Publications by authors named "Marc Schmalzing"

62 Publications

High Prevalence of Genital Human Papillomavirus Infection in Patients With Primary Immunodeficiencies.

Front Immunol 2021 16;12:789345. Epub 2021 Nov 16.

Rheumatology and Clinical Immunology, Asklepios Klinik Altona , Hamburg, Germany.

Background: Genital human papillomavirus (HPV)-infections are common in the general population and are responsible for relevant numbers of epithelial malignancies. Much data on the HPV-prevalence is available for secondary immunodeficiencies, especially for patients with human immunodeficiency virus (HIV)-infection. Little is known about the genital HPV-prevalence in patients with primary immunodeficiencies (PIDs).

Methods: We performed a cross-sectional study of patients with PIDs and took genital swabs from male and female patients, which were analyzed with polymerase chain reaction for the presence of HPV-DNA. Clinical and laboratory data was collected to identify risk factors.

Results: 28 PID patients were included in this study. 10 of 28 (35.7%) had HPV-DNA in their genital swabs. 6 patients had high-risk HPV-types (21.4%). Most patients had asymptomatic HPV-infections, as genital warts were rare (2 of 28 patients) and HPV-associated malignancy was absent. Differences in the HPV-positivity regarding clinical PID-diagnosis, duration of PID, age, sex, immunosuppression, immunoglobulin replacement, or circumcision in males were not present. HPV-positive PID patients had higher numbers of T cells (CD3), of cytotoxic T cells (CD3/CD8), of transitional B cells (CD19/CD38/CD10/IgD), and of plasmablasts (CD19/CD38/CD27/IgD) compared to HPV-negative.

Conclusion: PID patients exhibit a high rate of genital HPV-infections with a high rate of high-risk HPV-types. Regular screening for symptomatic genital HPV-infection and HPV-associated malignancy in PID patients seems recommendable.
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http://dx.doi.org/10.3389/fimmu.2021.789345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8637119PMC
November 2021

Whole-Body [F]FDG PET/CT Can Alter Diagnosis in Patients with Suspected Rheumatic Disease.

Diagnostics (Basel) 2021 Nov 9;11(11). Epub 2021 Nov 9.

Comprehensive Heart Failure Center, Department of Nuclear Medicine, University Hospital Würzburg, 97080 Würzburg, Germany.

The 2-deoxy-d-[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 [F]FDG PET/CT on change in initially suspected diagnosis in patients at the time of the scan. Thirty-four patients, who had undergone [F]FDG PET/CT, were enrolled and the initially suspected diagnosis prior to [F]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 [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 [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, [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), = 0.07), but not when compared to PMR + GCA (1.04 ± 0.14 (95%CI, 0.95-1.13), = 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); < 0.0001, respectively). In individuals with a suspected diagnosis of rheumatic disease, an inflammatory-directed [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.
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http://dx.doi.org/10.3390/diagnostics11112073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625716PMC
November 2021

Erratum zu: Apps in der Rheumatologie.

Z Rheumatol 2021 Dec;80(Suppl 2):76

Medizinische Klinik II, Abteilung für Rheumatologie und klinische Immunologie, Universitätsklinikum Würzburg, Oberdürrbacher Straße 6, 97080, Würzburg, Deutschland.

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http://dx.doi.org/10.1007/s00393-021-01121-0DOI Listing
December 2021

Lymphocyte subsets in the peripheral blood are disturbed in systemic sclerosis patients and can be changed by immunosuppressive medication.

Rheumatol Int 2021 Oct 25. Epub 2021 Oct 25.

Department of Medicine II, Rheumatology and Clinical Immunology, University Hospital of Würzburg, Oberdürrbacher Str. 6, 97080, Würzburg, Germany.

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.
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http://dx.doi.org/10.1007/s00296-021-05034-8DOI Listing
October 2021

[Apps in rheumatology : Is there a need for an app in therapy for axial spondyloarthritis?]

Z Rheumatol 2021 Oct 7. Epub 2021 Oct 7.

Medizinische Klinik II, Abteilung für Rheumatologie und klinische Immunologie, Universitätsklinikum Würzburg, Oberdürrbacher Straße 6, 97080, Würzburg, Deutschland.

Background: Digital health applications/apps (DiGA) are entering many medical disciplines and have the potential to revolutionize patient care. In rheumatology, the use for axial spondyloarthritis (axSpA) would be conceivable in the form of an exercise app. Therefore, a representative survey among axSpA patients was conducted to determine the need for an axSpA exercise app.

Materials And Methods: An anonymous online survey among axSpA patients of the German Bechterew's Disease Association was conducted using a questionnaire; data were analysed using Excel, and GraphPad Prism.

Results: Four hundred and thirty-five axSpA patients participated in the survey. Eighty-four percent of the participants responded that there is a need to develop an axSpA-specific exercise app, and the same proportion want to use it. Patients under 60 years, patients under 60 years on biologics or Janus kinase inhibitor therapy, and patients with frequent back pain reported a greater need than their respective control subgroups (p < 0.001 in each case).

Conclusion: The development of an exercise app for axSpA is considered necessary by a large proportion of the patients; younger and more intensively treated patients appear to have a greater need.
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http://dx.doi.org/10.1007/s00393-021-01104-1DOI Listing
October 2021

Immunological Adverse Events After Autologous Hematopoietic Stem Cell Transplantation in Systemic Sclerosis Patients.

Front Immunol 2021 3;12:723349. Epub 2021 Sep 3.

Department of Internal Medicine II, University Hospital of Wuerzburg, Wuerzburg, Germany.

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 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% 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.
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http://dx.doi.org/10.3389/fimmu.2021.723349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447845PMC
December 2021

Vasa vasorum of proximal cerebral arteries after dural crossing - potential imaging confounder in diagnosing intracranial vasculitis in elderly subjects on black-blood MRI.

Eur Radiol 2021 Aug 4. Epub 2021 Aug 4.

Department of Diagnostic and Interventional Radiology, University Hospital Wuerzburg, Faculty of Medicine, University of Wuerzburg, Oberduerrbacher Straße 6, 97080, Wuerzburg, Germany.

Objectives: Vessel wall enhancement (VWE) may be commonly seen on MRI images of asymptomatic subjects. This study aimed to characterize the VWE of the proximal internal carotid (ICA) and vertebral arteries (VA) in a non-vasculitic elderly patient cohort.

Methods: Cranial MRI scans at 3 Tesla were performed in 43 patients (aged ≥ 50 years) with known malignancy for exclusion of cerebral metastases. For vessel wall imaging (VWI), a high-resolution compressed-sensing black-blood 3D T1-weighted fast (turbo) spin echo sequence (T1 CS-SPACE prototype) was applied post gadolinium with an isotropic resolution of 0.55 mm. Bilateral proximal intradural ICA and VA segments were evaluated for presence, morphology, and longitudinal extension of VWE.

Results: Concentric VWE of the proximal intradural ICA was found in 13 (30%) patients, and of the proximal intradural VA in 39 (91%) patients. Mean longitudinal extension of VWE after dural entry was 13 mm in the VA and 2 mm in the ICA. In 14 of 39 patients (36%) with proximal intradural VWE, morphology of VWE was suggestive of the mere presence of vasa vasorum. In 25 patients (64 %), morphology indicated atherosclerotic lesions in addition to vasa vasorum.

Conclusions: Vasa vasorum may account for concentric VWE within the proximal 2 mm of the ICA and 13 mm of the VA after dural entry in elderly subjects. Concentric VWE in these locations should not be confused with large artery vasculitis. Distal to these segments, VWE may be more likely related to pathologic conditions such as vasculitis.

Key Points: • Vasa vasorum may account for concentric VWE within the proximal 2 mm of the ICA and 13 mm of the VA after dural entry in non-vasculitic elderly people. • Concentric enhancement within the proximal 2 mm of the intradural ICA and within the proximal 13 mm of the intradural VA portions should not be misinterpreted as vasculitis. • Distal of this, VWE is likely related to pathologic conditions, in case of concentric VWE suggestive of vasculitis.
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http://dx.doi.org/10.1007/s00330-021-08181-5DOI Listing
August 2021

Induction of IL-9 in Peripheral Lymphocytes of Rheumatoid Arthritis Patients and Healthy Donors by Th17-Inducing Cytokine Conditions.

Front Immunol 2021 29;12:668095. Epub 2021 Apr 29.

Department of Pediatrics, University Hospital Wuerzburg, Wuerzburg, Germany.

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.
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http://dx.doi.org/10.3389/fimmu.2021.668095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117786PMC
October 2021

Clonal expansion of large granular lymphocytes in patients with spondyloarthritis and psoriatic arthritis treated with TNFα inhibitors.

Rheumatol Int 2021 Nov 15;41(11):1979-1986. Epub 2021 May 15.

Schwerpunkt Rheumatologie/Klinische Immunologie, Medizinische Klinik Und Poliklinik II, Universität Würzburg, Würzburg, Germany.

To determine the prevalence of clonal T-large granular lymphocyte (T-LGL) cells in patients with spondyloarthritis (SpA) and psoriatic arthritis (PsA) and to define possible risk factors for this condition. We present a cross-sectional analysis with retrospective and prospective aspects. 115 SpA patients, 48 PsA patients and 51 controls were recruited between December 28, 2017 and January 23, 2019. Flow cytometry (FACS) was performed to screen for aberrant T-LGL cells. Molecular analysis was then employed to confirm the diagnosis in patients with suggestive FACS findings. Patients with clonal T-LGL populations were followed prospectively by FACS analysis. Electronic patient files were retrospectively analyzed to determine risk factors. Median age was 49 years for SpA, 55.5 years for PsA, and 54 years for controls. Median disease duration of SpA and PsA was 15 years and 11 years, respectively. 79.8% of patients had received biologics at some point, 75.5% had ever received tumor necrosis factor (TNF) inhibitors. 59.5% were treated with TNF inhibitors at the time of study inclusion. We identified clonal T-LGL expansions in 13 individuals equaling a prevalence of 6% (13/214). T-LGL patients were taking TNF inhibitors more frequently at the time of study inclusion (p = 0.022) and were more likely to have ever been treated with TNF inhibition (p = 0.046). Clonal T-LGL expansions can be detected in patients with SpA, PsA and also in healthy controls. Confirming earlier results, exposure to TNFα-blocking agents appears to increase the risk of developing clonal expansions of T-LGL cells.
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http://dx.doi.org/10.1007/s00296-021-04872-wDOI Listing
November 2021

A randomised, open-label trial to assess the optimal treatment strategy in early diffuse cutaneous systemic sclerosis: the UPSIDE study protocol.

BMJ Open 2021 03 18;11(3):e044483. Epub 2021 Mar 18.

Department of Rheumatology & Clinical Immunology, UMC Utrecht, Utrecht, The Netherlands.

Introduction: Systemic sclerosis (SSc) is a chronic, autoimmune connective tissue disease associated with high morbidity and mortality, especially in diffuse cutaneous SSc (dcSSc). Currently, there are several treatments available in early dcSSc that aim to change the disease course, including immunosuppressive agents and autologous haematopoietic stem cell transplantation (HSCT). HSCT has been adopted in international guidelines and is offered in current clinical care. However, optimal timing and patient selection for HSCT are still unclear. In particular, it is unclear whether HSCT should be positioned as upfront therapy or rescue treatment for patients refractory to immunosuppressive therapy. We hypothesise that upfront HSCT is superior and results in lower toxicity and lower long-term medical costs. Therefore, we propose this randomised trial aiming to determine the optimal treatment strategy for early dcSSc by comparing two strategies used in standard care: (1) upfront autologous HSCT versus (2) immunosuppressive therapy (intravenous cyclophosphamide pulse therapy followed by mycophenolate mofetil) with rescue HSCT in case of treatment failure.

Methods And Analysis: The UPSIDE (front autologous hematopoietic tem cell transplantation vs mmunosuppressive medication in early iffus cutaneous systemic sclerosis) study is a multicentre, randomised, open-label, controlled trial. In total, 120 patients with early dcSSc will be randomised. The primary outcome is event-free survival at 2 years after randomisation. Secondary outcomes include serious adverse events, functional status and health-related quality of life. We will also evaluate changes in nailfold capillaroscopy pattern, pulmonary function, cardiac MR and high-resolution CT of the chest. Follow-up visits will be scheduled 3-monthly for 2 years and annually in the following 3 years.

Ethics And Dissemination: The study was approved by the Dutch Central Committee on Research Concerning Human Subjects (NL72607.041.20). The results will be disseminated through patient associations and conventional scientific channels.

Trial Registration Numbers: NCT04464434; NL 8720.
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http://dx.doi.org/10.1136/bmjopen-2020-044483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978271PMC
March 2021

Use of Complementary and Alternative Medicine in Patients with Primary Immunodeficiency: a Multicentric Analysis of 101 Patients.

J Clin Immunol 2021 04 6;41(3):585-594. Epub 2021 Jan 6.

Division of Rheumatology and Clinical Immunology, University Hospital Würzburg, Oberdürrbacher Str. 6, 97080, Würzburg, Germany.

The term complementary and alternative medicine (CAM) describes a broad spectrum of health care practices that are not an integral part of the conventional health care system. Many patients worldwide use CAM on their own initiative, often in combination with their conventional medical therapy. CAM use is attractive especially to patients with primary immunodeficiency, since they suffer from frequent infections and autoimmunity. Those are frequently addressed by CAM providers. The aim of this multicentric study was to collect information on the use of CAM by these patients and to define characteristics that are associated with the use of CAM. A total of 101 patients with primary immunodeficiencies at German hospitals were surveyed on their CAM use (further 14 patients rejected to participate). Multiple psychological tests (MARS-D, WHO-5, PHQ9, EFQ) were conducted to investigate variations among personality traits associated with CAM use. Additionally, clinical and sociodemographic patient data was collected. A total of 72% of patients used CAM to treat their primary immunodeficiency. The three most frequently used methods were physical exercise or fitness training (65%), dietary supplements (58%), and homeopathy (49%). Most patients did not discuss CAM use with their doctors, mostly because they felt that there was no time for it. CAM plays an important role for patients with primary immunodeficiency in a high-resource health care setting such as Germany. In clinical practice, doctors should create a platform to discuss needs that go beyond conventional therapy.
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http://dx.doi.org/10.1007/s10875-020-00955-8DOI Listing
April 2021

Pro- and Anti-Inflammatory Responses in Severe COVID-19-Induced Acute Respiratory Distress Syndrome-An Observational Pilot Study.

Front Immunol 2020 6;11:581338. Epub 2020 Oct 6.

Department of Anesthesiology and Intensive Care Medicine, University Hospital Würzburg, Würzburg, Germany.

Objectives: The severity of Coronavirus Disease 2019 (COVID-19) is largely determined by the immune response. First studies indicate altered lymphocyte counts and function. However, interactions of pro- and anti-inflammatory mechanisms remain elusive. In the current study we characterized the immune responses in patients suffering from severe COVID-19-induced acute respiratory distress syndrome (ARDS).

Methods: This was a single-center retrospective study in patients admitted to the intensive care unit (ICU) with confirmed COVID-19 between March 14 and May 28 2020 (n = 39). Longitudinal data were collected within routine clinical care, including flow-cytometry of lymphocyte subsets, cytokine analysis and growth differentiation factor 15 (GDF-15). Antibody responses against the receptor binding domain (RBD) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike protein were analyzed.

Results: All patients suffered from severe ARDS, 30.8% died. Interleukin (IL)-6 was massively elevated at every time-point. The anti-inflammatory cytokine IL-10 was concomitantly upregulated with IL-6. The cellular response was characterized by lymphocytopenia with low counts of CD8+ T cells, natural killer (NK) and naïve T helper cells. CD8+ T and NK cells recovered after 8 to 14 days. The B cell system was largely unimpeded. This coincided with a slight increase in anti-SARS-CoV-2-Spike-RBD immunoglobulin (Ig) G and a decrease in anti-SARS-CoV-2-Spike-RBD IgM. GDF-15 levels were elevated throughout ICU treatment.

Conclusions: Massively elevated levels of IL-6 and a delayed cytotoxic immune defense characterized severe COVID-19-induced ARDS. The B cell response and antibody production were largely unimpeded. No obvious imbalance of pro- and anti-inflammatory mechanisms was observed, with elevated GDF-15 levels suggesting increased tissue resilience.
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http://dx.doi.org/10.3389/fimmu.2020.581338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573122PMC
November 2020

Therapeutic Cytokine Inhibition Modulates Activation and Homing Receptors of Peripheral Memory B Cell Subsets in Rheumatoid Arthritis Patients.

Front Immunol 2020 11;11:572475. Epub 2020 Sep 11.

Department of Medicine II, Rheumatology and Clinical Immunology, University of Würzburg, Würzburg, Germany.

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 ( = 40), the phenotypic analysis of RA patients ( = 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+ ( < 0.0001) and Ki-67+ ( < 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, 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 .
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http://dx.doi.org/10.3389/fimmu.2020.572475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518039PMC
June 2021

Low B cell counts as risk factor for infectious complications in systemic sclerosis after autologous hematopoietic stem cell transplantation.

Arthritis Res Ther 2020 08 8;22(1):183. Epub 2020 Aug 8.

Department of Medicine II, Rheumatology and Clinical Immunology, University Hospital of Würzburg, Oberdürrbacher Str. 6, 97080, Würzburg, Germany.

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 naïve 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.
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http://dx.doi.org/10.1186/s13075-020-02255-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414656PMC
August 2020

Immunizations in immunocompromised patients: a guide for dermatologists.

J Dtsch Dermatol Ges 2020 Jul;18(7):699-723

Department of Dermatology, Venereology and Allergology, University Hospital, Würzburg, Germany.

The increasingly frequent use of immunomodulatory agents in dermatology requires the observance of specific recommendations for immunization. These recommendations are developed and regularly updated by the German Standing Committee on Vaccination (STIKO), an independent advisory group at the Robert Koch Institute. Dermatological patients on immunosuppressive treatment should ideally receive all vaccinations included in the standard immunization schedule. Additionally, it is recommended that they also undergo vaccination against the seasonal flu, pneumococci, and herpes zoster (inactivated herpes zoster subunit vaccine for patients ≥ 50 years). Additional immunizations against Haemophilus influenzae type B, hepatitis B and meningococci may be indicated depending on individual comorbidities and exposure risk. Limitations of use, specific contraindications and intervals to be observed between vaccination and immunosuppression depend on the immunosuppressive agent used and its dosing. Only under certain conditions may live-attenuated vaccines be administered in patients on immunosuppressive therapy. Given its strong suppressive effect on the humoral immune response, no vaccines - except for flu shots - should be given within six months after rituximab therapy. This CME article presents current recommendations on immunization in immunocompromised individuals, with a special focus on dermatological patients. Its goal is to enable readers to provide competent counseling and to initiate necessary immunizations in this vulnerable patient group.
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http://dx.doi.org/10.1111/ddg.14156DOI Listing
July 2020

Impfen bei Immunsuppression: ein Leitfaden für die dermatologische Praxis.

J Dtsch Dermatol Ges 2020 Jul;18(7):699-725

Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Würzburg.

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http://dx.doi.org/10.1111/ddg.14156_gDOI Listing
July 2020

Autologous Stem Cell Transplantation in Common Variable Immunodeficiency: A Case of Successful Treatment of Severe Refractory Autoimmune Encephalitis.

Front Immunol 2020 25;11:1317. Epub 2020 Jun 25.

Schwerpunkt Rheumatologie/Klinische Immunologie, Medizinische Klinik und Poliklinik II, Universität Würzburg, Würzburg, Germany.

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.
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http://dx.doi.org/10.3389/fimmu.2020.01317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330058PMC
April 2021

Correction to: Sustained improvement in work outcomes in employed patients with rheumatoid arthritis during 2 years of adalimumab therapy: an observational cohort study.

Clin Rheumatol 2020 08;39(8):2491

Schwerpunkt Rheumatologie/Klinische Immunologie Medizinische Klinik und Poliklinik II, Universität Würzburg, Oberdürrbacher Strasse 6, Würzburg, Germany.

The original version of this article was published without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed.].
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http://dx.doi.org/10.1007/s10067-020-05168-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338815PMC
August 2020

Does concomitant methotrexate confer clinical benefits in patients treated with prior biologic therapy? Analysis of data from a noninterventional study of rheumatoid arthritis patients initiating treatment with adalimumab.

Medicine (Baltimore) 2020 May;99(19):e20201

Rheumatology/Clinical Immunology, University Hospital Würzburg.

Most studies of methotrexate (MTX) in combination with tumor necrosis factor (TNF) inhibitors have focused on treatment-naive patients with early disease. The goal of this study was to evaluate whether previous biologic therapy influenced the impact of concomitant MTX in patients initiating treatment with adalimumab.We retrospectively analyzed data from 2 large noninterventional studies of German patients with active rheumatoid arthritis (RA) who initiated adalimumab therapy during routine clinical practice. Patients were seen between April 2004 and February 2013 for study 1 and between April 2003 and March 2013 for study 2. Key outcomes were Disease Activity Score-28 joints (DAS28), patient global assessment of health (PGA), and pain. Subgroup analyses by prior biologic treatment were performed on patients treated with continuous adalimumab monotherapy or adalimumab plus MTX for 12 months and 2-sample t tests were used to evaluate differences. We also assessed outcomes in subgroups in which MTX had been added or removed at 6 months and compared outcomes with 1-sample t tests.Of 2654 patients, 1911 (72%) were biologic naive and 743 (28%) had received prior biologic therapy, usually with a TNF inhibitor. All subgroups showed improvements following initiation of adalimumab therapy. In patients with no previous biologic treatment, continuous adalimumab plus MTX was associated with greater improvements in DAS28, PGA, and pain at month 12 compared with continuous adalimumab monotherapy (P = .0006, .0031, and .0032, respectively). In patients with previous biologic treatment, concomitant MTX was associated with statistically significant benefits in pain only. Adding MTX at month 6 resulted in additional benefits in patients with no prior biologic therapy, but not those with previous biologics.We conclude that concomitant MTX resulted in additional improvements in DAS28 and PGA vs adalimumab monotherapy in patients with no previous biologic therapy, but changes were not statistically significant in patients treated with prior biologics. These findings may help inform the patient/provider treatment decision during routine clinical care.
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http://dx.doi.org/10.1097/MD.0000000000020201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220320PMC
May 2020

Older age onset of systemic sclerosis - accelerated disease progression in all disease subsets.

Rheumatology (Oxford) 2020 11;59(11):3380-3389

Department of Dermatology and Venereology, University Hospital Cologne.

Objectives: Systemic sclerosis is a heterogeneous, multisystem disease. It can occur at any age, but most patients develop the disease between the age of 40 to 50 years. There is controversial evidence on whether/how the age at disease onset affects their clinical phenotype. We here investigate the relationship between age at disease onset and symptoms in a large cohort of SSc patients (lcSSc, dcSSc and SSc-overlap syndromes).

Methods: Clinical data of the registry of the German Network for Systemic Scleroderma including 3281 patients were evaluated and subdivided into three age groups at disease onset (<40 years, 40-60 years, >60 years).

Results: Among all SSc patients, 24.5% developed their first non-Raynaud phenomenon symptoms at the age <40 years, and 22.5% were older than 60 years of age. In particular, older patients at onset developed the lcSSc subset significantly more often. Furthermore, they had pulmonary hypertension more often, but digital ulcerations less often. Remarkably, the course of the disease was more rapidly progressing in the older cohort (>60 years), except for gastrointestinal and musculoskeletal involvement. No significant difference was found for the use of corticosteroids. However, significantly, fewer patients older than 60 years received immunosuppressive treatment.

Conclusion: In this large registry, ∼25% of patients developed SSc at an age above 60 years with an increased frequency of lcSSc. In this age group, an onset of internal organ involvement was significantly accelerated across all three subsets. These findings suggest that, in the elderly cohort, more frequent follow-up examinations are required for an earlier detection of organ complications.
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http://dx.doi.org/10.1093/rheumatology/keaa127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590407PMC
November 2020

Sexual function in German women with systemic sclerosis compared to women with systemic lupus erythematosus and evaluation of a screening test.

Clin Exp Rheumatol 2020 May-Jun;38 Suppl 125(3):59-64. Epub 2020 Apr 14.

Centre for Interdisciplinary Rheumatology, Clinical Immunology and Autoimmune Diseases INDIRA and Internal Medicine II, University Hospital Tübingen, Germany.

Objectives: To assess and compare sexual dysfunction (SDF) in female patients with systemic sclerosis (SSc) or systemic lupus erythematosus (SLE), to correlate sexual function with disease characteristics and depression, and to evaluate a short questionnaire (Qualisex) as a screening test.

Methods: Female patients with systemic sclerosis or systemic lupus erythematosus in two German tertiary university hospitals were evaluated in a prospective study. A self-designed questionnaire, the Female Sexual Function Index (FSFI), the Qualisex, and the Beck's depression inventory were used.

Results: 171 female patients were included into the study (83 with SSc, and 88 with SLE). 62.6% (52 of 83) of SSc patients and 67.0% (59 of 88) of SLE patients were sexually active. Only 9.6% of SSc patients and 14.8% of SLE patients had ever discussed sexual problems with their physician. Significantly more SSc patients would wish to discuss sexuality with their physician more intensively (37.3% vs. 28.4% in SLE patients, p=0.011). Among the 51 sexually active and evaluable SSc patients a mean FSFI of 25.53 (±5.06) was found, with a FSFI value defining sexual dysfunction (SDF) (<26.55) in 49% of patients, which did not differ significantly compared to SLE patients (n=59, mean FSFI 26.92 (±5.17), SDF in 45.8%). The Qualisex correlated significantly with the FSFI, and both Qualisex and FSFI correlated with depressiveness.

Conclusions: Sexual dysfunction (SDF) is a frequent problem in female patients with SSc and SLE. Addressing sexual issues during medical consultation is an unmet need. The Qualisex constitutes a short questionnaire, which is suitable for addressing concerns on sexuality.
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September 2020

Sustained improvement in work outcomes in employed patients with rheumatoid arthritis during 2 years of adalimumab therapy: an observational cohort study.

Clin Rheumatol 2020 Sep 23;39(9):2583-2592. Epub 2020 Mar 23.

Schwerpunkt Rheumatologie/Klinische Immunologie Medizinische Klinik und Poliklinik II, Universität Würzburg, Oberdürrbacher Strasse 6, Würzburg, Germany.

Objective: The goal of this study was to evaluate the long-term impact of adalimumab therapy on work-related outcomes in employed patients with rheumatoid arthritis (RA).

Method: We utilized data from an observational cohort of German patients who initiated adalimumab treatment during routine clinical care. Analyses were based on employed patients (part-time or full-time) who continued adalimumab treatment for 24 months. Major outcomes were self-reported sick leave days in the previous 6 months, absenteeism, presenteeism, and total work productivity impairment as assessed by the Work Productivity and Activity Impairment (WPAI) questionnaire and disease activity assessments. The normal number of sick leave days was based on data from the German Federal Statistical Office.

Results: Of 783 patients, 72.3% were women, mean age was 47.9 years, and mean disease duration was 7.8 years. At baseline (before adalimumab initiation), 42.9% of patients had higher than normal sick leave days (> 5) in the previous 6 months. During 24 months of adalimumab treatment, 61% of patients with higher than normal sick leave days at baseline returned to normal sick leave values (≤ 5 days/6 months). Overall, mean sick leave days/6 months decreased from 14.8 days at baseline to 7.4 days at month 24. Improvements were observed in WPAI assessments and disease activity measures, although presenteeism levels remained high (32.2% at month 24).

Conclusions: Adalimumab treatment was associated with strong and sustained improvements in work-related outcomes in employed patients who continued on adalimumab for 24 months. Presenteeism appears to be the work outcome most resistant to improvement during RA treatment.

Trial Registration: NCT01076205 Key Points • Long-term adalimumab therapy was associated with sustained improvements in work outcomes in patients with rheumatoid arthritis. • Despite improvements in sick leave days and work absenteeism, presenteeism (impairment while at work) remained relatively high.
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http://dx.doi.org/10.1007/s10067-020-05038-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426289PMC
September 2020

Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party.

Haematologica 2021 02 1;106(2):375-383. Epub 2021 Feb 1.

Assistance Publique-Hopitaux de Paris, Saint-Louis Hospital, Paris, France.

Three randomized controlled trials in early severe systemic sclerosis demonstrated that autologous hematopoietic stem cell transplantation was superior to standard cyclophosphamide therapy. This European Society for Blood and Marrow Transplantation multi-center prospective non-interventional study was designed to further decipher efficacy and safety of this procedure for severe systemic sclerosis patients in real-life practice and to search for prognostic factors. All consecutive adult systemic sclerosis patients undergoing a first autologous hematopoietic stem cell transplantation between December 2012 and February 2016 were prospectively included in the study. Primary endpoint was progression free survival. Secondary endpoints were overall survival, non-relapse mortality, response and incidence of progression. Eighty systemic sclerosis patients were included. Median follow-up duration was 24 (6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulins conditioning for all, with CD34+ selection in 35 patients. At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (p< 0.001). By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival (Hazard ration 3.32) and 1.77, respectively). CD34+-selection was associated with better response (Hazard ration: 0.46). This study confirms the efficacy of autologous stem cell transplantation in real-life practice for severe systemic sclerosis using non myeloablative conditioning. Careful cardio-pulmonary assessment to identify organ involvement at patient referral, reduced cyclophosphamide doses and CD34+ selection may improve outcomes. The study was registered at ClinicalTrials.gov: NCT02516124.
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http://dx.doi.org/10.3324/haematol.2019.230128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849556PMC
February 2021

Use of a "critical difference" statistical criterion improves the predictive utility of the Health Assessment Questionnaire-Disability Index score in patients with rheumatoid arthritis.

BMC Rheumatol 2019 10;3:51. Epub 2019 Dec 10.

1Division of Rheumatology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany.

Background: The Health Assessment Questionnaire-Disability Index (HAQ-DI) is used to assess functional status in rheumatoid arthritis (RA), but the change required for meaningful improvements remains unclear. A minimum clinically important difference (MCID) of 0.22 is frequently used in RA trials. The aim of this study was to determine a statistically defined critical difference for HAQ-DI (HAQ-DI-d) and evaluate its association with therapeutic outcomes.

Methods: We retrospectively analyzed data from adult German patients with RA enrolled in a multicenter observational trial in which they received adalimumab therapy at the decision of the treating clinician during routine clinical care. The HAQ-DI-d, defined as the minimum change that can be reliably discriminated from random long-term variations in patients on stable therapy, was determined by evaluating intra-individual variation in patient scores. Other outcomes of interest included Disease Activity Score-28 joints and patient-reported pain and fatigue.

Results: The HAQ-DI-d was calculated as an improvement (decrease) from baseline of 0.68 in a discovery cohort ( = 1645) of RA patients on stable therapy and with moderate disease activity (mean DAS28 [standard deviation] of 4.4 [1.6]). In the full patient cohort ( = 2740), 22.1% of patients achieved a HAQ-DI-d improvement at month 6. Compared with patients with a small improvement in HAQ-DI (decrease of ≥0.22 to < 0.68) or no improvement (< 0.22), patients achieving a HAQ-DI-d at month 6 had better therapeutic outcomes at months 12 and 24, including stable functional improvements. Change in pain was the most important predictor of HAQ-DI improvement during the first 6 months of therapy.

Conclusions: A HAQ-DI-d of 0.68 is a reliable measure of functional improvement. This measure may be useful in routine clinical care and clinical trials.

Trial Registration: ClinicalTrials.gov NCT01076205. Registered on February 26, 2010 (retrospectively registered).
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http://dx.doi.org/10.1186/s41927-019-0095-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902502PMC
December 2019

Memory CD4+ T cells lacking expression of CCR7 promote pro-inflammatory cytokine production in patients with diffuse cutaneous systemic sclerosis.

Eur J Dermatol 2019 Oct;29(5):468-476

Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany.

Systemic sclerosis (SSc) is a predominantly T-cell-mediated autoimmune disorder with a characteristic sequence of Th1 and Th2 inflammation resulting in fibrosis. The contribution of differentiated memory T-cell subpopulations and methylation of CpG regions of Th1- or Th2-specific transcription factor genes on the inflammatory cytokine signature in SSc is not well understood. The study aimed to investigate phenotypic differentiation, the cytokine signature, sensitivity of memory T cells to in vitro suppression by autologous regulatory T cells (Tregs), and methylation of Th1- and Th2-specific transcription factor genes in patients with limited (lcSSc) and diffuse cutaneous SSc (dcSSc) compared to healthy donors (HD). Phenotype/intracellular cytokine production and methylation of Th1- and Th2-specific transcription factor genes were determined by flow cytometry and epigenetic analysis, respectively, and compared between patients with lcSSc, dcSSc and HD. Discrimination of CD4+ T cells that lack CCR7 expression revealed that CCR7- CD4+ memory T cells and effectors are producers of intracellular TNFα, IL-13 and IL-4, particularly in dcSSc. A proportional increase in CCR7- memory T cells was demonstrated by SSc-derived CD4+ T-cells after insufficient suppression by Tregs. A higher level of methylation of GATA3 or STAT4 (Th2- and Th1-specific transcription factor genes, respectively) was observed in dcSSc. An abundance of specific CD4+ memory T-cell subpopulations strongly contributes to the production of pro-inflammatory cytokines in dcSSc. Our results suggest that therapeutic concepts should focus more intensively on the memory phenotype to control T cell-mediated inflammation in SSc patients.
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http://dx.doi.org/10.1684/ejd.2019.3645DOI Listing
October 2019

The German National Registry of Primary Immunodeficiencies (2012-2017).

Front Immunol 2019 19;10:1272. Epub 2019 Jul 19.

Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.

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. 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. 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. 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.
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http://dx.doi.org/10.3389/fimmu.2019.01272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659583PMC
October 2020

Response to daratumumab in rituximab-resistant EBV-associated PTLD following allogenic stem cell transplantation from an EBV seronegative donor.

Leuk Lymphoma 2019 12 18;60(14):3573-3576. Epub 2019 Jul 18.

Universitatsklinikum Wurzburg, Medizinische Klinik und Poliklinik II, Wurzburg, Germany.

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http://dx.doi.org/10.1080/10428194.2019.1636981DOI Listing
December 2019

New insights into the prevalence of depressive symptoms and depression in rheumatoid arthritis - Implications from the prospective multicenter VADERA II study.

PLoS One 2019 28;14(5):e0217412. Epub 2019 May 28.

Rheumatologische Schwerpunktpraxis, Drs. Kleinert, Rapp, Ronneberger, Schuch u. Wendler, Rheumatology, Erlangen, Germany.

Objectives: To investigate the prevalence of depressive symptoms in rheumatoid arthritis (RA) patients using two previously validated questionnaires in a large patient sample, and to evaluate depressive symptoms in the context of clinical characteristics (e.g. remission of disease) and patient-reported impact of disease.

Methods: In this cross-sectional study, the previously validated Patient Health Questionnaire (PHQ-9) and Beck-Depression Inventory II (BDI-II) were used to assess the extent of depressive symptoms in RA patients. Demographic background, RA disease activity score (DAS28), RA impact of disease (RAID) score, comorbidities, anti-rheumatic therapy and antidepressive treatment, were recorded. Cut-off values for depressive symptomatology were PHQ-9 ≥5 or BDI-II ≥14 for mild depressive symptoms or worse and PHQ-9 ≥ 10 or BDI-II ≥ 20 for moderate depressive symptoms or worse. Prevalence of depressive symptomatology was derived by frequency analysis while factors independently associated with depressive symptomatology were investigated by using multiple logistic regression analyses. Ethics committee approval was obtained, and all patients provided written informed consent before participation.

Results: In 1004 RA-patients (75.1% female, mean±SD age: 61.0±12.9 years, mean disease duration: 12.2±9.9 years, DAS28 (ESR): 2.5±1.2), the prevalence of depressive symptoms was 55.4% (mild or worse) and 22.8% (moderate or worse). Characteristics independently associated with depressive symptomatology were: age <60 years (OR = 1.78), RAID score >2 (OR = 10.54) and presence of chronic pain (OR = 3.25). Of patients classified as having depressive symptoms, only 11.7% were receiving anti-depressive therapy.

Conclusions: Mild and moderate depressive symptoms were common in RA patients according to validated tools. In routine clinical practice, screening for depression with corresponding follow-up procedures is as relevant as incorporating these results with patient-reported outcomes (e.g. symptom state), because the mere assessment of clinical disease activity does not sufficiently reflect the prevalence of depressive symptoms.

Clinical Trial Registration Number: This study is registered in the Deutsches Register Klinischer Studien (DRKS00003231) and ClinicalTrials.gov (NCT02485483).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217412PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538160PMC
February 2020

Tofacitinib modulates the VZV-specific CD4+ T cell immune response in vitro in lymphocytes of patients with rheumatoid arthritis.

Rheumatology (Oxford) 2019 11;58(11):2051-2060

Department of Pediatrics, Pediatric Rheumatology/Special Immunology, Würzburg, Germany.

Objective: RA is a chronic inflammatory disease characterized by lymphocyte infiltration and release of inflammatory cytokines. Previous studies have shown that treatment with Janus kinase inhibitors, such as tofacitinib, increased the incidence rate of herpes zoster compared with conventional DMARDs. Therefore, this study aimed to investigate the effect of tofacitinib on the varicella-zoster-virus (VZV)-specific T cell immune response.

Methods: The effect of tofacitinib on the VZV-specific T cell immune response was determined by evaluating the IFNγ production, the proliferative capacity, the VZV-induced differentiation into effector and memory T cells, the expression of activation marker CD69 and helper T cell type 1 (Th1)-characteristic chemokine receptors, such as CXCR3 and CCR5, as well as cytotoxic activity (perforin and granzyme B expression) of CD4+ T cells of patients with RA compared with healthy donors upon stimulation with VZV antigen in vitro.

Results: Tofacitinib significantly reduced the IFNγ production, proliferation, activation, and CXCR3 expression of VZV-specific CD4+ T cells in a dose-dependent manner in short- and long-term lymphocyte culture. No effect on the distribution of naive, effectors or memory, or on the expression of perforin or granzyme B by VZV-specific CD4+ T cells was observed.

Conclusion: This study showed that tofacitinib significantly modulated the Th1 response to VZV. The poor VZV-specific cellular immune response in patients with RA may be considered in recommendations regarding appropriate vaccination strategies for enhancing the VZV-specific Th1 response.
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http://dx.doi.org/10.1093/rheumatology/kez175DOI Listing
November 2019
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