Real-life effectiveness of dupilumab in chronic rhinosinusitis with nasal polyps. Results from eight Hungarian centres with 12-month follow-up.

BACKGROUND: Research on the immune mechanism behind chronic rhinosinusitis (CRS) has revealed various new endotypes, leading to targeted therapies, especially for severe uncontrolled CRS. Biologics are novel therapeutic strategies providing targeted treatment for the difficult-to-treat recalcitrant CRSwNP patients. Dupilumab is a fully human-derived monoclonal antibody that binds to IL4Rα, inhibiting the signalling of both IL-4 and IL-13. In Hungary, it is approved for the treatment of uncontrolled CRSwNP according to criteria based on the EPOS2020 and the Hungarian guidelines. METHODOLOGY: This study aimed to collect and evaluate real-world therapeutic data of CRSwNP patients treated with dupilumab. One hundred thirty-five patients from eight different referral centres have been enrolled in this study, who received dupilumab since 2020. All subjects were adult patients (over 18 years) with uncontrolled CRSwNP. Baseline data collection included demographics, medical history, previous surgeries, related comorbidities, total endoscopic nasal polyp score (NPS), SNOT22, nasal congestion parameters measured with visual analogue scale (VAS) and nasal obstruction evaluation scale (NOSE), loss of smell score (LSS) and eosinophil count. 300 mg dupilumab was administered subcutaneously every second week. Follow up visits were performed after 6 and 12 months. RESULTS: After 6 and 12 months of treatment significant improvement was detected in all clinical parameters. Safety was proved, no severe side effects occurred, and no rescue treatment was necessary. CONCLUSIONS: Our real-life findings show that continuous dupilumab treatment is effective and safe in daily clinical practice in CRSwNP and other type 2 comorbidities such as bronchial asthma and NERD.

[Eosinophilic dermatoses]. / Eosinophile Dermatosen.

Eosinophilic dermatoses are a heterogeneous group of rare diseases that histopathologically display the defining pattern of an eosinophil-rich dermal infiltrate. In these eosinophilic dermatoses, a histopathologic pattern called flame figures, which result from degranulation of eosinophils in the tissue, can be observed. Although eosinophil granulocytes can also be detected in other dermatoses such as atopic dermatitis, urticaria, prurigo and bullous pemphigoid, the eosinophil-rich infiltrate is decisive for classic eosinophilic dermatoses. Accordingly, eosinophilic dermatoses include hypereosinophilic syndrome, eosinophilic fasciitis, granuloma faciale, pustular sterile eosinophilia, and angiolymphoid hyperplasia with eosinophilia. These eosinophilic dermatoses display clinical different patterns and are discussed in this article, as well as the interesting eosinophils and novel therapeutic options.

European Guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology - Part II.

This guideline has been initiated by the task force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology, including physicians from all relevant disciplines and patient organizations. It is a S3 consensus-based guideline that systematically reviewed the literature on mucous membrane pemphigoid (MMP) in the MEDLINE and EMBASE databases until June 2019, with no limitations on language. While the first part of this guideline addressed methodology, as well as epidemiology, terminology, aetiology, clinical presentation and outcome measures in MMP, the second part presents the diagnostics and management of MMP. MMP should be suspected in cases with predominant mucosal lesions. Direct immunofluorescence microscopy to detect tissue-bound IgG, IgA and/or complement C3, combined with serological testing for circulating autoantibodies are recommended. In most patients, serum autoantibodies are present only in low levels and in variable proportions, depending on the clinical sites involved. Circulating autoantibodies are determined by indirect IF assays using tissue substrates, or ELISA using different recombinant forms of the target antigens or immunoblotting using different substrates. The major target antigen in MMP is type XVII collagen (BP180), although in 10-25% of patients laminin 332 is recognized. In 25-30% of MMP patients with anti-laminin 332 reactivity, malignancies have been associated. As first-line treatment of mild/moderate MMP, dapsone, methotrexate or tetracyclines and/or topical corticosteroids are recommended. For severe MMP, dapsone and oral or intravenous cyclophosphamide and/or oral corticosteroids are recommended as first-line regimens. Additional recommendations are given, tailored to treatment of single-site MMP such as oral, ocular, laryngeal, oesophageal and genital MMP, as well as the diagnosis of ocular MMP. Treatment recommendations are limited by the complete lack of high-quality randomized controlled trials.

Adalimumab and infliximab survival in patients with hidradenitis suppurativa: a daily practice cohort study.

BACKGROUND: Biologics are often required for the treatment of hidradenitis suppurativa (HS). However, data on the drug survival of biologics in daily practice are currently lacking. OBJECTIVES: To assess the drug survival of antitumour necrosis factor biologics in a daily practice cohort of patients with HS and to identify predictors for drug survival. METHODS: A retrospective multicentre study was performed in two academic dermatology centres in the Netherlands. Adult patients with HS using biologics between 2008 and 2020 were included. Drug survival was analysed with Kaplan-Meier survival curves and predictors of survival with univariate Cox regression analysis. RESULTS: The overall drug survival of adalimumab (n = 104) at 12 and 24 months was 56·3% and 30·5%, respectively, which was predominantly determined by infectiveness. Older age (P = 0·02) and longer disease duration (P < 0·01) were associated with longer survival time. For infliximab (n = 44), overall drug survival was 58·3% and 48·6% at 12 and 24 months, respectively, and was predominantly determined by infectiveness and side-effects. Surgery during treatment was associated with a longer survival time (P = 0·01). CONCLUSIONS: Survival rates were comparable for adalimumab and infliximab at 12 months, and were mainly determined by ineffectiveness. Age, disease duration (adalimumab) and surgery (infliximab) are predictors for longer survival.

Frequency and prognosis of associated malignancies in 504 patients with lymphomatoid papulosis.

BACKGROUND: Lymphomatoid papulosis (LyP) can be associated with other haematological malignancies (HM), but reported percentages vary from 20% to over 50%. OBJECTIVE: To evaluate the frequency and prognostic significance of associated HM and non-HM in LyP patients. METHODS: In this multicentre cohort study, the complete Dutch LyP population was included from the Dutch Cutaneous Lymphoma Registry between 1985 and 2018. Clinical and histopathological information was retrieved from every individual patient. RESULTS: After a median follow-up of 120 months (range, 6-585), an associated HM was observed in 78/504 (15.5%) patients. Most common associated HM were mycosis fungoides (MF; n = 31) and anaplastic large-cell lymphoma (ALCL; n = 29), while 19 patients had another HM of B-cell (n = 14) or myeloid origin (n = 5). Even after a 25-year follow-up period, percentages of associated HM did not exceed 20%. Thirty-nine of 465 patients (8.4%) without a prior or concurrent associated HM developed an associated HM during follow-up, after a median of 68 months (range of 3-286 months). Nine of 78 patients died of associated HM, including 6/22 patients developing extracutaneous ALCL, while all patients with associated MF or skin-limited ALCL had an excellent prognosis. Compared with the general population, LyP patients showed an increased risk (relative risk, 2.8; 95% confidence intervals, 2.4-3.3) for non-HM, in particular cutaneous squamous cell carcinoma, melanoma and intestinal/lung/bladder cancer. CONCLUSIONS: An associated HM was reported in 15.5% of the LyP patients, particularly MF and ALCL. Although the frequency of associated HM is lower than suggested and the prognosis of most patients with associated HM is excellent, a small subgroup will develop aggressive disease, in particular extracutaneous ALCL. Furthermore, LyP patients have a higher risk of developing other malignancies. Clinicians should be aware of these risks, and LyP patients require close monitoring.

Surgical outcomes and the impact of major surgery on quality of life, activity impairment and sexual health in hidradenitis suppurativa patients: a prospective single centre study.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic debilitating skin disease, frequently located in the groin and anogenital area, leading to a substantial impact on quality of life and sexual health in patients with HS. Skin-tissue-sparing excision with electrosurgical peeling (STEEP) is a procedure with known low recurrence rates and high patient satisfaction in retrospective series. However, a prospective study to investigate the impact of any major surgery on specific aspects of the quality of life has not yet been performed. OBJECTIVE: To assess surgical outcomes and the effect of major surgery on the general quality of life, sexual health and activity impairment in patients with HS. MATERIALS AND METHODS: A single centre prospective survey study was conducted among 40 patients undergoing major surgery. Surveys were completed prior to the surgery and 2, 6, 12 and 26 weeks after surgery. Besides the objective parameters (time to wound closure and surface of the wound), patient-reported outcomes were reported. RESULTS: Thirty-nine patients with a total of 171 survey responses were included for analysis. Patients with Hurley stage I or II had a shorter time to wound closure (TTWC) compared to patients with Hurley stage III (P = 0.005). TTWC was significantly prolonged in patients treated with biologics (P < 0.001). Smoking did not significantly influence TTWC. For patient-reported outcomes, DLQI and ASEX scores did not significantly improve during the study period of 6 months. However, activity and overall work impairment showed considerable improvement after surgery. CONCLUSION: Time to wound closure is significantly prolonged by higher Hurley stage and treatment with biologics, contrastingly not by smoking. Major surgery improved the overall work and daily activity impairment.

Hidradenitis suppurativa/acne inversa: a practical framework for treatment optimization - systematic review and recommendations from the HS ALLIANCE working group.

Hidradenitis suppurativa (HS)/acne inversa is a debilitating chronic disease that remains poorly understood and difficult to manage. Clinical practice is variable, and there is a need for international, evidence-based and easily applicable consensus on HS management. We report here the findings of a systematic literature review, which were subsequently used as a basis for the development of international consensus recommendations for the management of patients with HS. A systematic literature review was performed for each of nine clinical questions in HS (defined by an expert steering committee), covering comorbidity assessment, therapy (medical, surgical and combinations) and response to treatment. Included articles underwent data extraction and were graded according to the Oxford Centre for Evidence-based Medicine criteria. Evidence-based recommendations were then drafted, refined and voted upon, using a modified Delphi process. Overall, 5310 articles were screened, 171 articles were analysed, and 65 were used to derive recommendations. These articles included six randomized controlled trials plus cohort studies and case series. The highest level of evidence concerned dosing recommendations for topical clindamycin in mild disease (with systemic tetracyclines for more frequent/widespread lesions) and biologic therapy (especially adalimumab) as second-line agents (following conventional therapy failure). Good-quality evidence was available for the hidradenitis suppurativa clinical response (HiSCR) as a dichotomous outcome measure in inflammatory areas under treatment. Lower-level evidence supported recommendations for topical triclosan and oral zinc in mild-to-moderate HS, systemic clindamycin and rifampicin in moderate HS and intravenous ertapenem in selected patients with more severe disease. Intralesional or systemic steroids may also be considered. Local surgical excision is suggested for mild-to-moderate HS, with wide excision for more extensive disease. Despite a paucity of good-quality data on management decisions in HS, this systematic review has enabled the development of robust and easily applicable clinical recommendations for international physicians based on graded evidence.

Evaluation of treatment results in multifocal primary cutaneous anaplastic large cell lymphoma: report of the Dutch Cutaneous Lymphoma Group.

BACKGROUND: There is no consensus on the treatment of multifocal primary cutaneous anaplastic large cell lymphoma (C-ALCL). Radiotherapy (RT) and methotrexate (MTX) are the current treatment options, but their efficacy is unknown. Recently, targeted therapies showed promising results in C-ALCL, and may therefore be an attractive first choice of treatment. OBJECTIVES: To assess the efficacy of conventional treatment strategies for patients with multifocal C-ALCL, and to define which patients may require novel targeted therapies. METHODS: In this multicentre study, treatment was evaluated in patients initially presenting (n = 24) or relapsing with multifocal C-ALCL (n = 17; 23 relapses). Distinction was made between patients with five or less lesions (n = 36) and more than five lesions (n = 11). RESULTS: Treatments most commonly used were RT (n = 21), systemic chemotherapy (n = 9) and low-dose MTX (n = 7) with complete response rates of 100%, 78% and 43%, respectively, and an overall response rate of 100%, 100% and 57%, respectively. Four patients showed complete spontaneous regression. In total, 16 of 24 patients (67%) first presenting with multifocal C-ALCL relapsed, including all five patients initially treated with CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone). Compared with patients presenting with two to five skin lesions, patients presenting with more than five lesions had a higher chance of developing extracutaneous relapse (56% vs. 20%) and more often died of lymphoma (44% vs. 7%). CONCLUSIONS: Patients with five or less lesions should be treated with low-dose RT (2 × 4 Gy). Maintenance low-dose MTX (20 mg weekly) is a suitable option in patients with more than five lesions. Targeted therapies may be considered in rare patients who are refractory to MTX or patients developing extracutaneous disease.

Recommendations for treatment in folliculotropic mycosis fungoides: report of the Dutch Cutaneous Lymphoma Group.

BACKGROUND: Folliculotropic mycosis fungoides (FMF) is an aggressive variant of mycosis fungoides (MF) and generally less responsive to standard skin-directed therapies (SDTs). Recent studies distinguished indolent (early-stage FMF) and more aggressive (advanced-stage FMF) subgroups. The optimal treatment for both subgroups remains to be defined. OBJECTIVES: To evaluate initial treatment results in patients with early- and advanced-stage FMF. METHODS: A study was undertaken of 203 patients (84 early-stage, 102 advanced-stage, 17 extracutaneous FMF) included in the Dutch Cutaneous Lymphoma Registry between 1985 and 2014. Type and results of initial treatment were retrieved from the Dutch Registry. Main outcomes were complete remission (CR); sustained complete remission; partial remission (PR), > 50% improvement; and overall response (OR; CR + PR). RESULTS: Patients with early-stage FMF were treated with nonaggressive SDTs in 67 of 84 cases resulting, respectively, in CR and OR of 28% and 83% for monotherapy topical steroids, 0% and 83% for ultraviolet B (UVB), and 30% and 88% for psoralen plus ultraviolet A (PUVA). In patients with advanced-stage FMF these SDTs were less effective (combined CR and OR 10% and 52%, respectively). In patients with advanced-stage FMF local radiotherapy (CR 63%; OR 100%), total skin electron beam irradiation (CR 59%; OR 100%) and PUVA combined with local radiotherapy (CR 5%, OR 75%) were most effective. CONCLUSIONS: The results of the present study demonstrate that not all patients with FMF should be treated aggressively. Patients with early-stage FMF may benefit very well from standard SDTs also used in early-stage classic MF and have an excellent prognosis.

Dose-dependent electrophysiological effects of the myosin activator omecamtiv mecarbil in canine ventricular cardiomyocytes.

Omecamtiv mecarbil (OM) is a myosin activator agent recently developed for treatment of heart failure. Although its action on extending systolic ejection time and increasing left ventricular ejection fraction is well documented, no data is available regarding its possible side-effects on cardiac ion channels. Therefore, the present study was designed to investigate the effects of OM on action potential morphology and the underlying ion currents in isolated canine ventricular myocytes using sharp microelectrodes, conventional patch clamp, and action potential voltage clamp techniques. OM displayed a concentration-dependent action on action potential configuration: 1 µM OM had no effect, while action potential duration and phase-1 repolarization were reduced and the plateau potential was depressed progressively at higher concentrations (10 - 100 µM; P < 0.05 compared to control). Accordingly, OM (10 µM) decreased the density of the transient outward K+ current (Ito), the L-type Ca2+ current (ICa) and the rapid delayed rectifier K+ current (IKr), but failed to modify the inward rectifier K+ current (IK1). It is concluded, that although the therapeutic concentrations of OM are not likely to influence cardiac ion currents significantly, alterations of the major cardiac ion currents can be anticipated at concentrations above those clinically tolerated.

Ustekinumab in hidradenitis suppurativa: clinical results and a search for potential biomarkers in serum.

BACKGROUND: Treatment of hidradenitis suppurativa (HS) is difficult and the search for effective therapies continues. OBJECTIVES: To evaluate the efficacy of ustekinumab and to discover a potential biomarker for HS. METHODS: Seventeen patients were included in this open-label study and treated with 45 or 90 mg ustekinumab at weeks 0, 4, 16 and 28. Proteomic technology and enzyme-linked assay analysis was applied to sera. RESULTS: Twelve patients completed the protocol. Moderate-to-marked improvement of the modified Sartorius score was achieved in 82% of patients at week 40 and the Hidradenitis Suppurativa Clinical Response 50 in 47%. With regard to the expression of 54 serum proteins, at baseline, a significant difference was observed between patients and healthy controls. Involved pathways were related to inflammation, immune cell signalling and tissue morphology/development. Good responders had milder disease and lower expression of leukotriene A4-hydrolase (LTA4H). Interleukin (IL)-2R, tumour necrosis factor-α, IL-17A and IL-17F were not elevated and did not change during treatment. CONCLUSIONS: The majority of patients improved with ustekinumab. Although no biomarker was discovered, low LTA4H concentrations with mild disease severity may be predictive of the effectiveness of ustekinumab.

Surgery under general anaesthesia in severe hidradenitis suppurativa: a study of 363 primary operations in 113 patients.

BACKGROUND: Treatment of hidradenitis suppurativa (HS) is a difficult undertaking, especially as there is no consensus on what surgical technique is preferred. At our centre severe HS (Hurley II/III) is operated under general anaesthesia, mostly with the STEEP procedure. OBJECTIVES: To investigate characteristics, surgical outcomes and patient satisfaction of HS patients who underwent deroofing or STEEP under general anaesthesia. METHODS: A clinical records-based retrospective analysis was conducted of all patients who had surgery under general anaesthesia between 1999 and 2013. Patient satisfaction was retrospectively investigated with questionnaires. RESULTS: A total of 482 operations (363 primary operations and 119 re-operations) were performed during the study period. The proportion of women in the included population was 68%. The median diagnostic delay (patient's and doctor's delay) was 6.5 years. Relapses occurred after 29.2% of primary operations. Women had higher relapse rates than men [odds ratio 2.85 (1.07;7.61)]. Hypergranulation of the wound was the most common complication and occurred in 7% of all operations. The median score patients attributed to the medical effect of surgery was eight of 10 (zero corresponding to very dissatisfied and 10 to very satisfied). CONCLUSION: The diagnostic delay in HS is long due to a lack of knowledge in both patients and health care professionals, indicating that there is a need for education. Deroofing and the STEEP are effective surgical procedures in severe cases of HS and lead to a relatively high patient satisfaction. The postoperative relapse risk is higher in women. Prospective studies are required for the development of clear guidelines on the appropriate choice of surgery.

Skin-Tissue-sparing Excision with Electrosurgical Peeling (STEEP): a surgical treatment option for severe hidradenitis suppurativa Hurley stage II/III.

BACKGROUND: Surgery is the only curative treatment for removal of the persistent sinus tracts in the skin that are characteristic of severe hidradenitis suppurativa (HS). Complete resection of the affected tissue by wide excision is currently regarded as the preferred surgical technique in these cases. However, relatively large amounts of healthy tissue are removed with this method and suitable skin-tissue-saving techniques aiming at creating less-extensive surgical defects are therefore needed in severe HS. METHOD: We describe a skin-tissue-saving surgical technique for HS Hurley stage II-III disease: the Skin-Tissue-sparing Excision with Electrosurgical Peeling (STEEP) procedure. DISCUSSION: In contrast to wide excisions that generally reach into the deep subcutaneous fat, the fat is maximally spared with the STEEP procedure by performing successive tangential excisions of lesional tissue until the epithelialized bottom of the sinus tracts has been reached. From here, secondary intention healing can occur. In addition, fibrotic tissue is completely removed in the same manner as this also serves as a source of recurrence. This tissue-sparing technique results in low recurrence rates, high patient satisfaction with relatively short healing times and favourable cosmetic outcomes without contractures.

Why you should ask your patients about their fishing hobbies.

Patients who use immunosuppressive agents, in particular medication that blocks tumour necrosis factor-a, are at risk for mycobacterial infections. Besides the typical Mycobacterium tuberculosis infection, a lso a typical mycobacterial disease may occur. Here we demonstrate two patients with such atypical mycobacterial infection due to swimming and fishing water contact. We propose that patients, before starting with immunosuppressive therapy, are counselled about risk factors for mycobacterial disease.

Langerhans cell histiocytosis first presenting in the skin in adults: frequent association with a second haematological malignancy.

BACKGROUND: Langerhans cell histiocytosis (LCH) in adults first presenting in the skin is rare. Guidelines for staging, treatment and follow-up are lacking. OBJECTIVES: To better define staging procedures, treatment results and clinical course in adult patients with LCH first presenting in the skin. METHODS: Eighteen adult patients with LCH first presenting in the skin were collected from five centres collaborating in the Dutch Cutaneous Lymphoma Group. Clinical records and (skin) biopsy specimens were reviewed and follow-up data were obtained. A literature search on adult patients with LCH presenting in the skin was performed. RESULTS: Staging procedures showed extracutaneous disease in three of 16 patients who were adequately staged. One patient had a histologically confirmed lytic LCH bone lesion, while two patients had a myelodysplastic syndrome. During follow-up two of 18 patients developed extracutaneous localizations of LCH. Five patients developed a second haematological malignancy, including (myelo)monocytic leukaemia (two cases), histiocytic sarcoma (one case), diffuse large B-cell lymphoma (one case) and peripheral T-cell lymphoma (one case). Review of the literature revealed six other adult patients with a second haematological malignancy preceding or following a diagnosis of LCH. CONCLUSIONS: The results of the present study suggest an increased risk of a second haematological malignancy in adult patients with LCH presenting in the skin. Extensive staging at presentation and long-term follow-up are therefore warranted in such patients.

Low-dose rituximab is effective in pemphigus.

BACKGROUND: Rituximab, an anti-CD20 antibody, was shown in open series studies to be effective in treating pemphigus at a dose of 4 × 375 mgm(-2) as approved for B-cell malignancies. OBJECTIVES: We investigated whether a lower dose of rituximab is also effective for pemphigus. METHODS: Patients with pemphigus were treated with a single course of two infusions of rituximab (500 mg each) at an interval of 2 weeks. Clinical consensus late end points, B-cell number, desmoglein 1 and desmoglein 3 indices were monitored. RESULTS: We enrolled 15 patients in the study: three with pemphigus foliaceus (PF) and 12 with pemphigus vulgaris (PV). The follow-up was 32-152 weeks (median 94). All 15 patients responded to therapy. Eight patients achieved complete remission in a median period of 5 weeks (four on minimal therapy, four off therapy). Seven patients achieved partial remission in a median period of 34·5 weeks (five on minimal therapy, two off therapy). Relapses (40%) were seen between 53 and 103 weeks (median 97) after start of therapy. B-cell numbers dropped to <1% after first infusion, and remained undetectable in patients with sustained remission. The antidesmoglein 1 index correlated well with the clinical severity in PF, but this was less obvious in PV. CONCLUSIONS: A low dose of rituximab is an effective and safe treatment for pemphigus. Relapses may occur, mostly at the end of the second year. Cost-effectiveness studies with a long follow-up are required to determine the proper dosage of this expensive drug in pemphigus.