@article{ScharbatkeBehrensSchmalzingetal.2016,
  author    = {Scharbatke, Eva C. and Behrens, Frank and Schmalzing, Marc and Koehm, Michaela and Greger, Gerd and Gnann, Holger and Burkhardt, Harald and Tony, Hans-Peter},
  title     = {Association of improvement in pain with therapeutic response as determined by individual improvement criteria in patients with rheumatoid arthritis},
  series = {Arthritis Care \& Research},
  volume    = {68},
  journal   = {Arthritis Care \& Research},
  number    = {11},
  doi       = {10.1002/acr.22884},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186817},
  pages     = {1607-1615},
  year      = {2016},
  abstract  = {Objective To use statistical methods to establish a threshold for individual response in patient-reported outcomes (PROs) in patients with rheumatoid arthritis. Methods We used an analysis of variance model in patients on stable therapy (discovery cohort) to establish critical differences (d(crit)) for the minimum change associated with a significant individual patient response (beyond normal variation) in the PRO measures of pain (0-10), fatigue (0-10), and function (Funktionsfragebogen Hannover questionnaire; 0-100). We then evaluated PRO responses in patients initiating adalimumab in a noninterventional study (treatment cohort). Results In the discovery cohort (n=700), PROs showed excellent long-term retest reliability. The minimum change that exceeded random fluctuation was conservatively determined to be 3 points for pain, 4 points for fatigue, and 16 points for function. In the treatment cohort (n=2,788), 1,483 patients (53.2\%) achieved a significant individual therapeutic response as assessed by Disease Activity Score in 28 joints (DAS28)-d(crit) (1.8 points) after 12 months of adalimumab treatment; 68.5\% of patients with a DAS28-d(crit) response achieved a significant improvement in pain, whereas approximately 40\% achieved significant improvements in fatigue or function. Significant improvements in all 3 PROs occurred in 22.7\% of patients; 22.8\% did not have any significant PRO responses. In contrast, significant improvements in all 3 PROs occurred in only 4.4\% of 1,305 patients who did not achieve a DAS28-d(crit) response at month 12, and 59.1\% did not achieve any significant PRO responses. Conclusion The establishment of critical differences in PROs distinguishes true responses from random variation and provides insights into appropriate patient management.},
  language  = {en}
}
@article{HeimAlmanzarSchmalzingetal.2021,
  author    = {Heim, Jana and Almanzar, Giovanni and Schmalzing, Marc and Gernert, Michael and Tony, Hans-Peter and Prelog, Martina},
  title     = {Induction of IL-9 in Peripheral Lymphocytes of Rheumatoid Arthritis Patients and Healthy Donors by Th17-Inducing Cytokine Conditions},
  series = {Frontiers in Immunology},
  volume    = {12},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2021.668095},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237838},
  year      = {2021},
  abstract  = {IL-9-producing Th9 cells display a group of helper T cells with similarities to Th17 and Th2 T cells and have been shown to be involved in synovial inflammation in rheumatoid arthritis (RA) patients. So far, it is unclear which parameters drive Th9 differentiation in lymphocytes derived from RA patients compared to immunologically healthy individuals and whether autocrine mechanisms are able to enhance Th9 polarization. Further, parallel pathways of induction of IL-17-producing cells with Th9 phenotype have to be distinguished from exclusively Th9-inductive mechanisms. Thus, the present study aimed to determine the parameters of Th9 induction by simulation in a standardized inflammatory cytokine milieu.Peripheral naive and non-naive T cells of RA patients and healthy donors (HD) were cultured under Th9 and Th17-driving conditions and phenotypically analyzed by flow cytometry and molecular analysis.Our findings indicate a similar differentiation pathway of Th9 and Th17 cells and similar distributions of IL-9+ T cells in RA and HD regardless of Th9- or Th17-promoting cytokine milieus. Whereas the magnitude and direction of Th9- or Th17-polarization was about the same in RA and HD, IL-17+ CD4+ T cells were significantly stimulated by Th17-inducing conditions in HD. In conclusion, the results indicate that Th9- and Th17-inducing cytokine conditions mimicking autoimmune inflammation in RA may have similar stimulatory effects regarding polarization of peripheral naive and non-naive T cells into Th9 or Th17 cells. The results suggest that the differentiation of Th9 cells may be also induced by Th17-driving conditions.},
  language  = {en}
}
@article{FroehlichSerflingHiguchietal.2021,
  author    = {Fr{\"o}hlich, Matthias and Serfling, Sebastian and Higuchi, Takahiro and Pomper, Martin G. and Rowe, Steven P. and Schmalzing, Marc and Tony, Hans-Peter and Gernert, Michael and Strunz, Patrick-Pascal and Portegys, Jan and Schwaneck, Eva-Christina and Gadeholt, Ottar and Weich, Alexander and Buck, Andreas K. and Bley, Thorsten A. and Guggenberger, Konstanze V. and Werner, Rudolf A.},
  title     = {Whole-Body [\(^{18}\)F]FDG PET/CT Can Alter Diagnosis in Patients with Suspected Rheumatic Disease},
  series = {Diagnostics},
  volume    = {11},
  journal   = {Diagnostics},
  number    = {11},
  issn      = {2075-4418},
  doi       = {10.3390/diagnostics11112073},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250227},
  year      = {2021},
  abstract  = {The 2-deoxy-d-[\(^{18}\)F]fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) is widely utilized to assess the vascular and articular inflammatory burden of patients with a suspected diagnosis of rheumatic disease. We aimed to elucidate the impact of [\(^{18}\)F]FDG PET/CT on change in initially suspected diagnosis in patients at the time of the scan. Thirty-four patients, who had undergone [\(^{18}\)F]FDG PET/CT, were enrolled and the initially suspected diagnosis prior to [18F]FDG PET/CT was compared to the final diagnosis. In addition, a semi-quantitative analysis including vessel wall-to-liver (VLR) and joint-to-liver (JLR) ratios was also conducted. Prior to [\(^{18}\)F]FDG PET/CT, 22/34 (64.7\%) of patients did not have an established diagnosis, whereas in 7/34 (20.6\%), polymyalgia rheumatica (PMR) was suspected, and in 5/34 (14.7\%), giant cell arteritis (GCA) was suspected by the referring rheumatologists. After [\(^{18}\)F]FDG PET/CT, the diagnosis was GCA in 19/34 (55.9\%), combined GCA and PMR (GCA + PMR) in 9/34 (26.5\%) and PMR in the remaining 6/34 (17.6\%). As such, [\(^{18}\)F]FDG PET/CT altered suspected diagnosis in 28/34 (82.4\%), including in all unclear cases. VLR of patients whose final diagnosis was GCA tended to be significantly higher when compared to VLR in PMR (GCA, 1.01 ± 0.08 (95\%CI, 0.95-1.1) vs. PMR, 0.92 ± 0.1 (95\%CI, 0.85-0.99), p = 0.07), but not when compared to PMR + GCA (1.04 ± 0.14 (95\%CI, 0.95-1.13), p = 1). JLR of individuals finally diagnosed with PMR (0.94 ± 0.16, (95\%CI, 0.83-1.06)), however, was significantly increased relative to JLR in GCA (0.58 ± 0.04 (95\%CI, 0.55-0.61)) and GCA + PMR (0.64 ± 0.09 (95\%CI, 0.57-0.71); p < 0.0001, respectively). In individuals with a suspected diagnosis of rheumatic disease, an inflammatory-directed [\(^{18}\)F]FDG PET/CT can alter diagnosis in the majority of the cases, particularly in subjects who were referred because of diagnostic uncertainty. Semi-quantitative assessment may be helpful in establishing a final diagnosis of PMR, supporting the notion that a quantitative whole-body read-out may be useful in unclear cases.},
  language  = {en}
}
@article{GernertTonySchwanecketal.2019,
  author    = {Gernert, Michael and Tony, Hans-Peter and Schwaneck, Eva Christina and Gadeholt, Ottar and Schmalzing, Marc},
  title     = {Autologous hematopoietic stem cell transplantation in systemic sclerosis induces long-lasting changes in B cell homeostasis toward an anti-inflammatory B cell cytokine pattern},
  series = {Arthritis Research \& Therapy},
  volume    = {21},
  journal   = {Arthritis Research \& Therapy},
  doi       = {10.1186/s13075-019-1889-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201004},
  pages     = {106},
  year      = {2019},
  abstract  = {Background Autologous hematopoietic stem cell transplantation (aHSCT) is performed in patients with aggressive forms of systemic sclerosis (SSc). The profile of B cell reconstitution after aHSCT is not fully understood. The aim of this study was to investigate changes of B cell subsets and cytokine production of B cells in patients with SSc after aHSCT. Methods Peripheral blood of six patients with SSc was collected at defined intervals up to 16 months after aHSCT. Immunophenotyping was performed, and B cell function was determined by measuring cytokine secretion in supernatants of stimulated B cell cultures. Results Within 1 month after aHSCT, a peak in the percentage of CD38\(^{++}\)/CD10\(^+\)/IgD\(^+\) transitional B cells and CD38\(^{++}\)/CD27\(^{++}\)/IgD\(^-\) plasmablasts was detected. Long-term changes persisted up to 14 months after aHSCT and showed an increased percentage of total B cells; the absolute B cell number did not change significantly. Within the B cell compartment, an increased CD27/IgD\(^+\) na{\"i}ve B cell percentage was found whereas decreased percentages of CD27\(^+\)/IgD\(^+\) pre-switched memory, CD27\(^+\)/IgD\(^-\) post-switched memory, and CD27\(^-\) /IgD\(^-\) double-negative B cells were seen after aHSCT. Cytokine secretion in B cell cultures showed significantly increased IL-10 concentrations 13 to 16 months after aHSCT. Conclusion A changed composition of the B cell compartment is present for up to 14 months after aHSCT indicating positive persisting effects of aHSCT on B cell homeostasis. The cytokine secretion profile of B cells changes in the long term and shows an increased production of the immune regulatory cytokine IL-10 after aHSCT. These findings might promote the clinical improvements after aHSCT in SSc patients.},
  language  = {en}
}
@article{GernertSchmalzingTonyetal.2022,
  author    = {Gernert, Michael and Schmalzing, Marc and Tony, Hans-Peter and Strunz, Patrick-Pascal and Schwaneck, Eva Christina and Fr{\"o}hlich, Matthias},
  title     = {Calprotectin (S100A8/S100A9) detects inflammatory activity in rheumatoid arthritis patients receiving tocilizumab therapy},
  series = {Arthritis Research \& Therapy},
  volume    = {24},
  journal   = {Arthritis Research \& Therapy},
  number    = {1},
  doi       = {10.1186/s13075-022-02887-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300523},
  year      = {2022},
  abstract  = {Background Assessing serological inflammation is difficult in tocilizumab (TCZ)-treated rheumatoid arthritis (RA) patients, as standard inflammation parameters, like erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are influenced by interleukin-6-receptor inhibition. Calprotectin in the serum, also named S100A8/S100A9, might be a more useful inflammation parameter in TCZ-treated patients. Methods Sixty-nine RA patients taking TCZ were included. Serum-calprotectin levels were assessed, as well as ESR, CRP, need for a change in disease-modifying anti-rheumatic drugs due to RA activity (= active RA), and the RA clinical disease activity score (CDAI). Forty-five RA patients taking tumor-necrosis factor-inhibitors (TNFi) were investigated for the same parameters. Results TCZ-treated patients with active RA had higher calprotectin values than not active RA patients (4155.5 [inter quartile range 1865.3-6068.3] vs 1040.0 [676.0-1638.0] ng/ml, P < 0.001). A calprotectin cut-off value of 1916.5 ng/ml resulted in a sensitivity and specificity of 80.0 \%, respectively, for the detection of RA disease activity. Calprotectin values correlated with CDAI-scores (r = 0.228; P = 0.011). ESR and CRP were less suitable to detect RA activity in TCZ-treated patients. Also TNFi-treated patients with active RA had higher calprotectin values compared to not active RA (5422.0 [3749.0-8150.8] vs 1845.0 [832.0-2569.0] ng/ml, P < 0.001). The calprotectin value with the best sensitivity and specificity for detecting RA activity was 3690.5 ng/ml among TNFi-treated patients. Conclusion Calprotectin in the serum can be a useful inflammation parameter despite TCZ-treatment.},
  language  = {en}
}
@article{GernertTonySchwaneketal.2022,
  author    = {Gernert, Michael and Tony, Hans-Peter and Schwanek, Eva Christina and Gadeholt, Ottar and Fr{\"o}hlich, Matthias and Portegys, Jan and Strunz, Patrick-Pascal and Schmalzing, Marc},
  title     = {Lymphocyte subsets in the peripheral blood are disturbed in systemic sclerosis patients and can be changed by immunosuppressive medication},
  series = {Rheumatology International},
  volume    = {42},
  journal   = {Rheumatology International},
  number    = {8},
  issn      = {1437-160X},
  doi       = {10.1007/s00296-021-05034-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266482},
  pages     = {1373-1381},
  year      = {2022},
  abstract  = {Systemic sclerosis (SSc) is a severe chronic disease with a broad spectrum of clinical manifestations. SSc displays disturbed lymphocyte homeostasis. Immunosuppressive medications targeting T or B cells can improve disease manifestations. SSc clinical manifestations and immunosuppressive medication in itself can cause changes in lymphocyte subsets. The aim of this study was to investigate peripheral lymphocyte homeostasis in SSc with regards to the immunosuppression and to major organ involvement. 44 SSc patients and 19 healthy donors (HD) were included. Immunophenotyping of peripheral whole blood by fluorescence-activated cell sorting was performed. Cytokine secretions of stimulated B cell cultures were measured. SSc patients without immunosuppression compared to HD displayed lower γδ T cells, lower T helper cells (CD3+/CD4+), lower transitional B cells (CD19+/CD38++/CD10+/IgD+), lower pre-switched memory B cells (CD19+/CD27+/IgD+), and lower post-switched memory B cells (CD19+/CD27+/IgD-). There was no difference in the cytokine production of whole B cell cultures between SSc and HD. Within the SSc cohort, mycophenolate intake was associated with lower T helper cells and lower NK cells (CD56+/CD3-). The described differences in peripheral lymphocyte subsets between SSc and HD generate further insight in SSc pathogenesis. Lymphocyte changes under effective immunosuppression indicate how lymphocyte homeostasis in SSc might be restored.},
  language  = {en}
}
@article{RauSchmittBergetal.2018,
  author    = {Rau, Monika and Schmitt, Johannes and Berg, Thomas and Kremer, Andreas E. and Stieger, Bruno and Spanaus, Katharina and Bengsch, Bertram and Romero, Marta R. and Marin, Jose J. and Keitel, Verena and Klinker, Hartwig and Tony, Hans-Peter and M{\"u}llhaupt, Beat and Geier, Andreas},
  title     = {Serum IP-10 levels and increased DPPIV activity are linked to circulating CXCR3+ T cells in cholestatic HCV patients},
  series = {PLoS ONE},
  volume    = {13},
  journal   = {PLoS ONE},
  number    = {12},
  doi       = {10.1371/journal.pone.0208225},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177674},
  pages     = {e0208225},
  year      = {2018},
  abstract  = {Background \& aims Serum interferon-gamma-inducible protein-10 (IP-10) is elevated in cholestatic liver diseases and predicts response to antiviral therapy in patients with chronic hepatitis C virus (HCV) infection. Dipeptidylpeptidase 4 (DPPIV) cleaves active IP-10 into an inactive form, which inhibits recruitment of CXCR3+ T cells to the liver. In this study the link between IP-10 levels, DPPIV activity in serum and CXCR3+ T cells is analysed in cholestatic and non-cholestatic liver patients. Methods In serum DPPIV activity (by enzymatic assay), IP-10 (by ELISA) and bile acids (BA) (by enzymatic assay) were analysed in 229 naive HCV genotype (GT) 1 patients and in 16 patients with cholestatic liver disease. In a prospective follow-up (FU) cohort of 27 HCV GT 1 patients peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ cells were measured by FACS. Results In 229 HCV patients serum IP-10 levels correlated positively to DPPIV serum activity. Higher IP-10 levels and DPPIV activity were detected in cholestatic and in cirrhotic HCV patients. Increased IP-10 serum levels were associated with therapeutic non-response to antiviral treatment with pegylated-interferon and ribavirin. In the HCV FU cohort elevated IP-10 serum levels and increased BA were associated with higher frequencies of peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ T cells. Positive correlation between serum IP-10 levels and DPPIV activity was likewise validated in patients with cholestatic liver diseases. Conclusions A strong correlation between elevated serum levels of IP-10 and DPPIV activity was seen in different cholestatic patient groups. Furthermore, in cholestatic HCV patients a functional link to increased numbers of peripheral CXCR3+ immune cells could be observed. The source of DPPIV release in cholestatic patients remains open.},
  language  = {en}
}
@article{StrunzFroehlichGernertetal.2021,
  author    = {Strunz, Patrick-Pascal and Froehlich, Matthias and Gernert, Michael and Schwaneck, Eva Christina and Fleischer, Anna and Pecher, Ann-Christin and Tony, Hans-Peter and Henes, Joerg Christoph and Schmalzing, Marc},
  title     = {Immunological Adverse Events After Autologous Hematopoietic Stem Cell Transplantation in Systemic Sclerosis Patients},
  series = {Frontiers in Immunology},
  volume    = {12},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2021.723349},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245574},
  year      = {2021},
  abstract  = {Autologous hematopoietic stem cell transplantation (aHSCT) represents an effective treatment for systemic sclerosis (SSc), but it also can cause immunological adverse events (iAEs). Therefore, we aimed to determine the frequency of iAEs [engraftment syndrome (ES) and secondary autoimmune disorder (sAD)] and to identify potential risk factors for their development in a retrospective analysis on 22 patients similarly transplanted due to SSc. While nine patients (41\%) suffered from ESs, seven sADs occurred in six patients (27\%). Patients who developed ES were older in our cohort (52.45 vs. 42.58 years, p = .0433, Cohen's d = 0.86), and cardiac involvement by SSc was associated with development of ES (OR = 40.11, p = .0017). Patients with manifestation of sAD had a higher modified Rodnan skin score (mRSS) reduction after aHSCT (90.50\% vs. 60.00\%, p = .0064, r = .65). Thus, IAEs are common after aHSCT for SSc and can occur in different stages during and after aHSCT with characteristic clinical manifestations. Good cutaneous response after aHSCT might be considered as a risk factor for sAD, and higher age at aHSCT and cardiac involvement might be considered as risk factors for the development of ES.},
  language  = {en}
}
@article{RechHueberFinzeletal.2016,
  author    = {Rech, Juergen and Hueber, Axel J. and Finzel, Stephanie and Englbrecht, Matthias and Haschka, Judith and Manger, Bernhard and Kleyer, Arnd and Reiser, Michaela and Cobra, Jayme Fogagnolo and Figueiredo, Camille and Tony, Hans-Peter and Kleinert, Stefan and Wendler, Joerg and Schuch, Florian and Ronneberger, Monika and Feuchtenberger, Martin and Fleck, Martin and Manger, Karin and Ochs, Wolfgang and Schmitt-Haendle, Matthias and Lorenz, Hanns-Martin and Nuesslein, Hubert and Alten, Rieke and Henes, Joerg and Krueger, Klaus and Schett, Georg},
  title     = {Prediction of disease relapses by multibiomarker disease activity and autoantibody status in patients with rheumatoid arthritis on tapering DMARD treatment},
  series = {Annals of the Rheumatic Diseases},
  volume    = {75},
  journal   = {Annals of the Rheumatic Diseases},
  number    = {9},
  doi       = {10.1136/annrheumdis-2015-207900},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-187519},
  pages     = {1637-1644},
  year      = {2016},
  abstract  = {Objective To analyse the role of multibiomarker disease activity (MBDA) score in predicting disease relapses in patients with rheumatoid arthritis (RA) in sustained remission who tapered disease modifying antirheumatic drug (DMARD) therapy in RETRO, a prospective randomised controlled trial. Methods MBDA scores (scale 1-100) were determined based on 12 inflammation markers in baseline serum samples from 94 patients of the RETRO study. MBDA scores were compared between patients relapsing or remaining in remission when tapering DMARDs. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining predictors of relapse. Results Moderate-to-high MBDA scores were found in 33\% of patients with RA overall. Twice as many patients who relapsed (58\%) had moderate/high MBDA compared with patients who remained in remission (21\%). Baseline MBDA scores were significantly higher in patients with RA who were relapsing than those remaining in stable remission (N=94; p=0.0001) and those tapering/stopping (N=59; p=0.0001). Multivariate regression analysis identified MBDA scores as independent predictor for relapses in addition to anticitrullinated protein antibody (ACPA) status. Relapse rates were low (13\%) in patients who were MBDA-/ACPA-, moderate in patients who were MBDA+/ACPA- (33.3\%) and MBDA-ACPA+ (31.8\%) and high in patients who were MBDA+/ACPA+ (76.4\%). Conclusions MBDA improved the prediction of relapses in patients with RA in stable remission undergoing DMARD tapering. If combined with ACPA testing, MBDA allowed prediction of relapse in more than 80\% of the patients. Trial registration number EudraCT 2009-015740-42.},
  language  = {en}
}
@article{GernertTonySchwanecketal.2020,
  author    = {Gernert, Michael and Tony, Hans-Peter and Schwaneck, Eva Christina and Fr{\"o}hlich, Matthias and Schmalzing, Marc},
  title     = {Low B cell counts as risk factor for infectious complications in systemic sclerosis after autologous hematopoietic stem cell transplantation},
  series = {Arthritis Research \& Therapy},
  volume    = {22},
  journal   = {Arthritis Research \& Therapy},
  doi       = {10.1186/s13075-020-02255-3},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229962},
  year      = {2020},
  abstract  = {Background Autologous hematopoietic stem cell transplantation (aHSCT) is a treatment option for a selected group of systemic sclerosis (SSc) patients with good available evidence but can be associated with considerable morbidity and mortality. The aim of this study was to describe infectious complications and distinct immune reconstitution patterns after aHSCT and to detect risk factors in lymphocyte subsets, which are associated with an elevated rate of infections after aHSCT. Methods Seventeen patients with SSc were included in this single-center retrospective cohort study. Clinical and laboratory data was collected before and for 12 months after aHSCT, including immunophenotyping of peripheral whole blood by fluorescence-activated cell sorting. Results Cytomegalovirus (CMV) reactivations were common in CMV-IgG-positive patients (50\%) and needed treatment. Mycotic infections occurred in 17.6\%. One patient died (resulting in a mortality of 5.9\%) due to pneumonia with consecutive sepsis. All patients showed decreased T helper cells (CD3\(^+\)/CD4\(^+\)) and within the B cell compartment decreased post-switched memory B cells (CD19\(^+\)/CD27\(^+\)/IgD\(^-\)) and elevated naive B cells (CD19\(^+\)/CD27\(^-\)/IgD\(^+\)) until 12 months after aHSCT. Patients who developed infections had significantly lower B cells before aHSCT than patients who did not develop infections. Conclusion After aHSCT, monitoring for infectious complications, especially for CMV reactivations, is crucial as the reconstitution of the immune system takes longer than 12 months. Low peripheral B cells might be a risk factor for an elevated infection rate.},
  language  = {en}
}
@article{MahmoodSchmalzingDoerneretal.2020,
  author    = {Mahmood, Zafar and Schmalzing, Marc and D{\"o}rner, Thomas and Tony, Hans-Peter and Muhammad, Khalid},
  title     = {Therapeutic Cytokine Inhibition Modulates Activation and Homing Receptors of Peripheral Memory B Cell Subsets in Rheumatoid Arthritis Patients},
  series = {Frontiers in Immunology},
  volume    = {11},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2020.572475},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212380},
  year      = {2020},
  abstract  = {Memory B cells have known to play an important role in the pathogenesis of rheumatoid arthritis (RA). With the emergence of B cell-targeted therapies, the modulation of memory B cells appears to be a key therapeutic target. Human peripheral memory B cells can be distinguished based on the phenotypic expression of CD27 and IgD, characterizing the three major B cell subpopulations: CD27+IgD+ pre-switch, CD27+IgD- post-switch, and CD27-IgD- double-negative memory B cells. We evaluated different memory cell populations for activation markers (CD95 and Ki-67) and chemokine receptors (CXCR3 and 4) expressing B cells in active RA, as well as under IL6-R blockade by tocilizumab (TCZ) and TNF-α blockade by adalimumab (ADA). Memory B cells were phenotypically analyzed from RA patients at baseline, week 12, and week 24 under TCZ or ADA treatment, respectively. Using flow cytometry, surface expression of CD95, intracellular Ki-67, and surface expressions of CXCR3 and CXCR4 were determined. Compared with healthy donors (n = 40), the phenotypic analysis of RA patients (n = 80) demonstrated that all three types of memory B cells were activated in RA patients. Surface and intracellular staining of B cells showed a significantly higher percentage of CD95+ (p < 0.0001) and Ki-67+ (p < 0.0001) cells, with numerically altered CXCR3+ and CXCR4+ cells in RA. CD95 and Ki-67 expressions were highest in post-switch memory B cells, whereas CD19+CXCR3+ and CD19+CXCR4+ expressing cells were substantially higher in the pre-switch compartment. In all subsets of the memory B cells, in vivo IL-6R, and TNF-α blockade significantly reduced the enhanced expressions of CD95 and Ki-67. Based on our findings, we conclude that the three major peripheral memory B cell populations, pre-, post-switch, and double-negative B cells, are activated in RA, demonstrating enhanced CD95 and Ki-67 expressions, and varied expression of CXCR3 and CXCR4 chemokine receptors when compared with healthy individuals. This activation can be efficaciously modulated under cytokine inhibition in vivo.},
  language  = {en}
}
@article{GernertTonyFroehlichetal.2022,
  author    = {Gernert, Michael and Tony, Hans-Peter and Fr{\"o}hlich, Matthias and Schwaneck, Eva Christina and Schmalzing, Marc},
  title     = {Immunosuppressive therapy after autologous hematopoietic stem cell transplantation in systemic sclerosis patients — high efficacy of Rituximab},
  series = {Frontiers in Immunology},
  volume    = {12},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2021.817893},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-254345},
  year      = {2022},
  abstract  = {Background Systemic sclerosis (SSc) patients often need immunosuppressive medication (IS) for disease control. If SSc is progressive despite IS, autologous hematopoietic stem cell transplantation (aHSCT) is a treatment option for selected SSc patients. aHSCT is effective with good available evidence, but not all patients achieve a treatment-free remission after aHSCT. Thus far, data about the need of IS after aHSCT in SSc is not published. The aim of this study was to investigate the use of IS after aHSCT, its efficacy, and the occurrence of severe adverse events (SAEs). Methods Twenty-seven patients with SSc who had undergone aHSCT were included in this single-center retrospective cohort study. Clinical data, including IS, SAEs, and lung function data, were collected. Results Sixteen of 27 (59.3\%) patients received IS after aHSCT. Methotrexate, rituximab, mycophenolate, cyclophosphamide, and hydroxychloroquine were most commonly used. The main reason for starting IS was SSc progress. Nine patients received rituximab after aHSCT and showed an improvement in modified Rodnan skin score and a stabilization of lung function 2 years after rituximab. SAEs in patients with IS after aHSCT (50.0\%) were not more common than in patients without IS (54.6\%). SAEs were mostly due to SSc progress, secondary autoimmune diseases, or infections. Two deaths after aHSCT were transplantation related and three during long-term follow-up due to pulmonary arterial hypertension. Conclusion Disease progression and secondary autoimmune diseases may necessitate IS after aHSCT in SSc. Rituximab seems to be an efficacious treatment option in this setting. Long-term data on the safety of aHSCT is reassuring.},
  language  = {en}
}
@article{FroehlichSchwaneckGernertetal.2020,
  author    = {Froehlich, Matthias and Schwaneck, Eva C. and Gernert, Michael and Gadeholt, Ottar and Strunz, Patrick-Pascal and Morbach, Henner and Tony, Hans-Peter and Schmalzing, Marc},
  title     = {Autologous Stem Cell Transplantation in Common Variable Immunodeficiency: A Case of Successful Treatment of Severe Refractory Autoimmune Encephalitis},
  series = {Frontiers in Immunology},
  volume    = {11},
  journal   = {Frontiers in Immunology},
  number    = {1317},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2020.01317},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206972},
  year      = {2020},
  abstract  = {Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults. It is associated with hypogammaglobulinemia, recurring infections and autoimmune phenomena. Treatment includes immunoglobulin substitution and immunosuppressants. Autoimmune neurological manifestations of CVID are rare and occur predominantly as granulomatous disease. We report the case of a 35-year-old woman with CVID who developed autoimmune encephalitis as demonstrated by double cerebral biopsy. Infectious or malignant causes could be excluded. Despite intensive immunosuppressive therapy with common regimens no significant improvement could be achieved. Ultimately, an autologous hematopoietic stem cell transplantation (HSCT) was performed, resulting in lasting complete remission of the encephalitis. To our knowledge, this is the first report of refractory autoimmune phenomena in CVID treated by autologous HSCT.},
  language  = {en}
}
@article{StephanTascilarYalcinMutluetal.2023,
  author    = {Stephan, Marlene and Tascilar, Koray and Yalcin-Mutlu, Melek and Hagen, Melanie and Haschka, Judith and Reiser, Michaela and Hartmann, Fabian and Kleyer, Arnd and Hueber, Axel J. and Manger, Bernhard and Figueiredo, Camille and Cobra, Jayme Fogagnolo and Tony, Hans-Peter and Finzel, Stephanie and Kleinert, Stefan and Wendler, J{\"o}rg and Schuch, Florian and Ronneberger, Monika and Feuchtenberger, Martin and Fleck, Martin and Manger, Karin and Ochs, Wolfgang and Schmitt-Haendle, Matthias and Lorenz, Hannes Martin and N{\"u}sslein, Hubert and Alten, Rieke and Henes, Joerg and Kr{\"u}ger, Klaus and Schett, Georg and Rech, J{\"u}rgen},
  title     = {Physical function of RA patients tapering treatment — a post hoc analysis of the randomized controlled RETRO trial},
  series = {Journal of Clinical Medicine},
  volume    = {12},
  journal   = {Journal of Clinical Medicine},
  number    = {11},
  issn      = {2077-0383},
  doi       = {10.3390/jcm12113723},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319349},
  year      = {2023},
  abstract  = {Several studies have shown that tapering or stopping disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients in sustained remission is feasible. However, tapering/stopping bears the risk of decline in physical function as some patients may relapse and face increased disease activity. Here, we analyzed the impact of tapering or stopping DMARD treatment on the physical function of RA patients. The study was a post hoc analysis of physical functional worsening for 282 patients with RA in sustained remission tapering and stopping DMARD treatment in the prospective randomized RETRO study. HAQ and DAS-28 scores were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50\% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and HAQ and DAS-28 scores were evaluated every 3 months. The effect of treatment reduction strategy on functional worsening was assessed in a recurrent-event Cox regression model with a study-group (control, taper, and taper/stop) as the predictor. Two-hundred and eighty-two patients were analyzed. In 58 patients, functional worsening was observed. The incidences suggest a higher probability of functional worsening in patients tapering and/or stopping DMARDs, which is likely due to higher relapse rates in these individuals. At the end of the study, however, functional worsening was similar among the groups. Point estimates and survival curves show that the decline in functionality according to HAQ after tapering or discontinuation of DMARDs in RA patients with stable remission is associated with recurrence, but not with an overall functional decline.},
  language  = {en}
}
@article{ElHelouBiegnerBodeetal.2019,
  author    = {El-Helou, Sabine M. and Biegner, Anika-Kerstin and Bode, Sebastian and Ehl, Stephan R. and Heeg, Maximilian and Maccari, Maria E. and Ritterbusch, Henrike and Speckmann, Carsten and Rusch, Stephan and Scheible, Raphael and Warnatz, Klaus and Atschekzei, Faranaz and Beider, Renata and Ernst, Diana and Gerschmann, Stev and Jablonka, Alexandra and Mielke, Gudrun and Schmidt, Reinhold E. and Sch{\"u}rmann, Gesine and Sogkas, Georgios and Baumann, Ulrich H. and Klemann, Christian and Viemann, Dorothee and Bernuth, Horst von and Kr{\"u}ger, Renate and Hanitsch, Leif G. and Scheibenbogen, Carmen M. and Wittke, Kirsten and Albert, Michael H. and Eichinger, Anna and Hauck, Fabian and Klein, Christoph and Rack-Hoch, Anita and Sollinger, Franz M. and Avila, Anne and Borte, Michael and Borte, Stephan and Fasshauer, Maria and Hauenherm, Anja and Kellner, Nils and M{\"u}ller, Anna H. and {\"U}lzen, Anett and Bader, Peter and Bakhtiar, Shahrzad and Lee, Jae-Yun and Heß, Ursula and Schubert, Ralf and W{\"o}lke, Sandra and Zielen, Stefan and Ghosh, Sujal and Laws, Hans-Juergen and Neubert, Jennifer and Oommen, Prasad T. and H{\"o}nig, Manfred and Schulz, Ansgar and Steinmann, Sandra and Klaus, Schwarz and D{\"u}ckers, Gregor and Lamers, Beate and Langemeyer, Vanessa and Niehues, Tim and Shai, Sonu and Graf, Dagmar and M{\"u}glich, Carmen and Schmalzing, Marc T. and Schwaneck, Eva C. and Tony, Hans-Peter and Dirks, Johannes and Haase, Gabriele and Liese, Johannes G. and Morbach, Henner and Foell, Dirk and Hellige, Antje and Wittkowski, Helmut and Masjosthusmann, Katja and Mohr, Michael and Geberzahn, Linda and Hedrich, Christian M. and M{\"u}ller, Christiane and R{\"o}sen-Wolff, Angela and Roesler, Joachim and Zimmermann, Antje and Behrends, Uta and Rieber, Nikolaus and Schauer, Uwe and Handgretinger, Rupert and Holzer, Ursula and Henes, J{\"o}rg and Kanz, Lothar and Boesecke, Christoph and Rockstroh, J{\"u}rgen K. and Schwarze-Zander, Carolynne and Wasmuth, Jan-Christian and Dilloo, Dagmar and H{\"u}lsmann, Brigitte and Sch{\"o}nberger, Stefan and Schreiber, Stefan and Zeuner, Rainald and Ankermann, Tobias and Bismarck, Philipp von and Huppertz, Hans-Iko and Kaiser-Labusch, Petra and Greil, Johann and Jakoby, Donate and Kulozik, Andreas E. and Metzler, Markus and Naumann-Bartsch, Nora and Sobik, Bettina and Graf, Norbert and Heine, Sabine and Kobbe, Robin and Lehmberg, Kai and M{\"u}ller, Ingo and Herrmann, Friedrich and Horneff, Gerd and Klein, Ariane and Peitz, Joachim and Schmidt, Nadine and Bielack, Stefan and Groß-Wieltsch, Ute and Classen, Carl F. and Klasen, Jessica and Deutz, Peter and Kamitz, Dirk and Lassy, Lisa and Tenbrock, Klaus and Wagner, Norbert and Bernbeck, Benedikt and Brummel, Bastian and Lara-Villacanas, Eusebia and M{\"u}nstermann, Esther and Schneider, Dominik T. and Tietsch, Nadine and Westkemper, Marco and Weiß, Michael and Kramm, Christof and K{\"u}hnle, Ingrid and Kullmann, Silke and Girschick, Hermann and Specker, Christof and Vinnemeier-Laubenthal, Elisabeth and Haenicke, Henriette and Schulz, Claudia and Schweigerer, Lothar and M{\"u}ller, Thomas G. and Stiefel, Martina and Belohradsky, Bernd H. and Soetedjo, Veronika and Kindle, Gerhard and Grimbacher, Bodo},
  title     = {The German national registry of primary immunodeficiencies (2012-2017)},
  series = {Frontiers in Immunology},
  volume    = {10},
  journal   = {Frontiers in Immunology},
  doi       = {10.3389/fimmu.2019.01272},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226629},
  year      = {2019},
  abstract  = {Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57\% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36\% of patients. Familial cases were observed in 21\% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74\%) and immune dysregulation (22\%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE-syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49\% of all patients received immunoglobulin G (IgG) substitution (70\%-subcutaneous; 29\%-intravenous; 1\%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.},
  language  = {en}
}