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  • 1
    In: Transplantation, 2000, Vol.69(4), pp.588-597
    Description: BACKGROUND.: Cyclosporine A (CsA) and tacrolimus prevent proliferation but not transendothelial migration of alloreactive lymphocytes into donor organs. As a result, serious adverse effects, such as nephrotoxicity and neurotoxicity, have been observed under CsA/tacrolimus therapy. The incorporation of new drugs with infiltration blocking properties might enhance the efficacy of the current immunosuppressive protocol, allowing lower CsA/tacrolimus dosage. Because Ca plays a critical role in cell-cell interaction, the Ca-channel blocker verapamil might be a good cany.didate for supporting CsA/tacrolimus-based therap METHODS.: A T-cell endothelial cell coculture model or immobilized immunoglobulin G globulin chimeras were employed to investigate how S- and R- verapamil interfere with the lymphocytic infiltration process. The expression and arrangement of membranous adhesion receptors and cytoskeletal F-actin filaments were analyzed by fluorometric method in the presence of. verapamil. RESULTS.: Both verapamil enantiomers strongly inhibited lymphocyte infiltration. CD4 and CD8 T-cells were influenced to a similar extent with regard to horizontal locomotion (CD4=CD8), but to a different extent with regard to adhesion and penetration (CD4 〉 CD8). Moreover, penetration was blocked to a higher extent than was adhesion. ID50-values were 31 μM (CD4-adhesion) and 11 μM (CD4-penetration). Verapamil reduced P-selectin expression on endothelial cells and effectively down-regulated binding of T-cells to immobilized P-selectin immunoglobulin G globulins (ID50=4.4 μM; CD4). A verapamil-induced reduction of intracellular F-actin in T-lymphocytes was proven to be mainly responsible for diminished cell locomotion. CONCLUSIONS.: The prevention of CD4 T-cell penetration by verapamil might argue for its use as an adjunct to CsA/tacrolimus-based immunosuppressive therapy.
    Keywords: Immunosuppression ; Endothelium ; Lymphocytes T ; Immunosuppressive Agents ; Cell Motility ; Verapamil ; Calcium Channel Blockers ; Experimental ; Function ; Immunology ; Calcium Channel Blockers ; Cell Motility ; Immunology ; Verapamil;
    ISSN: 0041-1337
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  • 2
    Language: English
    In: Gastroenterology, May 2014, Vol.146(5), pp.S-231-S-231
    Keywords: Medicine
    ISSN: 0016-5085
    E-ISSN: 1528-0012
    Source: ScienceDirect Journals (Elsevier)
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  • 3
    Language: English
    In: Gastroenterology, May 2014, Vol.146(5), pp.S-423-S-423
    Keywords: Medicine
    ISSN: 0016-5085
    E-ISSN: 1528-0012
    Source: ScienceDirect Journals (Elsevier)
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  • 4
    In: Rheumatology, 2016, Vol. 55(10), pp.1791-1795
    Description: Objective. ACPAs are associated with bone destruction in RA. The aim of this study was to evaluate the association between ACPA and bone destruction in patients with a distinct inflammatory disorder, PsA. Methods. We used baseline data from a large observational study of PsA patients preparing to initiate treatment with adalimumab to analyse demographic and disease characteristics by ACPA status. To ensure a homogeneous PsA study population, only patients with active psoriatic skin manifestations who met Classification of Psoriatic Arthritis criteria for PsA were included in the analyses, thereby minimizing the risk of including misdiagnosed RA patients. Multiple logistic regression analyses were used to explore potential associations between ACPA seropositivity and bone destruction. Results. Of 1996 PsA patients who met the strict inclusion criteria, 105 (5.3%) were positive for ACPA. ACPA-positive patients had significantly higher swollen joint counts and 28-joint DAS values than ACPA-negative patients and significantly higher rates of erosive changes and dactylitis. Multiple logistic regression analysis confirmed the association of ACPA seropositivity with a 2.8-fold increase in the risk of erosive disease. Conclusion. As has been previously shown for RA, ACPA is associated with bone destruction in PsA, suggesting that the osteocatabolic effect of ACPA is not confined to RA but is also detectable in the different pathogenetic context of a distinct disease entity. Trial registration: ClinicalTrials.gov, NCT01111240
    Keywords: Adalimumab ; Anti - Citrullinated Protein Antibodies ; Psoriatic Arthritis ; Osteoporosis ; Erosions ; Observational Study
    ISSN: 1462-0324
    E-ISSN: 1462-0332
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  • 5
    Language: English
    In: Rheumatology International, 2012, Vol.32(12), pp.3977-3983
    Description: The aim of this noninterventional study (NIS) was to analyze the changes in sickness absence, disease activity, and functional capacity in employed rheumatoid arthritis (RA) patients during adalimumab treatment. RA patients receiving adalimumab according to label instructions (40 mg every other week) were evaluated at regular intervals in a multicenter prospective NIS. Patients provided information on sickness absence in the 12 months preceding treatment initiation (baseline) and at months 6 and 12. Disease activity was assessed by the Disease Activity Score using 28 joints, and physical function was assessed via the Hannover Functional Ability Questionnaire, a patient self-questionnaire comparable with the Health Assessment Questionnaire-Disability Index. We present data on 1,157 patients who were employed (part time or full time) at baseline. Patients were categorized by the length of sickness absence at baseline. At baseline, patients with absences of 6 weeks or more in the previous year ( n  = 226 [19.5%]) accounted for 77% of the documented weeks of sickness absence, and patients with absences of more than 12 weeks ( n  = 98 [8.5%]) accounted for 54% of sickness absence weeks. During 12 months of adalimumab treatment, disease activity decreased, functional capacity improved, and sickness absence was reduced. The greatest decrease in sickness absence was observed in patients with more than 12 weeks of sick leave in the year prior to adalimumab therapy. These patients also showed gains in function comparable with those observed in other employed patients. We conclude that sustaining and improving functional capacity represent the key to preservation of work capability.
    Keywords: Arthritis, Rheumatoid ; Adalimumab ; Sickness absence ; Employment ; Function ; Cost of illness
    ISSN: 0172-8172
    E-ISSN: 1437-160X
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  • 6
    Language: English
    In: Dermatology, January 2017, Vol.232(5), pp.597-605
    Description: Early detection of psoriatic arthritis (PsA) remains a challenge in clinical practice. Tools such as the German Psoriasis Arthritis Diagnostic (GEPARD) questionnaire have been developed for this purpose. The aim of this study was to determine the performance of the GEPARD questionnaire in the detection of PsA in psoriasis patients following rheumatology evaluation in daily clinical practice in Germany. This was a multicenter study involving 59 dermatology units (university/general hospital/office based), and the GEPARD questionnaire was distributed to psoriasis patients. Patients who had a sum score of ≥4 positive answers were referred to a rheumatologist for evaluation of PsA. We recruited 1,512 patients, of whom approximately 50% were referred. One third of the referred patients were classified as having PsA after rheumatological assessment. Rates of PsA in university/general hospital settings were higher than those observed in a doctor's office-based setting (43.7 vs. 25.8%). The GEPARD questionnaire demonstrated easy screening of psoriasis patients for PsA.
    Keywords: Original Paper ; Dermatologist ; Rheumatologist ; Psoriatic Arthritis ; Gepard ; Caspar ; Referral ; Medicine
    ISSN: 1018-8665
    E-ISSN: 1421-9832
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  • 7
    Language: German
    Description: The healthy human organism shows a homeostatic balance within the cut which tolerates bacterial antigens or antigens derived from dietary sources. In inflammatory bowle disease (IBD) this mechanism is disrupted. The resulting inflammation seems to be T cell dependent and is caused by a disbalance of the pro- and anti-inflammatory immune response. CD44v7 is a costimulatory transmembran surface molecule. So far it could be shown, that the deletion of CD44v7 or the use of an antagonistic antibody protects from the development of a chemical induced colitis in mouse. The problem with most animal models is that the antigen is not defined. Aim of this thesis was to establish a new antigen-specific colitismodel to investigate the immunogenic and tolerogenic mechanism within the colon. Therefore, DO11.10 (OVA-TCR positive) TH1 cells were transferred into congenic BALB/c wildtyp mice. 24 h later, 50% ethanol and, 2 hours later, OVA protein was intrarectally applied in the distal colon. This was repeated at day 4. The mice developed an OVA-specific colitis that showed the same histological features as patients with Morbus Crohn. Additionally, a higher percentage of OVA-TCR positive cells could be detected in the lamina propria (LP). Isolated Lamina propria mononuclear cells show a higher production of INF-γ when restimulated in culture. Feeding OVA-protein between the intraluminal treatment leads to an abrogation of the OVA-specific colitis. This was accompanied with the induction of apoptosis in effector-T cells and the higher percentage of OVA-TCR – FoxP3+ CD4+ T cells in the LP. CD44v7-/- mice were protected from the development of an OVA-specific colitis if they only received wildtyp TH1 cells. If wildtyp macrophages were additionally transferred, mice developed a severe colitis. No differences could be observed in the application of CD44v7-/- OVA-TCR pos. TH1 cells or DO11.10 TH1 cells, respectively. Balb/c mice developed an OVA-specific colitis which also was abrogated after feeding OVA protein independent of the TH1 celltyp transferred. This result leads to the assumption that the expression of CD44v7 on macrophages but not on T cells plays an important role during the development of an OVA-specific colitis. This thesis explores a new approach to establish an antigen-specific colitis. This new method is easy in handling and fast to reproduce. It provides an animal model to investigate antigen-specific immunization versus tolerance in the gut mucosa. Furthermore it provides the opportunity to investigate the usage of knock-out mice and therapeutic substances.
    Keywords: 570 Life Sciences ; Ddc:570 ; 570 Biowissenschaften; Biologie ; Cd44v7 ; Ova-specific Colitis ; Inflammatory Bowel Disease (IBD) ; Oral Tolerance
    Source: Freie Universitat Berlin
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  • 8
    Language: English
    In: Dermatology, March 2015, Vol.230(3), pp.213-221
    Description: Background: The association between skin and joint manifestations in patients with psoriatic arthritis (PsA) requires further characterization. Objective: We evaluated the association between severity of skin disease and joint involvement and the effectiveness and safety of adalimumab in PsA patients by baseline psoriasis severity. Methods: Descriptive statistics and regression analyses were used to evaluate data from 1,918 PsA patients starting adalimumab treatment. Subgroup analyses were conducted on patients empirically grouped by baseline target lesion score as a marker of psoriasis severity. Results: Psoriasis severity was not associated with joint manifestations at baseline or after 12 months of treatment. All subgroups showed improvements in skin and joints during therapy, and adalimumab was safe and well tolerated in all subgroups. Conclusion: The severity of skin manifestations does not correlate with the severity of joint disease in PsA patients; even patients with mild skin disease may have extensive musculoskeletal involvement.
    Keywords: Original Paper ; Adalimumab ; Psoriasis ; Psoriatic Arthritis ; Target Lesion Score ; Treatment ; Medicine
    ISSN: 1018-8665
    E-ISSN: 1421-9832
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  • 9
    Language: English
    In: Rheumatology International, 2012, Vol.32(9), pp.2759-2767
    Description: The objective of this study was to use data from a noninterventional study to evaluate the effectiveness of adalimumab in rheumatoid arthritis (RA) patients during routine clinical practice and to explore the potential impact of patient and disease characteristics in response to adalimumab therapy. A total of 2,625 RA patients with specified data at baseline (prior to initiating adalimumab treatment) and 12 months entered this study between April 2003 and March 2009. We evaluated response to adalimumab therapy and conducted stepwise regression and subgroup analyses of factors influencing therapeutic response. During the 1-year adalimumab treatment period, disease activity decreased from a baseline mean disease activity score-28 joints (DAS28) of 5.9–3.9, while functional capacity improved from 59.0 to 68.4 Funktionsfragebogen Hannover (FFbH) percentage points. In multivariate regression models, high baseline DAS28 was the strongest positive predictor for decrease in disease activity, and high baseline functional capacity was associated with reduced gains in functional capacity. Male gender was a positive predictor of therapeutic response for both disease activity and functional capacity, while older age and multiple previous biologics were associated with a reduced therapeutic response. Subset analyses provided further support for the impact of baseline DAS28, FFbH, and prior biologic therapy on therapeutic response during treatment. We conclude that treatment with adalimumab leads to decreased disease activity and improved function during routine clinical practice. Patients with high disease activity and low functional capacity are particularly benefitted by adalimumab therapy.
    Keywords: Adalimumab ; Arthritis, rheumatoid ; Treatment outcome ; Regression analysis ; Antirheumatic agents
    ISSN: 0172-8172
    E-ISSN: 1437-160X
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  • 10
    Language: English
    In: The Journal of rheumatology, March 2016, Vol.43(3), pp.632-9
    Description: To examine the influence of concomitant methotrexate (MTX) with adalimumab (ADA) on outcomes in patients with psoriatic arthritis (PsA) using data from an observational study of ADA. Data from a German noninterventional study of patients with PsA starting treatment with ADA were analyzed retrospectively for effects of concomitant MTX on key outcomes, including Disease Activity Score-28 joints, tender and swollen joint counts, skin assessments, and safety. Patients were categorized into those with symptoms of axial involvement and those with no symptoms of axial involvement as judged by the examining clinician. A total of 1455 patients met the study criteria, 296 with axial involvement (ADA monotherapy = 165; plus MTX = 131) and 1159 with no axial involvement (ADA monotherapy = 658; plus MTX = 501). ADA, alone or combined with MTX, resulted in strong and comparable reductions in disease activity measures in patients with and those without axial disease over 24 months of therapy. In multiple regression analyses, concomitant MTX did not affect joint or skin outcomes in either the group with axial manifestations or the group without axial disease. Neither adverse event rates nor withdrawal rates were significantly influenced by concomitant MTX. ADA is an effective treatment option for patients with PsA with or without axial involvement. Compared with ADA monotherapy, the use of concomitant MTX with ADA does not improve articular or skin outcomes in patients with PsA regardless of axial symptoms. Clinicaltrials.gov NCT01111240.
    Keywords: Adalimumab ; Anti-Tumor Necrosis Factor Therapy ; Concomitant Therapy ; Methotrexate ; Psoriatic Arthritis ; Adalimumab -- Therapeutic Use ; Antirheumatic Agents -- Therapeutic Use ; Arthritis, Psoriatic -- Drug Therapy ; Methotrexate -- Therapeutic Use
    ISSN: 0315-162X
    E-ISSN: 14992752
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