Rheumatoid arthritis

presenting features, types, management and follow up of cases in Rheumatoid arthritis

1. Rheumatoid Arthritis Presenter : pardhu bharath Chair person : dr.lavanya

2. History The first description of RA is found in the dissertation of Augustin Jacob Landré-Beauvais from the year 1800. He hypothesized that these patients were suffering from a previously uncharacterized condition, which he named  Goutte Asthénique Primitive or “Primary Asthenic Gout .”   Alfred Garrod was the first to distinguish gout from other arthritic conditions. He found an excess of uric acid in the blood of patients suffering from gout, but not in the blood of patients with other forms of arthritis coined the term rheumatic gout. Archibald Garrod , the fourth son of Alfred Garrod, also conducted research on RA. In 1890 he authored the extensive  Treatise on Rheumatism and Rheumatoid Arthritis . In this book he coined the term “ Rheumatoid Arthritis ” to refer to the disease first described by Landré-Beauvais

3. EPIDEMIOLOGY RA affects approximately 0.5–1% of the adult population worldwide. T he overall incidence of RA has been decreasing in recent decades, whereas the prevalence has remained the same because individuals with RA are living longer. Occurs more commonly in females, with a 2–3:1 ratio. Given this preponderance of females, various theories have been proposed to explain the possible role of estrogen in disease pathogenesis. Experimental studies have shown that estrogen can stimulate production of tumor necrosis factor a (TNF- α)

4. Genetic considerations Risk of RA in a first-degree relative is 2–10 times greater than in the general population. Twin studies imply that genetic factors may explain up to 60% of the occurrence of RA but estimate falls in the range of 10–25%. The difference is due to gene–environment interactions. The alleles known to confer the greatest risk of RA are located within the major histocompatibility complex (MHC ). O ne-third of the genetic risk for RA resides within this locus. HLA-DRB1 gene , encodes the MHC II β-chain molecule.

5. Genetic considerations The disease-associated HLA-DRB1 alleles in the third hypervariable regions of the HLA-DR β-chain, share an amino acid sequence at positions 70–74 , termed the shared epitope (SE ) . Carrier ship of the SE alleles is associated with production of anti-CCP antibodies and worse disease outcomes.

6. Genetic considerations – Non MHC related genes T he risk loci mostly reside in genes encoding proteins involved in the regulation of the immune response. T he non-MHC loci identified as risk alleles for RA have only a modest effect on risk they also contribute to the risk for developing other autoimmune diseases. T he risk alleles identified by GWAS only account at present for approximately 5% of the genetic risk Among the best examples of the non-MHC genes contributing to the risk of RA is the gene encoding protein tyrosine phosphatase nonreceptor 22 ( PTPN22 )

7. Genetic considerations – Non MHC related genes PTPN22 encodes lymphoid tyrosine phosphatase , protein that regulates T and B cell function. Inheritance of the risk allele for PTPN22 produces a gain-of-function and is hypothesized to result in the abnormal thymic selection of autoreactive T and B cells and appears to be associated exclusively with anti-CCP-positive disease . The peptidyl arginine deiminase type IV ( PADI4 ) gene is another risk allele. Encodes an enzyme involved in the conversion of arginine to citrulline. Postulated to play a role in the development of antibodies to citrullinated antigens.

8. ENVIRONMENTAL FACTORS Chronic smoking: Smoking confers a relative risk of 1.5–3.5 for developing RA . Women who smoke cigarettes have a nearly 2.5 times greater risk of RA, risk persists even 15 years after smoking cessation. Smoking Stimulate citrullination of cellular proteins. Resulting in formation and exposure of neo epitopes and self reactivity . T he risk from smoking is almost exclusively related to RF and anti-CCP antibody-positive disease .

9. ENVIRONMENTAL FACTORS Microbes : M icrobial infections alters the immune system acting via TLR. TLR 2/3/4/9 are found abundantly in synovial fibroblasts. TLR when bind to specific ligands on microbial surface leads to up regulation of pro inflammatory cytokine production leading to amplification of inflammation in RA

10. Environmental factors Microbes :

11. Pathogenesis – pre clinical stage Under genetic and environmental influence Break down in self tolerance occurs, leading to formation of auto antibodies, seen many years before clinical disease. Auto antibodies include Rheumatoid factor ACPA

12. Rheumatoid factor A n autoantibody that binds to the Fc portion of IgG. RF can also fix and activate complement by the classic pathway. The RFs produced in RA differ from those produced by healthy individuals or from patients with paraproteins . The avidity of RF for the Fc portion of IgG is much greater in RA than in Waldenström’s macroglobulinemia or in cryoglobulins

13. Anticitrullinated Protein Antibodies (ACPAs) I mmunoglobulins that bind to citrullinated proteins. citrulline, derived from posttranslational modification of arginine by PADI Humans have four isoforms of PADI. PADI2 and PADI4 are especially abundant in synovium. ACPAs can activate the classical and the alternative complement pathways. IgE ACPAs from patients with RA can sensitize basophils and mast cells to degranulate .

14. Anticitrullinated Protein Antibodies (ACPAs) One interesting subset involves antibodies that recognize mutant citrullinated vimentin (MCV). Anti-MCV antibodies might be more specific for RA in established disease and also might be more predictive for radiographic progression than standard ACPA tests.

15. Pathogenesis Role of CD4 T cells : CD4 binds to invariant sites on MHC 2 with shared epitopes. CD4 memory T cells more in synovium of RA patient. CD4 T cells showed initiation of arthritis in animal modes. T Cell directed therapy has very good clinical efficacy. TH-17 sub set plays an important role in promoting joint inflammation, destroying cartilage and sub chondral bone.

16. Pathogenesis Activated T helper cells activate B cells, macrophages, fibroblast like synoviocytes by Mechanism of: Cell to cell contact. Release of soluble mediators. Activated synovial fibroblasts produce MMP , Proteases , IL1,6, TNF alpha.

17. Pathogenesis Role of TNF alpha: Up regulates adhesion molecules on endothelial cells Influx of leukocytes into synovium Activates synovial fibroblasts Stimulates angiogenesis Promotes pain receptor sensitizing pathways Drives osteoclastogenesis

18. Osteoporosis in RA Osteoprotegrin inhibits RANK-L by acting as a decoy receptor and binds to RANK-L Osteoclasts secrete Cathepsin K, cleaves collagen and reduces bone matrix.

19. Osteoporosis in RA Wnt – family of glycoproteins Promote osteoblast differentiation and bone formation. Induce OPG and hence reducing bone resorption. Wnt pathway is inhibited by DKK-1 Increased TNF alpha levels cause increase expression of DKK-1 Other contributing factors: Prolonged steroid usage Bed ridden state secondary to deformities

20. Clinical features – patterns of onset Insidious Onset Seen in 55 % to 65% of cases . Asymmetric initial presentations (often with increased symmetry developing later in the course of disease) are common. The reason for the symmetry of joint involvement compared with other forms of arthritis , such as the seronegative spondyloarthropathies, is unknown. Morning stiffness is a cardinal sign of inflammatory arthritis that can appear even before pain and may be related to the accumulation of edema fluid within inflamed tissues during sleep.

21. Clinical features – patterns of onset A subtle, early change in RA is the development of muscle atrophy around affected joints. Muscle efficiency and strength become diminished. Depression and anxiety can accentuate symptoms. A small but significant weight loss is common and reflects the catabolic effects of cytokines and associated anorexia . Acute or Intermediate Onset: 8% to 15% have an acute onset of symptoms that peak within a few days Acute-onset RA is difficult to diagnose and sepsis or vasculitis should be ruled out. An intermediate type of onset, in which symptoms develop over days or weeks, occurs in 15% to 20% of patients .

22. Clinical features - patterns of onset Palindromic Pattern: usually begins with pain in one joint or in periarticular tissues; symptoms worsen for several hours to a few days and are associated with swelling and erythema. Then , in reverse sequence, symptoms resolve, leaving no residua . Half of patients with palindromic rheumatism go on to develop RA, particularly those with HLA-DR4. Arthritis Robustus : Most patients are men whose disease is characterized by proliferative synovitis, often with deformity, which seems to cause little pain and even less disability . Patients invariably keep working (often at physical labor ). Periarticular osteopenia is unusual N ew bone proliferation. Bulky subcutaneous nodules develop. Subchondral cysts also develop, presumably from excessive pressure caused by synovial fluid within a thick joint capsule during muscular effort.

23. Clinical features – articular manifestations

24. clinical features – articular manifestations

25. Clinical features – articular manifestations

26. Clinical features – articular manifestations Flexor tendon tenosynovitis is a frequent hallmark of RA and leads to decreased range of motion, reduced grip strength and “trigger” fingers. subluxation of the first MCP joint with hyperextension of the first interphalangeal (IP) joint results in Z-line deformity. Although metatarsophalangeal (MTP) joint involvement in the feet is an early feature of disease, chronic inflammation of the ankle and mid tarsal regions usually comes later and may lead to pes planovalgus (“flat feet”). Valgus of ankle, pes planus, forefoot varus deformity of the left foot related to painful synovitis of the ankle, forefoot, and metatarsophalangeal joint

27. Clinical features – articular manifestations Inflammation about the ulnar styloid and tenosynovitis of the extensor carpi ulnaris may cause subluxation of the distal ulna , resulting in a “ piano-key movement ” of the ulnar styloid.

28. Clinical features – articular manifestations Atlantoaxial involvement of the cervical spine is clinically noteworthy because of its potential to cause compressive myelopathy and neurologic dysfunction. Neurologic manifestations may evolve over time with progressive instability of C1 on C2. The prevalence of atlantoaxial subluxation has been declining in recent years, and occurs now in less than 10% of patients

29. Extra articular manifestations

30. Rheumatoid nodules Subcutaneous nodules occur in 20–35% of patients with RA and are usually nontender , firm, fixed or mobile Occur most frequently over pressure point areas but also can overlie joints Rheumatoid nodules are strongly associated with rheumatoid factor (positive in >95% of cases) and in patients with RA who smoke. Rheumatoid nodules have characteristic histologic findings of central fibrinoid necrosis with a rim of palisading fibroblasts

31. Rheumatoid nodules A subset of rheumatoid patients, experience paradoxical accelerated nodulosis with methotrexate therapy . Nodules in these patients can be frequently found over the extensor aspect of the MCP and PIP joints. Methotrexate should be discontinued . Rheumatoid nodules in the lung may be solitary or multiple , and some are necrotic and difficult to distinguish from carcinoma. C aplans syndrome: Caplan described multiple rheumatoid nodules, some with cavitation, in the lungs of Welsh coal miners with RA. This pattern has also been reported in RA patients exposed to silica dust and asbestos.

32. SJÖGREN SYNDROME Approximately 30% of patients with RA have sicca symptoms due to secondary Sjögren syndrome . D/D : Chronic hepatitis C infection can cause polyarthritis, sicca symptoms, and rheumatoid factor. primary Sjögren syndrome with polyarthritis. SS-A/Ro and to SS-B/La are not prevalent in the secondary Sjögren syndrome associated with RA. H ypergammaglobulinemia , interstitial nephritis, and distal renal tubular acidosis uncommonly develop in patients with RA and secondary Sjögren syndrome.

33. PULMONARY INTERSTITIAL FIBROSIS The prevalence of clinically evident pulmonary fibrosis among RA patients is approximately 2–3 %. Virtually all patients with interstitial fibrosis are seropositive for rheumatoid factor and have anti-CCP antibodies Risk factors: male, Smoking Nonspecific interstitial pneumonitis (NSIP) and usual interstitial pneumonitis (UIP) are the most common pathologic types of fibrosis encountered. NSIP has a more uniform distribution on plain radiographs and a “ ground glass ” appearance on HRCT. UIP has a more basilar distribution of fibrosis; HRCT shows honeycomb patterns and, frequently, traction bronchiectasis.

34. PULMONARY INTERSTITIAL FIBROSIS NSIP is often responsive to glucocorticoids, but there are no current treatments capable of halting the progression of UIP . Trail of oral prednisone (1 mg/kg/d ) regardless of the whether the pathology Prednisone is then tapered in accordance with the clinical picture and the results of serial pulmonary function tests , especially the diffusing capacity . Little evidence for an ameliorative effect of anti-TNF agents on interstitial fibrosis . Patients with preexisting interstitial lung disease may be at increased risk for methotrexate-induced pneumonitis—a hypersensitivity reaction to the drug Because of this concern, many clinicians obtain a pretreatment chest radiograph

35. Other Pulmonary manifestations Cryptogenic organizing pneumonia produces a characteristic pattern of multiple patches of consolidation in the sub pleural areas on HRCT and is often responsive to glucocorticoids. Additional pulmonary complications of RA include : Bronchiectasis , which is present in approximately 3% of patients. Bronchiolitis obliterans , which is rare, is poorly responsive to therapy, frequently leads to severe pulmonary compromise with hypoxia . Pulmonary hypertension.

36. PLEURAL INVOLVEMENT Pleurisy or pleural effusion or both can be the initial manifestation of RA, preceding the onset of articular disease. This occurs in approximately 1–3% of patients , most of whom are male. Analysis of pleural fluid is necessary to exclude malignancy, bacterial empyema, and infections with Mycobacterium tuberculosis. Rheumatoid pleural fluid is exudative and characterized by an extremely low level of pleural-fluid glucose , with the result frequently approaching zero. L ow glucose is secondary to a defect in glucose transport across the pleural membrane .

37. PLEURAL INVOLVEMENT Treatment : R heumatoid pleuritis consists of moderate- to high-dose prednisone tapered in accordance with the clinical response. Pleurodesis or decortication may be required in unresponsive cases.

38. Cardiac involvement R isk of premature death in RA is largely due to an increased incidence of cardiovascular disease, primarily myocardial infarction and congestive heart failure It was reported that 70% of patients with nodular disease and 40% of those with non-nodular RA have some cardiac involvement The most frequent site of cardiac involvement in RA is the pericardium. C linical manifestations of pericarditis occur in less than 10% of patients with RA despite the fact that pericardial involvement may be detected in nearly one-half of the these patients by echocardiogram or autopsy studies .

39. Cardiac involvement Cardiomyopathy , manifestation of RA, whose involvement may also be subclinical and only identified by echocardiography or cardiac MRI. Necrotizing or granulomatous myocarditis Coronary artery disease Diastolic dysfunction. Mitral regurgitation is the most common valvular abnormality in RA . Complete heart block usually is permanent and is caused by rheumatoid granulomas in or near the atrioventricular node or bundle of His. Rarely , the heart muscle may contain rheumatoid nodules or be infiltrated with amyloid and amyloidosis can also be responsible for heart block.

40. HAEMATOLOGICAL ABNORMALITIES Most patients with active RA have a mild normocytic normochromic anemia that correlates with ESR elevation and the activity of the disease. A useful guide is that three-quarters of rheumatoid patients with anemia have the anemia of chronic disease, whereas one-quarter respond to iron therapy. Patients in both groups may have superimposed vitamin B12 or folate deficiency. Thrombocytosis is often associated with RA. A significant relationship has been noted between thrombocytosis and extra-articular manifestations of rheumatoid disease.

41. FELTY SYNDROME Felty syndrome develops in patients with longstanding (usually >10 years duration), erosive RA who are seropositive for rheumatoid factor and have anti-CCP antibodies . Patients with Felty syndrome have synovitis that appears bland and “burnt out.” The hallmarks of the syndrome are leukopenia (<4000 white blood cells/ mcL ), neutropenia (<1500 neutrophils/ mcL ), and splenomegaly. About one-third have evidence of rheumatoid vasculitis with necrotic leg ulcers. Some are positive for P-ANCA , anti-myeloperoxidase antibodies and cryoglobulins . Rarely, fibrosis develops in the hepatic portal system, which leads to portal hypertension, esophageal varices, congestive splenomegaly , and ascites.

42. T cell large granular lymphocyte leukemia (T-LGL) Patients have increased numbers of large granular lymphocytes in the peripheral blood , bone marrow, and liver. These lymphocytes contain many azurophilic granules in the cytoplasm and may account for more than 90% of mononuclear cells in blood . This syndrome is characterized by a chronic, indolent clonal growth of LGL cells , leading to neutropenia and splenomegaly . T he large granular lymphocyte syndrome in patients with RA has the same HLA-DR4 association as seen in Felty’s syndrome.

43. HAEMATOLOGICAL ABNORMALITIES Hence a proposal has been made that Felty’s syndrome and large granular lymphocyte syndrome represent different variants of a broader syndrome comprising RA neutropenia large granular lymphocyte expansions HLA-DR4 positivity variable splenomegaly There is a fourfold increased risk of lymphoma in RA patients compared with the general population. The most common histopathologic type of lymphoma is a diffuse large B cell lymphoma.

44. RHEUMATOID VASCULITIS D evelops after 10–15 years of disease . A lmost exclusively in patients who are seropositive for RF & anti-CCP antibodies. A pproximately 1–3% of patients affected. The pathologic finding in rheumatoid vasculitis is a pan arteritis. All layers of the vessel wall are infiltrated with mononuclear cells. Nail fold infarcts,typically are associated with rheumatoid factor positivity and active joint disease

45. RHEUMATOID VASCULITIS The most common form of rheumatoid vasculitis is a smoldering small-vessel vasculitis that produces painless nailbed infarctions. Less often, RA causes a medium-vessel vasculitis which clinical manifests as necrotic leg ulcers, digital gangrene, and mononeuritis multiplex . Rarely, a systemic necrotizing arteritis develops, which is indistinguishable from polyarteritis nodosum and can lead to infarction of small or large bowel . ANCAs, cryoglobulinemia and hypo complementemia are sometimes present. Initial treatment consists of high doses of glucocorticoids and, often, cyclophosphamide .

46. NEUROLOGIC MANIFESTATIONS The most common neurologic complications of RA are compression neuropathies (carpal tunnel syndrome). Rheumatoid vasculitis can cause mononeuritis multiplex a mixed motor-sensory peripheral neuropathy . Atlantoaxial subluxation and basilar invagination can produce cervical myelopathy and brainstem compression. U nusual complication of RA is pachymeningitis—inflammation and thickening of dura mater . P resents as Clouded sensorium , cranial nerve abnormalities, and retardation of motor activity. Once an infectious etiology has been excluded, pachymeningitis is treated vigorously with glucocorticoids and appropriate DMARDs.

47. DIAGNOSIS In 2010, a collaborative effort between the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) revised the 1987 ACR classification criteria for RA in an effort to improve early diagnosis.

48. Differential diagnosis

49. CLINICAL COURSE N atural history of RA affected by a number of factors including age of onset, gender, genotype, phenotype and comorbid conditions. A s many as 10 % of patients with inflammatory arthritis fulfilling ACR classification criteria for RA will undergo a spontaneous remission within 6 months (particularly seronegative patients ). The overall mortality rate in RA is two times greater than the general population, with ischemic heart disease being the most common cause of death followed by infection. Median life expectancy is shortened by an average of 7 years for men and 3 years for women compared to control populations. Patients at higher risk for shortened survival are those with systemic extra articular involvement, low functional capacity , low socioeconomic status, low education, and chronic prednisone use.

50. Treatment challenges in treatment : I dentifying markers that predict in a differential fashion who will respond to treatment or have side effects from the treatment. D eveloping methods that will allow to measure the amount of immunosuppression that agents are producing . T he most important paradigm shift for the treatment of RA has been the realization that patients should be treated early and to a target of low disease activity or remission.

51. Measures of disease activity

52. Remission on treatment

53. Drugs in rheumatoid arthritis

54. DMARD The definition of a DMARD is one that has the ability to change (for the better) the course of RA . DMARD show not only the ability to change the clinical course of the disease but also the ability to decrease or halt the radiographic progression. With the DMARDs listed above and using these drugs individually or in combinations of two, three, or four as is often done T here are 2569 possible combinations for each individual patient, assuming that biologics are not used in combinations with each other.

55. Conventional DMARD The conventional DMARDs in current use are methotrexate, sulfasalazine , hydroxychloroquine, leflunomide, and minocycline . These medications take 2–6 months to reach maximal effect. Therefore, other measures, such as low-dose glucocorticoid therapy, may be needed to control the disease while these medications show their effect. The choice of synthetic DMARD depends on the activity of the disease, comorbid conditions, concerns about toxicity, and monitoring issues .

56. Methotrexate Anchor drug in RA Methotrexate is administered as a single dose once a week , never on a daily basis. The typical starting dose is 7.5 mg orally once a week; the dose then is increased by 2.5 mg to 7.5 mg increments as needed to a maximum of 20–25 mg. Contraindications : P reexisting liver disease. I nfection with hepatitis B or C. O ngoing alcohol use. R enal impairment (Creatinine clearance <30ml/min)

57. Mechanism of action postulated anti-inflammatory and antiproliferative (immunosuppressive ) mechanisms : Inhibition of aminoimidazole carboxamide ribonucleotide (AICAR ) transformylase ( ATIC) results in increased intracellular and extracellular adenosine. I nhibition of thymidylate synthetase (TYMS) results in decreased pyrimidine synthesis. Inhibition of dihydrofolate reductase (DHFR ) results in inhibition of transmethylation reactions essential for cellular functioning. Adenosine’s anti-inflammatory effects R egulation of endothelial cell inflammatory functions counter regulation of neutrophils and dendritic cells cytokine modulation of monocytes and macrophages. R educed folate carrier ( RFC)

58. Methotrexate Toxicity : Oral ulcers, nausea, hepatotoxicity, bone marrow suppression and pneumonitis are the most commonly encountered toxicities. With the exception of pneumonitis(which is a hypersensitivity reaction) these toxicities respond to dose adjustments and are reduced by the concomitant use of folic acid . Pneumonitis, while rare, is unpredictable and may be fatal, particularly if the methotrexate is not stopped or is restarted . Oral folate (1–4 mg daily) reduces side effects and should be administered concomitantly .

59. Methotrexate Oral absorption of methotrexate is variable; therefore , subcutaneous methotrexate may be effective if the response to oral methotrexate is suboptimal. Patient on Methotrexate should be monitored for: B lood cell counts. Liver transaminase levels. S erum creatinine. Frequency of monitoring : Every 2–4 weeks during initiation or after dose adjustments. Every 12 weeks for the duration of methotrexate therapy .

60. LEFLUNOMIDE Activation of T cells results in progression from the resting phase to the G1 phase, where ribonucleotides are synthesized, and then to the S phase, where cellular DNA is replicated in preparation for mitosis. T cell activation requires significant increases in de novo pyrimidine and purine biosynthesis. Leflunomide, a pyrimidine antagonist , is immunomodulatory, with the net effect being a reduction in activated T lymphocytes. Because of enterohepatic recirculation , leflunomide has a very long half-life.

61. LEFLUNOMIDE Contraindications : Active infection WBC <3000/mm3, Platelet < 50,000/mL3 history of myelodysplasia or recent lymphoproliferative disorder LFT > 2 × ULN acute or chronic HBV or HCV pregnancy, lactation

62. Sulfasalazine Mechanism : Inhibition of arachidonic acid cascade SSZ downregulates neutrophil chemotaxis, migration, and proteolytic enzyme production and degranulation Inhibition of ATIC → ↑ Adenosine SSZ inhibits fibroblast proliferation and metalloproteinase synthesis. Finally, SSZ has been shown to inhibit the formation of osteoclasts and may be antiresorptive in RA One potential site of action for SSZ that may explain its systemic action despite low serum levels is the mucosa associated lymphoid tissue (MALT) in the small bowel .

63. Sulfasalazine Evidence that some of the efficacy of SSZ may be mediated via MALT is described as follows Treatment with SSZ has been shown to decrease circulating immunoglobulin (Ig) A-producing cells and serum levels of IgA, correlating with disease improvement. SSZ has been shown to reduce gut mucosa lymphocytes in treated patients Contra indications: Sulfa allergy Platelets < 50,000/mL3 LFT >2 ×ULN HBV/HCV

64. Anti Malarial Antimalarial agents have both immunomodulatory and anti-inflammatory properties. HCQ and CQ are weak bases , they can pass through cytoplasmic membranes into cytoplasmic vesicles and accumulate, thereby increasing the vesicle pH from around 4.0 to 6.0. This increased pH has immunoregulatory effects inform of stabilization of lysosomal membranes , attenuation of antigen processing and presentation , and inhibition of cell-mediated cytotoxicity. Macrophages and monocytes require precise pH concentrations for protein digestion and antigen processing, which is altered with an increased pH.

65. Anti Malarial An uncommon but serious complication is retinal toxicity , which correlates with cumulative dose and can be prevented by regular screening . toxicity increases substantially after 5–7 years of use or a cumulative dose of 1000 g . Annual ophthalmologic screening is warranted after initiation of treatment for more than 5 years.

66. GLUCOCORTICOIDS Glucocorticoid binds to the glucocorticoid receptor in the cytoplasm. Activation of transcription (transactivation) by binding of glucocorticoid receptor–glucocorticoid dimers to glucocorticoid-responsive elements of DNA up-regulates synthesis of regulatory proteins, thought to be responsible for metabolic effects and also some anti-inflammatory/ immunosuppressive effects . Interference of glucocorticoid receptor–glucocorticoid monomers with proinflammatory transcription factors, such as nuclear factor κB ( NFκB ), inhibits their binding to NFκB -responsive elements of DNA and transcription. This is called transrepression and down-regulates synthesis of predominantly inflammatory/immunosuppressive proteins .

67. GLUCOCORTICOIDS

68. GLUCOCORTICOIDS

69. GLUCOCORTICOIDS Can be administered in low to moderate doses to achieve rapid disease control before the onset of fully effective DMARD therapy. Can be used as a 1- to 2-week burst for the management of acute disease flares, with dose and duration guided by the severity of the exacerbation. Chronic administration of low doses (5–10 mg/d) of prednisone may also be warranted to control disease activity in patients with an inadequate response to DMARD therapy. High-dose glucocorticoids may be necessary for treatment of severe extraarticular manifestations of RA, such as ILD. I ntraarticular injection of triamcinolone acetonide for rapid control of inflammation in the setting of a limited number of affected joints.

70. GLUCOCORTICOIDS Osteoporosis ranks as an important long-term complication of chronic prednisone use. Strong recommendations for primary prevention with a bisphosphonate in patient receiving 5 mg/d or more of prednisone for greater than 3 months.

71. Biological DMARD They are protein therapeutics designed mostly to target cytokines and cell-surface molecules. The TNF inhibitors were the first biologicals approved for the treatment of RA. Patients are screened for latent tuberculosis prior to starting anti-TNF therapy. P atients are skin tested using an intradermal injection of purified protein derivative ( PPD) I ndividuals with skin reactions of more than 5 mm are presumed to have had previous exposure to tuberculosis and are evaluated for active disease and treated accordingly. The QuantiFERON IFN-γ release assay may also be used in selected circumstances to screen for previous exposure to tuberculosis.

72. TNF alpha inhibitors

73. TNF alpha inhibitors Postulated mechanism of action Adverse effects

74. Tocilizumab Previously referred to as myeloma receptor antibody (MRA ), tocilizumab is a humanized IgG1 monoclonal antibody that binds with high affinity to soluble and membrane-bound forms of the 80-kD component of the IL-6R . This agent has been shown to increase LDL cholesterol however , it is not known as yet if this effect on lipid levels increases the risk for development of atherosclerotic disease .

75. Abatacept Abatacept is a novel, fully human fusion protein comprising the extracellular portion of CTLA-4 and the Fc fragment of a human IgG-1. Abatacept is generally considered as a biologic option in RA patients with inadequate responses to TNF inhibitors.

76. Rituximab Rituximab is a chimeric mouse-human monoclonal antibody directed against the extracellular domain of the CD20 antigen. It initiates complement-mediated B cell lysis and may permit antibody-dependent, cell-mediated cytotoxicity when the Fc portion of the antibody is recognized by corresponding receptors on cytotoxic cells. Rituximab is currently indicated for the treatment of patients with moderate to severe RA who show no response, experience a loss of response with time, or have adverse effects to anti-TNF alpha agents. The findings of recently reported studies indicate that rituximab is also efficacious in a proportion of both treatment-naïve and methotrexate patients with RA, particularly if seropositive . Rare and lethal adverse effect progressivemultifocal leukoencephalopathy (PML),

77. Anakinra Anakinra blocks the activity of IL-1 by competitively inhibiting IL-1 binding to the IL-1RI receptor. Anakinra should not be combined with an anti-TNF drug due to the high rate of serious infections as observed with this regimen.

78. SMALL-MOLECULE INHIBITORS Because some patients do not adequately respond to conventional DMARDS or biologic therapy, other therapeutic targets have been investigated to fill this gap . I ntracellular signaling pathways that transduce the positive signals of cytokines and other inflammatory mediators that create the positive feedback loops in the immune response. These synthetic DMARDs aim to provide the same efficacy as biological therapies in an oral formulation.

79. Tofacitinib I nhibits JAK1 and JAK3 JAK 1/3 mediate signaling of the receptors for the common γ-chain-related cytokines IL-2,4,6,7,9,15 , and 21 as well as IFN-γ. These cytokines all play roles in promoting T and B cell activation as well as inflammation. Major adverse events include: E levated serum transaminases Neutropenia Dyslipidemia Elevation in serum creatinine Increased risk of infections. Tofacitinib can be used as monotherapy or in combination with methotrexate.

80. SMALL-MOLECULE INHIBITORS JAK 1- Filgotinib JAK 1/3 – T ofacitinib , peficitinib JAK 1/2 – Barcitinib JAK 3 – Decernotinib . Advantages : Oral administration Quicker onset of action within 1-2 weeks Equivalence or superiority over TNF biologics Halts radiological progression at Higher doses.

81. Treatment recommendations Factors associated with poor prognosis

82. Treatment recommendations- Early disease

83. Treatment recommendations- Established disease

84. Trails on DMARD’s in combination Blind trials of therapies in patients with active disease despite methotrexate (MTX)

85. Thank you