RHEUMATOID ARTHRITIS: A SYSTEMIC AUTOIMMUNE INFLAMMATORY DISEASE
SALAM KADHIM, PhD
Salam Kadhim is a pharmaceutical scientist with experience in drug discovery and development of small molecule compounds, biologics, siRNA, and cannabinoids in the areas of oncology, HBV, cardiovascular, ocular, and neurodegenerative disorders.
Topic Overview
Rheumatoid arthritis is a systemic autoimmune disease associated with a chronic inflammatory process primarily affecting the lining of the synovial joints in the hands, wrists, and knees. It may also involve extra-articular organs, including the heart, kidney, lungs, digestive system, eye, skin, and nervous system. The disease is associated with progressive disability, premature death, and socioeconomic burdens significantly impacting patients’ quality of life. This course provides insights into the definition and classification of adult rheumatoid arthritis, its epidemiology, diagnosis, risk factors, and available pharmacotherapy. Gap analysis of the current treatment practices is compared to the best practices to identify areas of improvement. Patient counseling and future management approaches for adult rheumatoid arthritis are also reviewed.
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Pharmacist 0669-0000-23-210-H01-P
Pharmacy Technician 0669-0000-23-211-H01-T
Credits: 2 contact hours of continuing education credit
Type of Activity: Knowledge
Media: Internet/Home study Fee Information: $6.99
Estimated time to complete activity: 2 contact hours, including Course Test and course evaluation.
Release Date: December 11, 2023 Expiration Date: December 11, 2026
Target Audience: This educational activity is for pharmacists.
How to Earn Credit: From December 11, 2023, through December 11, 2026, participants must:
Read the “learning objectives” and “author and planning team disclosures;”
Study the section entitled “educational activity;” and
Complete the Course Test and Evaluation form. The Course Test will be graded automatically. Following successful completion of the Course Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)
Credit for this course will be uploaded to CPE Monitor®.
Learning Objectives: Upon completion of this educational activity, participants should be able to:
Provide insights into the definition and classification of rheumatoid arthritis (RA)
Describe the diagnosis, epidemiology, and risk factors of RA
Describe current medications in the treatment of RA
Discuss current challenges and future directions in the management of RA
Disclosures
The following individuals were involved in developing this activity: _Salam Kadhim, PhD, and Pamela Sardo, PharmD, BS. Salam Kadhim, PhD, has no conflicts of interest or relationships regarding the subject matter. Pamela Sardo, PharmD, BS, was an employee of Rhythm Pharmaceuticals until March 2022 and has no conflicts of interest or relationships regarding the subject matter discussed. There are no financial relationships relevant to this activity to report or disclose by any of the individuals involved in the development of this activity.
© RxCe.com LLC 2023: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.
Introduction
Rheumatoid arthritis is a progressive disease that leads to disability and premature death in afflicted patients. Rheumatoid arthritis places a significant burden on healthcare. This course provides insights into the definition and classification of adult rheumatoid arthritis, its epidemiology, diagnosis, risk factors, and available pharmacotherapy. Patient counseling and future management approaches for adult rheumatoid arthritis are also reviewed.
Rheumatoid Arthritis and Its Prevalence
Rheumatoid arthritis (RA) is a systemic autoimmune disease that is characterized by a chronic inflammatory process that affects large joints (i.e., ankles, hips, elbows, shoulders, and knees) and small joints in the hands, wrists, and knees.1 It may also involve extra-articular organs, including the heart, kidney, lungs, digestive system, eye, skin, and nervous system.1,2 The disease places a heavy socioeconomic burden on society and is associated with progressive disability and premature death, significantly impacting the patient’s quality of life.3
Rheumatoid arthritis affects an estimated 17.6 million people worldwide.4 Adult RA arises more frequently in females, being 2–3 times more likely in women than men. It is predominantly observed in the elderly, with the onset of RA usually occurring at age 60–70.4
The prevalence of RA has risen by 14.1% from 1990 to 2020.4 The prevalence of RA ranges from 0.5% to 1% of the general population, depending on gender, race/ethnicity, and regional variation.5–7 Female smokers and those with a family history of RA are often the most affected.8 The largest increase is observed in the Spanish population.1 In Japan and Argentina, the prevalence ratios have decreased over the years.1 Currently, the global prevalence ratio of RA is approximately at 1%, with small continuous fluctuations and an apparent growth from south to north and from countryside to metropolitan areas.8
Etiology of Rheumatoid Arthritis
The exact etiology of the disease is unknown; however, genetics, autoimmunity, and environmental factors play a role in the pathogenesis of RA.7,8 The outcome of these mechanisms is the overproduction of pro- inflammatory cytokines such as TNF-α, IL-1β, IL-6, IL-7, IL-15, IL-17, IL-18, IL-23, interferon (IFN)-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF) that influence inflammation in RA.9 These cytokines stimulate the proliferation of synovial cells in joints resulting in subsequent pannus formation, cartilage destruction, and bone erosions.8,10,11
Definition of Rheumatoid Arthritis
Rheumatoid arthritis manifests itself when the body's immune system attacks the synovium, the lining of the membranes that surround the joints. This leads to persistent joint inflammation resulting in cartilage and bone damage, disability, and eventually systemic complications, including cardiovascular and pulmonary disorders. Damage to the joints causes deformities and bone erosion, associated with severe pain.12 Adult RA is a heterogeneous disease that encompasses several disease subsets with probable differences in underlying pathophysiology via a common chronic inflammatory pathway. Autoimmunity and the overall systemic and articular inflammation drive the destructive progression leading to the clinical presentation of arthritis. The disease is characterized by the presence of autoantibodies, typically rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA). The most specific autoimmunity known for RA is reflected by the generation of ACPA.13,14 The presence of ACPA in established RA is associated with disease severity, while the generation of ACPA at an early developmental phase has a strong predictive value for progressing to a full- blown disease. RA is fluctuant with episodic exacerbations, and in the absence of optimal treatment, symptoms gradually worsen until the joints are irreversibly damaged and physical and psychological functioning impaired, leading to reduced expectancy of life.15,16
Classification of Rheumatoid Arthritis
In 2010, a joint working group of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) developed a new set of classification criteria for RA that can be applied to identify patients with definite RA.17 It enables diagnosis and treatment earlier in the course of disease aimed at preventing long-term disease complications.18 These criteria provide a score of 0–10, with a score of ≥6 being indicative of the presence of definite RA. A patient with a score of ≤6 cannot be classified as having definite RA but might fulfill the criteria at a later point. To classify a patient as having or not having definite RA, a history of symptom duration, a thorough joint evaluation, at least 1 serologic test (RF or ACPA), and 1 acute-phase response measure of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) markers of inflammatory conditions must be obtained.17,18
The classification system includes conditions to which a certain score corresponds and must be re-examined over time:
2–10 large joints corresponding to 1
1–3 small joints (± large joints) corresponding to 2
4–10 small joints (± large joints) corresponding to 3
>10 joints (± 1 small joint + any others) corresponding to 5
Negative RF and negative ACPA corresponding to 0
Low-positive RF and/or ACPA≤3 x upper limit of normal for local laboratory assay corresponding to 2
High-positive RF and/or ACPA>3 x upper limit of normal corresponding to 3
Abnormal ESR and/or abnormal CRP corresponding to 1
Normal CRP and normal ESR corresponding to 0
Patient-reported pain, swelling, and tenderness ≥6 weeks corresponding to 1
The 2010 ACR/EULAR classification system provides a basis for a common approach to RA definition. It can be applied to all eligible patients to standardize recruitment into clinical trials and for comparison across studies and centers.
Causes and Risk Factors for Rheumatoid Arthritis
A complex interaction between genetic, hormonal, environmental, and random factors plays a role in the pathogenesis of RA.19 Normally, the immune system protects the body from infection; however, repeated activation of the innate and adaptive immune arms leads to a breakdown of immune tolerance, aberrant autoantigen presentation, and antigen-specific T and B cell activation. These events culminate in synovial hyperplasia and bone destruction leading to joint swelling, deformity, and systemic inflammation.20
The triggering risk factors include smoking, physical or emotional stress, age, gender, genetics, obesity, environmental exposure (air pollutants and occupational), as well as alterations in the gastrointestinal microbiota.21 The genetic risk for RA estimated by scientific studies is about 50%.22,23 Genetic and environmental risk factors could lead to an increased rate of post- translational modification, such as hypercitrullination and hyper- carbamylation.24 Autoantibodies against these post-translational modifications are produced (e.g., ACPA and anti-CarP) that can activate synovial macrophages via Fc receptors to release cytokines associated with inflammatory processes, stimulation of fibroblast-like synoviocytes (FLS) and
osteoclast activity.25 The underlying inflammatory cascade eventually results in clinically apparent arthritis.
Diagnosis of Rheumatoid Arthritis
An early and accurate diagnosis of RA is essential to establish definite RA and to differentiate it from other types of arthritis and autoimmune diseases. The current RA diagnosis is based on the 2010 ACR/EULAR classification criteria that is globally accepted as a benchmark for disease definition. This system evaluates a set of variables, such as risk factors, number and type of joints involved, and duration of symptoms, in addition to the detection of four serological biomarkers (RF, ACPA, ESR, CRP).17 Normally, RF and ACPA are serologically detectable in RA. About 80% of people with RA test positive for RF; however, the presence of RF is not specific to RA, since it may be present during infections and other diseases.26 Conversely, ACPA is highly specific, and it may be detected years before the onset of RA symptoms.24,27 About 60% to 70% of people living with RA have antibodies to ACPA. The ACPA could be associated with the extent of joint destruction; synovial fluid from RA joints contains citrullinated proteins, which in turn increase the local inflammation.27 Furthermore, synovial fluid from an affected joint may also be analyzed to rule out other conditions and establish an accurate diagnosis of RA.28 Genomics, transcriptomics, proteomics, and metabolomics have been recently utilized to discover new clinical biomarkers for diagnosis and therapeutic intervention in RA.29
The 2010 ACR/EULAR classification includes the use of imaging tools such as ultrasonography (UT), computed tomography (CT), and magnetic resonance imaging (MRI) that aid in early diagnosis of RA.17,30 The imaging tools have much higher accuracy than conventional radiography since X-ray examinations of joints cannot reveal the early presence of degradations and erosions.17,30-32 Additional strategies in medical imaging of RA include thermography, near infrared imaging (NIR), positron emission tomography (PET) and single-photon emission computerized tomography (SPECT).33
Regarding the use of UT, CT, and MRI, UT can detect small bone and cartilage erosions and explore structures in detail to differentiate active from inactive inflammatory tissues.32 The inherent advantage of UT over X-ray has been demonstrated in a case-control study, where sonography detected more erosions, especially in early RA.33
Magnetic resonance imaging is the most accurate imaging tool for the detection of early RA, except for detecting joint space widening, where CT is more appropriate. The contrast-enhanced MRI can generate a differential diagnosis between joint effusion and synovitis. It can detect early erosions and hypertrophies and is the gold standard for bone marrow edema detection.31,32
Computed tomography is rarely used in RA since it has limited soft tissue contrast and due to its ionizing radiation, and potential damage to DNA.31,32 However, it can be successfully used in medical cases where 3D imaging is required. Clinical trials conducted over time have demonstrated similarities between CT and MRI.31,32
The X-ray is still used as a diagnosis technique for late changes in the joints due to its availability, low cost, and more medical records. However, it has limitations due to radiation, low sensitivity in detecting early erosions, and since anatomical structures are only displayed in 2D.31 Moreover, a few radiographic hallmarks of RA have been identified, by X-ray, including symmetrical abnormalities, periarticular osteopenia, narrowing of the joint spaces and marginal degradation, swelling of the soft tissue, and synovial cysts and nodules.32,33
The utility of various imaging tools in RA depends on the disease stage of progression. For late changes in RA that occur in the joints, all imaging tools provide good results.
Differential Diagnosis of Rheumatoid Arthritis
Differential diagnosis is important to differentiate RA from other similar conditions such as systemic lupus erythematosus (SLE), Sjögren’s syndrome, adult-onset scleroderma, spondyloarthritis (SpA), psoriatic arthritis (PsA), polymyositis (PM), etc.34,35 Since these diseases are similar in signs and symptoms, differential diagnosis is supported by tissue biopsy.35 Patients who cannot be classified according to the 2010 ACR/EULAR criteria due to a duration of symptoms of ≤6 weeks may have viral infection (Parvovirus, Enterovirus) or Lyme arthritis.36 If more than four joints are affected by arthritis, the disease is denoted as Polyarthritis and is difficult to differentiate from OA and fibromyalgia when pain is the only symptom. Other differences concerning extra-articular manifestations have also been reported.34
Assessment of Rheumatoid Arthritis
Rheumatoid Arthritis requires adequate clinical assessment of patients’ responses to monitor disease activity and the impact of therapy. The ACR response criteria ACR 20/50/70/90 and the Disease Activity Score in 28 joints (DAS28) are the two most widely used sets of improvement criteria that facilitate the decision-making process for treatment initiation and alteration. The ACR20, ACR50, ACR70, and ACR90 responses 37–40 represent at least a 20%, 50%, 70%, and 90% improvement, respectively, in the tender and swollen joint counts and in three out of five additional criteria:
Patient global assessment of disease activity
Physician global assessment of disease activity
Patient assessment of pain
Health Assessment Questionnaire
CRP or ESR.
The DAS28 criteria is used to measure disease activity in patients with early RA. It was demonstrated that a DAS<1.6 score best correlates with ACR remission criteria.41 Subsequently, the corresponding cut-off point of <2.6 for
DAS28 was established.42 Even higher cut-off points of 2.81 and 2.66 have been reported to correspond to the ACR remission criteria in two separate patient populations.42,43 Both DAS<1.6 and DAS28<2.6 scores have been used in studies to define remission in RA.40,44,45 However, despite increasing reliance on DAS28 scores, concerns have been raised that DAS28 components were subject to measurement error.46
For clinical remission in RA, five or more of the following criteria must be fulfilled for at least 2 consecutive months.43
Duration of morning stiffness not exceeding 15 minutes
No fatigue
No joint pain by anamnesis
No joint tenderness or pain during motion
No soft tissue swelling in joints or tendon sheaths
ESR<30 mm/h for a female or <20 mm/h for a male
Treatment Approaches for Rheumatoid Arthritis
Rheumatoid Arthritis therapy is complex and includes pharmacological drugs with different routes of application as well as non-pharmacologic interventions. It aims to relieve pain and control inflammation with the final goal of achieving remission or lessening disease activity.
Pharmacological Approaches
According to ACR/EULAR recommendations, the current approach focuses on early treatment of RA with disease-modifying anti-rheumatic drugs (DMARDs). These are novel drugs that remain the mainstay of RA treatment and promote remission by suppressing autoimmune activity and delaying or preventing joint degeneration. There are 3 types of DMARDs:47,48
Conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs)
Biological disease-modifying anti-rheumatic drugs (bDMARDs)
Targeted-synthetic disease-modifying anti-rheumatic drugs (tsDMARDs)
Conventional Synthetic Disease-modifying Anti-rheumatic Drugs
The recommendation is to use csDMARD initially while the bDMARD, tsDMARDs, biosimilars, or combination therapies are followed if csDMARDs fail.49,50 The DMARD therapy is endorsed during the first 3 months after RA diagnosis.51 As an adjunctive therapy, symptomatic drugs such as analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids (GCs) are used to control pain and inflammation.52,53 NSAIDs (naproxen, ibuprofen, coxibs) and GCs (prednisone, hydrocortisone, prednisolone, dexamethasone) are only used short-term (up to 3–4 months) due to their well-known long- term adverse effects.21,54,55 These analgesics can be administered orally, intravenously, intramuscularly, and intra-articularly.56
Conventional synthetic disease-modifying anti-rheumatic drugs are typically used as first-line therapy for newly diagnosed RA. These consist of a heterogeneous class of small molecule drugs, including methotrexate (MTX), leflunomide (LEF), hydroxychloroquine (HCQ), and sulfasalazine (SSZ) and are more frequently used than other agents with a lower efficacy and safety profile, such as gold salts, azathioprine, d-penicillamine, cyclosporine, minocycline, and cyclophosphamide. The csDMARD mechanisms of action involve non-targeted suppression of the overactive immune system.1,21
Methotrexate is the first choice for RA due to the existing clinical experience with this drug as monotherapy and in combination with other DMARDs.57 It is an antifolate metabolite that interferes with DNA synthesis, repair, and replication.58 It usually starts at 15 mg/week and can be stepwise increased up to 25 mg/week. Combination with GCs is recommended.8 Due to its decreased bioavailability, the subcutaneous (sub-Q) route of administration is preferred.57 Side effects include nausea, mouth sores, blood problems, liver damage, and moderate hair loss. Prolonged treatment with MTX may lead to folic acid deficiency. If MTX cannot be used (e.g., due to intolerance or contraindications), it is
substituted with LEF (20 mg/week) or SSZ (2 g/day). In a placebo- controlled randomized controlled trial (RCT), both drugs showed similar efficacy.59
Leflunomide inhibits dihydroorotate dehydrogenase (DHODH) enzyme and prevents activated lymphocyte cell cycle transition from G1 to the S phase triggering apoptosis.60 Potential side effects include diarrhea, nausea, and elevation of liver enzymes. The changes in liver function are generally reversible with dose reduction or discontinuation however, in rare cases, hepatotoxicity can be severe.61 Transaminase elevation may occur if other comorbidities contribute to hepatotoxicity (e.g., concomitant NSAID or MTX therapy, previous or concurrent alcohol abuse, or viral or autoimmune hepatitis).62 Leflunomide is contraindicated during pregnancy.63
Sulfasalazine’s effects are on the gut bacterial flora, inflammatory cell functions, and immunological processes leading to reduced secretion of inflammatory cytokines.64 Adverse reactions include idiosyncratic effects (e.g., hypersensitivity, skin reactions, hepatitis, pneumonitis, or hematologic side effects) and dose-related effects, especially gastrointestinal, central nervous system, cutaneous, and hematologic adverse effects.65 Due to SSZ’s short half-life, it has only a minimal immunosuppressive effect and hence can be used perioperatively. It can be used during pregnancy and is unlikely to cause fetal harm.63 To increase safety, a concomitant folate supplementation before and during pregnancy is advised at a dose not exceeding 2 g/day to prevent neutropenia in newborns. SSZ can cause reduced male fertility; however, spermatogenesis recovers at about 2–3 months after withdrawal.63
Biological Disease-modifying Anti-rheumatic Drugs
Biological disease-modifying anti-rheumatic drugs are the newer option for RA treatment. They provide targeted therapy on specific arms of the immune system. These are genetically engineered proteins and humanized
monoclonal antibodies that provide therapeutic benefits in RA patients who had a poor response or are intolerant to csDMARDs.1,4 These drugs are divided into several classes, depending on their mechanism of action, as follows:1,4
TNF-α inhibitors (etanercept, infliximab, golimumab, adalimumab, certolizumab pegol)
B-cell depleters (rituximab, ofatumumab)
B-cell receptor inhibitors (belimumab, atacicept, tabalumab)
Antagonists of CD28 on T-cells (abatacept, belatacept)
IL-1 inhibitors (anakinra, canakinumab, rilonacept)
IL-6 inhibitors (tocilizumab, sarilumab, sirukumab, olokizumab, clazakizumab)
IL 12/23 inhibitor (ustekinumab)
IL-17 inhibitors (ixekizumab, secukinumab, brodalumab)
Granulocyte-macrophage colony-stimulating factor inhibitor (mavrilimumab, otilimab)
RANKL inhibitor (denosumab)
Biological disease-modifying anti-rheumatic drugs include the following:
Adalimumab (Humira). Is the most prescribed bDMARD for adult RA. In a randomized phase 3 clinical trial, adalimumab monotherapy in patients with RA who failed csDMARDs showed both statistically significant improvement in the disease activity and good safety profile.66 However, a meta-analysis of nine clinical trials of adalimumab in RA treatment demonstrated its association with a greater risk of serious infection and a dose-dependent increased risk of malignancies.67 The usual sub-Q dose is 40 mg every other week. Some patients not receiving MTX may benefit from increasing the dosage to 40 mg every week or 80 mg every other week.68
Etanercept (Enbrel). Is a soluble TNF receptor fusion protein that binds to TNF-alpha and TNF-beta.69 Clinical evaluation of etanercept in 549 RA patients showed that after 36 months of treatment, it achieved long- term efficacy with a favorable safety profile.70 Etanercept is
administered sub-Q twice weekly at 50 mg and has a beneficial role in reducing radiographic progression in RA patients. Based on SSATG and DANBIO registries, etanercept has the best drug survival rate of all TNF inhibitors.71 Some etanercept needle covers contain dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.72
Infliximab (Remicade). Is a chimeric monoclonal antibody that binds to all forms of TNF-α neutralizing its biological function.73 It is administered IV for treatment of moderate to severe active RA at 3 mg/kg induction dose at 0, 2, and 6 weeks followed by 3 mg/kg every 8 weeks as a maintenance regimen.73 Infliximab is given in combination with MTX. A decrease in IL-1, IL-6, and IL-8 was found after therapy with infliximab in RA patients.73 Medical evidence indicates that patients treated with Infliximab have a rapid response, and it has a good preventive effect on joint degeneration. The results show a good efficacy profile, with 37.5- 70.8% of patients achieving a favorable EULAR response.74 Infliximab infusions are safe, and severe acute adverse drug reactions are rare.75 It is contraindicated in doses >5 mg/kg in moderate or severe heart failure.76
Golimumab (Simponi). Is a human monoclonal antibody administered sub-Q once a month at 50 mg. It has a similar safety and efficacy profile to other TNFi; however, golimumab is less effective in individuals who have failed multiple bDMARD treatments.20 It is classified by the FDA as
Category B in pregnancy. It remains the TNF-α inhibitor with the lowest amount of data during pregnancy, and breastfeeding impact is unknown.77,78
Certolizumab Pegol (Cimzia). Is a PEGylated anti-TNF-α human monoclonal antibody administered sub-Q. The recommended dosing regimen in RA is 400 mg at weeks 0, 2, and 4, followed by 200 mg every 2 weeks.79 Limited data from the ongoing pregnancy registry on the use of certolizumab pegol in pregnant women are not sufficient to inform a risk of major birth defects or other adverse pregnancy outcomes. However, certolizumab pegol plasma concentrations obtained from two studies during the third trimester of pregnancy demonstrated that placental transfer of certolizumab pegol was negligible in most infants at birth, and low in other infants at birth.80
Abatacept (Orencia). Is a fusion protein that inhibits T-cell activation by blocking the interaction with CD28. In adult RA patients, it is administered by either IV infusion or SC injection. The initial IV infusion is followed by subsequent infusions at 2 and 4 weeks and every 4 weeks thereafter at 750 mg per 60 to 100 kg. The SC injections given at 125 mg may be administered after an IV-loading dose.81 A phase 3 trial in RA patients with a poor response to MTX compared Abatacept to Infliximab, demonstrating a similar efficacy profile for both drugs, but a better abatacept safety profile.82 However, in a world observational post-marketing study, exposure to abatacept compared with other bDMARDs was only substantially associated with an increased risk of reporting melanoma in RA patients.83
Tocilizumab (Actemra). Is a monoclonal antibody with an IL-6 inhibition mechanism. It is available as an infusion and can be administered sub-
Q. The recommended dosage for adult RA patients given as a single IV infusion is 4 mg/kg every 4 weeks, followed by an increase to 8 mg/kg every 4 weeks based on clinical response.84 The sub-Q dose for a patient weighing less than 100 kg is 162 mg sub-Q every other week, followed by an increase to every week based on clinical response. For patients
over 100 kg, 162 mg sub-Q weekly. Evidence from 14 phase 3 clinical trials suggested that the immunogenicity risk of tocilizumab is low, regardless of the route of administration.85 According to the ADACTA study, tocilizumab therapy was found to be more effective than adalimumab in terms of reducing signs and symptoms in RA patients with an inadequate response to MTX.86 The most common side effects reported in clinical trials were upper respiratory tract infections, nasopharyngitis, cellulitis, and high blood pressure.87
Rituximab (Rituxan). Is a humanized chimeric mouse/human monoclonal antibody targeting B-cell-specific antigen CD20. It leads to peripheral B-cell depletion of autoreactive B-cells. The approved dose of rituximab for adult RA is 2×1,000 mg infusions given 2 weeks apart.88 Rituximab has good efficacy in RA and can be an alternative for patients who fail treatment with MTX or TNFi.89 It is well-tolerated and not associated with an increased risk of infection. Meta-analysis data of infection rates between rituximab and placebo showed that the risk of serious infection with rituximab was low, even at higher doses.90
Anakinra (Kineret). Is a recombinant human IL-1a receptor antagonist with a short half-life administered sub-Q at a dose of 100 mg once a day. It is the first bDMARD approved for RA and showed only moderate effectiveness.91 Adverse effects include injection site reactions characterized by itching, pain, and redness at the site of injection. Between 1-10% of RA patients have severe infections, decreased white blood cells, or decreased platelets.92
Targeted-synthetic Disease-modifying Anti-rheumatic Drugs
Targeted-synthetic disease-modifying anti-rheumatic drugs are a recent class of Janus kinase inhibitors (JAKi) that represent the newest therapeutic option for RA.93,94 Janus kinase inhibitors are small molecule drugs disrupting JAK-STAT intracellular signaling pathways for multiple proinflammatory cytokines.1,55,93 According to their selectivity, JAKi can be divided into (i) first- generation consisting of non-selective inhibitors, and (ii) second-generation
inhibiting signaling of a narrower range of cytokines.95 In addition to good efficacy and safety, the JAKi are administered orally and have lower production costs compared to bDMARDs.96 The 2021 ACR guideline for the treatment of RA updated the recommendations on using JAKi when csDMARDs are ineffective.97
Targeted-synthetic disease-modifying anti-rheumatic drugs include the following:
Baricitinib (Olumiant). Is the first generation JAKi for the treatment of moderate to severe active RA in adult patients with inadequate response or intolerance to csDMARDs.98 It selectively inhibits JAK1/JAK2 by interacting with the active conformational site of the ATP-binding pocket.99 Baricitinib can be administered as a monotherapy or in combination with MTX. Phase 3 clinical trials showed efficacy in the treatment of DMARD-naïve patients and in patients with insufficient responses to csDMARDs or bDMARDs.100,101 The recommended oral dose is 2 mg/day once daily. For patients with inadequate response or intolerance to more than one DMARD, the dose is increased to 4 mg/day.102 Due to its renal elimination, it is necessary to reduce the dosage for patients with impaired kidney function from 4 mg to 2 mg daily.103 The most common side effect is elevated cholesterol. Other side effects include upper respiratory tract infections, herpes zoster, or pneumonia.104 A small number of patients treated with baricitinib show significant neutropenia.104 The drug is contraindicated in patients with severe hepatic impairment.102
Tofacitinib (Xeljanz). Is a non-selective first-generation inhibitor of JAK1, JAK2, JAK3 and, to some extent, TYK2 kinases.93 It has been shown to be effective in moderate and severe RA as monotherapy and in combination with MTX or csDMARDs.105,106 Tofacitinib is orally administered at 5 mg twice daily. The elimination is mostly hepatic; therefore, an adaptation to impaired kidney function is not necessary up to a GFR>30 mL/min. Consequently, the treatment of patients with end- stage renal failure with a GFR<30 mL/min with tofacitinib is possible
with reduced dosage.107 The common side effects include susceptibility to herpes zoster as well as headaches, hypertension, nausea, and diarrhea. Elevated levels of LDL, HDL, cholesterol, and liver enzymes have also been reported.55 In a post-marketing study, higher doses of tofacitinib showed an increased risk of deep vein thrombosis and pulmonary embolism. The recommended dosage of 5 mg twice daily, therefore, should not be exceeded.108
Upadacitinib (Rinvoq). Is a second-generation selective JAK1 inhibitor. The drug was approved at a dosage of 15 mg once daily for adults with moderately to severely active RA with inadequate response or intolerance to MTX.109 In phase 2 trials, upadacitinib showed significant improvements in clinical and functional outcomes versus MTX and anti- TNF-α therapy in the MTX and anti-TNF-α inadequate responders.110,111 Safety and efficacy of upadacitinib evaluated in Phase 3 trials in patients with active RA refractory to bDMARDs showed rapid and significant improvements compared to placebo.112 The drug has a good safety profile with mostly mild infections, nausea, headache, and transient increase in serum transaminases and lipid levels.111,112
Peficitinib (Smyraf). Is a second-generation pan-JAK inhibitor with a higher selectivity for JAK3 than other JAKs.113 The drug is approved in Japan for the treatment of RA in patients who have inadequate response to conventional therapies.114 The recommended dose is 150 mg or less, depending on the patient’s condition, as an after-meal single daily administration.115 Peficitinib efficacy and safety data from Phase 2 clinical trials in RA patients demonstrated statistically significant improvement in the ACR20 response rate at week 12 with a similar number of adverse events compared to placebo.116,117 The safety profile is in line with that of other available JAKi.
Nonpharmacological Interventions
The goal of the nonpharmacological intervention is to decrease RA risk factors such as anxiety, depression, pain, and fatigue associated with disease
activity and poor functional status. The use of natural supplements such as polyunsaturated fatty acids (PUFAs), adequate rest, occupational therapy, physical exercise, and joint surgery are several modalities of nonpharmacologic intervention. Existing medical evidence suggests that omega-3 PUFAs, including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are effective in the treatment of depression, anxiety, and pain.118–
120 RA-related fatigue may be improved through physical activity and, when associated with adequate rest, relieves stress on inflamed tissues and slows down RA progression.121,122 A systematic review of 42 articles related to the advantages of occupational therapy for RA patients showed a substantial increase in joint function.123 Psychosocial interventions, such as self- management programs, cognitive-behavioral approaches, and lifestyle interventions based on physical activity, have been also shown to be beneficial.122,124 In the severe stages of RA joint surgery, including tens- synovectomy, radio synovectomy, arthroscopy, osteotomy, joint fusion, metatarsal head excision arthroplasties or total joint replacement provides pain relief and restores joint function.125 In order to maximize therapeutic success, the nonpharmacological approaches should be associated with pharmacological treatments.
Analysis of the Current Treatment in Rheumatoid Arthritis
There has been significant progress toward achieving disease remission without joint deformity and in controlling inflammation during the long-term course of RA progression. However, several unmet medical needs remain to be addressed in the treatment of RA. A significant proportion of patients do not effectively respond to DMARDs and continue to be resistant to current medications. There is a lack of understanding of how different therapies result in comparable efficacies. New predictive response biomarkers linked to inflammation, such as mRNA expression, serum, and synovial biomarkers, are needed to understand RA heterogeneity and predict drug-free remission and RA disease-onset.
Complete control of the disease has not been achieved, so there is a need for new drugs with a greater focus on precision medicine.1,55,94 At present, different medication combinations are common strategies to relieve pain and joint inflammation. Due to the high heterogeneity of RA, such an approach is unable to recommend specific DMARDs custom-tailored to individual patients. Precision medicine is a major unmet medical tool and an emerging medical model that considers the genetics, environment, and lifestyle of patients for selection of best-suited therapy.94
Counseling Patients with Rheumatoid Arthritis
Pharmacy team members can support an interdisciplinary approach to care by creating a rapport with patients, fully explaining all medications, and emphasizing adherence. During prescription processing, pharmacy technicians ensure proper dosage forms, routes of administration, special handling, and administration instructions are applied because analgesics can be administered orally, intravenously, intramuscularly, and intra-articularly (by entering the joint). Pharmacy technicians also have a role in labeling and checking the routes of administration and special handling of biologics. Pharmacy teams should ensure the patient knows the correct route of administration for each medication.
Pharmacy teams should review the FDA-approved label of each product for boxed warnings and provide required Medication Guides to patients. Patients should be reminded that the information in the Medication Guides is helpful for them. Patients should be monitored closely for signs and symptoms
of tuberculosis and other infections. Patients should inform their provider if they believe they may have an infection before or during treatment. Some biologics can increase the risk of specific cancers, so healthcare providers should be informed if a patient has a history of cancer.
Future Approaches in the Management of Rheumatoid Arthritis
An essential part of RA management is the evaluation of clinical aspects, including signs and symptoms, prognostic laboratory biomarkers, differential diagnosis, complications, extra-articular manifestations, etc. Effective management of RA requires initiation of early aggressive therapy to obtain remission or at least a significant reduction in clinical signs without adverse effects. In recent years, interest in controlling autoimmune disease has grown, with testing new therapeutic approaches to patients with RA. Even though it is still incurable, patients’ quality of life has improved considerably. Future approaches in the management of RA include the use of genomics, proteomics, and metabolomics to identify new biomarkers of response to csDMARDs, bDMARDs, tsDMARDs and to guide treatment decisions. Disease prevention strategies, screening programs of people at risk and comprehensive information on the disease provided to the population can significantly improve epidemiological parameters.
Effective disease management requires an early and correct diagnosis, especially as several signs and symptoms are also associated with other autoimmune diseases. Proper use and interpretation of ACR-EULAR criteria, identification and quantification of diagnostic biomarkers, and correlation of data with imaging techniques will contribute to the establishment of an accurate diagnosis. The benefits of nonpharmacological interventions are greater the faster diagnosis of definite RA is established. The goal of RA management is to obtain full remission or at least a significant reduction in symptoms and clinical signs.
Summary
Adult RA is a chronic debilitating autoimmune disease. Multiple immune mechanisms involving the overproduction of pro-inflammatory cytokines and proteins contribute to its development and progression. The disease is triggered by genetic, hormonal, and environmental risk factors involving joints and extra-articular organs. The prevalence of RA is higher in females than males, predominantly observed in the elderly. An early and accurate diagnosis is important to differentiate RA from other types of autoimmune diseases. Advances in research led to the development of synthetic, biologic, and target- specific DMRDs that control inflammation and promote remission by suppressing autoimmune activity. Emerging approaches in the management of RA include the use of genomics, proteomics, metabolomics, and precision medicine. The goal of RA treatment is to achieve long-term remission, reduce morbidity/mortality, and improve quality of life.
Course Test
Which of the following is accepted as a benchmark definition of rheumatoid arthritis (RA)?
2010 ACR/EULAR classification
Response to tsDMARDs
Detection of ACPA
Detection of RF
Which of the following biomarkers is specific for RA?
RF
ACPA
ESR
CRP
Which of the imaging tools is most accurate for the detection of early RA?
Ultrasound
X-ray
Computed Tomography
Magnetic Resonance Imaging
Which of the following statement(s) is correct when using imaging tools to diagnose RA?
For late changes in RA that occur in the joints, all imaging tools provide good results.
Computed Tomography (CT) is widely used in RA since it has good soft tissue contrast.
Ultrasound (UT) cannot detect small bone and cartilage erosions and explore structures in detail.
X-ray is most effective in diagnosing early changes in the joints due to RA.
Which of the following is a bDMARD?
Methotrexate
Prednisone
Naproxen
Adalimumab
The ACR/EULAR recommendation for the treatment of RA is to use
as the first-line treatment and then turn to other DMARDs if it fails.
bDMARDs
tsDMARDs
csDMARDs
combination DMARD therapies
Which of the following is a tsDMARD?
Baricitinib
Anakinra
Leflunomide
Abatacept
Which of the following is a major unmet medical need for the treatment of RA?
Transciptomics
Precision medicine
New protein targets
New cytokine targets
Which of the following is not a risk factor for RA?
Environmental exposure
Genetics
Emotional stress
Metabolomics
Which statement is not accurate regarding patient counseling and monitoring?
Counseling the patient on the route of administration is important
Medication Guides can be discarded with the package insert
Patients should be monitored for infections such as tuberculosis
Inform the healthcare provider if a patient has a history of cancer
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