[Reality of inpatient vasoactive treatment with prostacyclin derivatives in patients with acral circulation disorders due to systemic sclerosis in Germany]. / Versorgungsrealität der stationären vasoaktiven Therapie mit Prostazyklinderivaten bei Patienten mit akralen Durchblutungsstörungen bei systemischer Sklerose in Deutschland.

BACKGROUND: Raynaud's phenomenon and the frequently ensuing digital ulcerations represent an early and very distressing symptom in patients with systemic sclerosis (scleroderma, SSc) causing significant limitations in the ability to work and quality of life. The use of vasoactive drugs (especially intravenous prostacyclin derivatives) is recommended to reduce the risk of hypoxic tissue damage up to the loss of fingers. METHODS: In order to obtain information about the current state of treatment of patients with prostacyclin derivatives in routine clinical life in Germany, a survey was conducted among the centers affiliated to the German Network for Systemic Scleroderma (DNSS). In addition, a separate patient survey was conducted by the schleroderma self-help group (Sklerodermie Selbsthilfe e. V.), which only covered the symptoms Raynaud's syndrome, digital ulcers and the use of intravenous prostacyclin derivatives. RESULTS: Of the 433 patients surveyed 56% stated that they had already been treated with prostacyclin derivatives (iloprost/alprostadil) because of their illness and symptoms. A total of 61% received the treatment for severe Raynaud's phenomenon and 39% for digital ulcerations. Most respondents not only experienced an improvement in Raynaud's phenomenon and digital ulcers but also a significant improvement of limitations in everyday life. They also needed significantly less outside help and absenteeism from work was much lower. CONCLUSION: Patients consistently reported a positive effect of treatment with prostacyclin derivatives on Raynaud's phenomenon, acral ulcerations, pain and daily restrictions and felt well and safely cared for during inpatient treatment. These positive effects in the patients' perceptions provide crucial information supporting and confirming the current European and international treatment recommendations.

Large Variability of Frequency and Type of Physical Therapy in Patients in the German Network for Systemic Sclerosis.

OBJECTIVE: To determine the type and frequency of physical therapy (PT) prescribed by physicians for patients in the registry of the German Network for Systemic Sclerosis. METHODS: The data for 4,252 patients were analyzed using descriptive statistics, chi-square tests, and odds ratios (ORs). RESULTS: Overall, 37.4% of patients (1,590 of 4,252) received PT at the end of a yearly follow-up. The most frequently used type of PT was lymphatic drainage (n = 1,061, 36.8%), followed by exercise therapy (n = 1,047, 36.3%) and heat therapy (n = 689, 23.9%). More than three-fourths of treated patients (82%) received 1 or 2 different forms of PT simultaneously. The prescription of PT was associated with the extent of skin fibrosis as measured by the modified Rodnan skin thickness score (<10 [41.8% of patients], 11-20 [55.8% of patients], and >21 [63.9% of patients]; P < 0.001). Patients with musculoskeletal involvement (e.g., arthritis, muscle weakness, joint contractures, tendon friction rubs) had a higher chance of receiving PT than patients without these symptoms, with corresponding ORs ranging from 1.96 (95% confidence interval [95% CI] 1.69-2.28) for joint contractures to 3.83 (95% CI 2.89-5.08) for arthritis. When comparing the type of PT prescription across the initial and all follow-up visits from 2003 to 2017, significant alterations with a decreasing frequency of patients receiving PT could be observed (P = 0.001). CONCLUSION: To our knowledge, this is the first study reporting the use of PT in patients with systemic sclerosis (SSc) in a large cohort. Although SSc is characterized by considerable disability and restriction of motion, <40% of patients received PT.

Use of vasoactive/vasodilating drugs for systemic sclerosis (SSc)-related digital ulcers (DUs) in expert tertiary centres: results from the analysis of the observational real-life DeSScipher study.

INTRODUCTION: DeSScipher is the first European multicentre study on management of systemic sclerosis (SSc), and its observational trial 1 (OT1) evaluated the efficacy of different drugs for digital ulcer (DU) prevention and healing. The aim of this study was to assess current use of vasoactive/vasodilating agents for SSc-related DU in the expert centres by analysing the baseline data of the DeSScipher OT1. METHOD: Baseline characteristics of patients enrolled in the OT1 and data regarding DU were analysed. RESULTS: The most commonly used drugs, in both patients with and without DU, were calcium channel blockers (CCBs) (71.6%), followed by intravenous iloprost (20.8%), endothelin receptor antagonists (ERAs) (20.4%) and phosphodiesterase 5 (PDE-5) inhibitors (16.5%). Of patients, 32.6% with DU and 12.8% without DU received two drugs (p < 0.001), while 11.5% with DU and 1.9% without DU were treated with a combination of three or more agents (p < 0.001). Sixty-five percent of the patients with recurrent DU were treated with bosentan and/or sildenafil. However, 64 out of 277 patients with current DU (23.1%) and 101 (23.6%) patients with recurrent DU were on CCBs alone. CONCLUSIONS: Our study shows that CCBs are still the most commonly used agents for DU management in SSc. The proportion of patients on combination therapy was low, even in patients with recurrent DU: almost one out of four patients with current and recurrent DU was on CCBs alone. Prospective analysis is planned to investigate the efficacy of different drugs/drug combinations on DU healing and prevention. Key Points • The analysis of DeSScipher, the first European multicentre study on management of SSc, has shown that the most commonly used vasoactive/vasodilating drugs for DU were CCBs, followed by intravenous Iloprost, ERAs and PDE-5 inhibitors. • More than half of the patients with recurrent DU received bosentan and/or sildenafil. • However, the proportion of patients on combination therapy of more than one vasoactive/vasodilating drug was low and almost one out of four patients with current and recurrent DU was on CCBs alone.

[Peripheral nerve involvement in rheumatic diseases]. / Periphere Nervenbeteiligung bei rheumatischen Erkrankungen.

Peripheral neuropathies are probably an under-diagnosed complication of many rheumatic diseases. In some cases they take a mild clinical course, in others they cause severe impairment of patients' quality of life. A precise diagnosis and etiological classification are of major importance for successful treatment and prognosis of peripheral neuropathies. A detailed patient history and physical examination are the foundation of every diagnostic approach. Electrophysiological studies are obligatory when peripheral neuropathy is suspected, whereas nerve or nerve-muscle biopsies are indicated only in selected cases. Therapeutic approaches are often complicated by a lack of evidence. They correspond to frequently tested immunosuppressive treatment of the underlying disease, such as glucocorticoids, cyclophosphamide, mycophenolate mofetil and intravenous immunoglobulins and are based on the symptomatic pain treatment of other neuropathies. As first-line treatment gabapentin, pregabalin, duloxetine, venlafaxine and tricyclic antidepressants are frequently used.

Classification, categorization and essential items for digital ulcer evaluation in systemic sclerosis: a DeSScipher/European Scleroderma Trials and Research group (EUSTAR) survey.

BACKGROUND: A consensus on digital ulcer (DU) definition in systemic sclerosis (SSc) has been recently reached (Suliman et al., J Scleroderma Relat Disord 2:115-20, 2017), while for their evaluation, classification and categorisation, it is still missing. The aims of this study were to identify a set of essential items for digital ulcer (DU) evaluation, to assess if the existing DU classification was useful and feasible in clinical practice and to investigate if the new categorisation was preferred to the simple distinction of DU in recurrent and not recurrent, in patients with systemic sclerosis (SSc). METHODS: DeSScipher is the largest European multicentre study on SSc. It consists of five observational trials (OTs), and one of them, OT1, is focused on DU management. The DeSScipher OT1 items on DU that reached ≥ 60% of completion rate were administered to EUSTAR (European Scleroderma Trials and Research group) centres via online survey. Questions about feasibility and usefulness of the existing DU classification (DU due to digital pitting scars, to loss of tissue, derived from calcinosis and gangrene) and newly proposed categorisation (episodic, recurrent and chronic) were also asked. RESULTS: A total of 84/148 (56.8%) EUSTAR centres completed the questionnaire. DeSScipher items scored by ≥ 70% of the participants as essential and feasible for DU evaluation were the number of DU defined as a loss of tissue (level of agreement 92%), recurrent DU (84%) and number of new DU (74%). For 65% of the centres, the proposed classification of DU was considered useful and feasible in clinical practice. Moreover, 80% of the centres preferred the categorisation of DU in episodic, recurrent and chronic to simple distinction in recurrent/not recurrent DU. CONCLUSIONS: For clinical practice, EUSTAR centres identified only three essential items for DU evaluation and considered the proposed classification and categorisation as useful and feasible. The set of items needs to be validated while further implementation of DU classification and categorisation is warranted. TRIAL REGISTRATION: Observational trial on DU (OT1) is one of the five trials of the DeSScipher project (ClinicalTrials.gov; OT1 Identifier: NCT01836263 , posted on April 19, 2013).

[Pulmonary fibrosis in rheumatic diseases]. / Lungenfibrose bei rheumatischen Erkrankungen.

Rheumatic diseases are frequently complicated by secondary pulmonary diseases, which often impair the quality of life and increase the mortality of patients. A correct classification of such pulmonary complications is important to ensure appropriate treatment and optimal prognosis. The diagnostic and therapeutic challenge is to find the precise diagnosis and appropriate therapy among the multitude of potential causes for respiratory symptoms. It is important to maintain a cautious approach to invasive diagnostics, even though the differential diagnostics of infections or toxic lung disease might be crucial. The situation is further complicated by the frequent lack of evidence for therapies. Especially in the case of pulmonary fibrosis which is comparable to cancer in its complexity and high mortality, the diagnostics and therapy should be discussed in appropriate interdisciplinary boards.

Interstitial lung disease increases mortality in systemic sclerosis patients with pulmonary arterial hypertension without affecting hemodynamics and exercise capacity.

Published data suggest that coexisting interstitial lung disease (ILD) has an impact on mortality in patients with systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH), but there is scarce knowledge if this is reflected by hemodynamics, exercise capacity, autoantibody profile, or pulmonary function. In this partially retrospective study, 27 SSc-PAH patients were compared to 24 SSc-PAH patients with coexisting ILD respecting to survival, pulmonary function, hemodynamics, exercise capacity, and laboratory parameters. Survival was significantly worse in SSc-PAH-ILD patients than in SSc patients with isolated PAH (1, 5, and 10-year survival rates 86, 54, and 54% versus 96, 92, and 82%, p = 0.013). Compared to isolated SSc-PAH patients, patients with SSc-PAH-ILD revealed lower forced expiratory volume after 1 s (FEV1) values at the time of PAH diagnosis as well as 1 and 2 years later (p = 0.002) without significant decrease in the PAH course in both groups. At PAH diagnosis, diffusion capacity for carbon monoxide (DLCO) values were lower in the ILD-PAH group. Coexisting ILD was not associated with lower exercise capacity, different FEV1/forced vital capacity (FVC) ratio, higher WHO functional class, or reduced hemodynamics. Higher levels of antibodies against angiotensin and endothelin receptors predict mortality in all SSc-PAH patients but could not differentiate between PAH patients with and without ILD. Our study confirmed an impact of ILD on mortality in SSc-PAH patients. Pulmonary function parameters can be used to distinguish PAH from PAH-ILD. The higher mortality rate cannot be explained by differences in hemodynamics, exercise capacity, or autoantibody levels. Mechanisms of mortality remain to be studied.

[Pulmonary fibrosis in rheumatic diseases]. / Lungenfibrose bei rheumatischen Erkrankungen.

Rheumatic diseases are frequently complicated by secondary pulmonary diseases, which often impair the quality of life and increase the mortality of patients. A correct classification of such pulmonary complications is important to ensure appropriate treatment and optimal prognosis. The diagnostic and therapeutic challenge is to find the precise diagnosis and appropriate therapy among the multitude of potential causes for respiratory symptoms. It is important to maintain a cautious approach to invasive diagnostics, even though the differential diagnostics of infections or toxic lung disease might be crucial. The situation is further complicated by the frequent lack of evidence for therapies. Especially in the case of pulmonary fibrosis which is comparable to cancer in its complexity and high mortality, the diagnostics and therapy should be discussed in appropriate interdisciplinary boards.

[Sex-specific differences of the immune system]. / Geschlechtsspezifische Unterschiede des Immunsystems.

BACKGROUND: Sex-specific differences in the prevalence and severity of immune disorders are well-known phenomena; however, it is only recently that we have begun to understand the possible causes of such differences. MATERIAL AND METHODS: A literature search on this topic was carried out and the results are summarized. RESULTS: In the last few years research has been guided by technological advances in gene sequencing and new insights into the microbiome of the gut, as well as an awareness of sex- and gender-specific risk factors for infections and autoimmunity. CONCLUSION: The knowledge acquired in recent years will not only improve diagnostics and early identification of these disorders but also influence future research, prevention and therapy of infections and autoimmune diseases.

The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis.

Lymphomas were studied in kindreds with autoimmune lymphoproliferative syndrome (ALPS; Canale-Smith syndrome), a disorder of lymphocyte homeostasis usually associated with germline Fas mutations. Fas (CD95/APO-1) is a cell surface receptor that initiates programmed cell death, or apoptosis, of activated lymphocytes. Lymphoma phenotype was determined by immunohistochemistry, frequency of CD3(+)CD4(-)CD8(-) T-cell-receptor alpha/beta cells by flow cytometry, nucleotide sequences of the gene encoding Fas (APT1, TNFRSF6), and the percentage of lymphocytes undergoing apoptosis in vitro. Of 223 members of 39 families, 130 individuals possessed heterozygous germline Fas mutations. Eleven B-cell and T-cell lymphomas of diverse types developed in 10 individuals with mutations in 8 families, up to 48 years after lymphoproliferation was first documented. Their risk of non-Hodgkin and Hodgkin lymphomas, respectively, was 14 and 51 times greater than expected (each P <.001). Investigation of these 10 patients and their relatives with Fas mutations revealed that all had defective lymphocyte apoptosis and most had other features of ALPS. The tumor cells retained the heterozygous Fas mutations found in the peripheral blood and manifested defective Fas-mediated killing. These data implicate a role for Fas-mediated apoptosis in preventing B-cell and T-cell lymphomas. Inherited defects in receptor-mediated lymphocyte apoptosis represent a newly appreciated risk factor for lymphomas.

Shift of aberrant antigen expression at relapse or at treatment failure in acute leukemia.

The flow cytometric detection of aberrant antigen expression is one method proposed for the quantification of minimal residual disease (MRD) in acute leukemias. The present study was designed to investigate the stability of the aberrant antigen expression at relapse or at treatment failure of initial chemotherapy. For this purpose, multiparameter immunophenotyping with a panel of 15 monoclonal antibodies was used at diagnosis as well as at relapse (43 patients with overall 65 aberrations) and at treatment failure (35 patients with overall 66 aberrations). There was a significant decrease in the percentage of the initially described aberrant antigen expression on leukemia blasts at relapse (P = 0.001; n = 65) as well as at treatment failure (P = 0.0001; n = 66) considering all aberrations in the whole leukemia population. Concerning only patients with acute myelogenous leukemia (AML), significant decreases in the aberrant expression could be detected at relapse (P = 0.031; n = 42) and at treatment failure (P = 0.0001; n = 52). The changes in patients with acute lymphoblastic leukemia (ALL) were significant only at relapse (P = 0.006; n = 23). Initially, the most informative aberration was not detectable in four patients at relapse and in seven patients at treatment failure. A decrease of under 50% of the initial value was observed in another 8 patients at relapse and in 10 patients at treatment failure. In further studies assessing the detection of aberrant antigen expression for MRD, quantification of the relapses should be explicitly analyzed regarding the persistence of the initially described aberrant antigen expression.

Clinical importance of prothrombotic risk factors in pediatric patients with malignancy--impact of central venous lines.

UNLABELLED: To evaluate the role of inherited thrombophilia in the development of central venous line (CVL)-related thrombosis, the following parameters were determined in 77 pediatric-oncologic patients with CVL: activated protein C (APC)-ratio, factor V (FV) G1691A and prothrombin G20210A mutation, protein C, protein S, antithrombin, coagulation factor XII, lipoprotein (a) and homocysteine. An inherited prothrombotic risk factor was found in 17 patients (23%). Four out of 14 patients with a single detect (hyperlipoproteinemia, heterozygous FV G1691A and prothrombin G20210A mutation, protein C deficiency type I) and all three patients with combined defects (heterozygous FV G1691A mutation combined with heterozygous prothrombin G20210A variant, protein S deficiency or hyperlipoproteinemia) suffered from CVL-related thrombosis. In 11 out of 77 patients (14%) a CVL-related thrombosis was detected. In 2 children thrombosis occurred a few days after asparaginase therapy and in another three thrombosis was associated with CVL-related septicemia caused by Staphylococcus epidermidis. After removal of CVL, thrombosis was detected in 5 children, in 2 without clinical symptoms but in the presence of inherited prothrombotic risk factors. CONCLUSION: The present study demonstrates the clinical importance of CVL in combination with inherited thrombophilia in the development of thrombosis in pediatric-oncologic patients. Before or shortly after insertion of CVL, patients should be tested for the presence of factor V G1691A mutation, prothrombin G20210A variant and increased lipoprotein (a) values.

Non-Hodgkin lymphoma (NHL) as a second neoplasm occurring after neuroblastoma treatment.

As far as we know, this is the first report of a non-Hodgkin lymphoma developing after successful treatment of neuroblastoma. A boy was found to have a mediastinal T-cell lymphoma at the age of 5. He had been treated for a neuroblastoma of the left adrenal region 4 years before, when by intensive chemotherapy and radiation a complete remission of the primary tumor was achieved. The second malignancy has also been controlled without evidence of recurrence 1 year after termination of treatment. We conclude that treatment of a neuroblastoma by cytostatic drugs and radiation may lead to a non-Hodgkin lymphoma as a second malignancy.

Tube feeding preferences among nursing home residents.

OBJECTIVE: To determine the preferences of nursing home residents regarding the use of tube feedings and to characterize the clinical, functional, and psychosocial factors that are associated with preferences. DESIGN: In-person survey. SETTING: Forty-nine randomly selected nursing homes. PATIENTS/PARTICIPANTS: Three hundred seventy-nine randomly selected, decisionally capable, nursing home residents. MAIN RESULTS: Thirty-three percent of participants would prefer tube feedings if no longer able to eat because of permanent brain damage. Factors positively associated with preferences for tube feedings include male gender. African-American race, never having discussed treatment preferences with family members or health care providers, never having signed an advance directive, and believing that tube feeding preferences will be respected by the nursing home staff. Twenty-five percent of the participants changed from preferring tube feedings to not preferring tube feedings on learning that physical restraints are sometimes applied during the tube feeding process. CONCLUSIONS: Demographic and social factors are associated with preferences for tube feedings. The provision of information about the potential use of physical restraint altered a proportion of nursing home residents' treatment preferences.

Impact of advance directive videotape on patient comprehension and treatment preferences.

OBJECTIVE: To examine the effects of an advance directive videotape on patient comprehension of advance directive concepts and preferences for resuscitation. DESIGN: Pilot study, randomized cohort trial. SETTING: Extended Care and Rehabilitation Center, Veterans Affairs Medical Center, Durham, NC. PARTICIPANTS: Thirty-six residents of the center; mean age, 69 years. INTERVENTIONS: Sixteen subjects observed an advance directive videotape, and 20 subjects observed a health-relative videotape. All subjects received written material and counseling on advance directives. MEASUREMENT: Structured interviews were conducted at three time points relative to the educational program (pretest, posttest, delayed posttest), measuring comprehension of two advance directive concepts (living will and cardiopulmonary resuscitation) and resuscitation preferences based on hypothetical clinical vignettes. Mean comprehension and mean resuscitation preference scores were derived for each time point. RESULTS: The mean comprehension score improved an average of 1.6 points for all subjects from pretest to delayed posttest (P < .001); however, score changes were not significantly different between the two video groups (P = .39). Mean resuscitation preference scores were stable over time, and there were no significant score differences between the two video groups. CONCLUSION: The advance directive videotape did not significantly affect resuscitation preferences or comprehension of selected advance directive concepts.

Nursing home residents' preferences for life-sustaining treatments.

OBJECTIVES: To determine life-sustaining treatment preferences among nursing home residents, whether information regarding cardiopulmonary resuscitation (CPR) affected these preferences, and with whom treatment preferences had been discussed, and to identify factors associated with CPR preferences. DESIGN: In-person survey. SETTING: Forty-nine randomly selected nursing homes. SUBJECTS: Four hundred twenty-one randomly selected nursing home residents capable of making decisions. MAIN OUTCOME MEASURES: Preferences regarding CPR, hospitalization, and enteral tube feedings, and individual factors associated with CPR preferences. RESULTS: Of 1458 randomly selected nursing home residents assessed for the ability to participate in the study, 552 residents (38%) were eligible to participate and 421 agreed to be interviewed. Sixty percent of participants able to participate in the decision reported that they would elect CPR, 89% would choose hospitalization if seriously ill, and 33% would elect enteral tube feedings if no longer able to eat because of permanent brain damage. Individual factors associated with preferences for CPR included the following: African-American ethnicity, high self-reported physical mobility, belief that most important medical care decisions should be made by the doctor, moderate-to-severe impairment in daily decision-making skills, and not having a spouse. Fourteen percent changed their preference from preferring CPR to not preferring CPR after receiving additional information about CPR procedures. Twelve percent reported having discussed preferences with health care providers, and 31% discussed preferences with family members. CONCLUSIONS: More than half of nursing home residents capable of making decisions preferred the use of CPR. Few had discussed their preferences with health care providers. Individual preferences should be assessed when considering the use of life-sustaining treatments.

Prolonged thrombocytopenia associated with procainamide in an elderly patient.

OBJECTIVE: To report a case of thrombocytopenia associated with the use of extended-release procainamide hydrochloride in a geriatric patient. CASE SUMMARY: A 77-year-old man was admitted to the hospital for four-vessel coronary artery bypass surgery. He subsequently developed new onset atrial fibrillation and was started on extended-release procainamide on hospital day 7. The patient's platelet count on admission was 229 x 10(9)/L. The platelet count began to decrease on hospital day 22 and was 79 x 10(9)/L by day 30 and 13 x 10(9)/L by hospital day 37. The patient exhibited gross hematuria and lower extremity petechiae. There were no signs of splenic sequestration and other hematologic indices were normal. Procainamide was discontinued on hospital day 32. There was full recovery of the platelet count to baseline 33 days after procainamide was discontinued. DISCUSSION: Other possible medical and drug-related causes of thrombocytopenia are reviewed and ruled out. Previous reports of procainamide-associated thrombocytopenia describe an immune-mediated peripheral destruction of platelets with platelet recovery within three to eight days after drug discontinuation. However, the prolonged recovery period and the presence of antiplatelet antibodies suggest an immune-mediated process in the bone marrow of this patient. CONCLUSIONS: Clinicians should be aware of the possible adverse hematologic effects of procainamide in the elderly.

[Encephalopathy in leukemia treatment in children]. / Enzephalopathie während der Leukämiebehandlung bei Kindern.

Side effects on the central nervous system by antileukemic treatment have been well known for a long time. We report on 2 patients suffering from a severe encephalopathy during antileukemic therapy. Furthermore the results of cerebral computer tomography in 50 children with acute leukemia have been analysed. In 21 patients morphological findings were evident. Four patients had CCT-changes already before the beginning of their treatment. Initially in 2 patients leukemic cerebral infiltrations were detected. The importance of the computer tomography for the detection of cerebral affections by disease and treatment is demonstrated.

[Thrombocytopenia after autologous bone marrow transplantation in in acute lymphatic leukemia]. / Thrombozytopenie nach autologer Knochenmarktransplantation bei akuter lymphatischer Leukämie.

There is reported about the treatment of refractory thrombocytopenia in a 9 years old boy following the autologous bone marrow transplantation for acute lymphoblastic leukaemia. The megakaryocytes were found diminished in the bone marrow smears. Controls of the thrombocyte count and the kinetics with radioactively labeled platelets of a donor spoke in favour of immunothrombocytopenia. Threatening bleeding complications challenged the use of all treatment possibilities. The irradiation of the spleen was without any success. After the splenectomy the thrombocyte count increased slowly, but after a remarkable lag phase, however. A diminished reproduction capacity of the bone marrow graft for special cell sorts has to be taken into account in such cases. The usual cytodynamics after splenectomy cannot be expected at all.