TMJ Arthroscopic Lysis and Lavage Compared to Operative Arthroscopy in Disc Displacement With Reduction.

1. BACKGROUND The temporomandibular joint (TMJ) is a bilateral joint comprised of two cartilage covered bone surfaces that articulates against each other during mouth opening and closing. A dense cartilage disc is situated between the two joint surfaces creating two separate joint compartments. Disc displacement (DD) is characterised by an improper position of the TMJ disc relative to the articulating surfaces and affects up to 30% of the population. DD with reduction (DDwR) is a sub-diagnosis of DD where the disc has got displaced, often in an anteromedial direction. During mouth opening the disc reduces into its right position with a snapping sound and on mouth closing the disc dislocates again. DDwR is often not affecting the patient but under somewhat unclear circumstances it might sometimes create pain and severe functional disability. A recent Swedish publication has shown that patients with TMJ disorders had significantly more days of work disability (2-3 times more) compared to a non-TMD cohort followed over a ten year period. The reliance on social security benefits in the group of patients that had TMJ surgery more than once were more accentuated compared to other TMJ disorder patients. The primary treatment for DDwR is non-surgical, most often physiotherapy and/or occlusal splint therapy. If non-surgical treatment fails the Swedish National Board of Health and Welfare primarily recommends open joint surgery, discectomy. TMJ arthroscopy in this situation has been assessed with a low level of evidence, thus not primarily recommended. Although, there are several publications rating arthroscopy as a potentially good DDwR treatment, but these publications often present their results mixing several TMJ diagnoses and most often in the form of retrospective case series, making clear conclusions hard to make. Another problem with present studies on TMJ arthroscopy due to DDwR is that successful treatment seldom is predefined as parameters to be fulfilled considering both clinical measurements and patient reported outcome. Instead, one parameter after another is analysed in singularity, which unfortunately do not give the reader the whole picture. Although, in a couple of studies a weighted success rate is demonstrated where arthroscopy seems very successful treating DDwR with rates between 81-90 %. This is well in parity with earlier studies on discectomy declaring around 85% success rate.When comparing the two different surgical methods discectomy and arthroscopy, arthroscopy is less invasive, almost no negative side effects, shorter operating time, and shorter rehabilitation and sick-leave. Arthroscopic treatment of DDwR has been described with two different methods, arthroscopic lysis and lavage (ALL) and operative arthroscopy with anterior release (OAA), never compared with each other in a randomised controlled fashion. ALL is performed with a rod-shaped lens inserted into the TMJ cavity enabling direct visualisation, The operative procedure involves manipulation of disc position, semi-blind release of adhesions (lysis), and irrigation (lavage) of the joint with either saline solution or Ringer's solution. Generally the procedure is performed under general anaesthesia, but there are reports on ALL performed in local anaesthesia or conscious sedation. OAA is basically an ALL expanded with an extra instrument canal/working cannula inserted into the TMJ enabling ablation of the anterior disc attachment and scarification (coagulation) of the posterior attachment under direct visualisation. The OAA procedure is performed under general anaesthesia. Comparing ALL and OAA has been done in a retrospective manner, and in patients with DDwR there were a 30% difference in MIO postoperative at 6 months in favour of OAA and almost the same difference when considering TMJ pain. Synovial fluid from the TMJ has been used since the mid-90's mostly for analysing inflammatory markers. Proteomics is a relatively new technique for analysing protein profiles and has only been applied a couple of times in the field of TMJ pathology. Since the aetiology of DD is still not known, proteomics provides a comprehensive insight of the protein profile of TMJ disorders. There are no RCT's comparing the outcome of ALL and OAA in patients with DDwR. The aim of this study is to evaluate outcome of ALL and OAA in treating DDwR in a double-blind fashion. A secondary aim is to describe the protein profile in patients with DDR and to see if patient-specific differences might be connected to surgical outcome, local inflammation, or local pain.
2. HYPOTHESIS/RESEARCH QUESTIONS OAA has a superior outcome compared to ALL treating patients with DDwR. The outcome will be longitudinally evaluated with a combination of maximum mouth opening capacity, patient reported TMJ pain and TMJ disability, and Quality of life (QoL) questionnaires at pre-determined time-points during a 24-month postoperative period. The primary research question is which of the two surgical methods that best improves the above stated variables. Secondary questions are:

• Is there an identifiable protein profile regarding DDwR.
• could any pre- or peri-operative variable/-s be identified as a predictor for outcome.
• what is the impact from DDwR on QoL and the surgical outcomes impact on QoL.
• are there any differences in how fast the patient recover after ALL and OAA, respectively.
• has the discs position been altered due to applied surgical intervention.
• can the patient-reported variable "TMJ disability" work as a possible substitute for JFSL-8.

1. METHODS 3.1. Study design

Randomised, double-blind, controlled trial where the outcome of ALL and OAA treatment due to DDwR is compared.

3.2. Data source

All patients referred to the Department of Oral- and Maxillofacial Surgery, Karolinska University Hospital, Stockholm, with the diagnosis DDwR and with a history of not responding to non-surgical treatment will be screened for inclusion.

3.3 Exposure/Intervention

Patients will be randomly assigned to either ALL or OAA. Both treatments will be performed under general anaesthesia. The randomisation will be made in blocks of two in a 1:1 ratio. A computer software provided by KTA (Karolinska Trial Alliance) will handle the randomisation process. At time of surgery, when the patient is under general anaesthesia and draped in sterile cloth, the patient will be allocated to either ALL or OAA. In this manner the intervention or placebo treatment will be blinded to the patient but not to the surgeon. The person evaluating the outcome of surgery (the assessor) will not know which treatment the patient has undertaken. The two surgical procedures are described below.

ALL: The surgical procedure is performed according to the original description of the technique. During the operation the joint space is irrigated with a minimum of 300 mL saline solution. A pressure infuser (InfuseITTM) set at 175 mmHg will be used to standardise the irrigation pressure. At the start of joint irrigation, the first 50 mL outflow irrigation fluid will be collected in a sterile container for later proteomic analysis. An extra stab incision will be performed approximately 2 cm ventral to the preauricular incision, in order to mimic an OAA intervention, please see below. At the end of surgery, the joint is flushed with 10 mL of Marcaine-Adrenaline (5.0 mg/mL). No other medication will be injected or otherwise introduced into the joint compartment. The incisions are sutured with a single non-resorbable suture, and a wound dressing is put over the incision. The described intervention is standardized and takes 20-30 minutes.

OAA: a description of the technique was made by McCain et al. The operation follows the steps of ALL, but adds instrumentation (coblation probe, Reflex Ultra 45, ArthroCare) of the joint under direct visualisation. An anterolateral release of the disc attachment is performed, the disc is mobilised with the blunt obturator, and a scarification/coagulation of the posterior ligament is performed with the coblation probe. During the operation the joint space is irrigated with a minimum of 300 mL saline solution. A pressure infuser (InfuseITTM) set at 175 mmHg will be used to standardise the irrigation pressure. At the start of joint irrigation, the first 50 mL outflow irrigation fluid will be collected in a sterile container for later proteomics. Finally, the joint is flushed with 10 mL of Marcaine-Adrenalin (5.0 mg/mL) and the incisions sutured with a single non-resorbable suture each. The intervention takes 30-40 minutes.

To keep the blinding intact for the patient and the assessor, the medical chart will be written as if all the patients had ALL performed.

Both the intervention groups will have postoperative physiotherapy training for a period of one month from the day after surgery in accordance with a specified home exercise program (see attachment). If needed, the home exercise program can be prolonged or individually adjusted after the first month for up to an additional month. If the patient uses an occlusal splint prior to surgery the splint may have to be adjusted and that has to be performed by the assessor.

After approximately 6 months postoperatively an MRI will be performed to monitor the discs position.

3.4. Outcome

Please, see "Outcome measures" below.

3.5. Sample size

48 patients in each intervention group, i.e. 96 patients in total, in accordance with the power analysis, see "Statistical analysis".

3.6. Inclusion and exclusion criteria

Please, see "Eligibility" below.

3.7. Data collection

At registration for surgery and after obtained informed consent, baseline data is collected by the surgeon designating the patient to surgery (see attachment). Predetermined follow-up visits are at 1 week when the surgeon will remove the stich and do a reinstruction for the home-exercise program, and at 1, 3, 6, 12, and 24 months postoperative when the assessor examine the patient according to the specific exam protocol (see attachment). The assessor/-s will be calibrated alongside the surgeon/-s before the start of the study in accordance with the DC/TMD criteria. At 6-month intervals the surgeons and assessors will have a meeting for re-calibrating purposes. To determine any change in disc position an MRI will be performed approximately 6 months postoperative.

Objective data only registered preoperative: name, personal identification number, age, sex, affected joint (left, right).

Objective data registered both pre- and post-operatively: MIO with and without pain (mm), lateral excursive movement (mm), protrusion (mm), pain upon palpating masticatory muscles, pain upon lateral joint palpation.

Subjective data registered both pre- and post-operatively: patient-reported TMJ disability (NRS 0-10), patient-reported TMJ pain (NRS 0-10), patient-reported psycho-social impairment because of TMJ disorder (NRS 0-10), patient-reported global pain (NRS 0-10), and quality of life questionnaire EQ-5D-5L, JFSL-8, and OHIP 14-S.

Perioperative data: antibiotic prophylaxis (yes/no), performed surgery (ALL/OAA), maximum assisted mouth opening (mm), duration of surgery (min), duration of general anaesthesia (min), lavage volume (mL), preauricular swelling due to lavage (yes/no), negative event during and due to surgery. Grading of intraarticular conditions will be made according to the scale proposed by Gynther et al.: synovitis (0-3), degenerative changes (0-3), and fibrosis/adhesions (0-2).[36, 37]

3.8 Revelation of blinding

At the 6-month visit the patients will be asked if they believe that they had ALL or OAA. The assessor will also give their opinion in that matter. After the 6-month follow-up, the blinding will be revealed to the patient if they want to. Patients with a non-successful outcome might be offered another therapy; non-surgical or surgical. Controls will be made at 12- and 24-months post-operative regarding all patients. Additional information about the surgical intervention (OAA) will be added to the affected patients' medical record.

3.9. Analysis of synovial fluid Proteomic analysis and protein quantification in synovial fluid will be performed at PainOmics laboratory, University hospital in Linköping. In this project, we will follow a discover and verification/validation schema. In the first step peptides and protein contents of the synovial fluid will be analysed using 2-DE in combination with mass spectrometry. With this technique it is possible to separate and quantify more than 1000 proteins and it is the only technique that allows separating and studying different protein isoforms. Quantification of the separated proteins is achieved by spot integration using specialized 2-DE software that makes it possible to compare protein patterns from different subjects/groups. Identification of the protein is performed by in-gel digestion of each protein, recovery of the fragments from the gel, and analysis by mass spectrometry (MS) using MALDI-T.

1. STATISTICAL ANALYSIS The primary objective is to evaluate the superiority of OAA compared to ALL in patients diagnosed with DDwR and not responding to non-surgical treatment. The outcome variable is dichotomous (successful/not successful) where a successful outcome in the OAA group is assessed to be 89 % and in the ALL group 64 %. With 80 % power and a 5 % significance level the groups must contain 44 patients each. Dropout rate of 10 % is accounted for which means that 48 patients/group must be included to verify superiority.

Statistical analyses will be performed using the Chi-Square test for bivariate data and the Students t-test (unpaired and paired) for mean values, as well as repeated measures ANOVA. Longitudinal data will be analysed with linear regression analysis and predictors for surgical outcome will be evaluated through logistic regression. The intention to treat analysis model will be used.

Potential known confounders may be adjusted for in the analysis and the risk of residual unknown confounders should be reduced by the randomisation process.