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CE: Pharmacist Continuing Education: 2021 Rheumatoid Arthritis Guideline Update and Therapy Review

17 Nov 2021 11:53 AM | Anonymous

Program Number:   2021-10-02
Approved Dates:    December 1, 2021-June 1, 2022
Approved Contact Hours:  One Hour(s) (1) CE(s) per session

Pharmacist Continuing Education: 2021 Rheumatoid Arthritis Guideline Update and Therapy Review Authors: Annie Ungerman, PharmD, BCPS, University Health - Kansas City, MO and Mary Beth Seipel, PharmD, BCACP, University Health - Kansas City, MO

 

Learning Objectives:

  1. Describe physical exam and laboratory findings that are common in those diagnosed with rheumatoid arthritis.
  2. Recognize initial treatment strategies for rheumatoid arthritis.
  3. Interpret levels of disease activity of the different instruments available to measure.
  4. Identify different therapies available used in treating rheumatoid arthritis and important monitoring parameters.
  5. Distinguish how special populations require alterations in treatment plans.

What is Rheumatoid Arthritis?

Rheumatoid arthritis (RA) is an autoimmune disorder with unknown etiology that is commonly characterized by chronic inflammation, severe pain, joint stiffness, fatigue, and limited mobility.1,2 RA usually leads to destruction of joints due to erosion of cartilage and bone, which may cause joint deformities. Onset can occur at any time, but incidence increases with age. Women are more likely to be diagnosed than men are (by two-to-three times). Other characteristics that are more common in those developing rheumatoid arthritis are women who have never given birth, cigarette smoking, and obesity.1,2 Early evaluation, diagnosis, and management are imperative in achieving adequate control of disease and prevention of further progression.3  

Early evaluation for suspected RA1

Diagnosis of RA often relies on a detailed past medical history, thorough physical examination, pertinent laboratory tests, and radiographic evidence consistent with joint damage. Radiographs of the hands, wrists, and feet are frequently used as a baseline for monitoring disease activity or progression.

Pertinent information to collect and examine may include, but is not limited to the following: 

  • Distribution of swollen or tender joints
  • Location & severity of joint pain/swelling
  • Duration of morning stiffness
  • Range of motion for affected joints
  • Length of symptoms

The following laboratory tests should be considered and may support a diagnosis of RA if positive and/or elevated:

  • Rheumatoid factor (RF)
    • Abnormal level: >14 IU/mL
  • Anti-citrullinated peptide antibodies (ACPA) 
    • Abnormal level: >20 EU/mL
  • Erythrocyte sedimentation rate (ESR) 
    • Abnormal level: >20 mm/hr
  • Serum C-reactive protein (CRP)
    • Mild inflammation: 1-5 mg/dL
    • Severe inflammation: >5-10 mg/dL
    • Serious processes/bacterial infection: >10 mg/dL

Diagnosis of RA4

Based on the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Classification criteria for RA (as described below), classification of “definite RA” is outlined as:

  • Presence of synovitis (swelling) in ≥ 1 joint
  • Lack of an alternative diagnosis that better explains the synovitis
  • Score of ≥6/10 (based on the criteria presented in Table 1 below)

Management of RA3

Pharmacological treatment of RA involves the following:

  • Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)
  • Biologic disease-modifying antirheumatic drugs (bDMARDs)
  • Targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs)
  • Glucocorticoids

A treat-to-target approach is recommended for individuals who have not been previously treated with or have experienced an inadequate response to bDMARDs or tsDMARDs. This approach involves frequent monitoring of disease activity levels through the use of validated instruments. Modifications to an individual’s treatment are implemented based on response to prescribed therapy, which is determined by a reduction in disease activity. The overall goal of pharmacological treatment is to achieve a predefined target of low disease activity or remission. It is recommended to reevaluate treatment decisions within a minimum of 3 months based on efficacy and tolerability of prescribed DMARDs.3

Instruments to measure RA disease activity are recommended by the ACR for use to further define levels of disease activity (low, moderate, high) based on a variety of factors, including patient-reported symptoms, provider assessments, laboratory values, and/or imaging modalities.5 Table 2 shares details regarding thresholds of disease activity based on the tool used. The DAS28, CDAI, and SDAI all require a 28 count of specific joints, stating if they are tender and/or swollen joints. They vary in whether they incorporate an inflammatory marker or patient/provider rating of global health. Both the RAPID-3 and PAS II have similar questions on patient reported ability in being able to carry out 10 different tasks, a pain assessment, and/or a personal assessment.6-10


Moderate-to-high disease activity:

In patients that have moderate-to-high disease activity and are DMARD naive, methotrexate is strongly recommended over hydroxychloroquine or sulfasalazine and bDMARDs or tsDMARD monotherapy. In this same patient population, methotrexate is conditionally recommended over leflunomide, dual or triple csDMARD therapy, or combination of methotrexate plus a TNF inhibitor.Methotrexate is recommended in this patient population due to its established efficacy and low cost. When initiating methotrexate, the oral formulation is preferred over subcutaneous as bioavailability is comparable at initial dosing and ease of use. If patients have issues tolerating oral methotrexate, management strategies include dividing the weekly dose over 24 hours, switching to a subcutaneous route of administration, or increasing folic acid dosing. These are all recommended over switching to an alternative DMARD.3 

Glucocorticoids:

The use of glucocorticoids for patients with moderate-to-high disease activity during initiation of csDMARD therapy for short-term (<3 months) or long-term (≥3 months) use is not recommended as the risks of toxicity outweigh the benefits. If a patient is unable to remain at target without glucocorticoids, it is conditionally recommended to add or switch DMARDs.3 

Low disease activity:

In patients with low disease activity and are DMARD naive, hydroxychloroquine is conditionally recommended over any other csDMARDs, sulfasalazine is conditionally recommended over methotrexate, and methotrexate is conditionally recommended over leflunomide.3 

Pharmacological Treatment:

DMARDs that were mentioned in the guidelines as treatment options for rheumatoid arthritis are listed in tables 3, 4 and 5. Typical dosing, adjustments and additional information are shared below.

TABLE 4: (download the PDF)


Recommendations for specific patient populations:

The 2021 RA guidelines address management of RA in individuals with specific comorbidities. Certain populations are discussed for the first time, including those with subcutaneous nodules, non-alcoholic fatty liver disease, and pulmonary disease.3

Subcutaneous nodules

Methotrexate is conditionally recommended over alternative DMARDs if subcutaneous nodules are present in an individual with moderate-to-high disease activity. However, in the presence of progressive subcutaneous nodules, switching to an alternative DMARD is conditionally recommended because methotrexate may be associated with accelerated nodulosis.3, 27 

Pulmonary disease

If moderate-to-high disease activity is present, methotrexate is conditionally recommended over alternative DMARDs for individuals with clinically diagnosed mild and stable airway or parenchymal lung disease, or incidental disease detected on imaging.3 Preexisting lung disease is a risk factor for methotrexate-related pneumonitis.28,29 However, its use remains conditionally recommended due to its efficacy and lack of alternatives with similar benefits or superior long-term safety profiles. Those with preexisting lung disease should be educated on their increased risk of methotrexate-related pneumonitis before starting treatment.3

Heart failure (HF)

Risk of worsened HF was observed in trials of TNF inhibitors given to individuals with New York Heart Association class III or IV HF without RA.30,31 The low quality of evidence available resulted in the conditional recommendations to follow. If an individual with NYHA class III or IV HF has an inadequate response to csDMARDs, addition of a non-TNF inhibitor bDMARD or tsDMARD is conditionally recommended over addition of a TNF inhibitor. Additionally, if an individual develops HF while taking a TNF inhibitor, switching to a non-TNF inhibitor bDMARD or tsDMARD is conditionally recommended.3

Lymphoproliferative disorder

For individuals with moderate-to-high disease activity and history of a previous lymphoproliferative disorder, rituximab is conditionally recommended over other DMARDs because it is not expected to increase risk of recurrence or worsening of these disorders.3

Hepatitis B infection

Those at risk for hepatitis B reactivation should be comanaged with a hepatologist. Prophylactic antiviral therapy is strongly recommended over frequent monitoring of viral load and liver enzymes alone for individuals starting rituximab who are hepatitis B core antibody positive, regardless of hepatitis B surface antigen status. If an individual is hepatitis B core antibody positive and hepatitis B surface antigen positive, prophylactic antiviral therapy is strongly recommended over frequent monitoring alone when initiating any bDMARD or tsDMARD. Due to uncertainty regarding benefit versus risk of prophylactic antiviral therapy and cost associated with use, frequent monitoring alone is conditionally recommended for individuals starting a bDMARD (other than rituximab) or a tsDMARD who are hepatitis B core antibody positive and hepatitis B surface antigen negative.3 

Nonalcoholic fatty liver disease (NAFLD)

For DMARD-naive individuals with moderate-to-high disease activity and NAFLD with normal liver enzymes, liver function tests, and no evidence of advanced liver fibrosis, methotrexate is conditionally recommended over alternative DMARDs. Consultation with a gastroenterologist or hepatologist should be considered prior to initiating methotrexate in individuals with NAFLD.3 

Persistent hypogammaglobulinemia without infection

The clinical significance of hypogammaglobulinemia in individuals without infection remains unknown. Continuation of rituximab for individuals at target is conditionally recommended over switching to an alternative bDMARD or tsDMARD in the setting of persistent hypogammaglobulinemia without infection. It is uncertain if switching to a different DMARD in those who are at target reduces infection risk to a larger degree while maintaining disease control versus continuation of rituximab.3  

Previous serious infection

The 2021 guidelines define a serious infection as an infection requiring intravenous antibiotics or hospitalization. Addition of csDMARDs is conditionally recommended versus bDMARD or tsDMARD for individuals with moderate-to-high disease activity who have experienced a serious infection within the past 12 months.3 This conditional recommendation is based on observational data, which suggests a lower risk of infection associated with combination csDMARDs compared to bDMARDs or tsDMARDs.32 

Nontuberculous mycobacterial (NTM) lung disease

Due to the variability of NTM lung disease severity and response to treatment, individuals should be closely comanaged with an infectious diseases or pulmonary specialist. Studies suggest an increased risk of NTM lung disease in individuals receiving inhaled or oral glucocorticoids.33,34 Therefore, discontinuation or use of the lowest possible dose of glucocorticoids is conditionally recommended for those with NTM lung disease.3 Due to lower expected risk of NTM lung disease, addition of csDMARDs is conditionally recommended versus bDMARD or tsDMARD for individuals with moderate-to-high disease activity.35 For individuals with NTM lung disease and moderate-to-high disease activity despite use of csDMARDs, abatacept is conditionally recommended over other bDMARDs and tsDMARDs.3 

Key takeaways and future considerations:

  1. Methotrexate is recommended as monotherapy for most individuals over other DMARDs and should generally be initiated first in those with moderate to high disease activity.3 
  1. Maximize the methotrexate dose prior to adding or switching medications. If an individual is not at target when prescribed oral methotrexate, changing to a subcutaneous route of administration should be considered versus switching to or adding a different DMARD.3
  1. If an individual has low disease activity, use of hydroxychloroquine over other csDMARDs (including methotrexate) is conditionally recommended due to a more favorable side effect profile.3 
  1. Minimize use of glucocorticoids if and when possible. Initiation of a csDMARD without prescribing a short-term course of glucocorticoids is conditionally recommended in those with moderate-to-high disease activity who have not previously taken a DMARD.3 
  1. New and updated recommendations for RA treatment in special populations may help inform clinical decisions.3 
  1. The 2021 RA guidelines are not a comprehensive compilation of current recommendations regarding RA management. Previous guidelines provide additional guidance on information such as pre-treatment screening and routine laboratory monitoring.36-38 
  1. Future guidelines will address approaches to non-pharmacologic treatment and vaccine use.3 

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References: 

  1. CDC. Rheumatoid arthritis (RA). www.cdc.gov/arthritis/basics/rheumatoid-arthritis.html. Accessed October 4, 2021.
  2. Kohler BM, Gunther J, Kaudewitz D, Lorenz HM. Current therapeutic options in the treatment of rheumatoid arthritis. J Clin Med. 2019;8(7):938.
  3. Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guidelines for the treatment of rheumatoid arthritis. Arthritis Care and Res. 2021;73(7):924-939.
  4. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010 Sep;62(9):2569-81.
  5. England BR, Tiong BK, Bergman MJ, et al. 2019 Update of the American College of Rheumatology recommended rheumatoid arthritis disease activity measures. Arthritis Care Res (Hoboken). 2019;71:1540–55.
  6. Fransen J, Stucki G, van Riel P. Rheumatoid arthritis measures: Disease Activity Score (DAS), Disease Activity Score-28 (DAS28), Rapid Assessment of Disease Activity in Rheumatology (RADAR), and Rheumatoid Arthritis Disease Activity Index (RADAI). Arthritis Rheum. 2003;49 Suppl:S214–24.
  7. Aletaha D, Nell VP, Stamm T, et al. Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score. Arthritis Res Ther. 2005;7:R796–806.
  8. Smolen JS, Breedveld FC, Schiff MH, et al. A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology (Oxford) 2003;42:244–57.
  9. Pincus T, Yazici Y, Bergman M. A practical guide to scoring a Multi-Dimensional Health Assessment Questionnaire (MDHAQ) and Routine Assessment of Patient Index Data (RAPID) scores in 10–20 seconds for use in standard clinical care, without rulers, calculators, websites or computers. Best Pract Res Clin Rheumatol. 2007;21:755–87.
  10. Wolfe F, Michaud K, Pincus T. A composite disease activity scale for clinical practice, observational studies, and clinical trials: the patient activity scale (PAS/PAS-II). J Rheumatol 2005;32:2410–5.
  11. Leflunomide. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
  12. Methotrexate. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
  13. Hydroxychloroquine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
  14. Sulfasalazine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
  15. Entanercept. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
  16. Adalimumab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
  17. Certolizumab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
  18. Golimumab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
  19. Infliximab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
  20. Abatacept. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
  21. Tocilizumab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
  22. Sarilumab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
  23. Rituximab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
  24. Tofacitinib. Rituximab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
  25. Baricitinib. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
  26. Upadacitinib. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
  27. Patatanian E, Thompson DF. A review of methotrexate-induced accelerated nodulosis. Pharmacotherapy. 2002;22:1157–62.
  28. Alarcon GS, Kremer JM, Macaluso M, et al. Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis: a multicenter, case-control study. Ann Intern Med. 1997;127:356–64. 
  29. Bartram SA. Experience with methotrexate-associated pneumonitis in northeastern England: comment on the article by Kremer et al [letter]. Arthritis Rheum. 1998;41:1327–8.
  30. Chung ES, Packer M, Lo KH, et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation. 2003;107:3133–40. 
  31. Mann DL, McMurray JJ, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation. 2004;109:1594–602.
  32. Ozen G, Pedro S, England BR, Mehta B, Wolfe F, Michaud K. Risk of serious infection in patients with rheumatoid arthritis treated with biologic versus nonbiologic disease-modifying antirheumatic drugs. ACR Open Rheumatol. 2019;1:424–32.
  33. Liu VX, Winthrop KL, Lu Y, et al. Association between inhaled corticosteroid use and pulmonary nontuberculous mycobacterial infection. Ann Am Thorac Soc. 2018;15:1169–76. 
  34. Liao TL, Lin CF, Chen YM, et al. Risk factors and outcomes of nontuberculous mycobacterial disease among rheumatoid arthritis patients: a case-control study in a TB endemic area. Sci Rep. 2016;6:29443.
  35. Brode SK, Jamieson FB, Ng R, Campitelli MA, Kwong JC,  et al. Increased risk of mycobacterial infections associated with anti-rheumatic medications. Thorax. 2015;70:677–82.
  36. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68:1–26.
  37. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59:762–84.
  38. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64:625–39.


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