Management of adult-onset Still's disease: evidence- and consensus-based recommendations by experts.

BACKGROUND: Adult-onset Still's disease (AOSD) is a rare condition characterized by fevers, rash, and arthralgia/arthritis. Most doctors treating AOSD in the Netherlands treat <5 patients per year. Currently, there is no internationally accepted treatment guideline for AOSD. OBJECTIVES: To conduct a Delphi panel aimed at reaching consensus about diagnostic and treatment strategies for patients with AOSD and to use the outcomes as a basis for a treatment algorithm. METHODS: The Delphi panel brought together 18 AOSD experts: rheumatologists, internists and paediatricians. The Delphi process consisted of 3 rounds. In the first two rounds, online list of questions and statements were completed. In the third round, final statements were discussed during a virtual meeting and a final vote took place. Consensus threshold was set at 80%. Two targeted literature searches were performed identifying the level of evidence of the consensus-based statements. RESULTS: Consensus was reached on 29 statements, including statements related to diagnosis and diagnostic tests, definition of response and remission, the therapy, the use of methotrexate, and tapering of treatment. The panel consented on reduction of the use of glucocorticoids to avoid side-effect, and preferred the use of biologics over conventional treatment. The role of interleukin-1 and interleukin-6 blocking agents was considered important in the treatment of AOSD. CONCLUSIONS: In this Delphi panel, a high level of consensus was achieved on recommendations for diagnosis and therapy of AOSD that can serve as a basis for a treatment guideline.

Two-year cost effectiveness between two gradual tapering strategies in rheumatoid arthritis: cost-utility analysis of the TARA trial.

OBJECTIVE: The aim of the current study was to evaluate the 2-year cost-utility ratio between tapering conventional synthetic disease-modifying antirheumatic drugs (csDMARD) first followed by the tumour necrosis factor (TNF)-inhibitor, or vice versa, in patients with rheumatoid arthritis (RA). METHODS: Two-year data of the Tapering strategies in Rheumatoid Arthritis trial were used. Patients with RA, who used both a csDMARD and a TNF-inhibitor and had a well-controlled disease (disease activity score ≤2.4 and swollen joint count≤1) for at least 3 months, were randomised into gradual tapering the csDMARD first followed by the TNF-inhibitor, or vice versa. Quality-adjusted life years (QALYs) were derived from the European Quality of life questionnaire with 5 dimensions. Healthcare and productivity costs were calculated with data from patient records and questionnaires. The incremental cost-effectiveness ratio and the incremental net monetary benefit were used to assess cost effectiveness between both tapering strategies. RESULTS: 94 patients started tapering their TNF-inhibitor first, while the other 95 tapered their csDMARD first. QALYs (SD) were, respectively, 1.64 (0.22) and 1.65 (0.22). Medication costs were significantly lower in the patients who tapered the TNF-inhibitor first, while indirect cost were higher due to more productivity loss (p=0.10). Therefore, total costs (SD) were €38 833 (€39 616) for tapering csDMARDs first, and €39 442 (€47 271) for tapering the TNF-inhibitor (p=0.88). For willingness-to-pay (WTP) levels <€83 800 tapering, the csDMARD first has the highest probability of being cost effective, while for WTP levels >€83 800 tapering the TNF-inhibitor first has the highest probability. CONCLUSION: Our economic evaluation shows that costs are similar for both tapering strategies. Regardless of the WTP, tapering either the TNF-inhibitor or the csDMARD first is equally cost effective. TRIAL REGISTRATION NUMBER: NTR2754.

Systemic lupus erythematosus (SLE): an unusual cause of ileocolic intussusception.

Intussusception is a rare diagnosis in adults. Gastrointestinal involvement is not unusual in systemic lupus erythematosus (SLE).1 A case of intussusception as first presenting symptom of SLE is described. A 50-year-old woman of Chinese origin came to the emergency room with symptoms of high fever, nausea, vomiting and weight loss of 10 kg. Three months before, an episode with abdominal pain due to ileal invagination in the colon occurred. Laboratory analysis showed: thrombocytopaenia, lymphopaenia, positive antinuclear antibody, antidouble-stranded DNA, Coombs tests and low C3 in combination with an active urine sediment and proteinuria. CT and positron emission tomography scan showed lymphadenopathy, but no other abnormalities. Axillar lymph node biopsy showed no abnormalities. The diagnosis new-onset SLE was made. Prednisone treatment was started and soon thereafter tapered, azathioprine and hydroxychloroquine were added. During follow-up, the SLE remained in remission. SLE is a rare cause of ileocolic intussusception and ileocolic intussusception may be the first presenting symptom.

Distinct monocyte gene-expression profiles in autoimmune diabetes.

OBJECTIVE: There is evidence that monocytes of patients with type 1 diabetes show proinflammatory activation and disturbed migration/adhesion, but the evidence is inconsistent. Our hypothesis is that monocytes are distinctly activated/disturbed in different subforms of autoimmune diabetes. RESEARCH DESIGN AND METHODS: We studied patterns of inflammatory gene expression in monocytes of patients with type 1 diabetes (juvenile onset, n = 30; adult onset, n = 30) and latent autoimmune diabetes of the adult (LADA) (n = 30) (controls subjects, n = 49; type 2 diabetic patients, n = 30) using quantitative PCR. We tested 25 selected genes: 12 genes detected in a prestudy via whole-genome analyses plus an additional 13 genes identified as part of a monocyte inflammatory signature previously reported. RESULTS: We identified two distinct monocyte gene expression clusters in autoimmune diabetes. One cluster (comprising 12 proinflammatory cytokine/compound genes with a putative key gene PDE4B) was detected in 60% of LADA and 28% of adult-onset type 1 diabetic patients but in only 10% of juvenile-onset type 1 diabetic patients. A second cluster (comprising 10 chemotaxis, adhesion, motility, and metabolism genes) was detected in 43% of juvenile-onset type 1 diabetic and 33% of LADA patients but in only 9% of adult-onset type 1 diabetic patients. CONCLUSIONS: Subgroups of type 1 diabetic patients show an abnormal monocyte gene expression with two profiles, supporting a concept of heterogeneity in the pathogenesis of autoimmune diabetes only partly overlapping with the presently known diagnostic categories.

Increased serum levels of MRP-8/14 in type 1 diabetes induce an increased expression of CD11b and an enhanced adhesion of circulating monocytes to fibronectin.

The recruitment of monocytes from the bloodstream is crucial in the accumulation of macrophages and dendritic cells in type 1 diabetic pancreases. Adhesion via integrins to endothelium and extracellular matrix proteins, such as fibronectin (FN), and the production of myeloid-related protein (MRP)-8, -14, and -8/14 by recently transmigrated monocytes are thought to be instrumental in such recruitment. We determined the FN-adhesive capacity and integrin expression of monocytes of type 1 and type 2 diabetic patients and related them to the subjects' serum levels of MRP-8, -14 and -8/14. Monocytes of type 1 diabetic patients displayed an increased adhesion to fibronectin in comparison with type 2 patients and healthy control subjects but had a normal expression of the FN binding integrins CD29, CD49a, CD49d, and CD49e (although CD11b and CD18 expression was increased). MRP-8/14, which was increased in the sera of type 1 diabetic patients, induced healthy donor monocytes to adhere to FN and upregulate CD11b expression in a dosage-dependent manner. The observed MRP-induced increased adhesion of monocytes to FN and upregulation of CD11b most likely contributed to a facilitated accumulation of monocytes and monocyte-derived cells at the site of inflammation, in this case the pancreatic islets.

The association between autoimmune thyroiditis, autoimmune gastritis and type 1 diabetes.

Type 1 diabetes mellitus (DM1), autoimmune thyroid disease (ATD) and autoimmune gastritis often occur together forming the so-called autoimmune polyendocrine syndrome (APS) type 3. Thyroid autoimmunity is evident in up to one third and gastric autoimmunity in up to a quarter of patients with DM1. Also relatives of DM1 patients, particularly mothers, have higher frequencies of these autoimmune conditions. Vice versa, gastric autoimmunity is present in one third of ATD patients and islet autoimmunity in one out ten. The BB-DP rat, the NOD mouse, the OS chicken and the neonatal thymectomy mouse model are animal models of APS type 3. In these models the autoimmune destruction of the various target tissues has been shown to be a multi-step process in which several genetic polymorphisms need to converge to induce both local anomalies in the target gland and anomalies in the immune system. With regard to environmental factors, excess iodine is well known to elicit/aggravate thyroid autoimmunity in these animal models. Screening DM1 patients and their relatives (particularly females) for thyroid autoimmunity is recommended. If positive, excess iodine should be avoided and thyroxin treatment considered. Whether autoimmune thyroiditis and autoimmune gastritis patients should be screened for islet Ab is not clarified.