Liberia has no rheumatology providers for the nation’s 4.7 million people. We proposed a short course format rheumatology curriculum to educate Liberian providers as an initial step in providing graduate medical education in musculoskeletal health. A 1-week training curriculum in rheumatology encompassing introduction to musculoskeletal exam and approach to rheumatology diagnosis and management was designed. The curriculum used multiple education methods including interactive lectures, bedside training, and hands-on learning. A 1-week rheumatology training curriculum for 24 local physicians was feasible. The execution of the designed rheumatology curriculum in Liberia relied upon a mixed method format that was both didactic and case-based. A survey of the Liberian trainees revealed that the curriculum was salient to care of patients and barriers to optimal learning such as time and space limitations were identified. A 1-week rheumatology training education program is possible and relevant to local providers, but training length and setting may need to be optimized. Future training will aim to minimize barriers to education and expand the cohort of providers with rheumatologic knowledge in Liberia.

OBJECTIVE:Immune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies. METHODS:We meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases. RESULTS:Our analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study. CONCLUSIONS:We have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.

OBJECTIVE:Activation of the type 1 interferon (IFN1) pathway is a prominent feature of dermatomyositis (DM) muscle and may play a role in the pathogenesis of this disease. However, the relevance of the IFN1 pathway in patients with other types of myositis such as the antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM) is largely unknown. Moreover, the activation of the type 2 interferon (IFN2) pathway has not been comprehensively explored in myositis. In this cross-sectional study, our objective was to determine whether IFN1 and IFN2 pathways are differentially activated in different types of myositis by performing RNA sequencing on muscle biopsy samples from 119 patients with DM, IMNM, AS, or IBM and on 20 normal muscle biopsies.METHODS:The expression of IFN1- and IFN2-inducible genes was compared between the different groups.RESULTS:The expression of IFN1-inducible genes was high in DM, moderate in AS, and low in IMNM and IBM. In contrast, the expression of IFN2-inducible genes was high in DM, IBM, and AS but low in IMNM. The expression of IFN-inducible genes correlated with the expression of genes associated with inflammation and muscle regeneration. Of note, ISG15 expression levels alone performed as well as composite scores relying on multiple genes to monitor activation of the IFN1 pathway in myositis muscle biopsies.CONCLUSIONS:IFN1 and IFN2 pathways are differentially activated in different forms of myositis. This observation may have therapeutic implications because immunosuppressive medications may preferentially target each of these pathways.

Objective Although more than a dozen myositis‐specific autoantibodies ( MSA s) have been identified, most patients with myositis are positive for a single MSA . The specific overexpression of a given myositis autoantigen in myositis muscle has been proposed as initiating and/or propagating autoimmunity against that particular autoantigen. The present study was undertaken to test this hypothesis. Methods In order to quantify autoantigen RNA expression, RNA sequencing was performed on muscle biopsy samples from control subjects, MSA ‐positive patients with myositis, regenerating mouse muscles, and cultured human muscle cells. Results Muscle biopsy samples were available from 20 control subjects and 106 patients with autoantibodies recognizing hydroxymethylglutaryl‐coenzyme A reductase (n = 40), signal recognition particles (n = 9), Jo‐1 (n = 18), nuclear matrix protein 2 (n = 12), Mi‐2 (n = 11), transcription intermediary factor 1γ (n = 11), or melanoma differentiation–associated protein 5 (n = 5). The increased expression of a given autoantigen in myositis muscle was not associated with autoantibodies recognizing that autoantigen (all q > 0.05). In biopsy specimens from both myositis muscle and regenerating mouse muscles, autoantigen expression correlated directly with the expression of muscle regeneration markers and correlated inversely with the expression of genes encoding mature muscle proteins. Myositis autoantigens were also expressed at high levels in cultured human muscle cells . Conclusion Most myositis autoantigens are highly expressed during muscle regeneration, which may relate to the propagation of autoimmunity. However, factors other than overexpression of specific autoantigens are likely to govern the development of unique autoantibodies in individual patients with myositis.

Objective: To investigate in a pilot study the safety and efficacy of infliximab in patients with refractory dermatomyositis (DM) and polymyositis (PM). Methods: A randomized, double-blind, placebo-controlled trial including subjects with active DM or PM. Participants had stable doses of immunosuppressive medication and prednisone (<= 0.5 mg/kg/day), and exhibited clinical signs of muscle weakness for at least 4 weeks prior to study entry. Participants received infusions of either placebo or infliximab 5 mg/kg at 0, 2, 6, and 14 weeks in blinded manner. The primary outcome was a >= 15% manual muscle strength (MMT) improvement at week 16 compared to week 0. The secondary outcome measures were improvement defined by the International Myositis Assessment and Clinical Studies Group (IMACS) criteria. At week 16, responders in each arm had the option of either continuing the same treatment or changing to the non-responder treatment for that study arm. Non-responders in the 5 mg/kg infliximab arm were increased to infliximab 7.5 mg/kg for weeks 22, 30, and 38. Non-responders in the placebo arm at week 16 received infliximab 5 mg/kg at weeks 16, 18, 22, 30, and 38. Outcomes were reassessed at week 40. Results: Twelve subjects completed the study to week 16. Six of the 12 subjects received infliximab treatment at the dose of 5 mg/kg with only one subject meeting the responder criteria at that dose. Of the remaining five subjects on infliximab, three crossed over to the infliximab 7.5 mg/kg dose. One of those three subjects responded. All six patients in the placebo arm crossed over to the 5 mg/kg dosing regimen after week 16, and two of those responded to infliximab. Conclusions: Infliximab therapy for patients with refractory PM and DM was well tolerated and may benefit a subset of patients. Published by Elsevier Inc.

Dear Editor, The Rheumatism Society of the District of Columbia (D.C. Rheum) is one of the oldest rheumatologic societies in the United States. Founding member Dr. Darrell C. Crain organized the first meeting on June 4, 1946. A photograph of that meeting (Fig. 1a)1 portrays many of the members, all of whom came from a variety of backgrounds, including rheumatology as well as orthopedic surgery, cardiology and pediatrics. Dr. Philip Hench, the speaker at the first meeting, had established one of the first dedicated rheumatologic services at the Mayo Clinic in 1926.2 Since rheumatology as a specialty was at that time in its infancy, it was not uncommon for fledgling rheumatologists to travel to the Mayo Clinic to receive specialist training under Hench's mentorship. Hench had established his clinic largely to serve a role in the pre-operative evaluation of patients undergoing orthopedic surgery, but as the subspecialty evolved it blossomed into one of the premier rheumatology divisions in the United States. Crain was among those who spent time with Hench at the Mayo Clinic and the two had a long friendship (Fig. 1b).3 The mission of D.C. Rheum, according to its constitution, was ‘to stimulate interest in and increase the knowledge of rheumatic diseases among physicians and laymen.’ It functioned as an interest group for physicians and its goals were largely achieved via outreach to local organizations, including the Arthritis Foundation. During this period, the pathogenesis of rheumatic disease was hotly debated. For a time, it was believed that rheumatoid arthritis (RA) was caused by chronic infection. Organs thought to harbor latent infection were removed in the hope of curing disease. Therapeutic vaccination against endogenous mycoplasma infection (called ‘auto-vaccination’) was also tried. As early as the 1930s, gold salts and antibiotics were also used for treatment of RA.4, 5 The first use of steroids, which went on to revolutionize the field of treating autoimmunity, was not until 1948, when Hench famously used cortisone to treat a patient with RA at the Mayo Clinic.6 Hench returned to give a presentation to D.C. Rheum in 1976 on the history of steroids and their clinical utility. During the 1940s and 1950s, D.C. Rheum members met several times per year to discuss rheumatic disease management, but at that time it was difficult to determine which rheumatologic therapies were truly effective. Case reports defined illness symptomatically and administered therapies without controlling for confounders. The 1950 establishment of the National Institute of Arthritis and Metabolic Diseases (NIAMD) sought to address some of these challenges by allocating federal funding to evidence-based research as well as funding subspecialty training for medical graduates. Eventually, the NIAMD was continued by its daughter institute, the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). The Cooperating Clinics of the Arthritis and Rheumatism Association also sought to improve the available data. Investigators in these clinics collaborated in the development of randomized controlled trials for gold therapy and other protocols. In the 1960s and 1970s, the goal of rheumatologic care became that of identifying more specific therapeutic targets for rheumatologic diseases. The 1968 discovery that cytotoxic agents were effective in treating RA was a huge breakthrough. Understanding the role of autoimmunity7 and its over-activation in rheumatic disease processes further propelled therapies. During this explosively productive period in the history of rheumatology, D.C. Rheum was beginning to solidify its place in the Washington, D.C. Rheumatology Community. Meetings were held on the third Wednesday of the month between September and June. Speakers included prominent rheumatologists, orthopedic surgeons, immunologists, basic scientists, radiologists and the U.S. Surgeon General. By 1979, there were designated nights devoted to talks by ‘local talent’, as the executive committee put it, and limitations on how many lectures could be given by orthopedists, signaling a distinction from the old view of rheumatology as pre-operative evaluation to orthopedic surgery. At this time, the society also began to foster international connections and was the host organization for the PanAmerican Rheumatism meeting. By the 1970s, archives show that the majority of D.C. Rheum members were dedicated rheumatologists with a handful of related specialists – including podiatrists, physical therapists and even a dentist – still attending. Meeting topics kept with the pace of scientific discovery, including the first description of drug-induced lupus presented by Lawrence Shulman, the first director of the NIAMS, on October 14, 1970. The society's founder, Dr. Darrell Crain (Fig. 2a),8 remained one of the most active members in the organization. In 1976, Dr. Joseph Croft (Fig. 2b) became the society's president. He organized notable scientific talks for members, which were, according to the meeting minutes, ‘well received by both clinicians and researchers’. Other members of the D.C. Rheum leadership included Ronald Lamont-Havers, Paul Rochmis, John Decker, Jack Klippel, Henry Roth, Nathan Zvaifler and Kenneth Austin. Many of these members also participated in national organizations for rheumatic disease such as the American Rheumatism Association. In the late 1970s, the continuing medical education (CME) survey became a standard component of monthly meetings. CME forms collected after each meeting were designed to elicit feedback and members’ ideas for future speakers. In 1983, D.C. Rheum also successfully applied for CME accreditation with the local Medical Society of the District of Columbia (Fig. 2c). Members of D.C. Rheum did not always agree about new developments in rheumatology and D.C. Rheum provided the perfect venue for scientific debate. For some time a hotly debated issue was whether chronic mycoplasma infection was the driver of RA.9 Other contested issues included the continued use of broad cytotoxic therapies, even as more specific biologic therapeutics were being developed. In 1989, the relationship between tumor necrosis factor alpha (TNF-α) and induction of inflammatory response via interleukin-1 was described by Drs. Ravinder Maini and Marc Feldmann.10 This finding drove the development of biologic therapies, in which monoclonal antibodies were developed against specific targets in immune response pathways. This change contrasted with the broad cytotoxic approach of prior decades but internationally revolutionized rheumatologic care. Like many novel medications, these agents were expensive. Dr. James O'Dell gained national recognition for his work, demonstrating that ‘triple therapy’ with hydroxychloroquine, methotrexate and sulfasalazine11 was a cheaper alternative to up-front therapy with TNF-α inhibitors, and presented this work to D.C. Rheum. As the society continued to grow and the workforce within rheumatology became more diverse, female physicians started to play a larger role in D.C. Rheum. Many women have pursued leadership roles within the society and, in recent years, the society has had several female presidents. While trainees and fellows were always welcome at D.C. Rheum meetings, in 2002, Dr. Arthur Weinstein created an Annual Fellows Forum for the society. This was an event at which Fellows-in-training in the area were able to present their work at a half-day conference. Prizes were awarded for best presentations in clinical research, basic science and case presentations. Guest speakers were invited to each Forum as well. In 2016 alone, 31 abstracts were submitted by over 25 trainees. Recent guest speakers have included Dr. John O'Shea, who presented his discovery of the Janus Kinase pathway's role in RA, and Dr. Robert Inman, who presented new developments in ankylosing spondylitis research, as well as Drs. Bevra Hahn and Brian Mandell. As technology has evolved, so too has the society. In 2011, Dr. Christopher Collins, who later served as the group's president, was asked to develop a web site for D.C. Rheum. The product was a modern interface which could facilitate networking within the society. Included was a calendar of upcoming and past events, access to information on job postings and a membership list. The newest initiative on the horizon, courtesy of current president Dr. Donald Thomas, is a platform to increase the interaction between D.C. Rheum and local rheumatologic non-profit groups. Another initiative, designed by Dr. Paul DeMarco, is a CME course in musculoskeletal ultrasound, one of the most rapidly growing practices in clinical rheumatology. Over the last 70 years, D.C. Rheum has grown and evolved in parallel with the field of rheumatology itself. From its origins as an interest group it developed into an organization dedicated to continuing medical education for rheumatologists, providing a forum for professional networking and debate. As a result, it has become a meeting place for the great minds of rheumatology and an interface between basic sciences and clinical practice in the field. This work would not have been possible without the historical and personal recollections of many current and former members of D.C. Rheum, including Drs. Herbert Baraf, Christopher Collins, Joseph Croft, Paul DeMarco, Gregory Dennis, Paul Plotz, Paul Rochmis, Raymond Scalettar and Arthur Weinstein. Other contributors included Mrs. Alice Makl and Drs. B.T. and Daniel Walsh, relatives of Darrell Crain and Bernard Walsh, respectively. Thanks also to the Rheumatism Society of the District of Columbia for providing archived meeting minutes and consultation regarding future directions for the society. D.C. Rheum is a 501(c)(03) charitable non-profit organization. The authors have no industrial affiliations or conflicts of interest to report.

BACKGROUND:Molecular diagnostics in the genetic myopathies often requires testing of the largest and most complex transcript units in the human genome (DMD, TTN, NEB). Iteratively targeting single genes for sequencing has traditionally entailed high costs and long turnaround times. Exome sequencing has begun to supplant single targeted genes, but there are concerns regarding coverage and needed depth of the very large and complex genes that frequently cause myopathies.OBJECTIVE:To evaluate efficiency of next-generation sequencing technologies to provide molecular diagnostics for patients with previously undiagnosed myopathies.METHODS:We tested a targeted re-sequencing approach, using a 45 gene emulsion PCR myopathy panel, with subsequent sequencing on the Illumina platform in 94 undiagnosed patients. We compared the targeted re-sequencing approach to exome sequencing for 10 of these patients studied.RESULTS:We detected likely pathogenic mutations in 33 out of 94 patients with a molecular diagnostic rate of approximately 35%. The remaining patients showed variants of unknown significance (35/94 patients) or no mutations detected in the 45 genes tested (26/94 patients). Mutation detection rates for targeted re-sequencing vs. whole exome were similar in both methods; however exome sequencing showed better distribution of reads and fewer exon dropouts.CONCLUSIONS:Given that costs of highly parallel re-sequencing and whole exome sequencing are similar, and that exome sequencing now takes considerably less laboratory processing time than targeted re-sequencing, we recommend exome sequencing as the standard approach for molecular diagnostics of myopathies.

Rarely, inflammation can be present in genetic myopathies, such as dysferlinopathies, facioscapulohumeral muscular dystrophy and GNE-myopathy (hereditary inclusion body myopathy). This may lead to erroneous initial diagnosis and unnecessary therapy which bear serious side effects. We report on an unusual case of mutations in the TTN gene presenting with inflammatory infiltrates in the muscle biopsy. Only after intensive immune-modulating therapies failed, a genetic myopathy was considered. Exome sequencing and search for mutated muscle protein-encoding genes disclosed compound heterozygous mutations in TTN: K26320T and A6135G. The parents carry one each of the mutations. Titinopathy could be considered also in patients presenting with inflammatory infiltrates resistant to therapy.

Dr. Norman Talal, a longtime, preeminent authority on Sjogren’s syndrome whose research offered novel perspectives on autoimmune diseases, died in his home in New York on April 24, 2015. For many decades after its first description, Sjogren’s syndrome was known as a disease that caused dryness of the eyes and mouth that could lead to tooth and eye problems but was not in itself considered serious or debilitating. Talal (Figure 1) and his group were among the first to recognize that Sjogren’s syndrome could also cause many other more serious and debilitating problems. He and his fellows, students, and associates have had a large role in shaping the modern view of Sjogren’s syndrome and disseminating knowledge of Sjogren’s and other autoimmune diseases throughout medicine. Talal’s major contribution using experimental animal models was the exploration of the role played by female hormones in the development of autoimmune disorders. Figure 1 Norman Talal. Talal was born in Brooklyn, educated at New York City public schools, and received his B.A. in 1954 from Columbia College and his MD in 1958 from the College of Physicians and Surgeons of Columbia University. In that year, he wrote the first of his more than 350 medical and scientific publications. He trained at the Presbyterian Hospital, spent a fellowship year at the Pasteur Institute with Professor Pierre Grabar, worked with Dr. Elliott Osserman at the Columbia University College of Physicians and Surgeons, and then began his career at the NIH as a research associate with Gordon Tompkins. He became a senior investigator at the National Institute of Arthritis and Metabolic Diseases (now the National Institute of Arthritis and Metabolic and Skin Diseases) and published his first paper on Sjogren’s syndrome with Dr. Joseph Bunim in 1964. Over the next several decades, he and his students and fellows examined, cared for, and closely observed hundreds of patients with Sjogren’s syndrome. They found virus-like structures in the salivary glands and helped use modern imaging techniques to observe the structure of those glands. They found that Sjogren’s patients can develop lymphomas that are often malignant, as well as serious kidney disease, neurologic disease, and life-threatening blood changes. Perhaps most importantly, he and his students and fellows studied the immune system of their patients and discovered that many abnormalities in Sjogren’s syndrome closely resembled those in the more common disease systemic lupus erythematosus (SLE). When he left the NIH in 1971, Talal carried on his medical career and his research studies as Professor of Medicine at the University of California at San Francisco and head of Rheumatology at the San Francisco VA Medical Center from 1971 to 1981 and then as Professor of Medicine and Microbiology and head of the Division of Clinical Immunology at the University of Texas in San Antonio. Although there was no animal equivalent of Sjogren’s syndrome, Talal devoted his laboratory research program for the rest of his research career to the study of the immunologic abnormalities in mice that spontaneously developed SLE. Among the many immunologic problems he worked on, he devoted much of his attention to the still incompletely understood reasons that many autoimmune diseases, including SLE and Sjogren’s syndrome, are far more common among females than among males. This sex disparity also holds true in most mouse models of lupus, and he and his colleagues and fellows wrote a number of important papers on that problem. Talal trained 80 fellows and collaborated with many, including physicians and scientists from Japan, Europe, North and South America, Israel, Egypt, and China, as well as the United States. Among them were Leon Sokoloff, Alfred Steinberg, Theodore Pincus, Haralampos Moutsopoulos, William Seaman, James Balow, Paul Plotz, Susumu Sugai, Takao Koike, and Shigemasa Sawada. Many had distinguished careers, rose to professorships, and led research and/or clinical divisions. Of particular note, six of his seven Japanese fellows rose to professorships in major medical universities. He strove for excellence and asked the same of his students. Talal was the recipient of the 1975 Philip Hench Award of the United States Pubic Health Service for his work in rheumatology, and in 1980, he won the William S. Middleton Award, the top award for medical research of the Veterans Administration. Over the years, he received awards from the Arthritis Foundation and the Hong Kong Society of Rheumatology, and several honorary doctorates from Europe and Japan. Talal was a member of the American Society for Clinical Investigation and served as vice president of the society in 1979–1980. He was also a member of the Association of American Physicians. He was active for many years in the Bay Area Council on Soviet Jewry on behalf of refuseniks, particularly Anatoly Scharansky. Talal was a broadly educated, enthusiastic art lover and collector. The shelves in his home were crowded with pre-Columbian art and other ancient art and artifacts, including tribal statues from New Guinea, huacas from Peru, clay jugs and beads from Ecuador, and 3,000-year-old religious objects from the First Temple period in Israel. He also delightedly collected almost 300 match-safes made out of various materials — gold, silver, brass, leather — fashioned into miniature trunks, outhouses, even overalls. And he told jokes brilliantly. Suffering toward the end of his life from several debilitating diseases, he returned to New York in 2000 and taught courses on achieving wellness through the arts with his wife, poet Dr. Marilynn Talal. He is survived by his wife; a daughter, Melissa Talal, of Boston; a son, Dr. Andrew Talal, Professor of Medicine and chief of the Department of Gastroenterology and Hepatology at SUNY Buffalo; a daughter-in-law, Dr. Marianthi Markatou; a granddaughter, Lillian; and many loving cousins and friends.

The idea that the body must and can protect itself from the hidden dangers of the outside world—microbes and poisons—and that it can learn from the experience and do it better next time has been recognized for thousands of years. During the plague of Athens, Thucydides had noticed that those who had recovered showed the most compassion for the sick. Since they knew that the same person was never struck a second time, they did not fear for themselves. King Mithradates VI of Pontus took small doses of poisons and noxious substances repeatedly to protect himself against fatal poisoning later, an idea clearly related to the modern idea of acquired immunity. Here is A. E. Housman’s wonderful account in his poem (A Shropshire Lad, LXII, Terence this is stupid stuff): There was a king reigned in the East: There, when kings will sit to feast, They get their fill before they think With poisoned meat and poisoned drink. He gathered all that springs to birth From the many-venomed earth; First a little, thence to more, He sampled all her killing store; And easy, smiling, seasoned sound, Sate the king when healths went round. They put arsenic in his meat And stared aghast to watch him eat; They poured strychnine in his cup And shook to see him drink it up: They shook, they stared as white’s their shirt: Them it was their poison hurt. —I tell the tale that I heard told. Mithradates, he died old.

Muscle disease shows extensive genetic and allelic heterogeneity, with many genes causing related phenotypes. Some of the gene loci causing muscular dystrophy are the largest in the human genome (e.g. titin, dystrophin) making molecular diagnostics particularly challenging and expensive. Next generation sequencing promises single-test approach to diagnostics. A commonly utilized nextgen approach is whole exome sequence (WES), where hybrid capture of exons enables parallel sequencing of most exons in a single sequencing run. However, WES has an exonic drop-out rate of about 10% – 1 in 10 dystrophin, nebulin, titin or other gene exons would remain ‘non-sequenced’ with the WES approach. Thus, a negative result on WES does not necessarily rule out common genetic causes of muscle disease. An alternative approach is targeted sequencing panels. Here, each exon of specific candidate myopathy genes is individually amplified by microbubble PCR (RainDance), and this highly enriched DNA is then subjected to nextgen sequencing. Here, we develop and test a targeted muscle disease gene panel for 45 of the most common myopathy genes (1851 amplimers). We report our experience with this panel in 89 myopathy patients. We found greater consistency in depth of coverage (average 1000-fold coverage), less drop-out (2% instead of 10% in exomes), and genotype/phenotype concordance with clinician-determined differential diagnosis. Overall, targeted re-sequencing panels allow for more definitive testing of known muscular dystrophy genes. We give some specific case examples, with mutation in titin (TTN), ryanodine receptor (RYR1), and nebulin (NEB) genes. Both WES and targeted sequencing panels permit more centralized testing at greatly reduced cost and more rapid turn-around compared to single gene testing. The routine implementation of nextgen sequencing approaches should streamline molecular diagnostics, genetic counseling, and patient navigation for clinical trials.

An Epidemic of Absence is a timely account of the hygiene hypothesis, and it delivers a rich lode of history, epidemiological data, immunological speculation and stories of human behavior.The author, Moises Velasquez-Manoff, was drawn to this subject by his near lifelong burdens of alopecia areata totalis, food allergies and asthma.I am slightly leery of researchers whose principal subject of interest is their own disease, but Velasquez-Manoff is a professional science writer, and the accounts of his own experiences in seeking to overcome his illnesses by self-infecting with helminths provide a compelling frame for his subject.Readers of this journal who have swallowed accounts of fecotherapy and read of respected medical centers carrying out studies of helminth therapy for multiple sclerosis and other diseases will be drawn into the fascinating body of knowledge and the theory that underlie this story.Velasquez-Manoff describes how the epidemic-the new appearance or rapidly rising incidence of a variety of inflammatory, immune, allergic and autoimmune diseases-might be due to improved general hygiene and water purification; the growth of cities; the decline of family size; and other largely nineteenth-century epidemiological phenomena.The mechanism for this epidemic is postulated to be the removal, or, as in the title, "absence, " of many widespread familiar immunological stimuli, such as worms, which, until they were mostly eliminated from the environment, had been stimulating the regulatory T cells that have a braking effect on adaptive immunity.This tale is amusingly told, though with an unequal weighing of the evidence in which single patients' stories are told more lovingly and at greater length than epidemiological or immunological observations.Velasquez-Manoff 's knowledge of the breadth of ways by which immune and inflammatory responses to infection are controlled appears incomplete, and his use of important terms such as 'inflammation' is quite loose.Some diseases and organisms are subject to deeper analysis: multiple sclerosis, asthma, inflammatory bowel disease, even autism, as well as several worms, Mycobacterium tuberculosis, Helicobacter pylori and the perennial favorite of immunologists, Epstein-Barr virus.These are

June-July 2008 www.igliving.com IG Living! Case Study A 26-year-old female was referred to the rheumatology service two years after the insidious onset of “walking funny” that progressed to significant proximal muscle weakness over a 10-month period. Early in the course of her illness, her creatine kinase (CK) was 4,000. Subsequent muscle biopsy revealed muscle fiber degeneration and regeneration in addition to numerous phagocytic cells. She was diagnosed with polymyositis but, despite treatment with high-dose corticosteroids, methotrexate (MTX), and monthly intravenous immunoglobulin (IVIG), she did not improve. At the time of presentation to rheumatology, her CK was 8,000, and she reported continued progression of muscle weakness and consequent frequent falls. Her family history was remarkable for a sister with the onset of similar symptoms at 30 years of age. Because of the lack of response to previous appropriate therapies and the family history, we suspected a hereditary myopathy. Her initial muscle biopsy results were consistent with the possibility of a hereditary myopathy, because some dystrophies do show inflammation. Repeat muscle biopsy was recommended for more extensive histopathologic evaluation. Upon immunohistochemical staining, the absence of dysferlin was discovered, consistent with a diagnosis of limb-girdle muscular dystrophy 2B. Introduction This case highlights the difficulty in diagnosing polymyositis and the need to think through the appropriate differential diagnosis and to use the appropriate diagnostic modalities when evaluating patients with suspected idiopathic inflammatory myopathy (IIM). Polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM) comprise the major IIM subsets in adults. A further categorization based on associated malignancy or other connective tissue disease features is useful in some circumstances, such as directing therapeutic interventions. Although the IIMs share the characteristics of immune-mediated attacks on skeletal muscle resulting in muscle weakness, they are in fact heterogeneous diseases with varied histopathological and clinical characteristics. Furthermore, these inflammatory myopathies can be confused with other myopathies that sometimes can have an inflammatory component, such as muscular dystrophies.

Pompe disease, a deficiency of lysosomal acid alpha-glucosidase, is a disorder of glycogen metabolism that can affect infants, children, or adults. In all forms of the disease, there is progressive muscle pathology leading to premature death. The pathology is characterized by accumulation of glycogen in lysosomes, autophagic buildup, and muscle atrophy. The purpose of the present investigation was to determine if myofibrillar dysfunction in Pompe disease contributes to muscle weakness beyond that attributed to atrophy. The study was performed on isolated myofibers dissected from severely affected fast glycolytic muscle in the alpha-glucosidase knockout mouse model. Psoas muscle fibers were first permeabilized, so that the contractile proteins could be directly relaxed or activated by control of the composition of the bathing solution. When normalized by cross-sectional area, single fibers from knockout mice produced 6.3 N/cm2 of maximum Ca2+-activated tension compared with 12.0 N/cm2 produced by wild-type fibers. The total protein concentration was slightly higher in the knockout mice, but concentrations of the contractile proteins myosin and actin remained unchanged. Structurally, X-ray diffraction showed that the actin and myosin filaments, normally arranged in hexagonal arrays, were disordered in the knockout muscle, and a lower fraction of myosin cross bridges was near the actin filaments in the relaxed muscle. The results are consistent with a disruption of actin and myosin interactions in the knockout muscles, demonstrating that impaired myofibrillar function contributes to weakness in the diseased muscle fibers.

PGC-1α is a transcriptional co-activator that plays a central role in the regulation of energy metabolism. Our interest in this protein was driven by its ability to promote muscle remodeling. Conversion from fast glycolytic to slow oxidative fibers seemed a promising therapeutic approach in Pompe disease, a severe myopathy caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA) which is responsible for the degradation of glycogen. The recently approved enzyme replacement therapy (ERT) has only a partial effect in skeletal muscle. In our Pompe mouse model (KO), the poor muscle response is seen in fast but not in slow muscle and is associated with massive accumulation of autophagic debris and ineffective autophagy. In an attempt to turn the therapy-resistant fibers into fibers amenable to therapy, we made transgenic KO mice expressing PGC-1α in muscle (tgKO). The successful switch from fast to slow fibers prevented the formation of autophagic buildup in the converted fibers, but PGC-1α failed to improve the clearance of glycogen by ERT. This outcome is likely explained by an unexpected dramatic increase in muscle glycogen load to levels much closer to those observed in patients, in particular infants, with the disease. We have also found a remarkable rise in the number of lysosomes and autophagosomes in the tgKO compared to the KO. These data point to the role of PGC-1α in muscle glucose metabolism and its possible role as a master regulator for organelle biogenesis - not only for mitochondria but also for lysosomes and autophagosomes. These findings may have implications for therapy of lysosomal diseases and other disorders with altered autophagy.