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Comunicação , Congressos como Assunto , Processos Grupais , Interface Usuário-Computador , COVID-19 , Humanos , SARS-CoV-2RESUMO
BACKGROUND: Systemic sclerosis (SSc)-overlap syndromes are a very heterogeneous and remarkable subgroup of SSc-patients, who present at least two connective tissue diseases (CTD) at the same time, usually with a specific autoantibody status. OBJECTIVES: To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited SSc (lcSSc) or diffuse cutaneous SSc (dcSSc). METHODS: The data of 3240 prospectively included patients, registered in the database of the German Network for Systemic Scleroderma and followed between 2003 and 2013, were analysed. RESULTS: Among 3240 registered patients, 10% were diagnosed as SSc-overlap syndrome. Of these, 82.5% were female. SSc-overlap patients had a mean age of 48±1.2â years and carried significantly more often 'other antibodies' (68.0%; p<0.0001), including anti-U1RNP, -PmScl, -Ro, -La, as well as anti-Jo-1 and -Ku antibodies. These patients developed musculoskeletal involvement earlier and more frequently (62.5%) than patients diagnosed as lcSSc (32.2%) or dcSSc (43.3%) (p<0.0001). The onset of lung fibrosis and heart involvement in SSc-overlap patients was significantly earlier than in patients with lcSSc and occurred later than in patients with dcSSc. Oesophagus, kidney and PH progression was similar to lcSSc patients, whereas dcSSc patients had a significantly earlier onset. CONCLUSIONS: These data support the concept that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct from lcSSc and dcSSc, due to a different progression of the disease, different proportional distribution of specific autoantibodies, and of different organ involvement.
Assuntos
Doenças do Tecido Conjuntivo/fisiopatologia , Escleroderma Sistêmico/fisiopatologia , Adulto , Autoanticorpos/imunologia , Cardiomiopatias/etiologia , Doenças do Tecido Conjuntivo/complicações , Doenças do Tecido Conjuntivo/imunologia , Bases de Dados Factuais , Progressão da Doença , Feminino , Gastroenteropatias/etiologia , Humanos , Hipertensão Pulmonar/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fibrose Pulmonar/etiologia , Esclerodermia Difusa/fisiopatologia , Esclerodermia Limitada/fisiopatologia , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/imunologia , SíndromeRESUMO
OBJECTIVE: The aim of this study was to find a new and less cardiotoxic conditioning regimen for high-dose chemotherapy and autologous stem cell transplantation (aSCT) in patients with severe SSc and pre-existing cardiac involvement. METHODS: Six patients with cardiac involvement were treated for SSc with a conditioning regimen including reduced-dose CYC plus the non-cardiotoxic alkylant thiotepa. All patients received an implantable cardioverter defibrillator (ICD) before aSCT. The response at months 6 and 12 was measured according to reduction of the modified Rodnan skin score (mRSS). CT histography was used to monitor pulmonary manifestations, as were echocardiography, N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin for the cardiac involvement. Cardiac events were defined as death or hospitalisation due to heart failure or appropriate discharge of the ICD. RESULTS: Between December 2008 and May 2012, four male and two female patients with a median age of 41 years received aSCT. The median mRSS significantly decreased from 26.5 to 18 and 17.5 at month 6 and 12, respectively. The total lung volume also significantly improved. Within the median follow-up of 1.6 years (range 1-3.8) two patients experienced a relapse of SSc, which results in a progression-free survival rate of 66.6%. Three patients experienced ICD discharge. CONCLUSION: For patients with SSc and cardiac involvement, the use of thiotepa and reduced-dose CYC is feasible and effective. The rate of ICD discharge underlines the need for protection in these endangered patients. This preliminary experience allowed us to use this regimen for our currently recruiting prospective trial (NCT01895244).
Assuntos
Ciclofosfamida/uso terapêutico , Cardiopatias/epidemiologia , Cardiopatias/terapia , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/terapia , Transplante de Células-Tronco , Tiotepa/uso terapêutico , Adulto , Doenças Autoimunes/epidemiologia , Comorbidade , Ciclofosfamida/efeitos adversos , Desfibriladores Implantáveis , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Seguimentos , Cardiopatias/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Prevalência , Estudos Retrospectivos , Fatores de Risco , Transplante de Células-Tronco/efeitos adversos , Tiotepa/efeitos adversos , Resultado do Tratamento , Troponina/sangueRESUMO
OBJECTIVE: Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease characterized by fevers, rashes, arthralgia, conjunctivitis, and sensorineural hearing loss. In MWS, NLRP3 gene mutations are associated with excessive interleukin-1 release. The aims of this study were to determine the otologic characteristics of MWS, define trajectories of hearing loss, and explore the association with distinct NLRP3 genotypes. METHODS: A prospective observational cohort study of children and adults diagnosed as having MWS was conducted at a single center. NLRP3 gene mutations were determined. Patients underwent standardized clinical, laboratory, and otologic assessments, including pure tone audiometry, vestibular organ testing, and tinnitus evaluation. Trajectories of hearing loss were defined for each genotype. The genotype-specific risk of progression of hearing loss was determined. RESULTS: A total of 33 patients ages 3-75 years who were members of 5 families with 4 different NLRP3 gene mutations were included. The majority of patients (67%) experienced bilateral sensorineural hearing loss. Even in cases of profound hearing loss vestibular reactivity remained normal. Fourteen adult patients reported nondebilitating tinnitus. Overall, hearing impairment progressed with age. Patients with the T348M mutation were at highest risk of rapid progression of sensorineural hearing loss. CONCLUSION: Patients with MWS are at risk of developing progressive sensorineural hearing loss without vestibular involvement. Hearing impairment starts at high frequencies and can subsequently progress to profound hearing loss. Progression is age dependent. Patients with different NLRP3 mutations had distinctly different trajectories of hearing loss, suggesting a mutation-specific risk that should be considered when making treatment decisions.
Assuntos
Proteínas de Transporte/genética , Síndromes Periódicas Associadas à Criopirina/epidemiologia , Síndromes Periódicas Associadas à Criopirina/genética , Perda Auditiva Neurossensorial/epidemiologia , Perda Auditiva Neurossensorial/genética , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Audiometria de Tons Puros , Criança , Pré-Escolar , Estudos de Coortes , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Progressão da Doença , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Genótipo , Perda Auditiva Neurossensorial/diagnóstico , Humanos , Interleucina-1beta/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR , Fatores de Risco , Adulto JovemRESUMO
The exact prevalence of psoriatic arthritis (PsA) among patients with psoriasis is still not conclusive. Data in the literature vary between 5.8 and 30 %. Objective of this study was to gain more information on the prevalence of PsA among patients with psoriasis in Germany. Between 09/2010 and 05/2011, consecutive patients from dermatological private practices and a university hospital with psoriasis were asked to fill out the validated German Psoriatic Arthritis Diagnostic (GEPARD) Questionnaire. Patients who answered ≥4 questions with "yes" were invited to come for a rheumatological check up. Those patients who refused a rheumatological examination were counted as "absence of PsA". Laboratory tests for inflammatory markers as well as the severity of skin manifestations were assessed. The diagnosis of PsA was made according to the CASPAR criteria, and imaging was performed in addition. A total of 404 questionnaires were evaluated; 50.5 % answered ≥4 questions positively; 19.3 % had a history of PsA confirmed by a rheumatologist; and in 10.9 %, PsA or spondyloarthritis was newly diagnosed during the present study. This leads to an overall prevalence of PsA in patients with psoriasis of 30.2 %. The frequency of psoriatic arthritis in the present study is higher than expected from previous studies in Germany. The prevalence is consistent with findings of a large observational survey from Scandinavia. Using the CASPAR criteria and imaging in all patients, certainty of the diagnosis is very high. The GEPARD Questionnaire is a helpful tool to identify people at risk for psoriatic arthritis.
Assuntos
Artrite Psoriásica/epidemiologia , Dermatologia , Psoríase/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Psoriásica/diagnóstico , Estudos Transversais , Feminino , Alemanha/epidemiologia , Inquéritos Epidemiológicos , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Prática Privada , Psoríase/diagnóstico , Inquéritos e Questionários , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Treatment with high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (aHSCT) is an intensive treatment option for patients with severe forms of systemic sclerosis (SSc). Even though associated with a high treatment related mortality, the results in this high-risk population are generally favourable. The knowledge on the potential mechanism of action of this therapy and how it can improve patients with SSc is crucial to better select the right patients for aHSCT. METHODS: This is a monocentric retrospective study from Tübingen, Germany, including 32 patients who underwent aHSCT. Peripheral blood samples were analysed for different lymphocyte subsets at various timepoints before and after aHSCT. Patients were divided into responders and non-responders according to the modified Rodnan skin score and lung function test in the three years following aHSCT. RESULTS: Responders showed significantly lower levels of cluster of differentiation (CD)4 positive T cells in the first months after aHSCT (month 1 and 3), B cells (month 3 and 6 after aHSCT) and natural killer cells (month 1). Mantel-cox test showed a significant deviation of the probability curves, i.e. patients with lower CD4 + T cells and natural killer cells one month and B cells after 3 months after stem cell transplantation had a higher probability to belong to the responder group. CONCLUSIONS: Taken together, this study supports the theory that a profound CD4 + T cell and B cell lymphopenia is important for patients with SSc to achieve a sustained response after aHSCT.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Escleroderma Sistêmico , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Estudos Retrospectivos , Transplante Autólogo/métodos , Transplante de Células-TroncoRESUMO
OBJECTIVES: To untangle the association between smoking and systemic sclerosis (SSc). METHODS: In the European Scleroderma Trials and Research cohort, the autoantibody status was compared between ever-smokers and never-smokers. Time until disease progression was assessed using Kaplan-Meier curves. Cox models were built to investigate the influence of smoking over 15 years of follow-up. All analyses were performed for the total cohort and stratified for sex and for positivity of anti-centromere (ACA) and anti-topoisomerase antibodies (ATA). RESULTS: Overall, 12 314 patients were included in the study. Of these, 10 393 were women (84%), 4637 were ACA-positive (38%), 3919 were ATA-positive (32%) and 4271 (35%) were ever-smokers. In men, but not in women, smoking was associated with mortality (HR 1.63, 95% CI 1.23 to 2.16, p=0.001). Ever-smoking women were at higher risk for skin progression (HR 1.10, 95% CI 1.00 to 1.22, p=0.046) and for 'any organ progression' (HR 1.07, 95% CI 1.00 to 1.13, p=0.036). In women, 34% of never-smokers were ATA-positive compared with 21% of ever-smokers (p<0.001). In the group of ever-smokers, higher exposure rates, reflected by the number of pack-years (OR 0.98, 95% CI 0.97 to 0.99, p<0.001) and by smoking duration (OR 0.96, 95% CI 0.95 to 0.97, p<0.001), were associated with lower frequency of ATA. In ACA-positive patients, the risk of mortality (HR 1.29, 95% CI 1.02 to 1.63, p=0.033), cardiac involvement (HR 1.25, 95% CI 1.03 to 1.43, p=0.001), skin progression (HR 1.21, 95% CI 1.03 to 1.42, p=0.018) and 'any organ progression' (HR 1.14, 95% CI 1.05 to 1.24, p=0.002) was increased among smokers. In ATA-positive smoking patients, mortality (HR 1.40, 95% CI 1.10 to 1.78, p=0.006), skin progression (HR 1.19, 95% CI 1.03 to 1.37, p=0.020) digital ulcers (HR 1.17, 95% CI 1.02 to 1.34, p=0.029) and 'any organ progression' (HR 1.11, 95% CI 1.00 to 1.22, p=0.048) occurred more frequently. CONCLUSIONS: Our stratified analysis demonstrates that smoking is associated with an increased risk for mortality in male SSc patients but not in women. Strikingly, smoking is associated with lower prevalence of ATA positivity, in particular in women. In both ATA-positive and ACA-positive patients, smoking is a risk factor for mortality, skin progression and 'any organ progression'.
Assuntos
Progressão da Doença , Escleroderma Sistêmico , Fumar , Humanos , Escleroderma Sistêmico/etiologia , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/mortalidade , Feminino , Masculino , Pessoa de Meia-Idade , Fumar/efeitos adversos , Fumar/epidemiologia , Adulto , Modelos de Riscos Proporcionais , Fatores de Risco , Autoanticorpos/sangue , Autoanticorpos/imunologia , Idoso , Estimativa de Kaplan-Meier , Estudos de CoortesRESUMO
OBJECTIVE: Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease caused by mutations in the NLRP3 gene that result in excessive interleukin-1 (IL-1) release. It is characterized by severe fevers, rashes, arthralgia, and conjunctivitis, leading to sensorineural deafness and amyloidosis. The recombinant IL-1 receptor antagonist anakinra blocks the biologic activity of IL-1. The aim of this study was to determine the short- and long-term efficacy and safety of anakinra therapy in children and adults with severe MWS. METHODS: A single-center observational study was performed. Standardized assessments included clinical features, the Disease Activity Score (DAS) for MWS, classic and novel markers of inflammation, and patient-derived measures of health status. The primary outcome was a score of <10 on the DAS for MWS at 2 weeks and at the last followup visit. Measures of MWS disease activity were investigated using descriptive statistics and paired comparative analysis. RESULTS: A total of 12 patients with severe MWS (5 children and 7 adults) received anakinra for a median of 11 months (range 5-14 months). The median followup was 11 months (range 5-14 months). Disease activity was significantly lower in all patients at 2 weeks (P = 0.0005). Organ manifestations of MWS improved, as did all patient-derived measures of health status, markers of inflammation, and hearing loss in 2 of the patients. Levels of the novel neutrophil activation biomarker S100A12 followed clinical disease activity. Treatment was well tolerated, and no serious adverse events were observed. CONCLUSION: Anakinra was found to be a safe and effective treatment of severe MWS, leading to a significant improvement in disease activity at 2 weeks as well as long-term. Anakinra therapy should therefore be considered in children and adults with severe MWS disease requiring IL-1 blockade.
Assuntos
Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Adolescente , Adulto , Fatores Etários , Idoso , Biomarcadores/metabolismo , Proteínas de Transporte/genética , Criança , Pré-Escolar , Síndromes Periódicas Associadas à Criopirina/genética , Síndromes Periódicas Associadas à Criopirina/imunologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR , Resultado do Tratamento , Adulto JovemRESUMO
Background: The purpose of this trial was to evaluate the effectiveness and safety of the IL-6 receptor antibody Tocilizumab (TCZ) in the treatment of Familial Mediterranean Fever (FMF). Methods: This was a randomized, double-blinded, placebo-controlled phase II trial in adult patients with active FMF and an inadequate response or intolerance to colchicine (crFMF). The physician's global assessment of disease activity (PGA), based on a five-point scale for six symptoms, was used as a clinical score, which had to be >2 at screening, together with elevated c-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) and serum amyloid A (SAA) levels, to be eligible for inclusion. Patients were randomized 1:1 to either receive monthly TCZ or a placebo over a period of 24 weeks. The primary endpoint was the number of patients achieving an adequate response to treatment at week 16, defined as a PGA of ≤2 and normalized ESR or CRP and normalized SAA. Results: We randomized 25 patients with a median age of 31 years. At week 16, an adequate treatment response was achieved by two patients in the TCZ and none of the patients in the placebo arm (p = 0.089). SAA levels normalized with TCZ, but not with the placebo (p = 0.015). Conclusion: In this first randomized, placebo-controlled study in patients with active crFMF, more patients in the TCZ arm experienced a response to treatment in comparison to those receiving the placebo. As the prevention of amyloidosis is a major treatment goal in FMF, the normalization of SAA in TCZ-treated patients is essential. These findings have to be confirmed in a larger trial.
RESUMO
Rituximab has only been approved in combination with methotrexate for the treatment of rheumatoid arthritis. As some patients have intolerance to methotrexate, alternative co-therapies are needed. This method involved retrospective analysis of ten patients treated with a combination of rituximab and leflunomide. Primary outcome measures were the DAS28 response at month 6 and the time to relapse. The median initial DAS 28 of 5.7 (3.2-7.2) was reduced to 3.5 (1.9-6.1) at month 6. 70% of the patients achieved a good or moderate response, whereas 30% showed no response. Two patients had to stop leflunomide due to adverse effects. Two patients had to reduce the leflunomide dose to 10 mg/day. 5/8 patients experienced a relapse after a median of 10 (6-30) months and were successfully re-treated with rituximab. This small case series suggests that leflunomide might offer an alternative DMARD combination option for the treatment of RA with rituximab.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Isoxazóis/uso terapêutico , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Murinos , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico , Quimioterapia Combinada , Feminino , Humanos , Isoxazóis/efeitos adversos , Leflunomida , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Rituximab , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: Vasculopathy is a key factor in the pathophysiology of systemic sclerosis (SSc) and the main cause for Raynaud phenomenon (RP), digital ulcers (DU), and/or pulmonary arterial hypertension (PAH). It is so far unknown how patients with SSc are treated with vasoactive agents in daily practice. To determine to which extent patients with SSc were treated with different vasoactive agents, we used data from the German Network for Systemic Scleroderma registry. METHODS: The data of 3248 patients with SSc were analyzed. RESULTS: Patients were treated with vasoactive drugs in 61.1% of cases (1984/3248). Of these, 47.6% received calcium channel inhibitors, followed by 34.2% treated with angiotensin-converting enzyme (ACE) inhibitors, 21.1% treated with intravenous (IV) prostanoids, 10.1% with pentoxifylline, 8.8% with angiotensin 1 receptor antagonists (AT1RA), 8.7% with endothelin 1 receptor antagonists (ET1RA), 4.1% with phosphodiesterase type 5 (PDE5) inhibitors, and 5.3% with others. Patients with RP received vasoactive therapy in 63.3% of cases, with DU in 70.1%, and with PAH in 78.2% of cases. Logistic regression analysis revealed that patients with PAH were significantly more often treated with PDE5 inhibitors and ET1RA, and those with DU with ET1RA and IV prostanoids. In addition, 41.8% of patients were treated with ACE inhibitors and/or AT1RA. Patients registered after 2009 received significantly more often ET1RA, AT1RA, and IV prostanoids compared with patients registered prior to 2005. CONCLUSION: These data clearly indicate that many patients with SSc do not yet receive sufficient vasoactive therapy. Further, in recent years, a marked change of treatment regimens can be observed.
Assuntos
Qualidade de Vida , Sistema de Registros , Escleroderma Sistêmico/tratamento farmacológico , Doenças Vasculares/tratamento farmacológico , Vasodilatadores/uso terapêutico , Adulto , Fatores Etários , Idoso , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Estudos de Coortes , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/epidemiologia , Índice de Gravidade de Doença , Fatores Sexuais , Resultado do Tratamento , Doenças Vasculares/diagnóstico , Doenças Vasculares/epidemiologia , Vasodilatadores/farmacologia , Adulto JovemRESUMO
BACKGROUND: Cardiac involvement in systemic sclerosis (SSc) is associated with a variable phenotype including heart failure, arrhythmias and pulmonary hypertension. The aim of the present study was to evaluate clinical characteristics, histopathological findings and outcome of patients with SSc and a clinical phenotype suggesting cardiac involvement. METHODS AND RESULTS: 25 patients with SSc and clinical signs of cardiac involvement were included between June 2007 and December 2010. They underwent routine clinical work-up including laboratory testing, echocardiography, left and right heart catheterization, holter recordings and endomyocardial biopsy. Primary endpoint (EP) was defined as the combination of cardiovascular death, arrhythmic endpoints (defined as appropriate discharge of implantable cardioverter defibrillator (ICD)) or rehospitalization due to heart failure. The majority of patients presented with slightly impaired left ventricular function (mean LVEF 54.1±9.0%, determined by echocardiography). Endomyocardial biopsies detected cardiac fibrosis in all patients with a variable area percentage of 8% to 32%. Cardiac inflammation was diagnosed as follows: No inflammation in 3.8%, isolated inflammatory cells in 38.5%, a few foci of inflammation in 30.8%, several foci of inflammation in 15.4%, and pronounced inflammation in 7.7% of patients. During follow up (FU) (22.5 months), seven (28%) patients reached the primary EP. Patients with subsequent events showed a higher degree of fibrosis and inflammation in the myocardium by trend. While patients with an inflammation grade 0 or 1 showed an event rate of 18.2%, the subgroup of patients with an inflammation grade 2 presented with an event rate of 25% versus an event rate of 50% in the subgroup of patients with an inflammation grade 3 and 4, respectively (p=0.193). Furthermore, the subgroup of patients with fibrosis grade 1 showed an event rate of 11%, patients with fibrosis grade 2 and 3 presented with an event rate of 33% and 42% respectively (p = 0.160). CONCLUSIONS: Patients with SSc and clinical signs of cardiac involvement presented with mildly impaired LVEF. Prognosis was poor with an event rate of 28% within 22.5 months FU and was associated with the degree of cardiac inflammation and fibrosis.
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Fibrose/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/fisiopatologia , Inflamação/fisiopatologia , Escleroderma Sistêmico/fisiopatologia , Adulto , Biópsia , Morte , Desfibriladores Implantáveis , Ecocardiografia , Feminino , Fibrose/mortalidade , Coração/fisiopatologia , Insuficiência Cardíaca/mortalidade , Humanos , Inflamação/mortalidade , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Escleroderma Sistêmico/mortalidade , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
AIM: Gastrointestinal (GI) involvement in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) is rare. METHOD: Medical charts of seven patients with GPA and MPA and GI involvement were reviewed regarding clinical presentation, outcome, diagnostic tools and therapy. Second, the cellular composition of the inflammatory infiltrate associated with the vascular lesions in histological samples (ileum, colon, rectum, duodenum) were investigated to identify possible treatment targets. Immunohistochemistry was done with antibodies against CD20, CD3 and CD34. Samples from a healthy control group (n = 15) were used for comparison. RESULTS: Mean age at onset of the first symptoms of vasculitis was 48 ± 21.3 years. At time of diagnosis GI symptoms were present in five out of seven patients (71%) and occurred during relapse of the vasculitis in two patients (29%). All patients had abdominal pain, four of seven (57%) had an acute kidney injury and three patients required renal replacement therapy. At the time of diagnosis five of seven patients (71%) required surgery and mean Birmingham Vasculitis Activity Score (BVAS) on admission was high (26.3 ± 7.7). Regarding outcome, one patient died due to gastrointestinal bleeding. Histological analysis showed significantly higher expression of CD3 in this patient compared to the control group (P = 0.02). Analysis of expression of CD20 and CD34 showed no statistically significant differences between patients with GPA and MPA with GI involvement compared to the control group. CONCLUSIONS: GI involvement in GPA and MPA is rare. Therapy directed at T cells might be an alternative treatment option.
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Gastroenteropatias/etiologia , Granulomatose com Poliangiite/complicações , Poliangiite Microscópica/complicações , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Antígenos CD20/análise , Antígenos CD34/análise , Biomarcadores/análise , Biópsia , Complexo CD3/análise , Endoscopia Gastrointestinal , Feminino , Gastroenteropatias/diagnóstico , Gastroenteropatias/imunologia , Gastroenteropatias/terapia , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/imunologia , Granulomatose com Poliangiite/terapia , Humanos , Imuno-Histoquímica , Masculino , Poliangiite Microscópica/diagnóstico , Poliangiite Microscópica/imunologia , Poliangiite Microscópica/terapia , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
The purpose of this study was to assess the impact of enteric-coated mycophenolate sodium (EC-MPS) on skin and pulmonary manifestations of patients with progressive systemic sclerosis (Ssc). A prospective, open-label single-centre trial with EC-MPS 2 × 720 mg/day over 12 months and a long-term follow-up of 50 months were conducted. Modified Rodnan skin score (mRSS) was used to assess the skin and pulmonary function tests to assess the pulmonary involvement. In order to quantify the extent of alveolitis/fibrosis via densitometry, the high attenuation value, median lung density and percentiles of lung tissue densities were obtained by high-resolution computed tomography. Eleven patients were included. Three patients had to stop medication before month 6 (2× side effects, 1× progression). For the remaining eight patients, the median mRSS was non-significantly reduced from 13.5 at baseline to 11 at month 12. According to the CT histography, median lung density and high attenuation values remained stable. However, the course of percentiles -200 to -300 and particularly -300 to -400 Hounsfield units slightly increased in seven of eight patients after 12 months, suggesting worsening of pulmonary involvement. Accordingly, median diffusing capacity for carbon monoxide showed a tendency to decline (75.1 % vs. 70.2) while forced vital capacity non-significantly improved (78.0 vs. 85.5 %) during the study. Four patients are still on EC-MPS without clinical signs of progression after 50 months follow-up. EC-MPS showed non-significant improvement of the skin. Pulmonary fibrosis remained stable with only a slight tendency towards progression which might be ascribed to the medication as well as the natural course of the disease. CT histography appears to be a sensitive method for the detection of progression of pulmonary fibrosis and therefore should be considered for further studies in Ssc.
Assuntos
Ácido Micofenólico/análogos & derivados , Fibrose Pulmonar/diagnóstico , Esclerodermia Difusa/tratamento farmacológico , Comprimidos com Revestimento Entérico/uso terapêutico , Adulto , Idoso , Monóxido de Carbono/análise , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/uso terapêutico , Estudos Prospectivos , Fibrose Pulmonar/complicações , Fibrose Pulmonar/tratamento farmacológico , Testes de Função Respiratória , Esclerodermia Difusa/complicações , Pele/patologia , Fatores de Tempo , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Millions of patients are treated with therapeutic monoclonal antibodies (Tmabs) for miscellaneous diseases. We investigated sera from six patients who received immune globulin, from one patient with refractory anti-neutrophil-cytoplasmic antibody (ANCA)-associated granulomatosis with polyangiitis (GPA) who developed two episodes of acute cholestatic liver disease, one after treatment with rituximab and a second after adalimumab and a healthy control group. METHODS: Three sera from the patient and six sera from patients who received immune globulin were analyzed for antibodies to rituximab and adalimumab by ELISA. Additionally, sera from the patients and from nine healthy blood donors were coated with the Fab fragment of an unrelated humanized monoclonal antibody, with human Fc proteins as well as a mouse IgG globulin. RESULTS: Viral serology for hepatitis A, B, C and autoantibodies specific for autoimmune liver disorders were negative. In all three sera from the patient antibodies to rituximab could be detected, but also antibodies to adalimumab were present even at time points when the patient had not yet received adalimumab, indicating cross reactivity between both substances. Testing against an unrelated human Fab fragment revealed positive results, indicating that the patient had antibodies against human Fab fragments in general. The Fc proteins were negative, and patients' sera did also not react with mouse IgG globulins. Remarkably, 2 out of 5 patients which were treated with immune globulin had antibodies against human Fab fragments in general whereas in none of the samples from healthy controls antibodies to Fab fragment could be detected. CONCLUSION: This is the first study demonstrating cholestatic liver disease induced by two different Tmabs. Cross - reacting antibodies to Fab2 fragments in general are probably involved. Further studies must show if these Fab2 antibodies in general are related with drug-induced side effects and accelerated drug clearance in patients on Tmab therapy.
Assuntos
Anti-Inflamatórios , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Anticorpos Monoclonais Humanizados , Anticorpos Monoclonais Murinos , Colestase Intra-Hepática , Fragmentos Fab das Imunoglobulinas/imunologia , Fatores Imunológicos , Vasculite do Sistema Nervoso Central , Doença Aguda , Adalimumab , Adulto , Idoso , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/farmacocinética , Anticorpos Anticitoplasma de Neutrófilos/sangue , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Anticorpos Monoclonais Murinos/imunologia , Anticorpos Monoclonais Murinos/farmacocinética , Colestase Intra-Hepática/sangue , Colestase Intra-Hepática/induzido quimicamente , Colestase Intra-Hepática/imunologia , Colestase Intra-Hepática/patologia , Reações Cruzadas , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/imunologia , Fatores Imunológicos/farmacocinética , Masculino , Camundongos , Pessoa de Meia-Idade , Rituximab , Vasculite do Sistema Nervoso Central/sangue , Vasculite do Sistema Nervoso Central/tratamento farmacológico , Vasculite do Sistema Nervoso Central/imunologia , Vasculite do Sistema Nervoso Central/patologiaRESUMO
OBJECTIVES: Muckle-Wells syndrome (MWS) is an autoinflammatory disease characterized by excessive interleukin-1 (IL-1) release, resulting in recurrent fevers, sensorineural hearing loss, and amyloidosis. IL-1 inhibition with anakinra, an IL-1 receptor antagonist, improves clinical symptoms and inflammatory markers. Subclinical disease activity is commonly observed. Canakinumab, a fully human IgG1 anti-IL-1ß monoclonal antibody, can abolish excess IL-1ß. The study aim was to analyze the efficacy and safety of these two anti-IL-1 therapies. METHODS: Two cohorts of patients with severe MWS and confirmed NLRP3 mutation were treated with anakinra and/or canakinumab. Clinical and laboratory features including ESR, CRP, SAA, and the neutrophil marker S100A12 were determined serially. Disease activity was captured by MWS disease activity scores (MWS-DAS). Remission was defined as MWS-DAS ≤5 plus normal CRP and SAA. Treatment efficacy and safety were analyzed. RESULTS: The study included 12 anakinra- and 14 canakinumab-treated patients; the median age was 33.5 years (3.0 years to 72.0 years); 57% were female patients. Both treatment regimens led to a significant reduction of clinical disease activity and inflammatory markers. At last follow-up, 75% of anakinra-treated and 93% of canakinumab-treated patients achieved remission. During follow-up, S100A12 levels mirrored recurrence of disease activity. Both treatment regimens had favorable safety profiles. CONCLUSIONS: IL-1 blockade is an effective and safe treatment in MWS patients. MWS-DAS in combination with MWS inflammatory markers provides an excellent monitoring tool set. Canakinumab led to a sustained control of disease activity even after secondary failure of anakinra therapy. S100A12 may be a sensitive marker to detect subclinical disease activity.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1/antagonistas & inibidores , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: Autologous stem cell transplantation (aSCT) for systemic sclerosis (SSc) has been shown to be effective in recent reports. This aggressive approach and the disease itself are associated with a high mortality. We report our experiences in 26 consecutive patients. METHODS: Between 1997 and 2009, 26 patients were scheduled for aSCT. Our standard transplant regimen consists of cyclophosphamide (CYC) and granulocyte colony-stimulating factor (GCSF) for mobilization and CYC plus antithymocyte globulin for conditioning before the retransfusion of CD34 selected stem cells. The major outcome variable was the response to treatment [reduction of modified Rodnan skin score (mRSS) by 25%] at Month 6. Secondary endpoints were the transplant-related mortality and the progression-free survival. RESULTS: Significant skin and lung function improvement of the mRSS was achieved in 78.3% of patients at Month 6. The overall response rate was 91%, as some patients improved even after Month 6. Three patients died between mobilization and conditioning treatment, 2 due to severe disease progression and 1 whose death was considered treatment-related (i.e., GCSF or CYC toxicity). Depending on definitions, transplant-related mortality was 4% and treatment-related mortality 11%. Seven patients experienced a relapse during the 4.4 years of followup. The progression-free survival was 74%. Four patients died during followup and the most frequent causes of death were pulmonary and cardiac complications of SSc. CONCLUSION: aSCT led to significant improvement in most patients with SSc. The procedure requires further optimization; hence we are modifying our screening and treatment strategy. To minimize infectious complications, CYC for mobilization and GCSF were reduced. We intensified our screening for cardiac involvement and modified our conditioning regimen in case of cardiac involvement.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Escleroderma Sistêmico/cirurgia , Adulto , Idoso , Antígenos CD34/imunologia , Soro Antilinfocitário/uso terapêutico , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/mortalidade , Índice de Gravidade de Doença , Células-Tronco/imunologia , Condicionamento Pré-Transplante/métodos , Transplante Autólogo/imunologia , Resultado do Tratamento , Adulto JovemRESUMO
CONCLUSION: The age-dependent disease progression requires accelerating diagnosis of Muckle-Wells syndrome (MWS) in order to start treatment as early as possible. The most frequent, but not obligate symptoms are familial fatigue, hearing loss, and arthralgia. The design of further clinical trials should focus on hearing in order to document the long-term effect of anti-interleukin (IL)-1 drugs on hearing preservation. OBJECTIVES: This paper describes the otologic features of a genetically defined syndrome causing progressive hearing loss by cochlear degeneration. This is the first study reporting the pretreatment otologic presentation of a selected population with familial MWS. METHODS: A single-center cohort was examined by audiologic and neurotologic methods including pure tone audiograms, vestibular testing, and tinnitus questionnaire. The audiograms of members of the same family were compared to describe the family-specific risk of hearing loss progression. RESULTS: Nineteen patients (aged 3-72 years) belonging to four families with three different mutations of the NLRP3 gene were examined. Almost all patients (89%, 17/19) demonstrated bilateral sensorineural hearing loss. Hearing loss started in the high frequencies and led to profound deafness in the most severe cases. Even in cases of profound hearing loss the vestibular caloric reactivity was normal. Nearly half of the adults reported intermittent or permanent tinnitus.
Assuntos
Proteínas de Transporte/genética , Síndromes Periódicas Associadas à Criopirina/complicações , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Adolescente , Adulto , Fatores Etários , Idoso , Limiar Auditivo/fisiologia , Criança , Pré-Escolar , Estudos de Coortes , Síndromes Periódicas Associadas à Criopirina/genética , Progressão da Doença , Feminino , Testes Auditivos , Humanos , Interleucina-1/fisiologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR , Adulto JovemRESUMO
RATIONALE AND OBJECTIVES: To investigate the diagnostic value of high-resolution dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for assessment of synovitis in erosive osteoarthritis (EOA) of the hand and compare the results with those acquired in its potential mimic, the psoriatic arthritis (PsA). MATERIALS AND METHODS: Twenty-six patients (17 PsA, 9 EOA) were examined at 3 T. The time course of synovial contrast uptake was measured by ROI analysis using a three-dimensional encoded spoiled gradient-echo sequence. Characteristic parameters of synovial uptake curves (time to peak [TTP], peak value, mean transit time [MTT], area under the curve [AUC], and maximum upslope) of PsA and EOA patients were compared using gamma variate analysis and calculation of the late relative enhancement 15 minutes after contrast administration. RESULTS: Enhancement curves of PsA and EOA patients paralleled each other at comparable levels in the early phase after contrast injection without statistical difference in the following calculated characteristic curve parameters: TTP, peak value, MTT, AUC, and maximum upslope. However, significant difference was found in the late relative enhancement 15 minutes after contrast injection (P = .0275) with higher values in EOA patients. CONCLUSION: DCE-MRI provides assessment of synovitis in both patients with EOA and PsA. Interestingly, synovial enhancement characteristics were comparable for the most part in these two disorders. However, late enhancement might help in differentiation which is essential for guiding therapy.