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Introduction: Giant cell arteritis (GCA) is a systemic granulomatous vasculitis affecting the large arteries. Abnormal lymphocyte function has been noted as a pathogenic factor in GCA. Mycophenolate mofetil (MMF) inhibits inosine monophosphate dehydrogenase and is therefore a highly lymphocyte-specific immunosuppressive therapy. We aimed to assess the efficacy of MMF for inducing remission in GCA. Methods: Seven patients (5 female, 2 male) with GCA under therapy with MMF and who were treated at the outpatient clinic for rare inflammatory systemic diseases at Hannover Medical School between 2010 and 2023 were retrospectively included in the study. All patients underwent duplex sonography, 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET), magnetic resonance imaging (MRI), and/or biopsy to confirm the diagnosis. The primary endpoints were the number of recurrences, CRP levels at 3-6 and 6-12 months, and the period of remission. Results: All patients in this case series showed inflammatory activity of the arterial vessels in at least one of the imaging modalities: duplex sonography (n = 5), 18F-FDG PET (n = 5), MRI (n = 6), and/or biopsy (n = 5). CRP levels of all patients decreased at the measurement time points 3-6 months, and 6-9 months after initiation of therapy with MMF compared with CRP levels before MMF therapy. All patients with GCA in this case series achieved disease remission. Discussion: The results of the present case series indicate that MMF is an effective therapy in controlling disease activity in GCA, which should be investigated in future randomized controlled trials.
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BACKGROUND: Melkersson-Rosenthal syndrome is a rare disease characterized by the triad of recurrent orofacial swelling with facial paralysis and fissured dorsal tongue. Histologically, noncaseating granulomatous inflammation occurs that confirms the diagnosis. Overlaps between granulomatous diseases such as sarcoidosis and Crohn's disease are described. Systemic corticosteroid therapy is the treatment of choice for acute attacks. CASE PRESENTATION: We here present a case of a 59-year-old White woman suffering from Melkersson-Rosenthal syndrome with a past history of sarcoidosis on therapy with leflunomide in combination with low-dose tacrolimus successfully treated with the anti-leprosy drug clofazimine after failure of systemic steroid therapy. CONCLUSIONS: We propose clofazimine as an alternative treatment in steroid-refractory cases.
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Doença de Crohn , Paralisia Facial , Síndrome de Melkersson-Rosenthal , Sarcoidose , Terapia Comportamental , Feminino , Humanos , Síndrome de Melkersson-Rosenthal/complicações , Síndrome de Melkersson-Rosenthal/diagnóstico , Síndrome de Melkersson-Rosenthal/tratamento farmacológico , Pessoa de Meia-Idade , Sarcoidose/complicações , Sarcoidose/diagnóstico , Sarcoidose/tratamento farmacológicoRESUMO
Giant cell arteritis (GCA) is a systemic granulomatous vasculitis clinically characterized by a prompt response to glucocorticoid therapy. Dendritic cells (DCs) play a central role in the pathogenesis of the disease and are increased in temporal arteries from GCA patients. The aim of this study was to determine the effects of glucocorticoid therapy on granulomatous infiltrates and on peripheral DCs of GCA patients. Immunohistochemical staining of temporal artery specimens from 41 GCA patients revealed a rapid reduction of the number of DCs after initiation of glucocorticoid treatment. TUNEL staining was performed to quantify apoptotic S100+ DC, CD3+ T cells, and CD68+ macrophages in the granulomatous infiltrates. An increase of apoptotic cells up to 9 ± 2% after 4-5 days of glucocorticoid therapy and up to 27 ± 5% (p < 0.001, compared to earlier timepoints) after 6-10 days was detected. A decrease of CCL19 and CCL21 expression was observed after starting glucocorticoid therapy. Granulocyte-macrophage colony-stimulating factor (GM-CSF) expression also significantly decreased under glucocorticoid therapy. No GM-CSF expression was detected in the control specimens. Glucocorticoid therapy leads to a rapid, time-dependent reduction of DCs in temporal arteries from GCA patients and reduction of mediators for cell migration. Our data suggest GM-CSF as a novel therapeutic target of GCA.
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Leukocyte cell-derived chemotaxin 2 (LECT2)-related amyloidosis (ALECT2) constitutes a subtype of systemic amyloidosis affecting the kidney. This is the first case describing mixed ALECT2 and Amyloid A renal amyloidosis in a Kazakh-German patient. Genetic analysis shows a polymorphism in the LECT2 gene and a homozygous mutation in the SAA1 gene. Notably, our patient has a body mass index of 61 kg/m2 and a pathological glucose tolerance test. ALECT2 was found in certain ethnic groups with a high incidence of diabetes. In our case, morbid obesity may have played a significant role in clinical manifestation of ALECT2 amyloidosis.
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OBJECTIVE: To investigate functional expression of NKG2D on CD4 and CD8 T-cells in patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR). METHODS: Peripheral blood was drawn from patients with GCA (n=16), PMR (n=78) and healthy controls (HC, n=64). Tissue samples were obtained from GCA patients and controls. Proliferation and cytokine production assays were performed using CFSE and intracellular IFN-γ or TNF-α staining, respectively, and flow cytometry analysis. Immunofluorescence and immunohistology were applied to analyse the presence of NKG2D-expressing T-cells and NKG2D-ligands in temporal arteries, respectively. mRNA levels of NKG2D-ligands were determined by RT-PCR. RESULTS: In both GCA and PMR patients, NKG2D was preferentially expressed on senescent CD4CD28(-) and CD8CD28(-), as well as on CD8CD28 T-cells. Frequencies of senescent T-cells were increased in GCA and PMR patients compared to HC. In GCA tissue samples, infiltrating T-cells were predominately CD28(-). NKG2D expressing T-cells concentrated around the vasa vasorum of the adventitia. Antigenic stimulation induced rapid up-regulation of NKG2D on CD4CD28(-) and CD4CD28 T-cells, whereas TNF-α and interleukin-15 enhanced NKG2D expression on senescent CD4 and CD8 T-cells only. NKG2D cross-linkage augmented anti-CD3 triggered proliferation, IFN-γ and TNF-α production of CD8 T-cells. In CD4CD28(-) T-cells, NKG2D ligation resulted in increased IFN-γ production only. NKG2D ligands were expressed in temporal arteries from GCA patients, particularly in the adventitial and medial layers of affected vessels. CONCLUSIONS: NKG2D is functionally expressed on CD4CD28(-) and CD8 T-cells in GCA and PMR. NKG2D-ligands are present in temporal arteries and may co-stimulate NKG2D expressing T-cells.
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Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Arterite de Células Gigantes/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Polimialgia Reumática/metabolismo , Idoso , Idoso de 80 Anos ou mais , Autoimunidade , Estudos de Casos e Controles , Senescência Celular , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interferon gama/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Artérias Temporais/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para CimaRESUMO
OBJECTIVES: The mainstay in the treatment of the large-vessel vasculitides giant cell arteritis (GCA) and Takayasu arteritis (TA) are glucocorticosteroids (GC) for induction of remission as well as for its maintenance in low doses for 1 to 2 years. However, clinical practice includes GC-resistant cases without sufficient response to standard GC for induction of remission and GC-dependent cases where a dose reduction of GC without relapse is impossible after successful induction of remission. The aim of this study was to evaluate the data on treatment options in these situations. METHODS: A literature search in PubMed matching the terms TA and GCA as well as temporal arteritis with all possible immunosuppressive and biological agents as well as with the terms 'treatment, therapy and management' was performed. RESULTS: Sixty-four publications were found. Five case series described large cohorts of patients with GCA (n=2) or TA (n=3) showing that 40.8% to 48% of GCA patients and 46% to 84% of TA patients require additional immunosuppressive agents to achieve remission and taper GC. Most were on biologic agents (mainly infliximab, 24 publications/123 patients), followed by methotrexate (MTX) (14/113), cyclophosphamide (CYC) (9/27), azathioprine (AZA) (8/51), cyclosporine A (CSA) (6/47), mycophenolate mofetil (MMF) (3/32), leflunomide (LEF) (2/2), chlorambucil (1/1) and antimalarials (1/36). There were also 2 case reports on autologous stem cell transplantation. The distribution of the two entities TA and GCA was as follows: MTX: 98% GCA, 2% TA; IFX: 26.8% GCA, 73.2% TA; CYC: 70.4% GCA, 29.6% TA; AZA: 100% GCA; LEF: 100% TA; MMF: 100% TA; antimalarials: 100% GCA, autologous stem cell transplantation: 100% TA. A distinction between GC-resistant and GC-dependent cases could not be made from the data available. However, 50 (79%) of the publications described GC-resistant cases. Whereas almost all case reports and retrospective case series (with the exception of CSA) revealed steroid-sparing effects, the 3 prospective randomised trials and 2 open prospective controlled trials on MTX gave conflicting results. However, a recent meta-analysis which recalculated the original data resulted in superiority of MTX after 24 months, there were less relapses and lower GC doses in the MTX group. The prospective controlled IFX trial where IFX was randomised against placebo after GC-induced remission of GCA did not show advantages for IFX over GC alone for maintenance of remission. The prospective controlled ETA trial, which comprised 17 GCA patients, showed small, non-significant advantages but was too small to draw definite conclusions. CONCLUSIONS: Although GCA is the commonest systemic vasculitis, prospective randomised trials on steroid sparing agents are rare and mostly included only small patient numbers. Inclusion and response criteria were heterogeneous, and observation periods and follow-up were often short. Criteria for GC-resistance or GC-dependence and for disease remission have not been uniformly defined. There is still an urgent need for prospective randomised trials with larger patient groups, longer follow-up and well defined inclusion criteria and criteria for response and relapse, using standardised disease activity scoring systems, in order to be able to give evidence-based recommendations for patients not responding to GC alone in the future.
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Resistência a Medicamentos , Arterite de Células Gigantes/tratamento farmacológico , Glucocorticoides/uso terapêutico , Imunossupressores/uso terapêutico , Arterite de Takayasu/tratamento farmacológico , Quimioterapia Combinada , Medicina Baseada em Evidências , Arterite de Células Gigantes/diagnóstico , Arterite de Células Gigantes/imunologia , Humanos , Recidiva , Indução de Remissão , Índice de Gravidade de Doença , Transplante de Células-Tronco , Arterite de Takayasu/diagnóstico , Arterite de Takayasu/imunologia , Fatores de Tempo , Resultado do TratamentoRESUMO
Psoriasis (Ps), psoriatic arthritis (PsA), and SAPHO syndrome are diseases of unknown etiology that share common clinical features; however, family studies support the hypothesis of a genetic background for each of these diseases. To study the two common single-nucleotide polymorphisms (SNP) in the murine-double-minute-2-(Mdm2) and p53 genes in patients with Ps, PsA, and SAPHO syndrome. Genomic DNA was obtained from 187 patients with Ps, 50 with PsA, and 36 with SAPHO as well as 478 healthy controls. Mdm2-gene SNP T309G and p53-gene SNP G72C genotypes were determined by the polymerase chain reaction. Genotype and allele frequencies were analyzed with chi(2)-tests. Among the patients with Ps and PsA, no differences in allele or genotype frequencies of the p53-gene SNP G72C and Mdm2-gene SNP T309G were detected. However, in the SAPHO patients group, the frequencies of the Mdm2 SNP309 G allele and the genotype SNP 309 GG were significantly increased compared with the controls (G allele: 51.4 vs. 38.7%, P = 0.034; genotype GG: 36.1 vs. 14.2%, P = 0.002). In addition, the frequencies of the p53 SNP72 C allele and the genotype SNP 72 CC were also increased in the SAPHO patients cohort (C allele: 36.1 vs. 25.6%, P = 0.05; genotype CC: 16.7 vs. 6.3%, P = 0.05). SAPHO syndrome may be linked to an imbalance between MDM2 and p53 regulation with a "weak" p53-response associated with the Mdm2 SNP 309 G allele. In contrast, the p53 network does not seem to play a major role in pathogenesis of Ps or PsA.
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Síndrome de Hiperostose Adquirida/genética , Artrite Psoriásica/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-mdm2/genética , Psoríase/genética , Proteína Supressora de Tumor p53/genética , Síndrome de Hiperostose Adquirida/metabolismo , Adolescente , Adulto , Idoso , Artrite Psoriásica/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Psoríase/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adulto JovemRESUMO
INTRODUCTION: The acronym SAPHO was introduced in 1987 to unify the various descriptions of a seronegative arthritis associated with skin manifestations and to show synovitis, acne, pustulosis, hyperostosis, and osteitis with and without sterile multifocal osteomyelitis. The etiology of SAPHO syndrome is unknown, but an association with infection by semipathogenic bacteria like Propionibacterium acnes has been suggested. We conducted an interventional study of SAPHO patients receiving antibiotics. METHODS: Thirty-seven patients met the clinical criteria of SAPHO syndrome, 21 of them underwent a needle biopsy of the osteitis lesion, and 14 of them showed positive bacteriological cultures for P. acnes. Thirty patients (14 bacteriological positive and 16 without biopsy) were treated with antibiotics for 16 weeks. The activity of skin disease and osteitis were assessed by a physician using a scoring model (from 0 to 6). In addition, patients completed a Health Assessment Score (HAS, from 0 to 6). The erythrocyte sedimentation rate was determined and a MRI (of the osteitis lesion, radiologic activity score from 0 to 2) was performed in week 1 (W1), week 16 (W16), and week 28 (W28, 12 weeks after antibiotics). RESULTS: Twenty-seven patients continued the medication (azithromycin, n = 25, 500 mg twice a week; clindamycin, n = 1, 300 mg daily; or doxycycline, n = 1, 100 mg daily) for 16 weeks. After W16 the scores for MRI (1.5 to 1.1, P = 0.01), skin activity (3.2 to 1.2, P = 0.01), osteitis activity (4.0 to 2.1, P = 0.02), and HAS (3.3 to 2.1, P = 0.01) decreased significantly. However, this was followed by increasing values for MRI scores (1.2 to 1.4, P = 0.08), skin activity (1.2 to 1.7, P = 0.11), osteitis activity (1.9 to 2.7, P = 0.01), and HAS (2.2 to 3.3, P = 0.02) from W16 to W28. The comparison of the scores in W1 and W28 in these 12 patients showed no significant differences. CONCLUSIONS: For the period of application, the antibiotic therapy seems to have controlled the disease. After antibiotic discontinuation, however, disease relapse was observed. SAPHO syndrome thus groups with other chronic inflammatory arthropathies with a need for permanent therapy.
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Síndrome de Hiperostose Adquirida/tratamento farmacológico , Síndrome de Hiperostose Adquirida/microbiologia , Antibacterianos/uso terapêutico , Infecções por Bactérias Gram-Positivas/complicações , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Adulto , Idoso , Azitromicina/uso terapêutico , Clindamicina/uso terapêutico , Doxiciclina/uso terapêutico , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Propionibacterium acnes , Resultado do Tratamento , Adulto JovemRESUMO
A total of 189 temporal artery biopsy samples from giant cell arteritis (GCA) patients were investigated using sensitive PCR targeting Chlamydia pneumoniae. Chlamydial DNA was detected in 17 samples, 11 of which were positive for chlamydial antigens. Our data did not reveal strong evidence that C. pneumoniae plays an important role in the pathogenesis of GCA.
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Infecções por Chlamydophila/complicações , Chlamydophila pneumoniae/isolamento & purificação , Arterite de Células Gigantes/etiologia , Idoso , Antígenos de Bactérias/isolamento & purificação , Chlamydophila pneumoniae/genética , DNA Bacteriano/isolamento & purificação , Feminino , Humanos , Imunoensaio/métodos , Masculino , Reação em Cadeia da Polimerase/métodosRESUMO
Interferon-gamma (IFNgamma)-mediated indoleamine 2,3-dioxygenase (IDO) expression, important in innate immunity, immune suppression, and tolerance, can be counteracted by ferrous iron (FeSO(4)). Elevation of intracellular iron levels during stimulation with IFNgamma impeded IFNgamma-induced IDO mRNA and protein expression in HEp-2 cells. Decreased IDO expression was accompanied by decreased tryptophan degradation. Accordingly, IFNgamma-mediated suppressing effects on Chlamydia trachomatis (CT) infection were reduced or even abolished in the presence of FeSO(4). Conversely, lowering intracellular iron levels by deferoxamine (DFO) did not increase IFNgamma-induced IDO expression but potentiated Chlamydia-suppressing effects by lowering intracellular iron availability. Additionally, DFO led to a CT-induced IDO expression in HEp-2 cells not treated with IFNgamma. In summary, this study demonstrates that iron acts as a regulatory element for modulating IDO expression, in addition to its function as an essential element for chlamydial growth. This may represent an important control mechanism of IDO expression at the transcriptional level.
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Infecções por Chlamydia/enzimologia , Chlamydia trachomatis/fisiologia , Regulação Enzimológica da Expressão Gênica , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Interferon gama/imunologia , Íons/metabolismo , Linhagem Celular , Infecções por Chlamydia/genética , Infecções por Chlamydia/imunologia , Infecções por Chlamydia/metabolismo , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Interferon gama/genética , Triptofano/metabolismoRESUMO
Chlamydophila pneumoniae (C. pneumoniae) has been detected in macrophages (Mø) and dendritic cells (DC) in vascular diseases. To understand the importance of these cell types in C. pneumoniae infection and transmission, we infected DC and cultivated them with Mø in a coculture model system which precludes cell-to-cell contact during chlamydial infection. C. pneumoniae inside living DC were labeled and tracked with a red fluorescent ceramide dye. Subsequently, red-coloured chlamydial inclusions were detected 3 and 5 days later in cocultured Mø. Moreover, standard assays revealed infectious elementary bodies in infected DC and cocultured Mø. Assays for chlamydial gene expression indicated vital and dividing chlamydiae in both cell types. In summary, the results suggest that the transwell system employed here is a suitable model to investigate the transmission of C. pneumoniae from DC to Mø. Importantly, the observations presented demonstrate that transmission is independent of cell-to-cell contact.