Rheumatology

1. Rheumatology On-anong Waleekhachonloet Usasiri Srisakul Faculty of Pharmacy Mahasarakham University

2. Objectives ??????????????????????????????????????????????????????? ????????????????????????????????????????????????????? ????????????????????????????????????????????????????????? ??????????????????????????????????????????????????????????? ?????????????????????????????????????? ??????????????????????????????????????????????????? ?????????????????????????????????????????????????????????????????????????

3. All contents Systemic arthritis - Rheumatoid arthritis (RA) - Reactive arthritis and spondyloarthritis - Ankylosing spondylitis - Psoriatic arthritis Diffuse connective tissue diseases - Systemic Lupus Erythematosus (SLE) - Scleroderma - Polymyositis and dermatomyositis - Sjogren�s syndrome - Antiphospholipid syndrome - Vasculitis

4. All contents (cont.) Metabolic diseases - Gout - Osteoporosis - Osteonecrosis Degenerative joint disease - Osteoarthritis - Back pain - Spinal stenosis Infectious arthritis - Bacterial, viral, fungal, tuberculous - Rheumatic fever Soft tissue rheumatism - Bursitis and tendinitis - Shoulder pain - Fibromyalgia syndrome

5. Contents for learning Introduction to Rheumatic diseases Osteoporosis Osteoarthritis (OA) Crystal induced arthritis Rheumatoid arthritis (RA) Systemic Lupus Erythematosus (SLE) Infectious arthritis Bursitis and tendinitis Myofascial pain syndrome (MPS) Fibromyalgia Scleroderma Back pain Drug used in rheumatology, pregnancy and lactation

6. Evaluation of Patients with Musculoskeletal Complaints Goals Accurate diagnosis Timely provision of therapy Avoidance of unnecessary diagnostic testing Approach Anatomic localization (articular vs. nonarticular) Nature of the pathologic process (inflammatory vs. noninflammatory) Extent of involvement (monoarticular, polyarticular, focal, widespread) Chronology (acute vs. chronic) Formulation of a differential diagnosis

8. Articular VS. Non-articular Deep or diffuse pain Limited range of motion on active and passive movement Swelling Crepitation Instability Locking Deformity Painful on active but not passive Demonstrate point or focal tenderness in regions Distinct from articular structures Have physical findings remote from the joint capsule. Seldom have crepitus, instability, or deformity.

9. Inflammatory disorders Cardinal signs of inflammation (erythema, warmth, pain, or swelling) Systemic symptoms (prolonged morning stiffness, fatigue, fever, weight loss) Laboratory evidence of inflammation [elevated erythrocyte sedimentation rate (ESR) or C-reactive protein,thrombocytosis, anemia of chronic disease, or hypoalbuminemia].

10. Examples of Inflammatory disorders infectious (infection with Neisseria gonorrhoea or Mycobacterium tuberculosis) Crystalinduced (gout, pseudogout) Immune-related (RA, SLE) Reactive (rheumatic fever, reiter�s syndrome) Idiopathic

11. Clinical history Patient profile: age, gender, race, and family history

12. GENDER More common in females - Rheumatoid arthritis 3-7:1 - Systemic Lupus Erythematosus 5-11:1 - Gonococcal arthritis 2:1 - Osteoarthritis 2:1 More common in males - Gout 9:1 - Ankylosing spondylitis 11:1 - Reiter�s syndrome 20:1 RACIAL White: polymyalgia rheumatica, giant cell arteritis Black: sarcoidosis and SLE FAMILY Ankylosing spondylitis, gout, RA, and Heberden�s nodes of osteoarthritis.

13. Onset Abrupt: trauma, septic arthritis, crystal induced arthritis Insidious: tuberculous arthritis, rheumatoid arthritis, OA Evolution Monoarticular: trauma, septic arthritis, gout, pseudogout, OA Oligoarticular, polyarticular type: - Gonococcal arthritis, Gouty arthritis, OA, SpA RA, SLE, connective tissue diseases eg scleroderma, dermato/ polymyositis, vasculitis Onset, evolution, and duration.

14. Duration Musculoskeletal disorders are typically classified as acute or chronic based upon 6 week period Acute: tend to be infectious, crystal-induced, or reactive. Chronic: noninflammatory and immunologic disorders such as osteoarthritis or RA, respectively.

15. Other considerations Precipitating factors: trauma, illness, medications, occupation, An associations with systemic features: - Fever (SLE, infection) - Rash (SLE, Reiter�s syndrome dermatomyositis) - Myalgias, weakness (polymyositis, polymyalgia rheumatica) - Morning stiffness (inflammatory arthritis).

16. Physical examination Examination of involved and uninvolved joints will determine whether pain, warmth, erythema, or swelling is present. Pain intensity: scale of 1 to 10 Muscle strength: - 0 for no movement - 1 for trace movement or twitch - 2 for movement with gravity eliminated - 3 for movement against gravity only - 4 for movement against gravity and resistance - 5 for normal strength.

17. Laboratory examination  ??????????????? (synovial fluid analysis) ??????????????????????????????? hyaluronic acid ?????????????????????? ??????????????????????? ???????????????????????????????????????????????? ???? ?????? ???????????????? ????????????????????????????????????????????? ???????????????????????????????????? ? ?????????????????????????????? ??????????????????????, ????????????, ??????? 3-5 mL(???????), pH 7.3-7.43

18. ??????????????????? - ??, ????????, ???????? ?????????????????????????????? ????????????????????? hyaluronidase ?????????? hyaluronic acid - ??????? clot formation ??????????????????????????? ??????????????????????? clotting factors ??????????????????????????????????? ???????????????????? 2. Mucin clot ??? ??????????????????????? hyaluronic acid ????????????????????????????????????????????????? ?????????????? hyaluronic acid ???????????????????????????????????????????? 3. ????????????????? 4. ??????????????????? ???? ?????????????????, LE cell ??????????????????

19. 5. ????????????? - monosodium urate crystal (MSU) ?????????????????, - calcium pyrophosphate dehydrate crystal (CPPD) ?????????????????????? 6. ???????????????????????? - ???????????????????????? ? ??????????????????????????????????? 1/3 ????????????????????? - ????????????????????????????????????????? 7. ??????????????????????????? ????????????????????????????? (hematrosis) ??????????????????????? 8. ?????????????????????????? - complement protein, rheumatoid factor, autoantibodies

21. Complete blood count (CBC) ????????????????? ? ??????????????????? Hb < 8 g/dL: iron deficiency, bleeding, ??????????????????????????????????? ????????????????????????? ???? ??????????? ??????? Leukocytosis: ???????????????????????????? ???????????????? ????????????????????????????: ?????????????? ?????????????????????? ??????????????????: ?????????????????????? ?????????????? ?????????????????????????????????????????: SLE

22. ESR ??? CRP acute phase protein ????????????????????????? ??????????, ???????????????????????????, ????????????, ????????????????????, ??????????????????? ????????????????????????????????? (psychosomatic) CRP ?????????????????????????????? ESR ??? CRP ????????????????????????????????? 1-2 ??? ???? 2 ?????????????????????????????????????????????? ??????????????????????????????? ???? ????????????????????, ?????????????????????, ???????? ESR (Erythrocyte Sedimentation Rate) ??? C-reactive protein (CRP)

23. Renal function test - SLE, chronic gout Liver function test - ?????????????????????????????????????????????? ?????? - ????????????????, ???????????????? - ??????????????????? (polymyositis) Renal and liver function test

24. Rheumatoid factor (RF) ??? autoantibody ???????????? IgG Circulating autoantibodies anti-double stranded DNA (Anti-dsDNA), Anti-Sm antibody antinuclear antibody (ANA) Serum complement proteins Lupus Erythematosus cell (LE cell) ?????????????????????? 60-70 ???????????????????? 100 ???????????????????????? Other tests

25. ?????????????????????????????? ??????????????????? ????????????????????????????? ???????????????? ??????????????????????, ???????????????????, ????????????????????????????? ????????????????????????????? ???????????? Radionucleide imaging Arthrogram Arthroscopy Other tests

27. OSTEOPOROSIS

28. Osteoporosis definition

29. Osteoporosis Bone resorption > Bone formation Low bone mass and bone density Bone fragility (abnormally thin trabeculae)? fractures (spine, femur, neck) Mineral content is normal Elderly ? fractures?morbidity and mortality

31. Remodeling is constant Teen years more bone is laid down than reabsorbed Peak bone mass or maximum density reached at around 30 years of age After age 30, bone is reabsorbed faster than it is laid down In women, bone loss is most rapid in the first years after menopause, but continues throughout postmenopausal years Approximately 55% of people over 50 have osteoporosis or low bone mass.

32. Men also lose bone density, but start out with more bone mass so takes longer. By age 90 about 17% of males have had a hip fracture, vs. 32 % of females Vertebral fractures also occur ? kyphosis Most common in whites, but affects all races. African Americans have about half the fracture rates of whites (higher peak bone mass)

34. Risk factors Family history White race Increased age Female sex Small stature Fair or pale skin Thin build Early menopause (natural or surgical) Late menarche

35. Risk factors cont. Nulliparity Obesity Weight below a healthy range Acidosis Low dietary calcium and vitamin D High caffeine intake Sedentary life style Smoker Excessive alcohol consumption Liver, kidney disease, rheumatoid arthritis, etc.

36. Risk factors cont. Medications - Glucocorticoids: prednisolone > 7.5 mg/day - Heparin (> 15,000-30,000 U/day, > 3-6 months) - Thyroid hormone - Anticonvulsants

37. Diagnosis - X-ray imaging: thin in trabeculae bone - Bone mass - Bone density (DEXA: Dual-energy x-ray absorptiometry) Osteoporosis

38. Often progresses silently for decades until fracture occurs Bones can fracture spontaneously Most severe in spine, wrist and hips Estrogens and androgens may be factors in both sexes Testosterone is converted into estrogen in peripheral tissues and decreases bone loss Rapid bone loss is osteoclast mediated Slow bone loss is osteoblast mediated

39. Clinical manifestations Pain and bone deformity Kyphosis caused by vertebral collapse Fractures of long bones Fatal complications include fat or pulmonary embolism, pneumonia, hemorrhage and shock 20 % die as a result of surgical complications

40. Clinical manifestations

44. Desired outcomes Achieve the highest peak bone mass until 30 yrs. Maintain BMD and minimize age-related and postmenopausal bone loss. Prevent osteoporosis in individuals with osteopenia. To increase BMD, prevent further bone loss, and prevent falls, fractures, and their complications in osteoporosis patients. To achieve adequate pain control, maximize rehabilitation to restore independence and QOL, and prevent subsequent fractures or death for those who experience an osteoporosis-related fracture.

46. Non pharmacologic prevention and treatment Having a balanced diet with adequate intake of calcium and vitamin D If adequate dietary intake cannot be achieved, calcium supplements are necessary. Although 2 to 5 cups of coffee produce small increases in calcium excretion, this effect can be offset by increased calcium intake. Smoking cessation increases BMD, whereas continued smoking decreases BMD and increases fracture risk. Weight-bearing aerobic and strengthening exercises may prevent bone loss and decrease falls and fractures.

48. Pharmacologic prevention and treatment Antiresorptive Therapy Calcium Vitamin D bisphosphonates Selective estrogen receptor modulators (SERM) Calcitonin Estrogen and hormonal therapy Phytoestrogens Testosterone and anabolic steroids Bone formation therapy Teriparatide (Parathyroid Hormone)

49. Antiresorptive Therapy Calcium Calcium carbonate - Contains the highest conc of elemental calcium (40%) - The least expensive - Should be ingested with meals to enhance absorption - It can create gas, causing flatulence or upset stomach Calcium citrate - Need not be taken with meals. - Absorption decreases with increasing dose, maximum single doses of = 600 mg of elemental calcium are recommended. Constipation is the most common ADR of Ca

50. Antiresorptive Therapy (Cont.) Vitamin D and metabolites Vitamin D deficiency results from insufficient intake, decreased sun exposure, decreased skin production, and decreased liver and renal metabolism. Supplemental vitamin D has been shown to increase BMD, and it may reduce fractures. Many experts recommend vitamin D intake 800 to 1000 units daily for adult.

51. Antiresorptive Therapy (Cont.) Bisphosphonates Bisphosphonates bind to hydroxyapatite in bone and decrease resorption, slow rates of bone turnover. Bisphosphonates provide the greatest BMD increases and fracture risk reductions among antiresorptive therapy. The BMD increases range from 5% to 8% at the lumbar spine and 2% to 4% at the femoral neck. The risk of fracture is reduced by 45% to 55% at all skeletal sites: vertebral, nonvertebral, and hip.

52. Bisphosphonates (cont.) BMD increases are greatest in the first year of therapy, continue for at least 2 to 3 years, and then plateau for the duration of therapy. After discontinuation, the increased BMD is sustained for at least 1 year and remains higher than that of nonusers. Combination with either estrogen therapy or raloxifene produces greater BMD increases Alendronate, risedronate, and ibandronate are FDA approved for prevention and treatment of postmenopausal osteoporosis. Alendronate is also approved for osteoporosis in men. Alendronate and risedronate are indicated for corticosteroid-induced osteoporosis.

53. Bisphosphonates (cont.) All bisphosphonates are poorly absorbed (bioavailability 1% to 5%) even under optimal conditions. Each oral tablet should be taken in the morning with at least 4 oz of plain tap water (not coffee, juice, mineral water, or milk) at least 30 minutes before consuming any food or any other supplement or medication. The patient should remain upright (sitting or standing) for at least 30 minutes after administration to prevent esophageal irritation and ulceration.

54. Bisphosphonates (cont.) Once-weekly administration is preferred by most patients to decrease GI tract drug exposure while achieve similar BMD results. Nausea, abdominal pain, and dyspepsia are common.

55. Selective Estrogen Receptor Modulators (SERMs) Raloxifene is an estrogen agonist in bone tissue but an antagonist in the breast and uterus. It is approved for prevention and treatment of postmenopausal osteoporosis. It increases spine and hip BMD by 2-3% and decreases vertebral fractures. Nonvertebral fractures are not prevented by raloxifene. Discontinuation of raloxifene results in the BMD decreasing immediately.

56. Selective Estrogen Receptor Modulators (SERMs) Raloxifene is associated with decreases in total and LDL cholesterol but slight increases in triglycerides Raloxifene can cause hot flushes occasionally cause women to discontinue therapy. Raloxifene is associated with a threefold increased risk of venous thromboembolism, similar to the risk with estrogen. Raloxifene is contraindicated in women with active thromboembolic disease. Therapy should be stopped if a significant period (several hours or more) of immobility is anticipated.

57. Calcitonin Salmon calcitonin is used clinically because it is more potent and longer lasting than the mammalian form. Calcitonin is indicated for osteoporosis treatment for women at least 5 years past menopause. It is not FDA approved for men. Calcitonin does not consistently affect hip BMD and does not decrease hip fracture risk. It is reserved for second-line treatment. It may provide pain relief to some patients with acute vertebral fractures, but this effect is minimal. The intranasal dose is 200 units daily, alternating nares every other day. Subcutaneous administration of 100 units daily is available but rarely used.

58. Estrogen and Hormonal Therapy This type of therapy are less effective than bisphosphonates or teriparatide but greater than those from raloxifene. ET and HT are not advocated for prevention of osteoporosis and fractures. The lowest dose of ET and HT necessary should still be used for preventing and controlling menopausal symptoms. Oral and transdermal estrogens have similar BMD effects.

59. Estrogen and Hormonal Therapy Most gains in BMD were seen within the first few years of treatment, with slight increases or a plateau thereafter. Effects on BMD are increased when ET or HT is combined with bisphosphonates or parathyroid hormone. When therapy was discontinued, bone loss was accelerated for a short time compared with placebo in most studies. They do not prevent primary or secondary CVD and may even increase events within the first years of use.

60. Phytoestrogen The isoflavonoids (soy proteins) and lignans (flaxseed) are the most common forms of phytoestrogens. Beneficial bone effects may be related to bone estrogen receptor agonist activity or effects on osteoblasts and osteoclasts. Evidence base data are inconsistencies. Use of this agent should be discouraged.

61. Testosterone and anabolic steroids In a few studies, women receiving oral methyltestosterone daily or testosterone implants every 3 months had increased BMD. Various salt forms of testosterone were associated with increased BMD in some studies in men. Anabolic steroids (nandrolone decanoate) have shown minimal to no effect on BMD but do increase muscle strength. Patients using them should be evaluated within 1-2 months of onset and then every 3-6 months.

62. Bone Formation Therapy Teriparatide (Parathyroid Hormone) Therapeutic doses of parathyroid for shorter periods improve BMD and reduce fracture risk. In postmenopausal women with osteoporosis and preexisting fractures, teriparatide reduced the risk of new vertebral fractures and new non vertebral fracture by 65% and 53%, respectively. In men with osteoporosis, teriparatide increased BMD, but its impact on fracture rate remains undetermined. The dose is 20 mcg administered subcutaneously in the thigh or abdominal area.

63. Teriparatide (Parathyroid Hormone)  The initial dose should be given with the patient either lying or sitting in case orthostatic hypotension occurs. Each prefilled 3-mL pen device delivers a 20-mcg dose each day for up to 28 days; the pen device should be kept refrigerated. Teriparatide is contraindicated in patients with Paget's disease of the bone, unexplained alkaline phosphatase elevations, or a history of previous skeletal radiation therapy. Teriparatide should not be used with alendronate. Teriparatide is reserved for patients at high risk of osteoporosis-related fracture who cannot or will not take or have failed bisphosphonate therapy.

64. Steroids and bone loss  Greatest loss occurs during the first 6 to 12 months Oral: = 7.5 mg of prednisone or equivalent Inhaled: = 800 to 1200 mcg of beclomethasone, = 800 to 1000 mcg of budesonide = 750mcg of fluticasone = 1000 mcg of flunisolide Baseline and follow up measurement of BMD in 6-12 months is recommended Bisphosphonates are the best choice for treating corticosteroid-induced osteoporosis.

65. Outcome evaluation Patients receiving pharmacotherapy for low bone mass should be examined at least annually. Patients should be asked about possible fracture symptoms (e.g., bone pain, disability) at each visit. Medication adherence and tolerance should be evaluated at each visit. Some clinicians measure BMD every 1 to 2 years after beginning therapy with the goal of identifying medication nonadherence or secondary osteoporosis. Others advocate no subsequent BMD measurement because of expense and lack of correlation to fracture risk reduction.

66. OSTEOARTHRITIS

68. Pathogenesis

71. Osteoarthritis Evaluation - Made through clinical assessment and radiologic studies, CT scan, arthroscopy and MRI

72. Non pharmacological treatment Patient education Dietary counseling for overweight OA patients Physical therapy with heat or cold and exercise Exercise programs Assistive and orthotic devices Surgical procedures

73. Pharmacological treatment Acetaminophen The first-line therapy for pain management of OA. Dose: 325 to 650 mg 4 times daily (maximum dose 4 g/day). Comparable to NSAIDs for reliefing of mild to moderate OA pain Chronic alcohol users (= 3 drinks daily) will increase risk of liver damage or GI bleeding with acetaminophen.

74. NSAIDs NSAIDs are used when acetaminophen proves ineffective or for patients with inflammatory OA. Analgesic effects begin within 1-2 hours, whereas anti-inflammatory benefits may require 2-3 weeks of continuous therapy. All NSAIDs have similar efficacy Combining two NSAIDs increases adverse effects without providing additional benefit

75. NSAIDs COX 2 selective inhibitors are recommended only in patients who have high risk for NSAID-related Gl effects and low risk for cardiovascular toxicity. Risk factors for NSAID-associated ulcers: - Age = 65 years - Comorbid medical conditions e.g., CVD - Concomitant corticosteroid or anticoagulant therapy - History of peptic ulcer disease or upper GI bleeding NSAIDS may use with PPI or misoprostol

76. Capsaicin Providing pain relief in OA when applied topically over affected joints Must be used regularly, and it may take up to 2 weeks to work Patients should be warned to wash their hands after application. Use is recommended 4 times daily, but tapering to twice-daily application may enhance long-term adherence with adequate pain relief.

77. Glucosamine and Chondroitin Dietary supplement Superior to placebo in alleviating pain from knee or hip OA in 17 double-blind, placebo-controlled studies. A meta-analysis found that glucosamine reduced joint space narrowing. An ongoing study sponsored by the NIH should help to define the role of these supplements in the treatment of OA

78. Corticosteroids Systemic use is not recommended. Intra-articular injections can provide relief when local inflammation or joint effusion exists, but their long-term benefit remains controversial Therapy is generally limited to 3 or 4 injections per year After injection, the patient should minimize joint activity and stress on the joint for several days

79. Hyaluronate Injections High-molecular-weight hyaluronic acid is a constituent of normal cartilage Available form: sodium hyaluronate (Hyalgan) and hylan G-F 20 (Synvisc). Dose: 2 mL intra-articular injection into the affected knee once weekly for 3 (hylan G-F 20) or 5 (sodium hyaluronate) consecutive weeks. Local swelling and skin reactions have been reported. Use for patients unresponsive to other therapy

80. Narcotic analgesics Low-dose narcotic analgesics are reserved for patients who experience no relief with other agents or have C/I for NSAIDs Low-dose narcotics should be used in combination with acetaminophen. Sustained-release offer better pain control when simple narcotics are ineffective.

81. Outcome evaluation Pain scale The clinician's global assessment Any signs of drug-related effects Baseline Scr, hematology profiles, and serum transaminases with repeat levels at 6- to 12-month intervals

82. GOUTY ARTHRITIS

83. Gouty arthritis ??????????????????????????????????????????????????????? ?????????????????????????????????????????? (hyperuricemia) ?????????????????????????????????????????????????????????????????? ??????????????????????????????????????????? 20-30 ?????????????????????????? Hyperuricemia: serum uric acid > mean + 2 SD ??????????????????????? 7-7.5 mg/dL ????????? 6-6.5 mg/dL

84. Conditions associated with hyperuricemia

85. Pathogenesis of GOUT ?????????????????????????????????: ???????? ???? end product ????????????????? (purine compounds) ???????? endogenous Purine synthesis ???????????????? 1/3 ??????????????????????????????????????????????????????????? ????????????????????????????????????? ??????????????????????????????????????????????????? ?????????????????????????????????????????????????????????????????????????? ???????????????? ??? feed back mechanism autoregulation

86. hypoxanthine ? xanthine ????????? ?????????? xanthine oxidase ?????????????????????????????????????????? ?????????????????????????????? serum uric acid ??? ??????????????????????????????????????????? ???????????????????????????????????????????????????? 1-1.2 mg/dL hyperuricemia ???????????????????????????? / ???????????????????????? ????????????????????? 2 ?????? ??????????????????????????????????????????? uricolysis ????????????? 2/3 ??????????????????????????????? Pathogenesis of GOUT

88. ??????????????????????????????????????????????????????????????????????? (metainterphalangeal joint) ?????????????????????????????????????????? ??????????????????????????????????? (acute gout arthritis) ???????????????????????????????????? ?????????????????????????????????????????????????? Tophi ?????????????????????????????????? (recurrent) ???????????????????????????????????? interstitial nephritis ??? renal calculi (????) , tubular necrosis ??? acute renal failure ???????????????????????????????????????????????????? ???? leukemias ????????????????????? chemotherapy Pathogenesis of GOUT

89. Gout: Tophi

90. Non Pharmacological Treatment Foods that should avoid Beer, other alcoholic beverages. Sardines in oil, fish roes, herring. Yeast. Organ meat (liver, kidneys) Legumes (dried beans, peas) Meat extracts, gravies. Mushrooms, spinach, asparagus, cauliflower, bamboo shoot.

91. Pharmacological Treatment

92. NSAIDs of choice Indomethacin is as effective as colchicine and is preferred because acute Gl toxicity occurs far less than with colchicine 75 mg of indomethacin may be given initially, followed by 50 mg every 6 hours for 2 days, then 50 mg every 8 hours for 1 or 2 days Other NSAIDs can be used as well Cautions: individuals with Hx of PU, HF, CKD, or coronary artery disease

93. Colchicine Dose Oral: 1 mg initially, followed by 0.5 mg every 2 hours until the joint symptoms subside IV: 2 mg diluted in NSS initially. If not relief, give 1 mg at 6 and 12 hrs ( total dose = 4 mg) It should be discontinued within 7 days after either IV or oral to reduce the risk of bone marrow toxicity GI toxicity is common

94. Steroids Use for resistant cases or for patients with contraindications to colchicine and NSAID Prednisone 30 to 60 mg orally once daily for 3 to 5 days then gradually taper and discontinue within 10-14 days for patient with multiple-joint involvement Intraarticular form may be useful for acute gout limited to one or two joints

95. Prophylactic therapy Use for for patients with frequent attacks of gouty arthritis (i.e., more than two or three per year) even if the serum uric acid concentration is normal or only minimally elevated Use for patient who had a severe attack of gouty arthritis, a complicated course of uric acid lithiasis, a substantially elevated serum uric acid (greater than 10 mg/dL), or a 24-hour urinary excretion of uric acid of more than 1000 mg Colchicine 0.5 mg twice daily

96. Uric lowering therapy Colchicine 0.5 mg twice daily Uricosuric drugs: - Probenecid: 250 mg twice daily for 1-2 weeks, then 500 mg twice daily for 2 weeks. Thereafter, increase dose 500-mg every 1-2 weeks. A maximum dose is 2 g/day - Sulfinpyrazone: 50 mg twice daily for 3 -4 days, then 100 mg twice daily, increase dose 100-mg each week up to 800 mg/day. - Common S/E: GI irritation, rash and hypersensitivity, precipitation of acute gouty arthritis, and stone formation

97. Uric lowering therapy Xanthine Oxidase Inhibitor Allopurinol 300 mg daily Allopurinol is the DOC in patients with a history of urinary stones or impaired renal function, in patients who have lymphoproliferative or myeloproliferative disorders Major S/E: skin rash, leukopenia, occasional GI toxicity, and increased attacks with the initiation of therapy. An allopurinol hypersensitivity syndrome (fever, eosinophilia, dermatitis, vasculitis, and renal and hepatic dysfunction) occurs rarely but is associated with a 20% mortality rate

98. Outcome evaluation The acute pain of an initial attack of gouty arthritis should begin to ease within about 8 hours of treatment initiation. Complete resolution of pain, erythema, and inflammation usually occurs within 48 to 72 hours.

99. RHEUMATOID ARTHRITIS

100. Rheumatoid Arthritis Systemic autoimmune disease that causes chronic inflammation of connective tissue Initially affects synovial membrane Later articular cartilage, joint capsule, ligaments and tendons, and bone Affects joints of hands, wrists, ankles, and feet, but shoulders, hips and cervical spine may also be involved Systemic effects on heart, kidney, lungs, skin and other organs

101. Rheumatoid Arthritis Mild to severe Destroys and distorts joints Reduces life expectancy Remission and exacerbation 1 � 2% of adult population Women : men = 3:1 Onset usually in 20�s or 30�s Symptoms lessen during pregnancy Seasonal variation

102. Rheumatoid Arthritis Idiopathic disease Immune-mediated destruction of joints Rheumatoid factors (IgM and IgG) target blood cells and synovial membranes forming antigen-antibody complexes Genetic predisposition Possibly bacterial or viral infection (Epstein-Barr)

105. Rheumatoid Arthritis Systemic effects: Generalized weakness and malaise Up to 35% develop granulomas called rheumatoid nodules Systemic inflammation of blood vessels � rheumatoid vasculitis Serous membranes may be affected

106. Rheumatoid Arthritis Evaluation : Physical examination X-ray Serologic tests for rheumatoid factor and circulating antigen-antibody complexes No cure

107. American Rheumatism Association Criteria for Rheumatoid Arthritis Morning stiffness at least 1 hour present at least 6 weeks Swelling of 3 or more joints for at least 6 weeks Arthritis of hand joints for at least 6 weeks Symmetric joint swelling for at least 6 weeks Rheumatoid nodules Serum rheumatoid factor Radiograph change Using at least 4 of 7 criteria for diagnosis

109. Treatment Goals Reduce pain Minimize stiffness and swelling Maintain mobility Become an informed health care consumer

110. Rheumatoid Arthritis Therapy: Relieve pain and swelling and retain as much joint function as possible Resting the joint, or binding or splinting Use of hot and cold packs Diet high in calories and vitamins Strengthening of associated muscles

112. Medication therapy NSAIDs Symptomatic relief, improved function No change in disease progression Low-dose prednisone (10 mg qd) May substitute for NSAID Used as bridge therapy If used long term, consider prophylactic treatment for osteoporosis Intra-articular steroids Useful for flares

113. Disease modifying drugs (DMARDs) Should be used in all patients except those with limited disease or those with class IV disease Early use results in more favorable outcomes First-line drugs: methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide Less frequently used drugs: azathioprine, penicillamine, gold salts (including auranofin), minocycline, cyclosporine, and cyclophosphamide Medication therapy

114. Disease modifying drugs (DMARDs) The recommended combination: 1. methotrexate plus cyclosporine 2. methotrexate plus sulfasalazine and hydroxychloroquine Medication therapy

115. Medication therapy Biological agents Anti-TNF agents (etanercept, infliximab, adalimumab) Interleukin-1 receptor antagonist (anakinra) Use for patients who fail treatment with other DMARDs.

116. Outcome evaluation Clinical signs of improvement Symptom improvement Joint radiographs Laboratory monitoring for detecting and preventing adverse drug effects Patients should be questioned about the presence of symptoms that may be related to adverse drug effects

117. SLE

118. ????????????????????????????????????????????? ????????????????????????????????????????????????????? ??????????????????? ??????????????????????????? autoantibody ???????????????????? ??????????????????????????????????????? ????????????????????????? ?????????????????????????????????????????????????????? ?????????????????????????????????????????????? ACR SLE (Systemic Lupus Erythematosus)

119. SLE: etiology Genetic: HLA DR2, DR3 ???????????????????????????????????????? ????? autoantibody ?????????? ?????????? B-cell, T-cell, NK cell, macrophage ? ??????????????????????????????????????????? ??????????? Hormone: female > male ??????? ?? ??????? ???????????

120. Diagnosis criteria of SLE

121. Clinical manifestation

125. SLE Pregnancy: ?????????????????????????????????????????????????????????????????????????? Steroids ?????????????????????????????????? Drug induced Lupus: Hydralazine, procainamide Quinidine, chlropomazine, isoniazid ????????????????????????????????? ???????????? ??????, ???, ??.?? , ????????????????????????????????????? ?? Anti-histone ???????????????????????????????

126. SLE: Laboratory investigation Diagnosis: Anti-dsDNA 50%, Anti-Sm 30% Follow-up/ prognosis: CBC: thrombocytopenia UA: Proteinuria > 1 g/d Scr Alb/ Glb: ??????????????????????? ESR/ CRP: ????????????????????? Anti-dsDNA + C4 ??? 20-25 wk ???????????? ? C3 ??? Biopsy: ?????????????????????????????????

127. SLE: Prognosis Control factors: ??????, ??????????, ???????????, ???????????, ??????????????????? ?????????????????? 2-10% ?????????????????????????????????????????????? ??????????. ??????????. ???, ???????????????, ??????????????????? ??????????????????? 30 ?? prognosis ?????????????????? 50 ?? ??????????????????????????????????

129. Non Pharmacological Treatment A balanced routine of rest and exercise while avoiding overexertion Avoidance of smoking Limit exposure to sunlight and use sunscreens to block the possible exacerbating effects of ultraviolet light Avoidance of products contain Alfafa

130. Pharmacological Treatment

131. Experimental treatment

132. INFECTIOUS ARTHRITIS

133. Infection Bacterial Non Gonococcal Bacterial Arthritis Gonococcal Bacterial Arthritis Viral Fungal Tuberculous

134. ????????????????????????????????????????????????

135. 1. ??????????????????????????????????????????????????????? (Non-gonococcal bacterial arthritis) ???????????????? ??????????????????????????????? Staphylococcus sp. ???????? 50 Streptococcus sp. ???????? 30 gram negative bacillus ?????? 20 salmonella sp., E. coli, Proteus mirabilis, klebsiella pneumoniae, Pseudomonas aeruginosa, enterobacter sp. mycobacterium ???????? 1

136. ????????????????????? 3 ??? ??? ????????????? - ?????????????????????: ???????, ????????????, ???????????? ?????????????????? 2. ?????????????????????????????????? - cellulitis, ?????????????????????????? (osteomyelitis) 3. ???????????????????????????? - ???????????????, ???????????????????????????????????????, ???????????? Non-gonococcal bacterial arthritis

137. Non-gonococcal bacterial arthritis ??????????? ????????????????????????????????? ?????????????????????????????????? ????????????????????? ? ????????????????? ??????????????????????????????????????????????? proteolytic enzyme ??????????????????? ?????????????????????????????????????????????? ??????????????????????????????????????????????

138. ??????????????? ????????????????????? ?????? ???????, ???????? ?????????? acute monoarticular arthritis: ????????, ???, ???, ???? ???? ??? limited rage of motion ????????????? 38 ???????????? ??????????????????????????????????????? NSAIDs, ???????????? ????????????????????? ?????????????????????? ????????????????: ???????, ??, ???????????? ????????? ?????????????????????????????? - RA, severe gout attack - ????????? ???????????????????????????? Non-gonococcal bacterial arthritis

139. ???????????????????????? ??????????????? - ?????????????????????? - ????????????????????, ?????? ?????????????????????????????????????????????????????????? ???????????????????????????????????? 2. ???????????????????? - ??????????????????????????????? - ??????????????????????????????????? - ?????????????????????????????????????????????????????, ??????????????????????????????? 3. ????????????????? 4. ?????????????????????????????????? - ????????????? ???? ???????, ?????????????????????? ??????????????????????????? ????????????????????????????????????????????????? Non-gonococcal bacterial arthritis

140. ???????? ???????????????? ???????????????????????????????????????????? Non-gonococcal bacterial arthritis

141. Non-gonococcal bacterial arthritis: ???????????????? ????????????????????????????????????? ???????????????????????????? ?????????????????????????????????????????? ???????????????????????? 3 ??????? ???????????????????????? 4-6 ??????? ??????????????????????????? 1-2 ??????? ????????????????????????????? --> ?????????????????????? ??????????????????? (drainage) ??????????????????????????????????????????????????? ????????????????????, ???????????????????, ?????????????????????? ???????? articular cartilage ? ??????, ????????????????????

143. Non-gonococcal bacterial arthritis: ???????????????????????????????????? ???????????????????????????? ???????????????????????????????????????????????????? ?????????????????????????????????????????????????? ????????????

144. ???????????????????????????????? (Gonococcal arthritis) ??????????? ???????????????????????????????????? Neisseria gonorrhea ???????????????????????????????????????????? (disseminated gonococcal infection; DGI) ????????????????????????? ?????????????????????????????????????

145. Gonococcal arthritis ??????????????? ?????????????????????????????? ???????????????????????? ?????????????????????????????????????????????????????????? 1 ??????????????????? ????? ???????????????????????????????? 2-3 ??????????????????????????????? ???????, ?????? ?????????? ????? tenosynovitis ????????????? (dermatitis) : hemorrhagic macule ???? papule ?????????? ????????????????????, ?????? ?????????? ???????????????????????????????????? ?????????????????????????? ??????? ??????????????????????: ??????????????, ????????, ?????, ???????????????????????????????????????????? ???????????????????????????????? 24-48 ???????

147. ???????????????????????????????? (Tuberculous arthritis) ??????????? ?????????????????????????? Mycobacterium tuberculosis ??????????????????????????????????????? (peripheral joints) ??????????????????????????????????????????????????????? (osteomyelitis) ???????????????????????????? (subchondral cartilage) ????????????????????? ??????????????????????????????????????????????? ????????????????????????? ?????????????????????????????????????????????????????????????????????????????????????????? ???? ????????????, ??

148. Tuberculous arthritis ?????????????????????????????????????????? ???????????????????????? ????????????????????????????????????????????? (immunocompromise host) chronic monoarthritis thoracolumbar spine ??????????????? spinal cord ???? nerve root compression ?????????????????? ??????????????????????????????? 40-50 ??????????????? ????????????????????????????????????? ????????????????????????????????????? ????????????, ?????????, ????????? ????????????????????????????? 50 ???????????????????????????, ??????????????????????? acid fast, ??????????????????????? ?????????????????????????????????????????????????????? 1-2 ??????? - BACTEC radiometric culture system ?????????????? polymerase chain reaction (PCR) ?????????????????????????????????????????????????

149. ???????????????????????????????????????? ????????????? - 2HRZE + 4 HR - 2HRZE + (7-12) HR - ???????????????????????????? ???????????? - ???????????????? ???? ??????????????????? ????????????????????????? ?????????????????????????????????????

150. BURSITIS & TENDINITIS

151. Bursitis and Tendinitis???????????????? ??? ?????????????? Tendinitis ????? ????????????????????????????? ?????????????? ????????????????????????? ????????, ???, ???? ????????????????????????????? ?????? ??????????????????, ?????????, ???? ????????: RA, SpA, gout, DM, thyroid, infections

152. Bursitis and Tendinitis ???????? 1. ??????????? Antibiotics: ?????????????? septic arthritis Drainage NSAIDs Intra-articular steroids (???????????????????????????????????????) Oral prednisolone 20-30 mg/d

153. Bursitis and Tendinitis ???????? 2. ??????????????????????????????????????????? ?????? Active movement ???????????????????????????? 3. ????????????

154. MYOFASCIAL PAIN SYNDROME

155. Myofascial Pain Syndrome (MPS)???????????????????????????????? ???????????????? ???????????? ???????????? 36 ????????????? 31-60 ?? ?????????????? ??????????????????????? ????????????????????????? ?????????????????? ?????????????????????? ?? trigger point, ????????????????????????????????? ?????????????: OA Precipitating factors: postural dysfunction, ??????????????????????????, ????????????????, B1-6-12, hypothyroid, ????????? ?????????? ?????????, ????????, vasomotors, ??????????????????, ??, ?????????????, ????????????????, ??????????, ??????

156. Myofascial Pain Syndrome (MPS)???????????????????????????????? ??????? ???????????????? ????????????????????????????????? ??????????????????????????? (stretching exercise) ??????, ????????????, ultrasound ?????????? ???????????????????????: Dry needing, lidocaine Intra-articular steroid ? ??????????? Botulinum toxin A

157. ???????? ???????????????? NSAIDs: analgesic Opioid antagonist: tramadol Antidepressants: amitriptyline Muscle relaxants ????????????????????????: ??????????????, ?????????????????? ? ????????, ????????? Myofascial Pain Syndrome (MPS)????????????????????????????????

158. FIBROMYALGIA

159. Fibromyalgia Connective tissue rheumatism Chronic but NOT inflammation Genetics, precipitating factors: infections, illness, stress and emotion Abnormal in endrocrine: Hypothalamus-pituitary-adrenal (HPA) axis, Hypothalamus-pituitary-thyroid axis, Hypothalamus-pituitary-growth hormone axis Sleeping abnormality, ??????????????????????? ??????????????????????????????????? ? ??????????????????????

160. Fibromyalgia ??????????? ???????????????????????????? 3 ????? ??????????? 11 ????? 18 ???

162. Fibromyalgia ??????????????? ??????????????? 20-50 ?? ????????????? 90 ????????????? ??? ???????? ????????????????: ??????????? Axial skeletal Regional pain ??????????? ??????? ??? ???????????????? Morning stiffness, diffuse althralgia, Raynaud�s phenomenon ????????????????? ?????????, ????????, ?????????????????, ??????????????, ??????????, ??????????????, ??????????, ??????????????? ?????????? ??????????: ??????????????, ???????????, ?????????????????????

163. Fibromyalgia ???????? ?????????????????????? ???????? Psychotropic drugs Tricyclic antidepressants Amitriptyline 10-80 mg/d SSRIs Fluoxetine, citalopam, sertraline hydrochloride, venlafaxine Anxiolytic drugs Alprazolam NSAIDs: analgesic Muscle relaxants ???????????? Aerobic exercise ??????????????????????????????????

164. Scleroderma Scleroderma or progressive systemic sclerosis (????????) Fibrosis ??? ????????????????????? ???????????????????????????????????????????? Raynaud�s phenomenon ?????????????? Other organs ???????????????????: autoimmune: ?????????????????????????????????????? ? fibrosis ????????????????????????????????????????????????????????????????????, ???????????????????????? ? thrombosis ??? fibrosis

167. Treatment Immunomodulators: chloroquine, hydroxychloroquine, azathioprine, chlorambucil, metrotrexate, cyclosporin, cyclophosphamide Fibroblast regulators: colchicine, D-penicillamine, interferon Vascular protection: CCB, ACEI, serotonin reuptake inhibitor, serotonin antagonist Cytokine inhibitor: anti TNF

168. Common prescriptions Combination therapy Nifedipine 5-10 mg 3-4 times/day Aspirin 60-75 mg/day Colchicine 0.6 mg 2 times/day Chloroquine 200 mg/day or D-penicillamine or shift to cyclophosphamide 1-2 mg/kg/day + prednisolone 15-30 mg/day if patients have lung complication Other therapy: ACEI for renal complications, metoclopramide and domperidone for GI complications

169. BACK PAIN

170. Back pain ??????????????????????????????????????????????????????????????????????? ????????????? 65-80 ????????????????????????????? ?????????????????????????????????????????????? 6-8 ??????? ????????????? 7-10 ????????????????????????? 6 ?????

171. Back pain: pathology ?????? 90 ?????????????????????????? ??????????/ ??????????/ ???????????? ??????10 ????????????????????? ?????? Traumatic ? acute or chronic Congenital/ developmental Metabolic Toxic Nerve Vessels- arterial or venous

172. ?????????????????????(???????????????????????) Entire back OA Osteoporosis Ankylosing spondylitis (AS) Lower back Acute/ chronic mechainical lumbosacral strain OA / osteoporosis/ spondylosis / Bursitis/ fracture/ infection/ referred pain Herniated disc (???????????????????????????) Poor posture Sacroiliac area Strain / AS/ psoriatic arthritis/ reiter�s syndrome

173. Herniated disc (???????????????????????????)

174. ?????????????????????? ???? / ??? ????????: acute / chronic ?????????????? Superficial somatic pain: cellulitis, Herpes zoster Deep somatic pain: ?????? ?????????? ???????? ????????????????????? ???? neurologic pain ????????????? ??????????? ? ??????????????? ???????????????? ? diabetic neuropathy

175. Back pain: Treatment ?????????????????????? ???????????? ????????? ???????? SpA ?????????????????? ??????????? ????????????????????????? ??????99 ?????????? Myofascial syndrome

176. Pharmacotherapy: Analgesic: Paracetamol, aspirin, tramadol, NSAIDs Opioids Muscle relaxants ???????????????? TCAs: amitriptyline 25-150 mg/d Carbamazepine 100-200 mgBID Phynetoin 100-300 mg/d

177. Education ?????????????? ???????????? 2-3??? ????????????????????????? (corsets and braces) ????????????????????????? ???????????????? ???????????????????? ?????????????????????????

178. ???????????????????????

180. Drug used in rheumatic diseases NSAIDs Pharmacology: ??????????? ?????????? ???????? ?????????????? NSAIDs 1.???????????????????????????? ???????????????????????????????????????????? 2.??????????????????????????? ????????????????: ????????????????????????????????????????????? ??????????? ?????????????????????????????????? ??????????????????????????????????????????????????????????? ?????? ??????????????????????

181. 1. NSAIDs ?????????????????????????????????????? Short duration T1/2 1-8 hr: Ibufrofen, diclofenac Intermediated: T1/2 10-20 hr: mefenamic acid, naproxen, salicylate, celecoxib Long duration: T1/2 24-36 hr: Nabumetone, piroxicam Very long duration: T1/2 > 24 hr: Phenylbutazone, tenoxicam

182. 2. Corticosteroid Anti-inflammation Immunosupression Metabolism: ????????????????? ????? ??????????????????? (glucoeogenesis) -> ???????????????? ??????????????, ????????????? ?????????????????????????? ???????????????? -> ketoacidosis

183. 4. Catabolism: ?????????????????????? ?????????? ????? ??????? ????????? supraphysiologic glucocorticoid -> ????????????????? ?????????? ????????? ? osteoporosis 5. Calcium, VitD, PTH ??? calcium ???????????????????? ??????? Ca ??????????????????? ??????????? Ca ???????? ?????????????????? vitD ????????????? PTH 2. Corticosteroid

184. 6. Hypothalamus-Pituitary-Adrenal Axis ??????????????????????? ???????????????????? ?????????????????????????????? 7.????????? CNS GI: ???????????????? ???????????????????????? Hematology: ?? Lymphocyte, monocyte, eosinophil ????? PMN, RBC, Plt 2. Corticosteroid

185. Corticosteroids: classification Short acting: T1/2 < 12 hr Cortisol, cortisone Intermediated acting: T1/2 12-36 hr Prednisolone, prednisone, methylprednisolone ?????????????????????????????????????????????? ?????????? ?????????????????????????????? Long acting: T1/2 > 48 hr Betamethasone, dexamethasone

186. Clinical use of corticosteroids ??????????? ?????????????????????????????????????? ????????????????????????????????? ???????????????????????????????????????? (minimal effective dose) ??????????????????????????????????????? ???? ??????? ????????? ????????????????? ??????????? ??????? ???????????????????????????????????????? ???? ????????????????????? ??????????????????? ???????????????????????????????????????? ???? ??????????? ???? ????

187. 7. ????????? ?????????????????????????? HPA-axis ?????????????????????????????????????? 8.?????????????????????????????????????????????????????? ???? ??????????????? 9. ???????????????????????????????????????????????? Clinical use of corticosteroids

188. ???????????????????????????? Systemic corticosteroid regimens 1.1 Daily high dose: > 15 mg/d ??????????????????????????????????????? ???????????????????????? ???? ?????????????????? ?????????? ?????????? ???????? ??????????? ?????????????????????? prednisolone > 80 mg/d ??????? HPA axis ????????????? 1 ??????? ???????????????????????????????????????????????????????

189. 1.2 Daily low dose: < 10 mg/d ?????????????????????? ?????????????????? avascular necrosis ????????????????????????????? < 5 mg/d ???? HPA axis ???? ????????????????????????? ????????????????????????????

190. 1.3 Pluse IV methylprednisolone (pulse MPS) MPS 1 g + D5W 50 mL IV 45 min 1-3 d ???????????? ?????????????????????????????? K ??? ??? Neutrophil ???????? 72 ??????? ???????? ???????????????????? ??????????????????+ ?????????????????????? ????????????????????????????

191. Pulse MPS ???????????? ????????????????? ????????????????????????? Steroid sparing ?????????????????????????????? ????????????????? ?????????????????????????????????????????????????? SLE, nephritis, vasculitis ????????????????????????????

192. 1.4 Alternate day dose ????????????????????????????????? ?????????????????????????????? ???? HPA axis ???? ????????????????????????? ????????????????????????????

193. 2. Local steroid injection Triamcinolone acenonide (KENACORT) Intra-articular steroid injection Preserve joint function ?????????????????????????????????????? ??????????????????? ??? ??????????????? ??????????????? chondrolysis osteonecrosis ???????????????????? 3-4 ????? ??????????? ?????????? ??????? ????????????????? ????????????????????????????

194. Tendon sheath injection, intrabursal injection ??????????????? ????????????????????????????? ??????????????? ??????????????????????????? ????????????????????????????

195. ?????????????????????????????

196. 3.Immunosuppressive Therapy in Autoimmune diseases ?????????????? ??????????????????????????? -> ??????????????????????????????????????????????????? ?????????????????????????????????????? ????????????????????????????? ??????????????????????????????????????????????????????????????????? ????????????????????????????????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????????????????? ????????????????????????????????????????????? ???????????????? ????????????? ????????????????????

197. Pregnancy and lactation Consider ???????????????????????????? (fertility) ????????????????????????????? ???????????????????????? Fertilization-implantation Embryo 2-8 weeks > 8 weeks