AVASCULAR NECROSIS OF THE FEMORAL HEAD – NOT TO BE OVERLOOKED SEQUELA AFTER COVID 19 INFECTION

BackgroundCOVID 19 infection could lead to different sequelae in survivors, known as post-COVID or long COVID 19 syndromes. Some of them are thought to be due to the thrombophylic changes observed in COVID 19 infection, but some are thought to be caused by the administrated (especially high dose) corticosteroid treatment. Avascular necrosis of the femoral head (AVNFH) is a multifactorial disease which leads to compromised vascular supply, ischemia and finally necrosis of the femoral head. As corticosteroids usage and thrombophylic states are among the main known risk factors for the development AVNFH [1], it could be presumed that the frequency of this disease will increase with the COVID 19 pandemic. The exact corticosteroid dose needed for the development of AVNFH is not clear, but it has been stated that a higher daily dose and a larger total cumulative dose increase substantially the risk for the development of osteonecrosis [2].ObjectivesTo describe in detail the characteristics of AVNFH diagnosed in patients after COVID 19 infection.MethodsThe study was done in a tertiary university rheumatological clinic. Data was extracted from the records of patients who have been referred to the clinic because of hip pain between June and December 2022. Inclusion criteria were: - a new onset of uni-or bilateral hip pain that started after a documented COVID 19 infection;and an MRI scan of the hip joints showing osteonecrosis of one or both femoral heads. Exclusion criteria were the presence of hip pain prior to the COVID 19 infection, anamnesis of traumatic injuries of the hips or pelvis, personal history of hypercoagulable states.ResultsNine patients (4 women and 5 men) with an average age 59.1 years (range 38-72) were included in the study. Four patients had been diagnosed with bilateral and five – with unilateral AVNFH, thus 13 hip joints were analysed in total (8 left and 5 right sided). The mean time lap between the COVID 19 infection and the start of the hip pain was 26.2 weeks (range 10-48 weeks). All patients had limited and painful movement in their symptomatic hip(s), especially internal rotation and four of the patients had also elevated CRP levels (mean 11.7 mg/L). The stage of the AVNFH was evaluated according to the Ficat-Arlet classification (0-IV stage). In four hips the AVNFH was stage I, five hips were classified as stage II and the remaining four joints - as stage III. All symptomatic hip joints exhibited effusion/synovitis on both ultrasound examination and the corresponding MRI scan. It should be noted that the presence of hip effusion was found to be related with a worse prognosis in AVNFH [1]. In three patients the amount of the effusion required arthrocentesis and fluid aspiration. The analysis of the joint fluid was consistent with a degenerative disease (i.e., low WBC count with predominant lymphocytes and no crystals). All patients included in our study had received corticosteroids during their COVID19 infection, while 6 of the patients had also been hospitalized due to more severe disease. According to the patients' documentation, the mean cumulative dose of the received corticosteroids was 936.2 mg prednisolone equivalent per patient (range 187-2272 mg).ConclusionAVNFH must not be overlooked in a new onset hip pain after COVID 19 infection. Our results show that corticosteroids administrated during the infection and the presence of hip joint effusion on ultrasound are especially suggestive for the development of osteonecrosis, as they were registered in all of our patients. The presence of these two factors necessitates patient referral for an MRI scan of the hips, in order that AVNFH be detected timely.References[1]Petek D, Hannouche D, Suva D. Osteonecrosis of the femoral head: pathophysiology and current concepts of treatment. EFORT Open Rev. 2019 Mar 15;4(3):85-97.[2]Kerachian MA, Séguin C, Harvey EJ. Glucocorticoids in osteonecrosis of the femoral head: a new understanding of the mechanisms of action. J Steroid Biochem Mol Biol. 2009 Apr;114(3-5):121-8.Acknowledgements:NIL.Disclosur of InterestsPLAMEN TODOROV Speakers bureau: speaker at national level for AbbVie, Novartis and UCB, Lily Mekenyan: None declared, Anastas Batalov Speakers bureau: Speaker at national level for AbbVie, Novartis, Pfizer, Stada, Elly Lilly.

REAL WORLD EXPERIENCE OF MODERATE DISEASE ACTIVITY STATE (MDAS) RA PATIENTS OVER 4-YEAR FOLLOW-UP

BackgroundIn recent years despite improved therapies for RA, there is an increased awareness of persistent pain in people with RA. Before the pandemic we assessed a large group of patients with RA with comprehensive joint ultrasound (US) and for presence of fibromyalgia (FM) meeting 2010 ACR diagnostic criteria. When combinations of synovitis and/or FM were made we noted 4 groups of patients. As well as some with only FM, we also noted a group we believe had peripheral non-inflammatory pain, a new concept in RA. Here we investigate if these different groups change over time in our T2T routine care pathway.ObjectivesTo assess the progress and outcomes patients with RA with different well defined pain states during 4 years of follow up including the COVID19 pandemic.MethodsThe TITRATE-ULTRASOUND patient cohort categorised patients with RA into 4 groups depending on the presence or absence FM and the presence or absence of power doppler synovitis (PD, defined as positive PD signal in ≥2 joints in a 44 joint US). We identified 72 patients with active RA (DAS28 3.2 – 5.1) from this cohort with sufficient clinical data during the study period and collected the following data on each follow up encounter: visit type, treatment changes and disease activity measures. In the COVID19 pandemic follow up visits were largely virtual without the ability to collect physician assessed disease activity scores. Progress assessment was performed as to whether the patient had improved, no change or worse with a numerical value of +1, 0 and -1 at each visit to calculate a score tracking patient progress during the pandemic. Statistical analysis was performed using 1-way ANOVA to assess for difference between the 4 groups.Results72 patients with were assigned into the following categories: FM-PD-, 12 (peripheral pain group);FM-PD+,18;FM+PD-, 29;FM+PD+, 13. Table 1 shows baseline characteristics of the 4 groups and reveals no significant difference by ANOVA between the 4 groups in total visits, face to face visits, telephone visits, tender joint count, treatment escalations, steroid prescriptions, csDMARD prescriptions, and progress score. Biologic prescriptions did vary significantly between the groups (p = 0.009).Table 1.FM-PD- (n=12)FM-PD+ (n=18)FM+PD- (n=29)FM+PD+ (n=13)ANOVA p-valueFemale (n, %)10 (83%)13 (72%)24 (83%)13 (92%)CCP+ve (n, %)4 (33%)12 (67%)14 (48%)6 (46%)Disease duration (years) (mean, SEM)11.04 (2.676)16.19 (2.889)12.29 (1.709)16.23 (3.340)On csDMARD (n, %)11 (92%)15 (83%)24 (83%)10 (77%)On bDMARD (n, %)4 (33%)5 (28%)7 (24%)8 (61.5%)Baseline DAS28 (mean, SEM)4.412 (0.1641)4.344 (0.1177)4.192 (0.08910)4.366 (0.1461)Total visits (mean, SEM)11.67 (2.647)10.50 (2.031)8.724 (1.039)8.308 (1.407)0.533F2F visits (mean, SEM)7.909 (2.164)7.944 (1.924)5.793 (1.033)5.769 (1.311)0.5959Telephone visits (mean, SEM)4.417 (1.474)2.556 (0.3154)2.931 (0.3327)2.538 (0.6162)0.2268Tender joint count (mean, SEM)3.604 (1.101)3.506 (0.6177)5.376 (0.6899)4.603 (1.246)0.3179Treatment escalations (mean, SEM)2.917 (1.062)3.722 (1.028)2.000 (0.5526)1.615 (0.6257)0.2671Steroid prescriptions (mean, SEM)1.833 (0.7160)1.611 (0.5310)1.000 (0.3908)0.7692 (0.5329)0.503csDMARD prescriptions (mean, SEM)0.7500 (0.3046)0.7778 (0.2070)0.5185 (0.1634)0.3636 (0.2787)0.5789Biologic prescriptions (mean, SEM)0.3333 (0.2247)1.778 (0.6291)0.3793 (0.1257)0.3077 (0.2371)0.009Progress score (mean, SEM)-1.167 (1.461)0.6111 (0.3889)-0.1379 (0.2366)0.4615 (0.6265)0.2579ConclusionOver the follow-up period we show the management of RA patients without active power doppler synovitis or fibromyalgia did not differ significantly from other categories of patients. Similar numbers of visits, treatment escalations, csDMARDs and corticosteroid prescriptions were observed. This illustrates how it can be difficult to define the specific causes of disease activity without access to US. Despite similar management strategies, FM-PD- patients tended towards worse progress scores, suggesting a potential unmet need in such patients.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of In erestsMark Gibson: None declared, Nadia Ladha Hassan: None declared, L Bruce Kirkham Speakers bureau: Abbvie, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, UCB, Consultant of: Abbvie, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, UCB, Grant/research support from: Eli Lilly.

Reactive Arthritis Following Coronavirus 2019 Infection in a Pediatric Patient: A Rare Case Report.

Reactive arthritis (ReA) following Coronavirus 2019 (COVID-19) infection has been described mainly in adults, and only two pediatric cases have been reported. We report a third case where ReA was found to be a sequela following COVID-19 infection. A 15-year-old right-handed Caucasian girl presented with severe left-wrist pain. She was experiencing fever, rash, and migratory oligoarthritis, and laboratory work-up showed elevated inflammatory markers and a positive COVID-19 IgG antibody test. Imaging revealed inflammatory arthropathy with wrist synovitis. The patient was diagnosed with ReA following COVID-19 infection and was treated surgically by wrist arthroscopic synovectomy after the failure of conservative management. It has been 1 year after her surgery, and she is doing well. Emerging case reports are linking ReA as a delayed response to COVID-19 infection; therefore, ReA should be included in the list of differential diagnoses in all patients with joint pain following COVID-19 infection.

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.

A review of fibroblast-like synoviocytes in the pathogenesis of Rheumatoid arthritis: Their activation and the inhibition of their apoptosis

Rheumatoid Arthritis (RA) is a systemic, autoimmune, inflammatory disease characterized by synovial hyperplasia, inflammatory cell infiltration in the synovial tissues, and progressive destruction of cartilage and bones. This disease often leads to chronic disability. More recently, activation of synovial fibroblasts (SFs) has been linked to innate immune responses and several cellular signalingpathways that ultimately result in the aggressive and invasive stages of RA. SFs are the major sources of pro-inflammatory cytokines in RA synovium. They participate in maintaining the inflammatory state that leads to synovial hyperplasia and angiogenesis in the inflamed synovium. The altered apoptotic response of synovial and inflammatory cells has been connected to these alterations of inflamed synovium. RA synovial fibroblasts (RASFs) have the ability to inhibit several apoptotic proteins that cause their abnormal proliferation. This proliferation leads to synovial hyperplasia. Apoptotic pathway proteins have thus been identified as possible targets for modifying the pathophysiology of RA. This review summarizes current knowledge of SF activation and its roles in the inhibition of apoptosis in the synovium, which is involved in joint damage during the effector phase of RA development.Copyright © 2022 Biomedpress.

When and What to Consider Knee Arthroscopy Surgery in Post-COVID 19 Infected Patients

Coronavirus disease 19 (COVID-19) is the worst pandemic ever recorded in history, as of this day more than 545 million people infected and more than 6 million cumulative deaths. COVID 19 is primarily respiratory disease, however non-respiratory presentations that could be manifested are venous and arterial thromboembolic events. Both pulmonary embolism (PE) and deep vein thrombosis (DVT) are the most frequently thrombotic events in COVID-19. Knee arthroscopy surgery is the one of the most common orthopedic surgical procedures nowadays, with the most common procedures are meniscectomy, meniscal repair and cruciate ligament reconstruction. Although knee arthroscopy is known to be a safe procedure, several complications could be found with the 3 most common complications are DVT, effusion and synovitis, and PE. We reported a case series of four patients with DVT post knee arthroscopy anterior cruciate ligament reconstruction during 2021. The DVT diagnosis was retained on clinical presentation and elevated of D-dimer testing. The patient's mean age was 35,25 years, and all of the patients had no risk factors of DVT, although they had COVID-19 infection within 3 months before surgery. The most common clinical presentation was swelling on the lower leg (around the ankle) with slightly pain and numbness. Only one patient had severe pain around the thigh. All of the patients had elevated D-dimer testing result with mean of D-dimer 1250 (normal value < 500). Only one patient had sonography testing and found proximal DVT. One of the patients had DVT at post operative day (POD) 3, one at POD 4 and the other two at POD 5. Three of the patients improved with oral anticoagulant therapy using rivaroxaban (XARELTO). In one patient the symptom was not improved after two days oral anticoagulant therapy and underwent thrombectomy by vascular surgeon. DVT is the most common complication of knee arthroscopy and also the most common non-respiratory events of COVID-19 infection. Routinely administration of thromboprophylaxis agent was not recommended, pre-operative risk assessment of DVT should be used, especially in post-COVID 19 patients.

A case of de novo seronegative inflammatory oligoarthritis associated with COVID-19 infection

Infection with SARS-CoV-2 (COVID-19) virus is characterized by an acute respiratory viral illness, often accompanied by extrapulmonary manifestations. Musculoskeletal symptoms such as myalgias and arthralgias are observed in 60 - 70% of cases. Inflammatory arthritis associated with SARS-CoV-2 infection has been reported in the literature, however, nearly all such cases describe a post-viral or reactive phenomenon occurring a few weeks following the infection. We report a unique case of de novo arthritis at the onset of a confirmed COVID-19 infection in a 55-year-old woman. Magnetic resonance imaging demonstrated synovial enhancement consistent with synovitis. Her disease was deemed refractory after failing several immunosuppressive agents. Lastly, we compare our patient's clinical presentation with two other similar cases to understand the natural history of this emerging syndrome.Copyright © 2022

New-Onset Arthritis Following COVID-19 Vaccination: A Systematic Review of Case Reports.

Coronavirus disease 2019 (COVID-19) vaccine has effectively suppressed the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and alleviated its symptoms, but there are also many adverse events. Joint diseases caused by COVID-19 vaccine have been reported in many studies. Some are well-controlled arthritis patients who developed arthritis after COVID-19 vaccination, while others are new-onset joint pain and swelling problems after COVID-19 vaccination. The purpose of this systematic review is to examine the literature reports in existing databases and analyze the incidence of new-onset arthritis after COVID-19 vaccination. We included 31 eligible articles and described 45 patients, ranging in age from 17 to over 90, with more females than males. The majority (84.4%) of patients received the adenovirus vector vaccine (ChAdOx1) and the mRNA-based vaccine (BNT126b2 and mRNA-1273). Most (64.4%) patients developed joint-related symptoms after the first dose of vaccine, and 66.7% developed symptoms within the first week of vaccination. The joint symptoms involved were mainly joint swelling, joint pain, limited range of motion, and so on. A total of 71.1% of the patients involved multiple joints, both large and small; 28.9% of patients involved only a single joint. Some (33.3%) patients were confirmed by imaging, and the most common diagnoses were bursitis and synovitis. Two nonspecific inflammatory markers, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), were monitored in almost all cases, and all patients showed varying degrees of increase in these two markers. Most of the patients received the treatment of glucocorticoid drugs or nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical symptoms markedly improved in most patients, with 26.7% making a full recovery and no relapse after a few months of follow-up. To determine whether there is a causal relationship between COVID-19 vaccination and the triggering of arthritis, large-scale and well-controlled research studies are needed in the future to verify this relationship and to further study its pathogenesis in detail. Clinicians should raise awareness of this complication with a view to early diagnosis and appropriate treatment.

Network Pharmacological Investigation of Sinomenine Action Against Synovitis

Background and Objective: Synovitis is characterized as the inflammation of the synovial membrane, which often occurs in osteoarthritis. The incidence of this medical condition may be related to age, immunological responses and other co-morbidities. Therefore, the objective of the study was to elucidate the anti-Synovitis potential of sinomenine. Materials and Methods: The associated targets about sinomenine and synovitis were investigated in Homo sapiens, which was then elucidated by the PPI network construction via STITCH database. Furthermore, Cytoscape and its plugin were used for gene ontology (GO) analysis. Results: The literature survey and the network revealed 25 potential target proteins to be associated with sinomenine, of which many proteins such as OPRD1, CHRM1 and DAMGO were found to be significantly related to the bioactive action of sinomenine in Homosapiens. Moreover,the GO terms which were associated with the functioning of sinomenine for its anti-Synovitis potential were found to befour, analyzed by the functional annotation gene clusters and abundance values of the target proteins. Conclusion: The results of the study demonstrate the anti-Synovitis potential of sinomenine, where its action is dependent upon the molecular mechanisms that exert its beneficial role against synovitis. The core mechanisms that may be related to its anti-synovitis action may be adenylate cyclase-activating G-protein coupled receptor signalling pathway, regulation of smooth muscle contraction, adenylate cyclase-inhibiting G-protein coupled acetylcholine receptor signalling pathway and positive regulation of nitric oxide metabolic process.

POTENTIAL CREDIBILITY in RHEUMATOID ARTHRITIS PATIENT REPORTED DAS28 SCORES

Background: Due to COVID-19 and the reduction of face to face clinic, the rheumatology telephone advice line service has been an integral part in identifying patients that need assessment the most (1). This however means relying on a patient's ability to conduct their own disease activity score (DAS28), which clinicians conduct to help drive patients with rheumatoid arthritis (RA) into remission. Current literature suggests that patient self-assessed joint counts are reliable and when compared to the joint count of the physician, have an acceptable level of accuracy (2-5). We present data from an NHS audit where we incidentally found that patients could conduct their own joint counts. Objectives: Our objective was to compare self-reported DAS28 scores with the clinical opinion of physicians during a face-to-face appointment. Methods: We identifed 10 patients with RA who attended a face-to-face appointment following a call to the helpline where a telephone DAS28 score was undertaken (with guidance from rheumatology specialist nurses). These scores were contrasted against the clinician's assessment of whether synovitis was present or not in a face-to-face consultation. Co-morbidities: fbromyal-gia (FM), osteoarthritis (OA) or both, were also recorded to examine whether these conditions influenced a patient's ability to perform an accurate DAS28 score. Results: There were 10 patient self-reported DAS 28 scores in total. 70% (7/10) of patients DAS 28 scores were over 4.01. In all these cases, clinicians con-frmed evidence of synovitis during their face-to-face consultation. 30% (3/10) of patients self-reported DAS 28 score was <4.01. Of these patients 2/3 have no evidence of synovitis according to their clinician. When considering co-morbidities, one individual also suffered from OA. This individual's self-assessed DAS28 score was over 4.01 and was also evidenced to have synovitis during their consultation with the clinician. Conclusion: This regional NHS audit found that patients who self-reported DAS28 scores over 4.01 accurately identifed a fare up, as confrmed by a diagnosis of synovitis at a face-to-face appointment. This is signifcant as it demonstrates that patients who score above 4.01, can reliably assess their own joint count. This may enable the Rheumatology service to become more patient-driven, empowering patients to accurately assess their condition.

KNEE ARTHRITIS by PARACOCCIDIOIDES BRASILIENSIS in A LONG-STANDING RHEUMATOID ARTHRITIS PATIENT

Background: Arthritis by Paracoccidioides brasiliensis is a remarkably unusual etiology of infectious joint disease. While osseous lesions can be present in systemic disease, intra-articular-restricted disease without typical lung or lymph node involvement is mostly anecdotal1,2. Objectives: We hereby describe a case of this fungal arthritis in a patient with rheumatoid arthritis (RA) without signifcant immunosuppression. Methods: Patient records review. Written informed consent was obtained. Results: A 65-year-old female Brazilian patient with a 35-year history of seropositive RA complained of a painful knee edema for the last three weeks. Skin surrounding the joint was erythematous, warm, and tender to the touch, which initially raised the suspicion of cellulitis. She had already received a 10-day course of amoxicillin-clavulanate, with no improvement. C-reactive protein was 17.8 mg/L, rest of blood chemistry panel was within reference range. Point-of-care ultrasound revealed joint effusion, and a diagnostic arthrocentesis was performed. Synovial fluid was slightly turbid, with 10,100 cells per mm3, of which 80% were lymphocytes. Cultures for bacteria and mycobacteria yielded negative results, but culture for fungi detected growth of P. brasiliensis. The patient had been solely on prednisone 5 mg once daily for the last year, given that, due to covid-19 pandemics, she lost regular follow-up and abandoned treatment with immunosuppressants. Aside from mild RA-related interstitial lung disease, she had no other comorbidity. She denied local trauma to the knee, which made hematogenous dissemination of the fungi the most probable source. Comprehensive work-up to search for organic involvement of paracoccid-ioidomycosis, including chest computed tomography and transthoracic echocardiogram, did not evidence any visceral compromise. Voricona-zole 200mg t.i.d. was started, with good response. Three months after the beginning of the azole, tofacitinib was started for moderate RA disease activity, which also responded satisfactorily. Repeat arthrocentesis and synovial biopsy were performed eight months after the start of antifun-gal treatment, the former being normal (770 cells per mm3, negative cultures), and the later only demonstrating non-specific chronic synovitis with fibrosis. Conclusion: We reported an exceedingly rare presentation of P. brasiliensis infection with exclusive joint involvement.

THE PATTERN of POST COVID-19 REACTIVE ARTHRITIS

Background: According to the recent medical literature, COVID-19 disease can lead to a constellation of clinical syndromes lasting well beyond the frst 30 days of infection. The most common post COVID sequalae includes pulmonary, nervous system and neurocognitive, mental, metabolic, cardiovascular, gastrointestinal and several other clinical manifestations. Regarding joint involvement and particularly reactive arthritis (ReA), literature data is limited and describes case reports or series of cases of patients diagnosed with this condition following COVID-19 disease. Objectives: To describe the pattern and the management of post-COVID reactive arthritis. Methods: We have conducted a descriptive study of consecutive adult patients who presented to rheumatology outpatient clinic for joint or peri-articular pain/swelling/stiffness and received a diagnosis of post-COVID 19 reactive arthritis, by excluding other types of rheumatological conditions. The assessed clinical variables were: visual analogue scale (VAS) pain, swollen joint count (SJC), tender joint count (TJC), duration of morning stiffness, presence of enthesitis/tendinitis and axial involvement. Biochemistry and serology was performed: rheumatoid factor, ACPA, ANA, HLA B27, antiChlamydia Trachomatis, Ureaplasma Urealyticum and Mycoplasma Hominis Ab, anti HBs and HBc Ab, and anti HCV. COVID-19 disease prior to diagnosis of ReA was confrmed by PCR test. Results: In the study were included 16 patients with confrmed post COVID-19 ReA. The mean age of the study group was 43.5±10.8 (range 21-60), the female: male ratio was 4:1 and the duration of joint symptoms was 10.4±11.8 (range 1-42) weeks. The severity of COVID-19 disease was mild in 68.7% cases, moderate in 18.7% and severe in only 6.2% of the cases. The duration between COVID-19 diagnosis and ReA varied between cases, with a mean value of 4.3±4.2 (range 1-12) weeks. In 43.7% of the cases patients had peripheral joint involvement (synovitis), in 37.5%-periarticular involvement (enthesitis), 6.25%-isolate axial involvement (sacroiliac joints), 6.25% enthesitis and axial involvement (cervical spine) and 6.25% synovitis and enthesitis. In patients with peripheral joint pattern, the distribution of pain was symmetric (71.4%). The pattern of synovitis was determined by a TJC of 6.25±5.2 (range 1-16) joints and SJC 1.6±2.4 (range 0-7) joints. Both TJC and SJC correlated positively with the duration of morning stiffness (r=0.9 and r=0.6), but did not correlate with the VAS pain scale. In most of the cases synovitis affected the hand (wrist, MCP and PIP) 62.5% and the knee, feet and ankles-50%. Two patients presented with monoarthritis, 1 with oligoarthritis and 5 with polyarthritis, in the majority of cases, involvement being symmetric (75%). Periarticular pattern was determined by enthesi-tis, affecting the elbow and shoulder (50%), costo-sternal enthesitis (25%) and trochanteritis (25%). From the entire study group, 31.2% had elevated serum infammatory markers (ESR and/or CRP). Patients responded well to NSAIDs alone in 68.7% cases, local (intra-articular or peri-articular infltrations) or and systemic corticoids (5 mg Prednisolone equivalent) were administered in 5.3% and 12.5% cases respectively, in 12.5% cases (two patients) Methotrexate was administered. Conclusion: Reactive arthritis represents a post COVID-19 sequelae. The time of onset of ReA varied between 1 and 12 weeks after COVID-19 diagnosis. The clinical pattern of the disease was expressed by joint or periarticular involvement, mainly affecting the hand, feet and knee symmetrically. Cases of axial manifestations were less common. Most of the patients responded well to NSAIDs, only in a few particular cases, low doses of corticoids and/or Methotrexate were recommended.

AURICULAR TRANSCUTANEOUS HI-FREQUENCY E-MMUNOTHERAPY SEQUENCES (ATHENS) for the TREATMENT of RHEUMATOID ARTHRITIS: 1-YEAR CHANGES in SYNOVITIS, OSTEITIS, and BONE EROSION

Background: Current pharmacological treatments remain inadequate for a signifcant proportion of patients with rheumatoid arthritis (RA), and thus alternative treatment approaches are needed. Prior results from the frst 12 weeks of a proof-of-concept (POC) study showed that ATHENS, a non-invasive high-frequency vagus nerve therapy, was well-tolerated with meaningful reductions in RA disease severity as measured by the American College of Rheumatology response criteria (ACR) and the Disease Activity Score using 28 joints (DAS28)[1]. Objectives: The current analysis assessed long-term changes (52 weeks total follow-up) in disease activity as measured by ACR, DAS28, and the following MRI-assessed changes: synovitis, osteitis, bone erosion, and cartilage loss. Methods: Following the completion of the 12-week POC study, patients achieving a reduction in DAS28-CRP of ≥1.2 were given the option to enroll in the 9-month open-label extension (OLE) study. During the extension phase, patients were to use the wearable device for 15 minutes per day. Adjustment of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or biologic disease-modifying antirheumatic drugs (bDMARDs) were allowed during the OLE. Changes from baseline were assessed at 12 weeks (end of initial POC) and 52 weeks (end of the OLE). Structural damage and disease progression were evaluated by standardized MRI of the wrist and hand, with and without intravenous gadolinium-based contrast. MRIs were evaluated by two independent, central readers, blinded to clinical information and visit-order of the images, and were scored for synovitis, osteitis and bone erosion using the OMERACT-RAM-RIS method. Cartilage loss was also determined using the 9-point cartilage loss scale (CARLOS). Results: Twenty-seven of 30 patients completed the initial 12-week study, of whom 19 consented and entered the OLE. Of those 19 patients, 4 (21%) discontinued due to lack of efficacy, while the remaining 15 completed the 9-month extension. Due to the COVID-19 pandemic, 7 patients were unable to complete a 52-week MRI scan;MRI evaluations at baseline, 12 weeks, and 52 weeks were available for 8 patients. DAS28-CRP mean (standard deviation [SD]) change from baseline was-1.78 (1.01) at 12 weeks (n=19;p<0.0001) and-2.30 (1.22) at 52 weeks (n=15;p<0.0001). ACR20, ACR50, and ACR70 response rates were 68%, 42%, and 21% at 52 weeks (n=19;discontinued participants were deemed non-responders). MRI analysis of synovitis, osteitis, bone erosion, and cartilage loss showed no evidence of disease progression through 52 weeks compared with baseline (Table 1). During the 9-month extension study, two new adverse events were reported (cornea transplant and right hand dysesthesia) in 2 (11%) patients;neither was treatment-related and both resolved without intervention. No serious adverse events were reported. Conclusion: In patients with an initial treatment response to the Nēsos ATHENS therapy in the 12-week POC study, reductions in DAS28-CRP were sustained through 52 weeks. Although results should be interpreted cautiously given the small sample size and lack of control arm, MRI evaluation of synovitis, osteitis, bone erosion, and cartilage loss suggested no disease progression.

Limping in a Pandemic

Introduction: Transient synovitis is a common cause of hip pain in children. Patients present with acute limp, hip pain or referred pain to the knee. The mainstay of treatment consists of antiinflammatory medications and activity limitations. While the exact etiology of transient synovitis is unknown, there has been a noted relationship with an antecedent viral illness. We present one of the first reported cases of transient synovitis caused by COVID-19. Case Description: A 10-year-old male presented with concerns for left knee pain and limp. Five days prior, the patient developed general URI symptoms and was diagnosed with COVID-19, via rapid testing. His maximum temperature was 38.5°C at home and his respiratory symptoms resolved. Two days prior to presentation, he complained of left knee pain, which progressed to limp, and refusal to bear weight. He denied known injuries, trauma, visible bruising, swelling, redness, or warmth. He was afebrile and non-weight-bearing on his left leg, otherwise in no apparent distress. On physical exam, he exhibited full, painless range of motion of left knee, no bony tenderness, effusion, or cutaneous changes. There was refusal to bear weight on left leg, and significant pain with internal rotation of left hip. Lab work revealed there was no leukocytosis. C-reactive protein level and sedimentation rate were unremarkable. Radiographs of bilateral hip and pelvis, and left knee were obtained, which revealed no osseous abnormalities or significant effusion. Patient was given ibuprofen and on follow up exam he exhibited improved discomfort and willingness to bear weight. With a negative workup and clinical improvement, he was discharged with crutches, instructions for supportive care, and outpatient follow-up. Mother reported no complications during his recovery. He was able to wean from the crutches within a few days and returned to his usual gait within 3 weeks. Discussion: Transient synovitis can be clinically distinguished from septic arthritis with features of overall well appearance, lack of swelling or redness to the joint, and normal range of motion with mild pain. For our patient, Kocher criteria were helpful in distinguishing transient synovitis from septic arthritis, as well as the clinical improvement with NSAIDs. A clinical dilemma could occur if elevated inflammatory markers were present, as one might expect with acute COVID-19. Though transient synovitis is thought to be related to a viral etiology, there does not appear to be an increase in cases amidst the pandemic described in published literature. Conclusion: This case illustrates a patient who had COVID-19 with transient synovitis, a previously unreported sequela. When evaluating similar patients, providers should consider the possibility of COVID-19 and ensure appropriate testing and isolation.

Familial mediterranean fever (FMF) in Apulia: rare, or actually not? A 14 year experience as Internist

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder characterized by recurrent attacks of fever and serosal inflammation. The clinical features consist of especially abdominal pain, chest pain and arthralgias, plus erysipelas-like manifestations. According to the available literature, most patients with FMF experience their first attack in early childhood, before the ages of 10 and 20 years in 65 and 90% of cases, respectively. Rarely, the initial attack can occur in individuals older than 50 years of age. We report our experience with FMF during the last 14 yrs [1], following case #1 aged 36 yrs. [2]. In the regions of Apulia and Basilicata, we could identify several family clusters due to historical and geographical roots. In the initial series of 60 cases, the five most frequent MEFV variants were E148Q/R761H (41.9%, compound heterozygosity), K695R (10.2%, heterozygosity), E148Q (8.2%, heterozygosity), E148Q/R761H/A744S (6.1% compound heterozygosity), and P369S (6.1%, heterozygosity). Notably, the mean disease onset was 22 yrs and the diagnostic delay was 15 yrs. The severity of symptoms was generally mild/intermediate but about 30% of this initial series had undergone unnecessary abdominal surgery. Females were significantly older than males (median 40 vs. 30 yrs., respectively, P = 0.03). Symptoms including fever were largely responsive to the average dose of colchicine 1 mg/day ad libitum. Only one case required canakinumab for resistance/intolerance to colchicine. We did not observe severe cases of secondary amyloidosis and kidney damage. Later, we extended our observations and concluded that the combination of available expert information with sensitive predictor tools could result in a more accurate interpretation of clinical consequences of MEFV gene variants, and a better genetic counselling and patient management, with respect to symptom severity as well [3, 4]. We recently reported the rare case of a very late onset of FMF symptoms in a patient aged 86 [5]. Further studies in FMF have focused the attention on environmental factors including intestinal microbiota [6], COVID-19 pandemic [7], blood-based test for diagnosis and functional subtyping of FMF by the ex vivo colchicine assay [8], and histopathological characteristics of synovitis in FMF [9]. Following these seminal observations, we conclude that the Apulia region represents a new endemic area for FMF, a puzzling inherited autoinflammatory disorder. Clinical presentation of FMF can be misleading and requires a complete and early workup to recognize the disease and avoid unjustified surgery. Colchicine remains the gold standard therapy to prevent FMF attacks and fatal long-term complications [10, 11].

The value of MRI for detecting subclinical joint inflammation in clinically suspect arthralgia.

In the last decade, much research has focused on the development of rheumatoid arthritis (RA) and the symptomatic phase preceding the onset of clinical arthritis. Observational studies on imaging have revealed that subclinical joint inflammation in patients with arthralgia at risk for RA precedes and predicts the onset of clinically apparent arthritis. Moreover, the results of two placebo-controlled randomised proof-of-concept trials in patients with arthralgia and MRI-detected subclinical inflammation studies will soon be available. The initial results are encouraging and suggest a beneficial effect of DMARD treatment on subclinical inflammation. Since this may increase the necessity to detect subclinical joint inflammation in persons with arthralgia that are at risk for RA, we will here review what has been learnt about subclinical inflammation in at-risk individuals by means of imaging. We will focus on MRI as this method has the best sensitivity and reproducibility. We evaluate the prognostic value of MRI-detected subclinical inflammation and assess the lessons learnt from MRIs about the tissues that are inflamed early on and are associated with the clinical phenotype in arthralgia at risk for RA, for example, subclinical tenosynovitis underlying pain and impaired hand function. Finally, because long scan times and the need for intravenous-contrast agent contribute to high costs and limited feasibility of current MRI protocols, we discuss progress that is being made in the field of MRI and that can result in a future-proof way of imaging that is useful for assessment of joint inflammation on a large scale, also in a society with social distancing due to COVID-19 restrictions.