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An add-on training program involving breathing exercises, cold exposure, and meditation attenuates inflammation and disease activity in axial spondyloarthritis – A proof of concept trial


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Objectives The primary objective of this trial was to assess safety and anti-inflammatory effects of an add-on training program involving breathing exercises, cold exposure, and meditation in patients with axial spondyloarthritis Methods This study was an open-label, randomised, one-way crossover clinical proof-of-concept trial. Twenty-four patients with moderately active axial spondyloarthritis(ASDAS >2.1) and hs-CRP ≥5mg/L were included and randomised to an intervention (n = 13) and control group (n = 11) group that additionally received the intervention after the control period. The intervention period lasted for 8 weeks. The primary endpoint was safety, secondary endpoints were change in hs-CRP, serum calprotectin levels and ESR over the 8-week period. Exploratory endpoints included disease activity measured by ASDAS-CRP and BASDAI, quality of life (SF-36, EQ-5D, EQ-5D VAS), and hospital anxiety and depression (HADS). Results We found no significant differences in adverse events between groups, with one serious adverse event occurring 8 weeks after end of the intervention and judged ‘unrelated’. During the 8-week intervention period, there was a significant decline of ESR from (median [interquartile range] to 16 [9–26.5] to 9 [5–23] mm/hr, p = 0.040, whereas no effect was found in the control group (from 14 [8.3–27.3] to 16 [5–37] m/hr, p = 0.406). ASDAS-CRP declined from 3.1 [2.5–3.6] to 2.3 [1.9–3.2] in the intervention group (p = 0.044). A similar trend was observed for serum calprotectin (p = 0.064 in the intervention group versus p = 0.182 in the control group), but not for hs-CRP. Conclusions This proof-of-concept study in axial spondyloarthritis met its primary endpoint with no safety signals during the intervention. There was a significant decrease in ESR levels and ASDAS-CRP upon the add-on training program in the intervention group. These findings warrant full-scale randomised controlled trials of this novel therapeutic approach in patients with inflammatory conditions. Trial registration; NCT02744014
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An add-on training program involving
breathing exercises, cold exposure, and
meditation attenuates inflammation and
disease activity in axial spondyloarthritis – A
proof of concept trial
G. A. Buijze
*, H. M. Y. De JongID
, M. Kox
, M. G. van de Sande
, D. Van
, R. M. Van Vugt
, C. D. Popa
, P. Pickkers
, D. L. P. Baeten
1Department of Orthopaedic Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, The
Netherlands, 2Department of Rheumatology and Clinical Immunology, Amsterdam UMC, University of
Amsterdam, Amsterdam Rheumatology and Immunology Center, Amsterdam, The Netherlands,
3Department of Intensive Care Medicine, Nijmegen Institute for Infection, Inflammation and Immunity,
RadboudUMC Nijmegen, Nijmegen, The Netherlands, 4Reade, Amsterdam Rheumatology and Immunology
Center, Amsterdam, The Netherlands, 5Department of Rheumatology and Clinical Immunology, Amsterdam
UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands, 6Department of Rheumatology, Sint
Maartenskliniek, Nijmegen, The Netherlands, 7Department of Rheumatology, RadboudUMC Nijmegen,
Nijmegen, The Netherlands
These authors contributed equally to this work.
The primary objective of this trial was to assess safety and anti-inflammatory effects of an
add-on training program involving breathing exercises, cold exposure, and meditation in
patients with axial spondyloarthritis
This study was an open-label, randomised, one-way crossover clinical proof-of-concept
trial. Twenty-four patients with moderately active axial spondyloarthritis(ASDAS >2.1) and
hs-CRP 5mg/L were included and randomised to an intervention (n = 13) and control
group (n = 11) group that additionally received the intervention after the control period. The
intervention period lasted for 8 weeks. The primary endpoint was safety, secondary end-
points were change in hs-CRP, serum calprotectin levels and ESR over the 8-week period.
Exploratory endpoints included disease activity measured by ASDAS-CRP and BASDAI,
quality of life (SF-36, EQ-5D, EQ-5D VAS), and hospital anxiety and depression (HADS).
We found no significant differences in adverse events between groups, with one serious
adverse event occurring 8 weeks after end of the intervention and judged ‘unrelated’. During
PLOS ONE | December 2, 2019 1 / 11
Citation: Buijze GA, De Jong HMY, Kox M, van de
Sande MG, Van Schaardenburg D, Van Vugt RM, et
al. (2019) An add-on training program involving
breathing exercises, cold exposure, and meditation
attenuates inflammation and disease activity in
axial spondyloarthritis – A proof of concept trial.
PLoS ONE 14(12): e0225749.
Editor: Johannes Fleckenstein, University of Bern,
Received: April 17, 2019
Accepted: November 7, 2019
Published: December 2, 2019
Copyright: ©2019 Buijze et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: All relevant data are
within the manuscript and its Supporting
Information files.
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
the 8-week intervention period, there was a significant decline of ESR from (median [inter-
quartile range] to 16 [9–26.5] to 9 [5–23] mm/hr, p = 0.040, whereas no effect was found in
the control group (from 14 [8.3–27.3] to 16 [5–37] m/hr, p = 0.406). ASDAS-CRP declined
from 3.1 [2.5–3.6] to 2.3 [1.9–3.2] in the intervention group (p = 0.044). A similar trend was
observed for serum calprotectin (p = 0.064 in the intervention group versus p = 0.182 in the
control group), but not for hs-CRP.
This proof-of-concept study in axial spondyloarthritis met its primary endpoint with no safety
signals during the intervention. There was a significant decrease in ESR levels and ASDAS-
CRP upon the add-on training program in the intervention group. These findings warrant
full-scale randomised controlled trials of this novel therapeutic approach in patients with
inflammatory conditions.
Trial registration; NCT02744014
Previous research in healthy individuals exposed to experimental endotoxemia showed that
the innate immune response can be voluntarily modulated by a training program involving
breathing exercises, exposure to cold and meditation (further referred to as: ‘add-on training
program’).[1,2] Practicing the techniques learned in the add-on training program induced
intermittent respiratory alkalosis and hypoxia, as well as profoundly increased plasma epi-
nephrine levels, indicating activation of the sympathetic nervous system. These changes corre-
lated with increased plasma levels of the anti-inflammatory cytokine IL-10 and attenuated
levels of pro-inflammatory mediators such as TNF-α, IL-6, and IL-8 during experimental
The study of Kox et al[2] evaluated short term effects of this add-on training program in a
controlled experimental model of acute inflammation in healthy individuals. It is unknown
whether the same intervention could potentially lead to suppression of inflammation in
patients with chronic inflammatory diseases. And, more importantly, it is not known whether
this training program can safely be applied in patients with a chronic inflammatory disorder.
We designed a proof of concept (PoC) trial aimed to assess whether this well-defined add-
on training program could modulate innate immune responses in a prototypical chronic
inflammatory disease. We selected axial spondyloarthritis (axSpA)[3] as model disease since
this chronic rheumatic inflammation of the spine a) involves altered innate immune
responses,[4,5] b) affects mainly young adults with few comorbidities and concomitant medi-
cation, allowing for an unbiased efficacy and safety assessment, and c) persists often for years
as stable mild-to-moderate disease. Despite recent advances in therapeutic options for axSpA
it is still not possible to sufficiently control disease activity in all patients, as only 60–70% of the
patients respond to treatment, of whom 30% only partially. Remission is only achieved in 20%
of the patients. This indicates a clear opportunity for additional treatment options, such as the
add-on training program, to improve the outcome in these patients.
Add-on training program in axial spondyloarthritis
PLOS ONE | December 2, 2019 2 / 11
This study addresses the following primary research question: Can this add-on training
program safely be applied in patients with active axial spondyloarthritis? C- reactive protein
(CRP), erythrocyte sedimentation rate (ESR) and calprotectin levels are evaluated as secondary
biological endpoints to investigate potential impact on inflammatory response. The explor-
atory outcomes are other inflammatory markers and the patient-reported outcomes
ASDAS-CRP, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), quality of life
measures (SF-36, EQ-5D, EQ-5D VAS), and hospital anxiety and depression (HADS). As this
is the first study to investigate the safety and efficacy of this intervention in patients with a
chronic inflammatory disease, we did not attempt to decipher the mechanism of action of the
add-on training program.
Study design
The study design used for this proof-of-concept trial was an open-label randomised one-way
crossover design to rule out regression to the mean (S1 Fig). This intervention is not suitable
to compare to a genuine placebo effect. A concealed computer-based system randomised par-
ticipants to an early intervention group or late intervention group in a 1:1 ratio. Stratification
was performed for duration of disease and disease activity by ASDAS-CRP.
The early intervention group started with the intervention at baseline and continued with
the intervention until week 8. Study visits in the intervention period were done at baseline,
week 4 and week 8. Sixteen weeks after the intervention period, thus at week 24, a follow-up
visit was done. The total study duration for the early intervention group was 24 weeks, in
which 4 study visits were done.
The late intervention group started with the control period that lasted for 8 weeks. Study
visits were performed at baseline, week 4 and week 8. After 8 weeks, the late intervention
group started with the intervention and continued with the intervention for 8 weeks. The week
8 visit of the control period also served as the baseline visit for the intervention period. Study
visits in the intervention period for the late control group were done after 4 and 8 weeks of
intervention (thus at week 12 and week 16). Sixteen weeks after the intervention period, thus
at week 32, a follow-up visit was done. The total study duration for the late intervention group
was 32 weeks, in which 6 study visits were done.
Data from the first 8 weeks of study participation of the late intervention group were used
as control data. Data from both intervention periods (of the early and late intervention group)
were combined in the analysis. In both groups, the 8-week intervention period was followed
by a 16-week safety follow-up period. Patients were enrolled between May and December
2016. Participating centres were the Academic Medical Centre (AMC) and Bernhoven Hospi-
tal. All training sessions took place in the AMC.
Patients aged between 18 and 55 years were eligible if they had a clinical diagnosis of axSpA
according to the treating physician, fulfilled the ASAS classification criteria[6] and had active
disease defined as ASDAS>2.1[7] and a high-sensitive CRP (hs-CRP) 5mg/L. Patients were
allowed to use concomitant non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids
(prednisone equivalent up to 10mg/day) and disease modifying anti-rheumatic drugs
(DMARDs) (both synthetic and biologic) provided they have been initiated at least 8 weeks
before screening (exception: two weeks for NSAIDs) and that the dose had been stable for at
least 6 weeks prior to screening. Doses also had to remain stable throughout the study (from
screening to end of intervention at week 8). Exclusion criteria were significant comorbidities
Add-on training program in axial spondyloarthritis
PLOS ONE | December 2, 2019 3 / 11
that, in the opinion of the investigators, could interfere with the study or lead to deleterious
effects for the patient, a recent history or persistence of an infection requiring hospitalization
or antibiotic treatment within 4 weeks of baseline and pregnancy.
All participants gave written informed consent. Patients received a travel allowance that
was dependent on the distance of the patients’ residence to the training site, but no other reim-
bursement. This study was approved by the Medical Ethics Committee of the Academic Medi-
cal Centre in Amsterdam under reference number 2015_328.
The intervention consisted of an 8-weeks add-on training program comprising three elements:
1) breathing exercises (further detailed below), 2) gradual cold exposure (immersions in ice
cold water), and 3) meditation (third eye meditation).
The breathing techniques consisted of two exercises. First, patients were asked to hyperven-
tilate for an average of 30 breaths. Subsequently, the patient exhaled and held their breath in
an unforced manor for *2–3 min until they felt a stimulus to inhale (“retention phase”). The
duration of breath retention was entirely at the discretion of the patient himself. For safety rea-
sons, it was instructed to not hold the breath longer than 3.5 minutes. Breath retention was fol-
lowed by a deep inhalation breath, which was held for 10 s. Subsequently a new cycle of hyper/
hypoventilation began. After the last cycle, patients were instructed to do a strenuous exercise
such as push-ups. The induced state of intermittent respiratory alkalosis and hypoxia typically
“empowers” the patient to outperform their standard capability in any physical exercise. The
second breathing exercise consisted of deep inhalations and exhalations in which every inhala-
tion and exhalation was followed by breath holding for 10 s, during which the patient tight-
ened all his body muscles. An additional element this part of the training program consisted of
strength exercises (e.g., push-ups and yoga balance techniques).
During the intervention period, patients voluntarily exposed themselves to cold in two
ways. During weekly training sessions, the patients immersed whole-body in ice-cold water
(0–1˚C) for several minutes, incrementally up to a maximum of 5 minutes (for safety reasons).
At home, daily cold showers were taken incrementally up to 5 minutes (10–14˚C).
The so-called “third eye meditation,” is a form of meditation including visualizations aimed
at total relaxation. It consisted of an unguided meditation (in silence) with the eyes closed in
any posture as desired by the patient for a period of 15–20 minutes. It was generally used at the
end of each training session.
Consistent with the previous study,[2] patients were trained at the academic rehabilitation
centre by a Dutch individual Wim Hof and four trainers who previously received an instructor
course by Wim Hof to become a trainer. Medical personnel were present during all training
sessions. During the first 4 weeks, participants had group trainings twice weekly, the second 4
weeks once weekly. During the intervention period, and after extensive written and oral
instructions, participants practiced the exercises daily at home and registered their progression
in a diary. In this diary the participants reported per day a) their progression in breath reten-
tion at home and b) their mental and physical state. The adherence to the training program
was discussed and assessed weekly by the trainers and during the study visits by the medical
Primary safety assessments included vital signs, physical examination, electrocardiogram, hae-
matology and chemistry at baseline, 4, 8, and 24 weeks and upon indication, and recording of
adverse events (AEs) and serious adverse events (SAEs). The number and severity of adverse
Add-on training program in axial spondyloarthritis
PLOS ONE | December 2, 2019 4 / 11
events was used to assess safety, other safety assessments, such as measuring blood pressure,
heart rate, body temperature and physical exam, were done to detect potential adverse events
that were not reported by the participants. Secondary endpoints were the change in serum hs-
CRP (mg/L) levels between baseline and week 8 of the intervention/control period as a quick
response measure, and erythrocyte sedimentation rate (ESR, mm/hr) and serum calprotectin
levels[8] (measured by ELISA). Exploratory end-points were disease activity measured by
ASDAS-CRP[6] and BASDAI[9], quality of life measured by the short-form 36 (SF-36)[10]
and the EuroQol-5D (EQ-5D)[11] and depressive symptoms measured by the Hospital Anxi-
ety Depression Score (HADS)[12]. All questionnaires were self-administered and used and
scored according to the test manuals.
Statistical analysis
Because of the PoC design with safety as primary outcome, sample size could not be calculated
and was estimated based on previous work[2]. All patients are included in the analysis of the
primary outcome. For the primary outcome, safety, Mann-Whitney U tests were performed.
For the secondary and exploratory outcome, a per protocol analysis was performed in which
only patients that completed the intervention period were included. For the analyses of the
intervention period, the intervention periods of the early and late intervention group were
combined. The control group consisted of the first 8 weeks of the late intervention group. Sec-
ondary and exploratory outcomes were primarily assessed within groups over the 8-week
intervention/control period using Wilcoxon signed rank tests comparing baseline and week 8.
Because of the proof-of-concept nature of this trial, we did not adjust for multiple testing. A p
value of <0.05 was considered statistically significant.
Patient and public involvement
This intervention has received extensive media attention in the past years, resulting in patients
with various conditions practicing this intervention. However there was little known about
safety and putative immunomodulatory effects. The importance of a research project that
would increase insight into these matters was highly appreciated by patients as mentioned in
patient panels. To properly set the training program for patients with axSpA, 3 patient experts
were consulted. As their strong preference was that all patients would receive the intervention,
the study was designed as a one-way crossover open-label randomized (within-group) con-
trolled trial. The results will be disseminated to study participants by personal communication
and press release.
Thirty-one patients were screened and 24 patients were randomised to either the early (n = 13)
or late intervention (n = 11) group (Fig 1). There were no statistical differences between both
groups in demographics, baseline characteristics and concomitant medication (Table 1). Two
patients in the early intervention group discontinued after 4 weeks of training: 1 because of an
adverse event (AE) and 1 because of a change in medication for a persisting arthritis. In the
control group, 3 patients discontinued after the control period (week 8). Two because of insuf-
ficient motivation for the intervention, 1 was lost to follow-up. In total 21 participants started
with the intervention, of whom 19 completed the intervention period. All 11 patients in the
late intervention group completed the control period.
Add-on training program in axial spondyloarthritis
PLOS ONE | December 2, 2019 5 / 11
Fig 1. Flow-chart and patients disposition.
Add-on training program in axial spondyloarthritis
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No serious adverse events occurred during the intervention period. During the intervention
period, 10 participants in the intervention group reported a total of 12 AEs (2 participants
reported 2 AEs), and 7 participants of the control group reported a total of 9 AEs (2 partici-
pants reported 2 AEs)(p = 0.268). The most common AE was common cold (4 vs. 2, respec-
tively, Table 2). Three AEs during the intervention period had a moderate severity (1 in the
intervention group and 2 in the control group). During the follow-up period (n = 19), there
was one SAE of a participant who experienced a hypertensive crisis 8 weeks after end of the
intervention and was hospitalised for one night. Upon further examination by a ophthalmolo-
gist there were signs of longstanding disease, therefore this SAE was judged ‘unrelated’ to the
study procedures and did not lead to discontinuation of the study.
Secondary endpoints
All secondary endpoints are listed in Table 3. In the intervention group, ESR significantly
declined over time: from 16[9–26.5] mm/hr at baseline to 9[5–23] mm/hr at week 8, p = 0.040,
while it did not in the control group: from 14[8.3–27.3] mm/hr to 16[5–37] mm/hr, p = 0.406).
Table 1. Demographics, characteristics and medication use at baseline.
Total study population
(n = 24)
Early intervention group
(n = 13)
Late intervention group
(n = 11)
Male sex, n(%) 15 (62.5) 8 (61.5) 7 (63.6)
Age, years 35.00 ±7.31 35.46 ±8.29 34.45 ±6.30
BMI, kg/m
23.22 ±6.39 24.46 ±3.22 21.44 ±9.25
HLA-B27 positive, n(%)
16/21 (76.1) 11/12 (91.7) 5/9 (55.5)
Hs-CRP at baseline, mg/L, median (IQR) 8.3 (5.4–16.4) 7.9 (6.3–16) 8.7 (5.2–17.2)
ASDAS-CRP 3.02 ±0.89 3.10 ±0.97 2.93 ±0.81
Fulfill mNY, n(%) 16 (66.7) 9 (69.2) 7 (63.6)
IBP, n(%) 23 (95.8) 13 (100) 10 (90.9)
Psoriasis, n(%) 1 (4.2) 1 (7.7) 0 (0)
IBD, n(%) 2 (8.3) 1 (7.7) 1 (9.1)
Enthesitis, n(%) 5 (20.8) 4 (30.8) 1 (9.1)
Arthritis, n(%) 9 (37.5) 5 (38.5) 4 (36.4)
Dactylitis, n(%) 1 (4.2) 1 (7.7) 0 (0)
Uveitis, n(%) 6 (25.0) 5 (38.5) 1 (9.1)
Family history positive for SpA, n(%) 8 (33.3) 6 (46.2) 2 (18.2)
Good response to NSAIDs, n(%) 22 (91.7) 11 (84.6) 11 (100)
Elevated hs-CRP, n(%) 24 (100) 13 (100) 11 (100)
NSAIDs, n(%) 22 (91.7) 11 (84.6) 11 (100)
Anti-TNFα, n(%) 3 (12.5) 2 (15.4) 1 (9.1)
Anti-IL17, n(%) 2 (8.3) 1 (7.7) 1 (9.1)
cDMARDs, n(%) 2 (8.3) 2 (15.4) 0 (0)
Corticosteroids, n(%) 1 (4.2) 1 (7.7) 0 (0)
General medication, n(%) 9 (37.5) 5 (38.5) 4 (36.4)
Except where indicated otherwise, values are mean ±SD
HLA-B27 status is missing in 3 patients
IBP inflammatory back pain, IBD inflammatory bowel disease, mNY criteria modified New York criteria, cDMARDs conventional disease modifying anti-rheumatic
drugs, NSAIDs non-steroidal anti-inflammatory drugs
Add-on training program in axial spondyloarthritis
PLOS ONE | December 2, 2019 7 / 11
Hs-CRP did not significantly change within both groups during the 8-week intervention
period (intervention group: from median [IQR] 10.2[6.5–17.1] mg/L to 6[3.9–15.6] mg/L,
p = 0.103, control group: from 8.7[5.2–17.2] mg/L to 13.2[7.9–20.1] mg/L, p = 0.286). Calpro-
tectin tended to decline in the intervention group (from 2295[1648–4923] pg/mL to 2165
[953–3734] pg/mL, p = 0.064), whereas it remained stable in the control group (2115[1300–
2571] pg/mL to 2279[1770–4989 pg/mL], p = 0.307).
Exploratory endpoints
All exploratory endpoints are listed in Table 3. There was a significant improvement in the
median ASDAS-CRP during the 8-week period in the intervention group (p = 0.044), but not
in the control group (p = 0.213). Median BASDAI declined significantly in the intervention
group (p = 0.012) but not in the control group (p = 0.755). The physical component score
(PCS) of the SF-36 increased significantly during the intervention period (p = 0.004) but not
in the control group (p = 0.859).The MCS of the SF-36 increased significantly in the interven-
tion group (p = 0.004) but not in the control group (p = 0.859).The EQ-5D did not signifi-
cantly change in the intervention group (p = 0.102) nor in the control group (p = 0.933).A
similar effect was observed for the EQ-5D VAS (p = 0.090 and p = 0.674 in the intervention
and control groups, respectively. There was no significant effect on the HADS anxiety and
depression scales within groups.
The main burden of the intervention assessed by patients themselves was the commuting
time to the academic center for group training and follow-up visits. The time spent on group
and personal trainings were assessed as purposeful and the burden of cold exposure was tran-
sient. The participation during the training sessions was judged as high by the trainers. The
adherence to the exercises at home was discussed in the group sessions and reviewed in the
diaries, and was also judged as high.
In the present trial we show that the add-on training program involving breathing exercises,
cold exposure, and meditation can safely be applied in patients with axial spondyloarthritis, a
prototype chronic inflammatory disease.
We observed no differences in the number and severity of adverse events in the interven-
tion group compared to the control group. There was a significant decrease in ESR levels over
time in the intervention group but not in the control group. This is in line with previous work
showing that the immune response can be modulated through the add-on training program in
Table 2. Adverse events during the intervention period, control period and follow-up period in absolute numbers and percentages.
Intervention period
(n = 24)
Control period
(n = 11)
Follow-up period
(n = 19)
Serious adverse event, n(%) 0 0 1(5.3)
1 adverse event, n(%) 12(57.1) 9(81.2) 7(36.8)
Anterior uveitis, n(%) 0 1(9.1)1(5.3)
Headache, n(%) 1(4.8)0 0
Common cold, n(%) 4(19.0) 2(18.2) 3(15.8)
Other infectious diseases, n(%) 2(9.5) 2(18.2) 1(5.3)
Other adverse events, n(%) 5(23.8) 4(36.4)2(10.5)
Adverse events with moderate severity
One out of four had a moderate severity
Add-on training program in axial spondyloarthritis
PLOS ONE | December 2, 2019 8 / 11
healthy participants during experimental endotoxemia[2]. The intervention also tended to
result in decreased serum calprotectin levels, a validated disease activity biomarker in axSpA
[8], although this did not reach a statistical significance. Various measures of disease activity
(ASDAS-CRP, BASDAI) and quality of life (SF-36) improved following the intervention. The
effects observed in the intervention group are unlikely to be due to regression to the mean as
there were no effects in the control group. Therefore, our results are indicative that voluntary
modulation of the immune response may not only be possible in acute inflammatory response
due to microbial stimulation but also in chronic inflammation related to immune-mediated
inflammatory diseases.
This study has several limitations. 1) As this study was a proof-of-concept trial the sample
size was small and not powered to investigate efficacy. However, despite this small sample size,
significant changes in the secondary and exploratory outcomes were found. Larger follow-up
studies are required to formally assess clinical efficacy.
2) The unblinded design of the study renders our results susceptible for a placebo effect. As
the studied intervention is not suitable for a genuine placebo treatment, we chose hs-CRP, ESR
and calprotectin as a secondary biologic endpoint that does not suffer from subjective influ-
ences or variability in the measurements. Furthermore, we used a delayed intervention group
to assess the impact of regression to the mean. With this design we neutralized the aforemen-
tioned components of placebo effect. Moreover, the data obtained did not suggest an effect of
regression to the mean since we observed changes in the intervention but not in the control
Table 3. Analysis of inflammatory markers in peripheral blood, ASDAS, BASDAI, SF-36, EQ-5D, EQ-5D VAS and HADS during the 8-week intervention period.
Intervention group Intra-group
p value
Control group Intra-group
p value
Baseline (n = 21) 4w
(n = 21)
(n = 19)
Baseline (n = 11) 4w
(n = 11)
(n = 11)
hs-CRP (mg/l) 10.2
.103 8.7
ESR (mm/hr) 16
Calprotectin (pg/ml) 2295 (1648–4923) 2245 (1273–3245) 2165 (953–3734) .064 2115 (1300–2571) 2086
SF-36 PCS 44.8 (36.0–48.8) 44.6 (39.9–47.4) 49.3 (40.7–54.7) .00441.8 (34.1–49.1) 42.1
SF-36 MCS 45.5
EQ-5D .81
.102 .81
EQ-5D VAS 66.5
.090 67.5
HADS-Anxiety 5.0
.369 5.0
HADS-Depression 3(1–6) 3(1–6) 2(1–6) .508 3(2–6) 4(1–5) 1(1–4) .137
Values are presented as median (interquartile range).
Wilcoxon signed rank test
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3) Our study design was not aimed at and therefore does not allow us to decipher the mech-
anism of action of this intervention. The mechanism of action behind the add-on training pro-
gram remains to be unraveled. Kox et al clearly showed the biological impact of the training
program on the innate immune response[2]. Firstly it is unknown whether it is necessary to
practice all three components of the training program, or whether the observed effect in
immune response is attained by one of the components. Secondly it is unknown what the min-
imally required intensity or duration of the training program should be to see similar results.
Future research should address these questions.
4) The adherence to the training program at home was not formally checked, although dis-
cussed weekly during the group sessions and study visits. The adherence to the group sessions
was high as on average the participants missed 1.5 out of 12 group sessions, due to holidays,
other obligations or sickness.
5) Although not a major part of the add-on training program, the strength exercises
(performed in conjunction with the breathing exercises) might play a role in the improve-
ments we found in the participants, since exercise is a pivotal part of the treatment of axial
In conclusion, the present study demonstrates that the add-on training program used in
this study can safely be applied in patients with axial spondyloarthritis and potentially modu-
lates inflammatory response. These findings warrant further clinical assessment of this novel
therapeutic approach. Future research should include a larger sample size to formally evaluate
clinical efficacy and should by focussed on further elucidation of the mechanism of action of
the combined and/or individual components of the training program.
Supporting information
S1 CONSORT 2010 Checklist.
S1 Fig. Study design.
S1 File. SPSS database.
We thank all the patients who participated in the study for their enthusiasm and participation.
We are appreciative of the support of Professor Piet van Riel to launch the study; Lisa van Maa-
nen, Sanne Pons, Wim Hof, Isa Hof, Henk van den Berg, Marianne Peper, Linda Hochsten-
bach, and Iris Premssler for their support during the study and training sessions. We thank dr.
Luitzen Groen and Marije Wolters for their support with the statistics of this study. Lastly, the
Centre for Rehabilitation; the Department of Technical Support and the Department of Secu-
rity from the Academic Medical Centre, Amsterdam, the Netherlands for providing training
space, technical and logistic assistance, respectively.
Author Contributions
Conceptualization: G. A. Buijze, M. Kox, P. Pickkers, D. L. P. Baeten.
Formal analysis: G. A. Buijze, H. M. Y. De Jong.
Funding acquisition: D. L. P. Baeten.
Add-on training program in axial spondyloarthritis
PLOS ONE | December 2, 2019 10 / 11
Investigation: H. M. Y. De Jong.
Methodology: G. A. Buijze, P. Pickkers, D. L. P. Baeten.
Project administration: G. A. Buijze, H. M. Y. De Jong.
Resources: D. L. P. Baeten.
Supervision: M. G. van de Sande, D. L. P. Baeten.
Validation: M. Kox, P. Pickkers.
Visualization: M. Kox.
Writing – original draft: G. A. Buijze, H. M. Y. De Jong, M. G. van de Sande, D. L. P. Baeten.
Writing – review & editing: M. Kox, M. G. van de Sande, D. Van Schaardenburg, R. M. Van
Vugt, C. D. Popa, P. Pickkers, D. L. P. Baeten.
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centration/meditation on autonomic nervous system activity and the innate immune response: a case
study. Psychosom Med. 2012; 74(5):489–94. PMID:
2. Kox M, van Eijk LT, Zwaag J, van den Wildenberg J, Sweep FCGJ, van der Hoeven JG, et al. Voluntary
activation of the sympathetic nervous system and attenuation of the innate immune response in
humans. Proc Natl Acad Sci U S A. 2014; 111(20):7379–84.
PMID: 24799686
3. Dougados M, Baeten D. Spondyloarthritis. Lancet. 2011; 377(9783):2127–37.
S0140-6736(11)60071-8 PMID: 21684383
4. Ambarus C, Yeremenko N, Tak PP, Baeten D. Pathogenesis of spondyloarthritis. Curr Opin Rheumatol.
2012; 24(4):351–8. PMID: 22488076
5. van Tok MN, Satumtira N, Dorris M, Pots D, Slobodin G, van de Sande MG, et al. Innate immune activa-
tion can trigger experimental spondyloarthritis in HLA-B27/Huβ2m Transgenic Rats. Front Immunol.
2017; 8(AUG):1–12.
6. Rudwaleit M, van der Heijde D, Landewe
´R, Listing J, Akkoc N, Brandt J, et al. The development of
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68(1):18–24. PMID: 18625618
8. Turina MC, Yeremenko N, Paramarta JE, Rycke L De, Baeten D. Calprotectin (S100A8 / 9) as serum
biomarker for clinical response in proof-of-concept trials in axial and peripheral spondyloarthritis.
9. Garrett S, Jenkinson T, Kennedy L, Whitelock H, Gaisford P, Calin A. A new approach to defining dis-
ease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheu-
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Add-on training program in axial spondyloarthritis
PLOS ONE | December 2, 2019 11 / 11
... The empirical research on conscious connected breathing with breath retention (CCBR) comes from an intervention that is often delivered by a specific teacher (i.e., Wim Hof 1 ) within a group retreat setting and combined with additional components (e.g., cold exposure, visualization meditation, strength exercises) [47][48][49][50]. These aspects limit accessibility to the intervention and also complicate conclusions that can be drawn regarding the efficacy and mechanisms of the intervention due to the many potential specific and non-specific treatment effects [51][52][53][54][55][56]. ...
... Much of the early research on this intervention include either Wim Hof as a case study or participants who were personally trained by him. [47]. Yet, CCBR alone has not been tested for its impact on chronic pain, including in those with cLBP. ...
... The duration of the breath retention is at the discretion of the participant, but the audio recording prompts participants to inhale after approximately 1-, 1.5-, and 2-min for rounds 1-3, respectively, increasing the time of the breath hold each round. Although previous studies on this breathing practice have shown that breath retention was safe up to 3.5 min [47,48], participants are clearly instructed to inhale when they feel an urge to breathe without forcing it or pushing beyond their limits (i.e., "just inhale when you need"). When the participant inhales to end the breath retention they are instructed to hold their breath again for 10-15 s. ...
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Background Chronic pain is a major source of human suffering, and chronic low back pain (cLBP) is among the most prevalent, costly, and disabling of pain conditions. Due to the significant personal and societal burden and the complex and recurring nature of cLBP, self-management approaches that can be practiced at home are highly relevant to develop and test. The respiratory system is one of the most integrated systems of the body, and breathing is bidirectionally related with stress, emotion, and pain. Thus, the widespread physiological and psychological impact of breathing practices and breathwork interventions hold substantial promise as possible self-management strategies for chronic pain. The primary aim of the current randomized pilot study is to test the feasibility and acceptability of a conscious connected breathing with breath retention intervention compared to a sham control condition. Methods The rationale and procedures for testing a 5-day conscious connected breathing with breath retention intervention, compared to a deep breathing sham control intervention, in 24 adults (18–65 years) with cLBP is described. Both interventions will be delivered using standardized audio recordings and practiced over 5 days (two times in-person and three times at-home), and both are described as Breathing and Attention Training to reduce possible expectancy and placebo effects common in pain research. The primary outcomes for this study are feasibility and acceptability. Feasibility will be evaluated by determining rates of participant recruitment, adherence, retention, and study assessment completion, and acceptability will be evaluated by assessing participants’ satisfaction and helpfulness of the intervention. We will also measure other clinical pain, psychological, behavioral, and physiological variables that are planned to be included in a follow-up randomized controlled trial. Discussion This will be the first study to examine the effects of a conscious connected breathing with breath retention intervention for individuals with chronic pain. The successful completion of this smaller-scale pilot study will provide data regarding the feasibility and acceptability to conduct a subsequent trial testing the efficacy of this breathing self-management practice for adults with cLBP. Trial registration, identifier NCT04740710 . Registered on 5 February 2021.
... e majority of the interventions ranged from 5 to 16 weeks (n � 35) , either solo (Y or M or P) or in combinations (YM, YP, MP, and YMP). ere were studies providing yoga (n � 2) (Y) [29,44], pranayama (n � 2) (P) [3,28], meditation (M) (n � 11) [14][15][16][17][18][19][20][49][50][51][52], meditation and pranayama (n � 2) (MP) [21,53], yoga and meditation (n � 4) (YM) [32,33,35,36], yoga and pranayama (n � 8) (YP) [22-24, 27, 30, 31, 54, 55], and yoga, meditation, and pranayama (n � 15) (YMP) [25,26,34,[37][38][39][40][41][42][43][45][46][47][48]56] as interventions. Most of the studies had two groups (intervention and control), while 6 studies were reported to have 3-experimental arms. ...
... Two studies had a combination of meditation and pranayama [21,53], ranging from a duration of 336 to 1200 minutes. IL-6, TNF-α [53], and hsCRP [21] were studied in these trials. ...
... Two studies had a combination of meditation and pranayama [21,53], ranging from a duration of 336 to 1200 minutes. IL-6, TNF-α [53], and hsCRP [21] were studied in these trials. ...
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Introduction: COVID-19, a multisystem disease, has implications for various immunity and infection biomarkers. Yoga (Y), meditation (M), and pranayama (P), and their combinations have shown positive changes on those biomarkers among other than COVID-19 patients and healthy people. So, we aimed to document the evidence of possible implication in a systematic way. Materials and methods: We screened 84 full texts, published in the last ten years, from three databases, from which only 44 met the eligibility criteria, and then extracted the data related to demographic characteristics, intervention, results, and strengths and limitations in two MS-Excel grids, and then presented them in tables and figures. Furthermore, we carried out meta-analysis including subgroup and sensitivity analysis using a random effects model of 11 RCTs and reported the mean difference, heterogeneity, and p value with 95% CI and presented them with forest and funnel plots and the tables. Results: Twenty-five biomarkers of 4023 participants (range, 15-413) from 13 countries, healthy and clinical, from both sexes above 18 years, and from mainly clinical settings, were reported. YMP intervention, in solitary or in different possible combinations with varied durations among clinical and pregnant (range, 960-4800 minutes) and healthy (960-8400 minutes, excluding two studies of 20 minutes only) participants, was reported. It was revealed that 25 biomarkers, nine among the apparently healthy, 14 among the patients, and two among the pregnant, changed favourably (p < 0.05). Furthermore, either in meta- or subgroup-analysis, mean differences of IL-6 (-1.44 pg/ml) (95% CI) (-2.33, -0.55), (p = 0.002, I 2 = 82%), Cortisol (-40.75 pg/ml) (95% CI) (-64.13, -17.38), (p = 0.0006, I 2 = 87%), and TNF-α (-3.40 pg/ml) (95% CI) (-4.83, -1.98), (p < 0.0001, I 2 = 79%) showed statistically significant changes. Nonetheless, considerable heterogeneity and publication bias were observed among the studies. Conclusion: Although more than two dozens of biomarkers in individual studies showed favourable changes, only IL-6, Cortisol, and TNF-α produced significant combined results, even then with much less certainty. Further meta-analysis of biomarkers of COVID-19 patients is highly recommended. Registration: CRD42021283894.
... Twenty publications focused on exercise, corresponding to 17 main studies (RCTs or CCTs), [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] and four post-hoc analysis (table 1 and online supplemental tables S6-S8). [40][41][42][43] The type, intensity and duration of exercise were very heterogeneous, ranging from Tai-Chi to high intensity exercise. ...
Objective To update the evidence of non-biological treatments for axial spondyloarthritis (axSpA), as a basis for the 2022 Assessment of SpondyloArthritis international Society-European Alliance of Associations for Rheumatology (ASAS-EULAR) recommendations for the management of axSpA. Methods A systematic literature review (2016–2021) on efficacy and safety of non-pharmacological and non-biological pharmacological treatments was performed, up to 1 January 2022. The research question was formulated according to the PICO format: Population: adult patients with r-axSpA and nr-axSpA; Intervention: non-pharmacological and non-biological pharmacological treatments; Comparator: active comparator or placebo; Outcomes: all relevant efficacy and safety outcomes. Type of studies included were: randomised controlled trials (RCTs), observational studies (for efficacy of non-pharmacological treatments, and safety), qualitative studies. Cohen’s effect size (ES) was calculated for non-pharmacological and risk ratio (RR) for pharmacological treatments. Results Of 107 publications included, 63 addressed non-pharmacological interventions, including education (n=8) and exercise (n=20). The ES for education on disease activity, function, mobility was small to moderate (eg. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), ES: 0.06–0.59). Exercise had moderate to high ES on these outcomes (eg. BASDAI, ES: 0.14–1.43). Six RCTs on targeted synthetic disease-modifying antirheumatic drugs (DMARDs) showed efficacy of tofacitinib, upadacitinib and filgotinib (phase 2 only) in r-axSpA (range RR vs placebo for ASAS20: 1.91–3.10), while apremilast and nilotinib were not efficacious. Studies on conventional synthetic DMARDs (n=3), non-steroidal anti-inflammatory drugs (NSAIDs, n=8) and other drugs (n=12) did not provide new evidence on efficacy/safety (efficacy of NSAIDs confirmed; limited efficacy of short-term glucocorticoids in one RCT). Conclusions Education, exercise and NSAIDs confirmed to be efficacious in axSpA. JAKi were proved efficacious in r-axSpA.
... Some MBI studies reported immune-related outcomes for not only rheumatoid arthritis patients, but also axial spondyloarthritis patients. Training programs consisted of breathing, exercise, and gradual cold exposure, and meditation significantly reduced the levels of ESR and ASDAS-CRP, but not levels of calprotectin and hs-CRP, after 8 weeks compared to the usual care control (n = 24) [68]. In these three RCTs for arthritis patients, MBIs report partially beneficial, at least not harmful, changes in immune-related outcomes among the investigated items. ...
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Recent findings suggest a correlation between COVID-19 and diabetes, although the underlying causes are still little understood. COVID-19 infection tends to induce severe symptoms in patients with underlying diabetes, increasing their mortality rate. Moreover, COVID-19 itself appears to be a diabetogenic factor. In addition, mental health conditions, such as depression due to lockdown and anxiety about infection, were found to affect glycemic control and immunity, highlighting the importance of mental health care during the pandemic. Mind–Body Intervention (MBI), which includes meditation, yoga, and qigong, has emerged as a tool for mental health management due to its effects on stress reduction and the promotion of mental and physical well-being. Here, we review the latest randomized controlled trials to determine the effects of MBI on glycemic control and the immune system and discuss the underlying mechanisms by which MBI facilitates the virtuous cycle of stress management, glycemic control, and immune modulation. Furthermore, we examine the actual utilization of MBI during the COVID-19 pandemic era through recent studies. With proper online education, non-pharmacological MBI may be more widely used as an important tool for self-health care that complements the usual treatment of COVID-19 patients and survivors.
... [3][4][5][6] There are only a few studies on this novel training program and its psychophysiological effects, but findings suggest that the WMH has positive effects on immune and endocrine functions. 1,2,5,6 A recent neuroimaging study using functional magnetic resonance imaging analyses showed that the WHM training program activates primary control centers for descending pain/ cold stimuli modulation in the periaqueductal gray, possibly initiating a stress-induced analgesic response. In addition, this study reported that the WHM activated the left anterior and right middle insula, which are associated with self-reflection, and that respiration practice may affect sympathetic activation. 2 The aim of this study was to investigate the effects of a WHM training program on psychological and neuroendocrine stress responses caused by extreme conditions during an expedition based at the J.G. ...
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Objective The aim of this prospective observational study was to investigate the effects of a novel Wim Hof psychophysiological training program on stress responses and hormone release in healthy participants during an Antarctic expedition. Methods All members of an Antarctic expedition were included in the study. The participants were healthy volunteers allocated to an intervention group (n = 6) and a control group (n = 7). The intervention consisted of 8 weeks of Wim Hof training. The training program comprised three integrated parts: breathing exercises, cold exposure and meditation. Psychometric measures (the Beck Depression Inventory and the Trauma Symptom Checklist-40) and neuroendocrine measures (cortisol, melatonin) were assessed pre- and post-intervention. Results The results showed that the 8-week training program significantly reduced stress responses, as indicated by a reduction in depressive symptoms. A non-significant reduction in cortisol was also observed. Conclusions These data constitute preliminary findings indicating that the Wim Hof Method may positively affect stress symptoms and adaptability of the hormonal system to respond adequately to the circadian rhythm in healthy volunteers who participated in an Antarctic expedition.
... Tanto es así que en ensayos clínicos controlados aleatorizados (ECCA) de endotoxemia en los humanos se ha observado que la meditación, los ejercicios respiratorios y el yoga disminuyen las concentraciones de CO 2 , mejoran las concentraciones de M.A. Bautista-Hernández, L.M. Castillo-Real, M.E.M. Castro-Gutiérrez, et al. O 2 y la sintomatología asociada; además de modular la frecuencia cardíaca, la presión arterial y la producción de citoquinas proinflamatorias 11,12 . Por otra parte, los resultados de diversos metaanálisis apoyan su uso en el manejo del dolor crónico 13 , la ansiedad 14 y la depresión 15 . ...
Resumen El tratamiento del cáncer de cabeza y cuello (CCC) implica desafíos en la supervivencia, la calidad de vida y el estado biopsicosocial de los pacientes. El tratamiento oncológico, ya sea cirugía, radioterapia o quimioterapia, incluye efectos secundarios a corto, mediano y largo plazo. Los odontólogos desempeñan un papel importante en las diferentes etapas, desde el diagnóstico precoz, restaurar la salud dental previa al tratamiento, así como el manejo de secuelas, lo que representa un acompañamiento continuo. Sin embargo, el manejo efectivo del dolor, causado por CCC y las complicaciones generadas por la quimioterapia y la radioterapia, sigue siendo difícil de alcanzar para recuperar la salud integral del paciente. Por lo que el objetivo de esta revisión es explorar la evidencia de las terapias complementarias en el manejo integral del paciente con CCC. Se siguieron las recomendaciones de la extensión PRISMA-ScR para las revisiones exploratorias, se utilizaron 4 bases de datos en la búsqueda, se incluyeron ensayos clínicos controlados, estudios observacionales y reportes de casos, integrando la evidencia de 15 artículos (11 de acupuntura, 2 de yoga y 2 de meditación) en los que se estudió el efecto de estas terapias complementarias para el manejo del dolor, la xerostomía, la disgeusia, la ansiedad y la depresión en los pacientes con CCC. Los tratamientos implementados, así como los resultados referidos, fueron muy heterogéneos; lo que impide realizar en el futuro un adecuado metaanálisis. Aunque la síntesis sugiere que estas terapias pueden ser una buena herramienta en el manejo integral del paciente con CCC, se requiere contar con más evidencia para emitir recomendaciones.
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The multi-dimensional measurement of complex biological systems and sub-systems is made possible by high-dimensional omics technologies. This frontier of research is promising for elucidating disease processes, physiological parameters, and therapeutic action mechanisms. Omics have potential merit for the integrative medicine field that is relatively early in terms of mechanistic research towards understanding the underlining therapeutic processes of mind-body interventions that show to affect multiple systems simultaneously. An inflammatory theory of disease has brought to light molecular and epidemiological evidence proposing that inflammation could be considered a unitary predictor across most disease typologies which may be treated as a central clinical entity. Relatively recent theorizations of disease have built upon epigenetic data showing that complex “interactomes”, or disease networks where genetic factors that have downward chain effects on transcriptional, proteomic domains, dynamically modulate in response to environmental, microbial, and immunological domains. Thus, complex conditions underlined by interactive disease networks and dynamics essentially require complex multi-levelled interventions. This is particularly germane for complex patient cases often seen in the integrative medicine clinic. Mind-body medicine may be part of such care programs that can be made accessible for all. To shed further light on the possibility of building the evidence base in integrative health towards this direction, we reviewed the current use of omics technologies in mind-body medicine within the last 5-years. Use of omics approaches within the field is still developing. Early findings appear to show beneficial impact upon genomic, transcriptional, and proteomic biomarkers across varied chronic inflammatory conditions, including disorders of the cardiovascular, central nervous, endocrine, immune, musculoskeletal, and respiratory, systems.
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A pranayama-inspired breathing technique, cold exposure, and their combined application were assessed for their potential to reduce perceived stress in adults and compared to a control group. An experiment involving four groups was conducted, yielding separate cells for breathing technique-only and cold exposure-only, as well as a combined treatment and a control group. Eighty-six individuals participated in the study. Perceived stress is measured employing the 10-item version of the Perceived Stress Scale (PSS-10) and the 20-item version of the Perceived Stress Questionnaire (PSQ). The instruments exhibit a substantial correlation (r = 0.842, p < 0.001). The combined group exhibited a medium to large positive effect on perceived stress compared to the control group. The breathing technique and cold exposure on their own were not found to yield substantial effects, indicating synergies between both exercises. Combinations of breathing techniques and cold exposure may be employed to decrease individuals' perceived stress.
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Objective To give an overview of the nature and methodological quality of studies on whole body cryotherapy (WBC) as add-on intervention for mental health problems. Methods A meta-analysis according to PRISMA guidelines was conducted (Prospero registration: CRD42020167443). Databases MEDLINE, PsycINFO and the Cochrane Library were searched. Risk of bias was scored according to the Cochrane ROBINS-I-tool to which an extra bias-dimension of allegiance bias was added. Within and between Hedges’ g pooled effect sizes were calculated for the main aspect of mental health measured. Treatment efficacy was examined using a random effects model. Heterogeneity was examined through identification of visual outliers and by I² statistics. Results Out of 196 articles coming up from the search, ten studies met all inclusion criteria, six of which were (randomized) controlled trials. Together these studies report on a total of 294 participants receiving WBC. The within-group pooled effect size for mental health problems is large (Hedges’ g = 1.63, CI: 1.05-2.21), with high heterogeneity (I² = 93%). Subgroup analyses on depressive symptoms and quality of life (QOL) showed a diminution of heterogeneity to moderate. Effect sizes for depressive symptoms are very large (Hedges’ g = 2.95, CI: 2.44-3.45) and for QOL medium (Hedges’ g = 0.70, CI: 0.15-1.24). The between-group pooled effect size is medium (Hedges’ g = 0.76, CI: 0.17-1.36). Conclusions Results indicate preliminary evidence for WBC as efficacious add-on intervention for mental health problems, especially depressive symptoms. Further research in the form of RCTs with larger numbers of participants is needed.
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This study was conducted to investigate body mass index (BMI), levels of cholesterol and triglycerides in prison inmates at the Institution for Reform and Rehabilitation in Southern Libya to be considered as an indication about their health and the provided foods. The results of this study showed that 26.5% of BMI of the prison inmates were found to be higher than the normal levels. Generally, the average level of cholesterol and triglycerides concentrations were found to be within normal range 142.6 mg/dl and 135.4 mg/dl, respectively. The findings also established that there were a significant relationship and direct correlation between BMI levels and age and concentration of cholesterol and triglycerides levels. The results of this showed that the served foods for these prison inmates are well balanced as indicated by their cholesterol and triglycerides levels.
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Spondyloarthritis (SpA) does not display the typical features of auto-immune disease. Despite the strong association with MHC class I, CD8+ T cells are not required for disease induction in the HLA-B27/Huβ2m transgenic rats. We used Lewis HLA-B27/Huβ2m transgenic rats [21-3 × 283-2]F1, HLA-B7/Huβ2m transgenic rats [120-4 × 283-2]F1, and wild-type rats to test our hypothesis that SpA may be primarily driven by the innate immune response. In vitro, splenocytes were stimulated with heat-inactivated Mycobacterium tuberculosis and cytokine expression and production was measured. In vivo, male and female rats were immunized with 30, 60, or 90 µg of heat-inactivated M. tuberculosis and clinically monitored for spondylitis and arthritis development. After validation of the model, we tested whether prophylactic and therapeutic TNF targeting affected spondylitis and arthritis. In vitro stimulation with heat-inactivated M. tuberculosis strongly induced gene expression of pro-inflammatory cytokines such as TNF, IL-6, IL-1α, and IL-1β, in the HLA-B27 transgenic rats compared with controls. In vivo immunization induced an increased spondylitis and arthritis incidence and an accelerated and synchronized onset of spondylitis and arthritis in HLA-B27 transgenic males and females. Moreover, immunization overcame the protective effect of orchiectomy. Prophylactic TNF targeting resulted in delayed spondylitis and arthritis development and reduced arthritis severity, whereas therapeutic TNF blockade did not affect spondylitis and arthritis severity. Collectively, these data indicate that innate immune activation plays a role in the initiation of HLA-B27-associated disease and allowed to establish a useful in vivo model to study the cellular and molecular mechanisms of disease initiation and progression.
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IntroductionBiomarkers complementing clinical evaluations may help to reduce the length and size of proof-of-concept (PoC) trials aimed to obtain quick ¿go/no go¿ decisions in the clinical development of new treatments. We aimed to identify and validate serum biomarkers with a high sensitivity to change upon effective treatment in spondyloarthritis (SpA) PoC trials.Methods The candidate biomarkers high sensitive-C-reactive protein (hs-CRP), interleukin-6 (IL-6), pentraxin-3 (PTX-3), alpha-2-macroglobulin (alpha-2-MG), matrix metalloproteinase-3 (MMP-3), calprotectin, and vascular endothelial growth factor (VEGF) were determined by enzyme-linked immunosorbent assay in healthy controls (n¿=¿20) and SpA patients before and after 2 weeks of infliximab (n¿=¿18) or placebo (n¿=¿19) treatment in cohort 1. Clinical outcome was evaluated at week 12. Results were validated in ankylosing spondylitis (AS) with infliximab (cohort 2, n¿=¿21) and peripheral SpA with etanercept (cohort 3, n¿=¿20).ResultsSerum levels of calprotectin, hs-CRP, PTX-3, VEGF (all P¿<¿0.001) and MMP-3 (P¿=¿0.062), but not IL-6 and alpha-2-MG, were increased in SpA versus healthy controls. Treatment with infliximab, but not placebo, significantly decreased calprotectin (P¿<¿0.001) and hs-CRP (P¿<¿0.001) levels, with a similar trend for MMP-3 (P¿=¿0.063). The standardized response mean (SRM), which reflects the ability to detect changes over time, was high for calprotectin.(¿1.26), good for hs-CRP (¿0.96) and moderate for MMP-3 (¿0.52). Calprotectin and hs-CRP, but not MMP-3, were good biomarkers for treatment response in axial and peripheral SpA as evaluated and confirmed in cohort 2 and 3 respectively.Conclusions Calprotectin and hs-CRP are good serum biomarkers with high sensitivity to change upon effective treatment at the group level in small-scale, short term PoC trials in SpA.
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Significance Hitherto, both the autonomic nervous system and innate immune system were regarded as systems that cannot be voluntarily influenced. The present study demonstrates that, through practicing techniques learned in a short-term training program, the sympathetic nervous system and immune system can indeed be voluntarily influenced. Healthy volunteers practicing the learned techniques exhibited profound increases in the release of epinephrine, which in turn led to increased production of anti-inflammatory mediators and subsequent dampening of the proinflammatory cytokine response elicited by intravenous administration of bacterial endotoxin. This study could have important implications for the treatment of a variety of conditions associated with excessive or persistent inflammation, especially autoimmune diseases in which therapies that antagonize proinflammatory cytokines have shown great benefit.
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In this case study, we describe the effects of a particular individual's concentration/meditation technique on autonomic nervous system activity and the innate immune response. The study participant holds several world records with regard to tolerating extreme cold and claims that he can influence his autonomic nervous system and thereby his innate immune response. The individual's ex vivo cytokine response (stimulation of peripheral blood mononuclear cells with lipopolysaccharide [LPS]) was determined before and after an 80-minute full-body ice immersion during which the individual practiced his concentration/meditation technique. Furthermore, the individual's in vivo innate immune response was studied while practicing his concentration/mediation technique during human endotoxemia (intravenous administration of 2 ng/kg LPS). The results from the endotoxemia experiment were compared with a historical cohort of 112 individuals who participated in endotoxemia experiments in our institution. The ex vivo proinflammatory and anti-inflammatory cytokine response was greatly attenuated by concentration/meditation during ice immersion, accompanied by high levels of cortisol. In the endotoxemia experiment, concentration/meditation resulted in increased circulating concentrations of catecholamines, and plasma cortisol concentrations were higher than in any of the previously studied participants. The individual's in vivo cytokine response and clinical symptoms after LPS administration were remarkably low compared with previously studied participants. The concentration/meditation technique used by this particular individual seems to evoke a controlled stress response. This response is characterized by sympathetic nervous system activation and subsequent catecholamine/cortisol release, which seems to attenuate the innate immune response.
In the course of developing a standardised, non-disease-specific instrument for describing and valuing health states (based on the items in Table 1), the EuroQol Group (whose members are listed In the Appendix) conducted postal surveys in England, The Netherlands and Sweden which indicate a striking similarity in the relative valuations attached to 14 different health states (see Table 3). The data were collected using a visual analogue scale similar to a thermometer (see Table 2). The EuroQol Instrument Is Intended to complement other quality-of-life measures and to facilitate the collection of a common data set for reference purposes. Others interested in participating in the extension of this work are invited to contact the EuroQol Group.
ABSTRACT– A self-assessment scale has been developed and found to be a reliable instrument for detecting states of depression and anxiety in the setting of an hospital medical outpatient clinic. The anxiety and depressive subscales are also valid measures of severity of the emotional disorder. It is suggested that the introduction of the scales into general hospital practice would facilitate the large task of detection and management of emotional disorder in patients under investigation and treatment in medical and surgical departments.
Spondyloarthritis (SpA) is a chronic immune-mediated inflammatory disease of unknown origin. Here we aim to review whether SpA is driven by T-cell and/or B-cell autoreactivity or by abnormal innate immune responses. SpA does not share genetic risk factors, female predominance, presence of disease-specific autoantibodies and response to T-cell or B-cell-targeted therapies with prototypical autoimmune diseases like rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Growing evidence indicates that increased responsiveness of innate immune cells such as macrophages, mast cells and neutrophils drives inflammation in SpA. The altered innate immune response may be related to nonantigen-presenting functions of HLA-B27, including the induction of an unfolded protein response, and can be triggered by bacterial and mechanical stress. Innate immune cells appear to be the main producers of both pro-inflammatory (tumor necrosis factor, IL-1, IL-23, IL-17) and anti-inflammatory (IL-10) cytokines in SpA. The predominance of myeloid above lymphoid alterations suggests an autoinflammatory rather than autoimmune origin of inflammation in SpA. Therefore, targeting innate cells or their inflammatory mediators may be more effective than T-cell or B-cell-directed therapies.