15 Management of refractory skin lupus

Management of refractory skin lesions in patients with lupus erythematosus involves combinations of local measures and systemic agents requiring adjustment to activity and development of the disease. The treatment options are fairly similar for the different cutaneous manifestations; however, no drugs have been licensed specifically for the treatment of skin lesions in this disease. Therefore, the aim of the European guideline was to achieve a broad consensus on treatment strategies for patients with cutaneous lupus erythematosus (CLE) by a European subcommittee, guided by the European Dermatology Forum (EDF) and supported by the European Academy of Dermatology and Venereology (EADV). Standard treatment of CLE includes preventive measures such as smoking cessation and photoprotection. Ultraviolet (UV) A and B light is one of the most important risk factors for CLE, clearly documented by photoprovocation studies in large patient cohorts. In the past years, several trials have been performed to investigate the preventive effect of sunscreens in patients with UV-induced CLE. A randomised controlled trial demonstrated that the application of a broad-spectrum sunscreen with a high protection factor prevents UV-induced skin lesions under standardised conditions. First-line treatment options in CLE include topical corticosteroids or calcineurin inhibitors. Currently available topical calcineurin inhibitors (0.03% and 0.1% tacrolimus ointment, 1% pimecrolimus cream) have been licensed for the use in patients with atopic dermatitis. The major advantage of these agents is their better safety profile when compared to topical corticosteroids. A multicentre, randomised, double-blind, vehicle-controlled trial showed significant improvement for oedema and erythema of CLE lesions using 0.1% tacrolimus ointment compared to the vehicle. In patients with disfiguring and widespread disease, systemic agents need to be applied. The first-line systemic treatment is antimalarials, such as hydroxychloroquine, chloroquine or quinacrine, which are particularly recommended in patients with a high risk of scarring and/or the development of systemic disease. In addition, systemic corticosteroids are recommended as first-line treatment in highly active and/or severe CLE. Second- and third-line systemic treatments include methotrexate, retinoids, dapsone and mycophenolate mofetil or mycophenolate acid, respectively. Thalidomide should only be used in selected therapy-refractory CLE patients, preferably in addition to antimalarials. Several new therapeutic options, such as B-cell- or interferon alpha-targeted agents, need to be further evaluated in clinical trials to assess their efficacy and safety in the treatment of patients with CLE. In 2011, the monoclonal antibody belimumab, a B lymphocyte stimulator-specific inhibitor, was introduced for SLE as an adjunct therapy for patients with autoantibody-positive disease who despite standard therapy show high disease activity, intolerance of other treatments, or an unacceptably high need for corticosteroids. Currently, a validated skin score is used to confirm the efficacy of belimumab on mucocutaneous manifestations. In summary, there is a high unmet need for new therapeutic strategies, such as B-cell- or interferon-targeted agents, focusing on cutaneous manifestations in lupus erythematosus. Therefore, innovative designs of randomised controlled trials are warranted to develop new therapeutic options for patients with refractory skin manifestations in this disease. Case 1: 40-year-old man with SLE and painful erythemato-violaceous lesions Marzia Caproni A 40-year-old man was diagnosed with systemic lupus erythematosus (SLE) in 2013 based on photosensitivity, Raynaud's phenomenon, positive direct Coombs test, ANA, anti-dsDNA, Sm, Ro, La, RNP antibodies and low complement, followed by malar rash and discoid lesions on the ears. He started hydroxychloroquine (HCQ) 400 mg/day, nicotinamide 500 mg/day, topical corticosteroids and calcineurin inhibitors with benefit, followed by reactivation of malar rash, worsening of immunological parameters, proteinuria and lupus nephritis two years later. Prednisone 25 mg/day and mycophenolate mofetil (MMF) 640 mg/day were added with good clinical and laboratory control. In March 2018 he was hospitalised because of suspected macrophage activation syndrome triggered by cytomegalovirus and MMF was withdrawn. As lupus reactivated, in May 2018 he restarted MMF 320 mg/day with prednisone 25 mg/day and HCQ 200 mg/day. In August 2018, rituximab was administered because of the development of sensory neuropathy with no improvement, thus he underwent intravenous immune globulin treatment with control. In 2020, he developed painful erythemato-violaceous lesions associated with small bullae and ulcers on the distal phalanges of the fingers and toes and of the tip of the nose. Skin lesions were consistent with chilblain lupus. Topical corticosteroid was added. Systemic treatments were replaced by belimumab. Discussion Points Specific and non-specific skin manifestations during SLE course Cutaneous lupus erythematosus (CLE) guidelines Chilblain lupus: differential diagnosis at the time of Covid-19 Case 2: 35-year-old female with SLE and erythemato-desquamative plaques Marzia Caproni A 35-year-old female was diagnosed with SLE in 2013 on the basis of discoid lesions of the face and head, photosensitivity, ANA positivity, lymphadenopathy, hypocomplementemia, leukopenia, low-grade fever and diffuse arthralgias. Comorbidities included Hashimoto's thyroiditis and fybromyalgia under L-tyroxine, baclofen and escitalopram treatment. She started HCQ 400 mg/day and prednisone 25 mg/day, tapering to 5 mg/day with initial control. After 2 years of treatment arthralgias worsened as well as skin lesions and laboratory findings. On examination, atrophic painful plaque of the scalp and erythemato-desquamative plaques on the face were revealed. Topical and IV corticosteroids were added without improvement. Patient also underwent methotrexate, cyclosporine, mycophenolate, rituximab and azathioprine treatment without improvement. We introduced mepacrine 100 mg/day with skin lesion improvement. Due to the difficulty in finding the drug, the patient stopped the treatment with reactivation of the skin manifestations and systemic involvement. We started belimumab 660 mg IV with HCQ 400 mg/day, prednisone 5 mg/day, azathioprine 50 mg/day and duloxetine 60 mg/day with control. Discussion Points Discoid lupus erythematosus: clinical and histopathological findings CLE guidelines: topical treatments of discoid lupus erythematosus CLE guidelines: mepacrine in recalcitrant cutaneous lupus erythematosus Belimumab and skin lesions in SLE Learning Objectives Discuss specific and non-specific skin manifestations of SLE Describe optimal clinical management of skin lupus in line with CLE guidelines and the role of biologic therapy Explain the challenges of differential diagnosis in patients with CLE References Fairley JL, Oon S, Saracino AM, Nikpour M. Management of cutaneous manifestations of lupus erythematosus: A systematic review. Semin Arthritis Rheum 2020;50:95–127. Chasset F, Frances C. Current concepts and future approaches in the treatment of cutaneous lupus erythematosus: A comprehensive review. Drugs 2019;79:1199–1215. Kuhn A, Aberer E, Bata-Csorgő Z, Caproni M, Dreher A, Frances C, Glaser R, Klotgen HW, Landmann A, Marinovic B, Nyberg F, Olteanu R, Ranki A, Szepietowski JC, Volc-Platzer B. S2k guideline for treatment of cutaneous lupus erythematosus – guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV). J Eur Acad Dermatol Venereol 2017;31:389–404

18 Cutaneous lupus

Case 1: 35-year-old Mestizo female Bernardo Pons-Estel A 35-year-old Mestizo female was diagnosed with systemic lupus erythematosus (SLE) in 2005 based on polyarthritis, malar rash, photosensitivity, mucosal ulcerations, positive ANA and anti-dsDNA, and low complement. She was treated with prednisone 20–30 mg/day and hydroxychloroquine (HCQ) 400 mg/day. In June 2010, lupus pneumonitis was diagnosed. In July 2018, she was first admitted to our hospital. She was cushingoid and had fever, fatigue, malar rash, oral ulcers, alopecia, polyarthritis, oedema, multiple purplish-red streaks, and active erythematous, palpable and painful subcutaneous indurated nodules/plaques located on her face, proximal lower extremities and abdomen; some were ulcerated. Laboratory tests RBC 3.8 (x1012/L), hemoglobin 11.8 g/dl, WBC 2,3 (x109/L), platelets 62 (x109/L), ESR 8 mm, CRP 0.8 mg/L, serum ferritin 1,487 ng/ml, ALAT 70 UI/ml, ASAT 26 UI/ml, GGT 64 U/L, BUN 43 mg/dl, serum creatinine 1.54 mg/dl, GFR 67 mL/min, cholesterol 186 mg/dL, triglycerides 149 mg/dl, proteinuria 210 mg/24 h, ANA 1/320, speckled pattern, anti-Sm (+) and anti-dsDNA, anti-U1RNP, anti-Ro and anti-La all (-). C3 75 mg/dl, C4 10, Coombs test (-), procalcitonin 0.29 ng/ml ( She was treated with IV methylprednisolone (500 mg/day/3 days), and high-dose intravenous immunoglobulin, and discharged with mycophenolate mofetil 1 g/day, HCQ 400 mg/day, prednisone 20 mg/day and TMS-SMX 860/160 BID for 5 days. A week later she was re-admitted with fever, pancytopenia, hepatosplenomegaly, lymphadenopathy and several painful, indurated erythematous lesions. Her SLEDAI was 13. A bone marrow aspiration and biopsy was interpreted as a macrophage activated syndrome in the context of SLE exacerbation and treated with IV dexamethasone, colony stimulating factor, and rituximab 1000 mg. Despite treatment, she remained severely ill with fever, asthenia, petechiae and purpura on her abdomen and thighs, and pancytopenia. Due to disease severity, treatment with etoposide was indicated. Finally, the patient presented an acute episode of respiratory distress followed by death. Discussion Points Interpreting the different skin manifestations in a patient with SLE Analyzing complications and differential diagnoses with other associated diseases Case 2: 28-year-old Caucasian female Annegret Kuhn A 28-year-old Caucasian female was diagnosed with systemic lupus erythematosus (SLE) in 1996 and presented with severe, erythematous, scarring discoid lesions on the scalp, face, and hands. She had been resistant to a high number of therapeutic agents including hydroxychloroquine, chloroquine, methotrexate, isotretinoin, and cyclophosphamide for several years and had developed various side effects. Moreover, the long-term medication for SLE had not influenced her skin lesions in the past months. In December 2009, the patient received alitretinoin, which was administered orally with a daily dose of 30 mg. The patient showed continuous improvement of the discoid skin manifestations over a period of 5 months and finally a total clearance of most lesions. No serious adverse events were recorded during treatment with alitretinoin; however, the patient experienced recurring headache, which was successfully treated with nonsteroidal anti-inflammatory drugs. Therefore, alitretinoin was reduced to a daily dose of 10 mg. The vitamin-A derivative, alitretinoin, has been approved for use in severe chronic hand eczema unresponsive to treatment with potent topical corticosteroids. This case suggests that alitretinoin could also be an effective alternative in the treatment of cutaneous manifestations in SLE; however, randomized controlled trials are needed to prove the efficacy and evaluate the safety of alitretinoin in this disease. Discussion Points Treatment of therapy-resistant cutaneous manifestations in SLE Therapeutic guidelines in cutaneous lupus erythematosus Learning Objectives Explain different possible skin manifestations in patients with SLE Discuss complications, differential diagnosis with allied diseases and treatment approaches Describe the spectrum of manifestations in cutaneous lupus, including: ACLE, CCLE, SCLE and ICLE Explain the therapeutic guidelines in cutaneous lupus Describe preventive strategies in cutaneous lupus including photoprotection Describe topical treatment options in cutaneous lupus Discuss common and experimental systemic treatment options in cutaneous lupus Reference Kuhn A, Patsinakidis N, Luger TA. Alitretinoin for cutaneous lupus erythematosus. J Am Acad Dermatol 2012;67:123–126

Concept maps to enable interdisciplinary research in cross-domain fusion

A sound basis for an interdisciplinary dialogue is highly important for cross-domain fusion (CDF) dealing with knowledge transfer between working groups situated in different research disciplines. In this paper, we present a literature-based concept map as one example to start an interdisciplinary dialogue between disciplines for the showcase of the concept “coast” and illustrate how such a concept map can be used to explicate various computer science challenges and provide inputs for CDF. We use the strengths of a concept map to display gathered knowledge and perspectives, and hence view the different disciplines have on “coast” and further highlight inter- and intra-categorical connections between several disciplines. With this example, we also want to point out the importance for the understanding of data originating from different disciplines and to raise awareness about the various methods and models that provide data and information for CDF approaches

Knowledge Integration and Good Marine Governance: A Multidisciplinary Analysis and Critical Synopsis

Our research addresses knowledge integration for the good governance of the environment and the oceans: (a) through a comprehensive legal, political science, and anthropological analysis; and (b) by providing an examination of crucial research foci and research gaps in the fields of environmental and marine governance, along the North–South divide. Our subsequent critical synopsis reveals how existing research within each discipline offers complementary insights for future research. We concludes with a call for further testing of tools, approaches, and methods to enable comprehensive research on the conceptualization of knowledge integration

Knowledge Integration and Good Marine Governance: A Multidisciplinary Analysis and Critical Synopsis

Our research addresses knowledge integration for the good governance of the environment and the oceans: (a) through a comprehensive legal, political science, and anthropological analysis; and (b) by providing an examination of crucial research foci and research gaps in the fields of environmental and marine governance, along the North–South divide. Our subsequent critical synopsis reveals how existing research within each discipline offers complementary insights for future research. We concludes with a call for further testing of tools, approaches, and methods to enable comprehensive research on the conceptualization of knowledge integration

Klimawandel und Teichwirtschaft: Auswirkungen des Klimawandels auf die Perspektiven in der sächsischen Teichwirtschaft

Die Veröffentlichung enthält differenzierte Analysen für die Entwicklung von Temperatur, Niederschlag und Sonnenscheindauer sowie deren Schwankungen für die sieben Gebiete in Sachsen, in denen sich die meisten Karpfenteichwirtschaften befinden. Dabei werden sowohl die Vergangenheit als auch die mögliche zukünftige Klimaentwicklung betrachtet. Die Broschüre richtet sich an Teichwirte, Fach- und Förderverwaltungen, Planer, Naturschutz-, Heimatschutz- und Tourismusverbände sowie die interessierte Öffentlichkeit

Operationalizing Ocean Health: Toward Integrated Research on Ocean Health and Recovery to Achieve Ocean Sustainability

Protecting the ocean has become a major goal of international policy as human activities increasingly endanger the integrity of the ocean ecosystem, often summarized as “ocean health.” By and large, efforts to protect the ocean have failed because, among other things, (1) the underlying socio-ecological pathways have not been properly considered, and (2) the concept of ocean health has been ill defined. Collectively, this prevents an adequate societal response as to how ocean ecosystems and their vital functions for human societies can be protected and restored. We review the confusion surrounding the term “ocean health” and suggest an operational ocean-health framework in line with the concept of strong sustainability. Given the accelerating degeneration of marine ecosystems, the restoration of regional ocean health will be of increasing importance. Our advocated transdisciplinary and multi-actor framework can help to advance the implementation of more active measures to restore ocean health and safeguard human health and well-being

Frequency of disease-associated and other nuclear autoantibodies in patients of the German network for systemic scleroderma: correlation with characteristic clinical features

Introduction In the present study, we analysed in detail nuclear autoantibodies and their associations in systemic sclerosis (SSc) patients included in the German Network for Systemic Scleroderma Registry. Methods Sera of 863 patients were analysed according to a standardised protocol including immunofluorescence, immunoprecipitation, line immunoassay and immunodiffusion. Results Antinuclear antibodies (ANA) were detected in 94.2% of patients. In 81.6%, at least one of the autoantibodies highly associated with SSc or with overlap syndromes with scleroderma features was detected, that is, anti-centromere (35.9%) or anti-topoisomerase I (30.1%), followed in markedly lower frequency by antibodies to PM-Scl (4.9%), U1-ribonucleoprotein (U1-RNP) (4.8%), RNA polymerases (RNAPs) (3.8%), fibrillarin (1.4%), Ku (1.2%), aminoacyl-transfer RNA synthetases (0.5%), To (0.2%) and U11-RNP (0.1%). We found that the simultaneous presence of SSc-associated autoantibodies was rare (1.6%). Furthermore, additional autoantibodies were detected in 55.4% of the patients with SSc, of which anti-Ro/anti-La, anti-mitochondrial and anti-p25/p23 antibodies were most frequent. The coexistence of SSc-associated and other autoantibodies was common (43% of patients). SSc-associated autoantibodies disclosed characteristic associations with clinical features of patients, some of which were previously not acknowledged. Conclusions This study shows that five autoantigens (that is, centromere, topoisomerase I, PM-Scl, U1-RNP and RNAP) detected more than 95% of the known SSc-associated antibody responses in ANA-positive SSc patients and characterise around 79% of all SSc patients in a central European cohort. These data confirm and extend previous data underlining the central role of the determination of ANAs in defining the diagnosis, subset allocation and prognosis of SSc patients