RESUMEN
BACKGROUND: Localized Scleroderma (LoS) encompasses a group of idiopathic skin conditions characterized by (sub)cutaneous inflammation and subsequent development of fibrosis. Currently, lack of accurate tools enabling disease activity assessment leads to suboptimal treatment approaches. OBJECTIVE: To investigate serum concentrations of cytokines and chemokines implicated in inflammation and angiogenesis in LoS and explore their potential to be utilized as biomarker of disease activity. Additionally, to investigate the implication of potential biomarkers in disease pathogenesis. METHODS: A 39-plex Luminex immuno-assay was performed in serum samples of 74 LoS and 22 Healthy Controls. The relation between a validated clinical measure of disease activity (mLoSSI) and serum analytes was investigated. Additionally, gene and protein expression were investigated in circulating cells and skin biopsies. RESULTS: From the total of 39, 10 analytes (CCL18, CXCL9, CXCL10, CXCL13, TNFRII, Galectin-9, TIE-1, sVCAM, IL-18, CCL19) were elevated in LoS serum. Cluster analysis of serum samples revealed CCL18 as most important analyte to discriminate between active and inactive disease. At individual patient level, CCL18 serum levels correlated strongest with mLoSSI-scores (rsâ¯=â¯0.4604, Pâ¯<â¯0.0001) and in longitudinal measures CCL18 concentrations normalised with declining disease activity upon treatment initiation. Additionally, CCL18 was elevated in LoS serum, and not in (juvenile) dermatomyositis or spinal muscular atrophy. Importantly, CCL18 gene and protein expression was increased at the inflammatory border of cutaneous LoS lesions, with normal expression in unaffected skin and circulating immune cells. CONCLUSION: CCL18 is specific for disease activity in LoS thereby providing relevance as a biomarker for this debilitating disease.
Asunto(s)
Biomarcadores , Quimiocinas CC/metabolismo , Esclerodermia Localizada/metabolismo , Biopsia , Quimiocinas/metabolismo , Quimiocinas CC/sangre , Quimiocinas CC/genética , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Esclerodermia Localizada/diagnóstico , Esclerodermia Localizada/etiología , Esclerodermia Localizada/terapia , Índice de Severidad de la Enfermedad , Pruebas CutáneasRESUMEN
In the Netherlands dapsone is used for the treatment of dermatitis herpetiformis, leprosy and Pneumocystis jiroveci pneumonia and prophylaxis in case of cotrimoxazole allergy. An idiosyncratic drug reaction, known as the dapsone hypersensitivity syndrome (DHS), appears in about 0.5-3.6% of persons treated with dapsone. DHS can be associated with fever, rash and systemic involvement. We present a 35-year-old woman who developed severe DHS seven weeks after starting dapsone. Six weeks after being discharged in a good clinical condition she died from fulminant myocarditis, 11 weeks after the first DHS symptoms and the discontinuation of dapsone.
Asunto(s)
Dapsona/efectos adversos , Hipersensibilidad a las Drogas/etiología , Corazón/efectos de los fármacos , Miocardio/patología , Adulto , Dapsona/uso terapéutico , Hipersensibilidad a las Drogas/diagnóstico , Resultado Fatal , Femenino , Humanos , Leprostáticos/efectos adversos , Leprostáticos/uso terapéutico , Lepra/tratamiento farmacológico , SíndromeRESUMEN
Antibodies against adeno-associated viral (AAV) vectors are highly prevalent in humans. Both preclinical and clinical studies showed that antibodies against AAV block transduction even at low titers, particularly when the vector is introduced into the bloodstream. Here we measured the neutralizing antibody (NAb) titer against AAV serotypes 2, 5, 6 and 8 in the serum and matched synovial fluid (SF) from rheumatoid arthritis patients. The titer in the SF was lower than that in the matched plasma samples, indicating a difference in distribution of NAb to AAV depending on the body fluid compartment. This difference was more evident for AAV2, against which higher titers were measured. Of all serotypes, anti-AAV5 antibodies were the least prevalent in both the serum and SF. We next evaluated the impact of B-cell depletion on anti-AAV antibodies in rheumatoid arthritis patients who received one or two courses of the anti-CD20 antibody rituximab as part of their disease management. A drop of NAb titer was observed in a subset of those subjects carrying NAb titers ≤1:1000; however, only in a minority of subjects titers dropped below 1:5. This work provides insights into strategies to overcome the limitation of pre-existing humoral immunity to AAV vectors.
Asunto(s)
Dependovirus/inmunología , Vectores Genéticos/inmunología , Inmunidad Humoral , Líquido Sinovial/inmunología , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Anticuerpos Neutralizantes/inmunología , Artritis Reumatoide/terapia , Linfocitos B/inmunología , Dependovirus/genética , Terapia Genética , Vectores Genéticos/sangre , Vectores Genéticos/genética , Humanos , Inmunoterapia , Rituximab , Transducción GenéticaRESUMEN
OBJECTIVES: The mechanism of action of treatment with tumour necrosis factor (TNF) blockers in rheumatoid arthritis (RA) is still not completely understood. The aim of this study was to test if adalimumab treatment could affect the influx of monocytes into the synovium. METHODS: A novel technique was used to analyse the migration of labelled autologous monocytes before and 14 days after initiation of adalimumab treatment using scintigraphy. CD14 monocytes were isolated from patients with RA, using a positive selection procedure with magnetic-activated cell sorting, and labelled with technetium-99m-hexamethylpropylene-amino-oxime. Scintigraphic scans were made 1, 2 and 3 h after re-infusion. RESULTS: As early as 14 days after the start of treatment with adalimumab a significant decrease in disease activity score evaluated in 28 joints was shown. There was no significant decrease in the influx of monocytes into the joint at this time. CONCLUSIONS: This study indicates that adalimumab treatment does not reduce the influx of monocytes into the synovium early after initiation of treatment. As previous studies showed a rapid decrease in macrophage infiltration after TNF-antibody therapy, which could not be explained by increased cell death, this points to an important role for enhanced efflux of inflammatory cells from the synovium.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Antirreumáticos/farmacología , Artritis Reumatoide/tratamiento farmacológico , Monocitos/efectos de los fármacos , Membrana Sinovial/patología , Adalimumab , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antirreumáticos/uso terapéutico , Artritis Reumatoide/patología , Movimiento Celular/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monocitos/fisiología , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
OBJECTIVES: Immunoglobulin (Ig) free light chains (FLCs) are short-lived B cell products that contribute to inflammation in several experimental disease models. In this study, FLC concentrations in inflamed joints of patients with rheumatoid arthritis (RA) as compared to patients with osteoarthritis were investigated. In addition, the relationship of FLCs and disease activity upon B cell depletion (rituximab) in patients with RA was studied. METHODS: Synovial fluid (SF) and tissue from patients with RA were analysed for local presence of FLCs using ELISA and immunohistochemistry. In addition, FLC concentrations were measured (at baseline, 3 and 6 months after treatment) in 50 patients with RA with active disease who were treated with rituximab. Changes in FLCs were correlated to changes in disease activity and compared to alterations in IgM, IgG, IgA, IgM-rheumatoid factor (RF) and IgG-anti-citrullinated protein antibody (ACPA) concentrations. RESULTS: FLCs were detected in synovial tissue from patients with RA, and high FLC concentrations were found in SF from inflamed joints, which positively correlate with serum FLC concentrations. Serum FLC concentrations significantly correlated with disease activity score using 28 joint counts, erythrocyte sedimentation rate (ESR) and C reactive protein, and changes in FLC correlated with clinical improvement after rituximab treatment. Moreover, effect of treatment on FLC concentrations discriminated clinical responders from non-responders, whereas IgM-RF and IgG-ACPA significantly decreased in both patient groups. CONCLUSIONS: FLCs are abundantly present in inflamed joints and FLC levels correlate with disease activity. The correlation of FLC concentrations and disease activity indicates that FLCs may be relevant biomarkers for treatment response to rituximab in patients with RA and suggests that targeting FLC may be of importance in the therapy of RA.
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Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Cadenas Ligeras de Inmunoglobulina/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD20/inmunología , Artritis Reumatoide/inmunología , Autoanticuerpos/metabolismo , Biomarcadores/metabolismo , Femenino , Humanos , Cadenas Ligeras de Inmunoglobulina/sangre , Inmunoglobulinas/metabolismo , Masculino , Persona de Mediana Edad , Osteoartritis de la Rodilla/inmunología , Péptidos Cíclicos/inmunología , Factor Reumatoide/metabolismo , Rituximab , Membrana Sinovial/inmunología , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVES: To analyse whether persistence of synovial B lineage cells and lack of clinical response to rituximab treatment in patients with rheumatoid arthritis (RA) are associated with low rituximab serum levels and anti-rituximab antibody (ARA) formation. METHODS: Fifty-eight patients with RA were treated with rituximab. The clinical response was determined 24 weeks after each treatment course using the Disease Activity Score evaluated in 28 joints (DAS28) and EULAR response criteria. Rituximab serum levels, ARAs and synovial B lineage cell numbers were determined before and after treatment. RESULTS: Four weeks after treatment rituximab serum levels were highly variable. Low rituximab levels were associated with ARA formation (in five patients (8.6%)) and high baseline erythrocyte sedimentation rate. Interestingly, serum rituximab levels were not related to persistence of synovial B lineage cells or clinical response. Furthermore, response to treatment and re-treatment was similar in ARA-positive and ARA-negative patients. CONCLUSION: There is clear variability in serum levels after rituximab treatment, but rituximab levels are not lower in patients with persistence of synovial B lineage cells or lack of clinical response. The current treatment schedule suffices to induce and maintain a clinical response, even when ARAs are formed.
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Anticuerpos Antiidiotipos/sangre , Anticuerpos Monoclonales/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Membrana Sinovial/inmunología , Anticuerpos Monoclonales/sangre , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales de Origen Murino , Artritis Reumatoide/sangre , Artritis Reumatoide/inmunología , Subgrupos de Linfocitos B/efectos de los fármacos , Subgrupos de Linfocitos B/inmunología , Estudios de Cohortes , Femenino , Humanos , Masculino , Rituximab , Índice de Severidad de la Enfermedad , Resultado del TratamientoAsunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos/sangre , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino , Femenino , Humanos , Infliximab , Masculino , Persona de Mediana Edad , RituximabRESUMEN
OBJECTIVE: Atacicept is a recombinant fusion protein that binds and neutralizes B lymphocyte stimulator and a proliferation-inducing ligand. The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of atacicept treatment in patients with rheumatoid arthritis (RA) and to collect exploratory data on clinical outcomes. METHODS: In this multicenter, phase Ib, randomized, placebo-controlled, dose-escalating trial, 73 patients were enrolled into 6 escalating-dose cohorts. Patients received atacicept or placebo as single doses (70, 210, or 630 mg) or as repeated doses given at 2-week intervals (3 doses of 70 mg, 3 doses of 210 mg, or 7 doses of 420 mg), followed by 10 weeks of trial assessments, with a followup assessment at 3 months after the final dose. RESULTS: Atacicept was well tolerated, with few differences between treatment groups and no obvious safety concerns. The pharmacokinetics profile was nonlinear, but was consistent and predictable across all doses and regimens. Treatment-related decreases in immunoglobulin (particularly IgM) and rheumatoid factor levels were evident, and a clear decrease in anti-citrullinated protein antibodies was observed in the cohort that received 7 doses of 420 mg. The B cell response was biphasic, with an initial transient increase (dominated by memory B cells) followed by a dose-related decrease (dominated by mature B cells). Clinical assessments showed trends toward improvement with the 3-month treatment. Little effect on the erythrocyte sedimentation rate or C-reactive protein levels was seen. CONCLUSION: Atacicept was well tolerated both systemically and locally. The results demonstrated that the biologic activity of atacicept was consistent with its mechanism of action.
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Antirreumáticos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Proteínas Recombinantes de Fusión/administración & dosificación , Antirreumáticos/efectos adversos , Antirreumáticos/farmacocinética , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Linfocitos B/inmunología , Biomarcadores/sangre , Cartílago/patología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Citometría de Flujo , Humanos , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Masculino , Persona de Mediana Edad , Placebos , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacocinética , Resultado del TratamientoRESUMEN
OBJECTIVE: To investigate the synovial tissue in patients with rheumatoid arthritis (RA) treated with rituximab and to identify possible predictors of clinical response. METHODS: A total of 24 patients with RA underwent synovial biopsy before, 4 and 16 weeks after initiation of rituximab treatment (without peri-infusional corticosteroids to prevent bias). Immunohistochemical analysis was performed and stained sections were analysed by digital image analysis. Linear regression analysis was used to identify predictors of clinical response. RESULTS: The 28-joint Disease Activity Score (DAS28) was unaltered at 4 weeks, but significantly reduced at 16 and 24 weeks. Serum levels of IgM-rheumatoid factor (RF) decreased significantly at 24 weeks and anti-citrullinated peptide antibody (ACPA) levels at 36 weeks. Peripheral blood B cells were depleted at 4 weeks and started to return at 24 weeks. Synovial B cells were significantly decreased at 4 weeks, but were not completely depleted in all patients; there was a further reduction at 16 weeks in some patients. We found a significant decrease in macrophages at 4 weeks, which was more pronounced at 16 weeks. At that timepoint, T cells were also significantly decreased. The reduction of plasma cells predicted clinical improvement at 24 weeks. CONCLUSIONS: The results support the view that B cells orchestrate local cellular infiltration. The kinetics of the serological as well as the tissue response in clinical responders are consistent with the notion that rituximab exerts its effects in part by an indirect effect on plasma cells associated with autoantibody production, which could help explain the delayed response after rituximab treatment.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Antirreumáticos/farmacología , Artritis Reumatoide/inmunología , Membrana Sinovial/efectos de los fármacos , Adulto , Anciano , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales de Origen Murino , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Autoanticuerpos/sangre , Subgrupos de Linfocitos B/efectos de los fármacos , Biomarcadores/metabolismo , Biopsia , Femenino , Estudios de Seguimiento , Humanos , Inmunoglobulina M/sangre , Masculino , Persona de Mediana Edad , Péptidos Cíclicos/inmunología , Pronóstico , Factor Reumatoide/sangre , Rituximab , Índice de Severidad de la Enfermedad , Membrana Sinovial/inmunología , Subgrupos de Linfocitos T/efectos de los fármacos , Resultado del TratamientoRESUMEN
Recent research has shown that the humoral response plays an important role in the pathogenesis of rheumatoid arthritis. B-cells produce rheumatoid factors and antibodies directed against cyclic citrullinated peptides (anti-CCP antibodies) and are able to present auto-antigens to T-cells. Furthermore, B-cells can produce cytokines and stimulate T-cells. B-cell depletion with rituximab, a monoclonal antibody directed against CD20, has a surprisingly strong and long-lasting therapeutic effect. After administration a sharp decrease of specific auto-antibody titres has been observed. Future developments in B-cell targeted therapy are expected to lead to further improvements in the treatment of rheumatoid arthritis and other autoimmune diseases.