RESUMEN
BACKGROUND: The phase 2a ALLEGRO trial (NCT02974868) investigated the safety and efficacy of ritlecitinib (PF-06651600) and brepocitinib (PF-06700841) in adults with alopecia areata. No randomized controlled trial for alopecia areata has evaluated correlations between clinician-assessed hair loss and patient-reported outcomes. OBJECTIVES: Report scores from the Alopecia Areata Symptom Impact Scale (AASIS; a patient-reported outcome tool) and explore the relationships of those scores with clinician-assessed Severity of Alopecia Tool (SALT) scores at baseline and week 24 of the ALLEGRO trial. METHODS: Adults with alopecia areata were randomized to ritlecitinib (n = 48), brepocitinib (n = 47) or placebo (n = 47). After 24 weeks, the mixed-effects model with repeated measures was used to calculate the active treatment groups' AASIS score least-squares mean differences. Relationships between AASIS and SALT scores at baseline and week 24 were evaluated by Pearson's correlation coefficients using pooled data. RESULTS: Baseline AASIS and SALT scores were similar among treatment groups. Both active treatment groups reported significant improvements in AASIS scores at week 24 (least-squares mean differences vs. placebo for ritlecitinib, -0.8 to -2.3; brepocitinib, -0.9 to -3.7; P < 0.05 for all). At week 24, the mean SALT scores (standard deviation) improved compared with baseline [ritlecitinib, 54.4 (40.3) vs. 89.4 (15.8); brepocitinib, 31.9 (35.7) vs. 86.4 (18.1)]. The correlation coefficients between AASIS global and subscale scores and SALT scores at week 24 ranged from 0.34 to 0.58; P < 0.05 for all. CONCLUSIONS: Patients randomized to ritlecitinib or brepocitinib reported significantly improved AASIS and SALT scores at week 24 of the ALLEGRO trial compared to placebo. At week 24, medium-to-large correlations can be seen between AASIS global and subscale scores and SALT scores. Our experience with AASIS instrument highlighted several aspects that suggest new patient-reported outcome tools are needed to accurately assess patients' relevant alopecia areata related signs, symptoms and daily functioning.
Asunto(s)
Alopecia Areata , Inhibidores de las Cinasas Janus , Adulto , Alopecia Areata/diagnóstico , Humanos , Inhibidores de las Cinasas Janus/uso terapéutico , Medición de Resultados Informados por el Paciente , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: PF-04965842 is an oral Janus kinase 1 inhibitor being investigated for the treatment of plaque psoriasis. OBJECTIVES: To evaluate the efficacy, safety and tolerability of PF-04965842 in patients with moderate-to-severe plaque psoriasis. METHODS: Patients in this phase II, placebo-controlled study (NCT02201524) were randomized to receive placebo, 200 mg once daily (OD), 400 mg OD or 200 mg twice daily (TD) PF-04965842 for 4 weeks. The primary endpoint was change from baseline in Psoriasis Area Severity Index (PASI) at week 4. Study enrolment was discontinued on 25 June 2015 due to changes in the sponsor's development priorities. RESULTS: Fifty-nine patients were randomized and received at least one dose of PF-04965842 or placebo. The estimated treatment effect (active -placebo PASI change from baseline) and 90% confidence interval at week 4 was -5·1 (-9·2 to -1·0), -5·6 (-9·6 to -1·6) and -10·0 (-14·2 to -5·8) for the 200 mg OD, 400 mg OD and 200 mg TD groups, respectively. At week 4, the proportion of patients achieving PASI 75 was 17% for the placebo and 200 mg OD groups, 50% for the 400 mg OD group and 60% for the 200 mg TD group. There were more abnormal laboratory test results of clinical interest (low neutrophil, reticulocyte and platelet counts) in the 200 mg TD group compared with the OD treatment groups. No serious infections or bleeding events related to neutropenia or thrombocytopenia, respectively, were reported. CONCLUSIONS: These results suggest that treatment with PF-04965842 improves symptoms and is well tolerated in patients with moderate-to-severe psoriasis.
Asunto(s)
Inhibidores de Proteínas Quinasas/administración & dosificación , Psoriasis/tratamiento farmacológico , Pirimidinas/administración & dosificación , Sulfonamidas/administración & dosificación , Administración Oral , Adolescente , Adulto , Anciano , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Janus Quinasa 1/antagonistas & inhibidores , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinética , Resultado del Tratamiento , Adulto JovenRESUMEN
This study's objective was to assess the effects of PD-0360324, a fully human immunoglobulin G2 monoclonal antibody against macrophage colony-stimulating factor in cutaneous lupus erythematosus (CLE). Patients with active subacute CLE or discoid lupus erythematosus were randomized to receive 100 or 150 mg PD-0360324 or placebo via intravenous infusion every 2 weeks for 3 months. Blood and urine samples were obtained pre- and post-treatment to analyse pharmacokinetics and pharmacodynamic changes in CD14(+) CD16(+) monocytes, urinary N-terminal telopeptide (uNTX), alanine/aspartate aminotransferases (ALT/AST) and creatine kinase (CK); tissue biopsy samples were taken to evaluate macrophage populations and T cells using immunohistochemistry. Clinical efficacy assessments included the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Among 28 randomized/analysed patients, peak/trough plasma concentrations increased in a greater-than-dose-proportional manner with dose increases from 100 to 150 mg. Statistically significant differences were observed between active treatment and placebo groups in changes from baseline in CD14(+) CD16(+) cells, uNTX, ALT, AST and CK levels at most time-points. The numbers, density and activation states of tissue macrophages and T cells did not change from baseline to treatment end. No between-group differences were seen in CLASI. Patients receiving PD-0360324 reported significantly more adverse events than those receiving placebo, but no serious adverse events. In patients with CLE, 100 and 150 mg PD-0360324 every 2 weeks for 3 months suppressed a subset of circulating monocytes and altered activity of some tissue macrophages without affecting cell populations in CLE skin lesions or improving clinical end-points.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Lupus Eritematoso Cutáneo/tratamiento farmacológico , Lupus Eritematoso Cutáneo/inmunología , Factor Estimulante de Colonias de Macrófagos/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Administración Intravenosa , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Aspartato Aminotransferasas/orina , Colágeno/orina , Creatina Quinasa/orina , Método Doble Ciego , Femenino , Histiocitos/efectos de los fármacos , Histiocitos/patología , Humanos , Inmunohistoquímica , Inmunoterapia , Receptores de Lipopolisacáridos/inmunología , Masculino , Persona de Mediana Edad , Receptores de IgG/inmunología , Índice de Severidad de la Enfermedad , Piel/efectos de los fármacos , Piel/patología , Adulto JovenRESUMEN
The lupus susceptibility interval Sle3/5 confers responsiveness to prolactin in C57BL/6 (B6) mice and hyperprolactinaemia induces a lupus-like phenotype in B6.Sel3/5 mice. In this study, the immunostimulatory effects of prolactin in B6 mice containing the Sle3 portion of the Sel3/5 interval (B6.Sle3 mice) were dissected. Because of the Sle3 interval's involvement in activation of myeloid cells, the effect of dendritic cells (DCs) from prolactin-treated B6.Sle3 mice on the phenotype of B6 mice was also evaluated. B cells from prolactin-treated B6 and B6.Sle3 mice and from B6 recipients of prolactin-modulated DCs from B6.Sle3 mice were tested for DNA-reactivity and resistance to B cell receptor (BCR)-mediated apoptosis. The expression of co-stimulatory molecules on lymphocytes and myeloid cells was also evaluated. In prolactin-treated B6.Sle3 mice, transitional type 2 B cells increased while type 1 B cells decreased as a consequence of prolactin-induced resistance to BCR-mediated apoptosis leading to the survival of DNA-reactive B cells. Follicular B cells from prolactin-treated mice expressed increased levels of CD40, B7·2 and IA(b), and DCs and monocytes had higher levels of CD44 and B7·2 than placebo-treated mice. Adoptive transfer of DCs from prolactin-treated B6.Sle3 mice to B6 recipients demonstrated the intrinsic ability of prolactin-modulated DCs to induce a development of lupus-like characteristics in B6 mice. Based on these results, prolactin accelerates the breakdown of immune tolerance in B6.Sle3 mice by promoting the survival, maturation and activation of autoreactive B cells, DCs and macrophages.
Asunto(s)
Linfocitos B/inmunología , Células Dendríticas/inmunología , Tolerancia Inmunológica/inmunología , Macrófagos/inmunología , Prolactina/farmacología , Traslado Adoptivo , Animales , Apoptosis/inmunología , Autoinmunidad , Antígenos CD40/metabolismo , Células Dendríticas/metabolismo , Glomerulonefritis/inmunología , Receptores de Hialuranos/metabolismo , Hiperprolactinemia/inmunología , Lupus Eritematoso Sistémico/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fenotipo , Prolactina/administración & dosificación , Prolactina/metabolismo , Estructura Terciaria de Proteína , Receptores de Antígenos de Linfocitos B/inmunología , Receptores de Antígenos de Linfocitos B/metabolismoRESUMEN
Clinical manifestations of lupus are encountered in a variety of disease entities, including isolated cutaneous lupus, undifferentiated connective tissue disease, mixed connective tissue disease, drug-induced lupus, overlap syndrome, and systemic lupus erythematosus (SLE). While each entity has been recognized as a specific disease with its own diverse clinical and serological pattern, one could argue that many findings are common. Could it be that all of these entities actually represent a spectrum of one disease? Could it be that rather than the genetic predisposition and hence controlled factors that govern this spectrum of diseases, that environmental factors associated with SLE could also play a role in the different entities of this spectrum? The traditional environmental triggers in SLE include sunlight and ultraviolet (UV) light, infections, smoking, and medications including biologics such as tumor necrosis factor alpha (TNF-a) blockers. In this review, we update and further substantiate these traditional factors in the various lupus-related syndromes. We will also discuss the association with vaccine exposure, industrial estrogens, and other factors.
Asunto(s)
Exposición a Riesgos Ambientales/efectos adversos , Lupus Eritematoso Cutáneo/etiología , Lupus Eritematoso Sistémico/etiología , Animales , Predisposición Genética a la Enfermedad , Humanos , Lupus Eritematoso Cutáneo/fisiopatología , Lupus Eritematoso Sistémico/fisiopatología , Luz Solar/efectos adversos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Rayos Ultravioleta/efectos adversosRESUMEN
OBJECTIVE: To respond to a pre-specified set of questions posed by the United States Food and Drug Administration (FDA) on defining the disease state to inform the clinical development of drugs, biological products, and medical devices for the prevention and treatment of osteoarthritis (OA). METHODS: An Osteoarthritis Research Society International (OARSI) Disease State working group was established, comprised of representatives from academia and industry. The Working Group met in person and by teleconference on several occasions from the Spring of 2008 through the Autumn of 2009 to develop consensus-based, evidence-informed responses to these questions. A report was presented at a public forum in December 2009 and accepted by the OARSI Board of Directors in the Summer of 2010. RESULTS: An operational definition of OA was developed incorporating current understanding of the condition. The structural changes that characterize OA at the joint level were distinguished from the patients' experience of OA as the 'disease' and 'illness', respectively. Recommendations were made regarding the evaluation of both in future OA clinical trials. The current poor understanding of the phenotypes that characterize OA was identified as an important area for future research. CONCLUSIONS: The design and conduct of clinical trials for new OA treatments should address the heterogeneity of the disease, treatment-associated structural changes in target joints and patient-reported outcomes.
Asunto(s)
Osteoartritis/diagnóstico , Ensayos Clínicos como Asunto/métodos , Medicina Basada en la Evidencia/métodos , Humanos , Imagen por Resonancia Magnética , Osteoartritis/etiología , Osteoartritis/terapia , Proyectos de Investigación , Estrés MecánicoRESUMEN
OBJECTIVE: To assess a walking model utilizing a set of standardized treadmill walks to measure acute analgesic response in osteoarthritis (OA) of the knee. DESIGN: Randomized, double-blind, placebo-controlled, multiple dose, three-period crossover study. Patients > or =45 years of age (N=22) with symptomatic knee OA were randomized to naproxen 500 mg bid, tramadol/acetaminophen 37.5 mg/325 mg in forced titration, or placebo in each of three periods. Patients performed multiple 20-minute treadmill walks on Day 1 and Day 3 at a consistent self-selected pace predetermined at screening. Pain intensity (PI) during the walks was assessed on an 11-point numerical rating scale at 0, 3, 6, 9, 12, 15, 18, and 20 min. The primary endpoint was the time-weighted average (TWA) change from baseline PI on Day 3 for the two self-paced walks for the active treatments vs placebo. Time to moderate pain (TTMP) was a key secondary endpoint. RESULTS: Compared with placebo, the TWA change from baseline PI on Day 3 was significantly better with tramadol/acetaminophen (P=0.043) but not with naproxen (P=0.089). TWA change from baseline on Day 1 was also significantly better with both tramadol/acetaminophen (P=0.001) and naproxen (P=0.048) compared with placebo. TTMP was significantly better for tramadol/acetaminophen and naproxen than placebo (P<0.001 to P=0.015) for walks on Day 1 after a single dose and on Day 3. CONCLUSIONS: This novel OA pain model was able to discriminate both tramadol/acetaminophen and naproxen from placebo after single and multiple doses. ClinicalTrials.gov identifier: NCT00772967.
Asunto(s)
Acetaminofén/uso terapéutico , Analgésicos/uso terapéutico , Naproxeno/uso terapéutico , Osteoartritis de la Rodilla/tratamiento farmacológico , Dolor/tratamiento farmacológico , Tramadol/uso terapéutico , Caminata , Acetaminofén/administración & dosificación , Anciano , Analgésicos/administración & dosificación , Estudios Cruzados , Método Doble Ciego , Combinación de Medicamentos , Prueba de Esfuerzo/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Osteoartritis de la Rodilla/fisiopatología , Dimensión del Dolor , Tramadol/administración & dosificaciónRESUMEN
The prevalence of systemic lupus erythematosus (SLE) is far higher in females than in males and numerous investigations to understand this gender bias have been conducted. While it is plausible that some sex-linked genes may contribute to the genetic predisposition for the disease, other likely culprits are the sex hormones estrogen and prolactin. In this chapter we review studies that have addressed the influence of sex hormones in SLE activity and discuss the recent data established in a BALB/c mouse transgenic for the heavy chain of an anti-DNA antibody. These mice are prone to develop lupus following exposure to exogenous sex hormones. We describe how estrogen and prolactin influence B cell maturation and selection, permitting B cells to mature to immunocompetence. Finally, we discuss the relevance and implications of these data for human disease.
Asunto(s)
Linfocitos B/inmunología , Estrógenos/farmacología , Lupus Eritematoso Sistémico/etiología , Animales , Autoanticuerpos/biosíntesis , Femenino , Predisposición Genética a la Enfermedad , Humanos , Tolerancia Inmunológica , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Masculino , Ratones , Ratones Transgénicos , Prolactina/farmacologíaRESUMEN
Immune dysregulation in HIV-infected patients, along with the new medications for treatment of AIDS that possess immunomodulating potential, may lead to an increased incidence of autoimmune diseases in this patient population. However, the presence of combined autoimmune diseases in an AIDS patient is rare. Relapsing polychondritis (RP) is an uncommon inflammatory disease manifested by recurrent attacks of auricular chondritis. The presence of type II and IX collagen antibodies, and their association with HLA-DR4 and other autoimmune diseases, suggests that antiself reactions may be present. Sarcoidosis is a granulomatous disease manifested by inflammation of the lungs, eyes and joints. In the peripheral blood there is depressed cellular immunity and enhanced humoral immunity. We here describe a case of coexisting RP and sarcoidosis in an AIDS patient.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Enfermedades Autoinmunes/complicaciones , Enfermedades del Oído/complicaciones , Policondritis Recurrente/complicaciones , Sarcoidosis/complicaciones , Adulto , Femenino , HumanosRESUMEN
Sensorineural hearing loss may occur in SLE, but aortic insufficiency has been very rarely reported. We are describing two patients with well-established SLE who developed bilateral hearing loss and aortic insufficiency, associated with serological evidence of active lupus. Neither patient had evidence of keratitis, and thus did not satisfy criteria for Cogan's syndrome. The aortic insufficiency in one patient stabilized after treatment with high doses of steroids while in the second patient, who refused medical treatment, it progressed requiring surgical valve replacement. Our observations suggest that the aortic valve and the inner ear may share some antigenic crossreactivity not shared by the cornea. In SLE patients, with sensorineural hearing loss, echocardiography should be performed looking for evidence of aortic insufficiency, which may be steroid responsive.
Asunto(s)
Insuficiencia de la Válvula Aórtica/complicaciones , Pérdida Auditiva Sensorineural/complicaciones , Lupus Eritematoso Sistémico/complicaciones , Adulto , Antirreumáticos/uso terapéutico , Insuficiencia de la Válvula Aórtica/tratamiento farmacológico , Insuficiencia de la Válvula Aórtica/patología , Femenino , Glucocorticoides/uso terapéutico , Pérdida Auditiva Sensorineural/tratamiento farmacológico , Pérdida Auditiva Sensorineural/patología , Humanos , Hidroxicloroquina/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/patología , Metilprednisolona/uso terapéutico , Persona de Mediana EdadRESUMEN
Estrogen can modulate autoimmunity in certain models of systemic lupus erythematosus. Recently, we have shown that it can mediate survival and activation of anti-DNA B cells in a mouse transgenic for the heavy chain of a pathogenic anti-DNA antibody. To identify whether estrogen effects reflect increased prolactin secretion, we characterized B-cell autoreactivity in transgenic mice given both bromocriptine (an inhibitor of prolactin secretion) and estradiol. Treatment of mice with estradiol plus bromocriptine led to reduced titers of anti-DNA antibodies and diminished IgG deposition in kidneys compared with treatment with estradiol alone. However, mice treated with estradiol plus bromocriptine showed an expansion of transgene-expressing B cells and enhanced Bcl-2 expression, similar to those of estradiol-treated mice. We identified anergic high-affinity anti-DNA B cells in mice treated with estradiol plus bromocriptine, and we showed by molecular analysis of anti-DNA hybridomas that their B cells derive from a naive repertoire. Thus, the estradiol-induced breakdown in B-cell tolerance can be abrogated by bromocriptine, which induces anergy in the high-affinity DNA-reactive B cells. These studies demonstrate that some of the effects of estrogen on naive autoreactive B cells require the presence of prolactin and, thus, suggest potential therapeutic interventions in lupus.
Asunto(s)
Bromocriptina/farmacología , Estradiol/farmacología , Tolerancia Inmunológica/efectos de los fármacos , Animales , Anticuerpos Antinucleares/genética , Anticuerpos Antinucleares/inmunología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Femenino , Hibridomas/inmunología , Tolerancia Inmunológica/inmunología , Inmunoglobulina G/inmunología , Inmunohistoquímica , Riñón/efectos de los fármacos , Riñón/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismoRESUMEN
Interleukin-12 (IL-12) is a pleiotropic cytokine with proinflammatory, immunoregulatory, antitumor, and antimetastatic properties. It plays a crucial role in the development of the Th1 response and subsequent interferon-gamma production and enhancement of cell-mediated cytotoxicity. Recently, IL-12 has been used as an experimental therapy for cancer. Given the multiple immunomodulatory properties of IL-12, there are potential concerns associated with its clinical use. Of special interest are the possible side effects of IL-12 therapy in patients with autoimmune diseases, especially those that are T cell mediated, such as rheumatoid arthritis (RA). We present a case of severe RA exacerbation caused by treatment with IL-12 for metastatic cervical cancer. This is the first reported case of RA flare caused by exogenous IL-12.
Asunto(s)
Artritis Reumatoide/inducido químicamente , Interleucina-12/efectos adversos , Femenino , Mano/diagnóstico por imagen , Humanos , Interleucina-12/uso terapéutico , Persona de Mediana Edad , Radiografía , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/secundarioRESUMEN
We describe a case of articular non-Hodgkin's lymphoma (NHL) with malignant lymphoma cells observed in synovial fluid. Bone involvement in NHL is common, but an English language Medline search revealed only 14 reported cases of synovial NHL. Although NHL is a well recognized complication of human immunodeficiency virus (HIV) infection, this is the first report of synovial NHL in an HIV infected patient.
Asunto(s)
Infecciones por VIH/patología , Articulación de la Rodilla/patología , Linfoma Relacionado con SIDA/patología , Linfoma no Hodgkin/patología , Sinovitis/patología , Adulto , Infecciones por VIH/complicaciones , Humanos , Linfoma Relacionado con SIDA/complicaciones , Linfoma no Hodgkin/complicaciones , Imagen por Resonancia Magnética , Masculino , Neprilisina/análisis , Líquido Sinovial/citología , Sinovitis/etiologíaRESUMEN
An aspergilloma is a fungus ball resulting from colonization of pre-existing pulmonary cavities, which usually represents a non-invasive form of aspergillosis. Spontaneous rupture of the cavity containing the fungi into the pleural space is an unusual complication that has been reported occasionally in patients with leukemia and invasive aspergillosis. We report on this unusual complication occurring in a patient with underlying interstitial lung disease, in whom the aspergilloma cavity abruptly ruptured into the pleural space with subsequent hydropneumothorax and pleural spillage of the fungi.
Asunto(s)
Aspergilosis/complicaciones , Enfermedades Pulmonares Fúngicas/complicaciones , Enfermedades Pulmonares Intersticiales/complicaciones , Enfermedades Pleurales/etiología , Humanos , Masculino , Persona de Mediana Edad , Rotura Espontánea/etiologíaRESUMEN
To determine the effect of lipoprotein lipase deficiency on the size distribution of fat cell populations in human adipose tissues, abdominal and femoral subcutaneous fat tissue biopsies were obtained from seven patients affected by familial hyperchylomicronaemia. These patients were characterized by massive accumulation of chylomicrons in the fasting state due to defective catabolism of plasma triglyceride-rich lipoproteins. They had no post-heparin plasma lipoprotein lipase activity and their fat tissues were deficient in lipoprotein lipase activity. The size distribution of adipocytes examined by scanning electron microscopy were similar to distributions observed in control subjects. Patient fat cell diameters were not statistically different from control fat cells obtained from subjects of similar body mass index. Mature fat cells contributed to 99% of the total fat tissue mass in lipoprotein lipase deficiency. Normal adiposity in lipoprotein lipase deficiency can thus be attributed to mature adipocytes and not to hyperplastic growth of immature fat cells. It is concluded that normal adipose tissue homeostasis is maintained in these patients in spite of the deficiency in lipoprotein lipase activity.