tacrolimus and Sclerosis

Dear Editor, cutaneous chronic graft versus host disease (cGVHD) is a pathological process consisting of donor-derived T-cells aimed at the antigens of the recipient. It exhibits a large range of clinical presentations resembling morphea and deep sclerosis/fasciitis, all characterized by both inflammation and progressive dermal and hypodermic fibrosis (1). Although classic scleroderma-like lesions in cGVHD are nummular or irregular plaques and linear bundles associated with hypo- or hyperpigmentation (2), we report an atypical case with ulcerative presentation. No other case-reports of morphea-like or scleroderma-like cGVHD with an ulcerated appearance after liver transplantation (LT) and magnetic resonance imaging (MRI) correlation have been found in the literature. CASE REPORT Ten months after LT due to an end-stage cirrhosis associated with multifocal hepatocarcinoma (HCC), a 61-year-old man on immunosuppressive therapy with Tacrolimus (1 mg) and Everolimus (10 mg) presented to our clinic for a skin lesion in the right scapular region. We observed a flat ulcerated plaque with areas of sclerosis, minimal necrosis, and well-defined slightly erythematous margins (Figure 1, a). On palpation, the plaque had a hard consistency and was slightly painful. The skin lesion had been preceded by subjective discomfort with stinging sensation for seven months before its onset. Gradually lesion developed starting from a small, flat, oval purplish plaque associated with a progressive increase in pain. Patient denied dysphagia, retrosternal heartburn, Raynaud's phenomenon, arthralgia, and dyspnea. A previous MRI (Figure 2, a,b) showed subcutaneous and muscle edema. Blood tests showed abnormal liver function indexes due to extrahepatic cholestasis, while C-reactive protein, erythrocyte sedimentation rate, and leukocytes were within normal ranges. Self-reactive antibodies were negative. Histological examination (Figure 1, b) identified rare dyskeratotic keratinocytes and basal lymphocyte infiltrate, a dermal dense fibrosis with the disappearance of the skin appendages, and large fibrous septa in the adipose panniculus. It led to the diagnosis of scleroderma/morphea, based on the patient's clinical history. The diagnosis of graft versus host disease scleroderma-like post liver transplant was established. The lesion was treated by topical application of 0.05% clobetasol once a day. We did not use systemic immunosuppressive therapy in order to prevent HCC recurrence. The pat

Topics: C-Reactive Protein; Clobetasol; Everolimus; Fibrosis; Graft vs Host Disease; Humans; Inflammation; Liver Transplantation; Magnetic Resonance Imaging; Male; Middle Aged; Scleroderma, Localized; Sclerosis; Skin Diseases; Tacrolimus; Ulcer

Extracorporeal photopheresis (ECP) is a second-line therapy for steroid-refractory chronic graft-versus-host disease (cGVHD).. We describe the long-term efficacy and tolerability of ECP according to the cutaneous phenotype of cGVHD and report on the reduced need for immunosuppressant drugs in this setting.. Fourteen patients (8 females) with cutaneous and/or mucosal cGVHD, treated with ECP between October 2010 and May 2016 within a single center, were included. Final analyses included patients who had received ECP for at least 12 months. We prospectively evaluated the efficacy of ECP using lesion-specific clinical scores and by recording changed doses of systemic immunosuppressants.. Of the 14 patients, sclerotic skin lesions were present in 10 (71%). The mRODNAN score decreased in all patients from month 9 onwards, with 40 and 77% reductions at 12 and 36 months, respectively. Six patients (43%) presented with cutaneous lichenoid lesions: this score was reduced in all patients by month 3, reaching a 93% reduction by month 12. Five patients (36%) experienced oral mucosal lichenoid lesions: these scores were decreased by 55% at month 12 and by 100% by month 33. The use of systemic immunosuppressants was reduced in all patients; 4 patients could stop all immunosuppressant drugs after 2 years. ECP was stopped in 3 patients after a complete response. No major ECP-associated adverse effects were observed.. ECP was an effective long-term therapy for oral and cutaneous cGVHD: consequently, dose levels of therapeutic immunosuppression could be reduced.

Topics: Adult; Chronic Disease; Cyclosporine; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lichenoid Eruptions; Male; Middle Aged; Mouth Diseases; Mouth Mucosa; Mycophenolic Acid; Photopheresis; Prednisone; Sclerosis; Skin; Tacrolimus

The Fischer-to-Lewis (LEW) rat model of kidney transplantation is a widely accepted and well-characterized model of chronic rejection. In contrast to transplantation in a clinical setting, however, the absence of treatment with immunosuppressants and only minor mismatch of major histocompatibility complexes (MHCs) are critical discrepancies. Here, we established a rat model of chronic rejection using fully MHC-mismatched strains in which kidney disease progresses even under immunosuppressive therapy.. LEW (RT1(l)) rats were used as donors and Brown Norway (BN, RT1(n)) rats as recipients. Intramuscular administration of 0.1mg/kg of tacrolimus was initiated on the day of transplantation. Post-transplantation, this dose was maintained until Day 9, suspended until Day 28 and then resumed from Day 29. Renal function, histopathology, and levels of donor-specific antibody (DSA) and several biomarkers of renal injury were assessed.. On Day 91 post-transplantation, recipients received tacrolimus treatment with short-term suspension exhibited reduced renal function and changes in histology. Those were characteristics of chronic rejection including glomerulosclerosis, interstitial fibrosis, and tubular atrophy in human transplantation recipients. Urinary protein excretion increased in a linear fashion, and elevated levels of several biomarkers of renal injury and DSA were observed even under administration of an immunosuppressant.. We established an allograft rejection model with impaired renal function and typical histopathological changes of chronic rejection in fully MHC-mismatched rats by controlling administration of an immunosuppressant. These findings suggest that this model more accurately reflects transplantation in a clinical setting than existing models and enables the evaluation of therapeutic agents.

Topics: Animals; Atrophy; Biomarkers; Chronic Disease; Disease Models, Animal; Feasibility Studies; Fibrosis; Graft Rejection; Histocompatibility Antigens; Humans; Immunosuppressive Agents; Isoantibodies; Kidney; Kidney Transplantation; Rats; Rats, Inbred BN; Rats, Inbred Lew; Sclerosis; Tacrolimus; Transplantation, Homologous

To study the clinical and pathological features of Denys-Drash syndrome (DDS).. Three DDS cases who were treated in our department from December 2009 to June 2011 were subjected to this study by reviewing of literature.. Both case 1 and case 2 were female, with karyotype 46, XX. Case 3 was male with bilateral cryptorchidism. The ages of nephropathy onset of the three cases were 1 year and 9 months, 2 years and 8 moths, and 3 months respectively. Proteinuria in case 2 and case 3 were evidenced to be resistant to steroid. Case 1 was partially responsive to tacrolimus, plasma albumin and cholesterol were improved, although proteinuria was persistent after Tacrolimus was administered. Remission was achieved in case 2 after administration of cyclosporine A and later tacrolimus, and her renal function remains normal till present (4 years and 9 months). Residue renal histology revealed diffused mesangial sclerosis (DMS) in all three patients. All of the three patients had developed right unilateral Wilms tumor. A novel WT1 missense mutation exon 9 c.1213C > G was detected in case 1. WT1 exon 9 c.1168C > T nonsense mutation and exon 8 c.1130A > T missense mutation were detected in case 2 and case 3, respectively.. The clinical manifestation of nephropathy in DDS is variable. The majority present with early onset nephropathy and reach renal failure before the age of 4 years. But in a few patients, nephropathy can also be present much later and progress slowly. Proteinuria in DDS is resistant to steroid but is responsive to calcineurin inhibitors, including Cyclosporine A. The effectiveness of tacrolimus was also observed in this study. DDS is evidently caused by WT1 mutation. DMS is the characteristic renal pathological change in DDS.

Topics: Cyclosporine; Denys-Drash Syndrome; Fatal Outcome; Female; Genes, Wilms Tumor; Heterozygote; Humans; Infant; Male; Mutation; Nephrotic Syndrome; Proteinuria; Sclerosis; Tacrolimus; Treatment Outcome; Wilms Tumor; WT1 Proteins

Cutaneous plasmacytosis is a rare condition affecting middle-aged individuals, characterized by multiple red-brown papules and plaques over the trunk. It has been reported mainly in Japan. The condition is accompanied by polyclonal hypergammaglobulinemia and superficial lymphadenopathy. Lung or retroperitoneal involvement occurs rarely. In the present study, 3 consecutive cases of cutaneous plasmacytosis were observed histologically to have abundant infiltration of IgG4-bearing plasma cells. All 3 were associated with superficial lymphadenopathy, one with interstitial lung involvement showing ground-glass opacity on computed tomography and the others with bone marrow plasmacytosis, showing histologic evidence of more IgG4-positive plasma cells. All 3 had polyclonal hypergammaglobulinemia, one had high serum concentration of IgG4, and all had elevated serum IL-6. The ratios of IgG4+ to IgG+ plasma cells were assessed using skin biopsy specimens with pemphigus (n = 7), discoid lupus erythematosus (n = 5), and morphea (n = 2) (mean ratios, 19%, 0%, and 0%, respectively); we noted the proportion of IgG4-positive plasma cells in cutaneous plasmacytosis (mean, 48%). IgG4-related sclerosing disease is a newly recognized systemic disorder characterized by lymphoplasmacytic infiltration and fibrosis and by a high serum IgG4 level and increased IgG4-positive plasma cells in the tissues. Skin manifestations of this disorder have not been described. Although cutaneous plasmacytosis could be a chronic allergic hypersensitivity reaction, our findings raise the possibility of a relationship in pathogenesis between cutaneous plasmacytosis and IgG4-related sclerosing disease.

Topics: Anti-Inflammatory Agents; Biopsy; Case-Control Studies; Cell Count; Dermatologic Surgical Procedures; Diagnosis, Differential; Fibrosis; Follow-Up Studies; Humans; Hypergammaglobulinemia; Immunoglobulin G; Immunohistochemistry; Immunosuppressive Agents; Inflammation; Interleukin-6; Japan; Lung; Lung Diseases, Interstitial; Lymphatic Diseases; Male; Middle Aged; Ointment Bases; Pemphigus; Plasma Cells; Prednisolone; Radiography; Sclerosis; Skin; Tacrolimus; Time Factors; Treatment Outcome