Download The Relationship between clinical disease activity and acute phase

The Relationship between clinical disease activity and acute phase response in
Behcet’s Disease
Abstract:
Objective: The evaluation of disease activity in Behcet’s Disease (BD) needs to be based on
the clinical features due to the fluctuating course of the disease and the absence of reliable
laboratory indices that are useful in reflecting the overall disease activity. The aim of this
study was to evaluate a possible relationship between acute phase reactants including ferritin,
pre-albumin, fibrinogen, haptoglobin (Hp), ceruloplasmin (Cp), and BD clinical disease
activity determined by a validated scale.
Methods: Seventy-eight patients with BD were included in our study in Dermatology and
Rheumatology departments of Ministry of Health Erzurum Regional Training and Research
Hospital between 2011-13. The disease activity was evaluated using the “BD Current Activity
Form” (BDCAF), which offers an easy-to-complete, valid and reliable method for assessing
the disease activity in BD. With this activity form, headache, mouth ulceration, genital
ulceration, erythema, skin pustules, arthralgia, arthritis, new involvements in the
gastrointestinal system (GIS), in the eye, in the nervous system, in the major vessels, and the
assessments of the patient and the physician of the overall disease activity scores were
analyzed. The levels of serum ferritin, Cp, pre-albumin, The Hp and the plasma fibrinogen of
the patients were also measured. The independent samples t test and the Pearson’s correlation
test were used to analyze the data.
Results: In the comparison of laboratory parameters of patients with or without the
components of BDCAF, no significant relation could be determined between headache,
erythema nodosum, superficial thrombophlebitis, skin pustules, GIS and eye involvement, and
the acute phase response parameters. However, we found significantly higher levels of ferritin
in patients with arthritis and higher levels of fibrinogen in patients with arthralgia and arthritis
than in those without joint involvement (p˂0,01; p=0,030 and p˂0,000; respectively).
Furthermore, the Hp levels in patients with genital ulceration and arthritis (p=0,005 and
p=0,002) and the Cp levels in patients with oral ulceration and arthritis were found to be
higher compared to patients without these involvements (p˂0,01 and p˂ 0,001). As a negative
acute phase reactant, pre-albumin was determined to be significantly lower in patients with
joint involvement than in patients without (p=0,023). There were also significant positive
correlations between the fibrinogen levels and the clinician’s overall perception of disease
activity and the BDCAF total score (p=0,012 and p˂0,01; respectively).
In conclusion, although there is no specific laboratory profile to determine the disease activity
in BD, the presence of newly developed oral and genital ulceration may be associated with
higher levels of Cp and Hp. Joint involvement seems to be a prominent clinical feature
representing a relationship with the acute phase response. The relationship between the
disease activity scores and the acute phase response, mainly fibrinogen, may contribute to the
overall disease activity perception in BD.
Key words: Behcet’s Disease, disease activity, acute phase response
Introduction
Behçet’s disease (BD) is a vasculitis described by the Turkish physician, Hulusi
Behçet in 1937 as a typical triad complex consisting of oral and genital ulcers and relapsing
uveitis (1). It is known that BD may also involve the cardiovascular, pulmonary, neurological,
articular, and gastrointestinal systems. BD shows a heterogeneous pattern of organ
involvement that occurs in recurrent episodes of acute inflammation throughout the course of
the disease (2). Due to the heterogeneous nature of involvements and the fluctuating course of
the disease, evaluation of the disease activity needs to be based on the clinical features in BD
(3-5). The absence of reliable clinical and laboratory indices, which are useful in reflecting
the overall disease activity in BD have led to several attempts to develop disease activity
measurements to achieve consistency in clinical practice.
On the other hand, several indices of inflammation have been investigated as
potentially related factors to clinical disease activity in BD. Although some of these mediators
appear to be associated with clinical involvements, previous data have shown different results
regarding the relationship between these indices and clinical disease activity in patients with
BD. Furthermore, due to the methodological differences in “disease activity” assessments in
BD, it is difficult to evaluate the conflicting results in these investigations.
The aim of this study was to evaluate a possible relationship between the acute phase
proteins including ferritin, pre-albumin, fibrinogen, haptoglobin (Hp) and ceruloplasmin (Cp)
and the BD clinical disease activity determined by a validated scale.
Patients and Methods:
Patients:
This study was investigated in Dermatology and Rheumatology departments of
Ministry of Health Erzurum Regional Training and Research Hospital between 2011-13.
Seventy eight patients with BD who had fulfilled the criteria of the International Study Group
for BD were included in this study after written informed consents were obtained from all the
participants (6). Patients with any infectious disease, malignant disease history, renal disease,
a coexistence of any rheumatic disease, anemia and pregnancy were excluded from the study.
Clinical assessments
The demographic properties including age, sex and the disease durations for all of the
patients with BD were recorded. The disease activity was evaluated with the “BD Current
Activity Form” (BDCAF), which offers an easy-to-complete, valid and reliable method of
assessing the disease activity in BD (7). BDCAF scores the history of clinical features that
have been present during the 4 weeks prior to the day of assessment. With this activity form,
headache, mouth ulceration, genital ulceration, erythema, skin pustules, arthralgia, arthritis,
gastrointestinal
system
involvement
(nausea/vomiting/abdominal
pain
and
diarrhoea+altered/frank blood per rectum), new eye involvement, new nervous system
involvement, and new major vessel involvement were analyzed. The BDCAF score was
calculated by adding the score of each index and this ranged between 0 and 12. The patients
and physicians also rated their assessments of the overall disease activity within the preceding
4 weeks by indicating it on a scale consisting of seven faces with different expressions on the
BDCAF. A Turkish version of BDCAF has been tested and validated for our population (8).
Laboratory assessments:
The serum ferritin level was measured using an automatic analyzer system (E170
Modular System, Roche Diagnostics). The plasma fibrinogen level was determined with a
commercial kit using an autoanalyzer (Dade-Behring Corp). The serum levels of Cp and prealbumin was measured by the nephelometric method using Beckman specific calibrators.
Statistical analysis
All the statistical analyses were performed using the SPSS 20.0 software package
program. The independent samples t test was used to compare data between patients with or
without a clinical involvement included in the BDCAF. The possible correlations between the
laboratory investigations and the clinical evaluations including the patient’s and the doctor’s
impression of disease activity and the total BDCAF score were analyzed by performing the
Pearson’s correlation test. Statistical significance was determined as a p value of ≤0.05.
Results:
After having excluded five patients due to anemia and infectious diseases, 73 patients
with BD were evaluated in this study. There were 42 female and 31 male patients, with an age
range of 18-54; 32.68± 6.82 year±standard deviation (SD). The disease durations of the
patients were between 12 and 240 months (72,80±44,19 month± SD). The age, the gender
ratio, the disease durations, the acute phase protein levels and the BDCAF total scores of the
patients with BD have been presented in Table 1.
In the comparison of the laboratory parameters of the patients with or without the
components of BDCAF, no significant relation could be determined between headache,
erythema nodosum, superficial thrombophlebitis, skin pustules, gastrointestinal system and
eye involvement and the acute phase response parameters. However, we found significantly
higher levels of ferritin in patients with arthritis and higher levels of fibrinogen in patients
with concurrent arthralgia and arthritis than in patients without joint involvement (p˂0,01;
p=0,030 and p˂0,000; respectively). Furthermore, the Hp levels in patients with genital
ulceration and arthritis (p=0,005 and p=0,002), and the Cp levels in patients with oral
ulceration and arthritis were found to be higher compared to patients without these
involvements (p˂0,01 and p˂ 0,001). Pre-albumin, as a negative acute phase reactant, was
determined to be significantly lower in patients with arthralgia and arthritis than in patients
without joint involvement (p=0,023 and p=0,004). In the evaluation of the possible
correlations between the laboratory parameters and the clinical evaluations, there were
significant positive correlations between the fibrinogen levels and the clinician’s overall
perception of disease activity and the BDCAF total score (p=0,012 and p˂0,01, respectively).
Since only one patient had new central nervous system involvement, and two patients had
new large vessel involvement, they were not included in our study. The other comparisons of
the laboratory parameters of the patients with or without the components of BDCAF and the
correlations between the laboratory markers and clinical evaluations have been displayed in
Table 2.
Discussion:
BD is clinically characterized by a relapsing and remitting pattern rather than a
persisting disease course (9). The symptoms may be separated by long or short intervals; they
may occur simultaneously or in sequence, and exhibit a pattern of exacerbation and remission.
Since there are no laboratory markers known to correlate well with the disease activity, the
disease activity evaluation needs to be based on the clinical features in BD (3-5). However,
the heterogeneous nature of the symptoms of BD disease makes it difficult to generate a
single score for the disease activity. One of the scales developed for the clinical disease
activity assessment in this disorder is the BDCAF, which is based on history of clinical
features and offers an easy-to-complete, valid and reliable method of assessing the disease
activity in BD (7). Since the clinical features in BD vary considerably over time, in order to
document this variation, new clinical features present over the preceding 28 days are scored in
this scale. This represents a result of the disease activity based on the clinical features on the
day of assessment, which may not represent the overall disease activity and the clinical
features present over a longer time duration. This point also served for our study, which aimed
to perform an analysis of a possible association of the “current” clinical disease activity with
routine laboratory acute phase response. As the acute phase response, we investigated ferritin,
pre-albumin, fibrinogen, haptoglobin (Hp) and ceruloplasmin (Cp) to evaluate a possible
relationship between the clinical activity and different natured reactants.
Previous studies have shown conflicting results on the relationship between the
clinical disease activity and the laboratory indices, including inflammatory mediators and the
acute phase response. Although it’s well known as an acute phase reactant, there are a few
reports that have investigated the ferritin levels in patients with BD with different outcomes.
Although there are studies presenting similar ferritin levels in active and inactive patients with
BD and healthy controls, there are also some studies showing significantly higher ferritin
levels in BD associated with clinical activity (11-14). The ferritin levels were also found to be
significantly higher in patients with papulopustular lesions and thrombophlebitis in patients
with BD (14). Odabas et al. found that patients with active BD had significantly higher ferritin
levels and suggested that ferritin may be an activity criterion for BD (12). Heterogeneity in
the design of the previous investigations may have led to the conflicting results in the
relationship between ferritin and the BD disease activity. Our data presented significantly
higher ferritin levels in patients with active arthritis than those without joint involvement.
Another parameter investigated in our study was pre-albumin, which was also found to be
significantly lower in patients with joint involvement as a negative acute phase reactant.
Despite the limited number of investigations on pre-albumin in BD, pre-albumin was found to
be decreased in different arthritides (15). In previous studies, the levels of fibrinogen were
reported to be higher in patients with BD than in healthy controls (16, 17). In our study,
beside the higher levels of fibrinogen in the presence of joint involvement, it represented
correlations with perceptions of disease activity and total disease activity scores. We also
determined higher Hp levels in patients with joint involvement and genital ulceration. In a
previous study investigating Hp and amyloid A in BD, it was demonstrated that Hp was only
over-expressed in active BD, but not in inactive BD or in healthy controls (18). Also, in
another study on serum Hp levels in ocular BD, there was a significant difference in Hp levels
between patients with active ocular disease and the controls. However, no significant
difference was observed between patients with active and inactive uveitis with regard to
serum Hp levels (19). The last parameter in our study was Cp, which is an acute phase protein
expressed at the surface of peripheral blood lymphocytes with antioxidant properties (13). The
Cp levels were found to be significantly higher in patients with oral ulcerations and joint
involvement in our study. In a previous investigation, Cp was found to be significantly
elevated in patients with different arthritides, including BD (15). The plasma levels of Cp
were also determined to be significantly higher in patients with BD than in controls (17).
However, in another study investigating the Cp levels in patients with BD and healthy
controls, despite the absence of significant differences between the two study groups when
comparing serum CP, a significant difference in the peripheral blood lymphocytes Cp was
found in BD patients (13).
Previous studies with conflicting results regarding the relationship between the clinical
disease activity and the laboratory indices including the acute phase response, have presented
highly heterogeneity in the design of the investigations. The patient groups that were created
according to “active or inactive disease” have revealed methodological differences due to the
difficulty in defining the disease activity in BD. What may have possibly rendered our study
different from the other researches is the investigation of the relationship between the clinical
disease activity and the laboratory indices using a valid standardized scale. With this
methodology, we could not demonstrate any association between the acute phase response
and involvements of the GIS, eye and dermatological findings, except for the higher Cp levels
in patients with oral ulceration and the higher Hp levels in patients with genital ulceration. On
the other hand, joint involvement was a remarkable clinical activity parameter due to its
relationships with all the acute phase reactants analyzed in our study. Another notable finding
was that fibrinogen was the only parameter evaluated in our study which represented
correlations with perceptions of the disease activity and the total disease activity scores. The
main weakness of our study was the inability of researching the relationship between the
acute phase response and the nervous system and large vessel involvements due to the
inadequate number of the patients with these involvements. Further studies are needed to
clarify the possible associations with these relatively rare and severe involvements of BD.
In conclusion, although there is no specific laboratory profile to determine the disease
activity in BD, the presence of a newly developed oral- genital- ulceration may be associated
with higher levels of Cp and Hp. Joint involvement seems to be a prominent clinical feature
representing the relationship with the acute phase response. The relationships between the
disease activity scores and the acute phase response, mainly fibrinogen, may contribute to the
perception of the overall disease activity in BD.
References:
1. Behçet H. Uber rezidivierende aphthouse durch ein virüs verursachte Geschwuere am
Mund, am Auge und an den Genitalien. Dermatol Monatsschr 1937; 105:1152–7.
2. Davatchi F. Behcet’s disease. In: Howe HS, Feng PH, editors.Textbook of clinical
rheumatology. Singapore: National ArthritisFoundation; 1998: 298–315.
3. Muftuoglu A, Yazici H, Yurdakul S, Tuzun Y, Pazarli H, Gungen G, et al. Behcet’s
disease. Relation of serum C-reactive protein and erythrocyte sedimentation rates to
disease activity. Int J Dermatol. 1986;25:235–9.
4. Lawton G, Bhakta B, Chamberlain M, Tennant A. The Behcet’s disease activity index.
Rheumatology. 2004;43:73.
5. Baltaci M. A review on disease activity scores in Behcet’s disease. Arthritis Res Ther.
2003;5(Suppl 2):7.
6. International Study Group for Behcet’s Disease. Criteria for the diagnosis of Behcet’s
Disease. Lancet 1990;335:1078–80.
7. Bhakta B, Brennan P, James T, Chamberlain M, Noble B, Silman A. Behcet’s disease:
evaluation of a new instrument to measure clinical activity. Rheumatology.
1999;38:728–33.
8. Hamuryudan V, Fresko I, Direskeneli H, Tennant MJ et al. Evaluation of the Turkish
translation of a disease activity form for Behçet’s syndrome. Rheumatology 1999;
38:734–6.
9. Melikoglu MA, Melikoglu M. The influence of age on Behcet's disease activity.
Eurasian J Med 2008; 40: 68-71.
10. Yildirim R, Gundogdu M, Erdem F, Kiki I, Bilici M. The Levels of Serum C-Reactive
Protein, Beta 2 Microglobulin, Ferritin, Lactate Dehydrogenase and Some Specific
Proteins in Patients with Non-Hodgkin’s Lymphoma Before and After Treatment
Eurasian J Med 2009; 41: 165-8.
11. Sepici-Dinçel A, Ozkan Y, Yardim-Akaydin S, Kaymak-Karataş G, Onder M, Simşek
B. The association between total antioxidant status and oxidative stres in Behcet's
disease. Rheumatol Int 2006;26:1005-9.
12. Odabas AR, Karakuzu A, Cetinkaya R, Selcuk Y, Keles S, Bilen H. Increased serum
ferritin levels in active Behcet's disease. Int J Clin Pract 2002;56:310-1.
13. Oliveira R, Banha J, Martins F, Paixγo E, Pereira D, Barcelos F, et al. Lymphocyte
ceruloplasmin and Behcet's disease. Acta Reumatol Port 2006;31:323-9.
14. Gonul M, Gul U, Cakmak SK, Soylu S, Kilic A. Serum iron and ferritin levels in
Behcet's disease. Indian J Dermatol Venereol Leprol. 2010;76:85.
15. Surrall KE, Bird HA, Dixon JS. Caeruloplasmin, prealbumin and alpha 2macroglobulin as potential indices of disease activity in different arthritides. Clin
Rheumatol. 1987;6:64-9.
16. Lee YJ, Kang SW, Yang JI, Choi YM, Sheen D, Lee EB, Choi SW, Song YW.
Coagulation parameters and plasma total homocysteine levels in Behcet's disease.
Thromb Res. 20021;106:19-24.
17. Doğan P, Tanrikulu G, Soyuer U, Köse K. Oxidative enzymes of polymorphonuclear
leucocytes and plasma fibrinogen, ceruloplasmin, and copper levels in Behçet's
disease. Clin Biochem. 1994;27:413-8.
18. Mao L, Dong H, Yang P, Zhou H, Huang X, Lin X, Kijlstra A. MALDI-TOF/TOFMS reveals elevated serum haptoglobin and amyloid A in Behcet's disease. J Proteome
Res. 2008;7:4500-7.
19. Yalcindag FN, Yalcindag A, Caglayan O, Ozdemir O. Serum haptoglobin levels in
ocular Behçet disease and acute phase proteins in the course of Behçet disease. Eur J
Ophthalmol. 2008;18:787-91.
Table 1: Age, gender ratio, disease durations and acute phase protein levels of patients
(mean±standard deviation)
PatientswithBehcet’sDisease n=73
Age (years±SD)
32.68± 6.82
Gender ratio (f/m)
42/31
BD duration (months±SD) 72,80±44,19
Ferritin (ng/mL)
73,54±44,12
Fibrinogen (mg/dl)
337,22±101,72
Haptoglobin (g/L)
154,67±67,70
Ceruloplasmin (mg/dl)
29,23 ±6,74
Pre-albumin (mg/ dl)
0,264±0,109
BDCAF score
2,76±1,54
BD: Behcet’s Disease; BDCAF: BD current activity form; SD: standard deviation
Table 2: Comparison of the laboratory parameters of patients with or without the
components of BDCAF and the correlations between these laboratory investigations and
patient’s- clinician’s overall perception of disease activity and total BDCAF score
BDCAF
Headache
+
p
Oral
ulceration
+
p
Genital
ulceration
+
p
Erythema
+
p
Skin pustules
+
p
Arthralgia
+
p
Arthritis
+
p
Nausea/
vomiting/
abdominal
pain
+
p
Diarrhoea+
altered/frank
blood per
Ferritin
(ng/mL)
Fibrinogen
(mg/dl)
Haptoglobin
(g/L)
Ceruloplasm Pre-albumin
in (mg/dl)
(mg/ dl)
75,49±59,19
78,20±48,71
NS*
335,5±102,8
357,4±96,2
NS*
153,5±67,0
169,5±84,5
NS*
29,47±5,81
26,82±13,99
NS*
0,26±0,11
0,21±0,01
NS*
49,89±36,99
54,30±40,39
NS*
333,9±107,6
340,2±97,6
NS*
144,3±57,6
164,0±75,4
NS*
27,7±6,4
30,4±6,9
0,015
0,3±0,13
0,2±0,07
NS
73,3±15,5
65,9± 18,4
NS*
360,4± 93,4
390,6±98,4
NS*
146,6±64,7
223,5±55,4
0,005
28,9±6,9
32,2±3,1
NS*
0,26±0,11
0,22±0,34
NS*
68,6±22,4
71,1±21,7
NS*
334,2±97,6
352,9±102,6
NS*
145,8±65,3
159,8±62,8
NS*
29,0±6,2
30,4±9,9
NS*
0,24±0,7
0,34±0,21
NS*
71,0±21,5
74,6±19,8
NS*
331,2±98,7
350,4±92,5
NS*
152,3±65,4
167,5±66,9
NS*
29,5±5,8
28,2±9,5
NS*
0,26±0,11
0,27±0,09
NS*
92,3±42,4
96,2±45,9
NS*
321,9±96,2
378,6±107,5
0,030
144,5±50,9
149,6±52,4
NS*
28,6±5,4
30,7±9,2
NS*
0,28±0,11
0,20±049
0,023
73,47±25,6
104,5±67,2
0,011
317,2±88,6
474,3±79,9
0,000
143,4±60,1
235,1±68,2
0,002
28,2±6,4
36,0±4,8
0,001
0,27 ±0,11
0,17 ±0,04
0,004
75,6±22,9
69,9±19,8
NS*
329,6±98,8
341,6±99,2
NS*
148,6±66,3
151,4±62,4
NS*
28,9±6,81
27,8±13,0
NS*
0,27±0,13
0,24±0,32
NS*
rectum
69,0±19,5
321,2±97,7
+
72,6±19,7
340,4±93,5
p
NS*
NS*
Eye
involvement
74,49±58,19 332,5±99,8
+
77,20±49,71 357,4±99,2
p
NS*
NS*
patient’s
perception of
disease
activity
(0-6)
p
NS
NS
clinician’s
overall
perception of
disease
activity(0-6)
p
NS
0,012**
BDCAF
score
0,01**
p
NS
*Mann-Whitney U test;**Pearson correlation.
142,3±64,4
157,5±69,9
NS*
28,5±5,4
26,2±8,5
NS*
0,27±0,10
0,28±0,19
NS*
157,5±64,2
160,5±82,5
NS*
28,48±5,84
26,12±13,00
NS*
0,27±0,15
0,24±0,12
NS*
NS
NS
NS
NS
NS
NS
NS
NS