Anti-interleukin-6 receptor antibody for the treatment of remitting seronegative symmetrical synovitis with pitting oedema: a new outlook?

We present the case of an elderly man with a small-joint polyarthritis, accompanied by pitting oedema, involving hands and feet, raising clinical suspicion of remitting seronegative symmetrical synovitis with pitting oedema (RS3PE). Treatment with corticosteroids was initiated with significant improvement, but unacceptable iatrogeny ensued, and tapering was not possible without disease flare-up. A trial of tocilizumab allowed disease activity control, slow weaning of corticosteroids and, ultimately, its suspension. RS3PE is a rare rheumatological entity, initially thought to be a variant of rheumatoid arthritis (RA), with shared traits with polymyalgia rheumatica (PMR), and other seronegative spondyloarthropathies, thereby implying a shared pathophysiological background. Elevated levels of interleukin 6 (IL-6) are found in patients with RA, have shown to mirror disease activity in PMR and have also been described in the serum and synovial fluid of patients with RS3PE. Tocilizumab, an anti-IL-6 receptor antibody, shows auspicious results in several other rare rheumatic diseases other than RA.

Plant-Based Approaches for Rheumatoid Arthritis Regulation: Mechanistic Insights on Pathogenesis, Molecular Pathways, and Delivery Systems.

Rheumatoid arthritis (RA) is classified as a chronic inflammatory autoimmune disorder, associated with a varied range of immunological changes, synovial hyperplasia, cartilage destructions, as well as bone erosion. The infiltration of immune-modulatory cells and excessive release of proinflammatory chemokines, cytokines, and growth factors into the inflamed regions are key molecules involved in the progression of RA. Even though many conventional drugs are suggested by a medical practitioner such as DMARDs, NSAIDs, glucocorticoids, etc., to treat RA, but have allied with various side effects. Thus, alternative therapeutics in the form of herbal therapy or phytomedicine has been increasingly explored for this inflammatory disorder of joints. Herbal interventions contribute substantial therapeutic benefits including accessibility, less or no toxicity and affordability. But the major challenge with these natural actives is the need of a tailored approach for treating inflamed tissues by delivering these bioactive agentsat an appropriate dose within the treatment regimen for an extended periodof time. Drug incorporated with wide range of delivery systems such as liposomes, nanoparticles, polymeric micelles, and other nano-vehicles have been developed to achieve this goal. Thus, inclinations of modern treatment are persuaded on the way to herbal therapy or phytomedicines in combination with novel carriers is an alternative approach with less adverse effects. The present review further summarizes the significanceof use of phytocompounds, their target molecules/pathways and, toxicity and challenges associated with phytomolecule-based nanoformulations.

Hidradenitis Suppurativa-Related Autoinflammatory Syndromes: An Updated Review on the Clinics, Genetics, and Treatment of Pyoderma gangrenosum, Acne and Suppurative Hidradenitis (PASH), Pyogenic Arthritis, Pyoderma gangrenosum, Acne and Suppurative Hidradenitis (PAPASH), Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis (SAPHO), and Rarer Forms.

Hidradenitis suppurativa (HS) is an autoinflammatory skin disorder of the terminal hair follicle, which can present in sporadic, familial, or syndromic form. A classification has been proposed for the latter, distinguishing cases associated with a known genetic condition, with follicular keratinization disorders or with autoinflammatory diseases. This review focuses on the clinical and genetic features of those entities (ie, pyoderma gangrenosum [PG], acne and HS; PG, acne, pyogenic arthritis and HS; psoriatic arthritis, PG, acne and HS; synovitis, acne, pustulosis, hyperostosis, osteitis; and so forth) for which the collective term HS-related autoinflammatory syndromes is proposed.

Ultrafast Doppler Imaging for Early Detection of Synovitis in Rheumatoid Arthritis.

OBJECTIVE: Current medical ultrasound systems possess limited sensitivity in detecting slow and weak blood flow during the early stages of rheumatoid arthritis (RA), leading to potential misdiagnosis. Ultrafast Doppler is capable of detecting slow and weak flow. This study was aimed at evaluating the diagnostic value of ultrafast Doppler for RA. METHODS: Thirty-three RA patients (19 established, 14 early stage) and 15 healthy participants were enrolled. A programmable imaging platform with ultrafast Doppler capability was used. The benchmark was a clinical system with conventional Doppler imaging. Standardized dorsal long-axis scanning of both wrists was performed. Both ultrafast and conventional power Doppler (PD) images were quantitatively analyzed with computer assistance and semiquantitatively scored with the Outcome Measures in Rheumatology (OMERACT) scoring system. RESULTS: Ultrafast PD revealed more blood area than conventional PD in both RA wrists and healthy wrists. Ultrafast PD OMERACT was positive in 65 of 66 RA wrists and 26 of 30 healthy wrists (sensitivity [SEN] = 0.985, accuracy [ACC] = 0.719), while conventional PD OMERACT was positive in 28 of 66 RA wrists and 0 of 30 healthy wrists (SEN = 0.424, ACC = 0.604). Ultrafast PD revealed a higher synovial PD area, dilated vessels and PD brightness in RA wrists. Peak synovial PD brightness had the best diagnostic value for RA (area under the receiver operating characteristic curve = 0.802, SEN = 0.909, ACC = 0.813). For early-stage RA patients, ultrafast peak synovial PD brightness had higher sensitivity and accuracy than conventional PD indexes. CONCLUSION: Ultrafast PD had an increase of 0.561 in sensitivity and 0.209 in accuracy when compared with conventional PD. With its high sensitivity, ultrafast PD can detect early synovitis and identify RA patients during the early phase.

Iron overload causes macrophages to produce a pro-inflammatory phenotype in the synovium of hemophiliac arthritis via the acetyl-p53 pathway.

AIM: Haemophiliac arthritis (HA) is caused by spontaneous intra-articular hemorrhage and repeated intra-articular hematomas, leading to iron overload, which, in turn, induces M1 macrophage polarisation and inflammatory cytokine secretion, resulting in synovitis. Here, we explored the mechanism by which iron overload in HA induces the polarisation of M1 macrophages, providing a new approach for the treatment of HA synovitis. METHODS: The synovium from the knee joints of normal amputees and patients with HA was collected. Pathological changes in the synovial tissues were analysed using hematoxylin and eosin staining. Iron tissue deposition was evaluated using the iron assay kit and Prussia Blue staining, while macrophage phenotype was determined using immunofluorescence. The levels of pro-inflammatory cytokines and p53 acetylation were determine using western blotting. An in vitro iron overload model was established by inducing THP-1 macrophages with ferric ammonium citrate, and the involvement of acetylated p53 in M1 macrophage polarisation was investigated. RESULTS: Compared to control samples, the iron content in the synovium of patients with HA was significantly increased. The protein levels of M1 macrophage markers, pro-inflammatory cytokines, and acetylated p53, were also significantly elevated in the synovial tissues of patients with HA. Similar results were observed in the in vitro iron overload model. Furthermore, the inhibition of p53 acetylation in vitro reversed these iron overload-induced effects. CONCLUSION: In patients with HA, iron overload induced synovial p53 acetylation, leading to macrophage polarisation toward the M1 phenotype and increased inflammatory cytokine secretion, resulting in synovitis. HIGHLIGHTS: Synovial iron overload is associated with changes in P53 acetylation in hemophiliac arthritis (HA). Acetylated p53, a known regulator of macrophage polarization, is highly expressed in HA synovium, suggesting a potential role in M1 polarization. HA synovial macrophages predominantly polarize into the pro-inflammatory M1 phenotype, secreting elevated levels of pro-inflammatory cytokines.

Relationship between pain and intra-articular pathology in patients with chronic lateral ankle instability.

PURPOSE: Repeated ankle sprains can lead to chronic lateral ankle instability (CLAI). It is unclear whether CLAI causes pain unless complicated by intra-articular lesions. This study aimed to analyze the characteristics of pain and the relationship between pain and intra-articular pathology in patients with CLAI. MATERIALS AND METHODS: Fifty-three ankles in 46 patients with CLAI who had undergone surgery were retrospectively reviewed. The self-administered foot evaluation questionnaire (SAFE-Q) was given to patients the day before surgery. Intra-articular lesions were assessed using arthroscopy and magnetic resonance imaging (MRI). In addition, the Hounsfield Unit (HU) on computed tomography (CT) of the medial gutter was measured. The relationship between pain and intra-articular findings was also analyzed. RESULTS: The pain and pain-related scores in the SAFE-Q were significantly correlated with synovitis in 96.3% (rs = - 0.532). HU ratios in the tibia and talus were also significantly correlated with pain (rs = - 0.603, - 0.534, respectively). The arthroscopic synovitis score and HU ratios in patients with high pain scores were significantly higher than those in patients with low pain scores. Forty ankles (75.5%) had synovitis and articular cartilage injuries were observed in 22 ankles (41.5%). Patients with fluid collection or bone marrow lesions (BML) scored significantly lower in pain than those without, but there was no significant difference between patients with and without cartilage injury. Multiple regression analysis revealed that a high synovitis score and HU ratio of the talus were significantly associated with high pain. CONCLUSIONS: Intra-articular lesions such as synovitis and BML were associated with pain in patients with CLAI. Osteosclerotic changes in the medial gutter also induced ankle pain, indicating that osteoarthritic changes had already begun. Therefore, lateral ankle ligament injuries after ankle sprain should be appropriately treated to avoid secondary degenerative changes.

SAPHO syndrome complicated by multiple venous thrombosis of left lower limb: A case report and literature review.

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is an uncommon clinical syndrome with the signs of skin problems and osteoarthropathy as its main features. The pathogenesis of SAPHO syndrome has not been fully elucidated, and multiple complications may be present, including thrombosis. A 39-year-old male patient was diagnosed with SAPHO syndrome, complicated by multiple venous thrombosis of the left lower limb. We conducted a brief review of the current available literature on thrombosis in patients with SAPHO syndrome and speculated that the presence of lower extremity thrombosis in this patient with SAPHO syndrome may be related to physiological structure or antiphospholipid syndrome. Whether positive lupus anticoagulant has an effect on thrombosis in patients with SAPHO syndrome remains to be investigated.

Sarcoid Uveitis in Children.

Sarcoidosis is a multi-system granulomatous disease that often presents with uveitis. Although sarcoidosis and sarcoid uveitis typically occur in adulthood, children also may be affected. There are two distinct clinical presentations of the pediatric disease, associated with younger and older age groups, and having different causations. "Early-onset sarcoidosis", beginning at age 5 years or less, is an autosomal dominant genetic disease, caused by a mutation in the NOD2 gene. It is also known as sporadic Blau syndrome or Jabs syndrome. "Adult-type sarcoidosis", usually beginning between the ages of 8 and 15 years, is believed to represent an excessive response to an environmental antigen. There is limited literature on the management of pediatric sarcoidosis, and treatment follows an approach applied to other forms of pediatric non-infectious uveitis. When systemic immunomodulatory therapy is indicated, methotrexate and/or adalimumab are often employed. The condition may persist into adulthood, and thus long-term follow-up is indicated.

Magnetic resonance imaging RAMRIS-SAFE score-A low-risk effective measure of rapid response to therapy in rheumatoid arthritis clinical trials.

AIM: To assess the rapidity of magnetic resonance imaging (MRI) measured synovitis (as measured by synovial thickening using the RAMRIS-SAFE score) and bone edema in active rheumatoid arthritis (RA) subjects treated with golimumab. Secondary aims: to correlate MRI measures with disabilities of the arm, shoulder, and hand (DASH), physician global (PhysG) and patient global (PatG) assessments. METHODS: Patients with active RA and inadequate response to methotrexate were recruited. Active RA was defined as RA with a Disease Activity Score of 28 joints - C-reactive protein ≥4.2 at screening AND active disease (synovitis and edema) of the chosen hand or wrist on MRI at screening, as determined by the central blinded MRI reader (PB). Outcomes measures were assessed at baseline, 2, 6, and 12 weeks. MRI results were interpreted by one experienced observer (PB), blinded to clinical measures. Pearson's correlation co-efficient (SPSS) was used to express the relationship between DASH, PhysG, PatG and MRI measures. RESULTS: Eighteen patients were included in the study. All subjects completed follow-up visits and MRI assessment. Mean age was 60.6 years (range 22-72), and 10 were female, 8 male, and disease duration was mean 4.72 years (range 1-28); all patients were taking background methotrexate. The changes in MRI synovial volume were evident by visit 2. The strongest correlations with the DASH for MRI parameters were total synovial thickening (0.923) and edema (0.921). CONCLUSION: Golimumab was associated with rapid improvement in clinical measures and patient-reported outcome measures. Mean synovial thickening demonstrated early rapid improvement. MRI synovial thickening demonstrated a strong correlation with DASH, PatG and PhysG.

Association of Interosseous Tendon Inflammation in the Hand With Different Early Arthritides in a 10-Year Magnetic Resonance Imaging Study.

OBJECTIVE: Inflammation around the tendons of the hand interosseous muscles (interosseous tendon inflammation [ITI]) was recently identified on magnetic resonance imaging (MRI) in a set of patients with rheumatoid arthritis (RA) and arthralgia. We conducted a large MRI study to assess the prevalence of ITI at diagnosis of RA and of other arthritides, as well as its relationship with clinical signs. METHODS: A total of 1,205 patients presenting with various types of early arthritis between 2010 and 2020 underwent contrast-enhanced hand MRI as part of the prospective Leiden Early Arthritis Cohort. MRI was evaluated with blinding for clinical data, for ITI lateral of metacarpophalangeal (MCP) joints 2-5, and for synovitis/tenosynovitis/osteitis. We assessed ITI presence at baseline per diagnosis and its relationship with clinical characteristics (ie, presence of hand arthritis, increased acute phase reactants, and local joint swelling and tenderness). Logistic regression and generalized estimating equations were used with adjustment for age and established local inflammation features (synovitis/tenosynovitis/osteitis). RESULTS: A total of 36% of patients with early RA (n = 532) had ITI; this was similar in patients with anti-citrullinated protein antibody (ACPA)-negative RA (37%) and those with ACPA-positive RA (34%; P = 0.53). ITI occurred regularly in remitting seronegative symmetrical synovitis with pitting edema (60%) and connective tissue diseases (44%) and less frequently in undifferentiated arthritis (14%), psoriatic arthritis (14%), inflammatory osteoarthritis (8%), reactive arthritis (7%), crystal arthritis (7%), and peripheral spondylarthritis (4%). ITI occurred more often in diagnoses with frequent arthritis of the hands (P < 0.001) and increased acute-phase reactants (P < 0.001). Within RA, ITI occurred together with local MCP joint synovitis (odds ratio [OR] 2.4, 95% confidence interval [95% CI] 1.7-3.4), tenosynovitis (OR 2.4, 95% CI 1.8-3.3), and osteitis (OR 2.2, 95% CI 1.6-3.1) on MRI. Moreover, ITI presence was associated with local MCP joint tenderness (OR 1.6, 95% CI 1.2-2.1) and swelling (OR 1.8, 95% CI 1.3-2.6), independent of age and MRI-detected synovitis/tenosynovitis/osteitis. CONCLUSION: ITI occurs regularly in RA and other arthritides with preferential involvement of hand joints and increased acute-phase reactants. At the MCP joint level, ITI associates independently with joint tenderness and swelling. Hence, ITI is a newly identified inflamed tissue mainly found in arthritides with particularly extensive and symptomatic inflammation.

Down-regulated GAS6 impairs synovial macrophage efferocytosis and promotes obesity-associated osteoarthritis.

Obesity has always been considered a significant risk factor in osteoarthritis (OA) progression, but the underlying mechanism of obesity-related inflammation in OA synovitis remains unclear. The present study found that synovial macrophages infiltrated and polarized in the obesity microenvironment and identified the essential role of M1 macrophages in impaired macrophage efferocytosis using pathology analysis of obesity-associated OA. The present study revealed that obese OA patients and Apoe-/- mice showed a more pronounced synovitis and enhanced macrophage infiltration in synovial tissue, accompanied by dominant M1 macrophage polarization. Obese OA mice had a more severe cartilage destruction and increased levels of synovial apoptotic cells (ACs) than OA mice in the control group. Enhanced M1-polarized macrophages in obese synovium decreased growth arrest-specific 6 (GAS6) secretion, resulting in impaired macrophage efferocytosis in synovial ACs. Intracellular contents released by accumulated ACs further triggered an immune response and lead to a release of inflammatory factors, such as TNF-α, IL-1ß, and IL-6, which induce chondrocyte homeostasis dysfunction in obese OA patients. Intra-articular injection of GAS6 restored the phagocytic capacity of macrophages, reduced the accumulation of local ACs, and decreased the levels of TUNEL and Caspase-3 positive cells, preserving cartilage thickness and preventing the progression of obesity-associated OA. Therefore, targeting macrophage-associated efferocytosis or intra-articular injection of GAS6 is a potential therapeutic strategy for obesity-associated OA.

[Remitting seronegative symetrical synovitis with pitting edema. One case report]. / Sinovitis simétrica seronegativa remitente con edema y fóvea. Presentación de un caso.

Background: RS3PE (remitting seronegative symmetrical synovitis with edema and pitting) is a rare entity of unknown etiology that has been related to genetic predisposition due to the presence of HLA-A2 in 50% of cases and less frequently HLA-B7. Its pathogenesis is unknown, but it has been related to growth factors, and some mediators (TNF, IL-6). It is common in elderly people and the course of this illness presents with acute symmetrical polyarthritis, accompanied by edema in hands and feet. The diagnosis requires a high index of suspicion and to differentiate it from other entities such as rheumatoid arthritis, complex regional pain syndrome, rheumatic polymyalgia, in addition to ruling out malignant neoplasms, since there are many reports of its association with both solid and hematological neoplasms, being of bad prognosis when there is association. When there is no association with cancer, it responds well to the use of low doses of steroids and its prognosis is usually favorable. Clinical case: 80-year-old woman with an acute onset with polyarthralgia, functional limitation associated with pitting edema in hands and feet. After approaching the patient and ruling out associated neoplasms, it was diagnosed RS3PE. It was managed with prednisone, observing a good response, with remission of the manifestations at 6 weeks and subsequent suspension of the steroid. Conclusions: RS3PE is a rare entity, and a high index of suspicion is required for the diagnosis. A complete approach is important to rule out cancer in patients affected with this syndrome. Prednisone continues to be the best therapeutic option.

Introducción: la RS3PE (sinovitis simétrica seronegativa remitente con edema y fóvea) es una entidad rara de etiología desconocida que se ha relacionado con predisposición genética por la presencia de HLA-A2 en el 50% de los casos y con menor frecuencia HLA-B7. Se desconoce su patogenia, pero se ha relacionado con factores de crecimiento y algunos mediadores (TNF, IL-6). Se presenta en personas de edad avanzada, cursa con poliartritis aguda simétrica, acompañada de edema en manos y pies. El diagnóstico requiere de un alto índice de sospecha y diferenciarlo de otras entidades como artritis reumatoide, síndrome de dolor regional complejo, polimialgia reumática, además de descartar neoplasias malignas, ya que existen muchos reportes de su asociación con neoplasias tanto sólidas como hematológicas y es de mal pronóstico cuando existe asociación. Cuando no existe asociación con cáncer tiene buena respuesta al uso de dosis bajas de esteroides y su pronóstico suele ser favorable. Caso clínico: mujer de 80 años con un cuadro de inicio agudo con poliartralgias, limitación funcional asociada a edema de manos y pies con fóvea. Después del abordaje y de descartar neoplasias asociadas, se diagnosticó RS3PE. Se manejó con prednisona y hubo buena respuesta, con remisión de las manifestaciones a las 6 semanas y suspensión posterior del esteroide. Conclusiones: la RS3PE es una entidad rara y para diagnosticarla se requiere un alto índice de sospecha. Es importante el abordaje completo para descartar cáncer en los pacientes afectados con este síndrome. La prednisona continúa siendo la mejor opción terapéutica.

Rare Case of Remitting Seronegative Symmetrical Synovitis with Pitting Edema Syndrome with Monoclonal Gammopathy of Undetermined Significance.

BACKGROUND Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare condition with underlying polyarthritis, pitting edema, and negative rheumatoid factor. It can be associated with an underlying rheumatological condition or can present as a paraneoplastic syndrome with malignancy. We present a rare case of RS3PE associated with monoclonal gammopathy of undermined significance (MGUS). CASE REPORT A 62-year-old man presented in ambulatory medicine clinic with 3-month swelling of distal lower extremities that progressed to distal upper extremities. He had pain and morning stiffness in hands, left elbow, and left shoulder. Examination revealed 3+ pitting edema in bilateral hands, feet, legs, and thighs. Laboratory studies revealed normal blood counts and renal and liver functions. Erythrocyte sedimentation rate was normal; C-reactive protein was mildly elevated (0.7 mg/dL). Echocardiogram and computed tomography of chest, abdomen, and pelvis revealed mild splenomegaly (14.5 cm). Serum protein electrophoresis revealed IgG kappa monoclonal peak of 0.1 g/dL. Beta-2 microglobulin was elevated (7.4 mg/L); LDH was elevated (264 U/L). No lytic lesions were present in bones. RS3PE was diagnosed based on established diagnostic criteria. Prednisone produced significant improvement in swelling within 72 h of start; however, he required a longer duration of steroid treatment due to relapse and continued periodic MGUS surveillance. CONCLUSIONS Our case highlights the importance of awareness of this condition in general practice to help with timely diagnosis and intervention, as this condition is steroid responsive. Also, it is important to screen for underlying autoimmune condition, hematological, and solid organ malignancies with appropriate workup.

Functional decline in persons with haemophilia and factors associated with deterioration.

INTRODUCTION: The World Haemophilia Federation advises regular musculoskeletal assessment covering all International Classification of Functioning and Health (ICF) domains, including limitations in activities and participation in persons with haemophilia (PWH). This enables clinicians to detect changes early and enable adjustments in personalized healthcare when needed. However, data on the course of physical functioning and occurrence of decline is lacking. The aim of this study is to describe changes in perceived limitations in activities of PWH and to identify factors associated with a change. METHODS: Data were collected from medical health records of regular check-up visits of adults with moderate and severe haemophilia in two time periods. Perceived limitations in activities was measured with the Haemophilia Activities List (HAL). Association between variables (e.g., age, body mass index, bleeding rate and synovitis) and change in perceived limitations was assessed using a generalized linear model. RESULTS: A total of 104 PWH were included. At T0, the median HAL sum score was 79.5 (IQR 62.1-93.6) and at T1 the median HAL sum score was 74.2 (IQR 57.5-88.3). A functional decline was found in 35.6% of PWH, 55.8% remained stable and 8.7% improved. Among other variables, a BMI > 30 kg/m2 appeared to be an important factor that negatively influenced the change in perceived functioning in adult PWH. With the included factors we could only explain a small part of this decline (R2 adj : .12). CONCLUSION: The majority of PWH remained stable in their perceived functional ability over mid-long term (median 3.5 years). However, about a third showed a clinical relevant decline in their functional ability.

Activated macrophage membrane-coated nanoparticles relieve osteoarthritis-induced synovitis and joint damage.

Osteoarthritis (OA) is a common joint condition that is a leading cause of disability worldwide. There are currently no disease-modifying treatments for osteoarthritis, which is associated with multiple kinds of inflammatory cytokines produced by M1 macrophages in the synovium of the joint. Despite recent therapeutic advancements with anti-cytokine biologics, the OA therapy response rate continues to be inadequate. To treat OA, the pro-inflammatory and anti-inflammatory responses of synoviocytes and macrophages must be controlled simultaneously. Therefore, the immune regulation capabilities of an ideal nano-drug should not only minimize pro-inflammatory responses but also effectively boost anti-inflammatory responses. In this paper, an M2H@RPK nanotherapeutic system was developed, KAFAK and shRNA-LEPR were condensed with polyethylenimine (PEI) to form a complex, which was then modified with hyaluronic acid (HA) to negatively charge to cover the M2 membrane. It was discovered that the repolarization of macrophages from the M1 to the M2 phenotype lowered pro-inflammatory responses while enhancing anti-inflammatory responses in macrophages and synoviocytes. In vitro and in vivo studies demonstrate that M2H@RPK dramatically decreases proinflammatory cytokines, controls synovial inflammation, and provides significant therapeutic efficacy by reducing joint damage. Overall, it has been demonstrated that M2H@RPK provides inflammation-targeted therapy by macrophage repolarization, and it represents a promising OA therapeutic strategy.

[Paraneoplastic syndromes in rheumatology]. / Paraneoplastische Syndrome in der Rheumatologie.

Paraneoplastic syndromes in rheumatology are a group of canonical rare rheumatic diseases with musculoskeletal involvement that occur in close temporal and causal association with malignancies. Knowledge of these possibly enables a prognostically relevant early diagnosis of the underlying malignant disease. In the era of immune checkpoint inhibitor treatment, there are first indications of an increase in the incidence and severity of paraneoplastic syndromes, so that they are becoming of increasing importance for the practicing rheumatologist. These nine syndromes, paraneoplastic arthritis, palmar fasciitis and polyarthritis, remitting seronegative symmetrical synovitis with pitting edema, pancreatic panniculitis with polyarthritis, paraneoplastic vasculitis, cancer-associated myositis, hypertrophic osteoarthropathy (Marie-Bamberger), eosinophilic fasciitis and tumor-induced osteomalacia, usually occur with characteristic courses and sometimes pathognomonic clinical manifestations, which are presented in this article accompanied by the rational use of a diagnostic algorithm for tumor detection. With frequently disappointing therapeutic response to glucocorticoids, nonsteroidal antirheumatic drugs and immunosuppressants, treatment of the underlying malignant disease represents the crucial step in the treatment of paraneoplastic syndromes.

Synovitis and joint health in patients with haemophilia: Statements from a European e-Delphi consensus study.

INTRODUCTION: Synovitis, a common feature in haemophilia, is triggered by the presence of blood in joints, and represents the first step towards the development of chronic arthropathy. Synovitis may be detected early by means of ultrasound or magnetic resonance imaging scan; clinical joint scores are less sensitive in this setting. Regular long-term prophylaxis with clotting factor concentrates, as primary prophylaxis and tailored to individual needs, has high efficacy in preventing synovitis. In general, higher factor levels lower bleeding risk, but no direct correlation between factor levels and synovitis incidence has been demonstrated. AIM: This study aimed to develop an expert consensus relating to the definition, pathophysiology, diagnosis, prevention, follow-up and treatment of synovitis, recognising its relevance for joint health and taking into account existing knowledge gaps. METHODS: A Delphi consensus study was designed and performed. An expert group prepared 22 statements based on existing literature; a wider expert panel subsequently voted on these. RESULTS: Retention of panellists was high. Four statements required amending and consensus on all statements was achieved after three rounds of voting. CONCLUSION: This e-Delphi consensus study addressed the importance of synovitis in joint health of people with haemophilia and highlighted knowledge gaps in this field. Studies on the natural course of synovitis are lacking and the biological mechanisms underlying this process are not yet fully elucidated. While basic and clinical research proceeds in this field, expert consensus can help guide clinicians in their routine clinical practice, and Delphi methodology is often used to produce best-practice guidelines.

The development of ankylosing spondylitis in a patient with familial hemophilia.

Hemophilia is a rare inherited disease which causes bleeding due to Factor VIII or Factor IX deficiency. It is usually X-linked recessive and typically affects males. Arthropathy occurs as a result of cartilage damage and chronic synovitis due to recurrent intra-articular bleeding in hemophilic patients and is mostly seen in the knee, shoulder, hip and ankle joints. There are many other diseases that cause chronic synovitis ankylosing spondylitis (AS), which is a subtype of spondyloarthropathies that cause chronic low back pain, more common in men younger than 45 years of age. In addition to axial involvement, peripheral arthritis, uveitis, enthesitis and dactylitis can be seen. Although the etiology is not fully known, genetic and environmental factors are responsible for the pathogenesis. In this study, we aimed to present congenital hemophilia and AS coexistence in a 22-year-old male patient.

Efficacy and safety of GLucocorticoid injections into InfrapaTellar faT pad in patients with knee ostEoarthRitiS: protocol for the GLITTERS randomized controlled trial.

BACKGROUND: Knee osteoarthritis (OA) is a prevalent disabling disorder that involves changes in articular cartilage damage, subchondral bone remodeling, synovitis, and abnormal infrapatellar fat pad (IPFP). Due to the complicated etiology and numerous phenotypes of knee OA, limited improvement is achieved for treatments among knee OA patients with different phenotypes. Inflammatory OA phenotype is a typical knee OA phenotype, and individualized treatment targeting inflammation is a promising way to obtain an optimal therapeutic effect for people with inflammatory knee OA phenotype. Glucocorticoid is a traditional anti-inflammatory drug for knee OA, and intra-articular glucocorticoid injections are recommended clinically. However, emerging evidence has shown that repeated intra-articular glucocorticoid injections in the long term would induce cartilage loss. IPFP and its adjacent synovium are considered as the main source of inflammation in knee OA. This GLITTERS trial aims to investigate if a glucocorticoid injection into the IPFP is effective and safe over 12 weeks among knee OA patients with an inflammatory phenotype. METHODS: GLITTERS is a multicenter, double-blinded, randomized, and placebo-controlled clinical trial among knee OA patients with both Hoffa-synovitis and effusion-synovitis. Sixty participants will be allocated randomly and equally to either the glucocorticoid group or the control group. Each group will receive an injection of glucocorticoid or saline into the IPFP with an intra-articular hyaluronic acid injection as a background treatment at baseline and be followed at 4, 8, and 12 weeks. The primary outcomes will be changes in knee pain on a visual analog scale and effusion-synovitis volume measured on magnetic resonance imaging (MRI). The secondary outcomes will be changes in the total score of Western Ontario and McMaster Universities Osteoarthritis Index score, MRI-detected Hoffa-synovitis score, quality of life, pain medication use, IPFP volume, and the incidence of adverse reactions. Data analyses based on the intention-to-treat principle will include mixed-effects regressions, Wilcoxon rank-sum tests, and chi-square tests (or Fisher's exact test). DISCUSSION: GLITTERS may provide high-quality evidence for the efficacy and safety of ultrasound-guided glucocorticoid injections into IPFP among people with inflammatory knee OA in a short term. The results of this trial are expected to provide a reliable reference for a longer-term risk-benefit profile of this treatment in the future. TRIAL REGISTRATION: ClinicalTrials.gov NCT05291650. Registered on 23 March 2022.