Age affects drug survival rates of interleukin (IL)-17 and IL-23 inhibitors in patients with plaque psoriasis: Results from a retrospective, multicentric, multi-country, cohort study.

BACKGROUND: Scarce data related to the drug survival of biologic agents in psoriasis patients aged ≥65 years is available. OBJECTIVES: To evaluate the drug survival of interleukin (IL)-23 or the IL-17 inhibitors approved for the treatment of moderate-to-severe psoriasis in elderly patients (aged ≥65 years), compared with younger adult patients (aged <65 years), and to identify clinical predictors that can influence the drug survival. METHODS: This retrospective multicentric cohort study included adult patients with moderate-to-severe psoriasis, dissecting two-patient subcohorts based on age: elderly versus younger adults. Kaplan-Meier estimator and proportional hazard Cox regression models were used for drug survival analysis. RESULTS: We included 4178 patients and 4866 treatment courses; 934 were elderly (1072 treatment courses), and 3244 were younger patients (3794 treatment courses). Drug survival, considering all causes of interruption, was higher in patients aged <65 years than in elderly patients overall (log-rank p < 0.006). This difference was significant for treatment courses involving IL-23 inhibitors (p < 0.001) but not for those with IL-17 inhibitors (p = 0.2). According to both uni- and multi-variable models, elder age was associated with an increased risk of treatment discontinuation (univariable analysis: HR: 1.229, 95% CI 1.062-1.422; p < 0.006; multivariable analysis: HR: 1.199, 95% CI 1.010-1.422; p = 0.0377). Anti-IL-23 agents were associated with a reduced likelihood of treatment discontinuation after adjusting for other variables (HR: 0.520, 95% CI 0.368-0.735; p < 0.001). Being previously treated with IL-17 inhibitors increased the probability of discontinuation. CONCLUSION: Elderly patients with psoriasis have an increased risk of biologic treatment discontinuation compared with younger adult patients, particularly, if being treated with IL-23 inhibitors. However, in stratified analyses conducted in elderly patients, IL-23 inhibitors showed higher drug survival rates than IL-17 inhibitors.

Impact of Single Nucleotide Polymorphisms of the Promoter of the TNF Gene on Adalimumab Treatment Responses in Hidradenitis Suppurativa.

BACKGROUND: Results of randomized clinical trials show great variation in response to treatment with adalimumab (ADA) in hidradenitis suppurativa (HS). This varied response may be associated with genetic polymorphisms. OBJECTIVES: The aim of the study was to study the association between carriage of single nucleotide polymorphisms (SNPs) in the promoter of the tumor necrosis factor (TNF) gene and their response to ADA. METHODS: Patients with moderate to severe HS who received ADA treatment for at least 12 weeks were enrolled. SNPs were analyzed with PCR-restriction fragment length polymorphism. Hidradenitis Suppurativa Clinical Response (HiSCR) score, International Hidradenitis Suppurativa Severity Scoring System 4 (IHS4) score, inflammatory lesion (AN) count, and draining tunnel (dT) count were collected at weeks 0, 12, 24, 36, and 48. RESULTS: HiSCR response after 12 weeks of ADA treatment was 71.8% among carriers of the common GGG haplotype and 50.0% among carriers of minor frequency SNP haplotypes (p: 0.031; odds ratio: 0.39). This significant difference persisted until week 36. Carriers of minor frequency SNP haplotypes also had a lower relative decrease of the AN count at weeks 12 and 24; the dT count and IHS4 were not statistically different between the two groups. CONCLUSIONS: Carriage of at least one minor frequency SNP haplotype of the promoter of the TNF gene is associated with a decreased response to ADA. This association may have an impact on treatment decision-making.

External Validation of the IHS4-55 in a European Antibiotic-Treated Hidradenitis Suppurativa Cohort.

BACKGROUND: Previously, a new dichotomous outcome was developed, calculated as 55% reduction in the International Hidradenitis Suppurativa 4 (IHS4-55) score. It was validated in datasets of adalimumab and placebo-treated HS patients. External validation is an important aspect of clinical outcomes. OBJECTIVES: We aimed to externally validate the novel dichotomous IHS4-55 in a non-biologic treated dataset of HS patients. METHODS: Data from a previously published European-wide prospective clinical study of antibiotic treatment of HS patients were used to assess the association of IHS4-55 achievement with individual reduction in inflammatory nodules, abscesses, and draining tunnels. Moreover, the associations between IHS4-55 positivity and achievement of the minimal clinically important differences (MCIDs) for Dermatology Life Quality Index (DLQI), Numerical Rating Scale (NRS) Pain, and NRS Pruritus were analyzed. RESULTS: Data were obtained from 283 individual patients, of which 36.4% (103/283) were treated with clindamycin and rifampicin and 63.6% (180/283) with tetracyclines for 12 weeks. Achievers of the IHS4-55 demonstrated a significant reduction the counts of inflammatory nodules, abscesses, and draining tunnels (all p < 0.001). Additionally, IHS4-55 achievers had an odds ratio for achieving the MCID of DLQI, NRS Pain, and NRS Pruritus of 2.16 (95% CI 1.28-3.65, p < 0.01), 1.79 (95% CI 1.10-2.91, p < 0.05), and 1.95 (95% CI 1.18-3.22, p < 0.01), respectively. CONCLUSIONS: This study shows the external validity of the novel IHS4-55 by demonstrating a significant association between IHS4-55 achievement and a reduction in inflammatory lesion counts as well as achievement of MCIDs for DLQI, NRS Pain, and NRS Pruritus in an antibiotic-treated cohort. These findings support the use of the IHS4-55 as a novel primary outcome measure in clinical trials.

A retrospective multicentric cohort study of checkpoint inhibitors-induced pruritus with focus on management.

BACKGROUND: Limited data on immune checkpoint inhibitor (ICI)-induced pruritus per se and efficacy of different therapeutic modalities in its management exist. OBJECTIVE: To study the quantitative and qualitative characteristics of ICI-induced pruritus per se and to assess the efficacy of the therapeutic modalities usually applied. METHODS: We retrospectively reviewed the records of 91 patients who were under treatment with ICIs for any kind of neoplasia and developed pruritus during treatment. RESULTS: Twenty out of 91 individuals (22.0%) with ICI-induced pruritus had pruritus as the only symptom, while 71/91 (78.0%) presented with pruritus coexisting with an additional cutaneous toxicity. Pruritus was treated with antihistamines (18/20, 90.0%) and/or topical regimens, as first-line choice. In resistant cases, as a second therapeutic intervention, narrow-band UVB (NBUVB), oral steroids and GABA analogs were added (70.0%). Statistical analysis revealed a significant difference in mean pruritus Numerical Rating Scale (NRS) scores between baseline and sequential visits. Moreover, subgroup analysis revealed a significant reduction in mean NRS scores in those treated with phototherapy. LIMITATIONS: Retrospective design, low number of patients and survivorship bias. CONCLUSION: Pruritus per se was present in a substantial portion of our cohort (22.0%). Our study confirms the efficacy of current treatment strategies and suggests NBUVB as a potential steroid-sparing therapeutic alternative.

Clinical associations and classification of immune checkpoint inhibitor-induced cutaneous toxicities: a multicentre study from the European Academy of Dermatology and Venereology Task Force of Dermatology for Cancer Patients.

BACKGROUND: Cutaneous immune-related adverse events (irAEs) represent the most frequent toxicities induced by immune checkpoint inhibitors (ICIs). OBJECTIVES: To investigate clinical associations of cutaneous toxicities induced by different ICI therapies. METHODS: This was a multicentre retrospective international cohort study of patients with cancer who developed cutaneous irAEs under ICI therapy. Analysis was performed of the rates and basic characteristics of all cutaneous toxicities, and identification of any associations was performed using univariate and multivariate models. RESULTS: In total, 762 patients were included, who developed 993 cutaneous toxicities. Forty different types of skin toxicities were identified. Psoriasis (175 patients, 23·0%) and pruritus (171 patients, 22·4%) were the most common toxicities, followed by macular rash (161 patients, 21·1%) and eczematous-type reactions (150 patients, 19·7%). Multivariate analysis showed that among patients with macular rash, vitiligo or multiple toxicities, patients received ICIs more frequently for melanoma than for NSCLC. Moreover, anti-CTLA4 was less frequent than anti-programmed death 1 treatment in patients with macular rash [odds ratio (OR) 0·11, 95% confidence interval (CI) 0·01-0·76] and vitiligo (OR 0·07, 95% CI 0·006-0·78). A significant association was also seen in patients treated with a combination of ICI and chemotherapy vs. ICI monotherapy. They less frequently developed psoriasis (OR 0·08, 95% CI 0·02-0·31), lichenoid reactions (OR 0·15, 95% CI 0·03-0·77) and eczematous reactions (OR 0·24, 95% CI 0·07-0·78), all compared with pruritic rash. CONCLUSIONS: Our study showed that skin-oriented toxicities do not share a single pattern and are related to several factors, including the specific agent administered and the underlying malignancy treated. Follow-up plans should be individualized in order to minimize the risk for severe reactions that could compromise optimum therapeutic outcome. What is already known about this topic? Patients with cancer treated with different immune checkpoint inhibitors (ICIs) carry an increased risk of developing various types of skin toxicities. What are the clinical implications of this work? In this multicentre cohort study we showed that ICI-related skin toxicities do not share a single pattern and may depend on several factors, including the specific agent administered and the underlying malignancy. Among patients with macular rash, vitiligo or multiple skin toxicities, patients received ICIs more frequently for melanoma than for non-small cell lung cancer. The combination of ICI and chemotherapy compared with ICI monotherapy occurred to a lesser extent in patients with psoriatic rash lichenoid and eczematous reactions, compared with patients with pruritus. Clinical awareness and specialized dermatological consultation should be advocated.

Evaluation of dermatoscopic criteria for early detection of squamous cell carcinoma arising on an actinic keratosis.

BACKGROUND: Advanced squamous cell carcinoma (SCC) can be discriminated easily from actinic keratosis (AK) based on clinical and dermatoscopic features. However, at the initial stage of dermal invasion, SCC might still be clinically flat and discrimination from AK remains challenging, even with the addition of dermatoscopy. OBJECTIVE: The aim of this study was to investigate the clinical and dermatoscopic criteria that could suggest early invasion and serve as potent predictors to discriminate early SCC from AK. METHODS: Clinical and dermatoscopic images of histopathologically diagnosed AKs and early SCCs were evaluated for the presence of predefined criteria by 3 independent investigators. RESULTS: A total of 50 early SCCs and 45 AKs were included. The main positive dermatoscopic predictors of early SCC were dotted/glomerular vessels (odds ratio [OR] 3.83), hairpin vessels (OR 12.12), and white structureless areas (OR 3.58), whereas background erythema represented a negative SCC predictor (OR 0.22). LIMITATIONS: The retrospective evaluation of images. Moreover, the differential diagnosis included in the study is restricted between AK and early SCC. CONCLUSIONS: We identified potent predictors for the discrimination of AK and early SCC that may better guide management decisions in everyday clinical practice.

Dysregulation of Plasma miR-146a and miR-155 Expression Profile in Mycosis Fungoides Is Associated with rs2910164 and rs767649 Polymorphisms.

Diagnosis of Mycosis Fungoides (MF) may be challenging, due to its polymorphic nature. The use of miRNAs as biomarkers to assist in diagnosis has been investigated, mainly in skin lesion biopsies. The purpose of this study is to evaluate the plasma levels of miR-146a and miR-155 in MF patients and to investigate their association with SNPs of their genes. Plasma miRNAs were quantified by RT-qPCR. Genomic DNA was used for SNPs' genotyping by Sanger sequencing. Plasma levels of miR-146a and miR-155 were significantly higher in patients vs. controls, in early MF patients vs. controls, and in advanced vs. early MF patients. Both miRNAs' levels were significantly higher in stage IIB vs. early-stage patients. miR-155 plasma levels were significantly higher in patients with skin tumors or erythroderma. CC genotype (rs2910164 C>G) was significantly more frequent in healthy controls and associated with lower MF risk and lower miR-146a levels. The AA genotype (rs767649 T>A) was significantly more frequent in patients and correlated with increased MF risk and increased miR-155 levels. The combination of GG+AA was only detected in patients and was correlated with higher MF susceptibility. Increased mir-146a and mir-155 plasma levels in MF is an important finding to establish putative noninvasive biomarkers. The presence of SNPs is closely associated with miRs' expression, and possibly with disease susceptibility.

The efficacy and tolerability of tetracyclines and clindamycin plus rifampicin for the treatment of hidradenitis suppurativa: Results of a prospective European cohort study.

BACKGROUND: Tetracyclines and clindamycin plus rifampicin combination therapy are both considered first-line therapy in current hidradenitis suppurativa guidelines. However, evidence for their efficacy is drawn from small studies, often without validated outcomes. OBJECTIVE: To assess the 12-week efficacy of oral tetracyclines and a combination of clindamycin and rifampicin. METHODS: A prospective, international cohort study performed between October 2018 and August 2019. RESULTS: In total, 63.6% of the included 283 patients received oral tetracyclines, and 36.4% were treated with clindamycin and rifampicin. Both groups showed a significant decrease in International Hidradenitis Suppurativa Severity Score System from baseline (both P < .001). The Hidradenitis Suppurativa Clinical Response (HiSCR) was achieved in 40.1% and 48.2% of patients, respectively (P = .26). Patient characteristics or disease severity were not associated with the attainment of HiSCR or the minimal clinically important differences for the Dermatology Life Quality Index and pain. LIMITATIONS: Cohort study. Respectively, 23.9% and 19.4% of patients had to be excluded from the HiSCR analysis for the tetracycline and combination therapy group because of a low abscess and nodule count at baseline. CONCLUSION: This study shows significant efficacy of both tetracycline treatment and clindamycin and rifampicin combination therapy after 12 weeks in patients with hidradenitis suppurativa. No significant differences in efficacy were observed between the 2 treatments, regardless of disease severity.

Challenges in sarcoidosis and sarcoid-like reactions associated to immune checkpoint inhibitors: A narrative review apropos of a case.

Sarcoidosis and sarcoid-like reactions (SLRs) may develop in association with various malignancies, as well as in association to certain oncologic drugs, including immune checkpoint inhibitors (ICIs). We aimed to perform a narrative review with regard to the development of ICIs-associated sarcoidosis or SLRs, and to discuss the corresponding diagnostic and therapeutic challenges raised in this scenario. Apropos of a melanoma patient developing SLRs while treated with ipilimumab and nivolumab, we searched for clinically evident, ICIs-associated sarcoidosis or SLRs in the English literature. We recorded the oncologic characteristics, including type of malignancy and type of ICI, the phenotypic characteristics of sarcoidosis/SLRs, as well as the impact on immunotherapy. Including our patient, we identified 80 ICIs-associated sarcoidosis or SLRs cases. Both sexes were equally affected (40 F/40 M) and the most common malignancy was melanoma (65/80, 81.3%). Concerning the oncologic treatment, there was a predilection for pembrolizumab (23/80, 28.7%), followed by the ipilimumab/nivolumab combination (21/80, 26.3%), ipilimumab (18/80, 22.5%), nivolumab (16/80, 20.0%). Although in the majority of the cases (52/80, 65.0%) there was no need for systemic prednisolone for the management of sarcoidosis, a significant proportion of patients finally discontinued ICIs treatment (44/80, 55.0%). Phenotypically, sarcoidosis and SLRs highly imitate oncologic progression posing diagnostic difficulties. A therapeutic dilemma is also raised when there is a need for systemic prednisolone, since the latter may jeopardize the therapeutic efficacy of immunotherapy. Sarcoidosis and SLRs, though rare, can present in oncologic patients treated with ICIs. Clinicians should be aware of this possibility and the related diagnostic and therapeutic challenges they have to face in this scenario.

Second primary melanomas in a cohort of 977 melanoma patients within the first 5 years of monitoring.

BACKGROUND: In retrospective studies, a second primary melanoma (SPM) develops in 2%-20% of melanoma patients. Scarce evidence exists on the usefulness of total-body photography (TBP) and digital dermatoscopic documentation (DDD) for detecting SPMs. OBJECTIVE: The primary aim was to quantify the risk and investigate the time of occurrence of SPMs. Secondary aims were to identify risk factors for SPM and to assess the usefulness of TBP and DDD for SPM detection. METHODS: This prospective cohort included patients with recently diagnosed melanoma that underwent sequential clinical and dermatoscopic examinations for up to 5 years. Life table analysis and Kaplan-Meier survival analysis were performed. Multivariate Cox models were constructed to identify factors affecting the outcome. RESULTS: An SPM developed in 46 of 977 (4.7%) patients. Life table analysis revealed a 5-year cumulative risk of 8.0% for SPM. High nevus count, fair phototype, and occupational sun exposure were potent predictors of SPM. Of all new melanomas, 17.3% were diagnosed by clinical and dermatoscopic examination, 48.1% by TBP, and 34.6% by DDD. LIMITATIONS: All patients followed the same protocol and diagnostic bias associated with sequential dermatoscopic imaging. CONCLUSION: In this cohort, melanoma patients were at 8% risk of an SPM developing within 5 years. TBP and DDD significantly contributed to the early detection of SPM.

Total IgE, eosinophils, and interleukins 16, 17A, and 23 correlations in severe bullous pemphigoid and treatment implications.

Bullous pemphigoid (BP) patients are predominantly above 70 years of age, with limited tolerance to the side effects of the immunosuppressive drugs. Advancements in our understanding of the pathophysiology of BP have led to the development of molecules which target specific pathways involved in induction and perpetuation of disease. Patients with BP Disease Area Index above 60 and less than 100 were split into two groups-one with high and the other with normal levels of IgE. The tested parameters included eosinophils' count, total IgE serum level, and interleukins (IL) 16, 17A, and 23 counts in the peripheral blood and skin bulla serum, before any therapeutic intervention. Thirty individuals fulfilled the criteria for enrollment. Patients with high IgE blood serum levels had significantly higher levels of IL17A and normal IL23 levels in blood and bulla serum. Patients with normal serum IgE levels had slightly higher IL23 levels in blood and bulla serum. The eosinophil count was positively related to IL17 blood serum level and negatively related to IL23. IL16 did not differ in the two groups. BP patients may represent a group of patients benefiting most substantially from the introduction of nonimmunosuppressive therapeutics into the treatment regimens for their disease. Clinical criteria and immune biomarkers are needed for making the best therapeutic choice.

The dermatoscopic spectrum of cutaneous lupus erythematosus: A retrospective analysis by clinical subtype with clinicopathological correlation.

The skin is the most common organ of involvement during the course of lupus erythematosus (LE). The literature data concerning the dermatoscopic patterns of the different clinical variants of cutaneous LE (CLE), namely chronic (CCLE), subacute (SCLE), and acute (ACLE), are scarce. To determine the dermatoscopic spectrum of CLE and to correlate the dermatoscopic features with the histological findings. This was a retrospective, observational, multicenter, cohort study. We evaluated the dermatoscopic features in a cohort of patients diagnosed with CLE. Furthermore, we investigated their frequency per clinical subtype and correlated them with the anatomic alterations. We included 79 patients. The most prevalent dermatoscopic features of CCLE included follicular plugs (86.4%, P < .01), patchy distribution (75%, P = .1) of mostly linear curved vessels (56.8%, P = .8), white scales (68.2%, P < .01), and structureless white color (68.2%, P < .01). The most common criteria of SCLE were patchy distribution (90%, P = .1) of mostly linear curved vessels (53.3%, P = .8) and fine white scales (60%, P < .01), while ACLE was characterized by erythema (100%, P < .05) and patchy distribution (100%, P = .1) of mostly dotted vessels (60%, P = .4). Follicular plugs/rosettes in dermatoscopy strongly correlated with follicular plugs in histology (rho = 0.919). Hyperkeratosis significantly correlated with white (rho = 0.644) and yellow/brown scales (rho = 0.225), telangiectasia with linear curved vessels (rho = 0.321) and white color with dermal fibrosis (rho = 0.623). Depending on CLE subtype, distinct dermatoscopic patterns are recognized. In CLE there is a high correlation between certain dermatoscopic criteria and the underneath anatomic alteration.

Protein and mRNA Expression Levels of Interleukin-17A, -17F and -22 in Blood and Skin Samples of Patients with Mycosis Fungoides.

This study investigated the expression of interleukin (IL)-17A, -17F and -22 in mycosis fungoides. Blood samples were collected from 50 patients with mycosis fungoides and 50 healthy controls. Skin samples were obtained from 26 patients with mycosis fungoides and 5 healthy controls. Protein levels of IL-17A, -17F and -22 were measured in serum by multiplex enzyme-linked immunosorbent assay, and mRNA expression levels were measured in blood and skin samples by real-time quantitative reverse transcription PCR. Both IL-17A and IL-17F mRNA expression levels were significantly lower in blood of patients with mycosis fungoides in comparison with healthy controls. IL-22 serum levels and expression levels of IL-22 mRNA in skin tissue, were significantly increased in patients with mycosis fungoides in comparison with healthy controls. These results suggest that low levels of IL-17A and IL-17F in mycosis fungoides may be connected to impaired immune surveillance contributing to tumourigenesis. Upregulation of IL-22 may play a role in the establishment of the tumour microenvironment in mycosis fungoides.

Dermoscopy of pagetoid reticulosis, with dermoscopic-pathologic correlation.

Pagetoid reticulosis (PR), also known as Woringer-Kolopp disease, is a rare variant of mycosis fungoides with distinctive clinicopathologic features. It clinically manifests as a solitary, erythematous, gradually enlarging, scaly, or verrucous plaque on the lower extremities, and due to its indolent course and nonspecific clinical features, may remain undiagnosed for years. In the current study, we describe the clinical and dermoscopic characteristics of a rare case of PR disease and correlate them with the corresponding histopathologic findings. Dermoscopy may prove beneficial in early diagnosis of this rare entity.