Ocular cicatricial pemphigoid. From a rheumatology and ophthalmology point of view / Penfigoide ocular cicatrizal, enfoque diagnóstico y terapéutico integral entre el oftalmólogo y el reumatólogo

ABSTRACT Ocular cicatricial pemphigoid (OCP) is a chronic, immune-mediated, bullous, cicatricial disease within the spectrum of mucocutaneous membranous pemphigoids (MMP). Although the diagnosis is often ophthalmological, due to the autoimmune nature of the pathology, it requires a joint approach with rheumatologists and immunologists. The objective of this narrative review was to explore the evidence available in the literature from 2000 to 2020 with respect to clinical manifestations, diagnosis, and treatment. The clinical presentation varies widely, from mild cases with slow progression of years of progression, to severe cases with a torpid and rapidly progressive evolution to fibrosis, refractory to multiple treatments. A com plete evaluation of the patient will help guide the diagnosis. The gold standard for diagnosis is conjunctival biopsy with direct immunofluorescence, although on occasions it can be reached if the symptoms are characteristic. Treatment is local and systemic according to its severity and evolution. The evidence on topical and systemic therapeutics is obtained mainly from uncontrolled observational and experimental studies. Immunomodulatory therapy has made it possible to preserve vision and, in many cases, prevent sequelae. The evolu tion is linked to the early diagnosis and immunosuppressive treatment, so it is essential to be aware of this disease, the diagnostic methods, as well as the immunomodulating and immunosuppressive therapies available.

RESUMEN El penfigoide ocular cicatrizal (POC) es una enfermedad crónica, inmunomediada ampollar, mucosinequiante, comprendida dentro del espectro de penfigoides membranosos mucocutáneos (PMM). El diagnóstico es, con frecuencia, oftalmológico, pero debido al carácter autoinmune de la patología, requiere el abordaje en conjunto con reumatólogos e inmunólogos. El objetivo de esta revisión narrativa fue explorar la evidencia disponible en la literatura, desde el año 2000 hasta el 2020, en lo que respecta a sus manifestaciones clínicas, diagnóstico y tratamiento. La presentación clínica varía ampliamente, desde casos leves con progresión lenta de años de evolución hasta casos severos con evolución tórpida y rápidamente progresiva a la fibrosis, refractarios a múltiples tratamientos. Una evaluación completa del paciente ayudará a guiar el diagnóstico. El estándar de oro diagnóstico es la biopsia conjuntival con inmunofluorescencia directa, si bien en ocasiones puede diagnosticarse por la clínica característica. El tratamiento es local y sistêmico de acuerdo con su severidad y evolución. En los últimos 20 anos, la evidencia sobre los tratamientos tópicos y sistêmicos corresponde en su mayoría a estudios observacionales y experimentales no controlados. Los métodos de tratamiento inmunomoduladores han permitido preservar la visión y, en muchos casos, prevenir secuelas. La evolución está ligada al diagnóstico temprano y a los tratamientos disponibles, por lo que es fundamental el conocimiento de esta patología, los métodos diagnósticos y los tratamientos inmunomoduladores e inmunosupresores.

Conversión de prueba cutánea de derivado proteico purificado durante el tratamiento con anti-TNF / Skin test conversion of purified protein derivative during treatment with anti-TNF

Introducción: los anti-TNF-α se asocian con mayor riesgo de desarrollar tuberculosis (TB). La prueba del derivado proteico purificado (purified protein derivative, PPD) se emplea para diagnosticar infección de tuberculosis latente (ITL). Se recomienda el cribado para TB previo al inicio de terapia anti-TNF-α y el seguimiento para evaluar la posible conversión de la PPD durante el tratamiento. El tratamiento de la ITL puede reducir el riesgo de desarrollar enfermedad activa en un 90%. Objetivos: actualmente los resultados de conversión de la PPD y su interpretación durante el tratamiento anti-TNF-α son variables, por tal motivo nos propusimos conocer la frecuencia de conversión de la PPD en este grupo de pacientes de nuestro medio. Materiales y métodos: realizamos un estudio descriptivo, observacional y retrospectivo que incluyó pacientes >18 años, diagnosticados con enfermedad reumática, tratados con anti-TNF-α. Resultados: se incluyeron 54 pacientes (46,7 ± a 12 años), de los cuales 36, presentaron diagnóstico de artritis reumatoidea, seis de artritis idiopática juvenil, cinco de espondilitis anquilosante, tres de artritis psoriásica, tres de uveítis y uno de queratitis intersticial. Los tratamientos fueron: 30 adalimumab, 17 certolizumab, siete etanercept, 44 metotrexato, 19 leflunomida, nueve hidroxicloroquina, dos sulfasalazina, dos azatioprina, uno mofetil micofenolato y glucocorticoides (28 de 54); la conversión de la PPD ocurrió en un solo paciente. Conclusiones: en el presente trabajo la seroconversión fue baja en contraste con otras series. La prueba de PPD es un método accesible, ampliamente disponible, adecuado y sensible para diagnosticar ITL.

Introduction: anti-TNF-α are associated with an increased risk of developing tuberculosis (TB). Purified protein derivative (PPD) is used to demonstrate a latent TB infection (LTBI). Screening is recommended for TB prior to the onset of anti-TNF-α and monitoring evaluating possible conversion of PPD during treatment. Treatment of LTBI can reduce the risk of active disease development by up to 90%. Objectives: currently the results of PPD conversion and its interpretation during anti-TNF-α treatment are variable and that is why we set out to know the frequency of conversion of PPD in this group of patients in our environment. Materials and methods: a descriptive, analytical, observational, retrospective study was conducted. Including patients >18 years old, diagnosed with rheumatic disease, treated with anti-TNF-α. Results: 54 patients were included (46.7 ± to 12 years), of which 36 presented a diagnosis of rheumatoid arthritis, 6 juvenile idiopathic arthritis, 5 ankylosing spondylitis, 3 psoriatic arthritis, 3 uveitis, 1 interstitial keratitis. The treatments were: 30 adalimumab, 17 certolizumab, 7 etanercept, 44 methotrexate, 19 leflunomide, 9 hydroxychloroquine, 2 sulfasalazine, 2 azathioprine, 1 mycophenolate mofetil and glucocorticoids (28/54). PPD conversion took place in 1 patient. Conclusions: in the present study, seroconversion was low in contrast to other series. The PPD test is an accessible, widely available, adequate and sensitive method for diagnosing LTBI, which the rheumatologist should use in his daily practice.

Chagas disease reactivation in rheumatologic patients: association with immunosuppressive therapy and humoral response.

Evidence for Chagas disease reactivation (CDR) in rheumatologic patients under rheumatologic treatments (RTs) is scarce. To screen and follow-up patients with rheumatic diseases and concomitant Chagas disease under RT to detect CDR and to describe a possible relationship between CDR and specific RT. An observational, longitudinal, prospective, consecutive study was carried out between 2018 and 2020. Included patients were evaluated during the follow-up for clinical and laboratorial manifestations of CDR. Direct blood parasitological examination (Strout method) and polymerase chain reaction (PCR) were employed to diagnose CDR. The dynamic of anti-T. cruzi-specific antibodies was also assessed by IHA and ELISA (total IgG and Anti-SAPA). Fifty-one patients were included (86% women). Rheumatoid arthritis was the predominant disease (57%). Classic DMARDs (86.3%) and corticosteroids (61%) were the most frequent RT. CDR was developed in 6 patients (11.7%), exhibiting both positive Strout and PCR. Symptomatic reactivation of CD (fever, asthenia, arthralgias, myalgias) occurred in two patients who had previously been diagnosed with it. Regardless of the different RT, all patients who experienced CDR had previously received more than ≥ 20 mg/day of prednisone equivalent. Despite immunosuppression, patients with CDR exhibited increased levels of specific anti-T. cruzi and anti-SAPA antibodies, which decreased after anti-parasitic treatment. CDR is possible in rheumatologic patients, especially after receiving high doses of corticosteroids. Since CDR symptoms may mimic rheumatic disease activity, monitoring of Chagas disease is highly recommended before, during and after immunosuppression. Key Points • Chagas disease reactivation (CDR) in the context of rheumatological treatment was associated to high doses of corticosteroids. • CDR was associated with an increase in anti-T. cruzi antibodies despite the immunosuppressive treatment. • Suspecting and anticipating CDR is mandatory in this patient population to diagnose and treat it.

[Anti-neutrophil cytoplasmic antibody-associated vasculitis. Clinical aspects and treatment]. / Vasculitis asociadas a anticuerpos anti-citoplasma de neutrófilos. Clínica y tratamiento.

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis, comprise a group of diseases characterized by inflammation of the wall of small vessels. We analyzed epidemiological and clinical characteristics in a series of 47 patients, 23 (49%) with Wegener granulomatosis (WG), 15 (32%) with microscopic polyangiitis (MPA) and nine (19%) with renal limited vasculitis (RLV). The mean age at onset of symptoms was 50.7 ± 14.9 years. The most frequent clinical manifestation was renal involvement in 41 (87%), followed by pulmonary manifestations in 26 (55%) and ENT involvement in 17 (36%). In 26 (55%) it presented with simultaneous pulmonary and renal involvement. The most frequent clinical category was the generalized form in 23 (49%), followed by the severe form in 18 (38%). Eighty nine percent of patients had positive ANCA test. Four (8%) received no immunosuppressive treatment. Of the 43 patients who were treated, 29 (67%) achieved complete remission with an average length of remission of 35.3 months. Eleven (26%) had a relapse, ten (91%) had a major relapse and one had a minor relapse. Twelve (28%) patients died, seven died early and five late during the course of the disease. Fifteen (31%) progressed to chronic renal failure. All 26 patients in follow-up had response to treatment and 20 (77%) were in remission at the end of the study. Despite the improvements achieved with immunosuppressive treatments, morbidity and mortality rates in ANCA-associated vasculitis remain high.

Vasculitis asociadas a anticuerpos anti-citoplasma de neutrófilos: Clínica y tratamiento / Anti-neutrophil cytoplasmic antibody-associated vasculitis: Clinical aspects and treatment

Las vasculitis asociadas a anticuerpos anti-citoplasma de neutrófilos (ANCA) comprenden a un grupo de enfermedades caracterizadas por la inflamación de la pared de pequeños vasos. Analizamos las características epidemiológicas y clínicas en una serie de 47 pacientes: 23 (49%) granulomatosis de Wegener (GW), 15 (32%) poliangeítis microscópica (PAM) y nueve (19%) vasculitis limitada al riñón (VLR). La edad media al inicio de los síntomas fue de 50.7 ± 14.9 años. La manifestación clínica más frecuente fue el compromiso renal en 41 (87%) pacientes, seguido por el pulmonar en 26 (55%) y el otorrinolaringológico en 17 (36%). En 26 (55%) se asoció compromiso renal y pulmonar. La forma clínica más frecuente fue la generalizada en 23 (49%), seguida por la grave en 18 (38%). El 89% presentaron determinaciones de ANCA positivas. Cuatro (8%) no recibieron tratamiento inmunosupresor de inicio. De los 43 que recibieron tratamiento de inicio, 29 (67%) tuvieron remisión completa, con un tiempo de remisión promedio de 35.3 meses. Once (26%) presentaron recaídas, diez (91%) recaídas mayores y uno (9%) menor. Doce (28%) fallecieron, siete en forma temprana y cinco durante la evolución de la enfermedad. Quince (31%) evolucionaron a insuficiencia renal crónica. Los 26 pacientes en seguimiento tuvieron respuesta al tratamiento y 20 (77%) de ellos estaban en remisión al finalizar el estudio. Las vasculitis asociadas a ANCA continúan siendo enfermedades de alta morbilidad y mortalidad, a pesar de las mejorías logradas con los tratamientos inmunosupresores.(AU)

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis, comprise a group of diseases characterized by inflammation of the wall of small vessels. We analyzed epidemiological and clinical characteristics in a series of 47 patients, 23 (49%) with Wegener granulomatosis (WG), 15 (32%) with microscopic polyangiitis (MPA) and nine (19%) with renal limited vasculitis (RLV). The mean age at onset of symptoms was 50.7 ± 14.9 years. The most frequent clinical manifestation was renal involvement in 41 (87%), followed by pulmonary manifestations in 26 (55%) and ENT involvement in 17 (36%). In 26 (55%) it presented with simultaneous pulmonary and renal involvement. The most frequent clinical category was the generalized form in 23 (49%), followed by the severe form in 18 (38%). Eighty nine percent of patients had positive ANCA test. Four (8%) received no immunosuppressive treatment. Of the 43 patients who were treated, 29 (67%) achieved complete remission with an average length of remission of 35.3 months. Eleven (26%) had a relapse, ten (91%) had a major relapse and one had a minor relapse. Twelve (28%) patients died, seven died early and five late during the course of the disease. Fifteen (31%) progressed to chronic renal failure. All 26 patients in follow-up had response to treatment and 20 (77%) were in remission at the end of the study. Despite the improvements achieved with immunosuppressive treatments, morbidity and mortality rates in ANCA-associated vasculitis remain high.(AU)

Vasculitis asociadas a anticuerpos anti-citoplasma de neutrófilos: Clínica y tratamiento / Anti-neutrophil cytoplasmic antibody-associated vasculitis: Clinical aspects and treatment

Las vasculitis asociadas a anticuerpos anti-citoplasma de neutrófilos (ANCA) comprenden a un grupo de enfermedades caracterizadas por la inflamación de la pared de pequeños vasos. Analizamos las características epidemiológicas y clínicas en una serie de 47 pacientes: 23 (49%) granulomatosis de Wegener (GW), 15 (32%) poliangeítis microscópica (PAM) y nueve (19%) vasculitis limitada al riñón (VLR). La edad media al inicio de los síntomas fue de 50.7 ± 14.9 años. La manifestación clínica más frecuente fue el compromiso renal en 41 (87%) pacientes, seguido por el pulmonar en 26 (55%) y el otorrinolaringológico en 17 (36%). En 26 (55%) se asoció compromiso renal y pulmonar. La forma clínica más frecuente fue la generalizada en 23 (49%), seguida por la grave en 18 (38%). El 89% presentaron determinaciones de ANCA positivas. Cuatro (8%) no recibieron tratamiento inmunosupresor de inicio. De los 43 que recibieron tratamiento de inicio, 29 (67%) tuvieron remisión completa, con un tiempo de remisión promedio de 35.3 meses. Once (26%) presentaron recaídas, diez (91%) recaídas mayores y uno (9%) menor. Doce (28%) fallecieron, siete en forma temprana y cinco durante la evolución de la enfermedad. Quince (31%) evolucionaron a insuficiencia renal crónica. Los 26 pacientes en seguimiento tuvieron respuesta al tratamiento y 20 (77%) de ellos estaban en remisión al finalizar el estudio. Las vasculitis asociadas a ANCA continúan siendo enfermedades de alta morbilidad y mortalidad, a pesar de las mejorías logradas con los tratamientos inmunosupresores.

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis, comprise a group of diseases characterized by inflammation of the wall of small vessels. We analyzed epidemiological and clinical characteristics in a series of 47 patients, 23 (49%) with Wegener granulomatosis (WG), 15 (32%) with microscopic polyangiitis (MPA) and nine (19%) with renal limited vasculitis (RLV). The mean age at onset of symptoms was 50.7 ± 14.9 years. The most frequent clinical manifestation was renal involvement in 41 (87%), followed by pulmonary manifestations in 26 (55%) and ENT involvement in 17 (36%). In 26 (55%) it presented with simultaneous pulmonary and renal involvement. The most frequent clinical category was the generalized form in 23 (49%), followed by the severe form in 18 (38%). Eighty nine percent of patients had positive ANCA test. Four (8%) received no immunosuppressive treatment. Of the 43 patients who were treated, 29 (67%) achieved complete remission with an average length of remission of 35.3 months. Eleven (26%) had a relapse, ten (91%) had a major relapse and one had a minor relapse. Twelve (28%) patients died, seven died early and five late during the course of the disease. Fifteen (31%) progressed to chronic renal failure. All 26 patients in follow-up had response to treatment and 20 (77%) were in remission at the end of the study. Despite the improvements achieved with immunosuppressive treatments, morbidity and mortality rates in ANCA-associated vasculitis remain high.

Vasculitis asociadas a anticuerpos anti-citoplasma de neutrófilos. Clínica y tratamiento. / [Anti-neutrophil cytoplasmic antibody-associated vasculitis. Clinical aspects and treatment].

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis, comprise a group of diseases characterized by inflammation of the wall of small vessels. We analyzed epidemiological and clinical characteristics in a series of 47 patients, 23 (49

) with Wegener granulomatosis (WG), 15 (32

) with microscopic polyangiitis (MPA) and nine (19

) with renal limited vasculitis (RLV). The mean age at onset of symptoms was 50.7 ± 14.9 years. The most frequent clinical manifestation was renal involvement in 41 (87

), followed by pulmonary manifestations in 26 (55

) and ENT involvement in 17 (36

). In 26 (55

) it presented with simultaneous pulmonary and renal involvement. The most frequent clinical category was the generalized form in 23 (49

), followed by the severe form in 18 (38

). Eighty nine percent of patients had positive ANCA test. Four (8

) received no immunosuppressive treatment. Of the 43 patients who were treated, 29 (67

) achieved complete remission with an average length of remission of 35.3 months. Eleven (26

) had a relapse, ten (91

) had a major relapse and one had a minor relapse. Twelve (28

) patients died, seven died early and five late during the course of the disease. Fifteen (31

) progressed to chronic renal failure. All 26 patients in follow-up had response to treatment and 20 (77

) were in remission at the end of the study. Despite the improvements achieved with immunosuppressive treatments, morbidity and mortality rates in ANCA-associated vasculitis remain high.

Benznidazole blocks NF-kappaB activation but not AP-1 through inhibition of IKK.

Previously, we demonstrated that benznidazole (BZL), known for its antiparasitic action on Trypanosoma cruzi, modulates pro-inflammatory cytokines and NO release in macrophages by inhibiting NF-kappaB. We now proceeded to elucidate the molecular mechanisms by which BZL exerts its inhibitory action on NF-kappaB. We demonstrated that the inhibitory effect of BZL is not extended to other macrophage responses, since it did not inhibit other typical hallmarks of macrophage activation such as phagocytosis, MHC-II molecules expression or production of reactive oxygen species (ROS) by NADPH oxidase. BZL was able to interfere specifically with the activation of NF-kappaB pathway without affecting AP-1 activation in RAW 264.7 macrophages, not only in LPS-mediated activation, but also for other stimuli, such as pro-inflammatory cytokines (IL-1beta, TNF-alpha), PMA or H(2)O(2). Also, BZL delayed the activation of p38 MAPK, but not that of ERK1/2 and JNK. Finally, treatment with BZL inhibited IkappaBalpha phosporylation and hence its degradation, whereas it did not block IkappaB kinase (IKK) alpha/beta phosphorylation. Collectively, BZL behaves as a broad range specific inhibitor of NF-kappaB activation, independently of the stimuli tested.