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

Anti-inflammatory actions of glucocorticoids Barnes PJ. 19981

• 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

Anti-inflammatory actions of glucocorticoids Barnes PJ. 19981

• GC inhibit the expression of multiple inflammatory genes

Anti-inflammatory actions of glucocorticoids Barnes PJ. 19981

• GC appear to inhibit cytokine gene expression by inhibiting transcription factors that regulate their expression, rather than by binding to their promotor regions.

Anti-inflammatory actions of glucocorticoids Barnes PJ. 19981

• 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.

Anti-inflammatory actions of glucocorticoids Barnes PJ. 19981

• 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.

Anti-inflammatory actions of glucocorticoids Barnes PJ. 19981

• 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.

Anti-inflammatory actions of glucocorticoids Barnes PJ. 19981

• 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.

Anti-inflammatory actions of glucocorticoids Barnes PJ. 19981

• Systemic GC increase pheripheral neutrophil counts, which may reflect the increased survival time due to an inhibitory action of neutrofil apoptosis.

Anti-inflammatory actions of glucocorticoids Barnes PJ. 19981

• 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.

Anti-inflammatory actions of glucocorticoids Barnes PJ. 19981

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

Anti-inflammatory actions of glucocorticoids Barnes PJ. 19981

• 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.

Anti-inflammatory actions of glucocorticoids Barnes PJ. 19981

• Rarely patients with chronic inflammatory diseases fail to respond to GC but there are however patients with GC resistance.

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

2

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.

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

Conclusion: 5-HT in the TMJ synovial fluid is associated with pain perceived upon movement of the joint and to decreased mandibular mobility

Pain and synovial fluid concentration of serotonin in arthritic temporomandibular joints. Alstergren P, Kopp S. 1997

3

4Immediate 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).

4Immediate 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).

Median IQR n

Age (years) 50 18 20

Duration of general joint involvem ent (years) 10 14 20

Duration of local TMJ involvem ent (years) 5 11 19

Num ber of involved joints (1 - 9) 6 3 20

Throm bocyte particle concentration (10 9/L) 289 95 14

% of patients

Erythrocyte sedim entation >28 m m /h (norm al: < 28 m m /h) 0

C-reactive protein >10 m g/L (norm al: < 10 m g/L) 19

Throm bocyte particle concentration >400 10 9/L (norm al: 150 - 400 10 9/L) 14

IQR = 25 th- 75 th percentile, n = num ber of patients

Table 1. Pretreatm ent data of 20 patients with chronic inflam m atory joint disease subjected to intra-articular glucocorticoid injections .

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

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.

C-reactive protein (mg/L) 0 0 16 20 0 12 13 38 n.s.

TMJ pain intensity

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.

Number of painful mandibular movements 3 1 20 90 2 2 20 80 n.s.

Tenderness to digital palpation

Lateral 1 1 20 95 1 1 20 60 0.028

Posterior 1 1 20 65 1 1 20 50 n.s.

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 20 55 13 667 20 65 n.s.

Serum (nmol/L) 898 506 14 100 670 547 11 91 n.s.

Plasma (nmol/L) 37 23 10 100 17 20 6 100 n.s.

Pretreatment Follow-up

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.

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.

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).

1A

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).

1B

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).

2A

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).

2B

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.