The VASCERN PPL working group patient pathway for primary and paediatric lymphoedema.

Lymphoedema is caused by an imbalance between fluid production and transport by the lymphatic system. This imbalance can be either caused by reduced transport capacity of the lymphatic system or too much fluid production and leads to swelling associated with tissue changes (skin thickening, fat deposition). Its main common complication is the increased risk of developing cellulitis/erysipelas in the affected area, which can worsen the lymphatic function and can be the cause of raised morbidity of the patient if not treated correctly/urgently. The term primary lymphoedema covers a group of rare conditions caused by abnormal functioning and/or development of the lymphatic system. It covers a highly heterogeneous group of conditions. An accurate diagnosis of primary lymphoedema is crucial for the implementation of an optimal treatment plan and management, as well as to reduce the risk of worsening. Patient care is diverse across Europe, and national specialised centres and networks are not available everywhere. The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) gathers the best expertise in Europe and provide accessible cross-border healthcare to patients with rare vascular diseases. There are six different working groups in VASCERN, which focus on arterial diseases, hereditary haemorrhagic telangiectasia, neurovascular diseases, lymphoedema and vascular anomalies. The working group Paediatric and Primary Lymphedema (PPL WG) gathers and shares knowledge and expertise in the diagnosis and management of adults and children with primary and paediatric lymphoedema. The members of PPL WG have worked together to produce this opinion statement reflecting strategies on how to approach patients with primary and paediatric lymphoedema. The objective of this patient pathway is to improve patient care by reducing the time to diagnosis, define the best management and follow-up strategies and avoid overuse of resources. Therefore, the patient pathway describes the clinical evaluation and investigations that lead to a clinical diagnosis, the genetic testing, differential diagnosis, the management and treatment options and the patient follow up at expert and local centres. Also, the importance of the patient group participation in the PPL WG is discussed.

Efficacy and safety of oral roflumilast for moderate-to-severe psoriasis-a randomized controlled trial (PSORRO).

Background: Roflumilast is a targeted inhibitor of phosphodiesterase (PDE)-4 and has been approved for treatment of severe chronic obstructive pulmonary disease for more than a decade. Generic versions are available in the United States. PDE-4 is involved in the psoriasis pathogenesis, but the efficacy and safety of oral roflumilast in patients with psoriasis have not previously been studied. Methods: A company-independent, multicenter, randomized, double-blind, placebo-controlled trial (ClinicalTrials.govNCT04549870). Patients were randomized 1:1 to receive monotherapy with oral roflumilast 500 µg once daily or placebo. At week 12, placebo patients were switched to open-label roflumilast through week 24. The primary endpoint was a 75% or greater reduction from baseline in the psoriasis area and severity index (PASI75) at week 12. Findings: In all, 46 patients were randomized (roflumilast, n = 23; placebo, n = 23). At week 12, significantly more patients in the active arm achieved PASI75 (8 of 23 patients [35%]) vs. placebo (0 of 23 patients [0%], with a difference vs. placebo of 8 [35%] patients, 95% CI: 3 [13%]-13 [57%] patients) (p = 0.014). At week 24, 15 (65%), 10 (44%), 5 (22%), and 2 (9%) of patients treated with roflumilast from week 0 had PASI50, PASI75, PASI90, and PASI100 responses (key secondary endpoints), respectively. The most prevalent, drug-related adverse events in both treatment groups were transient gastrointestinal symptoms, weight-loss, headache, and insomnia. A total of three patients (roflumilast n = 2; placebo, n = 1) discontinued therapy due to adverse events. Interpretation: Oral roflumilast was efficacious and safe in treating moderate-to-severe plaque psoriasis over 24 weeks. With generic versions available, this drug may represent an inexpensive and convenient alternative to established systemic psoriasis treatments. Funding: Financial support was received from Herlev and Gentofte Hospital, University of Copenhagen, and independent grants from private foundations in Denmark. No pharmaceutical company, including the market authorization holder of roflumilast, was involved in the study at any point.

Predictors of Response to Biologics in Patients with Moderate-to-severe Psoriasis: A Danish Nationwide Cohort Study.

Identifying patient characteristics associated with achieving treatment response to biologics in patients with psoriasis could prevent expensive switching between biologics. The aim of this study was to identify patient characteristics that predict the efficacy of treatment for biologics that inhibit tumour necrosis factor-α, interleukin-12/-23, and -17A. The study investigated biologic-naïve patients from the DERMBIO registry treated with adalimumab, etanercept, infliximab, secukinumab, or ustekinumab. Multivariable logistic models were conducted to assess associations between patient characteristics and treatment response. A total of 2,384 patients were included (adalimumab n = 911; etanercept n = 327; infliximab n = 152; secukinumab n = 323; ustekinumab n = 671). Smoking (odds ratio 0.74; 95% confidence interval (CI) 0.56-0.97; p = 0.03) and higher bodyweight (odds ratio 0.989; 95% CI 0.984-0.994; p < 0.001) reduced the odds of achieving response defined as Psoriasis Area and Severity Index ≤2.0 after 6 months of treatment. In conclusion, higher bodyweight and smoking were associated with a reduced probability of treatment response for tumour necrosis factor-α inhibitors, ustekinumab, and secukinumab.

Response to Biologics During the First Six Months of Therapy in Biologic-naïve Patients with Psoriasis Predicts Risk of Disease Flares: A Danish Nationwide Study.

Early response to treatment with biologics might be important for the stability of psoriasis and long-term outcome. The aim of this study was therefore to assess whether risk of flares and drug survival are associated with disease activity in the first 6 months of treatment of psoriasis with biologics. Biologic-naïve patients from the Danish nationwide registry, DERMBIO, were grouped based on absolute Psoriasis Area and Severity Index (PASI) during the first 6 months of treatment, as: PASI = 0, PASI > 0-≤2, PASI > 2-≤ 4, and PASI > 4. Among 1,684 patients, 746 achieved PASI= 0, 485 PASI > 0-≤2, 246 PASI > 2-≤4, and 207 PASI > 4. Longer flare-free period and drug survival were observed for patients with lower PASI in the first 6 months of treatment (adjusted hazard ratios for flares (95% confidence interval) with PASI= 0 as reference: PASI > 0-≤2 (1.35 (1.11-1.72]), PASI > 2-≤ 4 (2.32 [1.80-2.99]), and PASI > 4 (2.38 [1.80-3.15])). In conclusion, a low PASI in the first 6 months of treatment with biologics in biologic-naïve patients with psoriasis was associated with a more stable disease course, lower risk of flares, and longer drug survival.

Comorbidities, pain and fatigue in psoriatic arthritis, psoriasis and healthy controls: a clinical cohort study.

OBJECTIVES: To explore the prognostic value of pre-specified comorbidities on treatment outcomes in PsA, and to compare baseline data with cutaneous psoriasis without arthritis and healthy controls (HC). METHODS: Patients initiating conventional synthetic/biological disease-modifying antirheumatic drugs were enrolled in this clinical observational cohort study, and data on comorbidities, and clinical and patient-reported outcomes were retrieved at baseline and after 4 months. Pearson's chi-squared tests were performed to investigate the prognostic value of pre-specified comorbidities and achievement of ACR20, DAPSA50 and MDA. Mann-Whitney U tests were used to compare OMERACT PsA Core Outcome Set (COS) measures at baseline and follow-up for the pre-specified comorbidities. RESULTS: A total of 100 PsA patients were included at baseline. Statistically significantly fewer patients with obesity achieved DAPSA50 compared with patients without obesity (P =0.035), and fewer patients with hypertension (P =0.034) and Charlson Comorbidity Index (CCI) ≥1 (P =0.027), respectively, achieved MDA compared with patients without these comorbidities. Patients with obesity, hypertension, widespread pain, and CCI ≥1 had significantly worse COS measures at follow-up compared with patients without these comorbidities. At baseline, patients with PsA had higher disease burden compared with patients with cutaneous psoriasis and HC, including higher pain (P <0.001) and fatigue (P <0.001) scores, and more widespread pain (P =0.002). CONCLUSION: Obesity, hypertension and CCI ≥1 were prognostic factors for poorer treatment outcome rates in PsA. Pain and fatigue were more frequently reported among patients with PsA compared with patients with cutaneous psoriasis and HC. TRIAL REGISTRATION: The Danish National Committee on Health Research Ethics: H-15009080; Data Protection Agency: 2012-58-0004; ClinicalTrials.gov: NCT02572700.

Pretreatment with 5-Fluorouracil Cream Enhances the Efficacy of Daylight-mediated Photodynamic Therapy for Actinic Keratosis.

The efficacy of photodynamic therapy (PDT) with methyl aminolevulinate is reduced when treating actinic keratosis (AK) on the extremities in comparison with the face and scalp. Studies indicate that PDT efficacy can be improved by combining PDT with other treatment modalities. This randomized intra-individual study investigated whether pretreatment with topical 5% 5-fluorouracil (5-FU) enhanced the treatment efficacy of daylight-mediated PDT in 24 patients with AKs on the hands. One hand of each patient was given 7 days of pretreatment with 5-FU twice daily before daylight-PDT, whereas the other hand was treated with daylight-PDT alone. At 3-month follow-up the overall lesion response rate was significantly higher for the combination of 5-FU and daylight-PDT (62.7%) than for daylight-PDT alone (51.8%) (p = 0.001). Furthermore, pain and erythema in relation to treatment were similar in the 2 groups (p = 1.0 and p = 0.2, respectively). Combination therapy is a safe and effective method to improve daylight-PDT for acral AKs.

Thickness of Actinic Keratosis Does Not Predict Dysplasia Severity or P53 Expression.

The severity of dysplasia and expression of p53 in actinic keratosis (AK) is of importance for the transformation to squamous cell carcinoma. It is assumed that it is most important to treat thick AKs as they are believed to be more dysplastic than thin AKs. However, a relation between AK thickness and dysplasia or the expression of p53 has never been demonstrated. The aim of this study was to investigate this possible relation. Sixty-six AKs were included for clinical and histological examination. Prior to performing a punch biopsy, the clinical thickness of each AK was measured objectively using two scale bars with a thickness of 0.5 mm and 1 mm. Subsequently, the thickness of the epidermis, the severity of dysplasia and the expression of p53 were assessed histologically. We found a strong and significant positive correlation between measured clinical thickness of the AKs and the histological thickness of epidermis (p < 0.0001). However, the clinical thickness did not correlate with either the severity of dysplasia (p = 0.7) or the expression of p53 (p = 0.5). In conclusion, thin AKs show the same severity of dysplasia and expression of p53 as thicker AK lesions. Consequently, clinical thickness cannot predict aggressiveness.

Short-term chemical pretreatment cannot replace curettage in photodynamic therapy.

BACKGROUND: Guidelines for photodynamic therapy (PDT) recommend pretreatment with curettage/debulking to enhance intracellular formation of protoporphyrin IX (PpIX). However, studies suggest that new chemical pretreatment procedures may replace curettage/debulking. PURPOSE: To investigate how pretreatment with curettage and two combination ointments containing calcipotriol/betamethasone and salicylic acid/betamethasone affect PpIX fluorescence after the application of methyl aminolevulinate MAL and 5-aminolevulinic acid (BF-200 ALA). METHODS: Four fields on the forearms of 30 healthy volunteers were pretreated with curettage or short-term application of calcipotriol/betamethasone or salicylic acid/betamethasone for 20 min. Two fields were not pretreated, thus serving as reference. After pretreatment, MAL or BF-200 ALA was applied for 24 h, and PpIX fluorescence was measured hourly from 1 to 5 h and after 18, 21 and 24 h. RESULTS: Curettage significantly enhanced PpIX fluorescence for MAL from 1 to 21 h (P < 0.0041). For BF-200 ALA, curettage enhanced fluorescence from 1 to 5 h (P < 0.000064), while fluorescence was lower from 18 to 24 h. Pretreatment with salicylic acid/betamethasone and calcipotriol/betamethasone before BF-200 ALA application did not increase PpIX fluorescence from 1 to 5 h compared to no pretreatment, and both were significantly inferior to curettage (P < 0.0017 and 0.0024, respectively). CONCLUSION: Curettage significantly enhances PpIX fluorescence from 1 to 5 h and is superior to short-term chemical pretreatment. Our results support curettage as standard pretreatment in PDT.

Basal Cell Carcinoma is as Common as the Sum of all Other Cancers: Implications for Treatment Capacity.

Reliable estimates of disease incidence are fundamental to planning future healthcare services. However, in many countries registration of basal cell carcinoma (BCC) is often non-existent. This study examines how many BCC treatments were carried out in Denmark in 2013. The Danish Cancer Registry and the Danish Pathology Registry were used to examine how many BCC treatments were registered, and a test sample was taken from Bispebjerg Hospital to examine the number treated but not registered. The study showed that 21.7% of BCC treatments were performed solely on a clinical diagnosis. Furthermore, some records are inadequate in relation to BCC registration, as BCCs treated are 3 times the number of individuals in the Danish Cancer Registry, and there are nearly as many BCCs as the sum of all other cancers. The increasing BCC incidence will result in difficulties in ensuring treatment capacity.

Discovery of a sexual stage in Trichophyton onychocola, a presumed geophilic dermatophyte isolated from toenails of patients with a history of T. rubrum onychomycosis.

Trichophyton onychocola is a recently described geophilic dermatophyte that has been isolated from a toenail of Czech patient with a history of onychomycosis due to T. rubrum and clinical suspicion of relapse. In this study, we report a similar case from Denmark in an otherwise healthy 56-year-old man. The patient had a history of great toenail infection caused by T. rubrum in 2004 and presented with suspected relapse in 2011 and 2013. Trichophyton onychocola was the only microbial agent isolated at the second visit in 2013 and the identification was confirmed by DNA sequencing. Direct microscopic nail examination was positive for hyphae, however the etiological significance of T. onychocola was not supported by repeated isolation of the fungus. This new species may be an overlooked geophilic species due to the resemblance to some common species, for example, zoophilic T. interdigitale or some species of geophilic dermatophytes. We included differential diagnosis with phenotypically similar species; however, it is recommended that molecular methods are used for correct identification. The MAT locus of Danish strain was of opposite mating type than in the previously isolated Czech strain and the two isolates were successfully mated. The mating experiments with related heterothallic species T. thuringiense and Arthroderma melis were negative. The sexual state showed all typical signs of arthroderma-morph and is described by using optical as well as scanning electron microscopy. The sexual state was induced on a set of agar media, however low cultivation temperature and the presence of keratin source were crucial for the success rather than formulation of medium.

Hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs): classification of a Danish patient cohort according to EAACI/ENDA guidelines.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are reported to be the second most common cause of drug hypersensitivity. In 2011, experts from the EAACI/ENDA group and GA(2)LEN proposed a new classification system for NSAID hypersensitivity. The aim of this study was to classify a patient cohort with a history of NSAID hypersensitivity according to this system. METHODS: Patients with a clinical history of NSAID hypersensitivity referred to the Allergy Centre, Odense University Hospital between 2002 and 2011 and evaluated with oral provocation tests (OPTs) were included in the study. Medical records were retrospectively investigated with respect to the culprit NSAID(s), underlying diseases and symptoms at the primary reaction and during oral provocation tests (OPTs). Data was supplemented with a questionnaire. Classification according to EAACI guideline was based on these findings. RESULTS: In total 149 patients were included. Of those, 39 patients (26.2%) had a positive OPT. Twenty-nine patients were classified as cross-reactive responders and 9 patients as single NSAID responders after positive OPTs with the culprit NSAID, but not to acetylsalicylic acid. All single NSAID responders reacted to non-pyrazolone drugs. Only one patient could not be classified according to the EAACI/ENDA system. An overlap between respiratory and cutaneous symptoms was found in 15/39 (38%) of patients. CONCLUSIONS: All but one of our patients could be classified according to the EAACI classification system. Overlaps between different classes may occur much more commonly than expected.