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1.
J Clin Immunol ; 41(3): 585-594, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33403468

RESUMO

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.

2.
Front Immunol ; 11: 572475, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042152

RESUMO

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 (n = 40), the phenotypic analysis of RA patients (n = 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+ (p < 0.0001) and Ki-67+ (p < 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, in vivo 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 in vivo.

3.
Arthritis Res Ther ; 22(1): 183, 2020 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-32771029

RESUMO

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.

4.
Clin Exp Rheumatol ; 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32662413

RESUMO

OBJECTIVES: We aimed to measure long-term effectiveness and safety of tocilizumab in patients with rheumatoid arthritis in daily German practice. METHODS: ICHIBAN was a prospective, multi-centre, non-interventional study (ML22928) that enrolled adult patients with active moderate to severe rheumatoid arthritis. Patients were to be treated according to tocilizumab label and observed for up to two years. Effectiveness outcomes included DAS28-ESR remission, EULAR response, CDAI and HAQ. RESULTS: Overall, 3164 patients received at least one dose of tocilizumab. Patient mean age was 55.5±13.1 years (74.8% female). At baseline, 72.1% of patients had at least one comorbidity. Approximately 50.9% of patients received concomitant csDMARDs, mostly methotrexate, and 80.7% received concomitant glucocorticoids (GCs). In patients receiving GCs at baseline, the mean dose decreased from 9.32±16.36 mg/d to 4.60±4.48 mg/d at week 104. In the effectiveness population with no prior TCZ (n=2902), 61.4% of patients achieved the primary outcome, DAS28-ESR remission. Improvements were seen as early as week 4. At week 104, 77.9% of patients had DAS28-ESR low disease activity, 89.6% achieved good or moderate EULAR response, and 29.5% achieved a CDAI-based remission. Effectiveness outcomes were similar in all previous therapy subgroups. The incidence of serious infections was similar to the rates in former studies involving tocilizumab. Patients receiving GC at baseline experienced slightly higher rates of treatment-related serious adverse events, mainly infections. No new safety signals were observed. CONCLUSIONS: Long-term effectiveness and safety in ICHIBAN were in line with previously reported tocilizumab efficacy and safety studies.

5.
Front Immunol ; 11: 1317, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32670291

RESUMO

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.

6.
Artigo em Inglês | MEDLINE | ID: mdl-32699904

RESUMO

OBJECTIVES: This report provides data for the extent of B cell depletion and recovery, efficacy, safety and immunogenicity of Sandoz rituximab (SDZ-RTX; GP2013; Rixathon®) compared with reference rituximab (Ref-RTX) up to week 52 of the ASSIST-RA study. METHODS: Patients were randomized to SDZ-RTX or Ref-RTX in combination with methotrexate according to the RTX label. The primary endpoint was analysed at week 24. Responders (28-joint DAS [DAS28] decrease from baseline >1.2) at week 24 with residual disease activity (DAS28 ≥2.6) were eligible for a second treatment course between week 24 and 52. Endpoints after week 24 included change from baseline in peripheral B cells, DAS28, ACR 20% response rate (ACR20), Clinical and Simplified Disease Activity Indexes (CDAI, SDAI) and HAQ disability index (HAQ-DI). Safety and immunogenicity were assessed by the incidence of adverse events and antidrug antibodies. RESULTS: Primary and secondary endpoints up to week 24 were met. Overall, 260/312 randomized patients completed treatment up to week 52. SDZ-RTX resulted in B cell concentrations over time similar to Ref-RTX. The efficacy of SDZ-RTX was similar to Ref-RTX up to week 52, as measured by DAS28, ACR20/50/70, CDAI, SDAI and HAQ-DI. Safety of SDZ-RTX was similar to Ref-RTX regarding frequency, type and severity of adverse events, which were consistent with the known Ref-RTX safety profile. The incidence of antidrug antibodies was low and transient similarly across treatment groups. CONCLUSION: SDZ-RTX demonstrated similar B cell concentrations over time, efficacy, safety and immunogenicity to Ref-RTX over 52 weeks of the ASSIST-RA study.

7.
Clin Rheumatol ; 39(8): 2491, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32474886

RESUMO

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.].

8.
Medicine (Baltimore) ; 99(19): e20201, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32384515

RESUMO

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.


Assuntos
Adalimumab/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Metotrexato/uso terapêutico , Adalimumab/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/complicações , Produtos Biológicos , Progressão da Doença , Esquema de Medicação , Quimioterapia Combinada , Feminino , Nível de Saúde , Humanos , Masculino , Metotrexato/administração & dosagem , Dor/etiologia , Estudos Retrospectivos , Índice de Gravidade de Doença
9.
Clin Exp Rheumatol ; 38 Suppl 125(3): 59-64, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32301433

RESUMO

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.


Assuntos
Lúpus Eritematoso Sistêmico , Escleroderma Sistêmico , Feminino , Humanos , Estudos Prospectivos , Comportamento Sexual , Inquéritos e Questionários
10.
Clin Rheumatol ; 39(9): 2583-2592, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32206973

RESUMO

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.

11.
BMC Rheumatol ; 3: 51, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31867564

RESUMO

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-dcrit) 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-dcrit, 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-dcrit was calculated as an improvement (decrease) from baseline of 0.68 in a discovery cohort (N = 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 (N = 2740), 22.1% of patients achieved a HAQ-DI-dcrit 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-dcrit 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-dcrit 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).

12.
Eur J Dermatol ; 29(5): 468-476, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31789272

RESUMO

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.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Citocinas/biossíntese , Receptores CCR7/genética , Escleroderma Sistêmico/imunologia , Ilhas de CpG/genética , Metilação de DNA , Fator de Transcrição GATA3/genética , Expressão Gênica , Humanos , Antígenos Comuns de Leucócito/imunologia , Linfopenia/imunologia , Fator de Transcrição STAT4/genética , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/metabolismo , Proteínas com Domínio T/genética , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th2/imunologia
13.
Arthritis Res Ther ; 21(1): 106, 2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036055

RESUMO

BACKGROUND: Autologous hematopoietic stem cell transplantation (aHSCT) is performed in patients with aggressive forms of systemic sclerosis (SSc). The profile of B cell reconstitution after aHSCT is not fully understood. The aim of this study was to investigate changes of B cell subsets and cytokine production of B cells in patients with SSc after aHSCT. METHODS: Peripheral blood of six patients with SSc was collected at defined intervals up to 16 months after aHSCT. Immunophenotyping was performed, and B cell function was determined by measuring cytokine secretion in supernatants of stimulated B cell cultures. RESULTS: Within 1 month after aHSCT, a peak in the percentage of CD38++/CD10+/IgD+ transitional B cells and CD38++/CD27++/IgD- plasmablasts was detected. Long-term changes persisted up to 14 months after aHSCT and showed an increased percentage of total B cells; the absolute B cell number did not change significantly. Within the B cell compartment, an increased CD27/IgD+ naïve B cell percentage was found whereas decreased percentages of CD27+/IgD+ pre-switched memory, CD27+/IgD- post-switched memory, and CD27-/IgD- double-negative B cells were seen after aHSCT. Cytokine secretion in B cell cultures showed significantly increased IL-10 concentrations 13 to 16 months after aHSCT. CONCLUSION: A changed composition of the B cell compartment is present for up to 14 months after aHSCT indicating positive persisting effects of aHSCT on B cell homeostasis. The cytokine secretion profile of B cells changes in the long term and shows an increased production of the immune regulatory cytokine IL-10 after aHSCT. These findings might promote the clinical improvements after aHSCT in SSc patients.


Assuntos
Subpopulações de Linfócitos B/imunologia , Citocinas/imunologia , Transplante de Células-Tronco Hematopoéticas/tendências , Homeostase/fisiologia , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/terapia , Adulto , Subpopulações de Linfócitos B/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Citocinas/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Escleroderma Sistêmico/sangue , Transplante Autólogo/tendências , Adulto Jovem
14.
PLoS One ; 14(5): e0217412, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31136632

RESUMO

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).


Assuntos
Artrite Reumatoide/psicologia , Depressão/epidemiologia , Idoso , Artrite Reumatoide/epidemiologia , Comorbidade , Estudos Transversais , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários
15.
Rheumatology (Oxford) ; 58(11): 2051-2060, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31106368

RESUMO

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.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Linfócitos T CD4-Positivos/imunologia , Herpesvirus Humano 3/imunologia , Imunidade Celular/efeitos dos fármacos , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Artrite Reumatoide/imunologia , Artrite Reumatoide/virologia , Linfócitos T CD4-Positivos/virologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Interferon gama/metabolismo , Lectinas Tipo C/metabolismo , Receptores CCR5 , Receptores CXCR3/metabolismo , Células Th1/imunologia
16.
Clin Exp Rheumatol ; 37(6): 937-945, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31025930

RESUMO

OBJECTIVES: To evaluate early and late responses in biological-naïve patients with rheumatoid arthritis (RA) initiating tocilizumab and early tocilizumab non-responders who switched to rituximab. METHODS: In this open-label, non-randomised phase 3 study, RA patients with inadequate response to conventional synthetic DMARDs received tocilizumab 8 mg/kg intravenously at study begin and weeks 4, 8 and 12. After evaluation at week 16, early responders (Disease Activity Score based on 28 joints-erythrocyte sedimentation rate [DAS28-ESR] <2.6) completed the study; partial responders (DAS28-ESR decrease >1.2 or DAS28-ESR ≥2.6-≤3.2) were to continue tocilizumab through week 28; non-responders (DAS28-ESR decrease ≤1.2) switched to rituximab (1000 mg, weeks 16 and 18) with safety follow-up through week 66. RESULTS: Of 519 patients, 222 (42.8%) achieved early DAS28-ESR remission at week 16; 240 patients continued treatment, 213 (41.0%) received tocilizumab, and 27 (5.2%) switched to rituximab. At week 32 DAS28-ESR remission was achieved by 117/213 patients (54.9%) who continued tocilizumab and 4/27 patients (14.8%) who switched to rituximab; good EULAR response was achieved by 66.7% and 25.9% and CDAI remission by 19.2% and 14.8% of patients, respectively. Serious adverse events occurred through week 32 in 45/490 patients (9.2%) who received tocilizumab (serious infections, 2.7%) and through week 66 in 8/27 patients (29.6%) who switched to rituximab. CONCLUSIONS: Early response to tocilizumab was observed in 42.8% of patients. Half of early partial responders benefitted from continuing tocilizumab. Switching non-responders to rituximab seems feasible. No new safety signals were observed in patients treated with tocilizumab or switched to rituximab.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos , Artrite Reumatoide , Rituximab/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Método Duplo-Cego , Humanos , Indução de Remissão , Resultado do Tratamento
18.
Arthritis Care Res (Hoboken) ; 71(1): 88-94, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30295429

RESUMO

OBJECTIVE: Comparable clinical efficacy of the rituximab (RTX) biosimilar GP2013 and reference RTX has been established in blinded randomized trials. However, when switching from a reference biologic to a biosimilar, potential safety implications are often an important consideration. Therefore, the aim of this study was to evaluate the safety of switching from reference RTX to RTX biosimilar GP2013 compared with treatment continuation with reference RTX in patients with rheumatoid arthritis (RA). METHODS: In this multinational, randomized, double-blind, parallel-group safety study, 107 patients with RA who had previously received treatment (of any duration) with reference RTX as part of routine practice and who required continuation of treatment were randomized to receive either GP2013 or to continue treatment with reference RTX. All patients received a stable dosage of methotrexate and folic acid during the study. Study assessments included the incidence of hypersensitivity, infusion-related and anaphylactic reactions, immunogenicity (antidrug antibodies), and general safety. RESULTS: Regardless of whether patients switched to GP2013 or continued treatment with reference RTX, the incidences of hypersensitivity (9.4% and 11.1%, respectively) and infusion-related reactions (11.3% and 18.5%, respectively) were similarly low. Only 1 patient (in the reference RTX group) developed antidrug antibodies to RTX after starting study treatment. No neutralizing antidrug antibodies were observed. Antidrug antibodies were not associated with adverse events (AEs). No clinically meaningful differences in the rate of AEs were observed between treatment groups. CONCLUSION: No safety risks were detected when patients switched from reference RTX to GP2013. The safety profiles of patients in both treatment groups were similar, although the study was not powered for statistical testing of equivalence in safety.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Medicamentos Biossimilares/administração & dosagem , Substituição de Medicamentos/métodos , Internacionalidade , Rituximab/administração & dosagem , Adolescente , Adulto , Idoso , Anafilaxia/induzido quimicamente , Antirreumáticos/efeitos adversos , Artrite Reumatoide/epidemiologia , Medicamentos Biossimilares/efeitos adversos , Método Duplo-Cego , Substituição de Medicamentos/efeitos adversos , Substituição de Medicamentos/tendências , Feminino , Humanos , Fenômenos Imunogenéticos/efeitos dos fármacos , Fenômenos Imunogenéticos/fisiologia , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Rituximab/efeitos adversos , Adulto Jovem
19.
J Rheumatol ; 46(5): 460-466, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30504510

RESUMO

OBJECTIVE: To analyze the effect of a risk-stratified disease-modifying antirheumatic drug (DMARD)-tapering algorithm based on multibiomarker disease activity (MBDA) score and anticitrullinated protein antibodies (ACPA) on direct treatment costs for patients with rheumatoid arthritis (RA) in sustained remission. METHODS: The study was a posthoc retrospective analysis of direct treatment costs for 146 patients with RA in sustained remission tapering and stopping DMARD treatment, in the prospective randomized RETRO study. MBDA scores and ACPA status were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and direct treatment costs were evaluated every 3 months. MBDA and ACPA status were used as predictors creating a risk-stratified tapering algorithm based on relapse rates. RESULTS: RA patients with a low MBDA score (< 30 units) and negative ACPA showed the lowest relapse risk (19%), while double-positive patients showed high relapse risk (61%). In ACPA-negative and MBDA-negative (< 30 units), and ACPA or MBDA single-positive (> 30 units) groups, DMARD tapering appears feasible. Considering only patients without flare, direct costs for synthetic and biologic DMARD in the ACPA/MBDA-negative and single positive groups (n = 41) would have been €372,245.16 for full-dose treatment over 1 year. Tapering and stopping DMARD in this low-risk relapse group allowed a reduction of €219,712.03 of DMARD costs. Average reduction of DMARD costs per patient was €5358.83. CONCLUSION: Combining MBDA score and ACPA status at baseline may allow risk stratification for successful DMARD tapering and cost-effective use of biologic DMARD in patients in deep remission as defined by the 28-joint count Disease Activity Score using erythrocyte sedimentation rate.


Assuntos
Antirreumáticos/economia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Autoanticorpos/análise , Análise Custo-Benefício , Adulto , Algoritmos , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Biomarcadores/análise , Estudos de Coortes , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Indução de Remissão , Estudos Retrospectivos , Índice de Gravidade de Doença
20.
PLoS One ; 13(12): e0208225, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30507970

RESUMO

BACKGROUND & AIMS: Serum interferon-gamma-inducible protein-10 (IP-10) is elevated in cholestatic liver diseases and predicts response to antiviral therapy in patients with chronic hepatitis C virus (HCV) infection. Dipeptidylpeptidase 4 (DPPIV) cleaves active IP-10 into an inactive form, which inhibits recruitment of CXCR3+ T cells to the liver. In this study the link between IP-10 levels, DPPIV activity in serum and CXCR3+ T cells is analysed in cholestatic and non-cholestatic liver patients. METHODS: In serum DPPIV activity (by enzymatic assay), IP-10 (by ELISA) and bile acids (BA) (by enzymatic assay) were analysed in 229 naive HCV genotype (GT) 1 patients and in 16 patients with cholestatic liver disease. In a prospective follow-up (FU) cohort of 27 HCV GT 1 patients peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ cells were measured by FACS. RESULTS: In 229 HCV patients serum IP-10 levels correlated positively to DPPIV serum activity. Higher IP-10 levels and DPPIV activity were detected in cholestatic and in cirrhotic HCV patients. Increased IP-10 serum levels were associated with therapeutic non-response to antiviral treatment with pegylated-interferon and ribavirin. In the HCV FU cohort elevated IP-10 serum levels and increased BA were associated with higher frequencies of peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ T cells. Positive correlation between serum IP-10 levels and DPPIV activity was likewise validated in patients with cholestatic liver diseases. CONCLUSIONS: A strong correlation between elevated serum levels of IP-10 and DPPIV activity was seen in different cholestatic patient groups. Furthermore, in cholestatic HCV patients a functional link to increased numbers of peripheral CXCR3+ immune cells could be observed. The source of DPPIV release in cholestatic patients remains open.


Assuntos
Quimiocina CXCL10/sangue , Colestase/sangue , Dipeptidil Peptidase 4/sangue , Hepatite C/sangue , Receptores CXCR3/metabolismo , Linfócitos T/metabolismo , Ácidos e Sais Biliares/sangue , Complexo CD3/metabolismo , Antígenos CD4/metabolismo , Colestase/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Hepatite C/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , Masculino
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