Liver regeneration as treatment target for severe alcoholic hepatitis

Severe alcoholic hepatitis (AH) is a distinct entity in the spectrum of alcohol-related liver disease, with limited treatment options and high mortality. Supportive medical care with corticosteroids in selected patients is the only currently available treatment option, often with poor outcomes. Based on the insights into the pathogenetic mechanisms of AH, which are mostly obtained from animal studies, several new treatment options are being explored. Studies have implicated impaired and deranged liver regeneration processes as one of the culprit mechanisms and a potential therapeutic target. Acknowledging evidence for the beneficial effects of granulocyte colony-stimulating factor (G-CSF) on liver regeneration and immunomodulation in animal models, several human studies investigated its role in the treatment of advanced alcohol-related liver disease and AH. Contrary to the previously published studies suggesting benefits of G-CSF in the outcomes of patients with severe AH, these effects were not confirmed by a recently published multicenter randomized trial, suggesting that other options should rather be pursued. Stem cell transplantation represents another option for improving liver regeneration, but evidence for its efficacy in patients with severe AH and advanced alcohol-related liver disease is still very scarce and unconvincing, with established lack of efficacy in patients with compensated cirrhosis. In this review, we summarize the current knowledge on the pathogenesis and experimental therapies targeting liver regeneration. The lack of high-quality studies and evidence is a major obstacle in further treatment development. New insights into the pathogenesis of not only liver injury, but also liver regeneration processes are mandatory for the development of new treatment options. A reliable experimental model of the pathogenesis of AH and processes involved in liver recovery is still missing, and data obtained from animal studies are essential for future research.     

Corticosteroids and pentoxifylline for the treatment of alcoholic hepatitis: Current status

The treatment of choice for patients with severe alcoholic hepatitis (AH) is use of corticosteroids.Many randomized well designed studies have been reported from all over the world on the use of corticosteroids in the treatment of AH.However,the data on the efficacy of corticosteroids in these patients have been conflicting.Initial meta-analyses also failed to show beneficial effects of corticosteroids.Based on individual data meta-analysis showing clear benefit of corticosteroids amongst patients with severe AH (modified discriminant function of 32 or more),led American College of Gastroenterology to recommend use of corticosteroids as the first line treatment option amongst patients with severe AH.However,corticosteroids are relatively contraindicated amongst patients with severe AH and coexistent sepsis,gastrointestinal bleeding,and acute pancreatitis.These patients may be candidates for second line treatment with pentoxifylline.Further,specific treatment of AH with corticosteroids far from satisfactory with as many as 40%-50% of patients failing to respond to steroids,thus classified as nonresponsive to steroids.The management of these patients is a continuing challenge for physicians.Better treatment modalities need to be developed for this group of patients in order to improve the outcome of patients with severe AH.This article describes at length the available trials on use of corticosteroids and pentoxifylline with their current status.Route of administration,dosage,adverse effects,and mechanisms of action of these two drugs are also discussed.Finally,an algorithm with clinical approach to management of patients who present with clinical syndrome of AH is described.     

Alcoholic hepatitis: prognostic models and treatment

Alcoholic hepatitis is a distinct subset of alcoholic liver disease. Inflammation and oxidative stress are the two main pathogenetic mechanisms involved in its pathogenesis. Patients with mild disease usually improve with conservative management. However, about 30-50% of those with severe disease succumb to their illness within about 1 month. Therefore, assessment of disease severity is important and practical issue. Currently, hepatologists do not have an ideal scoring system available. With survival benefit of only about 50% with corticosteroids and pentoxifylline, there is need to develop newer and better treatment options to manage these patients. This article also deals with controversies surrounding the role and use of liver transplantation in patients with alcoholic hepatitis.     

Alcoholic hepatitis: A comprehensive review of pathogenesis and treatment

Alcoholic hepatitis (AH) is an acute hepatic inflammation associated with significant morbidity and mortality. Current evidence suggests that the pathogenesis is the end result of the complex interplay between ethanol metabolism, inflammation and innate immunity. Several clinical scoring systems have been derived to predict the clinical outcomes of patients with AH; such as Child-Turcotte-Pugh score, the Maddrey discriminant function, the Lille Model, the model for end stage liver disease scores, and the Glasgow alcoholic hepatitis score. At present, Corticosteroids or pentoxifylline are the current pharmacologic treatment options; though the outcomes from the therapies are poor. Liver transplantation as the treatment of alcoholic hepatitis remains controversial, and in an era of organ shortage current guidelines do not recommend transplantation as the treatment option. Because of the limitations in the therapeutic options, it is no doubt that there is a critical need for the newer and more effective pharmacological agents to treat AH.     

Novel therapies for sarcoidosis

The treatment of sarcoidosis remains controversial. Corticosteroids remain the cornerstone of therapy, but immunosuppressive, cytotoxic, and immunomodulatory agents have emerged as viable therapeutic options for patients failing or experiencing adverse effects from corticosteroids. Published data are most extensive with methotrexate, but favorable responses have been noted with leflunomide, azathioprine, antimalarial and antimicrobial agents, and tumor necrosis factor-alpha inhibitors. This review focuses on these novel therapies for sarcoidosis, including indications for use, efficacy, toxicity, and monitoring.     

The medical treatment for autoimmune hepatitis through corticosteroid to new immunosuppressive agents: a concise review

The treatment of autoimmune hepatitis is evolving as the natural history of the disease and newer agents become available. This concise review will outline the various treatment options in these patients. Treatment with current corticosteroids and azathioprine works in most patients but issues of intolerance and incomplete response arise. These situations led to the investigation of newer immunosupressants including mycophenolate mofetil, budesonide cyclosporine, tacrolimus and ursodeoxycholic acid. The newer agents have been studied in small patient numbers so they are not first-line treatment yet but do have a clear role in those patients with intolerance of incomplete response to standard corticosteroids and azathioprine.     

Current therapy of pediatric Crohn’s disease

Inflammatory bowel diseases(IBD), including Crohn's disease(CD) and ulcerative colitis, are chronic relapsing and remitting diseases of the bowel, with an unknown etiology and appear to involve interaction between genetic susceptibility, environmental factors and the immune system. Although our knowledge and understanding of the pathogenesis and causes of IBD have improved significantly, the incidence in the pediatric population is still rising. In the last decade more drugs and treatment option have become available including 5-aminosalicylate,antibiotics, corticosteroids, immunomodulators and biological agents. Before the use of anti-tumor necrosis factor(TNF)-α became available to patients with IBD, the risk for surgery within five years of diagnosis was very high, however, with anti-TNF-α treatment the risk of surgery has decreased significantly. In the pediatric population a remission in disease can be achieved by exclusive enteral nutrition. Exclusive enteral nutrition also has an important role in the improvement of nutritional status and maintained growth. In this review we summarize the current therapeutic treatments in CD. The progress in the treatment options and the development of new drugs has led to optimized tactics for achieving the primary clinical goals of therapy- induction and maintenance of remission while improving the patient's growth and overall well-being.     

Biological modifier therapy for the treatment of rheumatoid arthritis

The recent elucidation of pathogenic processes involving tumor necrosis factor alpha and interleukin-1beta in the pathogenesis and persistence of rheumatoid arthritis led to the development of biological modifier agents that have had significant impact on disease severity and progression. These agents--etanercept, infliximab, and anakinra--produce a dramatic reduction in RA disease activity with relatively low toxicity compared with currently available disease-modifying antirheumatic drugs. The main prohibition to their broader utilization is cost. The success of these agents underscores the investigative approaches to the pathogenesis of RA and the appropriate design of pharmaceutical agents to target specific proinflammatory molecules.     

Lessons learned in the use of tumor necrosis factor-alpha inhibitors in the treatment of rheumatoid arthritis

Tumor necrosis factor-alpha (TNFα) plays a central role in rheumatoid arthritis (RA) pathogenesis. There are cur-rently three available anti-TNFα agents for the treatment of RA—adalimumab, etanercept, and infliximab. These tar-geted therapies have select advantages over traditional disease-modifying antirheumatic drugs (DMARDs), agents that have long been the mainstay of RA treatment. Compared with conventional DMARDs, TNFα inhibitors display a rapid onset of action and have shown a significant effect in retarding the radiographic joint destruction that often char-acterizes RA disease progression. Although anti-TNFα drugs represent an important advance in RA treatment, postmarketing reports of serious infections, as well as other adverse events, highlight the need for continued postmarketing vigilance with the use of these agents. This review evaluates the unique attributes of the available TNFα inhibitors, focusing specifically on recent reports providing important insight into the understanding of drug-related efficacy and toxicity.     

Drug insight: anti-tumor necrosis factor therapies for the vasculitic diseases

The introduction of targeted biologic agents directed against tumor necrosis factor (TNF) has represented a novel and exciting avenue for investigation into therapies for the vasculitic diseases. In vasculitic diseases that are associated with granuloma formation, anti-TNF agents are a particularly attractive approach to treatment in that their mechanism of action targets immunologic pathways that are thought to have a role in disease pathogenesis. To date, a number of important trials have investigated the use of anti-TNF agents in patients with a vasculitic disease: most notably, Wegener's granulomatosis, giant-cell arteritis, Takayasu's arteritis, and Beh?et's disease. Randomized, placebo-controlled trials of anti-TNF therapies for vasculitic diseases have advanced our knowledge not only in terms of their clinical results but also by demonstrating that networks of researchers can conduct multicenter trials in these uncommon diseases. Experience with the use of anti-TNF agents in patients with Wegener's granulomatosis or giant-cell arteritis has emphasized the crucial role of randomized trials in determining whether a treatment is effective, even in the face of promising preliminary data. Caution is necessary in clinical practice until such data become available.     

Difficult treatment issues in sarcoidosis

The management of sarcoidosis includes several crucial decisions. Not all patients with sarcoidosis need treatment. At least a third of patients will never be treated. It is unclear whether asymptomatic patients ever need therapy, even if they have extensive lung disease. One reason that clinicians are reluctant to start therapy is that many patients who are started on corticosteroids have a difficult time getting off therapy, even after 2 years. In the chronic patient, alternatives to corticosteroids have been developed. These include drugs such as methotrexate, azathioprine and hydroxychloroquine. These agents have been the standard second line of therapy for patients with chronic disease. However, these drugs do not always work. In addition, they are associated with their own toxicities. Another group of sarcoidosis patients have also emerged. These are the refractory patients, who have progressive disease whilst on therapy. For these patients, new agents such as thalidomide and the monoclonal antibodies to tumour necrosis factor have been occasionally helpful. This paper reviews several important issues in the management of sarcoidosis.     

Cytokine blockers in psoriatic arthritis

The cellular events underlying the pathogenesis of psoriatic arthritis (PsA) and psoriasis have not yet been fully elucidated. Nevertheless, some clues to these conditions are beginning to emerge. In particular, a growing body of data supports the role of proinflammatory cytokines, such as tumour necrosis factor (TNF), in the pathophysiology of PsA and psoriasis. Raised levels of these cytokines are found in the joints of patients with PsA, as well as in psoriatic skin lesions. Physiotherapy, non-steroidal anti-inflammatory agents, corticosteroids, and disease modifying antirheumatic agents, such as methotrexate, are the most commonly used treatments for PsA. However, the data supporting the effectiveness of these treatments are limited, and disease resolution is usually incomplete. This study examined the effects of etanercept, a TNF inhibitor, in patients with PsA. Etanercept treatment was well tolerated and resulted in significant improvement in the signs and symptoms of PsA and in psoriatic skin lesions. Infliximab, another TNF inhibitor, has also been shown to be effective in patients with PsA. Such studies confirm the importance of proinflammatory cytokines in PsA, and hold out hope for patients who require new options for the treatment of their disease.     

Spielt TNF in der Pathogenese von soliden Tumoren eine Rolle?

Tumor necrosis factor (TNF)-α blocking agents play an important role in rheumatology. For this reason, questions about the pathogenic characteristics of TNF in carcinogenesis are of the utmost importance. The observation that TNF leads to necrosis in tumor tissue gave rise to the hope that an agent had been identified for the treatment of malignant tumors. However, this expectation remained unfulfilled, not the least due to the toxicity of systemically applied TNF. In addition, TNF is produced by many tumor cells. There is evidence that for some tumors TNF promotes tumor growth, invasiveness and metastasis. It is quite possible, therefore, that the inhibition of TNF-α has an inhibitive effect on carcinogenesis and/or tumor progression. In 2009 the US Food and Drug Administration (FDA) issued a cancer warning for the use of TNF inhibitors in children and adolescents. There is still some controversy as to whether TNF blocking therapy, co-medication or the rheumatic disease itself leads to an increased cancer risk in these young patients. In adults, safety information so far available suggests a favorable risk-benefit profile for the long-term use of TNF inhibitors. However, many questions remain unanswered as to the role TNF itself plays in the pathogenesis of solid tumors.     

Treatment update on spondyloarthropathy

PURPOSE OF REVIEW: The unexpected success of the tumor necrosis factor antagonists in ankylosing spondylitis and psoriatic arthritis has generated considerable enthusiasm regarding the therapeutic potential of these drugs. By contrast, concerns regarding the high cost and long-term safety of the tumor necrosis factor blocking agents have prompted investigators to take a closer look at more traditional anti-inflammatory agents and to explore novel therapeutic targets. The purpose of this review is to summarize treatment advances in spondylarthropathy over the past year and to discuss potential future therapies. RECENT FINDINGS: Recent studies indicate that the morbidity of ankylosing spondylitis and PsA are considerably higher than previously reported. Etanercept, infliximab and adalimumab safely and effectively relieved the signs and symptoms of psoriatic arthritis patients in phase III trials. Etanercept and infliximab were also effective in phase III trials in ankylosing spondylitis. Etanercept slowed radiographic progression in psoriatic arthritis trials, but it is not known whether tumor necrosis factor antagonists can prevent structural damage in ankylosing spondylitis. One trial showed that methotrexate may be effective for relieving the pain of axial disease in ankylosing spondylitis but these findings contradict two previous studies. For reactive arthritis and undifferentiated spondylarthropathy, a combination of antibiotics may be more effective than a single antibiotic for the relief of musculoskeletal symptoms. Last, potential therapeutic targets include interleukin-1, interleukin-12, B lymphocytes, accessory molecules on T lymphocytes, and angiogenic factors. SUMMARY: Phase III trials have confirmed that tumor necrosis factor antagonists are effective and safe for the treatment of ankylosing spondylitis and psoriatic arthritis. For patients who do not respond to tumor necrosis factor blockade, several treatment options are under study. Information from these trials will more clearly define the role of disease-modifying antirheumatic drugs, novel therapeutic agents, and antibiotics in the treatment of spondylarthropathy.     

Therapeutic options for sarcoidosis: new and old

The treatment of patients with sarcoidosis remains an important part of management. The role of corticosteroids has been questioned by some, while others have reported its value even in asymptomatic patients with interstitial lung disease. Cytotoxic agents have become standard therapy for some forms of chronic disease. Newer agents that modulate the immune response have been studied. A key cytokine in chronic sarcoidosis appears to be tumor necrosis factor. Drugs that inhibit its release or block its effect have been reported as effective for sarcoidosis.     

Adalimumab in ulcerative colitis: Ready for prime time

Ulcerative colitis is one of the two main types of inflammatory bowel disease and is a chronic condition with a significant impact on health-related quality of life. For many patients, currently available treatment options do not provide adequate efficacy or are poorly tolerated. Efforts to identify new agents for the treatment of ulcerative colitis have focused mainly on targeting tumour necrosis factor α, a pro-inflammatory cytokine believed to play a pivotal role in the initiation and progression of the disease. Until recently, there was only one anti-tumour necrosis factor α agent approved for treatment of ulcerative colitis, infliximab, although there were several other such agents approved for the related condition, Crohn's disease, including adalimumab. This year (2012), adalimumab has been approved by the European Medicines Agency for the treatment of ulcerative colitis. Here, the current evidence regarding use of adalimumab in the treatment of ulcerative colitis is reviewed, with results indicating that adalimumab has compelling efficacy in the treatment of moderate-to-severe ulcerative colitis.     

Once-daily use of inhaled corticosteroids: A new regimen in the treatment of persistent asthma

Asthma is a disease of chronic airway inflammation that is characterized clinically by bronchial hyper-responsiveness and airflow limitation. Chronic inflammation, coupled with ongoing repair of airways damaged by the persistent inflammatory process in asthma, results in permanent structural and functional airway changes (remodeling) that can lead to irreversible airflow obstruction. Current guidelines emphasize treatment of the underlying inflammatory process in asthma and recommend early, long-term anti-inflammatory treatment to diminish or prevent the irreversible component of airflow obstruction. Furthermore, they recognize that inhaled corticosteroids are the most effective anti-inflammatory agents available for the treatment of asthma. Patient adherence to prescribed inhaled corticosteroid medication is associated with decreased airway inflammation, improved pulmonary function and symptom control. Moreover, marked declines in morbidity and mortality due to asthma have been attributed to appropriate use of inhaled corticosteroids.Strict patient adherence with prescribed anti-inflammatory medication is crucial for obtaining optimal therapeutic benefit for patients with asthma. Despite the proven effectiveness of inhaled corticosteroids, patient adherence to prescribed therapy is often low, resulting in increased patient morbidity. Complex dosing regimens contribute greatly to patient non-adherence. Thus, new once-daily regimens of inhaled corticosteroid treatment have been introduced as means to improve patient adherence and provide optimal therapeutic benefit. In the present review, the complex inflammatory and remodeling processes in asthma and their contributions to the clinical manifestations of the disease will be discussed. Currently available, once-daily inhaled corticosteroid treatment options and the advantages of these therapeutic options in the treatment of persistent asthma also will be discussed.     

Alcoholic liver disease--established treatment and new therapeutic approaches

Alcoholic liver disease is the most frequent organ damage encountered in chronic alcoholics and the annual death rate attributed to alcohol-induced end-stage liver disease exceeds that of car accidents. Alcoholic liver damage occurs mainly due to the toxicity of its first metabolite acetaldehyde, and due to interactions with numerous macro- and micronutrients. Established treatment options comprise psychotherapy aiming to achieve abstinence, nutritional therapy, management of hepatological complications, and liver transplantation in selected individuals. Since these therapeutic approaches are unsuccessful in many patients, pharmacological therapies of alcoholic liver disease are being investigated. Many drugs failed to be beneficial or have even shown toxicity. However, some agents are promising, such as S-adenosyl-L-methionine (SAMe), pentoxifylline, metadoxin, polyenylphosphatidylcholine or inhibitors of the cytochrome P450 2E1 isoenzyme. In severely ill patients with alcoholic hepatitis, drugs with anti-tumor necrosis factor alpha activity are currently investigated in clinical trials. If and how far corticosteroids are beneficial remains controversial and their use should be restricted to selected patients. Anabolic steroids used to enhance the nutritional status may lead to serious side effects while having a marginal benefit. Silymarin has not been proven efficacious in alcoholic cirrhosis and clinical trials are ongoing which aim to elucidate its therapeutic value in less advanced stages of liver disease.     

Refractory Inflammatory Bowel Disease

Opinion statement Therapeutic options for refractory colonic inflammation in patients with ulcerative colitis or Crohn’s disease have recently been augmented by the introduction of biologic therapies. Intravenous corticosteroids and cyclosporin A remain the standard therapies for severe ulcerative colitis. Monoclonal antibodies directed at tumor necrosis factor alfa (TNF-α) have proven to be most efficacious in patients with severe or refractory Crohn’s disease. Immunomodulatory therapy with azathioprine, 6-mercaptopurine, or methotrexate has demonstrated efficacy for maintenance of remission in patients with refractory ulcerative colitis or Crohn’s disease. The use of experimental biologic agents may be considered for those patients who fail to respond to or remain dependent on corticosteroids. Surgical intervention is indicated for patients with severe colitis who fail to respond to medical therapy or develop life-threatening complications such as perforation or toxic megacolon.