Recurrent arthritis as an unexpected side effect associated with azacitidine in a patient with myelodysplastic syndrome

Introduction Hypomethylating agents have confirmed efficacy for myelodysplastic syndrome and acute myeloid leukemia and are widely used. Although arthralgia is common side effect associated with hypomethylating agents, arthritis has not been reported previously. Case Report We present the first recorded patient with arthritis after azacitidine treatment. The patient we presented here had severe cytopenias requiring transfusion with erythrocyte and platelet suspensions, and a complete hematological response was obtained for myelodysplastic syndrome after three cycles of azacitidine (AZA) treatment. However, interestingly, after each AZA treatment cycle, the patient had recurrent attacks of arthritis. Management and outcomes The episodes of arthritis were possibly acute flares of pre-existing crystal-induced arthritis, as exhibited with azacitidine treatments and were managed effectively with nonsteroidal anti-inflammatory drugs. Discussion Because it is a rare condition, clinicians should not overlook AZA as a possible cause of arthritis exacerbations when arthritis of unknown etiology develops in patients treated with AZA.

A Clinical Case of Acute Polyarthritis Unmasking Severe Comorbidity

Acute polyarthritis requires a comprehensive differential diagnosis in order to establish its etiology. Moreover, sometimes it may unfold unexpected comorbidities, thus necessitating an individualized management approach. This article describes the case of an elderly patient whose initial presentation of acute polyarthritis was interpreted as crystal induced-arthritis demonstrated by the presence of calcium pyrophosphate and lipid crystals in the synovial fluid. The clinical deterioration of the patient along with the suspicion of a systemic infection required interdisciplinary collaboration and led to his transfer to the infectious diseases department where the diagnosis of sepsis from unknown origin was added. Further investigations unmasked a large complicated pancreatic pseudocyst that eventually ruptured into the peritoneal cavity and led to the patient's death.

Polydatin Prevents Calcium Pyrophosphate Crystal-Induced Arthritis in Mice

Background: Polydatin is a stilbenoid with important antioxidant, anti-inflammatory, and immunomodulating properties. The aim of this study was to assess the anti-inflammatory preventive effect of polydatin in the mouse model of acute arthritis induced by calcium pyrophosphate (CPP) crystals. Methods: Acute arthritis was induced by the injection of a suspension of sterile CPP crystals into the ankle joint of Balb/c mice. Animals were randomized to receive polydatin or colchicine (the control drug) according to a prophylactic and a therapeutic protocol. The primary outcome was the variation of ankle swelling obtained after crystal injection and treatment, while histological parameters such as leukocyte infiltration, IL-1ß and CXCL1 levels and tissue expression were considered as secondary outcomes. Results: Prophylactic treatment with PD significantly diminished ankle swelling after 48 h from crystal injection. Secondary outcomes such as leukocyte infiltration, necrosis, edema, and synovitis were also decreased. PD caused a reduction in circulating levels of IL-1ß and CXCL1, as well as their tissue expression. By contrast, the therapeutic administration of PD did not have any beneficial effect. Conclusions: PD can effectively prevent acute inflammatory response to crystals in the mouse model of CPP crystal-induced arthritis. These results suggest that this bioactive compound might be used in the prevention of crystal-induced acute attacks in humans.

NEUTROPHIL EXTRACELLULAR TRAPS RELEASE IN GOUT AND PSEUDOGOUT DEPENDS ON THE NUMBER OF CRYSTALS REGARDLESS OF LEUKOCYTE COUNT

Objectives Microcrystal-induced arthritis is still an unresolved paradigm for medicine. Overt inflammation may be absent even when crystals occur in synovial fluid. Recently, the production of neutrophil extracellular traps (NETs) embedding monosodium urate crystals (MSU) has been proposed as a possible mechanism of the auto-resolution of the inflammatory phase during gout. We aimed to verify and quantify the release of NETs in synovial fluids during gout and pseudogout attacks and to compare any differences with respect to crystals and neutrophils number, and to analyze activation of necroptosis pathway in synovial fluid from crystal-induced arthritis. Methods Synovial fluid samples were obtained by arthrocentesis from 22 patients presenting acute crystal-induced arthritis, gout or pseudogout (n = 11 each group), and from 10 patients with acute non-crystal arthritis as controls. NETosis was quantified in synovial fluid by nucleic acid stain and by quantification of human neutrophil elastase. Activation of p-MLKL was assessed by western blot. Results We observed that synovial fluid neutrophils encountering MSU and CPPD crystals during episodes of gout and pseudogout release NETs in relation to the number of crystals in synovial fluid and irrespective of neutrophil density and type of crystal. This release was accompanied by necroptosis through the activation of the MLKL pathway. Conclusions Our findings suggest that a role of NETs in crystal-induced arthritis is to “trap extracellular particles”, including microcrystals. Embedding crystals in aggregates of NETs may be the basis of tophi and CPPD deposition and may have implications for disease evolution, rather than for spontaneous resolution of the acute attack.

OP0174 POLYDATIN PREVENTS CALCIUM PYROPHOSPHATE CRYSTAL-INDUCED ARTHRITIS IN MICE

Background:Acute calcium pyrophosphate (CPP) crystal-induced inflammation is characterized by the massive release of cytokines and pro-inflammatory mediators and, from a clinical point of view, pain and limited joint function. Contrary to the precipitation of urate crystals that can be prevented through the use of hypouricemic drugs, there is no pharmacological therapy that can prevent the formation of pyrophosphate crystals.Polydatin (PD),a natural precursor of resveratrol, is a stilbenoid mainly contained in grape juice and bark of Polygonum Cuspidate. Its antioxidant, anti-inflammatory and immunomodulating properties have been demonstrated in several experimental models. We have recently shown that this compound is able to prevent the inflammatory response to pathogenic crystals in vitro (1).Objectives:The aim of this study was to assess the anti-inflammatory preventing effect of polydatin in the mouse model of acute crystal-induced arthritis.Methods:A suspension of sterile CPP crystals (0.3 mg/20 μL PBS) have been injected intra-articularly (i.a.) into one ankle joint of Balb/c mice under isoflurane anesthesia. Animals were randomized in 5 groups: 1- CPP injection, 2- CPP + PD, 3- CPP + colchicine (control drug), 4- CPP + vehicle (control. N 1), 5- PBS injection (control N. 2). Polydatin and colchicine were administered by gavage (respectively 40 mg/kg and 1mg/kg in 200 μL PBS/EtOH/glucose) at 24, 15 and 1 h before and 1, 6 and 24 h after (prophylactic model) or 1, 6 and 24 h after (therapeutic model) i.a. injection of CPP crystals.Ankle swelling was measured at different time points using a precision caliper. After 48h (peak of the acute phase) mice were euthanized and blood and ankle joints were collected for inflammatory cytokine (IL-1ß and KC) determination and histological analysis, respectively.Results:The mean change in ankle swelling after i.a injection was 0.595±0.434 mm. Prophylactic treatment with PD and colchicine significantly diminished ankle swelling to 0.175±0.115 mm and 0.137±0.100 mm, respectively (Kruskal Wallis p 0.0025; Dunn’s post test p < 0.01 CPP vs PD+CPP). The therapeutic administration of PD did not have significant effects on delta swelling (0.468±0.372 mm - PD vs 0.243±0.152 mm - colchicine). In mice treated with CPP crystals, histological analysis revealed areas of edema and increased cell infiltrate in articular and periarticular tissues and the presence of reactive lymphnodes. Tissue necrosis around inflamed tissue has been observed. Treatment with PD importantly reduced cell infiltrate in the prophylactic but not in the therapeutic protocol.Serum IL-1ß and KC levels, which increased significantly (p<0.05) after 48h from i.a injection, diminished in non significant manner after prophylactic and therapeutic treatment. The gene expression study revealed a reduction of IL-1ß and KC mRNA after PD and colchicine treatment in both groups.Conclusion:PD can effectively prevent acute inflammatory response to crystals in the mouse model of CPP arthritis. Oral PD prophylactic treatment showed a similar effect of colchicine in reducing ankle swelling and cell infiltrate. However, only colchicine showed to be effective in the therapeutic protocol.These results raise the possibility that PD might have utility in the prevention of crystal-induced acute attacks in humans.References:[1]Oliviero F, et al. Polydatin and resveratrol inhibit the inflammatory process induced by urate and pyrophosphate crystals in thp-1 cells.Foods 2019 Nov 7;8(11). pii: E560.Disclosure of Interests:Francesca Oliviero: None declared, Francesca Galuppini: None declared, Anna Scanu: None declared, Paola Galozzi: None declared, Vanni Lazzarin: None declared, Paolo Sfriso: None declared, Gianpietro Ravagnan: None declared, Roberta Ramonda Speakers bureau: Novartis, Celgene, Janssen, Pfizer, Abbvie, Lilly, Paolo Spinella: None declared, LEONARDO PUNZI: None declared, Gianmaria Pennelli: None declared, Roberto Luisetto: None declared

Musculoskeletal problems

This chapter in the Oxford Handbook of General Practice explores musculoskeletal problems encountered in general practice. It covers symptoms of musculoskeletal disease, neck and low back pain, and problems with the shoulder, elbow, wrist, hand, hip, knee, ankle, and foot. It explores sports medicine and the management of sporting injuries. It examines bone disorders, rickets, osteomalacia, osteoporosis, osteoarthritis, rheumatoid arthritis, spondyloarthropathies, and crystal-induced arthritis. It also discusses connective tissue disease, polymyalgia and giant cell arteritis, tiredness, and chronic fatigue syndrome.

AB0060 STING AND PROINFLAMMATORY CYTOKINES IN SYNOVIAL FLUID OF PATIENTS WITH DIFFERENT ARTHRITIDES

Background:STING (stimulator of interferon genes) is a cytosolic protein that is found in endoplasmic reticulum (ER) membrane, mitochondria and mitochondria-associated membranes. Although it is well established that STING plays an important role in innate immune responses, its potential involvement in rheumatic disease processes remains to be clarified (1).Objectives:The aims of this study were to evaluate the levels of STING and its relationship with local inflammation in the synovial fluid (SF) of patients with psoriatic arthritis (PsA), rheumatoid arthritis (RA), gout, calcium pyrophosphate (CPP) crystal-induced arthritis (CPP-IA), osteoarthritis (OA) and OA with CPP crystals (OA+CPP).Methods:SF was collected from the knees of 60 untreated patients: 10 with PsA, 10 with RA, 10 with gout, 10 with CPP-IA, 10 with OA and 10 with OA+CPP. SF was examined under optical light microscopy. White cell count (WBC) and the polymorphonuclear cell (PMN) percentage were determined in SF according to standard procedures. SF IL-8, IL-6, IL-1β and extra- and intra-cellular STING levels were assayed by ELISA.Results:The levels of WBC were higher in SFs from gouty patients (27.7±20.56 103/mm3), while OA and OA+CPP patients showed the lowest WBC count (0.34±0.3 103/mm3, 0.3±0.28 103/mm3). SFs from inflammatory arthritis contained elevated percentages of PMN (gout: 85.5±10.86%, CPP-IA: 84±11.31%, RA: 80.33±8.14%, PsA: 42.6±35.97%). Extracellular STING was determined in OA (440±413.31 pg/ml), OA+CPP (225±205.06 pg/ml) and CPP-IA (475±7.07 pg/ml) SF, while was not detectable in RA, PsA and gout. Intracellular STING levels were similar and the highest in SFs from gout (96.4±35.44 pg/ml) and RA (90.64±23.13 pg/ml), while remained under detection limit only in SFs from PsA. SF concentration of IL-6 was lower in OA (354.87±377.56 pg/ml) and OA+CPP (389.56±104.14 pg/ml) as compared with inflammatory arthritides (PsA: 3807.14±489.86 pg/ml; RA: 17354±2334.87 pg/ml; gout: 19359±84.85 pg/ml; CPP-IA: 20389.56±104.14 pg/ml). The patients with gout and RA had the highest levels of IL-8 (2159.54±347.09 pg/ml; 2039.6±97.74 pg/ml) and IL-1β (35.93±20.46 pg/ml; 44.36±23.16 pg/ml), while OA showed the lowest concentrations (IL-8: 23.21±11.32 pg/ml; IL-1β: 0.47±0.13 pg/ml). In the total group of patients, we found a negative correlation between extracellular STING and IL-8 (r=-0.53; p=0.004) and IL-1β (r=-0.47; p=0.012). There was a positive correlation between intracellular STING and IL-8 (r=0.54; p=0.017), IL-1β (r=0.77; p<0.001) and IL-6 (r=0.69 p=0.009).Conclusion:This study is the first to define the presence of STING in SF of different arthritides. The high levels of extracellular STING in OA, OA+CPP and CPP-IA SFs may be due to the activation of factors that reduce its interaction with the ER. The effect of downregulating factors in PsA might explain the low concentration of intracellular STING in these patients.References:[1]Barber GN. STING: infection, inflammation and cancer. Nat Rev Immunol 2015;15:760-70.Disclosure of Interests:Anna Scanu: None declared, Roberto Luisetto: None declared, Francesca Oliviero: None declared, Paola Galozzi: None declared, Augusta Ortolan: None declared, Mariagrazia Lorenzin: None declared, Mara Felicetti: None declared, Andrea Doria Consultant of: GSK, Pfizer, Abbvie, Novartis, Ely Lilly, Speakers bureau: UCB pharma, GSK, Pfizer, Janssen, Abbvie, Novartis, Ely Lilly, BMS, Roberta Ramonda Speakers bureau: Novartis, Celgene, Janssen, Pfizer, Abbvie, Lilly