Pharmacologic therapy of Crohn's disease and ulcerative colitis

Important progress has been made in recent years in the understanding of pathogenesis of Crohn's disease and ulcerative colitis, but the cause of IBD remains obscure, so curative therapy is still lacking. Current treatment strategies as sulphasalazine, mesalasine, glucocorticosteroids are mainly anti-inflammatory. In the past years the greatest advances have been characterised by the more widespread use of topically acting steroids, immunosuppressants and by the introduction of immunomodulatory agents as cytokines and anticytokines. The author summarises the standard therapy and new possibilities of medical treatment for IBD and suggests some algorythms for clinical practice.     

原发肾病综合征并发医院感染的危险因素分析

目的 探讨原发肾病综合征患者并发医院感染的易感因素与防治措施。方法 采用回顾性调查法分析136例原发肾病综合征患者的有关临床资料。结果 原发肾病综合征患者医院感染率达35．6％；感染部位以呼吸道为主（46．4％），泌尿道次之（17．9％）；感染率高低与住院天数（P＜0．01），激素及免疫抑制剂联合应用、血清IgC水平低下有关；感染病原菌以及革兰阴性杆菌为主，真菌已成为其重要病原菌。结论 住院天数长、激素与免疫抑制剂的应用及血清IgG水平低下是造成医院感染的危险因素，对该类患者应相应加强防护。     

WHO: How It Is Making Public Health a Global Cause

ITP is a common disease that is sorely in need of better management. Treatment strategy requires consideration of both long-term benefits and long-term hazards of each available therapeutic option. This discussion reviews conventional therapy as well as newer approaches to refractory ITP, including immunosuppressants, vinca alkaloids, colchicine, androgens, tamoxifen, and plasmapheresis.     

Modulation of immunosuppressant drug treatment to improve SARS-CoV-2 vaccine efficacy in mice

The COVID-19 pandemic dramatically demonstrated the need for improved vaccination strategies and therapeutic responses to combat infectious diseases. However, the efficacy of vaccines has not yet been demonstrated in combination with commonly used immunosuppressive drug regimens. We sought to determine how common pharmaceutical drugs used in autoimmune disorders can alter immune responses to the SARS-CoV-2 spike protein vaccination. We treated mice with five immunosuppressant drugs (cyclophosphamide, leflunomide, methotrexate, methylprednisolone, and mycophenolate mofetil), each with various mechanisms of action prior to and following immunization with SARS-CoV-2 spike protein. We assessed the functionality of antibody responses to spike protein and compared immune cell populations in mice that received no treatment with those that received continuous or temporarily suspended immune suppressive therapy. All tested immunosuppressants significantly reduced the antibody titers in serum and functional antibody response against SARS-CoV-2 spike protein in immunized mice. Temporarily halting selected immunosuppressants (methylprednisolone and methotrexate, but not cyclophosphamide) improved antibody responses significantly. Through proof-of-principle experiments utilizing a mouse model, we demonstrated that immune suppression in autoimmune disorders through pharmaceutical treatments may impair vaccine response to SARS-CoV-2, and temporary suspension of immunosuppressant treatment may be necessary to mount an effective antibody vaccine response. This work provides feasibility for future clinical assessment of the impact of immunosuppressants on vaccine efficacy in humans.     

Spotlight on Mycophenolate Mofetil in Solid Organ Transplantation

Most pharmacoeconomic studies of mycophenolate mofetil have focused on its use as part of maintenance immunosuppression for renal transplantation, involving short-term (3–12 months) time frames. In general, mycophenolate mofetil reduced the treatment costs for rejection episodes and graft failure which offset its higher drug acquisition cost compared with azathioprine.Several cost analyses have been modeled on the large multicenter trials of adult renal transplant recipients. The use of mycophenolate mofetil was associated with either cost savings or no additional costs after 6 or 12 months in French, US and Canadian analyses of triple or quadruple immunosuppressant therapy. A further cost analysis utilizing a registry database of renal transplant recipients in the US found mycophenolate mofetil to be cost saving compared with azathioprine after 6.4 years when evaluating costs due to graft loss only.Of the limited cost-effectiveness analyses with the drug, one US study modeled the 1- and 10-year cost effectiveness of mycophenolate mofetil and various other immunosuppressants used in combined regimens. Long-term use of mycophenolate mofetil was less cost effective than other regimens, but the use of long-term mycophenolate mofetil in high-risk patients was shown to be a relatively cost-effective strategy. In another US analysis comparing mycophenolate mofetil with azathioprine as part of quadruple therapy, mycophenolate mofetil was associated with slightly lower costs during the first year after renal transplantation as well as improved clinical outcomes.In conclusion, pharmacoeconomic studies support the use of mycophenolate mofetil as part of immunosuppressant therapy in renal transplantation, at least in the short term. Although the cost effectiveness of mycophenolate mofetil in the long term is less clear, limited pharmacoeconomic data available appear promising. Among issues to be examined in future economic analyses in renal transplantation are the calcineurin-sparing potential of mycophenolate mofetil and the feasibility of using more efficient mycophenolate mofetil dosage regimens when using the drug on a long-term basis. Additional pharmacoeconomic analyses of mycophenolate mofetil are also needed in other types of solid organ transplantation.     

Corneal melting after ocular surgery in patients with auto-immune disorders

Two women aged 78 and 74 years respectively, both with dry eyes due to underlying auto-immune disorders, presented after uncomplicated cataract surgery with immunostromal corneal ulceration. Intensive topical lubrication combined with systemic immunosuppressants were necessary to control the corneal melt. Dry eyes are a frequently-encountered problem among patients with rheumatoid disorders and increase the risk of corneal melting. Auto-immune related corneal melting can occur spontaneously or after ocular surgery, it threatens visual acuity and ocular integrity and may be associated with systemic vasculitis. When treating patients with rheumatoid disorders, the presence of dry eyes and the accompanying risk of serious complications need to be ascertained. In patients at risk, pre-operative preventive measures to suppress any underlying systemic disorders and improve the ocular environment are necessary. When corneal melting is diagnosed, aggressive topical therapy combined with systemic immunosuppressants is indicated.     

Old but Fancy: Curcumin in Ulcerative Colitis—Current Overview

Ulcerative colitis (UC) is one of the inflammatory bowel diseases (IBD). It is a chronic autoimmune inflammation of unclear etiology affecting the colon and rectum, characterized by unpredictable exacerbation and remission phases. Conventional treatment options for UC include mesalamine, glucocorticoids, immunosuppressants, and biologics. The management of UC is challenging, and other therapeutic options are constantly being sought. In recent years more attention is being paid to curcumin, a main active polyphenol found in the turmeric root, which has numerous beneficial effects in the human body, including anti-inflammatory, anticarcinogenic, and antioxidative properties targeting several cellular pathways and making an impact on intestinal microbiota. This review will summarize the current knowledge on the role of curcumin in the UC therapy.     

Fatal multidrug-resistant Acinetobacter baumannii sepsis in a patient with travel history and recent onset of systemic lupus erythematosus: a case report

Severe infections are a common cause of death in patients suffering from systemic lupus erythematosus (SLE). We here report on a fatal multidrug-resistant Acinetobacter baumannii sepsis in a patient with newly diagnosed SLE, who had to be treated with immunosuppressants due to lupus nephritis. Detailed analysis of the patient's history revealed that colonisation probably had occurred during a recent hospitalisation of the patient in the Mediterranean region. E-test analysis indicated that resistance to carbapenems was mediated by a plasmid-encoded metallo-ß-lactamase. We conclude that travel history including previously visited health care facilities always should be carefully considered for decisions on anti-infective therapy, as travel activities increasingly facilitate spread of antimicrobial resistances.     

Inflammatory Bowel Disease Treatment and Non-melanoma Skin Cancer: A Case Report

Immunosuppressant medications for Inflammatory Bowel Disease can help with both symptoms and disease progression. However, like immunosuppressants used in transplant patients, they are now suspect of contributing to nonmelenoma skin cancer (NMSC). Presented is a case of a 57-year-old Jewish man with Crohn''s Disease who was diagnosed with a total of 84 NMSCs. We hope to elucidate the risk of immunosuppressants, particularly the thiopurines, on the development of NMSC.     

Late complications following renal transplantation

The number of renal transplant recipients is increasing steadily. Physicians from all specialties are ever more likely to encounter this vulnerable group of patients. They constitute a susceptible group because of increased mortality and morbidity. Half of the renal transplants are lost due to chronic transplant failure. The primary cause of chronic transplant failure is chronic allograft nephropathy. Other causes of transplant failure are calcineurin inhibitor toxicity, recurrence of the original renal disease such as glomerulonephritis and diabetes mellitus, stenosis of the renal artery in the transplant, and urological complications. The other half of the renal transplants are lost due to the death of the recipient. The primary cause of death is cardiovascular disease due to former chronic renal, hypertension and dyslipidemia following the use of immunosuppressants. In addition malignancies, infections and bone abnormalities do occur more frequently as compared to the normal populations. Alertness is warranted following kidney transplantation by both the patients themselves as well as all the treating specialists. Careful periodical monitoring for life is required because of the risk of the abovementioned complications.     

Various clinical patterns of relapsing polychondritis in six cases

Relapsing polychondritis is a relatively rare disease characterized by episodic inflammation and progressive destruction of cartilage involving ears, nasal and laryngotracheal cartilage, cardiovascular system and the eyes. The increasing awareness of its clinically distinct has resulted in recognition of at least 550 reported cases. Six cases are reported to demonstrate the wide variety of clinical pattern. The most common features of the disease are auricular and nasal cartilage inflammation and nondeforming arthritis. Ocular symptoms and vasculitis is relatively rare. Two cases of relapsing polychondritis with laryngotracheobronchial manifestations illustrate the severe clinical features of the disease. Relapsing polychondritis may associate with diverse forms of connective tissue disease, such as rheumatoid arthritis. It seems interesting to note the onset in childhood. Treatment has been primarily symptomatic. In situations of mild symptoms, initial treatment is with nonsteroidal antiinflammatory drugs. For cases with serious manifestation, corticosteroids and immunosuppressants are indicated.     

调整免疫抑制剂对肝移植感染全身炎症反应综合征的影响

目的探讨停用免疫抑制剂对肝移植感染炎症指标的影响。方法根据多器官功能障碍综合征(MODS)评分法对肝移植感染患者进行评分,当MODS 13～16分时停用免疫抑制剂(26例,停用组),观察患者体温、心率、呼吸和外周血白细胞的变化,并与感染未停用免疫抑制剂(13例,常规组)的患者比较。结果感染后,加强抗感染治疗或同时停用免疫抑制剂均可改善患者的体温、心率、呼吸和外周血白细胞(P0.05),但同时停用免疫抑制剂则更利于体温、心率、呼吸和外周血白细胞的改善(P0.05)。结论肝移植感染者,在加强抗感染治疗的基础上,同时停用免疫抑制剂更有利于控制感染。     

Update on parenteral iron therapy.

The role of parenteral iron therapy has been expanding with the growing use of erythropoietin therapy. Much of the clinical experience regarding the use of IV iron therapy in combination with erythropoietin therapy is based on the hemodialysis patient, but the combination therapy has been used in other patient populations as well. In addition, parenteral iron may be indicated in patients receiving long-term parenteral nutrition and in other clinical situations of iron deficiency when the absorption of iron is impaired or tolerance limited. Once the indication for parenteral iron therapy is established, a selection of the most appropriate agent is required. There are currently 3 parenteral iron preparations available, including iron dextran, sodium ferric gluconate, and iron sucrose. Although all agents have been shown to be effective in correcting iron deficiency, there are differences that exist between them. Both sodium ferric gluconate and iron sucrose have been associated with lower rates of serious adverse reactions than iron dextran, although comparative studies are lacking. In patients with previously documented intolerance to iron dextran, sodium ferric gluconate and iron sucrose have been safely administered. In addition to the immediate and delayed reactions associated with the use of parenteral iron, the risk of iron overload and the potential increased risk of infection are of concern. This article will review the clinical experience of the 3 parenteral iron preparations, discuss safety issues, and provide guidelines on proper dosing and administration.     

'Vegetable wasps and plant worms' and G-protein-coupled receptors

Following the discovery of an immunosuppressive substance isolated from one of the entomopathogenic fungi 'vegetable wasps and plant worms', FTY720, whose immunosuppressive action is more potent than that of cyclosporin, was developed. In contrast to classical immunosuppressants such as cyclosporin, FTY720 does not affect the growth, maturation and activation of lymphocytes, but causes a reduction in the number of circulating lymphocytes as a result of enhanced homing of lymphocytes to the secondary lymphoid organs. It has recently been reported that FTY720 is phosphorylated in vivo by sphingosine kinase, and the phosphorylated FTY720 is a ligand of the receptors of sphingosine 1-phosphate (S1P), which are G-protein-coupled receptors. S1P has been recognized most prominently as a platelet-derived lipid mediator which regulates several functions of endothelial and smooth muscle cells. In addition, recent studies have suggested the crucial roles for S1P in immunological, and inflammatory modulation.     

In vivo effects of maternal immunosuppression during pregnancy on the immune function of newborn infants

When used in pregnancy, immunosuppressants can cross the placental barrier and enter foetal circulation, possibly affecting the immune system of the foetus. This study evaluated the immune function in eight children born by mothers with connective tissue diseases who received immunosuppressants (cyclosporine A or dexamethasone) during pregnancy and in six babies from mothers with similar diseases, but who did not receive any treatment. Judging by the cytokine production of interleukin-2 and interferon-gamma in peripheral blood mononuclear cells stimulated by phorbol-myristate-acetate (PMA) and ionomycin, immunosuppressive drugs given for rheumatic disorders during pregnancy do not induce significant immunosuppression in babies.     

Antineutrophil cytoplasmic antibody-associated vasculitis with renal involvement: the evidence for treatment

Antineutrophil cytoplasmic antibody-associated vasculitis is an autoimmune disease involving small to medium blood vessels. It is an uncommon illness, but can have devastating consequences, particularly on kidney function and other vital organs. Exciting progress has been made in the treatment of the disease largely because of international collaboration in randomised clinical trials. Patient survival has improved dramatically with advancements in disease diagnosis and medical treatment. The long-term morbidity from the disease, although improving, remains substantial with up to 10% of survivors requiring dialysis or kidney transplantation. Clinical trials are underway using more specifically targeted immunosuppressants in the hope to improve the long-term patient outcomes. Advancements are also being made in understanding the pathogenesis of the disease and this will further assist disease treatment and outcomes in the future.     

Filial therapy for enhancing relationships in families

Filial therapy is a specific mode of child-centred play therapy. The parent or carer conducts structured weekly therapeutic play sessions with the child. The therapist provides coaching, detailed feedback, and support, but does not engage directly with the child. Filial therapy empowers parents and carers to become the agents of therapeutic change. Because parent and child work through problems together, children's attachments become more secure, and family relationships are enhanced. Filial therapy was developed in the 1960s by Louise and Bernard Guerney as an innovative form of child-centred play therapy for three- to 12-year-olds. It is a flexible mode of therapy with three main models currently in use, two of which are group models. Filial therapy is evidence-based. Empirical research has shown it to be effective for intact families, blended families, adoptive families, those with children in public (local authority) care, single parent families, and those in which grandparents or other relatives are the full-time carers. Research also shows it to be effective with families of different cultures and ethnicities. Filial therapy can help parents or carers help children who have experienced difficulties such as trauma and abuse, or who for other reasons have problems with behaviour, relationships and mental health. Filial therapy provides help over the long term and after the therapist has reduced or ended contact with a family. Once parents have learned the filial skills they can continue with play sessions for months, even years. They also naturally adapt the skills for use in every day life.     

The Costs of Change: Direct Medical Costs of Solid Organ Transplantation in British Columbia, Canada, 1995–2003

Objectives:  Solid organ transplantations are among the most expensive treatments yet relatively few investigators have reported well-characterized and reliable information on costs. The objective here was to compare the direct medical costs of kidney, liver, heart, and lung transplantations in British Columbia (BC), Canada.
Methods:  Using data from a province-wide population-based registry, resource utilization data were collated for 1333 patients who underwent solid organ transplantation between 1995 and 2003. Resource categories included hospital stays, physician fees, laboratory and diagnostic testing, and immunosuppressants. Mean costs (2003 $CDN) were derived for the index hospitalization and each of the 2 years after hospital discharge. To enable valid comparisons, the same costing methodology was applied to all four programs.
Results:  The mean costs of transplantation varied from $27,695 for kidney recipients to $89,942 for lung recipients, with inpatient hospital stays comprising the largest component. Mean costs for the first and second follow-up years ranged from $27,592 and $11,424 for lung recipients to $21,144 and $8086 for liver recipients. Immunosuppressants accounted for between two-thirds and three-fourths of costs by the second year. Within each program, variations in costs could not be accounted for by demographic factors.
Conclusions:  We observed in BC a threefold variation in mean costs of organ transplantation procedures, with the variations between programs diminishing during follow-up. Policymakers and decision-makers seeking to better understand the deployment of resources for transplantation may focus on clinical factors at the time of hospitalization and factors that influence use and costs of immunosuppressants during the induction and maintenance phases.     

Medical therapy of inflammatory bowel diseases: ulcerative colitis

There are fewer significant changes in the medical therapy of ulcerative colitis (UC) compared to Crohn's disease. The most important factors that determine therapy are disease extent and severity. 5-aminosalicylates (5-ASA) constitute the treatment of choice in mild-to-moderate UC. The efficacy of new compounds (e.g. mesalazine) is only mildly improved compared to sulphasalazine; however, their use has become more frequent due to a more favorable side effects profile. Topical medication is more effective in proctitis and distal colitis, and the combination of topical and orally-administered drugs is superior to oral therapy alone also in extensive disease. Thus, this latter regimen should be considered for cases where the escalation of treatment is required. Systemic steroids still represent the first line therapy in acute, severe UC, while in patients who do not respond to steroids, cyclosporine and infliximab should be considered as a second line therapy and as alternatives for colectomy. Maintenance treatment is indicated in all UC cases. 5-ASA compounds are suggested as first line maintenance therapy with the optimal dose still being under investigation. Topical compounds are effective also for maintenance in distal colitis or proctitis, if accepted by the patients. Immunosuppressives, especially azathioprine, should be considered in chronically active, steroid dependent or resistant patients. According to recent publications, azathioprine is almost equally effective in UC and CD. The question of chemoprevention is important during maintenance. There are increasing data supporting the notion that aminosalicylates may lower the risk for UC-associated colorectal cancer. The most important changes in the management of UC are the more frequent use of topical aminosalicylates and azathioprine, the availability of infliximab in severe UC, and increasing use of aminosalicylates for chemoprevention of colorectal carcinoma. Furthermore, adequate attention is needed to better organize the patient-doctor relationship and for greater adherence to medical therapy.     

The resurgence of tuberculosis in the tropics. An engineering approach to the control of Mycobacterium tuberculosis and other airborne pathogens: a UK hospital based pilot study

The world-wide occurrence of tuberculosis (TB) is very high, and in many parts of the world prevalence has reached epidemic proportions. While the WHO's global 'directly observed therapy short-course' (DOTS) programme has yielded some notable successes, it has reached only 12% of the world's TB cases (1996 data). This suggests that the use of drug therapy alone is not enough to solve the global TB problem and that prevention using public health engineering techniques may provide a complementary solution. There are a number of engineering control strategies, such as the use of ultraviolet germicidal irradiation (UVGI) and advanced ventilation techniques, which can be used to combat the spread of Mycobacterium tuberculosis and other airborne pathogens. This paper describes a pilot study currently being undertaken at the Leeds General Infirmary in the UK, which is investigating the use of UVGI to disinfect air in ward spaces.