Rheumatoid Arthritis: Early Diagnosis and Treatment


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Dr. Swamy Venuturupalli talks about Rheumatoid Arthritis, Early Diagnosis and Treatment at the James R. Klinenberg symposium on Rheumatic diseases in Pasadena, CA.

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  • Various pathogenetic pathways account for the heterogeneity of the early rheumatoid arthritis (RA) phenotype. During both the pre-articular phase (1) and the triggering of synovitis itself (2), genetic and environmental determinants together induce a combination of pathogenetic pathways whose common outcome is a syndrome of synovitis ultimately recognizable as RA (3). The relative contributions of the various pathways in turn define an individual's disease phenotype (4). It is hoped that the search for biomarkers will yield a means of stratifying early RA into prognostically and therapeutically relevant subsets.
  • -Score-based algorithm: Add score of categories A–D; a score of 6/10 is needed for classification of a patient as having definite RA.‡ Although patients with a score of <6/10 are not classifiable as having RA, their status can be reassessedand the criteria might be fulfilled cumulatively over time.§ Joint involvement refers to any swollen or tender joint on examination, which may be confirmed byimaging evidence of synovitis. Distal interphalangeal joints, first carpometacarpal joints, and firstmetatarsophalangeal joints are excluded from assessment. Categories of joint distribution are classifiedaccording to the location and number of involved joints, with placement into the highest category possible based on the pattern of joint involvement.“Large joints” refers to shoulders, elbows, hips, knees, and ankles.“Small joints” refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists.** In this category, at least 1 of the involved joints must be a small joint; the other joints can include anycombination of large and additional small joints, as well as other joints not specifically listed elsewhere(e.g., temporomandibular, acromioclavicular, sternoclavicular, etc.).†† Negative refers to IU values that are less than or equal to the upper limit of normal (ULN) for thelaboratory and assay; low-positive refers to IU values that are higher than the ULN but 3 times the ULNfor the laboratory and assay; high-positive refers to IU values that are 3 times the ULN for thelaboratory and assay. Where rheumatoid factor (RF) information is only available as positive or negative,a positive result should be scored as low-positive for RF. ACPA anticitrullinated protein antibody.‡‡ Normal/abnormal is determined by local laboratory standards. CRP C-reactive protein; ESR erythrocyte sedimentation rate.§§ Duration of symptoms refers to patient self-report of the duration of signs or symptoms of synovitis(e.g., pain, swelling, tenderness) of joints that are clinically involved at the time of assessment, regardlessof treatment status.
  • British journal of nursing (2013)  volume: 22  issue: 6  -308, 310, 318
  • Rheumatoid Arthritis: Early Diagnosis and Treatment

    1. 1. Rheumatoid Arthritis Early Diagnosis and Treatment Swamy Venuturupalli MD, FACR Clinical Chief, Division of Rheumatology, Cedars Sinai Medical Center Associate Clinical Professor of Medicine, UCLA Editor-in-Chief, Current Rheumatology Reviews www.drswamy.com
    2. 2. Overview  What is the pathogenesis of RA?  How do you diagnose RA?  What clinical manifestations must one be aware of?  Is there a window of opportunity to make a difference?  Current treatment principles:  Medications used  Treat to target  When to introduce newer agents  Complications of therapy
    3. 3. Introduction  Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint inflammation and destruction in association with serological evidence of autoreactivity.  Affects approximately 1% of the population and causes significant morbidity and mortality, with accelerated atherosclerosis impairing life expectancy.  In the past two decades, the therapy of RA has undergone revolutionary change, reflecting a paradigm shift in treatment approach as well as the introduction of new disease-modifying antirheumatic drugs (DMARDs), most prominently the biological agents, including the tumor-necrosis-factor (TNF) blockers.
    4. 4. Pathogenesis of Rheumatoid Arthritis. Choy EH, Panayi GS. N Engl J Med 2001;344:907-916.
    5. 5. Pathogenesis of RA 2: “Trigger” 1: “Pre-articular” phase • Genes Autoantibodies • Citrullination • • • • • 4: Early RA phenotype E.g: Minor trauma Infection Hormones Psychological Progressive, erosive RA T-cell Immunosenescence 3: Synovitis • Environment Impaired thymic selection • • • Smoking Infections (gingival disease, gut flora changes) Altered lymphocytesignaling thresholds • B S I O ? M A R K E ? R ‘Good-prognosis’ RA DMARD-responsive RA Anti-cytokine-responsive RA Deregulated TLR/cytokine signaling Anti-lymphocyte-responsive RA Self-limiting IP Legend: TLR: Toll like receptor; DMARD: Disease-modifying anti-rheumatic drug; IP: Inflammatory polyarthritis Adapted from Best Pract Res Clin Rheumatol. 2009 February; 23(1): 37–48.
    6. 6. Model for the Etiology of RA Autoreactivity/genetics Joint damage Activation of innate immunity Periphery DC FL S Synovial inflammation/cytokines Adaptive Immunity MΦ Recruitment autoantibodies Migration DC T T T T Adapted from Vibeke Strand, Medscape. B Legend: DC= dendritic cell; FLS= fibroblast-like synoviocyte; MΦ= macrophage; T= T cell
    7. 7. Severity of Arthritis Clinical Course of RA 4 Type 1 Type 2 Type 3 3 2 1 0 0 0.5 1 2 3 4 6 8 16 Years Type 1 = Self-limited—5% to 20% Type 2 = Minimally progressive—5% to 20% Type 3 = Progressive—60% to 90% Pincus. Rheum Dis Clin North Am. 1995;21:619.
    8. 8. Clinical Spectrum of RA Images courtesy of J. Cush, 2002.
    9. 9. Overview of joints affected • Joints most frequently affected in RA include: • The proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints of the hands • The wrists • The shoulders • The elbows • The knees • The ankles, and • The metarsophalangeal (MTP) joints of the feet • Distal interphalangeal (DIP) joints are typically spared in RA.
    10. 10. RA: It’s not just the joints CVD ∧ Osteoporosis 10 Years Earlier 6-9x ∧ serious infection rate Joint Destruction Disability Index 2x ∧ rate malignancy ∧ Pulmonary disease ∧ GI Bleeding
    11. 11. RA is a systemic disease with extraarticular manifestations Secondary Sjögren’s syndrome Heart Pericarditis Myocarditis Endocarditis Valvular fibrosis Liver Enzyme abnormalities due to drug reactions or Sjögren’s syndrome Blood / blood vessels Mild anemia Vasculitis Felty’s syndrome Eyes Keratoconjunctivitis Sicca syndrome Scleritis Episcleritis Keratitis corneal ulceration Choroiditis Retinal vacuities Episcleral nodules Lungs Pleuritis ± pleural effusions Pulmonary nodules Interstitial pulmonary fibrosis Skin Rheumatoid nodules Vasculitis Interstitial granulomatous dermatitis Firestein. ACP Medicine, Rheumatology II
    12. 12. Poor prognostic factors  Extra-articular signs and symptoms (e.g. Cutaneous ulcers, vasculitic rash, neuropathy, scleritis, subcutaneous nodules)  Female gender  Shared epitopes  Poor functional status  Involvement of multiple joints  Early radiographic evidence of erosive changes  Advanced age at onset of disease  High RF titer  Sustained elevation of acute-phase reactants (e.g. ESR)  Low socioeconomic status/educational level  High titre CCP antibody  Smoking Anaya JM, et al. Ann Rheum Dis. 1994;53:782–783; Pincus T, Callahan LF. Balliere’s Clin Rheumatol. 1992;6:161–191; Furst DE. Rheum Dis Clin North Am. 1994;20:309–319.
    13. 13. Cardiovascular Disease (CVD) in RA  Increased incidence of CVD and mortality in RA: 2-4 times  Not only traditional CVD risk factors (smoking, lipids, hypertension, DM) increased  Inflammation involved in pathogenesis of atherosclerosis  High index of suspicion; atypical, silent chest pain, CHF, and sudden death common  CVD accounts for much excess mortality in RA
    14. 14. Malignancy in RA  2-3x lymphoproliferative disease, in particular, diffuse large B-cell lymphoma  EBV-associated lymphomas increased in patients on methotrexate (MTX)  Chronic inflammation may be responsible for increased lymphoma  Lung cancer more common in RA, but may be due to cigarette smoking, a common risk factor  Anti-TNF medications may be associated with increased risk of lymphoma and skin cancer
    15. 15. Diagnosing RA
    16. 16. 1987 Revised ACR Classification of RA Criterion Definition Morning stiffness Lasting ≥ 1 hour before maximal improvement Arthritis ≥ 3 joints Clinical evidence of soft tissue swelling or fluid in right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints Arthritis of hand joints 1 or more swollen areas in wrist, MCP, or PIP joint Symmetric arthritis Simultaneous involvement of same joint areas on both sides of body (bilateral involvement of PIP, MCP, or MTP joints is acceptable without absolute symmetry) Rheumatoid nodules Clinical evidence of subcutaneous nodules over bony prominences, extensor surfaces, or in juxtaarticular regions Serum RF Elevated rheumatoid factor measured by any method in which positive results are found in < 5% of normal subjects Radiographic changes Erosions or unequivocal body decalcification localized in or adjacent to involved joints on posteroanterior hand and wrist radiographs Classification of RA is fulfilled when 4 of 7 criteria are present (first 4 criteria must be present for at least 6 weeks); another clinical diagnosis does not exclude RA. Arnett FC et al. Arthritis Rheum. 1988;31:315-324.
    17. 17. 2010 ACR/EULAR classification criteria for RA A score of ≥6/10 is needed to classify RA A. Joint involvement 1 large joint 2-10 large joints 1-3 small joints (with or without involvement of large joints) 4-10 small joints (with or without involvement of large joints) >10 joints (at least 1 small joint) Score 0 1 2 3 5 B. Serology (at least 1 test result is needed) Negative RF and negative ACPA Low-positive RF or low-positive ACPA High-positive RF or high-positive ACPA 0 2 3 C. Acute-phase reactants (at least 1 test result is needed) Normal CRP and normal ESR Abnormal CRP or abnormal ESR 0 1 D. Duration of symptoms <6 weeks ≥6 weeks 0 1 Aletaha et al. Arthritis Rheum. 2010;62:2569-2581 Aletaha et al. Ann Rheum Dis. 2010; 69:1580-1588
    18. 18. Antibodies to cyclic citrullinated peptides (anti-CCP)  Anti-CCP has high diagnostic specificity for RA (98%)  Found in 40% of patients who are RF negative  Citrullination is the post-translational modification of arginine to citrulline  Alters the structure, antigenicity, and function of proteins  Four candidate citrulllinated antigens have been established: fibrinogen, vimentin, type II collagen, -enolase Wegener et al. Immunological Rev. 2010;233:34
    19. 19. Rheumatoid factor (RF)  Antibody reactive against Fc fragment of IgG  80% of RA patients are ever seropositive for RF, <50% in early RA, and is associated with: • More radiological abnormalities • More disease activity • Worse functional ability • More extra-articular manifestations • More treatment with second line drugs  Not specific for RA: chronic infections, cirrhosis, malignancies, other rheumatic diseases.
    20. 20. Radiographic Assessment of Joint Disease in RA
    21. 21. Early changes in RA
    23. 23. Ultrasound
    24. 24. Is there a window of opportunity?
    25. 25. Window of opportunity  Several studies have shown greater improvements with earlier treatment.  Can that concept be taken to an extreme, so that these agents be started at the earliest point in diagnosis?  This has been codified as the “Window of opportunity hypothesis,” which posits that, early in its course, RA displays a unique phenotype in which immunoregulatory disturbances can be decisively or permanently blocked
    26. 26. RA Progression Inflammation Disability Severity (arbitrary units) Radiographs 0 5 10 15 20 Duration of Disease (years) Adapted from Kirwan JR. J Rheumatol. 2001;28:881–886. 25 30
    27. 27. HAQ as a determinant of long-term disability in RA  HAQ has a strong, positive correlation to radiographic damage.  Mean HAQ scores during first 3 months of treatment were the strongest predictor of 10-year disability outcomes.  HAQ>1.0, the odds ratio for disability at 10 years was 13.4 Lindqvist et al. Ann Rheum Dis. 2002;61:1055-1059 Wolfe and Hawley. J Rheumatol. 1998;25:2108-2117 Cohen et al. J Rheumatol. 2006;33:1936-1941 Drossaers-Bakker et al. Arthritis Rheum. 1999;2:1854 Welsing et al. Arthritis Rheum. 2001;44:2009-2017 Scott et al. Rheumatology. 2000;39:122-132 Aletaha et al. Arthritis Rheum. 2006;54:2784-2792
    28. 28. Relationship Between Change in CRP at 6 Months and Subsequent Change in HAQ 14 CRP reduced by < 50% in first 6 months (n = 44) Median HAQ Score 12 10 8 CRP reduced by ≥ 50% in first 6 months (n = 31)† 6 4 CRP normalized in first 6 months (n = 34)† 2 0 Baseline 6 Months 12 Months 24 Months †P < .005 vs. group with < 50% reduction in CRP. Prospective study of 109 consecutive RA patients with elevated CRP levels before steroid or DMARD therapy. Patients were grouped according to the change in CRP seen at 6 months. Devlin J et al. J Rheumatol. 1997;24:9-13.
    29. 29. Principles of Therapy EARLY initiation of therapy Treat to target Combine medications to achieve remission
    30. 30. Treatment: The Earlier the Better Delayed Treatment* (median treatment lag time = 123 days; n = 109) Early Treatment* (median treatment lag time = 15 days; n = 97) 14 Change in Median Sharp Score 12 10 8 6 4 2 0 0 6 12 Time (months) *Patients were treated with chloroquine or azathioprine. Lard LR, et al. Am J Med. 2001;111:446–451. 18 24
    31. 31. Radiographic changes in LERA (•) and VERA1 (□) patients, indicated by the Larsen score at baseline and after 12, 24 and 36 months of follow-up. Nell V P K et al. Rheumatology 2004;43:906-914 Rheumatology Vol. 43 No. 7 © British Society for Rheumatology 2004; all rights reserved
    32. 32. COBRA Trial Early Intervention Yields Long-Term Benefits Median Sharp Score 60 SSZ alone 45 30 COBRA P < 0.03 15 0 0 1 2 3 4 5 Years of Follow-up COBRA: Prednisolone (initially 60 mg/d, tapered in 6 weekly steps to 7.5 mg/d) + methotrexate 7.5 mg/wk x 40 wks + sulfasalazine 2 g/d. SSZ: Sulfasalazine 2 g/d. Landewé RBM, et al. Arthritis Rheum. 2002;46:347–356.
    33. 33. Quantitative Measures of Disease Activity Patient Only  Patient activity scale (PAS) or PASII  Routine assessment of patient index data 3 (RAPID 3) Patient and provider data  Clinical disease activity index (CDAI) Patient, provider, and lab data  Disease activity score with the 28-joint count (DAS28)  Simplified disease activity index (SDAI)
    34. 34. Features of Disease Activity Measurement Tools DAS28  Requires assessment of 28-joint count and either ESR or CRP level  Involves difficult calculation CDAI  Requires assessment of 28-joint count, physician global assessment, and patient global assessment  Does not require a laboratory test SDAI  Requires assessment of 28-joint count, physician global assessment, and patient global assessment, plus ESR RAPID 3  Requires 3 measures of physical function, pain, and patient global assessment of status  All 3 components reported by the patient  Involves simple addition of 3 measures
    35. 35. Assessing Disease Activity in RA Level of Disease Activity Instrument Remission Low Moderate High DAS28 (range, 0-9.4) < 2.6 ≥ 2.6 to < 3.2 ≥ 3.2 to ≥ 5.1 ≥ 5.1 PAS or PAS-II (range, 0-10) 0 to 0.25 0.26 to 3.7 3.71 to < 8.0 ≥ 8.0 CDAI (range, 0-76) ≤ 2.8 > 2.8 to 10.0 > 10.0 to 22.0 > 22.0 RAPID 3 (range, 0-30) 0 to 3.0 > 3.0 to 6.0 > 6.0 to 12.0 > 12.0 to 30.0 SDAI (range, 0-86) ≤ 3.3 > 3.3 to ≤ 11.0 > 11.0 to ≤ 26.0 > 26.0
    36. 36. BeSt: Treatment Strategies Group 1 Monotherapy Group 2 Step-Up Therapy Group 3 Combo Therapy Group 4 MTX + INF MTX MTX MTX + SSZ + PRED MTX + INF SSZ MTX + SSZ MTX + CsA + PRED SSZ LEF MTX + SSZ + HCQ MTX + INF LEF MTX + INF MTX + SSZ + HCQ + PRED MTX + CsA + PRED MTX + INF Legend: CsA = cyclosporin A; HCQ = hydroxychloroquine; INF = infliximab; LEF = leflunomide; MTX = methotrexate; PRED = predinisone; SSZ = sulfasalazine
    37. 37. BeST Study Treatment Strategies in Early Rheumatoid Arthritis: Clinical and Radiological Outcomes After 2-year Follow-Up 2.5 Seq. mono n=126 1 2 Step-up combo n=121 1.5 Initial combo w/prednisone n=133 1 Initial combo w/IFX n=128 0.5 0 TSS change from baseline
    38. 38. Triple Therapy: Proportion of Patients with Sustained Response Patients with 50% improvement in modified Paulus criteria (%) 100 All 3 drugs 80 24/31 (77%) Sulfasalazine and hydroxychloroquine 60 14/35 (40%) 12/36 (33%) 40 Methotrexate 20 0 0 6 12 18 24 Months P = 0.003, triple therapy vs. other treatment arms O'Dell. N Engl J Med. 1996.
    39. 39. Combination Methotrexate, Sulfasalazine, and Hydroxychloroquine (FIN-RACo Study) 75% Patients with ACR50 Responses (%) 80 70 60 Single DMARD Combination DMARDs 60% 71% 58% P = .028 at 1 year P = .058 at 2 years 50 40 30 20 10 0 1 Year 2 Years 199 patients with early RA were randomly assigned to combination therapy with methotrexate 7.5 mg/week, sulfasalazine 1 g/day, hydroxychloroquine 300 mg/day, and prednisolone 5 mg/day (with flexible dosage adjustment to achieve remission), or single DMARD therapy with sulfasalazine 2 g/day with or without prednisolone. If necessary because of adverse events or lack of efficacy, sulfasalazine was replaced by methotrexate and subsequently azathioprine Mottonen T et al. Lancet. 1999;353:1568-1573.
    40. 40. Principles of Therapy EARLY initiation of therapy Treat to target Combine medications to achieve remission
    41. 41. What to treat with
    42. 42. RA: Current Pharmacologic Options • Agents that are effective in controlling the signs and symptoms of RA, but have no effect on disease progression – NSAIDs reduce inflammation and pain – COX-2 inhibitors are similar to NSAIDs, but with improved GI safety and tolerability and higher cardiac side effects – Analgesics- these medicines do not affect inflammation, but work on pain pathways to decrease subjective feeling of pain. • DMARDs impact the signs, symptoms, and disease progression of RA, as well as improve the quality of life and functionality of the patient • Corticosteroids have anti-inflammatory and immunoregulatory activity, but nominal disease-modifying capability Irvine S, et al. Ann Rheum Dis. 1999;58:510–513; Madhok R, Capell HA. Lancet 1999;353:257–258; ACR Subcommittee on RA Guidelines. Arthritis Rheum. 2002;46:328–346; Goldbach-Mansky R, Lipsky PE. Annu Rev Med. 2003;54:197–216.
    43. 43. T C e lls A c tiv a te M u ltip le C e llu la r P ro c e s s e s th a t L e a d s to In fla m m a tio n a n d D e s tru c tio n A d a p te d fro m C ho y a nd P a na y i. N E n g l J M e d 2 0 0 1 ; 3 4 4 (1 2 ): 9 0 7 – 1 6 ; D M A R D = d ise a se -m o d ify ing a ntirhe um a tiic d rug
    44. 44. RA: Disease Modifying therapies Traditional DMARDs Biological DMARDS For example For example  Methotrexate  Leflunomide (Arava®)  Sulfasalazine (SSZ, Azulfidine®)  Hydroxychloroquine (HCQ, Plaquenil®)  Azathioprine, cyc losporine  TNF antagonists  Etanercept (Enbrel®)  Adalimumab (Humira®)  Infliximab (Remicade®)  Certolisumab pegol (Cimzia®)  Golimumab (Simponi®)  Abatacept (Orencia®)  Rituximab (Rituxan®)  Tocilizumab (Actemra®)  Tofacitinib (Xeljanz®)
    45. 45. Methotrexate  Most effective single DMARD (used as baseline therapy in most patients.) Typical dose is 15 mg/week.  Good benefit-to-risk ratio.  Screen Hepatitis serologies before use, ETOH counseling, LFT, CBC, creatinine prior to use and every 2-3 months.  Side effects include liver damage, oral and mucosal ulcers and rarely lung toxicity. Rarely may cause bone marrow suppression.  Must be taken with folic acid supplementation. 1mg every day except on day of MTX.  Avoid use with TMP/SMX: bone marrow suppression.
    46. 46. TNF antagonists  5 currently approved agents:  Etanercept, adalimumab, infliximab, certolizumab pegol, golimumab.  Subcutaneous (etanercept, adalimumab, certolizumab pegol, golimumab) and intravenous administration (infliximab and golimumab.)  Administration in combination with MTX is superior to monotherapy.  Time to onset: rapid (weeks)  Adverse events:  Infection, TB, multiple sclerosis/demyelination, lupus-like syndrome.  Malignancy: higher rates as compared with normal population but not higher than the background of lymphoma and solid tumors in RA population. Increased risk of non melanotic skin cancers.  Monitoring:  TB screening including PPD prior to therapy.  Periodic CBC, LFTs.  Infection.
    47. 47. 2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease‐modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis Arthritis Care & Research Volume 64, Issue 5, pages 625-639, 2 APR 2012 DOI: 10.1002/acr.21641 http://onlinelibrary.wiley.com/doi/10.1002/acr.21641/full#fig1
    48. 48. British Journal of Nursing (2013) volume: 22 issue: 6 – 308, 310, 318
    49. 49. British Journal of Nursing (2013) volume: 22 issue: 6 – 308, 310, 318
    50. 50. Special situations: Urgent issues Fever and infections Septic arthritis Dyspnea and cough in a patient on MTX Pre-op issues in long standing RA
    51. 51. Infections in RA  Infections in RA increased (up to 6 to 9 fold)  Immune dysfunction of RA.  Corticosteroids, even “low dose.”  Immunomodulatory drugs, in particular biologic therapies.  Assessing RA patient with fever, suspected infection  Prompt and thorough evaluation of symptoms  Prompt initiation of antibiotics (especially for patients on biologics)  Avoid use of trimethoprim/sulfamethoxazole (Bactrim®, Septra®) in patients on MTX  Usual bacterial culprits, skin and soft tissue infections, as well as rare infections  Opportunistic organisms (especially with biologics)  Mycobacterial (atypical or disseminated presentation)  Fungal (eg. Histoplasma, Coccidioides, Cryptococcus, Aspergillus, Candi da)  Viral (e.g. Zoster)
    52. 52. Conclusions  Early introduction of effective treatment with minimal delay in introduction of combination therapy, including prednisolone or TNF blockers.  Result-driven (for instance DAS <= 2.4 or remission) treatment.  Tight-controlled (based on measurement of disease activity) treatment.  New trials will help to fine tune the timing of the most effective drugs, which include the newer biologicals.