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1.
Pain Rep ; 9(2): e1143, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38680212

RESUMO

Introduction: The use of medicinal cannabis for managing pain expands, although its efficacy and safety have not been fully established through randomized controlled trials. Objectives: This structured, prospective questionnaire-based cohort was aimed to assess long-term effectiveness and safety of cannabis oil extracts in patients with chronic pain. Methods: Adult Israeli patients licensed to use cannabis oil extracts for chronic pain were followed prospectively for 6 months. The primary outcome measure was change from baseline in average weekly pain intensity, and secondary outcomes were changes in related symptoms and quality of life, recorded before treatment initiation and 1, 3, and 6 months thereafter. Generalized linear mixed model was used to analyze changes over time. In addition, "responders" (≥30% reduction in weekly pain at any time point) were identified. Results: The study included 218 patients at baseline, and 188, 154, and 131 at 1, 3, and 6 months, respectively. At 6 months, the mean daily doses of cannabidiol and Δ9-tetrahydrocannabinol were 22.4 ± 24.0 mg and 20.8 ± 30.1 mg, respectively. Pain decreased from 7.9 ± 1.7 at baseline to 6.6 ± 2.2 at 6 months (F(3,450) = 26.22, P < 0.0001). Most secondary parameters also significantly improved. Of the 218 participants, 24% were "responders" but could not be identified by baseline parameters. "Responders" exhibited higher improvement in secondary outcomes. Adverse events were common but mostly nonserious. Conclusion: This prospective cohort demonstrated a modest overall long-term improvement in chronic pain and related symptoms and a reasonable safety profile with the use of relatively low doses of individually titrated Δ9-tetrahydrocannabinol and cannabidiol.

2.
Cell ; 185(8): 1373-1388.e20, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35381199

RESUMO

Systemic sclerosis (scleroderma, SSc) is an incurable autoimmune disease with high morbidity and mortality rates. Here, we conducted a population-scale single-cell genomic analysis of skin and blood samples of 56 healthy controls and 97 SSc patients at different stages of the disease. We found immune compartment dysfunction only in a specific subtype of diffuse SSc patients but global dysregulation of the stromal compartment, particularly in a previously undefined subset of LGR5+-scleroderma-associated fibroblasts (ScAFs). ScAFs are perturbed morphologically and molecularly in SSc patients. Single-cell multiome profiling of stromal cells revealed ScAF-specific markers, pathways, regulatory elements, and transcription factors underlining disease development. Systematic analysis of these molecular features with clinical metadata associates specific ScAF targets with disease pathogenesis and SSc clinical traits. Our high-resolution atlas of the sclerodermatous skin spectrum will enable a paradigm shift in the understanding of SSc disease and facilitate the development of biomarkers and therapeutic strategies.


Assuntos
Escleroderma Sistêmico , Células Cultivadas , Fibroblastos/metabolismo , Fibrose , Humanos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/genética , Pele/metabolismo
3.
J Investig Med ; 70(2): 446-448, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35022250

RESUMO

Cannabis has a wide range of favorable clinical effects on pain, sleep, mood, gastrointestinal symptom, appetite and physical activity, factors that may affect the metabolic profile of the consumer. In this study, we prospectively evaluated patients recently starting medical cannabis treatment. All patients from the rheumatology clinic, who were just approved for medical cannabis treatment for resistant chronic pain, were recruited. After consent, demographic and clinical parameters were documented, including indication for medical cannabis treatment, way of consumption, type of cannabis and monthly dose of medical cannabis. Fasting morning blood glucose, hemoglobin A1c, insulin, lipid profile, cortisol and uric acid levels, in addition to body weight, were obtained just prior to and 3 months following cannabis consumption. Wilcoxon' sign rank test was used to compare baseline levels to those obtained 3 months later. Twenty-eight patients completed the study. Mean age of the patients was 47.8±9.1 years and ~70% were female patients. 75% of all the patients had fibromyalgia. Mean monthly consumed cannabis amount was 22.21±3.6 g, and 21 (75%) patients used extracts (oil). There was no significant change in any parameter evaluated. The results of our study seem to indicate that medical cannabis, mainly extracts, have no significant effect on any parameter of the metabolic profile of patients with chronic pain syndrome, during 3 months of initial use.


Assuntos
Dor Crônica/tratamento farmacológico , Maconha Medicinal/uso terapêutico , Adulto , Cannabis/efeitos adversos , Feminino , Hemoglobinas Glicadas , Humanos , Masculino , Pessoa de Meia-Idade , Extratos Vegetais , Estudos Prospectivos
4.
Isr Med Assoc J ; 22(9): 557-563, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33236554

RESUMO

BACKGROUND: Tocilizumab is an interleukin 6 (IL-6) receptor antagonist used treat moderate to severe active rheumatoid arthritis (RA). Both intravenous (IV) and subcutaneous (SC) routes are approved for the treatment of adults with RA. OBJECTIVES: To evaluate SC tocilizumab in a real-life clinical setting. METHODS: Our study was a multi-center, open-label, single-arm study. Participants were adults with a diagnosis of active RA, previously treated with disease-modifying antirheumatic drugs (DMARDs), with or without biologic agents. Participants received a weekly SC injection of tocilizumab 162 mg as monotherapy or in combination with methotrexate or DMARDs for 24 weeks. Efficacy, safety, and immunogenicity were assessed. RESULTS: Treatment of 100 patients over 24 weeks resulted in improvement in all efficacy parameters assessed: Clinical Disease Activity Index, Disease Activity Score using 28 joint counts and erythrocyte sedimentation rate, American College of Rheumatology response scores, Simplified Disease Activity Index, tender and swollen joint counts, and patient-reported outcomes including fatigue, global assessment of disease activity, pain, and Health Assessment Quality of Life Disease Index. Improvement was achieved as early as the second week of treatment. There were 473 adverse events (AEs)/100 patient-years (PY) and 16.66 serious AEs/100 PY. The most common AEs were neutropenia (12%), leukopenia (11%), and increased hepatic enzymes (11%). Of a total of 42 PY, the rates of serious infections and AEs leading to discontinuation were 4.8, and 11.9 events/100 PY, respectively. CONCLUSIONS: The safety, tolerability, and efficacy profile of tocilizumab SC were comparable to those reported in other studies evaluating the IV and SC routes of administration.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/efeitos adversos , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Injeções Subcutâneas , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente
5.
Eur J Clin Invest ; 50(9): e13268, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32478417

RESUMO

BACKGROUND: Mood disorders, such as anxiety and depression, are extremely prevalent among patients with rheumatoid arthritis (RA). In this study, we assessed the impact of treatment with tocilizumab (TCZ), an IL-6 antagonist, upon anxiety and depressive symptoms in a cohort of RA patients. MATERIALS AND METHODS: Study participants were adults diagnosed with RA who received a weekly subcutaneous injection of tocilizumab for 24 weeks. We used the Hamilton Depression (HDRS) and Anxiety (HAMA) scores in order to assess the severity of depression and anxiety, respectively. RA disease activity indices and depression and anxiety levels were assessed at baseline, 4 weeks and study completion. RESULTS: Ultimately, 91 patients were included in the study. The mean age was 54 years, and the majority were female (79%). The mean score in all disease activity indices as well as depression and anxiety levels decreased dramatically from baseline to study completion. Sixty patients (66%) demonstrated a significant decrease in anxiety and/or depression levels. When logistic regression was performed, an HDRS score indicative of depression at study baseline demonstrated an independent association with a significant psychiatric response whilst older age and increased baseline weight were negatively associated. HAMA and HDRA scores correlated with the following RA disease activity parameters, respectively; HAQ-DI (r = .4, .42), DAS28 (r = .29, .32) and CDAI (0.28 and 0.33), all of them were statistically significant (P < .01). CONCLUSIONS: This study has demonstrated a favourable impact of TCZ therapy on parameters reflecting depression and anxiety severity in patients with RA.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Ansiedade/psicologia , Artrite Reumatoide/tratamento farmacológico , Depressão/psicologia , Adulto , Fatores Etários , Idoso , Artrite Reumatoide/fisiopatologia , Artrite Reumatoide/psicologia , Peso Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento
6.
Sci Rep ; 9(1): 1351, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718650

RESUMO

Rheumatoid Arthritis (RA) causes chronic inflammation of joints. The cytokines TNFα and IFNγ are central players in RA, however their source has not been fully elucidated. Natural Killer (NK) cells are best known for their role in elimination of viral-infected and transformed cells, and they secrete pro-inflammatory cytokines. NK cells are present in the synovial fluids (SFs) of RA patients and are considered to be important in bone destruction. However, the phenotype and function of NK cells in the SFs of patients with erosive deformative RA (DRA) versus non-deformative RA (NDRA) is poorly characterized. Here we characterize the NK cell populations present in the blood and SFs of DRA and NDRA patients. We demonstrate that a distinct population of activated synovial fluid NK (sfNK) cells constitutes a large proportion of immune cells found in the SFs of DRA patients. We discovered that although sfNK cells in both DRA and NDRA patients have similar phenotypes, they function differently. The DRA sfNK secrete more TNFα and IFNγ upon exposure to IL-2 and IL-15. Consequently, we suggest that sfNK cells may be a marker for more severely destructive RA disease.


Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Células Matadoras Naturais/imunologia , Líquido Sinovial/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/sangue , Estudos de Casos e Controles , Feminino , Humanos , Interferon gama/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Receptores de Células Matadoras Naturais/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
7.
Isr Med Assoc J ; 20(4): 239-244, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29629732

RESUMO

BACKGROUND: Chronic fatigue is common among patients with rheumatoid arthritis (RA), affecting quality of life. Osteoporosis is a prevalent co-morbidity in RA patients. OBJECTIVES: To assess the effect of long-term treatment with tocilizumab on fatigue and bone mineral density (BMD) in RA patients with inadequate response to synthetic or biologic disease-modifying anti-rheumatic drugs. METHODS: In this multicenter, open-label, non-controlled, single-arm study, patients ≥ 18 years of age received intravenous tocilizumab 8 mg/kg every 4 weeks for 96 weeks. The primary outcome was the change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score from baseline to weeks 24, 48, 72, and 96. BMD was assessed before and 96 weeks after treatment. RESULTS: The study comprised 145 patients (mean age 53.4 ± 13.4 years, 83.4% women). Of these, 88 (60.7%) completed the 2 year treatment period. The mean FACIT-Fatigue score improved consistently starting from week 4 and showed a statistically significant increase of 5.0 ± 9.7, 6.8 ± 10.5, 7.3 ± 10.9, and 7.3 ± 10.4 from baseline to weeks 24, 48, 72, and 96, respectively (P < 0.0001). Mean BMD of femoral neck and total spine remained stable. Disease activity, acute phase reactants, and composite efficacy measures decreased during the study, while hemoglobin levels increased. Adverse events and serious adverse events were as expected for the known and previously described data. CONCLUSIONS: Tocilizumab therapy for 2 years significantly and clinically decreased fatigue. BMD remained stable and no new safety issue was reported.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Densidade Óssea/efeitos dos fármacos , Fadiga/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/efeitos adversos , Artrite Reumatoide/fisiopatologia , Doença Crônica , Fadiga/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
8.
Science ; 359(6382): 1376-1383, 2018 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-29519916

RESUMO

Obesity, diabetes, and related manifestations are associated with an enhanced, but poorly understood, risk for mucosal infection and systemic inflammation. Here, we show in mouse models of obesity and diabetes that hyperglycemia drives intestinal barrier permeability, through GLUT2-dependent transcriptional reprogramming of intestinal epithelial cells and alteration of tight and adherence junction integrity. Consequently, hyperglycemia-mediated barrier disruption leads to systemic influx of microbial products and enhanced dissemination of enteric infection. Treatment of hyperglycemia, intestinal epithelial-specific GLUT2 deletion, or inhibition of glucose metabolism restores barrier function and bacterial containment. In humans, systemic influx of intestinal microbiome products correlates with individualized glycemic control, indicated by glycated hemoglobin levels. Together, our results mechanistically link hyperglycemia and intestinal barrier function with systemic infectious and inflammatory consequences of obesity and diabetes.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Infecções por Escherichia coli/fisiopatologia , Hiperglicemia/fisiopatologia , Enteropatias/microbiologia , Enteropatias/fisiopatologia , Animais , Células CACO-2 , Reprogramação Celular , Citrobacter rodentium , Escherichia coli Enteropatogênica , Microbioma Gastrointestinal , Deleção de Genes , Glucose/metabolismo , Glucose/farmacologia , Transportador de Glucose Tipo 2/genética , Humanos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/fisiopatologia , Camundongos , Camundongos Endogâmicos , Obesidade/fisiopatologia , Permeabilidade , Receptores para Leptina/genética , Estreptozocina
9.
Rheumatol Int ; 34(6): 857-60, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23412691

RESUMO

Inflammatory large-vessel vasculitis in Behçet's disease may cause life-threatening arterial aneurysms that are prone to rupture. We report a patient with Behçet's disease with right ventricular thrombus and large aneurysms of the pulmonary arteries that led to recurrent episodes of hemoptysis. Following relapses and only partial response to repeated courses of cyclophosphamide and steroids, the patient was treated with adalimumab (Humira) and is now in clinical remission for over 30 months, with regression of her pulmonary lesions. Anti-TNFα treatment is a potential therapeutic option in patients with life-threatening complications due to large-vessel vasculitis.


Assuntos
Aneurisma/diagnóstico por imagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Síndrome de Behçet/tratamento farmacológico , Cardiopatias/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Artéria Pulmonar/diagnóstico por imagem , Trombose/diagnóstico por imagem , Adalimumab , Adulto , Aneurisma/etiologia , Síndrome de Behçet/complicações , Ecocardiografia , Feminino , Cardiopatias/etiologia , Hemoptise/etiologia , Humanos , Trombose/etiologia , Tomografia Computadorizada por Raios X , Resultado do Tratamento
10.
Immunol Res ; 56(2-3): 376-81, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23584986

RESUMO

We have previously shown that lupus antibodies directed against extracellular membrane components bind to the kidneys and cause damage. The target epitope was a peptide located at the globular part of the α-chain of laminin, designated VRT-101. The titers of anti-VRT-101 antibodies correlated with disease activity and demonstrated pathogenic properties. In the present study, we set out to test the feasibility and safety of treating SLE patients with extracorporeal immunoadsorption on the VRT-101 coupled column, Lupusorb, in an attempt to eliminate these pathogenic antibodies. Ten SLE patients were enrolled and treated with a single session of plasmapheresis combined with serum filtration through Lupusorb. The follow-up period was from recruitment until 8 weeks post-treatment. Monitoring of subjects included documentation of adverse events, anti-VRT-101 levels, SLE inflammatory markers (anti-DNA, CRP, C3, C4, urine protein) and clinical assessment (SLEDAI score). A total of 11 adverse experiences were documented in 7 patients, none of which required withdrawal from the study. Eight adverse experiences were unrelated or unlikely related to treatment. The remaining 3 were classified as possibly treatment related and were attributed to the plasmapheresis procedure. Following Lupusorb treatment, a statistically significant decrease was detected in the serum level of anti-VRT-101 antibodies (38.75% reduction; p = 0.009). Concomitantly, a favorable trend was observed in disease activity markers as well as in the SLEDAI score. Our data indicate that Lupusorb is a safe and effective modality for eliminating anti-VRT-101 antibodies. Additional studies are warranted to confirm its therapeutic potential.


Assuntos
Técnicas de Imunoadsorção , Laminina/imunologia , Inibidor de Coagulação do Lúpus/sangue , Lúpus Eritematoso Sistêmico/terapia , Adulto , Proteína C-Reativa/metabolismo , Complemento C3/metabolismo , Complemento C4/metabolismo , Progressão da Doença , Epitopos de Linfócito B/imunologia , Circulação Extracorpórea , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Mediadores da Inflamação/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Plasmaferese/métodos , Resultado do Tratamento
11.
J Rheumatol ; 39(8): 1628-31, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22753647

RESUMO

OBJECTIVE: To characterize the clinical manifestations of patients with antiphospholipid antibody syndrome (APS) and pulmonary hemorrhage (PH). METHODS: We performed a retrospective, single-center analysis of patients with APS who were followed up from 1980 to 2011. Of these patients, only those who fulfilled the Sydney criteria for APS were included. Patients with APS that manifested with PH were called the PHAPS group. The rest of the patients with APS served as controls. Clinical manifestations were compared between the PHAPS group and controls. RESULTS: Sixty-three patients fulfilled the criteria for APS. Thirteen experienced PH and were included in the PHAPS group. Seventy-five percent of the patients with PHAPS and 22% of the controls had mitral valve disease (p = 0.001). Central nervous system (CNS) involvement (cerebrovascular accident, seizures) was present in 61% and 16% of the patients with PHAPS and controls, respectively (p = 0.001). Skin involvement (livedo reticularis, chronic leg ulcers) was present in 54% and 8% of the patients with PHAPS and controls (p = 0.001). Pregnancy morbidity occurred in 87.5% and 32.5% of the patients with PHAPS and controls (p = 0.005). Ninety-two percent and 83% of the patients with PHAPS had high-titer immunoglobulin γ (IgG) anticardiolipin and ß(2)-glycoprotein I IgG antibodies compared to 43% and 30% of the controls (p = 0.002, p < 0.001, respectively). CONCLUSION: Patients with PHAPS were more likely than controls to have mitral valve disease, skin disease, CNS involvement, and pregnancy morbidity as well as high-titer APS. PHAPS seems to be a unique subgroup of all patients with APS.


Assuntos
Síndrome Antifosfolipídica/complicações , Hemorragia/etiologia , Pneumopatias/etiologia , Adulto , Anticorpos Anticardiolipina/imunologia , Síndrome Antifosfolipídica/imunologia , Feminino , Hemorragia/imunologia , Humanos , Pneumopatias/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
12.
Am J Dermatopathol ; 32(2): 118-28, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20010285

RESUMO

This study analyzes the histopathological findings in H syndrome, a recently recognized autosomal recessive genodermatosis characterized by indurated, hyperpigmented, and hypertrichotic skin in well-defined anatomical areas accompanied by various systemic manifestations. So far, descriptions of the histopathological skin changes in this disorder, as reported in a few small case series, were inconsistent, leading to diverse clinical interpretations. In an attempt to define standardized, diagnostic, morphological criteria that will distinguish this disorder from other fibrosing conditions, we studied skin biopsies from 10 patients with H syndrome. The characteristic morphology included widespread fibrosis (moderate in dermis and severe in subcutis); striking mononuclear infiltrates consisting mainly of monocyte-derived cells (small CD68 histiocytes and CD34 and FXIIIa dendrocytes) and plasma cells; and thickened, fragmented, and partially calcified elastic fibers, admixed with well-formed psammoma bodies, a previously unrecognized feature in nonneoplastic skin and subcutaneous conditions. In addition, the ultrastructure of CD68 small histiocytes exhibited distended endoplasmic reticulum and scarcity of lysosomes, features typical for fibroblasts but unusual for histiocytes. These unusual findings in the histiocytes pose a question as to their possible role in the fibrotic cascade in this disorder. We conclude that the above findings are essential for the diagnosis of H syndrome and that incisional biopsies are mandatory for recognition of the full spectrum of histopathological findings.


Assuntos
Hiperpigmentação/patologia , Hipertricose/patologia , Escleroderma Sistêmico/patologia , Dermatopatias/patologia , Adolescente , Adulto , Antígenos CD/metabolismo , Antígenos CD34/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Biópsia , Criança , Tecido Elástico/ultraestrutura , Retículo Endoplasmático/ultraestrutura , Feminino , Histiócitos/metabolismo , Histiócitos/patologia , Histiócitos/ultraestrutura , Humanos , Hiperpigmentação/diagnóstico , Hiperpigmentação/metabolismo , Hipertricose/diagnóstico , Hipertricose/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Lisossomos/ultraestrutura , Masculino , Plasmócitos/metabolismo , Plasmócitos/patologia , Plasmócitos/ultraestrutura , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/metabolismo , Pele/metabolismo , Pele/patologia , Pele/ultraestrutura , Dermatopatias/diagnóstico , Dermatopatias/metabolismo , Síndrome , Adulto Jovem
13.
Rheumatology (Oxford) ; 48(11): 1455-9, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19837680

RESUMO

OBJECTIVE: FMF is an autosomal recessive hereditary disease, associated with a single gene named MEFV. This gene is considered to be responsible only for FMF. In the present study, we tried to find out whether the MEFV gene is associated with or responsible for clinical conditions other than FMF. METHODS: We looked for patients who presented with signs and symptoms not typical for FMF but carried MEFV mutations. We also searched for reports about similar conditions in the English medical literature, and we surveyed the website 'Infevers' for MEFV mutations defined as associated with 'atypical FMF'. RESULTS: We encountered three patients carrying MEFV mutations who presented with distinct clinical presentations not typical of FMF. We identified additional reports about MEFV-related non-FMF disease entities such as palindromic rheumatism. By screening the 'Infevers' website, we further disclosed 13 cases with MEFV mutations that were defined as 'atypical FMF' and 4 cases categorized as 'recurrent arthritis'. CONCLUSIONS: These findings suggest that the MEFV gene is associated with clinical conditions other than FMF. Changing our concept regarding the MEFV gene and its link to such clinical phenotypes may call for a higher awareness of the existence of additional autoinflammatory diseases. Furthermore, a correct diagnosis of these MEFV gene mutation-associated syndromes will justify a therapeutic trial with colchicine, thereby relieving suffering of many patients who up to now have been misdiagnosed.


Assuntos
Proteínas do Citoesqueleto/genética , Doenças Hereditárias Autoinflamatórias/genética , Mutação , Adulto , Criança , Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/genética , Feminino , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Doenças Hereditárias Autoinflamatórias/patologia , Humanos , Masculino , Pirina , Dermatopatias Vasculares/tratamento farmacológico , Dermatopatias Vasculares/genética , Dermatopatias Vasculares/patologia , Moduladores de Tubulina/uso terapêutico , Adulto Jovem
14.
J Am Acad Dermatol ; 59(1): 79-85, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18410979

RESUMO

BACKGROUND: The association of cutaneous hyperpigmented, hypertrichotic, and indurated patches associated with hearing loss, short stature, cardiac anomalies, hepatosplenomegaly, scrotal masses, and hypogonadism has not, to our knowledge, been previously recognized as a disease entity. OBJECTIVE: We describe 10 patients with the above-mentioned findings. METHODS: Patients were clinically examined and extensive laboratory evaluation was performed. RESULTS: We describe 10 patients from 6 Arab consanguineous families with hyperpigmented, hypertrichotic, and indurated cutaneous patches involving the middle and lower parts of their bodies. In addition, patients displayed short stature, sensorineural hearing loss, cardiac anomalies, hepatosplenomegaly, and scrotal masses. Laboratory evaluation revealed growth hormone deficiency and hypergonadotropic hypogonadism with azoospermia. Cutaneous histopathologic examination showed hyperpigmentation of the basal layer with seborrheic-keratosis-like acanthosis, histiocytic infiltration, and a perivascular mononuclear infiltrate with plasma cells and mast cells throughout the dermis and subcutaneous fat. Comparison with several patients, recently reported in the medical literature, with similar cutaneous findings is made. LIMITATIONS: Laboratory evaluation in some patients was incomplete because of lack of cooperation. CONCLUSIONS: We suggest that our patients represent a novel multisystemic autosomal recessive inherited disorder. We call this constellation of symptoms the "H syndrome."


Assuntos
Perda Auditiva Neurossensorial/diagnóstico , Hiperpigmentação/diagnóstico , Hipertricose/diagnóstico , Dermatopatias Genéticas/diagnóstico , Adolescente , Adulto , Biópsia , Consanguinidade , Feminino , Fibrose , Doenças dos Genitais Masculinos/diagnóstico , Cardiopatias Congênitas/diagnóstico , Hepatomegalia/diagnóstico , Humanos , Linfonodos/patologia , Masculino , Fenótipo , Pele/patologia , Esplenomegalia/diagnóstico , Síndrome
15.
J Immunol ; 179(2): 1225-35, 2007 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-17617615

RESUMO

The synovial fluid (SF) cells of rheumatoid arthritis (RA) patients express a specific CD44 variant designated CD44vRA. Using a cellular model of this autoimmune disease, we show in this study that the mammalian lectin, galectin-8 (gal-8), is a novel high-affinity ligand of CD44vRA. By affinity chromatography, flow cytometry, and surface plasmon resonance, we demonstrate that gal-8 interacts with a high affinity (K(d), 6 x 10(-9) M) with CD44vRA. We further demonstrate that SF cells from RA patients express and secrete gal-8, to a concentration of 25-65 nM, well within the concentration of gal-8 required to induce apoptosis of SF cells. We further show that not all gal-8 remains freely soluble in the SF and at least part forms triple complexes with CD44 and fibrinogen that can be detected, after fibrinogen immunoprecipitation, with Abs against fibrinogen, gal-8 and CD44. These triple complexes may therefore increase the inflammatory reaction by sequestering the soluble gal-8, thereby reducing its ability to induce apoptosis in the inflammatory cells. Our findings not only shed light on the receptor-ligand relationships between CD44 and gal-8, but also underline the biological significance of these interactions, which may affect the extent of the autoimmune inflammatory response in the SF of RA patients.


Assuntos
Artrite Reumatoide/metabolismo , Galectinas/metabolismo , Receptores de Hialuronatos/metabolismo , Inflamação/metabolismo , Transdução de Sinais/imunologia , Doenças Autoimunes/metabolismo , Western Blotting , Cromatografia de Afinidade , Clonagem Molecular , Fibrinogênio/metabolismo , Citometria de Fluxo , Humanos , Imunoprecipitação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ressonância de Plasmônio de Superfície , Líquido Sinovial/química , Transfecção
16.
J Rheumatol ; 34(8): 1664-9, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17611986

RESUMO

OBJECTIVE: To investigate the distribution of the A2756G polymorphism of the methionine synthase reductase (MTR) gene in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) compared with a healthy control group; and to examine the relationships among the A2756G polymorphism, plasma total homocysteine (tHcy), serum folate and vitamin B12 levels, disease activity, and MTX toxicity in patients with RA. METHODS: A cross-sectional study was performed on 86 MTX-treated RA patients, consisting of a clinical interview and physical examination to determine disease activity and MTX-related adverse reactions. Genotype analysis of the MTR gene was performed. Fasting plasma tHcy, serum folate, and vitamin B12 levels were measured. Allele and genotype distributions were compared to a healthy control group. RESULTS: The frequency of the 2756GG genotype (16.3%) in the RA study group was higher than that expected in the general population (3.6%; p < 0.000001). This genotype was associated with MTX-induced accelerated rheumatoid nodulosis (MIARN). No association of disease activity variables or plasma homocysteine with MTR A2756G polymorphisms was observed. The MTR 2756GG genotype, low plasma vitamin B12 levels, and the presence of rheumatoid nodules predicted MIARN. No association of nodulosis with any other indicator of disease activity or medical treatment was found. CONCLUSION: In our population of MTX-treated RA patients the 2756GG genotype of the MTR gene was more common than expected and was associated with MIARN.


Assuntos
Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Ferredoxina-NADP Redutase/genética , Metotrexato/efeitos adversos , Polimorfismo de Nucleotídeo Único/genética , Nódulo Reumático/induzido quimicamente , Adulto , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/sangue , Estudos de Casos e Controles , Estudos Transversais , Feminino , Genótipo , Homocisteína/sangue , Humanos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Ácidos Pteroilpoliglutâmicos/sangue , Nódulo Reumático/genética , Índice de Gravidade de Doença , Vitamina B 12/sangue
17.
J Autoimmun ; 28(2-3): 99-113, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17383158

RESUMO

Selective targeting of cells engaged in pathological activities is a major challenge for medical research. We generated monoclonal antibodies (mAbs) that exclusively bind, at concentrations ranging from 2 to 100 microg/ml, to a modified CD44 variant (designated CD44vRA) expressed on synovial fluid cells from joints of rheumatoid arthritis (RA) patients. These mAbs cross-reacted with keratinocytes expressing wild type CD44vRA (CD44v3-v10) only at a relatively high concentration (200 microg/ml). Sequence analysis of CD44vRA cDNA revealed, in 33 out of 43 RA and psoriatic arthritis patients, an extra intron-derived trinucleotide, CAG, which allows translation of an extra alanine. This insertion imposes a configurational change on the cell surface CD44 of RA synovial fluid cells, creating an immunogenic epitope and potentiating the ability to produce disease-specific antibodies. Indeed, the anti-CD44vRA mAbs (designated F8:33) were able to induce apoptosis in synovial fluid cells from RA patients, but not in peripheral blood leukocytes from the same patients, in keratinocytes from normal donors or in synovial fluid cells from osteoarthritis patients. Furthermore, injection of anti-CD44vRA mAbs reduced joint inflammation in DBA/1 mice with collagen-induced arthritis. These findings show that anti-CD44vRA mAbs are both bioactive and RA-specific.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Artrite Experimental/terapia , Artrite Reumatoide/imunologia , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/imunologia , Adulto , Idoso , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/biossíntese , Artrite Experimental/genética , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Artrite Psoriásica/genética , Artrite Psoriásica/imunologia , Artrite Psoriásica/metabolismo , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Sequência de Bases , Western Blotting , Clonagem Molecular , Epitopos , Humanos , Receptores de Hialuronatos/metabolismo , Camundongos , Camundongos Endogâmicos DBA , Pessoa de Meia-Idade , Dados de Sequência Molecular , Líquido Sinovial/imunologia , Transfecção
19.
Am J Med Genet A ; 138A(2): 118-26, 2005 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-16152649

RESUMO

Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive syndrome characterized by the presence of spondyloepiphyseal dysplasia associated with pain, stiffness, and swelling of multiple joints, osteoporosis, and the absence of destructive bone changes. The disorder is caused by mutations of the WISP3 gene located on chromosome 6q22. We hereby report the molecular study of the WISP3 gene in nine unrelated consanguineous families originating from the Middle-East: three from Lebanon, five from Syria, and one from Palestinian Bedouin descent, all affected with PPD. Five different sequence variations were identified in the WISP3 gene, two of them being new mutations: the c.589G --> C transversion at codon 197, responsible for a splicing defect (A197fsX201); and the c.536_537delGT deletion (C179fsX), both in exon 3. In all other families, the affected patients were homozygous for a previously described nonsense mutation, namely c.156C --> A (C52X). Interestingly, in the latter families, the C52X mutation was always found associated with a novel c.248G --> A (G83E) variation, suggesting the existence of a founder effect.


Assuntos
Artrite Juvenil/genética , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Proteínas de Neoplasias/genética , Osteocondrodisplasias/genética , Adolescente , Adulto , Artrite Juvenil/patologia , Sequência de Bases , Proteínas de Sinalização Intercelular CCN , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão/métodos , Análise Mutacional de DNA/métodos , Saúde da Família , Feminino , Efeito Fundador , França , Humanos , Masculino , Oriente Médio/etnologia , Mutação , Osteocondrodisplasias/patologia , Linhagem
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