#147 Rheumatoid Arthritis for the Internist

April 8, 2019 | By Elena Gibson

Make rheum in your brain for advice from Dr Robert McLean

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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Credits

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

Time Stamps

• 00:35 Disclaimer, intro and guest bio
• 03:38 Guest onliner; Nudge (book) on behavioral economics
• 08:30 Favorite failure; Stuart’s pick of the week
• 12:24 Key historical features of RA
• 15:30 Differential diagnosis
• 19:20 Physical findings in RA
• 20:58 Initial labs orders for suspected inflammatory arthritis; CRP vs high sensitivity (cardio) CRP assays
• 27:45 Epidemiology of RA; Is there a utility for scoring systems?; A bit more on inflammatory markers
• 32:30 Recap and test interpretation
• 36:22 High yield physical exam in RA
• 40:56 Initial counseling after RA diagnosis
• 46:00 Therapeutic trial with NSAIDS or steroids for inflammatory arthritis
• 50:29 When to reach for the DMARDS
• 52:40 Are steroids considered DMARDS?
• 54:50 Primary care considerations for patients starting steroids or DMARDS (TB, vaccinations)
• 60:34 When and how long to hold DMARDS for surgery or acute illness
• 62:10 Drug-drug interactions and monitoring with methotrexate, hydroxychloroquine, sulfasalazine
• 70:10 Anti-inflammatory diets
• 73:30 Take home points
• 76:00 Outro

Rheumatoid Arthritis Pearls from Dr. McLean

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.

Rheumatoid Arthritis Show Notes

Arthritis Categories

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

Inflammatory vs. Mechanical Arthritis Evaluation

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 Evaluation

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.

Laboratory Evaluation

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.

CRP and ESR

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.

CCP Antibody and Rheumatoid Factor (RF)

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.

Physical Exam Evaluation

Palpate and examine of various joints for synovial thickening, swelling, and irritation. Have patients move their joints through a full range of motion.

Hands:

Palpate MCP and PIP joints for synovial thickening or swelling in the joints. Look for loss of the “valley” space between MCP joints.

Wrists:

Healthy wrist joints have thin synovium and easily palpated bones. Feel for thickening of this space and tenderness.

Elbows:

Inflammation often causes a mild flexion contracture. Attempt to passively straighten the elbow, it may not straighten beyond ~160-170°.  

Metatarsophalangeal (MTPs):

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.  

Rheumatoid Arthritis Diagnosis and Treatment

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.

“Explain uncertainty in certain terms”

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.

Assess Medication Response

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.

DMARD or Not?

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.

Primary Care Management Considerations

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.

Before a DMARD

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).  

Drug Interactions

Methotrexate

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

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).

Sulfasalazine

Similar to methotrexate, sulfasalazine necessitates monitoring for leukopenia and liver dysfunction.  

Anti-Inflammatory Diets

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.

Goals and Learning Objectives

Goal

Listeners will appreciate the complexity of rheumatoid arthritis and have a patient-centered framework for the evaluation and treatment of patients with rheumatoid arthritis.

Learning objectives

After listening to this episode listeners will…

1. Learn a simple approach to categorizing causes of polyarthritis
2. Learn what clinical findings may be suggestive of RA and what study findings can be used to support the diagnosis.
3. Be familiar with the physical examination and findings of joints in patients with RA
4. Appreciate the approach to initiating, advancing and stepping-up therapy in patients with RA.
5. Co-manage patients with RA alongside rheumatologists, specifically knowing what to look for as far as common adverse effects of certain medications

Disclosures

Dr McLean reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures.

Links from the show

1. Nudge: Improving Decisions about Health, Wealth and Happiness by Richard H. Thaler
2. The Orville Series (TV)

References

Links have been included in body of text above

1. Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010;376(9746):1094-108. [https://www.ncbi.nlm.nih.gov/pubmed/20870100]
2. Van der linden MP, Van der woude D, Ioan-facsinay A, et al. Value of anti-modified citrullinated vimentin and third-generation anti-cyclic citrullinated peptide compared with second-generation anti-cyclic citrullinated peptide and rheumatoid factor in predicting disease outcome in undifferentiated arthritis and rheumatoid arthritis. Arthritis Rheum. 2009;60(8):2232-41. [https://onlinelibrary.wiley.com/doi/full/10.1002/art.24716]
3. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388(10055):2023-2038.[https://www.ncbi.nlm.nih.gov/pubmed/27156434]
4. Wells G, Becker JC, Teng J, et al. Validation of the 28-joint Disease Activity Score (DAS28) and European League Against Rheumatism response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis. 2009;68(6):954-60. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674547/]
5. Caporali R, Crepaldi G, Codullo V, et al. 20 years of experience with tumour necrosis factor inhibitors: what have we learned? Rheumatology (Oxford). 2018;57(57 Suppl 7):vii5-vii10. [https://www.ncbi.nlm.nih.gov/pubmed/30289535]
6. Shea B, Swinden MV, Tanjong Ghogomu E, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2013(5):Cd000951. [https://www.ncbi.nlm.nih.gov/pubmed/23728635]
7. Crowson CS, Liao KP, Davis JM, et al. Rheumatoid arthritis and cardiovascular disease. Am Heart J. 2013;166(4):622-628.e1.[https://www.ncbi.nlm.nih.gov/pubmed/24093840]
8. Neame R, Hammond A. Beliefs about medications: a questionnaire survey of people with rheumatoid arthritis. Rheumatology: 2005; 44(6):762-767. [https://www.ncbi.nlm.nih.gov/pubmed/15741193]
9. Park JK, Lee YJ, Shin K, et al. Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial. Annals of the rheumatic diseases. 2018;77(6):898-904. [https://www.ncbi.nlm.nih.gov/pubmed/28468794]
10. Sparks JA. Rheumatoid Arthritis. Ann Intern Med. 2019;170(1):ITC1-ITC16. [https://www.ncbi.nlm.nih.gov/pubmed/30596879]
11. Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision). Ophthalmology. 2016;123(6):1386-1394. [https://www.ncbi.nlm.nih.gov/pubmed/26992838]

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