[Outpatient specialist medical treatment (ASV)-a new treatment level in rheumatology]. / Ambulante spezialfachärztliche Versorgung (ASV) ­ eine neue Versorgungsebene in der Rheumatologie.

Since April 2018, the new third level care model of outpatient specialist care (ASV) according to §116b of the Social Code Book V (SGBV) has been available for patients with chronic inflammatory rheumatic diseases in Germany. Not only is a multiprofessional cooperation between the disciplines involved in treating rheumatic diseases promoted but also the cooperation between specialized rheumatologists and other specialists in private practice and in hospitals is encouraged. As budget capping limiting services and number of cases do not apply in ASV, a significant improvement of patient care in rheumatology is expected due to an increase in provider capacity. At the end of May 2019, 72 rheumatologists in the first 9 newly approved ASV teams had qualified for this new care concept. Bureaucratic obstacles have so far delayed the implementation of ASV. Difficulties arose in building a team with different specialties, in the process of registration of the teams and the assessment of the registration by certain regional boards responsible for access control. The national associations of rheumatologists, the Professional Association of German Rheumatologists (BDRh), the VRA (Verband der Rheumatologischen Akutkliniken e. V.) and the German Society of Rheumatology (DGRh) campaign for an easier admission of providers to the ASV and for adequate financing of all specialties involved in the ASV. The aim is to realize the chance of the ASV for better rheumatological care nationwide with shorter waiting times for a medical appointment and a better cooperation between specialists.

[Inpatient rheumatology treatment in Germany]. / Stationäre rheumatologische Versorgung in Deutschland.

Acute inpatient treatment plays an important role in the care of patients with rheumatic diseases in Germany. Inpatient facilities are usually departments in general hospitals or highly specialized clinics. The introduction of the diagnosis-related groups (DRG) system has led to a change in form which is most obviously characterized by more homogeneous structures and shorter hospital stays. Many rheumatic patients are, however, treated in general hospitals due to a lack of specialized clinics. The presence of a department of rheumatology in medical schools is deficient which therefore leads to only a small number of specialists in rheumatology. The rheumatologists in inpatient facilities are also involved in the care of outpatients, whereby the number of licensed internal medical rheumatologists is declining. Further possibilities in outpatient treatment in hospitals were created with new governmental regulations (§116b). Changes are expected with the implementation of the new outpatient specialist medical care (ASV).

Patient-reported outcomes improve with etanercept plus methotrexate in active early rheumatoid arthritis and the improvement is strongly associated with remission: the COMET trial.

OBJECTIVES: To compare the effects of etanercept (ETN) 50 mg once weekly plus methotrexate (MTX) versus MTX alone on patient-reported outcomes (PROs) and the relationship between remission and PRO improvement. METHODS: In this double-blind, randomised clinical trial (COMET), PROs included: the Health Assessment Questionnaire (HAQ), EuroQoL health status, fatigue and pain visual analogue scales, Hospital Anxiety and Depression Scale, and Medical Outcomes Short-Form-36. Mean changes from baseline were analysed by analysis of covariance using the last observation carried forward method. Results from week 52 are presented. RESULTS: Most PROs demonstrated significantly greater improvements with ETN+MTX than MTX alone, including physical functioning, pain, fatigue and overall health status. A significantly greater improvement in HAQ score was observed in the ETN+MTX than the MTX group (-1.02 vs -0.72; p<0.001) and a greater proportion reached the minimal clinically important difference of 0.22 (88% vs 78%; p<0.006). The relationship between PRO score and clinical status indicated that improvement was greatest among patients achieving remission. CONCLUSIONS: Early treatment with ETN+MTX leads to significantly greater improvements in multiple dimensions of PROs than MTX alone. The close relationship between disease activity and PRO improvement suggests that early treatment, with remission as a goal, should maximise the chance of restoring normal functioning and HRQoL.

Mass spectrometric and peptide chip epitope analysis on the RA33 autoantigen with sera from rheumatoid arthritis patients.

As the potential of epitope chips for routine application in diagnostics relies on the careful selection of peptides, reliable epitope mapping results are of utmost interest to the medical community. Mass spectrometric epitope mapping in combination with peptide chip analysis showed that autoantibodies from patients who suffered from rheumatoid arthritis (RA) were directed against distinct surface structures on the full-length human autoantigen RA33 as well as against partial sequences. Using the combined mass spectrometric epitope extraction and peptide chip analysis approach, four sequence motifs on RA33 emerged as immuno-positive, showing that epitopes were not randomly distributed on the entire RA33 amino acid sequence. A sequential epitope motif ((245)GYGGG(249)) was determined on the C-terminal part of RA33 which matched with the Western blot patient screening results using the full-length protein and, thus, was regarded as a disease-associated epitope. Other epitope motifs were found on N-terminal partial sequences ((59)RSRGFGF(65), (111)KKLFVG(116)) and again on the C-terminal part ((266)NQQPSNYG(273)) of RA33. As recognition of these latter three motifs was also recorded by peptide chip analysis using control samples which were negative in the Western blot screening, these latter motifs were regarded as "cryptic epitopes". Knowledge of disease-associated epitopes is crucial for improving the design of a customized epitope peptide chip for RA and mass spectrometric epitope mapping pivotally assisted with selecting the most informative peptide(s) to be used for future diagnostic purposes.

[Diagnostic spectrum, treatment indication and symptom duration in initial referrals to the rheumatologist]. / Diagnosespektrum, Behandlungsindikation und Symptomdauer von Erstzuweisungen zum Rheumatologen.

There is evidence that early initiation of therapy in inflammatory rheumatic diseases, in particular rheumatoid arthritis (RA), has a positive effect on disease course.To investigate referral procedures, 198 German rheumatologists reported over a 3-month period and for each patient seen for the first time on: patient characteristics, specialization of the referring physician, symptom duration, time interval between making the appointment and the first visit, diagnoses and relevant drug history. Multivariate logistic regression analyses were performed to investigate the odds ratios for a first consultation within 3 months after symptom onset.The 17,908 newly referred adult patients were 54 years old on average and 72% were women. Inflammatory rheumatic disease was diagnosed in 53%. Mean disease duration was 30 ± 57 months (median 7.3 months). There was no apparent association between patient age, education, disease severity or specialisation of the referring physician; however, there was a clear association with waiting times to first consultation.A higher number of early arthritis clinics could significantly shorten the time to first rheumatological consultation. Therefore, more efforts need to be made to fast-track referrals from primary care physicians to rheumatologists as well as to optimise rheumatologists' appointment regulations for new patients. However, these efforts can only succeed with a significant increase in the number of rheumatologists, while ensuring a firm economic basis.

Different risk profiles of biologic agents for new-onset psoriasis in patients with rheumatoid arthritis.

OBJECTIVE: To investigate rates and risk factors for incident and recurrent psoriasis in rheumatoid arthritis (RA) patients treated with different biologic (b) and conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs). METHODS: RA patients enrolled in the German biologics register RABBIT without (n = 14,525) or with a history of psoriasis (n = 375) were analyzed separately. All first events of psoriasis reported until October 2017 were assigned to the treatments prescribed in the previous 3 months. Crude incidence rates (IR) of psoriasis were calculated per 1000 patient-years. To investigate risk factors for psoriasis, cox regressions with and without inverse probability weights were applied to adjust for confounding by indication. RESULTS: 117 incident and 37 recurrent psoriatic events were reported. Patients exposed to TNFi had a significantly higher incidence rate (IR = 3.04/1,000 PY) than those exposed to csDMARDs only (IR = 0.65), whereas IRs for abatacept, rituximab and tocilizumab did not differ significantly from csDMARDs. Adjusted Cox regression confirmed a higher risk for TNFi. Female sex (HR: 1.7) and smoking (HR: 2.1) were significantly associated with incident psoriasis while methotrexate decreased the risk (HR: 0.5). For recurrent psoriasis, IRs for TNFi, abatacept and rituximab were significantly higher than for csDMARDs. CONCLUSIONS: Our data confirm a previously observed increased risk of incident psoriasis in patients exposed to TNFi compared to csDMARDs. However, the overall risk is low and the event is usually non-serious. Comedication of TNFi with methotrexate seems to lower the risk of incident psoriasis. In patients with a history of psoriasis, recurrence as adverse event is rare.

Comparative effectiveness of tumour necrosis factor alpha inhibitors in combination with either methotrexate or leflunomide.

OBJECTIVE: The objective of this study was to compare the effectiveness of a combination of tumour necrosis factor alpha (TNFalpha) inhibitors with either methotrexate or leflunomide in the treatment of patients with rheumatoid arthritis in a real-world setting. METHODS: Data from 1769 outpatients enrolled in the German biologics register RABBIT who were treated with one of the TNFalpha inhibitors adalimumab, etanercept, or infliximab in combination with either methotrexate (n = 1375) or leflunomide (n = 394) were included in the analysis. Clinical status including disease activity as well as treatment data were documented by the treating rheumatologist at baseline and at 3, 6, 12, 18, 24, 30 and 36 months of follow-up. RESULTS: Patients treated with a combination of biologics with leflunomide had significantly higher baseline disease activity than those treated with methotrexate. The highest disease activity was found for patients treated with the combination infliximab/leflunomide. After 36 months, the discontinuation rates were 46.3%, 51.3% and 61.5% for combinations of etanercept, adalimumab and infliximab with methotrexate and 53.4%, 63.1% and 67.1% for combinations with leflunomide, respectively. European League Against Rheumatism response rates after 24 months ranged from 74% to 81% for combinations with methotrexate and 72% to 81% for combinations with leflunomide. CONCLUSION: The current clinical practice is to use methotrexate as a first choice for the combination with TNFalpha antagonists. In a number of patients methotrexate has to be replaced by another disease-modifying antirheumatic drug. Our data support the view that leflunomide is a useful alternative if methotrexate is contraindicated.

[Possibilities and limitations of genomic analyses in rheumatoid arthritis]. / Möglichkeiten und Grenzen genomischer Analysen bei rheumatoider Arthritis.

The application of genetic analyses in the molecular diagnosis of patients with rheumatoid arthritis (RA) has experienced an enormous increase in recent years. Despite significant growth in experimental data there is no direct benefit for the individual patient as yet. The search for validated genetic diagnostic markers is currently being continued by genome-wide association studies. Hopefully, by combining multiple genetic markers a genetic profile can be generated which will enable prediction of the risk for RA, the disease course and response to certain therapies.

[Bone densitometry in inflammatory rheumatic diseases : Characteristics of the measurement site and disease-specific factors]. / Knochendichtemessungen bei entzündlich-rheumatischen Erkrankungen : Besonderheiten der Messorte und krankheitsspezifische Einflussfaktoren.

Bone densitometry should be performed earlier in patients with inflammatory arthritis, since factors such as inflammation and drug therapy, in particular treatment with glucocorticoids, have an important impact on the development of osteoporosis. DXA (Dual energy X-ray Absorptiometry) is considered the gold standard for bone densitometry. According to the German guidelines for osteoporosis, bone densitometry plays a crucial role in the choice of therapy.In patients with rheumatoid arthritis, measurement of peripheral bone (forearm) density in addition to lumbar spine and hip is recommended, since local bone loss is pathognomonic for this disease. DXA measurements of the hand enable the diagnosis of juxtaarticular osteoporosis at an earlier stage; however, this has not yet been established in routine practise.Bone measurement in patients with ankylosing spondylitis can be performed in the lumbar spine and the hip at disease onset. In systemic lupus erythematosus, bone loss is more frequent in patients with high inflammatory activity. Patients with psoriasis arthritis frequently have osteoporosis in the case of a destructive development of the joints.

Transforming growth factor-beta and suppression of humoral immune responses in HIV infection.

We reported previously that PBMC from HIV+ patients spontaneously release increased levels of TGF beta 1, contributing to defects in cellular immune responses. This study defines the implications of TGF beta overexpression for humoral immunity in HIV infection. We found that upon Staphylococcus aureus Cowan I (SAC) stimulation of cells from HIV+ donors, B-lymphocyte proliferative responses were decreased. This deficiency correlated closely (r = 0.7, P less than 0.001) with increased TGF beta secretion by PBMC from HIV-infected donors. Conditioned medium from HIV+ PBMC and purified TGF beta 1 had similar inhibitory effects on SAC- or EBV-induced B-cell proliferation, and B cells from HIV-infected donors were as sensitive to inhibition by TGF beta as cells from normal donors. Antibodies to TGF beta 1 neutralized the inhibitory effect of HIV+ culture supernatants on normal B cells and increased low proliferative responses by HIV+ cells. Using PWM as stimulus for B cell differentiation, it was shown that activated TGF beta from HIV+ PBMC is able to significantly reduce the induction of immunoglobulins and this effect was also abrogated by anti-TGF beta. These studies support the concept that in HIV infection, TGF beta is a potent suppressor, not only of the cellular, but of the humoral immune responses as well.

Measurement of rat insulin. Enzyme-linked immunosorbent assay with increased sensitivity, high accuracy, and greater practicability than established radioimmunoassay.

Total immunoreactive insulin (IRI) is conventionally determined by radioimmunoassays. IRI measurement in rats can be made more sensitive, accurate, and practical, as demonstrated by a new modified enzyme-linked immunosorbent assay (ELISA). It is characterized by indirect binding of an anti-insulin antibody by an antiglobulin antibody and uses the principle of competitive saturation. In this ELISA, IRI can be determined in a wide range of concentrations, corresponding to the standards. The standard curve ranges from 100 to 0.049 ng/ml IRI (1 ng/ml approximately 23.4 microU/ml approximately 172 pM rat insulin). The statistical analysis shows between- and within-assay coefficients of variation of less than or equal to 15%.

Determination of transforming growth factor beta 2 in human blood samples by ELISA.

Transforming growth factors beta (TGF beta s) show pleotrophic functions in vitro and in vivo. Biological effects depend on the cell type, the TGF beta isoform, and the availability of active TGF beta. Bioassays for TGF beta have not proven to be reliable tools in the measurement of TGF beta in human blood samples. Previously described sandwich ELISAs for measuring TGF beta are limited to single TGF beta isoforms and have not been evaluated for use in human sera or plasma. We describe a simple procedure to quantitate not only TGF beta 1 but also TGF beta 2 in human blood samples using commercially available antibodies. The sensitivity of the TGF beta 2 ELISA was 11 pg/ml. There was no crossreactivity between the TGF beta 1 and TGF beta 3 isoforms. High concentrations of TGF beta 1 and TGF beta 3 in spiked samples did not interfere with TGF beta 2 determination. TGF beta 2 recovery was highest in EDTA plasma (> 88%), and the intra- and interassay variance was 6% and 8.5% respectively. Applying the ELISA to human plasma specimens a significant percentage of TGF beta 2 (3.7 +/- 0.8 ng/ml) was found (about 50% of the TGF beta 1 content).

A detailed protocol for the measurement of TGF-beta1 in human blood samples.

Quantification of the multifunctional cytokine Transforming Growth Factor-beta1 (TGF-beta1) in blood samples has aroused increasing interest in recent years, since an abnormal regulation of this cytokine appears to play a key role in the pathogenesis of different diseases, such as autoimmundiseases or malignant tumors. The measurement of TGF-beta1 is complicated by a lot of problems concerning the collection, preparation and handling of blood samples, the platelet contamination, and the TGF-beta1 activation procedure. Here, we recommend detailed instructions for measurement of TGF-beta1 in blood plasma samples which should be followed to exclude the determination of false positive or negative results.

Transforming growth-factor-Beta - a cytokine with multiple actions in oncology and potential clinical-applications (review).

The transforming growth factor beta s (TGF beta) represent a family of multifunctional cytokines that modulate growth and function of many cells including those with malignant transformation. The actions depend on the tissue involved, and on the presence of signaling TGF beta receptors. Both in vitro and in vivo studies indicate that TGF beta mediates not only tumor progression but also exerts strong suppressive effects on certain tumor cells. Besides direct TGF beta - cell interactions, the modulation of immunocompetent cells by TGF beta may influence tumor cell growth. Further studies on the beneficial TGF beta effects on tumors, and even on chemotherapy including adverse reactions are required to define the use of TGF beta or TGF beta modulating agents in cancer therapy.

Whole-body hyperthermia increases plasma-levels of transforming growth-factor-Beta.

The low bone marrow toxicity of high dose alkylating agents when given in combination with whole body hyperthermia (WBH) may be explained in part by the parallel induction of the granulocyte colony stimulating factor. Since transforming growth factor beta (TGF beta) is known to act synergistically with colony stimulating factors, we performed studies of TGF beta expression under WBH in 12 patients with histologically confirmed metastatic sarcoma. Each patient was given ifosfamide, carboplatin, and etoposide combined with WBH (41.8 degrees C, 1 h). Plasma specimens far determination of TGF beta levels were taken prior to WBH and at different time points after start of WBH. Immunoreactive TGF beta 1 and TGF beta 2 were measured by ELISA. Follow-up revealed a significant increase in TGF beta 1 and TGF beta 2 in 9 of 12 patients, starting 2 h after begin of WBH and peaking 10 h later. The mean value for TGF beta 1 prior to therapy was 3.3 ng/ml (range: 0.9-7.3 ng/ml), rising after 12 h to 5.3 ng/ml (range: 2.8-11,5 ng/ml) (p<0.05). The values for TGF beta 2 were 3.1 ng/ml (range: 1.9-4.1 ng/ml) and 3.9 ng/ml (range: 3.2-4.5 ng/ml) (p<0.05), respectively, Both TGF beta 1 and TGF beta 2 had to be activated in vitro by acidification, Initial TGF beta 1 and TGF beta 2 levels did not differ from those in healthy controls. Collectively, our data indicate enhanced TGF beta 1 and TGF beta 2 expression under WBH and support the thesis that TGF beta is a myeoloprotective factor because it stimulates granulopoiesis. The transient growth arrest of very early stem cells by TGF beta may be an additional factor contributing to the low myelotoxicity of alkylating agents when given under WBH.

Humoral immune response to Klebsiella capsular polysaccharides in HLA-B27-positive patients with acute anterior uveitis and ankylosing spondylitis.

Klebsiella is suggested to trigger ankylosing spondylitis (AS) and acute anterior uveitis (AAU) in HLA-B27-positive individuals. Previous investigations showed an increased antibody response to the Klebsiella capsular types K26, K36, and K50 in sera from HLA-B27-positive AS patients. In the present study the prevalence and titers of antibodies against Klebsiella capsular antigens were measured by means of an ELISA in 32 sera from HLA-B27-positive AAU patients either with (n = 10) or without AS (n = 22) and compared with sera from HLA-B27-negative AS-patients (n = 13). Sera from either HLA-B27-positive (n = 45) or negative (n = 40) healthy individuals served as control. Sera from HLA-B27-positive AAU with or without AS showed significantly higher antibody prevalence and IgG-titers against capsular antigens of the Klebsiella serotypes K26, K36, and K50 when compared with sera from HLA-B27-negative AS patients or with healthy controls. These results might be taken to indicate the predominance of these serotypes in the HLA-B27-associated AS and AAU.

Autoantibodies to cartilage collagens in relapsing polychondritis.

Relapsing polychondritis is a systemic disease associated with a destruction of cartilage in various parts of the body. Sera from six patients with relapsing polychondritis and one patient with microscopic polyarteritis nodosa as well as from six controls were analyzed by immunoblotting and ELISA. All patients had autoantibodies against native collagens II and IX. The serum from one patient showed a strong reaction with all three collagen chains of the high molecular weight fraction of collagen IX after denaturation; sera from four patients showed autoantibodies against alpha 2 (XI) and sera from three patients showed autoantibodies against the covalently cross-linked gamma component of collagen XI. The presence of autoantibodies against collagens II, IX, and XI, which form the major fibrillar scaffold in cartilage and mediate the interaction of collagen fibrils and proteoglycan, suggests that autoantibodies against cartilaginous collagen may play a crucial role in the pathogenesis of relapsing polychondritis and microscopic polyarteritis nodosa.

Interaction of transforming growth factor beta (TGF beta) with proteinase 3.

TGF beta is a multifunctional cytokine modulating onset and course of autoimmune diseases as shown in experimental models. Aim of this study was to investigate possible interactions of TGF beta with lysosomal enzymes identified as ANCA autoantigens (e.g. proteinase 3, PR3). This included TGF beta effects on the translocation the lysosomal enzymes to the cell surface of polymorphonuclear cells (PMN), and the presumabe activation of non bioactive, latent TGF beta by these enzymes. Flow cytometry analysis showed TGF beta 1 to be a potent translocation factor for PR3 comparable with other neutrophil activating factors such as interleukin 8 (IL8). The PR3 membrane expression on primed PMN increased by up to 51% after incubation with TGF beta 1. PR3 itself was revealed as a potent activator of latent TGF beta, thus mediating bioeffects of this cytokine. Patients with various types of systemic vasculitis (SV) showed marked TGF beta overexpression correlating with disease. Mean TGF beta 1 plasma levels in the ANCA associated vasculitis (AAV) patients ranged from 8.9 (Wegeners granulomatosis, WG) to 13.3 ng/ml (Churg-Strauss syndrome, CSS)(control: 4.2 ng/ml, p < 0.01) while TGF beta 2 levels were not elevated. Our findings, together with other features of TGF beta's such as induction of angiogenesis and its strong chemotactic capacity, indicate that TGF beta might serve as a proinflammatory factor in SV, especially in AAV.

Pro- and anti-inflammatory cytokines in primary systemic vasculitis.

The expression of cytokines that are potentially involved in the pathogenesis of vasculitis was studied in patients with primary systemic vasculitis (PSV). In extension of earlier reports, we detected an overexpression of transforming growth factor beta (TGF beta), interleukin 6 (IL6), and interleukin 8 (IL8), indicating that the whole cytokine cascade is activated to a significant extent in PSV.