Patient involvement in basic rheumatology research at Nijmegen: a three year's responsive evaluation of added value, pitfalls and conditions for success.

BACKGROUND: Empirical evidence for effective patient-researcher collaboration in basic research is lacking. This study aims to explore good working models and impact of patient involvement in basic rheumatology research and to identify barriers and facilitators. METHOD: A responsive evaluation of a three years' participatory research project in a basic and translational laboratory research setting. Several working models for patient involvement were piloted and adapted if considered necessary. The study comprised surveys, interviews, training days, meeting reports, Q-sort exercises and field notes, and regular reflective team sessions with participant involvement. A qualitative analysis using thematic coding focused on impact, barriers and facilitators. RESULTS: Thirteen patient research partners (PRPs) and fifteen basic researchers participated. PRPs experienced basic research as fascinating though complex to understand. Their initial role was mostly listening and asking questions. After several meetings equal and more meaningful relationships emerged. Researchers' motivation increased by listening to patient stories. They learned about disease impact on daily life and to speak in understandable language. This enabled PRPs to learn about research and the pathogenesis of their disease. It inspired them to stay involved over a longer period. After three years, both parties preferred 1:1 contacts over collaboration in team meetings. A common language and respectful communication were important facilitators. Limitations were the complexity of disease processes for patients and the time commitment for researchers. Impact was reported as a sincere dialogue with multiple advantages for patients and researchers, and to a lesser extent than expected on the research process and outcomes. CONCLUSION: Patient involvement contributes to motivating young scientists in performing basic research projects. Patients and researchers valued the benefits of long-term one-on-one collaboration. These benefits outweigh the lack of direct impact on basic research goals and performance. A plain language summary of the abstract is available (as) online Additional file 1.

Surgical management of deep lobe parotid tumours with and without involvement of the parapharyngeal space.

The diagnosis and treatment of deep lobe parotid tumours is challenging because of the complex surgical accessibility. There is a lack of studies describing the differences between deep lobe tumours that do and do not occupy the parapharyngeal space (PPS). Patients treated for deep lobe tumours occupying the PPS (PPS group) and not occupying the PPS (non-PPS group) were analysed retrospectively. A total of 227 patients were treated surgically for deep lobe parotid tumours between 1990 and 2019. Sixty patients (26.4%) presented with tumours that involved the PPS (PPS group), while 167 (73.6%) presented with tumours that did not occupy the PPS (non-PPS group). The majority of the PPS group tumours were removed using a transcervical or transcervical-transparotid approach. PPS group tumours were larger (P < 0.001), and tumour spill occurred more frequently in this group (benign tumours: P = 0.002; malignant tumours: P = 0.033). Complication rates did not differ between the PPS and non-PPS groups. A transcervical or transcervical-transparotid approach is the preferred method for the management of deep lobe parotid tumours that occupy the PPS in our practice. Tumour spill occurred more frequently in the PPS group, which is most probably due to the larger tumour size and more complex accessibility.

Effect of the dr. Bart application on healthcare use and clinical outcomes in people with osteoarthritis of the knee and/or hip in the Netherlands; a randomized controlled trial.

OBJECTIVE: To evaluate the short-term effects of use of the dr. Bart app, compared to usual care, on the number of secondary health care consultations and clinical outcomes in people with knee/hip OA in the Netherlands. METHOD: A randomized controlled design involving participants ≥50 years with self-reported knee and/or hip OA recruited from the community. The number of secondary health care consultations (primary outcome) and secondary outcomes were assessed at baseline, 3 and 6 months via online questionnaires. Data were analyzed using longitudinal mixed models, corrected for baseline values. Due to the design of this study, blinding of participants and researchers was not possible. RESULTS: In total, 427 eligible participants were allocated to either the dr. Bart group (n = 214) or usual care (n = 213). We found no difference between groups in the number of secondary (i.e., orthopaedic surgeon, rheumatologist, or physician assistant) health care consultations (incidence rate ratio (IRR) 1.20 (95% CI: 0.67; 2.19)). We found positive treatment effects of the dr. Bart app on symptoms (2.6 (95% CI: 0.4; 4.9)), pain (3.5 (95% CI: 0.9; 6.0)), and activities of daily living (2.9 (95% CI: 0.2; 5.6)) on a 0-100 scale, higher score indicating less complaints, but not in any other secondary outcome. CONCLUSION: The dr. Bart app did not change the number of secondary health care consultations compared to usual care. However, we found small positive effects (not clinically relevant) on pain, symptoms, and activities of daily living in people with knee/hip OA. TRIAL REGISTRATION: Dutch Trial Register (Trial Number NTR6693/NL6505) (https://www.trialregister.nl/trial/6505).

TGFß-mediated expression of TGFß-activating integrins in SSc monocytes: disturbed activation of latent TGFß?

INTRODUCTION: The pathophysiology of systemic sclerosis (SSc) is closely linked to overactive TGFß signaling. TGFß is produced and circulates in latent form, making its activation crucial for signaling. This activation can be mediated via integrins. We investigated the balance between active and latent TGFß in serum of SSc patients and investigated if this correlates with integrin expression on monocytes. METHODS: A TGFß/SMAD3- or BMP/SMAD1/5-luciferase reporter construct was expressed in primary human skin fibroblasts. Both acidified and non-acidified sera of ten SSc patients and ten healthy controls were tested on these cells to determine total and active TGFß and BMP levels respectively. A pan-specific TGFß1/2/3 neutralizing antibody was used to confirm TGFß signaling. Monocytes of 20 SSc patients were isolated using CD14+ positive selection, and integrin gene expression was measured using qPCR. Integrin expression was modulated using rhTGFß1 or a small molecule inhibitor of TGFBR1: SB-505124. RESULTS: SSc sera induced 50% less SMAD3-reporter activity than control sera. Serum acidification increased reporter activity, but a difference between healthy control and SSc serum was no longer observed, indicating that total TGFß levels were not different. Addition of a pan-specific TGFß1/2/3 neutralizing antibody fully inhibited SMAD3-reporter activity of both acidified and not-acidified control and SSc sera. Both HC and SSc sera induced similar SMAD1/5-reporter activity, and acidification increased this, but not differently between groups. Interestingly, expression of two integrin alpha subunits ITGA5 and ITGAV was significantly reduced in monocytes obtained from SSc patients. Furthermore, ITGB3, ITGB5, and ITGB8 expression was also reduced in SSc monocytes. Stimulation of monocytes with TGFß1 induced ITGA5 and ITGAV but lowered ITGB8 expression, whereas the use of the TGFß receptor inhibitor SB-505124 had the opposite effect. CONCLUSION: Total TGFß serum levels are not different between SSc patients and controls, but TGFß activity is. This coincides with a reduced expression of TGFß-activating integrins in monocytes of SSc patients. Because TGFß regulates expression of these integrins in monocytes, a negative feedback mechanism possibly underlies these observations.

Exploring longitudinal associations of histologically assessed inflammation with symptoms and radiographic damage in knee osteoarthritis: combined results of three prospective cohort studies.

OBJECTIVE: To explore the associations between different histologically assessed, inflammatory synovial characteristics and subsequent clinical and structural aspects in knee osteoarthritis (OA). DESIGN: Knee OA patients, ranging in stage from early to advanced, were recruited from three different ongoing studies. Synovial tissue biopsies were taken and histologically assessed for six features (four inflammatory related aspects, fibrosis and fibrin deposition). Clinical aspects (WOMAC pain, functioning and stiffness and SF-36 vitality) and structural aspects (Kellgren and Lawrence (KL)-grade, joint space narrowing (JSN; 0-3) and osteophytes (0-3), and reception of total knee replacement (TKR)) were repeatedly assessed during follow-up. Associations between histology and clinical and structural aspects were analysed using linear mixed model analyses and cox proportional hazards analysis. RESULTS: Biopsies of 83 patients (median complaint duration: 5 [2-8] years) were analysed. Follow-up was a median of 1.4 [0.8-2.7] years for clinical and 1.8 [0.2-5.2] years for structural aspects. Fibrosis and fibrin deposition were inversely correlated with the inflammatory features. A higher fibrosis score was associated with a lower scores for KL-grade, JSN and osteophytes, while higher scores for perivascular oedema, synovial lining thickness and vascularisation were associated with higher scores for structural aspects during follow-up. No associations were found between each of the histological features and any of the clinical aspects or the chance for TKR during follow-up. CONCLUSIONS: Inflammatory related histological aspects are associated with subsequent increased radiological severity in knee OA, while fibrosis seems to protect against this, providing a potential therapeutic target for OA treatment.

Lack of beneficial effects of low-dose radiation therapy on hand osteoarthritis symptoms and inflammation: a randomised, blinded, sham-controlled trial.

OBJECTIVES: Low-dose radiation therapy (LDRT) is widely used as treatment for osteoarthritis (OA) in some countries, while relatively unknown in others. Systematic literature review displayed a lack of high-level evidence for beneficial effects in clinical practice. The aim was to assess the efficacy of LDRT on symptoms and inflammation in hand OA patients in a randomised, blinded, sham-controlled trial, using validated outcome measures. DESIGN: Hand OA patients, ≥50 years, with pain ≥5 (scale 0-10) and non-responding to conservative therapy were included and randomised 1:1 to receive LDRT (6 × 1 Gy in 2 weeks) or sham (6 × 0 Gy in 2 weeks). Primary outcome was the proportion of OMERACT-OARSI responders, 3 months post-intervention. Secondary outcomes were pain and functioning (Australian/Canadian Hand Osteoarthritis Index; AUSCAN), quality of life (Short Form Health Survey; SF36) and inflammatory outcomes: erythrocyte sedimentation rate and C-reactive protein serum levels, effusion, synovial thickening and power Doppler signal on ultrasound (range 0-3). RESULTS: Fifty-six patients were included. After 3 months, no significant difference in responders was observed between groups (LDRT: 8 (29%); sham: 10 (36%); difference -7% (95%CI -31-17%)). Also, differences in clinical and inflammatory outcomes between groups were small and not significant. CONCLUSIONS: We were unable to demonstrate a substantial beneficial effect of LDRT on symptoms and inflammation in patients with hand OA, compared to sham treatment. Although a small effect can not be excluded, a treatment effect exceeding 20% is very unlikely, given the confidence interval. Therefore, in the absence of other high-level evidence, we advise against the use LDRT as treatment for patients with hand OA. CLINICAL TRIAL REGISTRATION NUMBER: NTR4574 (Dutch Trial Register).

Intravenous cyclophosphamide pulse therapy in interstitial lung disease associated with systemic sclerosis in a retrospective open-label study: influence of the extent of inflammation on pulmonary function.

Interstitial lung disease (ILD) is the primary cause of death in patients with systemic sclerosis (SSc). It is thought that chronic inflammation is a key component in SSc-ILD. Treatment, such as cyclophosphamide (CYC), targets this inflammation. We hypothesized that treatment with CYC might be more effective in the inflammatory phase. Therefore, we analyzed whether the extent of inflammation, as assessed by the proportion of ground glass compared to fibrosis, SSc disease duration, the extent of ILD, or baseline diffusion capacity of the lungs (DLCO) < 60%, modifies the effect of intravenous CYC pulse therapy (750 mg/m2) on pulmonary function (as measured by FVC, DLCO) in SSc-ILD patients, after 12, 24, and 36 months. Consecutive patients with SSc-ILD receiving CYC pulses between 2003 and 2015 were included. Pulmonary function tests were performed at 0, 6, 12, 24, and 36 months. There were 75 patients included. Forced vital capacity (FVC) (86% of predicted) and DLCO (42% of predicted) were stable after 12, 24 and 36 months of follow-up (p > 0.05). Forty-four patients completed 12 cycles of CYC. For the extent of ILD, proportion of ground glass compared to fibrosis, SSc disease duration, and baseline DLCO, there were no differences (all p > 0.05) in the course of FVC and DLCO. Treatment with CYC followed by maintenance therapy stabilizes pulmonary function in patients with SSc-ILD over a 3-year period. The extent of ILD, proportion of ground glass, SSc disease duration, and baseline DLCO < 60% did not influence the effect of CYC on pulmonary function.

Development of the Drooling Infants and Preschoolers Scale (DRIPS) and reference charts for monitoring saliva control in children aged 0-4 years.

OBJECTIVES: To develop and validate a parent questionnaire to quantify drooling severity and frequency in young children (the Drooling Infants and Preschoolers Scale - the DRIPS). To investigate development of saliva control in typically developing young children in the age of 0-4 years. To construct sex-specific reference charts presenting percentile curves for drooling plotted for age to monitor the development of saliva control in infancy and preschool age. STUDY DESIGN: The DRIPS was developed consisting of 20 items to identify severity and frequency of drooling during meaningful daily activities. Factor analysis was performed to test construct validity. A piecewise logistic regression was followed by a piecewise linear regression to construct sex-specific reference charts. RESULTS: We obtained 652 completed questionnaires from parents of typically developing children. The factor analysis revealed four discriminating components: drooling during Activities, Feeding, Non nutritive sucking, and Sleep. To illustrate the development of saliva control, eight sex-specific reference curves were constructed to plot the scores of the DRIPS by age group, at the 15th, 50th, 85th and 97th percentile. About 3-15% of the preschoolers in our cohort did not acquire full saliva control at the age of 4 years. CONCLUSIONS: With the DRIPS it is possible to validly compare and visualize the development of saliva control in an individual infant or preschooler and allow clinicians to timely initiate individually targeted interventions if children outperform.

There is a need for new systemic sclerosis subset criteria. A content analytic approach.

OBJECTIVES: Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets. METHODS: We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed. RESULTS: Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system had marginal value. Shortcomings of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold was arbitrary. Eighty-seven percent use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody-determined subsets, speed of progression, and age of onset (juvenile, elderly). CONCLUSIONS: We have synthesized an international view of the construct of SSc subsets in the modern era. We found a number of factors underlying the construct of SSc subsets. Considerations for the next phase include rate of change and hierarchal clustering (e.g. limited/diffuse, then by antibodies).

How should worsening in osteoarthritis be defined? Development and initial validation of preliminary criteria for clinical worsening in knee and hip osteoarthritis.

OBJECTIVES: There is a need to define and validate measures of clinical worsening in knee and hip osteoarthritis (OA). The objectives of this exploratory project were: (i) to characterize worsening criteria in knee and hip OA using psychometric methods; (ii) to estimate their sensitivity and specificity; and (iii) to validate and compare these criteria with worsening criteria previously described in the literature. METHOD: An Expert Group reached consensus on 10 sets of worsening criteria to be tested in observational data sets of patients with knee or hip OA who received multimodal conservative treatment. These sets included 219 patients (derivation cohort) and 296 patients (validation cohort). We estimated minimal clinically important worsening (MCIW) values for pain, function, stiffness, and patient global assessment, and tested candidate worsening criteria in the derivation cohort. Finally, using patient judgement, we examined the sensitivity and specificity of literature-based as well as candidate worsening criteria in the validation cohort. RESULTS: Literature-based worsening criteria were found to have high specificity (range 60-92%) but low sensitivity (range 22-59%). Two out of 10 candidate worsening criteria constructed by the Expert Group showed an acceptable combination of sensitivity and specificity in the derivation cohort, which was confirmed in the validation cohort (ranging from 54% to 65% and 67% to 74%, respectively). CONCLUSIONS: This is the first study to describe symptomatic worsening criteria based on expert consensus after examining the performance of candidate criteria derived from the literature applied to data in an observational study. The newly proposed worsening criteria show an acceptable combination of sensitivity and specificity.

The efficacy of hyperbaric oxygen therapy related to the clinical stage of osteoradionecrosis of the mandible.

This study aimed to evaluate the success of hyperbaric oxygen therapy (HBOT) and surgery in the treatment of mandibular osteoradionecrosis (ORN) in relation to the extent of the ORN. Twenty-seven patients with ORN were identified from a total of 509 patients with a history of primary oral or base of the tongue cancer; these patients had been treated with radiation therapy with curative intent between 1992 and 2006, with a radiation dose to the mandible of ≥50Gy. The ORN was staged according to the classification of Notani et al. The time from completion of radiation therapy to the development of ORN varied (median 3 years). Forty HBOT sessions were offered. After HBOT alone, 3 of 11 stage I lesions, 0 of 8 stage II lesions, and 0 of 8 stage III lesions had healed (P=0.0018). An absolute incidence of 5.3% ORN was found in this population. Of all sites irradiated in this study, the floor of the mouth was most associated with ORN (8.6%), whereas the cheek was least associated (0%). Based on the results of this study, HBOT can be recommended for stage I and II ORN and for selected cases of stage III ORN.

Vocal fold hyalinosis in Urbach-Wiethe disease, a rare cause of hoarseness.

BACKGROUND: Lipoid proteinosis is an autosomal recessive disorder characterized by hyalin deposits in the skin and mucosa of the upper aerodigestive tract; currently, no treatment exists. Nearly all patients experience hoarseness and speech difficulties, due to hyalin deposition in the vocal folds and diminished mobility in infiltrated lips, tongue, and palate. METHODS: We describe a patient with extensive hyalin plaques on the vocal folds, which resulted in near-aphonic hoarseness. Hyalin deposits in the vocal folds and skin were treated with laser resection. RESULTS: Both the vocal folds and skin improved in appearance, with smoother surface epithelium. However, the patient's speech remained impaired, due to extensive hyalin plaques in the mouth, tongue, and lips. The voice improved only temporarily. CONCLUSIONS: Laser resection of hyalin plaques in the vocal folds and skin is a feasible treatment for lipoid proteinosis. However, speech may remain severely limited, due to impaired tongue and lip movement.

Association between serum levels of the proinflammatory protein S100A8/A9 and clinical and structural characteristics of patients with established knee, hip, and hand osteoarthritis.

OBJECTIVES: To explore the association between S100A8/A9 serum levels with clinical and structural characteristics of patients with established knee, hip, or hand osteoarthritis (OA). METHOD: A cross-sectional exploratory study was conducted with 162 OA patients. Measures for pain, stiffness, and function included the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) questionnaire or the Australian Canadian Osteoarthritis Hand (AUSCAN) Index and for structural abnormalities, osteophytes and joint space narrowing grades. The association between S100A8/A9 and clinical or structural characteristics was analysed using linear regression or logistic regression where appropriate. RESULTS: The mean age of the OA patients was 56 years, 71% were female, and 61% had a Kellgren and Lawrence (K&L) score ≥ 2. The serum S100A8/A9 level did not differ between knee, hip, and hand OA patients and no association was found between serum S100A8/A9 and clinical characteristics. The serum S100A8/A9 level was negatively associated with the sum score of osteophytes after adjusting for sex and body mass index (BMI) [adjusted ß -0.015, 95% confidence interval (CI) -0.030 to 0.001, p = 0.062] and positively associated with erythrocyte sedimentation rate (ESR) > 12 mm/h (adjusted OR 1.002, 95% CI 1.000-1.004 p = 0.049) for each increase in S100A8/A9 of 1 ng/mL. For hand OA patients, a negative association of S100A8/A9 with sum score of joint space narrowing was found (adjusted ß -0.007, 95% CI -0.016 to 0.001, p = 0.099). CONCLUSIONS: The results from this cross-sectional exploratory study do not support an important role for serum S100A8/A9 levels as a biomarker for clinical and structural characteristics in established knee, hip, and hand OA patients. The inverse association with structural abnormalities and the positive association with ESR may reflect inflammatory synovial processes in patients with OA before structural abnormalities occur.

Frequency and impact of disease symptoms experienced by patients with systemic sclerosis from five European countries.

OBJECTIVES: Knowledge about the nature and impact of symptoms faced by patients with systemic sclerosis (SSc) is needed to identify targets for research and treatment. The aim of this study was to assess and compare the frequency and impact on everyday activities of SSc symptoms among patients from five European countries. METHODS: European patients with SSc were invited through announcements by patient associations to complete an online survey. The survey included items assessing the frequency of 40 SSc symptoms and the impact on daily activities, if present. Chi-square tests were utilised to assess the differences in frequency and impact of symptoms across countries. RESULTS: In total, 537 patients were included from France (n=111), the Netherlands (n=229), Spain (n=61), Switzerland (n=50), and the United Kingdom (n=86). Symptoms experienced by ≥ 70% of patients in all countries were fatigue, Raynaud's phenomenon, joint pain, and muscle pain. Twenty symptoms were experienced by ≥ 50% of patients in all countries. Thirty symptoms had an impact on daily activities in ≥ 50% of patients who reported that the symptom was present in all countries. There were significant differences among countries in the prevalence of 17 out of 40 symptoms. Furthermore, in 24 out of 40 symptoms significant differences in the proportion of patients reporting impact of a specific symptom on everyday activities were observed. CONCLUSIONS: European patients with SSc experience a broad range of symptoms that have an impact on everyday activities. International research initiatives should target common SSc symptoms cooperatively. Further research is needed to better understand the differences in SSc symptoms among countries.

A congenital mucocele of the anterior dorsal tongue.

We report on a new-born with a congenital mucocele on the anterior dorsal side of the tongue. The presentation as well as the differential diagnosis of congenital oral swellings is discussed. Because of breastfeeding problems the mucinous swelling was incised and drained two days after birth. Immediately after drainage the swelling disappeared. Congenital oral swellings are rare. Most of them are mucoceles. Post-partum treatment is surgically, but spontaneous remission has been described. High incidence of recurrence should be taken into account when (micro-)marsupialization or incision as sole treatment is performed.