Use Of Immunomodulatory Drugs Research Articles

Inflammatory profiles in severe pneumonia associated with the pandemic influenza A/H1N1 virus isolated in Mexico City

The immune mechanisms underlying the pathogenesis of severe pneumonia associated with the A/H1N1 virus are not well known. The objective of this study was to determine whether severe A/H1N1-associated pneumonia can be explained by the emergence of particular T-cell subsets and the cytokines/chemokines they produced, as well as distinct responses to infection. T-cell subset distribution and cytokine/chemokine levels in peripheral blood and bronchoalveolar lavage (BAL) were determined in patients with severe A/H1N1 infection, asymptomatic household contacts, and healthy controls. Cytokine and chemokine production was also evaluated after in vitro infection with seasonal H1N1 and pandemic A/H1N1 strains. We found an increase in the frequency of peripheral Th2 and Tc2 cells in A/H1N1 patients. A trend toward increased Tc1 cells was observed in household contacts. Elevated serum levels of IL-6, CXCL8, and CCL2 were found in patients and a similar cytokine/chemokine profile was observed in BAL, in which CCL5 was also increased. Infection assays revealed that both strains induce the production of several cytokines/chemokines at 24 and 72 h, however, IL-6, CCL3, and CXCL8 were strongly up-regulated in 72-h cultures in presence of the A/H1N1 virus. Several inflammatory mediators are up-regulated in peripheral and lung samples from A/H1N1-infected patients who developed severe pneumonia. In addition, the A/H1N1 strain induces higher levels of pro-inflammatory cytokines and chemokines than the seasonal H1N1 strain. These findings suggest that it is possible to identify biomarkers of severe pneumonia and also suggest the therapeutic use of immunomodulatory drugs in patients with severe pneumonia associated with A/H1N1 infection.

Pharmakoprophylaxe und Begleitmedikation bei spezifischer Immuntherapie

Drugs that are used in relation to allergen-specific immunotherapy (SIT) can be separated into pharmacoprophylaxis to avoid or decrease local and systemic adverse effects of SIT and in co-medications to treat other diseases. Regarding pharmacoprophylaxis, H1-antihistamines are able to reduce local and mild systemic, but not severe systemic side effects of SIT. H1-antihistamines do not attenuate the efficacy of SIT. Severe systemic side effects have been blocked in some cases with omalizumab; currently this agent can be used off-label during venom SIT. With regard to co-medication, the concomitant use of immunomodulating drugs during SIT must be individualized, if the effective profile and side effects of the immunomodulating drug are well-known and a negative effect on SIT is not likely. Recently approved immunosuppressive drugs and biologics are perceived critically due to their unpredictable immunologic effects. For forensic reasons cardioselective beta blockers should be discontinued although no data are available demonstrating adverse effects. If discontinuation is not justified and venom SIT is indicated, SIT can be performed while taking beta blockers. In contrast, ACE-inhibitors should always be stopped in patients with insect venom allergy.

Myeloma: making sense of a complex blood cancer

Myeloma is a challenging blood cancer characterized by bone destruction, hypercalcaemia, renal insufficiency and anaemia. Although myeloma remains incurable, recent advancements in treatments have resulted in significant improvements in morbidity. The use of immunomodulatory drugs-thalidomide, lenalidomide, pomalidomide (in clinical trials)-and the proteasome inhibitor, bortezomib, in conjunction with conventional chemotherapy and supportive therapies, have resulted in a significant shift in approaches to treatment and an improvement in patients' quality of life. Nurses must remain up-to-date with current treatments for myeloma and their related side-effects. In addition, nurses play a key role in the coordination of a multidisciplinary approach to care for myeloma patients.

Hospital Supply of Off‐label Immunomodulatory Drugs

ABSTRACTBackgroundThere has been an increase in the demand for new immunomodulatory drugs for the treatment of immune‐mediated inflammatory diseases. Many of these indications represent the off‐label use of immunomodulatory drugs.AimTo evaluate the spectrum of requests, clinical outcomes and costs for the hospital‐approved, off‐label use of immunomodulatory drugs.MethodA list of all new individual patient use approvals at a Sydney teaching hospital (February 2005 to June 2006) was obtained and the approved immunomodulatory drugs were selected for audit. A literature review was conducted to determine the level of evidence available for the approved immunomodulatory drugs.Results61 individual patient use approvals for off‐label immunomodulatory drugs were analysed. The most commonly requested drugs were infliximab (n = 22), mycophenolate (n = 13), rituximab (n = 10) and cyclosporin (n = 7). These drugs were initiated for treatment of a heterogeneous group of serious medical disorders. 10 hospital departments initiated the requests. The cost of new approvals was $458 301, accounting for 61% of the total cost of $749 236 for off‐label immunomodulatory drugs within the study period. The most expensive drugs were rituximab, infliximab and mycophenolate. Efficacy reports were available for 64% of approvals and a favourable therapeutic response was observed in 74% of cases. 4 deaths occurred and significant treatment‐related adverse events were noted in 24% of cases. High‐level evidence supported the use of immunomodulatory drugs for 41 individual patient use approvals.ConclusionOff‐label use of immunomodulatory drugs was diverse and supported by good evidence in over 50% of cases. Methods used to assess the response to immunomodulatory drugs were suboptimal and non‐standardised. Formalising the supply of immunomodulatory drugs may enable aggregation of data to inform future decisions and resource allocation.

Prediction of Thalidomide Response in the Newly Diagnosed Untreated Multiple Myeloma Patients Based on a Panel of Protein Biomarkers

Background: Multiple Myeloma (MM) is an incurable plasma cell malignancy. Recently, there have been major therapeutic advances in the treatment of MM, including the use of immunomodulatory drugs. Thalidomide alone or in combination represents an effective treatment strategy for newly diagnosed, relapsed and refractory MM patients. The identification of novel biomarkers could lead to more effective, individualized therapeutic strategies with improved patient outcomes.Patients, Method & Material: Serum samples of sixteen newly diagnosed multiple myeloma patients, who had had initial treatment with thalidomide based regimens were analyzed. Based on D100 re-staging, 8 responders and 8 non responders to thalidomide were identified. Samples were analysed using 2D-DIGE, a technique based on pre-electrophoretic labelling of samples with one of three spectrally resolvable fluorescent CyDyes (Cy2, Cy3, and Cy5) allowing multiplexing of samples into the same gel. Initially serum samples were immunodepleted, which specifically removes 14 high-abundant proteins representing approximately 94% of total protein mass. This allowed for easier analysis of low abundance proteins, which are more likely to be a source of potential biomarkers. All 2D-DIGE images were scanned and collected on a Typhoon Fluorescent Imager. Pooled samples were used as an internal standard to quantify expression changes with statistical significance. Statistics and quantitation of protein expression were carried out initially using DeCyder Biological Variation Analysis (BVA) software before performing subsequent Extended Data Analysis (EDA).Results: 18 proteins have been identified to be differentially expressed in non-responders compared to responders: 13 were up-regulated and 5 were down-regulated (t-test ≤ 0.02). All 18 proteins were >1.25-fold differentially expressed, with changes up to 6.62-fold. For example, Fig.1 shows statistical analysis of protein 1 using DeCyder BVA software. This protein was increased 2.24-fold in the immuno-depleted serum from non-responders compared to responders, (t-test 0.0046). Once the 18 panel proteins were established, further statistical analysis was performed using DeCyder EDA software. Principal Components Analysis (PCA) was used to separate the responders from the non-responders based on the panel of 18 statistically significant differentially expressed proteins (Fig.2). Each dot on this plot represents a clinical sample; clinical samples from the same experimental groups are located in the same distinct areas, i.e. contained in one half of the plot, confirming consistency of results.Conclusion: Accurate prediction of an individual patient's drug response is an important prerequisite of personalized medicine. Using a panel of proteomic biomarkers, we have demonstrated the feasibility of predicting sensitivity and response to thalidomide in previously untreated myeloma. We are in the process of identification of theses proteins and plan to confirm their predictive value in a larger group of patients. [Display omitted] [Display omitted]

Factors associated with the risk of secondary progression in multiple sclerosis

Objective To investigate factors associated with the risk of secondary progression in relapsing-remitting onset multiple sclerosis (MS). Methods We used Kaplan-Meier survival analyses and a multivariable Cox regression model to estimate the influence of the factors: gender, age at disease onset, use of immunomodulatory drugs (IMD), and clinical manifestation at disease onset on the time to secondary progression in a hospital-based cohort of 571 MS patients with a relapsing-remitting onset. Results Gender and onset manifestation had no significant influence on the timing of secondary progression. A higher age at disease onset was associated with a shorter time to secondary progression (multivariable hazard ratio per year increase: 1.02, 95% CI:1.01 - 1.03). The use of IMD was associated with a longer time to secondary progression (multivariable hazard ratio: 0.30, 95% CI: 0.15 - 0.61). Conclusions The inverse relationship between age at disease onset and onset of secondary progression is in keeping with previous natural history studies. The beneficial effect of IMD treatment on the time to secondary progression should be taken as hypothesis-generating rather than as proof of a treatment effect, and needs to be further evaluated in well-designed randomised controlled trials.

Predictive value of clinical characteristics for ‘benign’ multiple sclerosis

We studied a cohort of 496 patients who had multiple sclerosis (MS) for at least 10 years. Ten years after disease onset, 151 had benign MS defined as an Extended Disability Status Scale (EDSS) < or =3. Between benign and non-benign patients we compared gender, age at clinical onset, relapsing-remitting or primary progressive, symptoms at onset, recovery from first relapse, time between first and second relapse, number of relapses in the first 5 years, use of immunomodulatory drugs, and EDSS scores at 2, 5 and 10 years. A multivariate regression analysis showed that a relapsing-remitting course, a low EDSS score at 5 years, and a low number of relapses in the first 5 years were predictive for benign MS at 10 years. Other factors had no additional value. Thirty-five of the 51 patients (69%) with benign MS at 10 years were still benign at 20 years. A low 10-year EDSS score was the only clinical variable associated with a benign course at 20 years. Our results suggest that within the first 5 years from onset it is not possible to predict a benign course. Disease course, EDSS score and relapse rate at 5 years are predictors for benign MS at 10 years.

Therapeutic use of immunomodulatory drugs in the treatment of multiple myeloma

Immunomodulatory drugs, such as thalidomide, lenalidomide (Revlimid®, CC-5013) and actimid (CC-4047), have a broad spectrum of activity and have shown remarkable responses in patients with multiple myeloma and related hematological diseases, such as myelodysplastic syndrome. They are currently being tested in other cancer types. This review will focus on the preclinical and clinical activity of thalidomide and its more potent immunomodulatory derivatives that are used to treat multiple myeloma. They represent a new class of antitumor agents that not only target the tumor cell directly, but also have significant activity within the bone marrow milieu. These agents have shown high responses in all phases of multiple myeloma, including the upfront setting, relapsed refractory stage and also as maintenance therapy for the disease. They have been used in combination with dexamethasone, chemotherapy and, more recently, with other novel agents, such as proteasome inhibitors. Thalidomide and lenalidomide in combination with dexamethasone have recently been approved by the US FDA for the treatment of multiple myeloma.

Distribution of Conjunctival HLA-DR Expression and the Pathogenesis of Damage in Early Dry Eyes

To examine the expression of HLA-DR, a marker of inflammation, in the early stages of dry eye disease and to locate the appearance of this marker on specific areas of the bulbar conjunctiva. Dry eye patients were identified and their condition classified as mild (n = 16) or moderate (n = 16) based on Schirmer testing, vital staining, tear break-up time, and symptom questionnaire scores. Brush cytology was used to collect epithelial cells from the nasal, temporal, and superior conjunctivae of patients and age-matched controls. HLA-DR positive cells were detected by immunohistochemical staining and quantified. Patients with moderate dry eye had the highest rate of conjunctival HLA-DR-positive cells, with significantly higher rates than controls regardless of which region of the conjunctiva was sampled (P < 0.01). The mild dry eye group had similar rates of HLA-DR-positive cells in the superior conjunctival region compared with controls. However, in the nasal and temporal regions, they displayed a significantly higher rate of HLA-DR-positive cells than controls (P < 0.01) and the nasal region showed a significant difference (P < 0.01) when compared with the temporal one. Some of these mild dry eyes had no vital staining. The HLA-DR expression pattern in mild and moderate dry eyes appears to reflect disease progression. Overexpression of HLA-DR in mild dry eyes showing no vital staining suggests that inflammation may be a primary cause of ocular surface damage. These data support the use of immunomodulatory drugs in the treatment of dry eye disease.

Diretrizes para o tratamento da esclerosa mútipla com drogas imunomoduladoras

The treatment of patients with multiple sclerosis (MS) with immunomodulatory drugs, and more recently, with immunosuppressive drugs, have modified the natural history of the disease in the last years. The conclusions and recommendations elaborated by several authors based upon multicenter studies make us review and update concepts, proposing modifications to government institutions in order to improve the assistance to MS patients, the main purpose of this work. Herein, the Neuroimmunology Scientific Department of the Brazilian Academy of Neurology judged important to update the recommendations concerning MS diagnosis criteria, classification of progression patterns, foundation of reference centers and the use of immunomodulatory drugs.

Idiopathic Eosinophilic Esophagitis and Eosinophilic Gastroenteritis Successfully Treated with Azathioprine or 6-Mercaptopurine

Background: Idiopathic eosinophilic esophagitis (EE) is an increasingly recognized inflammatory disorder of the esophagus. The inflammatory pattern of EE is predominately associated with a TH 2-type allergic response. The disease has often chronic recurrent character and requires long-term treatment with topical or systemic corticosteroids. The aim of our study was to determine whether in severe cases with long-term systemic corticosteroid-dependency an immuno-modulating treatment may have a steroid-sparing effect? Methods: In three patients with proven severe idiopathic EE (1/3 also suffered from eosinophilic gastroenteritis) and chronically corticosteroid-dependency, we prospectively studied the clinical and histological response under treatment with azathioprine (2mg/kg BW po/die) or 6-mercaptopurine (1mg/kg BW po/die). Results: All patients experienced both symptomatical and histological relapse once steroid doses were tapered on several occasions. After administration of azathioprine in 2 patients and 6-mercatopurine in one patient, steroids could be stopped in all 3 patients without clinical relapse. Subsequent histological examinations showed complete disappearance of eosinophilic infiltration over a time span of months up to 8 years. One patient who stopped his treatment with azathioprine relapsed and became again steroid-dependent. In the follow-up, steroids could be stopped again after azathioprine had been reinstituted. In one patient, high blood counts of eosinophilic cells had been originally measured which also disappeared under azathioprine treatment. Conclusions: In severe steroid-dependent cases of idiopathic eosinophilic esophagatis and eosinophilic gastroenteritis, an immuno-modulationg treatment with purine analogues may be an helpful alternative to glucocorticoid therapy. At least in our patients, long-term use of immuno-modulating drugs was overall well tolerated and decreased morbidity due to EE. It could be speculated that the beneficial effect of azathioprine/6-mercaptopurine in treating EE is associated with their pro-apoptotic effect on T-lymphocytes.

Prise en charge diagnostique et thérapeutique du syndrome de Vogt-Koyanagi-Harada

To determine the most efficient diagnostic tools in Vogt-Koyanagi-Harada syndrome, taking into account the international diagnostic criteria, and to evaluate the therapeutic management of these patients. This study examined patients with a suspicion of VKH syndrome who presented between January 2001 and March 2003, including ocular and extraocular evaluation of the disease at the time of diagnosis. Each patient was classified according to the 1978 international diagnostic criteria and the revised 2001 criteria. In most cases, intravenous steroid pulses were administered. Immunosuppressors were initiated when inflammation was not controlled with steroids. Twenty-two patients were included. The mean age was 33.5 years (range, 15-49 years). Posterior segment involvement, which was observed in 21 patients, depended on the stage of the disease. Anterior segment inflammation was associated in eleven cases. Neurologic symptoms, including meningitis, cerebrospinal fluid lymphocytic pleocytosis, tinnitus, or hearing loss were observed in 12 patients. Fourteen patients had dermatologic signs. Five patients who developed VKH syndrome did not meet the 1978 criteria, and three patients did not meet the 2001 revised criteria. In 19 cases, intraocular inflammation was controlled with corticosteroids. In three cases, corticosteroids could not be discontinued. These patients were treated with immunosuppressive molecules: azathioprine, cyclophosphamide, interferon alpha. At the end of the follow-up period, inflammation was controlled in all patients. Revision of the diagnostic criteria provides a more subtle diagnosis of VKH syndrome. However, it is difficult to consider the variability of clinical symptoms during the duration of disease. Corticosteroids must be used at appropriate dosages, followed by slow tapering over 6 months. This attitude seems to reduce the duration of ocular inflammation and decreases the frequency of recurrence. The use of immunomodulating drugs could be reduced by early and appropriate use of systemic steroids. Interferon alpha seems to be a promising alternative in corticoresistant or corticodependent forms of the disease, but further controlled studies are required.

Rheumatic syndromes associated with malignancy.

The relation between rheumatic syndromes and an underlying malignancy is a complex one. As a result of autoimmunity, an aberrant immune response, or the use of immunomodulatory drugs, many of the rheumatic diseases appear to pose an increased risk for the development of malignancy. Unfortunately, for many of the same reasons, the presence of an underlying malignancy can result in the development of features of rheumatic disease. Awareness of the associations between rheumatic syndromes and malignancy will aid the clinician in the accurate diagnosis of underlying pathology, more effective treatment of both the symptoms and underlying disease, and appropriate surveillance for the development of later complications.

Hepatitis B and C virus infection in Crohn's disease.

Patients with Crohn's disease (CD) are at higher risk of hepatitis C (HCV) and B virus (HBV) infection, because of surgical and/or endoscopic procedures. However, the prevalence of HCV and HBV infection in CD is unknown. This issue may be relevant because of the growing use of immunomodulatory drugs in CD. The purpose of this study was to assess, in a multicenter study, the prevalence and risk factors of HCV and HBV infection in CD. The effect of immunomodulatory drugs for CD on the clinical course of hepatitis virus infections and of interferon-alpha (IFN-alpha) on the course of CD was examined in a small number of patients. Sera from 332 patients with CD and 374 control subjects (C) were tested for the following: hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), HBcAb, HBeAg, HBeAb, anti-HCV, and HCV-RNA. An additional 162 patients with ulcerative colitis (UC) were tested as a disease control group. Risk factors were assessed by multivariate statistical analysis. Infection by either HCV or HBV was detected in 24.7% of patients with CD. In the age groups younger than 50 years, HCV prevalence was higher in CD than in C (p = 0.01). HCV infection in CD was associated with surgery (OR 1.71; 95% CI 1.00-2.93; p = 0.04), blood transfusions (OR 3.39; 95% CI 1.04-11.04; p = 0.04), and age (OR 2.3; 95% CI 1.61-3.56; p < 0.001). The event CD-related surgery appeared to be the main risk factor for HCV infection in CD. HCV prevalence was higher in CD (7.4%) than in UC (0.6%) (p = 0.001). HBcAb positivity was higher in CD (10.9%) and UC (11.5%) than in C (5.1%) (CD vs. C: p = 0.016; UC vs. C: p = 0.02), associated with age (OR 2.08; 95% CI 1.37-3.17; p = 0.001) and female gender (OR 2.68; 95% CI 1.37-3.17; p = 0.001) in CD and to UC duration (OR 1.20; 95% CI 1.06-1.36; p = 0.002). Immunomodulatory drugs did not influence the course of HBV or HCV infection in seven patients with CD, and IFN-alpha for chronic hepatitis C did not affect CD activity in six patients with CD. It is concluded that HBV prevalence is higher in CD than in C at all ages, whereas HCV prevalence is increased in young patients with CD, because of a greater need for surgery. The higher HCV (but not HBV) prevalence in CD than in UC suggests that the host immune response may influence the risk of HCV infection. Although a relatively high proportion of patients with CD showed HBV and/or HCV infections, this should not influence treatment strategies for CD.

The immune compromised host in the twenty-first century: management of mucocutaneous infections.

Infectious diseases encountered in dermatology have changed tremendously during the past few decades with the emergence of the immunocompromised host. This change is a result of the human immunodeficiency virus epidemic, use of immunomodulating drugs, bone marrow transplantation, increasing prevalence of diabetes mellitus, and an aging population. New pathogens have been discovered and new disorders have occurred. In the compromised host, infection can be more aggressive and widespread locally, be caused by opportunistic pathogens, and be disseminated hematogenously from or to the skin. The prevalence of nonmelanoma skin cancer has increased, and squamous cell carcinomas can be more aggressive with more rapid local growth as well as frequency of metastasis.

Recent strategies for the chemotherapy of visceral leishmaniasis

Visceral leishmaniasis is a widespread and deadly disease. First-line drugs are antimonials, but amphotericin B and its lipid formulations B is used for treating visceral leishmaniasis that is unresponsive to antimony. New therapeutic approaches are being actively developed, including the following: use of drug carriers targeted specifically to the parasite location, thus reduce adverse effects of drug; use of immunomodulating drugs; evaluation of natural products; pharmacokinetic studies; and drug combinations. Recent clinical trials with paromomycin and miltefosine were successful and these drugs appear to be promising for the future therapy of visceral leishmaniasis. Furthermore, identification and therapeutic evaluation of specific targets in the Leishmania organism could lead to new compounds, such as antileishmanial drugs and reversal agents of drug resistance.

The role of T-cells in rheumatoid arthritis and the use of immunomodulating drugs.

Rheumatoid arthritis (RA) is a chronic inflammatory process of unknown etiology affecting 1% of the population worldwide. It results in excess morbidity in a majority of cases and early mortality in patients with aggressive disease. Early immunohistologic studies of the rheumatoid synovium demonstrate that T-cells, especially cluster of differentiation (CD)4(+) cells, are a major component of the infiltrating inflammatory cells. It has also been demonstrated that RA patients share a common major histocompatibility complex (MHC) class II molecule, HLA-DR4. Immune activation by T-cells requires the formation of the antigen recognition complex composed of the T-cell receptor, the MHC II molecule, and antigen. Many treatment modalities for RA have targeted the T-cell and/or the antigen recognition complex. These have varied from relatively crude methods such as leukopheresis to very specific monoclonal antibodies directed toward specific T-cell antigens such as the CD4 molecule itself. Not only have these therapies been effective, but also they have provided some interesting data on the pathogenesis of RA. Unfortunately, some have been associated with harmful side effects. To date, the safest and most effective modality has been immunomodulatory drugs such as cyclosporin and FK506, either alone or in combination with other agents. It appears that the earlier these treatments are started in the course of RA, the more effective they are, not only in controlling disease but also in achieving a potential remission.

Immunotherapy of Crohn's disease.

Although the initiating events of Crohn's disease are unknown, models of experimental colitis have provided new insights in the immunologically mediated pathways of mucosal inflammation. In Crohn's disease activated mucosal T lymphocytes produce proinflammatory cytokines within the mucosal compartment. With this understanding, there has been a shift in past years from the use of unspecific anti-inflammatory agents (corticosteroids, aminosalicylates) to the use of immunomodulatory drugs (azathioprine, methotrexate). Moreover, novel strategies have been designed for specific targets in Crohn's disease, in particular T lymphocytes and cytokines. In an open label study treatment of steroid-refractory Crohn's disease with anti- CD4+ antibodies was well tolerated and showed clinical benefit. However, a sustained depletion of the CD4+ cells precluded further clinical trials. In controlled clinical studies, anti-tumour necrosis factor (TNF-alpha) antibodies induced complete remissions and few side effects were observed. One study suggested efficacy in active Crohn's disease of recombinant interleukin-10. Long term treatment studies will have to answer questions about the indications for use, benefit and toxicity. Altogether, these results hold promise for future management of Crohn's disease, where disease-modifying interventions and strategies that effectively maintain disease remission will play a key role.