Updated S2 K guidelines for the management of bullous pemphigoid initiated by the European Academy of Dermatology and Venereology (EADV).

BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. This disease typically affects the elderly and presents with itch and localized or, most frequently, generalized bullous lesions. A subset of patients only develops excoriations, prurigo-like lesions, and eczematous and/or urticarial erythematous lesions. The disease, which is significantly associated with neurological disorders, has high morbidity and severely impacts the quality of life. OBJECTIVES AND METHODOLOGY: The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology sought to update the guidelines for the management of BP based on new clinical information, and new evidence on diagnostic tools and interventions. The recommendations are either evidence-based or rely on expert opinion. The degree of consent among all task force members was included. RESULTS: Treatment depends on the severity of BP and patients' comorbidities. High-potency topical corticosteroids are recommended as the mainstay of treatment whenever possible. Oral prednisone at a dose of 0.5 mg/kg/day is a recommended alternative. In case of contraindications or resistance to corticosteroids, immunosuppressive therapies, such as methotrexate, azathioprine, mycophenolate mofetil or mycophenolate acid, may be recommended. The use of doxycycline and dapsone is controversial. They may be recommended, in particular, in patients with contraindications to oral corticosteroids. B-cell-depleting therapy and intravenous immunoglobulins may be considered in treatment-resistant cases. Omalizumab and dupilumab have recently shown promising results. The final version of the guideline was consented to by several patient organizations. CONCLUSIONS: The guidelines for the management of BP were updated. They summarize evidence- and expert-based recommendations useful in clinical practice.

Biologic drug survival rates in the era of anti-interleukin-17 antibodies: a time-period-adjusted registry analysis.

BACKGROUND: Drug survival rates reflect efficacy and safety and may be influenced by the availability of alternative treatment options. Little is known about time-dependent drug survival in psoriasis and the effect of increasing numbers of biologic treatment options. OBJECTIVES: To determine whether drug survival is influenced by the availability of treatment options and by factors such as gender, psoriatic arthritis or previous biologic treatment. METHODS: This observational, retrospective, multicentre cohort study analysed data from patients registered in the Austrian Psoriasis Registry (PsoRA) who were treated with biologics between 1 January 2015 and 30 November 2019. RESULTS: A total of 1572 patients who received 1848 treatment cycles were included in this analysis. The highest long-term Psoriasis Area and Severity Index improvement was observed after treatment with ixekizumab, followed by ustekinumab and secukinumab, adalimumab and etanercept. Overall, ustekinumab surpassed all other biologics in drug survival up to 48 months. However, when adjusted for biologic naïvety, its superiority vanished and drug survival rates were similar for ixekizumab (91·6%), secukinumab (90·2%) and ustekinumab (92·8%), all of them superior to adalimumab (76·5%) and etanercept (71·9%) at 12 months and beyond. Besides biologic non-naïvety (2·10, P < 0·001), the introduction of a new drug such as secukinumab or ixekizumab (relative hazard ratio 1·6, P = 0·001) and female gender (1·50, P = 0·019) increased the risk of treatment discontinuation overall, whereas psoriatic arthritis did not (1·12, P = 0·21). CONCLUSIONS: The time-dependent availability of drugs should be considered when analysing and comparing drug survival. Previous biologic exposure significantly influences drug survival. Women are more likely to stop treatment.

Anti-BP180 autoantibody levels at diagnosis correlate with 1-year mortality rates in patients with bullous pemphigoid.

BACKGROUND: Bullous pemphigoid (BP) is the most frequent autoimmune blistering disease mainly affecting elderly patients. Among several published risk factors, a recent post hoc analysis linked anti-BP180 autoantibodies (AABs) to fatal outcomes in BP. To date, this finding has not been confirmed independently. OBJECTIVE: To investigate the potential of anti-BP180-AAB levels as a marker of prognosis and to identify a cut-off level indicative of an increased risk for early death. Secondly, to characterize parameters associated with mortality. METHODS: Retrospective, single-centre study of BP patients diagnosed between 2001 and 2012. Analyses included epidemiological and patient- and disease-specific characteristics as well as immunological parameters at diagnosis and during follow-up. Standardized mortality ratios as well as uni- and multivariate regression analyses were calculated. RESULTS: One hundred patients (56 women, 44 men) with a median age of 81 years (interquartile range 74-86) were followed up for a median of 775 days (interquartile range 162-1617). One-year mortality rates were 25.0% implying a 2.4-fold increased risk of death compared with the general population. High anti-BP180 autoantibody levels at diagnosis (CI95 1.30-2.89; P = 0.001), dementia (CI95 1.13-6.72; P =0.03), length of hospitalization (CI95 1.16-2.41; P = 0.01) and age (CI95 1.23-4.19; P = 0.009) correlated significantly with 1-year mortality. BP180-AAB concentrations of ≥61 U/mL characterized a subgroup of patients with a particular higher risk for early death compared with the general population (CI95 1.81-3.81; P < 0.0001). CONCLUSION: In bullous pemphigoid, serum concentrations of BP180 autoantibodies at diagnosis could help to identify patients at risk for death within the first year after diagnosis (cut-off value 61 U/mL).

Apremilast in psoriasis - a prospective real-world study.

BACKGROUND: Apremilast is a novel oral phosphodiesterase-4 inhibitor approved for psoriasis treatment. Randomized trials have documented its efficacy and safety, but data on real-world patients are scarce. OBJECTIVES: We aim to characterize psoriasis patients treated with apremilast in a real-world setting and calculate drug survival as an important measure of efficacy and compliance. METHODS: All patients with psoriasis who received apremilast between 1 April 2015 and 19 January 2017 were evaluated every 4 weeks, and we documented: age, weight, height, smoking status, family history of psoriasis, joint involvement, previous treatments, psoriasis area severity index (PASI) scores, and the onset and duration of adverse events (AE). Efficacy was analysed by PASI50, PASI75 and PASI90, reflecting the improvement of skin lesions compared to the PASI-baseline. Kaplan-Meier statistics were used for drug survival estimates. RESULTS: Forty-eight patients were included. The median apremilast drug survival was 12.5 weeks (range 1-87). Three patients (6.3%) reached PASI90, nine (18.8%) PASI75 and eight patients (16.7%) PASI50. Patient weight inversely correlated with a PASI50 response (P < 0.05, n = 37), and none of the obese patients (BMI > 30.0, n = 6) reached PASI75, compared to 32% of the non-obese patients (BMI < 30.0, n = 31). Thirty-one patients (64.6%) reported at least one AE, most frequently diarrhoea (n = 21, 43.8%), headache (n = 7, 14.6%) and joint pain (n = 5, 10.4%). CONCLUSIONS: Despite differences between real-world and trial patients, apremilast is safe and effective for the treatment of skin psoriasis in the daily practice. Up to 40% of patients will reach PASI50 or higher, but only few patients will reach PASI90. Bodyweight might affect drug efficacy.

Mycoplasma pneumoniae-associated mucositis--case report and systematic review of literature.

BACKGROUND: Mycoplasma pneumoniae, a bacterium known to be a common cause of pneumonia, has been documented to cause complications such as debilitating mucositis previously described as an atypical Stevens-Johnson syndrome without skin lesions. However, in the spectrum of epidermal dermatopathies, the condition is increasingly recognized as a separate entity, now termed M. pneumoniae-associated mucositis (MPAM). OBJECTIVES: We present a case of MPAM and systemically review the literature to discuss diagnostic and therapeutic options. METHODS: A systematic literature search was performed to find studies reporting MPAM in adults. We extracted and analysed patient demographics, disease symptomatology, diagnostic testing and treatment. RESULTS: Eleven articles, describing 12 patients and our own patient met the predefined criteria and were analysed. Respiratory, ocular and oral symptoms were present in all patients. Therapies predominantly included antibiotics (10 of 13) and immunosuppressive treatment (9 of 13) leading to complete resolution of symptoms in all patients. CONCLUSION: Our findings highlight that MPAM should be recognized as a distinct disease entity within the spectrum of epidermal dermatopathies. We discuss and show in our patient why M. pneumoniae IgA serum levels could prove to be more reliable diagnostic tools in the MPAM diagnosis than the widely used IgG and IgM titre levels.

Merkel cell carcinoma: mitoses, expression of Ki-67 and bcl-2 correlate with disease progression.

BACKGROUND: There are conflicting data on markers of disease progression and outcome of Merkel cell carcinoma. OBJECTIVE: We suggest to review histological and various immunohistochemical features of Merkel cell carcinoma specimens, in order to identify prognostic markers of clinical relevance. METHODS: We collected paraffin-embedded blocks from primary tumours from 26 patients diagnosed with Merkel cell carcinoma and determined the following: type and size of the tumour, number of mitoses, proliferation rate (Ki-67 antibody), (anti)-apoptosis rate (bcl-2, p53, p63 antibodies) and lymphatic vessel invasion (D2-40 antibody for podoplanin). Two authors blinded to clinical outcome, independently assessed and scored all samples. The findings were correlated with tumour progression, which was determined by local recurrence, lymph node- or distant metastases. RESULTS: During the average follow-up period of 63.4 months 12 (46%) patients had disease progression. Statistical analysis revealed Ki-67-staining (P = 0.005) as a marker of disease progression, high number of mitoses (P = 0.026) correlated with lymph node metastasis, while a tendency for increased Bcl-2 expression (P = 0.064) was found in patients with local recurrence. A higher number of invaded lymphatic capillaries showed a tendency in correlation with metastases (P = 0.072). CONCLUSION: The findings indicate that high numbers of mitoses, proliferation and survival of tumour cells as marked by Ki-67- and Bcl-2-staining, and infiltration of lymphatic vessels, might correlate with the biological behaviour of Merkel cell carcinoma.

Low-dose inhalation of interleukin-2 bio-chemotherapy for the treatment of pulmonary metastases in melanoma patients.

BACKGROUND: Interleukin-2 (IL-2) treatment for patients with metastatic melanoma has shown remarkable durable responses. Systemic administration of IL-2 may cause severe side effects, whereas local administration is considered to be a safe alternative. The lungs are common sites of metastases in melanoma patients causing considerable respiratory problems. We sought to evaluate the potential antitumoral effect of a low-dose inhalative IL-2 (lh-IL-2) regimen for patients with melanoma lung metastases. In addition, we explored the prophylactic potential of Ih-IL-2 after surgical removal of lung metastases in a study carried out in an outpatient setting. METHODS: Twenty patients with American Joint Committee on Cancer stage-IV (M1b and M1c) melanoma were enrolled in this study and treated with 3 × 3 million IU inhalative IL-2 q.d. together with monthly dacarbazine bolus injections. Five patients received lh-IL-2 after surgical resection of lung metastases to prevent recurrence of the disease (prophylaxis group, N=5). All other patients were enrolled in the treatment group (N=15). Clinical evaluations were carried out monthly and radiological follow-up was performed every third month. RESULTS: Nine patients in the treatment group had a clinical benefit with partial regression (27%) or stable disease (33%). Four patients had progression of lung metastases (26.7%) and two patients were not evaluable (13.3%). In the prophylaxis group, none of the patients developed new lung metastases during lh-IL-2 therapy. The median follow-up period was 7.8 months in the treatment group and 25.7 months in the prophylaxis group. In the majority of patients, treatment was well tolerated. CONCLUSIONS: Low-dose IL-2 inhalation might offer an effective and safe treatment option for lung metastases in melanoma patients. In addition, lh-IL-2 may have a prophylactic potential to prevent recurrence in the lungs after pulmonary melanoma metastasectomy. Administration can easily be performed in an outpatient setting, thus offering an attractive treatment option.

Direct eyelid defect closure: a prospective study of functional and aesthetic outcomes.

BACKGROUND/OBJECTIVES: Direct closure (DC) of eyelid defects has been retrospectively shown to give excellent outcomes. We present prospective outcome data as further evidence to promote its wider use. SUBJECTS AND METHODS: A consecutive, unselected, series of patients undergoing eyelid tumour resection was studied prospectively. DC was attempted at the time of biopsy in all of them. If DC proved impossible, delayed reconstruction using other techniques was later performed. Defect size, pre- and post-operative palpebral aperture (PA) measurements and the final visit patients' and surgeons' satisfaction scores for function and appearance were recorded. RESULTS: Seventy-three eyelids of 70 patients were studied. Mean resected specimen width was 16.4 mm (4-26 mm) in the DC group, versus 23.9 mm (11-42 mm) for other, non-DC reconstructions. Primary DC was achieved in 74% of this cohort. Mean final post-operative PA measurements in the DC group were 0.7 mm vertically (p = 0.003) and 0.8 mm horizontally (p = 0.009) less than preoperatively, but there was no statistical difference (p = 0.1) in the final horizontal measurements between the operated and un-operated sides in the DC group. DC satisfaction scores were excellent for both eyelid function and appearance. CONCLUSIONS: DC of eyelid defects, irrespective of per-operative PA distortion, gives excellent late post-operative outcomes. We recommend that DC, aligning the closure tension parallel to the lid margin, is attempted whenever wound margin approximation is possible in preference to alternative reconstruction techniques, regardless of any temporary PA distortion and globe displacement that this may cause. Eyelid function and appearance recover to near normal within 2 months.

Oncogenic KIT mutations in different exons lead to specific changes in melanocyte phospho-proteome.

UNLABELLED: Mutations in the proto-oncogene c-KIT (KIT) are found in several cancers, and the site of these mutations differs markedly between cancer types. We used site directed mutagenesis to induce KIT(559), KIT(642) and KIT(816) mutations in primary human melanocytes (PHM) and we investigated the impact of each mutation on KIT function. We studied canonical KIT-signaling pathways by immunoblotting, and we used stable isotope labeling by amino acids in cell culture (SILAC) and kinase prediction models to identify kinases differently activated in respective mutants. We validated our results with the analysis of phosphorylation levels of selected substrates for each kinase. We concluded that CK1 ε and δ are more active in cell clones harboring KIT(559) and KIT(642) mutations, whereas PAK4 is more active in clones with KIT(816) mutation. Our findings might help to develop further therapeutic options for tumors with specific KIT mutations in different domains. BIOLOGICAL SIGNIFICANCE: Different types of cancers harbor mutations in the oncogene KIT. The use of small molecules inhibitors directly targeting KIT had a limited success in the treatment of patients with KIT mutant cancers. Our study describes specific phospho-proteome changes due to different KIT mutations, and provides targets of further therapeutic options.

Combined Inhibition of MEK and Plk1 Has Synergistic Antitumor Activity in NRAS Mutant Melanoma.

About one-third of cancers harbor activating mutations in rat sarcoma viral oncogene homolog (RAS) oncogenes. In melanoma, aberrant neuroblastoma-RAS (NRAS) signaling fuels tumor progression in about 20% of patients. Current therapeutics for NRAS-driven malignancies barely affect overall survival. To date, pathway interference downstream of mutant NRAS seems to be the most promising approach. In this study, data revealed that mutant NRAS induced Polo-like kinase 1 (Plk1) expression, and pharmacologic inhibition of Plk1 stabilized the size of NRAS mutant melanoma xenografts. The combination of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) and Plk1 inhibitors resulted in a significant growth reduction of NRAS mutant melanoma cells in vitro, and regression of xenografted NRAS mutant melanoma in vivo. Independent cell cycle arrest and increased induction of apoptosis underlies the synergistic effect of this combination. Data further suggest that the p53 signaling pathway is of key importance to the observed therapeutic efficacy. This study provides in vitro, in vivo, and first mechanistic data that an MEK/Plk1 inhibitor combination might be a promising treatment approach for patients with NRAS-driven melanoma. As mutant NRAS signaling is similar across different malignancies, this inhibitor combination could also offer a previously unreported treatment modality for NRAS mutant tumors of other cell origins.

Control of hemoptysis by bronchial artery embolization.

Control of massive hemoptysis by embolization of bronchial arteries was achieved in two patients with bronchopleural fistula. Both patients would have been prohibitive risks for thoracotomy. The indications, contraindications, and technique of the procedure are presented as well as a review of the literature.

An evaluation of the effectiveness of CT vs. other imaging modalities in the diagnosis of atypical renal masses.

A retrospective review of 34 patients undergoing nephrectomy for suspected renal malignancy was undertaken to evaluate the effectiveness of computed tomography (CT), ultrasound, arteriography, and cyst puncture in providing a definitive preoperative diagnosis of benign vs. malignant renal abnormality. The predictive value of a test suggesting malignancy was 88% for angiography, 86% for ultrasound, 71% for cyst puncture, and 80% for CT. The predictive value of a test suggesting no malignancy for non-CT imaging modalities was poor. The predictive value of renal CT increased to 96%, when three or more characteristics are present which suggest the lesion is not a simple, benign renal cyst. Using these criteria all malignancies were identified, and all but one benign lesion excluded. Unusual lesions that have equivocal or indeterminate diagnostic studies and only one or two noncystic CT features should undergo selective exploration rather than radical nephrectomy.

Hepatic rupture associated with pregnancy: treatment with transcatheter embolotherapy.

Spontaneous rupture of the liver associated with pregnancy is a rare and very serious complication, usually occurring in association with eclampsia or preeclampsia. Survival has generally been dependent on early recognition of characteristic signs and symptoms and prompt surgical intervention. Even with surgery, maternal mortality approaches 40% and fetal mortality is even higher. The diagnosis can usually be firmly established based on the clinical and radiographic findings presented in this article. Reported is a patient with hepatic rupture successfully treated by transcatheter embolization of the hepatic artery. It is the authors' belief that if such a patient is clinically stable enough to undergo angiography, then transcatheter embolotherapy is a reasonable alternative to surgery.

Vascular complications of pancreatitis.

Hemorrhage is one of the most life-threatening complications of pancreatitis. It is usually due to erosion of a major pancreatic or peripancreatic vessel with massive bleeding into the gastrointestinal tract or abdominal cavity, or to formation and subsequent rupture of an arterial pseudoaneurysm. In addition, the inflammatory process of pancreatitis may cause thrombosis of the portal vein or its main tributaries, the splenic and superior mesenteric veins, resulting in compartmental portal hypertension with gastric, mesenteric, or colonic varices. Variceal hemorrhage is not an uncommon vascular complication of pancreatitis. The use of the newer, noninvasive imaging modalities of US, duplex Doppler US, and bolus-dynamic CT; earlier use of diagnostic and therapeutic angiography; and a more aggressive surgical approach have led to significant reductions in morbidity and mortality rates for patients with vascular complications secondary to pancreatitis. The radiologic diagnosis of vascular complications can be accomplished with US, CT, and angiography. US and CT may show formation of arterial pseudoaneurysms, evidence of hemorrhage into a pancreatic pseudocyst or fluid collection, or portal venous thrombosis with development of varices. The presence of flow in a pseudoaneurysm, or absence of flow due to portal venous thrombosis, can be confirmed by contrast-enhanced dynamic CT or duplex Doppler US. Angiography should be utilized in all patients, if possible, to show the precise site and source of bleeding. Although active bleeding can be diagnosed only by detection of contrast extravasation, the source of bleeding often can be identified by demonstration of an underlying vascular abnormality, such as a pseudoaneurysm or varices. Patients who are hemodynamically stable and who have angiographic evidence of bleeding can be treated with transcatheter embolization. This may result in permanent control of the bleeding, providing definitive treatment, or temporary control, thus allowing surgery to be performed on an elective or semi-emergent basis. Patients who are unstable or who have vascular involvement that is not amenable to transcatheter embolization should have emergency surgery. Preoperative angiography should be performed prior to surgery, if possible. Angiography can show the surgeon the exact vessel involved, as well as the surrounding vascular anatomy, thus facilitating the surgical approach. In selected patients, occlusion balloon catheters can be employed to obtain hemostasis during or after pancreatic surgery.

Severe complications from partial splenic embolization in patients with liver failure.

Transcatheter embolization of the spleen is gaining popularity as a non-surgical method of treatment for hypersplenism. While early reports documented frequent serious complications, a more recent study noted good results using a fractionated approach with only partial embolization of the periphery of the spleen. This technique was recently used on three patients with hypersplenism associated with severe liver disease. All had grave complications, including sepsis, pneumonia, abscess formation, and progressive liver failure, and all died within six weeks of the angiographic procedure in spite of good haematological responses. Since it is frequently this category of patient in whom the procedure is attempted, definitive surgical splenectomy is suggested following the embolization as soon as the clotting parameters return to normal.

Failure to visualise the abdominal portion of the inferior vena cava with computed tomography: a clue to underlying abdominal pathology.

Failure to visualise the intra-abdominal portion of the inferior vena cava (IVC) using contrast-enhanced computed tomography (CT) is unusual. A review of 1272 contrast-enhanced abdominal CT examinations revealed that the IVC was not visible at one or more levels in only 132 (10.4%). In 57 (43%), non-visualisation was due to pathological processes, most frequently metastatic carcinoma, causing compression or thrombosis of the IVC. In the remainder, technical factors or artefacts could explain the non-visualisation. Techniques and procedures to improve visualisation of the IVC are discussed. Failure to visualise the IVC on CT at any level unexplained by artefacts is abnormal.

Embolization for hepatoportal arteriovenous fistula.

The simultaneous occurrence of an intrahepatic hepatoportal fistula and portal hypertension generates questions about the priority and methods of treatment. Catheter embolization of the small-to-moderate fistula is not required, and surgical decompression of portal hypertension is recommended.

Successful embolization of the dorsal pancreatic artery to control massive upper gastrointestinal hemorrhage.

Selective arterial embolization is an established technique to control gastrointestinal bleeding in patients who are poor surgical risks and in whom bleeding is uncontrolled by other methods. This article describes the control of upper gastrointestinal bleeding by subselective embolization of a bleeding branch of the dorsal pancreatic artery in a patient with severe pancreatitis. This is the first recorded successful embolization of the dorsal pancreatic artery to control hemorrhage.