RESUMO
BACKGROUND: Biologics are effective for psoriasis, but little is known regarding patients treated with one biologic for an "ultra-long" duration. OBJECTIVE: To explore the prevalence, patient and treatment characteristics and treatment outcomes of "ultra-long users" of biologics for psoriasis. METHODS: From the prospective, multicenter BioCAPTURE cohort, patients with psoriasis who received continuous treatment with the same biologic for ≥10 years were included. Baseline characteristics of these "ultra-long users" were determined and compared to the total BioCAPTURE population. Additionally, the frequency of concomitant systemic treatment use and dose adjustments administered, the trajectory of Psoriasis Area and Severity Index (PASI) scores, and drug survival rates beyond 10 years were analysed. RESULTS: In BioCAPTURE, 30.5% of the patients with the potential to reach a treatment episode of ≥10 years achieved this treatment duration. These patients were treated with ustekinumab, etanercept, adalimumab and infliximab. The proportion of ultra-long users was highest for ustekinumab (37%). The ultra-long user cohort had a slightly longer disease duration at registry entry, and higher proportion of males and patients diagnosed with PsA, compared to the total BioCAPTURE population. A large percentage of ultra-long users (69.5%) had ≥1 comorbidities and 66% used no additional systemic antipsoriatic therapy. Dose adjustments were often applied, varying from dose escalation (30%), dose reduction (41%), or both (14%); only 16% consistently used the standard dose. The median PASI course for ultra-long users from month 6 onwards was continuously <3, with only a small proportion achieving complete clearance of their psoriasis (3.9-13.7% at the various time points). Drug survival beyond 10 years showed >60% was still treated with the same biologic after 15 years. CONCLUSION: Ultra-long use of the same biologic in patients with psoriasis was common in real-world practice, but varied between biologics. The median PASI was around 2.5 throughout the 10-year treatment course; complete clearance was often not reached. Remarkably, ultra-long use was reached also in patients having multiple comorbidities (including PsA) and a variety of dose adjustments of the biologics was applied. These results provide clinicians with important evidence on ultra-long biological treatment, thereby improving psoriasis care and management of treatment expectations.
Assuntos
Fármacos Dermatológicos , Substituição de Medicamentos , Interleucina-23 , Psoríase , Ustekinumab , Humanos , Psoríase/tratamento farmacológico , Psoríase/imunologia , Ustekinumab/uso terapêutico , Interleucina-23/antagonistas & inibidores , Interleucina-23/imunologia , Resultado do Tratamento , Feminino , Masculino , Fármacos Dermatológicos/uso terapêutico , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/uso terapêutico , Adulto , Índice de Gravidade de Doença , Estudos Retrospectivos , Adalimumab/uso terapêuticoRESUMO
Diminished suppressive capacity of regulatory T cells (Treg) has been demonstrated in blood and in lesional skin of psoriatic patients. Treatment with anti-TNFα restored the number and function of circulating Treg in psoriasis. We aimed to study Treg in the skin of psoriatic patients undergoing topical treatment with calcipotriol-betamethasone dipropionate (CBD) ointment (n = 12) or systemic treatment with anti-TNFα agent adalimumab (n = 10). Skin biopsies were collected from patients with chronic plaque psoriasis who responded to the above-mentioned treatments with a SUM-score improvement of at least 50% (at the end of treatment). Biopsies were processed for immunohistochemistry. As Treg function is associated with a numerical balance between Treg and effector T cells, Foxp3/CD4 ratios were calculated. It appeared that both treatments cause a significant decrease in the presence of Foxp3+ cells. However, in patients that were treated with CBD ointment, we observed lower Foxp3/CD4 ratios after 8 weeks of treatment compared to baseline (t = 0: 0.41 ± 0.08; t = 8: 0.22 ± 0.04, P = 0.033), whereas in patients who were treated with adalimumab we observed an increase of the Foxp3/CD4 ratios after 1.5 and 16 weeks of treatment compared to baseline (t = 0: 0.25 ± 0.04; t = 1.5: 0.32 ± 0.06; t = 16: 0.49 ± 0.10, P = 0.15). Based on Foxp3/CD4 ratios, we can conclude that adalimumab treated skin differs from CBD treated skin with regard to the anti-inflammatory/inflammatory balance. We suggest that, in contrast to CBD ointment, adalimumab favours local Treg function in the skin.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Betametasona/análogos & derivados , Calcitriol/análogos & derivados , Psoríase/tratamento farmacológico , Subpopulações de Linfócitos T/citologia , Linfócitos T Reguladores/citologia , Adalimumab , Administração Tópica , Idoso , Anti-Inflamatórios/química , Betametasona/administração & dosagem , Biópsia , Linfócitos T CD4-Positivos/citologia , Calcitriol/administração & dosagem , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imuno-Histoquímica , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Pomadas , Psoríase/fisiopatologia , Pele/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Psoriasis is a common chronic inflammatory skin disease that results from interplay between the immune system and the epithelium. In the light of very successful anticytokine therapies for psoriasis, the focus has been directed towards the adaptive immune system. Expression studies, genetic studies and treatments specifically targeting players of the IL-23/IL-17 pathway, point at an important role for IL-17 in the pathogenesis of psoriasis. IL-17 stimulates the keratinocytes to produce psoriasis-associated molecules, eventually leading to chronic skin inflammation. The current opinion is that IL-17 is mainly produced by T cells, so-called T-helper 17 (Th17) cells, in psoriasis. However, evidence is accumulating that cells of the innate immune system, like neutrophils, mast cells, γδ T cells and innate lymphoid cells are the main source of IL-17 in psoriasis, rather than T cells. The paradigm in this field of research is shifting. With this viewpoint article, we will address this novel concept by critically summarizing the current literature on this subject. In psoriatic arthritis and atherosclerosis, important conditions related to psoriasis, it was also found that the majority of IL-17 is associated with cells of the innate immune system. This new concept changes our view of IL-17. Blocking IL-17 with targeted treatments might be more far-reaching than previously thought; not only IL-17 production by T cells but also by innate immune cells is blocked. Furthermore, therapies specifically targeting IL-17 may not only improve psoriasis, but also comorbidity that is associated with the IL-17 pathway, hereby preventing serious complications on the long term.
Assuntos
Regulação da Expressão Gênica , Interleucina-17/imunologia , Mastócitos/imunologia , Neutrófilos/imunologia , Psoríase/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Movimento Celular , Proliferação de Células , Humanos , Imunidade Inata , Inflamação/imunologia , Queratinócitos/citologia , Camundongos , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Pele/metabolismo , Células Th17/imunologia , TranscriptomaRESUMO
BACKGROUND: In healthy skin, tape stripping induces a transient wave of histological changes resembling immune-mediated skin diseases, such as psoriasis. The response to surface trauma may harbor mechanisms which are also relevant to the development of Koebner-positive skin disorders. However, studies on newly discovered drivers of inflammation in regenerative skin are lacking. METHODS: The course of epidermal proliferation and keratinization as well as key representatives of innate and acquired immunity were studied during the first 72 h after tape stripping. RESULTS: Epidermal rupture rapidly activates various epidermal processes, which remain upregulated for 72 h. Elastase+ and IL-17+ cells dominate the acute phase and their numbers decrease rapidly thereafter. The number of T-Bet+ cells increases more gradually, reaching maximum levels several hours later when the other cell types decrease. CONCLUSIONS: This model permits investigations on the sequence of crucial inflammatory processes set off by cutaneous injury, which are presumed to play a role within the pathogenesis of immune-mediated skin diseases exhibiting the Koebner phenomenon.
Assuntos
Epiderme/imunologia , Epiderme/patologia , Queratinócitos/citologia , Regeneração/fisiologia , Dermatopatias/imunologia , Pele/lesões , Imunidade Adaptativa/fisiologia , Adolescente , Adulto , Biópsia por Agulha , Proliferação de Células , Dermatologia/métodos , Feminino , Voluntários Saudáveis , Humanos , Imunidade Inata/fisiologia , Imuno-Histoquímica , Queratinócitos/fisiologia , Masculino , Pessoa de Meia-Idade , Valores de Referência , Estatísticas não Paramétricas , Adulto JovemRESUMO
Clinical trials successfully using antibodies targeting IL-17 in psoriasis support the importance of IL-17 in the pathophysiology of this disease. However, there is a debate concerning the source and dynamics of IL-17 production in inflamed skin. Here we characterized IL-17-producing immune cells over time, using two established in vivo models of human skin inflammation that share many histological features with psoriasis, i.e., leukotriene B4 application and tape-stripping. Both treatments revealed a clear influx of neutrophils and T cells. Staining for IL-17 revealed that the majority of IL-17 was expressed by neutrophils and mast cells, in both models. Neutrophils, but not mast cells, coexpressed the IL-17-associated transcription factor RORγt and were able to form extracellular traps. While the presence of mast cells remained steady during the skin inflammatory process, the presence of neutrophils was clearly dynamic in time. Therefore, it is attractive to hypothesize that IL-17+/RORγt+ neutrophils contribute to human skin inflammation in vivo and possibly to the pathogenesis of skin diseases such as psoriasis. Surprisingly, T cells represented a minority of the IL-17-expressing cell population. These observations challenge the classical opinion that IL-17 is predominantly associated with T cells in skin inflammation.
Assuntos
Dermatite/imunologia , Dermatite/metabolismo , Interleucina-17/imunologia , Neutrófilos/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Imunidade Adaptativa/imunologia , Adolescente , Adulto , Biópsia , Dermatite/patologia , Feminino , Voluntários Saudáveis , Humanos , Imunidade Inata/imunologia , Interleucina-17/genética , Interleucina-17/metabolismo , Leucotrieno B4/administração & dosagem , Masculino , Mastócitos/imunologia , Mastócitos/metabolismo , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Psoríase/imunologia , Psoríase/metabolismo , Psoríase/patologia , Pele/efeitos dos fármacos , Pele/imunologia , Fita Cirúrgica/efeitos adversos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Adulto JovemRESUMO
Humanized mouse models offer a challenging possibility to study human cell function in vivo. In the huPBL-SCID-huSkin allograft model human skin is transplanted onto immunodeficient mice and allowed to heal. Thereafter allogeneic human peripheral blood mononuclear cells are infused intra peritoneally to induce T cell mediated inflammation and microvessel destruction of the human skin. This model has great potential for in vivo study of human immune cells in (skin) inflammatory processes and for preclinical screening of systemically administered immunomodulating agents. Here we studied the inflammatory skin response of human keratinocytes and human T cells and the concomitant systemic human T cell response.As new findings in the inflamed human skin of the huPBL-SCID-huSkin model we here identified: 1. Parameters of dermal pathology that enable precise quantification of the local skin inflammatory response exemplified by acanthosis, increased expression of human ß-defensin-2, Elafin, K16, Ki67 and reduced expression of K10 by microscopy and immunohistochemistry. 2. Induction of human cytokines and chemokines using quantitative real-time PCR. 3. Influx of inflammation associated IL-17A-producing human CD4+ and CD8+ T cells as well as immunoregulatory CD4+Foxp3+ cells using immunohistochemistry and -fluorescence, suggesting that active immune regulation is taking place locally in the inflamed skin. 4. Systemic responses that revealed activated and proliferating human CD4+ and CD8+ T cells that acquired homing marker expression of CD62L and CLA. Finally, we demonstrated the value of the newly identified parameters by showing significant changes upon systemic treatment with the T cell inhibitory agents cyclosporine-A and rapamycin. In summary, here we equipped the huPBL-SCID-huSkin humanized mouse model with relevant tools not only to quantify the inflammatory dermal response, but also to monitor the peripheral immune status. This combined approach will gain our understanding of the dermal immunopathology in humans and benefit the development of novel therapeutics for controlling inflammatory skin diseases.
Assuntos
Modelos Animais de Doenças , Inflamação/imunologia , Interleucina-17/biossíntese , Queratinócitos/imunologia , Transplante de Pele , Pele/imunologia , Animais , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/transplante , Diferenciação Celular , Ciclosporina/farmacologia , Elafina/genética , Elafina/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Injeções Intraperitoneais , Interleucina-17/imunologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/patologia , Queratinas/genética , Queratinas/imunologia , Antígeno Ki-67/genética , Antígeno Ki-67/imunologia , Selectina L/genética , Selectina L/imunologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos SCID , Sirolimo/farmacologia , Pele/efeitos dos fármacos , Pele/patologia , Transplante Heterólogo , beta-Defensinas/genética , beta-Defensinas/imunologiaRESUMO
The bacille Calmette-Guérin (BCG) vaccination protects against tuberculosis (TB)-related meningitis and disseminated tuberculosis. While severe complications after BCG vaccination are relatively rare, different cutaneous reactions have been reported. We report a patient with a 7-mm erythematous nodule at a distance of 4 cm from the BCG injection site. Histopathologically, a necrotizing granulomatous reaction pattern was seen in the dermis. Although complementary stainings did not detect acid fast bacilli, we suspected the lesion was caused by the attenuated strains of Mycobacterium bovis from the vaccine. This specific complication is called BCG-itis in the literature. After the excisional biopsy, the lesion disappeared and further treatment was not necessary. In defining the best treatment for this boy, we discovered a lack of knowledge on BCG-related lesions and their subsequent treatment options in the literature. We will list existing literature on this topic and demonstrate that treatment of BCG-related complications is poorly defined.