Prolonged Use Of Immunosuppressive Drugs Research Articles

A case report of surgical complications in a patient with ulcerative colitis

Rapidly rising prevalence of ulcerative colitis in developed countries among young population compels the medical community to pay attention not only to the problems of early diagnosis and therapy of this disease, but also to preventing the development of complications, that may lead to disability. This article reviews a clinical case of the development of surgical complications in a patient with a long-term active course of ulcerative colitis, who has been also suffering from autoimmune hepatitis and primary sclerosing cholangitis for 20 years. The prolonged active course of the disease and total damage to the colon, association with primary sclerosing cholangitis, as well as the patient’s low adherence to therapy were risk factors for the development of adenocarcinoma of the ascending colon, which required radical surgical treatment. The formation of adhesive disease and multiple abdominal abscesses can be noted as long-term complications, which led to the repeated use of invasive methods of treatment. Over the next few months, the patient experienced 2 more episodes of local purulent complications that required surgical treatment due to the ineffectiveness of antibiotic therapy. All episodes of purulent complications were accompanied by progressive leukopenia due to prolonged use of immunosuppressive drugs. In our opinion, in patients with ulcerative colitis who take cytostatic agents for a long time, special attention should be paid to monitoring and correcting leukopenia, as well as preventing the development of purulent complications.

A COVID-19 Overview from the Perspective of the Brazilian Kidney Transplantation Program

The Coronavirus disease 2019 (COVID-19) has significantly affected kidney transplantation activities around the world, thus resulting in a substantial decrease in both deceased and living transplants. This study presents a COVID-19 overview from the perspective of the Brazilian kidney transplant program by comparing its differences or similarities with the situations observed in other countries. During the first year of the pandemic, there was a 40% reduction in the number of kidney transplants worldwide. A similar scenario was observed in Brazil, which has the world’s largest public transplantation program. Beyond its effect on transplant activity, COVID-19 has influenced the outcomes of prevalent kidney transplant recipients (KTRs) because the prolonged use of immunosuppressive drugs and comorbidities increase the susceptibility of such patients to severe disease and death. In the pre-vaccination era, almost two-thirds of KTRs required hospitalization, more than 20% required dialysis, and one-third was admitted to the intensive care unit. In the pre-vaccination period in Brazil, 15% and 21% of KTRs died within 28 and 90 days of COVID-19 diagnosis, respectively. Although high vaccination coverage rates have altered the COVID-19 landscape in many populations, persistently low immunogenicity rates following sequential vaccination shots and the absence of targeted treatments for severe cases continue to classify KTRs as highly vulnerable, thus warranting significant concern.

Increased Risk of Malignancy with Immunosuppression: A Population-Based Analysis of Texas Medicare Beneficiaries.

Immunosuppressive drugs (IMD) are widely utilized to treat many autoimmune conditions and to prevent rejection in organ transplantation. Cancer has been associated with prolonged use of IMD in transplant patients. However, no detailed, systematic analysis of the risk of cancer has been performed in patients receiving IMD for any condition and duration. We analyzed Medicare data from Texas Medicare beneficiaries, regardless of their age, between 2007 and 2018, from the Texas Cancer Registry. We analyzed the data for the risk of cancer after IMD use associated with demographic characteristics, clinical conditions, and subsequent cancer type. Of 29,196 patients who used IMD for a variety of indications, 5684 developed cancer. The risk of cancer (standardized incidence ratio) was particularly high for liver (9.10), skin (7.95), lymphoma (4.89), and kidney (4.39). Patients receiving IMD had a four fold greater likelihood of developing cancer than the general population. This risk was higher within the first 3 years of IMD utilization and in patients younger than 65 years and minorities. This study shows that patients receiving IMD for any indications have a significantly increased risk of cancer, even with short-term use. Caution is needed for IMD use; in addition, an aggressive neoplastic diagnostic screening is warranted.

Mycophenolic acid and cancer risk in solid organ transplant recipients: Systematic review and meta-analysis.

Mycophenolic acid (MPA) is an immunosuppressive drug commonly used for prophylaxis of graft rejection in solid organ transplant recipients. The main concern with the prolonged use of immunosuppressive drugs is the risk of developing cancer. However, it remains unclear whether the immunosuppressive regimens containing MPA confer an increased degree of cancer risk. The present study aimed to determine the association between MPA exposure and the incidence of cancer in solid organ transplant recipients. A systematic search was performed on the PubMed, EMBASE and Cochrane Library databases. Relevant articles that had findings on the incidence (or event) of cancer in cohorts with and without MPA exposure were retrieved for data extraction. A meta-analysis was conducted by means of the random-effects model, and the relative risk (RR) and its 95% confidence interval (95% CI) were used as a summary effect measure. A total of 39 studies were eligible for inclusion, with 32 studies that enabled meta-analysis. MPA exposure was significantly associated with a lower risk of cancer when compared to azathioprine exposure (RR = 0.66, 95% CI = 0.53-0.81, P < .001) or no exposure to any additional treatments (RR = 0.85, 95% CI = 0.73-0.99, P = .04). There was no significant difference in cancer risk for the comparison between MPA exposure and mammalian target of rapamycin (mTOR) inhibitor exposure (RR = 1.54, 95% CI = 0.96-2.46, P = .07). MPA exposure was not associated with an increased risk of cancer and may even be associated with a lower risk of cancer when compared to azathioprine or no treatment.

Clinicopathological characteristics of T-cell non-Hodgkin lymphoma arising in patients with immunodeficiencies: a single-center case series of 25 patients and a review of the literature.

Although it is known that B-cell lymphomas occur more frequently in immunocompromised patients, thus far such an association has not been clearly established for T-cell lymphomas. Of the 251 patients who were diagnosed with a T-cell non-Hodgkin lymphoma in our center between 1999 and 2014, at least 25 were identified in immunocompromised patients. Herein, we retrospectively analyzed the clinical and pathological characteristics of these 25 cases. In addition, we searched the literature and present an overview of 605 previously published cases. The actual number of patients with B-cell chronic lymphocytic leukemia and patients on immunosuppressive drugs for inflammatory bowel disease or rheumatoid arthritis in the total cohort of 251 patients diagnosed with T-cell non-Hodgkin lymphoma was much higher than the number of patients expected to have these diseases in this cohort, based on their prevalence in the general population. This, together with the large number of additional cases found in the literature, suggest that the risk of developing T-cell non-Hodgkin lymphoma is increased in immunocompromised patients. Compared to T-cell non-Hodgkin lymphoma in the general population, these lymphomas are more often located extranodally, present at a younger age and appear to have a poor outcome. The observations made in the study herein should raise awareness of the possible development of T-cell non-Hodgkin lymphoma in immunodeficient patients, and challenge the prolonged use of immunosuppressive drugs in patients who are in clinical remission of their autoimmune disease.

Expression of CD64 on Circulating Neutrophils Favoring Systemic Inflammatory Status in Erythema Nodosum Leprosum.

Erythema Nodosum Leprosum (ENL) is an immune reaction in leprosy that aggravates the patient´s clinical condition. ENL presents systemic symptoms of an acute infectious syndrome with high leukocytosis and intense malaise clinically similar to sepsis. The treatment of ENL patients requires immunosuppression and thus needs to be early and efficient to prevent both disabilities and permanent nerve damage. Some patients experience multiple episodes of ENL and prolonged use of immunosuppressive drugs may lead to serious adverse effects. Thalidomide treatment is extremely effective at ameliorating ENL symptoms. Several mechanisms have been proposed to explain the efficacy of thalidomide in ENL, including the inhibition of TNF production. Given its teratogenicity, thalidomide is prohibitive for women of childbearing age. A rational search for molecular targets during ENL episodes is essential to better understand the disease mechanisms involved, which may also lead to the discovery of new drugs and diagnostic tests. Previous studies have demonstrated that IFN-γ and GM-CSF, involved in the induction of CD64 expression, increase during ENL. The aim of the present study was to investigate CD64 expression during ENL and whether thalidomide treatment modulated its expression. Leprosy patients were allocated to one of five groups: (1) Lepromatous leprosy, (2) Borderline leprosy, (3) Reversal reaction, (4) ENL, and (5) ENL 7 days after thalidomide treatment. The present study demonstrated that CD64 mRNA and protein were expressed in ENL lesions and that thalidomide treatment reduced CD64 expression and neutrophil infiltrates—a hallmark of ENL. We also showed that ENL blood neutrophils exclusively expressed CD64 on the cell surface and that thalidomide diminished overall expression. Patient classification based on clinical symptoms found that severe ENL presented high levels of neutrophil CD64. Collectively, these data revealed that ENL neutrophils express CD64, presumably contributing to the immunopathogenesis of the disease.

Long-term genotoxic effects of immunosuppressive drugs on lymphocytes of kidney transplant recipients

Immunosuppressive therapy can prevent rejection after organ transplantation. However, increased cancer risk is a serious complication among patients undergoing such therapy. We have evaluated whether prolonged use of immunosuppressive drugs is genotoxic. DNA instability was assessed, using the comet and micronucleus assays, in blood lymphocytes of 76 kidney transplant patients. DNA damage detected by the comet assay increased with time after transplantation. The estimated glomerular filtration rate of the patients did not influence the incidence of DNA damage. No association between micronucleated mononucleated cells and time elapsed after transplantation was observed. Our results suggest that prolonged use of immunosuppressive drugs in kidney transplant patients can induce genetic instability.

Epidemiology of de novo malignancies after solid-organ transplantation: Immunosuppression, infection and other risk factors

Organ transplantation is an increasingly used medical procedure for treating otherwise fatal end-stage organ diseases, and a large number of anti-rejection drugs have been developed to prolong long-term survival of both the individual and the transplanted organ. However, the prolonged use of immunosuppressive drugs is well known to increase the risk of opportunistic diseases, particularly infections and virus-related malignancies. Although transplant recipients experience a nearly twofold elevated risk for all types of de novo cancers, persistent infections with oncogenic viruses are associated with up to hundredfold increased risks. Women of the reproductive age are growing in number among the recipients of solid-organ transplants, but specific data on cancer outcomes are lacking. This article updates evidences linking iatrogenic immunosuppression, persistent infections with oncogenic viruses, other risk factors and post-transplant malignancies. Epidemiological aspects, tumourigenesis related to oncogenic viruses, clinical implications, as well as primary and secondary prevention issues are discussed to offer clinicians and researchers alike an update of an increasingly important topic.

Skin tumors and skin infections in kidney transplant recipients vs. patients with pemphigus vulgaris

Pemphigus vulgaris is an autoimmune disease of the skin and mucous membrane. Renal transplantation is a common procedure in Iraq, and these patients required prolonged use of immunosuppressive drugs. To study the frequency of skin tumors and infections in patients with pemphigus vulgaris compared with renal transplant recipients and normal controls. One hundred kidney transplant recipients, their ages ranged from 14 to 70 (46.65±4.74) years, and 50 patients with pemphigus vulgaris, their ages ranged from 22 to 70 (43.32±3.46) years, were studied in Baghdad Hospital from June 2009 to August 2010. Patients were treated with immunosuppressive drugs for 0.5-25years. Patients were examined for tumors and infections and compared with the general population as controls (100 individuals). In renal transplant recipients, the following infections were observed: herpetic, 25 patients (25%); bacterial, 11 (11%); and fungal, 22 (22%). These infections appeared early in the course of immunosuppression. Benign tumors increased, most importantly viral warts in 40 (40%) and actinic keratosis, 14 (14%). The malignant tumors were basal cell carcinomas in 4 (4%), squamous cell carcinomas 2 (2%), and Kaposi's sarcoma 3 (3%). These malignancies usually appeared late in the course of immunosuppression. Patients with pemphigus vulgaris showed no important skin infections or tumors. Healthy controls showed no infections apart from herpetic infections in 7 (7%) and viral warts in 9 (9%). No tumors were seen. Pemphigus vulgaris in prolonged immunosuppression is immunoprotective against skin infections and skin tumors while kidney transplant recipients are not protective.

Pyrimethamine treatment does not ameliorate lymphoproliferation or autoimmune disease in MRL/lpr−/− mice or in patients with autoimmune lymphoproliferative syndrome

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder of lymphocyte apoptosis leading to childhood onset of marked lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias, and increased risk of lymphoma. Most cases are associated with heterozygous mutations in the gene encoding Fas protein. Prolonged use of immunosuppressive drugs that do ameliorate its autoimmune complications fail to consistently lessen lymphoproliferation in ALPS. A case series had described children with ALPS, whose spleens (SPL) and lymph nodes decreased in size when treated weekly with pyrimethamine and sulfadoxine; parallel in vitro studies showed only pyrimethamine to promote apoptosis. On the basis of that experience, we undertook additional in vitro lymphocyte apoptosis assays, and measured SPL weights, lymphocyte numbers, and immunophenotypes in Fas-deficient MRL/lpr-/- mice to gain further insights into the utility of combined pyrimethamine/sulfadoxine or pyrimethamine alone. Moreover, seven children with ALPS enrolled in a study of escalating dose of pyrimethamine alone given twice weekly for 12 weeks to determine if their lymphadenopathy and/or splenomegaly would diminish, as assessed by standardized computerized tomography. Neither pyrimethamine alone or with sulfadoxine in the MRL/lpr-/- mice, nor pyrimethamine alone in ALPS patients proved efficacious. We conclude that these drugs do not warrant further use empirically or as part of clinical trials in ALPS Type Ia as a lympholytic agent.

Concurrent bartonellosis and babesiosis in a dog with persistent thrombocytopenia

A 12-year-old castrated male West Highland White Terrier was referred because of recurrent episodes of collapsing. The dog was mildly anemic and severely thrombocytopenic and had high serum alanine aminotransferase activity. Infection with Bartonella vinsonii (berkhoffii) was initially diagnosed on the basis of serologic testing. Despite treatment with a series of antimicrobials and prolonged use of immunosuppressive drugs, thrombocytopenia persisted. After 5 months of treatment, Babesia canis organisms were seen during examination of a direct blood smear. The dog was treated with imidocarb dipropionate for babesiosis, after which thrombocytopenia resolved, and administration of immunosuppressive drugs was discontinued. Retrospective review of blood smears failed to identify organisms; however, polymerase chain reaction (PCR) analysis of multiple stored blood samples obtained during the 5-month period of persistent thrombocytopenia identified DNA of B. canis vogeli. Babesiosis may cause persistent, unexplained thrombocytopenia in dogs that are not anemic. A PCR assay can facilitate a diagnosis of babesiosis when organisms are not evident or when serologic testing fails to detect Babesia-specific antibodies.

Dimethyl sulphoxide reduces anti-receptor antibody titres in experimental myasthenia gravis.

The basic abnormality in myasthenia gravis (MG) is a reduction of acetylcholine receptors (AChRs) at neuromuscular junctions, due to an autoimmune attack directed against the receptors. Several lines of evidence support the idea that humoral immune mechanisms play an important part in this process: anti-AChR antibodies are present in the sera of more than 80% of myasthenic patients; the pathogenicity of the antibodies has been demonstrated by passive transfer of IgG from myasthenic patients to mice which reproduces the typical features of MG in the recipient animals; finally, procedures that reduce levels of anti-AChR antibody, such as plasmapheresis, produce improvement in the clinical symptoms of MG. Present treatments of MG depend largely on the prolonged use of immunosuppressive drugs, which have significant drawbacks, for they usually produce only a slow fall in antibody titres, and have toxic side effects. An agent that could produce a rapid and sustained fall of autoantibody titre might have wide application in the treatment of MG and other autoimmune diseases. In the course of testing immunosuppressive drugs for their effect in treating experimental autoimmune MG (EAMG), we discovered that the vehicle used to dissolve some of these agents, dimethyl sulphoxide (DMSO), itself produced a rapid and sustained fall of anti-AChR antibody titre. We now report similar results for a controlled trial of DMSO treatment in rats with EAMG.