1. RHEUMATOID ARTHRITIS BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR EMAIL—drbashir123@gmail.com

2. Dr Bashir and Dr yashodhora leading group of medical students to meet noble prize winner in medicine at KL Malaysia

3. Dr Bashir at PBL Conference

4. Noble prize winner Prof Barry.J Marshall in recognition of his discovery Helicobacter pylori-most common cause for peptic ulcer

5. Precious moments with noble prize winner

7. Rheumatoid arthritis is autoimmune disorder in which Immune system identifies the synovial membrane as "foreign" and begins attacking it. Synovial membrane shown in picture

8. With long-term or intensive exposure to the antigen, normal antibodies become auto- antibodies that target self- antigens in the synovial membrane.

9. Once the antigen or immune complex reaches the synovial membrane.The antigen presenting cell deals with Fibrous capsule of synovial joint.

10. Rheumatoid Arthritis First, the APC usually a macrophage in synovium engulfs the antigen. Enzymes (peroxides) inside the APC break down the antigen into smaller particles.

11. Rheumatoid Arthritis The processed antigens are transported to the surface of the APC, where it binds with MHC (major histocompatibili ty complex)

12. This complex ie (part of a foreign substance and MHC) is now presented to T- cells (CD4 cells ie T-helper cell ) or CD8 (cytotoxic T cells) which the T- cell receptor (TCR) recognizes and binds to.

13. RHEUMATOID ARTHRITIS  Once the T-cell binds to the Antigen / MHC complex, the APC then secrete cytokines like  Interleukin-1 (IL-1)  Interferon-alpha (IFN-a)  Interferon-gamma (IFN-g)  Tumor necrosis factor (TNF)  And other factors that activate lymphocytes and other immune cells to respond to the antigens.

14. APC also Secretes Lysozymes, Elastases and Collagenases these enzymes cause cartilage breakdown. FGF & Angiogenesis Factors add to pannus formation Chemokines mediates chemo attraction (chemotaxis) RHEUMATOID ARTHRITIS

15. On exposure to IL-1, synoviocytes proliferate and produce following factors Interleukin-6 (IL-6) Prostaglandin's (e.g, PGE2), and platelet- activating factor, which are involved in the pain mechanism. Matrix Metalloproteases(e.g. stromelysin) that cause activation of collagenase, an enzyme required for cartilage breakdown. Effects of IL-1

16. IL-1 also activates endothelial cells and induce stimulation of adhesion molecule expression on endothelial cells. Enhances activity of NK cells and leads to Pyrogen (cause fever).

17. IL-1 also causes increased production of inducible nitric oxide synthase and consequently high levels of nitric oxide kill chondrocytes, the cells responsible for cartilage remodeling. Induce osteoblast apoptosis and thereby prevent new bone formation Prevent formation of the cartilage matrix by inhibition of proteoglycan synthesis. Effects of IL-1

18. The end result of these of IL-1 and TNF-a include activation and migration of leukocytes and lymphocytes from the blood into inflammatory tissues as well as formation of pannus and damage to cartilage and surrounding normal cells.

20. Microscopy RA Micro: dense perivascular inflammatory infiltrate of T lymphocytes, plasma cells (often with eosinophilic cytoplasmic inclusions called Russell bodies) inflammation extends to subchondral bone (relatively specific for rheumatoid arthritis); proliferative synovitis with synovial cell hyperplasia and hypertrophy, necrobiotic nodules and fibrosis; increased vascularity with hemosiderin deposition; organizing fibrin floating in joint space as rice bodies; neutrophils present on synovial surface;

21. Microscopy RA Neutrophils, lymphocytes, plasma cells, macrophages, and fibroblasts are responsible for increased cellularity. Superficial areas of necrosis are present and masses of inflammatory cells can be seen free above the synovial surface

23. The synovium red due to blood vessel diatations and thickened due to inflammation and cellular infiltration. Plus granulations form over the synovial membrane now called as pannus. Rheumatoid Arthritis

24. Early Destruction in RA

25. The inflammation can spread to soft tissues as shown in fig and destroy these structure causing laxity and deformity of joint. Muscles tendons ligaments

30. Mast cells Mast cells are implicated in the pathology associated with the autoimmune disorders rheumatoid arthritis.

31. Mast cells Mast cells are basophils that have "homed in" on tissues characteristically surrounding blood vessels and contains many granules rich in histamine and heparin.

32. Mast cells Mast cells has a receptor for the Fc region of IgE. As a result, mast cells are coated with IgE. Mast cells usually remain inactive until an allergen binds to IgE already in association with the cell.

33. It appears that binding of two or more IgE molecules is required to activate the mast cell. Mast cells

35. The molecules thus released by mast cell into the extracellular environment include: Cytokines Histamine/Serotonin/Heparin Eosinophil chemotactic factor Prostaglandin D2 leukotrienes C4 Platelet-activating factor TNFa Mast cells

36. Histamine and serotonin dilates capillaries activates the endothelium, and increases blood vessel permeability. This leads to local edema (swelling), warmth, redness, and the attraction of other inflammatory cells to the site of release. Mast cells

37. Increase in the permeability of blood vessels in the synovial membranes. This attracts several types of leukocytes and lymphocytes to the synovial membrane out of the circulation. Synovial inflammation (synovitis) RHEUMATOID ARTHRITIS

38. The phagocytes of inflammation (neutrophils and macrophages) ingest the immune complexes which releases powerful enzymes that degrade synovial tissue and articular cartilage. RHEUMATOID ARTHRITIS

39. Inflammation causes hemorrhage, coagulation, and fibrin deposits on the synovial membrane, in the intracellular matrix, and in the synovial fluid. RHEUMATOID ARTHRITIS

40. On the denuded areas of the synovial membrane, fibrin gets deposited and develops into granulation tissue called pannus, which is the earliest tissue produced in the healing process. RHEUMATOID ARTHRITIS

41. The pannus is a sheet of inflammatory granulation tissue that spreads from the synovial membrane and invades the joint in rheumatoid arthritis ultimately leading to fibrous ankylosis. RHEUMATOID ARTHRITIS

42. The synovial membrane undergoes hyperplasic thickening as its cells abnormally proliferate and enlarge. RHEUMATOID ARTHRITIS

43. These vascular derangements decrease blood flow to the synovial tissue and compromised circulation. This, coupled with increased metabolic needs due to hypertrophy and hyperplasia, causes hypoxia (oxygen depletion) and metabolic acidosis. RHEUMATOID ARTHRITIS

44. Acidosis stimulates the release of hydrolytic enzymes from synovial cells into the surrounding tissue, initiating erosion of the articular cartilage and inflammation spreads into the supporting ligaments and tendons. RHEUMATOID ARTHRITIS

45. The synovitis or inflammation, results in the warmth, redness, swelling, and pain that are typical symptoms of RA. RHEUMATOID ARTHRITIS

46. In this disease process, an interaction between antibodies and antigens occurs, and causes alterations in the composition of the synovial fluid. Infiltration of cells in it etc. RHEUMATOID ARTHRITIS

47. Once the composition of this fluid is altered, it is less able to perform the normal functions and results in soft tissue destruction that eventually leads to laxity in tendons and ligaments. RHEUMATOID ARTHRITIS

48. Stage One: Congestion and edema of the synovial membrane and joint capsule. RHEUMATOID ARTHRITIS

49. Stage Two: Formation of pannus occurs, covering the cartilage and eventually destroying the joint capsule and bone. RHEUMATOID ARTHRITIS

50. Stage Three: Fibrous ankylosis, which is a fibrous invasion of pannus and scar tissue that fills the joint space. Mal-alignment cause visible deformities and disrupt the articulation of opposing bones. This, in turn, causes muscle atrophy and imbalance that may also include partial dislocations (subluxations). RHEUMATOID ARTHRITIS

51. Stage Four: Fibrous tissue begins to calcify, resulting in bony ankylosis (total immobility). RHEUMATOID ARTHRITIS

52. Epidemiology RA affects 0.5-1.0% of population in USA Females > males 3:1 but people of any age can be affected Peak age 45-65 but onset early from age 20-45 yrs Smoking risk factor Genetic  70% of patients with RA express HLA-DR4  twins indicate a concordance of about 15%–20%

53. Diagnostic Criteria for RA ≥ 4 criteria present > 6 wks  Morning stiffness > 1 hour  Arthritis of ≥ 3 joints areas (PIP, MCP, wrist, elbow, knee, ankle, and MTP)  Arthritis of hand joints (wrist, MCP, PIP)  Symmetric arthritis  Rheumatoid nodules  RF+  Radiographic changes Erosions Unequivocal periarticular osteopenia

54. RHEUMATOID ARTHRITIS It occurs worldwide, affecting more than 6.5 million people in the U.S. alone. About 75% of these are women. The disease strikes women three times more often than men.

55. RHEUMATOID ARTHRITIS Although it can occur at any age, the peak onset period is between the ages of 35 and 50. The disease may come on slowly or may appear suddenly.

56. ETIOLOGY OF RA The cause of rheumatoid arthritis is unknown. Even though infectious agents such as viruses, bacteria, and fungi have long been suspected as well as smoking, but none has been proven as the cause. It is believed that the tendency to develop rheumatoid arthritis may be genetically inherited.

57. ETIOLOGY OF RA For example, the genetic marker HLA-DR4 has been identified in as many as 66% of patients with disease. This marker, which is present in white blood cells, plays a role in helping the immune system to distinguish between foreign cells (e.g., germs) and the body's own cells.

58. ETIOLOGY OF RA Because RA often is affected by pregnancy— symptoms improve before the infant is born and then worsen after delivery—it may be that hormones in the body influence disease development and progression.

59. ETIOLOGY OF RA Stress — Patients often report episodes of stress or trauma preceding the onset of their rheumatoid arthritis. Stressful "life events" (divorce, accidents, grief, etc) are more common in people with RA in the six months before their diagnosis compared to the general population.

60. ETIOLOGY OF RA All this might trigger the activation of the immune system in susceptible individuals. This misdirected immune system then attacks the body's own tissues. This leads to inflammation in the joints and sometimes in various organs of the body, such as the lungs or eyes.

61. SYMPTOMS AND SIGNS OF RHEUMATOID ARTHRITIS The joints of the hands are often the very first joints affected by rheumatoid arthritis. These joints are tender when squeezed, and the hand's grip strength is often reduced. Rheumatoid arthritis may lead to visible redness and swelling and pain of joints or entire the entire hand.

62. The joints of the hands are often the very first joints affected by rheumatoid arthritis. These joints are swollen red and tender when squeezed. Swelling due to synovitis

63. RA - hands

66. SYMPTOMS AND SIGNS OF RHEUMATOID ARTHRITIS Metacarpophalangeal and proximal inter phalangeal are involved. The joint stiffness is most bothersome in the morning and after sitting still for a period of time. The stiffness can persist for more than one hour.

67. SYMPTOMS AND SIGNS OF RHEUMATOID ARTHRITIS The symptoms of rheumatoid arthritis come and go, depending on the degree of tissue inflammation. When body tissues are inflamed, the disease is active. When tissue inflammation subsides, the disease is inactive (in remission).

68. SYMPTOMS AND SIGNS OF RHEUMATOID ARTHRITIS Remissions can occur spontaneously or with treatment and can last weeks, months, or years. During remissions, symptoms of the disease disappear, and people generally feel well. When the disease becomes active again (relapse), symptoms return.

69. SYMPTOMS AND SIGNS OF RHEUMATOID ARTHRITIS The return of disease activity and symptoms is called a flare. The course of rheumatoid arthritis varies among affected individuals, and periods of flares and remissions are typical.

70. SYMPTOMS AND SIGNS OF RHEUMATOID ARTHRITIS Muscle and joint stiffness are usually most notable in the morning and after periods of inactivity. Arthritis is common during disease flares. Also during flares, joints frequently become red, swollen, painful, and tender.

71. SYMPTOMS AND SIGNS OF RHEUMATOID ARTHRITIS This occurs because the lining tissue of the joint (synovium) becomes inflamed (synovitis), resulting in the production of excessive joint fluid (synovial fluid).

72. SYMPTOMS AND SIGNS OF RHEUMATOID ARTHRITIS In rheumatoid arthritis, multiple joints are usually inflamed in a symmetrical pattern (both sides of the body affected). The small joints of both the hands and wrists are often involved.

73. SYMPTOMS AND SIGNS OF RHEUMATOID ARTHRITIS Simple tasks of daily living, such as turning door knobs and opening jars, can become difficult during flares. The small joints of the feet are also commonly involved.

74. SYMPTOMS AND SIGNS OF RHEUMATOID ARTHRITIS Chronic inflammation can cause damage to body tissues, including cartilage, tendons, ligaments and bone.

75. SYMPTOMS AND SIGNS OF RHEUMATOID ARTHRITIS This leads to a loss of cartilage and erosion and weakness of the bones as well as the muscles, resulting in joint deformity, destruction, and loss of function which often leads to difficulty performing every day tasks (e.g., buttoning a shirt, opening a jar).

76. SYMPTOMS AND SIGNS OF RHEUMATOID ARTHRITIS Occasionally, only one joint is inflamed. When only one joint is involved, the arthritis can mimic the joint inflammation caused by other forms of arthritis, such as gout or joint infection.

77. COMPLICATIONS OF RHEUMATOID ARTHRITIS Certain characteristic hand deformities can occur with long-standing rheumatoid arthritis like Swan neck deformities Boutonniere deformities Z deformity of thumb Bow string sign The tendons on the back of the hand may become very prominent and tight, called the bow string sign.

78. Swan neck deformity The deformity arises from hyperextension of the proximal interphalangeal joint, while the distal interphalangeal joint is flexed.

80. Swan neck deformity In the PIP joint the strongest ligament is the volar plate. This ligament connects the proximal phalanx to the middle phalanx on the palm side of the joint. The ligament tightens as the joint is straightened and keeps the PIP joint from bending back too far (hyperextending). Swan neck deformity

81. Swan neck FDS rupture/ volar plate injury Lateral bands sublux dorsally PIP hyperextends and DIP flexes

84. Swan-neck deformity Although characteristic in RA, swan-neck deformity has several causes, including untreated mallet finger, laxity of the ligaments of the volar aspect of the PIP joint in old age or a normal variant. True swan-neck deformity does not affect the thumb, which has only one interphalangeal joint.

85. Mallet Finger Mallet finger is a simple flexion deformity of the distal interphalangeal joint preventing extension. This deformity results from an extensor tendon rupture.

86. Z- deformity of Thumb Severe hyperextension of the interphalangeal joint of the thumb with flexion of the metacarpophalangeal (MCP) joint can occur; this is called a duck bill, Z (zigzag) type, or 90°-angle deformity. With simultaneous thumb instability, pinch is greatly impaired.

87. Buttonhole Deformity Flexion of the PIP joint accompanied by hyperextension of the DIP joint. This deformity can result from tendon laceration, dislocation, fracture, osteoarthritis, or RA.

88. Buttonhole Deformity The tendons which straighten finger joints are like strings running from the sides and the back of the finger to a sheet on the top of the finger.

89. Buttonhole Deformity When the finger is hit or bent forcefully in just the wrong way, the sheet on the top of the finger (the central slip of tendon) tears away from its attachment to the top of the middle finger bone.

90. Buttonhole Deformity The tear in the tendon sheet looks like a buttonhole ("boutonniere" in French), and the end of the finger bone actually begins to stick through the hole. As a result, the tendons can't straighten the middle joint (which stays bent) and all of the force of the tendons bypasses the middle joint and goes to the end joint (which flips backward).

91. Buttonhole Deformity

93. Boutonniere deformity Flexion of the PIP joint accompanied by hyperextension of the DIP joint is boutoniere deformity in little finger.

94. Boutoniere deformity

98. COMPLICATIONS OF RHEUMATOID ARTHRITIS

99. Rheumatoid nodules Painless firm lumps that appear beneath the skin, often single or multiple, and range in size from millimeters to centimeters in diameter occur on the underside of the forearm and on the elbow.

100. Rheumatoid nodules But they can also occur on other pressure points, including the back of the head, the base of the spine, the Achilles tendon, and the tendons of the hand

101. Rheumatoid nodules Occur in about 25% of patients More common in men than women

102. Rheumatoid nodules These nodules may move easily when touched or they may be fixed to deeper tissues and cause pressure on surrounding nerves or can rupture, causing pain and discomfort in surrounding tissue.

103. Rheumatoid nodules Although nodules are mostly benign, complications such as infection, ulceration, and gangrene can occur following breakdown of skin overlying the nodules.

104. Rheumatoid nodules Usually no treatment is necessary unless nodules become debilitating, ulcerated, or infected. Surgical removal may be performed.

105. Skin complications of RA

106. Skin and muscles become atrophic (thin and wrinkled), making it fragile and easy to bruise

107. Skin complications of RA Skin on the back of the hands may become pale or even translucent Nails may become brittle and split length-wise

108. Skin complications of RA The palms become reddened (palmer erythema)

109. Skin complications of RA A rare, serious complication, usually with long-standing rheumatoid disease, is blood vessel inflammation (Vasculitis). Vasculitis can impair blood supply to tissues and lead to tissue death (necrosis). This is most often initially visible as tiny black areas around the nail beds or as leg ulcers. Atrophic skin

110. Skin complications of RA Dark purplish areas on the skin (purpura) are caused by bleeding into the skin from blood vessels damaged by rheumatoid arthritis.

111. Skin complications of RA Rheumatoid Vasculitis can cause many internal symptoms,, hepatomegaly (enlarged liver), splenomegaly (enlarged spleen), bowel ulcers, and haematuria (blood in urine ).

112. RA - Vasculitis

114. Skin complications of RA Skin ulcers (usually leg ulcers) may be extensive and painful Petechiae (purplish spots) or purpura Nail fold or edge breakdown Gangrene

115. Skin complications of RA Neutrophilic dermatoses Neutrophils are a type of white blood cell (leucocyte). They are present in bacterial infections. They are the prominent cell seen on skin biopsy of some uncommon inflammatory skin diseases known as neutrophilic dermatoses.

116. Skin complications of RA Sweet disease and pyoderma gangrenosum are other neutrophilic disorders sometimes seen in association with rheumatoid arthritis. Pyoderma gangrenosum

117. Skin complications of RA Interstitial granulomatous dermatitis. also known as ‘rheumatoid papules’, interstitial granulomatous dermatitis presents as skin coloured or red papules often on the trunk. It is rare.

118. Skin complications of RA RA can affect the glands located near the eyes and mouth, resulting in a condition called secondary Sjögren's syndrome. Decreased tear and saliva production can cause dry mouth, and dry eyes.

119. GASTRO-INTESTINAL COMPLICATIONS Dry mouth, related to Sjogren syndrome, is the most common symptom of gastrointestinal involvement. Gastritis (stomach inflammation) or stomach ulcer caused by NSAID therapy.

120. Urinary complications of RA The kidneys are not usually affected directly by rheumatoid arthritis. Kidney problems in rheumatoid arthritis are much more likely to be caused by medications used to treat the condition.

121. Hematological complications of RA Anemia Low white blood cell count (leukopenia) can occur from Felty's syndrome, a complication of rheumatoid arthritis that is also characterized by enlargement of the spleen.

122. Hematological complications of RA Immune thrombocytopenic purpura caused by an autoimmune reaction against platelets. drug induced neutropenia; thrombocytopenia, particularly autoimmune and drug induced thrombocytopenia; and hematological malignancy.

123. Nervous complications of RA Entrapment of nerves. Carpal tunnel syndrome or ulnar nerve neuropathy including sensory or motor neuropathy (loss of sensation)

125. Nervous complications of RA Formation of a Baker's cyst (a cyst filled with joint fluid and located in the hollow space at the back of the knee). Its herniation of posterior capsule

126. RESPIRATORY COMPLICATIONS OF RA CAPLANS SYNDROME The combination of RA and exposure to coal dust produces the condition. It develops especially in miners working in anthracite coal-mines and in persons exposed to silica and asbestos.

127. RESPIRATORY COMPLICATIONS OF RA CXR shows multiple, round, well defined nodules, usually 0.5 - 2.0 cm in diameter, which may cavitate and resemble tuberculosis. CT scanning gives a better picture of cavitation.

128. RESPIRATORY COMPLICATIONS OF RA well defined nodules, usually 0.5 - 2.0 cm in diameter, which may cavitate and resemble tuberculosis.

129. RESPIRATORY COMPLICATIONS OF RA The syndrome is named after Dr. Anthony Caplan, a physician on the Cardiff Pneumoconiosis Panel.

130. RESPIRATORY COMPLICATIONS OF RA Fibrosis of lung scattered all over lung

131. OCULAR COMPLICATIONS OF RA RA can also cause inflammation of the sclera (white part of the eye), which may make the sclera appear red or bluish in color.

132. OCULAR COMPLICATIONS OF RA Keratoconjunctivitis sicca

133. OCULAR COMPLICATIONS OF RA Episcleritis

134. OCULAR COMPLICATIONS OF RA Scleritis

135. OCULAR COMPLICATIONS OF RA Stromal corneal opacities with peripheral vascularisation

136. OCULAR COMPLICATIONS OF RA Iridocyclitis.

137. OCULAR COMPLICATIONS OF RA Marginal thinning of the cornea with keratolysis

138. Lysis of bones Punched out lytic changes in bones

139. Lytic changes in toes

140. RA - knees Joint spaces in knee is reduced due cartilage destruction.

141. Cock-up deformity or hammer toes

142. MTP Subluxation Abducto hallus vulgus

143. MCP Subluxation Subluxation of MCP joints.

144. Ulnar Deviation

147. Atlantoaxial Instability

148. Bow string sign The tendons on the back of the hand may become very prominent and tight, called the bow string sign. Ulnar deviation The direction of prominent tendons is like bow string

149. Rheumatoid Arthritis Differential Diagnosis – Rheumatic fever: migratory arthritis, elevated ASO and dramatic response to Aspirin – Systemic Lupus Erythematosus: Butterfly rash, discoid lupus erythematosus, photosensitivity, alopecia, high titers of Anti Ds-DNA, renal and CNS disease – Osteoarthritis: no constitutional manifestations and no evidence of joint inflammation – Gouty Arthritis: usually monoarticular initially but can become polyarticular in the later years

150. Rheumatoid Arthritis Differential Diagnosis – Pyogenic arthritis: usually monoarticular, fever and chills, abnormal joint fluid – Chronic Lyme disease: commonly monoarticular and associated with positive titers – Human Parvovirus infection: arthralgia more common than arthritis, rash may be present, serologic evidence of parvovirus B19 infection – Polymyalgia rheumatica is associated with proximal muscle weakness and stiffness

151. Rheumatoid Arthritis Differential Diagnosis – several cancers produce paraneoplastic syndromes including polyarthritis; e.g., hypertrophic pulmonary osteoarthropathy produced by lung and gastrointestinal cancers. Diffuse swelling of the palmar fascia has been associated with several cancers including ovarian cancer.

152. 152 Diagnostic Findings Rheumatoid Factor Elevated ESR C-reactive protein Anemia Thrombocytosis Antinuclear antibodies Synovial fluid: WBC >2000/mm3

153. Laboratory – RF Rheumatoid Factor – Antibody igM against the Fc fragment of IgG – Not sensitive 80% of RA patients – RF+ patients more likely to have More severe disease Extraarticular manifestations

154. Anti-CCP Anti-cyclic citrullinated peptide Specificity = 90% Sensitivity = 50-80%

155. TREATMENT OF RHEUMATOID ARTHRITIS Nonsteroidal anti inflammatory drugs (NSAIDs) are a class of drugs that reduce inflammation, pain, fever, and swelling and are commonly prescribed for the inflammation of the joints (arthritis) and other tissues, such as in tendinitis and bursitis.

156. Nonsteroidal anti inflammatory drugs Examples of NSAIDs include: Aspirin Indomethacin Ibuprofen Naproxen Piroxicam Nabumetone Diclofenac All NSAIDs should be taken with meals to prevent stomach upset.

157. Nonsteroidal anti inflammatory drugs NSAIDs work by blocking the production of prostaglandins, chemical messengers that often are responsible for the pain and swelling of inflammatory conditions.

158. Nonsteroidal anti inflammatory drugs Prostaglandins are made by two different enzymes, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The prostaglandins made by the two different enzymes have slightly different effects on the body.

159. Nonsteroidal anti inflammatory drugs COX-2 inhibitors are NSAIDs that selectively block the COX-2 enzyme and not the COX-1 enzyme. Blocking this enzyme impedes the production of prostaglandins.

160. Nonsteroidal anti inflammatory drugs Some of the prostaglandins made by COX-1 protect the inner lining of the stomach. Common NSAIDs such as aspirin block both COX-1 and COX-2.

161. Nonsteroidal anti inflammatory drugs When the COX-1 enzyme is blocked, inflammation is reduced, but the protection of the lining of the stomach also is lost. This can cause stomach upset as well as ulceration and bleeding from the stomach and even the intestines.

162. Nonsteroidal anti inflammatory drugs COX-2 enzyme is located specifically in areas of the body that commonly are involved in inflammation but not in the stomach.

163. Nonsteroidal anti inflammatory drugs When the COX-2 enzyme is blocked, inflammation is reduced; however, since the COX-2 enzyme does not play a role in protecting the stomach or intestine, therefore do not injure the stomach or intestines as compared to COX-1 inhibitors.

164. Nonsteroidal anti inflammatory drugs Older NSAIDs (for example, ibuprofen, naproxen, etc.) all act by blocking the action of both the COX-1 and COX-2 enzymes.

165. Nonsteroidal anti inflammatory drugs NSAIDs, including COX-2 inhibitors, may increase the risk of heart attacks, stroke, and related conditions. This risk may increase in patients with risk factors for heart disease and related conditions.

166. Nonsteroidal anti inflammatory drugs Aspirin Indomethacin 500-1000 mg every 6 hours or BD. Heart attacks are prevented with 50/75 or 325 mg daily. 50-200 mg per day split into 2-3 doses

167. Nonsteroidal anti inflammatory drugs Ibuprofen 200 or 400 mg every 6 hours. Individuals should not use ibuprofen for more than 10 days for the treatment of pain or more than 3 days for the treatment of a fever unless directed by a physician.

168. Nonsteroidal anti inflammatory drugs Naproxen Piroxicam Nabumetone Diclofenac 250-500 mg twice daily 20 mg once daily or 10 mg twice daily 1000 mg daily as a single dose. Some patients may respond better to 1500 or 2000 mg daily. The lowest effective dose should be used 50-100 mg /day

169. COX-2 inhibitors COX-2 inhibitors are Celecoxib Rofecoxib valdecoxib

170. COX-2 inhibitors Celecoxib. 100 or 200 mg twice daily. The lowest effective dose should be used for each patient.

171. Disease-Modifying Antirheumatic Drugs or DMARDs While "first-line" medications (NSAIDs and corticosteroids) can relieve joint inflammation and pain, they do not necessarily prevent joint destruction or deformity.

172. Disease-Modifying Antirheumatic Drugs or DMARDs For patients with an aggressively destructive form of rheumatoid arthritis, medications other than NSAIDs and corticosteroids are needed. These "second-line" or "slow-acting" medicines may take weeks to months to become effective.

173. Disease-Modifying Antirheumatic Drugs or DMARDs They are used for long periods of time, even years, at varying doses. If effective, they can promote remission, thereby retarding the progression of joint destruction and deformity. Sometimes a number of second-line medications are used together as combination therapy.

174. Disease-Modifying Antirheumatic Drugs or DMARDs Hydroxychloroquine is related to quinine, and is used in the treatment of malaria. It is used over long periods for the treatment of rheumatoid arthritis. Side effects include upset stomach, skin rashes, muscle weakness, and vision changes.

175. Disease-Modifying Antirheumatic Drugs or DMARDs The usual adult dose for treating malaria is 800 mg initially, followed by 400 mg 6 hours later then 400 mg on days 2 and 3. The dose for malaria prevention is 400 mg every week starting 1 or 2 weeks before exposure and for 4 weeks after leaving the high risk area.

176. Disease-Modifying Antirheumatic Drugs or DMARDs The recommended adult dose for rheumatoid arthritis is 400-600 mg daily for 4-12 weeks followed by 200-400 mg daily. Systemic lupus erythematosus is treated with 400 mg once or twice daily for several weeks then 200-400 mg daily. Hydroxychloroquine should be taken with food or milk in order to reduce stomach upset.

177. Disease-Modifying Antirheumatic Drugs or DMARDs Sulfasalazine is an oral medication traditionally used in the treatment of mild to moderately severe inflammatory bowel diseases, such as ulcerative colitis and Crohn's colitis.

178. Disease-Modifying Antirheumatic Drugs or DMARDs Sulfasalazine is used to treat rheumatoid arthritis in combination with anti- inflammatory medications. Sulfasalazine is generally well tolerated. Common side effects include rash and upset stomach. Because sulfasalazine is made up of sulfa and salicylate compounds, it should be avoided by patients with known sulfa allergies.

179. Disease-Modifying Antirheumatic Drugs or DMARDs Gold salts have been used to treat rheumatoid arthritis throughout most of this century. Gold thioglucose (SOLGANAL) and gold thiomalate (MYOCHRYSINE) are given by injection, initially on a weekly basis for months to years. Oral gold, auranofin (RIDAURA) was introduced in the 1980's.

180. Disease-Modifying Antirheumatic Drugs or DMARDs Side effects of gold (oral and injectable) include skin rash, mouth sores, kidney damage with leakage of protein in the urine, and bone marrow damage with anemia and low white cell count. Patients receiving gold treatment are regularly monitored with blood and urine tests. Oral gold can cause diarrhea.

181. Immunosuppressive Medicines Are powerful medications that suppress the body's immune system. A number of immunosuppressive drugs are used to treat rheumatoid arthritis. They include Methotrexate Azathioprine Cyclophosphamide Chlorambucil and Cyclosporine

182. Immunosuppressive Medicines Because of potentially serious side effects, immunosuppressive medicines (other than methotrexate) are generally reserved for those who have very aggressive disease or those with serious complications of rheumatoid inflammation, such as blood vessel inflammation (vasculitis).

183. Immunosuppressive Medicines The exception is methotrexate, which is not frequently associated with serious side effects and can be carefully monitored with blood testing. Methotrexate has become a preferred second-line medication as a result.

184. Immunosuppressive Medicines Methotrexate may be taken with or without food.7.5 mg dose weekly. Thinning of the bones due to osteoporosis may be prevented by calcium and vitamin D supplements.

185. Newer "second- line“ drugs or "biologic" medications Leflunomide Etanercept Infliximab Annakira Adalimumab Rituximab Abatacept Golimumab Certolizumab Tocilizumab

186. Newer "second- line“ drugs or "biologic" medications Each of these medications can increase the risk for infections, and the development of any infections should be reported to the health- care professional when taking these newer second-line drugs.

187. Newer "second- line“ drugs or "biologic" medications Etanercept, infliximab, adalimumab, golimumab, and certolizumab are biologic medications that intercept a messenger protein in the joints (tumor necrosis factor or TNF) that promotes inflammation of the joints in rheumatoid arthritis.

188. Newer "second- line“ drugs or "biologic" medications These TNF-blockers intercept TNF before it can act on its natural receptor to "switch on" the process of inflammation. This effectively blocks the TNF inflammation messenger from recruiting the cells of inflammation. Symptoms can be significantly, and often rapidly, improved in those using these drugs.

189. Newer "second- line“ drugs or "biologic" medications Etanercept must be injected subcutaneously once or twice a week. Infliximab is given by infusion directly into a vein (intravenously). Adalimumab is injected subcutaneously either every other week or weekly. Golimumab is injected subcutaneously on a monthly basis. Certolizumab pegol is injected subcutaneously every two to four weeks.

190. Newer "second- line“ drugs or "biologic" medications They are currently recommended for use after other second-line medications have not been effective. The biological response modifiers (TNF-inhibitors) are expensive treatments. They are also frequently used in combination with methotrexate and other DMARDs.

191. Newer "second- line“ drugs or "biologic" medications Furthermore, it should be noted that the TNF- blocking biologics all are more effective when combined with methotrexate. These medications should be avoided by persons with significant congestive heart failure or demyelinating diseases (such as multiple sclerosis) because they can worsen these conditions.

192. Newer "second- line“ drugs or "biologic" medications Rituximab is an antibody that was first used to treat lymphoma. It depletes B-cells, which are important cells of inflammation and in the production of abnormal antibodies.

193. Newer "second- line“ drugs or "biologic" medications Abatacept is a biologic medication given i/v that attaches to a protein on the surface of T-lymphocytes. By attaching to the protein, abatacept prevents the activation of the T-lymphocytes and blocks both the production of new T-lymphocytes and the production of the chemicals that destroy tissue and cause the symptoms and signs of arthritis.

194. Newer "second- line“ drugs or "biologic" medications DOSING: Abatacept is infused over 30 minutes. The initial dose of abatacept is followed by additional doses two and four weeks after the first infusion with further doses every 4 weeks thereafter. Patients weighing 100 kg a 1000 mg dose.

195. Newer "second- line“ drugs or "biologic" medications Tocilizumab blocks interleukin-6 (IL-6), which is a chemical messenger of the inflammation of rheumatoid arthritis. Tocilizumab (Actemra) is an intravenous infusion given monthly.

196. Newer "second- line“ drugs or "biologic" medications Adalimumab DOSING: Adalimumab is injected under the skin. The recommended dose for adults is 40 mg every other week, but some patients may need weekly administration.

197. Newer "second- line“ drugs or "biologic" medications Anakinra is a synthetic (man-made), injectable, interleukin- 1 receptor antagonist that blocks the effects of human interleukin-1. It is used in the treatment of rheumatoid arthritis. Interleukin-1 (IL-1) is a protein that is produced by many cells in the body. It is found in increased amounts within joints that are inflamed by arthritis.

198. Newer "second- line“ drugs or "biologic" medications The IL-1 attaches to receptors on the tissues within and surrounding the joints as well as on the cells that are responsible for inflammation, for example, white blood cells. The attachment of IL-1 activates the cells to promote inflammation and release enzymes. The enzymes destroy the cartilage and bone and contribute to pain and swelling of the joints.

199. Newer "second- line“ drugs or "biologic" medications Anakinra attaches to the IL-1 receptor and prevents IL-1 from attaching to the receptor. Thus, the inflammatory and enzyme-releasing effects of IL-1 are prevented and pain and swelling of the joints are reduced. Anakinra was approved by the Food and Drug Administration in November, 2001

200. Newer "second- line“ drugs or "biologic" medications DOSING: The daily dose of anakinra in rheumatoid arthritis is one subcutaneous injection of 100 mg daily. The dose should be administered at approximately the same time every day.

201. Newer "second- line“ drugs or "biologic" medications Infliximab is an antibody that blocks the effects of tumor necrosis factor alpha (TNF alpha). Infliximab is administered by intravenous infusion. There are two other injectable drugs that block TNF alpha--adalimumab(Humira) and etanercept (Enbrel).

202. Newer "second- line“ drugs or "biologic" medications TNF is a substance made by cells of the body which has an important role in promoting inflammation. Specifically, infliximab is used for treating the inflammation of Crohn's disease, rheumatoid arthritis, psoriasis, ankylosing spondylitis, and psoriatic arthritis. By blocking the action of TNF-alpha, infliximab reduces the signs and symptoms of inflammation. Infliximab does not cure Crohn's disease, psoriatic arthritis or rheumatoid arthritis; however, preliminary studies have demonstrated that infliximab can retard the destruction of joints by rheumatoid

203. Newer "second- line“ drugs or "biologic" medications DOSING: Infliximab is administered intravenously. For moderate to severe Crohn's disease the dose is 5 mg/kg administered as a single dose. For fistulizing Crohn's disease, the dose is 5 mg/kg followed by additional doses of 5 mg/kg two and six week after the first dose.

204. Newer "second- line“ drugs or "biologic" medications The recommended dose for the treatment of rheumatoid arthritis is 3 mg/kg as a single dose. The initial dose should be followed by additional 3 mg/kg doses two and six weeks after the first dose. Thereafter, the maintenance dose is 3 mg/kg every eight weeks.

205. Newer "second- line“ drugs or "biologic" medications Etanercept is an injectable drug that blocks tumor necrosis factor alpha (TNF alpha) and is used for treating rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. TNF alpha is a protein that the body produces during the inflammatory response, the body's reaction to injury.

206. Newer "second- line“ drugs or "biologic" medications TNF alpha promotes the inflammation and its associated fever and signs (pain, tenderness, and swelling) in several inflammatory conditions including rheumatoid arthritis and ankylosing spondylitis. Etanercept is a synthetic (man-made) protein that binds to TNF alpha. It thereby acts like a sponge to remove most of the TNF alpha molecules from the joints and blood.

207. Newer "second- line“ drugs or "biologic" medications This prevents TNF alpha from promoting inflammation and the fever, pain, tenderness and swelling of joints in patients with rheumatoid or psoriatic arthritis and ankylosing spondylitis. Etanercept reduces the signs and symptoms of rheumatoid arthritis, the arthritis of psoriasis, and ankylosing spondylitis. It prevents the progressive destruction of the joints in patients with rheumatoid arthritis and the arthritis of psoriasis.

208. Newer "second- line“ drugs or "biologic" medications DOSING: Etanercept is injected under the skin. Adults usually inject 25mg twice weekly. Children 4 to 17 years old should receive 0.4mg/kg (maximum 25mg) twice weekly. Etanercept has not been studied in children younger than 4 years.

209. Newer "second- line“ drugs or "biologic" medications While biologic medications are often combined with traditional DMARDs in the treatment of rheumatoid arthritis, they are generally not used with other biologic medications because of the unacceptable risk for serious infections.

210. Corticosteroid Therapy medications can be given orally or injected directly into tissues and joints. They are more potent than NSAIDs in reducing inflammation and in restoring joint mobility and function.

211. Corticosteroid Therapy Corticosteroids are useful for short periods during severe flares of disease activity or when the disease is not responding to NSAIDs. However, corticosteroids can have serious side effects, especially when given in high doses for long periods of time.

212. Corticosteroid Therapy These side effects include weight gain, facial puffiness, thinning of the skin and bone, easy bruising, cataracts, risk of infection, muscle wasting, and destruction of large joints, such as the hips.

213. Prosorba column Therapy The Prosorba column therapy involves pumping blood drawn from a vein in the arm into an apheresis machine, or cell separator. This machine separates the liquid part of the blood (the plasma) from the blood cells.

214. Prosorba column Therapy The Prosorba column is a plastic cylinder about the size of a coffee mug that contains a sand-like substance coated with a special material called Protein A. Protein A is unique in that it binds unwanted antibodies from the blood that promote the arthritis.

215. Prosorba column Therapy The Prosorba column works to counter the effect of these harmful antibodies. The Prosorba column is indicated to reduce the signs and symptoms of moderate to severe rheumatoid arthritis in adult patients with long-standing disease who have failed or are intolerant to disease-modifying antirheumatic drugs (DMARDs). The exact role of this treatment is being evaluated by doctors, and it is not commonly used currently.

217. Combination DMARD therapy MTX + SSZ + OH-Chloroquine O’Dell 1995 MTX + CSA Tugwell 1995 MTX + Etanercept MTX + Remicade MTX + Adalimumab MTX + Leflunomide excellent safety & improved efficacy over MTX alone

218. ODB Indications for Biologic Drugs RA: Failure of DMARD therapy Failure or Intolerance to – MTX 20mg/week sc or po x 3 months – Arava 20 mg po x 3 months – Any combination DMARD

219. Drugs & Pregnancy NSAIDS: safe until week 34 (patent ductus) OH-chloroquine: safe, ?cleft palate Sulfasalzine: continue if on it; safe Imuran: continue if on it; safe Methotexate: teratogen ??? ok in small doses; stop 3 months before conception Arava: teratogen may be present for 2 yrs Cyclophosphamide:? teratogen ? Safe > 2 nd trimester Biologic agents: unknown; stop 3 months before conception Steroids: non-fluorinated do NOT cross placenta

220. THANK YOU SO MUCH Trust the physician and the teacher, and drink his remedy in silence and tranquility. For his hand though heavy and hard is guided by tender hand of unseen. And the cup he brings, though it burn your lips has been fashioned of the clay which the potter have moistened with his tears and sacred feelings.