Dietary Interventions with or without Omega-3 Supplementation for the Management of Rheumatoid Arthritis: A Systematic Review

Rheumatoid Arthritis (RA) is a chronic autoimmune condition characterized by symptoms of inflammation and pain in the joints. RA is estimated to have a worldwide prevalence of 0.5–1%, with a predominance in females. Diet may play an important role in the symptoms of RA; however, little is known about the effects of various diets. The aim of this systematic review is to explore the effect of dietary interventions, with or without omega-3 supplementation for the management of RA. The electronic databases MEDLINE, EMBASE, CINAHL, and the Cochrane Library were systematically searched for clinical trials investigating dietary interventions, with or without omega-3 supplementation to retrieve papers from inception to April 2021. Randomized and non-randomized controlled trials of dietary interventions in adults with RA were eligible for inclusion. Twenty studies with a total of 1063 participants were included. The most frequently reported outcomes were pain, duration of morning stiffness, joint tenderness, grip strength and inflammatory markers. Dietary interventions with an anti-inflammatory basis may be an effective way for adults with RA seeking complementary treatments, potentially leading to improvements in certain parameters. However, there is a need for longer duration studies that are well-designed and sufficiently powered to investigate the influence of diet on RA.

Disease Modifying Treatment of Osteoarthritis with Triple Combination Anti-Microbial Therapy

Background: The study author, while still a medical student, observed microscopic evidence of chronic inflammation in joint tissue of patients suffering with osteoarthritis and hypothesized that osteoarthritis was caused by an infectious process. After graduating from medical school and entering into private practice, the study author had several patients who informed him that when they were on tetracycline therapy, for reasons other than arthritis, their arthritis symptoms diminished to some extent. After reporting improvement of arthritic symptoms with tetracycline, one of these patients subsequently received metronidazole and while taking both tetracycline and metronidazole reported that his arthritic symptoms improved to an even greater extent, as his joint pain further diminished but did not resolve. Subsequent treatment of osteoarthritis in other patients included the combination of tetracycline, metronidazole, other antibiotics and some natural products but only when L-lysine was added to the tetracycline and metronidazole combination therapy did the author observe yet further improvement in arthritic pain. Since L-lysine was reported to inhibit the growth of herpes simplex virus, the author and another colleague concluded that acyclovir might be a beneficial addition to the tetracycline, metronidazole, L-lysine combination. This four-component combination treatment resulted in total resolution or a marked diminution of osteoarthritis joint pain, joint tenderness and joint stiffness in most patients treated. It was further determined that L-lysine could be eliminated; that acyclovir could be replaced with valicyclovir; and that tetracycline could be replaced with minocycline or doxycycline. Preliminary studies of patients diagnosed with osteoarthritis and treated with tetracycline alone or the combination of tetracycline and metronidazole demonstrated improvement in their osteoarthritic symptoms. However the triple combination of doxycycline (broad spectrum antibiotic), metronidazole (antiprotozoal and antibacterial imidazole) and acyclovir (antiviral purine nucleoside) administered orally twice daily for eight weeks showed marked success in a group of patients suffering with osteoarthritis by substantially eliminating their joint pain, joint tenderness and joint stiffness while overcoming their fatigue and increasing their energy level. The data in this report substantiate that this triple combination is a disease modifying therapy that eliminates or markedly diminishes the symptomatology of osteoarthritis and further supports the hypothesis that osteoarthritis is an infectious disease. Objective: To evaluate the effect of the triple combination therapy of doxycycline, metronidazole, and acyclovir on the joint pain, joint stiffness and functionality in patients suffering with osteoarthritis. Design: Non-blinded study of treatment of patients suffering with osteoarthritis Setting: Primary care internal medicine practice in Alameda County, California. Sample: Six adult individuals suffering with osteoarthritis. Patients: Six patients, ages 53 through 82 years. Patient 1 was treated for 28 days and Patients 2 through 6 were treated for 56 days. Method: After obtaining informed consent, six patients suffering with osteoarthritis were prescribed a 56 day course of treatment with the triple combination of doxycycline, metronidazole, and acyclovir for treatment of their osteoarthritis. Utilizing the WOMAC index for assessment of the effectiveness of treatment of osteoarthritis, pre-treatment pain, stiffness and functional limitation, were compared to post-treatment pain, stiffness and functional limitations. Results: Three patients demonstrated total resolution of pain and stiffness and greater than 95% improvement in functional limitations. One of the remaining three patients demonstrated a 70% improvement in pain, total resolution of stiffness, and an 85% improvement in functional limitations; another one of the three remaining patients demonstrated an 86% improvement in pain, total resolution of stiffness, and a 79% improvement in functional limitations; while the last of the three remaining patients demonstrated at least an 85% improvement in pain, 67% improvement in stiffness, and a 63% improvement in functional limitations. Limitations: No randomization. No placebo. No control group. Small sample size. Conclusion: The results of treatment of these patients suffering the osteoarthritis support the hypothesis that osteoarthritis is an infectious disease. These results further suggest that osteoarthritis is, at a minimum, modifiable with the triple combination therapy of doxycycline, metronidazole, and acyclovir and is even curative of with this breakthrough treatment in many cases. The medical treatment reported in this article represents the first truly Disease Modifying medication therapy developed for osteoarthritis. Keywords: WOMAC index

Comparative analysis of efficacy and tolerability of tramadol versus diclofenac in treatment of knee osteoarthritis

Background: Present study was conducted on patients of osteoarthritis (OA) treated with the traditional drug diclofenac sodium and compares it with tramadol, with the primary objective for determining effectiveness and tolerability based on WOMAC scores.Methods: The study was conducted as a randomized clinical study of the effectiveness and tolerability of tramadol versus diclofenac in the treatment of knee OA, at Tertiary care institute of Gujarat in the department of orthopedics. Consecutive patients were allotted serially in two groups; tramadol group (n=75) One tablet orally twice daily for 8 weeks. Diclofenac group (n75) patients received 75 mg oral dose of diclofenac 2 times daily for a period of 8 weeks. Overall improvement was evaluated through various parameters.Results: About 33% decrease in the scoring of stiffness domain of the WOMAC OA index questionnaire in the tramadol group and a 21% decline in the diclofenac group was observed. There was a 65% decrease in the scoring of knee joint tenderness questionnaire in the tramadol group and a 44% reduction in the diclofenac group. Tramadol was found to be more effective in improving the WOMAC OA index. WOMAC score (overall) and knee joint tenderness scores were also improved by tramadol than diclofenac.Conclusions: There was a significant improvement in the standard of life in patients suffering from knee OA when treated with tramadol. Tolerability was better with tramadol than diclofenac.

An Italian Disease-Based Registry of Axial and Peripheral Spondyloarthritis: The SIRENA Study

Introduction: Data about the clinical presentation and management of early and mild spondyloarthritis (SpA) are limited.Objectives: The objective of this study was to describe the baseline characteristics of disease-modifying antirheumatic drug (DMARD)-naïve patients with axial or peripheral SpA.Methods: The Spondyloarthritis Italian Registry: Evidence from a National Pathway (SIRENA) study is an ongoing, Italian, multicenter, prospective registry of patients with a first or newly confirmed diagnosis of SpA according to the Assessment of SpondyloArthritis International Society (ASAS) criteria. To be included, patients had to be naïve to conventional, targeted, and biological DMARDs for SpA. Patients were enrolled between June 2017 and June 2019 and classified into groups according to disease presentation: predominantly axial or peripheral manifestations. The study is ongoing, and patients are being followed for 2 years, with an evaluation every 6 months according to clinical practice. Differences in baseline demographics, lifestyle, and clinical characteristics between axial and peripheral SpA were evaluated.Results: In this study, 350 patients were enrolled, of which 123 (35.1%) were axial and 227 (64.9%) were peripheral patients. Patients with axial SpA were significantly younger at enrollment (median age: 44 vs. 53 years), had significantly more anxiety/depression (13 vs. 2.6%), and expressed higher disease activity compared to patients with peripheral SpA. Patients with peripheral SpA had significantly more cardiometabolic disorders (33 vs. 18.7%), skin psoriasis (65.2 vs. 21.1%), and nail psoriasis (35.5 vs. 17.1%) than patients with axial SpA. Dactylitis, enthesitis, and fibromyalgia were observed, respectively, in 17.6, 51.2, and 5.7% of patients with axial SpA and 24.3, 40, and 3.1% of patients with peripheral SpA. In both disease groups, women tended to report depression, joint tenderness, and higher disease activity more frequently than their male counterparts. At inclusion, a new diagnosis of SpA was performed in 58% of axial and 77% of peripheral patients, with a median time from symptom onset to diagnosis of 36 and 24 months, respectively. At baseline, most patients with axial SpA (77%) started a biological DMARD, while over half of the peripheral patients started a conventional DMARD.Conclusions: Based on a well-characterized clinical registry of SpA, we provided real-world insights on the clinical features of DMARD-naïve SpA patients, pointing out major differences between axial and peripheral disease in terms of clinical characteristics and treatment pattern. Future prospective evaluations within the SIRENA study will improve knowledge on SpA and contribute to defining the best therapeutic approach.

Osteonecrosis as the presenting feature in a child with acute lymphoblastic leukaemia

A seven-year-old girl presented with pain in multiple joints and constitutional symptoms over a period of four months. There were no significant clinical findings apart from joint tenderness. Blood test results did not indicate any specific pathology and initial radiology imaging was normal. Subsequent careful examination of her X-ray images led to an MRI of her left knee, which revealed acute osteonecrotic changes. A following whole-body MRI examination demonstrated multifocal bony lesions. Bone marrow examination conclusively diagnosed acute lymphoblastic leukaemia (ALL). Acute osteonecrosis has classically been described as a complication of treatment in children with ALL and has not been recognised as a presenting feature until recently.

Migratory non-itchy rash

A 58-year-old man presented with 4-day history of multiple, erythematous, non-itchy, painless, patchy spots, along with fatigue and jaw pain. This rash started around the periumbilical area and then spread over his chest and right upper back (Figure 1,2). There was no involvement of face, mucous membranes, and extremities. He denied any sore throat, cough, or other symptoms. Besides the skin rash, his physical examination was unremarkable. There was no temporomandibular joint swelling, or joint tenderness. A month ago, he travelled along with the west coast of Michigan – a Lyme-endemic region of the USA and noted his exposure to mosquitoes. Shortly after his visit, he recalled having fever, chills, myalgia and a similar patchy groin rash which resolved in a few days. At that time, blood work by his family physician revealed mild transaminitis. At the current visit, repeat blood work and electrocardiogram were normal. A clinical diagnosis of early disseminated Lyme disease was made. Lyme Ab IgM and IgG were both elevated, as was his Western blot test. He was given a 10-day course of doxycycline. He reported complete resolution of his symptoms at follow up.

Immunopathogenesis and Immunotherapeutic Strategies in Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is a systemic autoimmune disease which results from failure of immune tolerance. Autoantibodies like Rheumatoid factor, Anti-Carbamylated Antibodies, Anti-Acetylated and Anti- Citrullinated Protein Antibodies keep on circulating in blood which target self-tissues. The major symptoms of RA are polyarticular inflammation of the synovial membrane, wrists and feet along with the joint tenderness and formation of nodules in the joints. There are many MHC alleles as well as non-MHC immunoregulatory genes which confer the genetic risk in Rheumatoid Arthritis. Immunotherapeutic strategies involved are dendritic cell targeted therapeutics, cell-based therapy and autoantibody-mediated refractoriness. The increase in the mortality rate of RA is recognized widely but different aspects of immunopathogenesis are not explained fully. The aim of the review article is to discuss all the factors that can contribute towards the immunopathogenesis of this disease and to screen out the most prominent immunotherapeutic strategies.

OP0217 IS METACARPOPHALANGEAL-JOINT PAIN AS AN EARLY SYMPTOM OF PATIENTS AT RISK FOR PROGRESSION TO INFLAMMATORY ARTHRITIS EXPLAINED BY MRI-DETECTED SUBCLINICAL INFLAMMATION? – A LARGE OBSERVATIONAL STUDY

Background:Pain in metacarpophalangeal (MCP)-joints in patients presenting with clinically suspect arthralgia (CSA) is one of the clinical features by which patients are considered at risk for progression to inflammatory arthritis (IA). As such this symptom is characteristic for CSA and therefore part of a list of clinical parameters determined by an EULAR-taskforce to identify a more homogeneous group of patients within CSA (the EULAR definition of arthralgia suspicious for progression to RA). MRI-detected subclinical inflammation is known to be present in patients with CSA. In general, arthralgia in CSA can be explained by this subclinical inflammation, however to date, the association of subclinical inflammation with pain in MCP-joints specifically is not clear. Subsequently, it is unknown whether this association differs pertinently when investigated with self-reported pain, or with pain in the form of tenderness at physical examination.Objectives:This study will investigate whether MCP-pain and MCP-joint tenderness are associated with MRI-detected subclinical inflammation in patients with CSA, and more specifically those who have progressed to IA.Methods:Between April 2012- February 2019, 602 patients were consecutively included in the Leiden clinically suspect arthralgia (CSA)-cohort. Follow-up ended when patients developed clinically apparent IA (determined at physical examination), or else after 2-years (median follow-up time 25 months). MCP-joints were assessed for self-reported joint pain by the patient using a mannequin and subsequently for joint tenderness by physical examination. Baseline unilateral MRIs of the MCP (2-5)-joints were scored by two readers, blinded for clinical data, on subclinical inflammation (synovitis, tenosynovitis, osteitis). Associations between MCP-pain or MCP-joint tenderness and MRI-detected subclinical inflammation were studied at patient level by logistic regression analyses, entering the mentioned MRI-detected features separately (univariable) and together (multivariable).Results:33% of 227 patients with self-reported MCP-pain had MRI-detected subclinical inflammation and 38% of 226 patients with MCP-joint tenderness had MRI-detected subclinical inflammation. Self-reported MCP-joint pain was univariable associated with subclinical inflammation and synovitis in particular (OR 2.00, 95% CI: 1.21-3.30, OR 2.87, 95% CI: 1.29-6.39). In multivariable analysis this MCP-pain was associated with synovitis (OR 2.54, 95% CI: 1.12-5.77). MCP-joint tenderness was univariable associated with subclinical inflammation, and synovitis and tenosynovitis in particular (OR 1.84, 95% CI: 1.29-2.63, OR 1.76, 95% CI: 1.10-2.81, OR 1.69, 95% CI: 1.12-2.55, respectively). In multivariable analysis, tenosynovitis remained significant (OR 1.54, 95% CI: 1.00-2.36). Of all patients with self-reported MCP-joint pain who developed IA, 50% had MRI-detected subclinical inflammation. For MCP-joint tenderness this was 61%. Patients with MCP-joint tenderness without subclinical inflammation who developed IA, developed clinical arthritis at a joint that was not scanned (85%), hence they may have had subclinical inflammation that was not imaged. The other 15% did develop arthritis in an MCP-joint, suggesting that subclinical inflammation developed after CSA-onset.Conclusion:Arthralgia in the MCP-joints is associated with subclinical inflammation in CSA, in particular with synovitis and tenosynovitis. The prevalence of subclinical inflammation is highest for tender joints at physical examination; this can be acknowledged when applying the EULAR definition of arthralgia suspicious for progression to RA.Disclosure of Interests:None declared

P196 Secukinumab provides sustained improvements in subgroup analyses of joint tenderness and swelling in patients with psoriatic arthritis: 5year results from the Phase3 FUTURE 2 study

Background/Aims We report the 5-year efficacy of secukinumab, an anti-interleukin17A inhibitor with long-term efficacy and tolerability in patients with psoriatic arthritis (PsA), on reduction of 78 tender joint count (TJC)/76 swollen joint count (SJC) scores in key subgroups of FUTURE 2: patients naive/with a prior inadequate response (IR) to tumour necrosis factor inhibitors (TNFis), and patients with/without concomitant methotrexate (MTX) use. Methods 397 patients with active PsA, who received ≤3 prior TNFis and/or concomitant MTX, were randomised to secukinumab (300, 150, 75 mg) or placebo at baseline, Weeks 1-4, and every 4 weeks thereafter. Placebo-treated patients were rerandomised to secukinumab 300 or 150 mg at Week 16 (nonresponders) or 24 (responders). Secukinumab dose could be escalated from 150 to 300 mg or from 75 to 150/300 mg following physician’s assessment from Week 128 and maintained thereafter. ACR20 response and changes in 78 TJC/76 SJC are reported over 5 years for secukinumab 300 and 150 mg (approved PsA doses) in TNFi-naive/IR and with/without concomitant MTX subgroups. Results The primary endpoint, ACR20 response at Week 24, is reported elsewhere. In the secukinumab 300 and 150 mg arms, 79.6% and 77.1% of TNFinaive patients achieved an ACR20 response versus 56.3% and 66.7% of TNFi-IR patients at Week 260. At the same timepoint, 62.5% and 73.5% of patients with concomitant MTX use achieved an ACR20 response versus 84.8% and 75.0% of patients without concomitant MTX use in the secukinumab 300 and 150 mg arms, respectively. At Week 260, mean change from baseline in adjusted 78 TJC/76 SJC scores for TNFi-naive and TNFi-IR patients was −13.1/−9.5 and −12.0/−8.9 for secukinumab 300 mg and −15.3/−8.8 and −14.4/−7.9 for secukinumab 150 mg, respectively (Table 1). At Week 260, mean change from baseline in adjusted 78 TJC/76 SJC scores for patients with and without concomitant MTX was −11.2/−8.9 and −14.4/−9.7 for secukinumab 300 mg and −14.7/−9.5 and −15.4/−7.5 for secukinumab 150 mg, respectively. P196 Table 1:Selected baseline characteristics and 78 TJC and 76 SJC results at Week 24 and Week 260Selected baseline characteristicsVariableSEC 300 mg SC(N = 100)SEC 150 mg SC (N = 100)PBO (N = 98)Mean adjusted 78 TJC scoreTotal population20.224.123.4Mean adjusted 76 SJC scoreTotal population11.211.912.178 TJC and 76 SJC results at Week 24 and Week 260EndpointWeek 24Week 260SEC300 mg SC (N = 100)SEC150 mg SC (N = 100)PBO-SEC300 mg SC (N = 45)PBO-SEC150 mg (N = 43)SEC300 mg SC (N = 100)SEC150 mg SCa (N = 100)PBO-SEC 300 mg SC (N = 45)PBO-SEC 150 mgb (N = 43)Adjusted 78 TJC (total population)Change from baseline (SD)−10.4 (10.8)−12.1 (16.5)−10.6 (14.1)−9.7 (13.6)−12.8 (10.7)−15.1 (15.9)−14.5 (15.4)−12.5 (10.6)Adjusted 76 SJC (total population)Change from baseline (SD)−7.2 (5.8)−6.3 (7.7)−9.7 (9.5)−9.6 (10.7)−9.3 (6.1)−8.5 (7.9)−9.5 (8.1)−8.3 (6.3)Adjusted 78 TJC (TNF status)TNFi-naiveChange from baseline (SD)−10.7 (10.8)−13.0 (16.6)−3.5 (13.9)−8.0 (10.7)−13.1 (11.1)−15.3 (16.7)−14.8 (16.0)−11.5 (10.2)TNFi-IRChange from baseline (SD)−9.8 (10.9)−10.3 (16.4)−11.0 (11.4)−13.4 (19.5)−12.0 (9.6)−14.4 (14.0)−14.0 (15.1)−15.7 (12.0)Adjusted 76 SJC (TNF status)TNFi-naiveChange from baseline (SD)−6.9 (4.8)−6.7 (8.2)−10.5 (11.0)−6.8 (6.2)−9.5 (5.7)−8.8 (8.8)−9.4 (9.0)−8.4 (6.9)TNFi-IRChange from baseline (SD)−7.8 (7.4)−5.7 (6.5)−7.8 (5.0)−15.6 (16.3)−8.9 (7.4)−7.9 (5.1)−9.6 (6.1)−7.9 (4.6)Adjusted 78 TJC (MTX use)Concomitant MTX useChange from baseline (SD)−10.3 (8.7)−10.6 (16.7)−8.7 (13.1)−7.6 (14.3)−11.2 (9.1)−14.7 (14.5)−12.7 (12.5)−11.4 (11.4)No concomitant MTX useChange from baseline (SD)−10.5 (12.3)−13.3 (16.4)−15.2 (16.8)−14.2 (12.0)−14.4 (12.0)−15.4 (17.5)−16.8 (18.6)−14.1 (9.6)Adjusted 76 SJC (MTX use)Concomitant MTX useChange from baseline (SD)−6.9 (6.1)−6.0 (8.5)−8.9 (8.6)−8.8 (9.7)−8.9 (6.0)−9.5 (9.1)−8.6 (5.3)−9.4 (7.2)No concomitant MTX useChange from baseline (SD)−7.4 (5.7)−6.6 (6.9)−11.6 (12.4)−11.2 (13.8)−9.7 (6.2)−7.5 (6.5)−10.6 (10.7)−6.6 (4.6)aSEC 150 mg arm includes 42 patients who were uptitrated to SEC 300 mg from Week 128.bPBO-SEC 150 mg arm includes 19 patients who were uptitrated to SEC 300 mg from Week 128. Data are reported as observed.N=number of randomised patients; n=number of patients with evaluation. IR, inadequate response; MTX, methotrexate; PBO, placebo; PsA, psoriatic arthritis; SC, subcutaneous; SD, standard deviation; SEC, secukinumab; SJC, swollen joint count; TJC, tender joint count; TNFi, tumour necrosis factor inhibitor. Conclusion Analysis of 78 TJC/76 SJC scores demonstrated that treatment with secukinumab significantly reduced joint tenderness and swelling at Week 24, which were sustained over 5 years, irrespective of TNFi history/concomitant MTX use. Disclosure I. McInnes: Grants/research support; Research grants, consultation fees, or speaker honoraria: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer and UCB. H. Chinoy: Grants/research support; Research grants, travel grants, consultancy or speaker honoraria: AbbVie, Amgen, Biogen, BMS, Janssen, Lilly, Novartis and UCB. D. Asquith: Shareholder/stock ownership; Employee of Novartis. Shareholder of Novartis. A. White: Shareholder/stock ownership; Employee of Novartis. Shareholder of Novartis. C. Gaillez: Shareholder/stock ownership; Employee of Novartis. Shareholder of Novartis and Bristol Myers Squibb.