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RHEUMATICdr. Pandji M,SpPD,KEMDTERMINOLOGIArtralgia;keluhan rasa nyeri sekitar sendi,Px taaArtritis ;kelainanan sendi obyektiv,berupa Px inflamasi komplit Mono artritis; artritis mengenai satu sendi saja Oligo artritis/pauzi artikular;artritis yg nyerang 2 sp 4 sendi kecil DIP(distal inter falang) PIP(proximal inter falang),MCP,MTP(me tatarsofalangeal)Cont terminologiPoli artritis;artritis yg menyerang lbh 4 sendi kecilSinovotis;inflamasi sinovia sendi yg klinis nyataTenosinovitis;inflamasi sarung tendonTendinitis;inflamasi tendonBursitis;inflamasi bursaEntesopati;inflamasi/kelainan entesis(tempat me melekatnya ligamen,tendon,kapsul sendi ke perios tulang Musculoskeletal disorders may manifest as acute, subacute, or chronic problems. Pain and interference with daily activities are what bring the patient to a physician and determine the impact of the condition. A general medical approach to the patient with rheumatic complaints is :an accurate history and a thoughtful physical examination. only limited additional testing is required to diagnosis most musculoskeletal disorders, but in some instances assessment with a number of laboratory analyses, imaging studies, and other disciplines may be necessary.Examination ComponentsThere are four essential steps in musculoskeletal physical examination.

A. Inspection Inspect for asymmetry, deformity, erythema, and swelling.B. Palpation Palpate for tenderness, warmth, synovial thickening and effusion, bony hypertrophy, and crepitus.

C.Range of Motion Take the joint through passive or active ROM (or a combination of both

D. Special Testing Perform an assessment of supporting structures (such as ligaments and tendons) or for conditions particular to a single region (such as Tinel's sign at the wrist for detection of carpal tunnel syndrome).

Objective Joint Findings A careful examination is critical in distinguishing articular from periarticular conditions.Joint tenderness alone is insufficient for diagnosis and must be correlated with the finding of an objective, visible, or palpable abnormality for a diagnosis of arthritis to be made. Joint redness (erythema) depends on the acuteness and severity of the underlying inflammation, and its presence may suggest the possibility of infection or crystalline arthritis.

Joint warmth also depends on the acuteness of the underlying inflammation. Joint swelling is a definitive sign of arthritis and may be caused by either a joint effusion (excess synovial fluid) or an inflamed and swollen synovial membrane (synovitis). Bony hypertrophy around a joint (osteophytic swelling) is characteristic of osteoarthritis. Crepitus refers to a continuous grating sensation that is felt by the examiner's hand during joint motion. Fine or velvety crepitus may denote chronic proliferative synovitis, whereas coarse crepitus may indicate either roughening of the cartilage surface or complete loss of hyaline cartilage. Joint damage and deformity are usually signs of prior arthritis or injury (ligamentous laxity, joint subluxation, tendon rupture, or contracture

Range of Motion

Both active and passive ROM are important in assessing joint function. Active ROM is patient-initiated movement of the joint; it tests integrated function and requires intact innervation and muscle and tendon function, as well as joint mobility. Passive ROM is examiner-initiated movement of a joint; it tests only joint mobility. The combined use of passive and active ROM minimizes the need for patient instruction and maximizes the speed and efficiency of the examination.

Whenever joint motion is anticipated to be painful, it is best to first observe active ROM, to appreciate the degree of pain and dysfunction, before gently attempting passive ROM.

Extra-articular Findings Because many rheumatic diseases are multisystem disorders, physical examination may document the presence of important extra-articular features. In RA, for example,these include subcutaneous nodules, digital vasculitis, and other systemic features as described

Classification

Clinical evaluation enables the establishment of which anatomic structures are inflamed, which are damaged, and how function is impaired. Nine types of rheumatic involvement can be identified as a framework for various diagnostic possibilities or hypotheses to be considered (see Fig. 277-1B ). The nine categories presented in the following paragraphs are listed in Table 277-1 along with typical diseases, examples of useful diagnostic tests, and treatments..

Synovitis

Inflammation of the synovial membrane lining of the joint is typical of inflammatory polyarthritides such as RA and other autoimmune diseases. Persistent synovitis in RA may lead to irreversible joint damage

EnthesopathyThe enthesis is the anatomic transition zone where tendons, ligaments, and joint capsules attach to bone. Inflammation in this region is the hallmark of the family of spondyloarthropathies, of which ankylosing spondylitis is the prototype. Other members of this group include reactive arthritis associated with enteric or urethral infection, the arthropathy associated with inflammatory bowel disease, and psoriatic arthritis. In ankylosing spondylitis, the sacroiliac joints and apophyseal joints of the spine show characteristic inflammation with a tendency to bony ankylosis (axial predominance), whereas in psoriatic arthritis there is frequently enthesitis with an oligopolyarthritis (peripheral predominance

Crystal-Induced Synovitis

Crystals of monosodium urate (gout), calcium pyrophosphate (pseudogout), or hydroxyapatite are capable of inducing an acute inflammatory reaction in both synovial fluid and synovium. Acute crystalline arthritis usually affects only one or at most a few joints at a time. Joint aspiration and synovial fluid analysis for crystals using polarized light microscopy establish the diagnosis. Calcium pyrophosphate deposition disease (CPPD) is often associated with the radiologic appearance of chondrocalcinosis of hyaline cartilage.

Joint Space Disease

Septic arthritis may develop from hematogenous spread of microorganisms into the joint space, through local extension from adjacent soft tissues or by joint penetration. Joint infections are usually associated with intense pain even at rest, and the diagnosis is confirmed by joint aspiration with Gram stain and culture of the synovial fluid. A joint prosthesis increases susceptibility to infection in that joint. Blood in the joint space, known as hemarthrosis, may result from microfractures, coagulopathy, or tumor

Cartilage Degeneration OA is defined as loss of articular cartilage with a bony response leading to the formation of osteophytes. Primary OA is thought to be caused by biochemical abnormalities in the cartilage that predispose to microfissures in the surface and subsequent degeneration of the cartilage. Secondary OA may develop as a consequence of inflammatory conditions such as RA, ankylosing spondylitis, septic arthritis, and CPPD. Previous trauma and joint hypermobility are other mechanical factors that may predispose to OA

Osteoarticular Disease

Osteopenia/osteoporosis may complicate many rheumatic conditionsOsteonecrosis, which results from collapse of the bony end plate due to vascular insufficiency, causes secondary crushing and fragmentation of the overlying articular cartilage. Osteonecrosis may be idiopathic or associated with systemic conditions such as sickle cell disease or liver disease; it may occur after treatment with high-dose corticosteroids. Inflammation of the periosteum, known as periostitis, may be associated with hypertrophic pulmonary osteoarthropathy and clubbing. This syndrome may be a clue to underlying lung cancer.

Inflammatory Myopathy

Inflammation and (usually painless) weakness of the proximal skeletal muscles are characteristic of inflammatory myopathies: polymyositis, dermatomyositis, inclusion body myositis. Elevatedcreatinekinaselevels, electromyographic abnormalities, and characteristic histologic abnormalities on muscle biopsy are present in inflammatory myopathies

Local and Regional Conditions

Nonarticular disorders such as tendonitis, bursitis, and neck and low-back strains are very common regional problems. They usually respond to analgesics or nonsteroidal anti-inflammatory drugs, physical therapy, protective splints, injection of corticosteroids

General Conditions

These nonarticular or extra-articular disorders are not usually associated with arthritis. This group includes polymyalgia rheumatica, complex regional pain syndrome/reflex sympathetic dystrophy, and fibromyalgia. Polymyalgia rheumatica usually affects Caucasians older than 50 years of age and causes proximal muscle pain in the neck, shoulders, and hips, with significant morning stiffness and a high erythrocyte sedimentation rate. It is sometimes associated with giant cell (temporal) arteritis. Fibromyalgia usually manifests in individuals younger than 50 years of age; is associated with widespread arthralgia and myalgia (deceptively inflammatory-sounding), morning stiffness, significant fatigue, and nonrestorative sleep. It is accompanied by the presence of tender points.

The pathogenetic mechanisms and feedback loops associated with structural damage to the cartilage structure and associated alteration in chondrocyte function are demonstrated in Figure 283-1 .

TABLE 283-2 --RECOMMENDATIONS FOR PHARMACOLOGIC MANAGEMENT OF OSTEOARTHRITIS OF THE HIP AND KNEE[*]ORAL AcetaminophenNonselective NSAID plus misoprostol or a proton pump inhibitor[]COX2-selective inhibitorNonacetylated salicylateOther pure analgesicsGlucosamine and/or chondroitin sulfateTramadolOpioidsCLASSIFICATION CRITERIA FOR RHEUMATOID ARTHRITIS[*] 1. Morning stiffness (1 hr) 2. Swelling (soft tissue) of three or more joints 3. Swelling (soft tissue) of hand joints (PIP, MCP, or wrist) 4. Symmetrical swelling (soft tissue) 5. Subcutaneous nodules 6. Serum rheumatoid factor 7. Erosions and/or periarticular osteopenia in hand or wrist joints seen on radiograph * Criteria 1 through 4 must have been continuously present for 6 wk or longer, and criteria 2 through 5 must be observed by a physician. A classification as rheumatoid arthritis requires that four of the seven criteria be fulfilled. MCP = metacarpophalangeal; PIP = proximal interphalangeal

TABLE 285-3 --DIFFERENTIAL DIAGNOSIS OF RHEUMATOID ARTHRITISDisorder Subcutaneous Nodules Rheumatoid Factor -Viral arthritis (hepatitis B and C, parvovirus, rubella, others) - Bacterial endocarditis + Rheumatic fever + - Sarcoidosis + + Reactive arthritis - - Psoriatic arthritis - - Systemic lupus erythematosus + Primary Sjgren's syndrome + Chronic tophus gout + - Calcium pyrophosphate disease - - Polymyalgia rheumatica - - Osteoarthritis (erosive) - - - = not present; + = frequently present; = occasionally present

EXTRA-ARTICULAR MANIFESTATIONS OF RHEUMATOID ARTHRITISSkin Nodules, fragility, vasculitis, pyoderma gangrenosum Heart Pericarditis, premature atherosclerosis, vasculitis, valve disease, and valve ring nodules Lung Pleural effusions, interstitial lung disease, bronchiolitis obliterans, rheumatoid nodules, vasculitis Eye Keratoconjunctivitis sicca, episcleritis, scleritis, scleromalacia perforans, peripheral ulcerative keratopathy Neurologic Entrapment neuropathy, cervical myelopathy, mononeuritis multiplex (vasculitis), peripheral neuropathy Hematopoietic Anemia, thrombocytosis, lymphadenopathy, Felty's syndrome Kidney Amyloidosis, vasculitis Bone OsteopeniaMedical Therapy

In the treatment of RA, three types of medical therapies are used: NSAIDs, glucocorticoids, DMARDs (both conventional and biologic).

Initial combination therapy appears to be preferred over monotherapy

I. Nonsteroidal Anti-inflammatory Drugs

NSAIDs are important for the symptomatic relief they provide to RA patients; however, they play only a minor role in altering the underlying disease process. Therefore, NSAIDs should rarely, if ever, be used to treat RA without the concomitant use of DMARDs. Many clinicians waste valuable time switching from one NSAID to another before starting DMARD therapy.Much has been written about the gastrointestinal toxicity of NSAIDs, and these concerns are particularly relevant to RA patients, who often have significant risk factors including age and concomitant steroid use. Therefore, cyclooxygenase-2 (COX2)-selective agents have been a popular choice for patients with RA. The recent evidence linking these agents to increased cardiovascular toxicity has been particularly troubling for patients with RA, who are already at high risk for myocardial infarction.

Therefore, if COX2-selective agents are used, they should be kept at a low dose. Consideration should be given to low-dose aspirin prophylaxis in RA, but this may increase the gastrointestinal toxicity of NSAIDs. The use of concomitant misoprostol or proton pump inhibitors should be considered in all patients with RA who are taking NSAIDs. Additionally, the potential for NSAIDs to decrease renal blood flow and to increase blood pressure should be kept in mind.II. Glucocorticoids

Glucocorticoids have had a significant role in the treatment of RA for more than half a century. Indeed, RA was chosen as the first disease to be treated with this new therapy, partly because it was thought that RA was a disease of glucocorticoid deficiency (an issue that remains unresolved). As was the case with the first patient treated in 1948, glucocorticoids are dramatically and rapidly effective in patients with RA. Not only are glucocorticoids useful for symptomatic improvement, but they significantly decrease the radiographic progression of RA. However, the toxicities of long-term therapy are extensive and potentially devastating. Therefore, the optimal use of these drugs requires an understanding of several principles

Glucocorticoids remain among the most potent anti-inflammatory treatments available; for this reason and because of their rapid onset of action, they are ideally suited to help control the inflammation in RA while the much slower-acting DMARDs are starting to work. Prednisone, the most commonly used glucocorticoid, should rarely be used in doses higher than 10 mg/day to treat the stiffness and articular manifestations of RA. This dose should be slowly tapered to the lowest effective dose, and the concomitant DMARD therapy should be adjusted to make this possible. Glucocorticoids should rarely, if ever, be used to treat RA without concomitant DMARD therapy. The paradigm is to shut off inflammation rapidly with glucocorticoids and then to taper them as the DMARD is taking effect (bridge therapy). In all patients receiving glucocorticoids, strong measure should be taken to prevent osteoporosis. Bisphosphonates have been shown to be particularly effective in this regard. Higher doses of glucocorticoids may be necessary to treat extra-articular manifestations, especially vasculitis and scleritisIII. Disease-Modifying Antirheumatic Drugs

DMARDs are a group of medications that have the ability to greatly inhibit the disease process in the synovium and modify or change the disabling potential of RA. In most cases, these drugs have the ability to halt or slow the radiographic progression of RA.Conventional DMARDs Included in this group of medications are methotrexate, sulfasalazine (Azulfidine), gold, antimalarials (Plaquenil and others), leflunomide (Arava), azathioprine (Imuran), minocycline. It is critically important that clinicians and patients understand that conventional DMARDs take 2 to 6 months to exert their maximal effect, and all require some monitoring ( Table 285-7 ). Therefore, other measures such as glucocorticoid therapy may be needed to control the disease while these medications are starting to work.32All of these DMARDs have been shown to be effective in treating both early and more advanced RA that remains active. Until additional research elucidates factors that allow selection of the best initial therapy for each patient, the choice will depend on patient and physician concerns about toxicity and monitoring issues, as well as the activity of disease and comorbid conditions. The critical factor is not which DMARD to start first but getting the DMARD therapy started early in the disease process.

METHOTREXATE.Methotrexate is the preferred DMARD of most rheumatologists, in part because patients have a more durable response, and because, with correct monitoring, serious toxicities are rare. Methotrexate is dramatically effective in slowing radiographic progression and is usually given orally in doses ranging from 5 to 25 mg/week as a single dose. This once-a-week administration is worthy of emphasis; prior experience with daily therapy in psoriasis has demonstrated the importance of allowing the liver time to recover between doses. Oral absorption of methotrexate is variable; subcutaneous injections of methotrexate may be effective if oral treatment is not.

Side effects of methotrexate include oral ulcers, nausea, hepatotoxicity, bone marrow suppression, and pneumonitis. With the exception of pneumonitis, these toxicities respond to dose adjustments. Monitoring of blood counts and liver blood tests (albumin and aspartate aminotransaminase [SGOT] or alanine aminotransferase [SGPT]) should be done every 4 to 8 weeks, with dosage adjustments as needed. Renal function is critical for clearance of methotrexate; previously stable patients may experience severe toxicities when renal function deteriorates. Pneumonitis, although rare, is less predictable and can be fatal, particularly if the methotrexate is not stopped or is restarted. Folic acid, 1 to 4 mg/day, can significantly decrease most methotrexate toxicities without apparent loss of efficacy. If methotrexate alone does not sufficiently control disease, it is combined with other DMARDs. Methotrexate in combination with virtually any of the other DMARDs (conventional or biologic) has been shown to be more effective than either drug alone.[2]LEFLUNOMIDE.

Leflunomide, a pyrimidine antagonist, has a very long half-life and is most commonly started at 10 to 20 mg/day orally. A loading dose of 100 mg/day for 3 days was previously recommended, but because it increases diarrhea, the most common toxic effect of this drug, loading treatment is no longer advocated. Diarrhea responds to dose reduction, and doses of leflunomide of 10 to 20 mg three to five times per week are frequently used. Also, because of its long half-life and its teratogenic potential, women wishing to become pregnant who have previously received leflunomide, even if therapy was stopped years ago, should have blood levels drawn. If toxicity occurs or if pregnancy is being considered, leflunomide can be rapidly eliminated from the body by treatment with cholestyramine. Laboratory monitoring for hematologic and hepatic toxicity should be done during treatment with leflunomide, as recommend for methotrexate.

ANTIMALARIAL DRUGS.The antimalarial drugs hydroxychloroquine (Plaquenil) and chloroquine are frequently used for the treatment of RA. They have the least toxicity of any of the DMARDs and do not require monitoring of blood tests. Yearly monitoring by an ophthalmologist is recommended to detect any signs of retinal toxicity (rare). Hydroxychloroquine is the most commonly used preparation and is given orally at 200 to 400 mg/day. These drugs are frequently used in combination with other DMARDs, particularly methotrexate.[2]

SULFASALAZINE. Sulfasalazine has been the most commonly used DMARD in Europe. It is an effective treatment when given in doses of 1 to 3 g/day. Monitoring of blood counts, particularly white blood cell counts, in the first 6 months is recommended.

MINOCYCLINE. Minocycline, 100 mg twice daily, has been shown to be an effective treatment for RA, particularly when used in early, RF-positive disease. Chronic therapy (longer than 2 years) with minocycline may lead to cutaneous hyperpigmentationGOLD.

Gold, the oldest DMARD, when given intramuscularly, remains an extremely effective therapy for a small percentage of patients. It is less commonly used because of its slow onset of action, need for intramuscular administration, frequent monitoring required (complete blood count and urinalysis), and frequent toxicities. Toxicities include skin rashes, bone marrow suppression, and proteinuria.Biologic DMARDs

Recent research has continued to elucidate the central role that cytokines, most notably TNF- and IL-1, play in the pathophysiology of RA. This has led directly to the development and clinical use of biologic agents directed against TNF-1 (etanercept [3] [Enbrel], infliximab [4] [Remicade], adalimumab [5] [Humira]) and IL-1 (anakinra [Kineret]). Two other biologicals have recently been approved: rituximab (Rituxan) and abatacept (Orencia). All RA patients receiving biologic therapies should be monitored by a rheumatologist, and their physicians should be aware of the risk for infections that are often atypical. Currently, biologic agents should not be used in combination with each other, because all studies to date have shown a significant increase in infections

ANTI-TNF- DRUGSThis category of drugs includes etanercept, a recombinant TNF receptor fusion protein that is administered by subcutaneous injection at 50 mg once weekly. Infliximab is a mouse/human chimeric monoclonal antibody against TNF- that is given intravenously (3 to 10 mg/kg) every 4 to 8 weeks. Adalimumab is a human monoclonal antibody against TNF- that is given subcutaneously at 40 mg every other week. All three anti-TNF agents have been shown to be highly effective against both clinical symptoms and radiographic progression of RA, particularly when used in combination with methotrexate. A rapid onset of action (days to weeks) is apparent and is a significant advantage that these treatments have over conventional DMARDs. Current disadvantages include cost and long-term toxicities, in particular infections (especially tuberculosis and others), and malignancies, [6] as well as heart failure, rare demyelinating, and autoimmune syndromes.

ANAKINRAAnakinra, a recombinant human IL-1 receptor antagonist, is given subcutaneously at 100 mg/day. It has been shown to be effective against signs and symptoms of RA as well as radiographic progression. Its onset of action is somewhat slower and less dramatic than that of the TNF inhibitors. Toxicities include injection site reactions and pneumonia (especially in patients with asthma

RITUXIMAB.Rituximab is a chimeric monoclonal antibody that targets CD20 + B cells and is given intravenously in two infusions of 500 to 1000 mg spaced two weeks apart. This results in marked reductions in circulating B cells for 6 to 12 months and significant clinical responses. The need for and timing of further courses is determined by the patient's ongoing response. Rituximab has been used for years to treat B cell lymphoma.

ABATACEPT.

Abatacept is made by genetically fusing the external domain of human CTLA4 to the heavy-chain of human IgG1 and binds both CD80 and CD86 on antigen presenting cells thus inhibiting T cells from receiving their second signal via CD28. It is administered intravenously 10 mg/kg on days 1, 15, 30 and then monthly

Treatment of Underlying Conditions

Optimal care of patients with RA requires recognition of the associated comorbid conditions, including :an increased risk of cardiovascular death, osteoporosis, infections (especially pneumonia),certain cancers

Cardiovascular Disease

Increasingly, cardiovascular disease is being recognized as the cause of much of the excess mortality in RA. A number of factors contribute to this mortality:sedentary lifestyle, glucocorticoid therapy, treatments that increase homocysteine levels, such as methotrexate and sulfasalazine. However, recently a strong association between chronic inflammation and cardiovascular disease was identified, and it is likely that this may be the most significant factor. Therapies that control RA earlier and better can be expected to decrease cardiovascular morbidity and mortality. Clinicians should consider RA a risk factor for cardiovascular disease and should aggressively address other cardiovascular risk factors in their rheumatoid patients.

Osteoporosis

Osteoporosis is common in patients with RA, and early treatment results in long-term dividends. Patients with RA are at an increased risk for infections, and some forms of treatment further increase this risk. Patients should be cautioned to seek medical attention early for even minor symptoms suggestive of infection, especially if receiving anti-TNF therapy. All patients with RA should receive a pneumococcal vaccine at appropriate intervals and yearly influenza vaccinations. Finally, patients with RA have an increased risk of lymphoma. Occasionally, B-cell lymphomas are associated with immunosuppression and regress after immunosuppression is discontinued. RA patients have significantly decreased risk (odds ratio, 0.2) of developing colon cancer. This is thought to be secondary to chronic inhibition of COX by NSAIDsTABLE 285-5 --KEYS TO OPTIMIZE OUTCOME OF TREATMENT OF RAEarly, accurate diagnosisEarly DMARD therapyStrive for remission in all patientsMonitor carefully for treatment toxicitiesConsider and treat comorbid conditions[*] DMARD = disease-modifying antirheumatic drug; RA = rheumatoid arthritis.

* Important comorbid conditions include cardiovascular disease, increased susceptibility to infections, and osteoporosis

TABLE 285-6 --GUIDELINES FOR USE OF GLUCOCORTICOIDSAvoid use of glucocorticoids without DMARDsPrednisone >10 mg/day is rarely indicated for articular diseaseTaper to the lowest effective doseUse as bridge therapy until DMARD therapy is effectiveRemember prophylaxis against osteoporosis DMARD = disease-modifying antirheumatic drug.

TABLE 285-7 --CAVEATS FOR MONITORING DMARD THERAPIES[*]

TABLE 285-7 --CAVEATS FOR MONITORING DMARD THERAPIES[*]Medication Caveats Prednisone Use as bridge to effective DMARD therapy, prophylaxis for osteoporosis? (see Table 285-6 ) Hydroxychloroquine Keep dosage lower than 6.5 mg/kg/day; yearly eye checkup by ophthalmologist Sulfasalazine CBC for neutropenia, initially every month, then every 6 mo Methotrexate CBC and SGOT/SGPT every 48 wk; many toxicities respond to folic acid or small dose reduction; if pneumonitis, stop and do not restart; decreasing renal function may precipitate toxicities; absolute contraindication in pregnancy Leflunomide CBC and SGOT/SGPT evert 48 wk; long half-life may require cholestyramine washout; absolute contraindication in pregnancy TNF inhibitors If fevers or infectious symptoms of any kind, stop until symptoms resolve; aggressively work-up and treat possible infections; may precipitate congestive heart failure, demyelinating syndromes, or lupus-like syndromes CBC = compete blood count; DMARD = disease-modifying antirheumatic drug; SGOT = serum glutamate oxaloacetate transaminase (aspartate aminotransferase); SGPT = serum glutamate pyruvate transaminase (alanine aminotransferase); TNF = tumor necrosis factor.

TABLE 294-1 --HYPERURICEMIA: CAUSES AND CLASSIFICATION[*] A. Uric acid overproduction 1. Primary hyperuricemia Idiopathic HGPRT deficiency (partial and complete) PRPP synthetase superactivity 2. Secondary hyperuricemia Excessive dietary purine intake Increased nucleotide turnover (e.g., myeloproliferative and lymphoproliferative disorders, hemolytic diseases, psoriasis, and Paget's disease of bone) Accelerated ATP degradation Ethanol abuse Glycogen storage diseases (types I, III, V, VII) Fructose ingestion, hereditary fructose intolerance Hypoxemia and tissue underperfusion Severe muscle exertion ? Hypertriglyceridemia (via metabolism of excess acetate. Uric acid underexcretion 1. Primary hyperuricemia Idiopathic (influenced by gender and ethnicity) Familial juvenile hyperuricemic nephropathy 2. Secondary hyperuricemia Diminished glomerular filtration rate Enhanced tubular urate reabsorption Dehydration Diuretics Insulin resistance (metabolic syndrome) Inhibition of tubular urate secretion Competitive anions (e.g., keto and lactic acidosis) Mechanism incompletely defined Hypertension Hyperparathyroidism Hypothyroidism Certain drugs (e.g., cyclosporine, pyrazinamide, ethambutol, and low-dose salicylates) Lead toxicity with nephropathy ATP = adenosine triphosphate; HGPRT = hypoxanthine-guanine phosphoribo-syltransferase; PRPP = phosphoribosylpyrophosphate

Clinical Manifestations

Gout is classically manifested as recurrent attacks of acute arthritis characterized by often excruciatingly painful articular and periarticular inflammation, including erythema and edema of the skin that can mimic bacterial cellulitis. Acute gouty arthritis is typically monarticular or oligoarticular. Stereotypical involvement of the first MTP joint is termed podagra. Acute polyarticular gout can also occur, particularly in the elderly and in transplant patients taking cyclosporine. This manifestation can be associated with substantial systemic leukocytosis and temperature elevation mimicking sepsis. Chronic gouty inflammation and proliferative, erosive arthritis in gout can also mimic rheumatoid arthritis.

Goutytophi can involve not only the synovium and cartilage of joints but also subchondral bone and soft tissues, including the olecranon bursa, the first MTP joint bursa, and the helix of the ear. Olecranon bursitis may occur in association with gout, but tophi in the olecranon bursa often remain clinically quiescent. Uric acid urolithiasis is a common manifestation of gout, particularly in acid urine. Excessive excretion of uric acid in the urinary tract also promotes calcium oxalate urolithiasis. Interstitial nephropathy, characterized by the deposition of monosodium urate in the renal medulla at physiologic pH, is currently a rare manifestation of gout, largely because of advances in recognition and treatment of gout and hypertension.

Onset of gout (with or without tophaceous crystal deposits) in early adulthood and a high incidence of uric acid urinary tract stones constitute the common clinical phenotype in both partial deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and milder forms of superactivity of 5-phosphoribosyl 1-pyrophosphate (PP-ribose-P) synthetase. Severe HGPRT deficiency is associated with spasticity, choreoathetosis, mental retardation, and self-mutilation (Lesch-Nyhan syndrome). In some subjects, regulatory defects in PP-ribose-P synthetase are accompanied by sensorineural deafness and neurodevelopmental defects. The genes for both HGPRT and PP-ribose-P synthetase are X-linked. Thus, homozygous males are affected, and postmenopausal gout and urinary tract stones can occur as the phenotype of carrier females. Hyperuricemia in prepubertal boys always suggests the need to determine whether one of these enzymatic defects is the etiology