Obesity and the prediction of minimal disease activity. A prospective study in Psoriatic Arthritis.

Abstract

OBJECTIVE: We prospectively evaluated whether obesity impacts on the achieving of Minimal Disease Activity (MDA) in subjects with Psoriatic Arthritis (PsA). METHODS: Among PsA subjects with an active disease starting a treatment with TNF-α blockers, 135 obese (Body Mass Index >30) and 135 normal-weighted patients (controls) were followed-up for 24 months. At baseline and at 12 and 24 months follow-up, all subjects underwent a clinical, rheumatologic and laboratory assessment.. RESULTS: With the exception for the prevalence of hypercholesterolemia and hypertriglyceridemia, case and control subjects were similar for all the clinical and demographical characteristics analyzed. At 12 months follow-up, both in cases and controls, no significant changes in the body weight was found (p always >0.05). MDA was achieved by 98/270 PsA individuals (36.3%). The prevalence of obesity was higher in those that did not achieve MDA than in those that did (64.0% vs 25.5%, p<0.001). After adjusting for all the other variables, obesity was associated with a higher risk of not achieving MDA (hazard ratio [HR]: 4.90, 95%CI:3.04-7.87, p<0.001). The HR of not achieving MDA was 3.98 (95%CI:1.96-8.06, p<0.001) and 5.40 (95%CI:3.09-9.43, p<0.001) in subjects with 1(st) degree (<30 BMI) and 2(nd) degree (30-35 BMI) obesity, respectively. Among the 98 subjects that had achieved MDA at the 12 months follow-up, the presence of obesity was associated with a poor probability of sustained MDA at 24-months follow-up (HR:2.04, 95%CI:1.015-3.61, p=0.014). CONCLUSIONS: Obesity is a negative predictor of achieving and maintaining MDA. © 2012 by the American College of Rheumatology.

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Obesity and the Prediction of Minimal Disease
Activity: A Prospective Study in Psoriatic Arthritis
MATTEO NICOLA DARIO DI MINNO,1ROSARIO PELUSO,1SALVATORE IERVOLINO,2
ROBERTA LUPOLI,1ANNA RUSSOLILLO,1RAFFAELE SCARPA,1AND GIOVANNI DI MINNO1
Objective. We prospectively evaluated whether obesity impacts achievement of minimal disease activity (MDA) in
subjects with psoriatic arthritis (PsA).
Methods. Among PsA subjects with an active disease and who were starting a treatment with tumor necrosis factor ?
blockers, 135 obese (body mass index [BMI] >30 kg/m2) patients and 135 patients of normal weight (controls) were
followed up for 24 months. At baseline and at the 12- and 24-month followup, all subjects underwent a clinical,
rheumatologic, and laboratory assessment.
Results. With the exception of the prevalence of hypercholesterolemia and hypertriglyceridemia, case and control
subjects were similar for all the clinical and demographic characteristics analyzed. At the 12-month followup, in both
cases and controls, no significant changes in body weight were found (P > 0.05 for all). MDA was achieved by 98 (36.3%)
of the 270 PsA individuals. The prevalence of obesity was higher in those that did not achieve MDA than in those that did
(64.0% versus 25.5%; P < 0.001). After adjusting for all the other variables, obesity was associated with a higher risk of
not achieving MDA (hazard ratio [HR] 4.90, 95% confidence interval [95% CI] 3.04–7.87; P < 0.001). The HR of not
achieving MDA was 3.98 (95% CI 1.96–8.06, P < 0.001) and 5.40 (95% CI 3.09–9.43, P < 0.001) in subjects with
first-degree (BMI <30 kg/m2) and second-degree (BMI 30–35 kg/m2) obesity, respectively. Among the 98 subjects who had
achieved MDA at the 12-month followup, the presence of obesity was associated with a poor probability of sustained MDA
at the 24-month followup (HR 2.04, 95% CI 1.015–3.61; P ? 0.014).
Conclusion. Obesity is a negative predictor of achieving and maintaining MDA.
INTRODUCTION
Subjects with rheumatic diseases, such as psoriatic arthri-
tis (PsA), exhibit an enhanced prevalence of the metabolic
syndrome and of some of its major features (obesity, hy-
pertension, hypercholesterolemia, hypertriglyceridemia,
and impaired fasting glucose) (1). As for other patients
with rheumatic diseases, clinical studies (2) show a high
prevalence of obesity in PsA patients as compared with the
general population. In view of the fact that chronic inflam-
mation in PsA acts synergistically with traditional vascu-
lar risk factors (VRFs) (3,4), a tight interrelation between
obesity and PsA can be suspected. By leading to an abnor-
mal expression of “adipokines” (e.g., tumor necrosis factor
? [TNF?], interleukin-6 [IL-6], leptin, adiponectin), obe-
sity leads to a proinflammatory status (5–7). In view of
this, obesity has been defined as a low-grade, chronic
systemic inflammatory disease (8,9). Further support for a
link between obesity and inflammation emerges from nu-
tritional intervention trials. In parallel with reducing obe-
sity, caloric restriction affects a variety of circulating in-
flammatory markers, thus affecting the inflammatory
status in humans (10). In this prospective study, we eval-
uated whether obesity impacts the clinical response in
PsA patients starting a treatment with TNF? blockers.
PATIENTS AND METHODS
During a 3-year period (January 2007–January 2010) we
enrolled, as the case group, 135 consecutive PsA subjects
with obesity (see below for obesity definition) who had a
PsA diagnosis according to Classification of Psoriatic Ar-
thritis (Study Group) criteria (11), who were nonre-
sponders to traditional disease-modifying antirheumatic
drugs (DMARDs), and who were referred to the Psoriatic
Arthritis Clinic of the Federico II University of Naples to
start a treatment with TNF? blockers. A total of 135 con-
1Matteo Nicola Dario Di Minno, MD, Rosario Peluso, MD,
PhD, Roberta Lupoli, MD, Anna Russolillo, MD, Raffaele
Scarpa, MD, Giovanni Di Minno, MD: Federico II Univer-
sity, Naples, Italy;
Maugeri Foundation IRCCS, Scientific Institute of Telese
Terme (BN), Italy.
Address correspondence to Matteo Nicola Dario Di
Minno, MD, Regional Reference Centre for Coagulation Dis-
orders, Federico II University, Via S. Pansini 5, 80131, Na-
ples, Italy. E-mail: dario.diminno@hotmail.it.
Submitted for publication January 31, 2012; accepted in
revised form August 28, 2012.
2Salvatore Iervolino, MD: Salvatore
Arthritis Care & Research
Vol. 65, No. 1, January 2013, pp 141–147
DOI 10.1002/acr.21711
© 2013, American College of Rheumatology
SPECIAL THEME ARTICLE: OBESITY AND THE RHEUMATIC DISEASES
141

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secutive PsA subjects of normal weight, referred during
the same time period to start a treatment with TNF? block-
ers, served as the control group.
Both case and control subjects had a clinically active
disease at the time of enrollment; both groups were clas-
sified into different clinical subsets according to the Moll
and Wright criteria (12). For all enrolled subjects, exclu-
sion criteria were the lack of informed consent signature,
age ?18 years, previous treatment with TNF? blockers,
malignancy, hematologic diseases, autoimmune diseases
other than PsA, unstable medical conditions, and ongoing
pregnancy. After informed consent signature, data about
age, sex, height, weight, disease duration, disease activity,
previous and/or current treatments, and VRFs were col-
lected from all patients as previously described (13). Ac-
cording to current guidelines (14), obesity was defined as a
body mass index (BMI) ?30 kg/m2. In view of this defini-
tion, both case and control subjects were stratified into 3
BMI groups as follows: 1) normal weight: BMI ?30 kg/m2;
2) first-degree obesity: BMI 30–35 kg/m2; and 3) second-
degree obesity: BMI 35–40 kg/m2. The National Choles-
terol Education Program criteria (15) define VRFs as fol-
lows: 1) hypertriglyceridemia as triglycerides levels ?150
mg/dl, 2) hypercholesterolemia with low high-density li-
poprotein (HDL) cholesterol as a total cholesterol of ?200
mg/dl, with HDL cholesterol ?40 mg/dl for men and ?50
mg/dl for women, 3) hypertension as a blood pressure
?130 and/or 85 mm Hg, and 4) impaired fasting glucose as
a fasting glucose ?100 mg/dl. All these criteria were em-
ployed to stratify cases and controls.
After baseline evaluation (T0), all subjects started treat-
ment with TNF? blockers and were followed up (every 3
months) for 12 months (T1). At baseline and at each fol-
lowup visit, all PsA subjects underwent a complete clini-
cal rheumatologic and laboratory evaluation that included
tender joint count (TJC), swollen joint count (SJC), tender
entheseal count, Psoriasis Area Severity Index (PASI),
Health Assessment Questionnaire (HAQ), visual analog
scale (VAS) for pain, patient global disease activity VAS
score, erythrocyte sedimentation rate (ESR), and C-reactive
protein (CRP) level. During the first 12 months of followup
(from T0 to T1), subjects were classified as having
achieved minimal disease activity (MDA) when fulfilling 5
of the following 7 outcome measures at T1: TJC ?1, SJC
?1, PASI score ?1 or body surface area ?3, VAS for pain
?15, patient global disease activity VAS score of ?20,
HAQ score ?0.5, and tender entheseal points ?1 (16).
Otherwise, the subjects were considered as not having
achieved MDA (non-MDA). Those that had achieved MDA
were reevaluated every 3 months thereafter during the
additional 12 months (T2) to test the achieving of sus-
tained MDA (s-MDA). S-MDA was defined as the fulfilling
of the same criteria employed for MDA in all the visits
carried out between T1 and T2. In addition to body weight
and BMI, cardiometabolic risk factors were evaluated at
each followup visit. To evaluate changes in nutritional
habits, a periodic nutritional interview was performed by
trained staff.
Statistical analysis was performed using SPSS, version
16.0. Continuous data were expressed as the mean ? SD;
categorical variables were expressed as the percentage.
The t-test was performed to compare continuous variables;
the chi-square test was employed to analyze categorical
data. When the minimum expected value was ?5, Fisher’s
exact test was used.
A Kaplan-Meier survival model (with the log rank test)
was adopted to evaluate the cumulative hazard of achiev-
ing MDA according to the presence of obesity. To adjust
for all the other variables and to evaluate the achieving of
MDA (or of s-MDA), Cox regression analyses (stepwise
method) were adopted, with achieving MDA (or s-MDA) as
the dependent variable, and obesity, TJC, SJC, tender en-
theseal count, PASI, HAQ, VAS for pain, patient global
VAS, ESR, CRP level, concomitant treatment with metho-
trexate, sex, age, disease duration, smoking habit, diabetes
mellitus, hypercholesterolemia, hypertriglyceridemia, and
hypertension as independent variables. Multicollinearity
effect in multivariable regression models was excluded by
a stepwise approach with each variable included for P
values less than 0.05 and excluded for P values greater
than 0.1. A tolerance test was employed to exclude models
in which the sum of the values exceeded the sum of the
variances for all variables. All the results are presented as
2-tailed values with statistical significance if P values were
less than 0.05.
As for the sample size calculation, when planning a
study with a minimal predefined hazard ratio (HR) ?1.5, a
1:1 ratio between case and control subjects, an accrual
interval of 3 years, and a followup of 24 months, at least
130 subjects for each group are needed to achieve a ?80%
power with a 5% alpha error.
RESULTS
Clinical and demographic characteristics of case and con-
trol populations are reported in Table 1. As to the TNF?
blockers used, adalimumab (40 mg/2 weeks) was em-
ployed in 80 (29.6%) subjects, etanercept (50 mg/week) in
111 (41.1%) subjects, and infliximab (5 mg/kg every 8
weeks) in 79 (29.3%) subjects.
With the exception of the prevalence of obesity, hyper-
cholesterolemia, and hypertriglyceridemia, the 2 study
groups did not significantly differ for other clinical and
demographic variables considered. Nor did they differ as
to the rheumatologic variables whose outcome measure-
ments have been shown to account for the achieving of
MDA (17,18). No difference in the prevalence of a concom-
Significance & Innovations
● Obesity has been recognized as a low-grade
chronic inflammation.
● Obesity-related inflammatory status can interact
with the immune-related inflammation in obese
subjects with psoriatic arthritis (PsA).
● Obesity is a negative predictor of achieving mini-
mal disease activity in PsA patients starting treat-
ment with tumor necrosis factor ? blockers.
142 Di Minno et al

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itant treatment with methotrexate was found between nor-
mal weight and obese PsA subjects (43.7% versus 38.5%;
P ? 0.458).
12-month followup (T0–T1). During the followup, no
changes in treatment schedules and/or in nutritional hab-
its of both case and control subjects were reported. When
comparing T0 and T1 data, no significant differences in
body weight, as well as in the metabolic variables ana-
lyzed, were found (P ? 0.05 for all by paired-sample t-test).
As a whole, MDA was achieved by 98 (36.3%) of 270 PsA
individuals.
As to the type of TNF? blocker used, MDA was achieved
in 33 (41.8%) subjects receiving infliximab, in 41 (36.9%)
of those receiving etanercept, and in 24 (30%) of those
receiving adalimumab (P ? 0.299 for trend). By evaluating
baseline measurements (Table 2), those that had achieved
MDA were more often males (P ? 0.001), of a younger age
(P ? 0.042), had a longer disease duration (P ? 0.004), a
higher ESR (P ? 0.001) and CRP level (P ? 0.001), and a
lower TJC (P ? 0.001) and tender entheseal counts (P ?
0.003) than those that did not. Among cardiometabolic risk
factors, hypercholesterolemia (P ? 0.001) and obesity (P ?
0.001) were more frequent in those that did not achieve
MDA compared with those that did.
With respect to the time elapsed from the beginning of
the TNF? blockers treatment, a Kaplan-Meier survival
model (Figure 1) showed a significant difference in achiev-
ing MDA according to the presence/absence of obesity (log
rank 41.77, P ? 0.001). After adjusting for all the other
demographic characteristics and for rheumatologic and
cardiovascular variables, obesity was the strongest predic-
tor of the risk of not achieving MDA (HR 4.90, 95% con-
fidence interval [95% CI] 3.04–7.87; P ? 0.001). A progres-
sively increasing HR of not achieving MDA was found for
increasing degrees of obesity (as evaluated by BMI) (Figure
2).
Together with obesity, low TJC (HR 1.15, 95% CI 1.08–
1.23; P ? 0.001), male sex (HR 2.25, 95% CI 1.47–3.43; P ?
0.001), and a high CRP level (HR 1.18, 95% CI 1.07–1.30;
P ? 0.001) were found to independently predict achieving
MDA in the regression model.
24-month followup (T1–T2). Among the 98 subjects that
had achieved MDA during the first 12 months of followup,
17 (17.3%) relapsed and 81 (82.7%) maintained their MDA
during the additional 12-month followup. In a separate
regression model that evaluated only those 98 subjects
achieving MDA during the first 12-month followup, obe-
sity was associated with a high risk of disease relapsing
during the additional 12 months of followup (HR 2.04,
95% CI 1.015–3.61; P ? 0.014).
Table 1. Baseline (T0) clinical and demographic characteristics of the
study population*
Variable
Normal-weight
patients
(n ? 135)
Obese
patients
(n ? 135)
P
Age, years
Male sex, no. (%)
Clinical subset, no. (%)
Axial and peripheral
Peripheral
Axial
Mutilans
Disease duration, months
ESR, mm/hour
CRP level, mg/dl
SJC
TJC
PASI score
HAQ score
VAS
Patient global VAS
Tender entheseal count
Hypercholesterolemia, no. (%)
Hypertriglyceridemia, no. (%)
Impaired fasting glucose, no. (%)
Hypertension, no. (%)
Smoking habit, no. (%)
Obesity, no. (%)
First-degree
Second-degree
51.12 ? 12.95
70 (51.9)
52.33 ? 9.83
54 (40.0)
0.386
0.067
46 (34.1)
52 (38.5)
26 (19.3)
11 (8.1)
114.71 ? 59.66
17.82 ? 12.27
2.93 ? 3.17
3.50 ? 3.77
11.44 ? 5.05
1.45 ? 0.70
2.65 ? 1.45
76.96 ? 22.23
75.11 ? 23.74
10.77 ? 5.23
60 (44.4)
36 (26.7)
9 (6.7)
29 (21.5)
27 (20.0)
0 (0)
0 (0)
0 (0)
49 (36.3)
43 (31.9)
38 (28.1)
5 (3.7)
107.02 ? 78.76
18.28 ? 14.09
2.35 ? 2.65
4.03 ? 4.36
12.41 ? 5.86
1.51 ? 0.72
2.49 ? 1.44
76.44 ? 17.84
73.40 ? 20.98
11.16 ? 5.57
79 (58.5)
56 (41.5)
11 (8.1)
28 (20.7)
38 (28.1)
135 (100)
100 (74.1)
35 (25.9)
0.799
0.308
0.115
0.196
0.367
0.779
0.110
0.291
0.147
0.497
0.147
0.833
0.533
0.559
0.028
0.014
0.817
1.000
0.154
? 0.001
? 0.001†
? 0.001†
* Values are the mean ? SD unless indicated otherwise. ESR ? erythrocyte sedimentation rate; CRP ?
C-reactive protein; SJC ? swollen joint count; TJC ? tender joint count; PASI ? Psoriasis Area Severity
Index; HAQ ? Health Assessment Questionnaire; VAS ? visual analog scale.
† P for trend.
Achieving MDA in Obese PsA Patients143

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DISCUSSION
In PsA subjects starting treatment with TNF? blockers, this
prospective study shows that obesity is associated with a
high risk of not achieving MDA. Analysis for increasing
BMI levels confirmed and extended this finding.
In the setting of PsA subjects, a variety of 6-month and
3-month clinical and laboratory predictors of response to
TNF? blockers have been identified (17,18). So far, how-
ever, no ad hoc study has tested obesity as a predictor of
success of the TNF? blockers treatment in PsA subjects.
A variety of markers (CRP level, C3, IL-6, and TNF?)
implicated in the etiology and the development of insulin
resistance, type 2 diabetes mellitus, and atherosclerosis
(19–21) are also important in the regulation of the inflam-
matory process (22) and, in turn, in the pathophysiology of
arthritides (23). Obesity is a central event in insulin resis-
tance and type 2 diabetes mellitus. Thus, an interaction
between obesity-related and immunity-related inflamma-
tory status may be postulated in obese PsA subjects. Inter-
vention studies (10) support such formulation. On the
other hand, major markers of atherosclerosis (carotid inti-
ma-media thickness and hepatic steatosis) that assess the
global damage secondary to metabolic and inflammatory
determinants (24) are severely affected in PsA subjects
(2,13,25). These data provide the rationale for testing
whether, among PsA subjects starting a treatment with
TNF? blockers, obesity would impact achieving MDA and
s-MDA.
Among the 98 (of 270) PsA patients who achieved MDA
at 12 months, the prevalence of obesity was significantly
lower than in those that did not. Accordingly, obesity was
associated with a high risk of not achieving MDA (P ?
0.001). This concept was strengthened by stratifying the
population according to increasing BMI degrees. More-
over, obesity was associated with a poor probability of
s-MDA at the 24-month followup (P ? 0.014). The com-
bined data lend credence to the possibility that obesity is
a negative predictor of achieving and maintaining MDA.
The relevance of obesity as an MDA predictor has been
analyzed in a regression model in which the large majority
of demographic, clinical, and laboratory variables known
to predict the achieving of MDA were present (18). The
HRs reported here have been computed after adjusting for
all these variables, and argue for obesity as being a major
determinant of achieving MDA.
At variance with the other TNF? blockers used, inflix-
imab needs a weight adjustment of dosages. The lack of a
meticulous dose adjustment might have hampered an op-
timal response to TNF? blocker treatment in obese PsA
subjects. However, in spite of its potential inherent limi-
Table 2. Clinical and demographic characteristics of the population according to the
achieving MDA at 12 months of followup*
Variable
Non-MDA
patients
(n ? 172)
MDA
patients
(n ? 98)
P
Age, years
Male sex, no. (%)
Clinical subset, no. (%)
Axial and peripheral
Peripheral
Axial
Mutilans
Disease duration, months
ESR, mm/hour
CRP level, mg/dl
SJC
TJC
PASI score
HAQ score
VAS
Patient global VAS
Tender entheseal count
Hypercholesterolemia, no. (%)
Hypertriglyceridemia, no. (%)
Impaired fasting glucose, no. (%)
Hypertension, no. (%)
Smoking habit, no. (%)
Obesity, no. (%)
First-degree
Second-degree
52.66 ? 10.60
65 (37.8)
50.08 ? 8.81
59 (60.2)
0.042
0.001
63 (36.6)
59 (34.3)
41 (23.8)
9 (5.2)
101.72 ? 74.01
14.35 ? 11.06
1.66 ? 1.83
3.75 ? 4.30
12.99 ? 5.62
1.49 ? 0.68
2.39 ? 1.41
77.50 ? 17.30
74.24 ? 21.08
11.71 ? 5.45
103 (59.9)
60 (34.9)
11 (6.4)
39 (22.7)
36 (20.9)
110 (64.0)
84 (48.8)
26 (15.1)
32 (32.7)
36 (36.7)
23 (23.5)
7 (7.1)
126.93 ? 58.83
20.16 ? 13.86
3.20 ? 3.28
3.80 ? 3.68
10.06 ? 4.71
1.45 ? 0.76
2.61 ? 1.52
75.30 ? 24.33
74.28 ? 24.62
9.66 ? 5.06
36 (36.7)
32 (32.7)
9 (9.2)
18 (18.4)
29 (29.6)
25 (25.5)
16 (16.3)
9 (9.2)
0.596
0.693
1.000
0.595
0.004
? 0.001
? 0.001
0.929
? 0.001
0.700
0.230
0.390
0.988
0.003
? 0.001
0.790
0.470
0.441
0.138
? 0.001
? 0.001†
? 0.001†
* Values are the mean ? SD unless indicated otherwise. MDA ? minimal disease activity; ESR ?
erythrocyte sedimentation rate; CRP ? C-reactive protein; SJC ? swollen joint count; TJC ? tender joint
count; PASI ? Psoriasis Area Severity Index; HAQ ? Health Assessment Questionnaire; VAS ? visual
analog scale.
† P for trend.
144Di Minno et al

Page 5

tations (the drug presentation is in 100-mg vials), special
attention has been paid to this issue during the study
period. As reported in the Results, no difference in achiev-
ing MDA was found when the data were stratified accord-
ing to type of TNF? blocker used (P ? 0.299 for trend).
Moreover, by evaluating only obese subjects, MDA was
achieved in 7 (15.6%) subjects receiving infliximab, in 10
(21.3%) of those receiving etanercept, and in 8 (18.6%) of
those receiving adalimumab (P ? 0.779 for trend).
By translating the results of the present study to clinical
practice, one has to argue that, in addition to being a
predictor of a poor response, obesity should be primarily
considered as an indication to adjust the dosing of TNF?
blockers in PsA.
Potential limitations of this study need to be addressed.
In the present setting, hypercholesterolemia and hypertri-
glyceridemia were more prevalent in the obese PsA group.
Based on the tight relationship between obesity and other
VRFs, this prevalence was expected. To overcome a poten-
tial bias, all the variables examined were included in the
regression model to obtain adjusted values of the HR.
As obesity is correlated with significantly higher levels
of major inflammatory markers (9), in addition to the ESR
and CRP level, differences in TNF? and IL-6 levels be-
tween obese and PsA subjects of normal weight could have
been of interest. However, these measurements were avail-
able only in few cases.
Among PsA subjects enrolled in the present setting, the
prevalence of an axial involvement is high (approximately
23%). However, at variance with most data in the litera-
ture, we have enrolled subjects experiencing a failure of
treatment with traditional DMARDs and with the indica-
tion to start a treatment with TNF? blockers. Because of its
high rate of refractoriness to DMARDs, the presence of an
axial subset has been recognized as a major criterion to
start treatment with TNF? blockers (26). The selection
criteria used could have determined such a high preva-
lence of axial subset in our study population.
Figure 1. Kaplan-Meier survival model for achieving minimal
disease activity (MDA) according to the presence of obesity. HR ?
hazard ratio.
Figure 2. Risk of not achieving minimal disease activity (MDA) at the 12-month fol-
lowup according to degrees of obesity (defined by body mass index). HR ? hazard ratio;
95% CI ? 95% confidence interval.
Achieving MDA in Obese PsA Patients145

Page 6

In addition to obesity, other demographic (male sex) and
rheumatologic (CRP level and TJC) variables predicted
achieving MDA. The multicollinearity effect was excluded
in the present setting by a stepwise approach in which
obesity was the strongest negative predictor of the achiev-
ing of MDA. Most previous studies in PsA subjects em-
ployed different criteria to define good clinical response.
We have chosen the criteria of achieving MDA proven to
be appropriate in providing an outcome measure for clin-
ical trials (17). As for variables known to predict MDA
other than obesity, the HRs found in the present study are
in line with those of previous reports (18).
In addition to their obvious pathophysiologic signifi-
cance, these data may have pharmacoeconomic implica-
tions (27). Because of their high cost and their side effects
(i.e., higher than normal risk of infections and malignan-
cies) (28), the identification of predictors of treatment suc-
cess with TNF? blockers is mandatory. By stratifying the
achieving of a good clinical response, a risk/benefit eval-
uation may be performed in each case and for each patient.
This, in turn, would hamper the use of TNF? blockers in
subjects with a low probability of success. Further studies
with a higher number of subjects are needed to address
this important issue. In this respect, determining whether,
in addition to its effect on weight loss, calorie restriction
lowers the levels of inflammatory markers in PsA is a
major direction to be pursued to strengthen the interrela-
tionship between obesity and inflammation.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors ap-
proved the final version to be submitted for publication. Dr.
M. N. D. Di Minno had full access to all of the data in the study
and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study conception and design. M. N. D. Di Minno, Peluso, Scarpa,
G. Di Minno.
Acquisition of data. Iervolino, Lupoli, Russolillo.
Analysis and interpretation of data. M. N. D. Di Minno, Peluso, G.
Di Minno.
REFERENCES
1. Tyrrell PN, Beyene J, Feldman BM, McCrindle BW, Silverman
ED, Bradley TJ. Rheumatic disease and carotid intima-media
thickness: a systematic review and meta-analysis. Arterioscler
Thromb Vasc Biol 2010;30:1014–26.
2. Di Minno MN, Iervolino S, Lupoli R, Russolillo A, Peluso R,
Coppola A, et al. Cardiovascular risk in rheumatic patients:
the link between inflammation and atherosclerosis. Semin
Thromb Hemost 2012;38:497–505.
3. Sattar N, McCarey DW, Capell H, McInnes IB. Explaining how
“high-grade” systemic inflammation accelerates vascular risk
in rheumatoid arthritis. Circulation 2003;108:2957–63.
4. Del Rincon ID, Williams K, Stern MP, Freeman GL, Escalante
A. High incidence of cardiovascular events in a rheumatoid
arthritis cohort not explained by traditional cardiac risk fac-
tors. Arthritis Rheum 2001;44:2737–45.
5. Peters MJ, van der Horst-Bruinsma IE, Dijkmans BA, Nurmo-
hamed MT. Cardiovascular risk profile of patients with spon-
dylarthropathies, particularly ankylosing spondylitis and
psoriatic arthritis. Semin Arthritis Rheum 2004;34:585–92.
6. Ahima RS, Flier JS. Adipose tissue as an endocrine organ.
Trends Endocrinol Metab 2000;11:327–32.
7. Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C-reactive
protein in healthy subjects: associations with obesity, insulin
resistance, and endothelial dysfunction: a potential role for
cytokines originatingfrom
Thromb Vasc Biol 1999;19:972–8.
8. Zulet MA, Puchau B, Navarro C, Marti A, Martinez JA. Inflam-
matory biomarkers: the link between obesity and associated
pathologies. Nutr Hosp 2007;22:511–27.
9. Rondinone CM. Adipocyte-derived hormones, cytokines, and
mediators. Endocrine 2006;29:81–90.
10. Hermsdorff HH, Zulet MA, Abete I, Martinez JA. Discrimi-
nated benefits of a Mediterranean dietary pattern within a
hypocaloric diet program on plasma RBP4 concentrations and
other inflammatory markers in obese subjects. Endocrine
2009;36:445–51.
11. Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P,
Mielants H, and the CASPAR Study Group. Classification
criteria for psoriatic arthritis: development of new criteria
from a large international study. Arthritis Rheum 2006;54:
2665–73.
12. Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum
1973;3:55–78.
13. Di Minno MN, Iervolino S, Peluso R, Scarpa R, Di Minno G,
on behalf of the CaRRDs study group. Carotid intima-media
thickness in psoriatic arthritis: differences between tumor
necrosis factor-? blockers and traditional disease-modifying
antirheumatic drugs. Artherioscler Thromb Vasc Biol 2011;
31:705–12.
14. World Health Organization. Obesity: preventing and manag-
ing the global epidemic. Report of a WHO Consultation.
World Health Organ Tech Rep Ser 2000;894:i–xii,1–253.
15. Di Minno MN, Tufano A, Guida A, Di Capua M, De Gregorio
AM, Cerbone AM, et al. Abnormally high prevalence of major
components of the metabolic syndrome in subjects with early-
onset idiopathic venous thromboembolism. Thromb Res
2011;127:193–7.
16. Coates LC, Helliwell PS. Validation of minimal disease activ-
ity criteria for psoriatic arthritis using interventional trial
data. Arthritis Care Res (Hoboken) 2010;62:965–9.
17. Coates LC, Cook R, Lee K, Chandran V, Gladman DD. Fre-
quency, predictors, and prognosis of sustained minimal dis-
ease activity in an observational psoriatic arthritis cohort.
Arthritis Care Res (Hoboken) 2010;62:970–6.
18. Iervolino S, Di Minno MN, Peluso R, Lofrano M, Russolillo A,
Di Minno G, et al. Predictors of early minimal disease activity
in patients with psoriatic arthritis treated with tumor necrosis
factor-? blockers. J Rheumatol 2012;39:568–73.
19. Dixon WG, Symmons DP. What effects might anti-TNF-?
treatment be expected to have on cardiovascular morbidity
and mortality in rheumatoid arthritis? A review of the role of
TNF-? in cardiovascular pathophysiology. Ann Rheum Dis
2007;66:1132–6.
20. Popa C, van den Hoogen FH, Radstake TR, Netea MG, Eijs-
bouts AE, den Heijer M, et al. Modulation of lipoprotein
plasma concentrations during long-term anti-TNF therapy in
patients with active rheumatoid arthritis. Ann Rheum Dis
2007;66:1503–7.
21. Libby P. Changing concepts of atherogenesis. J Intern Med
2000;247:349–58.
22. Rocha VZ, Libby P. The multiple facets of the fat tissue.
Thyroid 2008;18:175–83.
23. Van Kuijk AW, Reinders-Blankert P, Smeets TJ, Dijkmans BA,
Tak PP. Detailed analysis of the cell infiltrate and the expres-
sion of mediators of synovial inflammation and joint destruc-
tion in the synovium of patients with psoriatic arthritis: im-
plications for treatment. Ann Rheum Dis 2006;65:1551–7.
24. Di Minno MN, Iervolino S, Peluso R, Scarpa R, Di Minno G.
TNF-? blockers and carotid intima-media thickness: an
emerging issue in the treatment of psoriatic arthritis [letter].
Intern Emerg Med 2012;7 Suppl 2:97–8.
25. Di Minno MN, Iervolino S, Peluso R, Russolillo A, Lupoli R,
adipose tissue? Arterioscler
146 Di Minno et al

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Scarpa R, et al. Hepatic steatosis and disease activity in sub-
jects with psoriatic arthritis on TNF-? blockers. J Rheumatol
2012;39:1042–6.
26. Van der Heijde D, Sieper J, Maksymowych WP, Dougados M,
Burgos-Vargas R, Landewe R, et al. Assessment of Spondylo-
Arthritis international Society. 2010 update of the interna-
tional ASAS recommendations for the use of anti-TNF agents
in patients with axial spondyloarthritis. Ann Rheum Dis
2011;70:905–8.
27. Olivieri I, Mantovani LG, D’Angelo S, Padula A, de Portu S.
Psoriatic arthritis: pharmacoeconomic considerations. Curr
Rheumatol Rep 2009;11:263–9.
28. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL,
Montori V. Anti-TNF antibody therapy in rheumatoid
arthritis and the risk of serious infections and malignan-
cies: systematic review and meta-analysis of rare harmful
effects in randomized controlled trials. JAMA 2006;295:2275–
85.
Achieving MDA in Obese PsA Patients147