[The effect of intensified training therapy on axial spondylarthritis in day care units]. / Der Effekt intensivierter Trainingstherapie bei axialer Spondyloarthritis im teilstationären Setting.

BACKGROUND: Day care units are an essential part of psychiatric treatment in Germany. In rheumatology they are also regularly used. Axial spondylarthritis (axSpA) is an inflammatory rheumatic disease that causes pain, diminished quality of life, limitations in activities of daily living and ability to work, especially if insufficiently treated. The multimodal rheumatologic complex treatment with at least 14 days of inpatient care is an established tool to control exacerbated disease activity. The feasibility and effect of an equivalent treatment in a day care setting has not yet been evaluated. METHODS: The effect of a therapy in a day care unit comparable to the inpatient multimodal rheumatologic complex treatment was investigated using clinically established patient reported outcomes (NAS pain, FFbH, BASDAI, BASFI). RESULTS: Selected subgroups of axSpA patients can routinely and effectively be treated in day care units. Intensified multimodal as well as nonintensified treatment forms lead to reduced disease activity. Additionally, compared to nonintensified treatment, the intensified multimodal treatment approach leads to significantly reduced pain, and disease-related and functional limitations in daily life. CONCLUSION: If available, treatment in a day care unit can complement the established inpatient treatment modalities in selected axSpA patients. In cases with high disease activity and suffering, intensified multimodal treatment should be preferred due to better outcomes.

The influence of the SARS-CoV-2 lockdown on patients with inflammatory rheumatic diseases on their adherence to immunomodulatory medication: a cross sectional study over 3 months in Germany.

OBJECTIVES: To evaluate the influence of the SARS-CoV-2 pandemic on the adherence of patients with inflammatory rheumatic diseases (IRD) to their immunomodulatory medication during the three-month lockdown in Germany. METHODS: From 16th March until 15th June 2020, IRD patients from private practices and rheumatology departments were asked to answer a questionnaire addressing their behaviour with respect to their immunomodulating therapy. Eight private practices and nine rheumatology departments that included rheumatology primary care centres and university hospitals participated. A total of 4252 questionnaires were collected and evaluated. RESULTS: The majority of patients (54%) were diagnosed with RA, followed by psoriatic arthritis (14%), ankylosing spondylitis (10%), connective tissue diseases (12%) and vasculitides (6%). Most of the patients (84%) reported to continue their immunomodulatory therapy. Termination of therapy was reported by only 3% of the patients. The results were independent from the type of IRD, the respective immunomodulatory therapy and by whom the patients were treated (private practices vs rheumatology departments). Younger patients (<60 years) reported just as often as older patients to discontinue their therapy. CONCLUSION: The data show that most of the patients continued their therapy in spite of the pandemic. A significant change in behaviour with regard to their immunomodulatory therapy was not observed during the three months of observation. The results support the idea that the immediate release of recommendations of the German Society of Rheumatology were well received, supporting the well-established physician-patient relationship in times of a crisis.

[A cross sectional study on patients with inflammatory rheumatic diseases in terms of their compliance to their immunsuppressive medication during COVID-19 pandemic]. / Einstellung von Patienten mit entzündlich-rheumatischen Erkrankungen zur immunsuppressiven Therapie im Rahmen der COVID-19 Pandemie ­ eine Situationsanalyse.

The current COVID-19 pandemic inherits an unprecedented challenge for the treating rheumatologists. On the one hand, antirheumatic drugs can increase the risk of infection and potentially deteriorate the course of an infection. On the other hand, an active inflammatory rheumatic disease can also increase the risk for an infection. In the recommendations of the German Society for Rheumatology (www.dgrh.de), it is recommended that our patients continue the antirheumatic therapy to maintain remission or low state of activity despite the pandemic. In this study, patients with inflammatory rheumatic disease were asked in the first weeks of the pandemic on their opinion of their immunomodulating therapy. The result shows that over 90% of the patients followed the recommendation of the rheumatologist to continue the antirheumatic therapy, and only a small percentage of the patients terminated the therapy on their own. This result was independent of the individual anti-rheumatic therapy. Taken together, the results of this study illustrate not only the trustful patient-physician partnership in a threatening situation but also the high impact of state-of-the art recommendations by the respective scientific society.

[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.

[The rich diversity of Whipple's disease]. / Facettenreichtum des Morbus Whipple.

Whipple's disease (WD) is a rare, chronic multiorgan disease which can caused by Tropheryma whipplei, a ubiquitous gram positive bacterium. Detection of T. whipplei is mostly performed histologically using periodic acid-Schiff (PAS) staining in affected tissues to visualize characteristic PAS-positive macrophages and by the polymerase chain reaction (PCR). Clinically, WD is often characterized by gastrointestinal symptoms (diarrhea, colic-like abdominal pain and weight loss). Arthritis is a common presentation of WS, often leading to a misdiagnosis of seronegative rheumatoid arthritis and as a consequence to immunosuppressive therapy. The clinical presentation of WD is highly polymorphic affecting different organ systems (e. g. cardiac or neurological manifestation) and making an appropriate clinical diagnosis and even the diagnostic process itself difficult. This article reports on three cases presenting with completely different leading symptoms (initially misdiagnosed as seronegative rheumatoid arthritis, spondyloarthritis and adult onset of Still's disease, respectively) that illustrate the rich diversity of WD. The cases were chosen to draw attention to the fact that although WD is mainly associated with the field of gastroenterology and gastrointestinal (GI) involvement is common, it may appear without GI symptoms. In cases of a clinical suspicion of WD, diagnostic efforts should be made to detect the bacterium in the affected organ. The German S2k guidelines on GI infections and WD published in January 2015 summarized the current state of the art for WD. The currently recommended primary treatment is antibiotics that can infiltrate the cerebrospinal fluid, e. g. ceftriaxone, followed by cotrimoxazole, which should be maintained over several months.

Profile of gastrointestinal involvement in patients with systemic sclerosis.

Systemic sclerosis (SSc) is a chronic autoimmune connective tissue disease. Of the numerous organ manifestations, involvement of the upper and lower gastrointestinal tract (GIT) appears to be the most frequent with regard to the clinical symptoms. However, as the frequency and clinical relevance of GI involvement in patients with SSc are not known in detail, the German network of the systemic sclerosis (DNSS) has developed a detailed questionnaire to evaluate the extent and profile of gastrointestinal involvement in SSc patients. The multi-symptom questionnaire was used at baseline and after 1 year in registered patients of the DNSS. In addition, the results were compared with gastrointestinal disorders in patients with SSc and other rheumatic diseases, as well as with the medical history of the patients. In total, 90 patients were included in the study. The results of the study show that in reality, a much higher (nearly all) percentage of (98,9%) patients than expected suffer from GI-symptoms, regardless of the stage of their disease. Of these, meteorism (87,8%) was the most common followed by coughing/sore voice (77,8%), heartburn (daytime 68,9%, nighttime 53,3%), diarrhea (67,8%), stomach ache (68,9%) and nausea (61,1%). Although SSc patients were treated according to the respective recommendations, only limited improvements with regard to GI-symptoms could be achieved after 1 year of follow-up. In addition, the study revealed that the multi-symptom questionnaire is a useful tool to contribute to identify the gastrointestinal sequelae in systemic sclerosis.

[Treatment of patients with destructive arthritis with certolizumab pegol]. / Therapie mit Certolizumab pegol bei Patienten mit destruierender Arthritis.

Certolizumab pegol is a new anti-TNF-alpha inhibitor which has been approved for the treatment of rheumatoid arthritis since October 2009. Due to the modification of the antibody fragment by the adherence of polyethylene glycol (PEG) a sufficient distribution in inflammatory tissue was found in animal experiments. In two individual case reports a remission of therapy refractive arthritis was achieved by administration of certolizumab pegol.

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.

Cardiac toxicity of bone marrow transplantation: predictive value of cardiologic evaluation before transplant.

PURPOSE: This study analyses the risk of cardiac complications and its individual predictability in bone marrow transplantation (BMT). PATIENTS AND METHODS: One hundred seventy patients undergoing allogeneic (n = 150) or autologous (n = 20) BMT were evaluated by physical examination, history, rest and exercise ECG, chest x-ray, two-dimensional echocardiography, and radionuclide ventriculography (RNV) before BMT, and monitored for 3 months thereafter. RESULTS: Following BMT, cardiac toxicity occurred in eight patients (4.7%). Three patients (1.8%) developed life-threatening toxicity (pericardial effusion and left ventricular failure, n = 2; sudden cardiac arrest, n = 1). Thirty-eight patients (22%) had pathologic findings before BMT. In 22 patients, left ventricular ejection fraction (EF) determined by RNV was reduced to less than 55%. This was the only abnormality in 17 patients and was generally mild, with a lowest EF of 42%. There was no correlation between overall results of cardiologic evaluation before BMT and cardiac toxicity. Cardiotoxic events occurred more frequently in patients with a reduced EF (P < .05). However, this was restricted to minor cardiac events. Life-threatening cardiac toxicity was not significantly increased in patients with pathologic results before BMT. Moreover, none of the patients with an EF less than 50% developed cardiac toxicity. CONCLUSION: Life-threatening cardiac toxicity is rare after BMT, occurring in less than 2% of all patients. Although the occurrence of cardiac toxicity is correlated with a reduction of EF before BMT, life-threatening cardiac toxicity cannot be predicted in individual patients.

Randomized comparison of interferon alpha and hydroxyurea with hydroxyurea monotherapy in chronic myeloid leukemia (CML-study II): prolongation of survival by the combination of interferon alpha and hydroxyurea.

The optimum treatment conditions of interferon (IFN) alpha therapy in chronic myeloid leukemia (CML) are still controversial. To evaluate the role of hydroxyurea (HU) for the outcome of IFN therapy, we conducted a randomized trial to compare the combination of IFN and HU vs HU monotherapy (CML-study II). From February 1991 to December 1994, 376 patients with newly diagnosed CML in chronic phase were randomized. In all, 340 patients were Ph/BCR-ABL positive and evaluable. Randomization was unbalanced 1:2 in favor of the combination therapy, since study conditions were identical to the previous CML-study I and it had been planned in advance to add the HU patients of study I (n=194) to the HU control group. Therefore, a total of 534 patients were evaluable (226 patients with IFN/HU and 308 patients with HU). Analyses were according to intention-to-treat. Median observation time of nontransplanted living patients was 7.6 years (7.9 years for IFN/HU and 7.3 years for HU). The risk profile (new CML score) was available for 532 patients: 200 patients (38%) were low, 239 patients (45%) intermediate, and 93 patients (17%) high risk. Complete hematologic response rates were higher in IFN/HU-treated patients (59 vs 32%). Of 169 evaluable IFN/HU-treated patients (75%), 104 patients (62%) achieved a cytogenetic response that was complete in 12% (n=21), major in 14% (n=24), and at least minimal in 35% (n=59). Of the 534 patients, 105 (20%) underwent allogeneic stem cell transplantation in first chronic phase. In the low-risk group, 65 of 200 patients were transplanted (33%), 30 (13%) in the intermediate-risk group, and nine (10%) in the high-risk group. Duration of chronic phase was 55 months for IFN/HU and 41 months for HU (P<0.0001). Median survival was 64 months for IFN/HU and 53 months for HU-treated patients (P=0.0063). We conclude that IFN in combination with HU achieves a significant long-term survival advantage over HU monotherapy. In view of the data of CML-study I, these results suggest that IFN/HU is also superior to IFN alone. HU should be combined with IFN in IFN-based therapies and for comparisons with new therapies.

Hematopoietic colony formation after allogeneic bone marrow transplantation: enhancement by cyclosporin A and anti-gamma-(immune) interferon antiserum in vitro.

Bone marrow hematopoietic progenitors (CFU-GM, CFU-E, and BFU-E) were found to be markedly decreased in 21 bone marrow transplant recipients studied from one to 51 months after transplantation. In these patients, bone marrow colony formation could be significantly enhanced by in vitro incubation of the bone marrow target with cyclosporin A (CyA; 0.5 microgram/ml) or with a monoclonal anti-gamma-(immune) interferon (IFN-gamma) antibody. Both effects were highly correlated. The data indicate that (a) endogenous elaboration of IFN-gamma may contribute to decreased colony formation in allogeneic bone marrow transplant recipients, and (b) CyA may induce a gradual release of the progenitor cell pool from IFN-gamma-mediated suppression.

Hemopoietic reconstitution after bone marrow transplantation.

Forty-one patients underwent bone marrow transplantation (BMT) for treatment of severe aplastic anemia or hematologic malignancies. Hemopoietic reconstitution after BMT was monitored by peripheral blood counts, counts of bone marrow cellularity, and clonal assays for hemopoietic progenitors (CFUc, CFUe, and BFUe), along with bone marrow morphology. The number of transplanted nucleated cells and the number of transplanted progenitors (CFUc, CFUe, and BFUe) correlated significantly with the time of reticulocyte recovery. The number of transplanted CFUc correlated significantly with the time of granulocyte recovery. Platelet recovery occurred late and showed large variations. No correlation between the transplanted cells and the recovery of nucleated cells or hemopoietic progenitors (CFUc, CFUe, and BFUe) in the bone marrow was found. Bone marrow cellularity and hemopoietic progenitors showed a rapid, but incomplete, recovery during the first 56 days after BMT. Hematologic studies on seven long-term survivors with an uncomplicated posttransplantation course revealed subnormal bone marrow cellularity and hemopoietic progenitor incidence up to three years after BMT, despite normal peripheral blood counts. The low progenitor incidence could be explained by a proliferative defect of the stem cells, compensated for by an amplification in the more differentiated compartment of hemopoiesis.

Cyclosporine as an alternative to cyclophosphamide in the treatment of chronic graft-versus-host disease.

Four patients with progressive extensive chronic graft-versus-host disease or dose-limiting toxicity on conventional therapy (cyclophosphamide + prednisolone) were treated with a regimen of cyclosporine + prednisolone as induction therapy and cyclosporine as maintenance therapy. All 4 showed clinical improvement and 3 of 4 are alive at 9 months. The incidence of infections was not affected by this regimen, but steroid requirements were reduced.

Coagulation factor XIII A and B subunits in bone marrow and liver transplantation.

The polymorphism of the coagulation factor XIIIA and B subunits was determined before and after bone marrow or liver transplantation. It could be shown that the FXIIIA phenotype of the recipient was replaced by donor phenotype after bone marrow transplantation, whereas the phenotype of FXIIIB remained of recipient origin. In contrast, the FXIIIB phenotype changed to donor type after orthotopic liver transplantation but not the FXIIIA phenotype. The results indicate that the FXIIIA protein is produced in hemopoiesis, most likely in megakaryocytes and FXIIIB protein in the liver. Depending on the site of synthesis, FXIII alleles can be used as a marker in engraftment of FXIIIA-incompatible bone marrow transplantation or as a marker in FXIIIB-incompatible orthotopic liver transplantation.

Evidence for the involvement of host-derived OKT8-positive T cells in the rejection of T-depleted, HLA-identical bone marrow grafts.

The recent introduction of a variety of techniques for removing T cells from bone marrow grafts has reduced the incidence of graft-versus-host disease (GVHD)-associated morbidity and mortality. Whether this advance will be translated into improved patient survival is unclear at present, mainly because these procedures increase the risk of graft failure. Since 1983 we have transplanted 25 consecutive leukemia patients with HLA-identical sibling grafts purged of T cells by a single incubation with the monoclonal antibody Campath-1 and donor complement. This approach was successful in reducing T cell contamination of the graft and preventing acute and chronic GVHD. In this group of patients two suffered irreversible graft failure and one developed reversible graft failure. In a similarly sized group of patients previously transplanted with unpurged marrow according to the Seattle protocol, no episodes of graft failure occurred. Since other causes of graft failure, such as drug toxicity or viral infections, could be largely excluded, this suggested that the graft failures were specifically related to the purging process. In haploidentical bone marrow transplantation (BMT) O'Reilly has identified residual host-versus-graft activity (HVG) as a cause of graft failure. The causes and mechanisms of graft failure in T-depleted HLA-identical sibling transplants have not been extensively investigated to date. In the three graft failures observed by us, the loss of the graft was preceded by the appearance of a population of activated lymphocytes. We have determined the phenotype and origin of this population and investigated its interactions with donor hemopoietic tissue in vitro.

Single-drug oral antibacterial prophylaxis with ofloxacin in BMT recipients.

We evaluated the efficacy and safety of a new oral fluoroquinolone, ofloxacin (200 mg twice daily), as antibacterial prophylaxis after BMT in a non-comparative prospective study of patients nursed in either LAF plastic isolators or HEPA filtered single rooms. Of the 101 evaluable patients who were neutropenic (< 500 x 10(6)/l) for a median duration of 20 days, 92 (91%) had febrile episodes of varying length and causes. Infections were documented in 34 patients, of whom 14 had proven bacterial infection (13 with bacteremia and one with pneumonia). Mortality rate within 6 weeks after transplant was 6%. Only one patient died from bacterial infection. Univariate analysis using an array of potentially prognostic factors including the type of isolation was not helpful in identifying significant variables for predicting the development of documented infection. Tolerance was excellent. Oral ofloxacin was associated with a relatively low incidence of documented bacterial infection and related mortality, although it did not obviate the need for frequent empiric antimicrobial therapy due to a high incidence of febrile episodes.

Graft failure after T cell-depleted bone marrow transplantation: clinical and immunological characteristics and response to immunosuppressive therapy.

We have investigated the clinical and immunological features of 10 cases of graft failure after T cell-depleted marrow transplantation. In addition, the hypothesis that the process of graft failure can be reversed by immunosuppressive therapy with cyclosporin + steroids +/- monoclonal antibodies was tested in seven patients. Early graft failures (before day 50) presented a uniform clinical syndrome with a host T lymphocytosis preceding the loss of the graft. In the majority of cases of late graft failure (after day 50) a syndrome comprising delayed granulopoietic regeneration, fever of unknown origin and abdominal symptoms was observed. Surface marker analysis of peripheral blood and bone marrow lymphocytes implicated a population of CD3+, CD8+, DR+ host T lymphocytes with a frequent co-expression of the Leu7+ antigen in the pathogenesis of graft failure. Immunosuppressive therapy reversed graft failure in the three cases of incomplete graft failure (i.e. with residual reticulocytes) and failed in the four cases of complete graft failure (i.e. no residual reticulocytes).

Evaluation of remission state in chronic myeloid leukemia patients after bone marrow transplantation using cytogenetic and molecular genetic approaches.

The remission state of 13 Philadelphia positive chronic myeloid leukemia patients was studied after bone marrow transplantation (BMT) by cytogenetic and Southern blot analysis of the breakpoint cluster region (BCR) gene. Eight of 13 patients showed neither clinical nor genetic evidence of residual disease. In two patients hematological relapse was confirmed by cytogenetic and molecular analysis. Evidence for residual leukemic cells in otherwise complete remission was obtained genetically in three patients. One of the latter cases revealed BCR rearrangement despite negative cytogenetic findings, while in another patient cytogenetic relapse was observed without demonstrable rearrangement within the major BCR. Our results may indicate that cytogenetic and molecular genetic methods complement rather than replace each other for the detection of residual CML cells after BMT.

[Pulmonary complications following bone marrow transplantation as seen on the x-ray]. / Lungenkomplikationen nach Knochenmarktransplantation im Röntgenbild.

In a retrospective study chest radiographs of 87 bone marrow transplant recipients were analysed. 36 patients had pulmonary complications with lung opacifications. Interstitial changes were more frequent than airspace pneumonias. The latter were caused by bacteria and fungi only. The most common cause of pulmonary complications was cytomegalovirus pneumonia. It was characterised uniformly by a bilateral diffuse interstitial pattern. Idiopathic interstitial pneumonias were indistinguishable from CMV infection. Pneumonias caused by Epstein-Barr virus and protozoa, diffuse radiation pneumonitis and leukaemic infiltrates were rare and also associated with interstitial changes.