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1.
Nutr Metab Cardiovasc Dis ; 28(11): 1100-1105, 2018 11.
Article in English | MEDLINE | ID: mdl-30143407

ABSTRACT

BACKGROUND AND AIMS: Chronic inflammatory diseases (CID) are associated with a profound increase in cardiovascular (CV) risk resulting in reduced life expectancy. However, LDL-cholesterol is reported to be low in CID patients which is referred to as the "LDL paradoxon". The aim of the present study was to investigate whether LDL-particles in CID exhibit an increased content of the highly atherogenic small-dense LDL subfraction (sdLDL). METHODS AND RESULTS: In this prospective, single center, observational study we enrolled 141 patients with CID (RA n = 59, inflammatory bowel disease (IBD) n = 35, ankylosing spondylitis (SpA) n = 25, Psoriasis n = 22) in 2011 through 2013 to evaluate sdLDL levels before as well as 6 and 26 weeks after initiation of different anti-cytokine therapies (anti-TNFα, anti-IL-6R antibodies). sdLDL levels were compared to 141 healthy individuals in a case control design. Compared to healthy controls, all CID patients displayed a significantly higher sdLDL content within the LDL cholesterol fraction: RA 35.0 ± 9.2% (p < 0.001), SpA 42.5 ± 10.5% (p < 0.001), IBD 37.5 ± 7.1% (p < 0.001), Psoriasis 33.6 ± 4.6% (p < 0.01). Furthermore, the sdLDL/LDL ratio was significantly higher in male compared to female RA subjects (p < 0.05). Neither anti-TNFα nor anti-IL6R medication altered sdLDL levels despite a significant improvement of disease activity. CONCLUSION: In several different chronic inflammatory disease entities, LDL-cholesterol is shifted toward a pro-atherogenic phenotype due to an increased sdLDL content which might in part explain the LDL paradoxon. Since premature CV disease is a major burden of affected patients, specifically targeting lipid metabolism should be considered routinely in clinical patient care. CLINICAL TRIALS: Registration at German Clinical Trial Register (DRKS): DRKS00005285.


Subject(s)
Atherosclerosis/blood , Cholesterol, LDL/blood , Inflammatory Bowel Diseases/blood , Psoriasis/blood , Spondylitis, Ankylosing/blood , Adult , Aged , Anti-Inflammatory Agents/therapeutic use , Atherosclerosis/diagnosis , Atherosclerosis/immunology , Biomarkers/blood , Case-Control Studies , Chronic Disease , Female , Germany , Humans , Inflammatory Bowel Diseases/diagnosis , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/immunology , Male , Middle Aged , Particle Size , Phenotype , Prospective Studies , Psoriasis/diagnosis , Psoriasis/drug therapy , Psoriasis/immunology , Receptors, Interleukin-6/antagonists & inhibitors , Receptors, Interleukin-6/immunology , Risk Factors , Spondylitis, Ankylosing/diagnosis , Spondylitis, Ankylosing/drug therapy , Spondylitis, Ankylosing/immunology , Time Factors , Treatment Outcome , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/immunology
2.
Lupus ; 27(4): 600-609, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29050534

ABSTRACT

Objectives Low copy numbers and deletion of complement C4 genes are potent risk factors for systemic lupus erythematosus (SLE). However, it is not known whether this genetic association affects the clinical outcome. We investigated C4 copy number variation and its relationship to clinical and serological features in a Northern European lupus cohort. Methods We genotyped the C4 gene locus using polymerase chain reaction (PCR)-based TaqMan assays in 169 patients with SLE classified according to the 1997 revised American College of Rheumatology (ACR) criteria and in 520 matched controls. In the patient group the mean C4 serum protein concentrations nephelometrically measured during a 12-month period prior to genetic analysis were compared to C4 gene copy numbers. Severity of disease was classified according to the intensity of the immunosuppressive regimens applied and compared to C4 gene copy numbers, too. In addition, we performed a TaqMan based analysis of three lupus-associated single-nucleotide polymorphisms (SNPs) located inside the major histocompatibility complex (MHC) to investigate the independence of complement C4 in association with SLE. Results Homozygous deficiency of the C4A isotype was identified as the strongest risk factor for SLE (odds ratio (OR) = 5.329; p = 7.7 × 10-3) in the case-control comparison. Moreover, two copies of total C4 were associated with SLE (OR = 3.699; p = 6.8 × 10-3). C4 serum levels were strongly related to C4 gene copy numbers in patients, the mean concentration ranging from 0.110 g/l (two copies) to 0.256 g/l (five to six copies; p = 4.9 × 10-6). Two copies of total C4 and homozygous deletion of C4A were associated with a disease course requiring cyclophosphamide therapy (OR = 4.044; p = 0.040 and OR = 5.798; p = 0.034, respectively). Homozygous deletion of C4A was associated with earlier onset of SLE (median 24 vs. 34 years; p = 0.019) but not significant after correction for multiple testing. SNP analysis revealed a significant association of HLA-DRB1*0301 with SLE (OR = 2.231; p = 1.33 × 10-5). Conclusions Our findings confirm the important role of complement C4 genes in the development of SLE. Beyond the impact on the susceptibility for lupus, C4 copy numbers may be related to earlier onset and a more severe course of the disease. The association of homozygous deletion of C4A and SLE is accompanied by the presence of HLA-DRB1*0301 without a proven pathophysiological mechanism.


Subject(s)
Complement C4a/genetics , DNA Copy Number Variations , Gene Deletion , Gene Dosage , Homozygote , Lupus Erythematosus, Systemic/genetics , Adult , Aged , Case-Control Studies , Chi-Square Distribution , Complement C4a/deficiency , Complement C4a/immunology , Drug Therapy, Combination , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Germany , HLA-DRB1 Chains/genetics , Humans , Immunosuppressive Agents/therapeutic use , Logistic Models , Lupus Erythematosus, Systemic/diagnosis , Lupus Erythematosus, Systemic/drug therapy , Lupus Erythematosus, Systemic/immunology , Male , Middle Aged , Odds Ratio , Phenotype , Polymorphism, Single Nucleotide , Prognosis , Risk Factors , Severity of Illness Index , Time Factors , Young Adult
3.
Lupus ; 23(4): 428-30, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24482144

ABSTRACT

This case report describes two female lupus patients who both received biological treatment with tocilizumab and with belimumab. The disease course was remarkably similar in both cases. Tocilizumab resulted in a transient improvement in pleurisy and arthritis but was then followed by a clinical flare accompanied by an increase in autoantibodies and a drop in complement levels. Alike, both patients experienced a rapid and sustained improvement after institution of belimumab. The clinical benefit obtained is currently stable under ongoing belimumab therapy.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Lupus Erythematosus, Systemic/drug therapy , Autoantibodies/immunology , Complement System Proteins/immunology , Female , Humans , Immunosuppressive Agents/therapeutic use , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/physiopathology , Middle Aged , Severity of Illness Index , Treatment Outcome
4.
Z Rheumatol ; 71(4): 278-87, 2012 Jun.
Article in German | MEDLINE | ID: mdl-22699216

ABSTRACT

Pulmonary emergencies in rheumatic diseases are rare, potentially life-threatening conditions that occur either as a manifestation of the disease itself or as an adverse event of immunosuppressive treatment. Diffuse alveolar hemorrhage, tracheal stenosis, acute pneumonitis and drug-induced lung injury belong to this category. The management of these emergencies requires intensive cooperation between rheumatology and pulmonology. The latter contributes its experience in the care of related conditions, specific endoscopic techniques and local interventions as well as the indispensable and life-supporting forms of assisted ventilation. The present article summarizes the current knowledge on diagnostic and therapeutic procedures including the newly available B-cell directed treatments.


Subject(s)
Connective Tissue Diseases/diagnosis , Connective Tissue Diseases/therapy , Critical Care/methods , Emergency Medical Services/methods , Lung Diseases/therapy , Vasculitis/diagnosis , Vasculitis/therapy , Connective Tissue Diseases/complications , Humans , Lung Diseases/diagnosis , Lung Diseases/etiology , Vasculitis/complications
5.
Clin Exp Immunol ; 146(3): 409-16, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17100759

ABSTRACT

Inherited C1q deficiency is associated strongly with the development of systemic lupus erythematosus (SLE). The aim of our study was to evaluate the ability of monocytes from SLE patients without inherited C1q deficiency to up-regulate C1q-mRNA upon stimulation. Furthermore, we wanted to elucidate the physiological stimulus for up-regulation of C1q-mRNA. Peripheral blood mononuclear cell (PBMC)-derived monocytes from 10 SLE patients, 10 patients with rheumatoid arthritis (RA) and 10 healthy controls (HC) were stimulated with dexamethasone (DXM), interferon-gamma or both. Additionally, purified monocytes from HC were stimulated with interleukin (IL)-10. C1q-mRNA expression was measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR). C1q protein was detected using the standard alkaline phosphatase/anti-alkaline phosphatase (APAAP) technique. SLE monocytes were significantly less able to up-regulate C1q-mRNA when compared to RA or HC. IL-10 was identified as an important stimulus for C1q synthesis. In SLE patients there is a significant functional impairment of monocytes to synthesize C1q upon stimulation. As C1q is linked to the process of recognition and removal of apoptotic cells, this relative C1q deficiency is likely to contribute to the reduced phagocytosis of apoptotic material observed in SLE and thereby might be a central pathogenetic factor.


Subject(s)
Complement C1q/biosynthesis , Lupus Erythematosus, Systemic/immunology , Monocytes/immunology , Adult , Anti-Inflammatory Agents/pharmacology , Arthritis, Rheumatoid/immunology , Cells, Cultured , Complement C1q/genetics , Dexamethasone/pharmacology , Female , Humans , Immunoenzyme Techniques , Interferon-gamma/immunology , Interleukin-10/immunology , Middle Aged , RNA, Messenger/genetics , Up-Regulation/drug effects , Up-Regulation/immunology
6.
Ann Rheum Dis ; 63(12): 1681-3, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15547095

ABSTRACT

OBJECTIVE: To evaluate telomerase activity as a marker of lymphocyte proliferation in systemic lupus erythematosus (SLE). METHODS: CD19+, CD4+, and CD8+ lymphocytes were isolated from the peripheral blood of nine patients with SLE and nine healthy controls by means of magnetic bead-coupled antibodies and tested for telomerase activity with the TRAP assay. RESULTS: Telomerase activity was significantly increased in CD19+ B cells from patients with SLE. CD4+ and CD8+ T cells from lupus patients displayed increased mean telomerase activity, although the difference from normal controls did not reach statistical significance. CONCLUSIONS: Increased telomerase activity in the B and the T cell lineage might indicate activation and proliferation of these lymphocytes.


Subject(s)
B-Lymphocyte Subsets/enzymology , Lupus Erythematosus, Systemic/immunology , T-Lymphocyte Subsets/enzymology , Telomerase/blood , B-Lymphocyte Subsets/pathology , Cell Division/immunology , Female , Humans , Lupus Erythematosus, Systemic/genetics , T-Lymphocyte Subsets/pathology , Telomere/ultrastructure
7.
Ann Rheum Dis ; 63(11): 1518-20, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15479908

ABSTRACT

CASE REPORTS: A 66 year old female patient had relapsing fever and non-suppurative panniculitis suggestive of enigmatic "Weber-Christian disease" (WCD). Antineutrophil cytoplasmic antibodies with specificity for human leucocyte elastase (HLE-ANCA) were detected. A biopsy showed small vessel vasculitis and panniculitis. A 53 year old man had recurrent episodes of abdominal pain, erythematous rash, and myalgia. Fever attacks had stopped a few years ago. A biopsy showed panniculitis and fasciitis. In both patients mutations (R92Q, T50M) of the tumour necrosis factor receptor super family (TNFRSF) 1A gene were disclosed. Mutations of the TNFRSF 1A gene are the cause of tumour necrosis factor receptor associated periodic syndrome (TRAPS). Both patients responded favourably to treatment with the human soluble p75 TNF alpha receptor fusion protein etanercept (2 x 25 mg subcutaneously/week). DISCUSSION: Small vessel vasculitis and panniculitis have not been reported in TRAPS so far. The cases underline the importance of TNF alpha regulation in inflammatory processes including vasculitis. Genetically determined causes of fever may account for some cases of WCD.


Subject(s)
Panniculitis, Nodular Nonsuppurative/genetics , Panniculitis/genetics , Receptors, Tumor Necrosis Factor, Type I/genetics , Vasculitis/genetics , Aged , Antirheumatic Agents/therapeutic use , Etanercept , Female , Humans , Immunoglobulin G/therapeutic use , Male , Middle Aged , Mutation , Panniculitis/drug therapy , Panniculitis/immunology , Panniculitis, Nodular Nonsuppurative/drug therapy , Panniculitis, Nodular Nonsuppurative/immunology , Receptors, Tumor Necrosis Factor/therapeutic use , Syndrome , Vasculitis/drug therapy , Vasculitis/immunology
8.
Lupus ; 13(8): 605-6, 2004.
Article in English | MEDLINE | ID: mdl-15462491

ABSTRACT

There is evidence from animal and human studies that IL-1 might play an important role in the development and maintainence of inflammation in systemic lupus erythemathosus (SLE). We hypothesized that, in SLE, there might be a relative deficiency in the physiologic antagonist of IL-1, IL-1 receptor antagonist (IL-1RA). We therefore treated three patients with active SLE in whom conventional therapy has failed with the human IL-1RA, Anakinra. In two of the three patients there was a transient effect on muscle pain and/or polyarthritis. In one patient with lupus myositis there was no effect at all. The therapy was well tolerated and the only significant side effect was a transient drop in complement levels (C3 and C4) without clinical or laboratory signs of increased SLE activity in all three patients.


Subject(s)
Antirheumatic Agents/therapeutic use , Lupus Erythematosus, Systemic/drug therapy , Receptors, Interleukin-1/antagonists & inhibitors , Sialoglycoproteins/therapeutic use , Adult , Antirheumatic Agents/adverse effects , Female , Humans , Interleukin 1 Receptor Antagonist Protein , Lupus Erythematosus, Systemic/diagnosis , Middle Aged , Sialoglycoproteins/adverse effects
9.
Ann Rheum Dis ; 63(7): 870-3, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15194587

ABSTRACT

OBJECTIVE: To quantify 18-fluorodeoxyglucose (FDG) accumulation in large vessels in patients with polymyalgia rheumatica by positron emission tomography (PET), and to compare these data with serological markers of inflammation. METHODS: 13 untreated patients with active polymyalgia rheumatica underwent FDG positron emission tomography; eight were analysed in a second PET when in clinical remission. Six patients with other highly inflammatory conditions served as controls. For quantitative analysis, FDG uptake over nine defined vascular regions, divided by an individual background value, was expressed as a region of interest (ROI) index. These data were compared with the clinical status of the patient and with erythrocyte sedimentation rate (ESR), C reactive protein, haemoglobin, and platelet and leucocyte counts. RESULTS: By visual evaluation, 12 of the 13 patients showed an increased tracer uptake of the aorta or its major branches. By quantitative analysis, FDG uptake was significantly increased in polymyalgia rheumatica. In patients with active disease, the mean ROI index for all vascular regions exceeded that of controls by 70% (mean (SD): 1.58 (0.37) v 0.93 (0.12); p<0.001). In the eight patients who underwent follow up PET, the index declined substantially. In active polymyalgia rheumatica, FDG uptake was significantly correlated with C reactive protein (r = 0.8), ESR (r = 0.79), and platelet counts (r = 0.68). CONCLUSIONS: The observed FDG accumulation in the aorta and its branches and a strong correlation between tracer uptake and markers of inflammation is suggestive of large vessel arteritis. Quantitative ROI analysis appears to be a sensitive tool for detecting such inflammation.


Subject(s)
Aorta/diagnostic imaging , Fluorodeoxyglucose F18 , Polymyalgia Rheumatica/diagnostic imaging , Radiopharmaceuticals , Tomography, Emission-Computed , Aged , Arteritis/diagnostic imaging , Biomarkers/blood , Blood Sedimentation , C-Reactive Protein/analysis , Case-Control Studies , Female , Hemoglobins/analysis , Humans , Leukocyte Count , Male , Middle Aged , Platelet Count , Polymyalgia Rheumatica/blood , Polymyalgia Rheumatica/immunology , Remission Induction , Statistics, Nonparametric
13.
Am J Ophthalmol ; 123(6): 848-50, 1997 Jun.
Article in English | MEDLINE | ID: mdl-9535637

ABSTRACT

PURPOSE: To report a 31-year-old healthy patient with retinal venous occlusion in his left eye attributable to primary antiphospholipid antibody syndrome. METHODS: The patient was examined clinically. Multiple serologic and clinical investigations were performed to determine the causative disease. He was closely followed up for more than 3 years. RESULTS: The presence of lupus anticoagulant in our patient was indicated by a kaolin clotting time index of 27 (normal, <17) and confirmed by the demonstration of IgG antibodies against phospholipids. After long-term oral anticoagulant treatment for 2 years, lupus anticoagulant levels returned to normal, and therapy was stopped. No further thrombotic event occurred during follow-up. CONCLUSIONS: In retinal vascular occlusions of unexplained origin, antiphospholipid antibodies may play an important role in the pathogenesis. Detecting these antibodies in the serum of patients with retinal vascular occlusion helps determine the appropriate treatment with long-term oral anticoagulants.


Subject(s)
Antiphospholipid Syndrome/complications , Retinal Vein Occlusion/etiology , Adult , Anti-Inflammatory Agents/therapeutic use , Anticoagulants/therapeutic use , Antiphospholipid Syndrome/drug therapy , Antiphospholipid Syndrome/immunology , Drug Therapy, Combination , Fluorescein Angiography , Fundus Oculi , Humans , Immunoglobulin G/analysis , Lupus Coagulation Inhibitor/analysis , Male , Phospholipids/immunology , Prednisone/therapeutic use , Retinal Hemorrhage/etiology , Retinal Hemorrhage/pathology , Retinal Vein Occlusion/drug therapy , Retinal Vein Occlusion/immunology , Visual Acuity , Warfarin/therapeutic use
14.
Dtsch Med Wochenschr ; 121(36): 1084-9, 1996 Sep 06.
Article in German | MEDLINE | ID: mdl-8846753

ABSTRACT

HISTORY AND CLINICAL FINDINGS: For nine years a 54-year-old woman had been suffering from worsening treatment-resistant cold-dependent purpura of the limbs as well as cutaneous ulcerations and arthralgia, which recently had occurred even at a even slight decrease in room temperature. INVESTIGATIONS: A special form of cryofibrinogenemia was identified by affinity-chromatographic separation of a plasma cryoprecipitate. From this cryoprecipitate a monoclonal antifibrinogen antibody (IgG-kappa) was isolated which, in the cold, formed a precipitating complex with fibrinogen. Paraproteinaemia was not demonstrated by conventional serum and plasma electrophoresis. There was no evidence of neoplasma. TREATMENT AND COURSE: Attempted treatment with steroids, fibrinolytic agents and intravenous cyclophosphamide was unsuccessful. But long-term repeated plasmaphereses and anti-immunoglobulin adsorption improved the symptoms. After 5 years of this treatment-14 years after onset of symptoms-the patient died of the consequences of fulminant pulmonary embolism. CONCLUSION: To establish the diagnosis of monoclonal cryofibrinogenemia it is necessary, first, to identify the cryoprecipitate in plasma; secondly, to undertake affinity-chromatographic separation of the cryoprecipitate with subsequent analysis of its components.


Subject(s)
Antibodies, Monoclonal/isolation & purification , Autoantibodies/isolation & purification , Fibrinogens, Abnormal/immunology , Purpura/immunology , Chromatography, Affinity , Cryoglobulins/immunology , Drug Resistance , Female , Fibrinogens, Abnormal/metabolism , Humans , Middle Aged , Plasmapheresis , Purpura/drug therapy , Skin Ulcer/immunology
17.
Dtsch Med Wochenschr ; 116(28-29): 1081-8, 1991 Jul 12.
Article in German | MEDLINE | ID: mdl-2065594

ABSTRACT

14 female patients (mean age 28 [18-56] years) with severe systemic lupus erythematosus (SLE) were treated after discontinuing previous immunosuppressive therapy, according to an intensified protocol, with three plasmaphereses (days 1-3), followed by pulse cyclophosphamide (12 mg/kg i.v. each on days 3-5) and then oral immunosuppression (cyclophosphamide 1-5 mg/kg daily, depending on white blood cell count; prednisone equivalent 2.0 decreasing to 0.1 mg/kg, according to response, for 6 months). The aim of "synchronization" of plasmaphereses with subsequent cyclophosphamide pulse-therapy is to damage pathogenic lymphocyte clones during maximal compensatory activation induced by plasmapheresis. In all patients there was rapid improvement from the nephritis, pneumonitis, cytopenia, CNS abnormalities and polyserositis. The lupus activity index (SLAM) fell clearly, from initially 28.4 (13-37) points to 8.9 (2-13) after 6 months. Treatment was discontinued after this fall in 12 patients. A recurrence was observed in two patients, at 12 and 39 months respectively. Another patient died from liver cirrhosis of unknown aetiology. Nine patients are under observation but without treatment at present, in essential remission after 2 years (5-51 months), with a SLAM of 2.8 (0-7) points. "Synchronization" of plasmaphereses with subsequent pulse cyclophosphamide achieved rapid improvement and it resulted, for the first time, repeatedly in long-term treatment-free clinical remissions.


Subject(s)
Lupus Erythematosus, Systemic/therapy , Adolescent , Adult , Cyclophosphamide/administration & dosage , Drug Administration Schedule , Evaluation Studies as Topic , Female , Follow-Up Studies , Humans , Lupus Erythematosus, Systemic/drug therapy , Middle Aged , Plasmapheresis , Prednisone/administration & dosage , Recurrence , Time Factors
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