Glukokortikoid vid behandling av k

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Glukokortikoid vid behandling av käkledssjukdomar
- Finns koppling till serotonin?
Lars Fredriksson
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1. Anti-inflammatory actions of glucocorticoids
   Barnes PJ. 1998
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
3. Pain and synovial fluid concentration of
   serotonin in arthritic temporomandibular joints.
   Alstergren P, Kopp S. 1997
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

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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.

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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

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GC-receptor (GR)
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• 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

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560-561
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1
Anti-inflammatory actions of glucocorticoids
Barnes PJ. 1998

• GC inhibit the expression of multiple
  inflammatory genes

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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.

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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.

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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.
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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.

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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 IL-1beta and TNF-alfa.

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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 IL-Ibeta.

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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.

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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.

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1
Anti-inflammatory actions of glucocorticoids
Barnes PJ. 1998

• GC do not appear to have a direct inhibitory
  effect on mediator release from mastcells.

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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.

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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.

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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 n14, CO group n14, SA
group n13. 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.
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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.
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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) .
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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
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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).
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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.
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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
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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.

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Materials and Methods

• One male and nineteen female patients with
  inflammatory TMJ disorders participated (Table
  1).

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Results

• Treatment effect
• Table 2 shows the pretreatment and follow-up
  values of the clinical variables and synovial
  fluid levels of 5-HT.

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Table 2
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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).
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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
5-HT and change in pain intensity on mouth
opening after treatment (rs -0.57, n 13, p
0.041).
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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).
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2B
Pretreatment plasma level of 5-HT 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 5-HT and change in pressure-pain
threshold after treatment (rs 0.83, n 10, p
0.003).
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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.