Vol 54, No 1 (2023)
Original research article
Published online: 2022-11-14

open access

Page views 2702
Article views/downloads 447
Get Citation

Connect on Social Media

Connect on Social Media

Comparison of depressive, anxiety, and somatic symptoms in patients with essential thrombocythemia, polycythemia vera, and myelofibrosis treated with interferon alpha

Katarzyna Gibek1, Tomasz Sacha2, Katarzyna Cyranka34
Acta Haematol Pol 2023;54(1):18-30.

Abstract

Introduction: The study aims to analyze the occurrence of depression, anxiety, and somatic symptoms in patients with chronic myeloproliferative neoplasms (essential thrombocythemia, polycythemia vera, and myelofibrosis) and to check whether individual side effects of interferon alpha treatment may contribute to the occurrence of depression, anxiety, and somatic symptoms. In addition, it was decided to check whether there were any relationships between age, gender, duration of treatment, and the intensity of anxiety, divided by the occurrence of individual side effects.

Material and methods: The study involved 84 patients and was conducted at the Hematology Clinic of the University Hospital in Krakow and the Clinic of Hematology, Blood Cancer and Bone Marrow Transplantation in Wrocław. The following questionnaires were used: created by the author, David Goldberg General Health Questionnaire 28 (GHQ-28), and the Four-Dimensional Questionnaire (4DSQ).

Results: The most frequently reported side effects of treatment were abdominal pain, fatigue, and bone and joint pain. Almost 40% of the respondents obtained a moderately and strongly increased result on the depression scale, less than 50% on the anxiety scale, and over 60% on the somatization scale. Somatic symptoms had the greatest impact on the occurrence of mental disorders, with anxiety symptoms being second in significance. There are differences in the severity of depressive, anxiety, and somatic symptoms depending on the side effects of interferon alpha treatment.

Conclusions: The finding of the above study indicates the need for further research into the importance of detecting depressive, anxiety, and somatic disorders, and to addressing concomitant physical symptoms, both in patients with myeloproliferative neoplasms receiving interferon alpha and treated with other methods. In patients treated chronically, the occurrence of side effects of high intensity and lasting for a long time should alert medical personnel. The collected data on patients with myeloproliferative neoplasms who have to suffered from mental and physical symptoms of the disease or its treatment justifies the need for caring psychological, psychiatric, and educational care.

ORIGINAL RESEARCH ARTICLE

Acta Haematologica Polonica 2023

Number 1, Volume 54, pages 18–30

DOI: 10.5603/AHP.a2022.0058

ISSN 0001–5814

e-ISSN 2300–7117

Comparison of depressive, anxiety, and somatic symptoms in patients with Philadelphia-negative chronic myeloproliferative neoplasms treated with interferon alpha

Katarzyna Gibek1*Tomasz Sacha2Katarzyna Cyranka34
1Department of Hematology, Jagiellonian University Medical College, Kraków, Poland
2Chair and Department of Hematology, Jagiellonian University Medical College, Kraków, Poland
3Department of Psychiatry, Jagiellonian University Medical College, Kraków, Poland
4Department of Metabolic Diseases, Jagiellonian University Medical College, Kraków, Poland

*Address for correspondence: Katarzyna Gibek, Department
of Hematology, Jagiellonian University Medical College, Kopernika 17, 31–501 Kraków, Poland, e-mail: k.gibek@doctoral.uj.edu.pl

Received: 29.08.2022 Accepted: 01.11.2022

Abstract
Introduction: The aim of this study was to analyze the occurrence of depression, anxiety, and somatic symptoms in patients with chronic myeloproliferative neoplasms (essential thrombocythemia, polycythemia vera, and myelofibrosis) and to check whether individual side effects of interferon alpha treatment may contribute to the occurrence of depression, anxiety, and somatic symptoms. In addition, it was decided to check whether there were any relationships between age, gender, duration of treatment, and the intensity of anxiety, divided by the occurrence of individual side effects.
Material and methods: The study involved 84 patients and was conducted at the Hematology Clinic of the University Hospital in Krakow, Poland and the Clinic of Hematology, Blood Cancer and Bone Marrow Transplantation in Wrocław, Poland. The following questionnaires were used: the David Goldberg Questionnaire GHQ-28, and the four-dimensional 4DSQ Questionnaire.
Results: The most frequently reported side effects of treatment were abdominal pain, fatigue, and bone and joint pain. Almost 40% of the respondents obtained a moderately or strongly increased result on the depression scale, less than 50% on the anxiety scale, and over 60% on the somatization scale. Somatic symptoms had the greatest impact on the occurrence of mental disorders, with anxiety symptoms being second in significance. There are differences in the severity of depressive, anxiety, and somatic symptoms depending on the side effects of interferon alpha treatment.
Conclusions: The findings of this study indicate the need for further research into the importance of detecting depressive, anxiety, and somatic disorders, and to addressing concomitant physical symptoms, both in patients with myeloproliferative neoplasms receiving interferon alpha and in those treated with other methods. In patients treated chronically, the occurrence of side effects of high intensity and lasting for a long time should alert medical personnel. The available data on patients with myeloproliferative neoplasms who have suffered from mental and physical symptoms of the disease or its treatment justifies the need for caring psychological, psychiatric, and educational care.
Key words: depresson, anxiety, somatization, myeloproliferative neoplasms, essential thrombocythemia, polycythemia vera, myelofibrosis, interferon alpha
Acta Haematologica Polonica 2023; 54, 1: 18–30

Introduction

Chronic myeloproliferative neoplasms (MPNs) are a heterogeneous group of disorders characterized by the overproduction of mature cells from one or more myeloid lineages. The most common are polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (primary; PMF, or post-ET-MF or post-PV-MF), and chronic myeloid leukemia (CML), which is treated separately due to the presence of the Philadelphia chromosome and different treatments [1].

In most patients with myeloproliferative neoplasms without the Philadelphia chromosome, mutations in the JAK2 [2], MPL [3, 4] or CALR genes [5] are detected.

In the initial phase of the disease, a significant proportion of patients do not develop any clinical symptoms, and the disease is usually detected via routine blood tests. The exception is myelofibrosis, where, in more than half of cases, symptoms may appear in the form of significant weakness, bone and muscle pains, fever, itching of the skin, night sweats or discomfort in the abdominal cavity. The peripheral blood count of patients with MPN may include leukocytosis, thrombocythemia, or/and an increase in the number of erythrocytes, hemoglobin, and hematocrit. Typically, this type of cancer develops slowly and can affect people of all ages, but the most common age at incidence is between 50 and 70 years. In Poland, the annual incidences are: of polycythemia vera 2.5/100,000 population [men suffer more often than women (1–2:1)]; of essential thrombocythemia 1.5/100,000 of the population; of primary myelofibrosis 0.5–1.5/100,000 population; and of CML 0.7/100,000 population. The treatment used depends on the type of myeloproliferative disorder and on the presence of risk factors [6–10].

In the pharmacological treatment of PV, ET, and MF, interferon alpha (IFNα) [11–13] is often used, mainly in the form of peginterferon alpha-2a (Pegasys®) [14, 15] or ropeginterferon alpha-2b (Besremi®) [16]. Interferon alpha was introduced to the treatment of patients with myeloproliferative neoplasms without the Philadelphia chromosome more than 30 years ago [17]. This medication also has antiviral properties; therefore it is also used in the treatment of viral diseases such as hepatitis B and C and Kaposi’s sarcoma [18].

The side effects of interferon alpha in patients suffering from myeloproliferative neoplasms have been widely reported in the literature [19–21]. Apart from hematological, neurological, and rheumatological symptoms, the most common side effects include fatigue, loss of appetite, nausea, diarrhea, muscle pain, skin rash, headaches, and abnormal triglyceride levels [22–27].

Both cancer itself (with its mental and physical comorbidities) [28] and the side effects of treatment can contribute to the development of depression and anxiety symptoms [29]. Many researchers have presented this topic in their work on the occurrence of anxiety and depression among patients with myeloproliferative neoplasms, analyzing the influence of the disease (its symptoms) on the occurrence of depression or anxiety [30–34]. Many studies have also focused on the side effects of treatment with various forms of interferon alpha in MPN [35], and some indicate that depression is one of them [23, 35–37]. Raison et al. [38] indicated that significant depressive symptoms occur in 21–58% of patients receiving non-pegylated IFNα, with symptoms usually appearing within the first few months of treatment, and may be due to high medication dose, female gender, history of depression, and duration of treatment.

It is noteworthy that due to the use of different definitions of depression in research and various diagnostic tools and interviews, the word ‘depression’ can encompass various psychiatric or neurological symptoms not necessarily related to clinical depression.

The literature does not provide studies that analyze the coexistence of anxiety, depression, somatic symptoms, and side effects of MPN treatment together. Usually, the influence of chronic myeloproliferative neoplasms (including its symptoms) on the occurrence of depression and/or anxiety or the general side effects of the drug (where depression is one of the side effects) have been examined. However, it has not been investigated whether possible side effects of the drug (e.g. fatigue, diarrhea) may contribute to the emergence of anxiety/depression. One of the difficulties may be determining whether a particular disease symptom is a side effect of treatment, or a somatic symptom of the disease. To our best of our knowledge, only a study by Padrnos et al. [34] on symptoms of depression in patients with myeloproliferative neoplasms drew attention to the relationship between depression and other variables. It showed that side effects may influence the development of depressive disorders [34].

The Bioethics Committee at the Jagiellonian University in Krakow approved our study (No. 1072.6120.113.2020). Each participant obtained information about the study and gave their written consent to participate.

The aim of our study was to analyze the occurrence of depression, anxiety, and somatic symptoms in patients with chronic myeloproliferative neoplasms (ET, PV, and PMF) and to check whether individual side effects of interferon alpha treatment may contribute to the occurrence of depression, anxiety, and somatic symptoms. In addition to this, we decided to check for a relationship between the age and the sex of the patient as well as the duration of the treatment and the severity of depressive, anxiety, and somatic symptoms; the data was divided depending on the occurrence of the individual side effect. The aim of the study was not to diagnose depressive or anxiety disorders, but instead to check the possibility of their development during IFNα treatment.

Material and methods

The study was carried out at the Hematology Clinic of the University Hospital in Kraków and the Clinic of Hematology, Blood Cancer and Bone Marrow Transplantation in Wrocław, Poland. The study involved 105 adult patients on interferon alpha treatment for a minimum of three months who gave their written consent. The patients were diagnosed with essential thrombocythemia, or polycythemia vera, or primary myelofibrosis. 21 patients were excluded from the study because they met our exclusion criteria i.e.: psy­chiatric or psychological (psychotherapeutic) treatment during the study period or the three months before its start, discontinuation of interferon alpha treatment or switching to another drug, initiation of interferon alpha treatment during the study or up to three months before starting treatment, feeling similar symptoms to those mentioned in the questionnaire, and the presence of anemia or disorder of the thyroid gland at least one month before starting treatment with alpha interferon. Ultimately, 84 patients (65 women and 19 men) were enrolled into the study. Data on the prevalence of anemia or hypothyroidism was collected from laboratory test results performed on the day of the questionnaire. The mean age in the research group was 39 [standard deviation (SD) = 10.199] years. Median IFNα dosing was 45 μg/week, with a minimum value of 45 μg/week and a maximum of 180 μg/two weeks. Detailed characteristics of the study group are set out in Table I.

Table I. Description of study group

Variable

Me ± SD

(Min–
–max)

Age (years)

37.50 ± 10.199

(20–65)

Treatment time (years)

9.50 ± 6.185

(1–23)

Number of side effects

4.00 ± 2.781

(0–11)

Type of MPN

N

[%]

Essential thrombocythemia

32

38.1

Polycythemia vera

28

33.3

Primary myelofibrosis

24

28.6

Variable

N

[%]

Sex

Female

65

77.4

Male

19

22.6

Education

Basic vocational education

1

1.2

Secondary

36

42.9

Higher

47

56.0

Place of residence

City

63

25.0

Village

21

75.0

Residence status

Living alone

5

6.0

Living with family

79

94.0

Research tools

  1. Sociodemographic questionnaire, which includes questions about age, sex, place of residence, marital status, education, type of MPN (ET, PV, PMF, and others), duration of the disease, side effects of interferon alpha treatment divided into periods and their duration. The list of side effects of interferon alpha treatment was prepared based on the results of studies on its effects and toxicity [22, 23, 27].
  2. Goldberg’s General Health Questionnaire 28 (GHQ-28) [39] questionnaire was used to assess mental health in adults. This questionnaire is sometimes used as a screening tool to detect people at risk of developing mental disorders and to analyze four symptoms of mental disorders: depression, anxiety, somatic and social dysfunction. In this study, the general, current mental state of the respondents and three dimensions of mental health: depressive, anxiety, and somatic symptoms, were analyzed. Additionally, the focus was on identifying people who may be at risk of developing mental disorders.

Two scoring methods were used in the study: 1) the GHQ method, in which a dichotomous scale is used to identify people with a mental disorder, the cut-off point in this method being 6 points; and 2) a modified Likert scale from 0 to 3 points, which is used to check the general mental state of the respondents and to analyze three mental health factors: depressive, anxiety and somatic symptoms. Each scale contains seven questions, and a maximum of 21 points can be obtained. Sten norms were used to assess the results of general mental state.

  1. Four-Dimensional Symptom Questionnaire (4DSQ), measuring the severity of current depressive symptoms (six questions), anxiety (12 questions), somatic (16 questions), and distress (16 questions) [40]. This study focused on analyzing three out of four dimensions: depression, anxiety, and somatic symptoms. In the case of depressive symptoms, the maximum number of points that can be obtained is 12, for anxiety symptoms — 24, and for somatic symptoms — 32. The cut-off points for individual scales are presented in Table II.
Table II. Cut-off points for individual scales of the Four-Dimensional Symptom Questionnaire

Factor

Distress

Depression

Anxiety

Somatization

Moderate

>9

>2

>3

>10

High

>20

>5

>9

>20

The names of the scales in both questionnaires: depression, anxiety, and somatization should be treated as depressive, anxiety and somatic symptoms, respectively. The above tests are used as screening tests or for identifying people who may be at risk of developing mental disorders, and by themselves do not diagnose disorders. The diagnosis of depressive, anxiety, or somatic disorders requires the fulfillment of specific diagnostic criteria of the International Statistical Classification of Diseases and Related Health Problems 11th revision (ICD-11) or Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V) classification. In the presented study, depressive symptoms are not equivalent to the terms “depression” or “depressive disorder”.

Statistics

Statistical analyzes were performed using IBM SPSS Statistics version 26. It was used to perform a frequency analysis, basic descriptive statistics analysis, a series of multivariate linear regression analyses, a series of correlation analyses with Spearman’s rho coefficient, and a one-way ANOVA with repeated measures along with a post hoc test with Benferroni correction. The normality of the distribution was verified by the Kolmogorov-Smirnov test. The level of significance was α = 0.05.

Firstly, the basic descriptive statistics of the variables analyzed later in the work were calculated. For quantitative variables, mean values were presented with standard deviations, and nominal variables — with the frequency of occurrence.

Results

The most frequently reported side effects of treatment were abdominal pain (82.1%), fatigue (66.7%), and bone and joint pain (61.9%). Detailed data is set out in Table III.

Table III. Occurrence of side effects with division into time of their appearance and duration

Side effect

PLT
N [%]

PLNT
N [%]

L3T
N [%]

L3NT
N [%]

TOTAL TR
N [%]

TOTAL W
N [%]

Water retention

25 (29.8)

11 (13.1)

8 (9.5)

1 (1.2)

33 (39.3)

45 (53.6)

Frequent infections

15 (17.9)

3 (3.6)

15 (17.9)

18 (21.4)

Fatigue

45 (53.6)

6 (7.1)

5 (6.0)

50 (59.5)

56 (66.7)

Bruising

31 (36.9)

7 (8.3)

31 (36.9)

38 (45.2)

Diarrhea

9 (10.7)

19 (22.6)

5 (6.0)

9 (10.7)

33 (39.3)

Loss of appetite

25 (29.8)

14 (16.7)

25 (29.8)

39 (46.4)

Bone and joint pain

34 (40.5)

9 (10.7)

6 (7.1)

3 (3.6)

40 (47.6)

52 (61.9)

Nausea, indigestion

27 (32.1)

7 (8.3)

8 (9.5)

27 (32.1)

42 (50.0)

Abdominal pain

44 (52.4)

19 (22.6)

6 (7.1)

50 (59.5)

69 (82.1)

Cramps, muscle aches

30 (35.7)

8 (9.5)

5 (6.0)

5 (6.0)

35 (41.7)

48 (57.1)

Skin rash, itching

28 (33.3)

20 (23.8)

3 (3.6)

48 (57.1)

48 (57.1)

Anemia

18 (21.4)

2 (2.4)

1 (1.2)

1 (1.2)

19 (22.6)

21 (25.0)

Hypothyroidism

13 (15.5)

1 (1.2)

1 (1.2)

1 (1.2)

14 (16.6)

16 (19.0)

As the next step, the side effects that persisted until the day of the study (TOTAL TR) were analyzed.

The general mental state of the respondents was checked using the GHQ-28 questionnaire and GHQ scoring (0 no symptom, 1 symptom occurrence). Thirty patients (35.71%) at risk of developing mental disorders were identified. These people exceeded the threshold of 6 points, which is the cutoff point for identifying people with mental disorders. Tables IV and % present the results of the 4DSQ and GHQ-28 questionnaires.

Table IV. Incidence of depressive, anxiety and somatic symptoms measured with the Four-Dimensional Questionnaire (4DSQ)

All patients (n = 84)

4DSQ

Depression

Anxiety

Somatization

N

[%]

N

[%]

N

[%]

Moderate

24

28.6

31

36.9

43

51.2

High

8

9.5

10

11.9

19

22.6

Analysis of the occurrence of depressive, anxiety and somatic symptoms in patients with chronic myeloproliferative neoplasms showed that almost 40% of the respondents obtained a moderately or strongly increased result on the depression scale, less than 50% on the anxiety scale, and over 60% on the somatic symptoms scale (Table IV).

Using the GHQ-28 questionnaire and the 4DSQ questionnaire, the general mental state of the respondents and the influence of individual disorders on their severity were checked (Table V).

Table V. Overall score and score for individual scales of General Health Questionnaire 28 (GHQ-28) and the Four-Dimensional Questionnaire (4DSQ)

Questionnaire

Overall score

Somatization

Anxiety

Depression

F

M

SD

M

SD

M

SD

M

SD

GHQ-28

24.48

11.575

6.96a

3.338

6.10b

4.041

2.93b

3.104

70.577*

4DSQ

11.24a

7.996

3.29b

4.694

1.74c

2.523

138.988*

The overall result of the GHQ-28 test showed an average mental condition of the patients. Analysis with the use of a one-way analysis of variance in the intergroup scheme showed that somatic symptoms had the greatest impact on the occurrence of mental disorders, with anxiety symptoms being second in significance. Similar results were observed using the 4DSQ.

As the next step, the severity of depressive, anxiety, and somatic symptoms were checked, and divided into side effects of interferon alpha treatment, using the 4DSQ and GHQ-28 questionnaires (Table VI).

Table VI. Depressive, anxiety, and somatic symptoms divided by side effects of interferon alpha treatment

Side effect

Somatization

Anxiety

Depression

F

M

SD

M

SD

M

SD

Water retention

GHQ

7.48a

3.28

5.88b

3.91

3.24c

3.55

25.74*

DSQ

12.00a

7.76

3.67b

5.10

1.85c

2.69

65.31*

Frequent infections

GHQ

10.73a

2.87

8.73a

3.60

4.53b

3.38

22.10*

DSQ

15.80a

8.49

4.47a

5.44

2.87b

2.97

43.20*

Fatigue

GHQ

8.20a

2,85

7.46a

4.02

3.62b

3.24

42.79*

DSQ

12.52a

7.51

3.42b

4.38

1.80c

2.30

105.10*

Bruising

GHQ

8.23a

3.77

7.10b

4.11

3.19c

2.99

38.40*

DSQ

12.39a

7.82

3.81b

4.59

2.32b

2.88

59.10*

Diarrhea

GHQ

9.11a

3.14

8.22b

3.14

3.67c

3.80

70.58*

DSQ

12.44a

8.31

1.78b

1,56

1.67c

2.00

138.98*

Loss of appetite

GHQ

8.56a

3.34

7.84a

3.35

5.08b

3.14

23.01*

DSQ

12.36a

7.80

3.76b

4.48

2.36b

3.07

50.84*

Bone and joint pain

GHQ

8.13a

3.66

7.05b

3.80

3.83c

3.47

33.91*

DSQ

12.85a

8.42

3.73b

4.41

2.08c

2.56

72.17*

Nausea, indigestion

GHQ

7.93a

3.03

8.26a

3.28

4.41b

3.43

28.71*

DSQ

11.07a

6.87

3.67b

4.28

1.85b

2.69

54.78*

Abdominal pain

GHQ

8.30a

2.94

7.58a

3.24

4.14b

3.39

44.60*

DSQ

12.34a

7.57

3.68b

4,18

1.92c

2.47

140.88*

Cramps, muscle aches

GHQ

8.86a

3.02

8.00a

3.33

4.51b

3.51

24.90*

DSQ

13.66a

7.62

3.86b

4.59

2.34b

2.66

85.78*

Skin rash, itching

GHQ

6.69a

3.37

5.67b

4.39

3.54c

3.55

23.36*

DSQ

12.42a

9.10

3.48b

5.46

2.04b

2.77

72.99*

Anemia

GHQ

6.81a

0.90

5.75b

1.16

2.25b

0.72

13.44*

DSQ

10.31a

1.93

2.44a

1.16

1.38b

0.65

34.27*

Hypothyroidism

GHQ

8.48a

0.61

8.14b

0.47

6.43b

0.64

8.405*

DSQ

16.19a

1.84

5.24a

1.20

2.27b

0.74

47.19*

With the use of a one-way analysis of variance in the intergroup scheme, it was shown that there are differences in the severity of depressive, anxiety, and somatic symptoms depending on the side effects of interferon alpha treatment. In the case of the study with the GHQ-28 questionnaire, in most of the experienced side effects of interferon alpha treatment, the greatest influence on the occurrence of psychological disorders were somatic symptoms, followed by anxiety and anxiety-related insomnia. Only in the cases of side effects of nausea and indigestion was anxiety the leading factor in inducing mental disorders.

The side effects with the greatest severity of somatic symptoms were hypothyroidism-related symptoms, frequent infections, diarrhea, muscle cramps, and pain. Similar results were obtained for the deterioration of anxiety symptoms, but additional side effects with high scores were nausea and indigestion. In the case of depressive symptoms, the side effects obtaining the greatest results were: loss of appetite, frequent infections, and muscle pain. The 4DSQ survey showed that all experienced side effects of treatment were associated with increased levels of somatization and anxiety. In the case of depressive symptoms, elevated levels were observed, in order of severity: hypothyroidism-related symptoms, frequent infections, loss of appetite, muscle cramps and pain, bruising, diarrhea, bone, and joint pain, skin rash, and itching.

The next analysis examined whether there was any relationship between age and duration of treatment and the severity of depressive, anxiety, and somatic symptoms, divided by individual side effects (Table VII).

Table VII. Spearman’s correlation coefficients between anxiety, depressive and somatic symptoms [measured by General Health Questionnaire (GHQ) and Four-Dimensional Questionnaire (4DSQ)] and age and duration of treatment by perceived side effects of interferon alpha treatment

Side effect

Variables

Somatization

Anxiety

Depression

GHQ

DSQ

GHQ

DSQ

GHQ

DSQ

Water retention

Age

0.93

0.21

0.08

–0.03

–0.21

–0.02

Treatment time

0.11

–0.14

–0.25

–0.04

0.02

–0.17

Frequent infections

Age

0.26

–0.04

–0.19

–0.33

–0.18

0.13

Treatment time

0.13

0.43

0.25

–0.12

0.01

0.03

Fatigue

Age

–0.25

0.21

0,15

0.17

–0.09

0.17

Treatment time

–0.11

0.08

–0.02

0.08

–0.30*

–0.08

Bruising

Age

0.08

–0.09

0.31

0.29

–0.01

0.24

Treatment time

0.03

0.08

0.36*

0.40

0.02

–0.02

Diarrhea

Age

–0.21

0.05

–0.03

0.13

–0.18

0.08

Treatment time

0.04

–0.01

0.16

0.03

0.04

0.02

Loss of appetite

Age

–0.55**

–0.08

–0.09

0.18

–0.23

0.01

Treatment time

–0.57**

–0.12

–0.45**

–0.22

–0.62**

–0.23

Bone and joint pain

Age

–0.27

0.18

–0.03

–0.05

–0.24

–0.06

Treatment time

–0.24

–0,08

–0,13

–0,20

–0,37*

–0.27

Nausea, indigestion

Age

–0.34

–0,01

0,04

0,18

–0,08

0.11

Treatment time

–0.41

–0,08

–0,07

–0,02

–0,45*

–0.10

Abdominal pain

Age

–0.38**

0.04

0.15

0.17

–0.23

0.18

Treatment time

0.01

0.17

0.09

0.06

–0.07

0.05

Cramps, muscle aches

Age

–0.19

0.25

0.09

–0.17

0.15

–0.01

Treatment time

–0.08

0.15

0.04

–0.05

–0.35*

–0.14

Skin rash, itching

Age

–0.18

0.03

0.17

0.07

–0.18

–0,07

Treatment time

0.11

–0.08

–0.10

–0.23

–0.10

–0.37*

Anemia

Age

–0.10

0.37

–0.07

–0.65

–0.27

–0.18

Treatment time

0.00

0.48*

0.06

0.10

–0.46*

–0.20

Hypothyroidism

Age

–0.13

–0.40

–0.42

–0.17

–0.03

–0.27

Treatment time

–0.07

–0.38

–0.33

–0.36

–0.17

–0.38

Significant, high or moderate correlations occurred between the occurrence of anxiety (rs = –0.57), depression (rs = –0.45) and somatic (rs = –0.67) symptoms and the time of treatment. In these patients, the longer the treatment duration, the lower the intensity of depression, anxiety, and somatic symptoms. Additionally, in this group of respondents, there was a negative, high correlation (rs = –0.55) between the occurrence of anxiety symptoms and age. The older the person was, the lower the level of anxiety. There were also moderate negative correlations between the occurrence of individual symptoms of mental disorders and the age and duration of treatment in patients who experienced the following side effects of interferon treatment: fatigue, bone, and joint pain, nausea and indigestion, muscle cramps and pain, and skin rash and itching and anemia. Two positive correlations occurred between depressive symptoms and the duration of treatment (rs = 0.36), in people experiencing the side effect of bruising, and between anxiety symptoms and the duration of treatment in patients experiencing anemia (rs = 0.48).

The results of the analysis of the relationship between the severity of anxiety, depression, and somatic symptoms measured with the GHQ-28 questionnaire and age, gender, place of residence, number of side effects, and duration of treatment are set out in Table VIII.

Table VIII. Multidimensional relationships between severity of anx­iety, depression, and somatic symptoms and age, gender, place
of residence, number of side effects, and duration of treatment

Variables

B*

p

Somatization

Duration of treatment

0.009

0.849

Age

–0.024

0.408

Number of side effects

0.760

<0.001

Sex (male vs. female)

1.222

0.063

Place of residence (village vs. city)

1.899

0.004

Adjusted R2 = 0.447 (F = 14.438)

Anxiety

Duration of treatment

0.049

0.470

Age

–0.082

0.046

Number of side effects

0.749

<0.001

Sex (male vs. female)

0.329

0.718

Place of residence (village vs. city)

1.234

0.177

Adjusted R2 = 0.262 (F = 6.904)

Depression

Duration of treatment

–0.031

0.537

Age

–0.009

0.768

Number of side effects

0.635

<0.001

Sex (male vs. female)

–1.377

0.043

Place of residence (village vs. city)

–0.312

0.640

Adjusted R2 = 0.323 (F = 8.937)

In the analysis of the impact of the side effects of treatment on the severity of somatic, anxiety, and depression symptoms measured with the GHQ-28 questionnaire, regression models made it possible to explain to explain 45%, 27% and 32% of the variance.

Based on the results presented in Table VIII, we found that the number of side effects was a common predictor of the occurrence of somatic, anxiety, and depressive symptoms. The more the patient experienced them, the greater the severity of all symptoms of mental disorders.

Place of residence also turned out to be an important predictor of somatic symptoms. People living in the city felt more anxious than those living in the countryside. In the case of anxiety symptoms, age was also an important prognostic factor. The older the person was, the lower the intensity of anxiety symptoms. The analysis also showed that the female gender was an unfavorable prognostic factor for the occurrence of depressive symptoms.

In the study of the relationship between the severity of anxiety, depression, and somatic symptoms measured with the 4DSQ questionnaire and age, gender, place of residence, number of side effects and duration of treatment, neither model was statistically significant.

Next, a regression analysis was performed to verify the relationship between the severity of anxiety, depression and somatic symptoms measured by the GHQ-28 questionnaire and the incidence of side effects of interferon alpha treatment (Table IX).

Table IX. Relationships between severity of anxiety, depression, and somatic symptoms measured with General Health Questionnaire 28 (GHQ-28) and side effects of interferon alpha treatment

Side effect

B*

p

Somatization

Water retention

1.096

0.108

Frequent infections

3.240

<0.001

Fatigue

1.667

0.012

Bruising

0.717

0.296

Diarrhea

0.308

0.767

Loss of appetite

1.361

0.113

Bone and joint pain

–0.779

0.271

Nausea, indigestion

–0.117

0.879

Abdominal pain

0.641

0.417

Cramps, muscle aches

1.670

0.031

Skin rash, itching

–1.452

0.017

Anemia

–1.161

0.835

Hypothyroidism

0.695

0.335

Adjusted R2 = 0.481 (F = 6.917)

Anxiety

Water retention

–0.690

0.462

Frequent infections

2.229

0.068

Fatigue

2.036

0.027

Bruising

–0.066

0.946

Diarrhea

0.467

0.746

Loss of appetite

–0.869

0.463

Bone and joint pain

–0.638

0.515

Nausea, indigestion

2.694

0.013

Abdominal pain

1.056

0.336

Cramps, muscle aches

1.309

0.219

Skin rash, itching

–1.309

0.039

Anemia

1.042

0.335

Hypothyroidism

0.973

0.330

Adjusted R2 = 0.317 (F = 3.967)

Depression

Water retention

0.039

0.948

Frequent infections

0.422

0.588

Fatigue

–0.207

0.724

Bruising

–0.753

0,220

Diarrhea

–1.007

0.281

Loss of appetite

1.787

0.021

Bone and joint pain

–0.530

0.402

Nausea, indigestion

–0.089

0.897

Abdominal pain

1.939

0.007

Cramps, muscle aches

0.743

0.279

Skin rash, itching

1.173

0.031

Anemia

3.000

<0.001

Hypothyroidism

0.262

0.684

Adjusted R2 = 0.519 (F = 7.877)

The analysis showed that the prevalence of somatic symptoms was: frequent infections, fatigue, muscle cramps, and pain, as well as skin rash and itching. All side effects, with the exception of skin rash and itching (B = –1.452, p = 0.017), were positively associated with the response variable. Three side effects were predictors of anxiety symptoms: fatigue (B = 2.036, p = 0.027), nausea and indigestion (B = 2.694, p = 0.013), and skin rash and itching (B = –1.309, p = 0.039). In the case of depressive symptoms: loss of appetite (B = 1.787, p = 0.021), abdominal pain (B = 1.939, p ≤0.007), skin rash and itching (B = 1.173, p = 0.031), and anemia (B = 3.000, p ≤0.001) were significant predictors of the development of depressive disorders. All side effects of treatment were positively associated with the response variable.

In regression analysis between the severity of anxiety, depression, and somatic symptoms measured with the 4DSQ questionnaire and divided by side effects neither model was statistically significant.

Discussion

Many scientific studies have been devoted to side effects occurring during treatment with various types of interferon alpha.

The incidence and type of side effects of interferon alpha treatment reported in the literature and observed in our analyzed group of patients were similar.

Fatigue and flu-like symptoms (headache, muscle pain, back, and joints, fever, chills) were most frequently reported [35, 40, 41]. Skin rash, abdominal pain or hypothyroidism-related symptoms are side effects less common in people with myeloproliferative neoplasms, but they occur in other conditions treated with interferon alpha [42–46]. An analysis of the incidence of side effects of interferon alpha treatment depending on the period of their appearance and persistence showed that the most common side effects occurred at the beginning of treatment and are still ongoing, followed by those that occurred at the beginning of treatment, but do not exist anymore (Table III). The most common side effects in these groups were fatigue, skin rashes, and itching, and abdominal pain. Analysis of the occurrence of depressive, anxiety, and somatic symptoms in patients with chronic myeloproliferative neoplasms showed that, on average, every second person has at least one symptom of a mental disorder in the form of somatic, anxiety or depression symptoms, with the highest indication being of somatic symptoms, followed by anxiety symptoms (Tables IV, V).

These results suggest that these patients may develop a somatic disease, and additionally they may be affected by physiological symptoms of the disease and/or in some people there may be a tendency to somatize the symptoms of the disease. The obtained results do not differ from those presented in the literature; somatic, anxiety, or depressive symptoms are common in cancer patients [30, 31, 47]. Studies by Scherber et al., McFarland et al. and Brochmann et al. have indicated that depression or anxiety symptoms appear in 13–31% of patients with MPN [30, 33, 48].

In our study, somatic symptoms were the most frequent and severe symptoms in the study group. These results may indicate that the side effects of alpha interferon treatment may resemble typical somatic symptoms e.g. nausea, fatigue, abdominal pain, diarrhea, weight loss, and loss of appetite. Some of them could be aggravated by alpha interferon-induced hypothyroidism. In addition, the disease itself may also be characterized by similar symptoms, and the coexistence of anxiety or depressive disorders may indicate somatic symptoms. In a study by Katon et al. [49], in which patients suffered from diabetes, lung disease, heart disease, and arthritis, it was found that the presence of comorbid depression or anxiety disorders is associated with an increased burden of somatic symptoms in patients with chronic disease. On the other hand, the results of Akechi et al. [50] suggest that individual somatic symptoms in cancer patients differ in nature and that, for example, symptoms related to appetite and reduced thinking ability can be used to diagnose depression, while sleep disturbances and fatigue can not be used.

It is difficult to determine whether the somatic symptoms in patients with myeloproliferative neoplasms are related to the disease itself and the side effects of its treatment or to the accompanying anxiety or depressive symptoms. For this reason, subsequent analyzes attempted to determine to what extent the side effects of treatment may contribute to the development of somatic, anxiety, or depressive disorders.

Our study showed that individual side effects of interferon alpha treatment contribute to the occurrence and development of mental health disorders, and some of them (frequent infections, muscle cramps and pain, fatigue, nausea and indigestion, loss of appetite, abdominal pain, anemia and skin rash and itching) are prognostic factors for the occurrence of somatic, anxiety or depression symptoms (Tables VI and IX). The literature confirms that the numerous and troublesome side effects of interferon alpha treatment can contribute to the deterioration of the quality of life of patients [40, 51, 52] and the emergence of depressive and anxiety symptoms [53].

The study conducted into the relationship between the age of the patient, duration of the treatment, and the severity of depressive, anxiety and somatic symptoms, which was divided by the occurrence of individual symptoms, showed that patients experiencing side effects such as loss of appetite, bone and joint pain, nausea and indigestion, cramps and muscle pain as well as skin rashes and itching of the skin, were more likely to experience less severe mental disorder symptoms the longer the disease persisted.

On the other hand, among patients experiencing side effects such as loss of appetite and abdominal pain, the older the person is, the less frequent the occurrence of anxiety symptoms and the less severe. In patients who develop anemia as a result of interferon alpha treatment, the longer the patients were treated, the higher the occurrence of depressive symptoms (Table VII).

The results show that the group of patients experiencing certain side effects adapts better to the ongoing disease and more easily achieves the appropriate defense strategy. Numerous studies have emphasized that chronic disease and health problems resulting from it are a constant source of stress for patients, and various coping strategies (based on, among others, religion, meditation, trust in medical staff, positive attitude, patient’s own resources or social support) may contribute to effective adaptation in chronically ill people [54–59]. In contrast, in a study by Trask et al. [60] on the course of depression, fatigue, and quality of life before and during interferon therapy in patients with melanoma, it was observed that somatic complaints, depression, and fatigue as a side effect of interferon treatment increased significantly during therapy, and that the patient’s quality of life decreased in the areas of physical and functional well-being and additional symptoms [60]. These differences may be due to the type of interferon used, the duration of treatment, the dose administered, and/or the nature of the disease.

Our results on the variables that can influence the appearance of anxiety, depression, and somatic symptoms showed that the number of side effects was an important predictor of mental disorders (Table VIII). Similarly, in the study by Trask et al. [60], it was shown that fatigue, which is one of the main and most common side effects of interferon alpha treatment, can contribute to the development of mental health disorders. Another study by Brandberg et al. [61] on health-related quality of life in patients with melanoma taking interferon alpha-2b indicated a deterioration in the quality of life and several side effects associated with this treatment. The cited study did not analyze the relationship between these two variables but only focused on identifying side effects and quality of life during the treatment period [61]. The results of the studies in the analyzed group of patients are not surprising, as the occurrence of side effects of almost any treatment usually affects the quality of life of patients, but their number, type, duration, and coping strategy may significantly affect the presence of mental disorders.

Age was a predictor of anxiety symptoms. The older the person, the lower the intensity of anxiety symptoms. In a study by Brown et al. on the relationship between age and anxiety and depression symptoms in quality of life, 443 adults aged 30–98 years were examined. It showed that there is no difference between the psychological and social quality of life and age, while the environmental quality of life increases and the physical quality decreases with age [62]. Nickel’s studies [63] of depression and anxiety in patients with chronic heart disease showed that younger patients (under 65) experienced more anxiety and depression symptoms than patients over 65. Other studies have shown that the ability to adapt to changes increases with age [64, 65], and our own results confirm this.

Another analysis showed that women were more likely to develop depressive disorders; the results are identical to most of the data available in the literature, which indicate that women are more likely to develop anxiety or depressive disorders [47, 63, 66] or are more often diagnosed with depression [67]. However, some studies show no such relationship [33, 68].

The differences may be caused by the influence of additional variables on the obtained results, such as the homogeneity of the studied groups, the type of disease, the age of the patient, the duration of the treatment, taking antidepressants, quantity, and severity of the experienced side effects and their duration, social situation or the process of adaptation to the disease. There are some studies that suggest that women perceive and construct social reality differently than men; they play a protective role in relationships and are more sensitive, often at the expense of their own emotional stability [69–71].

Study limitations

The conducted research has some limitations. Despite the initial history of the side effects of treatment (whether they occurred before the drug was introduced or arose later), it is difficult to say with 100% certainty whether, for example, fatigue or diarrhea and its relationship with depressive, somatic, or anxiety symptoms are the effects of the disease itself (MPN), a side effect of the drug, or a depressive, anxiety or somatization disorder.

Another limitation of the study was the use of a non-validated symptom burden measurement tool (self-survey). Our rationale was to use the same questionnaire used in several previous studies in a different group of patients, which will be compared with the currently studied. The study was based on the most common side effects in patients with chronic myeloproliferative tumors and lymphoproliferation.

Another limitation was the use of self-description questionnaires, which are not used to diagnose depression or anxiety disorders but are only used to indicate the possibility of certain symptoms of mental disorders. To diagnose these disorders, the diagnostic criteria of ICD 11 or DSM 5 should be used. Therefore, the obtained results are exploratory and require further research.

Clinical implications

A questionnaire-based examination of the mental state of patients, both newly diagnosed with myeloproliferative neoplasms and those already undergoing treatment, may be an option that could be offered to patients; if the results of the questionnaire exhibited depressive, anxiety and/or somatic symptoms, the patient could then be offered psychiatric treatment and/or psychological support.

Another option that could be introduced is having the medical professionals consult with the patients about the possible side effects of the treatment as well as how to deal with them, which could increase the patient’s overall understanding of the process and in turn reduce possible depressive, anxiety and somatic symptoms.

Conclusions

Some of the side effects of interferon alpha treatment in patients with chronic myeloproliferative neoplasms influence the occurrence of depression, anxiety, and somatic symptoms and are a clear indicator of their severity. Somatic symptoms had the greatest impact on the occurrence of mental disorders, with anxiety symptoms being second in significance.

In the case of the relationship between the age of the respondents and the duration of treatment, divided by individually occurring side effects, patients experiencing the side effect in the form of loss of appetite, the person was younger and the duration of treatment was shorter, the severity of anxiety symptoms was lower.

In the case of all disorders of the mental sphere, significant predictors were the number of side effects, in addition to somatic symptoms — the place of residence (city), anxiety symptoms age (younger person), and depressive symptoms gender (woman).

The findings of our study indicate the need for further research into the importance of detecting depressive, anxiety, and somatic disorders, and addressing concomitant physical symptoms, both in patients with myeloproliferative neoplasms receiving interferon alpha and those treated with other methods.

In patients treated chronically, the occurrence of side effects of high intensity and lasting for a long time should alert medical personnel.

The collected data on patients with myeloproliferative neoplasms who have suffered from mental and physical symptoms of the disease or its treatment justifies the need for caring psychological, psychiatric, and educational care.

Authors’ contributions

KG — design of the study, literature search and analysis of data, original draft preparation. TS — design of the study, review and editing, supervision. KC — review and editing, supervision.

Conflict of interest

The authors declare no conflict of interest.

Financial support

None.

Ethics

The work described in this article has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans; EU Directive 2010/63/EU for animal experiments; Uniform Requirements for manuscripts submitted to Biomedical journals.

References

  1. Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. Cancer. 2009; 115(17): 3842–3847, doi: 10.1002/cncr.24440, indexed in Pubmed: 19472396.
  2. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005; 352(17): 1779–1790, doi: 10.1056/NEJMoa051113, indexed in Pub-med: 15858187.
  3. Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006; 3(7): e270, doi: 10.1371/journal.pmed.0030270, indexed in Pubmed: 16834459.
  4. Schnittger S, Bacher U, Haferlach C, et al. Characterization of 35 new cases with four different MPLW515 mutations and essential thrombocytosis or primary myelofibrosis. Haematologica. 2009; 94(1): 141–144, doi: 10.3324/haematol.13224, indexed in Pubmed: 19029146.
  5. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013; 369(25): 2391–2405, doi: 10.1056/NEJMoa1312542, indexed in Pubmed: 24325359.
  6. Budziszewska BK, Więckowska B, Lech-Marańda E, et al. Zachorowalność i chorobowość na nowotwory układu krwiotwórczego w Polsce (2009–2015) określone na podstawie analizy danych Narodowego Funduszu Zdrowia wykorzystanych w projekcie „Mapy potrzeb zdrowotnych — baza analiz systemowych i wdrożeniowych”. Hematologia. 2017; 8(2): 89–104, doi: 10.5603/hem.2017.0013.
  7. Góra-Tybor J. Czerwienica prawdziwa i nadpłytkowość samoistna — diagnostyka i terapia. Hematologia. 2014; 5(2): 105–114.
  8. Góra-Tybor J. 1.5. Pierwotna mielofibroza. Zalecenia postępowania diagnostyczno-terapeutycznego w nowotworach złośliwych 2019 rok. Onkol Prakt Klin Edu. 2020; 6(Suppl A): 66–76.
  9. Góra-Tybor J. 1.6. Nadłytkowość samoistna. Zalecenia postępowania diagnostyczno-terapeutycznego w nowotworach złośliwych 2019 rok. Onkol Klin Prakt Edu. 2020; 6(Suppl A): 78–85.
  10. Góra-Tybor J. 1.4. Czerwienica rawdziwa. Zalecenia postępowania diagnostyczno-terapeutycznego w nowotworach złośliwych 2019 rok. Onkol Klin Prakt Edu. 2020; 6(Suppl): 55–65.
  11. Hasselbalch HC. A new era for IFN-α in the treatment of Philadelphia-negative chronic myeloproliferative neoplasms. Expert Rev Hematol. 2011; 4(6): 637–655, doi: 10.1586/ehm.11.63, indexed in Pubmed: 22077528.
  12. Kiladjian JJ, Guglielmelli P, Griesshammer M, et al. Efficacy and safety of ruxolitinib after and versus interferon use in the RESPONSE studies. Ann Hematol. 2018; 97(4): 617–627, doi: 10.1007/s00277-017-3225-1, indexed in Pubmed: 29396713.
  13. Verger E, Cassinat B, Chauveau A, et al. Clinical and molecular response to interferon-α therapy in essential thrombocythemia patients with CALR mutations. Blood. 2015; 126(24): 2585–2591, doi: 10.1182/blood-2015-07-659060, indexed in Pubmed: 26486786.
  14. Forsyth CJ, Chan WH, Grigg AP, et al. Recommendations for the use of pegylated interferon-α in the treatment of classical myeloproliferative neoplasms. Intern Med J. 2019; 49(8): 948–954, doi: 10.1111/imj.14154, indexed in Pubmed: 30411442.
  15. Mascarenhas J, Kosiorek H, Prchal J, et al. A prospective evaluation of pegylated interferon alfa-2a therapy in patients with polycythemia vera and essential thrombocythemia with a prior splanchnic vein thrombosis. Leukemia. 2019; 33(12): 2974–2978, doi: 10.1038/s41375-019-0524-7, indexed in Pubmed: 31363161.
  16. Huang CE, Wu YY, Hsu CC, et al. Real-world experience with ropeginterferon-alpha 2b (Besremi) in Philadelphia-negative myeloproliferative neoplasms. J Formos Med Assoc. 2021; 120(2): 863–873, doi: 10.1016/j.jfma.2020.08.021, indexed in Pubmed: 32873465.
  17. Gisslinger H, Ludwig H, Linkesch W, et al. Long-term interferon therapy for thrombocytosis in myeloproliferative diseases. Lancet. 1989; 1(8639): 634–637, doi: 10.1016/s0140-6736(89)92142-9, indexed in Pubmed: 2564458.
  18. Pestka S, Krause CD, Walter MR. Interferons, interferon-like cytokines, and their receptors. Immunol Rev. 2004; 202: 8–32, doi: 10.1111/j.0105-2896.2004.00204.x, indexed in Pubmed: 15546383.
  19. Kiladjian JJ, Chomienne C, Fenaux P. Interferon-alpha therapy in bcr-abl-negative myeloproliferative neoplasms. Leukemia. 2008; 22(11): 1990–1998, doi: 10.1038/leu.2008.280, indexed in Pubmed: 18843285.
  20. Kiladjian JJ, Mesa RA, Hoffman R. The renaissance of interferon therapy for the treatment of myeloid malignancies. Blood. 2011; 117(18): 4706–4715, doi: 10.1182/blood-2010-08-258772, indexed in Pubmed: 21389325.
  21. Yoon SY, Won JH. The clinical role of interferon alpha in Philadelphia-negative myeloproliferative neoplasms. Blood Res. 2021; 56(S1): S44–S50, doi: 10.5045/br.2021.2020334, indexed in Pubmed: 33935035.
  22. Quesada JR, Talpaz M, Rios A, et al. Clinical toxicity of interferons in cancer patients: a review. J Clin Oncol. 1986; 4(2): 234–243, doi: 10.1200/JCO.1986.4.2.234, indexed in Pubmed: 2418169.
  23. Kirkwood JM, Bender C, Agarwala S, et al. Mechanisms and management of toxicities associated with high-dose interferon alfa-2b therapy. J Clin Oncol. 2002; 20(17): 3703–3718, doi: 10.1200/JCO.2002.03.052, indexed in Pubmed: 12202672.
  24. Sleijfer S, Bannink M, Van Gool AR. Side effects of interferon-alpha therapy. Pharm World Sci. 2005; 27: 423–431, doi: 10.1007/s11096-005-1319-7., indexed in Pubmed: 16341948.
  25. Daud A, Soon C, Dummer R, et al. Management of pegylated interferon alpha toxicity in adjuvant therapy of melanoma. Expert Opin Biol Ther. 2012; 12(8): 1087–1099, doi: 10.1517/14712598.2012.694421, indexed in Pubmed: 22694288.
  26. Mondello P, Di Mirto C, Cuzzocrea S, et al. Interferon alpha has a strong anti-tumor effect in Philadelphia-negative myeloproliferative neoplasms. Clin Lymphoma Myeloma Leuk. 2019; 19(8): e489–e495, doi: 10.1016/j.clml.2019.03.027, indexed in Pubmed: 31231012.
  27. Yacoub A, Mascarenhas J, Kosiorek H, et al. Pegylated interferon alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea. Blood. 2019; 134(18): 1498–1509, doi: 10.1182/blood.2019000428.
  28. Fitzgerald P, Lo C, Li M, et al. The relationship between depression and physical symptom burden in advanced cancer. BMJ Support Palliat Care. 2015; 5(4): 381–388, doi: 10.1136/bmjspcare-2012-000380, indexed in Pubmed: 24644172.
  29. Cella D, Nowinski CJ, Frankfurt O. The impact of symptom burden on patient quality of life in chronic myeloid leukemia. Oncology. 2014; 87(3): 133–147, doi: 10.1159/000362816, indexed in Pubmed: 25012261.
  30. Brochmann N, Flachs EM, Christensen AI, et al. Anxiety and depression in patients with Philadelphia-negative myeloproliferative neoplasms: a nationwide population-based survey in Denmark. Clin Epidemiol. 2019; 11: 23–33, doi: 10.2147/CLEP.S162688, indexed in Pubmed: 30588121.
  31. Harrison CN, Koschmieder S, Foltz L, et al. The impact of myeloproliferative neoplasms (MPNs) on patient quality of life and productivity: results from the international MPN Landmark survey. Ann Hematol. 2017; 96(10): 1653–1665, doi: 10.1007/s00277-017-3082-y, indexed in Pubmed: 28780729.
  32. McFarland DC, Shaffer KM, Polizzi H, et al. Associations of physical and psychologic symptom burden in patients with Philadelphia chromosome-negative myeloproliferative neoplasms. Psychosomatics. 2018; 59(5): 472–480, doi: 10.1016/j.psym.2018.01.006, indexed in Pubmed: 29506868.
  33. McFarland DC, Polizzi H, Mascarenhas J, et al. Psychological symptoms among patients With BCR-ABL-negative myeloproliferative neoplasms. J Natl Compr Canc Netw. 2016; 14(12): 1563–1570, doi: 10.6004/jnccn.2016.0168, indexed in Pubmed: 27956541.
  34. Padrnos L, Scherber R, Geyer H, et al. Depressive symptoms and myeloproliferative neoplasms: understanding the confounding factor in a complex condition. Cancer Med. 2020; 9(22): 8301–8309, doi: 10.1002/cam4.3380, indexed in Pubmed: 32976697.
  35. Kim SaR, Charos A, Damsky W, et al. Treatment of generalized deep morphea and eosinophilic fasciitis with the Janus kinase inhibitor tofacitinib. JAAD Case Rep. 2018; 4(5): 443–445, doi: 10.1016/j.jdcr.2017.12.003, indexed in Pubmed: 29984277.
  36. Pai SG, Kaplan JB, Giles FJ. Long-acting interferon for myeloproliferative neoplasms — an update. Expert Rev Hematol. 2016; 9(10): 915–917, doi: 10.1080/17474086.2016.1231571, indexed in Pub­med: 27584865.
  37. Quintás-Cardama A, Kantarjian H, Manshouri T, et al. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol. 2009; 27(32): 5418–5424, doi: 10.1200/JCO.2009.23.6075, indexed in Pubmed: 19826111.
  38. Raison CL, Demetrashvili M, Capuron L, et al. Neuropsychiatric adverse effects of interferon-α. CNS Drugs. 2005; 19(2): 105–123, doi: 10.2165/00023210-200519020-00002.
  39. Makowska Z, Merecz D. Polska adaptacja kwestionariuszy ogólnego stanu zdrowia Davida Goldberga: GHQ-12 i GHQ-28. Oficyna Wydawnicza IMP, Łódź 2001.
  40. Gill H, Leung GMK, Yim R, et al. Myeloproliferative neoplasms treated with hydroxyurea, pegylated interferon alpha-2A or ruxolitinib: clinicohematologic responses, quality-of-life changes and safety in the real-world setting. Hematology. 2020; 25(1): 247–257, doi: 10.1080/16078454.2020.1780755, indexed in Pubmed: 32567517.
  41. How J, Hobbs G. Use of interferon alfa in the treatment of myeloproliferative neoplasms: perspectives and review of the literature. Cancers (Basel). 2020; 12(7), doi: 10.3390/cancers12071954, indexed in Pubmed: 32708474.
  42. Zarour HM, Tawbi H, Tarhini AA, et al. Study of anti-PD-1 antibody pembrolizumab and pegylated-interferon alfa-2b (Peg-IFN) for advanced melanoma. J Clin Oncol. 2015; 33(15_Suppl): e20018–e20018, doi: 10.1200/jco.2015.33.15_suppl.e20018.
  43. Kruit WH, Goey SH, Monson JR, et al. Clinical experience with the combined use of recombinant interleukin-2 (IL2) and interferon alfa-2a (IFN alpha) in metastatic melanoma. Br J Haematol. 1991; 79(Suppl 1): 84–86, doi: 10.1111/j.1365-2141.1991.tb08128.x, indexed in Pub­med: 1931717.
  44. Veluru C, Atluri D, Chadalavada R, et al. Skin rash during chronic hepatitis C therapy. Gastroenterol Hepatol (N Y). 2010; 6(5): 323–325, indexed in Pubmed: 20567588.
  45. Dragomiretskaya N, Izha A, Kalinichenko N, et al. Use of antiviral therapy in patients with chronic hepatitis C. Open Med (Wars). 2015; 10(1): 209–215, doi: 10.1515/med-2015-0032, indexed in Pubmed: 28352697.
  46. Kjær L, Cordua S, Holmström MO, et al. Differential dynamics of CALR mutant allele burden in myeloproliferative neoplasms during interferon alfa treatment. PLoS One. 2016; 11(10): e0165336, doi: 10.1371/journal.pone.0165336, indexed in Pubmed: 27764253.
  47. Linden W, Vodermaier A, Mackenzie R, et al. Anxiety and depression after cancer diagnosis: prevalence rates by cancer type, gender, and age. J Affect Disord. 2012; 141(2-3): 343–351, doi: 10.1016/j.jad.2012.03.025, indexed in Pubmed: 22727334.
  48. Scherber RM, Kosiorek HE, Senyak Z, et al. Comprehensively understanding fatigue in patients with myeloproliferative neoplasms. Cancer. 2016; 122(3): 477–485, doi: 10.1002/cncr.29753, indexed in Pubmed: 26670597.
  49. Katon W, Lin EHB, Kroenke K. The association of depression and anxiety with medical symptom burden in patients with chronic medical illness. Gen Hosp Psychiatry. 2007; 29(2): 147–155, doi: 10.1016/j.genhosppsych.2006.11.005, indexed in Pubmed: 17336664.
  50. Akechi T, Nakano T, Akizuki N, et al. Somatic symptoms for diagnosing major depression in cancer patients. Psychosomatics. 2003; 44(3): 244–248, doi: 10.1176/appi.psy.44.3.244, indexed in Pubmed: 12724506.
  51. Mesa RA, Scherber RM, Geyer HL. Reducing symptom burden in patients with myeloproliferative neoplasms in the era of Janus kinase inhibitors. Leuk Lymphoma. 2015; 56(7): 1989–1999, doi: 10.3109/10428194.2014.983098, indexed in Pubmed: 25644746.
  52. Mazza GL, Mead-Harvey C, Mascarenhas J, et al. Myeloproliferative Neoplasms Research Consortium (MPN-RC) 111 and 112 trial teams. Symptom burden and quality of life in patients with high-risk essential thrombocythaemia and polycythaemia vera receiving hydroxyurea or pegylated interferon alfa-2a: a post-hoc analysis of the MPN-RC 111 and 112 trials. Lancet Haematol. 2022; 9(1): e38–e48, doi: 10.1016/S2352-3026(21)00343-4, indexed in Pubmed: 34971581.
  53. Berlim MT, Fleck MPA. Quality of life and major depression. In: Rits­ner MS, Awad AG. ed. Quality of life impairment in schizophrenia, mood and anxiety disorders. Springer, Dordrecht 2007: 241–252.
  54. Ben-Zur H, Gilbar O, Lev S. Coping with breast cancer: patient, spouse, and dyad models. Psychosom Med. 2001; 63(1): 32–39, doi: 10.1097/00006842-200101000-00004, indexed in Pubmed: 11211062.
  55. Kim HS. [The comparison of the stress and coping methods of cancer patients and their caregivers]. Taehan Kanho Hakhoe Chi. 2003; 33(5): 538–543, doi: 10.4040/jkan.2003.33.5.538, indexed in Pubmed: 15314405.
  56. Nissim R, Zimmermann C, Minden M, et al. Abducted by the illness: a qualitative study of traumatic stress in individuals with acute leukemia. Leuk Res. 2013; 37(5): 496–502, doi: 10.1016/j.leukres.2012.12.007, indexed in Pubmed: 23352641.
  57. Jagannathan A, Juvva S. Life after cancer in India: coping with side effects and cancer pain. J Psychosoc Oncol. 2009; 27(3): 344–360, doi: 10.1080/07347330902979150, indexed in Pubmed: 19544181.
  58. Jagannathan A, Juvva S. Emotions and coping of patients with head and neck cancers after diagnosis: a qualitative content analysis. J Postgrad Med. 2016; 62(3): 143–149, doi: 10.4103/0022-3859.184273, indexed in Pubmed: 27320951.
  59. White NE, Richter JM, Fry C. Coping, social support, and adaptation to chronic illness. West J Nurs Res. 1992; 14(2): 211–224, doi: 10.1177/019394599201400208, indexed in Pubmed: 1561786.
  60. Trask PC, Paterson AG, Esper P, et al. Longitudinal course of depression, fatigue, and quality of life in patients with high risk melanoma receiving adjuvant interferon. Psychooncology. 2004; 13(8): 526–536, doi: 10.1002/pon.770, indexed in Pubmed: 15295774.
  61. Brandberg Y, Aamdal S, Bastholt L, et al. Health-related quality of life in patients with high-risk melanoma randomised in the Nordic phase 3 trial with adjuvant intermediate-dose interferon alfa-2b. Eur J Cancer. 2012; 48(13): 2012–2019, doi: 10.1016/j.ejca.2011.11.019, indexed in Pubmed: 22196968.
  62. Brown PJ, Roose SP. Age and anxiety and depressive symptoms: the effect on domains of quality of life. Int J Geriatr Psychiatry. 2011; 26(12): 1260–1266, doi: 10.1002/gps.2675, indexed in Pubmed: 21351152.
  63. Nickel JT, Brown KJ, Smith BA. Depression and anxiety among chronically ill heart patients: age differences in risk and predictors. Res Nurs Health. 1990; 13(2): 87–97, doi: 10.1002/nur.4770130205, indexed in Pubmed: 2320761.
  64. Diener Ed, Suh E, Lucas R, et al. Subjective well-being: three decades of progress. Psychol Bull. 1999; 125(2): 276–302, doi: 10.1037/0033-2909.125.2.276.
  65. Ryff CD. Possible selves in adulthood and old age: a tale of shifting horizons. Psychol Aging. 1991; 6(2): 286–295, doi: 10.1037//0882-7974.6.2.286, indexed in Pubmed: 1863398.
  66. Murphy JM, Olivier DC, Monson RR, et al. Incidence of depression and anxiety: the Stirling County Study. Am J Public Health. 1988; 78(5): 534–540, doi: 10.2105/ajph.78.5.534, indexed in Pubmed: 3258479.
  67. Cochran S, Rabinowitz F. Men and depression: clinical and empirical perspectives. Academic Press, Cambridge 1999: 208.
  68. Scherber RM, Senyak Z, Kosiorek HE, et al. Treating Depression in the Myeloproliferative Neoplasms: The Role and Implications of Poorly Controlled Symptoms and Psychosocial Factors. Blood. 2016; 128(22): 5474–5474, doi: 10.1182/blood.v128.22.5474.5474.
  69. Baider L, Bengel J. Cancer and the spouse: gender-related differences in dealing with health care and illness. Crit Rev Oncol Hematol. 2001; 40(2): 115–123, doi: 10.1016/s1040-8428(01)00137-8, indexed in Pubmed: 11682318.
  70. Geyer HL, Kosiorek H, Dueck AC, et al. Associations between gender, disease features and symptom burden in patients with myeloproliferative neoplasms: an analysis by the MPN QOL International Working Group. Haematologica. 2017; 102(1): 85–93, doi: 10.3324/haematol.2016.149559, indexed in Pubmed: 27540137.
  71. Coyne JC, Smith DA. Couples coping with a myocardial infarction: a contextual perspective on wives’ distress. J Pers Soc Psychol. 1991; 61(3): 404–412, doi: 10.1037//0022-3514.61.3.404, indexed in Pubmed: 1941511.