Major (‘traditional’) cardiovascular risk factors, (4).
\\n\\n
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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
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Section I consists of nine chapters which discuss synthesis through innovative as well as modified conventional techniques of certain advanced ceramics (e.g. target materials, high strength porous ceramics, optical and thermo-luminescent ceramics, ceramic powders and fibers) and their characterization using a combination of well known and advanced techniques. Section II is also composed of nine chapters, which are dealing with the aqueous processing of nitride ceramics, the shape and size optimization of ceramic components through design methodologies and manufacturing technologies, the sinterability and properties of ZnNb oxide ceramics, the grinding optimization, the redox behaviour of ceria based and related materials, the alloy reinforcement by ceramic particles addition, the sintering study through dihedral surface angle using AFM and the surface modification and properties induced by a laser beam in pressings of ceramic powders. Section III includes four chapters which are dealing with the deposition of ceramic powders for oxide fuel cells preparation, the perovskite type ceramics for solid fuel cells, the ceramics for laser applications and fabrication and the characterization and modeling of protonic ceramics.",isbn:null,printIsbn:"978-953-307-505-1",pdfIsbn:"978-953-51-4464-9",doi:"10.5772/985",price:159,priceEur:175,priceUsd:205,slug:"advances-in-ceramics-synthesis-and-characterization-processing-and-specific-applications",numberOfPages:534,isOpenForSubmission:!1,isInWos:1,isInBkci:!0,hash:null,bookSignature:"Costas Sikalidis",publishedDate:"August 9th 2011",coverURL:"https://cdn.intechopen.com/books/images_new/474.jpg",numberOfDownloads:101697,numberOfWosCitations:231,numberOfCrossrefCitations:57,numberOfCrossrefCitationsByBook:13,numberOfDimensionsCitations:205,numberOfDimensionsCitationsByBook:23,hasAltmetrics:1,numberOfTotalCitations:493,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 18th 2010",dateEndSecondStepPublish:"November 15th 2010",dateEndThirdStepPublish:"March 22nd 2011",dateEndFourthStepPublish:"April 21st 2011",dateEndFifthStepPublish:"June 20th 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7,8",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"42599",title:"Prof.",name:"Costas",middleName:null,surname:"Sikalidis",slug:"costas-sikalidis",fullName:"Costas Sikalidis",profilePictureURL:"https://mts.intechopen.com/storage/users/42599/images/1711_n.jpg",biography:"Dr. Costas Sikalidis, born in Thessaloniki Greece in 1948, matriculated in the Chemistry Department at the Aristotle University of Thessaloniki in 1966. After earning his BSc, he served for three years as an officer in the Hellenic Army. He pursued postgraduate studies in Ceramic Technology at the University of Northstaffordshire, UK and completed training & professional development in the British Ceramic Industry. He worked as a production manager at Philkeram-Johnson, subsidiary of Johnson Tile manufacturers. In 1981 he joined the Department of Chemical Engineering as a faculty member holding a PhD in Chemical Engineering. A Professor and Head of the Laboratory of Industrial Inorganic Raw Materials and Industrial Ceramics, he has published more than 70 papers in peer-reviewed scientific journals, presented his research in more than 80 International Conferences, received several patents and has been a reviewer in 10 journals. Dr. Sikalidis has mentored more than 18 MSc graduates and produced 2 PhD graduates, whereas he has earned funding via a number of competitive European research grants. 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The concept of risk factors first appeared some fifty years ago with the publication of the Framingham Study (2). Since that time, advances in the field of epidemiology have made large scale clinical studies possible and have led to the identification of a series of cardiovascular disease risk factors that induce the formation of atheromatous plaques. The establishment of a specific biological characteristic, environmental factor or habit as a CRF requires: a standardised methodology; concordant prospective studies; an added effect when various risk factors concur in an individual; and, that the modification of the factor (in the case that the factor is modifiable) results in a diminution of the risk (3).
\n\t\t\tHistorically, there has been clear evidence of a series of ‘traditional’ CRFs (Table 1), such as hypercholesterolemia, hypertension, hyperglycaemia, nicotine poisoning, sedentarism, etc. which have been used in the stratification of individual risk (4). In the recent past, a number of important studies have proposed the inclusion of new or ‘emergent’ CRFs in the evaluation and stratification of cardiovascular risk and this has implications for preventive and therapeutic strategies.
\n\t\t\tNumerous documents and reports that include recommendations for the prevention of CVD and control of the main cardiovascular risk factors have been published by national and international scientific institutions and organisations (from the USA, Europe (5) etc.). Following the latest recommendations of the world renowned National Cholesterol Education Program (NCEP) (4), Table 1 lists the most significant \'traditional\' CRFs whilst Table 2 shows the ‘emergent’ factors. Some of the ‘new’ factors have been recognised for decades though they have been subject to debate and controversy, and consensus has not been reached on their inclusion in cardiovascular risk evaluation.
\n\t\t\tThe NCEP Panel III identifies three classes of CRFs that influence the possibilities of suffering CVD, although only the first two are relevant to the modification of treatment objectives: major CRFs, factors linked to lifestyles and emergent risk factors.
\n\t\t\t\n\t\t\t\t\t\t | Age and sex (men ≥ 45 years old, women ≥ 55 years old) | \n\t\t\t\t\t
\n\t\t\t\t\t\t | Nicotine poisoning | \n\t\t\t\t\t
\n\t\t\t\t\t\t | Arterial hypertension (BP ≥ 140/90 mmHg or undergoing antihypertensive treatment) | \n\t\t\t\t\t
\n\t\t\t\t\t\t | Increase LDL cholesterol | \n\t\t\t\t\t
\n\t\t\t\t\t\t | Fall in HDL cholesterol (< 40 mg/dl)* | \n\t\t\t\t\t
\n\t\t\t\t\t\t | Family history of premature coronary heart disease Male first degree relatives < 55 years Female first degree relatives < 65 years | \n\t\t\t\t\t
\n\t\t\t\t\t\t | Diabetes mellitus** | \n\t\t\t\t\t
\n\t\t\t\t\t\t | Lifestyle (overweight/obesity, sedentarism, atherogenic diet)*** | \n\t\t\t\t\t
\n\t\t\t\t\t\t | * Adapted from Panel III of the National Cholesterol Education Program (4). *If HDL cholesterol is ≥ 60 mg/dl, it is considered as a ‘negative’ risk factor”. **Diabetes mellitus carries a risk equivalent to a secondary prevention situation. ***These factors are not computed in the algorithms for stratification of risk. AP: arterial pressure; LDL: low density lipoproteins; HDL: high density lipoproteins. | \n\t\t\t\t\t
Major (‘traditional’) cardiovascular risk factors, (4).
Panel III recognises that, in addition to the main CRFs, CVD is influenced by the presence of other factors which modification can have a positive effect on some of the major CRFs and reduce risk; these therefore represent direct treatment objectives. These factors act through other intermediate elements or worsen independent risk factors such as, obesity, sedentarism, a family history of premature CVD, psychosocial conditions or being male. Although they do not figure in algorithm calculations on the stratification of risk (6), two of them, obesity and sedentarism, are considered as causal CRFs by the American Heart Association.
\n\t\tHypercholesterolemia is one of the main cardiovascular risk factors that are modifiable. The
The three main classes of lipoproteins are: Low-density lipoproteins (LDL); High-density lipoproteins (HDL); and Very low-density lipoproteins (VLDL). There is another class of lipoproteins known as Intermediate-density lipoproteins (IDL) that is between VLDL and LDL, though in clinical practice, it is included in the LDL category.
\n\t\t\t\tWith the exception of HDLs, that play a role in reverse cholesterol transport and therefore exercise a vasoprotector action, lipid particles are more atherogenic the more cholesterol that they transport. Chylomicrons carry such a small quantity of cholesterol that their increase in hyperchylomicronemia (Type I dyslipidemia) is not associated with atherosclerosis lesions. In contrast, with the accumulation of VLDLs, a fifth of which are made up of cholesterol, an increase in atherogenesis is observed. Given that LDLs are particles with a higher level of cholesterol, they are the main cause of atherogenesis when they are in excess.
\n\t\t\t\tAlthough LDLs receive most attention in clinical management, there is a growing body of evidence that indicates that VLDLs play an important role in atherogenesis.
\n\t\t\t\tLevels of HDL cholesterol are inversely related with the risk of CVD; they seem to play a protective role against the onset of atherosclerosis as they capture free cholesterol from the peripheric tissues such as the cells of the vascular wall. This cholesterol is transformed into cholesterol esters, a part of which is transferred to the VLDLs by the cholesterol esters transfer proteins (CETP) and returned to the liver by IDLs and LDLs and another part is transferred directly to the liver by the HDL particles. The liver reuses the cholesterol for the synthesis of VLDLs, for the synthesis of bile salts or excretes it directly into the bile. Therefore, HDLs tend to reduce cholesterol levels.
\n\t\t\tHypertension is a principal and independent CRF, but its damaging effect is increased when associated with other coronary risk factors such as smoking, diabetes and dyslipidemia. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure defines hypertension as a systolic arterial pressure of ≥140mmHg or diastolic ≥90mmHg or the need for antihypertensive treatment (8). A number of studies, for example the Framingham study, have demonstrated an increase in total mortality and cardiovascular risk in cases of increased levels of arterial pressure (diastolic and systolic), with a continuous and gradual relationship (9,10,11). The association applies to men and women, young and old alike.
\n\t\t\t\tSmoking
\n\t\t\t\tSmoking contributes clearly to CVD. The relationship between smoking and the risk of CVD is dose dependent and affects men and women equally. Observational studies suggest that stopping smoking leads to a substantial reduction of the risk of a cardiovascular event.
\n\t\t\t\tDiabetes
\n\t\t\t\tDiabetes is defined as the presence of a level of glucose, on an empty stomach, more than, or equal to, 126 mg/dL (12). The risk of cardiovascular disease is significantly increased for sufferers of diabetes mellitus type 1 and type 2 (13). The increase of risk attributed to hyperglycaemia is independent of other risk factors such as obesity, overweight or dyslipidemia that are often observed in diabetics.
\n\t\t\t\t80% of diabetes mellitus patient mortality is caused by complications associated with atherosclerosis with ischemic heart disease being responsible in 75% of cases (14). In addition, the risk of acute myocardial infarction in diabetes mellitus type 2 patients with no previous history of myocardial infarction is similar to non-diabetics who have previously suffered a heart attack (15).
\n\t\t\t\tAlthough it is probable that strict control of diabetes reduces micro-vascular disorders and other complications such as renal disease and retinopathies, statistics relative to the effects of glycemic control on coronary episodes are uncertain. Diabetics often present dyslipidemia, characterised by moderate hypercholesterolemia and hypertriglyceridemia with low concentrations of HDL cholesterol that involve increased cardiovascular risk. This is frequently associated with central obesity, hyperinsulinism and AHT. Therefore, the association of numerous CRFs explains why many individuals already exhibit disorders when they are diagnosed with diabetes mellitus.
\n\t\t\tTraditional factors can strongly predict the risk of cardiovascular disease but not completely (16). Thus, recently new biomarkers have emerged, although their predictive value still needs to be validated in multiple cohorts and different populations.
\n\t\t\t\n\t\t\t\t\t\t | Lipid Risk Factors | \n\t\t\t\t\t
\n\t\t\t\t\t\t | Total cholesterol quotient/HDL cholesterol | \n\t\t\t\t\t
\n\t\t\t\t\t\t | Apolipoproteins | \n\t\t\t\t\t
\n\t\t\t\t\t\t | HDL subclasses | \n\t\t\t\t\t
\n\t\t\t\t\t\t | Triglycerides | \n\t\t\t\t\t
\n\t\t\t\t\t\t | “Small and dense” LDL particles | \n\t\t\t\t\t
\n\t\t\t\t\t\t | Residual or remnant lipoproteins | \n\t\t\t\t\t
\n\t\t\t\t\t\t | Non-lipid Risk Factors | \n\t\t\t\t\t
\n\t\t\t\t\t\t | Markers of inflammation | \n\t\t\t\t\t
\n\t\t\t\t\t\t | Homocysteinaemia | \n\t\t\t\t\t
\n\t\t\t\t\t\t | Impaired fasting glycaemia | \n\t\t\t\t\t
\n\t\t\t\t\t\t | Thrombogenic / hemostatic factors | \n\t\t\t\t\t
\n\t\t\t\t\t\t | LDL: Low-density lipoproteins; HDL: High-density lipoproteins | \n\t\t\t\t\t
Emergent cardiovascular risk factors
Apolipoprotein A
\n\t\t\t\tA apolipoproteins are a group of proteins that are variably distributed among different lipoproteins. Apo A-I is the most abundant apolipoprotein in plasma and is nearly 90% of the HDL and 60-70% of the protein fraction of the sub-fractions HDL2 and HDL3, respectively. Apo A-I is initially synthesised in the liver and intestine as a protein precursor which is degraded to its mature form in plasma; it is a simple polypeptide chain that contains 243 amino acids. This protein participates in the reverse transport of cholesterol. The apolipoprotein apo A-II is the second highest concentration protein component of HDL, although it is absent in the HDL2 sub-fraction and plasma levels do not correlate with HDL-cholesterol levels.
\n\t\t\t\tThe measurement of the concentration of apo A-I in serum perfectly reproduces the predictive value of coronary disease of the concentration of HDL in serum. Nevertheless, this correlation is not valid in subjects with hypertriglyceridemia, in which the fraction of HDL is enriched with triglycerides and cholesterol is almost absent.
\n\t\t\t\tApolipoprotein B
\n\t\t\t\tB apolipoprotein is a protein of great molecular weight, present in chylomicrons, VLDL, and LDL lipoproteins. There are two molecular forms in plasma, apo B-100 (apo B) and apo B-48. Apo B is a unique polypeptide chain of 4536 amino acids (one of the biggest plasma proteins), synthesised in the liver and secreted in VLDLs. It is quantitatively maintained during the conversion of VLDL to IDL until LDL, of which it is the only protein component, and for this reason, levels of apo B are correlated with levels of these lipoproteins. Studies have established the relationship between B concentrations in serum and cardiovascular risk (17,18,19).
\n\t\t\t\tGiven that each particle of VLDL, IDL and LDL only contains one apo B molecule, its concentration in serum reflects the risk associated with all these atherogenic particles. Although considered as a risk factor by the NCEP, its determination is not recommended in clinical practice, due to the unavailability of clinical guides or risk stratification algorithms based on its concentration, although it can be useful in some situations.
\n\t\t\t\tNevertheless, from an experimental point of view, it can offer important additional information. The concentration of apo B in serum provides data on the number of particles, especially LDL particles, as they contain approximately 90% of total circulating apo B. It has been suggested that a LDL/ decreased apo B relationship is an indicator of the predominance of small and dense LDL particles (20).
\n\t\t\t\tThe estimation of LDL cholesterol using the Friedewald formula is inexact when levels of triglycerides are higher than 300mg/dL and, if no validated direct method or ultracentrifugation is available, the concentration of apo B can be used as an alternative for the stratification of risk and the setting of therapeutic objectives (21). A modification of the Friedewald formula has been described for the calculation of LDL cholesterol that includes apo B. The LDL cholesterol obtained in this way has been shown to be more independent of hypertriglyceridemia than calculations made with the Friedewald formula (22).
\n\t\t\t\tThe results of some studies have shown that the relationship between apo B/apo A-I is better for evaluating cardiovascular risk than the total cholesterol/HDL cholesterol relationship or LDL cholesterol/HDL (23,24). The number of particles and, in particular, the balance between them, that is to say, the apo B/apo A-I relationship, may be more important than the lipid quantity carried by each particle.
\n\t\t\tIn spite of the evidence put forward by some epidemiological studies on the relationship between hypertriglyceridemia and the incidence of CVD (25,26), the results of other, more recent, multivariate works do not allow the definitive classification of triglycerides as an independent CRF (4). This is due to the close relationship between increased levels of triglycerides and other lipid CRFs (the presence of residual lipoproteins or remnants of VLDLs and chylomicrons in plasma, the predominance of ‘small and dense’ particles of LDL in plasma or decreased plasma concentration of HDL cholesterol), non-lipid CRFs (hypertension) and emergent CRFs (glucose intolerance, prothrombotic state). The NCEP Panel III states that increases in levels of triglycerides (>200mg/dL) are associated with a higher risk of CVD. It is also commonly associated with other lipid and non-lipid risk factors and indicates that therapeutic objectives should be based on lifestyle changes (loss of weight, physical exercise, stopping smoking).
\n\t\t\tIn recent years, lipoprotein (a) (Lp(a)) has attracted enormous interest as a cardiovascular risk factor (27,28). Lp(a) is a spherical lipoprotein, rich in cholesterol esters and phospholipids, it has a composition that is similar to LDL and contains a specific glycoprotein, apolipoprotein (a), linked by a disulphide bridge to the apolipoprotein B-100. In addition, it has great structural homology to the plasminogen fibrinolytic proenzyme (Figure 1) (29).
\n\t\t\t\tA variety of mechanisms that may explain the relationship between lp(a) and cardiovascular disease have been described in published works. Firstly, it is argued that as lp(a) is an LDL particle it plays a role in the initiation, progression and possible rupture of the atheromatous plaque. Secondly, it is suggested that this particle competes with the plasminogen particle and inhibits thrombolytic activity (30). Finally, cell line studies with rats have shown that lipoprotein (a) inhibits NO synthesis (31).
\n\t\t\t\tStructure of lipoprotein (a).
Although an increase in the plasma concentration of lp(a) implies a higher risk of CVD, mainly in individuals at greater global risk (32), the principal consensus documents, such as the NCEP Panel III and the latest European STORE project proposal, do not include it among cardiovascular risk factors that are computable for the evaluation of overall risk. This is due to the fact that some studies do not corroborate independent prediction, based on lp(a) levels, of suffering CVD (33,34) and there is no evidence that elimination benefits the patient (35).
\n\t\t\tThe inflammatory process characterises all phases of atherothrombotic development. There are many studies that relate a variety of elements that intervene in the inflammatory process with the risk of CVD. These elements include: the intercellular-1 adhesion molecule (ICAM-1); the vascular-1 adhesion molecule (VCAM-1); E-selectin; P-selectin; proinflammatory cytokines, such as interleucine-6 (IL-6), and the tumor necrosis factor-alpha (TNF-α). All of the aforementioned have been shown to be predictors of CRFs (36). In clinical practice, difficulties in determining these markers and the short half-life of these molecules in circulatory blood mean that it is not possible to include them in the daily clinical routine. Of the other markers of inflammation that have been suggested, such as, serum amyloid A, the leukocyte count, fibrinogen, nitrotyrosine, myeloperoxidase and c-reactive protein (CRP), only the latter has been consolidated as a candidate due to its stability, analysis precision and accessibility (37). The AHA (American Heart Association) and CDC (Centers for Disease Control) say that of all the markers of inflammation, only ultra-sensitive CRP (US-CRP) has the characteristics necessary for use in clinical practice (38).
\n\t\t\t\tUltra-sensitive CRP (US-CRP) is currently the best characterised inflammation biomarker and has been established as a potential marker of cardiovascular risk. US-CRP in plasma is a firm candidate for use in clinical practice as it is considered as an independent predictor of coronary illness for the general population, for both sexes and for patients that have already presented clinical manifestations of CVD (36,37). However, sufficient evidence that reducing CRP levels prevents CHD events is lacking (16, 39).
\n\t\t\t\tCRP is a member of the pentraxin family of proteins which are characterised by having a pentameric structure and radial symmetry, formed by five protomers of 24 kD and 206 amino acids that are linked among themselves by non covalent bonds and have the capacity to bond to a great variety of substances, such as, phosphocholine, fibronectin, chromatin, histones and ribonucleoproteins (40).
\n\t\t\t\tThe differentiation of monocytes and macrophages, that takes place during atherosclerotic process, frees proinflammatory molecules that include interleukin-6 (IL-6) which activates, in the liver, the liberation of inflammation markers like CRP. High levels (>10 mg/dl) are registered in bacterial infections though ultra-sensitive analysis can detect very low levels (0-3 mg/dl) that are associated with the atherosclerotic process. Their half-life is more than 24 hours and their blood levels are not altered by diet.
\n\t\t\tIn the last decade, numerous studies have been published that relate increases homocysteinaemia (Hcy) to CVD (41-45). Nevertheless, the mechanism that controls this relationship is not completely understood. Homocysteine has a direct cytotoxic effect on endothelial cells in cultivation. An alteration in endothelial function has been observed, evaluated by echo-Doppler, in individuals with moderate hyperhomocysteinaemia and improvements have been noted on reducing the concentration of homocysteine by means of folic acid treatment. It should be remembered that levels of plasma homocysteine are related to levels of vitamin B12 and folic acid (46).
\n\t\t\t\tHomocysteine can promote LDL oxidation through the production of reactive oxygen species such as hydrogen peroxide and studies have described the promotion of the multiplication of smooth muscle cells and a reduction in DNA synthesis in endothelial cells. A large number of prospective and retrospective studies support the hypothesis that an excess of plasma homocysteine is associated with a higher risk of coronary illness, peripheral and cerebrovascular disease (44,47-49).
\n\t\t\tThe relationship established between a high concentration of asymmetric dimethylarginine (ADMA) and endothelial dysfunction and the possible relationship between high ADMA values and the incidence of cardiovascular accidents, has led a number of research groups to study the association between high ADMA and death by any cause.
\n\t\t\t\tSome studies indicate that ADMA plasma levels may predict the risk of cardiovascular events. In 2001, Valkonen
Zoccali et al. (52) showed that in haemodialysis patients, ADMA plasma levels are an independent predictor of mortality and cardiovascular risk. In their multivariate study, only ADMA and age were significantly predictive, independent of the incidence of cardiovascular episodes (such as chest angina and heart attack) and death by any cause. Patients whose concentration of plasma ADMA was above the percentile 75, had three times more risk of suffering a cardiovascular episode than patients whose initial ADMA levels were lower than the average.
\n\t\t\t\tThere are currently a number of case studies, controls and prospective clinical trials taking place with a variety of patient populations that are aimed at gaining greater understanding of the role of ADMA as an independent risk factor for CVD and mortality. The data generated by these studies will help in determining the significance of ADMA as a risk factor and explore its diagnostic importance in different illnesses and diseases.
\n\t\t\tThere is much research on the effect of physical activity on the alteration of risk factors associated with heart disease. The most beneficial effect of exercise is on the level of oxidative metabolism which influences levels of lipids in the blood. Aerobic exercise reduces levels of triglycerides and total cholesterol and may increase levels of HDLs, especially if accompanied by weight loss. Although reductions in total cholesterol and LDL cholesterol generated by physical exercise seem to be relatively small (in general, they are less than 10%), there are important increases in HDL cholesterol and significant reductions in triglycerides. Transversal studies with trained athletes and non-trained subjects unequivocally demonstrate that individuals with higher levels of aerobic activity have higher HDL levels and lower levels of triglycerides (53), even after a single session of exercise (54). Nevertheless, results from longitudinal studies, over relatively long periods of time, are much less clear. Many studies on physical exercise have described an increase in HDL and a reduction in triglycerides (53,55), but others have described very small changes or no changes at all. However, almost all studies have shown that proportions of LDL/HDL and total cholesterol/HDL fall after endurance training and this means less cardiovascular risk
\n\t\t\tThere are reliable data that demonstrate the effectiveness of physical exercise on the reduction in blood pressure in patients with mild or moderate hypertension. Endurance training can reduce systolic and diastolic arterial pressure (DAP) by approximately 10 mmHg in individuals with moderate essential hypertension.
\n\t\t\tWith regards to the other traditional cardiovascular risk factors, physical exercise can play a role in the reduction and control of weight and in the control of diabetes. Exercise has also been shown to be effective in the control and reduction of stress and anxiety (56).
\n\t\t\tWhilst the effect of exercise on ‘traditional’ CRFs is well documented, the effect of exercise on ‘emergent’ CRFs has not been studied in depth and results are not well known. It must not be forgotten that is very important the change in the volume of blood that affects plasma concentrations, independently of changes in total lipids, both in terms of lipids and the other biochemical parameters expressed as a concentration, for the evaluation of changes engendered by physical exercise. The failure to correctly take this factor into account could explain some of the controversies concerning studies on CRFs and physical exercise.
\n\t\t\tThe beneficial effects of exercise, leading to the reduction of levels of apolipoprotein B, have been widely reported, but this has not been the case with the relationship between exercise and levels of apolipoprotein A-I (57,58). Some authors have found that long-term, regular physical exercise does not seem to modify levels of apolipoproteins in comparison with sedentary groups (59). There is relatively little information available on levels of lipoprotein (a) in young people although some studies have confirmed a favourable relationship between regular physical exercise and levels of lipoprotein (a) (57,59), whilst others found no difference in lipoprotein (a) concentration between healthy sedentary individuals and professional endurance athletes (60).
\n\t\t\tThe previously mentioned studies have been undertaken by different authors with different population groups and there are no published works that, at the same time, analyse the influence of intense physical exercise and the influence of continuous physical exercise (training) on levels of apolipoproteins A-I, B and lipoproteins (a), in the same population group.
\n\t\t\tThe beneficial effects of physical exercise also seem to be related to the effect on the inflammatory process. In the short term, intense physical exercise produces a transitory inflammatory response which is reflected in an increase in acute phase reactants and cytokines that is proportional to the amount of exercise and muscle damage. Nevertheless, regular physical activity (training) is associated with a chronic anti-inflammatory response that influences levels of acute phase reactants such as ultra-sensitive CRP and also affects lipids and lipoproteins (61-64). However, Sadepghipour
Some factors (BMI, the sex of the subject, the moment when the post-exercise sample is taken, diet, etc.), can have an influence on the values measured of ultra-sensitive CRP in response to physical exercise (62). Another issue that must be taken into account is that many studies that have examined the effects of intense physical exercise on levels of ultra-sensitive CRP have not made a concentration correction in accordance with the changes in plasma volume after exercise (62). Results should be individually corrected according to the post-exercise levels of hemoconcentration or hemodilution (66).
\n\t\t\tWith regards to homocysteine, studies with large population groups have shown that regular physical exercise can reduce homocysteine plasma levels (47,67,68). However, other studies have concluded that intense physical exercise increases levels of Hcy (69,70). More recent studies, undertaken by our work group (71), demonstrate increased plasma homocysteine levels, both in total and reduced, after intense exercise. This increase is independent of the type of exercise and the vitamin levels but could be related to changes in renal function (71). The mechanism of this effect is not clearly understood though a study on alterations in the redox state of the homocysteine might lead to the comprehension of the underlying process. Furthermore, a study on its relationship with plasma concentrations of NO, ADMA and their proximate metabolites might lead to an understanding of how intense physical exercise produces an increase in levels of homocysteine, as long as regular, moderate physical exercise (training) seems to be a beneficial modulator of homocysteine. Also related to homocysteine, is the proven fact that regular physical exercise produces a series of beneficial effects on oxidative metabolism which result in less oxidative stress and a greater defensive capacity against oxidative damage; this is caused by the increase in activity of endogenous antioxidant systems and the greater resistance of the LDL particles to oxidation (71,72). All this signifies a reduction in oxidised LDL levels and systematic markers of inflammation, as explained by Arquer
In spite of the fact that the role of ADMA as a cardiovascular risk marker is reflected in an increasing number of clinical studies and scientific publications, very few studies have looked at the effect of intense or sustained (training) physical exercise on ADMA plasma levels, with contradictory results. While Schlager et al., in 2011, found that supervised exercise training, twice a week during six months, in peripheral arterial disease patients decreases ADMA (73), Seljeflot et al., in 2011, observed no effect of 4 weeks of exercise training in ADMA concentration in patients with chronic heart failure, speculating that the duration of the exercise protocol could be insufficient to find any effects of exercise into significant changes in ADMA (74).
\n\t\t\tIt is therefore recommended that studies should be undertaken on the effect of intense and sustained (training) physical exercise on emergent cardiovascular risk factors, especially on homocysteine and ADMA.
\n\t\tThe authors have no conflicts of interest
\n\t\tThis work has been made possible by the support of the Ministry of Science and Innovation, Carlos III Institute of Health, F.I.S. (PI020665)
\n\t\tChronic myeloproliferative disorders are a group of clonal diseases of the stem cell. It is a group of several diseases with some common features. They derive from a multipotential hematopoietic stem cell. A clone of neoplastic cells in all these neoplams is characterized by a lower proliferative activity than that of acute myeloproliferative diseases. In each of these diseases, leukocytosis, thrombocythemia, and polyglobulia may appear at some stage, depending on the diagnosis [1, 2].
The research on interferon has been going on since the 1950s [3]. Then, the attention was paid to its influence on the immune system. It has been noted that it can exert an antiproliferative effect by stimulating cells of the immune system [4]. In 1987, a publication by Ludwig et al. was published, which reported the effectiveness of interferon alpha in the treatment of chronic myeloproliferative disorders [5].
More and more new studies have been showing the effectiveness of interferon alpha in reducing the number of platelets, reducing the need for phlebotomies in patients with polycythemia vera and also in reducing the number of leukocytes. Moreover, interferon reduced the symptoms of myeloproliferative disorders such as redness and itching of the skin. Additionally, it turned out to be effective in reducing the size of the spleen.
Further studies on the assessment of remission using molecular-level response assessments indicate that the interferon action in chronic myeloproliferation diseases targets cells from the mutant clone with no effect on normal bone marrow cells [6].
Over the years, interferon alpha-2a and interferon alpha-2b have been introduced into the treatment of chronic myeloproliferation, followed by their pegylated forms. The introduction of pegylated forms allowed for a reduction in the number of side effects and less frequent administration of the drug to patients. In recent years, monopegylated interferon alpha-2b has been used to further increase the interval between drug administrations while maintaining its antiproliferative efficacy.
The exact mechanism of action of interferon alpha in the treatment of chronic myeloproliferative disease is still not fully understood, but it has an impact on JAK2 (Janus Kinase) signal transducers and activates the STAT signal pathway (Janus Kinase/SignalTransducer and Activator of Transcription).
Interferon alpha binds to IFNAR1 and IFNAR2c, which are type I interferon receptors. Interferon alpha has an impact on JAK2(Janus Kinase) signal transducers and activates the STAT signal pathway. The disturbances in this signaling pathway are observed in chronic myeloproliferative disorders [7].
Interferon inhibits the JAK-STAT signaling pathway by directly inhibiting the action of thrombopoietin in this pathway [8].
So far, three driver mutations have been described in the course of chronic myeloproliferative diseases that affect the functioning of the JAK-STAT pathway.
JAK2 kinase and JAK1, JAK3, and TYK2 kinases belong to the family of non-receptor tyrosine kinases. They are involved in the intracellular signal transduction of the JAK-STAT pathway. It is a system of intracellular proteins used by growth factors and cytokines to express genes that regulate cell activation, proliferation, and differentiation. The mechanism of JAK activation is based on the autophosphorylation of tyrosine residues that occurs after ligand binds to the receptor. JAK2 kinase transmits signals from the hematopoietic cytokine receptors of the myeloid lineage (erythropoietin, granulocyte-colony stimulating factor thrombopoietin, and lymphoid lineage [9].
A somatic G/T point mutation in exon 14 of the JAK2 kinase gene converts valine to phenylalanine at position 617 (V617F) in the JAK2 pseudokinase domain, which allows constitutive, ligand-independent activation of the receptor to trigger a proliferative signal [10].
Mutation of the MPL gene, which encodes the receptor for thrombopoietin, increases the sensitivity of magekaryocytes to the action of thrombopoietin, which stimulates their proliferation [11].
Malfunction of calreticulin as a result of mutation of the CARL gene leads to the activation of the MPL-JAK/STAT signaling pathway, which is independent of the ligand, as calreticulin is responsible, for the proper formation of the MPL receptor. Consequently, there is a clonal proliferation of hematopoietic stem cells [12].
Below, we provide an overview of some clinical studies on the efficacy of interferon in chronic myeloproliferative disorders.
Polycythemia vera (PV) is characterized by an increase in the number of erythrocytes in the peripheral blood.
Polycythemia vera is caused by a clonal mutation in the multipotential hematopoietic stem cell of the bone marrow. The mutation leads to an uncontrolled proliferation of the mutated cell clone, independent of erythropoietin and other regulatory factors. As the mutation takes place at an early stage of hematopoiesis, an increase of the number of erythrocytes as well as of leukocytes and platelets is observed in the peripheral blood. The cause of proliferation in PV independent from external factors is a mutation in the Janus 2 (JAK2) tyrosine kinase gene. The V617F point mutation in the JAK2 gene is responsible for about 96% mutation, and in the remaining cases the mutation arises in exon 12. Both mutations lead to constitutive activation of the JAK-STAT signaling pathway [13].
As a result of the uncontrolled proliferation, blood viscosity increases, which generates symptoms such as headaches and dizziness, visual disturbances, or erythromelalgia. As the number of all hematopoietic cells, including the granulocytes ones, increases, the difficult to control symptoms of their hyperdegranulation may appear, among which gastric ulcer or skin itching is often observed. During the disease progression, the spleen and liver become enlarged.
The most common complication of the disease is episodes of thrombosis, especially arterial one. During the course of the disease, it can also evolve into myelofibrosis or acute myeloid leukemia.
The treatment of PV is aimed at preventing thromboembolic complications, relieving the general symptoms, the appearance of hepatosplenomegaly as well as preventing its progression.
Each patient should receive an antiplatelet drug chronically, and usually acetylsalicylic acid is the choice. Most often, the treatment is started with phlebotomy in order to rapidly lower the hematocrit level. If cytoreductive therapy is necessary, the drugs of first choice are hydroxycarbamide and interferon [2].
However, the research on the mechanism of the action of interferons is still ongoing. In vitro studies with CD34+ cells from peripheral blood of patients diagnosed with polycythemia vera showed that interferon inhibits clonal changed cells selectively. It was found that interferon alpha-2b and pegylated interferon alpha-2a reduce the percentage of cells with JAK2 V617F mutation by about 40%. Pegylated interferon alpha-2a works by activating mitogen-activated protein kinase P38. It affects CD34+ cells of patients with polycythemia vera by increasing the rate of their apoptosis [6].
A case of a patient with PV with a confirmed chromosomal translocation t(6;8) treated with interferon alpha-2b, which resulted in a reduction of the clone with translocation by 50% from the baseline value, was also described [14].
In 2019, the results of a phase II multicenter study were published, which aimed at assessing the effectiveness of recombinant pegylated interferon alpha-2a in cases of refractory to previously hydroxycarbamide therapy. The study included 65 patients with essential thrombocythemia (ET) and 50 patients with polycythemia vera. All patients had previously been treated with hydroxycarbamide and showed resistance to this drug or its intolerance.
The assessment of the response was performed after 12 months of treatment. Overall response rate to interferon was higher in patients diagnosed with ET than in patients with polycythemia vera. In essential thrombocythemia, the percentage of achieved complete remissions was 43 and 26% of partial remissions. The remission rate in ET patients was higher if calreticulin CALR gene mutation was present. Patients with polycythemia vera achieved complete remission in 22% of cases and partial remission in 38% of cases.
Treatment-related side effects that follow to discontinuation of treatment were reported in almost 14% of patients [15].
The duration of response to treatment with pegylated interferon alpha-2a and the assessment of its safety in long-term use in patients with chronic myeloproliferative disorders was the goal of a phase II of the single-center study. Forty-three adult patients with polycythemia vera and 40 patients with essential thrombocythemia were enrolled in the study. The complete hematological response was defined as a decrease in hemoglobin concentration below 15.0 g/l, without phlebotomies, a resolution of splenomegaly, and no thrombotic episodes in the case of PV, and for essential thrombocythemia—a decrease platelet count below 440,000/μl and two other conditions as above. The assessment of the hematological response was performed every 3–6 months. The median follow-up was 83 months.
The hematological response was obtained in 80% of cases for the entire group. In patients with polycythemia vera, 77% of patients achieved a complete response (CR) while 7% a partial response (PR). The duration of response averaged 65 months for CR and 35 months for PR. In the group of patients diagnosed with essential thrombocythemia, CR was achieved in 73% and PR in 3%. The durance of CR was 58 months and PR was 25 months.
The molecular response for the entire group was achieved in 63% of cases.
The overall analysis showed that the duration of hematological remission and its achievement with pegylated interferon alpha-2a treatment is not affected neither by baseline disease characteristics nor JAK2 allele burden and disease molecular status. There was also no effect on age, sex, or the presence of splenomegaly.
During the course of the study, 22% of patients discontinued the treatment, because of toxicity. Toxicity was the greatest at the beginning of treatment. The starting dose was 450 μg per week and was gradually tapered off.
Thus, on the basis of the above observations, the researchers established that pegylated interferon alpha-2a may give long-term hematological and molecular remissions [16].
The assessment of pegylated interferon alpha-2a in group of patients diagnosed with polycythemia vera only was performed. The evaluation was carried out on a group of 27 patients. Interferon decreased the JAK2 V617F allele burden in 89% of cases. In three patients who were JAK2 homozygous at baseline, after the interferon alpha-2a treatment wild-type of JAK2 reappeared. The reduction of the JAK2 allele burden was estimated from 49% to an average 27%, and additional in one patient the mutant JAK2 allele was not detectable after treatment. It can therefore be postulated that the action of pegylated interferon alpha-2a is directed to cells of the polycythemia vera clone [17].
In 2005, the results of treatment by pegylated interferon alpha-2b of 21 patients diagnosed with polycythemia vera and 21 patients diagnosed with essential thrombocythemia were published. In the case of polycythemia vera in 14 patients, PRV-1 gene mutation was initially detected. In 36% of cases, PRV-1 expression normalized after treatment with pegylated interferon alpha-2b. For the entire group of 42 patients, the remission assessment showed that complete remission was achieved in 69% cases after 6 months of treatment. However, only in 19 patients remission was still maintained 2 years after the start of the study. Pegylated interferon alpha-2b was equally effective in patients with PV and ET. The use and the type of prior therapy did not affect the achievement of remission [18].
Another study with enrolled only PV patients included 136 patients. They were divided into two arms. One group received interferon alpha-2b and the other group received hydroxycarbamide. Interferon dosage was administered in 3 million units three times a week for 2 years and then 5 million units two times a week. Hydroxycarbamide was administered at a dose between 15 and 20 mg/kg/day.
In the group of patients treated with interferon, a significantly lower percentage of patients developed erythromelalgia (9.4%) and distal parasthesia (14%) compared with the group treated with hydroxycarbamide, for whom these percentages were respectively: 29 and 37.5%. Interferon alpha-2b was found to be more effective in inducing a molecular response, which was achieved in 54.7% of cases, in comparison with hydroxycarbamide—19.4% of cases, despite the fact that the percentage of achieved general hematological responses did not differ between the groups and amounted about 70%. The 5-year progression free period in the interferon group was achieved in a higher percentage (66%) than in the hydroxycarbamide group (46.7%) [19].
The most recent form of interferon approved by the
Thanks to these changes to the structure of the molecule, it was possible to achieve a significant increase in its half-life. Ropeginterferon can be administered subcutaneously to patients every 14 days. The clinical trials conducted so far have assessed the ropeginterferon dose from 50 micrograms to a maximum dose of 500 microgams administered as standard every 2 weeks. The possible dose change in case of side effects includes not only the reduction of the drug dose itself, but also the extension of the interval between doses. The extension of the dosing interval up to 4 weeks was assessed.
Ropeginterforn was approved in 2019 by the EMA for the use in patients diagnosed with polycythemia vera without splenomegaly, as monotherapy.
Ropeginterferon, like the previous forms of interferons used in treatment, is contraindicated in patients with severe mental disorders, such as severe depression. It is also a contraindication in patients with noncompensatory standard treatment of disorders of the thyroid gland as well as severe forms of autoimmune diseases. The safety profile of ropeginterferon is similar to that of other forms of alpha interferons. The most common side effects are flu-like symptoms [20].
Ropeginterferon has been shown to exhibit in vitro activity against JAK2-mutant cells. The activity of ropeginterferon against JAK2-positive cells is similar to that of other forms of interferons used actually for standard therapy. Ropeginterferon has an inhibitory effect on erythroid progenitor cells with a mutant JAK2 gene. At the same time, it has almost no effect on progenitor cells without the mutated allele (JAK2-wile-type) and normal CD34+ cells. A gradual decrease of JAK2-positive cells was observed in patients with PV during ropeginterferon treatment. The examination was performed after 6 and 12 months of treatment. In comparison, the reduction in the percentage of JAK2 positive cells in patients treated with hydroxycarbamide was significantly lower.
These results may suggest that ropeginterferon may cause elimination of the mutant clone, but further prospective clinical trials are needed to confirm this theory. The evaluation was performed on a group of patients enrolled in the PROUD-PV study who were treated in France [21].
In 2017, a multicenter study was opened in Italy. The study was of the second phase. In total, 127 patients with polycythemia vera were included in the study. All patients enrolled on the study had low-risk PV. The clinical trial consisted of two arms. Patients received phlebotomies and low-dose aspirin in one arm and ropeginterferon in the other arm. The aim of the study was to achieve a hematocrit of 45% or lower without any evidence of disease progression. Ropeginterferon was administered every 2 weeks at a constant dose of 100 μg.
The response to the treatment was assessed after 12 months. The reduction of hematocrit to the assumed level was achieved in significantly higher percentage of patients in the ropeginterferon group than of patients who received only phlebotomies and aspirin. In addition, none of the patients treated with ropeginterferon experienced disease progression during the course of the study, while among those treated with phlebotomies, 8% of patients progressed.
Grade 4 or 5 adverse events were not observed in patients treated with ropeginterferon, and the incidence of remaining adverse event (AE) was small and comparable in both arms. The most common side effects in the ropeginterferon group were flu-like symptoms and neutropenia; however, the third-grade neutropenia was the most common (8% of cases) [22].
One of the most important clinical studies on the use of ropeginterferon was the PROUD-PV study and its continuation: the CONTINUATION-PV study. These were three-phase, multicenter studies. The aim of the study was to compare the effectiveness of ropeginterferon in relation to hydroxycarbamide. The study included adult patients diagnosed with polycythemia vera treated with hydroxycarbamide for less than 3 years and no cytoreductive treatment at all. In total, 257 patients received this treatment. The patients were divided into two groups: those receiving ropeginterferon or the other being given hydroxycarbamide.
During the PROUD-study, drug doses were increased until the hematocrit was achieved below 45% without the use of phlebotomies, and the normalization of the number of leukocytes and platelets was reached.
The PROUD-PV study lasted 12 months. After this time, the patients continued the treatment under the CONTINUATION-PV study for further 36 months. After the final analysis performed in the 12th month at the end of PROUD study, it was found that the hematological response rates did not differ between the ropeginterferon and hydroxycarbamide treatment groups. These were consecutively 43% in the ropeginterferon arm and 46% in the control arm.
However, after analyzing the CONTINUATION- PV study, it turned out that after 36 months of treatment, the rates of hematological responses begin to prevail in the group of patients receiving ropeginterferon, 53% versus 38% in the control group. Thus, from the above data, it can be seen that the response rate to ropeginterferon increases with the duration of treatment [23].
Another analysis of patients participating in the PROUD and CONTINUATION studies was based on the assessment of treatment results after 24 months, dividing patients into two groups according to age (under and over 60 years).
The initial comparison of both groups of patients showed that older patients had a more aggressive course of the disease. Patients over 60 years of age had a higher percentage of cells with a mutant JAK2 allele. They experienced both general symptoms and some complications, such as thrombosis, more frequently. Both patients under 60 years of age and over 60 years of age in the ropeginterferon arm had a higher rate of molecular response, namely 77.1 and 58.7% compared with the HU remission: 33.3 and 36.1%, respectively. Significantly higher reductions in the JAK2 allele were observed in both groups of patients after ropeginterferon treatment: it was 54.8% for younger patients and 35.1% for elderly patients. For comparison, this difference in the group of patients treated with HU was 4.5 and 18.4%, respectively.
What is more, the age did not affect the frequency of ropeginterferon side effects. In addition, the incidence of adverse ropeginterferon disorders was similar to that observed in the hydroxycarbamide group [24].
Essential thrombocythemia is a clonal growth of multipotential stem cells in the bone marrow. The consequence of this is increased proliferation of megakaryocytes in the bone marrow and an increase in the number of platelets in the peripheral blood. The level of platelets above 450,000/μl is considered a diagnostic criterion.
Essential thrombocythemia may progress over time to a more aggressive form of myeloproliferation, i.e., myelofibrosis. The disease can also evolve into acute myeloid leukemia or myelodysplastic syndrome, both with very poor prognosis. Thromboembolic complications are serious, and they concern over 20% of patients. Thrombosis occurs in the artery and venous area. Moreover, in patients with a very high platelet count, above 1,000,000/μl, bleeding may occur as a result of secondary von Willebrand syndrome [1, 2].
The treatment of ET is primarily aimed to prevent thrombotic complications.
In low-risk patients, only acetylsalicylic acid is used. In cases of high-risk patients, hydroxycarbamide is the first-line drug for most patients. Anagrelide and interferon are commonly used as second-line drugs.
Due to the possible effects of hydroxycarbamide of cytogenetic changes in the bone marrow cells after long-lasting usage, some experts recommend the use of interferon in younger patients in the first line. Interferon is also used as the drug of choice in patients planning a pregnancy [25].
The efficacy of pegylated interferon alpha-2a was assessed on the basis of the group of 39 patients with essential thrombocythemia and 40 patients with polycythemia vera.
Of the overall group, 81% of patients were previously treated prior to the study entry. The patients received pegylated interferon alpha-2a in a dose of 90 μg once a week. The dose of 450 μg was associated with a high percentage of intolerance.
In patients with essential thrombocythemia, the complete remission was achieved in 76%, while the overall hematological response rate brought 81%. Moreover, the molecular remission was achieved in 38%, in 14% of cases, JAK2 transcript became not detectable.
Patients diagnosed with polycythemia vera achieved 70% complete hematological remission and 80% general hematological response to treatment. JAK2 transcript was undetectable in 6% of patients. Molecular remission was achieved in 54% of cases.
Pegylated interferon alpha-2a at the dose of 90 μg per week was very well tolerated. In total, 20% of patients experienced a grade of 3 or 4 of adverse reaction, which was neutropenia. In addition, an increase in liver function tests was observed. Grade 4 of AE was not observed among patients who started the treatment with 90 μg/week while grade 3 neutropenia was an adverse event in only 7% of cases [26].
The effect of interferon alpha-2b treatment in patients with ET and PV was investigated. The study was prospective. Some of the results concerning the group of patients with polycythemia vera are presented in the subsection on polycythemia vera. In total, 123 patients with diagnosed essential thrombocythemia participated in the study. All of them received interferon alpha-2b. The patients were divided into two groups depending on the presence of the JAK2 V617F mutation. The enrolled patients were between 18 and 65 years of age. The treatment they received was, sequentially, interferon alpha-2b in the dose of 3 million units three times a week for the first 2 years, after which time the dose was changed into a maintenance dose, which amounted to 5 million units two times a week.
The analysis showed that the patients with the JAK2 V617F mutation present in a higher percentage achieved an overall hematological response as well as a complete hematological response. The overall hematological response was achieved in 83% of patients with JAK2 mutation, and the complete hematological remission was achieved in 23 cases. In the group of ET patients without the JAK2 V617F mutation, overall hematological response was achieved in 61.4%, while the complete hematological remission was achieved in 12 patients. The 5-year progression-free survival was obtained in 75.9% in the JAKV617F group and only in 47.6% without the mutation.
A significant proportion of patients experienced mild side effects. Grade 3 and 4 of adverse events were severe, most of them being a fever. The isolated cases of elevated liver tests and nausea have also been reported [19].
Pegylated interferon alpha-2b in patients with essential thrombocythemia who were previously treated with hydroxycarbamide, anagrelide, and other forms of interferon alpha, however, due to the lack of efficacy or toxicity, the patients required a change of treatment, was assessed. Pegylated interferon alpha-2b turned out to be effective in these cases. It led to the complete hematological remission in 91% of patients after 2 months of therapy, and in 100% of patients after 4 months. However, merely 11 patients participated in the study. Also only two patients required treatment discontinuation due to the side effects such as depression and general fatigue grade 3 [27].
In case of pregnant patients, interferon is currently considered the only safe cytoreductive drug. Over the years, several analyses of the results of interferon treatment during pregnancy have been carried out.
The assessment of 34 pregnancies in 23 women diagnosed with ET was performed retrospectively. All the pregnancies included in the analysis were of high risk. This high risk was associated with a high platelet count above 1,500,000/μl, a history of thrombotic episode, severe microcirculation disorders, or a history of major hemorrhage.
It turned out that the use of interferon allowed the birth of an alive child in 73.5% of cases. There was no difference in efficacy between the basic and pegylated forms of interferon alpha. In pregnancies without interferon treatment, the percentage of live births was only 60%. Moreover, it was not found if the presence of the JAK2 V617F mutation had any influence on the course of pregnancy [28].
An analysis of the course of pregnancy in patients with ET was assessed in Italy. Data from 17 centers were taken into account. Data from 122 pregnancies were collected from 92 women. In patients diagnosed with essential thrombocythemia, the risk of the spontaneous loss of pregnancy is about 2.5 times higher than among the general population. In the contrary to the study quoted above, it was found that the presence of the JAK2 mutation increases the risk of pregnancy loss. The proportion of live births in patients exposed to interferon during pregnancy was 95%, compared with 71.6% in the group of patients not treated with interferon.
The multivariate analysis also showed that the use of acetylsalicylic acid during pregnancy had no effect on the live birth rate of patients with ET [29].
Whatever its form, interferon is the drug of first choice in pregnancy. Hydroxycarbamide and anagrelide should be withdrawn for about 6 months, and at least for 3 months, before the planned conception. Experts recommend the use of interferon in high-risk pregnancies [30]. A Japanese analysis of 10 consecutive pregnancies in ET patients showed 100% live births in patients who received interferon [31].
In myelofibrosis (MF), monoclonal megakaryocytes produce cytokines that stimulate the proliferation of normal, non-neoplastic fibroblasts and stimulate angiogenesis. The consequence of this is the gradual fibrosis of the bone marrow, impaired hematopoiesis in the bone marrow, and the formation of extramedullary location mainly in the sites of fetal hematopoiesis, i.e., in the spleen and the liver.
The production of various cytokines by neoplastic megakaryocytes leads to the proliferation of normal, noncancerous fibroblasts as well as to increased angiogenesis.
Progressive bone marrow fibrosis leads to worsening anemia and thrombocytopenia. On the other hand, the production of proinflammatory cytokines by megakaryoblasts leads to the general symptoms such as weight loss, fever, joint pain, night sweats, and consequently, progressive worsening of general condition.
The prognosis for myelofibrosis is poor. In about 20% of patients, myelofibrosis evolves into acute myeloid leukemia with poor prognosis.
Currently, the only effective method of treatment that gives a chance to prolong the life is allogeneic bone marrow transplantation. However, this method is only available to younger patients.
The goal of treatment of patients who have not been qualified for allotranspalntation is to reduce the symptoms and to improve the patient’s quality of life. In case of leukocytosis cytoreducing drugs, such as hydroxycarbamide, melphalan, or cladribine can be used. They cause a reduction in the number of leukocytes and may, to some extent, inhibit splenomegaly. Interferon alpha has been used successfully for the treatment of myelofibrosis for many years. The results of its effectiveness will be presented below [2].
Currently, the JAK2 inhibitor ruxolitinib is approved for the treatment of myelofibrosis with enlarged spleen in intermediate and high-risk patients. Ruxolitinib reduces the size of the spleen, reduces general symptoms, and improves the quality of life; however, it does not prolong the overall survival of patients [32].
In 2015, the results of a retrospective study were published to compare the histological parameters of the bone marrow before and after interferon treatment. Twelve patients diagnosed with primary myelofibrosis as well as post-PV MF and post-ET MF were enrolled in the study. Patients were treated with pegylated recombinant interferon alpha-2a or recombinant interferon alpha-2b in standard doses. The time of treatment was from 1 to 10 years. Some patients had previously been treated with hydroxycarbamide or anagrelide. In all cases, karyotype was normal. The prognostic factor of Dynamic International Prognostic Scoring System (DIPSS) was assessed at the beginning as well as during the treatment.
Bone marrow cellularity decreased in cases with increased bone marrow cellularity before the treatment. After the interferon treatment, a reduction in the degree of bone marrow fibrosis was found. The parameters, such as the density of naked nuclei and the density of megakaryocytes in the bone marrow, also improved.
It proves that if the JAK2 V617F mutation had been present, DIPSS was decreased after interferon treatment. This relationship was not observed in patients without the JAK2 V617F mutation. The improvement in peripheral blood morphological parameters and the overall clinical improvement correlated with the improvement in the assessed histological parameters of the bone marrow.
Before the initiation of interferon, seven patients had splenomegaly. During the treatment with interferon, the complete resolution of splenomegaly was achieved in 17% of patients (two cases), and its size decreased in 25% (three cases). A good clinical response was achieved in 83% during interferon therapy. There was no significant difference in response between the two types of interferon used [33].
A prospective study was also conducted in patients with low and intermediate-1 risk group myelofibrosis. Seventeen patients were enrolled. Patients received interferon alpha-2b (0.5–3 milion units/three times a week) or pegylated interferon alpha-2a (45–90 μg/week). The duration of therapy was on average 3.3 years.
Most of the patients responded to the treatment. Partial remission was found in seven patients and complete remission in two patients. Moreover, in four cases, the disease was stabilized and in one case the clinical improvement was achieved. Three patients did not respond to treatment at all and progressed to myelofibrosis. Additionally, the assessment in reducing spleen size was performed. At baseline, 15 patients have splenomegaly, nine of them achieved the compete regression of spleen size [34].
However, the efficacy of interferon in the treatment of myelofibrosis appears to be limited only to a less advanced form, when the bone marrow still has an adequate percentage of normal hemopoiesis and the marrow stroma is not significantly fibrotic. In more advanced stages, interferon was not shown to have any significant effect on the regression of the fibrosis process [35].
In 2020, the results of the COMBI study were published. That was a two-phase, multicenter, single-arm study that investigated the efficacy and safety of the combination of ruxolitinib and pegylated interferon alpha. Thirty-two patients with PV and 18 patients with primary and secondary myelofibrosis participated in the study. The patients were at age 18 and older. Remission was achieved in 44% of myelofibrosis cases, including 28% (5 patients) of complete remission. In patients with PV, the results were slightly worse: 31% of remissions, including 9% of complete remissions. Patients received pegylated interferon alpha-2a (45 μg/week) or pegylated interferon alpha-2b (35 μg/week) in low doses and ruxolitinib in doses of 5–20 mg twice a day.
For the entire group of patients (with PV and MF), the initial JAK2 allele burden was 47% at baseline, and after 2 years of treatment with interferon and ruxolitinib, it decreased to 12%.
The treatment toxicity was low. The highest incidence of side effects occurred at initiation of therapy. It was mostly anemia and thrombocytopenia.
The observations from the COMBI study show that, for the combination of interferon in lower doses with ruxolitinib, it may be effective and well tolerated even in the group of patients who had intolerance to interferon used as the only drug in higher doses. The combined treatment improved the bone marrow in terms of fibrosis and its cellularity. It also allowed to improve the value of peripheral blood counts [36].
It is currently known that some of the additional mutations are associated with a worse prognosis in patients with myelorpoliferation, including patients with myelofibrosis. Some of these mutations have been identified as high-risk molecular mutations. These are ASXL1, EZH2, IDH1/2, or SRSF2. Earlier studies have shown their association with a more aggressive course of the disease, worse prognosis, and shorter survival of patients, as well as a poorer response to treatment. Due to their importance, they have been included in the diagnostic criteria of myelofibrosis [37].
It is also known that the presence of driver mutations, i.e., JAK2, CALR, and MPL or triple negativity, may affect the course of myeloproliferation, including the incidence of thromboembolic complications.
The assessment of the influence of driver mutations and a panel of selected additional mutations on the effectiveness of interferon treatment in patients with myelofibrosis was performed on a group of 30 patients. Only the patients with low- and intermediate-1-risk were enrolled in the study. The treatment with pegylated interferon alpha-2a or interferon alpha-2b resulted in a complete remission in two patients and partial remission in nine patients. The disease progressed in three cases. One patient relapsed and four died. The remaining patients achieved a clinical improvement or disease stabilization. In the studied group, it was not found if the effectiveness of interferon treatment was influenced by the lack of driver mutations. Among the group of four patients with additional mutations, two died and one had disease progression. It was a mutation of ASXL1 and SRSF2. The treatment with interferon in patients without additional molecular mutations in the early stages of the disease may prevent further progression of the disease [38].
The side effects of interferon in the group of patients with myelofibrosis are similar to those occurring after the treatment of other chronic myeloproliferative diseases. The most frequently described are hematological toxicity- anemia and thrombocytopenia, less often is the appearance of leukopenia. Hematological toxicity usually resolves with dose reduction or extension of the dose interval. The most frequently nonhematological toxicity was fatigue, muscle pain, weakness, and depression symptoms. All symptoms are usually mild and do not exceed grade 2 [38].
However, the use of interferon in the treatment of myelofibrosis has not been recommended as a standard therapy. Interferon is still being evaluated in clinical trials, or it is used in selected patients as a nonstandard therapy in this diagnosis.
Mastocytosis is characterized by an excessive proliferation of abnormal mast cells and their accumulation in various organs.
The basis for the development of mastocytosis is ligand-independent activation of the KIT receptor, resulting from mutations in the KIT proto-oncogene. The KIT receptor is a trans membrane receptor with tyrosine kinase’s activity. Its activation stimulates the proliferation of mast cells. That excessive numbers of mast cells infiltrate tissues and organs and release mediators such as histamine, interleukine-6, tryptase, heparin, and others, which are responsible for the appearance of symptoms typical of mastocytosis. In addition, the infiltration of tissues for mast cells itself causes damage to the affected organs.
The prognosis of mastocytosis depends on the type of the disease. In the case of cutaneous mastocytosis (CM), in the majority of cases prognosis is good and the disease does not shorten the patient’s life, but in aggressive systemic mastocytosis (ASM), the average follow-up is about 40 months. Mast cell leukemia has a poor prognosis with a median follow-up of approximately 1 year.
Systemic mastocytosis usually requires the implementation of cytoreductive therapy. The first line of therapy is interferon alone or its combination with corticosteroids. In aggressive systemic mastocytosis, the first line in addition to interferon 2-CdA can be used. An effective drug turned out to be midostaurin in the case of the present KIT mutation. In patients without the KIT D816V mutation, treatment with imatinib may be effective. In the case of mast cell leukemia, multidrug chemotherapy is most often required, as in acute leukemias, followed by bone marrow transplantation [39].
Systemic mastocytosis requiring treatment is a rare disease, this is why the studies available in the literature evaluating various therapies concern mostly small groups of patients.
In 2002, the French authors presented their experiences on the use of interferon in patients with systemic mastocytosis. They included 20 patients. The patients received interferon alpha-2b in gradually increased doses.
The patients were assessed after 6 months. In cases in which bone marrow was infiltrated for mast cells at baseline, it still remained infiltrated after 6 months of treatment.
However, the responses were obtained in terms of symptoms related to mast cell degranulation. Partial remission was achieved in 35% of patients and minor remission in 30%. It concerns mainly skin lesions and vascular congestion. Moreover, the assessment of the histamine level in the plasma revealed a decrease of it in patients who previously presented symptoms related to the degranulation of mast cells, such as gastrointestinal disorders and flushing.
A high percentage of side effects were found during treatment. They concerned 35% of patients. Depression and cytopenia were most frequent ones [40].
Another analysis was a report of five patients with systemic mastocytosis treated with interferon and prednisolone. All patients received interferon alpha-2b in a dose of 3 million units three times a week and four patients additionally received prednisolone. Four patients responded to interferon treatment at varying degrees. One patient, who at baseline had bone marrow involvement by mast cells in above 10%, progressed to mast cell leukemia. In two patients, the symptoms C resolved completely and in one of them they partially disappeared. In one case, stabilizing disease was achieved [41].
In 2009, a retrospective analysis of patients treated with cytoreductive therapy due to mastocytosis was published. The authors collected data from 108 patients treated at the Mayo Clinic. This analysis allowed for the comparison of the efficacy of four drugs used in systemic mastocytosis. There were interferon alpha alone or in the combination with prednisone—among 40 patients, hydroxycarbamide—among 26 ones, imatinib—among 22 persons, and 2-chlorodeoxyadenosine (2-CdA)—among 22 patients.
After dividing the patients into three additional groups on the basis of the type of mastocytosis—indolent systemic mastocytosis, aggressive systemic mastocytosis, and systemic mastocytosis associated with another clonal hematological nonmast cell lineage disease (SM-AHNMD)—the effectiveness of each of type of therapy was assessed.
The highest response rates in indolent and aggressive mastocytosis were achieved with interferon treatment. They were 60% of the responses in both groups, and in the SM-AHNMD group of patients, the percentage was also one of the highest and amounted to 45%. The second most effective drug was 2-CdA. The response rates were 56% for indolent MS, 50% for aggressive MS, and 55% for SM-AHNMD. The patients treated with imatinib achieved response in 14, 50, and 9% by following groups, respectively. In contrast, patients with indolent and aggressive systemic mastocytosis did not respond to hydroxycarbamide treatment at all. The response rate in both groups was 0%. However, patients with MS associated with another clonal hematological nonmast cell lineage disease achieved 21% response to hydroxycarbamide. Additionally, it was found that only interferon relieved symptoms caused by the release of inflammatory mediators by mast cells.
The additional analysis showed no influence of the TET 2 mutation on the response to treatment [42].
In the literature, there are also single cases of mastocytosis presenting trials of nonstandard treatment. That is description of a patient with systemic mastocytosis with mast cell bone marrow involvement. Mutation of c-kit Asp816Val was present. Patient progressed despite treatment with dasatinib and 2-chlorodeoxyadenosine. The patient developed symptoms related to the degranulation of mast cells and increased ascites.
The patient was treated with pranlukast, which is an anti-leukotriene receptor antagonist due to an asthma episode. The rate of ascites growth decreased significantly after one administration. The patient required paracentesis every 10 days and not every 3 days, as before starting to take the drug. After 15 days of treatment with pranlukast, the patient received interferon alpha, which resulted in complete regression of ascites, resolution of pancytopenia, and complete disappearance of the c-kit mutation clone. The infiltration of mast cells in the bone marrow significantly decreased [43].
Interferon alpha was also effective in a patient with systemic mastocytosis associated with myelodysplastic syndrome with the c-kit D816V mutation, which was refractory to imatinib treatment [44].
Interferon alpha also proved to be effective in the treatment of osteoporotic lesions appearing in the course of mastocytosis.
The series of 10 cases with resolved mastocytosis and osteoporosis-related fractures was presented in 2011. The patients received interferon alpha in a dose of 1.5 million units three times a week as well as pamindronic acid. The patients were treated for an average of 60 months. For the first 2 years, pamindronate was given at a dose of 1 mg/kg every month, and then every 3 months.
During the course of the study, no patient had a new-bone fracture. The level of alkaline phosphatase decreased by 25% in relation to the value before treatment and tryptase by 34%. Bone density increased during treated with interferon and pamindronate. The increase was on average 12% in the spine bones and 1.9% in the hip bones. At the same time, there was no increase in the density of the hip bone and a minimal increase in the density of the spine in patients treated with pamindronate alone.
The results of this observation suggest that it is beneficial to add low doses of interferon alpha to pamindronate treatment in terms of bone density increase [45].
That experiences show that interferon used in systemic mastocytosis significantly improves the quality of life of patients by inhibiting the symptoms caused by degranulation of mast cells. They prevent bone fractures and, in some patients, they cause remission of bone marrow infiltration by mast cells.
Chronic neutrophilic leukemia (CNL) is a very rare disease. It is characterized by the clonal proliferation of mature neutrophils.
The diagnostic criteria proposed by the World Health Organization (WHO) comprise leukocyte counts above 25,000/μl (including more than 80% of rod and segmented
Physical examination often shows enlargement of the liver and spleen, moreover, patients complain on weight loss and weakness [1].
The prognosis varies. The average survival time for patients with CNL is less than 2 years.
Only few descriptions of chronic neutrophilic leukemia are available in the literature, and these are mostly single case reports.
Because it is an extremely rare disease, there are no established and generally accepted treatment standards. In most cases, patients are given hydroxycarbamide or interferon. Patients who are eligible for a bone marrow transplant may benefit from this treatment. Bone marrow allotransplantation remains the only method that gives a chance for a significant extension of life.
The German authors presented a series of 14 cases of chronic neutrophilic leukemia. The group of patients consisted of eight women and six men. The average age was 64.7 years. From the entire group of patients, longer survival was achieved only in three cases. One of these patients was treated with interferon alpha and achieved hematological remission, the other underwent bone marrow allotransplantation from a family donor, and the third one was treated with hydroxycarbamide and transfusions as needed. The follow-up period of the patient after allogeneic matched related donor transplantation (allo-MRD) was 73 months, and for the patient after interferon treatment it was 41 months.
The remaining patients died within 2 years of diagnosis. Six patients, the largest group, died due to intracranial bleeding, three patients died because of leukemia cell tissue infiltration, one patient because of the disease transformation into leukemia, and one patient because of pneumonia [46].
It can be seen from these experiences that treatment with interferon alpha can significantly extend the survival time of patients.
The case of a 40-year-old woman diagnosed with chronic neutrophilic leukemia is presented by Yassin and coauthors. Initially, the patient had almost 41,000 leukocytes in the peripheral blood. In a physical examination, splenomegaly and hepatomegaly were not present. Patient received pegylated interferon alpha-2a. The initially dose was 50 μg once a week for the first 2 weeks, then the dose was increased to 135 μg weekly for 6 weeks, and then the dose interval was extended to another 2 weeks. As a result of the treatment, the general condition of the patient improved and the parameters of peripheral blood counts were normalized [47].
Another case report presented in the literature describes a 41-year-old woman diagnosed with CNL accompanied by focal segmental glomerulosclerosis (FSGS). The patient had increasing leukocytosis for several months. On the admission to the hospital, leukocytosis was 94,000/μl. Moreover, the number of platelets in the morphology exceeded 1,000,000/μl. More than a year earlier, the patient had splenectomy due to splenomegaly and spleen infraction.
Additionally, JAK2 V617F mutation was found. Some authors suggest that the presence of JAK2 mutation may be associated with longer survival in CNL.
The patient received hydroxycarbamide for 3 months and reduction in the number of leukocytes was achieved. After this time, interferon alpha-2b was added to hydroxycarbamide. As a result, focal segmental glomerulosclerosis disappeared and the renal tests improved [48].
Another case of chronic neutrophilic leukemia with a JAK2 gene mutation concerns a 53-year-old man. The patient’s baseline leukocytosis was 33,500/μl, including the neutrophil count of 29,700/μl. The patient also had splenomegaly.
The treatment with interferon alpha-2b at a dose of 3 million units every other day was started. After a month of treatment, the number of leukocytes was reduced to less than 10,000/μl. Then the patient was treated chronically with interferon alpha-2b in doses of 3 million units every 2 weeks. As a result of the therapy, the number of leukocytes remains between 8 and 10,000/μl. The patient remains in general good condition [49].
A series of two CNL cases are also shown. The first patient was a 70-year-old woman with stable leukocytosis of about 35,000/μl and the remaining morphology parameters in normal range. The patient was only observed for 5 years until hepasplenomegaly progressed rapidly. Then, interferon alpha-2b was included. Due to the treatment, the rapid regression of hepatosplenomegaly was achieved.
The second case is a 68-year-old woman with baseline leukocytosis of almost 14,000/μl. In this case, the treatment with hydroxycarbamide was started immediately. However, no improvement was achieved. After 6 weeks of HU treatment, interferon alpha-2b 3 million units 3 times a week was implemented and leukocytosis decreased. Due to the interferon treatment, the disease stabilized for a long time. Because the patient experienced an adverse reaction, a severe flu-like syndrome, interferon was discontinued. After interferon withdrawal, the disease progressed gradually and the treatment attempts by busulfan and 6-mercaptopurine were unsuccessful. Therefore, interferon was readministered and the disease went into remission. Interferon treatment was continued at a reduced dose. The disease regression was achieved again.
Additionally, the patient showed an improvement in the function of granulocytes in terms of phagocytosis and an improvement in neutral killer (NK) cell function after treatment with interferon [50].
The above examples show that interferon alpha is effective in the treatment of chronic neutrophilic leukemia. The side effects are rare and can be managed with dose reductions. Moreover, in these cases, interferon is also effective in a reduced dose. Disease remission or regression can be achieved without typical of CNL complications, such as intracranial bleeding.
Interferon has been used in the past to treat chronic myeloid leukemia. The treatment with tyrosine kinase inhibitors is now a standard practice. However, in a small number of patients, they are ineffective or exhibit unmanageable toxicity. Therefore, the attempts are underway to use interferon in combination with TKI in lower doses, which is to ensure the enhancement of the antiproliferative effect while reducing the toxicity.
There are ongoing attempts to use ropeginterferon in patients diagnosed with chronic myeloid leukemia, in whom treatment with imatinib alone has not led to deep molecular response (DMR). The first phase study was conducted in a small group of patients with chronic myeloid leukemia. The patients in first chronic phase treated with imatinib who did not achieve DMR, but in complete hematologic remission and complete cytogenetic remission, were included in the study. Patients have been treated with imatinib for at least 18 months. Twelve patients were enrolled in the study, and they completed the study according to the protocol. These patients received additional ropeginterferon to imatinib and four achieved DMR. Low toxicity was observed during the treatment. Among the hematological toxicities, neutropenia was the most common. There was no nonhematological toxicity with a degree higher than 1/2 during the treatment. Moreover, it has been found that better effects and fewer side effects are obtained when ropeginterferon is administered for a longer time, but in lower doses. The comparison of the effectiveness of interferon in chronic myeloproliferative disorders based on selected articles is presented in Table 1 [51].
Source | Type of trial | Interferon | Diagnosis | No. | Prior treatment status | Response rate |
---|---|---|---|---|---|---|
Yacoubet al. [15] | Phase II, multicenter | Pegylated IFN alfa-2a | PV | 50 | Resistance to HU or HU intolerance | CR:22% PR:38% |
ET | 65 | CR:43% PR:26% | ||||
Masarova et al. [16] | Phase II, single-center | Pegylated IFN alfa-2a | PV | 43 | Untreated or previously treated with cytoreductive therapy | CR:77% PR:7% |
ET | 40 | CR:73% PR:3% | ||||
Samuelsson et al. [18] | Phase II | Pegylated IFN alfa-2b | PV | 21 | Untreated or previously treated with cytoreductive therapy | CR: 69% for the entire group |
ET | 21 | |||||
Huang BT et al. [19] | Open label, multicenter | IFN alfa-2b | PV | 136 | Untreated or previously treated with cytoreductive therapy | OHR:70% Molecular response:54.7% |
ET | 123 | OHR (JAK2+ patients):83% CHR:23 cases OHR (JAK2-patients): 61.4% CHR:12 cases | ||||
Gisslinger et al. [23] | phase III, multicenter | Ropeginterferon | PV | 257 | Previously treated | OHR:53% |
Quintás-Cardama et al. [26] | phase II | Pegylated IFN alfa-2a | PV | 40 | Untreated or previously treated with cytoreductive therapy | OHR:80% CR:70% Molecular remission:54% |
ET | 39 | OHR:81% CR:76% Molecular remission:38% | ||||
Sørensen et al. [36] | Phase III, multicenter, COMBI | Pegylated IFN alfa-2a with ruxolitinib or Pegylated IFN alfa-2b with ruxolitinib | PV | 32 | Untreated or previously treated with cytoreductive therapy | OHR:44% CR:28% |
MF | 18 | OHR:31% CR:9% | ||||
Casassus et al. [40] | Open label, multicenter | IFN alpha-2b | Mastocytosis | 20 | Untreated and previously treated | PR:35% Minor remission: 30% |
Comparison of the effectiveness of interferon in chronic myeloproliferative disorders.
PV: polycythemia vera; ET: essential thrombocythemia; MF: myelofibrosis; HU: hydroxycarbamide/hydroxyurea; CR: complete remission; PR: partial remission; and OHR: overall hematological response.
Interferon alpha appears to be an effective and safe drug in the most type of chronic myeloproliferative disorders. Nowadays, all forms of its using have similar effectiveness. Interferon alpha can be effective even in cases of resistance for first-line treatment. Trial research is currently underway to combine it with some new drugs, such as ruxolitinib, and to add it to the already well-established therapy, it is a promising option for patients with refractory disease.
From time to time, new forms of interferon, such as ropeginterferon, are introduced, which gives hope for better effectiveness, better safety profile, and greater comfort in its use for patients who have to be treated for many years. In the case of the use of interferons alpha in the treatment of chronic myeloproliferative diseases, there are still opportunities to extend its use and to study its combination with newly introduced drugs.
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