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Rheumatoid Arthritis: Many Management Strategies, No Cure

Publication
Article
Supplements and Featured PublicationsRheumatoid Arthritis:The Next Generation of Treatment
Volume 22
Issue 14

Rheumatoid arthritis (RA) is a chronic inflammatory syndrome characterized by synovitis, joint swelling, and debilitating pain that result from bone and cartilage erosion. Uncontrolled, severe RA leads to joint deformity, disability, and premature death. The etiology of RA is not completely understood, but it is known to involve interplay between environmental factors, susceptibility genes, epigenetic factors, and posttranslational modifications in genetically predisposed individuals. A positive family history is the strongest risk factor for RA, and genomewide association studies have identified over 100 susceptible loci associated with RA—most within the human leukocyte antigen region. The inflammatory course of RA involves innate and adaptive immune cells activated by exogenous factors and autologous antigens, such as antibodies to citrullinated proteins and rheumatoid factor. Mediators of the immune response, cytokines, such as tumor necrosis factor-alpha, play a key role in the progression of RA, and are the targets for biologic treatment of RA. While traditional treatment approaches have focused on disease-modifying antirheumatic drugs, biologic therapies are providing a more targeted approach to disease management in the long term. This article reviews current treatment guidelines for RA, with a focus on the role and relevance of traditional treatment options in the era of biologic therapeutics.

Am J Manag Care. 2016;22:-S0

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by joint inflammation (synovitis) and the formation of rheumatoid pannus, leading to erosion of adjacent cartilage and bone and resulting in joint deformity, pain, severe disability, and premature death.1-5 Due to its systemic comorbidities, which include rheumatoid nodules, vasculitis, and pulmonary and cardiovascular involvement, RA is often defined as a syndrome.2-4 In 2005, an estimated 1.5 million (0.6%) adults in the United States were affected by RA, with women slightly more susceptible than men.2,6 An epidemiological study in 2005 estimated the lifetime risk of RA to be 4% for women and 2% for men.2,7

The past decade has seen significant advances in the treatment of RA, along with recent updates to diagnosis and classification of the disease, with a focus on early recognition and treatment.1,4,8 Despite the significant strides, however, full remission in patients with RA, or continued remission after withdrawal of treatment, can be difficult to achieve.9 This article focuses on the application of conventional, new, and emerging treatment options for RA, and provides a review of current RA treatment recommendations and the challenges of current therapeutics.

Epidemiology and Etiology of RA

Although the etiology of RA is not yet completely understood, it is believed to result from a combination of environmental factors, susceptibility genes, epigenetic factors, and posttranslational modifications in individuals predisposed with a genetic susceptibility.4,5,10-12 A positive family history, considered the strongest risk factor for RA, increases the risk of RA more than 3 to 5 times.13 Studies have shown patterns of increased prevalence in specific ethnic populations, such as Pima Indians and Chippewa Indians, and in studies of migrant populations.11 The importance of genetic factors has further been demonstrated in studies with twins, where 50% to 60% of the occurrence of RA can be explained by genetic effects.11 The overall heritability of RA is 50% to 60%, with higher rates among those who are anticitrullinated protein antibody (ACPA) seropositive for RA (40%-55%) compared with those testing seronegative (20%).12,13 The clinical course of ACPA-positive RA is also much more aggressive than that of ACPA-negative RA. The presence or absence of ACPA denotes 2 genetically distinct diseases characterized by different antibodies.14,15

Genetic Factors

Genomewide association studies using single nucleotide polymorphisms have identified over 100 genetic susceptibility loci associated with RA. The largest and most influential association lies within the human leukocyte antigen (HLA) region, the HLA-DRB1 complex. This gene complex codes for the major histocompatibility complex (MHC) proteins responsible for immune regulation.12 Many of the loci identified implicate immune mechanisms, which may be shared with other chronic inflammatory diseases.4 Multiple risk alleles for RA within the HLA-DRB1 locus encode a 5-amino acid sequence motif known as a shared epitope (SE).16 This sequence motif is carried by the vast majority of patients with RA.16

Although the exact mechanism by which the SE contributes to the pathophysiology of RA is not known, it is hypothesized that the presence of these amino acid sequences alter binding and presentation of antigenic peptides to T-cell lymphocytes, triggering an abnormal immune response.17 The risk of RA in patients with a SE is also linked with seropositivity for ACPA and rheumatoid factor (RF), with a poor association in individuals that test negative for ACPA and RF.4,18 A SE is not only associated with disease susceptibility, but it has also been shown to have a significant impact on radiological severity of the disease, mortality, and treatment response.18

However, some evidence suggests that the relationship between HLA and RA is linked more to the severity of the disease, in addition to its development.19 The functional effect of the loci vary, as some genotypes contribute to small functional effects through altered signaling or activation pathways, while others are associated with more aggressive erosive disease and higher mortality.4 Additionally, data from studies of twins demonstrates that HLA only explains approximately half of the genetic contribution to RA. This has driven a search for non-MHC genes that may be implicated in RA, including linkage to genetic regions associated with autoimmune diseases such as insulin-dependent diabetes.19,20 Many of the loci associated with RA are also implicated in immune mechanisms shared with other chronic inflammatory diseases.4 Other loci, such as PTPN22 polymorphisms, PADI, and peptidyl arginine deiminase, may contribute to RA by interfering in critical processes, such as cytokine signaling, lymphocyte receptor activation threshold, post translational modification of peptides, and innate immune activation.4,21,22

Environmental Factors

In addition to alterations in the genetic code itself, modification of gene expression through environmental effects is also thought to play a significant role in the pathogenesis of RA.4 This includes recurrent exposure to exogenous, endogenous, and/or antimicrobial agents, and pollutants such as smoke and silica.4,21 Smoking is, by far, the most important and well-established environmental factor identified to increase the risk for developing RA,12,19 as studies have found that smoking dramatically increases the risk in the presence or absence of specific HLA genes.10 However, in the presence of HLA genes, the association between smoking and RA brings to light the importance of epigenetics in RA—specifically, changes caused by modification of gene expression due environmental factors rather than by an alteration in the genetic code itself.10

Smoking is associated with an increased risk for ACPAs in SE-positive RA.23 It has been suggested that specific peptides, upon citrullination, are more prone to binding with the MHC complex, thereby predisposing individuals with a SE to have a preferential immune response to citrullinated proteins. Because anticitrulline autoimmunity is linked with seropositivity of RF in RA, the relationship between SEs and ACPAs is also thought to give rise to the relationship between SEs and RF.10 In patients who are RF-positive, the relative risk of developing RA more than doubles in smokers with one SE compared with patients who are SE-negative. This risk increases more than 6-fold in smokers who have double SEs compared with nonsmokers with double SEs and smokers with a single SE.10

There is also accumulating evidence to suggest an association between chronic periodontitis and RA.24 This association may be a result of infection with Porphyromonas gingivalis, triggering or driving an autoimmune response in some subsets of patients with RA.24 Diabetes and a high body mass index have also been associated with an increased risk of developing RA, while higher social class and breast-feeding are associated with a decreased risk.25

Pathophysiology of RA

The pathophysiology of RA follows the course of induction, inflammation, and destruction. The course is complicated by the heterogeneous nature of RA, with varying epidemiology, environmental factors, genetics, clinical presentations, and biomarkers acting in tandem over a period of time to produce symptomatic disease.4,21 In genetically predisposed individuals, the combination of susceptibility genes, environmental factors, and epigenetic and posttranslational modifications during a preclinical phase (pre-arthritis) results in symptomatic disease characterized by swelling, pain, stiffness, and joint damage.4

Induction

A breach of tolerance occurs during the preclinical phase of RA that results in activities within the immune system generating a response toward target organs that ultimately result in cellular infiltrate and clinical disease.4,26 The process begins with activation of the innate immune response and is perpetuated in tandem with the adaptive immune response. Innate immune cells include monocytes, mast cells, innate lymphoid cells (eg, natural killer cells), and phagocytic cells (eg, macrophages and dendritic cells). Adaptive immune cells include T cells, B cells, plasmablasts, and plasma cells.

The activation is initiated by exogenous factors and antibodies to autologous antigens such as ACPAs and RF. ACPAs, which are produced by B cells, form complexes with citrulline-containing antigens and can subsequently bind to RF.4,26 These complexes are then presented to T cells through activated B cells and phagocytic cells (macrophages and dendritic cells).4,26,27 Although the exact nature of T-cell activities within the joint is unknown, T cells are known to stimulate the production of proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, and are responsible for endothelial activation, resulting in recruitment of inflammatory cells. Through concurrent and subsequent processes, the synovial membrane becomes infiltrated with inflammatory mediators and other contributors that lead to the destruction of cartilage and bone. The entire process is perpetuated through a feedback loop that propels the inflammatory cascade forward.4,26,27

Inflammation

Induction of immune complexes is followed by systemic inflammation and elevated levels of serum autoantibodies (ACPAs and RF) and acute phase proteins.3 Cytokines, specifically TNF-alpha, interleukin (IL)-6, IL-1 and IL-17 are key mediators of inflammation, with local and systemic effects.27 TNF-alpha is responsible for increased monocyte activation and cytokine release, and increased polymorphonuclear leukocyte priming, apoptosis, and oxidative burst. TNF-alpha also plays a critical role in decreasing the synthesis of collagen and increasing production of acute-phase proteins.27 The impact of ILs in RA is discussed in more detail in part 2 of this supplement. However, it is important to know that ILs play a critical role in the amplification of immune response and have synergistic activity with TNF-alpha and interferon-gamma.

Clinically, the inflammatory phase is characterized by synovitis, joint swelling, and pain that results from an aggressive tissue response to the infiltration of leukocytes within the synovial compartment.4 Bone and cartilage loss can also be promoted through ACPAs binding to membrane-bound citrullinated vimentin. Macrophage activation occurs, resulting in activation of osteoclasts, chondrocytes, and osteoblasts, which also produces clinical symptomology, as does B-cell activation and the formation of RF immune complexes. This inflammatory process is established in patients with RA long before clinical symptoms are evident.4,26

Bone Erosion and Destruction

The unchecked processes of induction and inflammation in RA ultimately result in tissue destruction and remodeling in the synovial tissue and bone, and in areas such as the lungs.4 While bone remodeling is a normal physiologic process, bone formation is disrupted in RA.28 Osteoclasts are multinucleated cells that regulate the process of mineral homeostasis under normal circumstances. In RA, they are the primary mediators of bone destruction.27 Through a process that is mediated by TNF-alpha, IL-6, and receptor activator of nuclear factor kappa-B ligand, continuous differentiation of osteoclasts in RA leads to an imbalance in the process of remodeling and results in bony erosions and chronic joint destruction.28

Diagnosing RA

The presence or absence of ACPAs and RF are key markers in the clinical diagnosis of RA.1 Both RF and ACPAs may be detected several years prior to symptomatic disease in the preclinical phase, confirming the general consensus that the spectrum of RA begins years before the onset of clinical symptoms.4,12,29

There are no definitive diagnostic criteria for RA; however, a clinical diagnosis may be established by a rheumatologist based on classification criteria developed by the American College of Rheumatology (ACR), in association with the European League Against Rheumatism.1 Diagnosis is a 2-part process that includes establishing a patient’s “eligibility” and classifying the patient. To be eligible for an RA classification, the patient must have at least 1 joint with synovitis (joint swelling) that is not explained by another disease.1 While the previous 1987 ACR crtieria relied on chronic and end-stage manifestations such as erosions and extra-articular features of disease, the updated criteria focus on identifying patients at an early stage. Early identification and treatment are critical in achieving control of disease and preventing joint injury and disability.

Continuous monitoring of the patient to measure disease activity or remission after treatment initiation is recommended using any one of a variety of instruments including the Patient Activity Scale (PAS) or PAS-II, Routine Assessment of Patient Index Data 3, Clinical Disease Activity Index, Disease Activity Score (DAS), and Simplified Disease Activity Index.8

Treating Patients With RA

The goals of treating patients with RA are focused on controlling symptoms (relieving pain and reducing inflammation) and slowing down or stopping structural damage, to maximize long-term health-related quality of life and normalize function.8,30 To achieve these goals in the long run, the 2015 ACR guidelines suggest consideration be given to cost of treatment and routine assessment of functional status.8

Treatments for patients with RA consist of traditional disease-modifying antirheumatic drugs (DMARDs), biologic therapies (TNF inhibitors and non-TNF biologics), glucocorticosteroids (mainly prednisone), and tofacitinib (a Janus kinase [JAK] inhibitor).8

Guideline-Based Care in RA

Regardless of disease activity level, the guidelines recommend a treat-to-target strategy for all patients.8 The target should be individualized based on the patient’s level of tolerance, comorbidities, or other factors. Ideally, the primary target should be low disease activity or remission. For patients with early disease, the guidelines recommend monotherapy with a DMARD. Methotrexate (MTX) is the recommended initial therapy for most patients with early (duration <6 months) active disease.8

Initial treatment with MTX (or another DMARD), with or without a glucocorticoid, is recommended in patients with moderate to high disease activity.8 Use of low-dose glucocorticoids (≤10 mg/day of prednisone) for a short duration is suggested as a bridge for patients until the effect of the DMARD can be realized. Triple therapy with MTX, sulfasalazine (SSZ), and hydroxychloroquine (HCQ) or a biologic is recommended (alone or in combination with previous treatment) if the patient does not respond adequately. The biologic may be a TNF inhibitor or a non-TNF biologic. ACR guidelines endorse the use of biologic therapy in combination with MTX over biologic monotherapy.8

Traditional Treatments Versus a Targeted Approach

Traditional DMARDs include MTX, HCQ, leflunomide (LEF), and SSZ. Although DMARDs are the mainstay of treatment for RA, they were not developed as targeted agents, and their mechanisms of action tend to be more general or systemic. However, they have demonstrated improvement in symptoms and the ability to slow disease progression.3,8,10,31,32

MTX is the most commonly used DMARD, and is the cornerstone of RA treatment. It is the drug of choice for initial treatment because it is a well-tolerated, long-term treatment with demonstrated efficacy and cost efficiency. This folate analogue increases extracellular adenosine, inhibits synovial cell proliferation, decreases macrophage and lymphocyte recruitment and activation, and reduces neutrophil activation and vascular permeability.31,32 Treatment with MTX has demonstrated multiple significant correlations with disease activity measures, including levels of IL-6 (r = 0.45, P <.0001 for swollen joints and r = 0.32, P = .002 for tender joints) and IL-8 (r = 0.25, P = .01 for swollen joints).33 These data not only demonstrate the profound and functional effect of MTX on disease outcomes, but also for immune measures of disease activity over 36 months.

In treatment-naïve patients with RA, combination therapy with nonbiologic DMARDs has demonstrated efficacy similar to biologics.34 The BeSt trial was an open-label study with 4 treatment arms. Group 1 included sequential monotherapy (MTX followed by SSZ followed by LEF). Group 2 initiated treatment with MTX and then stepped up to combination therapy with MTX + SSZ + HCQ + prednisolone. Group 3 initiated treatment with combination therapy (MTX + SSZ + HCQ + prednisolone). Finally, group 4 initiated treatment with a biologic (infliximab) in combination with MTX. Low disease activity, based on DAS, was attained in all 4 groups (53%, 64%, 71% and 74%, respectively), and approximately one-third of patients in each group experienced remission. Earlier functional improvement and less radiographic damage after 1 year was demonstrated in 2 groups with initial combination therapy, with either prednisone or infliximab, compared with either sequential monotherapy or step-up combination therapy in the other 2 groups.34

Each of the nonbiologic DMARDs is thought to prevent the progression of disease by altering known mechanisms in the pathogenesis of RA. HCQ decreases B- and T-cell hyperactivity and cytokine release; it has no effect on disease progression as monotherapy and is usually used in combination triple therapy.3,21 LEF represses de novo pyrimidine synthesis, and in doing so, inhibits activation of nuclear factor kappa-light-chain-enhancer of activated B cells and suppresses TNF-alpha and matrix metalloproteinase production.3,21 SSZ is a folate antagonist and an antimicrobial agent that inhibits the arachidonic acid cascade. It is less effective than MTX or LEF.3,21

Nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids suppress inflammation and are used symptomatically.3,8 NSAIDs offer pain relief, but are not disease-modifying, and therefore, are not considered DMARDs.35 Corticosteroids, such as prednisone, have demonstrated substantial and rapid reduction in the rate of radiologically detected disease progression. Only 22.1% of patient hands acquired erosions after 2 years of treatment with prednisone, compared with 45.6% with placebo (P = .007) Patients also had significantly greater reductions in pain and disability than patients in the placebo group (P <.05 for all).36 However, prednisone is associated with serious long-term adverse effects, limiting its use.35

Other conventional DMARDs include azathioprine, cyclosporine, and minocycline. However, their use is infrequent.8 Cyclosporine A inhibits calcium-dependent signaling pathways involved in lymphokine secretion, and suppresses type 17 T helper-cell differentiation and IL-17 production. Its use in RA is limited, and it appears to work best in chronic (rather than acute) phases of the disease.3 The mechanism of action of gold salts in RA is unclear. Although some studies have found them moderately effective, they have a poor adverse effect profile.3

Targeted Treatment Approach

Over the last 25 years, researchers have developed targeted disease-modifying biologic therapies that improve the clinical management of patients with active disease that persists despite the use of conventional therapies such as MTX.3,8 These biologics include monoclonal antibodies and recombinant fusion proteins, and are classified as TNF inhibitors and non-TNF biologics.8 TNF is a key regulator of the inflammatory cascade, and TNF inhibitors were the first class of biologics developed for the treatment of RA.3 There are 3 structural types of TNF inhibitors: monoclonal antibodies (adalimumab, infliximab, and golimumab); a pegylated fragment antigen-binding fragment (certolizumab), and a recombinant, soluble receptor fusion protein (etanercept).3 Thus far, TNF inhibitors have demonstrated efficacy in improving the signs and symptoms of RA and slowing the progression of, or preventing, structural damage in RA.32

Non-TNF inhibitors include treatments targeting cytokines or their receptors (other than TNF), antibodies targeting B lymphocytes, or costimulatory molecules. Anti-IL-1 drugs have not yet demonstrated significant efficacy.3 Treatments targeting inhibition of the IL-6 receptor have fared better than treatments targeting IL-6 itself, as is the case with tocilizumab.3 Abatacept, a cytotoxic T lymphocyte antigen-4, prevents T-cell activation and proliferation by blocking costimulation.3 Rituximab, a chimeric anticluster of differentiation 20 (CD20) monoclonal antibody, is a B-cell—depleting drug that was initially approved for use in non-Hodgkin’s lymphoma. It is approved for use with MTX in patients with RA.3 More recent research, focused on biologics and nonbiologics, has targeted the IL-17 and JAK pathways. Tofacitinib is the first JAK inhibitor approved for use in RA.

Shortcomings of Current Modalities

Patients with RA experience functional declines most rapidly in the early years of the disease. As RA progress and structural damage increases, the possibility of regaining functional capacity is less likely. Accurate diagnosis and early, aggressive treatment can prevent significant functional declines.

Biologics have demonstrated superior efficacy with a more rapid onset of action as compared with traditional nonbiologic DMARDs.35 However, this has been accompanied by significant safety issues, including an increased risk of serious infections and malignancies. Furthermore, the cost of treatment with the newer agents is sometimes prohibitive. Primary and secondary ineffectiveness have been a problem.32 Between 20% and 50% of adults and adolescents treated with TNF inhibitors fail to achieve a 20% improvement in ACR criteria (the current definition of responsiveness) with these agents.32,37-42 Over time, loss of responsiveness (called secondary inefficacy, secondary failure, or acquired therapeutic resistance) occurs in 10% to 50% of patients, as measured by the need to dose-intensify the biologic or co-therapy, switch to a different biologic, or discontinue biologic therapy altogether.43-45 Of significant concern is the development of antidrug antibodies, which not only decrease a drug’s efficacy by neutralizing the biologic agent, but also increase the biologic’s clearance. In patients treated with infliximab, patients with detectable levels of anti-infliximab antibodies after 6 weeks of treatment had an increased risk of adverse drug reactions (HR = 5.06; 95% CI 2.36, 10.84; P < .0001) compared with patients without anti-infliximab antibodies.46 Patients with detectable anti-infliximab antibodies at any time during the trial period (52-week follow-up) were less likely to achieve sustained minimal disease activity or remission.46 In general, approximately 60% to 80% of patients who experience loss of responsiveness are helped by switching to an alternative TNF inhibitor.47-50

In patients who failed to respond to the combination of infliximab + MTX (primary and secondary nonresponders and those who demonstrated toxicity), 38% achieved an ACR 20% response (ACR20) after 12 weeks of etanercept—38% of patients in the study achieved 20% improvement in tender or swollen joint counts and 20% improvement in 3 of the other 5 ACR criteria. These included 24% who achieved an ACR50 response (50% improvement in tender or swollen joint counts and 50% improvement in 3 of the other 5 ACR criteria) and 15% who achieved an ACR70 response (70% improvement in tender or swollen joint counts and 70% improvement in 3 of the other 5 ACR criteria). Among the primary nonresponders to infliximab, 42% achieved an ACR20, confirming the effectiveness of etanercept in patients who fail to respond to infliximab.47 Similarly, in patients who were secondary nonresponders to infliximab or etanercept, treatment with adalimumab restored a good clinical response with significant increases in DAS28 in as little as 3 months. ACR20 responses ranged between 70% and 78% in all groups switching to adalimumab.50 However, some observational data suggests that switching between TNF-inhibitors is more successful in patients who have had a secondary treatment failure (or a failure due to an adverse event) than in patients who are primary nonresponders, or in those who have failed more than 2 previous TNF biologics.51

Patients who are unresponsive or intolerant of biological therapies can often use biologics with alternative mechanisms of action. These include rituximab (an anti-CD20 B-cell—depleting therapy), abatacept (a T-cell costimulation blocking agent) and tocilizumab (anti-IL-6 receptor monoclonal antibody). A small molecule inhibitor, such as tofacitinib, can also be used.40

Unfortunately, the current guidelines base recommendations on broadly defined drug classes—DMARDs, TNF-inhibitors, or non-TNF biologics. They do not differentiate between the individual agents, leaving clinicians to determine a treatment plan for patients with inadequate response based on their familiarity with alternatives.8,43 Clearly, no current approach meets the goals of therapy for RA—slowing disease progression, while improving the patient’s well-being, and ideally, creating complete clinical remission that is verifiable by radiography and patient reports. Researchers continue to look for the exact cause of RA and interventions that will target specific pathways with fewer adverse effects.

Recent and Emerging Treatments and Recommendations

Polymorphisms in the HLA region are often used to define subsets of RA and potential interventions. Possible interventions involve classical cytokine blockades of TNF, IL-6, or IL-1. In addition, research is examining potential targets, including toll-like receptors and other molecules, chemokines, and chemokine receptors—such as IL-8 and its receptors.21 Studies focusing on the preclinical stages of RA will not only add to the understanding of disease pathophysiology, but also provide valuable insight leading to the development of early biomarkers for diagnosis and treatment targets.12 Currently available cytokine blockers used in treatment assumed that RA was a type 1 T helper-mediated immune inflammatory disease. Now, with research showing the involvement of other agents, treatment of RA can look toward hindering the disease along multiple pathways.52 However, caution must be observed. Currently, the hierarchy of pathophysiologic responses in RA is unclear, as is our understanding of how targeting subsets may impact the inflammatory process in the individual, especially the potential of systemic immunosuppression.27

Pharmaceutical Research and Manufacturers of America reports that of the 92 drugs and biologics that are in the development pipeline for all types of rheumatologic conditions, the majority (55) are for RA.53 Two paths of interest in RA are currently considered among the most promising: IL-17 and intracellular JAK. Agents targeting IL-17, which are already being used clinically for psoriatic arthritis, may represent the next generation of RA treatments, and may raise the bar for clinical intervention.54 Tofacitinib, an intracellular JAK inhibitor is currently approved by the FDA for RA unresponsive to MTX; there are several others, such as baricitinib, in regulatory review.55

Conclusion

Overall, advances in approaches to RA have changed dramatically in recent years, resulting in a paradigm shift in how RA is diagnosed and treated. Greater understanding of the aberrations of RA at the cellular level has resulted in the appreciation of the importance of early diagnosis, early therapy initiation, and targeted treatment. The end result of these efforts is to minimize disease progression and effectively achieve the goals of RA treatment over time.

Author affiliation: UCLA David Geffen School of Medicine, Los Angeles, CA.

Funding source: This activity is supported by an educational grant from Lilly.

Author disclosure: Dr McMahon has no relevant financial relationships with commercial interests to disclose.

Authorship information: Drafting of the manuscript; critical revision of the manuscript for important intellectual content; and supervision.

Address correspondence to: mmcmahon@mednet.ucla.edu

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