Rheumatoid Arthritis

Educational Objectives

The goal of this program is to improve management of rheumatoid arthritis (RA) and foot and ankle injuries. After hearing and assimilating this program, the clinician will be better able to:

1. Recognize patients at risk for RA.
2. Perform appropriate laboratory and imaging studies to assess for RA.
3. Select effective first-line therapies for treatment of RA.

Summary

Rheumatoid arthritis (RA): systemic autoimmune disease; almost always includes synovial manifestations (though not always first manifestation); causes osteoclast activation, increased fracture risk, and erosions; associated with doubling of cardiovascular risk (important to control cholesterol and other risk factors); ≈50% of RA patients have some lung disease; increased risk for influenza, pneumonia, and herpes zoster reactivation

Epidemiology: in United States, prevalence ≈1%; 2:1 female predominance; incidence varies by ethnicity (eg, significantly higher in Native Americans [most notably Pima]); reduces life expectancy by up to 10 yr; associated with ≈50% increased risk for premature mortality; vanishingly rare in Nigerian populations

Phases of RA: 1) certain genetic mutations associated with ≥4-fold increased risk for RA; 2) asymptomatic autoimmunity and inflammation; localized autoimmune response that spreads; 3) early symptoms (eg, articular disease, arthralgias, stiffness); 4) full-blown inflammatory arthritis with synovitis and joint destruction; systemic extra-articular manifestations (eg, lung disease) can occur without synovitis (rare); deformities occur only with significant inflammatory arthritis

Risk factors: shared epitope (SE) — particular genetic mutation that occurs in HLA-DRB1 locus; frequency in Europeans ≈17% (≈6% in blacks); not all individuals with SE develop RA; many other genetic associations seen in RA, but SE associated with 95% of disease risk; tobacco smoking — strong interaction between genetic risk and smoking; heavy smokers without SE have ≈4-fold increased risk for RA (≈10-fold increased risk with one copy of SE, and 77-fold increased risk with 2 copies of SE sand heavy smoking); patients who develop RA should stop smoking; smokers with SE represent >75% of new cases of RA

RA and periodontal disease: patients with RA at ≈2-fold increased risk of being edentulous or having periodontal disease; established RA patients much more likely to have periodontitis; Porphyromonas gingivalis expresses enzyme that converts particular side chains on proteins to citrulline; anticitrullinated peptide antibodies (ACPAs; newer antibodies much more specific for RA) expressed locally in periodontal tissues in patients with periodontal disease even without RA

RA and lung disease: cigarette smoking induces enzymes that produce citrullinated peptides; good evidence of localized production of rheumatoid factor (RF) and cyclic citrullinated protein (CCP) antibodies in lung tissue

Pathogenesis of RA: antigen-presenting cells no longer respond properly; present bacterial antigens; interact with autoreactive T cells, resulting in production of cytokines, interactions with other cells (eg, localized B cells, dendritic cells), and greater production of RF and anti-CCP antibodies; can cause immune complex deposition and activation of other cells; activated osteocytes cause bone erosions and increased risk for fracture

Symptoms: based on American College of Rheumatology (ACR) classification criteria; synovitis — joint swelling or tenderness; not stable in early disease (ie, cycles below or above threshold for detection); patients with early RA may not have tenderness, so important to consider history of symmetrical morning stiffness; distinguishing RA from osteoarthritis (OA) — OA more common in distal interphalangeal (DIP) joints than in metacarpophalangeal (MCP) or proximal interphalangeal (PIP) joints; RA almost always symmetrical (though most patients report that symptoms started on dominant side); RA can involve hands, wrists, and large joints; metatarsophalangeal (MTP) joint tenderness not uncommon in early disease (progresses to ankle involvement); involvement of large joints part of ACR criteria, but usually does not occur early (refer patients with unilateral inflammatory arthritis of large joints); criteria — score of ≥6 meets classification criteria; involvement of large and small joints; positive RF or positive CCP antibody; acute phase reactants (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]); duration of symptoms (cut-off of 6 wk)

Laboratory studies: RF — generic autoantibody; present in ≈80% of RA patients, and in many other conditions; associated with vasculitis and worse extra-articular disease in RA patients; CCP antibodies — specificity >90%; sensitivity 70% to 80% (predict worse joint disease); since many conditions cause positive RF, RA unlikely in patient with unilateral arthritis of large joint and positive RF; ≈4% of general population has positive RF (higher suspicion for RA needed, particularly if patient negative for CCP and positive for RF); autoantibodies predate disease in RA (patients may have positive autoantibody [eg, CCP] many years before disease); patients with positive CCP and no discernible arthritis highly likely to develop RA

Imaging studies: may not see changes on x-ray if RA detected before irreversible damage occurs; perform bilateral hand and foot x-rays; foot — first erosion usually in fifth MTP joint (in little toe); wrist — in RA, ulnar styloid typically first place erosion occurs; early erosion often missed; findings — significant narrowing of intercarpal joint space; carpal erosion; carpal collapse; MCP and PIP erosions in hands tend to be lateral (DIP erosion more common in ankylosing spondylitis); deformities (eg, swan neck and boutonniere) can occur later; erosions along all MTP joints progress from outside in; shoulder and knee erosions can be seen; in advanced RA, symmetrical narrowing of joint space more common than erosions in large joints; OA (particularly in knee) almost always occurs in medial side first, and not symmetrical

Treatment goals: treat aggressively; generally start patients on triple therapy, with or without steroids or biologic agents (if difficult to control within 3-4 mo), then slowly taper (eg, etanercept [Enbrel] can be used every 2 wk, adalimumab [Humira] once per month); rare to stop disease-modifying antirheumatic drugs (DMARDs; patients usually on low dose) or biologic agents

Effect of tight control for RA (TICORA study, 2004): looked at whether patients with early RA should be treated with multiple drugs upfront (with or without biologic agents) with particular goal in mind (ie, disease activity score); found that patients on intensive, multiple therapy had better outcomes and did not develop erosions

Steroids: result in rapid improvement of inflammatory markers and synovitis; methylprednisolone (eg, Depoject, Depo-Medrol, Depopred-80) self-tapers over 2 to 3 wk; start with ≈40 mg of prednisone, then taper

Methotrexate: multiple studies show that up to one-third of RA patients on methotrexate monotherapy have low disease activity; biologic agents alone not more effective than methotrexate alone; no specific ACR guidelines about starting dosage (speaker uses 12.5 mg once weekly); risks (eg, elevated liver function tests [LFTs], cytopenia) rare; subcutaneous methotrexate — more predictable than oral formulation; less expensive ($18/mo vs $77/mo); not associated with gastrointestinal side effects; lower risk for LFT elevation; works faster; laboratory testing — baseline complete blood cell count, comprehensive metabolic panel, CRP, and liver function panel; repeat 2 to 4 wk after start of treatment, then once every 2 to 3 mo (if dose unchanged); repeat laboratory testing 2 to 3 wk after increasing dose; bioavailability of subcutaneous methotrexate higher than oral methotrexate, particularly at high doses (eg, 20 mg); in contrast to subcutaneous methotrexate, no additional benefits with increasing dose of oral methotrexate

Hydroxychloroquine (Plaquenil): safe; not immunosuppressive; does not require laboratory monitoring; takes ≥3 mo to see effects; use in combination triple therapy; ≈5 mg/kg (≥400 mg/day) needed; expensive (≈$200/mo); eye toxicity — guidelines recommend starting eye screening at 5 yr; use cautiously in patients with renal disease or patients on tamoxifen

Increased risks: fracture — perform baseline Fracture Risk Assessment Tool (FRAX); measure vitamin D level (>30 mg/dL adequate; supplement with high-dose vitamin D); viral infection — patients on methotrexate do not respond to pneumococcal vaccine (give baseline vaccine before starting treatment); consider zoster vaccine before starting biologic agents; yearly influenza vaccine important (avoid intranasal vaccine); lymphoma — associated with RA itself, rather than use of methotrexate or biologic agents

Perioperative medication management: do not hold therapy (eg, tumor necrosis factor inhibitors, DMARDs, biologic agents) during surgery

Referrals: inform rheumatologist about history of small joint arthritis (particularly if symmetrical) and morning stiffness lasting >1 hr; provide x-rays, laboratory studies (eg, baseline inflammatory markers), and history of response to steroids

Conclusion: have high suspicion for early RA; steroids can be used as first-line therapy (long-term use not recommended); start methotrexate early and monitor patients; check inflammatory markers (eg, anti-CCP)

Readings

Goodman SM: Rheumatoid arthritis: Perioperative management of biologics and DMARDs. Semin Arthritis Rheum. 2015 Jun;44(6):627-32; Goodman SM et al: Outcomes related to methotrexate dose and route of administration in patients with rheumatoid arthritis: a systematic literature review. Clin Exp Rheumatol. 2015 Mar-Apr;33(2):272-8; Grigor C et al: Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004 Jul 17-23;364(9430):263-9; Katsuyama T et al: Prophylaxis for Pneumocystis pneumonia in patients with rheumatoid arthritis treated with biologics, based on risk factors found in a retrospective study. Arthritis Res Ther. 2014 Feb 5;16(1):R43; Kerr G et al: Associations of hydroxychloroquine use with lipid profiles in rheumatoid arthritis: pharmacologic implications. Arthritis Care Res (Hoboken). 2014 Nov;66(11):1619-26; Koziel J et al: The link between periodontal disease and rheumatoid arthritis: an updated review. Curr Rheumatol Rep. 2014 Mar;16(3):408; Lee YH et al: Gene-environmental interaction between smoking and shared epitope on the development of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: a meta-analysis. Int J Rheum Dis. 2014 Jun;17(5):528-35; Moreland LW et al: TEAR Investigators. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum. 2012 Sep;64(9):2824-35; Rau R: Glucocorticoid treatment in rheumatoid arthritis. Expert Opin Pharmacother. 2014 Aug;15(11):1575-83; Yunt ZX, Solomon JJ: Lung disease in rheumatoid arthritis. Rheum Dis Clin North Am. 2015 May;41(2):225-36.

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose.

Acknowledgements

Dr. Jeffries was recorded in Midwest City, OK, at the 20th Annual Primary Care Update, presented May 2-6, 2017, by the University of Oklahoma College of Medicine, Irwin H. Brown Office of Continuing Professional Development, the Department of Family and Preventive Medicine, and the Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center. For more information about this sponsor, please visit https://www.facebook.com/pg/The-Irwin-H-Brown-Office-of-Continuing-Professional-Development. The Audio Digest Foundation thanks the speakers and the University of Oklahoma College of Medicine for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

FP653801

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.