of Rheumatoid Arthritis: The Critical Role of Primary Care Learning - - PowerPoint PPT Presentation

Early Identification and Management

• f Rheumatoid Arthritis:

The Critical Role of Primary Care

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• Assess patients for symptoms and signs of rheumatoid arthritis (RA)
• Identify standard and novel therapies for RA and their appropriate use in

clinical practice

• Apply strategies to evaluate patients with RA for extra-articular

manifestations and comorbidities

Learning Objectives

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• 1.5 MILLION ADULTS in the

United States have RA

• 3x more women than men

Dadoun S, et al. Joint Bone Spine. 2013;80:29-33; Gonzalez A, et al. Arthritis Rheum. 2007;56:3583-3587; Humphreys JH, et al. Arthritis Care Res (Hoboken). 2014;66:1296-1301; Myasoedova E, et al. Arthritis Rheum. 2010;62:1576-1582; Sokka T, et al. Arthritis Res Ther. 2010;12:R42.

Prevalence of RA

= 10,000 people

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Environmental and Genetic Risk Factors for RA

• RA is thought to be associated with:

‒ Genetics ‒ Female sex

*Gut dysbiosis in patients with RA may result from an increased abundance of certain rare bacterial lineages. Managing RA by manipulating the gut microbiota is a new area of research. Abella V, et al. Life Sci. 2016;157:140-144; Chen J, et al. Genome Med. 2016;8:43; Yarwood A, et al. Rheumatology (Oxford). 2016;55:199-209.

Genetic background Environmental factors (eg, smoking, periodontitis, pollution, gut microbiota*, others) Asymptomatic Outcomes (disability, joint surgery) Intermittent mono- or oligo- arthritis Persistent symmetric polyarthritis Clinical (inflammation) Preclinical (autoimmunity)

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Pathogenesis of RA

Anti-CCP = cyclic citrullinated peptide; Cit = citrullinated peptide; DC = dendritic cell; MØ = macrophage; RF = rheumatoid factor. Adapted from: Smolen JS, et al. Nat Rev Drug Discov. 2003;2:473-488. Cytokines

Genetic factors and Environmental triggers Synovial inflammation

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Importance of Early Diagnosis in RA

• RA is progressive, not benign
• Structural damage and disability occur within first 2 to 3 years of disease
• Slower disease progression is linked to early treatment with DMARDs
• Once bone and cartilage are damaged, they never return to normal

Smolen JS, et al. Ann Rheum Dis. 2010;69:631-637; Smolen JS, et al. Ann Rheum Dis. 2017;76:960-977.

Disease

• nset

Optimal window of opportunity

• Severe functional decline
• Radiographic damage
• Work disability
• Premature death

Early Established End Stage

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Radiographic Progression of RA

1987 2007

Images courtesy of Brian Peck, MD and Rick Pope MPAS, PA-C.

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Articular Manifestations of RA

• Swelling, tenderness, warmth, and painful motion
• Morning stiffness

‒ May also appear after brief periods of inactivity

• Inflammation of synovial joints
• Joint and periarticular tissue destruction
• Joints most often involved:

‒ PIP ‒ Metacarpophalangeal (MCP) ‒ Wrists, elbows, shoulders, knees, ankles, and subtalar and metatarsophalangeal (MTP) joints

PIP Swelling

Haudenschild DR, et al. In: Kelley’s Textbook of Rheumatology, 9th ed. 2012. Image from: Ostendorf B, et al. Ann Rheum Dis. 2005;64:501-502.

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Early RA in a Young Woman

Image courtesy of Lester Miller, MD.

• Symmetrical joint swelling

in the hands

• Swelling prominent in the

PIP joints and in the left thumb interphalangeal (IP) joint

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Early RA in a Young Woman

Image courtesy of Lester Miller, MD.

• Swelling is particularly

prominent in the MTP joints, especially the 1st and 5th MTPs

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Case Study: Cameron, a 35-Year-Old Woman

• 3-month history of pain and stiffness in hands and right knee, as well as

chronic fatigue

• Morning stiffness >30 minutes and increased pain at work as a mail sorter at

the post office

• 2 MCP joints (left hand) and 1 PIP joint (right hand) are visibly swollen
• Height: 5 ft 2 in; weight: 150 lbs; BMI: 27.4 kg/m2; BP: 123/82 mm Hg
• Primary care clinician had diagnosed OA, prescribed an NSAID, and

suggested diet and exercise to lose weight

• Mother had “bad arthritis”
• Smoking status: 1/2 pack per day
• Alcohol consumption: drinks socially

NSAID = nonsteroidal anti-inflammatory drug; OA = osteoarthritis.

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Squeeze Test Assessment

• Squeeze test allows for

quick clinical evaluation

• f MTP/MCP joints
• Tenderness identified

by gentle palpation of the joints

Emery P, et al. Ann Rheum Dis. 2002;61:290-297.

\

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Common Disorders to Consider in the Differential Diagnosis

• f Arthritides

RA OA PsA Gout Peripheral disease Symmetric Asymmetric Asymmetric Asymmetric (monoarticular) Axial joint/spondylitis No No Yes Infrequent Stiffness Morning/ immobility With activity Morning/ immobility Yes Enthesitis No No Yes Yes Nail lesions No No Yes No Psoriasis Uncommon Uncommon Yes Uncommon Female:male ratio 3:1 Hand/knee > in women 1:1 1:3 to 1:4

Gottlieb A, et al. J Am Acad Dermatol. 2008;58:851-864; Jin HJ, et al. Front Med (Lausanne). 2020;7:339-346; Mease PJ, Armstrong AW. Drugs. 2014;74:423-441; Wallace KL, et al. J Rheumatol. 2004;31:1582-1587.

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Progression of Joint Damage in Subgroups

• f Early RA

Radiographic Joint Damage Score Time (Years)

Anti-CCP– Anti-CCP+

Key Biomarker in RA: Anti-CCP

Van der Helm-van Mil AH, et al. Arthritis Res Ther. 2005;7:R949-R958. 2 4 10 20 30 40

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Case Study (cont’d): Cameron’s Lab and Imaging Results

• ANA: 1:60 (positive)
• Anti-CCP: >250 U/mL (positive)
• CRP: 20.5 mg/L (positive)
• ESR: 48 mm/hr (positive)
• RF: 87 U/mL (positive)
• Uric acid: 4.5 mg/dL (normal)
• X-rays of hands and feet: normal

ANA = antinuclear antibodies; ESR = erythrocyte sedimentation rate.

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Case Study (cont’d): Next Steps

• Rheumatologist performs a full workup and concludes that Cameron has early,

moderately active RA

• Rheumatologist discusses with Cameron the advantages of treating RA

aggressively to achieve clinical remission (or at least low disease activity [LDA])

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Treatment Strategy for RA: Treat-to-Target Task Force Algorithm

Active RA

Clinical remission (eg, DAS) Clinical sustained remission

LDA Sustained LDA MAIN TARGET ALTERNATIVE TARGET

• Measure disease

activity about every 1-3 months

• Adapt therapy

accordingly

• Measure disease

activity about every 3-6 months

• Adapt therapy if

state is lost

DAS = disease activity score. Task Force definitions: active RA = DAS44 score >2.4; remission = absence of signs and symptoms of significant inflammatory disease activity; sustained remission = remission sustained for 3-6 months; LDA = DAS44 score ≥1.6 to ≤2.4; sustained LDA = LDA sustained for 3-6 months. Adapted from: Smolen JS, et al. Ann Rheum Dis. 2010;69:631-637. Grigor C, et al. Lancet. 2004;364:263-269.

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Criteria for Clinical Remission

*Patient Global Assessment = patient self-reporting questionnaire. ACR = American College of Rheumatology; EULAR = European League Against Rheumatism; SDAI = Simplified Disease Activity Index. Felson DT, et al. Ann Rheum Dis. 2011;70:404-413.

• Definition: absence of signs and symptoms of significant inflammatory

disease activity

• According to ACR and EULAR, remission is

achieved when: ‒ Tender joint count, swollen joint count, CRP level (in mg/L), and Patient Global Assessment* (on a scale of 0-10 cm) are all ≤1; or ‒ SDAI score is ≤3.3

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• MTX is the anchor drug

for treatment of RA

ACR Guideline for Early RA: How it Applies to Cameron

Combination traditional DMARDs or TNFi +/- MTX or non-TNF biologic +/- MTX See established RA algorithm

Treat to target

Moderate or high disease activity Low disease activity DMARD monotherapy DMARD monotherapy Moderate or high disease activity Moderate or high disease activity

Strong recommendation Conditional recommendation

Cameron

DMARD-naïve early RA

MTX = methotrexate; TNFi = tumor necrosis factor inhibitor. Singh JA, et al. Arthritis Care Res (Hoboken). 2016;68:1-25.

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Case Study (cont’d): Cameron’s Management Plan

• Cameron is prescribed MTX (20 mg/week orally) and folic acid
• She is counseled on:

‒ Need for reliable contraception ‒ No alcohol within 24 hours of MTX dose ‒ Smoking cessation ‒ Diet and exercise to reduce weight

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Case Study (cont’d): 3-month Follow-up

• Cameron complains that she’s had only minimal improvement in

symptoms and that she has some nausea, vomiting, and hair loss from the MTX

• Other findings

‒ Has reduced alcohol intake as instructed ‒ Has lost 5 lbs ‒ Hasn’t stopped smoking ‒ Still has 2 swollen MCP joints and knee pain

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• MTX is the anchor drug

for treatment of RA

ACR Guideline for Early RA: Where Cameron Is Now

Strong recommendation Conditional recommendation

Cameron

Singh JA, et al. Arthritis Care Res (Hoboken). 2016;68:1-25.

Combination traditional DMARDs or TNFi +/- MTX or non-TNF biologic +/- MTX See established RA algorithm

Treat to target

Moderate or high disease activity Low disease activity DMARD monotherapy DMARD monotherapy Moderate or high disease activity Moderate or high disease activity

DMARD-naïve early RA

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*Contraindicated prior to and during pregnancy and breastfeeding, as well as in patients with active bacterial infection, active herpes zoster virus infection, active or latent tuberculosis, or acute or chronic hepatitis B or C. AE = adverse event. Hydroxychloroquine [prescribing information]. Sanofi-Aventis; 2019; Minocycline [prescribing information]. Medicis; 2011; Rigby WF, et al. Int J

• Rheumatol. 2017:9614241; Saag KG, et al. Arthritis Rheum. 2008;59:762-784; Singh JA, et al. Arthritis Care Res (Hoboken). 2012;64:625-639;

Singh JA, et al. Arthritis Care Res. 2016;68:1-25; van Vollenhoven RF. Nat Rev Rheumatol. 2009;5:531-541.

Conventional Synthetic DMARDs for RA

Agent Risks and AEs Routine Laboratory Monitoring Hydroxychloroquine Nausea, vomiting, diarrhea, rash/hyperpigmentation, cytopenia, myopathy, cardiac dysrhythmias, retinopathy None Leflunomide* Hypertension, hepatotoxicity, myelotoxicity, severe diarrhea Complete blood count, liver transaminase levels, serum creatinine Methotrexate* Hepatotoxicity, fibrosing alveolitis, myelotoxicity,

• pportunistic infection, teratogenicity, nausea, vomiting

Minocycline Nausea, vomiting, diarrhea, dyspepsia, dizziness, skin rash, teratogenicity Sulfasalazine Hepatotoxicity, hypersensitivity reactions, myelotoxicity, reversible male infertility

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aContraindicated in patients with active bacterial infection, active herpes zoster virus infection, active or latent tuberculosis, or acute or chronic hepatitis B or C. bLive vaccines should be avoided in patients currently taking immunosuppressive agents or likely to start immunosuppressive therapy within 6 to 12 weeks.

ABA = abatacept; ADA = adalimumab; CTZ = certolizumab pegol; ETN = etanercept; GLM = golimumab; IFX = infliximab; RTX = rituximab. Furst DE, et al. Ann Rheum Dis. 2012;71(Suppl 2):i2-i45; Saag KG, et al. Arthritis Rheum. 2008;59:762-784; Singh JA, et al. Arthritis Care Res (Hoboken). 2012;64:625-639; van Vollenhoven RF. Nat Rev Rheumatol. 2009;5:531-541.

Agenta,b Risks and AEs Routine Laboratory Monitoring TNF blockade Adalimumab Certolizumab pegol Etanercept Golimumab Infliximab Injection site reactions, infections, exacerbation or new onset demyelinating disease, worsening or new onset heart failure, lymphoma, melanoma ADA: None CTZ: None ETN: None GLM and IFX: Liver enzymes, neutrophils and/or platelets, serum creatinine T-cell costimulation blockade Abatacept Infusion reactions, infections ABA: None B-cell depletion Rituximab Infusion reactions, infections RTX: Liver enzymes, neutrophils and/or platelets, serum creatinine

Biologic and Targeted Synthetic DMARDs for RA

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aContraindicated in patients with active bacterial infection, active herpes zoster virus infection, active or latent tuberculosis, or acute or chronic hepatitis B or C. bLive vaccines should be avoided in patients currently taking immunosuppressive agents or likely to start immunosuppressive therapy within 6 to12 weeks.

BCB = baricitinib; SRB = sarilumab; TCZ = tocilizumab; TOF = tofacitinib; UPA = upadacitinib; URI = upper respiratory infection. Baricitinib [prescribing information]. Lilly USA; 2019; Furst DE, et al. Ann Rheum Dis. 2012;71(Suppl 2):i2-i45; Saag KG, et al. Arthritis Rheum. 2008;59:762-784; Sarilumab [prescribing information]. Sanofi-Aventis; 2018; Singh JA, et al. Arthritis Care Res (Hoboken). 2012;64:625-639; Upadacitinib [prescribing information]. AbbVie Ireland NL BV; 2019; van Vollenhoven RF. Nat Rev Rheumatol. 2009;5:531-541.

Agenta,b Risks and AEs Routine Laboratory Monitoring IL-6 receptor blockade Sarilumab Tocilizumab Infusion reactions, infections, neutropenia, reduced platelet counts, elevated liver enzymes, elevated lipids, GI tract perforation SRB: Liver enzymes, neutrophils and/or platelets; infection, tuberculosis TCZ: Lipids, liver enzymes, neutrophils and/or platelets JAK inhibition Baricitinib Tofacitinib Upadacitinib URIs, shingles, headache, diarrhea, nasopharyngitis, lymphoma, nonmelanoma skin cancer, GI tract perforation, lipid abnormalities BCB: Infection, tuberculosis, hepatitis B TOF: Lipids, liver enzymes, neutrophils and/or platelets UPA: Lipids, liver enzymes, neutrophils, hemoglobin, lymphocytes IL-1 receptor blockade Anakinra Injection site reactions, infections, neutropenia None

Biologic and Targeted Synthetic DMARDs for RA (cont’d)

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Case Study (cont’d): After 6 Months, Cameron’s RA Remains Moderately Active

• At Cameron’s last visit to the rheumatologist, the rheumatologist:

⎻ Switched her from oral to SC MTX to address her nausea and vomiting ⎻ Added the TNF inhibitor adalimumab ⎻ Continued folic acid; added folinic acid weekly

• Cameron still hasn’t quit smoking
• Continues to work on losing weight with diet and exercise
• Now, after 3 months of SC MTX + adalimumab therapy, Cameron:

⎻ Has morning stiffness and pain that impair her ability to work ⎻ Feels fatigued ⎻ Has problems tolerating MTX, even in SC form

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Case Study (cont’d): Adjusting Treatment

• To reach the target of clinical remission for Cameron, the rheumatologist:

‒ Discontinues adalimumab and MTX ‒ Switches her to the IL-6 inhibitor sarilumab

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• Frequent disease activity

assessments (1-3 months for active disease) recommended to assess treatment response

• If no improvement by 3 months or

target has not been reached by 6 months, treatment adjustment is warranted

Adjusting Treatment to Achieve the Therapeutic Target

Singh JA, et al. Arthritis Care Res (Hoboken). 2012;64:625-639; Smolen JS, et al. Ann Rheum Dis. 2010;69:631-637; Smolen JS, et al. Ann Rheum Dis. 2017;76:960-977. Active RA Clinical remission (eg, DAS) Clinical sustained remission LDA Sustained LDA MAIN TARGET ALTERNATIVE TARGET

• Measure disease

activity about every 1-3 months

• Adapt therapy

accordingly

• Measure disease

activity about every 3-6 months

• Adapt therapy if

state is lost

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JAK Inhibitors (Targeted Synthetic DMARDs) in Treatment

• f Moderate to Severe RA
• Tofacitinib

‒ For patients with an inadequate response to MTX ‒ Do not use with biologic DMARDs or potent immunosuppressants

• Baricitinib

‒ For patients with inadequate response to ≥1 TNF inhibitor(s) ‒ Do not use with other JAK inhibitors, biologic DMARDs, or potent immunosuppressants (eg, azathioprine, cyclosporine)

• Upadacitinib (most recently approved DMARD for RA)

‒ For patients with inadequate response to or intolerance of MTX ‒ Do not use with other JAK inhibitors, biologic DMARDs, or potent immunosuppressants

Olumiant [prescribing information]. Lilly USA; 2019; Rinvoq [prescribing information]. AbbVie: 2019; Xeljanz [prescribing information].Pfizer; 2019.

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Some Emerging Treatments for Moderate to Severe RA

• Filgotinib (phase 3)

‒ JAK1 selective inhibitor

• Otilimab (phase 3)

‒ Granulocyte-macrophage colony stimulating factor (GM-CSF) inhibitor

ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT03025308?term=NCT03025308&draw=2&rank=1. Accessed October 19, 2020; ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT04333147?term=otilimab&draw=2&rank=2. Accessed October 19, 2020.

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Responsibilities of Primary Care Clinicians as Part of a Multidisciplinary Team in RA

• Symptom management
• Monitor for comorbidities and

extra-articular manifestations

• AE monitoring
• Smoking cessation counseling
• Nutrition and weight management
• Referrals as needed to:

– Rheumatology – Cardiology – Occupational therapy – Physical therapy – Psychiatry – Pulmonary

• Pregnancy counseling

Hill J, et al. Musculoskeletal Care. 2003;1:5-20; Hooker RS, et al. Health Soc Care Community. 2012;20:20-31; Solomon DH, et al. Arthritis Care Res (Hoboken). 2014;66:1108-1113.

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Don’t Neglect CVD Risk in Patients With RA

Agca R, et al. Ann Rheum Disease. 2017;76:17-28; Chodara AM, Curr Rheumatol Rep. 2017;19:16; Peters MJ, et al. Ann Rheum Dis. 2010;69:325-331.

• RA is an independent risk factor for CVD
• Patients with RA have an increased risk of CVD and a 50% to 70% greater risk
• f heart disease compared to the general population
• EULAR recommendations for CVD risk management in RA

‒ Assess CVD risk regularly ‒ Include total cholesterol and high-density lipoprotein cholesterol as part of risk assessment ‒ Measure lipids when disease activity is stable or in remission ‒ Consider screening for asymptomatic atherosclerotic plaques with carotid ultrasound

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Extra-Articular Manifestations and Common Comorbidities in RA

• RA is a systemic disease with sequelae

beyond joint damage

• Extra-articular manifestations include:

‒ CVD ‒ Myopathies ‒ Neuropathies ‒ Nodules ‒ Ocular inflammation ‒ Osteopenia/osteoporosis ‒ Pulmonary disease

Atzeni F, et al. Autoimmun Rev. 2013;12:575-579; Avina-Zubieta JA, et al. Arthritis Rheum. 2008;59:1690-1697; Cutolo M, et al. Semin Arthritis

• Rheum. 2014;43:479-488; Furst DE, et al. Ann Rheum Dis. 2012;71(Suppl 2):i2-i45; Klodzinski T, et al. Reumatologia. 2018;56:288-233; Makol

A, et al. Rheum Dis Clin North Am. 2012;38:771-793; Primdahl J, et al. Ann Rheum Dis. 2013;72:1771-1776; Singh JA, et al. Arthritis Care Res (Hoboken). 2016;68:1-25; Young A, Koduri G. Best Pract Res Clin Rheumatol. 2007;21:907-927.

• Comorbidities include:

‒ CV, lung, and kidney diseases ‒ Depression ‒ GI disorders ‒ Infections ‒ Malignancies

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• Older male patient with moderately

severe interstitial lung disease (ILD), primarily involving the mid- and lower lung fields

• Most common form of ILD in RA is

interstitial pneumonitis

Rheumatoid Lung in an Elderly Man

Image courtesy of Lester Miller, MD.

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• Scleritis in an older woman with

long-standing RA

• Inflammation causes the sclera to

become thinner and translucent

• Result is the sclera having a bluish

hue from the underlying choroid layer of the eye

Ocular Scleritis in RA

Image courtesy of Lester Miller, MD.

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Vaccine Considerations in RA

Live vaccines to be avoided when using biologics

• Herpes zoster (shingles) [Zostavax only]*
• Live attenuated viral/intranasal spray for influenza
• Adenovirus
• Cholera
• Measles, mumps, rubella
• Measles, mumps, rubella, varicella
• Rotavirus
• Typhoid (live attenuated bacterial oral)
• Varicella
• Vaccinia (smallpox)
• Yellow fever

Important points to remember

• Inactivated influenza and pneumococcal

vaccines are strongly recommended and are safe, but therapeutic response may be reduced

• If a live vaccine is indicated, administer 4

weeks before starting therapy

• Routine immunizations should be up to

date before travel

*Shingrix is an inactivated recombinant, adjuvanted (non-live) vaccine for herpes zoster. Centers for Disease Control and Prevention. www.cdc.gov/vaccines/pubs/pinkbook/downloads/appendices/appdx-full-b.pdf. Accessed October 19, 2020; Wine-Lee L, et al. J Am Acad Dermatol. 2013;69:1003-1013.

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Coordinating Multidisciplinary Treatment Teams

Taal E, et al. Clin Rheumatol. 2006;25:189-197.

• Develop relationships with at least

1 or 2 rheumatologists to facilitate timely referrals

• Multidisciplinary teams do not have

to practice together in the same building or setting

RA PATIENT Rheumatology Specialty Care

Primary Care Clinician Cardiology Pulmonology Physical Therapy Psychology Orthopedics Social Work

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ACR: RA Treatment Recommendations in the Context of COVID-19

CQ = chloroquine; HCQ = hydroxychloroquine; LEF = leflunomide; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SSZ = sulfasalazine. Mikuls TR, et al. Arthritis Rheum. 2020;72:e1-e12.

• Patients exposed to SARS-CoV-2

‒ HCQ/CQ, SSZ, NSAIDs may be continued ‒ Temporarily halt pending negative test for COVID-19 or 2 weeks of symptom-free

• bservation:
• Biologics

– TNFi’s, abatacept, anakinra, rituximab

• JAK inhibitors

‒ IL-6 inhibitors may be continued in select circumstances, as part of a shared decision-making process

• Patients with documented or presumptive

COVID-19 ‒ Regardless of COVID-19 severity, HCQ/CQ may be continued ‒ SSZ, MTX, LEF, biologics, and JAK inhibitors should be stopped ‒ If severe respiratory symptoms, NSAIDs should be stopped ‒ IL-6 inhibitors may be continued in select circumstances, as part of a shared decision-making process

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Case Conclusion

• Cameron’s PCR test for COVID-19 was negative, and she did not develop symptoms
• She achieved clinical remission 3 months after switching to sarilumab monotherapy
• She finally quit smoking
• Lost 15 lbs by increasing exercise and reducing calorie intake
• Multidisciplinary team will continue to monitor her RA disease activity and quality of

life, assess for any radiologic changes, and follow for AEs, extra-articular manifestations, and comorbidities

PCR = polymerase chain reaction.

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PCE Action Plan

✓ Discuss with patients that the goal is to achieve clinical remission ✓ Adjust treatment if the therapeutic target has not been achieved in 6 months ✓ Consider RA as an independent risk factor for CVD ✓ Identify members of your expanded care team and promote collaborative care PCE Promotes Practice Change