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Nowadays, tumor necrosis factor-alpha (TNFα) inhibitors have revolutionised the treatment of inflammatory arthritides by demonstrating efficacy with an acceptable toxicity profile. However, autoimmune phenomena and clinical entities have been reported ranging from an isolated presence of autoantibodies to full-blown autoimmune diseases, including drug-induced lupus (DIL).Case Presentation:A 62-year-old woman with rheumatoid arthritis (RA) refractory to methotrexate and prednisone was treated with adalimumab (ADA). 4 months later, she presented acute cutaneous eruptions after sun exposure, positive ANA (1/640 fine speckled pattern), Ro (SSA) and anti- Smith (Sm) antibodies with no other clinical or laboratory abnormalities. The diagnosis of DIL was made, ADA was discontinued, and she was treated successfully with prednisone plus local calcineurin inhibitors.Conclusion:Thus, we review the literature for cases of DIL development in patients treated with TNFα inhibitors. Rheumatologists should be aware of the possible adverse events and the requirement of careful clinical evaluation and monitoring.

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affecting mostly the respiratory system, but several other organs and systems can be involved. Extrapulmonary manifestations and autoimmune phenomena following SARS-CoV-2 infection are frequent events occurring during the first 2 weeks or in later stages of the disease course. These can be expressed as an isolated discovery of autoantibodies, mostly antinuclear or antiphospholipid antibodies, through to full-blown autoimmune organ-specific and systemic diseases. Joint pain is a frequent complain in most patients, but to our knowledge, frank arthritis has not been reported so far. A 46-year-old woman developed symmetrical polyarthritis 2 months after SARS-CoV-2 infection. Laboratory tests showed high acute phase reactants, while the immunological profile was negative. Hand and wrists X-rays revealed soft tissue swelling as well as bone erosions at the ulnar base of the third and fourth metacarpophalangeal joint of the right hand and carpal bones. The patient responded well to small doses of prednisone and methotrexate and after 4 months she had a sustained clinical and laboratory improvement. This is the first report making an association between SARS-CoV-2 infection and erosive polyarthritis. Physicians dealing with patients infected from SARS-CoV-2 should be aware for the possible development of musculoskeletal disorders, among them symmetrical polyarthritis. Thus, a close follow-up and monitoring is mandatory.

Idiopathic inflammatory myopathies (IIMs) are rare autoimmune disorders affecting primarily muscles, but other organs can be involved. This review describes the clinical features, diagnosis and treatment for IIMs, namely polymyositis (PM), dermatomyositis (DM), sporadic inclusion body myositis (sIBM), immune-mediated necrotizing myopathy (IMNM), and myositis associated with antisynthetase syndrome (ASS). The diagnostic approach has been updated recently based on the discovery of circulating autoantibodies, which has enhanced the management of patients. Currently, validated classification criteria for IIMs allow clinical studies with well-defined sets of patients but diagnostic criteria to guide the care of individual patients in routine clinical practice are still missing. This review analyzes the clinical manifestations and laboratory findings of IIMs, discusses the efficiency of modern and standard methods employed in their workup, and delineates optimal practice for clinical care. Α multidisciplinary diagnostic approach that combines clinical, neurologic and rheumatologic examination, evaluation of electrophysiologic and morphologic muscle characteristics, and assessment of autoantibody immunoassays has been determined to be the preferred approach for effective management of patients with suspected IIMs.

Fibroblastic rheumatism (FR) is an uncommon disease of the skin, characterized by the presence of non-tender cutaneous nodules accompanied often by other rheumatic manifestations. This condition shows male predominance, no age preference and unpredictable course, resulting frequently in permanent joint damage. A 60-year-old man came to our department with a 4-year history of multiple non-tender nodules and morning stiffness affecting mainly the upper extremities. Clinical examination revealed arthritis of the hands, confirmed by imaging tests. Laboratory exams were unremarkable. A skin nodule biopsy showed a dermal collagenous lesion with myxoid areas composed of spindle and stellate cells. Immunohistochemical staining demonstrated positivity for CD68 and negativity for CD34, S100, EMA and desmine. FR was diagnosed and the patient started methylprednisolone 16 mg/day. Hydroxychloroquine 400 mg/day and methotrexate 15 mg/weekly were further added as steroid-sparing agents with clinical benefit. Clinicians should be aware of this underreported entity, which can rapidly lead to irreversible deformities.

INTRODUCTION The EMENO (National Morbidity and Risk Factors) survey is one of the first and most representative population-based surveys in Greece due to its study design and sampling procedure. We aimed to estimate the prevalence of smoking, secondhand smoking (SHS) and their potential associations with other socioeconomic and unhealthy lifestyle risk factors. METHODS EMENO is a cross-sectional health status survey conducted in Greece from May 2013 to June 2016. The survey was performed using face-to-face interviews and enrolled 6006 adults. Data were collected through questionnaires administered by trained interviewers. Current smoking (CS) and SHS were based on self-reporting. Analysis accounted for study design. RESULTS Information on smoking was available for 5862 individuals (97.6%). Overall, 37.8% were current and 16.1% former smokers. More males (44.3%) than females (31.6%) were current smokers. CS increased during adulthood and declined sharply in the elderly (p7 glasses/ week, OR=2.52; 95% CI: 1.97–3.23) and lower education level in men were positively associated with ever smoking. Moreover, women aged >35 years and respondents with low adherence to the Mediterranean diet (MD) (high/ low, OR= 0.35; 95% CI: 0.21–0.58) had higher odds to be current smokers than former smokers. Finally, the overall prevalence of exposure to SHS at work, home and public places was 38.8%, 30% and 44.6 %, respectively. CONCLUSIONS Unhealthy lifestyles of smokers, increased rates of CS in vulnerable groups, such as females and young adults, and early age of smoking initiation constitute alarming public health issues in Greece.

Objective Anemia of chronic disease is a frequent consequence in rheumatoid arthritis and is associated with major clinical and patient outcomes. The present cross-sectional study explored the role of hepcidin (HEP) in anemia of chronic disease in rheumatoid arthritis by studying its relationships with markers of anemia, iron metabolism, inflammation, and erythropoiesis. Methods Blood samples from anemic (n = 43) and nonanemic (n = 43) rheumatoid arthritis patients were analyzed for markers of anemia (hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, red cells distribution width, and reticulocyte hemoglobin), iron metabolism (iron, total iron binding capacity, ferritin, transferrin saturation, soluble transferrin receptor), inflammation (erythrocyte sedimentation rate, C-reactive protein, and interleukin 6), and erythropoiesis (erythropoietin and HEP). Correlation analysis was used to identify relationships between HEP and all other variables. Principal component analysis was used to identify common underlying dimensions representing linear combinations of all variables. Results HEP had statistically significant mostly moderate-to-large correlations with markers of anemia (0.30–0.70, all p < 0.01), small correlation with markers of iron metabolism and markers of inflammation (r = 0.20–0.40, all p < 0.01), and moderate correlations with markers of erythropoiesis. Principal component analysis revealed two underlying components (factors) capturing approximately 50% of total variability. Factor 1 comprised mainly of markers of anemia, iron metabolism, and erythropoiesis and was related to “erythrocyte health status,” while factor 2 comprised mainly markers of inflammation and iron metabolism and was related to “acute phase reactants.” HEP was the only variable demonstrating substantial loadings on both factors. Conclusions HEP is related to markers of anemia, iron metabolism, inflammation, and erythropoiesis. In addition, when all variables are “reduced” to a minimum number of two “latent” factors, HEP is loaded on both, thus underlying its pivotal role in the complex interaction of the erythropoietic response in inflammation-induced anemia and/or functional iron deficiency.

Purpose: The randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated BRAFV600 mutation–positive advanced melanoma. We report long-term follow-up of coBRIM, with at least 5 years since the last patient was randomized. Patients and Methods: Eligible patients were randomized 1:1 to receive either oral cobimetinib (60 mg once daily on days 1–21 in each 28-day cycle) or placebo in combination with oral vemurafenib (960 mg twice daily). Results: 495 patients were randomized to cobimetinib plus vemurafenib (n = 247) or placebo plus vemurafenib (n = 248). Median follow-up was 21.2 months for cobimetinib plus vemurafenib and 16.6 months for placebo plus vemurafenib. Median OS was 22.5 months (95% CI, 20.3–28.8) with cobimetinib plus vemurafenib and 17.4 months (95% CI, 15.0–19.8) with placebo plus vemurafenib; 5-year OS rates were 31% and 26%, respectively. Median PFS was 12.6 months (95% CI, 9.5–14.8) with cobimetinib plus vemurafenib and 7.2 months (95% CI, 5.6–7.5) with placebo plus vemurafenib; 5-year PFS rates were 14% and 10%, respectively. OS and PFS were longest in patients with normal baseline lactate dehydrogenase levels and low tumor burden, and in those achieving complete response. The safety profile remained consistent with previously published reports. Conclusions: Extended follow-up of coBRIM confirms the long-term clinical benefit and safety profile of cobimetinib plus vemurafenib compared with vemurafenib monotherapy in patients with BRAFV600 mutation–positive advanced melanoma.

Current data demonstrated that severe cases of coronavirus-disease-19 (COVID-19) require treatment with antiviral therapy, dexamethasone, supportive care, as well as some anti-rheumatic drugs, among them, cytokine inhibitors and colchicine. Colchicine is an anti-inflammatory drug that is being used in rheumatology for many years to treat mostly gout, calcium pyrophosphate deposition disease, and Familial Mediterranean Fever. Here, we present for the first time, two patients suffering from gout being treated with colchicine, who were affected from severe acute respiratory coronavirus-2 (SARS-CoV-2) syndrome. Both patients presented with mild symptoms of COVID-19 expressed with myalgias, arthralgias, and sore throat, while laboratory investigations showed only high acute phase reactants. Four weeks later, both patients were free of symptoms with negative SARS-CoV-2 tests and without any complications. To our knowledge, there are no other studies of gout arthritis and SARS-CoV-2 infection published so far. Thus, our preliminary conclusion is that chronic use of colchicine may mitigate the clinical picture and disease course of COVID-19 in gout arthritis patients. Further studies with a large number of patients are needed to confirm the above beneficial effect of colchicine.

This study aimed to assess the reliability of opportunistic screening programs in estimating the prevalence, treatment, and control rate of hypertension in the general population. Two recent epidemiological surveys obtained data on hypertension in the adult general population in Greece. The EMENO (2013–2016) applied a multi-stage stratified random sampling method to collect nationwide data. The MMM (2019) collected data through opportunistic (voluntary) screening in five large cities. Hypertension was defined as blood pressure (BP) ≥ 140/90 mmHg (single occasion; average of 2nd–3rd measurement; electronic devices) and/or use of antihypertensive drugs. Data from a total of 10,426 adults were analyzed (EMENO 4,699; MMM 5,727). Mean age (SD) was 49.2 (18.6)/52.7 (16.6) years (EMENO/MMM, p

To examine whether patients with inflammatory arthritis (IA) treated with conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs) and/or biologic (b) DMARDs, could be affected from SARS-CoV-2 infection and to explore the COVID-19 disease course and outcome in this population. This is a prospective observational study. During the period February–December 2020, 443 patients with IA who were followed-up in the outpatient arthritis clinic were investigated. All patients were receiving cs and/or bDMARDs. During follow-up, the clinical, laboratory findings, comorbidities and drug side effects were all recorded and the treatment was adjusted or changed according to clinical manifestations and patient’s needs. There were 251 patients with rheumatoid arthritis (RA), 101 with psoriatic arthritis (PsA) and 91 with ankylosing spondylitis (AS). We identified 32 patients who contracted COVID-19 (17 RA, 8 PsA, 7 AS). All were in remission and all drugs were discontinued. They presented mild COVID-19 symptoms, expressed mainly with systemic manifestations and sore throat, while six presented olfactory dysfunction and gastrointestinal disturbances, and all of them had a favorable disease course. However, three patients were admitted to the hospital, two of them with respiratory symptoms and pneumonia and were treated appropriately with excellent clinical response and outcome. Patients with IA treated with cs and/or bDMARDs have almost the same disease course with the general population when contract COVID-19.

Objective To assess the efficacy and safety of the IL-1b inhibitor canakinumab in all adults with refractory Still's disease identified from the National Organization For Medicines for off-label drug use. Methods : In a retrospective longitudinal multicenter cohort of 50 patients (median age 39 years) with active Still's disease despite treatment with corticosteroids (n = 11), conventional and synthetic (n = 34) and/or biologic disease modifying anti-rheumatic drugs (n = 30), we assessed the efficacy of canakinumab 150–300 mg administered every 4 (n = 47) or 8 weeks (n = 3) as combination therapy or monotherapy (n = 7) during a median follow-up of 27 (3–84) months. Results Α complete response was initially observed in 78% of patients within 3 months (median), irrespective of age at disease onset. A partial response was evident in 20%. One patient had resistant disease. Treatment de-escalation was attempted in 15 of 39 complete responders and a complete drug discontinuation in 21 patients for 8 months (median). Eleven patients (22%) relapsed during treatment, one during de-escalation process, and 11 after treatment discontinuation. Overall, 9 of 11 relapses were successfully treated with canakinumab treatment intensification or re-introduction. At last visit, 18% of patients were off treatment due to remission and 26% due to disease activity. Canakinumab had a significant corticosteroid sparing effect allowing weaning in 21 of 41 cases. Infections (20%, severe 4%) and leucopenia (6%) led to treatment cessation in one patient. Conclusion High rates of sustained remission were observed in this, largest so far, real-life cohort of adult patients with refractory Still's disease treated with canakinumab.

Background: Rheumatoid arthritis (RA) may affect any diarthrodial joint with a predilection on the peripheral skeleton in a symmetrical manner. When the axial skeleton is affected, it is the cervical spine (CS) that gets involved with potentially detrimental effects, if not treated promptly. Case: A 60-year-old female suffering from RA presented with severe neck pain and stiffness, difficulty of standing and walking with brisk tendon reflexes, Babinski sign positive, and clonus. Despite the high inflammatory markers and high titres of autoantibodies (rheumatoid factor and anticitrullinated protein antibodies), she never received proper treatment. She was using only paracetamol and non-steroidal anti-inflammatory drugs. Conventional radiography (CR) of CS showed extensive degenerative changes affecting the C3–C5 vertebral level. Magnetic Resonance Imaging of the neck showed sub-axial subluxation (SAS) and spinal cord compression at C3 level, and to a lesser extent, in other levels. A multi-level cervical laminectomy and spinal cord decompression were deployed with good results. To this end, literature review was performed until September 2020 and showed that the frequency of radiological findings varies substantially, ranging between 0,7–95% in different studies. The most common radiological feature is the atlanto-axial subluxation (AAS) followed by SAS. Because CS involvement can often be clinically asymptomatic, its assessment should not be forgotten by physicians and should be assessed using CR, which is an easy-to-perform technique and gives important information as a screening tool. On the other hand, RA patients need to be treated in a prompt and efficient manner in order to avoid any potentially fatal complications.

Objectives Predicting serious infections (SI) in patients with rheumatoid arthritis (RA) is crucial for the implementation of appropriate preventive measures. Here we aimed to identify risk factors for SI and to validate the RA Observation of Biologic Therapy (RABBIT) risk score in real-life settings. Methods A multi-centre, prospective, RA cohort study in Greece. Demographics, disease characteristics, treatments and comorbidities were documented at first evaluation and one year later. The incidence of SI was recorded and compared with the expected SI rate using the RABBIT risk score. Results A total of 1557 RA patients were included. During follow-up, 38 SI were recorded [incidence rate ratio (IRR): 2.3/100 patient-years]. Patients who developed SI had longer disease duration, higher HAQ at first evaluation and were more likely to have a history of previous SI, chronic lung disease, cardiovascular disease and chronic kidney disease. By multivariate analysis, longer disease duration (IRR: 1.05; 95% CI: 1.005, 1.1), history of previous SI (IRR: 4.15; 95% CI: 1.7, 10.1), diabetes (IRR: 2.55; 95% CI: 1.06, 6.14), chronic lung disease (IRR: 3.14; 95% CI: 1.35, 7.27) and daily prednisolone dose ≥10 mg (IRR: 4.77; 95% CI: 1.47, 15.5) were independent risk factors for SI. Using the RABBIT risk score in 1359 patients, the expected SI incidence rate was 1.71/100 patient-years, not different from the observed (1.91/100 patient-years; P = 0.97). Conclusion In this large real-life, prospective study of RA patients, the incidence of SI was 2.3/100 patient-years. Longer disease duration, history of previous SI, comorbidities and high glucocorticoid dose were independently associated with SI. The RABBIT score accurately predicted SI in our cohort.

OBJECTIVE The evidence on the epidemiology of hypertension in Greece is limited. The prevalence and control of hypertension was assessed in randomly selected adults of the general population in Greece within the nationwide epidemiological study EMENO. METHOD On the basis of 2011 census, EMENO applied a multistage stratified random sampling method involving 577 areas throughout Greece (2013-2016). Participants were assessed at home visits with standardized questionnaires, blood tests and triplicate seated blood pressure (BP) measurements (validated upper-arm automated oscillometric device Microlife BPA100 Plus). Hypertension was defined as BP at least 140/90 mmHg (average of second--third measurement) and/or use of antihypertensive drugs. Sampling weights were applied for study design and post-stratification weights to match the age/sex distribution to the general population in Greece. Nonresponse was adjusted by inverse probability weighting. RESULTS A total of 6006 individuals were recruited and 4699 with valid data were analysed [mean (SD) age 49.2 (18.6) years, men 48.6%, BMI 28.2 (5.7) kg/m2]. The prevalence of hypertension was 39.6% and was higher in men than women (42.7 vs. 36.5%, P

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multiorgan involvement, including heart. Pericarditis-the most common cardiac manifestation-occurs in up to 50% of cases, resulting in positive treatment outcomes. Rarely, it evolves to hazardous complications. A 50-year-old woman with SLE in clinical remission, receiving hydroxychloroquine 400 mg/day, presented to us with severe chest pain and low-grade fever. Physical examination revealed a friction rub and decreased breath sounds at the right lung base. Laboratory evaluation demonstrated leukopenia, thrombocytopenia, low C4 levels, and high acute phase reactants. Chest X-ray exhibited cardiomegaly, calcified pericardium, and right pleural effusion, confirmed by CT scan. PPD skin test and IGRA were both negative. Pericardial fluid, blood, and urine cultures for bacteria and fungi, as well as Gram and Ziehl-Neelsen stains were negative. Serological tests for viruses were also negative. The patient was diagnosed with calcified constrictive pericarditis (CP) due to SLE. She was treated with cyclophosphamide and methylprednisolone pulses, without improvement. Her clinical condition deteriorated, developing signs and symptoms compatible with cardiac tamponade (TMP), which was confirmed by Doppler echocardiography. The patient underwent pericardiectomy. A dramatic response was noted and she was discharged with prednisone 50 mg/day and azathioprine 100 mg/day. Thus, we review and discuss the relevant literature of SLE cases with CP or TMP. When an SLE patient presents with CP, infectious causes should be excluded first. To the best of our knowledge, this is the only case of SLE and calcified CP leading to TMP, hence physicians should be aware of this complication.

Introduction: Rheumatoid arthritis (RA) is an autoimmune disease that is characterized by progressive joint disorders with significant pain and stiffness. In the past, RA was a difficult -to-treat ailment, but nowadays with the advent of biologics and better treatment strategies, disease remission is an achievable goal. Tumor necrosis factor α (TNFα) inhibitors were the first category of biologics to emerge with adalimumab being the first fully human TNFα.Areas covered: the authors provide an overview of the historical events that led to the discovery of TNFα inhibitors and more specifically the drug adalimumab. Several key trials are presented regarding the safety of the drug as well as its successful journey, but there is also a narrative description of the drug's future after patent expiration.Expert opinion: Adalimumab is a fully human TNFα inhibitor with a fairly rapid onset of action. It has a generally good safety and efficacy profile. Clinicians must be aware of the possible side effects and treat them in a timely manner or discontinue the drug where appropriate. Due to the success of the bio-originator adalimumab, a multitude of biosimilars have emerged but not, thus far, for all of the indications of the bio-originator.

The spondyloarthritides are a group of chronic systemic inflammatory joint diseases, the main types being ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Evidence accumulating during the last decades suggests that patients with AS or PsA carry an increased risk for cardiovascular disease and cardiovascular death. This risk appears to be mediated by systemic inflammation over and above classical cardiovascular risk factors. The excess cardiovascular risk in those patients has been formally acknowledged by scientific organizations, which have called physicians’ attention to the matter. The application by Rheumatologists of new effective anti-rheumatic treatments and treat-to-target strategies seems to benefit patients from a cardiovascular point of view, as well. However, more data are needed in order to verify whether anti-rheumatic treatments do have an effect on cardiovascular risk and whether there are differences among them in this regard. Most importantly, a higher level of awareness of the cardiovascular risk is needed among patients and healthcare providers, better tools to recognize at-risk patients and, ultimately, commitment to address in parallel both the musculoskeletal and the cardiovascular aspect of the disease.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation that, if left untreated, can cause joint destruction and physical impairments. The inflammatory process is systematic, and it is associated with increased morbidity and mortality. Over the last years, mortality presents a decreasing trend; still, there is a high burden of cardiovascular disease (CVD) in RA that seems to be related to coronary atherosclerosis. Chronic inflammation, physical inactivity, and drugs used to treat RA are some of the reasons. Thus, the management of CVD risk is essential and involves the patient's stratification using distinct parameters that include assessment of the blood lipid profile. However, 'dyslipidemia' in RA patients follows a different pattern under the impact of inflammatory processes, while therapies that target the underlying disease change the levels of specific lipid components. In this review, we explore the relationship between blood lipids and inflammation in the so-called ΄lipid paradox΄ in RA, and we present the existing knowledge over the influence of antirheumatic drugs on the lipid profile of RA patients.

Osteopoikilosis, a rare benign bone disease, is usually an incidental radiographic finding without therapeutic considerations. It is characterized by multiple sclerotic bone lesions, which are asymptomatic in most of cases. The challenge is to distinguish osteopoikilosis from other, especially malignant, bone diseases. In this case report, we present a 65-year-old male patient, who was incidentally diagnosed with osteopoikilosis in our department. The diagnosis was based on the exclusion of differential diagnosis, typical imaging findings in X-rays, CT scan and PET/CT scan. In this work, we discuss recent literature on the disease, including prevalence, pathogenesis, clinical manifestation, as well as differential diagnosis.

Background European data indicate that systemic sclerosis (SSc)-related death rates are increasing, thus raising concerns about SSc’s optimal management. Herein, we describe current treatment modalities and drug survival in a real-life SSc cohort. Methods Details on immunosuppressive/antiproliferative (methotrexate, mycophenolate, cyclophosphamide, azathioprine, rituximab, tocilizumab) and vasoactive agent [(endothelin receptor antagonists (ERAs), sildenafil, iloprost, and calcium channel blockers (CCB)] administration during the disease course (11.8 ± 8.4 years, mean + SD) of 497 consecutive patients examined between 2016 and 2018 were retrospectively recorded. Drug survival was assessed by Kaplan–Meier analysis. Results Methotrexate was the most frequently administered immunosuppressive/antiproliferative agent (53% of patients), followed by cyclophosphamide (26%), mycophenolate (12%), and azathioprine (11%). Regarding vasoactive agents, CCB had been ever administered in 68%, ERAs in 38%, iloprost in 7%, and sildenafil in 7% of patients; 23% of patients with pulmonary fibrosis had never received immunosuppressive/antiproliferative agents, 33% of those with digital ulcers had never received ERAs, iloprost, or sildenafil, whereas 19% of all patients had never received either immunosuppressive/antiproliferative or other than CCB vasoactive agents. Survival rates of methotrexate, cyclophosphamide, and mycophenolate differed significantly, being 84/75%, 59/43%, and 74/63% at 12/24 months, respectively, with inefficacy being the most frequent discontinuation cause. Conversely, CCB, ERAs, and sildenafil had high and comparable retention rates of 97/91%, 88/86%, and 80/80%, respectively. Conclusions Existing therapeutic limitations indicate that more evidence-based treatment is warranted for successful management of SSc. Vasculopathy seems to be managed more rigorously, but the low retention rates of immunosuppressive/antiproliferative drugs suggest that effective and targeted disease-modifying agents are warranted.

The treatment of inflammatory arthritides has been changed dramatically in the past two decades with the introduction of the biological (b) disease-modifying anti-rheumatic drugs (DMARDs) as well as the targeting synthetic (ts) DMARDs that can be used as monotherapy or in combination with conventional synthetic (cs) DMARDs. The concept of treat to target (T2T) and tight control monitoring of disease activity represents a therapeutic paradigm of modern rheumatology. In rheumatoid arthritis (RA), this treatment approach has proven to be effective in many clinical trials and is now a well-established approach. The most common treatment strategies rely on the combination of csDMARDs (mainly methotrexate, sulfasalazine and hydroxychloroquine). This comes from different studies which compare the outcomes of combination therapies versus csDMARD monotherapy or versus methotrexate plus biologics in early RA patients. Here, we review the literature of the most important T2T studies for RA patients. The results showed that a tight control strategy appears to be more important than a specific drug to control RA. T2T approach aiming for remission or low disease activity can be achieved in early RA patients using less expensive drugs in comparison to newer drugs and this may need to be recognised in the future recommendations for the management of RA. KEY POINTS: • Tight-control and treat-to-target (T2T) strategies are the cornerstone in achieving remission or low disease activity in rheumatoid arthritis (RA) • A plethora of clinical trials has confirmed the efficacy of csDMARDs when the tight-control and T2T strategies are applied • T2T and tight-control strategies are a less expensive option in comparison to newer drugs and may be recognised in the future recommendations for the management of RA. • Treatment decisions and strategies are more important than just the drugs.

We report the use of two corneal grafts derived from a donor, with a history of early stage keratoconus, for lamellar and penetrating keratoplasty. The first graft was used to perform Descemet stripping automated endothelial keratoplasty (DSAEK) in a patient with endothelial dysfunction and advanced pseudoexfoliative glaucoma. The second graft was used for an emergency penetrating keratoplasty in a patient with corneal perforation secondary to uncontrolled herpes keratitis. In the first case, 1 year postoperatively, the graft was clear and attached with no signs of rejection or failure. In the second case, the perforation did not relapse after keratoplasty and the globe retained its structural integrity during the 1-year follow-up.

Objectives To investigate humoral responses and safety of mRNA SARS-CoV-2 vaccines in systemic autoimmune and autoinflammatory rheumatic disease (SAARD) patients subjected or not to treatment modifications during vaccination. Methods A nationwide, multicenter study, including 605 SAARD patients and 116 controls, prospectively evaluated serum anti-SARS-CoV-2 S1-protein IgG antibody titers, side-effects, and disease activity, one month after complete vaccination, in terms of distinct treatment modification strategies (none, partial and extended modifications). Independent risk factors associated with hampered humoral responses were identified by data-driven multivariable logistic regression analysis. Results Patients with extended treatment modifications responded to vaccines similarly to controls as well as SAARD patients without immunosuppressive therapy (97.56% vs 100%, p = 0.2468 and 97.56% vs 97.46%, p > 0.9999, respectively). In contrast, patients with partial or without therapeutic modifications responded in 87.50% and 84.50%, respectively. Furthermore, SAARD patients with extended treatment modifications developed higher anti-SARS-CoV-2 antibody levels compared to those without or with partial modifications (median:7.90 vs 7.06 vs 7.1, p = 0.0003 and p = 0.0195, respectively). Mycophenolate mofetil (MMF), rituximab (RTX) and methotrexate (MTX) negatively affected anti-SARS-CoV-2 humoral responses. In 10.5% of vaccinated patients, mild clinical deterioration was noted; however, no differences in the incidence of deterioration were observed among the distinct treatment modification SAARD subgroups. Side-effects were generally comparable between SAARD patients and controls. Conclusions In SAARD patients, mRNA SARS-CoV-2 vaccines are effective and safe, both in terms of side-effects and disease flares. Treatment with MMF, RTX and/or MTX compromises anti-SARS-CoV-2 antibody responses, which are restored upon extended treatment modifications without affecting disease activity.

ObjectiveΤo report outcomes of breakthrough COVID-19 in comparison with COVID-19 in unvaccinated patients with systemic rheumatic diseases (SRDs).MethodsPatients with SRD with COVID-19 (vaccinated and unvaccinated) were included by their rheumatologists in a registry operated by the Greek Rheumatology Society in a voluntarily basis. Type, date and doses of SARS-CoV-2 vaccines were recorded, and demographics, type of SRD, concurrent treatment, comorbidities and COVID-19 outcomes (hospitalisation, need for oxygen supplementation and death) were compared between vaccinated and unvaccinated patients.ResultsBetween 1 March 2020 and 31 August 2021, 195 patients with SRD with COVID-19 were included; 147 unvaccinated and 48 vaccinated with at least one dose of a SARS-CoV-2 vaccine (Pfizer n=38 or AstraZeneca n=10). Among vaccinated patients, 29 developed breakthrough COVID-19 >14 days after the second vaccine dose (fully vaccinated), while 19 between the first and ConclusionsVaccinated patients with SRD with breakthrough COVID-19 have better outcomes compared with unvaccinated counterparts with similar disease/treatment characteristics.

Hair dye (HD) and its component para-phenylenediamine (PPD) are commonly used to enhance beauty and youth. HD is associated with allergic contact reactions and the development of autoimmune phenomena. A 28-year-old woman presented to us complaining of pain and swelling affecting the small joints of the hands bilaterally lasting for 7 weeks. Laboratory evaluation was remarkable only for an increase of acute-phase reactants, while the rest of laboratory tests including serological tests for viruses, as well as immunological tests were negative or within normal limits. She noticed a close correlation between the onset of symmetrical polyarthritis and the use of HD product. Thus, after excluding other possibilities of inflammatory arthritides, the diagnosis of HD-induced arthritis was made. The patient was treated with naproxen, and after 3 weeks, she had a complete clinical response with decrease of acute-phase reactants. Thus, we review and discuss the relevant literature of cases related with the use of HD and arthritis development. This is the first described case of HD-induced arthritis. Physicians must be aware and recognize these symptoms and signs of patients exposed to HD and treat them appropriately.

We describe an effective technique for the management of graft-host interface haze associated with interface deposits after Descemet-stripping automated endothelial keratoplasty (DSAEK) with bimanual irrigation/aspiration. A Tan marginal dissector was used to separate the graft from the stroma in the nasal two-thirds of the graft-host interface. The aspiration handpiece was inserted in the interface through the nasal side-port corneal incision and a separate irrigation tip was placed in the anterior chamber (AC) through the temporal corneal paracentesis. Meticulous rinsing of the two-thirds of the interface area and the AC was performed. At the end of the procedure, air was injected into the AC to float the donor graft against the host stromal bed and facilitate graft adherence. Postoperative anterior segment optical coherence tomography and slit-lamp examination confirmed elimination of the interface haze-deposits and a well-attached graft. An improvement in visual acuity was noted.

Background Advanced pellucid marginal degeneration is a debilitating disease that warrants the use of surgery when the visual acuity is reduced and contact lenses are not tolerated anymore. It is traditionally managed with corneal transplantation, however alternative surgical options exist. Corneal wedge resection allows for good visual rehabilitation without the risks of tissue rejection. However topographical and refractive results are in some instance fluctuating. We present here the use of corneal cross-linking in order to stabilize the parameters on the long term. Case presentation We present here the case of a 53 years old patient with bilateral advanced pellucid marginal degeneration. As he is now intolerant to contact lenses a surgical option is offered to him. In order to avoid using donated tissue through corneal grafting we decide to perform a sectorial lamellar crescentric wedge excision of the thinner inferior part of the cornea involving the pellucid marginal degeneration and suture it. The first eye shows initial good results however after few months regression is observed. The second eye is then treated with the same surgical technique combined with cornea cross-linking. Long-term follow-up shows stabilization and absence of regression in the second eye up to eight months after the surgery. Conclusion Combining corneal cross-linking with corneal wedge resection in the case of advanced pellucid marginal degeneration patients could be a good option in order to stabilize topographical and refractive results and reduces the risk of regression.

Multi-family therapy for Bulimia Nervosa (MFT-BN) was developed in response to the modest outcomes following both Family Therapy and Cognitive Behavior Therapy for adolescents with BN. BN impacts individuals and their family members with high levels of carer stress. MFT-BN targets barriers to treatment including low motivation to change, hostility and criticism, negative affect alongside emotion dysregulation and common comorbidities. MFT-BN enhances treatment, providing a community of support and acquisition of emotional regulation and interpersonal skills. The study describes the clinical characteristics of the group of participants to whom MFT-BN is offered and presents the outcomes of families who have participated in it. Prior to MFT-BN, adolescents who received it were more likely to have self-harmed and had elevated levels of eating disordered cognitions than those who did not receive MFT-BN. Following MFT-BN, parents report decreases in the negative experiences of caregiving and in their own symptoms of anxiety. Adolescents report reductions in anxiety and depression alongside improvement in emotion regulation. Improvements in symptoms of eating disorders include reductions in eating disorder cognitions and modest reductions in binge and purge symptoms after 14 weeks of treatment. Adolescents who participated in MFT-BN were less likely to drop out of outpatient treatment.

We report a case of occult spontaneous ocular perforation presenting as conjunctival chemosis in a patient with Marfan’s syndrome (MFS). A 38-year-old female with MFS presented with bilateral conjunctival chemosis since 6 months. Best-corrected visual acuity was 20/20 in both eyes. On slit-lamp examination, a diffuse conjunctival chemosis was observed in both eyes without any signs of ocular hypotony (decreased visual acuity, low intraocular pressure, shallow anterior chamber, pupil distortion, hypotony maculopathy, and chorioretinal folds). Anterior-segment optical coherence tomography revealed a corneoscleral fistula at the left nasal limbus, without any similar finding in the right eye. A scleral patch was performed at the site of the perforation. At 3 month’s follow-up, the left chemosis had regressed, with a stable best-corrected visual acuity in both eyes. However, on ultrasound biomicroscopy, another fistula at the right superior limbus was found, and the patient was referred for treatment with a scleral patch. In conclusion,conjunctival chemosis in a patient with MFS should raise the suspicion of an occult spontaneous ocular perforation.

Rheumatoid arthritis (RA) is an autoimmune disease that is characterised by synovial inflammation and progressive joint disorder with significant pain and stiffness, which lead to functional disability and systemic complications if left untreated. Although methotrexate (MTX) is the cornerstone in the RA therapy, it is ineffective or intolerable in up to 50% of patients. In addition, tumour necrosis factor (TNF) inhibitors which are regarded as the standard of care for those patients, have not been proven a panacea creating a therapeutic gap. In this direction, other cytokines such as the interleukin (IL)-6 in combination with MTX or as monotherapy have been approved. Sarilumab has already been approved for the treatment of moderate to severe RA, but more studies are on their way including polymyalgia rheumatica, giant cell arteritis, juvenile idiopathic arthritis, and indolent systemic mastocytosis. On the other hand, a study was prematurely discontinued after approximately 1.5 years, when the ankylosing spondylitis development program was discontinued due to lack of efficacy. Regarding safety, efficacy and tolerability of the molecule, three pivotal clinical trials have established sarilumab as one of the safe and efficacious choices for the treatment of RA (mobility, target and monarch trials). Significant decreases in progression of structural damage have been demonstrated. Infections and neutropenia are two of the most common adverse events. Sarilumab is beyond any doubt another molecule that can be added to the clinicians' armamentarium for the treatment of patients with moderate to severe RA with a good safety and efficacy profile.

Introduction To present a novel intraoperative application of photoactivated chromophore for infectious keratitis–corneal cross-linking (PACK-CXL) in the management of post-penetrating keratoplasty (PKP) multiresistant fungal keratitis in a patient with irradiation-related local immunosuppression. Case report A 62-year-old female underwent uneventful PKP for the management of post-irradiation actinic keratopathy. Three months postoperatively, she presented with a diffuse corneal melting abscess that was infiltrating the donor-recipient junction. Despite intensive antibiotic and antifungal therapy, corneal melting progressed to graft perforation. A repeat PKP combined with intraoperative PACK-CXL was performed. PACK-CXL was applied initially on the infected graft, involving the corneoscleral rim and then following placement of the donor button. No intra- or postoperative graft-related complications were encountered. No signs of infection were noted, and the graft remained clear during the 9-month follow-up period. Conclusion Intraoperative PACK-CXL combined with PKP appears to be a safe and effective technique for the management of post-PKP resistant fungal keratitis.

Jeanne Martine Gunzinger, Nafsika Voulgari, Aleksandra Petrovic, Kattayoon Hashemi, Georgios KymionisLausanne University, Cornea and Refractive Surgery Department, Jules-Gonin Eye Hospital, Lausanne, SwitzerlandPurpose: To report the findings of anterior segment optical coherence tomography (AS-OCT) and in vivo confocal microscopy (IVCM) in two patients with peripheral hypertrophic subepithelial corneal degeneration (PHSD).Methods: Case series by retrospective chart review and imaging analysis of AS-OCT and IVCM.Results: Slit lamp examination of the two patients revealed a bilateral subepithelial-elevated fibrous tissue of the superior-nasal quadrant, as well as inferior-nasal in one of the patients. Best corrected visual acuity ranged from 20/25 to 20/15. AS-OCT showed continuous, homogenous, well-demarked hyperreflective subepithelial band associated with hyperreflectivity in the anterior stroma. IVCM demonstrated normal epithelial cell morphology and arrangement and a fibrous structure subepithelial and in the anterior stroma.Conclusion: AS-OCT and IVCM can facilitate the diagnosis of PHSD and differentiate it from other corneal entities that present peripheral opacifications.Keywords: peripheral hypertrophic subepithelial corneal degeneration, anterior segment optical coherence tomography, in vivo confocal microscopy, peripheral corneal opacification

Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the synovial membrane, leading to joint damage and bone destruction. Conventional radiography (CR) of the hands and wrists has been, for many years, the primary imaging modality used to diagnose and monitor RA. On the other hand, many investigators in clinical trials and observational studies used CR of the hands and wrists to demonstrate drug effectiveness and structural damage progression. The purpose of this review is to discuss the evaluation and interpretation of the hands and wrists by CR in RA patients and the radiographic changes occurring in a specific joint. Thus, the literature was reviewed until January 2019 for studies regarding RA radiological evaluation of the hands and wrists, as well as radiological progression using CR. The assessment of joint pathology in RA patients should begin with CR which is the best imaging modality to evaluate any subtle changes occurring at the bone level. Once high-quality radiographs are obtained in appropriate views/projections, then an accurate evaluation can often be made without any further imaging studies. Therefore, CR is a valuable tool for RA screening. It is an easy-to-perform technique and gives important information assisting in differentiating between RA from other arthritides. In contrary CR does not provide good information when early RA changes start to appear, such as synovial inflammation or other soft-tissue structural changes. Nevertheless, it still remains the most commonly used imaging tool in rheumatology and has a number of advantages: it is easily available in most rheumatologists and readily accessible in most patients. It is inexpensive and relatively safe. It provides immediate information and can be interpreted easily by the requested rheumatologist. Finally, the data are reproducible and can be used for serial evaluation and follow-up.

Objectives To estimate the size of unmet needs in the treatment of early Rheumatoid Arthritis (eRA), using all the conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and/or biological DMARDs (bDMARDs) in a long-term observational study. Materials and methods 538 patients with eRA were evaluated. The 2010 ACR/EULAR classification criteria were used. All patients were csDMARDs and bDMARDs-naive with disease duration less than one year. They were treated according to EULAR and ACR recommendations for RA. All the csDMARDs and bDMARDs were used. Clinical, laboratory findings with the disease activity score-28 and treatment decisions were all recorded as well as adverse drug reactions, reason of therapy termination, disease complications and comorbidities. Results Methotrexate (58%) and Infliximab (37%) where the first csDMARD and bDMARD choice respectively. During follow-up, 14 patients were lost and 7 developed comorbidities. The final results are referred to 517 patients. Among those, 66% were treated with csDMARDs as monotherapy or in combination therapy with sustained low disease activity (LDA). However, 3.2% from this group neither achieved LDA, nor received bDMARDs, due to comorbidities. On the other hand, 34% were treated with bDMARDs with or without csDMARDs. The majority of them demonstrated sustained LDA. From this group, 17.7% never achieved LDA, despite that they switched and received all bDMARDs. Thus, 20.9% of our patients never achieved LDA. Conclusions Using the current recommendations for RA therapy we successfully treated the majority of our patients. However, we found that the size of gap and the unmet needs for treatment is about 20%.

Non-sustained ventricular tachycardia (NSVT) is a potentially lethal arrhythmia that is most commonly attributed to coronary artery disease. We hypothesised that among patients with NSVT and preserved ejection fraction, cardiovascular magnetic resonance (CMR) would identify a different proportion of ischaemic/non-ischaemic arrhythmogenic substrates in those with and without autoimmune rheumatic diseases (ARDs). In total, 80 consecutive patients (40 with ARDs, 40 with non-ARD-related cardiac pathology) with NSVT in the past 15 days and preserved left ventricular ejection fraction were examined using a 1.5-T system. Evaluated parameters included biventricular volumes/ejection fractions, T2 signal ratio, early/late gadolinium enhancement (EGE/LGE), T1 and T2 mapping and extracellular volume fraction (ECV). Mean age did not differ across groups, but patients with ARDs were more often women (32 (80%) vs. 15 (38%), p &lt, 0.001). Biventricular systolic function, T2 signal ratio and EGE and LGE extent did not differ significantly between groups. Patients with ARDs had significantly higher median native T1 mapping (1078.5 (1049.0–1149.0) vs. 1041.5 (1014.0–1079.5), p = 0.003), higher ECV (31.0 (29.0–32.0) vs. 28.0 (26.5–30.0), p = 0.003) and higher T2 mapping (57.5 (54.0–61.0) vs. 52.0 (48.0–55.5), p = 0.001). In patients with ARDs, the distribution of cardiac fibrosis followed a predominantly non-ischaemic pattern, with ischaemic patterns being more common in those without ARDs (p &lt, 0.001). After accounting for age and cardiovascular comorbidities, most findings remained unaffected, while only tissue characterisation indices remained significant after additionally correcting for sex. Patients with ARDs had a predominantly non-ischaemic myocardial scar pattern and showed evidence of diffuse inflammatory/ischaemic changes (elevated native T1-/T2-mapping and ECV values) independent of confounding factors.

The aim of this study is to explore the role of labial minor salivary gland (LMSG) focus score (FS) in stratifying Sjögren's Syndrome (SS) patients, lymphoma development prediction and to facilitate early lymphoma diagnosis. Ιn an integrated cohort of 1997 patients, 618 patients with FS ≥ 1 and at least one-year elapsing time interval from SS diagnosis to lymphoma diagnosis or last follow up were identified. Clinical, laboratory and serological features were recorded. A data driven logistic regression model was applied to identify independent lymphoma associated risk factors. Furthermore, a FS threshold maximizing the difference of time interval from SS until lymphoma diagnosis between high and low FS lymphoma subgroups was investigated, to develop a follow up strategy for early lymphoma diagnosis. Of the 618 patients, 560 were non-lymphoma SS patients while the other 58 had SS and lymphoma. FS, cryoglobulinemia and salivary gland enlargement (SGE) were proven to be independent lymphoma associated risk factors. Lymphoma patients with FS ≥ 4 had a statistically significant shorter time interval from SS to lymphoma diagnosis, compared to those with FS 4 (4 vs 9 years, respectively, p = 0,008). SS patients with FS ≥ 4 had more frequently B cell originated manifestations and lymphoma, while in patients with FS 4, autoimmune thyroiditis was more prevalent. In the latter group SGE was the only lymphoma independent risk factor. A second LMSG biopsy is patients with a FS ≥ 4, 4 years after SS diagnosis and in those with FS 4 and a history of SGE, at 9-years, may contribute to an early lymphoma diagnosis. Based on our results we conclude that LMSG FS, evaluated at the time of SS diagnosis, is an independent lymphoma associated risk factor and may serve as a predictive biomarker for the early diagnosis of SS-associated lymphomas.

International audience; Background: Emerging data suggest that the combination of MEK inhibitors and immunotherapeutic agents may result in improved efficacy in melanoma. We evaluated whether combining MEK inhibition and immune checkpoint inhibition was more efficacious than immune checkpoint inhibition alone in patients with previously untreated BRAF V600 wild-type advanced melanoma. Patients and methods: IMspire170 was an international, randomized, open-label, phase III study. Patients were randomized 1 : 1 to receive cobimetinib (60 mg, days 1-21) plus anti-programmed death-ligand 1 atezolizumab (840 mg every 2 weeks) in 28-day cycles or anti-programmed death-1 pembrolizumab (200 mg every 3 weeks) alone until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. The primary outcome was progression-free survival (PFS), assessed by an independent review committee in the intention-to-treat population. Results: Between 11 December 2017, and 29 January 2019, 446 patients were randomized to receive cobimetinib plus atezolizumab (n ¼ 222) or pembrolizumab (n ¼ 224). Median follow-up was 7.1 months [interquartile range (IQR) 4.8-9.9] for cobimetinib plus atezolizumab and 7.2 months (IQR 4.9-10.1) for pembrolizumab. Median PFS was 5.5 months [95% confidence interval (CI) 3.8-7.2] with cobimetinib plus atezolizumab versus 5.7 months (95% CI 3.7-9.6) with pembrolizumab [stratified hazard ratio 1.15 (95% CI 0.88-1.50); P ¼ 0.30]. Hazard ratios for PFS were consistent across prespecified subgroups. In exploratory biomarker analyses, higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms. The most common grade 3-5 adverse events (AEs) were increased blood creatine phosphokinase (10.0% with cobimetinib plus atezolizumab versus 0.9% with pembrolizumab), diarrhea (7.7% versus 1.9%), rash (6.8% versus 0.9%), hypertension (6.4% versus 3.7%), and dermatitis acneiform (5.0% versus 0). Serious AEs occurred in 44.1% of patients with cobimetinib plus atezolizumab and 20.8% with pembrolizumab. Conclusion: Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAF V600 wild-type advanced melanoma.

Background Nationwide data on cardiovascular risk factors prevalence is lacking in Greece. This work presents the findings of the national health examination survey EMENO (2013–2016) regarding the prevalence of hypertension, hypercholesterolemia, diabetes, obesity and smoking. Methods A random sample of adults (≥18 years) was drawn by multistage stratified random sampling based on 2011 Census. All EMENO participants with ≥1 measurement of interest [blood pressure (BP), fasting glucose, HbA1c, total cholesterol (TC), Body Mass Index (BMI)] were included. Hypertension was defined as BP ≥ 140/90 mmHg and/or antihypertensive treatment; diabetes as fasting glucose≥126 mg/dL and/or HbA1c ≥ 6.5% or self-reported diabetes; hypercholesterolemia as TC ≥ 190 mg/dL. Sampling weights were applied to adjust for study design and post-stratification weights to match sample age and sex distribution to population one. Non-response was adjusted by inverse probability weighting. Results Of 6006 EMENO participants, 4822 were included (51.5% females, median age:47.9 years). The prevalence of hypertension was 39.2%, higher in men (42.4%) than in women (36.1%); of hypercholesterolemia 60.2%, similar in men (59.5%) and women (60.9%); of diabetes 11.6%, similar men (12.4%) and women (10.9%); of obesity 32.1%, higher in women (33.5% vs 30.2%), although in subjects aged 18–40 year it was higher in men; of current smoking 38.2%, higher in men (44.0%) than in women (32.7%). The prevalence of all risk factors increased substantially with age, except smoking, which followed an inverse U shape. Conclusions The burden of cardiovascular risk factors among Greek adults is alarming. There is considerable preventive potential and actions at health care and societal level are urgently needed.

Opioids are used for severe forms of acute and cancer pain. Over the last years, their potential use in patients with noncancer pain such as those with rheumatoid arthritis (RA) has been postulated. A recent population-based comparative study showed that chronic opioid use was 12% vs. 4% among RA and non-RA patients, respectively. Another study showed an increase from 7.4% to 16.9% (2002 to 2015). In general, there has been an increasing tendency to use opioids in recent years.The authors have performed an extensive literature search using PubMed for articles including noncancer pain and the use of the mu opioid receptor (MOR) agonists in patients with RA.Data is not sufficient to support opioid use for the treatment of chronic pain in patients with RA. Data is scarce and inconclusive. Rheumatologists should think and ponder the question: Why is this patient in pain? Differential diagnosis should include a disease flare, degenerative changes of the musculoskeletal system, and fibromyalgia. And while there are new strategies for opioid administration currently being researched, unfortunately, they are far from being applied to human subjects in the everyday clinical setting, and are still being evaluated at an experimental level.

Fish bone and/or spine puncture injuries can result in infection of the upper extremities with aquatic bacterial pathogens. Additionally, in such injuries, the inoculation of foreign organic material is frequent and may further complicate the clinical presentation and course of the resulting infection. We describe the case of a 45-year-old female patient with a minimal fish rostrum puncture trauma acquired during preparation of fresh fish meal, which resulted in a galloping hand cellulitis. The alarming clinical presentation and the prompt response of the skin infection to clindamycin obscured the presence of inoculated fish rostrum remnants in the tissue that, three weeks later, gave rise to a foreign body granuloma, from which Aeromonas hydrophila was isolated. Final resolution was achieved with an additional two-week doxycycline treatment. In conclusion, the reported case highlights the potential of the accidentally implanted organic material, as are fish bones, not only to transfer uncommon pathogens but also to offer a sanctuary that favors microbial survival despite antibiotic therapy thus enabling latent or recurrent infections.

Objectives To study the clinical, serological and histologic features of primary Sjogren's syndrome (pSS) patients with early (young ≤35 years) or late (old ≥65 years) onset and to explore the differential effect on lymphoma development. Methods From a multicentre study population of 1997 consecutive pSS patients, those with early or late disease onset, were matched and compared with pSS control patients of middle age onset. Data driven analysis was applied to identify the independent variables associated with lymphoma in both age groups. Results Young pSS patients (19%, n = 379) had higher frequency of salivary gland enlargement (SGE, lymphadenopathy, Raynaud's phenomenon, autoantibodies, C4 hypocomplementemia, hypergammaglobulinemia, leukopenia, and lymphoma (10.3% vs. 5.7%, p = 0.030, OR = 1.91, 95% CI: 1.11-3.27), while old pSS patients (15%, n = 293) had more frequently dry mouth, interstitial lung disease, and lymphoma (6.8% vs. 2.1%, p = 0.011, OR = 3.40, 95% CI: 1.34-8.17) compared to their middle-aged pSS controls, respectively. In young pSS patients, cryoglobulinemia, C4 hypocomplementemia, lymphadenopathy, and SGE were identified as independent lymphoma associated factors, as opposed to old pSS patients in whom SGE, C4 hypocomplementemia and male gender were the independent lymphoma associated factors. Early onset pSS patients displayed two incidence peaks of lymphoma within 3 years of onset and after 10 years, while in late onset pSS patients, lymphoma occurred within the first 6 years. Conclusion Patients with early and late disease onset constitute a significant proportion of pSS population with distinct clinical phenotypes. They possess a higher prevalence of lymphoma, with different predisposing factors and lymphoma distribution across time.

Background: To compare the clinical, serological and histologic features between male and female patients with Sj&ouml, gren&rsquo, s syndrome (SS) and explore the potential effect of gender on lymphoma development. Methods: From a multicenter population (Universities of Udine, Pisa and Athens, Harokopion and Ioannina (UPAHI)) consisting of consecutive SS patients fulfilling the 2016 ACR/EULAR criteria, male patients were identified, matched and compared with female controls. Data-driven multivariable logistic regression analysis was applied to identify independent lymphoma-associated factors. Results: From 1987 consecutive SS patients, 96 males and 192 matched female controls were identified and compared. Males had a higher frequency of lymphoma compared to females (18% vs. 5.2%, OR = 3.89, 95% CI: 1.66 to 8.67, p = 0.0014) and an increased prevalence of serum anti-La/SSB antibodies (50% vs. 34%, OR = 1.953, 95% CI: 1.19 to 3.25, p = 0.0128). No differences were observed in the frequencies of lymphoma predictors between the two genders. Data-driven multivariable logistic regression analysis revealed negative association of the female gender with lymphoma and positive association with lymphadenopathy. Conclusion: Male SS patients carry an increased risk of lymphoma development. Although statistics showed no difference in classical lymphoma predictors compared to females, data-driven analysis revealed gender and lymphadenopathy as independent lymphoma-associated features.

Purpose: To report the evolution of corneal flattening after repeated corneal cross-linking (CXL) in a patient with progressive keratoconus during a 6-year follow-up. Methods: Case report. Results: A 27-year-old female underwent CXL for progressive keratoconus. Postoperatively, corneal topography revealed keratoconus progression with an increase of 1.20 diopters (D) in maximum keratometry (Kmax) and CXL was repeated. After the second treatment, a continuing significant corneal flattening (up to 16.00 D in Kmax) was observed during the first 5 years followed by stabilization during the last sixth year of follow-up. Both uncorrected and corrected distance visual acuity were improved while corneal thickness was decreased. There were no complications such as corneal opacification or endothelial cells decrease during the follow-up period. Conclusion: Repeated CXL can induce an excessive corneal flattening more pronounced during the first years of follow-up followed by stabilization thereafter.

During the last two decades, the therapeutic decisions and strategies for rheumatoid arthritis (RA) management have improved dramatically. Today, the therapeutic armamentarium is significantly augmented, and by using both old and new drugs, remission or low disease activity is a reasonable goal. The use of conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs) in combination with biologic (b) or targeted synthetic (ts) DMARDs has revolutionized RA treatment. Methotrexate administration is considered fundamental among other csDMARDs for the treatment of RA. It is recommended as the initial drug (monotherapy), or in combination with other csDMARDs, bDMARDs, and tsDMARDs in a step-up strategy. Furthermore, it can be used with other csDMARDs as initial combination-therapy. On the other hand, despite the fact that bDMARDs and ts DMARDs are highly efficacious and can also be used as monotherapy in certain cases, cost-effectiveness is still questionable when compared with csDMARDs. In this direction, the classic argument of utmost importance has to do with the most appropriate treatment strategy that shall be initially applied: csDMARD combination-therapy versus monotherapy, or step-up combinationtherapy with bDMARDs, especially tumor necrosis factor-α (TNFa) blockers. For this reason, a literature review of the most important csDMARDs combination and bDMARDs combination studies has been deployed. The results showed that the triple csDMARDs therapy approach is more effective and less expensive. In addition, workers’ productivity is higher than any other treatment options for RA. Triple-therapy constitutes a smart, efficacious, and significantly cheaper choice for RA therapeutic management.

To present the interaction between brain/heart and emphasize the role of combined brain/heart magnetic resonance imaging (MRI) in patients with rheumatoid arthritis (RA) and other seronegative spondyloarthropathies (SNA). Both traditional cardiovascular disease (CVD) risk factors and intrinsic RA/SNA features contribute to the increased CVD-related morbidity/mortality. CVD in RA usually occurs a decade earlier than age- and sex-matched controls, and RA patients are twice more likely to develop myocardial infarction irrespective of age, history of prior CVD, and traditional CVD risk factors. RA also increases risk of non-ischemic heart failure (HF), valvular disease, and myo-pericarditis. CVD in SNA affects more commonly patients with long-standing disease. Ascending aortitis, aortic/mitral insufficiency, conduction defects, and diastolic dysfunction are the commonest findings in ankylosing spondylitis (AS). CVD is also the leading cause of death in psoriatic arthritis (PsA), due to myopericarditis, diastolic dysfunction, and valvular disease. Brain damage, due to either ischemic or hemorrhagic stroke and silent vascular damage, such as white matter hyperenhancement (WMH), is increased in both RA/SNA and may lead to cognitive dysfunction, depression, and brain atrophy. Magnetic resonance imaging (MRI) is ideal for serial brain/heart evaluation of patients with systemic diseases. RA/SNA patients are at high risk for brain/heart damage at early age, irrespectively of classic risk factors. Until more data will be obtained, a combined brain/heart MRI evaluation can be proposed in RA/SNA with new onset of arrhythmia and/or HF, cognitive dysfunction and/or depression.

Objective To describe the clinical spectrum of cryoglobulinemic vasculitis (CV) in primary Sjogren's syndrome (pSS), investigate its relation to lymphoma and identify the differences with hepatitis C virus (HCV) related CV. Methods From a multicentre study population of consecutive pSS patients, those who had been evaluated for cryoglobulins and fulfilled the 2011 classification criteria for CV were identified retrospectively. pSS-CV patients were matched with pSS patients without cryoglobulins (1:2) and HCV-CV patients (1:1). Clinical, laboratory and outcome features were analyzed. A data driven logistic regression model was applied for pSS-CV patients and their pSS cryoglobulin negative controls to identify independent features associated with lymphoma. Results 1083 pSS patients were tested for cryoglobulins. 115 (10.6%) had cryoglobulinemia and 71 (6.5%) fulfilled the classification criteria for CV. pSS-CV patients had higher frequency of extraglandular manifestations and lymphoma (OR=9.87, 95% CI: 4.7–20.9) compared to pSS patients without cryoglobulins. Purpura was the commonest vasculitic manifestation (90%), presenting at disease onset in 39% of patients. One third of pSS-CV patients developed B-cell lymphoma within the first 5 years of CV course, with cryoglobulinemia being the strongest independent lymphoma associated feature. Compared to HCV-CV patients, pSS-CV individuals displayed more frequently lymphadenopathy, type II IgMk cryoglobulins and lymphoma (OR = 6.12, 95% CI: 2.7–14.4) and less frequently C4 hypocomplementemia and peripheral neuropathy. Conclusion pSS-CV has a severe clinical course, overshadowing the typical clinical manifestations of pSS and higher risk for early lymphoma development compared to HCV related CV. Though infrequent, pSS-CV constitutes a distinct severe clinical phenotype of pSS.

Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease and an exclusion diagnosis that includes all forms of arthritis that persists for more than 6 weeks under the age of 16. Although there is not yet a cure for JIA, and recent advances in the therapeutic field have created a more hopeful present and future for the patients. In the past, therapies for JIA have depended on non-steroidal medication, conventional synthetic disease-modifying antirheumatic drugs and corticosteroids. However, over the last decades, the advent of biologic therapies in JIA contributed to the preservation of functional activity, control of pain, avoidance of joint damage, and extra-articular manifestations. Furthermore, over the last years, international institutions, such as the American College of Rheumatology, have released recommendations and guidelines for rheumatologists for optimal JIA management. All the above have revolutionized the treatment of JIA with promising outcomes. To this end, the relevant literature is reviewed and discussed appropriately.

Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting mainly the peripheral skeleton in a symmetrical manner rather than the axial skeleton, but when it occurs it can affect the cervical spine (CS). Although CS involvement is a frequent radiographic finding in RA, the clinical features are scarce, but potentially life-threatening with severe neurological deficits or even death due to brain stem compression. The commonest site of inflammation of the CS is the articulation between C1 and C2 vertebrae, the atlanto-axial region. The radiological finding observed in this region is the atlanto-axial subluxation (AAS). For the evaluation of CS in RA the classical diagnostic technique used mostly is conventional radiography (CR). Since CR does not provide good information regarding synovial inflammation, other imaging modalities are used such as magnetic resonance imaging and computed tomography. However, CR is the most valuable tool for screening CS in RA patients. Thus, we reviewed the literature until December 2019 for studies regarding CS radiological manifestations using CR in RA patients. We found that the frequency of radiological findings varies substantially, ranging between 0.7–95% in different studies. The commonest radiological feature was the AAS followed by subaxial subluxation. Because CS involvement can often be clinically asymptomatic, its assessment should not be forgotten by physicians and should be assessed using CR which is an easy to perform technique and gives important information as a screening tool.

Background: Psoriasis (Pso) is a common chronic inflammatory disease affecting the skin, both sexes, and all ages. It can be associated with other chronic inflammatory musculoskeletal disorders and certain drugs, including tumor necrosis factor α (TNFα) antagonists. Case Presentation: A 64-year-old man with seronegative rheumatoid arthritis (RA) refractory to leflunomide and prednisone was treated with SB-4 (Benepali), an etanercept biosimilar 50mg/week subcutaneously. He responded well to the treatment, but a year later, he developed erythematous skin eruptions affecting mainly in the palms of both hands. Skin biopsy showed a picture compatible with Pso. SB-4 was discontinued, and the skin lesions disappeared with the addition of topical steroid therapy. This is the only case of psoriatic skin lesions associated with SB-4 treatment. Conclusion: Thus, we review and discuss the relevant literature of Pso cases related to SB-4 and other anti-TNFα biosimilars. Rheumatologists dealing with patients on anti-TNFα biosimilars should be aware of and recognize these complications.

We have read with interest the article by Kopp et al that has been published recently in the Annals of the Rheumatic Diseases. The article deals with the risk of neuroinflammatory events (NIEs) in patients with inflammatory arthritides (IA), receiving tumour necrosis factor alpha (TNFα) inhibitors.1 Their cases were identified from the nationwide registries of Sweden and Denmark, in a prospective observational study. The authors found an increased risk of NIEs after anti-TNFα therapy in patients with spondyloarthropathies (SpAs) as compared with those not receiving TNF blockers, while no consistent and significant risk of NIEs after anti-TNFα treatment in rheumatoid arthritis (RA) patients. They concluded that the risk profile of NIEs in patients receiving TNFα inhibitors differs among patients with different IA which has an impact on decision-making in clinical practice. In a prospective imaging and electrophysiological study of our clinic, patients with RA and SpAs who were eligible for anti-TNFα therapy had been investigated, during the period May 2009 to December 2011.2 Before …