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Glukokortikoid vid behandling av
käkledssjukdomar Finns koppling till serotonin?
Lars Fredriksson
I.
Anti-inflammatory actions of glucocorticoids
Barnes PJ. 1998
II.
Short-term effects of intra-articular sodium
hyaluronate, glucocorticoid, and saline
injections on rheumatoid arthritis of the
temporomandibular joint Kopp S, Akerman
S, Nilner M. 1991
III. Pain and synovial fluid concentration of
serotonin in arthritic temporomandibular
joints. Alstergren P, Kopp S. 1997
IV. Immediate effects of the serotonin antagonist
granisetron on temporomandibular joint pain
in patients with systemic inflammatory
disorders. Voog O, Alstergren P, Leibur E,
Kallikorm R, Kopp S. 2000
1
Anti-inflammatory actions of glucocorticoids Barnes PJ. 1998
• GC are widely used for the suppression of
inflammation in chronic inflammatory
diseases such as asthma, RA, inflammatory
bowel disease and autoimmune diseases, all
with increased expression of inflammatory
genes.
Anti-inflammatory actions of glucocorticoids Barnes PJ. 1998
• GC bind to GC-receptors in the cytoplasm
which then dimerize and translocate to the
nucleus, where they bind to GC response
elements (GRE) on GC-responsive genes,
resulting in increased transcription for genes
coding for anti-inflammatory proteins
GC-receptor (GR)
•GCS bind to GR in the cytoplasm which then dimerize and translocate to the nucleus,
where they bind to GC response elements (GRE) on GC-responsive genes, resulting in
increased transcription for genes coding for anti-inflammatory proteins
560-561
1
Anti-inflammatory actions of glucocorticoids Barnes PJ. 1998
• GC inhibit the expression of multiple
inflammatory genes
1
Anti-inflammatory actions of glucocorticoids Barnes PJ. 1998
• GC appear to inhibit cytokine gene
expression by inhibiting transcription
factors that regulate their expression, rather
than by binding to their promotor regions.
1
Anti-inflammatory actions of glucocorticoids Barnes PJ. 1998
• GC decrease the transcription of genes
coding for certain receptors that are
involved in the inflammatory process.
GC increase the
syntesis of
lipocortin-1, that
has inhibitory
effect on
phospholipas A2
and therefore
inhibit the
production of
lipid mediators as
well as inhbit
genes coding for
COX-2.
1
Anti-inflammatory actions of glucocorticoids Barnes PJ. 1998
• GC reduce the survival of eosinophils and
T-lymfocytes, since eosinophils are
dependent of IL-5 and GM-CSF which are
blocked by GC which leads to apoptosis of
eosinophils and T-lymfocytes.
1
Anti-inflammatory actions of glucocorticoids Barnes PJ. 1998
• Adhesion molecules play a key role in
trafficking of inflammatory cells to the sites
of inflammation. The expression of many
adhesion molecules on endothelial cells is
induced by cytokines and GC may
indirectly to a reduced expression via their
inhibitory effects on cytokines such as IL1beta and TNF-alfa.
1
Anti-inflammatory actions of glucocorticoids Barnes PJ. 1998
• Inhaled GC reduce the secretion of
chemokines and pro-inflammatory
cytokines from alveolar macrophages in
patients with asthma. Oral prednisolone
inhibits the increased gene expression of ILIbeta.
1
Anti-inflammatory actions of glucocorticoids Barnes PJ. 1998
• Systemic GC increase pheripheral
neutrophil counts, which may reflect the
increased survival time due to an inhibitory
action of neutrofil apoptosis.
1
Anti-inflammatory actions of glucocorticoids Barnes PJ. 1998
• GC inhibit the increased transcription of the
IL-8 gene induced by TNF-alfa in cultured
human airway epithelial cells in vitro.
• GC decrease the transcription of
inflammatory proteins including iNOS,
COX-2, cPLA2 and endothelin-1.
1
Anti-inflammatory actions of glucocorticoids Barnes PJ. 1998
• GC do not appear to have a direct inhibitory
effect on mediator release from mastcells.
1
Anti-inflammatory actions of glucocorticoids Barnes PJ. 1998
• GC may inhibit several aspects of neurogenic
inflammation including the synthesis of tachykinins by
repression of the preprotachykinin-A gene, reduced
expression of tachykinin receptors and by increasing
expression of neural endopeptidase which degrades
tachykinins.
1
Anti-inflammatory actions of glucocorticoids Barnes PJ. 1998
• Rarely patients with chronic inflammatory
diseases fail to respond to GC but there are
however patients with GC resistance.
2
Short-term effects of intra-articular sodium hyaluronate, glucocorticoid, and saline
injections on rheumatoid arthritis of the temporomandibular joint Kopp S, Akerman S,
Nilner M. 1991
AIM: To investigate the short-term subjective and clinical effects of sodium
hyaluronate on TMJ arthritis in individuals with RA and to compare these effects
with those of glucocorticoid and saline.
M and M: Forty-one patients with RA. Three groups: HA gruop n=14, CO group
n=14, SA group n=13.
RESULTS:
After treatment
Fig 1. 75% of the patients in the CO group were much improved or symptom
free.
Subjective symptoms (VAS) decreased with 34 mm in the CO group.
Pain at rest was significantly lower in the CO group.
Tenderness to digital palpation of the lateral and posterior aspect were
significantly eliminated or reduced in the CO group.
The maximum voluntary moth opening was increased by 6 mm in the CO group.
2
Short-term effects of intra-articular sodium hyaluronate, glucocorticoid, and saline
injections on rheumatoid arthritis of the temporomandibular joint Kopp S, Akerman S,
Nilner M. 1991
Conclusion: Sodium hyaluronate has a benefical effect on
subjective symptoms as well as clinical signs of TMJ
arthritis in patients with chronic RA, although not as good as
that of glucocorticoids.
3
Pain and synovial fluid concentration of serotonin in arthritic temporomandibular joints.
Alstergren P, Kopp S. 1997
AIM: To investigate the relation between 5-HT in the synovial fluid and pain of
arthritic TM joints.
M and M: Eleven patients with chronic inflammatory joint disease. One male
and 10 females (22 joints).
RESULTS:
After treatment
PM was positively correlated to SF-5-HT on the corresponding side (r = 0.51, P
= 0.014, n = 22) Fig 1.
The maximum voluntary mouth opening capacity was negatively correlated to
the SF-5-HTSum when the influence of S-5-HT was acconted for (rP = -0.73, P =
0.012, n = 11) .
3
Pain and synovial fluid concentration of serotonin in arthritic temporomandibular joints.
Alstergren P, Kopp S. 1997
Conclusion: 5-HT in the TMJ synovial fluid is associated
with pain perceived upon movement of the joint and to
decreased mandibular mobility
4
Immediate effects of the serotonin antagonist granisetron on temporomandibular joint pain
in patients with systemic inflammatory disorders. Voog O, Alstergren P, Leibur E,
Kallikorm R, Kopp S. 2000
AIM: To investigate if the 5-HT3 receptor antagonist granisetron reduces TMJ
pain in patients with systemic inflammatory joint disease.
M and M: Sixteen patients with chronic inflammatory joint disease. Four males
and 12 females. Table 1.
RESULTS:
After treatment with granisetron
Granisetron group: VASRest was decreased 10 minutes after i.a. injection of
granisetron (p = 0.028) but not after 20 minutes (Fig. 1). VASMVM was decreased
after 20 minutes (p = 0.002), but not after the first 10 minutes (Fig.2). PPT was
increased after 20 minutes (p = 0.036).
Difference between groups: VASRest before injection was similar in both groups.
The patients in the granisetron group had signoficantly lower VASRest than the
patients in the saline group 10 minutes after injection (p = 0.033; Fig. 1).
4
Immediate effects of the serotonin antagonist granisetron on temporomandibular joint pain
in patients with systemic inflammatory disorders. Voog O, Alstergren P, Leibur E,
Kallikorm R, Kopp S. 2000
Conclusion: Granisetron has an immediate, shortlasting and
specific pain reducing effect in TMJ inflammatory arthritis.
The 5-HT3 receptor may therefore be involved in the
mediation of TMJ pain in systemic inflammatory joint
disorders.
Serotonergic mechanisms influence the
response to glucocorticoid treatment in
TMJ arthritis
Lars Fredriksson, DDS, PhD Student, Per Alstergren DDS,
PhD, Associate Professor, Sigvard Kopp, DDS, PhD,
Professor and Chairman
AIM
• To investigate the influence of synovial
fluid and blood levels of 5-HT on the effects
by intra-articular injections of
glucocorticoid on pain and allodynia of the
TMJ in patients with chronic and systemic
inflammatory disorders of the TMJ.
Materials and Methods
• One male and nineteen female patients with
inflammatory TMJ disorders participated
(Table 1).
Table 1. Pretreatment data of 20 patients with chronic inflammatory joint disease subjected to
intra-articular glucocorticoid injections.
Median
IQR
n
Age
(years)
50
18
20
Duration of general joint involvement
(years)
10
14
20
Duration of local TMJ involvement
(years)
5
11
19
(1 - 9)
6
3
20
(10 9 /L)
289
95
14
Number of involved joints
Thrombocyte particle concentration
%
of patients
Erythrocyte sedimentation >28 mm/h
C-reactive protein >10 mg/L
9
Thrombocyte particle concentration >400 10 /L
th
th
IQR = 25 - 75 percentile, n = number of patients
(normal: < 28 mm/h)
0
(normal: < 10 mg/L)
19
9
(normal: 150 - 400 10 /L)
14
Results
Treatment effect
Table 2 shows the pretreatment and follow-up values of the
clinical variables and synovial fluid levels of 5-HT.
Table 2. General and local (temporomandibular joint; TMJ) disease activity before and five weeks after
intra-articular administration of glucocorticosteroid in 20 patients with chronic inflammatory joint
disease.
Pretreatment
Table 2
Follow-up
Median IQR
n %>0
Median IQR
n %>0
p
General disease activity
General joint pain intensity
(VAS score)
46
33
20 100
30
36 15
87
n.s.
Erythrocyte sedimentation rate
(mm/first h)
9
11
16 100
18
16 15 100
n.s.
(mg/L)
0
0
16
20
0
12 13
38
n.s.
At rest
(VAS score)
50
41
20
95
25
42 20
80
0.028
Upon maximal mouth opening
(VAS score)
51
40
13 100
37
40 13
92
n.s.
3
1
20
90
2
2 20
80
n.s.
Lateral
1
1
20
95
1
1 20
60
0.028
Posterior
1
1
20
65
1
1 20
50
n.s.
C-reactive protein
TMJ pain intensity
Number of painful mandibular movements
Tenderness to digital palpation
Pressure-pain threshold
Temporomandibular joint
(kPa)
136
95
20 100
141 104 20 100
n.s.
Glabella
(kPa)
240
94
14 100
237 119 14 100
n.s.
Serotonin levels
Synovial fluid
(nmol/L)
16 126
Serum
(nmol/L)
898 506
Plasma
(nmol/L)
37
23
20
55
13 667 20
65
n.s.
14 100
670 547 11
91
n.s.
6 100
n.s.
10 100
17
20
Pain intensity was assessed with a 100-mm visual analogue scale (VAS), the number of mandibular
movements that provoked pain in the TMJ (maximum mouth opening, laterotrusion to both sides and
protrusion) was counted for each side, tenderness to digital palpation of the lateral and posterior
aspects of the TMJ on each side was recorded as one unit if the patient reported tenderness and two
units if the palpation caused a pain reflex, the pressure-pain threshold was recorded over the palpable
lateral pole of the TMJ condyle and over glabella, n.s. = not significant. IQR = 25th- 75th percentile, n =
number of patients, %>0 = percent observations exceeding 0.
1A
Change in temporomandibular
joint (TMJ) resting pain intensity
(A) after intra-articular
glucocorticoid treatment in 9
patients with undetectable and 11
patients with detectable
pretreatment levels of serotonin
(5-HT) in the TMJ synovial fluid
and chronic inflammatory joint
disease. There was a negative
correlation between 5-HT and
change in resting pain after
treatment (rs = -0.52, n = 20, p =
0.018).
1B
Change in TMJ pain intensity on
mouth opening (B) in 8 patients
with undetectable and 5 patients
with detectable pretreatment
levels of 5-HT in TMJ synovial
fluid and chronic inflammatory
joint disease. There was a
negative correlation between 5HT and change in pain intensity
on mouth opening after treatment
(rs = -0.57, n = 13, p = 0.041).
2A
Pretreatment plasma levels of
serotonin (5-HT) in patients with
chronic inflammatory joint
disease, 7 with a decrease and 3
with an increase of
temporomandibular joint (TMJ)
resting pain intensity (A) after
intra-articular glucocorticoid
treatment. There was a positive
correlation between 5-HT and
change in resting pain intensity
after treatment (rs = 0.66, n = 10,
p = 0.040).
2B
Pretreatment plasma level of 5HT in 5 patients with a decrease
and 5 patients with an increase of
TMJ pressure-pain threshold (B)
after this treatment. There was a
positive correlation between 5HT and change in pressure-pain
threshold after treatment (rs =
0.83, n = 10, p = 0.003).
Conclusions
• This study shows that local and systemic
serotonergic mechanisms partly determine
the effect of intra-articular glucocorticoid
treatment on TMJ pain in patients with
chronic TMJ arthritis of systemic nature,
while change in pressure pain threshold
over the TMJ are influenced by systemic
serotonergic mechanisms.