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Editorial:
Prof Kalla |
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| Editorial:
Prof Kalla It is difficult to believe that it is once again time for the SARAA Congress, which means that close to 2 years have gone by already. This edition of Rheumatology News consists of several papers by local Rheumatologists as well as abstracts from international Rheumatology journals. The main feature is the report from our President, Dr Anne Halland. It is, indeed, a while since the Association has been so actively engaged in the discussion of issues and a great deal of time and effort has gone into the revamping of our Constitution. The task force who tackled this activity has done a sterling job and the committee needs to be congratulated on their efforts. You will see from the report that our President has been engaged in several activities on behalf of SARAA and I believe that the benefits of these efforts will be seen for a long time. Unfortunately, the regional committees have not accepted the challenge of using their regional meetings to generate material to be included in Rheumatology News. These groups have also not been reporting their activities to the Editor. Memebers are urged to take the time to read the amended Constitution and to avail themselves at the Special General Meeting, at which the changes need to be ratified. The team at Chris Hani Baragwanath Hospital have put together a very informative article on the relationships between systemic lupus erythematosus and infections. On the one hand, SLE may predispose to the development of infection, either as a direct consequence of the disease and its effect on the white blood cells or as a result of the immunosuppressive therapy that is being used increasingly for life-threatening disease activity. Alternatively, SLE may be due to a deficiency of complement. This complement deficiency can lead to a susceptibility to certain infections, especially meningococcus. Thirdly, infections may precipitate an attack of SLE and the differential diagnosis for fever in the SLE patient could become a daunting task, even for the experienced Rheumatologist. The group has done an excellent job of placing these relationships in perspective and the article is highly informative. Dr Cathy Spargo, now in Private Practice, is becoming a regular contributor to the journal and this time she reports on her highlights of the recent ACR Congress. Perhaps, not surprisingly, many of the presentations discussed the newer developments in management of rheumatoid arthritis, especially the TNF-receptor blocking agents (viz., Infliximab and Enbrel). Her paper summarises some of the highlights of the meeting and will be of broad interest to medical practitioners. Anne Halland has also contributed a useful article on the clinical role of metallomatrix proteinase inhibitors (MMPI) in the treatment of osteo arthritis. Unfortunately, it seems that these drugs have not lived up to expectations and the major drawback appears to be the development of cancers in the active treatment group, which are significantly higher than in RA patients not receiving MMPI's. This short paper is easy to read and provides a useful description of the issues involved and the need to develop DMARD therapy for OA. Research is continuing in the field and it is possible that newer approaches to the management of OA will be developed soon. Abstracts from international Rheumatology journals were selected to inform readers about the type of research that is being reported in the literature. The editor does not apologise for any obvious bias which may be reflected in the selection of articles, but we trust that these will have a broad appeal to the reader. The calendar of rheumatological events will help interested readers to plan their visit to different meetings around the world. Important events to remember are the SARAA meeting in Pretoria, the EULAR meeting in Prague and the ACR meeting in San Francisco. Happy reading!! Asgar Ali Kalla. |
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BONE AND JOINT DECADE l 2000 - 2010 - FOR PREVENTION AND TREATMENT OF MUSCULO-SKELETAL DISORDERS PRESS RELEASE - October 11, 2000 Bone and Joint Decade 'Action Week' October 12-20, 2000 Arthritis, osteoporosis, road traffic safety, spine, and trauma experts and advocates find unusual common ground in the Bone and Joint Decade [LUND, SWEDEN] October 11, 2000 - The Bone and Joint Decade declares October 12-20, 2000 its first annual 'Action Week' to highlight worldwide collaboration among organizations to reduce the burden of musculoskeletal disorders and to call for increased research and education for prevention and treatment. From Vatican church bells ringing to employee education events to hospital emergency rooms' 'moments of silence' to scientific symposia throughout the world, the Bone and Joint Decade salutes action-oriented organizations. Examples include organizations such as the International League of Associations in Rheumatology, the European Parliament's European Agency for Safety and Health, the World Bank's Global Road Safety Partnership, and the International Osteoporosis Foundation. Musculoskeletal conditions affects hundreds of millions of people around the world. This figure is projected to increase sharply with the predicted doubling of the number of people older than age fifty by the year 2020, according to a 1996 report by the World Health Organization and the World Bank entitled The Global Burden of Disease. "Through coordinated worldwide efforts, significant rates of death and disability from musculoskeletal disorders can be prevented by, first and foremost, awareness, then increased research, pervasive education and accessible treatments," said Prof. Lars Lidgren, M.D., chairman of the Decade's International Steering Committee. Since its international launch in January of 2000-2010 as the Bone and Joint Decade, the initiative has been endorsed by the United Nations, the World Health Organization, the World Bank, the Vatican, 26 nations, and 700 patient advocacy and health professional organizations. Worldwide activities highlighted during the week of October 12-20 include: October 12: World Arthritis Day Arthritis is the leading chronic condition reported by the elderly and is the number one cause of activity limitation, more than heart disease, cancer or diabetes. Statistics from the U.S. Public Health Centers for Disease Control and Prevention indicate that there are 43 million American children and adults affected by the 100 forms of arthritis and that number is expected to reach an epidemic proportion of 60 million by the year 2020. Representing 80 national rheumatology societies concerned about arthritis care and treatment, the International League of Associations in Rheumatology (www.ilar.org/default.asp), have joined with Arthritis and Rheumatism International (ARI), representing the Arthritis Foundation and patient organizations to "think global, act local" to raise awareness of the growing burden of arthritis. October 16: World Spine Day The prevention of back pain and musculoskeletal disorders have been given priority because of the large and increasing number of workers affected and the economic consequences involved. According to a recent European survey, 30% of workers complain of back pain, 17% complain of muscular pain in arms and legs, and 45% reported working in painful positions. In some countries musculoskeletal disorders is now the most prevalent occupational disease. 'Turn your back on musculoskeletal disorders' is the theme of workplace education in the 15 European Union Member States by the European Agency for Safety and Health at Work "Back to Future" week (http://osha.eu.int/ew2000). October 17: World Trauma Day Every 30 seconds someone dies on the world's roads. Annually over 1 million people die and over 25 million are injured or permanently disabled from road accidents. Seventy-five percent of the fatalities and injuries occur in the developing world. The problem is growing. The Global Burden of Disease Report predicts that road traffic accidents will move from ninth place to third place on the list for worldwide death and disability. The Vatican church bells will ring on this day to honor those killed. In addition, the Tuscany church of the Bishop of Brescia will ring every 30 seconds for twenty-four hours. The Bone and Joint Decade is working with the Global Road Safety Partnership (GSRP), a collaboration of the World Bank and the International Federation of Red Cross and Red Crescent Societies to develop programs for prevention and treatment of road traffic injuries. October 20: World Osteoporosis Day Osteoporosis was only recognized as a disease in the last decade. Worldwide, the lifetime risk for osteoporotic fractures in women is at least 30% and probably closer to 40%. In men the risk is 13%, according to the IOF. The lifetime risk of hip fracture in women is larger than the sum of lifetime risks of having breast, endometrial and ovarian cancer. The lifetime risk of hip fracture in men is greater than that of prostate cancer. According to the World Health Organization, the number of hip fractures worldwide could rise from 1.7 million in 1990 to 6.3 million by 2050. In the Western world more people die each year from complications following a hip fracture than die from gastric or pancreatic cancer. 'Invest in your bones' is the theme of educational activities of the International Osteoporosis Foundation (www.osteofound.org) which includes the release of the Millennium One-Minute Osteoporosis Risk Test, the theme song "Bone of My Own," international journalism awards, public service spots, and remarks by IOF patron Queen Rania of Jordan. The IOF consists of 96 member national societies in 56 countries. THE BONE AND JOINT DECADE is an independent global non-profit organization whose mission is to improve the health-related quality of life for people affected by musculoskeletal disorders worldwide. It is the umbrella organization by which National Action Networks, professional medical societies, patient advocacy groups, governments, industry and researchers partner to effect change by: (1) Raising awareness of the growing burden of musculoskeletal disorders on society; (2) Empowering patients to participate in their own care; (3) Promoting cost-effective prevention and treatment; and (4) Advancing understanding of musculoskeletal disorders through research to improve prevention and treatment. For more information, visit the web site at www.boneandjointdecade.org. |
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African Rheumatism and Arthritis Association Presidents Report: September 1999 - March 2001 Rheumatic diseases unit, J47 Old Main Building, Groote Schuur Hospital, Observatory 7925 (Dr) Anne Halland, Physician Rheumatologist, President, SA Rheumatism and Arthritis Association. 136 Delmar Medical Centre, Panorama 7500 Cape Town, South Africa telephone 021-9396106 fax 021-9308934 email drhalland@mweb.co.za cell 0828977050 This has been an unusually short term of office but I believe a very busy and fruitful one. The mission of this Exco has been to put SARAA and Rheumatology firmly on Healthcare map, both within the private and state sectors, hopefully thereby ensuring that patients with Rheumatic Diseases in South Africa enjoy the priority they deserve. Enhancement of communication and personal relationships between the various roleplayers within SARAA has been a focus of this presidency. I believe we have achieved this through the use of email, regular newsletters, as well as more frequent opportunities to interact with one other at congresses and at the Arthritis Forum. The latter has consisted of a core group of practitioners who have met on a national basis 3-4 times per annum to discuss various matters of importance to SARAA. Issues have included the revision of the SARAA constitution, public relations, research and education. The Forum was initiated by a Pharmaceutical partner and has been very beneficial to SARAA. Quarterly academic meetings, also under pharmaceutical sponsorship, have continued both in Cape Town and Gauteng. These have likewise been a resounding success, enjoying increased attendance with the advent of CPD points. Rheumatology News has continued to be published with circulation both to SARAA and AFLAR members. More support of this journal is needed to keep it alive and relevant to the South African situation. The constitution of SARAA has been completely rewritten, under the guidance of a committee consisting of myself, Drs Christopher Lyddell, Ebbie Bhettay, Alan Tooke, and Dave Whitelaw. The existing constitution was vague, outdated and completely inadequate. In rewriting the constitution we referred to various sources including other similar organisations within South Africa, the South African Medical Association (SAMA)'s suggested constitution for special interest groups, as well as organisations such as the British and Australian Societies of Rheumatology. The new constitution defines membership and voting rights, determines the objectives of the organisation, and brings it in line with other similar professional organisations within South Africa. I trust that it will be ratified at the special general meeting called for this purpose. Establishment of communication lines with key organisations has been another area of endeavour during this period. This includes communication with the Health Professionals Council of South Africa, SAMA, the Medicines Control Council, the Department of Health and the Colleges of Medicine of South Africa. Issues addressed have included accreditation of Rheumatology Subspecialists by an Accreditation committee created for this purpose, representation on private practice committees of SAMA, presing for fast-tracking of registration of novel anti - rheumatic drugs, and concerns about the threat to academic Rheumatology Training Centres respectively. A disturbing situation pertaining to the training of Rheumatology subspecialists was brought to the attention of Exco during November 2000. The Department of Health has developed a policy document concerning the rationalisation of specialist training posts at state institutions. The curtailment of Rheumatology registrar posts has been proposed ostensibly due to the low numbers of Rheumatologists who have subspeciality registration in this country (currently 26). This would be a seriously retrogressive step for Rheumatology in this country. SARAA has responded vigorously to this potential threat with a carefully worded letter to Prof Gumbi at the Department of Health, expressing our concern and stating our objections to such a move. We have asked for personal representation on committees called to advise on the rationalisation. Letters of support have been received from several prominent overseas colleagues including Prof Matt Liang and Prof Jan Dequeker. To date the Department has not acknowledged our letters. Private practice issues have enjoyed considerable attention during this period. More than half of the registered Rheumatologists in South Africa are in private practice and face an increasingly difficult task with Healthcare Funders. At present private Rheumatologists continue to be represented formally at SAMA's Private Practice committees by Dr Les Kernoff the physician representative. SARAA has observer status only since we have chosen not to seek formal affiliation with SAMA. However we are kept informed of meetings and decisions and regular contact with Dr Kernoff has been maintained. Furthermore invaluable dialogue has been opened with the Medical Advisors Group. These colleagues help define the policies and practice of the individual medical aids, and are therefore are pivotal contact persons within the Private Healthcare sector. Informal meetings with the Medical Advisors Group in Cape Town have been held and similar meetings in Gauteng are envisaged. These have been most beneficial and have encouraged open discussion on a wide range of topics. A brief document outlining suggested good clinical practice was drawn up at the request of the Medical Advisors Group, and will be used to assist both practitioners and Healthcare Funders. These will assist in defining indications for the use of costly drugs and procedures. During August 2000 Prof Girish Mody, current president of AFLAR, and a former President of SARAA, called an inaugural meeting to establish a multidisciplinary steering committee for the Bone and Joint Decade (BJD). Representatives from the Arthritis Foundation, SARAA, the Osteoporosis Foundation, the Physiotherapy Association and the Orthopedic Association attended, with support from the Occupational Therapy Society. An interim National Action Network of South Africa for the Bone and Joint Decade (NANSA) was formed and has received recognition from the International BJD Steering Committee in Sweden. Following this meeting, Prof Mody was able to secure moral endorsement from Mrs Kotzenberg, the Director of chronic Diseases and Geriatrics at the Department of Health. During November I was priviledged to represent NANSA at a BJD meeting hosted by the Health Ministry of Oman. Forty seven delegates from around the globe were present, however sadly only three from Africa (Nigeria, Egypt and South Africa.) Our attendance at this meeting signalled our interest in joining with global partners working for the betterment of patients with bone and joint disorders over the next decade. I believe that our participation in the BJD adds value to the international initiative and improves our status and credibility in the international community. SARAA is continuing to spearhead the BJD initiative in South Africa and will host the next meeting of NANSA where concrete plans will be made for further activities. One of the most exciting projects planned is the development of the BJD website which we will be able to utilize for the benefit of patients and practitioners in South Africa. You can view the current homepage at www.boneandjointdecade.org. This homepage is currently being developed and Dr David Gotlieb has been given the mandate to develop a South African homepage relevant to local needs. I firmly believe that SARAA should give its full support to the BJD, in order to strengthen relationships between key players within South Africa and beyond our borders. Together we can achieve so much more than on our own. I want to thank everyone who has participated in SARAA's activities over the last 18 months for the wonderful support which I have received both from the Exco as well as the larger membership. I believe that we are at the threshold of a Rheumatology Renaissance, a period characterised by a global upswing in interest in Rheumatology, alongside the availability of ever improving drugs for the rheumatic diseases. |
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FROM THE 2000 ACR CONGRESS, PHILADELPHIA, November 2000 Dr C E Spargo. Rheumatology Registrar, University of Cape Town, SA. There were a number of themes running through this year's congress, which were fairly prominent. These included: o New uses of TNF inhibitors, as well as new concerns about some safety aspects emerging as the long-term usage increase. o New therapies emerging for Systemic Lupus, most notably the use of DHEA o New treatments in development for Rheumatoid arthritis (which was widely mis-reported as being the find of a "cure" for arthritis.) There was also significant emphasis placed on the relationship of Rheumatoid arthritis and atherosclerotic cardiovascular disease, as well as discussion regarding the problem of Hepatitis C virus and its musculoskeletal complications, (which is more of a problem in the United States than it is in South Africa.) Abbreviations - SLE, DHEA, SLAM, SLEDAI, VAS, FNF, FBC, DMARD. New approaches to the treatment of SLE As a result of a study, the results of which were presented at the ACR, DHEA is going to be presented to the FDA in early 2001 for registration in the use of patients with SLE. In this study, 381 females with mild to moderate SLE and baseline Prednisone doses of 0 to 10 mg per day were evaluated in a randomised, double-blind placebo comparison of oral DHEA 200mg daily or placebo, for 12 months. Responders were patients whose mean on-treatment values of each of 4 instruments (2 disease activity scores: SLAM and SLEDAI; 2 quality of life measures: patient VAS and the Keitel Functional status score) stabilised or improved compared to baseline, and who had no clinical deterioration. Baseline DHEA levels were particularly low in patients receiving steroids. The DHEA-treatment group had more responders, fewer patients with SLE flare, and showed strong trends for improvement in patient VAS and other scores. Patients with active SLE, especially those receiving steroids showed the greatest treatment effect. Additionally, bone mineral density significantly improved in the treatment group. Adverse events and biochemical changes were primarily androgenic (acne and mild hirsutism). Although this does not in any way suggest that DHEA is a cure for SLE, it is the first new drug in our daily armamentarium that may offer significant advantages to a relatively large SLE population. There are ongoing studies still in the laboratory stage, or in early clinical trials, which nonetheless hold considerable promise, notably LJP 394, anti-CD40 ligand, and monoclonal antibodies to T lymphocytes. It was generally felt that for the first time in very many years, there appears to be light at the end of the tunnel in the treatment of our Lupus patients. New applications for TNF inhibition and reported adverse events in post-marketing surveillance Two major groups of adverse events have led to recent label updates, but these have to be considered in the light of the in-excess of 80000 patients (> 60 000 patient-years of exposure) who have received Etanercept alone. There have been reported rare cases of pancytopaenia, including aplastic anaemia but it is important to note that most of these patients were on concomitant therapy associated with a risk of marrow suppression (including Methotrexate, Azathioprine and Cyclophosphamide). No definite causal link has been found between these events and the use of the TNF inhibitors. There have been no changes in the recommendations for laboratory monitoring of the FBC. Recently, there have also been reports of CNS events associated with demyelination in patients on TNF inhibitors. The described events have included multiple sclerosis, myelitis and optic neuritis. Once again a definite causal relationship has been established; however, patients with multiple sclerosis who have been treated with TNF antagonists have shown increased activity of their M.S. There have also been infrequent reports of serious infection, some with fatal outcomes. Etanercept has now been proven clinically and statistically to improve Psoriasis and Psoriatic arthropathy. Patients showed continued improvement during the 6-month trial extension, and substantial Methotrexate and steroid tapers were achieved. Projected future uses of TNF inhibitors in the Rheumatic diseases include: Still's disease in adults, Ankylosing spondylitis, uveitis in children, scleroderma, Poly and dermatomyositis and Wegener's granulomatosis. Studies looking at the use of Etanercept as a treatment for Adult Onset Still's disease have shown it to be effective for the joint component, but its effect on the systemic component of the disease is less dramatic. The rationale for using TNF inhibitors in Ankylosing spondylitis, includes the fact that certain TNF polymorphisms are associated with Ankylosing spondylitis, and that TNF mRNA/protein is present in inflamed SI joints in AS. It would appear that the TNF inhibitors affect both axial and peripheral features, and that both outcome and signs and symptoms may be improved. In scleroderma, elevated serum TNF correlates with pulmonary fibrosis and there is strong in-situ TNF expression by skin infiltrating lymphocytes and dermal fibroblasts. The summary statement is that rheumatic diseases in which TNF blockade may be beneficial continue to be identified. New Treatments in development for Rheumatoid arthritis A completely new approach to the treatment of Rheumatoid arthritis based on B lymphocyte depletion was very successful in the first 10 patients in whom it was used. These patients all had longstanding Rheumatoid arthritis, average duration 22 years and were unresponsive to DMARDS. Six of the ten achieved an ACR 70 response, as reported by Dr Jonathan Edwards (University College London). The study was not controlled, and used a 3 drug combination aimed at depleting B-lymphocytes. The main drug was an anti-CD20 monoclonal antibody, Rituximab, which is manufactured by Roche. It has already been used in more than 80 000 lymphoma patients with lymphoma and has a good safety profile. Additional B-cell depletion was achieved by combining the Rituximab with intravenous Cyclophosphamide and oral Prednisone. The aim was to remove the B cells which produce the Rheumatoid factors and then hope that within a few months, normal B cells producing "normal" antibodies would return. Roche currently has a controlled clinical trial of 150 patients in progress. Further information on this and other ACR research is available on a new Rheumatology website: www.jointandbone.org Rheumatoid arthritis and Acute coronary syndromes Rheumatoid arthritis is a risk factor for coronary artery disease. The proposed reasons for this have included: side effects of therapy, common genetic or environmental risk determinants or a sharing of pathogenic pathways. Cornelia Weyand and others from the Mayo Clinic have hypothesised that RA-induced vascular injury exacerbates atherosclerotic disease. According to their hypothesis and clinical research, infiltration of the atherosclerotic plaque by T-cells and macrophages with subsequent plaque erosion is an extra-articular manifestation of Rheumatoid Arthritis. |
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METALLOPROTEINASE INHIBITORS - WHAT'S HAPPENING? Cartilage is a unique component of the musculoskeletal system, lacking its own blood supply and yet more involved in dynamic processes than previously thought. The integrity of articular cartilage is critical for the protection of underlying bone and for the normal articulation of joints. Both Rheumatoid Arthritis (RA) and Osteoarthritis (OA) eventually result in destruction of articular cartilage which in turn leads to joint failure. Since these two diseases are the major contributors to disability from joint disease, much research has focussed on the physiology, genetics and potential therapeutic targets within articular cartilage. Articular cartilage consists of two major components. Type II collagen in a triple helix provides the 3 dimensional network within which the hydrophilic proteoglycans matrix is found. The proteoglycans matrix has a rapid turnover and seems able to repair if damaged. The collagen network appears to be more resistant however undergoes irreversible change once damaged. Naturally occurring proteolytic enzymes the matrix metalloproteinases (MMPs) assist in regulating cartilage homeostasis. MMPs are a family of Zinc containing proteases including collagenase 1,2 and 3, stromolysins 1 and 2 and gelatinase A and B. Cytokines such as interleukin -1 and Tumor necrosis factor (TNF) released from inflammatory cells increase the concentration of collagenases, and result in cleavage of the triple helix of collagen approximately three quarters along the helical region. Elevated levels of these enzymes have been found in the synovium of animals and humans with RA and OA, and are thought to be pathogenetic. A recent study from the Netherlands demonstrated a correlation between radiological damage in early RA, particularly joint space narrowing and serum levels of matrix metalloproteinase-3. The development of Metalloproteinase inhibitors (MMPI's) has therefore been a logical step in the search for disease modifying therapies for both RA and OA. The first generation of MMPI's were peptide - like broad spectrum inhibitors which induced unacceptable musculoskeletal side effects. More selective nonpeptide inhibitors are in clinical development. MMPI's have efficacy in RA with low toxicity; they have no effect on Rheumatoid synovitis per se but protect against the cytokine driven elevations of MMPs in the RA synovium. In OA, MMPI's may improve cartilage homeostasis, retard cartilage degradation and hence reduce pain, loss of joint function and resultant disability. Other conditions where MMPs have been implicated include cancer, corneal and periodontal disease and inflammatory bowel disease. Sadly, one of the first multicentre phase III trials on an MMP inhibitor for Primary OA of the hip (some South African centres were involved) was abruptly withdrawn during 1999. Reasons given were poor efficacy of the drug in preliminary analyses and concerns with regard to cancer induction. We hope that this is not the end of the road for these drugs which have so much promise. Phase III clinical trials with another collagenase inhibitor in RA patients are ongoing and we await the outcome with great expectancy. |
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FLIP SIDE OF INFECTIONS IN SYSTEMIC LUPUS ERYTHEMATOSUS Romela Benitha FCP and Mohammed Tikly FRCP Rheumatology Unit, Chris Hani Baragwanath Hospital and the University of the Witwatersrand, Johannesburg For many clinicians, the fascination and challenge of SLE lies in the autoimmune phenomena associated with the condition. However, with the improvement in survival of patients with systemic lupus erythematosus (SLE), there has been a paradoxical rise in morbidity and mortality from infections in SLE1,2. Patients are at risk of fatal infections throughout the course of their illness. There are numerous factors that contribute to the increased incidence of infections. SLE patients are susceptible to infections due to inherent defects in the immune system. The use of immunosuppressive agents and corticosteroids further compounds this risk. Patients on immunosuppressive agents are more likely to develop opportunistic infections and have sepsis at unusual sites. This can result in a fatal outcome especially if the diagnosis is delayed and appropriate therapy not instituted. This review focuses on the reasons for the increased incidence of infections in SLE as well as the diagnostic dilemma this can pose. The relationship between HIV and SLE is discussed and the problem this poses locally is highlighted. EPIDEMIOLOGY Controlled studies have demonstrated that the infection rate in SLE is ten times that of rheumatoid arthritis and five times that of nephrotic patients3. Thirty to 50% of patients with SLE develop a major infection during the course of their disease. Infection is one of the major causes of hospitalisation in SLE4. The clinical dilemma in these patients is that infection can simulate a flare due to SLE. IMMUNE DYSFUNCTION DUE TO SLE Polymorphonuclear Leucocytes Many of the functions of the polymorphs are abnormal in patients with SLE. SLE patients may also occasionally have an immune mediated neutropaenia. Qualitative defects of neutrophils are more common. Chemotaxis is abnormal in SLE due to a reduction in complement derived chemotactic factor, abnormal migration of neutrophil, and the presence of a inhibitor to complement chemotaxis. The inability to recognise and attach to micro- organisms also contributes to the increased risk of infection. Phagocytosis and oxidative metabolism may be impaired. Macrophages Macrophage dysfunction can arise from intrinsic problems with the macrophage, cytokine imbalances and autoantibodies. The net effect is reduced phagocytosis and superoxide degeneration. Complement Inherited complement deficiencies predispose to SLE and infection. Inherited deficiencies of proteins of the earlier classic pathway, C2 and C4, predispose to the development of SLE. Patients with inherited deficiencies of complement are more prone to Neisserial infections because of lack of the membrane attack complex. Patients with SLE also have deficiency of red cell complement receptor, CR1. Immunoglobulin and antibodies Hypergammaglobulinaemia is usually present in SLE. Some SLE patients have hypogammaglobulinaemia especially IgA and IgG. These patients are prone to develop respiratory tract and urinary tract infections. T-cells Lymphopaenia is common in untreated SLE and correlates with the flare of the disease. The lymphopaenia may be aggravated by steroid therapy. This results in defective T-cell mediated cytolytic activity. The degree of T helper cell dysfunction correlates with disease activity5. Splenic dysfunction Functional splenic dysfunction is found in SLE and this predisposes to infection. With the control of disease activity this can be reversed6. The reticuloendothelial system is depressed in SLE. As mentioned above, the CR1 receptor on red cells is also reduced, hence the capacity of red cells to carry immune complexes to the spleen is impaired. CLINICAL PREDICTORS OF INFECTIONS Patients with SLE are generally more prone to develop infections. However, certain inherent clinical factors increase the risk for infections in SLE (Table 1). In the Hopkins Lupus Cohort, disease activity was an independent predictor of later hospitalisation for infection4. Numerous case series have shown various aspects of renal disease ranging from active urinary sediments to renal failure predispose to infection. Corticosteroids increase the infection rate due to their diverse effects on the immune system7. They have a multitude of immunosuppressive effects on polymorphonuclear leucocytes, including circulation, accumulation at the site of inflammation, adherence, chemotaxis, recognition and phagocytosis, oxidative metabolism, and degranulation. Corticosteroids affect cellular immunity at multiple levels, including antigen processing, lymphocyte activation and proliferation, response to mediators and cell-mediated cytotoxicity. Immunoglobulins and complement metabolism is also impaired. The net result is that patients are at higher risk of infection by gram-positive and gram-negative organisms. Although any dose of steroids doubles the infection rate, doses > 20mg increase the risk considerably. However steroid use can be of benefit in patients with SLE by improving the immune response to infection. Corticosteroids suppress the abnormally functioning cells hence improving the functioning of the immune system8. Immunosuppressive agents, in the majority of case series, have been found to predispose to infection. Both azathioprine and cyclophosphamide predispose to herpes zoster and cyclophosphamide in addition is a risk factor for fatal infections. CAUSATIVE ORGANISMS In the hospitalised SLE patients, the majority of infections are due to bacteria. Staphylococcus aureus is most often the causative organism resulting in skin sepsis, septic arthritis, pneumonia, gangrene, abscess and other sites of sepsis. Gram-negative infections, is often found. Patients with renal failure are at particular risk of gram-negative infections, especially Eschereria coli. Streptococcus pneumonia, neisserial infections and Salmonella infections are more prevalent because of splenic dysfunction, complement deficiencies and reticuloendothelial dysfunction. Neisserial and Salmonella infections commonly present as septic arthritis. SLE patients are at increased risk of mycobacterial infections because of the defects in cell-mediated immunity and macrophage function. Infections due to tuberculosis varied from 5-33% in endemic areas9,10. These series demonstrated that miliary tuberculosis as well as advanced pulmonary involvement were present. Extrapulmonary sites delayed the diagnosis of tuberculosis. Patients with severe SLE on higher doses of corticosteroids are at risk of fatal outcome. Patients with SLE are also prone to opportunistic infections. These infections are often fatal. The major risk factors include high doses of corticosteroids and immunosuppressive therapy. Fungal infections especially Candida, cryptococcus and aspergilosis occur in SLE. PCP is one of the most common pulmonary opportunistic infections. Steroid, immunosuppressive therapy and lymphopaenia are risk factors for PCP infections. Respiratory failure occurs in 50% of PCP and the mortality is about 32%11. PCP prophylaxis is not recommended until there is evidence of severe immunosuppresion such as oral thrush because SLE patients are at increased risk of sulpha allergies lupus flares. Herpes zoster is the most common viral infection and disseminates in 11%12. SITES OF INFECTION Infections can occur at the following sites skin, bladder, joints and bursa, brain, pulmonary. Patients can develop multiple infections that are deep seated. SLE patients are more prone to bacteraemia, DIC and ARDS. DIAGNOSTIC DILEMMA Infections can masquerade as active lupus as well as precipitate a flare. Based on clinical variables alone it often difficult to separate a flare from infection. Numerous laboratory markers have been tested to assist with making the distinction between a flare and systemic infection. However there is no single universal laboratory test to assist in this regard. In Stahl's series13 an increased WCC, chills, normal dsDNA favoured infection. Other series have found an increase ESR and a low C3 to be indicative of infection. An elevated CRP, greater than 60mg/dl, in the absence of serositis indicates infection14. HIV AND SLE This is one of the most challenging problems facing rheumatologists working in countries like South Africa, where the incidence of HIV infection is rapidly increasing. Firstly, there is the difficulty in many cases of distinguishing HIV from SLE. Secondly, management of patients with SLE who subsequently develop HIV is often problematic. Finally, there is the question of the effect of HIV infection on the course of disease in SLE. HIV and SLE share numerous clinical features. This can pose diagnostic difficulties since ANA has been found to be positive in HIV and patients with SLE have a false positive HIV test. There has also been the suggestion that the two conditions are mutually exclusive, based on fact that thus far only 13 adults cases of both conditions have been reported in the literature15,16. The low e CD4 count of HIV infection is thought to prevent the development of SLE. Conversely, the increased antibody production in SLE may inhibit HIV infection. Furthermore, chloroquine, which is commonly used in SLE, is known to inhibit replication of the HIV in vitro. However, SLE patients are more likely to receive blood products and 7 of the 12 patients who were infected with HIV from blood transfusions had been on chloroquine prior to being infected. Of course, the negative association between the 2 conditions may simply be a case of underreporting, particularly from regions worst affected by the HIV pandemic. SLE appears to improve clinically and serologically following HIV infection especially when the CD4 counts become low. The effects of SLE on HIV have not been well established. There is a suggestion that SLE or immunosuppressive drugs may accelerate the progression to AIDS. Patients with SLE have high T-cell activity and this may accelerate HIV replication. Clearly, the challenges posed by the various interactions of SLE and HIV infection are more acute in southern Africa, where neither condition is rare, than in most other parts of the globe. As such well-designed local prospective studies are urgently needed. Table 1. Risk factors for
infection in SLE REFERENCES
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