Neil Jonathan Freedman, MD

• Professor of Medicine
• Professor in Cell Biology

https://medicine.duke.edu/faculty/neil-jonathan-freedman-md

Relationships Among Type and Stage of Kidney Disease and Clinical Presentations Tables 143 blood pressure chart pediatric 12.5mg coreg visa, 144 heart attack female cheap coreg 12.5 mg, and 145 show the relationships between stage of kidney disease and clinical features for diabetic kidney disease blood pressure is determined by coreg 6.25 mg low price, nondiabetic kidney diseases hypertension frequent urination cheap 12.5mg coreg overnight delivery, and diseases in the kidney transplant heart attack under 30 coreg 12.5 mg line. Approach 259 Utility of Proteinuria in Diagnosis blood pressure normal level discount coreg 6.25mg free shipping, Prognosis, and Treatment Proteinuria is a key finding in the differential diagnosis of chronic kidney disease. Proteinuria is a marker of damage in diabetic kidney disease (Table 143), in glomerular diseases occurring in the native kidney (Table 144), and in transplant glomerular disease and recurrent glomerular disease in the transplant (Table 145). In these diseases, the magnitude of proteinuria is usually 1,000 mg/g (except in early diabetic kidney disease), and may approach nephrotic range (spot urine protein-to-creatinine ratio 3,000 mg/g). On the other hand, proteinuria is usually mild or absent in vascular diseases, tubulointerstitial diseases, and cystic diseases in the native kidney and in rejection and drug toxicity due to cyclosporine or tacrolimus in the transplant. It is well-known that nephrotic range proteinuria is associated with a wide range of complications, including hypoalbuminemia, edema, hyperlipidemia, and hypercoagulable state; faster progression of kidney disease; and premature cardiovascular disease. However, it is now known that elevated urine protein excretion below the nephrotic range is also associated with faster progression of kidney disease and development of cardiovascular disease. Furthermore, the reduction in proteinuria is correlated with a subsequent slower loss of kidney function. The benefit of antihypertensive therapy, especially with angiotensin-converting enzyme inhibitors, to slow the progression of kidney disease is greater in patients with higher levels of proteinuria compared to patients with lower levels of proteinuria. Treatments to slow the progression of chronic kidney disease in adults in are shown in Table 146. However, few patients with chronic kidney disease have been included in population-based epidemiologic studies of cardiovascular disease or long-term randomized clinical trials. Approach 261 cardiovascular disease risk factors and risk factor reduction strategies that are potentially safe and effective for patients with chronic kidney disease is shown in Table 147. Consultation with a nephrologist may be necessary to establish the diagnosis and treatment of the type of kidney disease. Consultation and/or co-management with a kidney disease care team is advisable during Stage 3, and referral to a nephrologist in Stage 4 is recommended. A multidisciplinary team approach may be necessary to implement and coordinate care. This classification could then be transformed to an ``evidence model' for future development of additional practice guidelines regarding specific diagnostic evaluations and therapeutic interventions (Executive Summary). The Work Group sought to develop an ``evidence base' for the classification and clinical action plan, derived from a systematic summary of the available scientific literature on: the evaluation of laboratory measurements for the clinical assessment of kidney disease; association of the level of kidney function with complications of chronic kidney disease; and stratification of the risk for loss of kidney function and development of cardiovascular disease. Two products were developed from this process: a set of clinical practice guidelines regarding the classification and action plan, which are contained in this report; and an evidence report, which consists of the summary of the literature. The Work Group consisted of ``domain experts,' including individuals with expertise in nephrology, epidemiology, laboratory medicine, nutrition, social work, pathology, gerontology, and family medicine. In addition, the Work Group had liaison members from the National Institute of Diabetes, Digestive and Kidney Diseases and from the National Institute on Aging. The first task of the Work Group members was to define the overall topic and goals, including specifying the target condition, target population, and target audience. They then further developed and refined each topic, literature search strategy, and data extraction form (described below). The Work Group members were the principal reviewers of the literature, and from these detailed reviews they summarized the available evidence and took the primary roles of writing the guidelines and rationale statements. The Evidence Review Team consisted of nephrologists (one senior nephrologist and three nephrology fellows) and methodologists from New England Medical Center with expertise in systematic review of the medical literature. They were responsible for coordinating the project, including coordinating meetings, refinement of goals and topics, creation of the format of the evidence report, development of literature search strategies, initial review and assessment of literature, and coordination of all partners. The Evidence Review Team also coordinated the methodological and analytic process of the report, coordinated the meetings, and defined and standardized the methodology of performing literature searches, of data extraction, and of summarizing the evidence in the report. They performed literature searches, retrieved and screened abstracts and articles, created forms to extract relevant data from articles, and tabulated results. Throughout the project, and especially at meetings, the Evidence Review Team led discussions on systematic review, literature searches, data extraction, assessment of quality of articles, and summary reporting. Based on their expertise, members of the Work Group focused on the specific questions listed in Table 8 and employed a selective review of evidence: a summary of reviews for established concepts (review of textbooks, reviews, guidelines, and selected original articles familiar to them as domain experts) and a review of primary articles and data for new concepts. The development process included creation of initial mock-ups by the Work Group Chair and Evidence Review Team followed by iterative refinement by the Work Group members. The refinement process began prior to literature retrieval and continued through the start of reviewing individual articles. The refinement occurred by e-mail, telephone, and in-person communication regularly with local experts and with all experts during in-person meetings of the Evidence Review Team and Work Group members. Data extraction forms were designed to capture information on various aspects of the primary articles. Forms for all topics included study setting and demographics, eligibility criteria, causes of kidney disease, numbers of subjects, study design, study funding source, population category (see below), study quality (based on criteria appropriate for each study design, see below), appropriate selection and definition of measures, results, and sections for comments and assessment of biases. The various steps involved in development of the guideline statements, rationale statements, tables, and data extraction forms were piloted on one of the topics (bone disease) with a Work Group member at New England Medical Center. The ``in-person' pilot experience allowed more efficient development and refinement of subsequent forms with Work Group members located at other institutions. It also provided experience in the steps necessary for training junior members of the Evidence Review Team to develop forms and to efficiently extract relevant information from primary articles. Training of the Work Group members to extract data from primary articles subsequently occurred by e-mail as well as at meetings. Classification of Stages Defining the stages of severity was an iterative process, based on expertise of the Work Group members and synthesis of evidence developed during the systematic review. The ideal study design to assess prevalence would be a crosssectional study of population representative of the general population. Criteria for evaluation of cross-sectional studies to assess prevalence are listed in Table 150. The ideal study design for diagnostic test evaluation would be a crosssectional study of a representative sample of patients who are tested using the ``gold' 268 Part 10. Data from baseline assessments of patients enrolled in the Canadian Multicentre cohort study of patients with chronic kidney disease were used for Figures 28, 29, 36, 37, 38, 40, and 42. Studies that provided data for various levels of kidney function were preferred; how- 270 Part 10. Members of the Work Group provided individual patient data that were used for some analyses. Stratification of Risk (Prognosis) the appropriate study to assess the relationship of risk factors to loss of kidney function and development of cardiovascular disease would be a longitudinal study of a representative sample of patients with chronic kidney disease with prospective assessment of factors at baseline and outcomes during follow-up. Because it can be difficult to determine the onset of chronic kidney disease and cardiovascular disease, prospective cohort studies were preferred to case-control studies or retrospective studies. Clinical trials were included, with the understanding that the selection criteria for the clinical trial may have lead to a non-representative cohort. Appendices 271 known association between diabetes and cardiovascular disease, diabetic and nondiabetic patients were considered separately. The association between diabetic kidney disease and other diabetic complications was evaluated using reviews of cross-sectional studies and selected primary articles of cohort studies. Review articles, editorials, letters, or abstracts were not included (except as noted). Studies for the literature review were identified primarily through Medline searches of English language literature conducted between February and June 2000. These searches were supplemented by relevant articles known to the domain experts and reviewers. The Medline literature searches were conducted to identify clinical studies published from 1966 through the search dates. Development of the search strategies was an iterative process that included input from all members of the Work Group. Search strategies were designed to yield approximately 1,000 to 2,000 titles each. The searches were limited to studies on humans and published in English and focused on either adults or children, as relevant. In general, studies that focused on hemodialysis or peritoneal dialysis were excluded. Potential papers for retrieval were identified from printed abstracts and titles, based on study population, relevance to topic, and article type. In general, studies with fewer than 10 subjects were not included (except as noted). After retrieval, each paper was screened to verify relevance and appropriateness for review, based primarily on study design and ascertainment of necessary variables. Overall, 18,153 abstracts were screened, 1,110 articles were reviewed, and results were extracted from 367 articles. Detailed tables contain data from each field of the components of the data extraction forms. These tables are contained in the evidence report but are not included in the manuscript. Summary tables describe the strength of evidence according to four dimensions: study size, applicability depending on the type of study subjects, results, and methodological quality (see table on the next page, Example of Format for Evidence Tables). Within each table, studies are ordered first by methodological quality (best to worst), then by applicability (most to least), and then by study size (largest to smallest). Study Size the study (sample) size is used as a measure of the weight of the evidence. In general, large studies provide more precise estimates of prevalence and associations. Appendices 273 large studies are more likely to be generalizable; however, large size alone does not guarantee applicability. A study that enrolled a large number of selected patients may be less generalizable than several smaller studies that included a broad spectrum of patient populations. The study population is typically defined by the inclusion and exclusion criteria. The target population was defined to include patients with chronic kidney disease and those at increased risk of chronic kidney disease, except where noted. A designation for applicability was assigned to each article, according to a three-level scale. In making this assessment, sociodemographic characteristics were considered, as were the stated causes of chronic kidney disease and prior treatments. Studies without a vertical or horizontal line did not provide data on the mean/median or range, respectively. For studies of prevalence, the result is the percent of individuals with the condition of interest. For diagnostic test evaluation, the result is the strength of association between the new measurement method and the criterion standard. Associations were represented according to the following symbols: the specific meaning of the symbols is included as a footnote for each table. Because studies with a variety of types of design were evaluated, a three-level classification of study quality was devised: 276 Part 10. The use of published or derived tables and figures was encouraged to simplify the presentation. Each guideline contains one or more specific ``guideline statements,' which are presented as ``bullets' that represent recommendations to the target audience. Each guideline contains background information, which is generally sufficient to interpret the guideline. A discussion of the broad concepts that frame the guidelines is provided in the preceding section of this report. Appendices 277 and classifications of markers of disease (if appropriate) followed by a series of specific ``rationale statements,' each supported by evidence. The guideline concludes with a discussion of limitations of the evidence review and a brief discussion of clinical applications, implementation issues and research recommendations regarding the topic. Strength of Evidence Each rationale statement has been graded according the level of evidence on which it is based (see the table, Grading Rationale Statements). Medline was the only database searched, and searches were limited to English language publications. Hand searches of journals were not performed, and review articles and textbook chapters were not systematically searched. In addition, search strategies were generally restricted to yield a maximum of about 2,000 titles each. However, important studies known to the domain experts that were missed by the literature search were included in the review. In addition, essential studies identified during the review process were also included. Exhaustive literature searches were hampered by limitations in available time and resources that were judged appropriate for the task. The search strategies required to capture every article that may have had data on each of the questions frequently yielded upwards of 10,000 articles. The difficulty of finding all potentially relevant studies was compounded by the fact that in many studies, the information of interest for this report was a secondary finding for the original studies. Due to the wide variety of methods of analysis, units of measurements, definitions of chronic kidney disease, and methods of reporting in the original studies, it was often very difficult to standardize the findings for this report. The prevalence of microalbuminuria and proteinuria by age, sex, race, and diabetes are tabulated to show the frequency with which these abnormalities are present in the population. Standardized questionnaires were administered in the home, followed by a detailed physical examination at a Mobile Examination Center. Data on physiologic variation in creatinine were obtained in a sample of 1,921 participants who had a repeat creatinine measurement.

This change in bioconversion means that a larger amount of provitamin A carotenoids heart attack blood pressure generic coreg 12.5mg, and therefore darkly colored arteriosclerotic heart disease coreg 25 mg overnight delivery, carotenerich fruits and vegetables blood pressure by age purchase coreg 6.25mg online, is needed to meet the vitamin A requirement blood pressure chart readings for ages coreg 12.5mg lowest price. With low doses blood pressure of 12080 best 25 mg coreg, the conversion is as high as 2:1; developers of composition information for dietary supplements should use this higher conversion factor arteria circumflexa scapulae generic coreg 12.5mg fast delivery. Little is known about the bioconversion of the forms of bcarotene that are added to foods, so fortification of forms of b-carotene should be assumed to have the same bioconversion as food forms, 12:1. The highest reported intake at the 95th percentile was 1,503 mg/day for lactating women. Special Considerations Individuals susceptible to adverse effects: People with high alcohol intake, preexisting liver disease, hyperlipidemia, or severe protein malnutrition may be distinctly susceptible to the adverse effects of excess preformed vitamin A intake. Foods fortified with vitamin A are margarine and low-fat and non-fat (skim and partly skimmed) milk. Major contributors as provitamin A carotenoids to dietary intake include: b-carotene found in carrots, broccoli, squash, peas, spinach, and cantaloupe; carrots as a-carotene; and fruits as the sole contributors of b-cryptoxanthin. Bioavailability Factors such as dietary fat intake, intestinal infections, the food matrix, and food processing can affect the absorption of vitamin A by the body. Dietary fat appears to enhance absorption, whereas absorption is diminished in individuals with diarrhea, intestinal infections, and infestations. For example, serum b-carotene concentration was significantly lower when individuals consumed b-carotene from carrots than from b-carotene supplements. For example, absorption is greater from cooked compared to raw carrots and spinach. Dietary Interactions There is evidence that vitamin A may interact with certain nutrients and dietary substances (see Table 2). It was reported that iron deficiency alters the distribution of vitamin A concentration between the plasma and liver. Zinc deficiency influences the mobilization of vitamin A from the liver and its transport into the circulation. However, human studies have not established a consistent relationship between zinc and vitamin A status. It has been suggested that zinc intake may positively affect vitamin A status only in individuals with moderate to severe proteinenergy malnutrition. Because both retinol and ethanol are alcohols, there is potential for overlap in the metabolic pathways of these two compounds. Although the effect on vitamin A is due, in part, to liver damage associated with chronic alcohol intake and to malnutrition, the reduction in liver stores of vitamin A is also a direct effect of alcohol consumption. Night blindness is the first ocular symptom to be observed with vitamin A deficiency; however, it does respond rapidly to treatment with vitamin A. Other adverse effects associated with vitamin A deficiency include decreased immune function and an increased risk of infectious morbidity and mortality, such as respiratory infection and diarrhea. Although vitamin A supplementation has been shown to reduce the severity of diarrhea, it has had little effect on the risk or severity of respiratory infections, except when associated with measles. Furthermore, the American Academy of Pediatrics recommends vitamin A supplementation for children in the United States who are hospitalized with measles. More research is needed to clarify whether chronic vitamin A intake may lead to loss in bone mineral density and a consequent increased risk of hip fracture in certain population groups, particularly among premenopausal and postmenopausal women. Human and animal data show a strong causal association between excess vitamin A intake and liver abnormalities because the liver is the main storage site and target organ for vitamin A toxicity. These abnormalities range from reversibly elevated liver enzymes to widespread fibrosis, cirrhosis, and sometimes death. Special Considerations Teratogenicity: Concern for the possible teratogenicity of high vitamin A intake in humans is based on the unequivocal demonstration of human teratogenicity following high-dose supplementation of vitamin A. The critical period for susceptibility appears to be during the first trimester of pregnancy. The primary birth defects associated with excess vitamin A intake are those derived from cranial neural crest cells, such as craniofacial malformations and abnormalities of the central nervous system (except neural tube defects), thymus, and heart. Adverse effects in infants and children: There are several case reports of toxic effects of vitamin A in infants, toddlers, and children who have ingested excess vitamin A for a period of months to years. Other effects of toxicity in infants and children include bone tenderness and pain, increased intracranial pressure, desquamation, brittle nails, mouth fissures, alopecia, fever, headache, lethargy, irritability, weight loss, vomiting, and hepatomegaly. There is currently insufficient evidence to support a recommendation that requires a certain percentage of dietary vitamin A to come from provitamin A carotenoids in meeting the vitamin A requirement. However, existing recommendations for the increased consumption of carotenoid-rich fruits and vegetables for their health-promoting benefits are strongly supported. Good sources of provitamin A carotenoids are fruits and vegetables, including carrots, broccoli, squash, peas, spinach, and cantaloupe. The most specific clinical effect of inadequate vitamin A intake and deficiency is xerophthalmia, an irreversible drying of the conjunctiva and cornea. Rich food sources of vitamin B6 include highly fortified cereals, beef liver and other organ meats, and highly fortified, soy-based meat substitutes. The clinical signs and symptoms of vitamin B6 deficiency have only been observed during depletion with very low levels of the vitamin and have never been seen at intakes of 0. No adverse effects have been associated with high intakes of the vitamin from food sources. Very large oral doses (2,000 mg/ day or more on a chronic basis) of supplemental pyridoxine have been associated with the development of sensory neuropathy and dermatological lesions. Vitamin B6 can be bound to proteins in tissues, which limits accumulation at very high intakes. When this capacity is exceeded, nonphosphorylated forms of vitamin B6 are released by the liver and other tissues into the circulation. At pharmacological doses of vitamin B6, high amounts accumulate in the muscle, plasma, and erythrocytes when other tissues are saturated. Vitamin B6 is oxidized in the liver and then released and primarily excreted in the urine. The highest reported intake at the 95th percentile was 21 mg/day in pregnant females aged 14 through 55 years, most of which was pyridoxine from supplements. The risk of adverse effects resulting from excess intake of vitamin B6 from food and supplements appears to be very low at these intake levels. Especially rich sources of vitamin B6 include highly fortified cereals; beef liver and other organ meats; and highly fortified, soy-based meat substitutes. Bioavailability the bioavailability of vitamin B6 from a mixed diet is approximately 75 percent. Oral contraceptives: Studies have shown decreased vitamin B6 status in women who receive high-dose oral contraceptives. Plasma concentrations of the nutrient are lowered, but the decrease is quite small. Preeclampsia: Lowered vitamin B6 status is observed in preeclampsia and eclampsia, suggesting a potentially increased requirement for the vitamin in preeclampsia. Very large oral doses (2,000 mg/day or more) of supplemental pyridoxine, which are used to treat many conditions, including carpal tunnel syndrome, painful neuropathies, seizures, premenstrual syndrome, asthma, and sickle cell disease, have been associated with the development of sensory neuropathy and dermatological lesions. Rich food sources of vitamin B6 include highly fortified cereals, beef liver and other organ meats, and highly fortified, soybased meat substitutes. Other contributors to vitamin B6 intake include mixed foods with meat, fish, or poultry as the main ingredient; white potatoes and other starchy vegetables; and noncitrus fruits. Clinical signs and symptoms of vitamin B6 deficiency have only been observed during depletion with very low levels of the vitamin and have never been seen at intakes of 0. The signs and symptoms of vitamin B6 deficiency are seborrheic dermatitis, microcytic anemia, epileptiform convulsions, and depression and confusion. No adverse effects have been associated with high intakes of vitamin B6 from food sources. Very large oral doses (2,000 mg/day or more) of supplemental pyridoxine have been associated with the development of sensory neuropathy and dermatological legions. An adequate supply of vitamin B12 is essential for normal blood formation and neurological function. The requirements for vitamin B12 are based on the amount needed to maintain hematological status and normal serum vitamin B12 values. Individuals with vitamin B12 deficiency caused by a lack of intrinsic factor require medical treatment. The major cause of vitamin B12 deficiency is pernicious anemia, a condition in which the stomach does not produce intrinsic factor. The hematological effects that occur with this deficiency are identical to those that accompany folate deficiency. No adverse effects have been associated with excess vitamin B12 intake from food or supplements in healthy individuals. The apparent low toxicity of the vitamin may be because, when high doses are given orally, only a small percentage of it can be absorbed from the gastrointestinal tract. Vitamin B12 is processed in the stomach and the small intestine before being released into the circulation. The liver takes up approximately 50 percent of circulating nutrient; the remainder is transported to other tissues. Therefore, for this publication, a conservative adjustment for the bioavailability of naturally occurring vitamin B12 was used. In particular, it is assumed that 50 percent of dietary vitamin B12 is absorbed by healthy adults with normal gastric function. If there is a lack of intrinsic factor (as in the case of pernicious anemia), malabsorption of the vitamin results. If untreated, this may lead to potentially irreversible neurological damage and possibly life-threatening anemia. In healthy individuals, most of it is reabsorbed and available for metabolic functions. However, in the absence of intrinsic factor, essentially all the vitamin B12 from the bile is excreted in the stool rather than recirculated. Thus, deficiency develops more rapidly in individuals who have no intrinsic factor or who malabsorb vitamin B12 for other reasons than it does in those who do not ingest it (such as those with complete vegetarian diets). The excretion of vitamin B12 is proportional to body stores; it is excreted mainly in the stool but also in the urine and through the skin. Special Considerations Aging and atrophic gastritis: Vitamin B12 status tends to decline with age, perhaps due to a decrease in gastric acidity and the presence of atrophic gastritis and of bacterial overgrowth accompanied by malabsorption of food-bound vitamin B12. Thus, it is advisable for those older than 50 years to meet their needs mainly by consuming foods fortified with vitamin B12 or by taking a supplement that contains it. Individuals with increased needs: A person with any malabsorption syndrome will likely require increased amounts of vitamin B12. Patients with atrophic gastritis, pancreatic insufficiency, or prolonged omeprazole treatment will have decreased bioavailability of food-bound vitamin B12 and will require normal amounts of crystalline vitamin B12 (either in fortified foods or in a supplement). Furthermore, there appear to be no risks associated with intakes from supplemental B12 that are more than two orders of magnitude higher than the 95th percentile intake. However, this does not mean that there is no potential for adverse effects to occur with high intakes. For women, the second highest contributor to intake was milk and milk beverages; for men it was beef. Fortified ready-to-eat cereals contributed a greater proportion of dietary vitamin B12 for women than for men. Although milk is a good source of vitamin B12, cooking it may greatly reduce its vitamin content. For example, boiling milk for 10 minutes reduces vitamin B12 content by about 50 percent. Dietary Supplements In the United States, cyanocobalamin is the only commercially available vitamin B12 preparation used in supplements and pharmaceuticals. For adults over age 60 years who took supplements and participated in the Boston Nutritional Status Survey, median supplemental vitamin B12 intakes were 5. Because of a lack of data on dairy foods and most forms of red meat and fish, a conservative adjustment for the bioavailability of naturally occurring vitamin B12 was used for this publication. Dietary Interactions There is evidence that vitamin B12 may interact with certain nutrients (see Table 2). The hematological effects of vitamin B12 deficiency include weakness, fatigue, shortness of breath, and palpitations. This results in megaloblastic change, which causes the production of largerthan-normal erythrocytes (macrocytosis).

Medication Potential benefit must be balanced against potential side-effects zofran arrhythmia coreg 12.5 mg without prescription, especially in the elderly arteria pack generic coreg 6.25 mg on-line. Intra-articular corticosteroid injections produce short-term improvement when there is a painfuljointeffusion arteria umbilical unica consecuencias purchase coreg 12.5 mg otc. Thesafetyofhipandkneereplacementsisnowequal blood pressure medication raise blood sugar buy discount coreg 25 mg,witha complication rate of about 1% pulse pressure of 100 buy coreg 25mg, loosening and late blood-borne infection being the most serious pulse pressure healthy range cheap coreg 25 mg with amex. Resurfacing hip surgery has become popular but may have higher complication rates in women, particularly with metal on metal resurfacing. Uni-compartmental knee replacement is a less major procedure and may be appropriate in some cases. There may be evidence of recent viral illness (rubella, hepatitis B or erythrovirus), rheumatic fever, or a tick bite and skin rash (Lyme disease). Earlyinflammatorypolyarthritis Undifferentiated polyarthritis requires urgent referral to a rheumatologist for diagnosis and treatment,includingtheearlyintroductionofdisease-modifyingagentswhenindicated(seep. Thereispersistent synovitis, causing chronic symmetrical polyarthritis with systemic inflammation. Aetiologyandpathogenesis There has been a greater understanding of genetic and environmental factors in the last two decades. The increased understanding of the immunopathogenesis of this disease has informed the development of targeted biological therapies (Fig. Normal synovium is thin, comprising a lining layer a few cells thick that contains fibroblast-like synoviocytes and macrophages overlying loose connective tissue. The normally sparse surface layer of lining cells becomes hyperplastic and thickened (Fig. Fibroblasts from the proliferating synovium also grow along the course of blood vessels between the synovial margins and the epiphyseal bone cavity, and damage the bone. Lesscommonly(15%),arapidonset canoccuroverafewdays(orexplosivelyovernight),withaseveresymmetrical,polyarticular involvement, especially in the elderly. Thisbenefitofearliertreatmentis evidence-based and has been shown to reduce the risk of the development of damage and permanentjointdeformities. This form can be confused with psoriatic arthropathy, which has a similar distribution(seepp. About50%ofpatients go on to develop typical chronic rheumatoid synovitis after a delay of months or years. Inimmunosuppressed patients, the affected joints may not display the typical signs of inflammation with accompanying fever found in patients with an intact immune system. Inflamed flexor tendon sheaths increase functional impairment and may cause a carpal tunnelsyndrome. Inlatedisease, flexion may be lost and severe difficulties with feeding result, especially combined with shoulder,handandwristdeformities. Appropriate broad, deep, cushioned shoes are essential but rarely wholly adequate, and walkingisoftenpainfulandlimited. Knees Massive synovitis and knee effusions occur but respond well to aspiration and steroid injection(seep. Inlaterdisease,erosionofcartilageandbonecauseslossofjointspace on X-ray and damage to the medial and/or lateral and/or retropatellar compartments of the knees. Depending on the pattern of involvement, the knees may develop a varus or valgus deformity. Subluxation and local synovial swelling may damage the spinal cord, producing pyramidal and sensory signs. Otherjoints the temporomandibular, acromioclavicular, sternoclavicular, cricoarytenoid and any other synovialjointcanbeaffected. Softtissuesurroundingjoints Subcutaneous nodules are firm and intradermal, generally occurring over pressure points: typically, the elbows, the finger joints and the Achilles tendon in patients with seropositive erosivedisease. Tenosynovitis of flexor tendons in the hand can cause stiffness and occasionally a trigger finger. Kidneys Amyloidosis causes proteinuria, nephrotic syndrome and chronic kidney disease. Diagnosisandinvestigations Diagnosis relies on the clinical features described above. Anyone with early inflammatory arthritis should be referredtoaspecialistarthritisclinicwithin3monthsofonset. The doctor should have a positive approach and remind the patient that, with the help of drugs,mostpeoplecontinuetoleadamoreorlessnormallife,astheaimoftherapyisdisease remission; 25% will recover completely. The earliest years are often the most difficult and peopleshouldbehelpedandencouragedtostayatwork,as30%losetheirjobwithin2years of diagnosis. Patients adjust and cope remarkably with time and support from the specialist team in a rheumatology unit (including doctors, nurses, physiotherapists, podiatrists and psychologists)andfromleaflets,websitesandlocalpatientgroups. Biological therapies (known as biologics) are recombinant proteins: most commonly, monoclonal IgG1 antibodies directed against specific immunologicaltargetsorfusionproteinscontainingtheFcportionofIgG1joinedtoreceptorblocking proteins. These drugs are increasingly used earlier in disease to reduce disease activityanddamage. Searchingforpersistentsynovitisinpatientsinapparentremissionusing Doppler ultrasound leads to more intensive therapeutic regimes to reduce longer-term disability. Corticosteroids the early use of corticosteroids slows down the course of the disease but intensive short coursesinveryearlyarthritisdonotappeartostopprogressivedisease. Corticosteroidsare themostcommoncauseofsecondaryosteoporosisandtheriskoffractureisincreasedbyas much as 75% within the first 3months of treatment. Intra-articularinjections with semi-crystalline steroid preparations have a powerful but sometimesonlyshort-livedeffect. Oral corticosteroids are powerful disease-controlling drugs but cause a number of problems(Box18. Corticosteroids are invaluable to people with severe disease who have extra-articular manifestationssuchasvasculitis. Despite their mechanism of action being incompletely understood, they have been shown to reduce inflammation, joint swelling and plasma acutephasereactants,andtoslowthedevelopmentofjointerosionsaswellasirreversibledamage. It is well tolerated, although nausea or poor absorptionmaylimititsefficacy,inwhichcaseitisgivenbysubcutaneousinjection. Sulfasalazine Sulfasalazine is a combination of sulfapyridine and 5-amino-salicylic acid. A pre-treatment chest X-ray is recommended, with a specialist review for high-risk groups. Tuberculosis should be treated before these agents are prescribed, and a course of prophylaxis is used in latent disease. Gold (sodium aurothiomalate) is given by deep intramuscular injection and can induce remission. Physiotherapistsadviseacombinationofrest for active arthritis and exercises to maintain joint range and muscle power. Surgery Surgeryhasausefulroleinthelong-termapproachtopatientmanagementbutislessfrequently needed as therapeutic disease control becomes more effective. The Assessment of Spondyloarthritis International Society has developed classification criteria for both axial and peripheral SpA, which were developed to enhance diagnosis,treatmentanddesignofclinicaltrials. Criteriafor classifyinginflammatory backpain as axial spondyloarthritis are shown in Box 18. Non-spinal complications (uveitis or costochondritis) suggest the diagnosis of spondyloarthritis(Box18. Prognosis With exercise and pain relief, the prognosis is excellent and over 80% of patients are fully employed. People with reactive arthritis are not more susceptible to infection but appear to respond differently. There are other organisms that also trigger reactive arthritis but have a different genetic basis;seepost-streptococcalarthritis(pp. In these conditions, theborderline betweenreactive arthritisandseptic arthritisismoreindistinctandtheycancauseboth. Clinicalfeatures Thearthritisistypicallyanacute,asymmetrical,lower-limbarthritis,occurringafewdaystoa couple of weeks after the infection. The arthritis may be the presenting complaint if the infectionismildorasymptomatic. In susceptible individuals with reactive arthritis, sacroiliitis and spondylitis may also develop. Management Treating persisting infection with antibiotics alters the course of the arthritis, once it has developed. Themajorityof individuals with reactive arthritis have a single attack that settles, but a few develop a disabling relapsing and remitting arthritis. Selective mucosal leakiness may expose the individual to antigens that triggersynovitis. The joint symptoms may predate the developmentofboweldiseaseandleadtoitsdiagnosis. Crystalarthritis Aetiology the two main types of crystal-induced arthritis are caused by sodium urate and calcium pyrophosphate crystals, which are distinguished by their different shapes and refringence properties under polarized light with a red filter (Fig. Goutandhyperuricaemia Gout is an inflammatory arthritis associated with hyperuricaemia and intra-articular sodium uratecrystals. Asian populations are also increasingly at risk as their diet becomes more Western. This rising prevalence is due to changing diets with purine-rich foods, high saturated fats and fructose-containing drinks; alcohol misuse; increasing co-morbidities that promote hyperuricaemia; and suboptimal management. Gout is more common in men than women (5:1); it rarely occurs before young adulthood (when it suggests a specific genetic defect), and seldom in pre-menopausal females. The last two steps of purine metabolism in humans are the conversion of hypoxanthine to xanthine,andofxanthinetouricacid,catalysedbytheenzymexanthineoxidase. Some90%ofpeoplewithgouthaveimpairedexcretionofuricacid(10%haveincreased production due to high cell turnover and <1% due to an inborn error of metabolism). The attack may be precipitated by excess food, alcohol, dehydration or diuretic therapy. In severe attacks, overlying crystal cellulitis makes gout difficult to distinguish clinically frominfectivecellulitis. Dietaryadvice the first attacks may be separated by up to 2years and are managed symptomatically. Adviceto reducealcoholintake,especiallybeer,whichishighinpurinesandfructose,andconsumption ofnon-dietcarbonatedsoftdrinks,whicharealsohighinfructose,isessential;otherdietary changeincludereductionoftotalcalorieandcholesterolintake,andavoidanceofpurine-rich foods, such as offal, red meat, shellfish and spinach. These modifications can reduce serum urate by 15%anddelaythe need for drugs that reduce serumurate levels. Itissaferinrenalimpairment,asitundergoeshepatic metabolism rather than renal excretion, and is helpful in patients who cannot tolerate allopurinol; however, there is evidence that itmay increase cardiovascular risks,and this is beingmonitoredinongoingobservationalstudies. Pegloticase Pegloticase, a pegylated recombinant uricase given intravenously, lowers urate levels dramaticallybutitsplaceintherapyisunclear. Chronictophaceousgout Individualswithpersistentlyhighlevelsofuricacidcanpresentwithchronictophaceousgout, as sodium urate forms smooth white deposits (tophi) in skin and around joints, on the ear, fingers(Fig. Tophaceous gout is often associated with renal impairment and/or the long-term use of diuretics. Whenever possible, diuretics should be stopped or changed to less urate-retaining ones, such as bumetanide. Shedding of crystals into a joint precipitates acute synovitis that resemblesgout,exceptthatitismorecommoninelderlywomenandusuallyaffectsthekneeor wrist. Diagnosis the diagnosis is made by detecting rhomboidal, weakly positively bi-refringent crystals in jointfluid(seeFig. Management Unlike in gout, there is no specific treatment to eliminate calcium pyrophosphate crystals. If infection can be excluded, an intra-articular injection of a corticosteroid helps. Inpatientswithunderlyingprogressivearticularchanges,theresponse to medical therapy is usually less rewarding. Total joint replacement may be required for patientswithseveredestructivearthropathyinlargejoints. InfectionsofJoints Joints become infected by direct injury or by blood-borne infection from an infected skin lesionorothersite. Therisingglobalincidenceofthisconditionhas been linked with an ageing population, increased immunosuppressive use, musculoskeletal prosthesesandsurgicalprocedures.

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