: Rapamycin is a new antifungal antibiotic produced by Streptomyces hygroscopicus NRRL 5491. It was isolated from the mycelium by solvent extraction, purified by silica gel column chromatography and crystallized as a colorless solid which melts at 183 approximately to 185 degrees C and has the empirical formula C56H89NO14. From its characteristic ultraviolet absorption spectrum rapamycin can be classified as a triene. It is highly active against various Candida species, especially Candida albicans. Its activity is compared with that of amphotericin B, candicidin and nystatin.

Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization.:II. FERMENTATION, ISOLATION AND CHARACTERIZATION

The four main types of inflammatory muscle disease — dermatomyositis, polymyositis, necrotizing autoimmune myositis, and inclusion-body myositis — are summarized. Pathogenesis, differential diagnosis, and treatment approaches are discussed.

/pdf/inflammatory-muscle-diseases-5270giyz06.pdf

Inflammatory Muscle Diseases

188th ENMC International Workshop: Inclusion Body Myositis, 2-4 December 2011, Naarden, The Netherlands.

We describe a long-term observational study of a large cohort of patients with sporadic inclusion body myositis and propose a sporadic inclusion body myositis weakness composite index that is easy to perform during a clinic. Data collection from two groups of patients (Paris and Oxford) was completed either during a clinic visit (52%), or by extraction from previous medical records (48%). One hundred and thirty-six patients [57% males, 61 (interquartile range 55-69) years at onset] were included. At the last visit all patients had muscle weakness (proximal British Medical Research Council scale <3/5 in 48%, distal British Medical Research Council scale <3/5 in 40%, swallowing problems in 46%). During their follow-up, 75% of patients had significant walking difficulties and 37% used a wheelchair (after a median duration from onset of 14 years). The sporadic inclusion body myositis weakness composite index, which correlated with grip strength (correlation coefficient: 0.47; P < 0.001) and Rivermead Mobility Index (correlation coefficient: 0.85; P < 0.001), decreased significantly with disease duration (correlation coefficient: -0.47; P < 0.001). The risk of death was only influenced by older age at onset of first symptoms. Seventy-one (52%) patients received immunosuppressive treatments [prednisone in 91.5%, associated (in 64.8%) with other immunomodulatory drugs (intravenous immunoglobulins, methotrexate or azathioprine) for a median duration of 40.8 months]. At the last assessment, patients who had been treated were more severely affected on disability scales (Walton P = 0.007, Rivermead Mobility Index P = 0.004) and on the sporadic inclusion body myositis weakness composite index (P = 0.04). The first stage of disease progression towards handicap for walking was more rapid among patients receiving immunosuppressive treatments (hazard ratio = 2.0, P = 0.002). This study confirms that sporadic inclusion body myositis is slowly progressive but not lethal and that immunosuppressive treatments do not ameliorate its natural course, thus confirming findings from smaller studies. Furthermore, our findings suggest that immunosuppressant drug therapy could have modestly exacerbated progression of disability. The sporadic inclusion body myositis weakness composite index might be a valuable outcome measure for future clinical trials, but requires further assessment and validation.

https://ibmmyositis.com/Brain-2011-Benveniste-3176-84.pdf

Long-term observational study of sporadic inclusion body myositis

The idiopathic inflammatory myopathies, including adult and juvenile dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM), are rare systemic autoimmune diseases that are characterized by chronic proximal muscle inflammation and weakness. In previous decades, there were few commonly used outcome measures in myositis, and those outcome measures were not validated. Thus, in the past the assessment of outcomes in therapeutic trials was focused on non-standardized measurement of muscle strength and function only.

Over the last decade, however, two international collaborative groups, the International Myositis Assessment and Clinical Studies Group (IMACS) and the Paediatric Rheumatology International Trials Organisation (PRINTO), have defined consensus core set measures to assess myositis disease activity and damage in adults and children and have begun to validate and standardize these measures (1;2). IMACS and PRINTO have also developed preliminary definitions of improvement, which can be used as outcomes for therapeutic trials. These response criteria combine the core set activity measures to determine clinically meaningful improvement (3;4). Our section on myositis assessment focuses first on these core set measures of disease activity, quality of life (which is part of the PRINTO core set of activity, but a separate assessment domain for IMACS), and disease damage. To date, most of the validation data available for these core set measures are in patients with juvenile DM, with more limited validation in adult patients with DM or PM. Despite these efforts, there are still important gaps in validation of these core set measures, and no validation studies have yet been performed in patients with IBM, although they are now being used frequently in myositis therapeutic trials.

We end the chapter with tools that have been used primarily in research studies and a few therapeutic trials, which have some supporting validation in certain subgroups of patients with myositis. These tools are primarily organ-specific measures, including strength and functional assessments and cutaneous assessment tools. Quantitative muscle testing and the IBM Functional Rating Scale are the most commonly used instruments to assess patients with IBM, and although they have little supporting validation in myositis, quantitative muscle testing has been well validated in other myopathies and has been used frequently as an endpoint in therapeutic trials for IBM.

Although the methods for the assessment of myositis patients have been limited in their scope, great strides have been made in the last decade in the development of new partially validated tools (see Table 1) and international multidisciplinary consensus in using these measures that should enhance our understanding of the diverse effects of myositis on many organ systems and the development of new therapies.



Table 1

Summary of Measures of Disease Activity in Myositis




Physician and Patient/Parent Global Activity
General Description


Purpose 
An overall rating of the disease activity related to myositis, defined as potentially reversible pathology or physiology resulting from the underlying disease process (1).

Measures of adult and juvenile dermatomyositis, polymyositis, and inclusion body myositis.

Sporadic inclusion-body myositis (sIBM) is the most common disabling, adult-onset, inflammatory myopathy histologically characterized by intense inflammation and vacuolar degeneration. In spite of T cell-mediated cytotoxicity and persistent, clonally expanded and antigen-driven endomysial T cells, the disease is resistant to immunotherapies. Alemtuzumab is a humanized monoclonal antibody that causes an immediate depletion or severe reduction of peripheral blood lymphocytes, lasting at least 6 months. We designed a proof-of-principle study to examine if one series of Alemtuzumab infusions in sIBM patients depletes not only peripheral blood lymphocytes but also endomysial T cells and alters the natural course of the disease. Thirteen sIBM patients with established 12-month natural history data received 0.3 mg/kg/day Alemtuzumab for 4 days. The study was powered to capture ≥10% increase strength 6 months after treatment. The primary end-point was disease stabilization compared to natural history, assessed by bi-monthly Quantitative Muscle Strength Testing and Medical Research Council strength measurements. Lymphocytes and T cell subsets were monitored concurrently in the blood and the repeated muscle biopsies. Alterations in the mRNA expression of inflammatory, stressor and degeneration-associated molecules were examined in the repeated biopsies. During a 12-month observation period, the patients’ total strength had declined by a mean of 14.9% based on Quantitative Muscle Strength Testing. Six months after therapy, the overall decline was only 1.9% (P < 0.002), corresponding to a 13% differential gain. Among those patients, four improved by a mean of 10% and six reported improved performance of daily activities. The benefit was more evident by the Medical Research Council scales, which demonstrated a decline in the total scores by 13.8% during the observation period but an improvement by 11.4% (P < 0.001) after 6 months, reaching the level of strength recorded 12 months earlier. Depletion of peripheral blood lymphocytes, including the naive and memory CD8+ cells, was noted 2 weeks after treatment and persisted up to 6 months. The effector CD45RA+CD62L­ cells, however, started to increase 2 months after therapy and peaked by the 4th month. Repeated muscle biopsies showed reduction of CD3 lymphocytes by a mean of 50% (P < 0.008), most prominent in the improved patients, and reduced mRNA expression of stressor molecules Fas, Mip-1a and αB-crystallin; the mRNA of desmin, a regeneration-associated molecule, increased. This proof-of-principle study provides insights into the pathogenesis of inclusion-body myositis and concludes that in sIBM one series of Alemtuzumab infusions can slow down disease progression up to 6 months, improve the strength of some patients, and reduce endomysial inflammation and stressor molecules. These encouraging results, the first in sIBM, warrant a future study with repeated infusions (Clinical Trials. Gov NCT00079768).

Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis

Short-term outcomes following organ transplantation have improved considerably since the availability of cyclosporine ushered in the modern era of immunosuppression. In spite of this, many of the current limitations to progress in the field are directly related to the existing practice of relatively non-specific immunosuppression. These include increased risks of opportunistic infection and cancer, and toxicity associated with long-term immunosuppressive drug exposure. In addition, long-term graft loss continues to result in part from a failure to adequately control the anti-donor immune response. The development of a safe and reliable means of inducing tolerance would ameliorate these issues and improve the lives of transplant recipients, yet given the improving clinical standard of care, the translation of new therapies has become appropriately more cautious and dependent on increasingly predictive preclinical models. While convenient and easy to use, rodent tolerance models have not to date been reliably capable of predicting a therapy's potential efficacy in humans. Non-human primates possess an immune system that more closely approximates that found in humans, and have served as a more rigorous preclinical testing ground for novel therapies. Prior to clinical adaptation therefore, tolerance regimens should be vetted in non-human primates to ensure that there is sufficient potential for efficacy to justify the risk of its application.

/pdf/induction-of-transplantation-tolerance-in-non-human-primate-abybv7y884.pdf

Induction of transplantation tolerance in non-human primate preclinical models

Challenges in therapeutic strategies for transplantation: where now from here?

RT-1l recipient)were sensitized with whole blood 0.5cc IP. Total IgG/ IgM and DSA titers were analyzed by ELISA and flow cytometry, respectively. Orthotopic liver transplantation and heterotopic heart transplantation were performed using standard techniques. Sensitized animals (SA) underwent transplantation 14 days after transfusion. C3d deposition and endothelial cell integrity were evaluated by immunohistochemistry. Plasmapheresis was performed using a 2 25% plasma volume centrifugation protocol (3d-preop/1daypostop). Blockade of classical complement cascade was performed with 10mg/kg anti-C5 mAb IV q4hr 5 doses.

https://www.journalacs.org/article/S1072-7515(06)00777-0/pdf

David A. Bruno

Papers

Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis

Induction of transplantation tolerance in non-human primate preclinical models

Challenges in therapeutic strategies for transplantation: where now from here?

Alefacept (LFA3-Ig), portal venous donor specific transfusion (PVDST), and sirolimus prolong renal allograft survival in non-human primates

Liver and pancreas transplantation immunobiology