Osteoarticular disorders in sickle cell disease

Different organs can be affected secondary to sickle cell disease, including the central nervous system, kidneys, gastrointestinal tract, respiratory system, cardiovascular system, bone, and joints. This can lead to increased morbidity and mortality events among the affected patients. Osteoarticular complications represent a severe set of events for patients with sickle cell disease. These complications might include gouty, septic, juvenile, and erosive arthritis, dactylitis, bone infarction, and osteomyelitis. These are the most common complications reported in the literature, and some case reports even reported other types of complications that develop secondary to the previously mentioned ones. Adequate diagnosis might be challenging in some cases. Therefore, clinicians must be crucial in determining the appropriate clinical and radiographic manifestations. Treating these cases is also challenging. Consequently, clinicians should be aware of these complications to enhance the prognosis of the affected patients. Further research is needed for the standardization of the diagnostic and management approaches in these events.

Erosive arthritis in systemic lupus erythematosus: not only Rhupus

Systemic lupus erythematosus (SLE)–related arthritis has been traditionally defined as non-erosive and is therefore considered a minor manifestation requiring a mild treatment. However, the concept of non-erosive arthritis in SLE has been challenged with the advent of sensitive imaging techniques, such as high-resolution ultrasound with power Doppler or magnetic resonance. The application of these new imaging tools has demonstrated that up to 40% of SLE patients with joint involvement can develop erosive damage. Thus, this more aggressive phenotype can be identified not only in patients overlapping with rheumatoid arthritis (RA). This issue has been considered for the first time in the classification criteria proposed by Systemic Lupus International Collaborating Clinics in 2012, in which the old definition of “non-erosive arthritis” was replaced with either synovitis or tenderness in two or more joints with morning stiffness, suggesting the possible presence of an erosive phenotype. Accordingly, the 2019 EULAR/ACR’s SLE recommendations advise treatment with immunosuppressant or biological drugs for patients with RA-like moderate arthritis. As a result, several studies have investigated the presence of biomarkers associated with SLE erosive damage. A relevant role seems to be played by the autoantibodies directed against post-translational modified proteins: above all, a significant association has been observed with antibodies directed against citrullinated and carbamylated proteins. Conversely, the rheumatoid factor was not associated with this more aggressive SLE-related arthritis. Nonetheless, some pro-inflammatory factors have been associated with erosive damage in SLE patients. These results suggest new pathogenic mechanisms underlining erosive arthritis, only partially shared with RA. Hence, in the present narrative review, we summarized available data about erosive arthritis in SLE patients, in the light of its impact on therapeutic decisions.

Paramagnetic block copolymers: An effective tool for targeted radiography of rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterized by erosive arthritis. Accurate diagnosis of RA mostly depends on the quality of magnetic resonance imaging (MRI). To obtain stable and clear imaging signals, it is necessary to design and develop a superstable and highly sensitive contrast agent. This study synthesized a diblock polymer polyethylene glycol–tert-butyl polyacrylate (PEG-b-PAA) by in situ polyol polymerization, coated it with ultrasmall paramagnetic iron oxide (USPIO), and conjugated folic acid to the PEG-b-PAA/USPIO surface to impart targeting function. The addition of USPIO effectively enhanced MRI quality in delayed T2-weighted images (T2WI), as observed through synovial signal changes other than morphological changes, early monitoring RA lesions, and drug treatment response. Enhanced T2WI helped evaluate the characteristics of synovial perfusion, which further confirmed the feasibility of MRI using FA-PEG-b-PAA/USPIO. These results showed that FA-PEG-b-PAA/USPIO has great potential in the clinical application of MRI for RA diagnosis.

A case of macrophage activation syndrome in a patient with anti-synthetase syndrome

ABSTRACT Anti-synthetase syndrome (ASS) is an autoimmune disease characterized by autoantibodies against an aminoacyl transfer RNA synthetase with clinical features including interstitial lung disease, non-erosive arthritis, myositis, Raynaud’s phenomenon, unexplained fever and/or mechanic’s hands. Macrophage activation syndrome (MAS) is a potentially fatal hyper- inflammatory syndrome that can occur as a complication of systemic rheumatic diseases. However, the association of MAS and ASS has rarely been reported in the literature. Here, we report this association in a patient with overlap ASS and anti-CCP positive rheumatoid arthritis. First line management with steroids was complicated by diabetic ketoacidosis, hence requiring use of anti-IL1 therapy (anakinra) for disease control.

POS0099 CLINICAL REMISSION IN RHEUMATOID ARTHRITIS PATIENTS TREATED WITH TOFACITINIB IS ASSOCIATED WITH LOW BASELINE EXPRESSION OF GENES RELATED TO ENERGY METABOLISM AND WITH CELLULAR CAPACITY OF THEIR UPREGULATION DURING FOLLOW-UP

Background:Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology, which is characterized by erosive arthritis (synovitis) and systemic inflammation. Tofacitinib (TFCN) is a small molecule Janus kinase (JAK) inhibitor that targets JAK1/JAK3. Identification of patients sensitive to TFCN before treatment could significantly improve therapy outcome. Presently it is not possible to predict TFCN efficacy in every patient while some patients are non-responsive to the drug that may produce adverse effects. TFCN function in RA patients has been recently associated with alterations in bioenergetics, mitochondrial function, and ATP production [1]. Therefore, we hypothesized that baseline metabolic status of RA patients prior to drug administration can predict the therapeutic outcome.Objectives:To investigate the importance of baseline expression of genes involved in energy generation in RA patients, which could serve prognostic biomarkers for treatment response to tofacitinib.Methods:Peripheral blood of 28 RA patients aged 52.2±15.6 years old, average disease duration 3.5 years (range 0.6-19) treated with TFCN (5-10 mg twice a day) during three months and 26 healthy age-matched control subjects were examined. Clinical response was assessed by disease activity score (DAS28-ESR), serum levels of ACPA antibodies, rheumatoid factor (RF), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Clinical remission was assessed according to ACR criteria and DAS28 (DAS28 <2.6). Protein concentrations were measured using ELISA. Total RNA was isolated and used in gene expression studies performed with quantitative real-time RT-PCR.Results:All of the patients were Steinbrocker’s radiographic stage II-III at baseline. The majority of patients demonstrated erosive arthritis (23 out of 28), they were ACPA- (25 out of 28) and RF- (24 out of 28) positive. TFCN treatment significantly decreased the disease activity according to DAS28. At the end of the study the majority of patients demonstrated moderate disease activity (3.2< DAS28 <5.1), four patients retained high disease activity while 8, attained remission (DAS28 <2.6). This was accompanied by significant decrease in CRP and the number of swollen and tender joints. ESR values were not changed significantly. Gene and protein expression analysis revealed that RA patients, which attained clinical remission after TFCN treatment demonstrated significantly lower baseline expression of genes associated with glycolysis (pyruvate kinase), oxidative phosphorylation (succinate dehydrogenase and uncoupling protein (UCP) 2) compared to other examined RA patients and control subjects. Moreover, these gene expressions increased in RA patients who attained clinical remission in the course of follow-up while in refractory for TFCN treatment patients these gene expressions were tending to downregulate.Conclusion:Clinical remission attainment in RA patients treated with tofacitinib is associated with lower baseline expression of genes associated with energy generation pathways (pyruvate kinase, succinate dehydrogenase, and UCP2) compared to other examined subjects. Non-responsiveness to tofacitinib is accompanied by high baseline expression of genes related to glycolysis and oxidative phosphorylation compared to controls.References:[1]McGarry et al. JAK/STAT Blockade Alters Synovial Bioenergetics, Mitochondrial Function, and Proinflammatory Mediators in Rheumatoid Arthritis. Arthritis Rheumatol, 2018; 70:1959.Acknowledgements:Russian Ministry of Education and Science (Project No. AAAA-A19-11-9021190145-2 to EVT).Disclosure of Interests:None declared

Smoking associates with distinct clinical phenotypes in patients with systemic lupus erythematosus: a nationwide Danish cross-sectional study

ObjectivesSLE displays large clinical heterogeneity that beyond genetic factors may be determined by environmental exposures. In this Danish nationwide study, we aimed to determine if clinical subsets of SLE were associated with smoking history.MethodsAt each of six participating centres, incident or prevalent inpatients and outpatients with SLE were consecutively included. Manifestations forming the basis of SLE classification were registered in an electronic chart system. Patients also provided questionnaire-based data on environmental exposures, including smoking history. Hierarchical cluster analysis was conducted to determine and characterise subsets of patients with similar traits of disease manifestations. Levels of smoking exposure by pack-years were correlated to the identified SLE subsets, as well as discrete SLE manifestations.ResultsThe cohort consisted of 485 patients (88% women and 92% Caucasian) with SLE of which 51% were ever smokers. Common disease manifestations comprised non-erosive arthritis (81%), malar rash (57%), lymphopenia (55%), photosensitivity (50%) and persistent proteinuria (41%). We identified three distinct phenotypic clusters characterised by their preponderance of (A) neurological, serosal and mucosal involvement; (B) renal, haematological and immunological disorders; and (C) acute and chronic skin manifestations. Cluster B was the youngest and had the lowest level of smoking exposure. Age-adjusted regression analyses showed that compared with never smokers a smoking history of >20 pack-years was associated with neurological disorder (OR=3.16), discoid rash (OR=2.22), photosensitivity (OR=2.19) and inversely with haematological disorder (OR=0.40), renal disorder (OR=0.40) and non-erosive arthritis (OR=0.45), p<0.05 for all.ConclusionsOur findings support that SLE presents in varying clinical phenotypes and suggest that they may have differentiated associations with smoking history.

Human osteoclastogenesis in Epstein-Barr virus-induced erosive arthritis in humanized NOD/Shi-scid/IL-2Rγnull mice

Many human viruses, including Epstein-Barr virus (EBV), do not infect mice, which is challenging for biomedical research. We have previously reported that EBV infection induces erosive arthritis, which histologically resembles rheumatoid arthritis, in humanized NOD/Shi-scid/IL-2Rγnull (hu-NOG) mice; however, the underlying mechanisms are not known. Osteoclast-like multinucleated cells were observed during bone erosion in this mouse model, and therefore, we aimed to determine whether the human or mouse immune system activated bone erosion and analyzed the characteristics and origin of the multinucleated cells in hu-NOG mice. Sections of the mice knee joint tissues were immunostained with anti-human antibodies against certain osteoclast markers, including cathepsin K and matrix metalloproteinase-9 (MMP-9). Multinucleated cells observed during bone erosion stained positively for human cathepsin K and MMP-9. These results indicate that human osteoclasts primarily induce erosive arthritis during EBV infections. Human osteoclast development from hematopoietic stem cells transplanted in hu-NOG mice remains unclear. To confirm their differentiation potential into human osteoclasts, we cultured bone marrow cells of EBV-infected hu-NOG mice and analyzed their characteristics. Multinucleated cells cultured from the bone marrow cells stained positive for human cathepsin K and human MMP-9, indicating that bone marrow cells of hu-NOG mice could differentiate from human osteoclast progenitor cells into human osteoclasts. These results indicate that the human immune response to EBV infection may induce human osteoclast activation and cause erosive arthritis in this mouse model. Moreover, this study is the first, to our knowledge, to demonstrate human osteoclastogenesis in humanized mice. We consider that this model is useful for studying associations of EBV infections with rheumatoid arthritis and human bone metabolism.