Disease phenotypes in adult patients with suspected undifferentiated autoinflammatory diseases and PFAPA syndrome: Clinical and therapeutic implications.

BACKGROUND: Undifferentiated autoinflammatory diseases are characterized by recurrent or persistent fever, usually combined with other inflammatory manifestations, and negative or inconclusive genetic studies for monogenic autoinflammatory disorders. AIMS: To define and characterize disease phenotypes in adult patients diagnosed in an adult reference center with undifferentiated autoinflammatory diseases, and to analyze the efficacy of the drugs used in order to provide practical diagnostic and therapeutic recommendations. METHODS: Retrospective study (2015-2022) of patients with undifferentiated autoinflammatory diseases among all patients visited in our reference center. Demographic, clinical, laboratory features and detailed therapeutic information was collected. RESULTS: Of the 334 patients with a suspected autoinflammatory disease, 134 (40%) patients (61% women) were initially diagnosed with undifferentiated autoinflammatory diseases. Mean age at disease onset and at diagnosis was 28.7 and 37.7 years, respectively. In 90 (67.2%) patients, symptoms started during adulthood. Forty-four (32.8%) patients met diagnostic/classification criteria for adult PFAPA syndrome. In the remaining patients, four additional phenotypes were differentiated according to the predominant manifestations: a) Predominantly fever phenotype (n = 18; 13.4%); b) Predominantly abdominal/pleuritic pain phenotype (n = 9; 6.7%); c) Predominantly pericarditis phenotype (n = 18; 13.4%), and d) Complex syndrome phenotype (n = 45; 33.6%). Prednisone (mainly on demand), colchicine and anakinra were the drugs commonly used. Overall, complete responses were achieved with prednisone in 41.3%, colchicine in 40.2%, and anakinra in 58.3% of patients in whom they were used. By phenotypes, prednisone on demand was more effective in adult PFAPA syndrome and colchicine in patients with the abdominal/pleuritic pain pattern and PFAPA syndrome. Patients with complex syndrome achieved complete responses with prednisone (21.9%), colchicine (25.7%) and anakinra (44.4%), and were the group more often requiring additional immunosuppressive drugs. CONCLUSIONS: The analysis of the largest single-center series of adult patients with undifferentiated autoinflammatory diseases identified and characterized different disease phenotypes and their therapeutic approaches. This study is expected to contribute to increase the awareness of physicians for an early identification of these conditions, and to provide the best known therapeutic options.

Can Ultrasound Examinations Generate Pain in Hidradenitis Suppurativa Patients? Results from a Multicentric Cross-Sectional Study.

BACKGROUND: Pain is not a trivial issue for hidradenitis suppurativa (HS) patients and has been considered a domain in the Core Outcome Set. To date, there is no evidence about pain caused by the ultrasound examinations. OBJECTIVE: The aim of the study was to assess the presence of pain generated by the ultrasound examinations of HS patients. METHODS: A multicentric cross-sectional study for detecting pain during the ultrasound examinations of HS patients using a validated verbal questionnaire immediately after the imaging studies. Statistical analysis included demographic data and possible associations with sex, age, location, clinical (Hurley), and ultrasonographic scoring (SOS-HS). The statistical tests were two proportions Z test, χ2 test, Student's t test, and ANOVA. A p < 0.05 was considered significant. RESULTS: 317 patients met the criteria. 77.3% of them did not present pain. Of cases with pain, 59.8% were mild, 16.7% moderate, and 23.6% severe. No significant association was found with sex, age, staging, location, or the number of affected regions. Although nonsignificant, severe pain cases were more frequent in the clinical Hurley III and ultrasonographic SOS-HS III stages. CONCLUSION: Pain generated by the ultrasound examination of HS patients is infrequent.

Diagnostics Using Non-Invasive Technologies in Dermatological Oncology.

The growing incidence of skin cancer, with its associated mortality and morbidity, has in recent years led to the developing of new non-invasive technologies, which allow an earlier and more accurate diagnosis. Some of these, such as digital photography, 2D and 3D total-body photography and dermoscopy are now widely used and others, such as reflectance confocal microscopy and optical coherence tomography, are limited to a few academic and referral skin cancer centers because of their cost or the long training period required. Health care professionals involved in the treatment of patients with skin cancer need to know the implications and benefits of new non-invasive technologies for dermatological oncology. In this article we review the characteristics and usability of the main diagnostic imaging methods available today.

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.

Severe blistering eruptions induced by immune checkpoint inhibitors: a multicentre international study of 32 cases.

Among dermatologic adverse events induced by immune checkpoint inhibitors (ICI), bullous life-threatening reactions are rare. To better define the clinical and histological features, treatment, and prognosis of ICI-related severe blistering cutaneous eruptions. This retrospective case series was conducted between 2014/05/15 and 2021/04/15 by the dermatology departments of four international registries involved in drug reactions. Inclusion criteria were age ≥18 years old, skin eruption with blisters with detachment covering ≥1% body surface area and at least one mucous membrane involved, available pictures, and ICI as suspect drug. Autoimmune bullous disorders were excluded. Each participant medical team gave his own diagnosis conclusion: epidermal necrolysis (EN), severe lichenoid dermatosis (LD), or unclassified dermatosis (UD). After a standardized review of pictures, cases were reclassified by four experts in EN or LD/UD. Skin biopsies were blindly reviewed. Thirty-two patients were included. Median time to onset was 52 days (3-420 days). Cases were originally diagnosed as EN in 21 cases and LD/UD in 11 cases. After review by experts, 10/21 EN were reclassified as LD/UD. The following manifestations were more frequent or severe in EN: fever, purpuric macules, blisters, ocular involvement, and maximal detachment. Most patients were treated with topical with or without systemic corticosteroids. Eight patients (25%) died in the acute phase. The culprit ICI was not resumed in 92% of cases. In three patients, another ICI was given with a good tolerance. Histology did not reveal significant differences between groups. Severe blistering cutaneous drug reactions induced by ICI are often overdiagnosed as EN. Consensus for management is pending.

Timeline of Adverse Events during Immune Checkpoint Inhibitors for Advanced Melanoma and Their Impacts on Survival.

Immune-related adverse events (irAEs) are frequent and could be associated with improved response to immune checkpoint inhibitors (ICIs). A prospective cohort of advanced melanoma patients receiving ICI as first-line therapy was retrospectively reviewed (January 2011−February 2019). A total of 116 of 153 patients presented with at least one irAE (75.8%). The most frequent irAEs were dermatological (derm irAEs, 50%), asthenia (38%), and gastrointestinal (29%). Most irAEs appeared within the first 90 days, while 11.2% appeared after discontinuation of the therapy. Mild grade 1−2 derm irAEs tended to appear within the first 2 months of therapy with a median time of 65.5 days (IQR 26-139.25), while grade 3−4 derm irAEs appeared later (median 114 days; IQR 69-218) and could be detected at any time during therapy. Only derm irAE occurrence was related to improved survival (HR 6.46). Patients presenting derm irAEs showed better 5-year overall survival compared to those with no derm irAEs (53.1% versus 24.9%; p < 0.001). However, the difference was not significant when adjusting for the duration of therapy. In conclusion: the timeline of immune-related-AEs differs according to the organ involved. The (apparent) improved survival of patients who present derm AEs during immunotherapy could be partially explained by longer times under treatment.

Multicentric Study on High-Frequency Ultrasound Characterization of Calcium Deposits in Dermal and Subcutaneous Calciphylaxis and Calcinosis.

OBJECTIVES: Calcium depositions are frequent in multiple inflammatory dermatosis, they can be explored by ultrasound (US) but the patterns of these depositions have not yet been described. The aim of this study is to describe different patterns of calcium deposition in inflammatory dermatoses. METHODS: The clinical and US data of 58 patients from 7 different centers with inflammatory dermatosis showing ultrasonography-detected calcium depositions was retrospectively reviewed. RESULTS: Dystrophic calcinosis represented 86.2%, calciphylaxis 8.6%, and metastatic calcinosis 5.2%. Three different sonographic patterns of calcium deposition were found: 1) thin hyperechoic bands, parallel to the surface of the epidermis, generating a strong and wide posterior acoustic shadow; 2) hyperechoic spots or lumps with a narrow acoustic shadow; and 3) a linear hyperechoic band parallel to the walls of a blood vessel with also a narrow acoustic shadow. The predominant pattern in metastatic calcifications was type 1, in dystrophic calcifications type 2, and in calciphylaxis type 3. In dystrophic calcinosis, cutis deposits were longer and wider than in calciphylaxis (P < .05). CONCLUSION: New data on inflammatory dermatoses with calcium deposition may be useful for the diagnosis and monitoring of calcium deposits and could avoid the performance of more invasive tests, such as a skin biopsy.

High-Frequency Ultrasound to Assess Activity in Connective Tissue Panniculitis.

Determining disease activity from clinical signs in patients with connective tissue panniculitis (CTP) is often challenging but is essential for therapeutic decision making, which largely relies on immunosuppressant treatment. High-frequency ultrasound (HFUS) may be useful in supporting such decisions by accurately determining CTP activity. This study aimed to investigate the accuracy of HFUS in identifying signs of CTP activity or inactivity and assess its usefulness in therapeutic decision making. A prospective cohort study of consecutive patients with biopsy-proven CTP receiving HFUS was conducted in a tertiary university hospital (2016-2020). HFUS was performed at inclusion and at each 3- or 6-month follow-up visit, depending on disease activity. Twenty-three patients with CTP were included, and 134 HFUSs were performed. In 59.7% (80) of the evaluations, the clinical presentation did not show whether CTP was active or not. In these cases, HFUS showed activity in 38.7% (31) and inactivity in 61.3% (49). In 71.25% (57) of the visits, HFUS was the determinant for therapeutic decisions. Further follow-up showed consistent clinical and HFUS responses in all unclear cases after treatment modification. HFUS appears to be a useful adjunct to the clinical examination for CTP to assess activity and make therapeutic decisions.