Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Allison B. Reiss
 + 2910 word(s) 2910 2021-12-28 07:10:55 |
2 format correct
Bruce Ren
 Meta information modification 2910 2022-01-19 01:53:19 | |
3 Expanded CV risk for JAK inhibitor section
Steven E Carsons
 + 24 word(s) 2934 2022-01-20 20:25:55 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Reiss, A.B.; Ahmed, S.; Jacob, B.; Carsons, S.; De Leon, J. Treatment of Cardiovascular Disease in Rheumatoid Arthritis. Encyclopedia. Available online: https://encyclopedia.pub/entry/18451 (accessed on 17 May 2024).
Reiss AB, Ahmed S, Jacob B, Carsons S, De Leon J. Treatment of Cardiovascular Disease in Rheumatoid Arthritis. Encyclopedia. Available at: https://encyclopedia.pub/entry/18451. Accessed May 17, 2024.
Reiss, Allison B., Saba Ahmed, Benna Jacob, Steven Carsons, Joshua De Leon. "Treatment of Cardiovascular Disease in Rheumatoid Arthritis" Encyclopedia, https://encyclopedia.pub/entry/18451 (accessed May 17, 2024).
Reiss, A.B., Ahmed, S., Jacob, B., Carsons, S., & De Leon, J. (2022, January 18). Treatment of Cardiovascular Disease in Rheumatoid Arthritis. In Encyclopedia. https://encyclopedia.pub/entry/18451
Reiss, Allison B., et al. "Treatment of Cardiovascular Disease in Rheumatoid Arthritis." Encyclopedia. Web. 18 January, 2022.
Treatment of Cardiovascular Disease in Rheumatoid Arthritis
Edit
This entry is adapted from the peer-reviewed paper 10.3390/ph15010011

Rheumatoid arthritis (RA) carries significant risk for atherosclerotic cardiovascular disease (ASCVD). Traditional ASCVD risk factors fail to account for this accelerated atherosclerosis. Shared inflammatory pathways are fundamental in the pathogenesis of both diseases. Considering the impact of RA in increasing cardiovascular morbidity and mortality, the characterization of therapies encompassing both RA and ASCVD management merit high priority. Despite little progress, several drugs discussed here promote remission and or lower rheumatoid disease activity while simultaneously conferring some level of atheroprotection. Methotrexate, a widely used disease-modifying drug used in RA, is associated with significant reduction in cardiovascular adverse events. MTX promotes cholesterol efflux from macrophages, upregulates free radical scavenging and improves endothelial function. Likewise, the sulfonamide drug sulfasalazine positively impacts the lipid profile by increasing HDL-C, and its use in RA has been correlated with reduced risk of myocardial infraction.

methotrexate hydoxychloroquine TNF-α cholesterol atherosclerosis rheumatoid arthritis cytokines ABC transporters

1. Introduction

Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disorder associated with the breakdown of immune tolerance [1]. It affects women disproportionately and usually presents between the ages of 40–60 [2][3]. Worldwide prevalence of RA is approximately 0.5–1% [4]. This disorder primarily manifests as joint pain, swelling and stiffness. Over time, uncontrolled inflammation leads to disease progression, irreversible destruction of cartilage and bone, and ultimately to reduced range of motion and severe physical disability [5]. Since RA is a systemic disease, extra-articular manifestations can affect multiple organ systems. Lung involvement is the most common, but vasculitis and rheumatoid nodules on the skin are also observed [6][7][8].
Dyslipidemia and atherosclerosis are major comorbidities associated with RA [9]. It is well established that RA confers increased risk for atherosclerotic cardiovascular disease (ASCVD), a chronic inflammatory and lipid-depository disease [10][11]. Traditional ASCVD risk factors fail to fully account for this increase, making it difficult to identify and treat these patients at the preclinical stage [12][13][14]. In comparison to the general population, RA patients have a CVD risk approximately 50% higher and a 1.6 times higher rate of acute myocardial infarction and ischemic stroke [15][16]. The risk of myocardial infarction is on a par with that of persons with diabetes mellitus [17].
ASCVD adds to the substantial burden on RA patients, contributing to overall morbidity, decline in physical function, and diminished quality of life [18][19].

2. Treatment of RA—Does It Address CVD Risk?

Considering the significant impact on RA morbidity and mortality, the development of treatments that incorporate ASCVD management would be expected to merit high priority, but surprisingly little progress has been achieved. The current goal of RA therapy is remission or low disease activity, characterized as a state with minimal joint pain and swelling, prevention of joint deformities and radiographic damage, maintenance of quality of life and control of extra-articular manifestations [20][21][22] obtainable in approximately 10–50% of patients
Given the substantial strain this chronic disease carries for both the individual and society, extensive research into its treatment has been conducted. DMARDs, which are slow-acting agents beneficial in improving the symptoms and radiographic progression, remain at the forefront of therapy [23][24][25]. Methotrexate has dominated the DMARDs as the medication of choice; however, alternatives include leflunomide, sulfasalazine and hydroxychloroquine. Numerous studies have led to the understanding that combination therapies are more effective than mono-therapies. Considering the significant role cytokines and other molecules play in the pathology of the disease, relatively newer treatments utilizing these biological targets have also emerged in recent times [23][24]. These drugs accomplish their goal via four main mechanism: blockade of TNF-α, inhibiting IL-6, blocking T-cell co-stimulation as well as depletion of B-cell. While non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids can relieve pain and inflammation, they do not prevent progressive joint damage and their long-term use may be harmful [25][26]. Ancillary therapies including physical activity, exercise, muscle strengthening and diets supporting a healthy microbiome are also implemented. In severe cases, when the damage is too advanced total joint replacement, most commonly of the hip or knee, may be required.
The NIH funded clinical trial, Treatments Against RA and Effect on FDG-PET/CT (fluorodeoxyglucose-positron emission tomography with computed tomography) (TARGET, NCT02374021) [27], aims to determine whether anti-inflammatory DMARDs used to treat RA also reduced the risk of CVD. This will be accomplished by comparing two separate therapies, administration of methotrexate (MTX) combined with a TNF-α inhibitor or triple therapy with MTX, sulfasalazine and hydroxychloroquine. This paper explores the effects of cholesterol-lowering therapy and of the individual drugs used in TARGET on development of ASCVD as we move toward discovering which, if any, combinations confer optimal atheroprotection.

3. ASCVD Management in RA

3.1. Cardiovascular-Specific Use of Statins

Currently, the front-line pre-emptive method to address atherosclerosis is the use of statins regardless of LDL levels [28][29][30]. The beneficial effects of statins include not only lipid-lowering, but also immunomodulation and quelling of inflammation [31]. Statins subdue vascular inflammation by reducing expression of IL-6, high-sensitivity C-reactive protein, and homocysteine [32][33]. Their cholesterol-independent pleiotropic effects extend to improving endothelial function and lowering oxidative stress [34]. They inhibit vascular smooth muscle proliferation and platelet aggregation [35]. They modulate the functions of adhesion molecules and reduce monocytes adhesion to endothelial cells. Statins have not been found to change the course of RA itself and thus are given specifically for cardiovascular risk reduction [36].

3.2. Drugs That Treat RA and Their Impact on ASCVD

Therapies directed against RA that also mitigate some of the associated CVD risk would be particularly valuable and there are several to be discussed here and summarized in Table 1. Disease-modifying anti-rheumatic drugs (DMARDs), which decrease the inflammation common to RA and ASCVD have a variable track record in atheroprotection. Studies such as TARGET are intended to delve into whether a reduction in inflammation via DMARDs does, in fact, reduce the risk of CVD [27].
Table 1. Therapies Effective Against RA and ASCVD.
DMARDs
Name of Drug Mechanism of Action  
  Anti-rheumatic Properties Atheroprotective Properties
Methotrexate Inhibits dihydrofolate reductase
and several immune pathways involved in purine and pyrimidine synthesis.		 Enhances macrophage cholesterol efflux and prevents foams cell differentiation and activation. Upregulates free radical scavenging; improves
endothelial function.
Sulfasalazine Reduces production of inflammatory cytokines, likely through
inhibition of NF-κB activation.		 Prevents arachidonic acid-mediated platelet aggregation, decreases adhesion of monocytes and leukocytes, and increases HDL-C.
Hydroxychloroquine Interferes with toll-like receptor signaling, reduces calcium signaling in B and T cells and matrix metalloprotease activity Positively impacts insulin sensitization, promotes anti-atherogenic lipid profile. Anti-thrombotic and anticoagulant properties.
Tumor Necrosis Factor (TNF)-α Inhibitors
Etanercept
Infliximab
Adalimumab		 Biologics that inactivate TNF-α.
Etanercept is a fusion protein of human immunoglobulin 1 Fc domain and TNF-α receptor.
Infliximab is a mouse-human chimeric anti-human TNF-α antibody
Adalimumab is a human anti-human TNF-α antibody		 TNF-α promotes numerous inflammatory responses associated with atherosclerosis, including induction of vascular adhesion and monocyte/macrophage proliferation. TNF-α impacts lipid metabolism by stimulating liver triglyceride production.
IL-6 Inhibitors
Tocilizumab Inhibits IL-6 which contributes to
inflammation and antibody production through its action on T cells, B cells, monocytes and neutrophils		 Decreases inflammatory proteins such as serum amyloid A, and restores the anti-atherogenic function of HDL by increasing HDL cholesterol efflux capacity.
JAK Kinase Inhibitors
Tofacitinib Small molecules that target the JAK-STAT signaling pathway. Reduce expression of cytokine related genes. Risk of adverse cardiovascular events still being evaluated. Many studies show no difference compared to placebo or biologic
Upadacitinib More JAK1 selective

3.2.1. Methotrexate

One such DMARD investigated by the TARGET study is MTX, a folic acid analog that inhibits dihydrofolate reductase and reduces the levels of tetrahydrofolate in cells. MTX also inhibits purines and pyrimidines necessary for DNA and RNA synthesis [37]. Another mechanism by which it reduces inflammation is by lowering levels of NF-κB activity [38]. MTX is widely used in the treatment of various inflammatory and autoimmune disorders and it is the initial therapy of choice for RA [39][40]. MTX possesses cardioprotective properties that may reduce CVD morbidity and mortality in patients with RA [41][42][43][44].
Low dose MTX, the gold standard RA treatment, broadly inhibits several immune pathways involved in purine and pyrimidine synthesis, transmethylation reactions, translocation of NF-κB to the nucleus, signaling via the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway and nitric oxide production [45]. The benefits of MTX in reducing joint symptoms in RA can be attributed to these anti-inflammatory mechanisms described above. The protective effects of MTX against CVD can occur indirectly via anti-inflammatory actions and also directly via antiatherogenic effects, such as enhancing cholesterol transport out of monocytes and macrophages and preventing the differentiation and activation of foams cells [46][47][48]. Low-dose MTX also promotes release of the anti-inflammatory endogenous nucleoside adenosine, which acts on its receptors to increase production of ABCA1 and ABCG1, proteins involved in cholesterol efflux from macrophages [49]. MTX also upregulates free radical scavenging and improves endothelial function by reducing the expression of adhesion molecules, consequently inhibiting the recruitment of proinflammatory T cells and monocytes [50]. Of note, by depleting tetrahydrofolate, which is needed for conversion of homocysteine to methionine, MTX may have negative effects on cardiovascular health by raising plasma homocysteine levels, thus contributing to oxidative stress [51]. However, folate supplementation can mitigate this rise in homocysteine, promoting an overall anti-atherogenic effect [50].
In a multicenter prospective cohort study of 2044 US veterans with RA, Johnson et al. [52] found that the use of MTX was associated with a significant reduction in CVD related adverse events. In this study, CVD risk reduction by MTX was independent of age, BMI, traditional CVD risk factors, and RA disease activity. The cardioprotective properties of MTX were not solely due to amelioration of RA disease activity, suggesting that MTX may have direct cardiovascular advantages for patients with RA.

3.2.2. Sulfasalazine

Sulfasalazine, an older anti-rheumatic drug also being investigated in the TARGET study, is a prodrug synthesized from the fusion of the antibiotic sulfapyridine and an NSAID, 5-aminosalicylic acid via an azo bond. This oral sulfonamide drug possesses antithrombotic properties. It inhibits platelet thromboxane synthetase and therefore thromboxane production [53]. Sulfasalazine can prevent arachidonic acid-mediated platelet aggregation, an inhibition equivalent to that produced by aspirin given for protection against CVD [54]. Sulfasalazine decreases proliferation of lymphocytes, and adhesion of monocytes and leukocytes [55]. Sulfasalazine reduces production of inflammatory cytokines, likely through inhibition of NF-κB. As noted previously, NF-κB is a major regulator of genes that promote inflammation and adhesion in cell types involved in atherogenesis [56][57]. Sulfasalazine acts on the NF-κB pathway by preventing the phosphorylation and successive degradation of IκB, the inhibitory subunit of NF-κB [58][59]. Inhibition of NF-κB is considered a viable approach to protection from atherosclerosis development [60].
Sulfasalazine positively impacts the lipid profile, increasing HDL-C and reducing the atherogenic ratio [61][62][63]. Observational data from a QUEST-RA longitudinal cohort study also indicated that longer exposure to sulfasalazine correlated with a reduced risk of CVD events and myocardial infarction [64].

3.2.3. TNF-α Inhibitors

Based upon the pro-atherogenic actions of TNF-α, the reduction in systemic inflammation with the use of biologics such as TNF inhibitors (TNFi) could be expected to contribute to improvements in endothelial function and confer atheroprotection [65][66][67][68]. Commonly used TNF-α inhibitors include etanercept, infliximab and adalimumab [69]. Etanercept is a dimeric fusion protein consisting of the extracellular portion of the human TNF receptor linked to the Fc portion of human immunoglobulin 1 (IgG1). It targets free TNF-α and TNF-β. Infliximab is a chimeric monoclonal antibody with a murine variable region that specifically binds to human TNF-α. Adalimumab is a fully human monoclonal anti-TNF-α antibody. All exert their effect by neutralizing circulating TNF-α.
A 5-year study that compared RA patients who were biologic-naïve receiving only synthetic DMARDs and those taking a TNFi (either etanercept, infliximab or adalimumab) found that the risk of myocardial infarction decreased by 39% in the latter group [70]. Vegh et al. showed that one year of TNFi treatment significantly improved pulse–wave velocity, a marker of arterial stiffness and resulted in no significant increase in common carotid intima-media thickness in a mixed cohort of RA and ankylosing spondylitis patients [71]. Serum levels of biomarkers for atherosclerosis may be reduced by TNFi treatment in RA patients. Pusztai et al. followed 53 RA patients on TNFi for one year and found that this treatment significantly decreased the level of circulating complexes of oxLDL bound to β2-glycoprotein [72]. These complexes can be taken up into macrophages to form foam cells and are associated with the development of acute coronary syndromes [73].
Additionally, higher levels of TNF-α may amplify standard cardiac risk factors such as diabetes and dyslipidemia in patients with RA [74][75]. Insulin resistance has been associated with elevated levels of TNF-α in RA patients [76]. TNF-α promotes insulin resistance by directly suppressing activities of insulin-induced insulin receptor substrate-1 and peroxisome proliferator-activated receptor gamma (PPAR-γ) [74][75]. TNFi increases insulin sensitivity in RA patients compared to patients not receiving biologics [77].
The effects of TNFi on lipid profile are unclear, with some studies showing an increase in LDL with treatment [78]. However, other studies show no effect, and a recent study from Korea found no detrimental impact over a four year period [79][80][81].

3.2.4. IL-6 Inhibitors

The introduction of biologic drugs has considerably improved the outcome for patients with RA, but at the same time certain drugs, specifically the IL-6 inhibitors (i.e., tocilizumab), have been a source of controversy in terms of their effects on cardiovascular health, especially with regard to their effects on the lipid profile [82]. A representative prospective study revealed that in patients undergoing tocilizumab therapy, serum concentrations of total cholesterol, LDL, HDL and triglycerides increased during the first 24 weeks of treatment [83]. The results of several randomized clinical trials also showed increased LDL levels in tocilizumab-treated RA patients, of a magnitude greater than the increase seen in RA patients treated with conventional DMARDs [84][85]. Nevertheless, recent studies have shown encouraging data regarding major adverse cardiovascular events with tocilizumab compared to other biologic DMARDs. Two studies conducted underscored a significant decrease in cardiovascular events with this drug [86][87]. Zhang et al., revealed that tocilizumab reduced the risk of myocardial infarction significantly more than abatacept, another biologic DMARD [86]. Kim et al. indicated better cardiovascular outcomes with tocilizumab when compared to TNFi [87]. Furthermore, tocilizumab decreases inflammatory proteins such as serum amyloid A and may restore the anti-atherogenic function of HDL [88]. Effects on HDL are observed directly in recent studies that found tocilizumab to increase HDL cholesterol efflux capacity in RA [89][90]. Cholesterol efflux capacity is considered a strong negative ASCVD risk determinant [91]. The atherogenic lipoprotein Lp(a) was also reduced by tocilizumab [92][93].

3.2.5. JAK Kinase Inhibitors

JAK inhibitors, small molecules that target the JAK-STAT signaling pathway, are targeted synthetic DMARDs for the treatment of RA and other immune-mediated inflammatory diseases [94][95]. Unlike the protein-based biologic DMARDs, the JAK inhibitors do not cause formation of anti-drug antibodies and can be taken orally [96]. Unfortunately, the JAK inhibitors are associated with risk of venous thromboembolism and pulmonary embolism [97]. The effect of these drugs on cardiovascular risk has not yet been determined as data is inconclusive. Charles-Schoeman et al. pooled data from multiple studies on the first generation JAK inhibitor tofacitinib showed low incidence of cardiac adverse events, comparable to that found with placebo [98]. A further study by Charles-Shoeman with post hoc analysis, after 24 weeks of tofacitinib showed increased HDL levels which was associated with lower cardiovascular event risk [99]. A long-term study over 9.5 years found incidence rates for major adverse cardiovascular event with tofacitinib of 0.4 with events per 100 patient-years, which is comparable to those seen with biologic agents [100]. Upadacitinib, a newer and more selective JAK1 inhibitor, has shown comparable effects on cardiovascular risk to placebo and other JAK inhibitors. It raised both HDL and LDL while leaving the HDL-to-LDL ratio constant [101]. Recent studies have demonstrated an increased risk of cardiovascular events in patients taking higher doses of JAK inhibitors. This risk is enhanced for smokers.  The overall cardiac event risk from these drugs appears low, but more studies are in progress [102][103].

3.2.6. HCQ: A Potential Double Agent

Despite its original intended purpose as an anti-parasitic agent, the therapeutic impact of HCQ extends beyond malaria to multiple autoimmune diseases in which it acts as an immunomodulator and its potential benefits continue to emerge [25][104][105][106]. HCQ can improve the survival rates of patients with various autoimmune diseases including RA and systemic lupus erythematosus (SLE) via its immunosuppressive and anti-inflammatory activity [107][108][109].
HCQ is a weak basic 4-aminoquinoline compound that differs from chloroquine by the placement of a single hydroxyl group [106][107]. This subtle alteration decreases toxicity while conserving efficacy, rendering it safer and therefore preferable to chloroquine [105]. The drug is administered orally, as a sulfate tablet, and appears to be well-tolerated, with efficient absorption, a large volume of distribution and bioavailability, as well as a prolonged half-life of about 40–50 days [110]. Approximately 50% of HCQ remains plasma bound and is metabolized into three metabolites, desethyl-chloroquine, desethyl-hydroxychloroquine, and bis-desethyl-hydroxychloroquine, in the liver.
Although the exact mechanisms of action of this compound remain uncertain, it is postulated that immunosuppression results from its ability to block the stimulation of toll-like receptors, suppress T-cell proliferation, inhibit autophagy and reduce macrophage-mediated cytokine production and calcium signaling in B and T cells [111][112]. Its atheroprotective attributes may be due to the reduction in circulating cytokines such as Il-1, IL-6 and TNF-α [113].
In addition to its role as an anti-rheumatic drug, HCQ has anti-diabetic and cardioprotective capabilities. It improves glycemic control, positively impacts insulin sensitivity and metabolism, favorably influences the lipid profile and has anti-thrombotic and anticoagulant properties [105][107][114][115][116][117]. In RA patients, HCQ improves microvascular endothelial function in RA [118].
Additionally, HCQ is a favorable candidate for not only RA treatment but also the management of CVD in these patients as there are few contraindications and adverse effects. The most common side effects predominantly relate to the gastrointestinal issues, such as nausea, vomiting and diarrhea [119]. Although rare, the possibility of developing retinal, neuromuscular, cardiac, and hematological impairments, including retinopathy, does exist [120]. Despite its limited efficacy in the treatment of RA when used alone, HCQ’s utilization in combination therapies may have a significant impact on the cardiovascular risks associated with this rheumatic disease, thereby reducing the burden for both the individual and society [121].

References

  1. Gibofsky, A. Epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis: A synopsis. Am. J. Manag. Care 2014, 20 (Suppl. 7), S128–S135.
  2. Safiri, S.; Kolahi, A.A.; Hoy, D.; Smith, E.; Bettampadi, D.; Mansournia, M.A.; Almasi-Hashiani, A.; Ashrafi-Asgarabad, A.; Moradi-Lakeh, M.; Qorbani, M.; et al. Global, regional and national burden of rheumatoid arthritis 1990–2017: A systematic analysis of the global burden of disease study 2017. Ann. Rheum. Dis. 2019, 78, 1463–1471.
  3. Tedeschi, S.K.; Bermas, B.; Costenbader, K.H. Sexual disparities in the incidence and course of SLE and RA. Clin. Immunol. 2013, 149, 211–218.
  4. Hunter, T.M.; Boytsov, N.N.; Zhang, X.; Schroeder, K.; Michaud, K.; Araujo, A.B. Prevalence of rheumatoid arthritis in the United States adult population in healthcare claims databases, 2004–2014. Rheumatol. Int. 2017, 37, 1551–1557.
  5. McInnes, I.B.; Schett, G. Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet 2017, 389, 2328–2337.
  6. García-Patos, V. Rheumatoid nodule. Semin. Cutan. Med. Surg. 2007, 26, 100–107.
  7. Yunt, Z.X.; Solomon, J.J. Lung Disease in Rheumatoid Arthritis. Rheum. Dis. Clin. N. Am. 2015, 41, 225–236.
  8. Prete, M.; Racanelli, V.; Digiglio, L.; Vacca, A.; Dammacco, F.; Perosa, F. Extra-articular manifestations of rheumatoid arthritis: An update. Autoimmun. Rev. 2011, 11, 123–131.
  9. Toms, T.E.; Symmons, D.P.; Kitas, G.D. Dyslipidaemia in rheumatoid arthritis: The role of inflammation, drugs, lifestyle and genetic factors. Curr. Vasc. Pharmacol. 2010, 8, 301–326.
  10. Holmqvist, M.E.; Wedrén, S.; Jacobsson, L.T.; Klareskog, L.; Nyberg, F.; Rantapää-Dahlqvist, S.; Alfredsson, L.; Askling, J. Rapid increase in myocardial infarction risk following diagnosis of rheumatoid arthritis amongst patients diagnosed between 1995 and 2006. J. Intern. Med. 2010, 268, 578–585.
  11. Koren Krajnc, M.; Hojs, R.; Holc, I.; Knez, Ž.; Pahor, A. Accelerated atherosclerosis in premenopausal women with rheumatoid arthritis—15-year follow-up. Bosn. J. Basic Med. Sci. 2021, 21, 477–483.
  12. Skeoch, S.; Bruce, I.N. Atherosclerosis in rheumatoid arthritis: Is it all about inflammation? Nat. Rev. Rheumatol. 2015, 11, 390–400.
  13. del Rincón, I.D.; Williams, K.; Stern, M.P.; Freeman, G.L.; Escalante, A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum. 2001, 44, 2737–2745.
  14. Björsenius, I.; Rantapää-Dahlqvist, S.; Berglin, E.; Södergren, A. Extent of atherosclerosis after 11-year prospective follow-up in patients with early rheumatoid arthritis was affected by disease severity at diagnosis. Scand. J. Rheumatol. 2020, 49, 443–451.
  15. Aviña-Zubieta, J.A.; Choi, H.K.; Sadatsafavi, M.; Etminan, M.; Esdaile, J.M.; Lacaille, D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: A meta-analysis of observational studies. Arthritis Rheum. 2008, 59, 1690–1697.
  16. Semb, A.G.; Kvien, T.K.; Aastveit, A.H.; Jungner, I.; Pedersen, T.R.; Walldius, G.; Holme, I. Lipids, myocardial infarction and ischaemic stroke in patients with rheumatoid arthritis in the Apolipoprotein-related Mortality RISk (AMORIS) Study. Ann. Rheum. Dis. 2010, 69, 1996–2001.
  17. Lindhardsen, J.; Ahlehoff, O.; Gislason, G.H.; Madsen, O.R.; Olesen, J.B.; Torp-Pedersen, C.; Hansen, P.R. The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: A Danish nationwide cohort study. Ann. Rheum. Dis. 2011, 70, 929–934.
  18. Cross, M.; Smith, E.; Hoy, D.; Carmona, L.; Wolfe, F.; Vos, T.; Williams, B.; Gabriel, S.; Lassere, M.; Johns, N.; et al. The global burden of rheumatoid arthritis: Estimates from the global burden of disease 2010 study. Ann. Rheum. Dis. 2014, 73, 1316–1322.
  19. Ghosh-Swaby, O.R.; Kuriya, B. Awareness and perceived risk of cardiovascular disease among individuals living with rheumatoid arthritis is low: Results of a systematic literature review. Arthritis Res. Ther. 2019, 21, 33.
  20. Solomon, D.H.; Bitton, A.; Katz, J.N.; Radner, H.; Brown, E.M.; Fraenkel, L. Review: Treat to target in rheumatoid arthritis: Fact, fiction, or hypothesis? Arthritis Rheumatol. 2014, 66, 775–782.
  21. Bugatti, S.; De Stefano, L.; Manzo, A.; Sakellariou, G.; Xoxi, B.; Montecucco, C. Limiting factors to Boolean remission differ between autoantibody-positive and -negative patients in early rheumatoid arthritis. Ther. Adv. Musculoskelet. Dis. 2021, 13, 1759720X211011826.
  22. Smolen, J.S.; Landewé, R.; Bijlsma, J.; Burmester, G.; Chatzidionysiou, K.; Dougados, M.; Nam, J.; Ramiro, S.; Voshaar, M.; van Vollenhoven, R.; et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann. Rheum. Dis. 2017, 76, 960–977.
  23. Wasserman, A.M. Diagnosis and management of rheumatoid arthritis. Am. Fam. Physician 2011, 84, 1245–1252.
  24. Burmester, R.; Pope, J.E. Novel treatment strategies in rheumatoid arthritis. Lancet 2017, 389, 2338–2348.
  25. Abbasi, M.; Mousavi, M.J.; Jamalzehi, S.; Alimohammadi, R.; Bezvan, M.H.; Mohammadi, H.; Aslani, S. Strategies toward rheumatoid arthritis therapy; the old and the new. J. Cell Physiol. 2019, 234, 10018–10031.
  26. Kavanaugh, A.; Wells, A.F. Benefits and risks of low-dose glucocorticoid treatment in the patient with rheumatoid arthritis. Rheumatology 2014, 53, 1742–1751.
  27. Giles, J.T.; Rist, P.M.; Liao, K.P.; Tawakol, A.; Fayad, Z.A.; Mani, V.; Paynter, N.P.; Ridker, P.M.; Glynn, R.J.; Lu, F.; et al. Testing the Effects of Disease-Modifying Antirheumatic Drugs on Vascular Inflammation in Rheumatoid Arthritis: Rationale and Design of the TARGET Trial. ACR Open Rheumatol. 2021, 3, 371–380.
  28. Liao, K.P. Cardiovascular disease in patients with rheumatoid arthritis. Trends Cardiovasc. Med. 2017, 27, 136–140.
  29. Masson, W.; Rossi, E.; Alvarado, R.N.; Cornejo-Peña, G.; Damonte, J.I.; Fiorini, N.; Mora-Crespo, L.M.; Tobar-Jaramillo, M.A.; Scolnik, M. Rheumatoid Arthritis, Statin Indication and Lipid Goals: Analysis According to Different Recommendations. Rheumatol. Clin. 2021.
  30. Chhibber, A.; Hansen, S.; Biskupiak, J. Statin use and mortality in rheumatoid arthritis: An incident user cohort study. J. Manag. Care Spec. Pharm. 2021, 27, 296–305.
  31. Abeles, A.M.; Pillinger, M.H. Statins as anti-inflammatory and immunomodulatory agents: A future in rheumatologic therapy? Arthritis Rheum. 2006, 54, 393–407.
  32. Asher, J.; Houston, M. Statins and C-reactive protein levels. J. Clin. Hypertens. 2007, 9, 622–628.
  33. Koushki, K.; Shahbaz, S.K.; Mashayekhi, K.; Sadeghi, M.; Zayeri, Z.D.; Taba, M.Y.; Banach, M.; Al-Rasadi, K.; Johnston, T.P.; Sahebkar, A. Anti-inflammatory Action of Statins in Cardiovascular Disease: The Role of Inflammasome and Toll-Like Receptor Pathways. Clinic. Rev. Allerg. Immunol. 2021, 60, 175–199.
  34. Oesterle, A.; Laufs, U.; Liao, J.K. Pleiotropic effects of statins on the cardiovascular system. Circ. Res. 2017, 120, 229–243.
  35. Oesterle, A.; Liao, J.K. The Pleiotropic effects of statins—From coronary artery disease and stroke to atrial fibrillation and ventricular tachyarrhythmia. Curr. Vasc. Pharmacol. 2019, 17, 222–232.
  36. van Boheemen, L.; Turk, S.; Beers-Tas, M.V.; Bos, W.; Marsman, D.; Griep, E.N.; Starmans-Kool, M.; Popa, C.D.; van Sijl, A.; Boers, M.; et al. Atorvastatin is unlikely to prevent rheumatoid arthritis in high risk individuals: Results from the prematurely stopped STAtins to Prevent Rheumatoid Arthritis (STAPRA) trial. RMD Open 2021, 7, e001591.
  37. Sramek, M.; Neradil, J.; Veselska, R. Much more than you expected: The non-DHFR-mediated effects of methotrexate. Biochim. Biophys. Acta Gen. Subj. 2017, 1861, 499–503.
  38. Pang, Z.; Wang, G.; Ran, N.; Lin, H.; Wang, Z.; Guan, X.; Yuan, Y.; Fang, K.; Liu, J.; Wang, F. Inhibitory Effect of Methotrexate on Rheumatoid Arthritis Inflammation and Comprehensive Metabolomics Analysis Using Ultra-Performance Liquid Chromatography-Quadrupole Time of Flight-Mass Spectrometry (UPLC-Q/TOF-MS). Int. J. Mol. Sci. 2018, 19, 2894.
  39. Singh, J.A.; Saag, K.G.; Bridges, S.L., Jr.; Akl, E.A.; Bannuru, R.R.; Sullivan, M.C.; Vaysbrot, E.; McNaughton, C.; Osani, M.; Shmerling, R.H.; et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2016, 68, 1–25.
  40. Smolen, J.S.; Landewé, R.B.M.; Bijlsma, J.W.J.; Burmester, G.R.; Dougados, M.; Kerschbaumer, A.; McInnes, I.B.; Sepriano, A.; van Vollenhoven, R.F.; de Wit, M.; et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann. Rheum. Dis. 2020, 79, 685–699.
  41. Choi, H.K.; Hernán, M.A.; Seeger, J.D.; Robins, J.M.; Wolfe, F. Methotrexate and mortality in patients with rheumatoid arthritis: A prospective study. Lancet 2002, 359, 1173–1177.
  42. Verhoeven, F.; Prati, C.; Chouk, M.; Demougeot, C.; Wendling, D. Methotrexate and cardiovascular risk in rheumatic diseases: A comprehensive review. Expert Rev. Clin. Pharmacol. 2021, 1–8.
  43. Sun, K.J.; Liu, L.L.; Hu, J.H.; Chen, Y.Y.; Xu, D.Y. Methotrexate can prevent cardiovascular events in patients with rheumatoid arthritis: An updated meta-analysis. Medicine 2021, 100, e24579.
  44. Coomes, E.; Chan, E.S.; Reiss, A.B. Methotrexate in atherogenesis and cholesterol metabolism. Cholesterol 2011, 2011, 503028.
  45. Cronstein, B.N.; Aune, T.M. Methotrexate and its mechanisms of action in inflammatory arthritis. Nat. Rev. Rheumatol. 2020, 16, 145–154.
  46. Reiss, A.B.; Cronstein, B.N. Regulation of foam cells by adenosine. Arterioscler. Thromb. Vasc. Biol. 2012, 32, 879–886.
  47. Reiss, A.B.; Carsons, S.E.; Anwar, K.; Rao, S.; Edelman, S.D.; Zhang, H.; Fernandez, P.; Cronstein, B.N.; Chan, E.S. Atheroprotective effects of methotrexate on reverse cholesterol transport proteins and foam cell transformation in human THP-1 monocyte/macrophages. Arthritis Rheum. 2008, 58, 3675–3683.
  48. Chen, D.Y.; Chih, H.M.; Lan, J.L.; Chang, H.Y.; Chen, W.W.; Chiang, E.P. Blood lipid profiles and peripheral blood mononuclear cell cholesterol metabolism gene expression in patients with and without methotrexate treatment. BMC Med. 2011, 9, 4.
  49. Reiss, A.B.; Grossfeld, D.; Kasselman, L.J.; Renna, H.A.; Vernice, N.A.; Drewes, W.; Konig, J.; Carsons, S.E.; DeLeon, J. Adenosine and the Cardiovascular System. Am. J. Cardiovasc. Drugs 2019, 19, 449–464.
  50. Atzeni, F.; Rodríguez-Carrio, J.; Popa, C.D.; Nurmohamed, M.T.; Szűcs, G.; Szekanecz, Z. Cardiovascular effects of approved drugs for rheumatoid arthritis. Nat. Rev. Rheumat. 2021, 17, 270–290.
  51. Chaabane, S.; Messedi, M.; Akrout, R.; Ben Hamad, M.; Turki, M.; Marzouk, S.; Keskes, L.; Bahloul, Z.; Rebai, A.; Ayedi, F.; et al. Association of hyperhomocysteinemia with genetic variants in key enzymes of homocysteine metabolism and methotrexate toxicity in rheumatoid arthritis patients. Inflamm. Res. 2018, 67, 703–710.
  52. Johnson, T.M.; Sayles, H.R.; Baker, J.F.; George, M.D.; Roul, P.; Zheng, C.; Sauer, B.; Liao, K.P.; Anderson, D.R.; Mikuls, T.R.; et al. Investigating changes in disease activity as a mediator of cardiovascular risk reduction with methotrexate use in rheumatoid arthritis. Ann. Rheum. Dis. 2021, annrheumdis-2021-220125.
  53. Stenson, W.F.; Lobos, E.A. Inhibition of platelet thromboxane synthetase by sulphasalazine. Biochem. Pharmacol. 1983, 32, 2205–2209.
  54. MacMullan, P.A.; Madigan, A.M.; Paul, N.; Peace, A.J.; Alagha, A.; Nolan, K.B.; McCarthy, G.M.; Kenny, D. Sulfasalazine and its metabolites inhibit platelet function in patients with inflammatory arthritis. Clin. Rheumatol. 2016, 35, 447–455.
  55. Day, A.L.; Singh, J.A. Cardiovascular Disease Risk in Older Adults and Elderly Patients with Rheumatoid Arthritis: What Role Can Disease-Modifying Antirheumatic Drugs Play in Cardiovascular Risk Reduction? Drugs Aging 2019, 36, 493–510.
  56. Kim, I.; Moon, S.O.; Kim, S.H.; Kim, H.J.; Koh, Y.S.; Koh, G.Y. Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-kappa B activation in endothelial cells. J. Biol. Chem. 2001, 276, 7614–7620.
  57. Pamukcu, B.; Lip, G.Y.; Shantsila, E. The nuclear factor—kappa B pathway in atherosclerosis: A potential therapeutic target for atherothrombotic vascular disease. Thromb. Res. 2011, 128, 117–123.
  58. Tabit, C.E.; Holbrook, M.; Shenouda, S.M.; Dohadwala, M.M.; Widlansky, M.E.; Frame, A.A.; Kim, B.H.; Duess, M.A.; Kluge, M.A.; Levit, A.; et al. Effect of sulfasalazine on inflammation and endothelial function in patients with established coronary artery disease. Vasc. Med. 2012, 17, 101–107.
  59. Wahl, C.; Liptay, S.; Adler, G.; Schmid, R.M. Sulfasalazine: A potent and specific inhibitor of nuclear factor kappa B. J. Clin. Investig. 1998, 101, 1163–1174.
  60. Pateras, I.; Giaginis, C.; Tsigris, C.; Patsouris, E.; Theocharis, S. NF-κB signaling at the crossroads of inflammation and atherogenesis: Searching for new therapeutic links. Expert Opin. Ther. Targets 2014, 18, 1089–1101.
  61. Park, Y.B.; Choi, H.K.; Kim, M.Y.; Lee, W.K.; Song, J.; Kim, D.K.; Lee, S.K. Effects of antirheumatic therapy on serum lipid levels in patients with rheumatoid arthritis: A prospective study. Am. J. Med. 2002, 113, 188–193.
  62. Atzeni, F.; Turiel, M.; Caporali, R.; Cavagna, L.; Tomasoni, L.; Sitia, S.; Sarzi-Puttini, P. The effect of pharmacological therapy on the cardiovascular system of patients with systemic rheumatic diseases. Autoimmun. Rev. 2010, 9, 835–839.
  63. Karimifar, M.; Sepehrifar, M.S.; Moussavi, H.; Sepehrifar, M.B.; Mottaghi, P.; Siavash, M.; Karimifar, M. The effects of conventional drugs in the treatment of rheumatoid arthritis on the serum lipids. J. Res. Med. Sci. 2018, 23, 105.
  64. Naranjo, A.; Sokka, T.; Descalzo, M.A.; Calvo-Alén, J.; Hørslev-Petersen, K.; Luukkainen, R.K.; Combe, B.; Burmester, G.R.; Devlin, J.; Ferraccioli, G.; et al. Cardiovascular disease in patients with rheumatoid arthritis: Results from the QUEST-RA study. Arthritis Res. Ther. 2008, 10, R30.
  65. Zanten, J.; Sandoo, A.; Metsios, G.S.; Kalinoglou, A.; Ntoumanis, N.; Kitas, G.D. Comparison of the effects of exercise and anti-TNF treatment on cardiovascular health in rheumatoid arthritis: Results from two controlled trials. Rheumatol. Int. 2019, 39, 219–225.
  66. Barnabe, C.; Martin, B.J.; Ghali, W.A. Systematic review and meta-analysis: Anti-tumor necrosis factor α therapy and cardiovascular events in rheumatoid arthritis. Arthritis Care Res. 2011, 63, 522–529.
  67. Ntusi, N.A.B.; Francis, J.M.; Sever, E.; Liu, A.; Piechnik, S.K.; Ferreira, V.M.; Matthews, P.M.; Robson, M.D.; Wordsworth, P.B.; Neubauer, S.; et al. Anti-TNF modulation reduces myocardial inflammation and improves cardiovascular function in systemic rheumatic diseases. Int. J. Cardiol. 2018, 270, 253–259.
  68. Ait-Oufella, H.; Libby, P.; Tedgui, A. Anticytokine Immune Therapy and Atherothrombotic Cardiovascular Risk. Arterioscler. Thromb. Vasc. Biol. 2019, 39, 1510–1519.
  69. Thalayasingam, N.; Isaacs, J.D. Anti-TNF therapy. Best Pract. Res. Clin. Rheumatol. 2011, 25, 549–567.
  70. Low, A.S.; Symmons, D.P.; Lunt, M.; Mercer, L.K.; Gale, C.P.; Watson, K.D.; Dixon, W.G.; Hyrich, K.L.; British Society for Rheumatology Biologics Register for Rheumatoid Arthritis, BSRBR-RA; BSRBR Control Centre Consortium. Relationship between exposure to tumour necrosis factor inhibitor therapy and incidence and severity of myocardial infarction in patients with rheumatoid arthritis. Ann. Rheum. Dis. 2017, 76, 654–660.
  71. Végh, E.; Kerekes, G.; Pusztai, A.; Hamar, A.; Szamosi, S.; Váncsa, A.; Bodoki, L.; Pogácsás, L.; Balázs, F.; Hodosi, K.; et al. Effects of 1-year anti-TNF-α therapy on vascular function in rheumatoid arthritis and ankylosing spondylitis. Rheumatol. Int. 2020, 40, 427–436.
  72. Pusztai, A.; Hamar, A.; Horváth, Á.; Gulyás, K.; Végh, E.; Bodnár, N.; Kerekes, G.; Czókolyová, M.; Szamosi, S.; Bodoki, L.; et al. Soluble Vascular Biomarkers in Rheumatoid Arthritis and Ankylosing Spondylitis: Effects of 1-year Antitumor Necrosis Factor-α Therapy. J. Rheumatol. 2021, 48, 821–828.
  73. Greco, T.P.; Conti-Kelly, A.M.; Anthony, J.R.; Greco, T., Jr.; Doyle, R.; Boisen, M.; Kojima, K.; Matsuura, E.; Lopez, L.R. Oxidized-LDL/beta2-glycoprotein I complexes are associated with disease severity and increased risk for adverse outcomes in patients with acute coronary syndromes. Am. J. Clin. Pathol. 2010, 133, 737–743.
  74. Karpouzas, G.A.; Bui, V.L.; Ronda, N.; Hollan, I.; Ormseth, S.R. Biologics and atherosclerotic cardiovascular risk in rheumatoid arthritis: A review of evidence and mechanistic insights. Expert Rev. Clin. Immunol. 2021, 17, 355–374.
  75. Grimble, R.F. Inflammatory status and insulin resistance. Curr. Opin. Clin. Nutr. Metab. Care 2002, 5, 551–559.
  76. Chung, C.P.; Oeser, A.; Solus, J.F.; Gebretsadik, T.; Shintani, A.; Avalos, I.; Sokka, T.; Raggi, P.; Pincus, T.; Stein, C.M. Inflammation-associated insulin resistance: Differential effects in rheumatoid arthritis and systemic lupus erythematosus define potential mechanisms. Arthritis Rheum. 2008, 58, 2105–2112.
  77. Avouac, J.; Elhai, M.; Forien, M.; Sellam, J.; Eymard, F.; Molto, A.; Banal, F.; Damiano, J.; Dieudé, P.; Larger, E.; et al. Influence of inflammatory and non-inflammatory rheumatic disorders on the clinical and biological profile of type-2 diabetes. Rheumatology 2021, 60, 3598–3606.
  78. Wijbrandts, C.A.; Leuven, S.I.; Boom, H.D.; Gerlag, D.M.; Stroes, E.G.; Kastelein, J.J.; Tak, P.P. Sustained changes in lipid profile and macrophage migration inhibitory factor levels after anti-tumor necrosis factor therapy in rheumatoid arthritis. Ann. Rheum. Dis. 2009, 68, 1316–1321.
  79. Min, H.K.; Kim, H.R.; Lee, S.H.; Shin, K.; Kim, H.A.; Park, S.H.; Kwok, S.K. Four-year follow-up of atherogenicity in rheumatoid arthritis patients: From the nationwide Korean College of Rheumatology Biologics Registry. Clin. Rheumatol. 2021, 40, 3105–3113.
  80. Cacciapaglia, F.; Anelli, M.G.; Rinaldi, A.; Serafino, L.; Covelli, M.; Scioscia, C.; Iannone, F.; Lapadula, G. Lipid profile of rheumatoid arthritis patients treated with anti-tumor necrosis factor-alpha drugs changes according to disease activity and predicts clinical response. Drug Dev. Res. 2014, 75 (Suppl. 1), S77–S80.
  81. Daïen, C.I.; Duny, Y.; Barnetche, T.; Daurès, J.P.; Combe, B.; Morel, J. Effect of TNF inhibitors on lipid profile in rheumatoid arthritis: A systematic review with meta-analysis. Ann. Rheum. Dis. 2012, 71, 862–868.
  82. Cacciapaglia, F.; Anelli, M.G.; Rinaldi, A.; Fornaro, M.; Lopalco, G.; Scioscia, C.; Lapadula, G.; Iannone, F. Lipids and Atherogenic Indices Fluctuation in Rheumatoid Arthritis Patients on Long-Term Tocilizumab Treatment. Mediat. Inflamm. 2018, 2018, 2453265.
  83. Jones, G.; Sebba, A.; Gu, J.; Lowenstein, M.B.; Calvo, A.; Gomez-Reino, J.J.; Siri, D.A.; Tomsic, M.; Alecock, E.; Woodworth, T.; et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: The AMBITION study. Ann. Rheum. Dis. 2010, 69, 88–96.
  84. Kawashiri, S.Y.; Kawakami, A.; Yamasaki, S.; Imazato, T.; Iwamoto, N.; Fujikawa, K.; Aramaki, T.; Tamai, M.; Nakamura, H.; Ida, H.; et al. Effects of the anti-interleukin-6 receptor antibody, tocilizumab, on serum lipid levels in patients with rheumatoid arthritis. Rheumatol. Int. 2011, 31, 451–456.
  85. Smolen, J.S.; Beaulieu, A.; Rubbert-Roth, A.; Ramos-Remus, C.; Rovensky, J.; Alecock, E.; Woodworth, T.; Alten, R.; OPTION Investigators. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): A double-blind, placebo-controlled, randomised trial. Lancet 2008, 371, 987–997.
  86. Zhang, J.; Xie, F.; Yun, H.; Chen, L.; Muntner, P.; Levitan, E.B.; Safford, M.M.; Kent, S.T.; Osterman, M.T.; Lewis, J.D.; et al. Comparative effects of biologics on cardiovascular risk among older patients with rheumatoid arthritis. Ann. Rheum. Dis. 2016, 75, 1813–1818.
  87. Kim, S.C.; Solomon, D.H.; Rogers, J.R.; Gale, S.; Klearman, M.; Sarsour, K.; Schneeweiss, S. Cardiovascular Safety of Tocilizumab Versus Tumor Necrosis Factor Inhibitors in Patients With Rheumatoid Arthritis: A Multi-Database Cohort Study. Arthritis Rheumatol. 2017, 69, 1154–1164.
  88. Castagné, B.; Viprey, M.; Martin, J.; Schott, A.M.; Cucherat, M.; Soubrier, M. Cardiovascular safety of tocilizumab: A systematic review and network meta-analysis. PLoS ONE 2019, 14, e0220178.
  89. Cacciapaglia, F.; Perniola, S.; Venerito, V.; Anelli, M.G.; Härdfeldt, J.; Fornaro, M.; Moschetta, A.; Iannone, F. The Impact of Biologic Drugs on High-Density Lipoprotein Cholesterol Efflux Capacity in Rheumatoid Arthritis Patients. J. Clin. Rheumatol. 2020.
  90. Ormseth, M.J.; Yancey, P.G.; Solus, J.F.; Bridges, S.L., Jr.; Curtis, J.R.; Linton, M.F.; Fazio, S.; Davies, S.S.; Roberts, L.J., 2nd; Vickers, K.C.; et al. Effect of Drug Therapy on Net Cholesterol Efflux Capacity of High-Density Lipoprotein-Enriched Serum in Rheumatoid Arthritis. Arthritis Rheumatol. 2016, 68, 2099–2105.
  91. Anastasius, M.; Luquain-Costaz, C.; Kockx, M.; Jessup, W.; Kritharides, L. A critical appraisal of the measurement of serum “cholesterol efflux capacity” and its use as surrogate marker of risk of cardiovascular disease. Biochim. Biophys. Acta. Mol. Cell. Biol Lipids 2018, 1863, 1257–1273.
  92. Pierini, F.S.; Botta, E.; Soriano, E.R.; Martin, M.; Boero, L.; Meroño, T.; Saez, M.S.; Lozano Chiappe, E.; Cerda, O.; Brites, F. Effect of Tocilizumab on LDL and HDL Characteristics in Patients with Rheumatoid Arthritis. An Observational Study. Rheumatol. Ther. 2021, 8, 803–815.
  93. Ferraz-Amaro, I.; Hernández-Hernández, M.V.; Tejera-Segura, B.; Delgado-Frías, E.; Macía-Díaz, M.; Machado, J.D.; Diaz-González, F. Effect of IL-6 Receptor Blockade on Proprotein Convertase Subtilisin/Kexin Type-9 and Cholesterol Efflux Capacity in Rheumatoid Arthritis Patients. Horm. Metab. Res. 2019, 51, 200–209.
  94. Bechman, K.; Yates, M.; Galloway, J.B. The new entries in the therapeutic armamentarium: The small molecule JAK inhibitors. Pharmacol. Res. 2019, 147, 104392.
  95. Moura, R.A.; Fonseca, J.E. JAK inhibitors and modulation of B cell immune responses in rheumatoid arthritis. Front. Med. 2020, 7, 607725.
  96. Strand, V.; Goncalves, J.; Isaacs, J.D. Immunogenicity of biologic agents in rheumatology. Nat. Rev. Rheumatol. 2021, 17, 81–97.
  97. Mori, S.; Ogata, F.; Tsunoda, R. Risk of venous thromboembolism associated with Janus kinase inhibitors for rheumatoid arthritis: Case presentation and literature review. Clin. Rheumatol. 2021, 40, 4457–4471.
  98. Charles-Schoeman, C.; Wicker, P.; Gonzalez-Gay, M.A.; Boy, M.; Zuckerman, A.; Soma, K.; Geier, J.; Kwok, K.; Riese, R. Cardiovascular safety findings in patients with rheumatoid arthritis treated with tofacitinib, an oral Janus kinase inhibitor. Semin. Arthritis Rheum. 2016, 46, 261–271.
  99. Charles-Schoeman, C.; DeMasi, R.; Valdez, H.; Soma, K.; Hwang, L.J.; Boy, M.G.; Biswas, P.; McInnes, I.B. Risk Factors for Major Adverse Cardiovascular Events in Phase III and Long-Term Extension Studies of Tofacitinib in Patients with Rheumatoid Arthritis. Arthritis Rheumatol. 2019, 71, 1450–1459.
  100. Wollenhaupt, J.; Lee, E.B.; Curtis, J.R.; Silverfield, J.; Terry, K.; Soma, K.; Mojcik, C.; DeMasi, R.; Strengholt, S.; Kwok, K.; et al. Safety and efficacy of tofacitinib for up to 9.5 years in the treatment of rheumatoid arthritis: Final results of a global, open-label, long-term extension study. Arthritis Res. Ther. 2019, 21, 89.
  101. Conaghan, P.G.; Mysler, E.; Tanaka, Y.; Da Silva-Tillmann, B.; Shaw, T.; Liu, J.; Ferguson, R.; Enejosa, J.V.; Cohen, S.; Nash, P.; et al. Upadacitinib in Rheumatoid Arthritis: A Benefit-Risk Assessment Across a Phase III Program. Drug Saf. 2021, 44, 515–530.
  102. Xie, W.; Huang, Y.; Xiao, S.; Sun, X.; Fan, Y.; Zhang, Z. Impact of janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: Systematic review and meta-analysis of randomised controlled trials. Ann. Rheum. Dis. 2019, 78, 1048–1054.
  103. Xie, W.; Zhang, Z. Tofacitinib in cardiovascular outcomes: Friend or foe? Rheumatology 2020, 59, 1797–1798.
  104. Rainsford, K.D.; Parke, A.L.; Clifford-Rashotte, M.; Kean, W.F. Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology 2015, 23, 231–269.
  105. Wu, C.L.; Chang, C.C.; Kor, C.T.; Yang, T.H.; Chiu, P.F.; Tarng, D.C.; Hsu, C.C. Hydroxychloroquine Use and Risk of CKD in Patients with Rheumatoid Arthritis. Clin. J. Am. Soc. Nephrol. 2018, 13, 702–709.
  106. Ben-Zvi, I.; Kivity, S.; Langevitz, P.; Shoenfeld, Y. Hydroxychloroquine: From malaria to autoimmunity. Clin. Rev. Allergy Immunol. 2012, 42, 145–153.
  107. Schrezenmeier, E.; Dörner, T. Mechanisms of action of hydroxychloroquine and chloroquine: Implications for rheumatology. Nat. Rev. Rheumatol. 2020, 16, 155–166.
  108. Shi, N.; Zhang, S.; Silverman, G.; Li, M.; Cai, J.; Niu, H. Protective effect of hydroxychloroquine on rheumatoid arthritis-associated atherosclerosis. Anim. Model Exp. Med. 2019, 2, 98–106.
  109. Hu, C.; Lu, L.; Wan, J.P.; Wen, C. The Pharmacological Mechanisms and Therapeutic Activities of Hydroxychloroquine in Rheumatic and Related Diseases. Curr. Med. Chem. 2017, 24, 2241–2249.
  110. Fan, H.W.; Ma, Z.X.; Chen, J.; Yang, X.Y.; Cheng, J.L.; Li, Y.B. Pharmacokinetics and Bioequivalence Study of Hydroxychloroquine Sulfate Tablets in Chinese Healthy Volunteers by LC-MS/MS. Rheumatol. Ther. 2015, 2, 183–195.
  111. Wallace, D.J.; Gudsoorkar, V.S.; Weisman, M.H.; Venuturupalli, S.R. New insights into mechanisms of therapeutic effects of antimalarial agents in SLE. Nat. Rev. Rheumatol. 2012, 8, 522–533.
  112. Eugenia Schroeder, M.; Russo, S.; Costa, C.; Hori, J.; Tiscornia, I.; Bollati-Fogolín, M.; Zamboni, D.S.; Ferreira, G.; Cairoli, E.; Hill, M. Pro-inflammatory Ca++-activated K+ channels are inhibited by hydroxychloroquine. Sci. Rep. 2017, 15, 1892.
  113. Silva, J.C.; Mariz, H.A.; Rocha, L.F., Jr.; Oliveira, P.S.; Dantas, A.T.; Duarte, A.L.; Pitta, I.; Galdino, S.L.; Pitta, M.G. Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients. Clinics 2013, 68, 766–771.
  114. Mercer, E.; Rekedal, L.; Garg, R.; Lu, B.; Massarotti, E.M.; Solomon, D.H. Hydroxychloroquine improves insulin sensitivity in obese non-diabetic individuals. Arthritis Res. Ther. 2012, 14, R135.
  115. Sharma, T.S.; Wasko, M.C.; Tang, X.; Vedamurthy, D.; Yan, X.; Cote, J.; Bili, A. Hydroxychloroquine Use Is Associated with Decreased Incident Cardiovascular Events in Rheumatoid Arthritis Patients. J. Am. Heart Assoc. 2016, 5, e002867.
  116. Wasko, M.C.; Hubert, H.B.; Lingala, V.B.; Elliott, J.R.; Luggen, M.E.; Fries, J.F.; Ward, M.M. Hydroxychloroquine and risk of diabetes in patients with rheumatoid arthritis. JAMA 2007, 298, 187–193.
  117. Guevara, M.; Ng, B. Positive effect of hydroxychloroquine on lipid profiles of patients with rheumatoid arthritis: A Veterans Affair cohort. Eur. J. Rheumatol. 2020, 8, 62–66.
  118. Mangoni, A.A.; Woodman, R.J.; Piga, M.; Cauli, A.; Fedele, A.L.; Gremese, E.; Erre, G.L.; EDRA Study Group. Patterns of Anti-Inflammatory and Immunomodulating Drug Usage and Microvascular Endothelial Function in Rheumatoid Arthritis. Front. Cardiovasc. Med. 2021, 8, 681327.
  119. Kedia, A.K.; Mohansundaram, K.; Goyal, M.; Ravindran, V. Safety of long-term use of four common conventional disease modifying anti-rheumatic drugs in rheumatoid arthritis. J. R. Coll. Physicians Edinb. 2021, 51, 237–245.
  120. Doyno, C.; Sobieraj, D.M.; Baker, W.L. Toxicity of chloroquine and hydroxychloroquine following therapeutic use or overdose. Clin. Toxicol. 2021, 59, 12–23.
  121. Rempenault, C.; Combe, B.; Barnetche, T.; Gaujoux-Viala, C.; Lukas, C.; Morel, J.; Hua, C. Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: A systematic review and meta-analysis. Ann. Rheum. Dis. 2018, 77, 98–103.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Rheumatology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Allison B. Reiss
,
Saba Ahmed
,
Benna Jacob
,
Steven Carsons
,
Joshua De Leon
View Times: 544
Revisions: 3 times (View History)
Update Date: 20 Jan 2022
Table of Contents
    1000/1000
    Hot Most Recent
    Feedback