Arthrocentesis

Resource and cost data were gathered as part of the “Cost of Haemophilia across Europe – a Socioeconomic Survey (CHESS)”, a prospective observational study in severe haemophilia A and B across five European countries (France, Germany, Italy, Spain, and the United Kingdom) undertaken in 2015 [15 (link)]. One hundred and thirty-nine haemophilia specialists provided demographic and clinical information for 1285 adults (≥18 years) via a web-based survey. A corresponding questionnaire covering indirect costs and health-related quality of life (HRQOL) measures was completed by patients.
Non drug-related direct costs (NDDCs) were an amalgam of 12-month ambulatory and secondary care costs gathered within the CHESS study, specifically incorporating: haematologist and other specialist consultant consultations, medical tests and examinations, surgeries relating to joint damage, bleed-related hospital admissions, and payments to professional care providers [15 (link)]. A unit cost database was developed for each country using publicly available information. A breakdown of individual cost elements of NDDCs is presented in Table 1.Table 1

National costs for CHESS resource units

Resource item	Baseline unit price (EUR)
	Francea	Germanyb	Italyc	Spaind	UKe
Ambulatory care
Haematologist visit (per visit)	25.99–45.99	20.88	27.32–23.17	65.69–113.54	124.71–228.57
Nurse visit (per visit)	81.74	34.28–38.42	15.11	20.92–37.46	19.36
Other specialist visit (per visit)	14.99–45.99	7.30–228.88	18.21–27.32	16.42–160	65.91–612.03
Blood test (per test)	1.89–53.96	0.50–112.50	2.11–17.22	4.78–98.37	4.29–7.67
Other test/examination (per test)	10.79–69.00	5.50–124.60	2.19–134.27	7.49–249.21	1.69–228.24
Hospitalisation
Target joint surgery† (per surgery)	28.81–534.40	12.02–1719.43	33.48–1032.91	169.75–2156.33	1161.93–8397.52
Bleed event: ward stay (per day)	290.85	514.29	265	708.71	562.88
Bleed event: ICU stay (per day)	1174.60	1265	366	1559.24	1056.82
Professional caregiver (per hour)	8.30	27.43	7.39	13.66	24.56

Note. Ranges presented where more than one price is possible; ICU: intensive care unit; IU: International Units

†Arthrocentesis, arthrodesis, arthroplasty, arthroscopy, synovectomy

^aSources: Ameli, sante.gouv, ViDAL.fr, Catalogue Commun des actes médicaux

^bSources: Kbv.de, meinpharmaversand.de, Einheitlicher Bewertungsmaßstab, rote-liste service

^cSources: AIFA, agenziafarmaco.gov

^dSources: Oblikue e-salud, Agencia Española de Medicamentos y Productos Sanitarios

^eSources: National Schedule of Reference Costs, Electronic Medicines Compendium

Study exclusion criteria was limited to patients diagnosed with an inhibitor at the time of study capture (n = 52), due to a differing risk profile for bleeds and subsequent target joint development among these patients, and a higher utilisation of medical resources [16 (link), 17 (link)].

SF samples were obtained by arthrocentesis from meta-carpophalangeal (MCP) joints of 8 horses with OA and 8 horses without joint diseases at the Veterinary Teaching Hospital, University of Helsinki. Most of the horses were of warmblood breeds, but 1 Standardbred and 1 Estonian riding pony were also included. Informed owner consent was obtained for each animal, and ethical approval for SF collection and use was provided by the Viikki Campus Research Ethics Committee of the University of Helsinki (Statement 1/2018). The sampling was conducted immediately after medically-induced euthanasia (0.01–0.02 mg/kg detomidine hydrochloride, 0.01–0.02 mg/kg butorphanol tartrate, 0.05–0.1 mg/kg midazolam, 2.2 mg/kg ketamine hydrochloride, T-61 euthanasia solution) due to lameness or non-OA-related reasons including colic, back pain, leg injury, wound, sinusitis, neurological disease, and guttural pouch mycosis. The decisions to euthanize the animals had been made previously without any relation to the research protocol or sampling. The unprocessed SF samples were immediately frozen in liquid nitrogen and stored at –80°C until analysed. MCP OA was diagnosed post-mortem by experienced equine veterinarians based on the presence of wear lines, erosion of articular cartilage, and osteophytes. Joint surfaces were scored according to OA severity as follows: 0 = normal, 1 = mild OA, 2 = moderate OA, and 3 = severe OA [19 (link)]. SF samples were also harvested from CL MCP joints. Only one of them was classified as normal, and the rest had mild-to-moderate OA. In the post-mortem examination of control joints, the MCP joint surfaces either had no macroscopic abnormalities or revealed mild periarticular changes. Regarding medication, 3 control and 2 CL/OA horses had been treated with nonsteroidal anti-inflammatory drugs, 1 control and 1 CL/OA horse had received antibiotics, and 1 CL/OA horse had been treated with antifungals.

The patients were randomly separated into two groups by simple randomization method by computer. No conservative treatment was applied before arthrocentesis. Only arthrocentesis was given to patients in the control group (n:14), while the TX group (n:16) received both arthrocentesis and a 2-ml injection of tenoxicam (Oksamen-L, Mustafa Nevzat İlaç Sanayi, Istanbul, Turkey) to the temporomandibular joint (Fig. 1) The preauricular area was cleaned with 10% povidone-iodine solution. Ultracaine D-S Forte® (Sanofi-Aventis, İstanbul, Turkey) was used as a local anesthetic. The entry point was along the lateral canthus-tragus line (Holmlund-Hellsing line), 10 mm away from the anterior tragal midline and 2 mm under it. The second point was along the lateral canthus-tragus line, 20 mm away from the anterior tragal midline and 10 mm under it [22 ].Fig. 1

Arthrocentesis procedure

Preoperative measurements and arthrocentesis procedures were performed by the same surgeon (GYY). All patients were irrigated with approximately 100 ml of Ringer’s lactate. In the control group, no additional injections were given, but in the TX group, 2 ml(20 mg) of tenoxicam was injected intraarticularly following arthrocentesis. A drug containing paracetamol was prescribed to relieve post-procedure pain. A soft diet was recommended to the patients. Physical therapy, occlusal splint or other preventive treatments were not applied during the follow-up period. The form in which the data of the patients is processed is given in Fig. 2.Fig. 2

A patient form sample

Patients were followed for 6 months. The outcome variables were pain scores on a visual analog scale (VAS), VAS joint sounds (crepitus sounds), and maximum mouth opening (MMO), which were measured at baseline, one week, one month, three months, and six months after the arthrocentesis. To measure the VAS value, a 10-cm-long numbered line was created. The patient chose a point on the line, the corresponding value was measured with a ruler, and a score was given. MMO was gauged between the incisal edges of the maxillar and mandibular central incisors. Outcome variables were evaluated postoperatively by the surgeon (AK), who was unaware of the treatment procedures for all patients.

Patients with JIA were enrolled at the University Medical Center Utrecht (The Netherlands) (Supplementary file 1). A total of nine JIA patients were included in this study. Of these, n=2 were diagnosed with extended oligo JIA, n=2 with rheumatoid factor negative poly-articular JIA, and n=5 with oligo JIA, according to the revised criteria for JIA (Petty et al., 1998 (link)). The average age at the time of inclusion was 13.1 years (range 3.2–18.1 years) with a disease duration of 7.3 years (range 0.4–14.2 years). Patients included for CyTOF and TCR sequencing analysis of two affected knee joints were all treated with non-steroidal anti-inflammatory drugs (NSAIDs) or methotrexate, but no biologicals at the time of sampling. For sequential TCR sequencing analysis, we included patients with a relapsing disease course. At the first time point, all patients were treated with NSAIDs or methotrexate, but no biologicals. During the follow-up (after experiencing a relapse of disease), patients were treated with disease-modifying anti-rheumatic drugs (leflunomide) and/or biologicals (humira).
PB of JIA patients was obtained via veni-puncture or intravenous drip, while SF was obtained by therapeutic joint aspiration of affected joints. Informed consent was obtained from all patients either directly or from parents/guardians when the patients were younger than 12 years of age. The study was conducted in accordance with the Institutional Review Board of the University Medical Center Utrecht (approval no. 11-499/C), in compliance with the Declaration of Helsinki. PB from n=3 healthy children (average age 15.1 years with range 14.7–15.4 years) was obtained from a cohort of control subjects for a case-control clinical study (Supplementary file 1).