Differentiation factor Fms-like tyrosine kinase 3 ligand is a modulator of cell responses in autoimmune diseases

Fms-like tyrosine kinase 3 (Flt3) is a receptor on common stem cell progenitors and has a crucial role in hematopoesis, regulating cell proliferation and differentiation in man and mice. The growth factor Flt3 is activated by its soluble ligand, Flt3-L, leading to differentiation of multipotent stem cells and lymphoid progenitors. Flt3-L functions as a differentiation factor for dendritic cells (DC) in the periphery. These properties of the Flt3/Flt3-L system lead us to further investigate the role of the growth factor Flt3-L in rheumatic disease. In paper I, Flt3-L was found to be strongly expressed at the site of inflammation in human RA, the joint. Levels of Flt3-L were significantly higher in the synovial fluid compared to serum in RA patients and levels of Flt3-L in RA synovial fluid were significantly higher compared to synovial fluid from non-inflammatory joint diseases. Furthermore, intra-articular administration of a B-cell line overexpressing Flt3-L resulted in highly erosive arthritis while inoculation of the same B-cell line without hyperexpression of Flt3-L did not induce erosivity and caused arthritis in a minority of cases. Thus, Flt3-L is expressed at the site of inflammation in human RA and facilitates tissue destructive properites in the joint cavity. In paper II, mice with antigen-induced arthritis, mBSA-arthritis, were treated with the Flt3-inhibitor sunitinib. Treatment was started together with mBSA immunization or together with the induction of arthritis. Abrogation of Flt3 signalling reduced the intensity of synovitis and the frequency of bone destruction. Inhibition of Flt3 reduced also the number of differentiated (mature) dendritic cells concomitant with reduction of antibody production and bone metabolism. In addition to this, we investigated the ability of mouse bone marrow cells to migrate towards Flt3-L in a migration assay. Flt3-L was found to be a potent chemoattractant facilitating mobilization of Flt3+ cells from the bone marrow. Thus, the processes of antigen presentation, influx of leukocytes into synovial tissue and bone remodelling are mediated by Flt3 signalling in antigen-induced arthritis. In paper III, Flt3-L in CSF correlated to levels of Tau and pTau of patients with Sjögrens syndrome, fibromyalgia and Alzheimers disease, implying involvement of Flt3L in brain homeostasis. Furthermore, CSF Flt3-L in pSS correlated to a marker for microglia activation, MCP-1. Levels of Flt3-L in CSF were significantly decreased in pSS, and AD, compared to FM. Low levels of Flt3-L were associated to low levels of amyloid degradation peptides in pSS and AD patients. Thus, in CNS of patients with pSS Flt3-L is strongly correlated to neuroaxonal plasticity and microglia activation and reduced levels of CSF-Flt3-L in pSS are linked to changes in tau and amyloid turnover resembling processes ongoing in AD patients. Taken together, these results indicate that Flt3-L is involved in the inflammatory and tissue remodelling processes in joints and neuroaxonal structures of the brain. Flt3/Flt3-L signalling is an essential regulator of antigen-induced processes in autoimmune diseases

Pituitary dysfunction in granulomatosis with polyangiitis

Purpose: Granulomatosis with polyangiitis (GPA) is a multisystem disease, characterized by necrotizing small-vessel vasculitis, which mainly affects the respiratory tract and the kidneys. Pituitary involvement in GPA is rare, present in about 1% of all cases of GPA. To date, only case reports or small case series have been published. Herein we report clinical features, imaging findings, treatment and outcomes in three patients with GPA-related pituitary dysfunction (PD). Methods: A retrospective analysis of three cases of GPA-related PD was conducted, followed by systematic review of the English medical literature using PubMed. Results: The three cases include three women aged between 32 and 37 years. PD was the presenting feature in one and two developed PD in the course of the disease. All patients had a pituitary lesion on MRI. Conventional treatment with high doses of glucocorticoids and cyclophosphamide led to resolution or improvement of the MRI abnormalities, whereas it was not effective in restoring PD. A systematic review identified 51 additional patients, showing that GPA can lead to partial or global PD, either at onset or, during the course of the disease. Secondary hypogonadism is the predominant manifestation, followed by diabetes insipidus (DI). Sellar mass with central cystic lesion is the most frequent radiological finding. Conclusion: GPA should be carefully considered in patients with a sellar mass and unusual clinical presentation with DI and systemic disease. Although conventional induction-remission treatment improves systemic symptoms and radiological pituitary abnormalities, hormonal deficiencies persist in most of the patients. Therefore, follow-up should include both imaging and pituitary function assessment

Cardiovascular risk factors in gout, psoriatic arthritis, rheumatoid arthritis and ankylosing spondylitis: a cross-sectional survey of patients in Western Sweden

Objectives We aimed to compare traditional (trad) cardiovascular risk factors (CVRFs) among patients with gout, psoriatic arthritis (PsA), rheumatoid arthritis (RA) and ankylosing spondylitis (AS) stratified by sex.Methods A survey was sent to patients with gout (n=1589), PsA (n=1200), RA (n=1246) and AS (n=1095). Patients were retrieved from Sahlgrenska University Hospital, the hospitals of Uddevalla and Skövde, and 12 primary care centres in Western Sweden. The prevalence of self-reported trad-CVRFs was compared between diagnoses by age standardisation with the 2018 population of Sweden as the standard population.Results In total, 2896 (56.5%) of 5130 patients responded. Hypertension was the most frequently found comorbidity, reported by 65% of patients with gout, 41% with PsA, 43% with RA and 29% with AS. After age standardisation, women and men with gout had significantly more obesity (body mass index ≥30 kg/m2), hypertension, diabetes, hyperlipidaemia and multiple trad-CVRFs, compared with those with PsA, RA and AS. Obesity was significantly more common in PsA than in RA. In women, obesity, hypertension and multiple trad-CVRFs were more frequently reported in PsA than in RA and AS, whereas similar prevalence of CVRFs and coexistence of multiple trad-CVRFs were found in men with PsA, RA and AS.Conclusions Women and men with gout had the highest prevalence of trad-CVRFs. Differences in occurrence of CVRFs by sex were found in patients with PsA, RA and AS. In women, patients with PsA had higher occurrence of trad-CVRFs than those with RA and AS, whereas in men the distribution of CVRFs was similar in PsA, RA and AS

Short-term glucocorticoids reduce risk of chronic NSAID and analgesic use in early methotrexate-treated rheumatoid arthritis patients with favourable prognosis: subanalysis of the CareRA randomised controlled trial

Objective To explore non-steroidal anti-inflammatory drug (NSAID) and analgesic use in early rheumatoid arthritis (eRA) patients with a favourable risk profile initiating methotrexate (MTX) with or without glucocorticoid (GC) bridging.Methods Patients with eRA (≤1 year) and favourable risk profile (no erosions, negative rheumatoid factor and anticitrullinated protein antibodiesor low disease activity) in the 2-year CareRA trial were randomised to MTX 15 mg with a step-down GC scheme (COBRA Slim), or MTX without oral GCs, Tight-Step-Up (TSU). Used analgesics were recorded, including frequency, start/end date and indication. Chronic intake (≥90 consecutive days in trial) of NSAIDs, acetaminophen, opioids including tramadol and antidepressants for the indication of musculoskeletal (MSK) pain was considered. Treatments were compared using χ2 and analysis of variance with Holm’s correction for multiple testing.Results In total, 43 patients were randomised to COBRA Slim and 47 to TSU. At study inclusion, 33/43 (77%) of patients in the COBRA Slim and 32/47 (68%) in the TSU arm had been using analgesics (p=0.5). During the trial, 67 NSAID and analgesics were used for MSK pain in 26/43 (60%) COBRA Slim patients of which 9/43 (21%) daily chronically (DC), while 107 NSAID and analgesics were used in 43/47 (92%) TSU patients, of which 25/47 (53%) DC. The total number of patients on NSAID and analgesics at any time during the study (p<0.01) and chronically (p=0.01) was significantly different between treatment arms. Number of patients on DC NSAIDs was also significantly different (p<0.01) between COBRA Slim 6/43 (14%) and TSU 19/47 (40%).Conclusion In eRA patients considered to have a favourable prognosis, initial oral GC bridging resulted in lower chronic NSAID and analgesic use.Trial registration number NCT01172639

Smoking is Associated with Reduced Leptin and Neuropeptide Y Levels and Higher Pain Experience in Patients with Fibromyalgia

Smoking deregulates neuroendocrine responses to pain supporting production of neuropeptide Y (NpY) by direct stimulation of nicotinic receptors or by inhibiting adipokine leptin. Present study addressed the effect of cigarette smoking on adipokines and pain parameters, in 62 women with fibromyalgia (FM) pain syndrome with unknown etiology. Pain was characterized by a visual analogue scale, tender point (TP) counts, pressure pain threshold, and neuroendocrine markers NpY and substance P (sP). Levels of IGF-1, leptin, resistin, visfatin, and adiponectin were measured in blood and cerebrospinal fluid. Current smokers ( = 18) had lower levels of leptin compared to ex-smokers ( = 25, = 0.002), while the expected NpY increase was absent in FM patients. In smokers, this was transcribed in higher VAS-pain ( = 0.04) and TP count ( = 0.03), lower pain threshold ( = 0.01), since NpY levels were directly related to the pain threshold (rho = 0.414) and inversely related to TP counts (rho = −0.375). This study shows that patients with FM have no increase of NpY levels in response to smoking despite the low levels of leptin. Deregulation of the balance between leptin and neuropeptide Y may be one of the essential mechanisms of chronic pain in FM