RESUMO
OBJECTIVE: To develop recommendations for cardiovascular risk (CVR) management in gout, vasculitis, systemic sclerosis (SSc), myositis, mixed connective tissue disease (MCTD), Sjögren's syndrome (SS), systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). METHODS: Following European League against Rheumatism (EULAR) standardised procedures, a multidisciplinary task force formulated recommendations for CVR prediction and management based on systematic literature reviews and expert opinion. RESULTS: Four overarching principles emphasising the need of regular screening and management of modifiable CVR factors and patient education were endorsed. Nineteen recommendations (eleven for gout, vasculitis, SSc, MCTD, myositis, SS; eight for SLE, APS) were developed covering three topics: (1) CVR prediction tools; (2) interventions on traditional CVR factors and (3) interventions on disease-related CVR factors. Several statements relied on expert opinion because high-quality evidence was lacking. Use of generic CVR prediction tools is recommended due to lack of validated rheumatic diseases-specific tools. Diuretics should be avoided in gout and beta-blockers in SSc, and a blood pressure target <130/80 mm Hg should be considered in SLE. Lipid management should follow general population guidelines, and antiplatelet use in SLE, APS and large-vessel vasculitis should follow prior EULAR recommendations. A serum uric acid level <0.36 mmol/L (<6 mg/dL) in gout, and disease activity control and glucocorticoid dose minimisation in SLE and vasculitis, are recommended. Hydroxychloroquine is recommended in SLE because it may also reduce CVR, while no particular immunosuppressive treatment in SLE or urate-lowering therapy in gout has been associated with CVR lowering. CONCLUSION: These recommendations can guide clinical practice and future research for improving CVR management in rheumatic and musculoskeletal diseases.
Assuntos
Síndrome Antifosfolipídica , Doenças Cardiovasculares , Gota , Lúpus Eritematoso Sistêmico , Doença Mista do Tecido Conjuntivo , Doenças Musculoesqueléticas , Miosite , Doenças Reumáticas , Escleroderma Sistêmico , Síndrome de Sjogren , Vasculite , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/tratamento farmacológico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Gota/complicações , Fatores de Risco de Doenças Cardíacas , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Doença Mista do Tecido Conjuntivo/complicações , Doenças Reumáticas/complicações , Doenças Reumáticas/tratamento farmacológico , Fatores de Risco , Escleroderma Sistêmico/complicações , Síndrome de Sjogren/complicações , Ácido Úrico , Vasculite/complicaçõesRESUMO
Three prospective controlled clinical trials and numerous small series and case reports have confirmed that durable, drug-free remission in systemic sclerosis is possible via an autologous hematopoietic stem cell transplantation. Similar results have been seen in other autoimmune diseases. The exact mechanism by which this immune "reset" was achieved in some but not all cases remains elusive, but includes major reduction of autoreactive immune competent cells, re-establishment of T- and B cell regulatory networks and normalization of tissue niche function, particularly vascular. Some aspects regarding mobilization, conditioning and graft manipulation still remain open, but clearly a significant toxicity is associated with all effective regimens at present, and therefore patient selection remains a key issue. In the hematology/oncology arena, major efforts are being made to reduce genotoxic and other collateral toxicity induced by current mobilization and conditioning protocols, which may also translate to autoimmune disease. These include developments in rapid mobilization and antibody drug conjugate conditioning technology. If effective, such low-toxicity regimens might be applied to autoimmune disease at an earlier stage before chronicity of autoimmunity has been established, thus changing the therapeutic paradigm.
Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Imunoconjugados/uso terapêutico , Escleroderma Sistêmico/terapia , Condicionamento Pré-Transplante/métodos , Ensaios Clínicos Controlados como Assunto , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estudos Prospectivos , Escleroderma Sistêmico/imunologia , Transplante Autólogo/efeitos adversos , Transplante Autólogo/métodos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/métodos , Resultado do TratamentoRESUMO
PURPOSE OF REVIEW: To summarize the current clinical experience in the use of autologous hematopoietic stem cell transplantation (HSCT) in autoimmune disease and to explore the concept of durable remission induction and tissue de-remodeling via restoration of normal niche function and "immune reset.' RECENT FINDINGS: Controlled clinical trials in systemic sclerosis, multiple sclerosis, and Crohn's disease as well as extensive uncontrolled trial and registry data have established the unique role of HSCT in selected cases. Although HSCT for multiple sclerosis and systemic sclerosis has recently entered several official treatment guidelines, mechanistic studies are few but indicate some possible modes of action, for example, increase of regulatory T cells. Toxicity of HSCT remains high but is improving with protocol modifications and more precise patient selection. SUMMARY: For the first time, it has been demonstrated that strategies exist which may permanently reprogram an autoaggressive immune system to one of self-tolerance independent of ongoing immunosuppression. In addition, some tissues have the capacity to repair damage via normal regenerative processes. The exact mechanism(s) as to how this is achieved in certain cases and not others are emerging. Such knowledge, together with adoption of recently developed less toxic and more targeted regimens from the hematology/oncology field may translate to a safer yet still effective treatment for autoimmune disease.
Assuntos
Doenças Autoimunes/terapia , Transplante de Células-Tronco Hematopoéticas , Terapia de Imunossupressão , HumanosRESUMO
The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.
Assuntos
Gastroenteropatias/terapia , Hipertensão Pulmonar/terapia , Nefropatias/terapia , Doença de Raynaud/terapia , Escleroderma Sistêmico/terapia , Úlcera/terapia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Técnica Delphi , Antagonistas dos Receptores de Endotelina/uso terapêutico , Europa (Continente) , Dedos , Fluoxetina/uso terapêutico , Gastroenteropatias/etiologia , Glucocorticoides/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Hipertensão Pulmonar/etiologia , Nefropatias/etiologia , Pneumopatias/etiologia , Pneumopatias/terapia , Inibidores da Fosfodiesterase 5/uso terapêutico , Prostaglandinas I/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Doença de Raynaud/etiologia , Reumatologia , Escleroderma Sistêmico/complicações , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Úlcera/etiologiaRESUMO
Since the start of the international stem cell transplantation project in 1997, over 2000 patients have received a haematopoietic stem cell transplant (HSCT), mostly autologous, as treatment for a severe autoimmune disease, the majority being multiple sclerosis (MS), systemic sclerosis (SSc) and Crohn's disease. There was an overall 85% 5-year survival and 43% progression-free survival. Around 30% of patients in all disease subgroups had a complete response, often durable despite full immune reconstitution. In many cases, e.g. systemic sclerosis, morphological improvement such as reduction of skin collagen and normalization of microvasculature was documented, beyond any predicted known effects of intense immunosuppression alone. It is hoped that the results of the three running large prospective randomized controlled trials will allow modification of the protocols to reduce the high transplant-related mortality which relates to regimen intensity, age of patient, and comorbidity. Mesenchymal stromal cells (MSC), often incorrectly called stem cells, have been the intense focus of in vitro studies and animal models of rheumatic and other diseases over more than a decade. Despite multiple plausible mechanisms of action and a plethora of positive in vivo animal studies, few randomised controlled clinical trials have demonstrated meaningful clinical benefit in any condition so far. This could be due to confusion in cell product terminology, complexity of clinical study design and execution or agreement on meaningful outcome measures. Within the rheumatic diseases, SLE and rheumatoid arthritis (RA) have received most attention. Uncontrolled multiple trial data from over 300 SLE patients have been published from one centre suggesting a positive outcome; one single centre comparative study in 172 RA was positive. In addition, small numbers of patients with Crohn's disease, multiple sclerosis, primary Sjögren's disease, polymyositis/dermatomyositis and type II diabetes mellitus have received MSC therapeutically. The possible reasons for this apparent mismatch between expectation and clinical reality will be discussed.
Assuntos
Doenças Autoimunes/cirurgia , Transplante de Células-Tronco Mesenquimais , Transplante de Células-Tronco , Transplante de Células-Tronco Hematopoéticas , Humanos , Doenças Reumáticas/cirurgiaRESUMO
IMPORTANCE: Case reports and series suggest hematopoietic stem cell transplantation (HSCT) may benefit some patients with Crohn disease. OBJECTIVE: To evaluate the effect of autologous HSCT on refractory Crohn disease. DESIGN, SETTING, AND PARTICIPANTS: Parallel-group randomized clinical trial conducted in 11 European transplant units from July 2007 to September 2011, with follow-up through March 2013. Patients were aged 18 to 50 years with impaired quality of life from refractory Crohn disease not amenable to surgery despite treatment with 3 or more immunosuppressive or biologic agents and corticosteroids. INTERVENTIONS: All patients underwent stem cell mobilization before 1:1 randomization to immunoablation and HSCT (n = 23) or control treatment (HSCT deferred for 1 year [n = 22]). All were given standard Crohn disease treatment as needed. MAIN OUTCOMES AND MEASURES: Sustained disease remission at 1 year, a composite primary end point comprising clinical remission (Crohn Disease Activity Index (CDAI) <150 [range, 0-600]), no use of corticosteroids or immunosuppressive or biologic drugs for at least the last 3 months, and no endoscopic or radiological evidence of active (erosive) disease anywhere in the gastrointestinal (GI) tract. Secondary outcomes were individual components of the primary composite outcome and other measures of disease activity, laboratory results, quality of life and functional status, and GI tract imaging. RESULTS: Twenty-three patients underwent HSCT and 22 received standard Crohn disease treatment (controls). Sustained disease remission was achieved in 2 patients undergoing HSCT (8.7%) vs 1 control patient (4.5%) (absolute difference, 4.2% [95% CI, -14.2% to 22.6%]; P = .60). Fourteen patients undergoing HSCT (61%) vs 5 control patients (23%) had discontinued immunosuppressive or biologic agents or corticosteroids for at least 3 months (difference, 38.1% [95% CI, 9.3% to 59.3%]; P = .01). Ten vs 2 patients had a CDAI less than 150 (remission) at the final evaluation, 8 (34.8%) vs 2 (9.1%) for 3 or more months (difference, 25.7% [95% CI, 1.1% to 47.1%]; P = .052). Eight (34.8%) vs 2 (9.1%) patients were adjudicated free of active disease on endoscopy and radiology at final assessment (difference, 25.7% [95% CI, 1.1% to 47.1%]; P = .054). There were 76 serious adverse events in patients undergoing HSCT vs 38 in controls. One patient undergoing HSCT died. CONCLUSIONS AND RELEVANCE: Among adult patients with refractory Crohn disease not amenable to surgery who had impaired quality of life, HSCT, compared with conventional therapy, did not result in a statistically significant improvement in sustained disease remission at 1 year and was associated with significant toxicity. These findings do not support the widespread use of HSCT for patients with refractory Crohn disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00297193.
Assuntos
Doença de Crohn/terapia , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas/métodos , Adulto , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Indução de Remissão , Fatores de Tempo , Condicionamento Pré-Transplante/métodos , Transplante Autólogo , Resultado do TratamentoRESUMO
OBJECTIVES: This study describes clinical characteristics, prognostic factors, and quality of life in patients with newly diagnosed (incident) digital ulcers (DU). METHODS: Observational cohort study of 189 consecutive SSc patients with incident DU diagnosis identified from the EUSTAR database (22 centres in 10 countries). Data were collected from medical charts and during one prospective visit between 01/2004 and 09/2010. RESULTS: Median age at DU diagnosis was 51 years, majority of patients were female (88%), and limited cutaneous SSc was the most common subtype (61%). At incident DU diagnosis, 41% of patients had one DU and 59% had ≥2 DU; at the prospective visit 52% had DU. Pulmonary arterial hypertension (PAH) and multiple DU at diagnosis were associated with presence of any DU at the prospective visit (odds ratios: 4.34 and 1.32). During the observation period (median follow-up was 2 years) 127 patients had ≥1 hospitalisation. The event rate of new DU per person-year was 0.66, of DU-associated complications was 0.10, and of surgical or diagnostic procedures was 0.12. At the prospective visit, patients with ≥1 DU reported impairment in daily activities by 57%, those with 0 DU by 37%. The mean difference between patients with or without DU in the SF-36 physical component was 2.2, and in the mental component 1.4. DU patients were not routinely prescribed endothelin receptor antagonists or prostanoids. CONCLUSIONS: This real world cohort demonstrates that DU require hospital admission, and impair daily activity. PAH and multiple DU at diagnosis were associated with future occurrence of DU.
Assuntos
Dedos/irrigação sanguínea , Escleroderma Sistêmico/epidemiologia , Úlcera Cutânea/epidemiologia , Atividades Cotidianas , Adulto , Efeitos Psicossociais da Doença , Bases de Dados Factuais , Europa (Continente)/epidemiologia , Feminino , Hospitalização , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/epidemiologia , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prognóstico , Estudos Prospectivos , Qualidade de Vida , Recidiva , Fatores de Risco , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/fisiopatologia , Escleroderma Sistêmico/psicologia , Escleroderma Sistêmico/terapia , Úlcera Cutânea/diagnóstico , Úlcera Cutânea/fisiopatologia , Úlcera Cutânea/psicologia , Úlcera Cutânea/terapia , Fatores de TempoRESUMO
Mesenchymal stromal cells (MSC), often incorrectly called stem cells, have been the intense focus of in vitro studies and animal models of rheumatic and other diseases over more than a decade. Despite multiple plausible mechanisms of action and a plethora of positive in vivo animal studies, few randomised controlled clinical trials have demonstrated meaningful clinical benefit in any condition so far. This could be due to confusion in cell product terminology, complexity of clinical study design and execution or agreement on meaningful outcome measures. It could also indicate that MSC as currently employed are ineffective. Within the rheumatic diseases, SLE, rheumatoid arthritis (RA) and osteoarthritis (OA) have received most attention. Uncontrolled multiple trial data from over 300 SLE patients have been published from one centre suggesting a positive outcome; one single centre comparative study in 172 RA was positive and no human studies have compared intra-articular MSC therapy to non-MSC techniques for osteoarthritis in the absence of surgery. Two randomised studies suggested benefit from the addition of bone marrow derived MSC and peripheral blood mononuclear cells added to surgical "standard of care" in knee OA and knee focal cartilage defects, respectively. The possible reasons for this apparent mismatch between expectation and clinical reality will be discussed.
Assuntos
Artrite Reumatoide/terapia , Lúpus Eritematoso Sistêmico/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/imunologia , Osteoartrite/terapia , Artrite Reumatoide/imunologia , Comunicação Celular/imunologia , Ensaios Clínicos como Assunto , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/patologia , Lúpus Eritematoso Sistêmico/imunologia , Células-Tronco Mesenquimais/citologia , Modelos Imunológicos , Osteoartrite/imunologia , Resultado do TratamentoRESUMO
Haematopoietic stem cell transplantation (HSCT) following intensive immune suppression has been used in >2000 patients with severe autoimmune diseases for 18 years, including 300 with SSc. The concept is to profoundly reduce the bulk of auto-aggressive immune competent cells and then rescue the patient's ablated haematopoiesis via an autologous HSCT. An early analysis of uncontrolled phase I/II data suggested that approximately one-third of these achieved a substantial improvement, with a relapse rate of 25% and a treatment-related mortality ranging from 6% to 23% across different studies. These early results led to three prospective randomized controlled trials, two of which are completed, confirming that HSCT shows clear advantages over conventional immunosuppression, but with significant toxicity. In some patients, sustained complete normalization of skin changes, reversal of positive autoantibody status and withdrawal of immunosuppressive medication were observed. These results attest to the profound effects of HSCT.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Escleroderma Sistêmico/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Escleroderma Sistêmico/mortalidade , Análise de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVE: Human bone marrow mesenchymal stromal cells (hBM-MSC) are being applied in tissue regeneration and treatment of autoimmune diseases (AD). Their cellular and immunophenotype depend on isolation and culture conditions which may influence their therapeutic application and reflect their in vivo biological functions. We have further characterised the phenotype induced by fibroblast growth factor 2 (FGF2) on healthy donor hBM-MSC focusing on the osteoimmunological markers osteoprotegerin (OPG), receptor activator of nuclear factor kB (RANK), RANK ligand (RANKL) and HLA-DR and their regulation of expression by the inflammatory cytokines IL1ß and IFNγ. METHODS: RANK, RANKL, OPG and HLA-DR expression in hBM-MSC expanded under specific culture conditions, were measured by RT-PCR and flow cytometry. MAPKs induction by FGF2, IL1ß and IFNγ in hBM-MSC was analysed by immunoblotting and RT-PCR. RESULTS: In hBM-MSC, OPG expression is constitutive and FGF2 independent. RANKL expression depends on FGF2 and ERK1/2 activation. IL1ß and IFNγ activate ERK1/2 but fail to induce RANKL. Only IL1ß induces P38MAPK. The previously described HLA-DR induced by FGF2 through ERK1/2 on hBM-MSC, is suppressed by IL1ß through inhibition of CIITA transcription. HLA-DR induced by IFNγ is not affected by IL1ß in hBM-MSC, but is suppressed in articular chondrocytes and lung fibroblasts. CONCLUSIONS: RANKL expression and IL1ß regulated MHC-class II, both induced via activation of the ERK1/2 signalling pathway, are specific for progenitor hBM-MSC expanded in the presence of FGF2. HLA-DR regulated by IL1ß and ERK1/2 is observed on hBM-MSC during early expansion without FGF2 suggesting previous in vivo acquisition. Stromal progenitor cells with this phenotype could have an osteoimmunological role during bone regeneration.
Assuntos
Células da Medula Óssea/metabolismo , Fator 2 de Crescimento de Fibroblastos/imunologia , Antígenos HLA-DR/genética , Interferon gama/imunologia , Interleucina-1beta/imunologia , Células-Tronco Mesenquimais/metabolismo , Osteoprotegerina/genética , Ligante RANK/genética , Receptor Ativador de Fator Nuclear kappa-B/genética , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Antígenos HLA-DR/efeitos dos fármacos , Humanos , Interferon gama/metabolismo , Interferon gama/farmacologia , Interleucina-1beta/metabolismo , Interleucina-1beta/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/imunologia , Quinases de Proteína Quinase Ativadas por Mitógeno/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Osteoprotegerina/efeitos dos fármacos , Osteoprotegerina/metabolismo , Ligante RANK/efeitos dos fármacos , Ligante RANK/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
OBJECTIVE: SSc is clinically and aetiopathogenically heterogeneous. Consensus standards for more uniform trial design and selection of outcome measures are needed. The objective of this study was to develop evidence-based points to consider (PTCs) for future clinical trials in SSc. METHODS: Thirteen international SSc experts experienced in SSc clinical trial design were invited to participate. One researcher with experience in systematic literature review and three trainees were also included. A systematic review using PubMed and the Cochrane Central Register of Controlled Trials was conducted and PTCs when designing clinical trials in SSc were developed. As part of that development we conducted an Internet-based Delphi exercise regarding the main points to be made in the consensus statement. Consensus was defined as achieving a median score of ≥7 of 9. RESULTS: By consensus, the experts decided to develop PTCs for each individual organ system. The current document provides a unifying outline on PTCs regarding general trial design, inclusion/exclusion criteria and analysis. Consensus was achieved regarding all the main points of the PTCs. CONCLUSION: Using European League Against Rheumatism suggestions for PTCs, a general outline for PTCs for controlled clinical trials in SSc was developed. Specific outlines for individual organ systems are to be published separately. This general outline should lead to more uniform and higher-quality trials and clearly delineate areas where further research is needed.
Assuntos
Ensaios Clínicos como Assunto/normas , Ensaios Clínicos como Assunto/tendências , Avaliação de Resultados em Cuidados de Saúde , Escleroderma Sistêmico/terapia , Ensaios Clínicos como Assunto/ética , Técnica Delphi , Europa (Continente) , Medicina Baseada em Evidências , Humanos , Seleção de Pacientes , Fatores de TempoRESUMO
OBJECTIVES: To identify predictive parameters for the progression of skin fibrosis within 1â year in patients with diffuse cutaneous SSc (dcSSc). METHODS: An observational study using the EUSTAR database was performed. Inclusion criteria were dcSSc, American College of Rheumatology (ACR) criteria fulfilled, modified Rodnan skin score (MRSS) ≥7 at baseline visit, valid data for MRSS at 2nd visit, and available follow-up of 12±2â months. Worsening of skin fibrosis was defined as increase in MRSS >5 points and ≥25% from baseline to 2nd visit. In the univariate analysis, patients with progressive fibrosis were compared with non-progressors, and predictive markers with p<0.2 were included in the logistic regression analysis. The prediction models were then validated in a second cohort. RESULTS: A total of 637 dcSSc patients were eligible. Univariate analyses identified joint synovitis, short disease duration (≤15â months), short disease duration in females/patients without creatine kinase (CK) elevation, low baseline MRSS (≤22/51), and absence of oesophageal symptoms as potential predictors for progressive skin fibrosis. In the multivariate analysis, by employing combinations of the predictors, 17 models with varying prediction success were generated, allowing cohort enrichment from 9.7% progressive patients in the whole cohort to 44.4% in the optimised enrichment cohort. Using a second validation cohort of 188 dcSSc patients, short disease duration, low baseline MRSS and joint synovitis were confirmed as independent predictors of progressive skin fibrosis within 1â year resulting in a 4.5-fold increased prediction success rate. CONCLUSIONS: Our study provides novel, evidence-based criteria for the enrichment of dcSSc cohorts with patients who experience worsening of skin fibrosis which allows improved clinical trial design.
Assuntos
Progressão da Doença , Esclerodermia Difusa/patologia , Pele/patologia , Adulto , Estudos de Coortes , Creatina Quinase/sangue , Bases de Dados Factuais , Técnicas de Apoio para a Decisão , Transtornos de Deglutição/etiologia , Dispneia/etiologia , Feminino , Fibrose , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Esclerodermia Difusa/sangue , Esclerodermia Difusa/complicações , Índice de Gravidade de Doença , Fatores Sexuais , Sinovite/etiologia , Fatores de TempoRESUMO
IMPORTANCE: High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials. OBJECTIVE: To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide. DESIGN, SETTING, AND PARTICIPANTS: The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation-registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013. INTERVENTIONS: HSCT vs intravenous pulse cyclophosphamide. MAIN OUTCOMES AND MEASURES: The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure. RESULTS: A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years. CONCLUSIONS AND RELEVANCE: Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN54371254.
Assuntos
Ciclofosfamida/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/administração & dosagem , Esclerodermia Difusa/tratamento farmacológico , Adulto , Autoenxertos , Ciclofosfamida/efeitos adversos , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
OBJECTIVES: Classification criteria for systemic sclerosis (SSc) are being developed. The objectives were to develop an instrument for collating case data and evaluate its sensibility; use forced-choice methods to reduce and weight criteria; and explore agreement among experts on the probability that cases were classified as SSc. STUDY DESIGN AND SETTING: A standardized instrument was tested for sensibility. The instrument was applied to 20 cases covering a range of probabilities that each had SSc. Experts rank ordered cases from highest to lowest probability; reduced and weighted the criteria using forced-choice methods; and reranked the cases. Consistency in rankings was evaluated using intraclass correlation coefficients (ICCs). RESULTS: Experts endorsed clarity (83%), comprehensibility (100%), face and content validity (100%). Criteria were weighted (points): finger skin thickening (14-22), fingertip lesions (9-21), friction rubs (21), finger flexion contractures (16), pulmonary fibrosis (14), SSc-related antibodies (15), Raynaud phenomenon (13), calcinosis (12), pulmonary hypertension (11), renal crisis (11), telangiectasia (10), abnormal nailfold capillaries (10), esophageal dilation (7), and puffy fingers (5). The ICC across experts was 0.73 [95% confidence interval (CI): 0.58, 0.86] and improved to 0.80 (95% CI: 0.68, 0.90). CONCLUSIONS: Using a sensible instrument and forced-choice methods, the number of criteria were reduced by 39% (range, 23-14) and weighted. Our methods reflect the rigors of measurement science and serve as a template for developing classification criteria.
Assuntos
Pesquisa Biomédica/instrumentação , Técnicas de Apoio para a Decisão , Escleroderma Sistêmico/classificação , Consenso , Estudos de Viabilidade , Humanos , Reprodutibilidade dos Testes , Escleroderma Sistêmico/diagnósticoRESUMO
The successful use of a chimeric monoclonal antibody targeting TNF alpha (infliximab) to treat rheumatoid arthritis (RA) two decades ago, ushered in a new era of therapy with the so-called biopharmaceuticals, commonly referred to as "biologics". Their use rapidly spread to other indications such as Crohns disease, and their commercial success led to rapid extension of the concept using other forms of monoclonal antibodies and receptor recombinant molecules with specificities to other cytokines, growth factors and immune cell subsets. Soon after their introduction into the clinic, the first indications of increased risk of infection appeared in the form of reactivation of tuberculosis, mostly in the first months after treatment and often extrapulmonary. It was later recognised that an overall increased risk of bacterial infection under TNF-alpha blockade exists with a relative increased risk of around 2 - 3, and that classical symptoms of infection may be masked by cytokine blockade. Biologics against other cytokines such as IL-6, co-stimulatory molecules, and anti B cells seem less associated with infection, though this may be in part related to more careful patient monitoring. Increasing experience led to guidelines concerning pre-treatment screening, vaccination and perioperative advice, as well as the use of biologics in the presence of chronic viral infection, e. g. HIV, hepatitis B and C. Biologics have changed the outcome for patients with RA and other autoimmune diseases, but this success should not lead to complacency when assessing potential infectious complications of treatment in individual patients.