RESUMO
Kimura disease (KD) is a rare, chronic angiolymphoproliferative inflammatory disease appearing to be mostly restricted to the skin and soft tissue. Cutaneous involvement of KD includes head and/or neck nodules showing suggestive histological features, frequently associated with an atopic dermatitis-like or prurigo-like presentation. KD is challenging to treat, with high rate of recurrence using current therapeutic strategies. Evidence for involvement of a T-helper type 2 (Th2) immune response in KD pathogenesis has been found in previous studies. Consequently, this study aimed to determine the efficacy and safety of dupilumab, a human monoclonal antibody that inhibits signalling of key Th2 cytokines, interleukin (IL)-4 and IL-13, within a single-centre cohort of patients with cutaneous KD. Two adults with a diagnosis of refractory (failure of at least one treatment line) cutaneous-restricted KD based on clinical, biological, histological, molecular and imaging findings received dupilumab for KD, and showed dramatic response with a good safety profile.
Assuntos
Anticorpos Monoclonais Humanizados , Doença de Kimura , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Masculino , Adulto , Doença de Kimura/tratamento farmacológico , Doença de Kimura/patologia , Pessoa de Meia-Idade , Feminino , Resultado do Tratamento , Interleucina-4 , Interleucina-13/antagonistas & inibidoresRESUMO
Unicentric Castleman disease (UCD) is a lymphoproliferative disease of unknown cause. Paraneoplastic pemphigus (PNP) is a major complication shown to be associated with a poor prognosis, with particular severity in patients with bronchiolitis obliterans (BO). This study describes the clinical and biological characteristics of UCD-PNP patients in a large Western cohort. A total of 148 patients diagnosed with UCD were identified, including 14 patients with a defined PNP. PNP was significantly associated with myasthenia gravis (MG) and FDC sarcoma during follow-up (FDCS). PNP was also significantly associated with reduced survival. These data, together with a multivariate analysis by principal components, led to the identification of UCD-PNP as a group at risk of MG, FDCS and death. PDGFRB sequencing performed on UCD lesions from six patients found the gain-of-function p.N666S variant in two. Interestingly, both patients had hyaline-vascular UCD subtype, were in the UCD-PNP subgroup and had FDCS. Sera from 25 UCD-PNP patients and 6 PNP patients without UCD were tested for PNP-associated autoantibodies. Sera from UCD-PNP patients had a strong reactivity against the N-terminal domain of recombinant periplakin (rPPL, 82%) and showed reactivity against at least two domains of rPPL. These features were not found in patients with UCD alone or in the PNP group without UCD. These data indicate that UCD-PNP patients belong to a subgroup sharing strong clinical and biological identity that might help to decipher the different dynamics of UCD natural history.
Assuntos
Hiperplasia do Linfonodo Gigante , Miastenia Gravis , Síndromes Paraneoplásicas , Pênfigo , Humanos , Pênfigo/diagnóstico , Pênfigo/etiologia , Hiperplasia do Linfonodo Gigante/patologia , Autoanticorpos , Miastenia Gravis/diagnóstico , Síndromes Paraneoplásicas/etiologia , Síndromes Paraneoplásicas/diagnósticoRESUMO
Scleromyxedema is a rare skin and systemic mucinosis that is usually associated with monoclonal gammopathy (MG). In this French multicenter retrospective study of 33 patients, we investigated the clinical and therapeutic features of MG-associated scleromyxedema. Skin molecular signatures were analyzed using a transcriptomic approach. Skin symptoms included papular eruptions (100%), sclerodermoid features (91%), and leonine facies (39%). MG involved an immunoglobulin G isotype in all patients, with a predominant λ light chain (73%). Associated hematologic malignancies were diagnosed in 4 of 33 patients (12%) (smoldering myeloma, n = 2; chronic lymphoid leukemia, n = 1; and refractory cytopenia with multilineage dysplasia, n = 1). Carpal tunnel syndrome (33%), arthralgia (25%), and dermato-neuro syndrome (DNS) (18%) were the most common systemic complications. One patient with mucinous cardiopathy died of acute heart failure. High-dose IV immunoglobulin (HDIVig), alone or in combination with steroids, appeared to be quite effective in nonsevere cases (clinical complete response achieved in 13/31 patients). Plasma cell-directed therapies using lenalidomide and/or bortezomib with dexamethasone and HDIVig led to a significant improvement in severe cases (HDIVig refractory or cases with central nervous system or cardiac involvement). The emergency treatment of DNS with combined plasmapheresis, HDIVig, and high-dose corticosteroids induced the complete remission of neurological symptoms in 4 of 5 patients. Quantitative reverse-transcriptase polymerase chain reaction analysis of 6 scleromyxedema skin samples showed significantly higher profibrotic pathway levels (transforming growth factor ß and collagen-1) than in healthy skin. Prospective studies targeting plasma cell clones and/or fibrotic pathways are warranted for long-term scleromyxedema management.
Assuntos
Paraproteinemias/complicações , Paraproteinemias/terapia , Plasmócitos/patologia , Escleromixedema/complicações , Escleromixedema/terapia , Adulto , Idoso , Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Dexametasona/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Lenalidomida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Paraproteinemias/genética , Paraproteinemias/patologia , Plasmócitos/efeitos dos fármacos , Plasmócitos/metabolismo , Plasmaferese , Estudos Retrospectivos , Escleromixedema/genética , Escleromixedema/patologia , Pele/metabolismo , Pele/patologia , TranscriptomaRESUMO
BACKGROUND: Scleromyxedema (SME) is a rare mucinosis associated with monoclonal gammopathy. Several biochemical peculiarities of monoclonal immunoglobulins (Ig) in SME patients were reported in case reports or short series, such as IgGλ over-representation, cationic migration, and partial deletion. METHODS: Monoclonal immunoglobulins (Ig) from the serum of 12 consecutive patients diagnosed with scleromyxedema (SME) were analyzed using electrophoretic and immunoblotting techniques. RESULTS: All monoclonal Ig from 12 SME were of IgG1 subclass, with an overrepresentation of the lambda-type light chain and a cationic mobility on standard zone electrophoresis, as compared with 21 cases of monoclonal gammopathy of undetermined significance (MGUS) of IgG1 subclass. Reactivity with specific monoclonal antibodies demonstrated no evident deletion of the heavy chain constant domains, which was also confirmed by analysis of Ig heavy chain molecular weight on a purified monoclonal component from one case. CONCLUSIONS: Significant isotype restriction of both heavy and light chains, and peculiar biochemical properties suggest that monoclonal Ig might be involved in pathophysiological events of SME.
Assuntos
Paraproteinemias , Escleromixedema , Anticorpos Monoclonais , Humanos , Imunoglobulina G , Cadeias lambda de ImunoglobulinaAssuntos
Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Linfoma Cutâneo de Células T , Humanos , Recidiva Local de Neoplasia , Nitrilas , Linfoma Cutâneo de Células T/tratamento farmacológico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Estudos Retrospectivos , Doença CrônicaAssuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Humanos , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologiaAssuntos
Cútis Laxa/epidemiologia , Cútis Laxa/patologia , Paraproteinemias/epidemiologia , Paraproteinemias/patologia , Adulto , Distribuição por Idade , Idoso , Biópsia por Agulha , Comorbidade , Feminino , Humanos , Imuno-Histoquímica , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos de Amostragem , Índice de Gravidade de Doença , Distribuição por SexoRESUMO
Cutaneous involvement of chronic graft-versus-host disease (cGVHD) has a wide range of manifestations including a lichenoid form with a currently assumed mixed Th1/Th17 signature and a sclerotic form with Th1 signature. Despite substantial heterogeneity of innate and adaptive immune cells recruited to the skin and of the different clinical manifestations, treatment depends mainly on the severity of the skin involvement and relies on systemic, high-dose glucocorticoids alone or in combination with a calcineurin inhibitor. We performed the first study using RNA sequencing to profile and compare the transcriptome of lichen planus cGVHD (n = 8), morphea cGVHD (n = 5), and healthy controls (n = 6). Our findings revealed shared and unique inflammatory pathways to each cGVHD subtype that are both pathogenic and targetable. In particular, the deregulation of IFN signaling pathway was strongly associated with cutaneous cGVHD, whereas the triggering receptor expressed on myeloid cells 1 pathway was found to be specific of lichen planus and likely contributes to its pathogenesis. The results were confirmed at a protein level by performing immunohistochemistry staining and at a transcriptomic level using real-time quantitative polymerase chain reaction.
Assuntos
Doença Enxerto-Hospedeiro , Líquen Plano , Esclerodermia Localizada , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/genética , Humanos , Líquen Plano/genética , Líquen Plano/patologia , Esclerodermia Localizada/genética , Esclerodermia Localizada/patologia , Análise de Sequência de RNA , Pele/patologiaRESUMO
Background: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are associated with cutaneous manifestations. Next-generation sequencing (NGS) is a tool capable of identifying clonal myeloid cells in the skin infiltrate and thus better characterize the link between hematological diseases and skin lesions. Objective: To assess whether skin lesions of MDS/CMML are clonally related to blood or bone marrow cells using NGS. Methods: Comparisons of blood or bone marrow and skin samples NGS findings from patients presenting with MDS/CMML and skin lesions in three French hospitals. Results: Among the 14 patients recruited, 12 patients (86%) had mutations in the skin lesions biopsied, 12 patients (86%) had a globally similar mutational profile between blood/bone marrow and skin, and 10 patients (71%) had mutations with a high variant allele frequency (>10%) found in the myeloid skin infiltrate. Mutations in TET2 and DNMT3A, both in four patients, were the most frequent. Two patients harbored a UBA1 mutation on hematopoietic samples. Limitations: Limited number of patients and retrospective collection of the data. Blood and skin sampling were not performed at the exact same time point for two patients. Conclusion: Skin lesions in the setting of MDS/CMML are characterized by a clonal myeloid infiltrate in most cases.
Assuntos
Leucemia Mielomonocítica Crônica/complicações , Leucemia Mielomonocítica Crônica/patologia , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/patologia , Células Mieloides/patologia , Dermatopatias/diagnóstico , Dermatopatias/etiologia , Idoso , Idoso de 80 Anos ou mais , Biópsia , Medula Óssea/patologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Evolução Clonal/genética , Gerenciamento Clínico , Feminino , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mielomonocítica Crônica/etiologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/etiologia , Avaliação de SintomasRESUMO
IMPORTANCE: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a recently described severe adult-onset autoinflammatory disease that is associated with myeloid lineage-restricted ubiquitin-activating enzyme 1 (UBA1) somatic variations that primarily affect the skin (Sweet syndrome), cartilage, and bone marrow. Skin symptoms have been poorly described. OBJECTIVE: To better describe clinical and pathological skin manifestations and their pathophysiology in VEXAS syndrome. DESIGN, SETTING, AND PARTICIPANTS: This multicenter retrospective case series study of clinical and histological features of 8 patients with VEXAS syndrome and skin involvement was conducted in France from December 2007 to March 2021, with molecular data obtained from March to April 2022. Any UBA1 variations were detected by Sanger or next-generation sequencing that was performed on bone marrow and formalin-fixed paraffin-embedded tissue sections of skin lesion biopsies. RESULTS: All 8 patients were men, and the median age at symptom onset was 65.5 years (interquartile range, 54-76 years). All patients had neutrophilic dermatosis skin lesions, including tender red or violaceous papules, sometimes edematous, without fever, arthralgia, recurrence or pathergy, inflammatory edematous papules on the neck and trunk (sometimes umbilicated), and firm erythematous purpuric or pigmented infiltrated plaques and nodules. Three patients had livedo racemosa. The infiltrates were perivascular and consisted of mature neutrophils with leukocytoclasia, which were admixed with myeloperoxidase-positive CD163-positive myeloid cells with indented nuclei and lymphoid cells in all cases. A sequencing analysis of paired bone marrow samples and skin lesion biopsies identified the same loss-of-function UBA1 variation in both samples for all patients. CONCLUSIONS AND RELEVANCE: This case series study describes the different clinical presentations of skin lesions found in VEXAS syndrome, which is characterized histologically by neutrophilic dermatosis. The findings suggested that the dermal infiltrates seen in VEXAS skin lesions are derived from the pathological myeloid clone. This suggests that using therapies that target the pathological clone may be effective in the long-term management of the disease.
Assuntos
Síndrome de Sweet , Enzimas Ativadoras de Ubiquitina , Adulto , Medula Óssea , Humanos , Masculino , Mutação , Estudos Retrospectivos , Síndrome de Sweet/diagnóstico , Enzimas Ativadoras de Ubiquitina/genéticaRESUMO
OBJECTIVE: To describe safety and efficacy of rituximab in patients with systemic sclerosis. METHODS: We included 13 patients with systemic sclerosis treated with rituximab and pooled with 40 additional patients from the literature. SSc rituximab untreated patients were matched to rituximab treated ones. RESULTS: Thirteen patients who received rituximab and 26 rituximab-untreated patients were included. In comparison to 26 patients who did not received rituximab, FVC changes were not significantly different, whereas DLCO improved in 13 patients who received rituximab (0 [-4; 4] vs loss of -7 [-19; 0]; p=0.05). Considering 7 rituximab treated and 14 untreated diffuse SSc, FVC was improved during the 24 [12; 46] months of follow up in dSSc who received rituximab (gain of 12 [7.5:14] % vs loss of 1.5 [-16.8; 2.5], (p=0.003)). Pooled analysis of 53 patients (40 literature patients and 13 from personal series) showed significant improvement of median mRSS from 18 [8; 32] at baseline to 9 [4; 18] at M6 (p=0.007), 13 [8; 18] at M12 (p=0.008) and 10 [4; 16] at the last follow-up (p=0.0002). FVC increased from 71% [66; 80] at baseline to 84% [75; 90] at M12 (p=0.001). DLCO increased from 58% [39; 65] at M0 to 63% [53; 78] at M12 (p=0.04). CONCLUSION: Our personal data and pooled literature analysis suggest the efficacy of rituximab in the subset of diffuse SSc in particular in skin and interstitial disease involvements. The safety of rituximab seems to be reasonable and similar to previous data in other autoimmune diseases.