[Pain in rheumatic diseases : What can biologics and JAK inhibitors offer?] / Schmerz bei rheumatischen Erkrankungen : Was haben Biologika und Januskinaseinhibitoren zu bieten?

Persistent pain despite adequate inflammation control poses a big challenge in many rheumatic diseases for patients as well as physicians. The focus of drug development over the past years was on anti-inflammatory therapies. Enormous progress has been made and several treatment options have been added. It has been observed that pain triggered by inflammation can be effectively treated by inflammation control; however, the chronic pain component remains a problem, is little studied and specific treatment options are missing. Pain is influenced by inflammatory mediators, such as cytokines, which act on peripheral nociceptors and lead to peripheral sensitization. If inflammation continues, this can potentially lead to central sensitization and chronification of pain via immigration of immune cells and/or local activation of e.g. microglia. This leads to increasing autonomization and uncoupling of pain from the actual inflammatory process. The present review deals with the question if bDMARD or tsDMARD also show benefits concerning pain processes in addition to the profound inhibitory effects on inflammation. There are preclinical data that show an influence on sensitization following the use of cytokine inhibitors. On the other hand, so far clinical data show that bDMARDs as well as tsDMARDs consistently rapidly and reliably reduce nociceptive inflammatory pain across disease entities. An effect especially on the process of central sensitization and therefore on chronification of pain cannot be finally evaluated based on the currently available data.

[Success quotas in exercise questions in the discipline of rheumatology in preparation for the written state examination in German universities from 2012 to 2016 : Evaluation of the AMBOSS databank according to professorships in rheumatology with and without freedom of instruction in German universities]. / Erfolgsquote bei Übungsfragen zum Fach Rheumatologie zur Vorbereitung auf das schriftliche Staatsexamen an deutschen Hochschulen von 2012 bis 2016 : Auswertung der AMBOSS-Datenbank nach weisungsfreien und nicht-weisungsfreien rheumatologischen Lehrstühlen an deutschen Hochschulen.

The discipline rheumatology is underrepresented in German universities with only seven professorial chairs with freedom of instruction. The teaching positions with and without freedom of instruction are associated with a different quantity of teaching. The effect of the teaching position on the quality of teaching and on the training of medical students is unclear. In order to approach the answer to this question we have evaluated 2,610,217 examination questions from 32,166 students over a time period of 4 years according to location and freedom of instruction, which are documented on the teaching platform AMBOSS. In total, in the evaluated examination performance in the discipline of rheumatology, the majority of students just about achieved the grade of "sufficient". Locations with freedom of instruction had significantly better grades; however, these differences had no relevance with respect to the complete state examination. The examination pressure on German medical students to learn for the examination discipline of rheumatology can be estimated as rather low.

[Rheumatism, jet lag and the body clock]. / Rheuma, Jetlag und die innere Uhr.

Circadian rhythms play an important role in the function of the body. Among others, the activity of the immune system is subject to daily variability which explains the different intensity of rheumatic symptoms during the day (e.g. morning stiffness). Circadian rhythms are subject to continuous adaptation via external time signals (zeitgebers), such as light-dark periods, time of food intake, as well as daily activity and resting periods. Following an acute phase shift of these external zeitgebers, e.g. via transmeridian travel (east-west or west-east), the body has to adjust all circadian systems to these new circumstances during an adjustment response, which lasts for several days. The classical symptoms of jet lag, such as tiredness during the day, mood swings and cognitive malfunction occur during this adjustment period. The impact of acute phase shifts as a result of transmeridian travel in subjects with rheumatic disorders, as well as strategies to prevent jet lag will be discussed in the following article.

Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases.

Energy regulation (EnR) is most important for homoeostatic regulation of physiological processes. Neuroendocrine pathways are involved in EnR. We can separate factors that provide energy-rich fuels to stores [parasympathetic nervous system (PSNS), insulin, insulin-like growth factor-1, oestrogens, androgens and osteocalcin] and those that provide energy-rich substrates to consumers [sympathetic nervous system (SNS), hypothalamic-pituitary-adrenal axis, thyroid hormones, glucagon and growth hormone]. In chronic inflammatory diseases (CIDs), balanced energy-rich fuel allocation to stores and consumers, normally aligned with circadian rhythms, is largely disturbed due to the vast fuel consumption of an activated immune system (up to 2000 kJ day(-1)). Proinflammatory cytokines such as tumour necrosis factor or interleukins 1beta and 6, circulating activated immune cells and sensory nerve fibres signal immune activation to the rest of the body. This signal is an appeal for energy-rich fuels as regulators are switched on to supply energy-rich fuels ('energy appeal reaction'). During evolution, adequate EnR evolved to cope with nonlife-threatening diseases, not with CIDs (huge negative selection pressure and reduced reproduction). Thus, EnR is inadequate in CIDs leading to many abnormalities, including sickness behaviour, anorexia, hypovitaminosis D, cachexia, cachectic obesity, insulin resistance, hyperinsulinaemia, dyslipidaemia, fat deposits near inflamed tissue, hypoandrogenaemia, mild hypercortisolaemia, activation of the SNS (hypertension), CID-related anaemia and osteopenia. Many of these conditions can contribute to the metabolic syndrome. These signs and symptoms become comprehensible in the context of an exaggerated call for energy-rich fuels by the immune system. We propose that the presented pathophysiological framework may lead to new therapeutical approaches and to a better understanding of CID sequence.

Serum BAFF strongly correlates with PsA activity in male patients only--is there a role for sex hormones?

OBJECTIVES: To determine the relationship between serum levels of B cell activating factor belonging to the TNF family (BAFF) and disease activity (DAS28) in psoriatic arthritis (PsA) patients. METHODS: Twenty-two male and 31 female psoriasis patients fulfilling the CASPAR criteria for PsA were recruited for the study. Disease activity was recorded using the disease activity score for 28 joints (DAS28). Whole blood and serum samples were analysed for serum BAFF, estradiol, and testosterone levels. RESULTS: Serum BAFF levels were positively correlated with DAS28 only in male PsA patients (r=0.669, p<0.001). In male but not female patients, serum testosterone was negatively correlated with DAS28 (r=-0.632, p=0.002), and serum BAFF (r=-0.520, p=0.018), respectively. The serum BAFF/ serum testosterone (B/T) ratio showed a strong correlation with DAS28 in male patients (r=0.743, p<0.0001) and, again, no correlation was found in female participants (r=0.019, p=0.93). A linear regression analysis showed that the B/T is a good predictor of DAS28 (r2=0.586, p<0.001). On the other hand, estradiol levels did neither correlate with PsA activity in male nor female patients in our study population. CONCLUSIONS: Even though a role for B cells in the pathogenesis of PsA has not been established, BAFF levels correlate with disease activity in male PsA patients. Furthermore, serum testosterone in male patients negatively correlates with disease activity and BAFF, respectively. The serum BAFF/serum testosterone ratio might be used as predictor of disease activity in male PsA patients.

Persistent parvovirus B19 infection detected by specific CD4+ T-cell responses in a patient with hepatitis and polyarthritis.

We, here, report the case of a parvovirus B19 infection in an immunocompetent male patient presenting with acute hepatitis and polyarthritis. To follow the course of infection, we used a previously established enzyme-linked immunosorbent spot assay (ELISPOT) technique to detect CD4+ T cells specific for viral proteins. Even though symptoms of arthritis and hepatitis resolved in the immunocompetent individual within a few weeks, viral DNA in serum and CD4+ T cells specific for the viral protein VP1 unique region were still detectable more than 6 month after the onset of symptoms, thus pointing to a persistent state of infection. On the basis of this observation, we hypothesize that the intensity of liver involvement correlates with the likelihood of developing persistent parvovirus B19 infection. The described ELISPOT technique to detect virus-specific CD4+ T cells provides an excellent tool to analyse the state of parvovirus B19 infection for future studies to test this hypothesis.

Acute cold stress in rheumatoid arthritis inadequately activates stress responses and induces an increase of interleukin 6.

OBJECTIVE: Acute stress in patients with rheumatoid arthritis (RA) should stimulate a strong stress response. After cryotherapy, we expected to observe an increase of hormones of the adrenal gland and the sympathetic nervous system. METHODS: A total of 55 patients with RA were recruited for whole-body cryotherapy at -110 degrees C and -60 degrees C, and local cold therapy between -20 degrees C and -30 degrees C for 7 days. We measured plasma levels of steroid hormones, neuropeptide Y (sympathetic marker), and interleukin (IL)6 daily before and after cryotherapy. RESULTS: In both therapy groups with/without glucocorticoids (GC), hormone and IL6 levels at baseline and 5 h after cold stress did not change over 7 days of cryotherapy. In patients without GC, plasma levels of cortisol and androstenedione were highest after -110 degrees C cold stress followed by -60 degrees C or local cold stress. The opposite was found in patients under GC therapy, in whom, unexpectedly, -110 degrees C cold stress elicited the smallest responses. In patients without GC, adrenal cortisol production increased relative to other adrenal steroids, and again the opposite was seen under GC therapy with a loss of cortisol and an increase of dehydroepiandrosterone. Importantly, there was no sympathetic stress response in both groups. Patients without GC and -110 degrees C cold stress demonstrated higher plasma IL6 compared to the other treatment groups (not observed under GC), but they showed the best clinical response. CONCLUSIONS: We detected an inadequate stress response in patients with GC. It is further shown that the sympathetic stress response was inadequate in patients with/without GC. Paradoxically, plasma levels of IL6 increased under strong cold stress in patients without GC. These findings confirm dysfunctional stress axes in RA.

Immunologic reactivity in marrow graft recipients receiving cyclosporine to prevent graft-versus-host disease.

In vitro and in vivo immunologic parameters were determined in 26 patients treated continuously with cyclosporine to prevent graft-versus-host-disease (GVHD) after allogeneic bone marrow transplantation (BMT) for acute and chronic leukemia and for aplastic anemia. A group of 18 patients was tested 6 months after BMT and another group of 10 patients was tested after one year. At 6 months after BMT, 94% of the patients had normal serum IgG and IgM levels, whereas at one year 29% of them had low IgA levels. The proportion of patients with normal lymphocyte responses in vitro at 6 months after BMT was 69% and 76% for the responses to concanavalin A and to soluble antigens; 75% and 53% for the responses to allogeneic cells and pokeweed mitogen, respectively; and 89% for the response to phytohemagglutinin. All but one were able to generate suppressor cells upon con A stimulation. At one year after the graft, only one patient had demonstrable multiple abnormalities in in vitro tests. Skin test reactivity at one year was comparable to pre-graft reactivity. After BMT a lymphopenia persisted for 6 months. The rate of infectious complications was high during the first 3 months after BMT, and it diminished progressively as immune functions returned to normal. Infection was the cause of death in two cases (one disseminated cytomegalovirus infection and one septicemia). GHVD occurred in 12 patients; in nine of them the disease was transient and mild, only 1 patient developed severe chronic GVHD. Acute GVHD did not influence the tempo of immunologic reconstitution. In comparison to other studies, it seems that cyclosporine does not delay immune restoration, or increase morbidity from infection, while preventing GVHD and its complications efficiently.

Platelet activation in embolic and preembolic status of patients with nonrheumatic atrial fibrillation.

STUDY OBJECTIVE: Information on platelet activation possibly associated with a preembolic or embolic status in nonrheumatic atrial fibrillation (AF) with special regard to the role of platelet membrane activation markers (P-selectin and CD63). STUDY POPULATION: The study included 60 patients with nonrheumatic AF; 28 of them had a history of an embolic event. The age-matched control group consisted of 28 healthy subjects (13 men and 15 women). INTERVENTIONS: Patients underwent transesophageal echocardiography to detect eventual intracardiac thrombus or spontaneous echo contrast that would represent a preembolic status. Blood samples were taken from all persons to evaluate markers for platelet activation under these conditions. RESULTS: Measurements of hematologic variables did not differ significantly between normal subjects and patients presenting with AF but no preembolic or embolic status. Elevated concentrations of fibrinogen were significantly related to the presence of left atrial spontaneous echo contrast. The amount of circulating platelets expressing P-selectin and CD63 was significantly higher in the patients positive for both spontaneous echo contrast and left atrial thrombus or embolic events. Furthermore, in these groups, significantly more leukocyte-platelet conjugates were present. CONCLUSION: Platelet activation indicated by platelet membrane activation markers occurs in embolic and preembolic status of patients with nonrheumatic AF.

Closure of bronchial defects using a pedicled pericardial flap.

A technique for closure of lateral or terminal defects in the bronchial wall after tissue-saving procedures, which obviates the need for sleeve resection in few selected situations, is described. Its main advantages are a low risk of surgical complications at the suture line and easy performance.

Assessment of cardiac adrenergic supply in mitral valve prolapse using m-[123I]iodobenzylguanidine scintigraphy.

Presynaptic as well as postsynaptic adrenergic regulation abnormalities are reported in symptomatic patients with mitral valve prolapse. This study was undertaken to evaluate presynaptic sympathetic supply by m-[123I]iodobenzylguanidine scintigraphy in 17 preselected patients with mitral valve prolapse and symptoms suggestive of hyperadrenergic dysautonomia as compared to normal scintigraphic findings. Mitral valve prolapse was echocardiographically proven within the left parasternal long axis view. Percentual activity of m-[123I]iodobenzylguanidine in 33 sectors of all oblique slices along the short axis was calculated relative to the maximal uptake, set at 100%. In general, no significant differences of mean values of sectoral quantitative uptake of m-[123I]iodobenzylguanidine were detectable between patients and the control group. Only in two sectors of the basal anterolateral region P values < 0.01 were present. Thus, using m-[123I]iodobenzylguanidine scintigraphy as marker of cardiac adrenergic supply, no evidence of altered presynaptic hyperadrenergic supply was present in patients with mitral valve prolapse. These findings suggest postsynaptic regulation abnormalities to be preponderant in this condition.

Limitations of Doppler echocardiography in the assessment of prosthetic valve hemodynamics.

The purpose of this study was to determine the relationship between effective orifice areas of mechanical valves in the aortic position assessed by Doppler echocardiography, and published data from in vitro studies. Eighty-six patients with a normally functioning Standard St. Jude Medical (n = 56) or Björk-Shiley (n = 30) prosthesis in the aortic position were studied. Valve sizes varied between 19 and 27 mm. Pressure gradient was calculated by the Bernoulli, and effective orifice area by the continuity equation. Published data on prosthetic orifice areas from in vitro pulsatile flow experiments using the Gorlin formula were used for comparison. A weak correlation was present between Doppler derived pressure gradient and in vitro estimated effective orifice area, which significantly decreased with increasing valve size (R = -0.61; p < 0.0001). There was only a moderate correlation between Doppler derived and in vitro estimated effective orifice areas whether sewing ring diameter or left ventricular outflow tract diameter was used in the Doppler studies (R = 0.75 and R = 0.71, p < 0.0001, respectively). The difference between in vitro measured and Doppler derived areas was greater with Standard St. Jude Medical than with Björk-Shiley valves, both using the sewing ring diameter (1.04 +/- 0.61 cm2 vs. 0.53 +/- 0.39 cm2, p < 0.0003) and the outflow tract diameter (1.20 +/- 0.68 vs. 0.68 +/- 0.46 cm2, p < 0.006). The presence of atrial fibrillation, concomitant mitral valve replacement, small prosthesis size (19 to 23 mm) or a postoperative interval of less than one year did not change the uniform underestimation of prosthetic orifice areas by Doppler echocardiography. These findings are attributable to pressure recovery and localized transprosthetic velocities, and should be taken into account in the case of a suspected prosthesis malfunction.

Evaluating intraoperative radiation therapy (IORT) and external beam radiation therapy (EBRT) in non-small cell lung cancer (NSCLC). Five years experience.

A pilot study on intraoperative radiation therapy (IORT) combined with external beam radiation therapy (EBRT) in nonresectable non-small cell lung cancer (NSCLC) was performed in 31 patients (mean age: 66.2 years, range: 51-80; 10 anatomically and functionally, 21 functionally, nonresectable; 20 squamous-cell, 11 adenocarcinoma). The tumor was exposed by lateral thoracotomy and a staging lymph node dissection was performed (final staging 7 T1, 16 T2, 8 T3; 11 nodal positive). Ten to 20 Gy IORT (energy: 7-20 MeV electrons) were delivered to the tumor. Unilateral continuous positive airway pressure ventilation of the diseased lung was used to reduce the amount of healthy lung tissue in the IORT port and to minimize the ventilatory movement. Secondary collimation and direct shielding of radio-sensitive structures within the IORT port by aluminium sheets were used to further reduce collateral damage. Four weeks after IORT, 46 Gy EBRT (2 Gy/day 5 times a week; 8-23 MeV photons) were administered to the mediastinum and to the tumor-bearing area on an outpatient basis. In nodal positive cases the mediastinal dose was increased to 56 Gy. Twenty-three patients were evaluable. In 13 complete, in 8 partial (50-97% regression) and in 2 minor response has been achieved. Five patients experienced a recurrence (local only: 2; local and distant: 1; distant only: 2). Twelve patients died of underlying cardio-respiratory disorders within 6 to 25 months after IORT; 7 died of cancer. The overall 5-year survival rate including the incidental deaths is 14.7%. The recurrence-free survival rate is 53.2%.

[Hemolytic effect of Listeria innocua on sheep erythrocytes]. / Hämolysewirkungen durch Listeria innocua auf Schaferythrozyten.

The influence of culture medium composition on hemolytic effects produced by Listeria innocua on sheep blood agar has been investigated. Neither alpha- nor beta-hemolysis could be observed around L. innocua colonies grown on sheep erythrocyte agar lacking glucose. However, green zones of hemolytic phenomena were observed around colonies grown on such agar which contained 0,6% (w/v) glucose. By using L. innocua cell suspensions and culture filtrates this glucose-associated hemolysis only occurred in media which were weakly buffered (1 m M Na-PBS). This hemolytic phenomenon was attributed to the resulting acidification of the culture medium caused by the metabolic breakdown of glucose by Listeria. The results of this study demonstrate the necessity of including adequate buffer conditions when assaying the hemolytic property of a Listeria strain. It was found that the addition of 20 mM Na-PBS to the assay medium was sufficient to eliminate artificial "acidic-hemolysis". Moreover, the hemolysis observed with known hemolytic Listeria strains was unaffected by this buffering, as was in fact the case even when conditions of higher buffering capacity were employed. By testing in this manner, no evidence has been found which would suggest the existence of an hemolysin, either intra- or extracellular, produced by Listeria innocua. An accurate method for the determination of hemolysis caused by strains of the genus Listeria is proposed. This method of assaying hemolysis in a liquid grown medium has proven effective in determining the hemolytic properties of strains which appeared negative or questionable on blood agar as well as strains which in virulence tests were negative. The ability to accurately assess the hemolytic properties of Listeria strains, is essential in determining the association of Listeria hemolysin with pathogenicity of this genus. Together with current investigations on the genetics of hemolysin production by Listeria the determination of hemolytic activities will eventually allow to understand better the pathogenic principle of hemolytic strains of Listeria monocytogenes.

Doppler echocardiographic determination of geometric orifice areas in mechanical aortic valve prostheses.

In 63 St. Jude bileaflet and 34 Bjoerk-Shiley tilting disk aortic valve prostheses, Doppler continuity areas were compared to their corresponding geometric areas defined by the opening angle of the occluders. Continuity areas correlated significantly with geometric areas in Bjoerk-Shiley (p = 0.68) and St. Jude prostheses (p = 0.86). Differences between continuity and geometric areas were greater in St. Jude than in Bjoerk-Shiley valves (0.87 +/- 0.45 cm2 vs. 0.06 +/- 0.47 cm2, p < 0.0001). Exclusion of patients with atrial fibrillation, with a postoperative interval of less than 1 year or valve sizes of 19 and 21 mm did not change the results. Thus, underestimation of geometric areas is present in the St. Jude bileaflet aortic valves, while geometric and continuity areas are not significantly different in Bjoerk-Shiley prostheses. These results are attributable to the effect of valve-type-dependent velocity profiles.

Ambulatory blood pressure monitoring: quantification of the early morning rise in blood pressure in normal case and in patients with symptoms of orthostatic dysregulation.

Though various parameters can be evaluated in ambulatory blood pressure monitoring, there is still a lack of reliable parameters for exact quantification of the early morning rise. Noninvasive ambulatory blood pressure monitoring (Space Labs 90207) was performed in 50 normotensive persons and in 52 patients with symptoms of orthostatic dysregulation. Twenty-two of the 52 patients showed normal and 19 showed sympathicotonic reactions in the orthostatic test by Thulesius. After smoothing the 24-h blood pressure profiles by Fourier analysis, the derivative was calculated from the profiles (differentiation) and the following parameters were determined: the beginning and the length of the early morning rise as well as time and point of the maximum rise. The maximum rise was compared to the difference between the nocturnal trough and the morning peak (absolute value) as well as to the percentage rise, where we found significant statistic correlations. Patients with sympathicotonic orthostatic dysregulation showed in comparison to the 50 normotensive persons a significantly lower (p < 0.05) maximum rise in blood pressure. Thus, Fourier analysis of 24-h blood pressure profiles allows determination of reliable parameters of the early morning rise in blood pressure and can be used for more precise differential diagnosis in patients with orthostatic dysregulation.