Rheumatology 101: Rheumatology For Dummies
RA in 2016 It’s not what it Used to Be! Or is it? Richard S. Pope MPAS, PA-C Dept of Rheumatology Western CT Health Network Danbury, CT 06810 RA throughout history Modern disease or Ancient? Archaeological investigations have turned up evidence of injuries, degenerative disease, infections, and tumors in ancient skeletons, but no signs of rheumatoid arthritis. "It isn’t clear how old rheumatoid arthritis is," says Nortin Hadler, MD, a professor of rheumatology and microbiology/immunology at the University of North Carolina at Chapel Hill. "The more you look for it in history, the less you find it.“ The first confirmed cases of RA were probably in the late 1800s Current Hypothesis of Rheumatoid Arthritis RA is not a disease of recent origin, and was both present and problematic hundreds, possibly thousands of years ago, potentially with a geographic distribution distinct from its current profile. RA occurs as a response to an environmental stimulus or stimuli experienced by genetically susceptible individuals. The identities and origins of these stimuli or inciting events are still incompletely known, although tantalizing clues have emerged. Distinct environmental triggers may be important in subsets of patients with RA. For example, smoking may be a more important risk factor in RA patients who carry an MHC allele that encodes the shared-epitope and who have autoantibodies to citrulline-containing proteins. Thus, the historical analysis of RA needs to incorporate the likely possibility that what we currently define as RA is more than one disease. 6/ Historical perspective on the etiology of Rheumatoid Arthritis Hand Clin. 2011 Feb; 27(1): 1–10. 1
Evidence from Art Peter Paul Reubens 1638 “The Three Graces” Famous people with Rheumatoid Arthritis Kathleen Turner Lucille Ball Objectives 1. Recognize how Rheumatoid Arthritis (RA) presents 2. Review the differential diagnosis of RA 3. Evaluate and recognize significance of extra articular manifestations of RA 4. Review the latest developments in treatment 2
References American College of Rheumatology Slide Collection of Rheumatic Diseases, online library at www.rheumatology.org Klippel, John H., M.D., editor. Primer on the Rheumatic Diseases, Edition 13. Atlanta: Arthritis Foundation; 2008. West, Sterling, M.D. Rheumatology Secrets, 3rd Edition. 2015 US Natural Library of Medicine, National Institute of Health Hand Clin. 2011 Feb; 27(1): 1–10. My personal practice in Danbury, CT at Western CT Health Network Case 1 45 year old male Chief complaint: – Bilateral joint stiffness for 8 months. – Seen by orthopod and given cortisone joint injections with success about 5 months ago – Works as a contractor, married, smokes 1.5 ppd. FH: one aunt with RA Physical exam Pt smelled of smoke Poor dentition Tinel’s at the right wrist Synovitis seen in both hands. 3
Physical exam 1. What is the one hallmark for RA that is required to make the diagnosis? a) b) c) d) e) RF and/or anti-CCP Erosions on radiograph Presence of joint swelling Elevated ESR or CRP All of the above Physical exam 1. What is the one hallmark for RA that is required to make the diagnosis? a) b) c) d) e) RF and/or anti-CCP Erosions on radiograph Presence of joint swelling Elevated ESR or CRP All of the above Which one of these shows synovitis? 4
Physical Exam Squeeze test What are the hallmark locations for RA? Wrists, MCPs, PIPs What labs would you order as initial lab for patients with Joint Pains? Acute-phase reactants RF Anti-CCP antibody Antinuclear antibody (ANA) Lyme titer Parvovirus antibody, IgG, and IgM Hepatitis B and C – ESR – CRP – CBC with differential Comprehensive metabolic panel ANA, antinuclear antibody; IgG, immunoglobulin G; IgM, immunoglobulin M; CBC, complete blood count 5
Here are the results Lab results: – CBC WBC 7.5 Platelets are 371,000 Hgb, Hct normal Comprehensive metabolic profile normal ESR - 22 Anti-CCP 300 (extremely high) RF 128 (nml 11.9) What would you order next? Hand with wrists What is the Correct diagnosis? 1. 2. 3. 4. 5. Polyarticular gout Inflammatory osteoarthritis Early rheumatoid arthritis RF and CCP rheumatoid arthritis Psoriatic arthritis 6
What is the Correct diagnosis? 1. 2. 3. 4. 5. Polyarticular gout Inflammatory osteoarthritis Early rheumatoid arthritis RF and CCP rheumatoid arthritis Psoriatic arthritis Case 2 23 year old Hispanic female diffuse arthralgias and swelling HPI:2 months of gradual onset of mild wrist arthralgias, followed by tingling and weakness of her fingers and dropping things. 1 month later she was waking up with hand swelling, particularly in the wrists bilaterally. She had AM stiffness lasting 30-45 minutes. Then in the last two weeks she had bilateral ankle swelling (L R). When she kneels it hurts severely and feels like her “knees will explode”. She took two weeks of doxycycline given to her by the Americares clinic. No tick bite history, no rash, no flu lke syndrome. Denied fevers, chills, weight loss. Denies alopecia, rash, photosensitivity, pleurisy, oral or genital ulcers. No change in bowel habits. Case 2 FMHx: - for autoimmune disease SH: engaged, dental assistant and home health care assistant, past smoker, history of social alcohol use. Allergies: NKA 7
Case 2 Physical Exam: Tinel sign bilaterally, tender/swollen joints in several PIP and MCP joints bilaterally, tender wrists, and elbows tender and unable to fully extend. 10/18 tenderpoints . Case 2 Anti-CCP RF Lyme and tick panel Parvovirus B-19 HIV ½ HLA B-27 ESR CBC 20.9 (up to 20.0) RF – 8.6 IU/ml ( 11.9) negative IgG, IgM negative negative negative 32 (uln is 20) CBC – HgB 11.5 – – plt ct 414 MCI normal Case 2 Before x-rays are taken in a female Of child bearing years always take a What test? Serum pregnancy test 8
Foot and hand X-rays Normal The truths about x-rays in RA Early in disease, x-rays are not diagnostic – Support the physical findings of soft tissue swelling and joint effusion. Later, help determine extent of cartilage destruction and bone erosion, especially when monitoring impact of Rx with DMARDs, biologic response modifiers or small molecule targeted RA meds. If you ordered X-rays and they were not normal what would be the description of Rheumatoid hands with advanced disease? Rheumatoid Mouse bite erosions Ulnar deviation or drift MCP and PIP involvement Periarticular osteopenia Symmetrical narrowing (No excess bone) 9
What is the sensitivity specificity of RF? Which of the following is True Regarding the RF autoantibodies 1. RF tests are diagnostic of RA? 2. Only 80-85% of RA patients are ever positive for RF? 3. RF should be serially monitored as a marker for disease activity? Which of the following is True Regarding the RF autoantibodies 1. RF tests are diagnostic of RA? 2. Only 80-85% of RA patients are ever positive for RF? 3. RF should be serially monitored as a marker for disease activity? The diagnosis is clinical with support from lab and x-rays 10
The truths about Rheumatoid Factor 50% of pts are positive within the first 6 months Only 80-85% of pts are ever positive Not specific for RA: chronic infections, active TB, cirrhosis, malignancies, other rheumatic diseases High titer in early RA worse prognosis Once positive, not necessary to check again Lindqvist E, et al. Ann Rheum Dis. 2005;64(2):196-201. Erhardt CC, et al. Ann Rheum Dis. 1989;48(1):7-13. Wolfe F, et al. Arthritis Rheum. 2003;48(6):1530-1541. Anticyclic Citrullinated Peptide antibodies (Anti-CCP) Antibodies against CCPS: Fibrinogen, enolase, collage II, vimentin and others May be seen earlier than RF Similar or higher sensitivity for RA than RF – Found in up to 40% of patients who are RF negative – Not all RA pts are anti-CCP Higher specificity for RA than RF: close to 90-99% Predictive of poor prognosis (erosions, joint damage) Schellekens GA, et al. Arthritis Rheum. 2000;43(1):155-163. Lee DM, et al. Ann Rheum Dis. 2003;62(9):870-874. Jansen LMA, et al. J Rheumatol. 2002;29(10):2074-2076. Nielen MMJ, et al. Arthritis Rheum. 2004;50(2):380-386. Vallbracht I, et al. Ann Rheum Dis. 2004;63(9):1079-1084. van Gaalen FA, et al. Ann Rheum Dis. 2005;64(10):1510-1512. Acute Phase Reactants Erythrocyte Sedimentation Rate Male age/2 Female (age 10)/2 Causes of elevated ESR Infection CTD Malignancy Pregnancy Anemia Obesity 11
Acute Phase Reactants C-Reactive Protein Male age/50 Female age/50 0.6 Rises and falls more quickly than ESR Making the Diagnosis Does your patient have: Swollen or tender joints Either 1 large or 1 small joint of the hands or feet, or Positive squeeze test (pain when gently squeezing across the MCP/MTP joints) Symptoms lasting 6 weeks If patient has swollen joints or a positive squeeze test as above for 6 weeks, refer to a rheumatologist for provisional RA If the patient does not meet these criteria but has at least 1 swollen or tender joint and a positive RF or anti-CCP test, he or she should be referred to a rheumatologist What are the risk factors? 1. Genetics - monozygotic twins 12-15% concordance rate, fraternal 2-3% HLA DR-4, lesser extent DR1 and DR14 2. Environmental - smoking, bacteria in the microbiome of the mouth, lung, gut (periodontal disease) 3. Initiation of disease – unknown 4. Perpetuation of disease - both innate immune response and adaptive immune response are involved. This creates options for Rx at different levels and thus different drugs developed with separate MOAs. 12
What is the patient’s prognosis? High RF and high CCP show a worse prognosis over time The key is to treat the patient aggressively to shut down the disease. Case 3 New Milford CT 60 year old Caucasian male referred sudden onset of bilateral hand pain and knee pain with no observed swelling. 3 separate occasions over the prior 3 weeks he described shaking chills and the 3rd episode he took his temp and it was 101º F. He described fullness and stiffness in his hands which is now lasting 1-2 hrs and improves as the day wears on. Tick bite documented by MD over this right hip. Tick panel xs 2 was negative and six weeks apart. – Then developed an abrupt onset of left followed by right wrist swelling and swelling behind the left knee. Case 3 New Milford CT ROS: No anorexia, no weight loss or gain, no history of Raynaud’s, malar rash, alopecia, muscle weakness or other autoimmune symptoms. Not sleeping well due to the pain, no history of anxiety, depression. Social History: recently retired, social ETOH intake, Married does not smoke and never smoked FMHx: Mother had RA PMHx: Barrett’s esophagus, GERD, hypertension, hyperlipidemia. Current meds: Chlorthalidone, enalapril, pantoprazole, simvastatin, Vitamin D3 1,000 ius, 13
Case 3 New Milford CT Labs: BC x’s 2 were negative ESR 54 CRP 45.5 mg/L Uric acid 8.3 Hgb 11.9 normal MCI Case 3 New Milford CT Platelets 410,000 (ULN 400,000) WBC 12.1 (has been on prednisone) Chem. profile BS-noon-fasting 135, Creatiinine Anti-CCP 300 RF 17.6 (negative is 11.9) HLA B-27 negative Hep B and C negative X-rays of both hands – for erosions or symmetrical narrowing Would you expect the x-ray to Show erosions? Case 3 New Milford CT With the shaking chill xs 3 we were concerned about a septic event We ordered a transthoracic echocardiogram Results – for valvular lesion were negative Treatment: What would you do for treatment for this patient 14
Case 2 How to improve patient outcomes Primary care Rheumatologist Collaboration Provisional diagnosis Early referral to rheumatologist Monitor for disease progression, medication toxicities and co-morbidities Confirm diagnosis Initiate early and aggressive DMARD Rx Monitor for disease progression, medication toxicities, and comorbidities RA: Initial Management Symptomatic relief while waiting for rheumatology referral – NSAIDs (short term) Assess CV, renal, GI bleed, CHF risk Consider GI protectives (PPI, H2RA, misoprostol) Preference to COX-2 selective when possible – Acetaminophen 4 g/d Screen for other OTC acetaminophen sources to avoid toxicity – Systemic corticosteroids Short term only 10 mg/d prednisone (or equivalent) or less – Simple opioid analgesia as “rescue” CV, cardiovascular; GI, gastrointestinal; PPI, proton pump inhibitor; H2RA, H2 receptor antagonists; OTC, over the counter Combe B, et al. Ann Rheum Dis. 2007;66(1):34-35. Steroids Generally use only low doses for RA (prednisone 10 mg/day) Intra-articular steroids might reduce a flare Use steroids as a bridge with DMARDs while waiting for DMARDs to work Should not be used as solo therapy van Everdingen AA, et al. Ann Intern Med. 2002;136(1):1-12. Kirwan JR. N Engl J Med. 1995;333(3):142-146. 15
What Are DMARDs? Disease-modifying antirheumatic drugs – – – – Alter natural course of disease Decrease RA severity, disability, and mortality Lower rates of RA complications Control of inflammation may decrease cardiac and malignancy risks – Declining rates of lower-extremity orthopedic surgical procedures in recent years Weisman M. Ann Rheum Dis. 2002;61(4):287-289. Wolfe F, et al. J Rheumatol. 2001;28(6):1423-1430. Weiss RJ, et al. Ann Rheum Dis. 2006(3);65:335-341. Pap G, et al. Curr Opin Rheumatol. 2001;13(3):214-218. Hakala M, et al. J Rheumatol. 1994;21(8):1432-1437. Weinblatt ME. Ann Rheum Dis. 2003;62 Suppl 2:ii94-96. “Window of Opportunity” in RA Radiographic Score (Disease Progression) DMARDs are associated with a decrease in radiographic progression 70 60 50 P 0.05 at 2 years 40 NO DMARD DMARD 30 20 10 0 0 1 2 3 4 5 Years of Disease Lard LR, et al. Am J Med. 2001;111(6):446-451. Weisman M. Ann Rheum Dis. 2002;61(4):287-289. DMARDs: Traditional vs Biologic Traditional Biologic For example For example TNF antagonists MTX Leflunomide Sulfasalazine (SSZ) Hydroxychloroquine (HCQ) – – – – – Etanercept Adalimumab Infliximab Certolizumab pegol Golimumab Abatacept Rituximab Tocilizumab Tofacitinib 16
Methotrexate Time to onset: 6–12 weeks Dosing weekly (7.5–25 mg), oral or subcutaneous Administered with folic acid 1 mg QD or folinic acid Contraindications – Renal insufficiency dialysis – Active infection/chronic hepatitis B/C infection – Liver disease Adverse events – GI intolerance – Elevated LFTs – Pneumonitis – Hematologic – Teratogenicity Monitoring – Hepatitis serologies before use, alcohol counseling, LFTs, CBC, creatinine – Avoid trimethoprim/sulfa with MTX: bone marrow suppression Weinblatt ME. Ann Rheum Dis. 2003;62 Suppl 2:ii94-96. LFT, liver function test Hydroxychloroquine Time to onset 12–16 weeks Dosing once or twice daily, usual total dose 400 mg Adverse effects – – – – Nausea Rash Skin/hair discoloration Retinopathy Every 6–12 months screening by ophthalmology Rare at doses 400 mg/d Caution with preexisting eye disease – Neuromyopathy (very rare) Used in pregnancy and lactation Monitoring – Eye examination at least yearly Ruiz-Irastorza G, et al. Ann Rheum Dis. 2010 Jan;69(1):20-28. 17
TNF Antagonists 5 currently approved agents: Subcutaneous (etanercept, adalimumab, certolizumab pegol, golimumab) and IV administration (infliximab) Administration in combination with MTX is superior to monotherapy Time to onset: rapid (weeks) Adverse events – Etanercept, adalimumab, infliximab, certolizumab pegol, golimumab – 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 Monitoring – TB screening including PPD prior to therapy – Periodic CBC, LFTs – Infection O'Dell JR. N Engl J Med. 2004;350(25):2591-2602. T-Cell Costimulatory Blockade: Abatacept Approved for RA patients who did not respond to nonbiologic or biologic DMARDs Inhibits the activation of T lymphocytes Monthly IV administration over 30 minutes Time to onset: initial response after several weeks but maximal effect not seen for several months Adverse events – Infections (bacterial) uncommon – Infusion reactions – Increased infections in COPD – Never administered with another biologic DMARD Monitoring – – – – PPD before use Infection Complete immunizations before use Avoid live virus vaccination COPD, chronic obstructive pulmonary disease Gartlehner G, et al. J Rheumatol. 2006;33(12):2398-2408. Leff L. J Infus Nurs. 2006;29(6):326-337. Kountz DS, et al. J Fam Pract. 2007 Oct;56(10 Suppl A):59A-73A. B-Cell Depletion: Rituximab Approved for RA patients who did not respond to TNF antagonists Binds to CD20 expressed on B lymphocytes IV administration with corticosteroid pretreatment – – Effects may be sustained 6–9 months or longer after single treatment course Adverse effects – – – 2 doses separated by 2 weeks Time to onset: several weeks to months – Rapid and prolonged decrease in circulating B-cell population Infection: bacterial and possible viral reactivation (cytomegalovirus, hepatitis B, slow virus [progressive multifocal leukoencephalopathy]) Repeated administration associated with decreased immunoglobulin levels Immunization responses may be impaired Monitoring – – – – Infection Complete immunizations before use Avoid live virus vaccination Infusion reactions Gartlehner G, et al. J Rheumatol. 2006;33(12):2398-2408. Leff L. J Infus Nurs. 2006;29(6):326-337. Kountz DS, et al. J Fam Pract. 2007 Oct;56(10 Suppl A):59A-73A. 18
IL-6 Blockade: Tocilizumab Approved for RA patients who did not respond to biologic DMARDs Monoclonal antibody that blocks the IL-6 receptor Monthly IV administration over 60 minutes Starting dose 4 mg/kg with escalation to 8 mg/kg given as monotherapy or in combination with MTX Response within weeks including reduction in CRP Adverse events – Infections – Increased lipids – Elevated LFTs – Infusion reactions uncommon – Neutropenia (rare) – Colonic perforation (rare) Monitoring – PPD before use – Avoid live virus vaccination – Infection – CBC, LFTS, and lipid – Lipid-lowering drugs Gartlehner G, et al. J Rheumatol. 2006;33(12):2398-2408. Leff L. J Infus Nurs. 2006;29(6):326-337. Kountz DS, et al. J Fam Pract. 2007 Oct;56(10 Suppl A):59A-73A. JAK Inhibitors Tofacitinib JAK 3 inhibitor approved for RA for those who could not tolerate or are non-responsive to methotrexate Interferes with the JAK-STAT pathway which transmits extracellular information into the cell nucleus, influencing DNA transcription. Oral 5mg BID with responses within weeks in clinical and lab parameters Adverse events: – Lymphoma other malignancies, serious infections, TB, bacterial, invasive fungal, viral. Concern over risk of GI perforations for thos at risk – Laboratory Monitoring: CBC watch for lymphopenia, neutropenia, LFTs and lipid increases – Immunizations with live vaccines should be avoided. Killed vaccines should be administered RA, DMARDs, and Infection Risk 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 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, Candida) Viral (eg, zoster) Listing J, et al. Arthritis Rheum. 2005;52(11):3403-3412. Kroesen S, et al. Rheumatology (Oxford). 2003;42(5):617-621. Dixon WG, et al. Arthritis Rheum. 2006;54(8):2368-2376. Greenberg JD, et al. Ann Rheum Dis, 2010 Feb;69(2):380-386. Solomon DH, et al. Arthritis Rheum. 2008;58(4):919-928. Strangfeld A, et al. JAMA. 2009;301(7):737-734. 57 19
Immunizations in RA RA patients have reduced responses to immunizations; medications may blunt these responses further No evidence that vaccinations exacerbate or precipitate rheumatic disease Influenza and pneumococcal vaccinations are recommended – Postimmunization titers may be lower Hepatitis B immunization if appropriate Ravikumar R, et al. Curr Rheumatol Rep. 2007 Oct;9(5):407-415. CDC. MMWR. 2004;53(1):Q1-Q4. Avery RK. Rheum Dis Clin North Am. 1999 Aug;25(3):567-584. Chalmers A, et al. J Rheumatol. 1994;21(7):1203-1206. Harpaz R, et al. MMWR Recomm Rep. 2008;57(RR-5):1-30. Herpes zoster (shingles) vaccine guidelines for immunocompromised patients. American College of Rheumatology web site. 008 08 01 shingles.asp. 58 DMARDS and Immunizations in RA Live virus vaccines should be avoided in patients on immunomodulators: – Intranasal influenza, mumps/measles/rubella (MMR), yellow fever, typhoid, oral polio – Wait at least 2 weeks after giving these vaccines before initiating immunomodulators Zoster vaccine should be avoided in patients on biologic agents – May be given to patients on MTX and prednisone 20 mg/d Other immunizations are safe: – Influenza (injection), tetanus, pneumococcus, meningococcus, hepatitis A, hepatitis B, H. influenzae B (HiB), human papillomavirus (HPV) Ravikumar R, et al. Curr Rheumatol Rep. 2007 Oct;9(5):407-415. CDC. MMWR. 2004;53(1):Q1-Q4. Avery RK. Rheum Dis Clin North Am. 1999 Aug;25(3):567-584. Chalmers A, et al. J Rheumatol. 1994;21(7):1203-1206. Harpaz R, et al. MMWR Recomm Rep. 2008;57(RR-5):1-30. Herpes zoster (shingles) vaccine guidelines for immunocompromised patients. American College of Rheumatology web site. 008 08 01 shingles.asp. 59 Ongoing Monitoring for RA Patients in Primary Care Follow-up laboratories Infections PPD Immunizations CV risk monitoring – Smoking cessation – Lipids Cancer surveillance Contraception (if appropriate) 20
Alarm Bells in an RA Patient: Urgent Rheumatologist Discussion Fever and infections: be particularly concerned about any infection in a patient on steroids, MTX, leflunomide, or biologics Consider septic arthritis when there is – Isolated monoarthritis when all other joints stable – Swelling and tenderness in a total joint replacement RA patients may not mount a febrile response and the white blood cells may not be elevated in this setting Dyspnea and cough in a patient on MTX: this could be MTX pneumonitis 21
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We rarely see this in our waiting rooms anymore 24
4 take away Messages 1. Synovitis is the hallmark of RA and if seen either refer the patient or work them up. 2. ACR recommends early referral for the instition of aggressive treatment to prevent joint and organ damage. 3. Lab tests are helpful but the diagnosis is still clinical. 4. RA is a systemic disease and can affect the skin, eyes, lungs, and heart. 5. Remember pts on Biologic response modifiers need quick evaluation for infections of any sort. Thank you Questions? Feel free to e-mail me at: Richard.pope@wchn.org 25
Synovial fluid orders Gram Stain* Culture* Differential (Can be estimated with minimal fluid) Crystal Search Cell Count *Can Be Done With Minimal Fluid ACR 1987 criteria for the classification of acute rheumatoid arthritis Need at least four of seven criteria: 1. Morning stiffness lasting at least 1 hr 2. Soft- tissue swelling or fluid in at least 3 joint areas simultaneously 3. At least one area swollen in a wrist, MCP, or PIP joint* 4. Symmetric arthritis* 5. Rheumatoid nodules 6. Abnormal amounts of serum rheumatoid factor 7. Erosions or bony decalcification on radiographs of the hand and wrist * For classification purposes, a patient shall be said to have rheumatoid arthritis if he/she has satisfied at least 4 or these 7 criteria. Criteria 1 through 4 must have been present for at least 6 weeks. 26
3 References American College of Rheumatology Slide Collection of Rheumatic Diseases, online library at www.rheumatology.org Klippel, John H., M.D., editor .
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