Rheumatoid arthritis

DIAGNOSIS AND RECENT ADVANCES IN MANAGEMENT OF RHEUMATOID ARTHRITIS

1. DIAGNOSIS AND RECENT ADVANCES IN MANAGEMENT OF RHEUMATOID ARTHRITIS PRESENTED BY: DR MUKESH SHUKLA , MD SENIOR RESIDENT MEDICINE , KGMU LUCKNOW

2. Introduction Commonest inflammatory joint disease seen in clinical practice affecting approx 1% of population. Chronic multisystem disease of unknown cause. Characterized by persistent inflammatory synovitis leading to cartilage damage, bone erosions, joint deformity and disability.

3. Rheumatoid arthritis: Indian scenario Prevalence of RA is around 0.5 - 1% in industrialized nations with 5 - 50 new cases per 100,000 population annually 1 Predominantly occurs in female and elderly population 1 Prevalence of RA in Indian population is around 0.5 - 0.75% 1 It is the commonest inflammatory polyarthritis seen in clinical practice 2 1. JAPI. 2013;61. 2. JAPI. 2013;61:529.

4. Onset Although Rheumatoid arthritis may present at any age, patients most commonly are first affected in the third to sixth decades. Female: male 3:1 Initial pattern of joint involvement could be:- Polyarticular : most common Oligoarticular Monoarticular Morning joint stiffness > 1 hour and easing with physical activity is characteristic. Small joints of hand and feet are typically involved.

5. Relative incidence of joint involvement in RA MCP and PIP joints of hands & MTP of feet 90% Knees, ankles & wrists- 80% Shoulders- 60% Elbows- 50% TM, Acromio - clavicular & SC joints- 30%

6. Joints involved in RA Don’t forget the cervical spine !! Instability at cervical spine can lead to impingement of the spinal cord. Thoracolumbar, sacroiliac, and distal interphalangeal joints (DIP)of the hand are NOT involved.

7. SUBLUXATION OF CERVICAL SPINE

8. PIP Swelling

9. SWAN NECK DEFORMITY

10. Ulnar Deviation, MCP Swelling, Left Wrist Swelling

11. Extraarticular Involvement Constitutional symptoms ( most common) Rheumatoid nodules (30%) Hematological - normocytic normochromic anemia leucocytosis /leucopenia thrombocytosis Felty’s syndrome- Chronic nodular Rheumatoid Arthritis Splenomegaly Neutropenia Caplan Syndrome- Pneumoconiosis following silica exposure Rheumatoid Arthritis

12. RHEUMATOID NODULE

13. Respiratory - pleuritis ( MC ), pleural effusion, pneumonitis , pleuro -pulmonary nodules, ILD CVS -asymptomatic pericarditis , pericardial effusion, cardiomyopathy , mitral regurgitation (mc valvular abnormality in RA ) Rheumatoid vasculitis - mononeuritis multiplex, cutaneous ulceration, digital gangrene, visceral infarction CNS - peripheral neuropathy, cord-compression from atlantoaxial / midcervical spine subluxation , entrapment neuropathies EYE - kerato cunjunctivitis sicca , episcleritis , scleritis

14. EXTRAARTICULAR MANIFESTATIONS

15. Laboratory investigations in RA CBC ( TLC, DLC, Hb ) Acute phase reactants ( ESR, CRP ) Rheumatoid Factor (RF). Anti- CCP antibodies (most specific ).

16. Rheumatoid Factor (RF) Antibodies that recognize Fc portion of IgG . Can be IgM , IgG , IgA 85% of patients with RA over the first 2 years become RF positive. A negative RF may be repeated 4-6 monthly for the first two year of disease, since some patients may take 18-24 months to become seropositive . PROGNISTIC VALUE - Patients with high titres of RF, in general, tend to have POOR PROGNOSIS, MORE EXTRA ARTICULAR MANIFESTATION.

17. serum anti-CCP antibodies The presence of serum anti-CCP antibodies has about the same sensitivity as serum RF for the diagnosis of RA. However, its specificity approaches 95%. A positive test for anti-CCP antibodies in the setting of an early inflammatory arthritis is useful for distinguishing RA from other forms of arthritis. There is some incremental value in testing for the presence of both RF and anti-CCP, as some patients with RA are positive for RF but negative for anti-CCP and visa versa. The presence of RF or anti-CCP antibodies also has prognostic significance, with anti-CCP antibodies showing the most value for predicting worse outcomes.

18. Other Lab Abnormalities : Elevated APRs( ESR, CRP ) Thrombocytosis Leukocytosis ANA 30-40% Inflammatory synovial fluid Hypoalbuminemia

19. Radiographic Features Peri-articular osteopenia Uniform symmetric joint space narrowing Marginal subchondral erosions Joint Subluxations Joint destruction Collapse Ultrasound detects early soft tissue lesions. MRI has greatest sensitivity to detect synovitis and marrow changes.

20. DIAGNOSIS

21. ACR Criteria (1987) 1.Morning Stiffness ≥1 hour 2.Arthritis of ≥ 3 joints observed by physician. 3.Arthritis of hand joints- PIP,MCP,wrist 4. Symmetric arthritis 5. Rheumatoid nodules 6. Positive Rheumatoid Factor 7. Radiographic Erosions or periarticular osteopenia in hand or wrist joints . Criteria 1-4 must be present for ≥6 wks Must have ≥4 criteria to meet diagnosis of RA

22. 2010 ACR/EULAR Classification Criteria a score of ≥6/10 is needed for classification of a patient as having definite RA A. Joint involvement SCORE 1 large joint 0 2−10 large joints 1 1 −3 small joints (with or without involvement of large joints ) 2 4−10 small joints (with or without involvement of large joints ) 3 >10 joints (at least 1 small joint)†† 5 B. Serology (at least 1 test result is needed for classification) Negative RF and negative ACPA 0 Low-positive RF or low-positive ACPA 2 High-positive RF or high-positive ACP A , 3 C. Acute-phase reactants (at least 1 test result is needed for classification) Normal CRP and normal ESR Abnormal CRP or abnormal ESR 1 D. Duration of symptoms <6 weeks ≥6 weeks 1

23. Management

24. Goals of management Focused on relieving pain Preventing damage/disability Patient education about the disease Physical Therapy for stretching and range of motion exercises Occupational Therapy for splints and adaptive devices Treatment should be started early and should be individualised . EARLY AGGRESSIVE TREATEMNT

25. Treatment modalities for RA NSAIDS Steroids DMARDs Biological therapies Surgery

26. NSAIDS Non-Steroidal anti- inflammatories (NSAIDS) for symptom control : Reduce pain and swelling by inhibiting COX Do not alter course of the disease. Chronic use should be minimised . Most common side effect related to GI tract.

27. Corticosteroids in RA Corticosteroids , both systemic and intra- articular are important adjuncts in management of RA. Indications for systemic steroids are:- For treatment of rheumatoid flares. For extra- articular RA like rheumatoid vasculitis and interstitial lung disease. As bridge therapy for 6-8 weeks before the action of DMARDs begin. Maintainence dose of 10mg or less of predinisolone daily in patients with active RA. Sometimes in pregnancy when other DMARDs cannot be used.

28. Disease Modifying Anti-rheumatic Agents Drugs that actually alter the disease course . Should be used as soon as diagnosis is made. Appearance of benefit delayed for weeks to months. NSAIDS must be continued with them until true remission is achieved . Induction of true remission is unusual .

29. DMARDs Commonly used Less commonly used Methotrexate Chloroquine Hydroxychloroquine Gold( parenteral &oral) Sulphasalazine CyclosporineA Leflunomide D- penicillamine / bucillamine Minocycline / Doxycycline Levamisole Azathioprine,cyclophosphamide , chlorambucil

30. Clinical information about DMARDs NAME DOSE SIDE EFFECTS MONITORING ONSET OF ACTION Hydroxycloroquine 200mg twice daily x 3 months, then once daily Skin pigmentation , retinopahy ,nausea, psychosis, myopathy Fundoscopy & perimetry yearly 2-4 months 2) Methotrexate 7.5-25 mg once a week orally,s /c or i /m G I upset, hepatotoxicity , Bone marrow suppression, pulmonary fibrosis Blood counts,LFT 6-8 weekly,Chest x-ray annually, urea/ creatinine 3 monthly; Liver biopsy 1-2 months

31. Clinical information about DMARDs contnd .. NAME DOSE SIDE EFFECTS MONITORING ONSET OF ACTION 3) Sulphasalazine 2gm daily p.o Rash, myelosuppression , may reduce sperm count Blood counts ,LFT 6-8 weekly 1-2 months 4) Leflunomide Loading 100 mg daily x 3 days, then 10-20 mg daily p.o Nausea,diarrhoea,alopecia , hepatotoxicity LFT 6-8 weekly 1-2 months

32. When to start DMARDs? DMARDs are indicated in all patients with RA who continue to have active disease even after 3 months of NSAIDS use. The period of 3 months is arbitary & has been chosen since a small percentage of patients may go in spontaneous remission. The vast majority , however , need DMARDs and many rheumatologists start DMARDs from Day 1.

33. How to select DMARDs? There are no strict guidelines about which DMARDs to start first in an individual. Methotrexate has rapid onset of action than other DMARD. Taking in account patient tolerance, cost considerations and ease of once weekly oral administration METHOTREXATE is the DMARD of choice, most widely prescribed in the world.

34. Should DMARDs be used singly or in combination? Since single DMARD therapy (in conjunction with NSAIDS) is often only modestly effective , combination therapy has an inherent approach . DMARD combination is specially effective if they include methotrexate as an anchor drug. Combination of methotrexate with leflunamide are synergestic since there mode of action is different.

35. Limitations of conventional DMARDs The onset of action takes several months. The remission induced in many cases is partial. There may be substantial toxicity which requires careful monitoring. DMARDs have a tendency to lose effectiveness with time-(slip out). These drawbacks have made researchers look for alternative treatment strategies for RA- The Biologic Response Modifiers.

36. BIOLOGICS IN RA Cytokines such as TNF- α ,IL-1,IL-10 etc. are key mediators of immune function in RA and have been major targets of therapeutic manipulations in RA. Of the various cytokines,TNF - α has attaracted maximum attention. Various biologicals approved in RA are:- Anti TNF agents : Infliximab Etanercept Adalimumab IL-1 receptor antagonist : Anakinra IL-6 receptor antagonist : Tocilizumab Anti CD20 antibody : Rituximab T cell costimulatory inhibitor : Abatacept

37. Agent Usual dose/route Side effects Contraindications Infliximab (Anti-TNF) 3 mg/kg i.v infusion at wks 0,2 and 6 followed by maintainence dosing every 8 wks Has to be combined with MTX. Infusion reactions, increased risk of infection, reactivation of TB ,etc Active infections,uncontrolled DM,surgery (with hold for 2 wks post op) Etanercept (Anti-TNF) Active infections,uncontrolled DM,surgery (with hold for 2 wks post op) Adalimumab (Anti-TNF) 40 mg s/c every 2 wks( fornightly ) May be given with MTX or as monotherapy Same as that of infliximab Active infections . 25 mg s/c twice a wk May be given with MTX or as monotherapy . Injection site reaction,URTI , reactivation of TB,development of ANA,exacerbation of demyelenating disease.

38. Abatacept (CTLA-4-IgG1 Fusion protien ) Co-stimulation inhibitor 10 mg/ kg body wt. At 0, 2 , 4 wks & then 4wkly Infections, infusion reactions Active infection TB Concomittant with other anti-TNF- α Rituximab (Anti CD20) 1000 mg iv at 0, 2, 24 wks Infusion reactions, Infections Same as above Tocilizumab ( Anti IL-6) 4-8 mg/kg 8 mg/kg iv monthly Infections, infusion reactions,dyslipidemia Active infections Agent Usual dose/route Side effects . Anakinra 100 mg s/c once daily May be given with MTX or as monotherapy . Injection site pain,infections , neutropenia Active infections Contraindications IL – 1 receptor antagonist

39. 2012 ACR Update

40. How to monitor Tt in RA? Disease activity is assesed by several parameters… duration of morning stiffness,tender joint count,swollen joint count, visual analogue scale for pain, health assessment questionnaire,ESR,NSAID pill count,DAS score etc.. Patient on MTX,SSZ or leflunamide show clinical improvement in 6-8 wks. Patient should be observed for 6 months before declaring a DMARD ineffective.

41. How long should Tt . be continued? Once remission is achieved , maintenance dose for long period is recommended. Relapse occurs in 3-5 months (1-2 months in case of MTX) if drug is discontinued in most instances. DMARDs are discontinued by patients because of toxicity or secondary failure (common after 1-2 yrs) and such patients might have to shift over different DMARDs over 5-10 yrs. Disease flare may require escalation of DMARD dose with short course of steroids.

42. Surgical Approaches Synovectomy is ordinarily not recommended for patients with rheumatoid arthritis, primarily because relief is only transient. However, an exception is synovectomy of the wrist, which is recommended if intense synovitis is persistent despite medical treatment over 6 to 12 months. Total joint arthroplasties , particularly of the knee, hip, wrist, and elbow, are highly successful. Other operations include release of nerve entrapments (e.g., carpal tunnel syndrome), arthroscopic procedures, and, occasionally, removal of a symptomatic rheumatoid nodule.

43. Rheumatoid arthritis in pregnancy Most patients with RA go into remission during pregnancy. Methotrexate and leflunomide should be discontinued for at least 3 months before trying to conceive. Paracetamol is the oral analgesic of choice during pregnancy. Corticosteroids may be used to control disease flares DMARDs that may be used: sulfasalazine , hydroxychloroquine , azathioprine or ciclosporin if required to control inflammation. DMARDs that must be avoided: methotrexate , leflunomide,cyclophosphamide , gold and penicillamine . Biological therapies: safety during pregnancy is currently unclear.

44. Rheumatoid arthritis in elderly Older individuals may receive less aggressive treatment due to concerns about increased risks of drug toxicity. Conventional DMARDs and biologic agents are equally effective and safe in younger and older patients. Due to comorbidities,many elderly patients have an increased risk of infection. Aging also leads to a gradual decline in renal function that may raise the risk for side effects from NSAIDs and some DMARDS, such as methotrexate . Renal function must be taken into consideration before prescribing methotrexate , which is mostly cleared by the kidneys.

45. RHEUMATOID ARTHRITIS IN 2017 There is considerable interest in picking up RA in its preclinical state when disease is immunologically nascent, the concept of preclinical RA . Pre- clinical RA is an exiting concept that stimulates identification of pre – clinical didease . Research is currently focused on genetic predisposition and environmental risk factors in rheumatoid arthritis. Genome wide association study analyses have identified various RA associated genes such as HLA- DRB1, PTPN22, TNFAIP3,STAT4 and CCR6.

46. The next decade is likely to witness a better price rationalization due to variety of factors making biologics accessible to many. Enormous amount of research is going on small molecules targeting various intracellular pathways like janus associated kinases (JAKs), spleen tyrosine kinase (SYK) and brutons tyrosine kinase (BTK) . Tofacitinib , a small molecule inhibitor has shown excellent efficacy in management of RA.

47. Currently we have choices of synthetic (s DMARD) and biological disease modifying antirheumatoid drugs (b DMARD) that can enable us to achieve remarkable improvement in clinical outcome including remission. The future seems promising with our better understanding of RA pathogenesis, better strategies and newer molecules .

48. TAKE HOME MESSAGE The earlier we control of inflammation in RA, the better is the outcome. The current treatment strategy should be to make diagnosis early, be aggressive with therapy after diagnosis and aim should be to reach clinical remission. ‘Hit early and hit hard’ should be the motto .

49. Thank you.

50. Instruments to measure disease activity and to define remission

51. HOW TO CALCULATE DAS28 SCORE

52. ACR/EULAR Provisional Definition of Remission in Rheumatoid Arthritis

53. MCQ

54. MCQ : 1 A 45 year old women presents to the rheumatology opd clinic with a three months history of stiff hands and wrists. She mentions that the pain is particularly bad in the morning. On examination , the wrist , MCP joints and PIP joints are swollen and warm . A diagnosis of rheumatoid arthritis is suspected. Which of the following is most specific for confirming the diagnosis- X – rays Rheumatoid factor levels Anti-CCP levels Erythrocyte sedimentation rate

55. MCQ : 2 A 50 year old women , who has received a recent diagnosis of rheumatoid arthritis ,presents to her GP with ongoing pain and stiffness in her hands and feet . Which joints are usually spared at onset of rheumatoid arthritis ? Proximal interphalangeal joints Distal interphalangeal joints Wrist Metacarpophalangeal joint

56. MCQ : 3 Which of the following is not a criterion for remission in rheumatoid arthritis (RA) according to the ACR/EULAR 2011 criteria? C-reactive protein (CRP) ≤1 mg/ dL Swollen joint count ≤1 Tender joint count ≤1 Physician global assessment ≤1

57. MCQ : 4 . Which of the following regarding Infliximab is most true? Is a monoclonal antibody to the glycoprotein IIb-IIIa receptor Is authorized for the treatment of severe ulcerative colitis Is licensed for the treatment of RA It prevents relapse of Crohn’s disease in patients who are in remission Must not be used in combination with methotrexate due to increased toxicity

58. MCQ : 5 A 45-year-old female teacher presents complaining of severe left knee pain. She has a long-term history of rheumatoid arthritis, which has been well controlled for several years on a multidrug regimen of methotrexate , hydroxychloroquine , and a nonsteroidal anti-inflammatory drug (NSAID). Which of the following symptoms suggests secondary degenerative joint disease (rather than rheumatoid arthritis) as a cause of her knee pain? Prolonged morning stiffness Pain that is exacerbated by activity Increased fatigue Multiple joint complaints Weight loss

59. MCQ- 6 A 33-year-old female accountant with rheumatoid arthritis has severe neck pain and occipital headaches. A flexion-extension radiograph of her neck shows minimal widening of the preodontoid space. Which of the following is the most appropriate course for this patient? Refer the patient to a neurologist for treatment of chronic headache Change the patient’s current NSAID to another class Obtain a cervical spine magnetic resonance image (MRI) with gadolinium Check the patient’s erythrocyte sedimentation rate and RF levels Initiate use of a soft collar for 2 weeks

60. MCQ- 7 A 22-year-old male automobile mechanic who was recently diagnosed with rheumatoid arthritis presents complaining of difficulty holding his wrench and other tools. He also notes an occasional “electric shock” sensation in his right index and middle fingers. Physical examination reveals bilateral (right greater than left) wrist synovitis . He has a solid handgrip and no muscle atrophy. Which of the following is the most likely cause of his symptoms? Tendonitis of the abductor pollicis brevis Keinbock’s syndrome DeQuervain’s tenosynovitis Rupture of the fourth and fifth extensor tendons Carpal tunnel syndrome

61. MCQ- 8 A 37-year-old female bus driver is referred by her primary care physician for evaluation of a polyarthritis of 3 months’ duration. On examination, she has a symmetrical distribution of synovitis that is consistent with rheumatoid arthritis; radiographs show periarticular demineralization and soft-tissue swelling. Which of the following is the most appropriate course of therapy for this patient? A .Methotrexate (12.5 mg/wk) and prednisone (7.5 mg/day) B .Pulse methylprednisolone sodium succinate C. Six week course of NSAIDs followed by reevaluation Cyclosporine (1.5 mg/kg/day) D. Tumor -necrosis factor (TNF) α-inhibitor (25 units subcutaneously, biweekly

62. ANSWERS 1. C 2. B 3. D 4. C 5. B 6. C 7. E 8. A