Treatment of oral chronic graft-versus-host disease: a retrospective cohort study / Tratamento da doença do enxerto contra hospedeiro crônica oral: um estudo de coorte retrospectivo

ABSTRACT Objective The aim of this study was to evaluate patients with complete response of oral chronic graft-versus-host disease to immunosuppressive treatment. Methods A total of 29 patients submitted to allogeneic hematopoietic stem cell transplantation, with oral chronic graft-versus-host disease, were enrolled in this retrospective study, from September 2012 to February 2018. Patients were treated with combined topical dexamethasone solution and topical tacrolimus ointment, combined topical dexamethasone and topical tacrolimus, systemic immunosuppressive medication, and topical dexamethasone only. Results The mean time of complete response of lichenoid lesions, erythema, and ulcers using dexamethasone and systemic immunosuppressive medication was of 105, 42 and 42 days, respectively (p=0.013).When we associated dexamethasone, tacrolimus and systemic immunosuppressive medication, the mean time of complete response of lichenoid lesions, erythema and ulcers was of 91,84 and 77 days (p=0.011). When dexamethasone was used alone, the mean time of complete response of lichenoid lesions, erythema and ulcers was 182, 140, 21 days, respectively (p=0.042). Conclusion Our study shows that lichenoid lesions require more time to heal. Notably, lichenoid lesions tend to respond better to dexamethasone combined with tacrolimus and systemic immunosuppressive medication, whereas erythema and ulcers respond better to dexamethasone combined with systemic immunosuppressive medication and dexamethasone only, respectively.

RESUMO Objetivo Avaliar os pacientes com resposta completa da doença do enxerto contra hospedeiro crônica oral ao tratamento com imunossupressor. Métodos Vinte e nove pacientes submetidos ao transplante alogênico de células tronco hematopoiéticas, com doença do enxerto contra hospedeiro crônica oral, foram incluídos neste estudo retrospectivo, de setembro de 2012 a fevereiro de 2018. Os pacientes foram tratados com dexametasona para bochecho associada ao tacrolimo pomada, dexametasona para bochecho associada ao tacrolimo tópico, tratamento imunossupressor sistêmico, e dexametasona tópica apenas. Resultados O tempo médio para resposta completa das lesões liquenoides, eritema e ulcerações usando dexametasona e imunossupressor sistêmico foi de 105, 42 e 42 dias, respectivamente (p=0,013). Quando a dexametasona estava associada ao tacrolimo e a medicação imunossupressora sistêmica, o tempo médio para resposta completa das lesões liquenóides, eritema e ulcerações foi de 91, 84 e 77 dias (p=0,011). Quando foi utilizada apenas dexametasona, o tempo médio para resposta completa das lesões liquenoides, eritema e ulcerações foi de 182, 140 e 21 dias, respectivamente (p=0,042). Conclusão Nosso estudo mostra que as lesões liquenoides requerem mais tempo para cicatrização completa. É notável que as lesões liquenoides tendem a responder melhor ao tratamento da dexametasona combinada com o tacrolimo e o imunossupressor sistêmico. Já o eritema e as ulcerações respondem melhor à dexametasona combinada com medicação imunossupressora sistêmica, e dexametasona apenas, respectivamente.

Síndrome doloroso por inhibidores de la calcineurina: reporte de 4 casos en pacientes con retrasplante renal / Calcineurin-inhibitor induced pain syndrome: a 4-case report on patients with kidney retransplantation

INTRODUCCIÓN: El trasplante renal es el tratamiento de elección para pacientes con insuficiencia renal crónica. Los inmunosupresores como los inhibidores de la calcineurina pueden estar asociados a efectos adversos. El Síndrome Doloroso por Inhibidores de la Calcineurina (SDIC) se caracteriza por dolores óseos simétricos, agudos e incapacitantes de miembros inferiores, e imágenes características en la resonancia magnética. Se presentan 4 casos de SDIC con retrasplante renal, uso de tacrolimus como inmunosupresor y diagnóstico por resonancia magnética. MATERIAL Y MÉTODOS: Cuatro pacientes (3 mujeres y 1 varón) que se retrasplantaron con riñones cadavéricos, entre marzo de 2014 y septiembre de 2015, presentaron fuertes dolores en miembros inferiores. Tacrolimus fue el principal agente inmunosupresor. Se realizaron resonancias magnéticas de miembros inferiores, se indicó tratamiento y ajuste en la dosis de tacrolimus. RESULTADOS: El SDIC comenzó a los 2 meses del trasplante y 2 semanas de la detección de niveles tóxicos de tacrolimus. El cuadro doloroso permaneció aproximadamente 2 semanas y fue cediendo. La localización fue exclusiva de miembros inferiores (rodillas, tobillos y pies). El dolor fue referido por los pacientes como agudo, punzante, incapacitante y empeoraba de pie. La resonancia magnética confirmó el diagnóstico, revelando un patrón de edema de médula ósea en meseta tibial y astrágalos. Todos los casos fueron reversibles con el tratamiento indicado. CONCLUSIONES: Reportamos la aparición de SDIC en 4 pacientes con retrasplante renal, uso de tacrolimus y buena evolución. El diagnóstico se basó en sospecha clínica, forma de presentación e imágenes típicas en las resonancias magnéticas

INTRODUCTION: Kidney transplant is the first-line therapy for chronic kidney disease. Immunosuppressants such as calcineurin-inhibitors may be associated with side effects. Calcineurin-inhibitor induced pain syndrome (CIPS) is characterized by symmetrical, severe and disabling bone pain in the lower limbs and can be easily identified by magnetic resonance imaging due to its typical patterns. Four CIPS cases after kidney retransplantation are presented, confirmed by MRI and with immunosuppressive therapy consisting of tacrolimus. METHODS: Four patients (3 females and 1 male) with cadaveric kidney retransplantation, performed between March 2014 and September 2015 showed intense pains in their lower limbs. Tacrolimus was the main immunosuppressive agent. MRI scans of the lower limbs were performed; tacrolimus treatment and dosage adjustment were indicated. RESULTS: CIPS started 2 months after transplantation and 2 weeks after detection of tacrolimus toxic levels. Pain lasted around 2 weeks and it gradually became less severe. Symptoms were exclusively located in the lower limbs (knees, ankles and feet). Patients described the pain as sharp, throbbing, disabling, and becoming worse when standing. MRI confirmed the diagnosis, revealing a pattern of bone marrow edema in tibial plateau and tali. All cases were reversible with the indicated treatment. CONCLUSIONS: This study registers 4 cases of CIPS in patients who had undergone kidney retransplantation and had taken tacrolimus with good response. Diagnosis was reached by clinical suspicion, form and location of pain, and characteristic patterns in the MRI scans

Therapy of tacrolimus combined with corticosteroids in idiopathic membranous nephropathy

We evaluated the efficacy and safety of tacrolimus (TAC) combined with corticosteroids in treating patients with idiopathic membranous nephropathy (IMN). One hundred seventy-seven biopsy-proven IMN patients were recruited in this retrospective clinical study. Sixty patients received TAC (target blood concentration of 4–8 ng/mL) and 117 patients received daily cyclophosphamide (CYC, 100 mg) combined with prednisone. Remission rates at the end of the first, second and third month in the TAC group were significantly higher than that in the CYC group (1st: 35.0 vs 19.7%, P<0.05; 2nd: 56.7 vs 38.5%, P<0.05; 3rd: 76.7 vs 59.0%, P<0.05). In the first 3 months, daily urinary protein and serum albumin in the TAC group obtained a better improvement than that in the CYC group (P<0.05). At the end of the sixth and the twelfth month, the remission rates, daily urinary protein and serum albumin were all comparable between the two groups (P>0.05). No significant difference of relapse rate between the groups was found (16.3 vs 12.0%, P>0.05). Patients were more likely to develop glucose intolerance in the TAC group. The TAC regimen obtained more benefits in treating IMN patients, especially in the first 3 months, than the CYC regimen.

Prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation

OBJECTIVE: Chronic rejection remains a major cause of graft failure with indication for re-transplantation. The incidence of chronic rejection remains high in the pediatric population. Although several risk factors have been implicated in adults, the prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation are not known. Hence, the current study aimed to determine the factors involved in the progression or reversibility of pediatric chronic rejection by evaluating a series of chronic rejection cases following liver transplantation. METHODS: Chronic rejection cases were identified by performing liver biopsies on patients based on clinical suspicion. Treatment included maintaining high levels of tacrolimus and the introduction of mofetil mycophenolate. The children were divided into 2 groups: those with favorable outcomes and those with adverse outcomes. Multivariate analysis was performed to identify potential risk factors in these groups. RESULTS: Among 537 children subjected to liver transplantation, chronic rejection occurred in 29 patients (5.4%). In 10 patients (10/29, 34.5%), remission of chronic rejection was achieved with immunosuppression (favorable outcomes group). In the remaining 19 patients (19/29, 65.5%), rejection could not be controlled (adverse outcomes group) and resulted in re-transplantation (7 patients, 24.1%) or death (12 patients, 41.4%). Statistical analysis showed that the presence of ductopenia was associated with worse outcomes (risk ratio=2.08, p=0.01). CONCLUSION: The presence of ductopenia is associated with poor prognosis in pediatric patients with chronic graft rejection.

An analysis of tacrolimus-related complications in the first 30 days after liver transplantation

OBJECTIVES: Orthotopic liver transplantation has improved survival in patients with end-stage liver disease; however, therapeutic strategies that achieve ideal immunosuppression and avoid early complications are lacking. To correlate the dose and level of Tacrolimus with early complications, e.g., rejection, infection and renal impairment, after liver transplantation. From November 2011 to May 2013, 44 adult liver transplant recipients were studied in this retrospective comparative study. RESULTS: The most frequent indication for liver transplantation was hepatitis C cirrhosis (47.7%), with a higher prevalence observed in male patients (68.18%). The ages of the subjects ranged from 19-71 and the median age was 55.5 years. The mean length of the hospital stay was 16.1±9.32 days and the mean Model for End-stage Liver Disease score was 26.18±4.28. There were five cases of acute cellular rejection (11.37%) and 16 cases of infection (36.37%). The blood samples that were collected and analyzed over time showed a significant correlation between the Tacrolimus blood level and the deterioration of glomerular filtration rate and serum creatinine (p<0.05). Patients with infections had a higher serum level of Tacrolimus (p = 0.012). The dose and presence of rejection were significantly different (p = 0.048) and the mean glomerular filtration rate was impaired in patients who underwent rejection compared with patients who did not undergo rejection (p = 0.0084). CONCLUSION: Blood Tacrolimus levels greater than 10 ng/ml were correlated with impaired renal function. Doses greater than 0.15 mg/kg/day were associated with the prevention of acute cellular rejection but predisposed patients to infectious disease. .

Tacrolimus tópico nas lesões cutâneas refratárias da dermatomiosite juvenil / Topical tacrolimus in refractory skin lesions of juvenile dermatomiosytis

A dermatomiosite juvenil (DMJ) é uma doença inflamatória crônica idiopática que afeta principalmente músculos e pele. As lesões cutâneas podem persistir apesar do controle bem-sucedido da miosite. O tacrolimus tópico é um novo agente imunossupressor que tem sido usado no tratamento da dermatite atópica, com poucos relatos de seu uso em miopatias inflamatórias na faixa etária pediátrica. Foram descritos três pacientes com DMJ (dois meninos) com idade atual de 5,7 a 10,6 anos. A terapia inicial administrada para esses pacientes foi: corticosteróide (sistêmico em três e tópico em um), antimalárico em três e metotrexato em dois. Todos apresentavam lesões cutâneas refratárias (eritema malar, eritema difuso e/ou vasculite cutânea) após melhora significativa da fraqueza muscular. Tacrolimus tópico 0,03 por cento foi usado duas vezes ao dia após falha do tratamento prévio. As características das lesões foram avaliadas de acordo com a extensão e a gravidade no início do uso do fármaco e após oito e 16 semanas. Na segunda avaliação (oito semanas), notavelmente um paciente apresentou melhora completa do eritema malar e do eritema difuso em membros e tronco, e dois tiveram melhora parcial do eritema malar e da vasculite cutânea. Na terceira avaliação (16 semanas), dois pacientes tiveram resolução completa das lesões e um apresentava eritema malar persistente e eritema moderado em glúteos e região lombar. No último paciente, a melhora das lesões cutâneas foi alcan-çada apenas após o uso de ciclosporina por 16 semanas. Nenhum deles teve efeitos adversos. Tacrolimus tópico pode ser considerado em pacientes com DMJ e manifestações cutâneas refratárias. Estudos posteriores controlados e randomizados com esse fármaco devem ser realizados nessa doença inflamatória.

Juvenile dermatomyositis (JDM) is a rare idiopathic chronic inflammatory disease that affects mainly muscle and skin. Cutaneous lesions may persist despite successful treatment of myositis. Of note, topical tacrolimus is a new immunosuppressive agent that has been used to treat atopic dermatitis with few reports in pediatric inflammatory myopathies. Three JDM patients (two males) were described, current age from 5.7 to 10.6 years. The initial therapy administered for these patients were: corticosteroid (oral in three and topical in one), antimalarial in three and methotrexate in two. All of them had refractory skin lesions (malar rash, extensive rash and/or cutaneous vasculitis) after significant improvement of muscle weakness. Topical tacrolimus 0.03 percent was used twice daily after failure of previous treatment. The features of lesions were evaluated according to extension and severity at start of drug and after 8 and 16 weeks. At the second evaluation (8 weeks), remarkably one patient had complete improvement of malar rash and extensive rash in limbs and trunk, and two had partial improvement of malar rash and cutaneous vasculitis. At the third evaluation (16 weeks), two patients had complete resolution of lesions and one had persistent malar rash and moderate lumbar and gluteus rash. In the last patient, the improvement of skin lesions was reached only after 16 weeks of cyclosporine use. None of them had adverse effects. Topical tacrolimus could be considered in JDM patients with refractory cutaneous manifestations. Further randomized controlled trials with this agent should be performed in this inflammatory disease.