RESUMEN
Since their introduction in 1999, anti-tumour necrosis factor-α (anti-TNF-α) therapies have been suspected repeatedly to be associated with the occurrence of central nervous system (CNS) demyelinating disorders, including multiple sclerosis (MS). However, recent publications were restricted to descriptions of monophasic demyelinating events or cases of relapsing-remitting MS (RRMS). We here provide the first case report of primary progressive MS (PPMS) onset upon anti-TNF-α therapy as well as a literature review of previously published cases of anti-TNF-α therapy-associated MS onset. The 51-year old male patient was treated with adalimumab due to psoriasis arthritis. About 18 months after treatment initiation, he developed slowly progressing neurological deficits including gait impairment, paraesthesia of the lower limbs, strangury and visual impairment, which led to the discontinuation of adalimumab therapy. Magnetic resonance imaging of the brain and the spinal cord revealed multiple inflammatory lesions and cerebrospinal fluid examination showed slight pleocytosis and positive oligoclonal bands. Thus, PPMS was diagnosed according to the 2017 revision of the McDonald criteria. As PPMS often causes only subtle symptoms in the beginning and early treatment discontinuation of anti-TNF-α therapy seems essential to improve the patient's outcome, we think that it is important to increase the awareness of slowly progressing neurological deficits as a potential adverse event of anti-TNF-α therapy among all clinicians involved in the initiation and monitoring of these drugs. In addition, the occurrence of both RRMS and progressive MS upon anti-TNF-α therapy might suggest a shared TNF-α-mediated pathophysiological mechanism in the evolution of all MS subtypes.
RESUMEN
Epidermal Langerhans cells (LC) are potent APCs surveying the skin. They are crucial regulators of T cell activation in the context of inflammatory skin disease and graft-versus-host disease (GVHD). In contrast to other dendritic cell subtypes, murine LC are able to reconstitute after local depletion without the need of peripheral blood-derived precursors. In this study, we introduce an experimental model of human skin grafted to NOD-SCID IL2Rγ(null) mice. In this model, we demonstrate that xenografting leads to the transient loss of LC from the human skin grafts. Despite the lack of a human hematopoietic system, human LC repopulated the xenografts 6 to 9 wk after transplantation. By staining of LC with the proliferation marker Ki67, we show that one third of the replenishing LC exhibit proliferative activity in vivo. We further used the skin xenograft as an in vivo model for human GVHD. HLA-disparate third-party T cells stimulated with skin donor-derived dendritic cells were injected intravenously into NOD-SCID IL2Rγ(null) mice that had been transplanted with human skin. The application of alloreactive T cells led to erythema and was associated with histological signs of GVHD limited to the transplanted human skin. The inflammation also led to the depletion of LC from the epidermis. In summary, we provide evidence that human LC are able to repopulate the skin independent of blood-derived precursor cells and that this at least partly relates to their proliferative capacity. Our data also propose xeno-transplantation of human skin as a model system for studying the role of skin dendritic cells in the efferent arm of GVHD.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Epidermis/inmunología , Células de Langerhans/inmunología , Activación de Linfocitos/inmunología , Trasplante de Piel/inmunología , Trasplante Heterólogo/inmunología , Animales , Linfocitos T CD8-positivos/patología , Linfocitos T CD8-positivos/trasplante , Muerte Celular/inmunología , Muerte Celular/efectos de la radiación , Diferenciación Celular/inmunología , Diferenciación Celular/efectos de la radiación , Movimiento Celular/inmunología , Movimiento Celular/efectos de la radiación , Proliferación Celular/efectos de la radiación , Células Cultivadas , Modelos Animales de Enfermedad , Epidermis/patología , Epidermis/trasplante , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Humanos , Células de Langerhans/patología , Células de Langerhans/trasplante , Activación de Linfocitos/efectos de la radiación , Masculino , Ratones , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Ratones Transgénicos , Trasplante de Piel/patología , Trasplante Heterólogo/patologíaRESUMEN
A cyclic adenosine monophosphate binding abnormality in psoriatic erythrocytes that could be corrected by retinoid treatment has been reported. It was tested whether this binding abnormality is specific for psoriasis and the effects of treatment were compared with etretinate, cyclosporine A, or anthralin on 2-(3)H-8-N(3)-cyclic adenosine monophosphate binding to the regulatory subunit of protein kinase A in erythrocyte membranes. One hundred and fifteen individuals were evaluated, including: (i) 34 healthy persons; (ii) 15 patients with nonatopic inflammatory skin diseases (eczema, erythroderma, tinea, Grover's disease, erysipelas, urticaria); (iii) eight with other dermatoses mediated by immune mechanisms (systemic lupus erythematosus, lichen planus, necrotizing vasculitis, erythema nodosum, systemic sclerosis); (iv) 14 with generalized atopic dermatitis; and (v) 44 with psoriasis vulgaris clinically assessed by Psoriasis Area and Severity Index. In psoriasis, the course of the binding of 2-(3)H-8-N(3)-cyclic adenosine monophosphate to erythrocytes was measured in nine patients during a 10 wk treatment with etretinate, in 21 patients during a 10 wk treatment with cyclosporine A, and one patient under topical treatment with anthralin for 4 wk. We found the following femtomolar binding per mg protein: (i) healthy persons (1064 +/- 124, mean +/- SD); (ii) nonatopic inflammatory skin diseases (995 +/- 103); (iii) immune dermatoses (961 +/- 92); (iv) atopic dermatitis (960 +/- 110); and (v) psoriasis (645 +/- 159; p < 0.0001 compared with nonpsoriatics, Mann-Whitney U test). Treatment of psoriasis with etretinate, cyclosporine A, or anthralin normalized the binding of cyclic adenosine monophosphate, which was inversely correlated to the Psoriasis Area and Severity Index score. It was concluded that the decreased binding of cyclic adenosine monophosphate to protein kinase A in erythrocytes is specific for psoriasis and normalizes after successful treatment.
Asunto(s)
Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , AMP Cíclico/análogos & derivados , AMP Cíclico/metabolismo , Membrana Eritrocítica/enzimología , Psoriasis/metabolismo , Administración Tópica , Adolescente , Adulto , Marcadores de Afinidad/metabolismo , Anciano , Antralina/uso terapéutico , Antiinflamatorios/uso terapéutico , Azidas/metabolismo , Ciclosporina/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Membrana Eritrocítica/efectos de los fármacos , Etretinato/uso terapéutico , Femenino , Humanos , Queratolíticos/uso terapéutico , Masculino , Persona de Mediana Edad , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Psoriasis/tratamiento farmacológico , Retinoides/uso terapéutico , Índice de Severidad de la EnfermedadRESUMEN
Pimecrolimus, an ascomycin macrolactam derivative, is an inhibitor of T-cell and mast-cell activation, developed and launched by Novartis for the potential treatment of psoriasis and allergic, irritant and atopic dermatitis. The topical formulation had been launched in the US by February 2002 for mild-to-moderate atopic dermatitis in patients aged two years and older. At that time, an oral formulation was in development for which launch was anticipated for 2006. In March 2002, pimecrolimus was approved in Denmark, becoming the first non-steroid prescription cream approved for patients from as young as 3 months of age through to adulthood. At this time, Novartis planned to seek approvals in other European countries during 2002 under the Mutual Recognition Procedure, and elsewhere around the globe. In December 2000, Merrill Lynch predicted sales of SFr 100 million in 2002, rising to SFr 330 million in 2004, and in February 2001, the analysts predicted sales of SFr 120 million in 2002, rising to SFr 574 million in 2005. Later in August 2001, Deutsche Bank estimated sales of SFr 150 million in 2002, rising to SFr 550 million in 2005. Following FDA approval in 2002, Morgan Stanley Dean Witter cautiously predicted sales of SFr 60 million rising to SFr 860 million by 2007.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Antiinflamatorios/uso terapéutico , Tacrolimus/análogos & derivados , Tacrolimus/uso terapéutico , Administración Tópica , Animales , Antiinflamatorios/efectos adversos , Antiinflamatorios/metabolismo , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/metabolismo , Ensayos Clínicos como Asunto , Dermatitis/tratamiento farmacológico , Dermatitis/metabolismo , Humanos , Tacrolimus/efectos adversos , Tacrolimus/metabolismoRESUMEN
BACKGROUND: Psoriatic skin lesions in patients with Crohn's disease or psoriatic arthritis have shown improvement during infliximab treatment. OBJECTIVE: The purpose of our study was to systematically assess the effects of infliximab in patients with psoriatic skin lesions. METHODS: Eight patients with severe psoriasis were enrolled in an open-label clinical trial. Patients received infliximab, 5 mg/kg, intravenously at weeks 0, 2, and 6. The Psoriasis Area and Severity Index (PASI) was used to monitor disease activity at weeks 0, 2, 4, 6, 8, 10, and 14. Week 10 was the end point of the treatment phase; week 14 was the follow-up end point. Pruritus was assessed on a scale of 0 to 3. Histologic sections were prepared from biopsy specimens of uninvolved skin and of psoriatic lesions at weeks 0, 1, and 10 to measure epidermal thickness with the use of a microscopic micrometer grid. RESULTS: The PASI diminished from 21.8 +/- 4.2 (mean +/- SE) at week 0 to 3.4 +/- 2.0 at week 10, corresponding to 10.7% +/- 4.3% of the original values (100%); on follow-up at week 14, the PASI was 7.1 +/- 2.7 (or still 33.3% +/- 11.3% of the values at week 0). Pruritus decreased from 2.5 +/- 0.26 at week 0 to 0.43 +/- 0.2 at week 10 and to 0.83 +/- 11.3 at week 14. Likewise, epidermal thickness (acanthosis) tended to normalize from 0.41 +/- 0.06 mm at week 0 to 0.14 +/- 0.02 mm at week 10. No adverse effects other than fatigue during infusion on some occasions were reported. CONCLUSION: Although psoriasis tends to recur beyond 2 months of the infusions, this open study provides evidence that infliximab is an effective treatment.