Study protocol for a randomised controlled trial of diacerein versus placebo to treat knee osteoarthritis with effusion-synovitis (DICKENS).

BACKGROUND: There is an unmet need for treatments for knee osteoarthritis (OA). Effusion-synovitis is a common inflammatory phenotype of knee OA and predicts knee pain and structural degradation. Anti-inflammatory therapies, such as diacerein, may be effective for this phenotype. While diacerein is recommended for alleviating pain in OA patients, evidence for its effectiveness is inconsistent, possibly because studies have not targeted patients with an inflammatory phenotype. Therefore, we will conduct a multi-centre, randomised, placebo-controlled double-blind trial to determine the effect of diacerein on changes in knee pain and effusion-synovitis over 24 weeks in patients with knee OA and magnetic resonance imaging (MRI)-defined effusion-synovitis. METHODS: We will recruit 260 patients with clinical knee OA, significant knee pain, and MRI-detected effusion-synovitis in Hobart, Melbourne, Adelaide, and Perth, Australia. They will be randomly allocated to receive either diacerein (50mg twice daily) or identical placebo for 24 weeks. MRI of the study knee will be performed at screening and after 24 weeks of intervention. The primary outcome is improvement in knee pain at 24 weeks as assessed by a 100-mm visual analogue scale (VAS). Secondary outcomes include improvement in volumetric (ml) and semi-quantitative (Whole-Organ Magnetic Resonance Imaging Score, 0-3) measurements of effusion-synovitis using MRI over 24 weeks, and improvement in knee pain (VAS) at 4, 8, 12, 16, and 20 weeks. Intention-to-treat analyses of primary and secondary outcomes will be performed as the primary analyses. Per protocol analyses will be performed as the secondary analyses. DISCUSSION: This study will provide high-quality evidence to determine whether diacerein improves pain, changes disease trajectory, and slows disease progression in OA patients with effusion-synovitis. If diacerein proves effective, this has the potential to significantly benefit the substantial proportion (up to 60%) of knee OA patients with an inflammatory phenotype. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry ACTRN12618001656224 . Registered on 08 October 2018.

Reactive synovitis of the knee joint after COVID-19 vaccination: The first ultrastructural analysis of synovial fluid.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus 2019 disease (COVID-19) have spread all around the world since 2019 and have affected millions of people. The development of COVID-19 vaccines helped to decelerate the spread of the virus. However, as in the case of vaccines against other infectious diseases, adverse events can also present with COVID-19 vaccines. CASE PRESENTATION: We report here a rare case of a 53-year-old man with knee-joint synovitis, after the first dose of messenger RNA vaccine, with no fever and a negative COVID-19 reverse transcription polymerase chain reaction test. During a clinical examination the suspicion of pyogenic arthritis was excluded by blood tests and by a complex joint effusion examination, including a microbiological and cytological-energy analysis of the synovial fluid. The treatment received by our patient consisted of 3 doses of dexamethasone administered intravenously over a period of 3 days. All the symptoms improved after this therapy, and in the 3-week follow-up period we recorded full recovery with no consequences. CONCLUSION: Case reports on patients undergoing COVID-19 vaccination should be examined in order to detect rare and long-term side-effects. This is the first report to present the outcomes of an ultrastructural analysis of post-vaccination synovitis.

Can SARS-CoV-2 infection trigger Rheumatoid Arthritis? A case-report (preprint)

A 38-year-old female developed chronic joint pain one month after testing positive for SARS-CoV2. Physical examination revealed warmth and tenderness of the wrists and small joints of the hands. Rheumatoid factor and anti-CCP were elevated. Hands MRI showed synovitis of small joints. The patient was diagnosed with rheumatoid arthritis (RA).

METHODS - A randomised controlled trial of METhotrexate to treat Hand Osteoarthritis with Synovitis: study protocol for a randomised controlled trial.

BACKGROUND: Hand osteoarthritis is a common and disabling problem without effective therapies. Accumulating evidence suggests the role of local inflammation in causing pain and structural progression in hand osteoarthritis, and hand osteoarthritis with synovitis is a commonly encountered clinical phenotype. Methotrexate is a well-established, low-cost, and effective treatment for inflammatory arthritis with a well-described safety profile. The aim of this multicentre, randomised, double-blind, placebo-controlled trial is to determine whether methotrexate reduces pain over 6 months in patients with hand osteoarthritis and synovitis. METHODS: Ninety-six participants with hand osteoarthritis and synovitis will be recruited through the Osteoarthritis Clinical Trial Network (Melbourne, Hobart, Adelaide, and Perth), and randomly allocated in a 1:1 ratio to receive either methotrexate 20 mg or identical placebo once weekly for 6 months. The primary outcome is pain reduction (assessed by 100 mm visual analogue scale) at 6 months. The secondary outcomes include changes in physical function and quality of life assessed using Functional Index for Hand Osteoarthritis, Australian Canadian Osteoarthritis Hand Index, Health Assessment Questionnaire, Michigan Hand Outcomes Questionnaire, Short-Form-36, tender and swollen joint count, and grip strength, and structural progression assessed using progression of synovitis and bone marrow lesions from magnetic resonance imaging and radiographic progression at 6 months. Adverse events will be recorded. The primary analysis will be by intention to treat, including all participants in their randomised groups. DISCUSSION: This study will provide high-quality evidence to address whether methotrexate has an effect on reducing pain over 6 months in patients with hand osteoarthritis and synovitis, with major clinical and public health importance. While a positive trial will inform international clinical practice guidelines for the management of hand osteoarthritis, a negative trial would be highly topical and change current trends in clinical practice. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000877381. Registered 15 June 2017, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373124.

"Lessons from Rare Forms of Osteoarthritis".

Osteoarthritis (OA) is one of the most prevalent conditions in the world, particularly in the developed world with a significant increase in cases and their predicted impact as we move through the twenty-first century and this will be exacerbated by the covid pandemic. The degeneration of cartilage and bone as part of this condition is becoming better understood but there are still significant challenges in painting a complete picture to recognise all aspects of the condition and what treatment(s) are most appropriate in individual causes. OA encompasses many different types and this causes some of the challenges in fully understanding the condition. There have been examples through history where much has been learnt about common disease(s) from the study of rare or extreme phenotypes, particularly where Mendelian disorders are involved. The often early onset of symptoms combined with the rapid and aggressive pathogenesis of these diseases and their predictable outcomes give an often-under-explored resource. It is these "rarer forms of disease" that William Harvey referred to that offer novel insights into more common conditions through their more extreme presentations. In the case of OA, GWAS analyses demonstrate the multiple genes that are implicated in OA in the general population. In some of these rarer forms, single defective genes are responsible. The extreme phenotypes seen in conditions such as Camptodactyly Arthropathy-Coxa Vara-pericarditis Syndrome, Chondrodysplasias and Alkaptonuria all present potential opportunities for greater understanding of disease pathogenesis, novel therapeutic interventions and diagnostic imaging. This review examines some of the rarer presenting forms of OA and linked conditions, some of the novel discoveries made whilst studying them, and findings on imaging and treatment strategies.

Remitting seronegative symmetrical synovitis with pitting oedema following BNT162b2 mRNA COVID-19 vaccination.

Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) is a rare inflammatory condition that occurs in older adults. Here, we report a case of an 80-year-old man with no history of rheumatic disease who presented with acute onset of bilateral hand pain, pitting oedema and synovitis after the second dose of the BNT162b2 mRNA C0VID-19 vaccine. Laboratory workup revealed elevated inflammatory markers and negative autoantibodies. Significant improvement was noted with prednisolone. This is the first reported case of RS3PE in an elderly patient with no previous rheumatic disease following mRNA COVID-19 vaccination.

Post nCoV-2 limping Child: Report of two cases and a rapid Review (preprint)

Background: Identification of the etiology of acute limping in children is challenging. Both benign and life- threatening disorders can present with limp. However, among atraumatic conditions, benign conditions including toxic synovitis and post infectious arthritis are the most common causes of this dilemma. Case Presentation: During the recent COVID-19 pandemic in Kerman, South East of Iran; two pediatric patients referred to the Rheumatology clinic with new onset gait disturbance. One 8 years old boy and the other 6 years old girl who presented with hip joint pain and limping. Both of them had joint effusion jackknife of mild respiratory symptoms and fever. Altogether, precise history taking and accurate physical examination, alongside radiological investigations and positive laboratory results for coronavirus infection emphasized the diagnosis of post Coronavirus arthritis.  They treated with rest and Non-Steroidal Anti-Inflammatory Drugs (NSAID) successfully, and fallowed at least for one month later.Conclusions: Here, we described the first report of post n-CoV-2 arthritis in the world in two Iranian pediatric patients, who presented with limp. Contrary to preliminary phantasms, this may indicate that the Corona virus has some rheumatogenic specifications.