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2.
Int J Mol Sci ; 22(1)2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33374446

RESUMO

Adequate tissue engineered models are required to further understand the (patho)physiological mechanism involved in the destructive processes of cartilage and subchondral bone during rheumatoid arthritis (RA). Therefore, we developed a human in vitro 3D osteochondral tissue model (OTM), mimicking cytokine-induced cellular and matrix-related changes leading to cartilage degradation and bone destruction in order to ultimately provide a preclinical drug screening tool. To this end, the OTM was engineered by co-cultivation of mesenchymal stromal cell (MSC)-derived bone and cartilage components in a 3D environment. It was comprehensively characterized on cell, protein, and mRNA level. Stimulating the OTM with pro-inflammatory cytokines, relevant in RA (tumor necrosis factor α, interleukin-6, macrophage migration inhibitory factor), caused cell- and matrix-related changes, resulting in a significantly induced gene expression of lactate dehydrogenase A, interleukin-8 and tumor necrosis factor α in both, cartilage and bone, while the matrix metalloproteases 1 and 3 were only induced in cartilage. Finally, application of target-specific drugs prevented the induction of inflammation and matrix-degradation. Thus, we here provide evidence that our human in vitro 3D OTM mimics cytokine-induced cell- and matrix-related changes-key features of RA-and may serve as a preclinical tool for the evaluation of both new targets and potential drugs in a more translational setup.

3.
Clin Exp Rheumatol ; 38(6): 1056-1067, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33253107

RESUMO

OBJECTIVES: Despite availability of efficacious treatments, unmet needs still exist, preventing optimal and comprehensive management of rheumatoid arthritis (RA). Evolving the management of RA (eRA) is a European-wide educational initiative aiming to support improved patient care through practical and educational tools addressing specific unmet needs. METHODS: A multidisciplinary Steering Committee (17 members, 12 countries) identified unmet needs within the management of RA and prioritised those with the greatest impact on patient outcomes. Practical educational tools addressing priority needs were then developed for dissemination and implementation by the rheumatology community across Europe. RESULTS: Five areas of priority need were identified: increasing early recognition of RA and treatment initiation; treating RA to target; optimal, holistic approach to selection of treatment strategy, including shared decision-making; improving identification and management of comorbidities; and non-pharmacological patient management. A suite of 14 eRA tools included educational slides, best-practice guidance, self­assessment questionnaires, clinical checklists, a multidisciplinary team training exercise, an interactive patient infographic, and case scenarios. By April 2020, rheumatology professionals in 17 countries had been actively engaged in the eRA programme; in 11 countries, eRA tools were selected by national leaders in rheumatology and translated for local dissemination. A web platform, with country-specific pages, was developed to support access to the translated tools (https://www.evolvingthemanagementofra.com/). CONCLUSIONS: The eRA programme supports comprehensive management of RA across Europe through development and dissemination of practical educational tools. The eRA tools address priority needs and are available free of charge to the rheumatology community.

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.
Curr Med Res Opin ; 36(9): 1559-1567, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32609555

RESUMO

BACKGROUND: Golimumab (GLM) has shown its efficacy and safety in various clinical trials. We aimed to assess the effect of GLM on socio economic and health economic parameters in daily clinical practice. SETTING: Rheumatology offices in Germany. METHOD: Analysis of socio economic and health economic parameters of the non-interventional, multicentre, prospective study GO-NICE. Analyses were performed in an exploratory manner using descriptive statistical methods. Further, p-values on socio economic variables were calculated based on one-sample t-test on the differences between baseline and follow-up visits. RESULTS: A total of 1458 patients were evaluable, of whom a total of 664 patients completed the 24-month observation period. The proportions of hospitalizations decreased statistically significantly (p ≤ .05) from 10.4/7.6/14.0% at baseline (BL) to 1.7/2.2/0.8%, and the in-patient rehabilitations decreased from 3.3/3.7/7.5% at BL to 0.6/1.8/2.1% at month 24 in patients with RA, PsA, and AS. When considering a 30-day period, the mean number of sick leave days decreased statistically significantly (p ≤ .005) from 4.0 at BL to 0.9 at month 24 (greatest improvement in RA), and the mean number of days with impaired capability decreased statistically significantly (p ≤ .001) from 14.9 at BL to 4.5 at month 24 (greatest improvement in patients with AS). There was also a reduction in the number of consultations and remedies. CONCLUSION: This evaluation shows improvements in socio economic and health economic parameters on GLM treatment.

6.
Kidney Int ; 2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32592813

RESUMO

Systemic lupus erythematosus is a systemic and chronic autoimmune disease characterized by loss of tolerance towards nuclear antigens with autoreactive CD4+ T cells implicated in disease pathogenesis. However, very little is known about their receptor specificity since the detection of human autoantigen specific CD4+ T cells has been extremely challenging. Here we present an analysis of CD4+ T cells reactive to nuclear antigens using two complementary methods: T cell libraries and antigen-reactive T cell enrichment. The frequencies of nuclear antigen specific CD4+ T cells correlated with disease severity. These autoreactive T cells produce effector cytokines such as interferon-γ, interleukin-17, and interleukin-10. Compared to blood, these cells were enriched in the urine of patients with active lupus nephritis, suggesting an infiltration of the inflamed kidneys. Thus, these previously unrecognized characteristics support a role for nuclear antigen-specific CD4+ T cells in systemic lupus erythematosus.

7.
Thromb Res ; 191: 90-96, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32408093

RESUMO

BACKGROUND: Fibrin(ogen) derivatives, crosslinked fibrin and fibrinolysis play important roles in inflammation and are involved in pathogenesis of rheumatoid arthritis (RA). About 2/3 of RA patients exhibit anti-citrullinated protein antibodies (ACPA) that target deiminated fibrinogen. Genetic variants of ß-fibrinogen (FGB) (rs1800790G>A) and factor XIII A-subunit (F13A) Val34Leu (rs5985) are known to influence interactively inflammatory processes. It is hypothesized that predisposition for dense fibrin clots is related to better inflammation control. METHODS: To test this hypothetical model a cohort of 924 patients (288 RA and 636 non-RA patients) (3545 observations) was genotyped for FGB (rs1800790G>A, rs1800788C>T), α-fibrinogen (FGA) (rs6050A>G, rs2070006G>A, rs2070016T>C), γ-fibrinogen (FGG) (rs1049636T>C), F13A Val34Leu (rs5985) and α2-antiplasmin (A2AP) Arg6Trp (rs2070863). Genotype constellations potentially predisposing for dense fibrin clots were defined and their relation to inflammatory activity as measured by C-reactive protein (CRP) and disease activity score of 28 joints (DAS28) was assessed in univariate and multivariate analyses. The relation of these genotype constellations with presence of ACPA was tested. RESULTS: Genotype constellations involving FGB rs1800790G>A and FGA rs2070016T>C were inversely associated with CRP levels (≥10 mg/L) (OR: 0.49, P < 10-8/7adj = 0.0001; OR: 0.52, P < 0.0005/Padj = 0.01). In RA, both genotype constellations were observed with higher frequencies of low disease activity (DAS28 ≤ 3.2) (OR: 2.66, P = .009; OR 2.78, P = .01) and lower frequencies of high disease activity (DAS28>5.1) (OR: 0.52, P < .03, OR: 0.42, P = .01). Associations with CRP depended on A2AP 6Arg/Arg genotype known to be necessary for optimal anti-fibrinolytic capacity (P = .001). Finally, Genotype constellations involving FGB rs1800790G>A and FGA rs2070016T>C were found to be associated with ACPA-positivity in RA (OR: 2.18, P < .03; OR: 1.95, P = .09). CONCLUSIONS: These results support the hypothesis that genotypes, which increase fibrin clot density and anti-fibrinolytic capacity, reduce inflammatory activity and are related to humoral autoimmunity in RA.

8.
Rheumatol Ther ; 7(2): 371-382, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32303994

RESUMO

INTRODUCTION: While golimumab (GLM) has demonstrated efficacy in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) in several randomized clinical trials with biologic-naïve patients, observational data from biologic-experienced patients are sparse. We aimed to assess the effectiveness of GLM used as the first-, second-, or at least third-line biologic agent in RA, PsA, and AS patients in a real-world setting. METHODS: Post hoc analysis of the noninterventional, prospective, 24-month GO-NICE study of RA, PsA, and AS patients who initiated GLM 50 mg subcutaneously once monthly in a real-world setting in Germany. RESULTS: In 1454 patients with RA, PsA, or AS, GLM was administered as the first-line (n = 305, 286, 292, respectively), second-line (n = 104, 136, 130, respectively), or at least third-line (n = 64, 79, 58, respectively) biologic agent. In RA patients (n = 473), the time since first diagnosis was 9.7, 10.1, and 14.3 years, respectively. The DAS28 score at BL was 5.0, 4.9, and 5.1 in patients using GLM as a first-, second-, and third-line biologic agent, respectively, and dropped significantly in all groups. After 3 months of treatment, 27.5%, 19.5%, and 14.5% of patients were in remission; the corresponding values after 24 months were 45.3%, 50.0%, and 33.3%, respectively. In PsA patients (n = 501), time since fist diagnosis was 12.4, 13.7, and 13.8 years, respectively. Based on PsARC, a response was achieved at 24 months in the first-, second-, and third-line use of GLM in 76.4%, 51.0%, and 50.0% of the patients. In AS patients (n = 480), the time since first diagnosis was 9.4, 9.8, and 12.4 years in patients using GLM as the first-, second-, and at least third-line biologic agent, respectively. After 24 months of treatment, the mean BASDAI scores decreased significantly (p < 0.001 vs. BL) to 2.1, 2.9, and 2.9 in the patients using GLM as the first-, second-, and at least third-line treatment, respectively. CONCLUSIONS: Golimumab is an effective treatment in patients with RA, PsA, and AS, irrespective of any pretreatment with biologic agents. STUDY REGISTRATION: ClinicalTrials.gov NCT01313858.

10.
Int J Mol Sci ; 21(3)2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32013232

RESUMO

Both inflammatory diseases like rheumatoid arthritis (RA) and anti-inflammatory treatment of RA with glucocorticoids (GCs) or non-steroidal anti-inflammatory drugs (NSAIDs) negatively influence bone metabolism and fracture healing. Janus kinase (JAK) inhibition with tofacitinib has been demonstrated to act as a potent anti-inflammatory therapeutic agent in the treatment of RA, but its impact on the fundamental processes of bone regeneration is currently controversially discussed and at least in part elusive. Therefore, in this study, we aimed to examine the effects of tofacitinib on processes of bone healing focusing on recruitment of human mesenchymal stromal cells (hMSCs) into the inflammatory microenvironment of the fracture gap, chondrogenesis, osteogenesis and osteoclastogenesis. We performed our analyses under conditions of reduced oxygen availability in order to mimic the in vivo situation of the fracture gap most optimal. We demonstrate that tofacitinib dose-dependently promotes the recruitment of hMSCs under hypoxia but inhibits recruitment of hMSCs under normoxia. With regard to the chondrogenic differentiation of hMSCs, we demonstrate that tofacitinib does not inhibit survival at therapeutically relevant doses of 10-100 nM. Moreover, tofacitinib dose-dependently enhances osteogenic differentiation of hMSCs and reduces osteoclast differentiation and activity. We conclude from our data that tofacitinib may influence bone healing by promotion of hMSC recruitment into the hypoxic microenvironment of the fracture gap but does not interfere with the cartilaginous phase of the soft callus phase of fracture healing process. We assume that tofacitinib may promote bone formation and reduce bone resorption, which could in part explain the positive impact of tofacitinib on bone erosions in RA. Thus, we hypothesize that it will be unnecessary to stop this medication in case of fracture and suggest that positive effects on osteoporosis are likely.


Assuntos
Inibidores de Janus Quinases/farmacologia , Janus Quinases/metabolismo , Osteogênese/efeitos dos fármacos , Piperidinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Diferenciação Celular/efeitos dos fármacos , Hipóxia Celular , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Condrogênese/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Humanos , Janus Quinases/antagonistas & inibidores , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo
11.
13.
Cells ; 8(10)2019 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614462

RESUMO

An acquired deficiency of interleukin-2 (IL-2) and related disturbances in regulatory T cell (Treg) homeostasis play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Low-dose IL-2 therapy was shown to restore Treg homeostasis in patients with active SLE and its clinical efficacy is currently evaluated in clinical trials. Lupus nephritis (LN), a challenging organ manifestation in SLE, is characterized by the infiltration of pathogenic CD4+ T cells into the inflamed kidney. However, the role of the Treg-IL-2 axis in the pathogenesis of LN and the mode of action of IL-2 therapy in the inflamed kidneys are still poorly understood. Using the (NZB × NZW) F1 mouse model of SLE we studied whether intrarenal Treg are affected by a shortage of IL-2 in comparison with lymphatic organs and whether and how intrarenal T cells and renal inflammation can be influenced by IL-2 therapy. We found that intrarenal Treg show phenotypic signs that are reminiscent of IL-2 deprivation in parallel to a progressive hyperactivity of intrarenal conventional CD4+ T cells (Tcon). Short-term IL-2 treatment of mice with active LN induced an expansion the intrarenal Treg population whereas long-term IL-2 treatment reduced the activity and proliferation of intrarenal Tcon, which was accompanied by a clinical and histological amelioration of LN. The association of these immune pathologies with IL-2 deficiency and their reversibility by IL-2 therapy provides important rationales for an IL-2-based immunotherapy of LN.


Assuntos
Interleucina-2/administração & dosagem , Interleucina-2/deficiência , Rim/imunologia , Nefrite Lúpica/tratamento farmacológico , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Injeções Subcutâneas , Interleucina-2/farmacologia , Rim/efeitos dos fármacos , Nefrite Lúpica/imunologia , Camundongos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia
14.
J Dtsch Dermatol Ges ; 17(9): 913-921, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31538737

RESUMO

OBJECTIVE: Comparison of fluorescence optical imaging (FOI) with grayscale (GS) and power Doppler ultrasound (PDUS) to detect joint inflammation in patients with confirmed or suspected psoriatic arthritis (PsA). METHODS: Patients (n = 60) with psoriasis and tenderness and/or swelling of joints were separated into two groups: diagnosis confirmed by the treating dermatologist before the start of the study (n = 26), and suspected PsA (n = 34). GS/PDUS of the hand most clinically affected was performed with a dorsal/palmar view (wrist, MCP, PIP, DIP2-5). FOI examination was carried out in a standardized manner by analyzing the predefined Phases 1-3. RESULTS: FOI was found to be more sensitive than ultrasound (US) for detection of inflammation in PIP/DIP joints (p = 0.035). Confirmed PsA patients showed more findings in FOI P2 and P3, while suspected PsA patients showed more findings in P1. In the confirmed PsA group, most involved joints were MCP joints, while in the suspected PsA group, more involved wrist joints and DIP joints (p = 0.006) were detected with FOI. CONCLUSIONS: The differences between the confirmed and suspected groups indicate that FOI is helpful in the detection of early PsA since P1 may correspond to acute inflammation, whereas P2 and P3 enhancement reflect chronic inflammation. Fluorescence optical imaging might therefore be a novel diagnostic tool for early PsA diagnosis.


Assuntos
Artrite Psoriásica/diagnóstico por imagem , Adulto , Idoso , Diagnóstico Precoce , Edema/diagnóstico por imagem , Feminino , Articulações dos Dedos/diagnóstico por imagem , Dermatoses da Mão/diagnóstico por imagem , Humanos , Masculino , Microscopia de Fluorescência/métodos , Pessoa de Meia-Idade , Dor Musculoesquelética/diagnóstico por imagem , Imagem Óptica/métodos , Ultrassonografia , Articulação do Punho/diagnóstico por imagem
16.
Arthritis Res Ther ; 21(1): 209, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533820

RESUMO

BACKGROUND: Fluorescence optical imaging (FOI) enables visualization of inflammation in the hands in rheumatic joint diseases with currently a lack of long-term follow-up studies. OBJECTIVE: To investigate FOI for treatment monitoring in a homogenous cohort of patients with early (disease duration < 2 years) and active (DAS28 > 3.2) RA over a period of 12 months. METHODS: Thirty-five RA patients (24 (68.6%) females, mean age 53.3 years (SD 13.6)) were investigated clinically by DAS28, tender joint count (TJC) and swollen joint count (SJC) and by FOI in phases 1-3 and PrimaVistaMode (PVM) before therapy change and after 12 months. The FOI activity score (FOIAS) was calculated based on individual joint scores from 0 to 3 in 30 joints per patient, adding up to a sum score (0-90). RESULTS: We found a statistically significant reduction of FOIAS in phase 1 from baseline (median 5.0, IQR 24.96) to follow-up (median 1.0, IQR 4.0) in all patients (p = 0.0045), both in responders and non-responders according to EULAR response criteria by DAS28. Statistically significant reductions over 12 months were found for median DAS28(ESR) 5.61 to 3.31, TJC 7.0 to 1.0, and SJC 5.0 to 1.0 (each p <  0.001). No statistically significant correlations were detected between the FOIAS change in phase 1 and DAS28(ESR), TJC, or SJC. Correlations between the other phases and clinical outcomes were weak to moderate. CONCLUSION: Reduced early enhancement in FOI phase 1 can be observed in clinically responding and non-responding early RA patients under treatment. Regarding potential marker performance, FOI probably shows a reduction of inflammation more objectively.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico , Imagem Óptica/métodos , Idoso , Artrite Reumatoide/tratamento farmacológico , Feminino , Fluorescência , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fatores de Tempo
17.
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(3): 367-378, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30156760

RESUMO

OBJECTIVE: To evaluate ixekizumab safety in adults with psoriatic arthritis (PsA). METHODS: Safety data from 2 integrated data sets are presented: 1) 24-week, double-blind, placebo-controlled period of SPIRIT-P1 and SPIRIT-P2; and 2) all ixekizumab-treated patients of SPIRIT-P1 and SPIRIT-P2 plus SPIRIT-P3 open-label period. We report adverse event (AE) frequency and exposure-adjusted incidence rates per 100 patient-years at 12-week intervals to week 96. RESULTS: The placebo-controlled period had 678 patients (safety population): 224 placebo, 229 ixekizumab every 4 weeks, and 225 ixekizumab every 2 weeks. Overall, 1,118 patients received ixekizumab (total exposure 1,373.4 patient-years). In the placebo-controlled period, the frequencies of ixekizumab-treated patients experiencing ≥1 treatment-emergent AE (TEAE) and those experiencing serious AEs were 68.1% (56.7% placebo) and 4.4% (2.7% placebo), respectively. Injection site reactions (ISRs) were very common (21.4% ixekizumab [4.5% placebo]), with ISR discontinuation rates of 1.1% (ixekizumab) and 0.4% (placebo). Through week 96, the incidence rates of ISRs decreased with increasing ixekizumab exposure. The frequencies of AEs of special interest were 32.8% (ixekizumab) and 27.7% (placebo); for serious infections, the frequencies were 1.3% and 0%, respectively; Candida infections, 2.6% and 0.4%; confirmed major adverse cardiac events, 0% and 0%; malignancy, 0.4% and 0%; hypersensitivities, 5.3% and 1.8%; and depression-related, 1.8% and 1.3%. The frequency of Crohn's disease and ulcerative colitis (investigator-reported) was 0% in both groups, and the frequencies of sponsor-determined inflammatory bowel disease were 0.2% in the ixekizumab group and 0% in the placebo group. Overall, no active tuberculosis, invasive Candida infections, anaphylaxis, or suicide/self-injury behaviors were reported. CONCLUSION: The PsA ixekizumab safety integrated data set reached 1,373.4 patient-years total exposure. Ixekizumab-treated patients had higher rates of overall TEAEs, serious infections, mucocutaneous Candida, hypersensitivities (non-anaphylactic), and ISRs than placebo-treated patients. No unexpected safety outcomes were reported.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Psoriásica/diagnóstico , Artrite Psoriásica/tratamento farmacológico , Ensaios Clínicos Fase III como Assunto/métodos , Fármacos Dermatológicos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Candidíase/induzido quimicamente , Candidíase/diagnóstico , Fármacos Dermatológicos/efeitos adversos , Método Duplo-Cego , Hipersensibilidade a Drogas/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto/métodos
19.
Semin Arthritis Rheum ; 48(6): 976-982, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30316460

RESUMO

OBJECTIVE: To investigate the impact of indicators of unfavorable prognosis ("poor prognostic factors") on the achievement of low disease activity (LDA)/remission in patients with rheumatoid arthritis (RA). METHODS: Biologic DMARD-naïve patients with RA from three observational cohorts were examined. N = 713 patients started their 1st csDMARD, n = 1613 switched to the 2nd csDMARD and n = 388 to the 1st TNF-inhibitor. High disease activity (DAS28 > 5.1), autoantibodies (RF/ACPA positive), prevalent erosions, functional limitation (HAQ ≥ 1.2), comorbidities, obesity (BMI > 30 kg/m2), and smoking were evaluated as prognostic factors. Generalized regression analyses were applied to investigate prognostic factors regarding the achievement of LDA (DAS28 < 3.2) or remission (DAS28 < 2.6) within six months. RESULTS: At baseline, RF/ACPA positivity was most frequent in all cohorts (60.3-75.3%), followed by DAS28 > 5.1 (35-57.7%), HAQ ≥ 1.2 (40.5-52.5%), ≥ 2 comorbidities (31.4-54.1%) and erosions (17.1-46.1%). Remission was achieved by 39% (1st-csDMARD), 26% (2nd-csDMARD) and 30% (1st-TNFi). In adjusted regression models DAS28 > 5.1 (OR: 0.41 [0.30;0.56]), HAQ ≥ 1.2 (0.56 [0.42;0.74]), current smoking (0.72 [0.53;0.97], obesity (0.66 [0.49;0.89] and ≥ 2 comorbidities (0.57 [0.40;0.80]) were independently associated with a lower chance to achieve remission within six months (ORs for 2nd-csDMARD). The proportion of patients in LDA/remission declined by 6-12%-points if DAS28 > 5.1 was present at baseline and by 15-27%-points if functional limitation, comorbidities and obesity were additionally present. In all cohorts RF/ACPA positivity and erosions were not associated with achieving LDA/remission. CONCLUSIONS: While RF/ACPA status and erosions do not affect the achievement of LDA/remission, high disease activity, functional limitation, comorbidities and obesity should be considered as unfavorable prognostic factors in patients starting the 1st or 2nd DMARD strategy.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Tomada de Decisão Clínica , Adulto , Idoso , Artrite Reumatoide/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Índice de Gravidade de Doença , Fumar , Resultado do Tratamento
20.
Sarcoidosis Vasc Diffuse Lung Dis ; 36(4): 274-284, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32476963

RESUMO

Objective: To identify serum cytokines which predict mortality and/or disease progression in patients with systemic sclerosis, especially with pulmonary involvement. Methods: Serum cytokines (IL-6, IL-7, IL-8, IL-10, CCL2, CCL4, TGF-ß, TNF-α) were measured in 125 SSc patients, who were recruited and observed in our outpatient clinic. Of these, 60 had pulmonary involvement, classified as either interstitial lung disease (ILD, 43 patients), pulmonary arterial hypertension (PAH, 7 patients) or pulmonary hypertension and ILD (PH-ILD, 10 patients). The association of serum cytokines with clinical features was analysed and their correlation with BAL cytokines measured in a subset of SSc patients with ILD. Results: Serum cytokines were detected at different levels: high (TGF-ß, median 287.5 pg/ml; CCL2, median 89.7 pg/ml; CCL4, median 104.2 pg/ml), low (IL-6, median 3.2 pg/ml; IL-7 median 2.3 pg/ml; IL-8, median 5.2 pg/ml; TNF-α, median 0 pg/ml but with a bimodal distribution) and very low (IL-10, median 0.4 pg/ml). IL-6 and IL-7 were predictive for death in a Cox regression analysis in all SSc patients as well as in all patients with pulmonary involvement; IL-6 was predictive for mortality in SSc-ILD patients. In a multivariate analysis, cytokine levels could also predict a change in lung function, e.g. IL-7 was a predictor for a decline of diffusion capacity (DLCO) by 20 or 30% in ILD patients. In a subset of ILD patients, serum cytokines were compared to BAL cytokines, but revealed only few correlations. Conclusion: In conclusion, the analysis of serum cytokines implicates a role as biomarkers, distinct from BAL.


Assuntos
Citocinas/sangue , Doenças Pulmonares Intersticiais/sangue , Hipertensão Arterial Pulmonar/sangue , Escleroderma Sistêmico/sangue , Adulto , Idoso , Biomarcadores/sangue , Progressão da Doença , Feminino , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/mortalidade , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/imunologia , Hipertensão Arterial Pulmonar/mortalidade , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/mortalidade
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