- Email: [email protected]
Aquagenic pruritus in polycythemia vera: a cross-sectional study
Accepted Manuscript Aquagenic pruritus in polycythemia vera: a cross-sectional study Edyta Lelonek, MD, Assoc. Prof. Łukasz Matusiak, MD, Prof. Tomasz Wróbel, MD, Prof. Jacek C. Szepietowski, MD PII:
S0190-9622(17)32577-X
DOI:
10.1016/j.jaad.2017.10.021
Reference:
YMJD 12069
To appear in:
Journal of American Dermatology
Received Date: 23 February 2017 Revised Date:
29 September 2017
Accepted Date: 11 October 2017
Please cite this article as: Lelonek E, Matusiak Ł, Wróbel T, Szepietowski JC, Aquagenic pruritus in polycythemia vera: a cross-sectional study, Journal of American Dermatology (2017), doi: 10.1016/ j.jaad.2017.10.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Aquagenic pruritus in polycythemia vera: a cross-sectional study
2
Edyta Lelonek, MD1; Assoc. Prof. Łukasz Matusiak, MD1; Prof. Tomasz Wróbel, MD 2; Prof. Jacek
3
C Szepietowski MD 1
4
1
5
University, 50-368 Wrocław, Chałubińskiego 1, Poland;
6
2
7
Wroclaw Medical University, 50-367 Wrocław, Pasteura 4, Poland;
SC
Department and Clinic of Hematology, Blood Neoplasms and Bone Marrow Transplantation,
8
10
Corresponding author: Edyta Lelonek, [email protected]
Chałubińskiego 1, 50-368 Wrocław, Poland; tel.: +48717842286; fax: +48713270942
11
1. Manuscript word count: 521
13
2. References: 5
14
3. Number of tables: 2
TE D
12
15
M AN U
9
RI PT
Department and Clinic of Dermatology, Venereology and Allergology, Wroclaw Medical
Conflict of interest disclosures: The authors declare no competing financial interests.
17
Funding Sources: none.
18
IRB approval: The study was approved by the Ethic Committee of Wroclaw Medical
19
University (No. 355/2016).
AC C
20
EP
16
21
22
1
ACCEPTED MANUSCRIPT To the Editor: Polycythemia vera-associated pruritus and more specifically aquagenic pruritus
24
(AP) is characterized by the development of intense itching sensation without observable skin
25
lesions and brought on by contact with water of any temperature1. Although AP is recognized
26
as the most excruciating aspect of PV, the knowledge about its pathophysiology and precise
27
character is still vague. Therefore, this study was undertaken to analyze the clinical features of
28
AP and its associations with laboratory results.
29
The group of 102 patients with confirmed molecularly PV (present JAK2V617F mutation)
30
was examined. Demographic data, disease history, PV status and treatment modalities were
31
collected from all participants. AP intensity was evaluated with the visual analogue scale
32
(VAS), verbal rating scale (VRS) and a 4-item Itch Questionnaire (4-IQ). Furthermore, all
33
study participants underwent laboratory tests. Complete blood count, serum levels of lactate
34
dehydrogenase (LDH), uric acid (UA) and immunoglobulin E (IgE) were done. The detailed
35
characteristic of the study group is given in Table 1.
36
AP was present in 41.2% (42/102) of PV patients. A significant negative correlation between
37
hemoglobin concentration (HGB), hematocrit level (HCT) and pruritus severity assessed with
38
VRS and 4-IQ was found (p<0.05, for all correlations). Such a trend was also observed for
39
VAS, however did not reach statistical significance. Of note, the alterations in HGB or HCT
40
levels did not condition the presence or absence of AP among patients with PV (p>0.05)
41
(Table 2). Moreover, only morphology parameters (incl. HGB and HCT) were independent
42
factors responsible for increase/decrease of AP intensity, with no drug influence on PV-
43
associated itching.
44
The significant negative correlations between the intensity of pruritus and HGB or HCT noted
45
in our study seem to be consistent with previously reported data2. In contrast to our study,
46
some other authors discerned the presence of generalized pruritus due to the iron depletion
47
after phlebotomy3. However, iron replacement therapy has not been consistently effective in
AC C
EP
TE D
M AN U
SC
RI PT
23
2
ACCEPTED MANUSCRIPT the treatment of AP4. This means that the root cause of the presence or intensity of AP in PV
49
patients is hidden elsewhere.
50
The correction of hematological parameters in PV is one of the main recommended strategies
51
for the improvement of PV-related systemic symptoms including pruritus2. Taking into
52
account the antiplatelet treatment, we did not find any significant associations with the
53
intensity of AP.
54
However, our data presented some contrasting findings showing that, lower HCT and HGB
55
levels (but within the normal range), could intensify itching among AP patients. It is not
56
completely clear if AP development was due to the decrease of HCT/ HGB levels, or occurred
57
because of another mechanism. This phenomenon could be explained by the symptomatic
58
action of these drugs without, in fact, affecting the clinical course of disease. It could be
59
further confirmed by the recent data with regards to treatment with JAK2-/JAK1-inhibitors5,
60
which could bring relief in the general symptoms such as fatigue, night sweats or itching due
61
to the targeting of the signal pathways of the EPO-receptor.
62
In conclusion, AP is a frequent, although seemingly underestimated, problem among PV
63
sufferers. Further research on the morphologic parameters and their associations with pruritus
64
could contribute to better understanding of the pathophysiology of AP and its management.
66 67 68 69
SC
M AN U
TE D
EP
AC C
65
RI PT
48
70 71 72 73
3
ACCEPTED MANUSCRIPT 74 75 76 77
References: 1. Steinmann HK, Graeves MW. Aquagenic pruritus. J Am Acad Dermatol 1985; 13: 91–6. 2. Siegel FP, Tauscher J, Petrides. Aquagenic pruritus in polycythemia vera:
79
Characteristics and influence on quality of life in 441 patients. Am. J. Hematol., 88:
80
665–669.
82
3. Gangat N, Strand JJ, Lasho TL, et al. Pruritus in polycythemia vera is associated with
SC
81
RI PT
78
a lower risk of arterial thrombosis. Am J Hematol 2008; 83: 451–3. 4. Jackson N, Burt D, Crocker J, et al. Skin mast cells in polycythaemia vera:
84
relationship to the pathogenesis and treatment of pruritus. Br J Dermatol 1987; 116:
85
21–9.
89 90 91 92 93 94 95
TE D
88
in myelofibrosis. N Engl J Med 2011; 365: 1455–1457.
EP
87
5. Tefferi A, Litzow MR, Pardanani A. Long term outcome of treatment with ruxolitinib
AC C
86
M AN U
83
96 97 98 99
4
ACCEPTED MANUSCRIPT 100 101 102
Table 1. Characteristics of studied group
AP
women
65
31
men
37
11
Age (years)†
66.9 ± 12.7
64.0 ± 13.8
69.0 ± 11.6
NS
BMI (kg/m2)†
26.8 ± 4.2
26.9 ± 4.7
26.8 ± 3.8
NS
Duration of PV (years)†
6.2 ± 5.9
6.8 ± 7.9
5.7 ± 4.1
NS
60.8 ± 12.5
57.2 ± 13.0
63.3 ± 11.5
0.02
26
15
11
NS
35
13
22
42
42
0
NA
3
0
3
NA
1
0
1
NA
5-hydroxyurea
75
30
45
NS
phlebotomy
66
28
38
acetylsalicylic acid
33
17
16
clopidogrel
5
4
1
anagrelid
4
3
1
pipobroman
6
1
5
Episodes of thrombosis (n)
arterial
AP senile pruritus atopic itch PV treatment (n)
EP
Presence of pruritus (n)
TE D
venous
M AN U
Age at diagnosis of PV (years)†
p-value*
34
NS
26
SC
Gender (n)
Non-AP
RI PT
Total
AC C
103
5
ACCEPTED MANUSCRIPT 104
105 106
* – AP vs. non-AP, † – mean ± SD; AP – aquagenic pruritus, PV – polycythemia vera, NA – not applicable, NS – not significant
107
109
RI PT
108
Table 2. Characteristics of AP patients
6.6 ± 8.6
p-value*
NA
NA
5.2 ± 2.4
NA
NA
4.8 ± 1.9
NA
NA
28.6
NA
NA
38.1
NA
NA
21.4
NA
NA
11.9
NA
NA
6.0 ± 2.9
NA
NA
12.1 ± 14.4
14.4 ± 24.6
NS
5.4 ± 1.7
4.7 ± 1.2
NS
15.0 ± 2.9
15.3 ± 2.4
NS
45.6 ± 8.6
55.5 ± 66.0
NS
PLT (103/µL)
441.3 ± 227.9
435.0 ± 409.3
NS
LDH (U/L)
296.2 ± 148.7
320.6 ± 282.8
NS
UA (mg/dL)
5.1 ± 1.9
5.7 ± 1.4
NS
IgE (kU/L)
29.8 ± 46.4
20.7 ± 28.0
NS
AP duration (years)†
VASmax (points)† VASmean (points)† VRS (%)
‘mild’ ‘moderate’
TE D
‘severe’ ‘very severe’
4-item Itch Questionnaire (points)†
WBC (103/µL) RBC (106/µL)
AC C
HGB (g/dL)
EP
Laboratory results†
HCT (%)
M AN U
AP intensity
110 111 112 113
Non-AP
SC
AP
* – AP vs. non-AP, † – mean ± SD; AP – aquagenic pruritus, WBC – white blood cell count, RBC – red blood cell count, HGB – hemoglobin concentration, HCT – hematocrit level, PLT – platelet count, LDH – lactate dehydrogenase, UA – uric acid, IgE – immunoglobulin E; VAS – visual analogue scale, VRS – verbal rating scale, VASmax – maximum intensity of
6
ACCEPTED MANUSCRIPT
EP
TE D
M AN U
SC
RI PT
pruritus during the last 3 days, VASmean – mean intensity of pruritus during the last 3 days, NA – not applicable, NS – not significant
AC C
114 115
7
S0190-9622(17)32577-X
DOI:
10.1016/j.jaad.2017.10.021
Reference:
YMJD 12069
To appear in:
Journal of American Dermatology
Received Date: 23 February 2017 Revised Date:
29 September 2017
Accepted Date: 11 October 2017
Please cite this article as: Lelonek E, Matusiak Ł, Wróbel T, Szepietowski JC, Aquagenic pruritus in polycythemia vera: a cross-sectional study, Journal of American Dermatology (2017), doi: 10.1016/ j.jaad.2017.10.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Aquagenic pruritus in polycythemia vera: a cross-sectional study
2
Edyta Lelonek, MD1; Assoc. Prof. Łukasz Matusiak, MD1; Prof. Tomasz Wróbel, MD 2; Prof. Jacek
3
C Szepietowski MD 1
4
1
5
University, 50-368 Wrocław, Chałubińskiego 1, Poland;
6
2
7
Wroclaw Medical University, 50-367 Wrocław, Pasteura 4, Poland;
SC
Department and Clinic of Hematology, Blood Neoplasms and Bone Marrow Transplantation,
8
10
Corresponding author: Edyta Lelonek, [email protected]
Chałubińskiego 1, 50-368 Wrocław, Poland; tel.: +48717842286; fax: +48713270942
11
1. Manuscript word count: 521
13
2. References: 5
14
3. Number of tables: 2
TE D
12
15
M AN U
9
RI PT
Department and Clinic of Dermatology, Venereology and Allergology, Wroclaw Medical
Conflict of interest disclosures: The authors declare no competing financial interests.
17
Funding Sources: none.
18
IRB approval: The study was approved by the Ethic Committee of Wroclaw Medical
19
University (No. 355/2016).
AC C
20
EP
16
21
22
1
ACCEPTED MANUSCRIPT To the Editor: Polycythemia vera-associated pruritus and more specifically aquagenic pruritus
24
(AP) is characterized by the development of intense itching sensation without observable skin
25
lesions and brought on by contact with water of any temperature1. Although AP is recognized
26
as the most excruciating aspect of PV, the knowledge about its pathophysiology and precise
27
character is still vague. Therefore, this study was undertaken to analyze the clinical features of
28
AP and its associations with laboratory results.
29
The group of 102 patients with confirmed molecularly PV (present JAK2V617F mutation)
30
was examined. Demographic data, disease history, PV status and treatment modalities were
31
collected from all participants. AP intensity was evaluated with the visual analogue scale
32
(VAS), verbal rating scale (VRS) and a 4-item Itch Questionnaire (4-IQ). Furthermore, all
33
study participants underwent laboratory tests. Complete blood count, serum levels of lactate
34
dehydrogenase (LDH), uric acid (UA) and immunoglobulin E (IgE) were done. The detailed
35
characteristic of the study group is given in Table 1.
36
AP was present in 41.2% (42/102) of PV patients. A significant negative correlation between
37
hemoglobin concentration (HGB), hematocrit level (HCT) and pruritus severity assessed with
38
VRS and 4-IQ was found (p<0.05, for all correlations). Such a trend was also observed for
39
VAS, however did not reach statistical significance. Of note, the alterations in HGB or HCT
40
levels did not condition the presence or absence of AP among patients with PV (p>0.05)
41
(Table 2). Moreover, only morphology parameters (incl. HGB and HCT) were independent
42
factors responsible for increase/decrease of AP intensity, with no drug influence on PV-
43
associated itching.
44
The significant negative correlations between the intensity of pruritus and HGB or HCT noted
45
in our study seem to be consistent with previously reported data2. In contrast to our study,
46
some other authors discerned the presence of generalized pruritus due to the iron depletion
47
after phlebotomy3. However, iron replacement therapy has not been consistently effective in
AC C
EP
TE D
M AN U
SC
RI PT
23
2
ACCEPTED MANUSCRIPT the treatment of AP4. This means that the root cause of the presence or intensity of AP in PV
49
patients is hidden elsewhere.
50
The correction of hematological parameters in PV is one of the main recommended strategies
51
for the improvement of PV-related systemic symptoms including pruritus2. Taking into
52
account the antiplatelet treatment, we did not find any significant associations with the
53
intensity of AP.
54
However, our data presented some contrasting findings showing that, lower HCT and HGB
55
levels (but within the normal range), could intensify itching among AP patients. It is not
56
completely clear if AP development was due to the decrease of HCT/ HGB levels, or occurred
57
because of another mechanism. This phenomenon could be explained by the symptomatic
58
action of these drugs without, in fact, affecting the clinical course of disease. It could be
59
further confirmed by the recent data with regards to treatment with JAK2-/JAK1-inhibitors5,
60
which could bring relief in the general symptoms such as fatigue, night sweats or itching due
61
to the targeting of the signal pathways of the EPO-receptor.
62
In conclusion, AP is a frequent, although seemingly underestimated, problem among PV
63
sufferers. Further research on the morphologic parameters and their associations with pruritus
64
could contribute to better understanding of the pathophysiology of AP and its management.
66 67 68 69
SC
M AN U
TE D
EP
AC C
65
RI PT
48
70 71 72 73
3
ACCEPTED MANUSCRIPT 74 75 76 77
References: 1. Steinmann HK, Graeves MW. Aquagenic pruritus. J Am Acad Dermatol 1985; 13: 91–6. 2. Siegel FP, Tauscher J, Petrides. Aquagenic pruritus in polycythemia vera:
79
Characteristics and influence on quality of life in 441 patients. Am. J. Hematol., 88:
80
665–669.
82
3. Gangat N, Strand JJ, Lasho TL, et al. Pruritus in polycythemia vera is associated with
SC
81
RI PT
78
a lower risk of arterial thrombosis. Am J Hematol 2008; 83: 451–3. 4. Jackson N, Burt D, Crocker J, et al. Skin mast cells in polycythaemia vera:
84
relationship to the pathogenesis and treatment of pruritus. Br J Dermatol 1987; 116:
85
21–9.
89 90 91 92 93 94 95
TE D
88
in myelofibrosis. N Engl J Med 2011; 365: 1455–1457.
EP
87
5. Tefferi A, Litzow MR, Pardanani A. Long term outcome of treatment with ruxolitinib
AC C
86
M AN U
83
96 97 98 99
4
ACCEPTED MANUSCRIPT 100 101 102
Table 1. Characteristics of studied group
AP
women
65
31
men
37
11
Age (years)†
66.9 ± 12.7
64.0 ± 13.8
69.0 ± 11.6
NS
BMI (kg/m2)†
26.8 ± 4.2
26.9 ± 4.7
26.8 ± 3.8
NS
Duration of PV (years)†
6.2 ± 5.9
6.8 ± 7.9
5.7 ± 4.1
NS
60.8 ± 12.5
57.2 ± 13.0
63.3 ± 11.5
0.02
26
15
11
NS
35
13
22
42
42
0
NA
3
0
3
NA
1
0
1
NA
5-hydroxyurea
75
30
45
NS
phlebotomy
66
28
38
acetylsalicylic acid
33
17
16
clopidogrel
5
4
1
anagrelid
4
3
1
pipobroman
6
1
5
Episodes of thrombosis (n)
arterial
AP senile pruritus atopic itch PV treatment (n)
EP
Presence of pruritus (n)
TE D
venous
M AN U
Age at diagnosis of PV (years)†
p-value*
34
NS
26
SC
Gender (n)
Non-AP
RI PT
Total
AC C
103
5
ACCEPTED MANUSCRIPT 104
105 106
* – AP vs. non-AP, † – mean ± SD; AP – aquagenic pruritus, PV – polycythemia vera, NA – not applicable, NS – not significant
107
109
RI PT
108
Table 2. Characteristics of AP patients
6.6 ± 8.6
p-value*
NA
NA
5.2 ± 2.4
NA
NA
4.8 ± 1.9
NA
NA
28.6
NA
NA
38.1
NA
NA
21.4
NA
NA
11.9
NA
NA
6.0 ± 2.9
NA
NA
12.1 ± 14.4
14.4 ± 24.6
NS
5.4 ± 1.7
4.7 ± 1.2
NS
15.0 ± 2.9
15.3 ± 2.4
NS
45.6 ± 8.6
55.5 ± 66.0
NS
PLT (103/µL)
441.3 ± 227.9
435.0 ± 409.3
NS
LDH (U/L)
296.2 ± 148.7
320.6 ± 282.8
NS
UA (mg/dL)
5.1 ± 1.9
5.7 ± 1.4
NS
IgE (kU/L)
29.8 ± 46.4
20.7 ± 28.0
NS
AP duration (years)†
VASmax (points)† VASmean (points)† VRS (%)
‘mild’ ‘moderate’
TE D
‘severe’ ‘very severe’
4-item Itch Questionnaire (points)†
WBC (103/µL) RBC (106/µL)
AC C
HGB (g/dL)
EP
Laboratory results†
HCT (%)
M AN U
AP intensity
110 111 112 113
Non-AP
SC
AP
* – AP vs. non-AP, † – mean ± SD; AP – aquagenic pruritus, WBC – white blood cell count, RBC – red blood cell count, HGB – hemoglobin concentration, HCT – hematocrit level, PLT – platelet count, LDH – lactate dehydrogenase, UA – uric acid, IgE – immunoglobulin E; VAS – visual analogue scale, VRS – verbal rating scale, VASmax – maximum intensity of
6
ACCEPTED MANUSCRIPT
EP
TE D
M AN U
SC
RI PT
pruritus during the last 3 days, VASmean – mean intensity of pruritus during the last 3 days, NA – not applicable, NS – not significant
AC C
114 115
7