RESUMO
BACKGROUND: Human tapasin deficiency is reported to cause an autosomal-recessive inborn error of immunity characterized by substantially reduced cell surface expression of major histocompatibility complex class I (MHC-I). OBJECTIVE: We evaluated the immunologic and clinical consequences of tapasin deficiency. METHODS: A novel homozygous variant in TAPBP was identified by means of whole genome sequencing. The expression of tapasin and both subunits of the transporter associated with antigen presentation (TAP) were evaluated by Western blot analysis. Cell surface and intracellular expression of MHC-I were evaluated by flow cytometry. Small interfering RNAs were used for silencing TAPBP expression in HEK293T cells. RESULTS: We identified a deletion in TAPBP (c.312del, p.(K104Nfs∗6)) causing tapasin deficiency in a patient with bronchiectasis and recurrent respiratory tract infections as well as herpes zoster. Besides substantial reduction in TAP1 and TAP2 expression, peripheral blood mononuclear cells from this patient and TAPBP-knockdown HEK293T cells, displayed reduced cell surface expression of MHC-I, while reduction in intracellular expression of MHC-I was less prominent, suggesting a defect in MHC-I trafficking to the plasma membrane. IFN-α improved cell surface expression of MHC-I in tapasin deficient lymphocytes and TAPBP-knockdown HEK293T cells, representing a possible therapeutic approach for tapasin deficiency. CONCLUSION: Tapasin deficiency is a very rare inborn error of immunity, the pathomechanism and clinical spectrum of which overlaps with TAP deficiencies.
RESUMO
The interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a transcriptional regulator, functioning a transcriptional corepressor by interacting with the interferon regulatory factor-2. The ubiquitous expression of IRF2BP2 by diverse cell types and tissues suggests its potential involvement in different cell signalling pathways. Variants inIRF2BP2have been recently identified to cause familial common variable immunodeficiency (CVID) characterized by immune dysregulation. This study investigated three rare novel variants inIRF2BP2, identified in patients with primary antibody deficiency and autoimmunity by whole exome-sequencing (WES). Following transient overexpression of EGFP-fused mutants in HEK293 cells and transfection in Jurkat cell lines, we used fluorescence microscopy, real-time PCR and Western blotting to analyze their effects on IRF2BP2 expression, subcellular localization, nuclear translocation of IRF2, and the transcriptional activation of NFκB1(p50). We found altered IRF2BP2 mRNA and protein expression levels in the mutants compared to the wild type after IRF2BP2 overexpression. In confocal fluorescence microscopy, variants in the C-terminal RING finger domain showed an irregular aggregate formation and distribution instead of the expected nuclear localization compared to the variants in the N-terminal zinc finger domain and their wildtype counterpart. Immunoblotting revealed an impaired IRF2 and NFκB1 (p50) nuclear localization in the mutants compared to the IRF2BP2 wildtype counterpart. LPS stimulation reduced IRF2BP2 mRNA expression in the variants compared to the wild type. Our findings significantly contribute to understanding the clinical significance of IRF2BP2 mutations in the pathogenesis of immunodeficiency and immune dysregulation. We observed impairment of the nuclear translocation of IRF2 and NFκB1 (p50) due to the upregulation of IRF2BP2, potentially affecting specific gene expressions involved in immune regulation.
Assuntos
Autoimunidade , Imunodeficiência de Variável Comum , Humanos , Células HEK293 , Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/imunologia , Autoimunidade/genética , Células Jurkat , Fator Regulador 2 de Interferon/genética , Fator Regulador 2 de Interferon/metabolismo , Fator Regulador 2 de Interferon/imunologia , Masculino , Feminino , Mutação , Subunidade p50 de NF-kappa B/genética , Subunidade p50 de NF-kappa B/metabolismo , Sequenciamento do Exoma , Proteínas Correpressoras/genética , Proteínas de Ligação a DNA , Fatores de TranscriçãoRESUMO
OBJECTIVES: Early diagnosis of inflammatory arthritis is critical to prevent joint damage and functional incapacities. However, the discrepancy between recommendations of early diagnosis and reality is remarkable. The Rheuma-VOR study aimed to improve the time to diagnosis of patients with early arthritis by coordinating cooperation between primary care physicians, specialists and patients in Germany. METHODS: This prospective non-randomised multicentre study involved 2340 primary care physicians, 72 rheumatologists, 4 university hospitals and 4 rheumatology centres in 4 German Federal States. The two coprimary endpoints (time to diagnosis and screening performance of primary care physicians) were evaluated for early versus late implementation phase. Additionally, time to diagnosis and secondary endpoints (decrease of disease activity, increase in quality of life and overall well-being, improvement of fatigue, depression, functional ability, and work ability, reduction in drug and medical costs and hospitalisation) were compared with a reference cohort of the German Rheumatism Research Centre (DRFZ) reflecting standard care. RESULTS: A total of 7049 patients were enrolled in the coordination centres and 1537 patients were diagnosed with a rheumatic disease and consented to further participation. A follow-up consultation after 1 year was realised in 592 patients. The time to diagnosis endpoint and the secondary endpoints were met. In addition, the calculation of cost-effectiveness shows that Rheuma-VOR has a dominant cost-benefit ratio compared with standard care. DISCUSSION: Rheuma-VOR has shown an improvement in rheumatological care, patient-reported outcome parameters and cost savings by coordinating the cooperation of primary care physicians, rheumatologists and patients, in a nationwide approach.
Assuntos
Artrite Reumatoide , Doenças Reumáticas , Humanos , Artrite Reumatoide/diagnóstico , Qualidade de Vida , Estudos Prospectivos , Doenças Reumáticas/diagnóstico , Doenças Reumáticas/terapia , Atenção à SaúdeRESUMO
OBJECTIVES: To unveil biological milieus underlying low disease activity (LDA) and remission versus active systemic lupus erythematosus (SLE). METHODS: We determined differentially expressed pathways (DEPs) in SLE patients from the PRECISESADS project (NTC02890121) stratified into patients fulfilling and not fulfilling the criteria of (1) Lupus LDA State (LLDAS), (2) Definitions of Remission in SLE remission, and (3) LLDAS exclusive of remission. RESULTS: We analysed data from 321 patients; 40.8% were in LLDAS, and 17.4% in DORIS remission. After exclusion of patients in remission, 28.3% were in LLDAS. Overall, 604 pathways differed significantly in LLDAS versus non-LLDAS patients with an false-discovery rate-corrected p (q)<0.05 and a robust effect size (dr)≥0.36. Accordingly, 288 pathways differed significantly between DORIS remitters and non-remitters (q<0.05 and dr≥0.36). DEPs yielded distinct molecular clusters characterised by differential serological, musculoskeletal, and renal activity. Analysis of partially overlapping samples showed no DEPs between LLDAS and DORIS remission. Drug repurposing potentiality for treating SLE was unveiled, as were important pathways underlying active SLE whose modulation could aid attainment of LLDAS/remission, including toll-like receptor (TLR) cascades, Bruton tyrosine kinase (BTK) activity, the cytotoxic T lymphocyte antigen 4 (CTLA-4)-related inhibitory signalling, and the nucleotide-binding oligomerization domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome pathway. CONCLUSIONS: We demonstrated for the first time molecular signalling pathways distinguishing LLDAS/remission from active SLE. LLDAS/remission was associated with reversal of biological processes related to SLE pathogenesis and specific clinical manifestations. DEP clustering by remission better grouped patients compared with LLDAS, substantiating remission as the ultimate treatment goal in SLE; however, the lack of substantial pathway differentiation between the two states justifies LLDAS as an acceptable goal from a biological perspective.
Assuntos
Lúpus Eritematoso Sistêmico , Indução de Remissão , Transcriptoma , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Feminino , Adulto , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Estudos de CoortesRESUMO
PURPOSE: To describe the clinical characteristics of refugees with HIV from Ukraine that seek continuation of medical care in Germany. METHODS: Fourty-six refugees with HIV that had left Ukraine between 24 February and 30 December 2022 were examined. Information on patients' history was obtained using a standardized questionnaire for clinical care. Interviews were conducted in Russian during their first clinical presentation. RESULTS: Fourty-six persons (41 females and 5 males) were included and their mean age was 39.6 (±8.4) years. The mean time since HIV diagnosis was 8.0 (median, IQR 7.15) years and 70.3% of participants currently received tenfofovir-DF, lamividine and dolutegravir. Most refugees had an undetectable HIV viral load and their current mean CD4 T cell count was 702 (SD ± 289) per µL. Serology revealed previous hepatitis B infection in 50.4% without evidence for replication, with undetectable anti-hepatitis B surface antigen in the remaining refugees. Antibodies against hepatitis C were present in 23 refugees (50%), but only 10 patients had been diagnosed with hepatitis C previously. Five refugees had undergone successful antiviral treatment for hepatitis C. Detectable HCV-RNA was evident in nine patients (19.6%). Sixteen (38.6%) refugees had a positive tuberculosis (TB) interferon gamma release assay, and four were on TB treatment for previously diagnosed infection. One had been diagnosed with multidrug-resistant (MDR) TB, two with pre-extensively drug-resistant (pre-XDR) TB and two with XDR TB and were treated with combinations of second-line and novel agents according to WHO guidelines. CONCLUSIONS: Based on this preliminary analysis of a not fully representative cohort, refugees with HIV from Ukraine were young, mostly healthy females highly adherent to antiretroviral therapy. The rate of transmittable co-infections urges early diagnostic evaluation and treatment.
Assuntos
Infecções por HIV , Hepatite C , Refugiados , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Masculino , Feminino , Humanos , Adulto , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Ucrânia/epidemiologia , Tuberculose/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Hepatite C/tratamento farmacológico , Hepacivirus , Antituberculosos/uso terapêuticoRESUMO
OBJECTIVES: We investigated whether the effectiveness of upadacitinib in rheumatoid arthritis (RA) treatment is affected by baseline CRP levels in a real-world setting. METHODS: UPwArds was a prospective, non-interventional study. Patients had moderate-to-severe RA and an inadequate response or intolerance to ≥1 disease-modifying anti-rheumatic drug (DMARD). The primary endpoint was clinical remission (Clinical Disease Activity Index [CDAI] ≤2.8) at 6 months. Secondary endpoints at 12 months included clinical remission and low disease activity assessed by CDAI and Simple Disease Activity Index criteria, DAS28-CRP <2.6/≤3.2, and patient-reported outcomes. The impact of baseline CRP levels (normal vs. above the upper limit of normal [ULN]) on primary and secondary endpoints was evaluated. The effect of concomitant MTX and prior inadequate response to biologic or targeted synthetic DMARDs (b/tsDMARD-IR) on the effectiveness of upadacitinib was also assessed. Safety was evaluated through 12 months. RESULTS: 518 patients were included in the effectiveness analyses. At 6 months, 24.4% of patients achieved the primary endpoint (CDAI ≤2.8). At 12 months, similar proportions of patients with normal CRP and CRP above the ULN at baseline achieved CDAI ≤2.8 (27.3% and 29.1%) and other key secondary endpoints. The effectiveness of upadacitinib was comparable with and without concomitant MTX and in b/tsDMARD-naive and b/tsDMARD-IR patients. The safety results were consistent with the known safety profile of upadacitinib; no new safety signals were identified. CONCLUSIONS: Upadacitinib therapy was effective for RA in a real-world setting. Baseline CRP levels had no significant impact on the effectiveness of upadacitinib.
Assuntos
Antirreumáticos , Artrite Reumatoide , Compostos Heterocíclicos com 3 Anéis , Humanos , Metotrexato/uso terapêutico , Proteína C-Reativa , Estudos Prospectivos , Método Duplo-Cego , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Antirreumáticos/efeitos adversos , Resultado do TratamentoRESUMO
In recent years Janus kinase inhibitors (JAKi) have joined tumor necrosis factor inhibitors (TNFi) and interleukin (IL)-17 inhibitors (IL-17i) as approved disease modifying anti-rheumatic drugs (DMARD) for moderate to severe forms of axial spondyloarthritis (axSpA). Drug survival in axSpA patients has not been well studied in a real-world outpatient scenario since the approval of JAKi. We aimed to analyze the three drug classes based on modes of actions (MoA) for their persistence rates among German axSpA outpatients. A retrospective analysis of the RHADAR database for axSpA patients with a new initiation of TNFi, IL-17i, or JAKi treatment between January 2015 and October 2023 was conducted. Analyses included Kaplan-Meier curves and adjusted Cox regressions for drug discontinuation. 1222 new biological DMARD (TNFi [n = 954], IL-17i [n = 190]) or JAKi (n = 78) treatments were reported. The median drug survival was 31 months for TNFi, 25 for IL-17i, and 18 for JAKi. The corresponding 2-year drug survival rate was 79.6%, 72.6%, and 62.8% for TNFi, IL-17i, and JAKi, respectively. The probability for discontinuation for JAKi was significantly higher compared with TNFi (HR 1.91 [95% CI 1.22-2.99]) as well as for IL-17i compared with TNFi (HR 1.43 [95% CI 1.02-2.01]), possibly related to more frequent use of TNFis as first-line therapy. IL-17i and JAKi discontinuation probabilities were similar. Primary non-response was the reason for drug discontinuation in most cases across all MoA. TNFi treatment might persist longer than JAKi and IL-17i in German axSpA outpatients, possibly related to more severe or refractory disease in patients with JAKi-treated or IL-17i-treated axSpA.
RESUMO
Airport malaria is uncommon but increasing in Europe and often difficult to diagnose. We describe the clinical, epidemiological and environmental investigations of a cluster of airport malaria cases and measures taken in response. Three Frankfurt International Airport employees without travel histories to malaria-endemic areas were diagnosed with Plasmodium falciparum malaria in Germany in 2022. Two cases were diagnosed within 1â¯week, and the third one after 10â¯weeks. Two cases had severe disease, all three recovered fully. The cases worked in separate areas and no specific location for the transmissions could be identified. No additional cases were detected among airport employees. In June and July, direct flights from Equatorial Guinea, Nigeria and Angola and one parcel originating in Ghana arrived at Frankfurt airport. No vector-competent mosquitoes could be trapped to identify the source of the outbreak. Whole genome sequencing of P. falciparum genomes showed a high genetic relatedness between samples of the three cases and suggested the geographical origin closest to Ghana. A diagnosis of airport malaria should prompt appropriate and comprehensive outbreak investigations to identify the source and to prevent severe forms of falciparum malaria.
Assuntos
Malária Falciparum , Malária , Animais , Humanos , Aeroportos , Viagem , Malária Falciparum/diagnóstico , Malária Falciparum/epidemiologia , Malária/epidemiologia , Alemanha/epidemiologia , Plasmodium falciparum/genéticaRESUMO
BACKGROUND: Granulomatous and lymphocytic interstitial lung disease (gl-ILD) is a major cause of morbidity and mortality among patients with common variable immunodeficiency. Corticosteroids are recommended as first-line treatment for gl-ILD, but evidence for their efficacy is lacking. OBJECTIVES: This study analyzed the effect of high-dose corticosteroids (≥0.3 mg/kg prednisone equivalent) on gl-ILD, measured by high-resolution computed tomography (HRCT) scans, and pulmonary function test (PFT) results. METHODS: Patients who had received high-dose corticosteroids but no other immunosuppressive therapy at the time (n = 56) and who underwent repeated HRCT scanning or PFT (n = 39) during the retrospective and/or prospective phase of the Study of Interstitial Lung Disease in Primary Antibody Deficiency (STILPAD) were included in the analysis. Patients without any immunosuppressive treatment were selected as controls (n = 23). HRCT scans were blinded, randomized, and scored using the Hartman score. Differences between the baseline and follow-up HRCT scans and PFT were analyzed. RESULTS: Treatment with high-dose corticosteroids significantly improved HRCT scores and forced vital capacity. Carbon monoxide diffusion capacity significantly improved in both groups. Of 18 patients, for whom extended follow-up data was available, 13 achieved a long-term, maintenance therapy independent remission. All patients with relapse were retreated with corticosteroids, but only one-fifth of them responded. Two opportunistic infections were found in the corticosteroid treatment group, while overall infection rate was similar between cohorts. CONCLUSIONS: Induction therapy with high-dose corticosteroids improved HRCT scans and PFT results of patients with gl-ILD and achieved long-term remission in 42% of patients. It was not associated with major side effects. Low-dose maintenance therapy provided no benefit and efficacy was poor in relapsing disease.
Assuntos
Doenças Pulmonares Intersticiais , Humanos , Corticosteroides/uso terapêutico , Imunossupressores/uso terapêutico , Pulmão/diagnóstico por imagem , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/etiologia , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Systemic lupus erythematosus (SLE) is an autoimmune disease with variable clinical presentation and organ involvement. Early diagnosis and rapid achievement of low disease activity or remission reduces organ damage and improves prognosis. Therapeutic principles can be divided into so-called basic measures and immunosuppressive treatment. Novel drugs have been developed in recent years, with new classes of agents being added for the treatment of SLE. These include biologic therapies and approved therapeutic options for the treatment of lupus nephritis. In light of improved treatment options, good disease control can now frequently be achieved; with savings on glucocorticoids, combination therapies are increasingly being used. Of great importance is the consistent use of basic measures, which include the use of hydroxychloroquine, optimization of cardiovascular risk factors, UV protection, bone-protective measures, and the implementation of vaccinations. In the treatment of lupus nephritis, conservative therapeutic measures for nephroprotection play a crucial role in renal prognosis. Finally, non-pharmacological therapy options such as exercise therapy are of great importance for improving quality of life.
Assuntos
Medicina Baseada em Evidências , Imunossupressores , Lúpus Eritematoso Sistêmico , Humanos , Lúpus Eritematoso Sistêmico/terapia , Imunossupressores/uso terapêutico , Resultado do Tratamento , Terapia por Exercício , Hidroxicloroquina/uso terapêutico , Terapia Combinada , Antirreumáticos/uso terapêutico , Glucocorticoides/uso terapêuticoRESUMO
Sjögren's syndrome (SjS) is the most common connective tissue disease with a prevalence of 1:200. Predominantly affecting women, SjS is associated with destruction of the exocrine glands, leading to xerophthalmia and xerostomia. In over 50% of patients, there are also extraglandular manifestations, leading to multiple organ manifestations including polyneuropathies and interstitial lung disease as well as symptoms such as fatigue and arthralgia. Diagnostic procedures include biomarkers, in particular anti-SS-A/Ro antibodies, histology of salivary glands, and salivary gland sonography. There are currently no licensed immunosuppressive drugs for SjS, so current treatment is often based on off-label use of drugs. The European League Against Rheumatism (EULAR) has recently published treatment recommendations based on the prevailing organ manifestations. Several promising controlled trials with novel compounds and concepts are currently in progress.
Assuntos
Doenças Reumáticas , Síndrome de Sjogren , Humanos , Feminino , Síndrome de Sjogren/diagnóstico , Glândulas Salivares/patologia , Imunossupressores/uso terapêutico , Doenças Reumáticas/tratamento farmacológico , BiomarcadoresRESUMO
BACKGROUND: Head-to-head studies are important to select the optimal treatment in terms of efficacy and side effect profiles when several drugs are available. AIM OF THE WORK: This article describes all studies comparing the use of disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA) in head-to-head studies or in which a DMARD was at least included in an active comparison arm. RESULTS: A total of 23 studies comparing DMARDs were identified. These included comparisons of Janus kinase (JAK) inhibitors with methotrexate and with adalimumab as well as the oral surveillance study. DISCUSSION: There are already an exceptionally large number of head-to-head studies in RA, both for comparisons of efficacy and safety of DMARDs. Nevertheless, more such comparative studies are needed, for example to clarify whether adverse events of tofacitinib observed in the oral surveillance study are specific to the JAK 1/JAK 3 inhibitor or are a class effect of all JAK inhibitors.
RESUMO
Objectives There is a need for more specific biomarkers to diagnose and predict disease course in patients with axial spondyloarthritis (axSpA). This study aimed to study immunological plasma biomarkers, at different time-points in radiographic (r)-axSpA patients overall and stratified by sex and compare these biomarker pattern in r-axSpA patients concerning disease phenotypes and disease activity. Methods Plasma samples were analysed from r-axSpA patients at and prior (Pre-Backbone) inclusion in the Backbone study. Interferon gamma, interleukin-10, -17A, -17F, -22, -23, -6, MCP-1, TNF-α, VEGF-A, MIF, IgA anti-CD74, zonulin, ESR, hsCRP, white blood cell count, and blood lipids were measured. Results Biomarker pattern discriminated significantly between r-axSpA patients in Backbone and Pre-Backbone compared with controls. When stratifying by sex, it was possible to discriminate between male and female r-axSpA patients in Backbone vs controls and between male r-axSpA patients in pre-Backbone and controls. In Backbone, markers with high discriminative capacity were MIF, IgA anti-CD74, and MCP-1. In Pre-Backbone, IL-6, TNF-α, MIF, triglycerides, cholesterol, IL-10, and zonulin displayed high discriminative capacity. Conclusion Based on their temporal pattern and mutual relationship, we suggest studying MIF, IgA anti-CD74, and MCP-1 in depth, at more time points, to further elucidate disease-driving mechanisms in this complex disease.
RESUMO
[This corrects the article DOI: 10.1371/journal.ppat.1008560.].
RESUMO
BACKGROUND AND AIMS: Detection of autoantibodies is a mainstay of diagnosing autoimmune hepatitis (AIH). However, conventional autoantibodies for the workup of AIH lack either sensitivity or specificity, leading to substantial diagnostic uncertainty. We aimed to identify more accurate serological markers of AIH with a protein macroarray. APPROACH AND RESULTS: During the search for more-precise autoantibodies to distinguish AIH from non-AIH liver diseases (non-AIH-LD), IgG antibodies with binding capacities to many human and foreign proteins were identified with a protein macroarray and confirmed with solid-phase ELISAs in AIH patients. Subsequently, polyreactive IgG (pIgG) was exemplarily quantified by reactivity against human huntingtin-interacting protein 1-related protein in bovine serum albumin blocked ELISA (HIP1R/BSA). The diagnostic fidelity of HIP1R/BSA binding pIgG to diagnose AIH was assessed in a retrospective training, a retrospective multicenter validation, and a prospective validation cohort in cryoconserved samples from 1,568 adults from 10 centers from eight countries. Reactivity against HIP1R/BSA had a 25% and 14% higher specificity to diagnose AIH than conventional antinuclear and antismooth muscle antibodies, a significantly higher sensitivity than liver kidney microsomal antibodies and antisoluble liver antigen/liver pancreas antigen, and a 12%-20% higher accuracy than conventional autoantibodies. Importantly, HIP1R/BSA reactivity was present in up to 88% of patients with seronegative AIH and in up to 71% of AIH patients with normal IgG levels. Under therapy, pIgG returns to background levels of non-AIH-LD. CONCLUSIONS: pIgG could be used as a promising marker to improve the diagnostic workup of liver diseases with a higher specificity for AIH compared to conventional autoantibodies and a utility in autoantibody-negative AIH. Likewise, pIgG could be a major source of assay interference in untreated AIH.
Assuntos
Autoanticorpos/sangue , Hepatite Autoimune/diagnóstico , Imunoglobulina G/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Diagnóstico Diferencial , Feminino , Hepatite Autoimune/sangue , Hepatite Autoimune/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVES: Gut inflammation commonly occurs in axial SpA (axSpA), and is linked to disease activity and outcome. Given the role of IgA in mucosal immunity, we explored the association between anti-CD74 IgA antibodies, gut inflammation and axSpA. METHODS: Anti-CD74 IgA was measured by ELISA in serum samples of axSpA patients, fulfilling the 2009 Assessment of SpondyloArthritis international Society classification criteria. A group of fibromyalgia (FM) and RA patients served as non-inflammatory and inflammatory controls. Newly diagnosed axSpA patients underwent ileocolonoscopy; mucosal biopsies were histopathologically assessed as normal, acute or chronically inflamed. Optimal anti-CD74 IgA cut-off values were determined with a receiver operating characteristics curve. RESULTS: axSpA patients (n = 281) showed higher anti-CD74 IgA levels [mean (s.d.) 18.8 (12.4) U/ml] compared with 100 FM patients [10.9 (5.0) U/ml, P < 0.001] and 34 RA patients [13.7 (9.6) U/ml, P = 0.02]. The area under the receiver operating characteristics curve for diagnosis (axSpA vs FM) was 0.70, providing a sensitivity of 60% and specificity of 87% (cut-off 15 U/ml). Antibody concentrations were not significantly different between axSpA patients with (n = 40) and without (n = 69) gut inflammation (P = 0.83), yielding an area under the receiver operating characteristics curve of 0.51. Anti-CD74 IgA levels were not associated with degree of bone marrow oedema on MRI of the sacroiliac joints, CRP or any other disease-specific feature such as the use of NSAIDs or biological treatment. CONCLUSION: Serum anti-CD74 IgA is a potentially useful diagnostic biomarker for axSpA. However, antibody levels do not correlate with any phenotypical feature, including microscopic gut inflammation, suggesting this to be a disease-specific rather than an inflammatory marker.
Assuntos
Espondiloartrite Axial , Fibromialgia , Espondilartrite , Espondilite Anquilosante , Humanos , Espondilite Anquilosante/diagnóstico , Espondilartrite/diagnóstico , Inflamação , Imageamento por Ressonância Magnética , Imunoglobulina ARESUMO
BACKGROUND: The diagnostic yield of next-generation sequencing (NGS) technologies in the diagnosis of monogenic inborn errors of immunity (IEI) remains limited, rarely exceeding 30%. Monoallelic pathogenic germline variants in cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) result in variable immunodeficiency and immune dysregulation. The genetic diagnosis of CTLA-4 insufficiency can affect follow-up procedures and may lead to consideration of treatment with CTLA-4-Ig. OBJECTIVES: The aim of the study was to identify the genetic cause of familial immunodeficiency and immune dysregulation in cases where single nucleotide variant analysis of short-read NGS data yielded no diagnostic result. METHODS: Analysis of copy number variants (CNVs) was applied on short-read NGS data. RESULTS: We identified a novel monoallelic deletion-insertion variant in CTLA-4 (c.445_568-544delinsTTTGCGATTG) resulting in familial autoimmunity. This is the second larger scale variant in CTLA-4, which despite consistently reduced expression of CTLA-4 displayed variable expressivity, ranging from typical juvenile idiopathic arthritis to common variable immunodeficiency-like immunodeficiency. CONCLUSIONS: Our report suggests the significance of integration of CNV analysis in routine evaluation of NGS, which may increase its diagnostic yield in IEI.
Assuntos
Imunodeficiência de Variável Comum , Síndromes de Imunodeficiência , Humanos , Testes Genéticos/métodos , Antígeno CTLA-4/genética , Variações do Número de Cópias de DNA , Abatacepte/genética , Síndromes de Imunodeficiência/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Imunodeficiência de Variável Comum/genéticaRESUMO
Sjögren's syndrome (SjS) is a possible autoimmune cause of interstitial lung disease. The diagnostic pathway for SjS, however, is largely undefined in comparison to other systemic autoimmune diseases. Subjective sicca symptoms, anti-SS-A/Ro antibodies and even ANA as screening tests all have relevant limitations in sensitivity and/or specificity. Against this background, in an interdisciplinary discussion we have developed a consensus for the clarification of SjS, which is presented here for broader discussion. In addition to ANA and anti-SS-A/Ro antibodies, antibodies against alpha-fodrin should be included. Objective measures of dryness, such a Schirmer and Saxon tests are important, as is a salivary gland biopsy in the absence of typical autoantibodies.
Assuntos
Doenças Pulmonares Intersticiais , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/patologia , Anticorpos Antinucleares , Autoanticorpos , Doenças Pulmonares Intersticiais/diagnósticoRESUMO
BACKGROUND AND OBJECTIVE: The work situation is an important dimension of professional life and wellbeing, and a policy lever to strengthen recruitment and retention. This study aims to explore the work situation of physicians and residents in internal medical rheumatology, considering the impact of the coronavirus pandemic COVID-19. METHODS: A questionnaire-based online survey was conducted in early 2021 at the Hannover Medical School, supported by the German Society of Rheumatology. Target groups were all rheumatology physicians and residents in Germany. The main areas of investigation included work hours, task delegation, and collaboration; workload and mental health issues; discrimination and sexual harassment experiences; and the impact of COVID-19. Descriptive statistical analysis was performed for the standardized items and qualitative content analysis for the free-text information. RESULTS: The respondents (nâ¯= 101) expressed positive attitudes towards cooperation and task delegation to medical assistants, especially those specialized in rheumatology, while attitudes towards cooperation with GPs pointed to blockades. There was a strong mismatch between actual and desired work hours both in the group of women and in the group of men. 81% rated their workload as high or very high; every sixth rheumatologist has suffered from stress or burnout syndromes at least once in the past. Experiences of gender discrimination and sexual harassment/violence were frequently reported, mostly by women. COVID-19 was an amplifier of stress, with major stressors being digitalization and increased demand for communication and patient education. CONCLUSION: There is an urgent need to improve the work situation of rheumatologists and reduce stress and mental health risks.
Assuntos
COVID-19 , Reumatologia , Masculino , Humanos , Feminino , Reumatologistas/psicologia , Alemanha/epidemiologia , Inquéritos e QuestionáriosRESUMO
BACKGROUND: With the introduction of biologics the treatment landscape for patients with rheumatoid arthritis (RA) has rapidly expanded; however, according to German and European treatment guidelines the use of biologic disease-modifying antirheumatic drugs (bDMARD) is only indicated after insufficient response under methotrexate (MTX) doses of at least 20â¯mg/week (first-line treatment). The aim of the study was to analyze the guideline compliance of MTX prescription in the outpatient sector prior to treatment with biologics. MATERIAL AND METHODS: Claims data from the AOK Lower Saxony from 2013 to 2016 were provided for all insured patients with a diagnosis of RA and bDMARD prescription during the study period. Within a patient-specific observational period of 180 days prior to the first bDMARD prescription, the maximum prescribed MTX dosage was examined. RESULTS: Data from 90 incident and 315 prevalent RA patients were analyzed. A maximum MTX prescription of <â¯20â¯mg/week was observed in 60.0% of incident patients and in 67.0% of prevalent patients. Men had a higher mean MTX maximum dose (17.1⯱ 4.8â¯mg) than women (14.9⯱ 5.0â¯mg; pâ¯< 0.0001). Of the study population 29.6% received oral only prescriptions during the observational period. In 12.4% of patients a switch to parenteral administration was made. DISCUSSION: Targeted use of the full spectrum of therapies provided prior to initiation of bDMARD treatment may contribute to cost-effective RA care. This study showed indications for potential deficits in outpatient MTX prescription practice and can raise awareness for efficient treatment.