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1.
Rheumatol Int ; 41(8): 1495-1501, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34110466

RESUMO

Fibrodyplasia ossificans progressiva (FOP) is a rare hereditary disease, which has a variable course characterized by occasional flare-ups of heterotopic ossification (HO) in soft tissues that are followed by swelling, stiffness, pain and warmth. Here, we report for the first time a case of a 45-year-old female patient with known FOP recovering from COVID-19 with disease progression potentially linked with the viral illness. In December 2020 the patient contracted a mild form of COVID-19 infection without need for hospital admission. Since January 2021, the patient felt unwell, with occasional abdominal pain which progressively intensified. In March 2021 she presented with new onset of HO, complaining of pain, swelling and thickening sensation in the lower abdomen and left part of the neck. Computerized tomography (CT) and cytokine analysis were performed. CT scan revealed new heterotopic bone formation in multiple soft tissue areas of the neck indicating clear radiological progression. Radiotherapy, which has proven to be an efficient tool to control HO in this patient, was not able to halt HO formation after COVID-19 infection. Cytokine analysis of a plasma sample obtained during a flare-up after COVID-19 infection showed a significantly elevated pro-inflammatory cytokines compared to a flare-up panel prior to infection. Of the 23 analyzed levels of cytokines, a staggering number of 21 were above normal levels. This case is the first confirmation of uncontrolled post-COVID-19 effects in a FOP patient, which manifested with flare-ups followed by progressive HO, possibly caused by a thus far, never described form of post-COVID syndrome.


Assuntos
COVID-19/imunologia , Citocinas/sangue , Mediadores da Inflamação/sangue , Miosite Ossificante/imunologia , Ossificação Heterotópica/imunologia , SARS-CoV-2/imunologia , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/virologia , Feminino , Interações Hospedeiro-Patógeno , Humanos , Pessoa de Meia-Idade , Miosite Ossificante/diagnóstico , Miosite Ossificante/virologia , Ossificação Heterotópica/diagnóstico , Ossificação Heterotópica/virologia , SARS-CoV-2/patogenicidade , Exacerbação dos Sintomas
2.
Curr Osteoporos Rep ; 17(6): 387-394, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31721068

RESUMO

PURPOSE OF REVIEW: Heterotopic ossification (HO) is associated with inflammation. The goal of this review is to examine recent findings on the roles of inflammation and the immune system in HO. We examine how inflammation changes in fibrodysplasia ossificans progressiva, in traumatic HO, and in other clinical conditions of HO. We also discuss how inflammation may be a target for treating HO. RECENT FINDINGS: Both genetic and acquired forms of HO show similarities in their inflammatory cell types and signaling pathways. These include macrophages, mast cells, and adaptive immune cells, along with hypoxia signaling pathways, mesenchymal stem cell differentiation signaling pathways, vascular signaling pathways, and inflammatory cytokines. Because there are common inflammatory mediators across various types of HO, these mediators may serve as common targets for blocking HO. Future research may focus on identifying new inflammatory targets and testing combinatorial therapies based on these results.


Assuntos
Inflamação/imunologia , Miosite Ossificante/imunologia , Ossificação Heterotópica/imunologia , Ferimentos e Lesões/imunologia , Imunidade Adaptativa/imunologia , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Artroplastia de Quadril , Traumatismos por Explosões/imunologia , Lesões Encefálicas Traumáticas/imunologia , Queimaduras/imunologia , Diferenciação Celular/imunologia , Citocinas/imunologia , Humanos , Hipóxia/imunologia , Imunossupressores/uso terapêutico , Inflamação/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Macrófagos/imunologia , Mastócitos/imunologia , Células-Tronco Mesenquimais , Miosite Ossificante/tratamento farmacológico , Ossificação Heterotópica/tratamento farmacológico , Complicações Pós-Operatórias/imunologia , Pirazóis/uso terapêutico , Receptores do Ácido Retinoico/agonistas , Transdução de Sinais , Sirolimo/uso terapêutico , Traumatismos da Medula Espinal/imunologia , Estilbenos/uso terapêutico , Receptor gama de Ácido Retinoico
3.
Med Hypotheses ; 131: 109313, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443758

RESUMO

Fibrodysplasia ossificans progressiva (FOP) is a rare hereditary disease caused by a mutation in the intracellular domain of the activin A receptor type I and is characterized by episodes (flare-ups) of progressive heterotopic endochondral ossification (HO) in the soft tissues. The mutation alone is not sufficient for the occurrence of HO since flare-ups are triggered by inflammation and activation of the innate immune system. A number of cellular and humoral mediators have been implicated in animal and in vitro models. Observations in humans support the inflammatory nature of the condition, but data on the involved mediators are variable. We hypothesize that for induction of flare-ups in patients with FOP increase in at least one of the pro-inflammatory cytokines is both essential and sufficient to trigger the entire process of the inflammatory cells influx resulting in the novel ectopic bone formation and we suggest that C-C motif ligand 5 (CCL5), a pro-inflammatory chemokine also known as Regulated on activation, normal T-cell expressed and secreted (RANTES), might be the key candidate. CCL5 is a chemoattractant for all cellular types implicated in HO and is produced by the cells of the tissue microenvironment at the sites of HO as well as by the pro-inflammatory cellular mediators. CCL5 induces ossification in cultured human pluripotent mesenchymal cells (hMSCs) and in the primary culture of monocytes from FOP patients (but not from their healthy relatives), stimulation with lipopolysaccharide induces CCL5 expression. Finally, in a pilot study we used a panel of 23 cytokines and chemokines to screen the plasma samples of three subjects: a female patient with FOP during a flare-up; a female patient with hyperostosis corticalis generalisata (van Buchem disease), another rare disease characterized by excessive bone formation at the sites where it regularly occurs that does not include inflammatory events; and a healthy woman without bone disorders. There appeared a rather clear-cut signal of a 2-fold higher level of CCL5 in the FOP patient vs. the healthy subject and the van Buchem patient. Evaluation of the hypothesis would require an international prospective study, with main motivation being the lack of a conclusive treatment as the major unmet need in FOP. A treatment targeting CCL5 receptor already exists and is used in HIV-infected patients.


Assuntos
Quimiocina CCL5/sangue , Terapia de Alvo Molecular , Miosite Ossificante/sangue , Ossificação Heterotópica/sangue , Quimiocina CCL5/antagonistas & inibidores , Citocinas/fisiologia , Feminino , Humanos , Inflamação , Lipopolissacarídeos/farmacologia , Células-Tronco Mesenquimais/metabolismo , Modelos Imunológicos , Monócitos/metabolismo , Miosite Ossificante/tratamento farmacológico , Miosite Ossificante/imunologia , Ossificação Heterotópica/imunologia , Osteocondrodisplasias/sangue , Células-Tronco Pluripotentes/metabolismo
4.
JCI Insight ; 3(22)2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30429363

RESUMO

BACKGROUND: Inflammation helps regulate normal growth and tissue repair. Although bone morphogenetic proteins (BMPs) and inflammation are known contributors to abnormal bone formation, how these pathways interact in ossification remains unclear. METHODS: We examined this potential link in patients with fibrodysplasia ossificans progressiva (FOP), a genetic condition of progressive heterotopic ossification caused by activating mutations in the Activin A type I receptor (ACVR1/ALK2). FOP patients show exquisite sensitivity to trauma, suggesting that BMP pathway activation may alter immune responses. We studied primary blood, monocyte, and macrophage samples from control and FOP subjects using multiplex cytokine, gene expression, and protein analyses; examined CD14+ primary monocyte and macrophage responses to TLR ligands; and assayed BMP, TGF-ß activated kinase 1 (TAK1), and NF-κB pathways. RESULTS: FOP subjects at baseline without clinically evident heterotopic ossification showed increased serum IL-3, IL-7, IL-8, and IL-10. CD14+ primary monocytes treated with the TLR4 activator LPS showed increased CCL5, CCR7, and CXCL10; abnormal cytokine/chemokine secretion; and prolonged activation of the NF-κB pathway. FOP macrophages derived from primary monocytes also showed abnormal cytokine/chemokine secretion, increased TGF-ß production, and p38MAPK activation. Surprisingly, SMAD phosphorylation was not significantly changed in the FOP monocytes/macrophages. CONCLUSIONS: Abnormal ACVR1 activity causes a proinflammatory state via increased NF-κB and p38MAPK activity. Similar changes may contribute to other types of heterotopic ossification, such as in scleroderma and dermatomyositis; after trauma; or with recombinant BMP-induced bone fusion. Our findings suggest that chronic antiinflammatory treatment may be useful for heterotopic ossification.


Assuntos
Receptores de Ativinas Tipo I/sangue , Inflamação/complicações , Miosite Ossificante/complicações , NF-kappa B/sangue , Ossificação Heterotópica/etiologia , Quimiocinas/sangue , Citocinas/sangue , Humanos , Inflamação/sangue , Macrófagos/metabolismo , Monócitos/metabolismo , Miosite Ossificante/sangue , Miosite Ossificante/imunologia , Ossificação Heterotópica/sangue , Ossificação Heterotópica/imunologia , Transdução de Sinais , Fator de Crescimento Transformador beta/sangue , Proteínas Quinases p38 Ativadas por Mitógeno/sangue
5.
Cytometry B Clin Cytom ; 94(4): 613-622, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-28985649

RESUMO

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder caused by sporadic heterozygous mutations in ACVR1 gene which progressively leads to severe heterotopic ossification. FOP is characterized by episodic flare-ups triggered by different factors such as viral infections, tissue injuries, vaccinations, or occurring without a recognizable cause. The sporadic course of the disease, the documented presence of an important inflammatory reaction in early lesions and the partial response to corticosteroids support the idea that the immune system, and in particular the innate component, may play a role in FOP pathogenesis. However, an extensive expression profile of the peripheral blood mononuclear cells (PBMC) of FOP patients has never been done. METHODS: In this study, we carried out a wide PBMC immunophenotyping on a cohort of FOP patients and matching controls by multiparametric analysis of the expression of a panel of 37 markers associated with migration, adhesion, inhibition, activation, and cell death of circulating immune cells. RESULTS: We observed a statistically significant increase of the expression of DNAM1 receptor in patients' monocytes as compared to controls, and little but significant differences in the expression profile of CXCR1 (CD181), CD62L, CXCR4 (CD184), and HLA-DR molecules. CONCLUSIONS: DNAM1 had been previously shown to play a pivotal role in monocyte migration through the endothelial barrier and the increased expression detected in patients' monocytes might suggest a role of this surface receptor during the early phases of FOP flare-ups in which the activation of the immune response is believed to represent a crucial event. © 2017 International Clinical Cytometry Society.


Assuntos
Antígenos de Diferenciação de Linfócitos T/biossíntese , Leucócitos Mononucleares/imunologia , Miosite Ossificante/imunologia , Adolescente , Adulto , Criança , Feminino , Humanos , Imunofenotipagem , Leucócitos Mononucleares/metabolismo , Masculino , Miosite Ossificante/metabolismo , Regulação para Cima , Adulto Jovem
6.
BMJ Case Rep ; 20172017 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-28751434

RESUMO

We report a case of an 18-year-old woman, with bilateral acute inflammatory pain on the hip area, during the premenstrual period, and progressive increase in volume and rigidity of both hips. Bilateral exuberant soft tissue calcifications were present on the radiographic exams, and the patient also presented with bilateral short-length hallux valgus. A heterozygous mutation in the protein kinase domain of ACVR1 gene was found, allowing the diagnosis of fibrodysplasia ossificans progressive. Due to the relation between the disease flares and the premenstrual period, the patient was put into a chemically induced amenorrhea, with no new inflammatory crises since.This case illustrates the importance of an accurate diagnosis to prevent unnecessary diagnostic procedures, as well as the need to develop specific treatment strategies to address each patient's particular needs.


Assuntos
Quadril/patologia , Menstruação , Miosite Ossificante/diagnóstico , Receptores de Ativinas Tipo I/genética , Adolescente , Amenorreia/induzido quimicamente , Feminino , Hallux Valgus/diagnóstico , Humanos , Menstruação/imunologia , Mutação , Miosite Ossificante/etiologia , Miosite Ossificante/imunologia
7.
Semin Cell Dev Biol ; 49: 30-6, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26706149

RESUMO

The progressive transformation of one organ system into another is a fundamental signature of fibrodysplasia ossificans progressiva (FOP), the most catastrophic form of extraskeletal bone formation in humans. In all affected individuals, FOP is caused by heterozygous missense gain-of-function mutations in Activin receptor A type I (ACVR1), a bone morphogenetic protein (BMP) type I receptor. Loss of autoinhibition of the mutant receptor (mACVR1) results in dysregulated BMP pathway signaling, and is necessary for the myriad developmental features of FOP, but does not appear sufficient to induce the episodic flare-ups that lead to disabling post-natal heterotopic endochondral ossification (HEO) and that are a hallmark of the disease. Post-natal FOP flare-ups strongly implicate an underlying immunological trigger involving inflammation and the innate immune system. Recent studies implicate canonical and non-canonical TGFß/BMP family ligands in the amplification of mACVR1 signaling leading to the formation of FOP lesions and resultant HEO. BMP and Activin ligands that stimulate mACVR1 signaling also have critical regulatory functions in the immune system. Cross-talk between the morphogenetic and immunological pathways that regulate tissue maintenance and wound healing identifies potential robust therapeutic targets for FOP. Here we review current evidence for an immunological trigger for flare-ups and HEO in FOP, propose a working schema for the pathophysiology of observed phenomena, and highlight outstanding questions under investigation.


Assuntos
Miosite Ossificante/imunologia , Ossificação Heterotópica/imunologia , Receptores de Ativinas Tipo I/genética , Ativinas/fisiologia , Animais , Proteínas Morfogenéticas Ósseas/fisiologia , Humanos , Imunidade Inata , Mutação de Sentido Incorreto , Miosite Ossificante/genética , Ossificação Heterotópica/genética , Transdução de Sinais
8.
Med Hypotheses ; 63(3): 407-8, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15288357

RESUMO

Fibrodysplasia ossificans progressiva (FOP) is a severe, progressive disease of the musculoskeletal system. Muscles, tendons and other connective tissues ossify after minor trauma, and patients often become encased in a second immobile skeleton. There is no known cure or treatment for FOP. It has been found that lymphocytes from FOP patients elaborate excess levels of bone morphogenic protein-4 (BMP-4). Given this, it has been suggested that allogenic bone marrow transplantation (BMT) possibly could be a cure for FOP, and drawn attention to a previously unappreciated case of an FOP patient who had successful BMT for aplastic anemia with apparent short- and medium-term arresting of the FOP disease process. However, BMT has non-trivial associated morbidity and mortality. Here, it is noted that if B cells are found to be the lymphocytes responsible for excess BMP-4 production in FOP, use of Rituximab, a monoclonal anti-CD20 antibody which effectively targets B cells, could be a less permanent and less risky treatment alternative for FOP.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Miosite Ossificante/tratamento farmacológico , Miosite Ossificante/imunologia , Anticorpos Monoclonais Murinos , Transplante de Medula Óssea/métodos , Ensaios Clínicos como Assunto , Medicina Baseada em Evidências , Humanos , Miosite Ossificante/cirurgia , Rituximab , Resultado do Tratamento
9.
Clin Orthop Relat Res ; (346): 19-25, 1998 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9577406

RESUMO

A 2-year-old child with fibrodysplasia ossificans progressiva underwent a muscle biopsy of a very early lesion, and had findings that showed the earliest stage ever seen in the histopathology of fibrodysplasia ossificans progressiva. This very early stage consisted of intense perivascular lymphocytic infiltration into normal appearing skeletal muscle. A nearly identical histopathologic sequence was noted in a cat with phenotypic features similar to those of fibrodysplasia ossificans progressiva in humans. These new findings represent the earliest documented changes that have ever been noted in fibrodysplasia ossificans progressiva, and provide further histopathologic support for the recent discovery that lymphocytes may play a role in the pathogenesis of heterotopic ossification in fibrodysplasia ossificans progressiva.


Assuntos
Linfócitos/patologia , Miosite Ossificante/imunologia , Animais , Antígenos CD20/análise , Proteína Morfogenética Óssea 2 , Proteína Morfogenética Óssea 4 , Proteínas Morfogenéticas Ósseas/análise , Complexo CD3/análise , Gatos , Movimento Celular , Pré-Escolar , Humanos , Imuno-Histoquímica , Antígenos Comuns de Leucócito/análise , Linfócitos/química , Masculino , Fator de Crescimento Transformador beta/análise
10.
Clin Orthop Relat Res ; (346): 66-70, 1998 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9577412

RESUMO

Fibrodysplasia ossificans progressiva is a rare heritable disorder of connective tissue characterized by skeletal malformations and by progressive heterotopic ossification. It has been suggested that the genetic marker human leukocyte antigen B27 may be associated with fibrodysplasia ossificans progressiva, as it is with ankylosing spondylitis, another disorder with less severe hyperostosis. Genomic deoxyribonucleic acid from 23 classically affected patients with fibrodysplasia ossificans progressiva was screened for the human leukocyte antigen B27 allele by polymerase chain reaction. Only two of the 23 patients (9%) with fibrodysplasia ossificans progressiva who were examined showed the presence of the human leukocyte antigen B27 allele, an incidence that corresponds to the 8% frequency of individuals within the general population not affected with ankylosing spondylitis. These data suggest that the human leukocyte antigen B27 allele does not occur more commonly in the genotype of patients with fibrodysplasia ossificans progressiva than in the general population, and that the pathogenesis of heterotopic bone in fibrodysplasia ossificans progressiva differs from that of ankylosing spondylitis and other human leukocyte antigen B27 positive disorders.


Assuntos
Antígeno HLA-B27/genética , Miosite Ossificante/imunologia , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase
11.
Acta méd. colomb ; 18(1): 75-9, ene.-feb. 1993. ilus, tab
Artigo em Espanhol | LILACS | ID: lil-183271

RESUMO

La fibrodisplasia arterial es causa poco conocida de enfermedad vascular. Presentamos un paciente que consultó por lesiones úlcero-necróticas en extremidades. La arteriografía revelaba patrón rosariforme en los vasos, los exámenes de laboratorio eran normales y la biopsia evidenció hiperplasia medial que comprometía vasos arteriales y venosos. Es el primer informe en la literatura de hiperplasia medial en arterias digitales y en vasos venosos. Resaltamos la importancia de reconocer esta patología por los diagnósticos diferenciales que plantea, en especial las vasculitis. Debemos pensar en fibrodisplasia en pacientes que consultan por episodios vasculares oclusivos, sin manifestaciones sistémicas, con exámenes de laboratorio normales y hallazgos radiológicos sugestivos.


Assuntos
Humanos , Masculino , Adulto , Miosite Ossificante/classificação , Miosite Ossificante/complicações , Miosite Ossificante/diagnóstico , Miosite Ossificante/tratamento farmacológico , Miosite Ossificante/epidemiologia , Miosite Ossificante/etiologia , Miosite Ossificante/imunologia , Miosite Ossificante/mortalidade , Miosite Ossificante/patologia , Miosite Ossificante/fisiopatologia , Miosite Ossificante/terapia
14.
J Rheumatol ; 3(3): 313-20, 1976 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-978667

RESUMO

Heterotopic ossification following hip surgery occurred in three patients with ankylosing hyperostosis of the spine. No technical difficulty during surgery was encountered in these individuals. The occurrence of this postoperative complication, coupled with the appearance of bony outgrowths at sites of ligament attachment throughout the axial and extra-axial skeleton in patients with ankylosing hyperostosis of the spine, suggests the presence of an underlying ossifying diathesis, diffuse idiopathic skeletal hyperostosis (DISH). A significant number of patients with DISH possess the second segregant series antigen, HLA-B27, a feature they share with individuals with other arthropathies characterized by abundant ossification; this gene may be closely related to one which influences bone formation. The possible association of postoperative heterotopic ossification and ankylosing hyperostosis of the spine indicates that a radiographic examination of the vertebral column in patients undergoing hip surgery may be a useful screening procedure.


Assuntos
Exostose/cirurgia , Quadril/cirurgia , Miosite Ossificante/etiologia , Complicações Pós-Operatórias , Espondilite Anquilosante/cirurgia , Idoso , Exostose/diagnóstico por imagem , Antígenos HLA , Humanos , Masculino , Pessoa de Meia-Idade , Miosite Ossificante/diagnóstico por imagem , Miosite Ossificante/imunologia , Radiografia , Espondilite Anquilosante/diagnóstico por imagem
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