Arthroscopic synovectomy versus intra-articular injection of corticosteroids for the management of refractory psoriatic or rheumatoid arthritis of the wrist: study protocol for a randomized controlled trial (ARCTIC trial).

BACKGROUND: Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are inflammatory diseases that often affect the wrist and, when affected, can lead to impaired wrist function and progressive joint destruction if inadequately treated. Standard care consists primarily of disease-modifying anti-rheumatic drugs (DMARDs), often supported by systemic corticosteroids or intra-articular corticosteroid injections (IACSI). IACSI, despite their use worldwide, show poor response in a substantial group of patients. Arthroscopic synovectomy of the wrist is the surgical removal of synovitis with the goal to relieve pain and improve wrist function. The primary objective of this study is to evaluate wrist function following arthroscopic synovectomy compared to IACSI in therapy-resistant patients with rheumatoid or psoriatic arthritis. Secondary objectives include radiologic progress, disease activity, health-related quality of life, work participation and cost-effectiveness during a 1-year follow-up. METHODS: This protocol describes a prospective, randomized controlled trial. RA and PsA patients are eligible with prominent wrist synovitis objectified by a rheumatologist, not responding to at least 3 months of conventional DMARDs and naïve to biological DMARDs. For 90% power, an expected loss to follow-up of 5%, an expected difference in mean Patient-Rated Wrist Evaluation score (PRWE, range 0-100) of 11 and α = 0.05, a total sample size of 80 patients will be sufficient to detect an effect size. Patients are randomized in a 1:1 ratio for arthroscopic synovectomy with deposition of corticosteroids or for IACSI. Removed synovial tissue will be stored for an ancillary study on disease profiling. The primary outcome is wrist function, measured with the PRWE score after 3 months. Secondary outcomes include wrist mobility and grip strength, pain scores, DAS28, EQ-5D-5L, disease progression on ultrasound and radiographs, complications and secondary treatment. Additionally, a cost-effectiveness analysis will be performed, based on healthcare costs (iMCQ questionnaire) and productivity loss (iPCQ questionnaire). Follow-up will be scheduled at 3, 6 and 12 months. Patient burden is minimized by combining study visits with regular follow-ups. DISCUSSION: Persistent wrist arthritis continues to be a problem for patients with rheumatic joint disease leading to disability. This is the first randomized controlled trial to evaluate the effect, safety and feasibility of arthroscopic synovectomy of the wrist in these patients compared to IACSI. TRIAL REGISTRATION: Dutch trial registry (CCMO), NL74744.100.20. Registered on 30 November 2020. CLINICALTRIALS: gov NCT04755127. Registered after the start of inclusion on 15 February 2021.

Behçet's disease, hospital-based prevalence and manifestations in the Rotterdam area.

INTRODUCTION: Behçet's disease is most prevalent in countries along the former Silk Road. Prevalence varies from 70-420 per 100,000 in Turkey, and 13.5-20 and 1-2 per 100,000 in Asia and Western Europe, respectively. Additionally, disease severity and morbidity might be correlated with ethnicity. We studied demography and morbidity in the Dutch cohort of patients with Behçet's disease and compared those with known figures. PATIENTS AND METHODS: The prevalence of Behçet's patients in the Rotterdam area was determined by comparing the total number of patients within the ethnic population with the number of patients diagnosed with Behçet's disease. Patient files of the Erasmus University Medical Centre (Erasmus MC) were reviewed for morbidity figures and compared with existing data. RESULTS: In total 84 Behçet's patients of Dutch, Turkish or Moroccan descent were identified in the Rotterdam area. Prevalence of Behçet's disease differed per ethnicity: 1, 71 and 39 per 100,000 for Dutch-Caucasians, Turks, and Moroccans, respectively. These figures are comparable with occurrence in West Turkey and Morocco. Within the studied Erasmus MC cohort no significant differences in morbidity appeared between the ethnic groups. However, uveitis and pustules were significantly more common in the Erasmus MC cohort as compared with UK, German, Turkish and Moroccan cohorts. DISCUSSION AND CONCLUSIONS: We present the first epidemiological study of Behçet's disease in the Netherlands. The prevalence of Behçet's disease in the studied Dutch region and in countries of ancestry is similar. Morbidity is equally spread, compared with other countries, but uveitis and pustules seem to be more common in the Netherlands.

[Clinical reasoning and decision-making in practice. A patient with fever and pancytopenia]. / Klinisch denken en beslissen in de praktijk. Een patiënt met koorts en pancytopenie.

An 82-year-old man was admitted with a 1-week history of chilling fever and dry cough. Laboratory tests revealed pancytopenia and elevated levels of C-reactive protein and lactic dehydrogenase (LDH). Screening for infectious diseases was negative. A bone marrow biopsy showed aspecific findings. The combination of pancytopenia, persistent fever, elevated LDH and hepatomegaly (demonstrated by ultrasound examination of the abdomen) was suggestive of the haemophagocytic syndrome. This was confirmed by very high levels of ferritin and soluble interleukin-2 receptor in the blood. In addition, re-examination of the bone marrow showed several haemophagocytic histiocytes. A polymerase chain reaction for Epstein-Barr virus (EBV) revealed a very high viral load. Since the patient had a history of an increased level of anti-EBV immunoglobulin-G, this was explained by a reactivation of the EBV infection. On the sixth day in hospital the patient developed signs of bilateral pneumonia and subsequent multiple organ failure. Despite intensive treatment the patient died. Autopsy revealed no haematological or other malignancies, but did show haemophagocytosis in many organs. It was then concluded that the patient had a virus-associated haemophagocytic syndrome, due to a reactivation of EBV, for which no underlying cause was found.

A reduced IL2R (CD25) expression level in first and second degree female relatives of autoimmune thyroid disease patients. A sign of a poor capability to preserve tolerance?

There is room for immune markers other than TPO-Abs to identify an increased risk to develop autoimmune thyroid disease (AITD). Our aim was to test the hypothesis that activation of CD4+ T cells is such marker in relatives of AITD patients, who have an increased risk to develop AITD. We established a controlled study on 20 TPO-Ab positive and 20 TPO-Ab negative euthyroid female relatives. All these cases had at least one 1st or 2nd degree relative with a documented autoimmune hyper- or hypothyroidism in whom we studied the percentages of circulating subsets of activated (MHC class-II, CD25 (IL-2R), CD71 or CD69+) CD4+ T cells and the level of the soluble (s)-IL2R in serum. We found that euthyroid female relatives did not show an activation of their T cell system, but a reduced expression of CD25 on CD4+ T cells. The level of the shed IL2R in serum was also lower in comparison with levels found in healthy control females. A reduced T cell activity was found in both TPO-Ab positive and negative relatives. In conclusion, female relatives with at least one 1st or 2nd degree relative with an AITD show signs of a reduced expansion capability of their T cell pool. It is hypothesized that this reduced expansion capability may affect T cell tolerance mechanisms more than T effector mechanisms.

An increased MRP8/14 expression and adhesion, but a decreased migration towards proinflammatory chemokines of type 1 diabetes monocytes.

In the early development of type 1 diabetes macrophages and dendritic cells accumulate around the islets of Langerhans at sites of fibronectin expression. It is thought that these macrophages and dendritic cells are derived from blood monocytes. Previously, we showed an increased serum level of MRP8/14 in type 1 diabetes patients that induced healthy monocytes to adhere more strongly to fibronectin (FN). Here we show that MRP8/14 is expressed and produced at a higher level by type 1 diabetes monocytes, particularly after adhesion to FN, creating a positive feedback mechanism for a high fibronectin-adhesive capacity. Also adhesion to endothelial cells was increased in type 1 diabetes monocytes. Despite this increased adhesion the transendothelial migration of monocytes of type 1 diabetes patients was decreased towards the proinflammatory chemokines CCL2 and CCL3. Because non-obese diabetic (NOD) mouse monocytes show a similar defective proinflammatory migration, we argue that an impaired monocyte migration towards proinflammatory chemokines might be a hallmark of autoimmune diabetes. This hampered monocyte response to proinflammatory chemokines questions whether the early macrophage and dendritic cell accumulation in the diabetic pancreas originates from an inflammatory-driven influx of monocytes. We also show that the migration of type 1 diabetes monocytes towards the lymphoid tissue-related CCL19 was increased and correlated with an increased CCR7 surface expression on the monocytes. Because NOD mice show a high expression of these lymphoid tissue-related chemokines in the early pancreas it is more likely that the early macrophage and dendritic cell accumulation in the diabetic pancreas is related to an aberrant high expression of lymphoid tissue-related chemokines in the pancreas.

Animal models of endocrine/organ-specific autoimmune diseases: do they really help us to understand human autoimmunity?

Organ-specific or endocrine autoimmune diseases are complex, polygenic afflictions the penetrance of which is heavily dependent on various environmental influences. Important target tissues are the thyroid, the islets of Langerhans, gastric parietal cells and steroid-producing cells in the adrenal and ovary. The etiology of these diseases remains to be clarified. The pathogenesis is strongly associated with autoimmune phenomena. None of the current treatment approaches provides a cure; rather they represent replacement therapy. An important objective in the treatment of endocrine/organ-specific autoimmune diseases is the detection of individuals at risk for the development of such diseases and the development of interventions to prevent an outbreak of the diseases. This requires an exquisite knowledge of the early etio-pathogenic stages of these diseases. This review concentrates on the usefulness of animal models for a precise understanding of these very early stages. It must be emphasized that studying animal models cannot answer all the problems presented by endocrine/organ-specific autoimmune diseases as seen in the clinic. It must be expected - considering the different etiologies in the different animal models (see below) - that the causes of the diseases in the human and the involvement of various genes and environmental factors may also vary. Yet, particularly in the study of the pre-autoimmune phases of the diseases, there is hardly any alternative to the study of animal models. Only limited series of experiments can be carried out in human subjects at risk to develop such diseases. Moreover, a general semblance (blueprint) of the etio-pathogenesis found in the animal models can lead the way for human studies. Efforts to understand the patho-physiology of the early stages of endocrine/organ-specific autoimmune diseases have mainly involved animal models that "spontaneously" develop such diseases. Of these the bio-breeding diabetes-prone (BB-DP) rat and the non-obese diabetes (NOD) mouse are the most well studied, yet many studies have also been carried out in the obese strain (OS) chicken. Apart from these spontaneous models there are animal models that are induced by environmental perturbations (viruses, toxic substances), by thymectomy procedures or by genetic manipulations, e.g., the RIP-LCMV model and the BDC 2.5 TCR mouse model. A general blueprint has emerged from the studies into the early stages of the pathogenesis of endocrine/organ-specific autoimmune diseases in these animal models: animals at risk to develop endocrine/organ-specific autoimmune diseases show various pre-autoimmune aberrancies in their target glands, T cells, macrophages (Mphi) and dendritic cells (DC). The presumably aberrant target cells, T cells, DC and Mphi need to interact abnormally before autoimmune disease can fully develop. In this abnormal interaction additional aberrancies in other regulatory systems may play a role in a further exacerbation of the self-directed immune response, such as defects in the hypothalamus pituitary adrenal (HPA) axis system. The various aberrancies are partly genetically determined by a variety of separate genes, particularly MHC-related genes, but they may also be environmentally induced (e.g., via viruses, high iodine diet, and other experimental manipulations). Recently evidence has been gathered for pre-autoimmune aberrancies similar to the animal models in the DC/ Mphi compartment and the HPA axis in humans at risk to develop endocrine/organ-specific autoimmune diseases. However, analogous pre-autoimmune abnormalities in human target glands or in T cell function have not yet been found with certainty. We believe that animal models of endocrine/organ-specific autoimmune disease still hold immense promise for the discovery of pathways, genes and environmental factors that determine the development of endocrine/organ-specific autoimmune diseases. Animals affected by such diseases provide a unique opportunity to uncover disease-associated pathways, which are complicated to define in man.