rheumatology 101: rheumatology for dummies

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Rheumatology 101: Rheumatology for DummiesWestern CT Health Network Danbury, CT 06810
Or is it?
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.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119866/ Historical perspective on the etiology of Rheumatoid Arthritis Hand Clin. 2011 Feb; 27(1): 1–10.
“The Three Graces”
Kathleen Turner Lucille Ball
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
3
References
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
– 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
• Synovitis seen in both hands.
Physical exam
1. What is the one hallmark for RA that is required to make the diagnosis?
a) + RF and/or anti-CCP
b) Erosions on radiograph
Physical exam
1. What is the one hallmark for RA that is required to make the diagnosis?
a) + RF and/or anti-CCP
b) Erosions on radiograph
Which one of these shows synovitis?
5
Wrists, MCPs, PIPs
What labs would you order as initial lab for patients with Joint Pains?
• RF
• Hepatitis B and C
ANA, antinuclear antibody; IgG, immunoglobulin G; IgM, immunoglobulin M; CBC, complete blood count
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• Hand with wrists
1. Polyarticular gout
2. Inflammatory osteoarthritis
5. Psoriatic arthritis
1. Polyarticular gout
2. Inflammatory osteoarthritis
5. Psoriatic arthritis
• 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
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
– MCI normal
Case 2
What test?
• 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)
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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
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• <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
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.
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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
• Current meds: Chlorthalidone, enalapril, pantoprazole, simvastatin, Vitamin D3 1,000 ius,
14
• Labs: BC x’s 2 were negative
ESR 54
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
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Primary care
• Provisional diagnosis
Rheumatologist
• Monitor for disease progression, medication toxicities, and comorbidities
Collaboration
– NSAIDs (short term)
• Consider GI protectives (PPI, H2RA, misoprostol)
• Preference to COX-2 selective when possible
– Acetaminophen ≤4 g/d
– Systemic corticosteroids
– Simple opioid analgesia as “rescue”
Combe B, et al. Ann Rheum Dis. 2007;66(1):34-35. CV, cardiovascular; GI, gastrointestinal; PPI, proton pump inhibitor; H2RA, H2 receptor antagonists; OTC, over the counter
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.
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– 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
Years of Disease
R a d
ro g
DMARDs are associated with a decrease in radiographic progression
Lard LR, et al. Am J Med. 2001;111(6):446-451. Weisman M. Ann Rheum Dis. 2002;61(4):287-289.
P<0.05 at 2 years
0
10
20
30
40
50
60
70
NO DMARD
(HCQ)
• Abatacept • Rituximab • Tocilizumab • Tofacitinib
• Dosing weekly (7.5–25 mg), oral or subcutaneous
• Administered with folic acid 1 mg QD or folinic acid
• Contraindications – Renal insufficiency dialysis
– Liver disease
– Elevated LFTs – Teratogenicity
– Avoid trimethoprim/sulfa with MTX: bone marrow suppression
Weinblatt ME. Ann Rheum Dis. 2003;62 Suppl 2:ii94-96. LFT, liver function test
Ruiz-Irastorza G, et al. Ann Rheum Dis. 2010 Jan;69(1):20-28.
Hydroxychloroquine
• Dosing once or twice daily, usual total dose 400 mg
• Adverse effects – Nausea
• Rare at doses ≤400 mg/d
• Caution with preexisting eye disease
– Neuromyopathy (very rare)
• Monitoring
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• 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
• Monitoring – TB screening including PPD prior to therapy
– Periodic CBC, LFTs
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
• Monitoring
– Complete immunizations before use
– Avoid live virus vaccination
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. COPD, chronic obstructive pulmonary disease
B-Cell Depletion: Rituximab
• Approved for RA patients who did not respond to TNF antagonists
• Binds to CD20 expressed on B lymphocytes
– Rapid and prolonged decrease in circulating B-cell population
• IV administration with corticosteroid pretreatment
– 2 doses separated by 2 weeks
• Time to onset: several weeks to months
– Effects may be sustained 6–9 months or longer after single treatment course
• Adverse effects
– Repeated administration associated with decreased immunoglobulin levels
– Immunization responses may be impaired
• Monitoring
– Infection
– 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.
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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
• Monitoring
– Avoid live virus vaccination – Lipid-lowering drugs
– Infection 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”
• 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)
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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.
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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
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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.
http://www.rheumatology.org/publications/hotline/2008_08_01_shingles.asp.
• 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:
59
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.
http://www.rheumatology.org/publications/hotline/2008_08_01_shingles.asp.
• Follow-up laboratories
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
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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
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•Crystal Search
•Cell Count
ACR 1987 criteria for the classification of acute
rheumatoid arthritis
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