Join(t) us in learning about rheumatoid arthritis care for the internist with Robert McLean MD, rheumatologist, Associate Clinical Professor at Yale, and President Elect of the ACP! We discuss the complexity of rheumatoid arthritis, how to differentiate from other arthritic conditions, and how to have a patient-centered framework for the evaluation and treatment of affected patients. ACP members can claim CME-MOC credit at https://acponline.org/curbsiders.
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Writer (Interview & CME questions): Cyrus Askin MD
Show Notes and Infographic by: Elena Gibson MS4
Hosts: Matthew Watto MD, Stuart Brigham MD
Editors: Matthew Watto MD, Emi Okamoto MD
Guest: Robert McLean MD
Consider two polyarthritis categories: inflammatory arthritis vs. mechanical/degenerative arthritis.
Evaluate for morning stiffness by asking “How do you feel in the morning?” or “What do your feet feel like in the morning?”. At least 30-60 minutes of morning stiffness points towards an inflammatory arthritis such as rheumatoid arthritis (RA).
RA presents in a bimodal distribution: young females and the elderly.
Order a CRP and ESR to evaluate for inflammation and look for ESR >30. Avoid ordering cardioselective high-sensitivity CRP. Order a rheumatoid factor and anti-CCP to assess for RA, and look for levels ~3x the upper limit of normal. CBC and CMP can check for other causes of systemic disease.
Avoid ordering excessive laboratory tests (e.g., ANA, HLA-B27, ANCA) when not clinically appropriate.
Palpate joints for synovial thickening and tenderness. Examine joints for full range of active and passive motion. Patents may have a mild flexion contracture of the elbow. Examine the metatarsophalangeal (MTP) joints for pain by applying pressure to the ball of the foot.
RA is a clinical diagnosis! Consider it if a patient has any/all of the following: 1) small joint arthritis (often symmetric) 2) elevated ESR/CRP levels 3) positive rheumatoid factor or anti-CCP.
Initial treatment for most patients with RA will be NSAIDs and/or steroids. Treatment will then be escalated to immunomodulators, methotrexate, or biologics (DMARDs).
Before a patient starts a biologic agent, administer zoster, pneumonia, flu, hepatitis B and HPV vaccinations. Check hepatitis serologies and TB testing prior to treatment with a TNF inhibitor.
Patients on methotrexate require folic acid substitution and monitoring for leukopenia. Avoid combining Trimethoprim-sulfamethoxazole and methotrexate (MTX). This drug interaction increases MTX levels & risk for toxicity.
There is not great evidence for anti-inflammatory diets. However, if patients want to try a diet, encourage them to try elimination and reintroduction.
Dr. McLean describes two primary categories of polyarthritis with additional subcategories:
1) Inflammatory Arthritis: autoimmune (rheumatoid arthritis), spondyloarthropathies (psoriatic arthritis, ankylosing spondylitis, IBD associated), infection-related autoimmune arthritis (hepatitis, parvovirus, Lyme), reactive arthritis (Chlamydia, Campylobacter, Shigella, etc.), septic, crystalline (gout, pseudogout)
2) Mechanical/Degenerative Arthritis: osteoarthritis
Consider how long the symptoms have been present to evaluate for infectious etiologies. Evaluate the patient for morning stiffness by asking “How do you feel in the morning?”, but avoid leading questions like “Are you stiff in the morning?”. Then ask specifics about how long this lasts. Patients with inflammatory arthritis will report at least 30-60 minutes of morning stiffness while patients with osteoarthritis will report worsening pain at the end of the day. Consider which joints are involved. RA classically affects bilateral small joints, including the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the hands. If the DIP joints are involved, it is likely osteoarthritis or possibly psoriatic arthritis.
Rheumatoid arthritis affects ~1% of adults in industrialized countries (Scott et al. 2010).There is a bimodal distribution of disease 1) mostly female patients 20-40 years old and 2) elderly patients 60-80 years old with an equal gender distribution.
Initial laboratory evaluation of patients should include 1) C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) to identify inflammation, 2) rheumatoid factor and cyclic citrullinated peptide antibody (anti-CCP) to evaluate more specific markers of RA, and finally 3) complete blood count (CBC) and complete metabolic panel (CMP) to look for other causes of systemic illnesses (e.g., vasculitis and paraneoplastic syndromes). This was not mentioned on the show, but we also routinely send a urinalysis looking for significant proteinuria, dysmorphic RBCs or casts, which can provide additional diagnostic clues.
Dr. McLean avoids checking an antinuclear antibody (ANA) or an HLA-B27. An ANA is helpful for a lupus evaluation, but widespread screening will lead to high numbers of false positives and patient anxiety. Comparatively, HLA-B27 is present in 90% of patients with spondyloarthropathies, but ordering it in the setting of a non-specific arthritis will not provide high value.
There are two CRP assays: the routine CRP and the cardioselective/high-sensitivity CRP (hs-CRP). Use only the routine CRP in arthritis evaluation. The hs-CRP is used in risk-stratification for heart disease in persons without inflammation. In practice Dr.McLean notes that most patients with RA have an elevated ESR over 30. If the ESR is <30, RA is less likely. However CRP/ESR are frequently normal in spondyloarthropathies.
Both CRP and ESR increase with age.The sedimentation rate is driven by rouleaux formation caused by gamma globulins and fibrinogen, and ESR will always be normal in dysfibrinogenemia or sickle cell anemia. These are cheap and easy tests, and normal results help Dr. McLean reassure low-risk patients without objective signs of arthritis that no further workup is needed.
RF is an IgM directed at the Fc portion of an IgG antibody. The anti-CCP is newer, more specific for RA, and seems to correlate with disease activity, so there is potential to monitor the anti-CCP level for disease activity (Van der linden 2009). Dr. McLean estimates ~80-90% of classic RA patients have a positive RF and/or anti-CCP, and one review estimates 50-70% had this at time of diagnosis (Smolen 2016). Look for a fairly high titer (~3x the normal range) because many antibodies cross-react with these.
Palpate and examine of various joints for synovial thickening, swelling, and irritation. Have patients move their joints through a full range of motion.
Palpate MCP and PIP joints for synovial thickening or swelling in the joints. Look for loss of the “valley” space between MCP joints.
Healthy wrist joints have thin synovium and easily palpated bones. Feel for thickening of this space and tenderness.
Inflammation often causes a mild flexion contracture. Attempt to passively straighten the elbow, it may not straighten beyond ~160-170°.
Squeeze the ball of the foot together to assess for soreness. Ask “what do your feet feel like when you wake up in the morning?” Patients with RA might describe walking on marbles or rocks.
In clinical practice, Dr. McLean does not recommend using a score/criteria to diagnose RA, but describes their use in tracking a diagnosis (Wells 2009). Instead, RA should be considered if a patient has any or all of the following findings: 1) small joint arthritis (often symmetric) 2) elevated ESR/CRP levels 3) positive rheumatoid factor or anti-CCP. The tests are helpful, but not definitive, as RA is a clinical diagnosis. The role of advanced imaging (US, MRI) is still unclear.
When counseling a patient, Dr. McLean describes how the immune system is “turned on” and causing inflammation in various joints. Dr. McLean discusses how a trigger prompted a gene to turn on cells which make inflammatory proteins known as cytokines. Available medications block the production or effect of cytokines. Although you are not able to give a definitive diagnosis in all cases, for example with borderline lab results, you have to explain uncertainty in certain terms. Patients can be reassured hearing it is not other diseases, like cancer or lupus.
Dr. McLean recommends asking patients what they have been taking for arthralgias. Assess for response to NSAIDs. If NSAIDs aren’t working, he tries prednisone 10mg twice a day. This will make most patients with RA/inflammatory arthritis feel much better, and a positive response can be used as a diagnostic clue or to induce remission.
Disease-modifying antirheumatic drugs (DMARDs) classically include methotrexate, immunomodulators (e.g., sulfasalazine, hydroxychloroquine), and biologics. Both NSAIDs and steroids are anti-inflammatories, not DMARDs, though steroids have been shown to positively affect the progression of disease. If patients have very high laboratory values and disease burden, Dr. McLean starts with prednisone then 2-4 weeks later starts a disease-modifying antirheumatic drug (DMARD), usually sulfasalazine or hydroxychloroquine. All DMARDs take 4-6 weeks to start working, so a longer, low-dose steroid taper is needed. Recognize that patients have many concerns about these medications, and proper counseling can improve adherence (Neame 2005). Of note, DMARDs can be dangerous for sick and hospitalized patients, particularly methotrexate and biologics.
Most patients are started on NSAIDs and treatment is escalated in a bottom up fashion. Dr McLean recommends that PCPs try to avoid starting steroids (if possible) and arrange for patient evaluation by a rheumatologist. There are many subtle medication interactions, treatment strategies, and monitoring parameters with which a rheumatologist should assist.
Prior to initiation of an immunomodulator or biologic medication, Dr. McLean recommends confirming or providing the following vaccinations: herpes zoster, pneumococcal, influenza, hepatitis B and human papillomavirus. A recent study identified an improved immunogenic response to influenza vaccination associated with short-term methotrexate discontinuation (Park et al. 2018). Before starting a biologic agent, viral hepatitis and tuberculosis screening should be completed. When targeted biologics block the action of tumor necrosis factor (TNF), tuberculosis can reactivate because TNF is an important cytokine for granuloma maintenance (Caporali et al. 2018).
Methotrexate is a sulfa drug that affects folic acid metabolism. Monitoring for leukopenia and liver dysfunction is warranted. Patients should take folic acid supplementation to reduce the occurence of associated side effects such as mucositis, mucosal ulcerations, hair thinning and alopecia (Shea et al. 2013). Dr. McLean has not found the interactions with penicillins, PPIs and NSAIDs to be clinically significant. However, the use of trimethoprim-sulfamethoxazole (Bactrim) with methotrexate can lead to significant leukopenia and should be avoided. If necessary, monitor WBC count at initiation and in one week. Methotrexate commonly causes a mild elevation in liver enzymes, but persistent elevations require further evaluation (Sparks 2019).
Hydroxychloroquine does not require blood test monitoring, but it does require retinopathy screening and the American Academy of Ophthalmology recommends daily doses ≤5.0 mg/kg actual weight (Marmor 2016).
Similar to methotrexate, sulfasalazine necessitates monitoring for leukopenia and liver dysfunction.
Dr.McLean describes a lack of evidence to support anti-inflammatory diets but suggests discussing with patients how many different environmental antigens could trigger inflammatory responses. If patients are trying an anti-inflammatory elimination diet, encourage them to look for potential patterns in diet and symptoms by eliminating and re-introducing different components of the diet.
Listeners will appreciate the complexity of rheumatoid arthritis and have a patient-centered framework for the evaluation and treatment of patients with rheumatoid arthritis.
After listening to this episode listeners will…
Dr McLean reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures.
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