout extract (BSE) is being studied as a potential treatment for disorders of keratinization.<sup>19</sup> Sulforaphane, an isothiocyante and key ingredient in BSE, has been shown to increase expression of healing keratins 16 and 17 in mice. A recent study looked at whether these effects are seen in humans.<sup>19</sup> Five healthy individuals were recruited to apply topical BSE to the inner aspect of 1 arm and vehicle only to the other arm daily for 1 week.<sup>19</sup> Both BSE and vehicle treated skin sites were biopsied after 1 week. While 1 patient had to be excluded for poor tissue quality, the remaining 4 patients showed 3.6 higher levels of keratin-17 messenger RNA (<i>P</i>=.0022). Indirect immunofluorescence also showed increased induction of keratin-17 in BSE-treated skin. Keratin-16 expression was increased 10 to 14 times in the 2 female individuals and 4 times in 1 male individual. There was no difference in keratin-16 expression in the other male individual. Indirect immunofluorescence showed elevated keratin-16 in the suprabasal layer of BSE-treated skin in 3 patients. No statistical difference was found in keratin 5, 6, and 15 RNA expression levels. Further studies are needed including patients with epidermolysis bullosa simplex to determine whether topical BSE is a potential treatment option.<sup>19</sup></p>
<p><i>Treatment of Cutaneous Manifestations of Tuberous Sclerosis With Topical Sirolimus </i></p>
<p>Cutaneous manifestations of tuberous sclerosis include angiofibromas, shagreen patches, hypomelanotic macules, and periungual fibromas. Since 2010, several studies have been published on the efficacy of topical sirolimus for treating facial angiofibromas, but none on other cutaneous manifestations.<sup>20</sup> In a recent study on topical sirolimus for facial angiofibromas, cephalic plaques, shagreen patches, hypomelanotic macules, and periungual fibromas, 25 patients used topical sirolimus daily and were followed for 18 months.<sup>20</sup> Half of the patients had clinical clearance of their facial angiofibromas after 9 months of treatment. Among 7 of the 12 patients who agreed to use a maintenance regimen of 3 times weekly application, 6 had recurrence of facial angiofibromas within 2 months. No significant response was seen with topical tacrolimus for fibrous cephalic plaques, shagreen patches, hypomelanotic patches, and periungual fibromas. No series adverse effects were seen over 18 months. There was mild aggravation of facial acne in 3 patients, aseptic folliculitis at the site of application in 1 patient, and mild irritation in 8 patients. Topical sirolimus is an effective and safe treatment for angiofibromas but must be used regularly to maintain clearance. It is not effective for other cutaneous manifestations of tuberous sclerosis.<sup>20</sup> </p>
<p><i>Cyclosporine May Provide Mortality Benefit in SJS</i></p>
<p>To date, the role of corticosteroids, intravenous immunoglobulin, cyclosporine, and other immunomodulators in the treatment of Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) remains unclear. Lee and colleagues evaluated the effect of cyclosporine for SJS/TEN patients at a large academic hospital by comparing SCORTEN predicted mortality to actual mortality.<sup>21</sup> Twenty-four patients were randomized to receive cyclosporine 3 mg/kg for 10 days, 10 mg/kg for the next 10 days, and then 1 mg/kg/day for 10 days. Twenty patients received only supportive care. Patients who received cyclosporine were younger (50 years of age; <i>P</i>=.009) and had a lower incidence of cardiac disease (<i>P</i>=.035). There was no difference in terms of disease classification, SCORTEN scores on admission, or maximum body surface area. </p>
<p>In the cyclosporine group, SCORTEN predicted 7.2 deaths, and 3 actual deaths occurred. In the supportive care only group, SCORTEN predicted 5.9 deaths, and 6 deaths occurred. Among the 19 patients who only received cyclosporine and no other immunomodulatory therapies (intravenous immunoglobulin or systemic steroids), 2 deaths were observed while 5.3 were predicted. Nine patients did have to stop cyclosporine during the study due to worsening renal function. This study is the first trial to show survival benefit with the use of cyclosporine in SJS/TEN.<sup>21</sup></p>
<p><i>Bullous Pemphigoid and Malignancy </i></p>
<p>The association with bullous pemphigoid (BP) and malignancy is controversial. While some studies have demonstrated an association, others have not. A recent systemic review of all studies on BP and malignancy found an association between BP and hematologic malignancies, including Hodgkin lymphoma, non-Hodgkin lymphoma, mature natural killer/T-cell lymphoma, myeloid leukemia, and leukemia unspecified.<sup>22</sup> Hematological malignancy preceded the diagnosis of BP in half of the patients. There were no other malignancies with significant associations with BP. These findings are limited due to the retrospective and observational nature of all available studies on BP and malignancy. It is important to ensure all newly diagnosed patients with BP are up-to-date on age-appropriate cancer screening, but further investigational workup is not recommended.<sup>22</sup></p>
<div class="small-image left-image"><strong><img alt="vitiligo on fingers" data-align="left" data-entity-type="file" data-entity-uuid="e923eae0-40d1-4175-9c1c-df0e10ba2ae0" src="/sites/default/files/inline-images/Screen%20Shot%202017-12-27%20at%208.25.32%20AM.png" />Vitiligo</strong></div>
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<p><i>Repigmentation With Phototherapy </i></p>
<p>Treatment options for vitiligo include phototherapy such as psoralen–UV-A (PUVA) and narrowband UV-B, laser therapy, and various topical agents. Phototherapy, a popular treatment option, has varying rates for repigmentation and duration of treatment. A database review examined all prospective trials on phototherapy for vitiligo.<sup>23</sup> Regimentation with narrowband UV-B was mild (>25% repigmentation) in 75% of 512 patients and marked (>75% response) in 35.7% of 540 patients. The face and neck responded best with 44% of 153 patients showing a marked repigmentation response. No repigmentation was seen on the hands and feet in 172 patients. PUVA phototherapy had lower rates of repigmentation with mild response in 61.6% of 72 patients at 12 months and marked response in 13.6% of 72 patients. Based on these findings, 1 year is needed to see the maximal response from phototherapy for vitiligo lesions.<sup>23</sup></p>
<p><i>Oral Simvastatin and Vitiligo</i></p>
<p>Vitiligo is thought to be a T<sub>h</sub>1-cell-mediated autoimmune disease with high levels of interferon (IFN)-γ and chemokines CXCL0 and CXCL10 promoting depigmentation. In mouse models, simvastatin has been shown to inhibit the activation of STAT1, which prevents IFN-γ induced signaling of CXCL10. Repigmentation in a patient with vitiligo on simvastatin has been described in the literature. A recent double-blind, placebo-controlled, phase 2 clinical trial failed to show repigmentation in any of the patients.<sup>24</sup> Fifteen patients with vitiligo were randomly assigned to simvastatin 40 mg daily for 1 month followed by 90 mg daily for another 5 months or placebo. All other treatments were discontinued prior to the study with washout periods. Worsening of vitiligo was seen in 26% of patients in the oral simvastatin group (<i>P</i>=.094), and no effect was seen on serum levels of CXCL10. These results do not support the use of oral simvastatin in the treatment of vitiligo.<sup>24</sup> </p>
<p><i>Janus Kinase Inhibitors for Treating Vitiligo </i></p>
<p>Janus kinase (JAK) inhibitors, specifically JAK 1/2, have been shown to inhibit IFN-γ signaling and are potential treatments for vitiligo. Two studies on JAK inhibitors for vitiligo have been recently published. In a phase 2 clinical trial, 11 patients with vitiligo used topical ruxolitinib 1.5% cream (Jakafi), a JAK 1/2 inhibitor, twice daily for more than 20 weeks.<sup>25</sup> Application of topical ruxolitinib was restricted to 10% body surface area or 3.75 g of topical ruxolitinib per exposure. Based on Vitiligo Area Scoring Index scores, four of 11 patients with facial vitiligo experienced 75% improvement at week 20 (<i>P</i>=.001). Repigmentation was minor and not significant at other body sites. Erythema at the application site occurred in 8 of 11 patients and was the most common adverse effect. Two patients experienced a transient, mild papular eruption on the face that resolved. No laboratory monitoring was performed during this study.<sup>25</sup> </p>
<p>Ten patients with vitiligo took oral tofacitinib (Xeljanz), a JAK 1/3 inhibitor, for an average of 10 months in another study.<sup>26</sup> Baseline laboratory analysis was obtained. Patients received either 5 to 10 mg oral tofacitinib daily or twice daily. While 5 of 10 patients did experience repigmentation, repigmentation occurred only in sun-exposed areas in 3 of the 5 patients. The other 2 patients with repigmentation were also being treated concurrently with narrowband UV-B. Of the five patients with no repigmentation, only 1 reported sun exposure while the remaining 4 practiced sun avoidance. Four patients had mild elevated lipid levels. Two patients experienced an upper respiratory tract infection. JAK inhibitors may require light exposure to achieve repigmentation based on data from both of these studies.<sup>25,26</sup></p>
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<p><strong>Hair</strong></p>
<p><i>Systemic Tofacitinib as a Treatment for Alopecia Areata and its Variants</i></p>
<p>Use of tofacitinib as a treatment for AA and its variants was discussed in last year’s Year in Review article<sup>27</sup>; however, further data regarding safety and efficacy in a variety of age groups and use of topical formulations have been added to the literature this year. Multiple single-site, retrospective studies have been performed evaluating tofacitinib in the treatment of AA and its variants.<sup>28,29</sup> </p>
<p>The study by Ibrahim and colleagues evaluated 13 adult patients (7 had alopecia universalis (AU), 2 had alopecia totalis (AT), and 4 had AA treated with tofacitinib. Mean pretreatment scalp hair loss was 93%. Patients were treated with tofacitinib 5 mg twice a day, monotherapy, with other treatments for AA ceased prior to initiation of tofacitinib. The tofacitinib was
