Prednisone Combination Therapy Research Articles

PROact: A prospective phase II study to evaluate olaparib plus abiraterone and prednisone combination therapy in patients with metastatic hormone sensitive prostate cancer with HRR gene mutation.

PROact: A prospective phase II study to evaluate olaparib plus abiraterone and prednisone combination therapy in patients with metastatic hormone sensitive prostate cancer with HRR gene mutation.

Combination Therapy of Prednisone, Azathioprine, and Hydroxychloroquine in Patient with Dermatomyositis

manifestations of inflammatory myopathy accompanied by cutaneous involvement. In patients with cutaneous DM, for the first line of therapy can be given photoprotection, topical steroids, Hydoroxychloroquin (HCQ) or Chloroquine and Quinacrine, while the gold standard in DM myopathy is systemic corticosteroids. Inadequate therapeutic regimens can result in morbidity or complications, especially calcinosis. Case Presentation: A 29-year-old woman had reddish spots on her face and hands accompanied by pain in her hands, hips, knees and elbows making it difficult for the patient to walk. Found it exists Heliotrop sign, Gottron papule and Gottron sign. The main aim of providing therapy to DM patients is to reduce inflammation, such as minimizing symptoms, especially those related to muscle weakness and improving the patient's quality of life. Glucocorticoids remain the first line therapy option for DM with the choice of oral prednisone 1mg/kgBW/day. Meanwhile, moderate to severe DM specifically should be treated with a combination which contains steroids and immunosuppressants, such as Methotrexate (MTX), Azathioprine (AZA), or Mycophenolate Mofetil (MMF). The therapy regimen must be given appropriately and adequately to minimize the occurrence of complications. Conclusion: A combination of Prednisone, Azathioprine, andHydoroxychloroquin is effective as a therapy for Dermatomyositis. This can be proven by an increase in muscle strength and the red spots disappearing in this patient.

Retrospective evaluation of leflunomide as an adjunctive therapy in dogs with non-associative immune-mediated thrombocytopenia: 20 cases (2008-2021).

To describe leflunomide as an adjunctive therapy in the treatment of non-associative immune-mediated thrombocytopenia. A retrospective study of dogs with a diagnosis of non-associative immune-mediated thrombocytopenia treated with leflunomide March 2008 to September 2021 was conducted. Data collected included signalment, clinical signs, physical examination findings and diagnostic testing performed. Medications administered, duration of hospital stay, time to platelet concentration >150×109/L and adverse events during leflunomide therapy were recorded. Relapses within a year of diagnosis were reported. A total of 20 client-owned dogs met inclusion criteria. Nineteen of 20 dogs (95%) achieved a platelet concentration >150×109/L with leflunomide and prednisone combination therapy and four dogs (21.1%) relapsed during treatment or shortly after treatment. Adverse effects included diarrhoea (n=5), mild lymphopenia (n=9) and mild intermittent anaemia (n=1). A single dog developed hepatotoxicity presumed to be secondary to leflunomide therapy that resolved after drug discontinuation. One dog was treated for aspiration pneumonia during treatment. Two dogs were euthanased while receiving leflunomide. Length of hospitalisation, time to platelet recovery, treatment response and relapse rate were comparable with alternative treatment protocols. Most adverse effects did not require leflunomide dose adjustment; however, two dogs died while undergoing leflunomide treatment and there is compelling evidence that one of these dogs experienced fatal infection secondary to immune-suppression. Hepatotoxicity remains a known complication of leflunomide treatment and serial biochemistry testing is recommended.

175TiP A prospective phase II study to investigate the efficacy and safety of olaparib plus abiraterone and prednisone combination therapy in mHSPC patients with HRR gene mutation

Homologous recombination repair (HRR) genes are a common type of mutation in advanced prostate cancer, approximately 10-15% of metastatic hormonal sensitive prostate cancer (mHSPC) patients harbor loss-of-function mutations in the HRR genes. Olaparib plus Abiraterone and Prednisone combination therapy has significantly prolonged radiographic progress free survival in metastatic castration-resistant prostate cancer patients with or without HRR mutation. The efficacy of combination therapy at mHSPC stage deserves further exploration.

Comparison between low disease activity or DAS remission as treatment target in patients with early active rheumatoid arthritis

ObjectivesTo compare outcomes of targeted treatment aimed at either low disease activity or remission in patients with early active rheumatoid arthritis (RA).MethodsFive-year outcomes were compared in 133 patients with early...

The clinical activity of arsenic trioxide, ascorbic acid, ifosfamide and prednisone combination therapy in patients with relapsed and refractory multiple myeloma.

This study aimed to investigate the activity of arsenic trioxide (As2O3) combined with ascorbic acid, ifosfamide, and prednisone chemotherapy in patients with repeatedly relapsed and refractory multiple myeloma (MM). Here, we retrospectively analyzed medical data of 30 MM patients showing progressive disease after receiving at least two previous lines of treatment including an immunomodulatory agent (thalidomide or lenalidomide) and a proteasome inhibitor. There were 19 men and eleven women, aged 54–73 (median 65) years, in this study. The distribution of different isotypes included immunoglobulin G(IgG) (12 patients), IgA (six patients), IgD (three), and light chain (nine patients). All the patients were Durie–Salmon stage III and had relapsed at least three times; the median cycles of prior therapies was 15 (range 10–18). The patients were treated with As2O3, ascorbic acid, and CP (ifosfamide 1 g on day 1, day 3, day 5, and day 7; prednisone 30 mg taken orally for 2 weeks). As2O3 was administered as an intravenous infusion at a dose of 10 mg/d and ascorbic acid at a dose of 2 g/d for 14 days of each 4-week cycle. The results showed that after 2 cycles of therapy, there were five patients that attained partial response, 15 had minimal response, five had no change, and five had progressive disease. The overall response rate was 66.7% (20/30 cases), 50% (10/20 cases), and 40% (2/5 cases), respectively, after 2, 4, and 6 cycles of the therapy. But there were no patients that attained complete remission. The median time of overall survival and progression-free survival were 48 (29–120) and 6 (2–8) months, respectively. The most common treatment-related adverse events included neutropenia, fatigue, anemia, thrombocytopenia, and infection that could be tolerated. The results showed that As2O3 combined with ascorbic acid, ifosfamide, and prednisone chemotherapy may be a choice treatment for repeatedly relapsed and refractory MM patients.

Central Diabetes Insipidus as the Presenting Symptom of Granulomatosis With Polyangiitis

Granulomatosis with polyangiitis (Wegener's; GPA) is a necrotizing granulomatous vasculitis that can affect any organ system; however, central nervous system involvement is uncommon. We present 2 cases where central diabetes insipidus was the presenting manifestation of GPA. Pituitary involvement was documented by magnetic resonance imaging. Both patients were female and responded to combination therapy of prednisone and cyclophosphamide. We also review the literature for all reported cases of pituitary involvement in GPA. We conclude that pituitary involvement in GPA seems more common in females and may be the initial presenting clinical feature and may occur in the absence of systemic disease. Early recognition and treatment may prevent pituitary necrosis and irreversible damage.

S2K-Leitlinie zur Diagnostik und Therapie der idiopathischen Lungenfibrose

Idiopathic pulmonary fibrosis is a fatal lung disease with a variable and unpredictable natural history and limited treatment options. Since publication of the ATS-ERS statement on IPF in the year 2000 diagnostic standards have improved and a considerable number of randomized controlled treatment trials have been published necessitating a revision. In the years 2006 - 2010 an international panel of IPF experts produced an evidence-based guideline on diagnosis and treatment of IPF, which was published in 2011. In order to implement this evidence-based guideline into the German Health System a group of German IPF experts translated and commented the international guideline, also including new publications in the field. A consensus conference was held in Bochum on December 3rd 2011 under the protectorate of the "Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin (DGP)" and supervised by the "Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften" (AWMF). Most recommendations of the international guideline were found to be appropriate for the german situation. Based on recent clinical studies "weak negative" treatment recommendations for pirfenidone and anticoagulation were changed into "weak positive" for pirfenidone and "strong negative" for anticoagulation. Based on negative results from the PANTHER-trial the recommendation for the combination therapy of prednisone plus azathiorpine plus N-acetlycsteine was also changed into strong negative für patients with definite IPF. This document summarizes essential parts of the international IPF guideline and the comments and recommendations of the German IPF consensus conference.

Idiopathic pulmonary fibrosis in 2011: key updates on guidelines and therapeutics Concluding remarks

This was a very successful meeting, which brought together leading experts in the treatment and research of IPF and provided a forum for the discussion and sharing of new developments, committee guidance and clinical experience. The 2011 guidelines from the ATS/ERS/JRS/ALAT joint committee [1] provide a very good background for physicians managing patients with IPF, giving great detail in terms of the approach to diagnosing patients. Newly refined criteria were published, which gave a central role to the usefulness and implementation of high-resolution computed tomography scanning in the diagnostic algorithm. During the meeting, there was much discussion around the daily challenges faced by physicians who have patients with IPF, which remain even after the publication of the updated guidelines. Although considered highly useful by the majority of attendees, it was generally felt that an update to the 2011 publication would be useful, to fully incorporate research outcomes that weren’t included in the existing analysis, such as the complete dataset regarding the efficacy of pirfenidone and the closing of studies of warfarin treatment, along with safety data regarding the N-acetylcysteine, azathioprine and prednisone combination therapy. It is now possible to reassess the treatment recommendations of these agents. In addition, the presentations and discussions held at the meeting identified specific issues within the diagnosis recommendations. By addressing these points, we will have an even stronger platform on which to base our patient management approaches, and will be able to provide a more confident diagnosis along with the most effective treatment options available to date. This is a very exciting time in IPF research, and we, as physicians, are driving the progress and trying to improve the outlook for patients with this difficult-to-treat disease. A key take-home message from this meeting is that each patient should be viewed as an individual case when considering the diagnostic and disease management approaches. As previously mentioned, with continuing support and enthusiasm from its attendees, the AIR Meeting should become an annual event in the calendar for respiratory physicians and researchers dedicated to advancing the treatment and management of patients with IPF.

A Phase II Study of Low-Dose Pomalidomide (0.5mg/day) and Prednisone Combination Therapy in Patients with Myelofibrosis and Significant Anemia

AbstractAbstract 1728 Introduction:Pomalidomide (POM) is an investigational immunomodulatory drug (IMID) that has shown efficacy in preliminary studies, with or without prednisone, as therapy for myelofibrosis (MF) with anemia, by eliminating the need for red blood cell (RBC) transfusions. In our experience, however, single agent low dose POM (0.5 mg/d) has very modest efficacy in achieving RBC transfusion independence in MF patients (Shastri A et al Blood 2011; 118). To further understand and define its activity, we have undertaken a single center phase II open label study to assess the efficacy of low dose POM in combination with prednisone therapy. In a prior study this combination resulted in a 36% response rate according to International Working Group for Myelofibrosis Research and Therapy (IWG-MRT) response criteria (Tefferi A, et al. JCO 2009; 27:4563). In the current study, benefit was assessed by the RAND-Delphi consensus criteria, which has been suggested as a better tool to evaluate RBC transfusion dependence/independence in clinical trials (Gale RP et al. Leuk Res 2011; 35:8) than IWG-MRT criteria. Patients were also evaluated for an increase in hemoglobin of at least 2g/dL for duration of 8 weeks, without transfusion support.Table 1RAND-Delphi criteria for RBC transfusion dependence/independenceRBC-transfusionsSurveillance intervalRBC-transfusion-dependence≥2 U/month3 monthsRBC-transfusion-independenceNone3 monthsReduced RBC-transfusion-dependence50% decrease3 months Patients & Results:21 patients, 14 male and 7 female, were enrolled in the study: 2 (10%) had post essential thrombocythemia MF, and 19 (90%) had primary MF. Median age was 69 years (range 48–85) and 15 (71%) were previously treated; 5 had been treated with other IMIDs previously. Four (19%) had splenomegaly; 1 had prior splenectomy. Seven (33%) had abnormal cytogenetics and 10 (48%) had JAK2V617F mutation. All patients had hemoglobin <10g/dL at study entry; patients with higher hemoglobin that were transfusion dependent were allowed to enroll if it was a result of a blood transfusion given just prior to enrollment. Median hemoglobin was 8.5 g/dL (range 7.3–11.1), WBC 4.7×109/L (1–20.7), and platelets 155×109/L (35–1191). The use of anagrelide during the study was allowed to control high platelets, if indicated; other concomitant therapies, including growth factors, were not allowed. Patients were administered POM 0.5mg continuously daily in 28-day cycles and prednisone was administered as 30mg daily for the first month, 15mg daily for second month, 15mg every other day for third month and then stopped. Thirteen (62%) patients were transfusion dependent by the RAND-Delphi consensus criteria.After a median follow up of 7.8 months (3.3–11.9), 6 (28%) patients were still on the therapy. The median number of cycles administered to patients was 6 (2–12). Fourteen patients were taken off the study for lack of response (N=12) or for loss of a response (N=2). One patient was taken off due to the development of grade 3 pneumonitis. Three died from unrelated causes. Three patients were noted to have RBC transfusion response per RAND-Delphi criteria. One of the responders had JAK2V617F mutation. Median time to response was 52.7 days (48 – 55 days). No patient had an increase in hemoglobin of at least 2g/dL for at least 8 weeks. This is an ongoing trial and updated results along with complete toxicity profile will be presented at the meeting. Conclusion:POM administered in combination with prednisone to patients with MF and significant anemia has modest efficacy, comparable to single agent POM. A Phase III blinded, placebo-controlled study is underway globally for MF patients with significant anemia and RBC transfusion dependency. Disclosures:Verstovsek:Celgene: Research Funding.

Bullous pemphigoid: a case series with emphasis on long-term remission off therapy

Background: Bullous pemphigoid (BP) is the most common blistering autoimmune skin disease. Combination methotrexate (MTX) and prednisone therapy is an effective short-term treatment for BP. Objective: To determine the average length and frequency with which MTX and prednisone combination therapy leads to long-term remission off therapy. Methods: A retrospective chart review of 16 of our patients with BP was conducted. Patients were treated with the combination regimen of MTX and prednisone, followed by us for at least 1 year, and had long-term follow-up data. Results: The average length of time from initiating MTX and prednisone therapy to complete disease control was 3.8 months. Eight of 16 patients were in remission off BP therapy with combination MTX and prednisone therapy. The average length of treatment in this subgroup was 25.3 months and patients were followed for a mean of 5.5 years since initiating therapy. Three additional patients were in remission (with a mean treatment time short of the 25.3 month average) undergoing tapering of BP therapy. Conclusions: Two year MTX and prednisone combination therapy is a safe, inexpensive, and effective treatment for BP that can result in long-term remission off therapy.

Clinical outcomes in children with Henoch–Schönlein purpura nephritis grade IIIa or IIIb

Henoch-Schönlein purpura (HSP) is one of the most common causes of systemic vasculitis in children. The incidence of HSP nephritis (HSPN) among HSP patients has been reported to be 15-62%. Even so, what constitutes severe HSPN is controversial. In the study reported here, we retrospectively reviewed the clinical features and prognosis of 101 children with HSPN, ISKDC grade IIIa/IIIb, from January 1992 to November 2008. Patients with isolated hematuria and/or proteinuria <50 mg/kg/day received triptolide alone, and those with nephrotic range proteinuria received a combination therapy of prednisone and triptolide. Nephrotic syndrome was the most common clinical manifestation (45.5%). There were no significant differences in the clinical features (χ(2) = 2.756, P = 0.252), the side effects related to treatment (χ(2) = 2.259, P = 0.894), prognosis between IIIa and IIIb (χ(2) = 3.013, P = 0.222), or prognosis in grade IIIa patients receiving triptolide alone or triptolide and prednisone (χ(2) = 1.207, P = 0.272) and grade IIIb patients (χ(2) = 1.158, P = 0.282). No significant difference in clinical manifestations and long-term prognosis of our HSPN patients with grade IIIa or grade IIIb were found, implying that our patients with International Study and Kidney Disease in Children (ISKDC) grade IIIb were not the most severe cases of HSPN. Our results may also suggest that treatment with steroid may not alter the clinical outcome of such grade IIIa or IIIb patients.

Comparison of the therapeutic effects of leflunomide and mycophenolate mofetil in the treatment of immunoglobulin A nephropathy manifesting with nephrotic syndrome

To evaluate the therapeutic effects and safety of a combination therapy of leflunomide (LEF) and prednisone for the treatment of immunoglobulin A (IgA) nephropathy manifesting with nephrotic syndrome. 40 patients with IgA nephropathy manifesting with nephrotic syndrome were randomly divided into two groups. The treatment group was administered with a combination therapy of prednisone and LEF, and the control group with a combination therapy of prednisone and MMF. For the following comparison 24-h urinary protein excretion and the serum levels of albumin, cholesterol, and creatinine before and after the therapy were assessed. In the treatment group, the medication was markedly effective in 5 cases and effective in 7 cases; the total efficacy rate was 60.0%. In the control group, the treatment was markedly effective in 5 cases and effective in 8 cases; the total efficacy rate was 65.0%. The IgA levels in both groups decreased after therapy. There were no significant differences between the results for the two groups (p > 0.05). The treatments were well tolerated in both groups. LEF is a safe and effective drug for the treatment of IgA nephropathy manifesting with nephrotic syndrome.

SUBCONJUNCTIVAL INTERFERON α-2A APPLICATION IN A CASE WITH SERPIGINOUS CHOROIDOPATHY.

Serpiginous choroidopathy (SC) is a chronic, inflammatory disease which progresses with recurrences leading to visual loss. Diverse immunosuppressive regimens have been used for treatment. In case of an unanticipated side effect with immunosuppressive agents, alternative modalities in SC are limited. A 38-year-old woman presented with slight deterioration in visual acuity in her right eye. She had had a visually devastating episode of SC in the left eye 8 months previously. She received combination therapy of prednisone, cyclosporine, and intravitreal triamcinolone for the left eye. With that treatment, vision in her left eye declined to light perception due to macular involvement and renal functions were impaired. Eight months later, she was hospitalized with the diagnosis of SC in the right eye. In the quest for an alternative modality, a combination of antituberculosis medications was given initially, because of the high PPD reading. Despite 10 days of treatment, the lesion persistently progressed. Subsequently, interferon (INF) α-2a therapy was initiated solely as daily injections of 1 million unit (MIU) subconjunctivally. The frequency of injections was tapered within the course. Currently, injections are still being dispensed once a month. Throughout the 12 months of follow-up, the patient had no major side effects due to INF α-2a therapy. At present, SC in the right eye is inactive and the macula is safe in terms of incurring. The vision is 20/20 in the right eye, whereas it is light perception in the left eye. Interferon α-2a administration in SC can be an efficient modality and is free of immunosuppression related side effects. Subconjunctival application seems to be a promising and safe tool for treatment.

Combination Therapy of Prednisone and ACE Inhibitor Versus ACE-Inhibitor Therapy Alone in Patients With IgA Nephropathy: A Randomized Controlled Trial

Recent studies have shown that both steroids and angiotensin-converting enzyme (ACE) inhibitors improve kidney survival and decrease proteinuria in patients with immunoglobulin A nephropathy. In this study, we aim to investigate whether the addition of steroids to ACE-inhibitor therapy produces a more potent antiproteinuric effect and better protection of kidney function than an ACE inhibitor alone. Randomized controlled trial. Patients with biopsy-proven immunoglobulin A nephropathy with proteinuria of 1 to 5 g/d of protein. 63 patients were randomly assigned to either cilazapril alone (ACE-inhibitor group; n = 30) or steroid plus cilazapril (combination group; n = 33). The primary end point was kidney survival, defined as a 50% increase in baseline serum creatinine level. After follow-up for up to 48 months, 7 patients in the ACE-inhibitor group (24.1%) reached the primary end point compared with 1 patient (3%) in the combination group. Kaplan-Meier kidney survival was significantly better in the combination group than the ACE-inhibitor group after 24 and 36 months (96.6% versus 75.7%, 96.6% versus 66.2%; P = 0.001). Urine protein excretion significantly decreased in patients in the combination group compared with the ACE-inhibitor group (time-average proteinuria, 1.04 +/- 0.54 versus 1.57 +/- 0.86 g/d of protein; P = 0.01). Multivariate analysis showed that combination treatment (hazard ratio, 0.1; 95% confidence interval, 0.014 to 0.946) and time-average proteinuria (hazard ratio, 14.3; 95% confidence interval, 2.86 to 71.92) were independent predictors of kidney survival. Small sample size, a single center, and slight imbalances at baseline. Our results suggest that the addition of steroid to ACE-inhibitor therapy provided additional benefit compared with an ACE inhibitor alone. However, this was a pilot study with a small number of participants achieving the end points, and thus further validation is necessary.

Strawberry‐Like Gingival Tumor as the First Clinical Sign of Wegener's Granulomatosis

Wegener's granulomatosis (WG) is a complex disease, characterized by a necrotizing vasculitis that usually involves the upper airways, lungs, and kidneys; occasionally, other organs may also be affected. Because of the severity and rapid progression of the disease, early diagnosis and treatment are critical; this type of vasculitis is potentially fatal if left unchecked. A 64-year-old woman presented with a chief complaint of a gingival mass that had appeared 2 months before and had grown rapidly. In the previous months she complained of malaise without weight loss. An intraoral examination revealed the presence of a solitary gingival mass, 2 cm in diameter, affecting the area above the upper central incisors. The lesion displayed a granular, erythematous, speckled surface with petechiae, characteristic of WG. A biopsy of the lesion, a thoracic computed tomography, and the presence of high titers of antineutrophil cytoplasmic antibodies (ANCA) in the blood established the diagnosis of WG. An initial combination therapy of prednisone and cyclophosphamide successfully abated most of the patient's symptoms. The occurrence of an extremely rare tumor-like form of strawberry gingiva was the primary clinical sign that led to a diagnosis of WG. This case emphasizes the important role of the dentist in the diagnosis of this potentially fatal disease.

Therapy of lupus nephritis with mycophenolate mofetil

Mycophenolate mofetil is an immunosuppressive agent used in transplantation and subsequently in a variety of autoimmune conditions. It inhibits both B and T lymphocyte proliferation, and also has nonimmune effects on the kidney. The major experience in systemic lupus erythematosus has focused on proliferative lupus nephritis. In our study we treated 8 female patients having proliferative lupus nephritis with combination therapy of prednisone (1 mg/kg body weight) and mycophenolate mofetil (2 g per day). Complete remission was defined as a value for urinary protein excretion that was less than 0.5 g per 24 hours, with normal urinary sediment, a normal serum albumin concentration and improved or stable serum creatinine. Partial remission was defined as a daily proteinuria below 2g in the previously nephrotic patient or minimum 30% from starting values, with normal urinary sediment, serum albumin of minimum 30 g/L and stable serum creatinine. Two patients had a complete remission after 7 and 2 months respectively. Five patients had a partial remission after 5.2 +/- 4.3 months of therapy. One patient did not react to therapy. There were no side effects during the course of therapy. Considering the fact that 7/8 patients have had nephrotic range proteinuria and that 50% of patients were refractory on standard induction therapy, the results of this study are a good indicator of value of mycophenolate mofetil in the therapy of proliferative forms of lupus nephritis. Mycophenolate mofetil has satisfactory results in the treatment of proliferative forms of lupus nephritis with minimal side effects.

Treatment options and pregnancy outcome in women with idiopathic recurrent miscarriage: a randomized placebo-controlled study.

To compare the use of enoxaparin alone with combination therapy of prednisone, aspirin and progesterone in the treatment of women with idiopathic recurrent miscarriage (IRM) in terms of live births and pregnancy outcome. A prospective, randomized, single-blinded, placebo-controlled trial was conducted at a tertiary referral obstetric hospital. The participants were 170 women with a diagnosis of IRM. Women were recruited after full investigative screening. Women with > or =3 fetal losses and after exclusion of all known causes of recurrent miscarriage were randomly allocated to receive either enoxaparin alone, combination treatment consisting of prednisone, aspirin, and progesterone or placebo. Rates of live births, antenatal complications, delivery and neonatal outcomes were recorded prospectively. Data were statistically analyzed as appropriate. Ten patients were dropped out after random assignment. Eighty-one percent of the enoxaparin (46/57) group and 85% of the combination-treated group (45/53) were delivered of live infants compared to 48% (24/50) of the placebo (P < 0.05). Women who were treated with combination therapy had a 4.2% higher live birth rate than enoxaparin group. This difference was not significant. Miscarriage rates were significantly lower in the treated groups compared with placebo (P < 0.05). There were no significant differences in late obstetric complications or neonatal mortality between groups. A combination treatment consisting of high-dose, low-duration prednisone, progesterone and aspirin might be an effective treatment as enoxaparin alone. Both regimens were associated with a good pregnancy outcome.

Membranous Glomerulonephritis and Nephrotic Syndrome as a Late Manifestation of Chronic Graft-Versus-Host Reaction Following Allogeneic Transplantation for Hematologic Malignancy.

Chronic GVHD is an immunologically mediated complication of allogeneic transplantation with multi-organ involvement and the presence of antibodies against host cell antigens, often requiring long-term immunosuppression for control of symptoms and disease. Although multiple organs can be involved, the major targets generally include skin, liver, GI tract, lung, bone marrow and oral mucosa associated with immunodeficiency independent of treatment. Renal manifestations of chronic GVHD are very unusual and generally caused by nephrotoxic medications used to treat the disease. Membranous glomerulonephritis is the most common cause of nephrotic syndrome in the adult, characterized by a thickening of the glomerular basement membrane, deposits of antibody and complement, and is associated with either infections, systemic autoimmune disease and medications. Although chronic GVHD is not generally associated with this syndrome, we have seen and evaluated eight patients who developed nephrotic syndrome as a late manifestation of chronic GVHD.Eight patients (three males and five females), ages 44–60, presented with nephrotic syndrome (24 hour urine protein 7–18 grams/day) in the setting of pre-existing chronic GVHD with other manifestations, including skin, liver, oral mucosa and conjunctiva. One patient received an unrelated donor transplant and seven had related donors as treatment for hematologic malignancy (AML 3, MDS 3, CML 1, malignant histiocytosis 1). All patients underwent kidney biopsy which showed changes consistent with membranous glomerulonephritis with immunologic characterization consistent with this diagnosis. At the time of diagnosis all patients had 100% chimerism for T and B cells. In seven of eight cases the development of glomerulonephritis and nephrotic syndrome followed, sometimes by several years (range four months to eight years), other manifestations of chronic GVHD and in seven/eight patients it occurred while patients were on chronic immunosuppressive therapy. Treatment included the combination therapy of Prednisone and Cyclosporin, Prednisone, Cellcept and Cyclosporin or, in two cases, Rituxan targeted to the B cell component of the immunopathology. The overall response rate to treatment was 100% with all patients showing reduction in urine protein excretion (normal to 1.6 grams/day) with preservation of renal function. An evaluation for other causes, including systemic autoimmune disease, recurrent malignancy and infection, were negative and all patients remain alive and in remission. We conclude:Nephrotic syndrome following allogeneic transplantation can be caused by membranous glomerulonephritis as a manifestation of chronic GVHD.The syndrome generally occurs in the setting of existing well controlled chronic GVHD and can occur late in the course of the disease.Membranous glomerulonephritis can be successfully treated with immunosuppressive therapy used in the treatment of other manifestations of GVHD, including Rituxan.

The Effect of Tacrolimus Based Combination Therapy on Muscle and Bone Rejection in a Pre-Clinical Composite Tissue Allograft Model

212 The purpose of this study is to measure the effect Tacrolimus (FK506), Mycophenolate Mofetil (MMF), Prednisone combination therapy has on rejection of muscle and bone in a pre-clinical composite tissue allotransplant (CTA) model. We used CTA flaps created on the forelimbs of 22 pigs. The flaps consisted of radial bone, flexor muscle/tendon, supplying nerves and vessels and skin. For immunosuppression, we used a combination of orally administered FK506 (15 mg/kg/d), MMF (500 mg/d) and Prednisone (0.2 mg/kg/d). Animals were allotted into 3 groups: Group I (n=6) animals received FK506/MMF/Prednisone therapy and a CTA, Group II (n=4) animals received no drugs and a CTA, and Group III (n=12) animals served as controls receiving no therapy and no CTA. Group I animals were followed for 90 days. At the end of the experiment, animals were euthanized and bone, muscle, and tendon specimens were harvested, fixed in formaldehyde (10%) and stained with H&E. The following parameters were analyzed in all specimens in a blind fashion; bone-mononuclear infiltration, fibroblastic proliferation, irregular cortical thickening, nonviable trabeculae, intratrabecular fibrosis, filigree osteoid formation, and hemorrhage/necrosis, muscle-mononuclear infiltration, fibroblastic proliferation/replaced muscle fibers, muscle fiber degeneration, myocyte necrosis, and vascular inflammation, tendon-mononuclear infiltration, perivascular inflammation, fibrosis, degeneration, and necrosis.(Table)TableBased on our results in this pre-clinical CTA model we conclude, that FK 506 based combination therapy reduces the incidence of acute rejection episodes in bone, muscle and tendon. This effect was more pronounced in bone and tendon than in muscle.