Jane M. Prosser, MD

• Fellow, Medical Toxicology
• New York City Poison Center
• New York University Medical Center

Patients whose tumour has neither oestrogen nor progesterone receptors do not receive hormonal Biological therapy Recently sleep aid valerian 200 mg provigil otc, there has been huge interest in the development of biological agents sleep aid jaw support purchase 100 mg provigil otc, which are the therapeutic fruits of 40 years of basic science research in to the molecular aetiology of cancer insomnia late pregnancy provigil 100 mg buy overnight delivery. Living cells react to signals in their environment through signal transduction pathways sleep aid comparisons best buy provigil. Cell surface receptors are stimulated by external molecules (ligands) causing conformational changes in their intracellular component which in turn starts a series of molecular signals that is transduced to the cell nucleus and results in altered gene expression insomnia 8 year old buy on line provigil. If a cell has acquired a genetic mutation in one of the messengers (such as k-ras) or genetic amplification of one of the messengers (both are frequent events in cancer) then the cell behaves as though the pathway is being stimulated regardless of the presence of external stimuli. This can result in unchecked proliferation, invasion of adjacent tissues or other properties characteristic of the malignant phenotype. Therefore molecular testing to identify patients suitable for a particular biological therapy is crucial. As biological agents target pathways which are more critical to cancer cells than normal cells they are generally less toxic than chemotherapy and in some cases more effective. Targeting of these pathways to which a cancer is so dependent (known as synthetic lethality) appears to be a particularly effective strategy and is currently being exhaustively researched. For the most part therapies are either monoclonal antibodies which target growth factors/cell surface receptors or small molecules which can enter cells and inhibit signal transduction (many are tyrosine kinase inhibitors). The molecular targets and diseases treated with some of these are listed in Table 15. This translocation between the long arms of chromosomes 9 and 22 results in the formation of a bcr-abl fusion protein that functions as a constitutively active tyrosine kinase in the cell. In terms of tolerability and efficacy this represents a considerable improvement compared with previous treatments used in the same patient group. The drug is generally well tolerated with the main reported toxicities being oedema, nausea, rash and musculoskeletal pain. The efficacy of the drug is much higher in patients who have activating mutations of c-kit compared with those who do not. Trastuzumab has demonstrated single-agent activity against metastatic breast cancer when given by intravenous infusion either weekly or 3-weekly. The efficacy is increased when given in combination with chemotherapy such as docetaxel but care must be taken to monitor for cardiotoxicity. Resection of both sites of disease revealed diffentiated teratoma with no malignant elements present. Any potential benefit must be weighed against the risk of significant cardiac dysfunction (occurs in up to 7% of cases). Left ventricular ejection fraction should be monitored regularly throughout treatment. Intravenous pre-hydration and post-hydration as well as osmotic diuresis (if required) are used to minimise this toxicity. This is prevented as much as possible by using prophylactic antiemetics such as aprepitant, granisetron and dexamethasone. Other significant toxicities include neurotoxicity, ototoxicity (eighth cranial nerve damage), electrolyte disturbance, decreased fertility and myelosuppression. Chemotherapy for metastatic testicular cancer Clinical scenario A 40-year-old man presented with swelling of his right testicle. Adverse effects Common side effects include alopecia, nausea and vomiting, decreased fertility (amenorrhoea +/- early menopause), hypotension, mucositis, abdominal pain and myelosuppression. Cancer therapeutics 195 Adjuvant chemotherapy for breast cancer Clinical scenario A 36-year-old woman presented with a 2-week history of a lump in the right breast which measured 18 × 7 × 12 mm on ultrasound. Pathology review showed that there had been a pathological complete response in breast and nodes (no residual viable invasive breast cancer cells). Adverse effects Side effects include alopecia, myelosuppression, emesis, extravasation, mucositis, taste disturbance, fatigue, cardiotoxicity (arrythmias or reduced ejection fraction), decreased fertility and teratogenicity. Adverse effects Significant toxicities include emesis, alopecia, myelosuppression, decreased fertility, teratogenicity, haemorrhagic cystitis, diarrhoea, mucositis and skin rash. Docetaxel chemotherapy Mechanism Microtubules form the mitotic spindle and their dynamic activity is necessary for cell division. Docetaxel binds to and stabilises these microtubules preventing their depolymerisation and thereby inhibiting cellular proliferation. Side effects include alopecia, myelosuppression, neuropathy, fatigue, stomatitis, fluid retention, skin rashes, nausea, diarrhoea and hypersensitivity reactions. Drug therapy can be complex and patient education and support from the Rheumatology Nurse Specialist is essential. In addition to the important role of drugs in the treatment of patients with inflammatory joint disease, non-pharmacological strategies must be considered. This involves input from several Allied Health Professions including Physiotherapy, Occupational Therapy and Podiatry. Compound analgesics like co-codamol give little extra analgesic benefit and their use is complicated by adverse effects such as confusion, especially in elderly patients, and constipation. Pharmacokinetics the pharmacokinetics of aspirin are complex and if used in high dosage for long periods of time, plasma aspirin levels should be monitored. Elimination normally follows first order kinetics but after very large doses, the enzymes that metabolise aspirin become saturated. Dyspepsia, gastric irritation and frank or occult blood loss are common adverse effects particularly when aspirin is associated with alcohol ingestion. Inhibition of prostaglandin synthesis is probably responsible because some prostaglandins increase gastric mucosal blood flow and have other protective effects. Prolonged bleeding time may result from the inhibition of thromboxane synthesis and impaired platelet aggregation or reduced clotting factor synthesis. Bronchospasm, urticaria or hay fever may rarely occur in sensitive individuals and appear to result from release of immune mediators secondary to prostaglandin synthesis inhibition. Tinnitus, dizziness and deafness are dose- and plasma-level-related adverse effects. None of these propioinic acid derivatives has been shown to interact significantly with warfarin and if a patient must also receive warfarin this group of drugs may be preferable. However, the majority of patients who use aspirin will do so in the lower doses used for prevention of vascular disease, usually 75 mg/day. Fenamates the long-established mefenamic acid is mildly effective in inflammatory joint disease, but shares the problems of the salicylates to which it is chemically related. Indometacin and related drugs Indometacin has been widely used for the treatment of inflammatory joint disease in the past. Gastric adverse effects are predictable, but headache, confusion and dizziness can also present problems. Salt and water retention with oedema may exacerbate cardiac failure or hypertension and the efficacy of antihypertensive drugs may be reduced. A 75 g sustained-release capsule is designed to deliver 25 mg of the drug immediately and the remaining 50 mg over the next 8­12 hours. Etodolac is another member of this group and is extensively metabolised and excreted in both urine and bile. The kinetics of etodolac are unchanged in the elderly and in renal impairment and its once daily dosage in slow-release form can make it easy to take. Piroxicam and related oxicams Piroxicam is an anti-inflammatory agent that is chemically unrelated to other drugs. Nabumetone this is a non-acidic compound and a poor inhibitor of prostaglandin synthesis. After absorption, it is metabolised rapidly in the liver in to an acidic metabolite that has effective anti-inflammatory actions. Propionic acid derivatives A large number of agents from this group of drugs have been marketed. They are well absorbed orally and have fewer gastric adverse effects than plain aspirin. They have been shown to reduce gastrotoxicity with a decrease in the incidence of ulcers, perforations and bleeds. They may increase the incidence of 200 Drugs and inflammatory joint disease There is good evidence for the use of these three agents in combination to achieve better disease control without a significant increase in adverse events. With increasingly effective combination therapy and the advent of the biologic era, older drugs like chloroquine, auranofin and penicillamine are rarely if ever now used. It also finds use in patients with milder disease who struggle to tolerate more potent drugs. The mechanism of action may be by lysosome stabilisation and inhibition of phagocytic functions. It is well absorbed orally, taken up by many tissues and then very slowly excreted in urine. The most concerning potential toxic effect, though very rare, is retinopathy as a result of gradual accumulation of drugs in the retina. Rashes and marrow toxicity are very rare side effects and there is no requirement for regular blood monitoring. The usual starting dose is 200 mg bd, reduced to 200 mg/400 mg on alternate days in patients who weigh less than 62 kg. Steroids Steroids are used in inflammatory joint disease by the oral, intramuscular and intra-articular routes. Steroid therapy is an effective means by which the inflammatory response can be suppressed and symptoms alleviated, but is not an effective long-term strategy because of the significant side effects associated with long-term use of steroids (see Chapter 17). In the gut, these two moieties are liberated following bacterial reduction of the azo bond. Sulfapyridine is thought to be the principal antirheumatic agent, while 5-aminosalicylic acid is the active anti-inflammatory agent when sulfasalazine is used in the treatment of inflammatory bowel disease. If blood abnormalities occur, it is normally early in the course of treatment and reversible when the drug is stopped. Male patients should be warned of a reversible lowering of sperm count, not sufficiently reliable to be used as contraception. Sulfasalazine tablets are orange and can give rise to an orangetinged discolouration of body fluids. The dose is usually 500 mg/day, increasing at weekly increments of 500 mg to a target dose of 40 mg/kg. Patients need to be aware that the onset of action is slow and it will be in the order of 12 weeks before they start to see benefit. Leflunomide Leflunomide inhibits the mitochondrial enzyme dihydroorate dehydrogenase which is involved in the synthesis of pyrimidines. Hypertension is a side effect although the mean rise in blood pressure is relatively small. Its metabolites have a long half-life and a wash-out with cholestyramine is used in the case of significant adverse effects or prior to conception. Leflunomide is given in a once daily dose of 20 mg, though this can be reduced to 10 mg if tolerance is problematic. Methotrexate Methotrexate is a folic acid antagonist which has become the anchor drug in the treatment of inflammatory arthritis, administered weekly either orally or less commonly subcutaneously. The more minor adverse effects, which nonetheless can be troubling to patients and therefore limit dose escalation, include nausea and anorexia, particularly on the day of and day after administration, hair thinning and a metallic taste in the mouth. The serious side effects which are less common but necessitate monitoring, are myelosuppression and hepatotoxicity. A rare side effect is the development of methotrexate related interstitial lung disease and all patients should have a baseline chest radiograph. Methotrexate is potentially teratogenic and male and female patients need to be informed of the requirement to use effective contraception. As it is excreted renally, gold was sometimes felt to be a good choice for patients with abnormal liver function. After a 10 mg test dose, 50 mg is given weekly for about 16 weeks or until a response is seen, reducing to 4-weekly thereafter. Rash is the commonest adverse effect and presents in many forms including oral ulceration. Proteinuria secondary to a membranous glomerulonephritis occurs in about 10% but resolves on stopping treatment ­ urinalysis for protein must be performed prior to each injection. Marrow toxicity is a potentially fatal side effect and can develop suddenly, especially in the context of other illness. They are usually developed following elucidation of such important pathophysiological pathways which appear amenable to immunomodulation. Biological therapies can target the cells mediating immune responses, or their soluble products, usually cytokines. These drugs are avoided in patients with chronic infection or recent malignancy and all patients require to be screened and if necessary treated for tubercular infection prior to initiation of treatment. A detailed description of biological agents in current use can be found in Chapter 17. He is on bendroflumethiazide for hypertension and drinks 30 units of alcohol each week. An acute attack of gout is extremely painful and effective anti-inflammatory drugs should be used immediately. These drugs should be avoided in renal disease, heart failure and those on oral anticoagulants or with peptic ulcer disease 2 Colchicine is used in acute gout and to cover the introduction of allopurinol. Diarrhoea, nausea and abdominal pain are the commonest side effects and are dose related 3 Low dose oral steroid. Chronic gout, with formation of tophi, occurs after years of acute intermittent gout. In managing gout it is important to differentiate the following: 1 Management of the acute attack 2 Long-term management Long-term management Lifestyle advice pertaining to reduction of alcohol, dietary intake of purine and obesity management, is paramount. Patient information leaflets are available Drugs and inflammatory joint disease and useful in this regard.

Instead insomnia up all night buy generic provigil 200 mg, emphasis should be on adequate resuscitation and restoration of circulating volume xpn sleep aid provigil 100 mg purchase with mastercard, normalization of hemodynamics sleep aid kroger brand provigil 200 mg purchase line, and use of appropriate antibiotic therapy insomnia heart palpitations provigil 200 mg with mastercard. Once a patient has been optimized preoperatively sleep aid geriatric order provigil overnight delivery, attention is then turned to operative techniques to minimize the development of a stula. Performance of anastomoses in healthy, well-perfused bowel without tension provides the best chance for healing. Testing of the rectal and sigmoid anastomoses with intraoperative air insu ations has been shown to reduce "radiologic" leak rate through guiding placement of additional sutures as needed. Usually, these patients exhibit signs of organ dysfunction in the days prior to their catastrophic deterioration, including reduced level of consciousness, tachycardia, and mild renal impairment. In both scenarios, restoration of intravascular volume usually crystalloid is appropriate with or without inotropic support as determined by physiologic monitoring. A recent Cochrane Database Systematic Review showed no di erence in outcome in critically ill patients managed with crystalloid versus colloid and therefore recommended crystalloid as the preferable resuscitation uid. Patients with postoperative peritonitis have increased probability of having multiresistant microorganisms and should receive broader-spectrum antibiotics. Uncontrolled infection with the development of a septic response and the concomitant uid imbalance and malnutrition are the leading causes of mortality in modern series of enterocutaneous stulas. Percutaneous management of localized abscesses accompanied by appropriate antibiotic therapy and supportive measure is usually su cient to resolve infection in this subgroup. In general, the generalized nature of the infection precludes successful therapy with percutaneous drainage and therefore an operative approach is indicated. Anastomotic dehiscence/ enterotomy should generally be managed by exteriorization of the a ected bowel. Whether this is performed via a single stoma site or with separate stomas (ie, end stoma plus mucous stula) depends on the speci c scenario. Obviously, if one is able to exteriorize the intestinal defect, the likelihood of a postoperative enteric stula is markedly reduced. It is attractive to hope that a surgically repaired enterotomy or leaking enterotomy might heal primarily, given the obvious simplicity of the procedure. However, this is rarely successful in the setting of di use peritoneal infection, and therefore this approach is not recommended. Reoperation after this misjudgment is fraught with potential di culty, in that the surgeon is faced with the need to reoperate on the patient in the early postoperative period. Under these circumstances, there should be consideration of a proximal defunctioning stoma if technically feasible. A number of anatomical circumstances may also preclude exteriorization of a leaking anastomosis. Most important among these is the rectal or sigmoid anastomosis where the distal end can be neither exteriorized nor closed. Unless the anastomosis is greater than 50% disrupted, it is reasonable to defunction with an ileostomy or a colostomy upstream and drain the site of the hookup. Concurrent with drainage of sepsis, a plan to control stula drainage and provide local skin care will prevent continued irritation of the surrounding skin and abdominal wall structures. Obviously, stulas created following percutaneous drainage of abscesses are usually well managed by the drain itself. Indeed, the drainage of a local infection is frequently su cient to permit closure of the stula. In less controlled circumstances, particularly in the setting of the open abdomen, control of the e uent is not straightforward and must be managed aggressively. A skilled enterostomal therapist can often provide useful insight in to these issues and should work in concert with a dedicated nursing team. Use of a drainable wound pouch that is tailored to the size of the open wound is e ective. Vacuum-assisted closure devices have been reported to aid in the care of these complicated wounds, including the promotion of closure. For example, Wainstein and coauthors reported promising results after reviewing their 10-year experience with it. In this study, stula output was profoundly suppressed soon after commencing use of the device and spontaneous closure was achieved in 46% of patients. Some authors have reported a small number of patients developing new enteric stulas with the vacuum device. While stula output does not correlate with the rate of spontaneous closure, reduction in stula drainage may facilitate wound management and decrease the time to closure. Further, reduced output enhances the ease of uid and electrolyte management and may make local wound care easier. In the absence of obstruction, prolonged nasogastric drainage is not indicated and may even contribute to morbidity in the form of patient discomfort, impaired pulmonary toilet, alar necrosis, sinusitis or otitis media, and late esophageal stricture. Measures to decrease the volume of enteric secretions include administration of histamine antagonists or proton pump inhibitors. Reduction in acid secretion will also aid in the prevention of gastric and duodenal ulceration as well as decrease the stimulation of pancreatic secretion. As recently reviewed, these agents did not accomplish this, although the data suggest that stula output is reduced and time to spontaneous closure is lessened. Chapter 10 Abdominal Abscess and Enteric Fistulae 209 One would speculate that their greatest e cacy would be in the setting of a long tract, without epithelialization and with low output. Recently, endoscopic insertion of a silicone-covered stent across the stula opening related to gastrojejunal leak following gastric bypass surgery has been described as a means of allowing early feeding and promoting stula closure. Clearly, no consensus regarding use of this approach has been achieved, given the small patient numbers described. Provision of nutritional support and time may be all that are necessary for spontaneous healing of enterocutaneous stulas. Alternatively, should operative intervention be required, normalization of nutritional parameters will optimize patients in preparation for their surgery. Malnutrition, identi ed by Edmunds in 1960 as a major contributor to mortality in these patients, may be present in 55­90% of patients with enterocutaneous stulas. Parenteral nutrition has long been the cornerstone of support for patients with enterocutaneous stulas. Parenteral nutrition can be commenced once sepsis has been controlled and appropriate intravenous access has been established. Additionally, parenteral nutrition is expensive and requires dedicated nursing care to prevent undue morbidity and mortality from line insertion, catheter sepsis, and metabolic complications. As achieving goal rates of enteral feeding may take several days, patients are often maintained on parenteral nutrition as tube feedings are advanced. Enteral feeding may occur per os or via feeding tubes placed nasogastrically or nasoenterically. Enteral support typically requires 4 ft of small intestine and is contraindicated in the presence of distal obstruction. Drainage from the stula may be expected to increase with the commencement of enteral feeding, although this does not uniformly occur and is often dependent on stula location and size of the stula defect; however, spontaneous closure may still occur, often preceded by a decrease in stula output. It is far less expensive, safer, and is easier to administer (particularly if the intent is to manage the patient as an outpatient). In patients with high-output proximal stulas, it has been suggested to provide enteral nutrition by a technique called stuloclysis. In stuloclysis, an enteral feeding tube is placed directly in to the matured high-output stula. While able to promote intestinal mucosal epithelial cell proliferation; increase levels of total proteins, albumin, bronectin, and prealbumin; and transfer and reduce nitrogen excretion, its clinical role has not been clearly de ned. Patients who develop postoperative enterocutaneous stulas require considerable psychological support. In aggregate, all of these factors lead to psychological distress for patient and their families and should be addressed once the acute disease is dealt with. Fistulograms down drainage tracts will elucidate the length, course, and relationships of the stula tract. If the stula is spontaneous, the nature of the local pathological process from which the stula arises may be determined. Because patients with enterocutaneous stulas are frequently referred to larger centers for management, it is essential that all notes, particularly operative notes, be obtained from the referring hospital. A long, narrow stula tract originating from a small leak in a colonic anastomosis with no evidence of distal obstruction and a well-drained perianastomotic abscess is almost certain to close spontaneously. By contrast, a small bowel defect revealing itself as a mucosal bud in the middle of an open abdomen is unlikely to heal as the tract is short and epithelialized, in essence mimicking a stoma. Fistulas in the setting of malignancy or irradiated bowel are particularly resistant to closure and would suggest the need for earlier operative intervention. Most authors agree that once resuscitation, wound care, and nutritional support are established, 90­95% of stulas that will spontaneously close typically do so within 4­8 weeks of the original operation. Like any surgical procedure, weighing of the risk and bene ts of surgical intervention is critical prior to proceeding to operation. Some patients are perfectly well, are tolerating a regular diet, and have stula e uent that is trivial in volume and requires only coverage with dry gauze. Early operation is only indicated to control sepsis not amenable to percutaneous intervention. Very early closure appears to be contraindicated because the patient condition is generally not optimized. Further, from a technical standpoint, adhesions tend to be dense and vascular, therefore rendering the procedure di cult. Patient factors such as nutritional status, ease of managing the stula, and family support may in uence decision making. Some authors talk about the "soft" abdomen and prolapse of the stula as being a valuable clinical signs that peritoneal conditions are reasonable to proceed with surgery. In addition to repairing the stula, many of these patients require complex abdominal wall closures. Before de nitive management, the patient should have achieved optimal nutritional parameters and be free of all signs of sepsis. As for all operations, the patient should be fully apprised of the nature of the procedure and its potential for complications. Connolly and colleagues reported a very high incidence of complications following intestinal reconstructive surgery (82. Some of the anxiety of the patient may be related to mistrust of physicians in general following a previously complicated operation. Clearly, the sensitive nature of reoperation for prior complications requires a strong physician-patient relationship to minimize patient anxiety prior to the planned procedure. It is critically important for the operating surgeon to fully understand the nature of the prior surgeries. One should also be very liberal about using preoperative contrast imaging or endoscopy to completely de ne the anatomy. In the hypothetical case of reoperation after a colonic anastomotic dehiscence, the need for de nition of the anatomy varies according to the initial source control procedure. A prior operation consisting of exteriorization of an end colostomy with nearby mucus stula or exteriorization of the disrupted anastomosis Chapter 10 Abdominal Abscess and Enteric Fistulae 211 is a circumstance where investigation is probably unnecessary. Closure of a defunctioning ileostomy or colostomy should also be preceded by investigation of the downstream anastomosis. Finally, contrast studies are essential when complex stulas exist and are to be treated by reoperative surgery. Orthograde intestinal lavage by mouth as well as distally via the defunctioned limb has been recommended for mechanical preparation of the bowel. However, the evidence underlying this recommendation is limited and, in fact, recent studies show that mechanical bowel preparation for elective colon surgeon does not improve outcome and may have some deleterious e ects. Clearance of inspissated mucus in the rectal stump with an enema may facilitate advancement of the stapler proximally. Finally, prophylactic intravenous antibiotics with broad-spectrum coverage of both facultative gram-negative enterics as well as anaerobic bacteria are indicated. Concomitant lithotomy positioning is often helpful, particularly when reconstruction involves the left colon or rectum, where transanal access for endoscopy or stapling may be useful. Careful planning of the location and type of incision are mandatory prior to making the initial incision. It is preferable to enter the peritoneal cavity through a previously unoperated area of the abdominal wall, thereby avoiding the areas where the most intense adhesions would be expected, that is, beneath the previous abdominal wall incision and in the region of the abdomen where the in ammation might have been the most severe. Inadvertent enterotomy is relatively common during reoperation, occurring in approximately 20% of patients, and is associated with a higher rate of postoperative complication and a longer postoperative hospital stay. Other approaches may include unilateral or bilateral subcostal incisions, transverse incisions, ank incisions, or thoracoabdominal incisions. In general, these should be considered when a speci c area of the abdomen is operated on, because they generally a ord less access to the overall peritoneal cavity. When placing new incisions, care should be taken not to render intervening tissue bridges ischemic. It is preferable to use the previous paramedian incision with extension in to the midline above or below. When the stula opening is in the center of a reepithelialized section of the abdomen with no underlying fascia/muscle, one should preferably enter the abdomen as described above, either cephalad and caudad to the previously operated area. When this is not possible, one should consider placing the initial incision along the line of the fascial edge, rather than though the reepithelialized portion. In the latter operative eld, the skin may be very adherent to the underlying bowel, therefore increasing the chance of bowel injury. Upon entering the peritoneal cavity, adhesions between the anterior abdominal wall and the underlying omentum and bowel must be released.

Mononeuritis multiplex can arise as a result of different forms of vasculitis causing nerve injury insomnia vitamins buy provigil canada. Mechanical problems in the spine may lead to nerve or cord compression depending on the level of injury and its severity sleep aid quetiapine order provigil overnight. Careful evaluation of the nervous system is important in any patient with back pain insomnia questionnaire buy cheap provigil 200 mg online, especially if they have a history of pain or numbness in a peripheral limb insomnia disorder provigil 200 mg order on-line. Bronchial and tracheal ulceration and inflammation leading to stenosis are characteristic findings in granulomatosis with polyangiitis sleep aid apps cheap 200 mg provigil with amex. Patients with Sjögren syndrome can develop dryness in the trachea and bronchi, leading to cough, and predisposing to chest infections through impaired clearance of secretions. Liver function abnormalities are common in patients treated with methotrexate, leflunomide and sulfasalazine. Rheumatoid lung nodules may be seen as isolated peripheral shadows on a chest radiograph, raising suspicion of tumour; they may even liquefy in the centre, giving rise to a fluid level and concern about possible abscess. Occasionally lung nodules occur prior to the onset of joint symptoms, causing considerable diagnostic confusion. Patients with systemic vasculitis affecting small vessels may develop alveolar inflammation and haemorrhage, typically in microscopic polyangiitis and antiglomerular basement membrane disease (Goodpasture syndrome). Dyspareunia due to dryness of the vagina is relatively common in patients with Sjögren syndrome, although patients may not raise the issue owing to embarrassment, or thinking that it is not connected to their rheumatic disease. All such patients should have their blood pressure checked, urine tested for blood and protein, and renal function assessed regularly. Unexplained haematuria should be investigated thoroughly in patients who have been treated with cyclophosphamide to look for evidence of urothelial cancer. Immunosuppressive drugs used to treat rheumatic diseases carry a significant risk of infection, especially the more potent agents. Better management of arthritis has resulted in substantial improvement in overall survival, including a significant fall in the number of cases of amyloid. In some cases, resistant to systemic immunosuppression, splenectomy is justified, but patients will need pneumococcal vaccine prior to splenectomy followed by lifelong penicillin V administration. If patients are treated with immunosuppressive drugs, such as azathioprine, the risk may double. Other clinical manifestations include sore throat, lymphadenopathy and/or 254 rheumatology splenomegaly, and liver dysfunction. This is attributable to complex presentation and, at times, a relentless progression requiring constant screening of renal, pulmonary, cardiovascular and cerebral function, along with complications from long-term therapy. For ease of consideration, these diseases have been classified by a characteristic feature of pyrexia or rash. Overlap between these diseases is common, to such an extent that the diagnostic label may change with time as the true nature of the disease becomes apparent. As a result, it is essential to perform regular monitoring of symptoms, signs and laboratory screening tests to challenge early diagnoses and re-evaluate therapy. To avoid repetition, this section focuses on paediatric aspects of inflammatory disease and, where relevant, the reader is referred to other sections for a more general account of the disease. Kawasaki disease should be considered early in any child with a high spiking pyrexial illness (39­ 40°C) with negative blood cultures and unresponsive to antibiotics. This is because timely treatment with intravenous immunoglobulins and aspirin will avert life-threatening coronary aneurysms. The diagnosis is made when there are four of five diagnostic criteria in addition to 5 days of fever: (i) conjunctivitis and (ii) oral mucosal changes each occur in 90% of cases, (iii) rash in 80%, and (iv) lymphadenopathy and (v) palmar erythema occur in 70%. In an infant, some criteria may be absent, but inconsolable irritability in the absence of meningitis should raise suspicion. Other important diagnoses to consider are leukaemia, lymphoma and neuroblastoma, which may present with fever and constitutional disturbance. A blood count and film discussed with the haematologist may help in the diagnosis of leukaemia, the commonest childhood malignancy to result in musculoskeletal pain and arthritis, but a bone marrow aspirate is definitive. It may be accompanied by a salmon-pink or urticarial rash, and may precede the polyarthropathy by months. Periodic fever syndromes and vasculitic syndromes may also present with fever, rash and arthritis. They are often distinguished by the key features and investigations identified in Table 18. Of the microbiological investigations the throat swab is important in determining the presence of streptococcus. The periodic fever syndromes are rare, but important, systemic conditions that cause intermittent episodes of systemic inflammation, with organ involvement, especially in the abdomen, joints and skin. They are inherited disorders of the immune system, due to defects in the genes that control cytokine function. Treatment includes steroids and methotrexate, but in severe cases cyclophosphamide is used. Systemic nonarticular manifestations of rheumatoid arthritis: focus on inflammatory mechanisms. A retrospective analysis for aetiology and clinical findings of 287 secondary amyloidosis cases in Turkey. Newton and Raashid Luqmani Cases relevant to this chapter 37, 41, 45, 53, 63, 73, 82, 92, 95, 98 19 6. There is a 10­30% increase in mortality in the 12 months following a hip fracture. Osteoporosis is defined as a condition of skeletal fragility characterized by reduced bone mass and microarchitectural deterioration predisposing a person to an increased risk of fracture. The following mechanisms are responsible either alone or in combination: a failure to achieve adequate peak bone mass, an increase in bone resorption and a reduction in bone formation. Fragility fractures are the main consequence of osteoporosis, and can present either with fracture or with pain or loss of height with development of a thoracic kyphosis. If the osteoporosis is secondary to another disorder, for example Cushing syndrome, features of the underlying disease may be the initial presenting complaint. The bones most frequently affected by a fragility fracture are the hip, vertebra and wrist. The risk is related directly to age, and is due to a combination of age-related bone loss and an increased rate of falls (Box 19. There may also be an increase in the initiation of new bone remodelling cycles (activation frequency). The resorption phase is faster than the formation phase, which can further contribute to osteoporosis when the activation frequency is high. Genetic factors contribute strongly to peak bone mass and to the rate of bone loss after peak mass has been achieved. Oestrogen has a central role in both men and women, but men do not have the same dramatic changes in sex hormone levels during middle age as women do (Table 19. Lifestyle modification measures should be discussed with all patients, including improving calcium intake (equivalent of 1 pint of milk a day or 600 mg/day), supplemental vitamin D (50­ 75 nmol/l), weight-bearing exercise, healthy body mass index, smoking cessation and reduction of alcohol consumption if excessive. Balance and exercise classes promote increased bone density, but also help in fall prevention. Hip protectors have been advocated, but compliance is poor and effectiveness has been questioned. Monitoring treatment includes the use of bone turnover markers to assess whether remodelling rates have been significantly suppressed by antiresorptive medication. In a minority of patients treated with bisphosphonates, atypical subtrochanteric fractures occur, and in patients undergoing cancer therapy with intravenous zoledronate, osteonecrosis of the jaw has occurred. Hence therapy is usually recommended for 5 years, after which the need for future treatment is reviewed. The clinical picture is called rickets or osteomalacia, depending upon whether it is before or after cessation of growth respectively. The first, the 25-hydroxylation step to become 25-hydroxycholecalciferol, occurs in the liver, and the second, in which the 25-hydroxycholecalciferol is converted to 1,25-dihydroxycholecalciferol (calcitriol), takes place in the kidney for endocrine function but in most body tissues for autocrine/paracrine actions. The signs and symptoms of osteomalacia are often vague and the diagnosis may be missed unless considered specifically. These clinical features and the typical radiological findings are listed in Table 19. The main cause of hypovitaminosis D is a lack of sun exposure; the two largest at-risk groups are women and children screened from the bone disorders 261 Box 19. Renal osteodystrophy encompasses the spectrum of bone disease in association with chronic renal failure. The main components are hyperparathyroidism, adynamic bone disease and osteomalacia. Darker skin requires longer sun exposure to generate the same amount of vitamin D. Protocols for vitamin D replacement depend upon the severity of the deficiency and the compliance of the patient. It is rare at less than 50 years of age and affects both sexes, with a slight predominance in men. The lesions are highly localized and progress slowly, but relentlessly, once present without treatment. There is excessive bone resorption and, due to the tightly coupled nature of osteoclast and osteoblast activity, this is followed by the rapid laying down of disorganized, weak, abnormal bone. Current hypotheses are based around an environmental insult in a genetically predisposed individual. Osteoblasts are normal, but have increased activity due to increased stimulation from factors released by the osteoclasts. The initial lesion is, therefore, osteolytic followed by the rapid laying down of weak disorganized bone. Other reasons for medical treatment include sequelae of the disease: fractures and nerve root compression from the expanded bone. Prior to surgery, treatment may be indicated because pagetic bone is more vascular and consequently bleeds more. Bisphosphonates inhibit osteoclast activity and promote osteoclast apoptosis, and are the mainstay of treatment. A single infusion of 5 mg zoledronate is sufficient to control disease for many years. However, this should not be used in those with partial fractures in weight-bearing areas because of the risk of fracture completion. In these patients, oral therapy with risedronate and correction of occult vitamin D deficiency are indicated. Calcium levels are usually normal unless there has been a recent fracture or prolonged immobility. An isotope bone scan is indicated to distinguish monostotic from polyostotic disease. Radiographic imaging of weightbearing areas is essential to exclude occult partial fractures. There is a high incidence of bilateral involvement in atraumatic cases involving the femoral head, femoral condyles and humeral head. There is some linear high signal within the longitudinal axis of the Achilles tendon. Prevention by the recognition and management of treatable disorders such as hyperlipidaemia and alcoholism is crucial. Early diagnosis and intervention improves outcome, so a high index of suspicion is important. Management includes conservative treatment to reduce the use of the affected joint and simple analgesics. Surgery is often required and the commonest procedures are core decompression and joint replacement. There is some narrowing of the joint space medially with sclerosis 266 rheumatology Table19. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. Swellings of the musculoskeletal system can be classified as neoplastic (benign), neoplastic (malignant), inflammatory or miscellaneous. A neoplasm is an abnormal growth of cells over which control of growth has been lost. Removal of the stimulus that caused it does not stop it growing, and the tissue is clonal (has arisen from a clone ­ an almost identical mother cell). Sometimes the tumour may become malignant, but only if the classification of the tumour changes (for example, an enchondroma to a chondrosarcoma). A soft-tissue swelling that is pain-free, static or slowly growing, superficial and less than 5 cm in size has only a tiny chance of being malignant. Radiotherapy, tamoxifen, vitamin C may help Difficult to resect locally and may recur after many years. Occasionally de-differentiates to myxoid sarcoma In retroperitoneum and gastrointestinal tract may have malignant potential May be congenital or acquired. Large ones in children may require multidisciplinary approach because of skin involvement Usually benign on a major nerve. Central nidus with lytic ring and surrounding sclerosis Large lytic metaphyseal lesion Epiphyseal Bubbly, lytic within cortex. Bony destruction results in extended joint replacement surgery Part of a systemic disorder of histiocytes. The bone has chance to react and often does so by expansion with cortical changes. Treatment is frequently a biopsy-cum-curettage to remove the majority of macroscopic tumour without causing morbidity. In most benign bone tumours, this allows bone healing to eradicate remaining microscopic tumour.

It may be necessary to obtain an ultrasound scan to confirm the diagnosis and exclude a solid tumour insomnia jet lag provigil 100 mg buy online. Other ganglion cysts arise from the semimembranosus tendon sheath and from torn menisci sleep aid overdose death buy genuine provigil online. Arthrodesis of these joints is the surgical treatment of choice in intractable pain insomnia kitchen provigil 100 mg buy on-line. There may be a spindle shank insomnia reviews 200 mg provigil purchase free shipping, a red shiny hairless foot with poor nail quality and small ulcers insomnia cookies calories order provigil 100 mg without prescription, or even dry gangrene of toes. This may indicate peripheral arterial disease and care should be taken to palpate the dorsalis pedis and posterior tibial arteries. Inability to feel these or identify them on Doppler ultrasonography may mean a reduced chance of healing after major surgery on the knee or below. This may indicate the presence of a deep venous thrombosis ­ a frequent event after major lower-limb surgery and a risk factor for pulmonary embolus. Alternatively, venous incompetence may be the cause, in which case venous ulceration may be identified just proximal to the medial malleolus. Long-standing diabetes mellitus will cause microvascular disease and peripheral neuropathy. This leads to pressure areas breaking down, and secondary osteomyelitis and amputation of toes may be necessary. Sometimes a frank woody cellulitis affects the whole forefoot or hindfoot and necessitates a trans-tibial amputation. A Charcot joint is one that is destroyed rapidly and is usually associated with a peripheral neuropathy; the ankle is typically affected. The destruction of capsule and tendons together with toe subluxations can cause a valgus deformity of the foot. Carefully moulded footwear to diminish contact forces on pressure areas is vital for skin care and to reduce pain. Flat foot (pes planus) is a common condition, present in about 5% of the population in school studies (see Chapter 24). Extra-articular extension of rheumatoid disease may cause rupture of the tibialis posterior tendon leading to a painful flat foot. Radiographs of the underlying bone may reveal the first metatarsal in varus (metatarsus primus varus) and the great toe in valgus (hallux valgus). Clinical examination may reveal evidence of congenital joint laxity with a somewhat splayed forefoot (laxity of the intermetatarsal ligaments) with correction of the bunion by gentle compression across the metatarsal heads. The Masai tribe in Africa has hallux valgus, but rarely pain on inflammation and by tradition they do not wear shoes. In contrast, Western fashions may be associated with narrow shoe wear, which can lead to a painful, inflamed bunion. Management should include education about sensible footwear; trainers are often helpful. A firm moulded insole will elevate the medial arch and help to correct the splaying and reduce pain in about 40%, but compliance is difficult. Conservative treatment will include shoewear modifications to improve shock absorption at heel strike and orthoses to block painful movement at the ankle. Together with forefoot splaying, the extensor tendons of the toes can shorten causing hammering (fixed distal interphalangeal joint flexion) or clawing (fixed proximal interphalangeal joint flexion) of the toes. The metatarsal heads may be prominent on the sole of the forefoot when this happens, causing pain over the heads (metatarsalgia) and callosities to form over their plantar surfaces. This may be amelanotic (pale), and careful examination is necessary to make the diagnosis. Factors distinguishing septic arthritis from transient synovitis of the hip in children. Most books cover diseases, yet normal variants and normal developmental stages cause considerable anxiety to parents and doctors. It is important to eliminate neurological causes (upper motor neurone lesions such as cerebral palsy exhibit increased muscle tone, upgoing plantar reflexes and sustained clonus) and to exclude in-toeing due to metatarsus varus of the feet or internal tibial torsion. Lax ligaments cause inefficient proprioception (clumsiness) and produce less remodelling force on the femoral neck, which is anteverted 40° at birth but only 16° by age 16 years. Interventions do not alter the natural history; therefore, reassurance and explanation are important. Most children improve with age under peer pressure, but all will continue to in-toe with inattention or when tired. Fetal moulding from compression by the uterus before birth produces hip flexion and external rotation contractures, such that all children initially walk out-toed with their hips and knees flexed. Genu valga is maximal between ages 3 and 4 years, and may be more marked in children who have ligament laxity or are overweight. Bow legs beyond age 2 1 2 years or knock-knees before 18 months are probably pathological, in which case rickets or an inherited skeletal dysplasia that can cause either genu vara or valga should be excluded. If detected early, it can readily be corrected surgically by a medial periosteal release. If detected late, complex osteotomies are required to correct this tri-planar deformity. Recent research suggests that children who suffer growing pains have a low pain threshold. Most outgrow the pain, but a significant minority have anterior knee pain throughout life. The deformity corrects with stretching exercises and as the powerful calf muscles gain tone. The patella carries up to 12 times body weight and is one of the most heavily loaded joints in the body. During the adolescent growth spurt, the forces on the still immature patella increase markedly. Postural flat feet occur in 97% of children at 18 months but in only 4% of 10-year-olds. Knock-knees make flat feet look worse, which explains why flat feet are most apparent between the ages of 3 and 4 years. Insoles or heel cups do not alter the natural history of postural flat feet, although orthoses can 304 paediatrics adversely affect the child psychologically. Bare-foot walking helps the normal development of the foot, but is not always feasible in cold climates. Trainers often have an in-built arch support which may help if shoe-wear is excessive and, unlike orthoses, will not label the child as different from their peers. An older child with aching postural flat feet, particularly in association with ligament laxity, may find an arch support helpful. A very athletic child with flat feet may also benefit in performance and symptoms from a customized arch-supporting insole. Structural flat feet may be flexible with the primary pathology being tight calf muscles, or rigid. A painful stiff flat foot suggests subtalar pathology such as a tarsal coalition (see Chapter 25), infection, juvenile arthritis, trauma or severe neurological abnormality. In addition to minimal (but usually painful) subtalar movement, there is often associated calf wasting and muscle spasm, causing the foot to evert or, occasionally, to invert. If performed before the appearance of degenerative change, excision of a calcaneo-navicular bar can successfully restore some subtalar movement and relieve most of the pain. Excision of a talo-calcaneal coalition is less effective, unless the bar occupies less than 30% of the talo-calcaneal joint surface; therefore, in most cases, subtalar fusion is necessary to relieve pain. Where the rigid flat foot is secondary to trauma, chronic inflammation or severe neurological abnormality, it may be difficult to achieve mobility and balance. Some symptoms may be relieved by use of a shoe insert or ankle-foot orthoses combined with appropriately fitted footwear, although great care is necessary if there is impaired sensation in the foot. During rapid growth the growth plate becomes thicker and weaker, providing less support to the apophysis. Treatment comprises restricting activity within the bounds of the pain, calf-stretching exercises and possibly wedge-heel trainers (which partially defunction the calf muscles). Similar traction apophysites can occur at the insertion of peroneus brevis in to the fifth metatarsal base, at the insertion of the glutei in to the greater trochanter, and at the insertion of the medial hamstrings and adductor magnus in to the ischium. The fourth toe is most frequently involved, but the third and occasionally the fifth can be affected. Occasionally, pain secondary to shoe pressure on the nail or proximal interphalangeal joint warrants surgical division of the flexor tendons. An overriding second toe is common in the podgy infant foot, but resolves as the foot slims and spreads with weight-bearing. Congenital anomalies such as syndactyly, polydactyly, macrodactyly, delta phalanx and absence of a toe and/or metatarsal often occur in association with other congenital abnormalities. Claw, mallet and hammer toe deformities (see Chapter 25) are usually developmental and become problematic only in later childhood. It is often associated with the Klippel­Feil syndrome (congenital fusion of cervical vertebrae and other musculoskeletal and systemic abnormalities). The scapula is tethered to the cervical spine by a bony, cartilaginous or fibrous band. Treatment is surgical, to excise the tether and bring the scapula down to its normal position. The duplication is either postaxial (of the little finger) or preaxial (of the thumb;. The extra digit may be a soft-tissue tag or may comprise partial or complete bony and soft-tissue duplication of the digit. Often the thumb is fixed in flexion, although early on it can be extended passively. Birth weight is the chief aetiological factor, not the expertise of the delivery staff. The injury affects the roots of the brachial plexus, most commonly the upper ones. The outcome depends largely on the severity of the lesion, which is described by the Narakas classification (Table 25. All muscles and sympathetic function Outcome 90% recover fully 65% recover fully; the rest have permanent deficit 1­2% recover fully; the rest have significant permanent deficit None recovers fully; all have severe permanent deficit Initial treatment is with physiotherapy to prevent joint contractures due to muscle imbalance. In group 4 cases with no biceps recovery by 4­6 months, nerve repair by grafting or nerve transfers may restore useful, but never good, function. Partial recovery produces muscle imbalance, particularly at the shoulder, which limits function and may cause dislocation of the shoulder. Surgery to weaken the internal rotators or muscle transfers to strengthen the external rotators prevents dislocation and improves function. The arch of the foot is maintained by the conforming shape of the bones, ligaments and muscles, both intrinsic and from the calf. Maintenance of this medial or longitudinal arch is reliant upon normal muscle action, especially at push-off when walking. A transverse metatarsal arch is also present, although it is less obviously so; in the elderly this arch may be lost along with flattening of the medial arch as the weakening foot pronates. When the tilt is subtalar, involving the heel, the terms eversion and inversion correspond. As with the hand, the midfoot and forefoot are said to pronate when they roll internally, often in conjunction with eversion of the heel, and to supinate when they roll externally with the first metatarsal raised above the fifth and the heel inverted. Similarly, medial deviation of the forefoot (metatarsals and toes) in the horizontal plane is adduction, the opposite being abduction. Provided the forefoot alignment is correctable and there is no element of supination, the condition can be ignored and will lessen during the early years of shoe-wear. Hallux varus or adductus is highly unusual; this congenital condition may require soft-tissue correction later in childhood. A family history is often identified, reaching its peak with identical twins when the condition is seen in 33% of siblings. This involves a programme of carefully applied plaster casts that gradually correct the deformity. This usually offers excellent correction of the deformity but about 30% of babies will also require a percutaneous Achilles tenotomy (division) to correct residual hindfoot equinus. The correction is then maintained by the child wearing a foot abduction splint at night until approximately 2­4 years of age. Surgery is reserved for feet that have relapsed or for those presenting late where there is fixed skeletal deformity. The former resolves completely, although a strong shoe with an insole, or plaster cast support for a month or two, may be helpful if it is symptomatic. An extension osteotomy of the metatarsal neck may relieve metatarsalgia, although the dorsal bony swelling persists. Four principal patterns of neurological imbalance produce these chronic changes in the foot: 1. Weakness of ankle dorsiflexion resulting in over-action of the long toe extensors 3. The prognosis for clubfoot is related to the severity of the presenting deformity, graded from postural to mild, moderate or severe. Atypical syndromic clubfeet are also encountered: the deformities may be very stiff in conditions, such as arthrogryposis, or they may correct more rapidly than the idiopathic forms, potentially leading to over-correction if surgery is undertaken. This autosomal dominant progressive local demyelinating disorder produces an initially correctible and then a rigid deformity associated with painful calluses. Clinical assessment should include neurological examination (loss of light touch, vibration or proprioception; diminished deep reflexes; ataxia and dysarthria; clonus and overt muscle wasting). Imaging of the brain and spinal cord may also be necessary, and both nerve conduction studies and electromyography are helpful in ruling out overt nerve deficit. Treatment consists of: · Soft-tissue surgery (releases and tendon transfers) · Osteotomies (first metatarsal, midfoot, calcaneum) · Triple arthrodesis of the talus, calcaneum and cuboid. Surgical excision of the prominence is necessary only if there is rubbing from shoe-wear or localized pain at the synchondrosis. Tarsal coalition this produces a rigid structural flat foot and the normal appearance of a medial arch is absent if the child stands on tiptoe.

The effectiveness of multidisciplinary rehabilitation in the treatment of fibromyalgia: a randomized controlled trial sleep aid mouth guard discount provigil 200 mg without prescription. Self-management of fibromyalgia: the role of formal coping skills training and physical exercise training programs sleep aid vitamin discount 100 mg provigil amex. Radiographic and autopsy surveys show a steady agerelated increase in prevalence from the age of 30 years sleep aid gabapentin buy provigil 200 mg line. The joints most frequently affected are the spine insomnia 36 hours order generic provigil online, hips insomnia bipolar purchase provigil 200 mg with amex, knees, and some of the small joints of the hands and feet. Joint failure occurs when mechanical stresses overwhelm the capacity of articular tissues to resist and repair the damage. Structural failure of the articular cartilage, bone and periarticular tissues can result from abnormal mechanical stresses damaging previously normal tissues, or from the failure of pathologically impaired joint tissues in response to physiologically normal mechanical forces. Obesity, joint mal-alignment, occupational trauma and muscle weakness are all important, potentially modifiable, biomechanical risk factors that determine the site and severity of the disease. In many cases these processes reach a state of non-progressive equilibrium, but in others there is symptomatic failure of the joint characterized by progressive degeneration of the articular cartilage with fibrillation, fissuring, ulceration and, eventually, fullthickness focal loss of cartilage at sites of joint loading. The biomechanical properties of the cortical and subchondral bone play an important role in protecting articular cartilage following impact loading. The consequent loss of bone viscoelasticity results in steep stiffness gradients in the bone. This in turn results in stretching and fibrillation of the overlying articular cartilage, as well as focal osteonecrosis and the formation of bone cysts. Early increases in matrix hydration and articular cartilage thickness follow disruption of the collagen fibre network, loss of tensile strength in the superficial zone of the articular cartilage and swelling of the negatively charged, highmolecular-weight proteoglycan, aggrecan. Usually insidious in onset and 194 rheumatology intermittent at first, the pain is typically aching in character. Initially, it is provoked by weight-bearing or movement of the joint, and relieved by rest, but as the disease progresses the pain may be more prolonged and experienced at rest, and may become severe enough to wake the patient at night. Prolonged early morning stiffness is not a feature as it is in rheumatoid arthritis and other predominantly inflammatory joint diseases, but a few minutes of early morning stiffness and transient stiffness (gelling) after rest are common. Pain may result from increased pressure or microfractures in the subchondral bone, from low-grade synovitis, inflammatory effusions, capsular distension, enthesitis or muscle spasm, and nocturnal aching may be associated with hyperaemia in the subchondral bone. Associated anxiety and depression are not uncommon, and these can amplify pain and disability. Patients may develop painless functional impairment due to restricted movement in the hands, hips or knees. Typically, patients present with pain in the groin on exercise, but referred pain in the buttock, anterior thigh, knee and even the lower leg are not uncommon. With increasing severity it radiates down to the knee, is constant on exercise, and begins to cause stiffness and inability to reach down to tie shoe-laces. Enjoyment of active hobbies is curtailed, and progression to joint destruction and fixed flexion contracture can be the end result in some patients. It occurs more frequently in women, is more frequently bilateral, and less frequently progresses. A Trendelenburg gait is rare, but a coxalgic (Duchenne) gait is more common due to a desire to off-load the hip abductor muscles and hence reduce the joint reaction force, which is often three times body weight in single-leg stance. Range of movement reveals a global deficit and fixed flexion; reduced adduction and internal rotation are often seen. The medial compartment is most frequently affected, and leads to a varus deformity. Forces that occur on weightbearing will pass medial to the knee and this increases point-loading in the medial compartment. Typically, patients present with anterior or medial knee pain aggravated by walking on uneven ground and by ascending or descending stairs. On examination they frequently have a characteristic antalgic gait and bilateral, symmetrical varus deformities. The onset, which is sometimes subacute with considerable pain, swelling and local inflammation, is often in the perimenopausal period, and may be triggered by oestrogen withdrawal and other endocrine changes at this time. Although multiple joints in both hands are frequently affected, the onset is typically episodic and additive in pattern, with each joint going through a sequence of changes over a number of months. Once the inflammation has settled, patients are left with relatively pain-free, knobbly fingers. Although the lesions can be associated with considerable deformity and subluxation, serious disability is unusual. Focal, rather than uniform, joint space narrowing and the presence of osteophytes are the main radiographic features, with subchondral bone sclerosis and cysts in more advanced cases. Ossified synovial loose bodies and chondrocalcinosis can also sometimes be detected on plain radiography. Standing radiographs are required to assess the extent to which joint space narrowing reflects loss of articular cartilage in the tibio-femoral joints. For example, measurements of serum calcium and alkaline phosphatase are critical for the diagnosis of primary hyperparathyroidism and hypophosphatasia; measurement of serum ferritin is required for the diagnosis of haemochromatosis; and detection of homogentisic acid in the urine will confirm a diagnosis of ochronosis. The initial focus should be on self-help and patient-driven treatments, rather than on passive therapies delivered by health professionals. The evidence that these agents may also have structure-modifying effects in slowing the progression of articular cartilage loss remains inconclusive. Non-pharmacological therapies should be continued in such patients and surgical treatments should be considered. Replacement arthroplasties are effective and cost-effective interventions for patients with significant symptoms and/or functional limitations associated with a reduced health-related quality of life, despite conservative therapy, irrespective of age. Patients unfit for general anaesthesia can often be considered for surgery using regional anaesthesia, but severe dementia, active sepsis, leg ulcers and significant peripheral vascular disease are important contraindications. The first durable hip replacement, the Charnley low-friction arthroplasty, was 198 rheumatology developed by Sir John Charnley in the early 1960s, and some of his patients still have their implants to this day. His solution to the difficult problem of developing a durable surface with little wear-debris and a low coefficient of friction was to articulate a metal ball within a polyethylene (plastic) socket. In recent years younger patients have been deemed suitable for metal-on-metal hip replacements, which simply resurface the joint. Currently there is interest in the potential effects of metal ions on tissues in patients who have received a metal-onmetal joint replacement. Overall, about one-quarter of hip replacement surgery is for revision of an implant. About 90% of patients achieve a pain-free hip once recovery from the operation is complete. Overall, the risks of surgery are: death, 1%; infection, 1­2%; dislocation, 1­2%; and loosening 1% per annum to 10 years. Individual surgeon, implant and patient factors will greatly modify these broad figures. Infection after joint arthroplasty is a major concern and is often impossible to eradicate. It is possible that almost every joint is colonized by bacteria at the time of implantation, but frank infection occurs only on the rare occasions when the balance of host response to pathogen virulence favours infection. Also difficult to treat is the skin-borne Staphylococcus epidermidis, which now contributes to more than half of infected arthroplasties. Later infections cause loosening of the implant or cement interface with bone, and these need to be revised. Total joint replacement, however, results in pain relief and improved function within 4 months of surgery, but the range of movement may not be improved. Infection is difficult to eradicate in total joint arthroplasty, and very occasionally transfemoral amputation is undertaken for intractable infection. The risk­benefit analysis is otherwise very similar to that for total hip arthroplasty. Reasons should be sought; these include a congenitally hypoplastic lateral femoral condyle, inflammatory arthritis and an arthritic hip causing an adducted thigh. In patients with unicompartmental disease, unicompartmental knee replacement is effective, although a total knee replacement may prove more durable. Clinical and radiographic deterioration does, however, occur in one-third to two-thirds of patients followed up for 15 years despite frequent early improvement in pain and mobility. Crystal formation is also favoured by falls in local temperature, pH and by the presence of crystal nucleators. Microcrystals usually stimulate inflammation only after being shed in to synovial joints or bursae following loosening in the adjacent connective tissue matrix. The microcrystals have a highly negatively charged, reactive surface that can be directly membranolytic, as well as having the capacity to activate leucocytes and bind numerous serum and cell membrane proteins. Although crystal-induced inflammation is largely a neutrophil-dependent process, driven by the capacity of protein-coated crystals to activate and recruit leucocytes, the initial interaction may be with resident macrophages through Toll-like receptors. Subsequent activation of complement and vascular endothelial cells leads to vasodilation, increased blood flow and ingress of polymorphonuclear leucocytes with release of cascades of inflammatory mediators. Shedding of crystals in to the joint can provoke an attack of acute synovitis (pseudo-gout) and also a more chronic pyrophosphate arthropathy. Pyrophosphate arthropathy is two to three times more common in women than in men and usually presents in patients over the age of 70 years. Chondrocalcinosis, pseudo-gout and many cases of chronic pyrophosphate arthropathy can, however, be secondary to a range of inherited or acquired disorders associated with changes in pyrophosphate metabolism (Table 15. The menisci and articular cartilage of the knees are most frequently affected, but radiographic chondrocalcinosis can also be seen in the triangular cartilage of the wrists, the intervertebral discs, the symphysis pubis and the labrum of the acetabulum of the hip, and occasionally at other sites. The prevalence of radiographic chondrocalcinosis in the knees increases from less than 5% in people under the age of 70 years to nearly 30% in those aged over 85 years. Although the presence of chondrocalcinosis is not usually associated with symptoms of joint disease, the age-adjusted Table15. The knee is the site of more than half of all attacks, the duration of which can vary from a few days to 4 weeks. As its name implies, pseudo-gout can resemble acute gout with severe joint pain, swelling, tenderness and effusion associated with erythema of the overlying skin and systemic symptoms, so it is always important to consider the possibility of joint sepsis in the differential diagnosis. Chronic pyrophosphate arthropathy is more common than pseudo-gout and occurs more frequently in elderly women. Symptoms and signs vary according to the intensity of the associated inflammation. Radiographs may show evidence of chondrocalcinosis in fibro-cartilage or hyaline articular cartilage. They are also responsible for metastatic calcification in a number of metabolic disorders, and for ectopic, dystrophic calcification in a number of autoimmune rheumatic diseases and in many situations where there has been damage to the connective tissue matrix (Table 15. The shoulder region (supraspinatus tendon) is most frequently affected in middle-aged men or women, but monoarticular and polyarticular attacks can also occur in the region of the hip, knee, ankle, elbow or wrist. Rarely, calcific periarthritis is familial, or secondary to metabolic disorders, such as chronic renal failure or hyperparathyroidism. Definitive crystal identification involves X-ray diffraction, infra-red spectroscopy or electron microscopy, but is not required in clinical practice. Aspiration and/or corticosteroid injection may be necessary, but surgical excision is required only very rarely if massive deposits are the cause of painful impingement. Apatite-associated destructive arthropathy (cuff tear arthropathy; Milwaukee shoulder/knee syndrome) is a relatively uncommon but distinctive type of destructive arthritis seen in the elderly. The shoulders and knees are the main joints involved, but the wrists, hips and mid-tarsal joints are occasionally affected. Sudden onset of pain and swelling in a shoulder associated with the presence of a large cool effusion and the rapid development of joint subluxation and destruction are characteristic. Ultrasonography or radiography shows evidence of rotator cuff defects with upward migration and destruction of the humeral head, with relatively little osteophyte formation or bone remodelling. Clinical manifestations include acute arthritis, bursitis, tenosynovitis and cellulitis, tophaceous deposits, chronic arthritis, renal disease and urolithiasis. Prolonged hyperuricaemia is necessary but not sufficient for the development of gout. Gout and hyperuricaemia can be primary or secondary to drugs or disorders that interfere with uric acid excretion or augment the production of uric acid (Table 15. Levels are influenced by age, sex, body mass, ethnicity and genetic constitution as well as by dietary intake of purines and alcohol. Primary gout occurs predominantly in men, and gouty arthritis is exceptionally rare in women before the menopause. Gout in older women is usually secondary and often associated with renal insufficiency, hypertension and/or diuretic drug therapy. Primary gout is the most common cause of inflammatory arthritis in men over the age of 40 years and is an increasingly frequent cause of inflammatory arthritis in postmenopausal women. Uric acid is the end product of purine metabolism in humans, who lack the enzyme uricase that degrades uric acid to allantoin in most mammals. More than half of this is derived from endogenously synthesized purine nucleotides and the rest from ingested dietary purines. Sixty per cent of the uric acid pool is replenished daily from the catabolism of purine nucleotides and bases. Two-thirds of the uric acid formed each day is excreted by the kidney and onethird is eliminated via the gastrointestinal tract. Origin and fate of uric acid in normal humans clinical features Acute gout presents most frequently as an acute monoarthritis in one of the distal joints of the foot or hand. The onset may be insidious, but more typically is explosively sudden, frequently waking the patient from sleep. Very acute attacks may be accompanied by fever and systemic symptoms of inflammation, and are sometimes preceded by prodromal symptoms of anorexia, nausea or change in mood. Untreated first attacks will typically resolve spontaneously and completely in 1­2 weeks, sometimes with pruritus and desquamation of the overlying skin. Some patients suffer a single attack or experience another only after many years, but most patients will have a second attack within 12­18 months. If left untreated, patients tend to suffer recurrent acute or subacute attacks with increasing frequency. In such individuals, polyarticular acute gouty arthritis, bursitis and cellulitis are not uncommon and can lead to diagnostic confusion.

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