Nicola Stein

Technische Universität München, München, Bavaria, Germany

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Publications (9)48.05 Total impact

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    ABSTRACT: Background With more than 100.000 affected individuals worldwide, Familial Mediterranean Fever (FMF) is the most prevalent episodic fever syndrome. Besides recurrent attacks of fever and painful serositis as typical and life-quality affecting symptoms, the dreaded complication of an inadequately controlled disease is the development of secondary amyloidosis, which is the major cause of mortality in FMF patients. Colchicine is the established first-line therapy to control disease activity, to achieve remission and to prevent secondary amyloidosis. However, about one third of patients with FMF are non- or only partial responders to colchicine and therewith have promoted the experience of other immunosuppressive agents in FMF. Objectives Here, we present the first case series of five patients with Familial Mediterranean Fever (FMF) refractory to treatment with colchicin and/or anakinra, who have been switched to monthly treatment with tocilizumab. Methods We report on five patients who have been treated with tocilizumab because of inadequate clinical and/or serological response to colchicine and inadequate response or intolerance of ankinra. Tocilizumab was administered at a dosage of 8 mg/kg bodyweight every 28 days. Colchicin was continued in four patients and discontinued in one patient. Treatment with anakinra, previously given in three patients, was discontinued. Results Four patients showed a good clinical and serological response to tocilizumab with a significant decrease of serum amyloid A (SAA) levels. Remission of FMF symptoms was achieved in three patients with the first application of tocilizumab. A normalization of increased levels of SAA and CRP was documented after the first application of tocilizumab in one patient and after the third application in another patient (depending on initial SAA levels). The therapy was well tolerated in all five patients with no relevant side effects (one uncomplicated urinary tract infection). In the first treated patient tocilizumab has already been switched back to colchicin alone after the ninth infusion because of complete remission for 6 months. The patient who did not respond to tocilizumab with persistent arthralgia and a relapse of abdominal pain after the third infusion, responded well to a switch of treatment to anakinra. In the other three patients tocilizumab infusions are still continuing with a median treatment duration of four months. Conclusions This is the first documentation of a successful treatment of FMF with tocilizumab. Of note, interference with IL-6 activity did not only result in complete clinical remission in four of the five patients previously resistant to immunosuppressive therapy, but also in complete serological remission as indicated by normalization of SAA and CRP in two individuals. These data strongly argue in favour of IL-6 as a main inflammatory cytokine in FMF and, thus, as a promising target in this disease. Disclosure of Interest None Declared
    No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases
  • N. Stein · H. Schulze-Koops · C. Reindl

    No preview · Article · Sep 2013 · Zeitschrift für Rheumatologie
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    ABSTRACT: Objective To investigate the clinical relevance of grade 1 findings on gray-scale ultrasound (GSUS) of the joints in patients with rheumatoid arthritis (RA). Methods We examined the wrists and small joints of 100 patients with early or established RA and 30 healthy controls, using GSUS and power Doppler ultrasound (PDUS). Independent clinical assessment of all joints for tenderness and swelling according to the European League Against Rheumatism examination technique was performed. Joints with grade 1 findings on GSUS were identified, and associations with swelling, pain, and findings on PDUS were assessed. Grade 1 findings on GSUS in patients with early RA were reassessed after 6 months of antirheumatic treatment. ResultsGrade 1 results represented the majority of all GSUS findings in patients with RA and were also frequently recorded in healthy controls. Grade 1 GSUS findings were not associated with tenderness, swelling, or positive results on PDUS. In comparison to joints with grade 2 and grade 3 findings on GSUS, joints with grade 1 findings were less likely to respond to treatment. Conclusion The present results indicate that grade 1 findings on GSUS have limited clinical relevance.
    No preview · Article · Jul 2013 · Arthritis & Rheumatology
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    ABSTRACT: OBJECTIVE: To investigate the clinical relevance of grade 1 grey scale findings detected with arthrosonography in patients with rheumatoid arthritis (RA). METHODS: We examined wrists and small joints of 100 patients with early and established RA and of 30 healthy controls (HC) with grey scale and power Doppler ultrasound (GSUS and PDUS, respectively). All joints were independently assessed clinically for tenderness and swelling according to the EULAR examination technique. Joints with grade 1 GSUS findings were identified and evaluated for their association with swelling, pain and PDUS findings. Grade 1 GSUS findings of early RA patients were reassessed after 6 months of antirheumatic treatment. RESULTS: Grade 1 GSUS findings represented the majority of all GSUS findings in RA patients and were also found frequently in HC. Grade 1 GSUS findings were not associated with tenderness, swelling and PD positivity. In comparison to grade 2 and grade 3 GSUS findings, grade 1 findings were less susceptible to treatment. CONCLUSION: The clinical relevance of grade 1 GSUS findings appears to be rather limited. © 2013 American College of Rheumatology.
    No preview · Article · Apr 2013 · Arthritis & Rheumatology
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    ABSTRACT: WNT5A has recently been implicated in inflammatory processes, but its role as a bone marrow stromal cell (BMSC)-derived mediator of joint inflammation in arthritis is unclear. Here, we investigated whether inflammatory stimuli induce WNT5A in BMSC to control inflammatory responses. WNT5A levels were determined in human BMSC after stimulation with lipopolysaccharide (LPS) or tumor necrosis factor α (TNF-α,) and in synovial cells and tissue of patients with rheumatoid arthritis (RA) and human TNF-α transgenic (hTNFtg) mice. A microarray analysis of WNT5A-treated murine osteoblasts was performed using Affymetrix gene chips. The regulation of cytokine/chemokine expression was confirmed by qPCR, ELISA, and Luminex technology in BMSC after stimulation with WNT5A or WNT5A knockdown. Relevant signaling pathways were identified using specific inhibitors. Migration of MACS-purified T lymphocytes and monocytes was assessed using the FluoroBlok system. WNT5A expression was increased threefold in BMSC after stimulation with LPS or TNF-α. Synovial fibroblasts from patients with RA showed a twofold increase of WNT5A expression compared with control cells, and its expression was highly induced in the synovial tissue of patients with RA and hTNFtg mice. Microarray analysis of WNT5A-treated osteoblasts identified cytokines and chemokines as targets. The induction of IL-1β, IL-6, CCL2, CCL5, CXCL1, and CXCL5 by WNT5A was confirmed in BMSC and depended on the activation of the NF-κB, mitogen-activated protein (MAPK), and Akt pathways. Accordingly, knockdown of WNT5A markedly reduced the basal and LPS-induced cytokine/chemokine production. Finally, migration of monocytes and T cells toward the supernatant of WNT5A-treated BMSC was increased by 25% and 20%, respectively. This study underlines the critical role of BMSC-derived WNT5A in the regulation of inflammatory processes and suggests its participation in the pathogenesis of RA.
    Preview · Article · Mar 2012 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
  • Martina Rauner · Nicola Stein · Lorenz C. Hofbauer
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    ABSTRACT: Bone is the major constituent of the skeleton which is a hallmark of all higher vertebrates. Besides the protection of internal organs and the support of body structures, the most important functions of bone are to serve as an attachment site for muscles allowing locomotion and provide a cavity for hematopoiesis in the bone marrow (Mendez-Ferrer et al. 2010; Zaidi 2007). Moreover, bone has a central role in mineral homeostasis as it functions as a reservoir for inorganic ions that can be mobilized rapidly on metabolic demand.
    No preview · Chapter · Jan 2012
  • Nicola Stein · Martina Rauner · Lorenz C. Hofbauer
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    ABSTRACT: The following chapter gives an overview of the clinical data of RANKL-inhibition by denosumab in conditions of bone loss in postmenopausal osteoporosis (PO), rheumatoid arthritis (RA), and malignant bone disease (MBD). Poor bone quality with reduced bone strength in localized as well as generalized form is associated with an increased incidence of fractures, high health care costs, and increased mortality. Additionally an increased need of painkillers due to malignant bone pain, painful joint dysfunction due to insufficient fracture healing are also associated with a wide spectrum of secondary disease conditions. Medical reduction and prevention of bone loss is therefore expected to be crucial in therapy of PO, RA and MBD.
    No preview · Chapter · Jan 2012

  • No preview · Article · May 2011 · Bone
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    ABSTRACT: Glucocorticoids (GCs) regulate various physiological processes, including bone remodeling. Whereas physiological amounts of GCs are required for proper human osteoblast differentiation, prolonged exposure to GCs leads to substantial bone loss in vivo predominantly by inhibiting osteoblast functions. Compound A (CpdA) is a novel GC receptor modulator with the potential of an improved benefit/risk profile. Here we tested the osteoimmunological effects of CpdA on primary human osteoblasts and their paracrine interactions with osteoclasts. To assess the antiinflammatory potential of CpdA in human bone marrow stromal cell (BMSC)-derived osteoblasts, cells were stimulated with lipopolysaccharide and cytokine expression was determined. Similar to dexamethasone (DEX), CpdA profoundly suppressed lipopolysaccharide-induced TNF-α (-63%), IL-1β (-38%), and IL-6 (-36%) (P < 0.05) mRNA levels. Of note, CpdA failed to induce osteogenic differentiation of BMSCs, whereas DEX and budesonide enhanced matrix mineralization an d increased runt-related transcription factor 2 and alkaline phosphatase mRNA levels up to 5-fold in a dose-dependent manner. Interestingly, each substance promoted cell proliferation by 7-10% and suppressed apoptosis by 25-30% at low concentrations and early differentiation stages, whereas high concentrations (1 μm) suppressed proliferation and stimulated apoptosis in mature osteoblasts. Finally, CpdA did not increase the receptor activator of nuclear factor-κB ligand to osteoprotegerin mRNA ratio as compared with DEX and did not stimulate the formation of osteoclasts in coculture with BMSCs. In summary, CpdA displays dissociated osteogenic and immunological effects in human BMSCs that are distinct from those of conventional GCs. Whether the specific osteoimmunological profile of CpdA translates into a relevant in vivo effect needs to be further explored.
    No preview · Article · Nov 2010 · Endocrinology
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    ABSTRACT: Endothelial cells of the bone vasculature modulate development, remodeling, and repair of bone by secreting osteotropic cytokines and hormones, which can act on osteoblastic and osteoclastic lineage cells. RANKL is the essential factor for differentiation, activation, and survival of osteoclasts, whereas osteoprotegerin (OPG) is a soluble decoy receptor and inhibitor for RANKL. In this study, we analyzed the regulation of OPG by T helper 2 (Th2) cytokines interleukin (IL)-4 and the closely related IL-13 in human umbilical vein endothelial cells (HUVECs), the underlying signaling pathway, and its functional relevance on osteoclastic resorption. IL-4 and IL-13 induced OPG mRNA levels and protein secretion in HUVEC by up to 4-fold in a dose- and time-dependent fashion (maximum effect after 48 h and at 10 ng/ml). Activation of the transcription factor STAT6 preceded IL-4-induced OPG expression, and blockade of IL-4-induced STAT6 activation by the phospholipase C-specific inhibitor D609 decreased OPG expression. Soluble IL-4 receptor (sIL-4R) dose-dependently abolished both IL-4-induced STAT6 phosphorylation and OPG expression. RANKL stimulated the activity of osteoclasts, which was antagonized by HUVEC-derived supernatant containing OPG. The inhibitory effect on osteoclastogenesis was completely and specifically abrogated by a neutralizing OPG antibody in unstimulated HUVEC supernatant and partially in IL-4-stimulated HUVEC supernatant. In summary, IL-4 and IL-13 induced OPG expression through activation of STAT6 in endothelial cells, and HUVEC-derived OPG is an IL-4/IL-13-induced inhibitor of osteoclastic resorption. These data underline the impact of Th2 cytokines on bone resorption through modulation of endothelial cell-derived cytokines.
    Full-text · Article · Jun 2008 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research

Publication Stats

111 Citations
48.05 Total Impact Points


  • 2013
    • Technische Universität München
      München, Bavaria, Germany
  • 2008-2012
    • Technische Universität Dresden
      • Medical Clinic III
      Dresden, Saxony, Germany
  • 2010
    • Center for Regenerative Therapies, Dresden
      Dresden, Saxony, Germany