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Sarcoidosis is an inflammatory multisystem disease characterised by non-necrotising granulomas that typically affect the lungs, lymph nodes, eyes, skin, liver, spleen, heart, bones and joints. Although rare, necrotising granulomas can also occur. In this report, we present a case of a healthy woman in her 60s who presented with a 1-year history of fatigue and generalised body aches. A comprehensive diagnostic workup, including a detailed history, physical examination, blood tests, imaging studies (CT and positron emission tomography-CT) and biopsies, was conducted to identify the underlying cause. Biopsy results confirmed the presence of necrotising granulomas, leading to a diagnosis of extrapulmonary sarcoidosis after excluding other aetiologies. The patient was treated with a multiregimen therapeutic approach, including adalimumab, which resulted in significant clinical improvement., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Primary antiphospholipid syndrome (PAPS) has been associated with an increase in clinical events associated with atherosclerotic vascular disease. Intima media thickness (IMT) of carotid arteries is a surrogate marker of atherosclerotic vascular disease., Objectives: To conduct a systematic review and meta-analysis of studies evaluating IMT and their clinical correlates in PAPS., Methods: Systematic search of EMBASE and PubMed databases from January 2000 to December 2023; we employed random effect meta-analyses for continuous outcomes and Peto's odds ratio for rare events., Results: The meta-analysis included 21 studies (20 case control and 1 cohort) showing that PAPS patients (n = 1103) had thicker IM than controls (n = 832) (p < 0.0001) with wide heterogeneity (I 2  = 86.9 %); PAPS patients (n = 782) also had a greater pooled prevalence of carotid plaques than controls (n = 537) (13.1 % vs 2.97 %, p < 0.0001). A sensitivity analysis by meta-regression indicated that mean age, gender, disease duration, lipid profile, blood pressures, smoking and statin use all explained the heterogeneity variance; a sensitivity analysis by subgroups confirmed smoking status and statin use as explanatory variables with the addition of ethnicity., Conclusion: Atherosclerosis of the carotid artery represents a clinical feature of PAPS in relation to the traditional risk factors and to statin use. Minimising the atherogenic risk with statins could reduce the late arterial atherothrombotic risks of PAPS., Competing Interests: Declaration of competing interest The authors have no financial or non-financial competing interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Case: A 53-year-old male patient presented to the dermatology clinics with a three-week history of painful necrotic patches coalescent of the lateral malleolus of the right and left ankles. History goes back to when the patient reported developing pruritic papules two weeks after receiving his second shot of the Pfizer BioNTech COVID-19 vaccine (BNT162b2). Punch biopsy was consistent with leukocytoclastic vasculitis. He was prescribed a four-week course of systemic corticosteroids and antibiotics as per cultures. Vascular assessment confirmed normal peripheral arterial and venous system. Two months later, the patient re-presented with fever and worsening of his lower extremity ulcers. He underwent debridement of his wounds. Intra-operative cultures revealed multidrug resistant bacteria. He required an additional debridement session a few days later and a 14-day course of Piperacillin-Tazobactam. The patient was subsequently discharged on corticosteroids and Azathioprine and followed up in the vascular surgery and rheumatology clinics. At four months follow-up, the patient's wounds were almost completely healed., Conclusion: This article highlights a case of severe new-onset COVID-19 vaccine-associated leukocytoclastic vasculitis complicated with infected ulcers that required debridement twice in addition to a prolonged course of antibiotics and immunosuppression therapy. To our knowledge, none of the cases reported in the literature were this severe in nature. In this post-pandemic era, it must remain high on the differential list, and healthcare specialists should maintain a high index of suspicion when evaluating sudden new-onset skin lesions that do not have an immediately apparent etiology., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: To perform a meta-analysis on articles evaluating the common femoral vein wall thickness (VWT) in Behcet's disease and its possible clinical, laboratory and treatment correlates (BD)., Methods: Systematic search of EMBASE and PubMed databases from inception to October 2023; we employed random effect meta-analyses for continuous outcomes., Results: The meta-analysis included 9 case-control and 1 cohort study: the VWT was greater in BD (n = 650) than in controls (n = 396) (p < 0.0001) with wide heterogeneity (I 2  = 94.4%); a sensitivity analysis that included mean age of BD participants, gender, disease duration and activity, C-reactive protein, smoking status, immune-suppressive and anti-inflammatory medication, revealed that the heterogeneity variance was partly explained by age (p < 0.0001), male gender (p = 0.03), disease duration (p < 0.0001) and smoking (p = 0.06). The VWT was greater in BD with thrombotic/vascular (n = 189) than in non-thrombotic/vascular BD (n = 140) (p = 0.006) with no heterogeneity., Conclusion: VWT is greater in BD than controls: age, male gender, disease duration and smoking relate to VWT that was greater in BD patients with a history of thrombotic/vascular disease. Prospective studies are required to assess whether VWT may be considered a vascular marker of disease activity., Competing Interests: Declaration of Competing Interest None of the authors declares any financial or non-financial competing interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

To evaluate the intima media thickness of carotid arteries (IMT) and its clinical, laboratory and treatment correlates in Behcet's disease (BD). Systematic search of EMBASE and PubMed databases from January 2016 to October 2022; we employed random effect meta-analyses for continuous outcomes and Peto's odds ratio for rare events. The meta-analysis included 36 case control studies: the IMT was greater in BD (n = 1103) than in controls (n = 832) (p < 0.0001) with wide heterogeneity (I 2  = 86.9%); a sensitivity analysis that included mean age of BD participants, gender, disease duration and activity, atherogenic index of plasma, blood pressure, C-reactive protein, ethnicity, smoking status, anti-inflammatory and immune suppressive agents, revealed that male gender, mean age of participants and azathioprine use (the latter two in inverse fashion) partly explained the heterogeneity variance (p = 0.02, p = 0.005, and p = 0.01). The IMT was greater in vascular (n = 114) than in non-vascular BD (n = 214) (p = 0.006). BD patients (n = 782) had a greater pooled prevalence of carotid plaques than controls (n = 537) (13.1% vs. 2.97%, p < 0.0001). Subclinical carotid artery atherosclerosis represents a vascular feature of BD, independently of the traditional cardiovascular risk factors. The inverse correlations between IMT, age and azathioprine use suggest that thicker carotid arteries at disease onset eventually regress with immune suppressive treatment: this assumption needs verification on adequately designed clinical trials., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objectives: Illustration of a case of systemic mastocytosis mimicking reactive arthritis in the absence of an infectious etiology., Methods: Review of the patient's medical records., Results: We report a case of systemic mastocytosis relapse, presenting with pancytopenia accompanied by knee monoarthritis, cystitis, and bilateral conjunctivitis occurring simultaneously at the same time interval within 2-4 days, mimicking reactive arthritis in the absence of an infectious etiology., Conclusion: Our case demonstrated reactive arthritis features (triad of urethritis, conjunctivitis, and arthritis) without an infectious trigger but rather a relapse of mastocytosis. We should think outside the box when faced with such a clinical scenario in the absence of an infectious etiology. Paraneoplastic reactive arthritis is to be considered after excluding an underlying infection., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2023 Oussama G. Nasrallah et al.)

Thrombosis associated with thrombocytopaenia is an apparent paradox that is present across a wide spectrum of disorders. While thrombocytopaenia has been a controversial clinical classification criterion for APS, as initial reports failed to demonstrate a relation between low platelet count with other clinical or laboratory manifestations of the syndrome, recent data highlight the association between mild-moderate thrombocytopaenia and the risk of thrombosis. Although aPL antibodies may induce platelet activation in vitro, additional stimuli may contribute to their activation in vivo, among which are reactive oxygen and nitrogen species and lipid peroxidation products, which are elevated in patients with APS; an excess of the same stimuli may induce megakaryocyte and platelet apoptosis that leads to decreased platelet production and increased destruction, resulting ultimately in thrombocytopaenia. Herein we provide a novel plausible framework involving free radicals that could add to the understanding of the thrombocytopaenia-thrombosis paradox in APS., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

There is a significant variation in symptoms and clinical presentation of connective tissue disorders (CTD) associated with interstitial lung disease (ILD) (CTD-ILD). This presents difficulties in the diagnosis and treatment of CTD-ILD. Early detection and treatment of CTD-ILD using a multidisciplinary approach have been shown to enhance patient outcomes. This exercise aims to explore clinical components to develop a screening tool for pulmonologists for early detection of CTD in ILD and to provide a framework for a multidisciplinary approach in managing CTD-ILD. This in turn will lead to early treatment of CTD-ILD in collaboration with rheumatologists. A panel of 12 leading rheumatologists from the Middle East and North Africa (MENA) region met virtually to select the most relevant clinical findings to aid in identifying CTD-ILD. Twelve panellists opted to investigate seven of the most common inflammatory autoimmune disorders. The panel discussed how to improve the early detection of CTD-ILD. Clinical characteristics were categorized, and a nine-item questionnaire was created. A biphasic algorithm was developed to guide early referral to a rheumatologist based on the presence of one of nine clinical features of CTD (Phase 1) or the presence of CTD-specific antibodies (Phase 2). A brief questionnaire has been developed to serve as a simple and practical screening tool for CTD-ILD detection. Additional research is needed to validate and evaluate the tool in longitudinal cohorts., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Namas et al.)

Eosinophilic fasciitis (EF) is a rare connective-tissue disorder that is characterised by subacute onset of erythema, oedema, and induration of the skin and soft tissues of the limbs and trunk. Although several triggers have been hypothesised to be associated with EF, the aetiology of eosinophilic fasciitis (EF) is still unclear, and several treatment regimens have been proposed to treat this disease. In this article, we report a case of a 72-year-old gentleman with multiple comorbidities who presented to the clinic for diffuse skin thickening present on his forearms, thighs, legs bilaterally, and over the pelvis. The patient was diagnosed with EF and failed multiple treatment regimens including prednisone, methotrexate, rituximab, but finally responded and was maintained on tocilizumab. In this article, we will review the current understanding of EF, diagnostic approach, popular treatments and review other cases of EF in which tocilizumab was used., Competing Interests: The authors declare no conflict of interest., (© 2023 The Mediterranean Journal of Rheumatology (MJR).)

Background: the prevalence of venous thromboembolism (VTE) in Behcet's disease (BD) is around 40%, though recognition of BD in a thrombosis clinic has been poorly addressed., Objective: to evaluate the prevalence of signs and symptoms leading to the diagnosis of BD in a thrombosis clinic compared to patients attending a general haematology clinic and to healthy controls. Design: cross-sectional case-double control anonymous questionnaire survey. Participants: consecutive patients with spontaneous VTE (n=97) attending a thrombosis clinic, consecutive patients from a general haematology (GH) clinic (n=89) and controls (CTR)., Results: BD was diagnosed in 1.03% of VTE participants, in 2.2% of GH participants and in 1.2% of healthy CTR. Exhaustion was more common reported in participants from the VTE group (15.6%) than in those from the GH group (10.3%) and from the healthy CTR (3%) (p=0.06); the sum of signs and symptoms of BD clustered in the VTE group (89.5%) compared to the GH (72.4%) and the CTR (59.7%) (p<0.0001)., Conclusions: BD may be diagnosed in 1 every 100 patients with VTE attending a thrombosis clinic and in 2 every 100 patients attending a GH clinic: awareness must be raised not to under-diagnose or misdiagnose BD in these settings as management of VTE in BD deviates from the norm., Competing Interests: The authors declare no conflict of interest., (© 2023 The Mediterranean Journal of Rheumatology (MJR).)

Aim: To perform a systematic review and meta-analysis of studies reporting data on atherosclerosis and inflammatory markers in familial Mediterranean fever (FMF)., Methods: EMBASE and PubMed databases were screened according to PRISMA guidelines from inception to January 2022 for articles reporting measurements of the intima media thickness (IMT) of carotid arteries and eventually carotid plaques; random effect meta-analyses for continuous outcomes and Peto's odds ratio for rare events were employed., Results: The screening and selection search strategy yielded 18 case controls studies (16 full papers and 2 abstracts); the IMT was greater in FMF (n = 1112) than in controls (n = 901) (p < 0.0001) with wide heterogeneity (I 2  = 86.4%); a sensitivity analysis according to mean age of participants, male to female ratio, disease duration, C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen (FNG), atherogenic index of plasma (AIP), colchicine use and NOQAS revealed that the heterogeneity variance was partly explained by CRP (p = 0.01) and to a much lesser extent by the AIP (p = 0.10). The pooled prevalence of carotid plaques was greater in FMF (n = 137) than in controls (n = 156) (19% vs 8.3%, p = 0.02) with low heterogeneity., Conclusion: FMF is characterised by premature atherosclerosis expressed as a thicker intima media and a greater prevalence of carotid plaques, partially related to the C-reactive protein, as expected by the autoinflammatory nature of FMF. Key Points • Familial Mediterranean fever is characterised by premature atherosclerosis. • C-reactive protein relates to intima media thickness in keeping with the autoinflammatory nature Familial Mediterranean fever. • Targeting the inter-critical low-grade inflammation may be relevant to minimise the additional cardiovascular risk posed by premature atherosclerosis., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Aim:  To evaluate the relevance of plasma homocysteine (HC) in Behcet's disease (BD) and its clinical manifestations., Methods:  Systematic review of EMBASE and PubMed databases according to PRISMA guidelines from inception to July 2021; random-effects meta-analyses for continuous outcomes., Results:  The search strategy retrieved 48 case-control (2,669 BD and 2,245 control participants) and 5 cohort studies (708 BD participants). Plasma HC was higher in BD than in controls ( p  < 0.0001) with wide heterogeneity ( I2  = 89.7%) that remained unchanged after sensitivity analysis according to year of article publication, age of BD participants, study size, study quality, method of HC determination, and male/female ratio >1.5; some pooled ethnicities explained a small part of the heterogeneity ( I2  = 16.3%). Active BD participants had higher HC than inactive ones ( p  < 0.0001), with moderate heterogeneity (I2  = 49.2%) that disappeared after removal of an outlier study with very high disease activity. BD participants with any vascular involvement had higher HC than those without ( p  < 0.0001) with wide heterogeneity ( I2  = 89.7%); subgroup analysis on venous thrombosis only changed neither effect size ( p  < 0.0001) nor heterogeneity ( I2  = 72.7%). BD participants with ocular involvement had higher HC than those without ( p  < 0.0001) with moderate heterogeneity ( I2  = 40.3%)., Conclusion:  Although causality cannot be inferred, the consistency of the elevation of plasma HC in BD, particularly in patients with active disease, with vascular and ocular involvement suggests an intrinsic involvement of HC in these clinical manifestations., Competing Interests: None declared., (Thieme. All rights reserved.)

Introduction/objective: The relationship between autoimmune haemolytic anaemia (AIHA) and antiphospholipid antibodies (aPL) has never been addressed via a meta-analysis in the paediatric age group. We evaluated the link between AIHA and aPL in childhood systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS)., Methods: EMBASE and PubMed were screened from inception to May 2020 and Peto's odds ratio for rare events was employed for the between group comparisons., Results: The meta-analysis included 11 articles for a total of 575 children: the pooled prevalence of AIHA was greater in (1) IgG aCL-positive than IgG aCL-negative children (39.7% vs 20.9%, p = 0.005); (2) in APS-positive than APS-negative SLE children (36.8% vs 13.2%, p = 0.01); and (3) in SLE-related APS than in primary APS children (53% vs 16.2%, p = 0.008)., Conclusions: The pooled prevalence of AIHA is greatest in SLE with aPL/APS, low-moderate in SLE without aPL/APS, and lowest in primary APS. Key Points • Antiphospholipid antibodies strongly relate to autoimmune haemolytic anaemia. • Autoimmune haemolytic anaemia is more common in systemic lupus erythematosus with antiphospholipid antibodies.

Objectives: The primary objective was to develop an educational video to teach patients with rheumatoid arthritis (RA) self-assessment of their disease activity. Secondary objectives were to validate the video, identify the challenges in producing it, and the responses to these challenges., Methods: Rheumatologists from 7 Middle Eastern Arab countries (MEAC) discussed unmet needs in the education of patients with RA. They reviewed pre-existing educational audiovisual material and drafted the script for a new video in Arabic. The video was produced in collaboration with a technical team, then validated by patients using a standardized interview. At each step of production, challenges were identified., Results: Twenty-three rheumatologists from MEAC identified unmet needs in patients' education. A video was produced, explaining the concepts of treat-to-target and showing a patient performing self-assessment using DAS-28. Sixty-two patients were interviewed for validation and found the video to be useful and easy to understand, albeit not replacing the physician's visit. Most common challenges encountered included acceptance of patient empowerment, agreement on DAS-28 as composite measure, production of a comprehensible written Arabic text, and addressing the population cultural mix., Conclusion: Despite challenges, the video was well accepted among patients and can be used for clinical and research purposes. It is particularly useful in pandemic periods where social distancing is recommended., (© 2021 The Mediterranean Journal of Rheumatology (MJR).)

The dual positivity (DP) and triple positivity (TP) concepts bypass the poor comparability of immune/clotting assay for the laboratory classification of antiphospholipid syndrome (APS). To evaluate intensity of immune/clotting assays and DP/TP through different clinical severity groups (CSG) as follows: (1) non-thrombotic asymptomatic carriers of aPL (N-THR), thrombotic primary APS (THR), deceased (D) for recurrent and fatal thrombosis. Activated partial thromboplastin time ratio (aPTTr), dilute Russell viper venom time ratio (DRVVTr), IgG/IgM anticardiolipin (aCL) and anti β-2-glycoprotein-I (aβ2GPI). Participants: 33 N-THR, 64 THR and 11 D. The frequency of DP and TP (DRVVTr or aPTTr partnered with respective IgG aCL or aβ2GPI) increased across CSG (p = 0.006 and p = 0.003); mean DRVVTr and IgG aCL/aβ2GPI were always greater in TP versus non-TP within each CSG and progressively increased across the CSG. The intensity of individual lupus anticoagulants partnered with their corresponding IgG aPL related to the frequency of multiple positivity throughout CSG suggesting that of intensity of immune/clotting assays and multiple positivity are the different faces of the same diagnostic coin in our thrombotic PAPS cohort.

The relationship between antiphospholipid antibodies (aPL) and sickle cell disease (SCD) has never been systematically addressed. Our aim was to evaluate potential links between SCD and aPL in all age groups. EMBASE/PubMed was screened from inception to May 2020 and Peto odds ratios for rare events were calculated. The pooled prevalence (PP) of IgG anticardiolipin antibodies (aCL) was higher in individuals with SCD than in controls (27.9% vs 8.7%, P < 0.0001), that of IgM aCL was similar in the two groups (2.9% vs 2.7%); only individuals with SCD were positive for lupus anticoagulant (LA) (7.7% vs 0%, P < 0.0001). The PP of leg ulcers was similar between aPL positive and negative individuals (44% vs 53%) and between patients in acute crisis and stable patients (5.6% vs 7.3%). Reporting of aPL as a binary outcome and not as a titer precluded further interpretation. The results indicate that a prospective case-control study with serial measurements of a panel of aPL in SCD patients might be warranted, in order to understand further the possible pathogenic role of aPL in SCD.

Aim: To evaluate the clinical relevance of antiphospholipid antibodies (aPL) in patients with lower extremity peripheral artery disease (PAD)., Data Sources: EMBASE and MEDLINE databases were searched from inception to March 2020 for clinical studies reporting on the association between of aPL [IgG/IgM anticardiolipin (aCL) and lupus anticoagulant (LA)] and PAD., Methods: We determined the pooled prevalence (PP) of patients positive for aPL in PAD or the PP of PAD in patients positive for aPL; we employed Peto's odds ratio with random effect for the meta-analysis., Results: Twenty-one studies comprising 6,057 patients were evaluated: in patients with PAD, the PP of IgG aCL was 12% vs 4.1% in those without, IgM aCL was 13.2% vs 2.1%, and LA 13.3% vs 3.3%, respectively. The PP of patients with LA was greater in critical limb ischemia than in the control group (19.3% vs 4.2%). Also, the PP of patients with LA was greater in the failed than in the successful revascularisation group (35.8% vs 15.8%). The PP of post-procedural revascularisation failures was similar in the groups given or not given oral anticoagulation (59.2% vs 61.9%)., Conclusion: All the aPL related to PAD regardless of diagnostic definition used, whereas LA related also to critical limb ischaemia and failed revascularisation. Data expressed as percentage of participants positive for aPL limit the interpretation of these relationships., Competing Interests: Declaration of Competing Interest None of the authors declares any conflict of interest, (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: The relationship between autoimmune hemolytic anemia and antiphospholipid antibodies (aPL) and/or antiphospholipid syndrome has never been systematically addressed., Methods: Systematic review of EMBASE and PubMed databases performed according to PRISMA guidelines from inception to March 2020; meta-analysis performed by Peto's odds ratio for rare events., Findings: Forty-five studies with different outcomes met the inclusion/exclusion criteria. The pooled prevalence (PP) of IgG anticardiolipin antibodies (aCL) positivity was greater in end-stage renal disease (ESRD) than controls (20.2% vs. 2.6%, P = 0.001, I 2  >80%; I 2 = heterogeneity), particularly in hemodialysis patients (18.3% vs. 8%, I 2 = 0%). The PP of lupus anticoagulant was greater in ESRD than controls (8.7% vs. 0.2%, P < 0.0001, I 2 = 0%). The standardized mean difference of IgG aCL favored ESRD rather than controls (P < 0.0001, I 2 =97%). The PP of fistula occlusion was greater in IgG aCL-positive patients than negative patients (39% vs. 27%, I 2 =97%); the PP of IgG aCL positivity was greater in patients with fistula occlusion than without fistula occlusion (26.9% vs. 23.2%, P = 0.01, I 2 =72%); the same applied to the PP of lupus anticoagulant positivity (23% vs. 0.3%, P < 0.0001, I 2 = 0%). The standardized mean difference of IgG aCL favored fistula occlusion (P = 0.004, I 2 = 91%)., Discussion: Lupus anticoagulant relates to ESRD regardless of management whereas IgG aCL relates specifically to ESRD on hemodialysis, but only lupus anticoagulant associates with fistula occlusion. The expression of aPL as patients positive for aPL rather than as titers precludes further assumptions on the relationship., (© 2020 International Society for Hemodialysis.)

The relationship between antiphospholipid antibodies (aPL) and autoimmune haemolytic anaemia (AIHA) has never been systematically addressed. The aim of this study is to assess the link between aPL and AIHA in adult systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). This study performed an EMBASE/PubMed search from inception to June 2019 and meta-analysis using Peto's odds ratios. The pooled prevalence (PP) of IgG/IgM anticardiolipin (aCL) and lupus anticoagulant (LA) was greater in AIHA +ve than AIHA -ve patients (34.7% vs. 27.6%, p = 0.03; 33.3% vs. 21.8%, p < 0.0001; 20.9% vs. 8.3%, p = 0.01). The PP of AIHA was greater in: (1) IgG and IgM aCL +ve than -ve patients (21.8% vs. 11.1%, p = 0.001 and 18.7% vs. 6.3%, p < 0.0001), (2) in SLE related APS than in primary APS patients (22.8% vs. 3.9% p < 0.0001), (3) in APS +ve than APS -ve SLE patients (23.2% vs. 8.4%, p = 0.01), and (4) in thrombotic APS than non-thrombotic APS/SLE patients (26.8% vs. 10%, p = 0.03). The PP of IgG/IgM aCL and LA was greater in DAT +ve than DAT -ve patients (42.4% vs. 12.8%, p < 0.0001; 26.2% vs. 12.8%, p = 0.03 and 29.2% vs. 15.7%, p = 0.004 respectively). It was found that AIHA prevalence is maximal in SLE with aPL/APS, low-moderate in SLE without aPL and minimal in PAPS. Moreover, AIHA is rightly included among the classification criteria for SLE but not for APS/aPL. The significance of an isolated DAT positivity remains unclear in this setting.

Objective: To evaluate the effect of antiphospholipid antibodies (aPL) on renal allograft outcome after kidney transplantation., Methods: A systematic search of EMBASE and PubMed databases from inception to July 2018 was run according to PRISMA guidelines; Peto's odds ratio (OR) for rare events was used for the meta-analysis., Results: Our inclusion/exclusion criteria were met by 22 cohort studies having different outcomes: allograft thrombosis (n = 9) and thromboprophylaxis (n = 3), allograft loss from any cause (n = 9), allograft malfunction (n = 3), duration (n = 2), glomerular filtration rate at 1 year (n = 3) and allograft rejection (n = 5). The pooled prevalence of allograft thrombosis and of thrombotic microangiopathy was greater in aPL+ve than negative recipients (10.4% vs 1.7%, p < 0.0001 and 10.2% vs 0%, p = 0.005, respectively). The pooled prevalence of allograft thrombosis was 75% in patients not taking anticoagulation whereas none of the anticoagulated recipients developed thrombosis (p < 0.0001). The pooled prevalence of allograft loss was greater in aPL+ve recipients (28% vs 18% respectively, p < 0.0001); the pooled prevalence of aPL was greater in allograft loss recipients compared to those who did not lose it (51% vs 33%, p < 0.0001). The pooled prevalence of allograft malfunction and rejection was similar in aPL-ve and aPL+ve recipients (32.2% vs 40.3% and 14.9% vs 14.4%, respectively) but graft duration was shorter in aPL+ve than aPL-ve recipients (p = 0.001) and glomerular filtration rate at 1 year was lower in aPL + ve than aPL-ve recipients (p < 0.0001)., Conclusion: APL relate strongly to allograft thrombosis, loss and duration but not to allograft malfunction and rejection. Oral antivitamin K anticoagulants effectively prevent allograft thrombosis in aPL recipients. The debate on the role of aPL in renal transplant is limited by the expression of data as percentage of recipients positive for aPL rather than aPL titres in many studies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Septic arthritis is a common rheumatologic condition with myriad microbiological causative agents. Moraxella is one of the very rare causes of septic arthritis. We hereby present the third case of Moraxella nonliquefaciens septic arthritis and the first case in a hematopoietic stem cell transplant patient (HSCT) along with a brief review of the literature., Methods: We used PubMed with google search engine to search the literature for reported cases of moraxella septic arthritis., Results: Information on 19 other cases of moraxella infectious arthritis was found. M. catarrhalis was the most common species isolated. Only 2 reports on M. nonliquefaciens were found; the first one in a multiple myeloma patient and the second one in a diabetic patient on hemodialysis. Predisposing conditions included inflammatory arthritis, prosthetic joints, diabetes, Human Immunodeficiency Virus (HIV) infection, Hepatitis C, hemodialysis, esophageal cancer, valve replacements, alcoholism and Intravenous (IV) drug use. The age group of the reported cases ranged from 3 months to 78 years., Conclusion: Infectious arthritis with Moraxella spp. is a very rare entity which can occur in any age group and in the setting of various underlying medical conditions., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To further the knowledge of oxidative stress in systemic sclerosis (SSc), we performed a systematic review and meta-analysis on studies measuring isoprostane, a vasoactive agent deriving from arachidonic acid and implicated in the vasculopathy of SSc., Methods: Systematic search following the PRISMA guidelines in PubMed and EMBASE between January-1990/December-2017 using the terms: oxidative stress, isoprostane, systemic sclerosis and scleroderma., Results: After the screening process, 8 studies including 240 SSc patients and 192 controls were included in the systematic review and meta-analysis, 6 investigating urinary and 2 serum isoprostane: random effect meta-analysis revealed isoprostane overgeneration in SSc (p < .001) with wide heterogeneity (I 2  = 75%). Subgroup analysis on urinary isoprostane favoured excess excretion in SSc (p = .009) with slightly lower heterogeneity (I 2  = 67%); further subgroup analysis according to unit of measurement revealed no increased isoprostane excretion when expressed as pg/mg creatinine but increased when expressed as pmol/mmol creatinine (p = .05) with medium heterogeneity (I 2  = 32%). Subgroup analysis on serum isoprostane favoured overproduction in SSc (p < .0001) with no heterogeneity., Conclusion: There is some evidence for isoprostane overgeneration in SSc that confirms the occurrence of oxidative stress in this setting: further prospective studies with specified outcomes are needed to evaluate the prognostic value of this functional biomarker.

Clinical practice guidelines can assist rheumatologists in the proper prescription of newer treatment for rheumatoid arthritis (RA). The objective of this paper is to report on the recommendations for the management of patients with RA in the Eastern Mediterranean region. We adapted the 2015 American College of Rheumatology guidelines in two separate waves. We used the adolopment methodology, and followed the 18 steps of the "Guidelines 2.0" comprehensive checklist for guideline development. For each question, we updated the original guidelines' evidence synthesis, and we developed an Evidence Profile (EP) and an Evidence to Decision (EtD) table. In the first wave, we adoloped eight out of the 15 original questions on early RA. The strength changed for five of these recommendations from strong to conditional, due to one or more of the following factors: cost, impact on health equities, the balance of benefits, and harms and acceptability. In the second wave, we adoloped eight out of the original 44 questions on established RA. The strength changed for two of these recommendations from strong to conditional, in both cases due to cost, impact on health equities, balance of benefits and harms, and acceptability. The panel also developed a good practice recommendation. We successfully adoloped 16 recommendations for the management of early and established RA in the Eastern Mediterranean region. The process proved feasible and sensitive to contextual factors.

In the original version of this article the first name of the co-author was incorrectly spelled as "Khaled A. Alnaqbi". The correct spelling should have been "Khalid A. Alnaqbi". This is now presented correctly in this article.

Systemic sclerosis (SSc) is a multisystem autoimmune disease: characterised from the clinical side by progressive vasculopathy and fibrosis of the skin and different organs and from the biochemical side by fibroblast deregulation with excessive production of collagen and increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). The latter contributes to an overproduction of reactive oxygen species that through an autocrine loop maintains NOX4 in a state of activation. Reactive oxygen and nitrogen species are implicated in the origin and perpetuation of several clinical manifestations of SSc having vascular damage in common; attempts to dampen oxidative and nitrative stress through different agents with antioxidant properties have not translated into a sustained clinical benefit. Objective of this narrative review is to describe the origin and clinical implications of oxidative and nitrative stress in SSc, with particular focus on the central role of NOX4 and its interactions, to re-evaluate the antioxidant approaches so far used to limit disease progression, to appraise the complexity of antioxidant treatment and to touch on novel pathways elements of which may represent specific treatment targets in the not so distant future.

Competing Interests: Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Background: Familial Mediterranean Fever (FMF) is one of the most common hereditary auto-inflammatory diseases especially among Arabs, Armenians, Jews, and Turks characterized by recurrent attacks of fever, abdominal pain and arthritis.Whether the prevalence of ankylosing spondylitis (AS) is increased in FMF patients is a matter of debate. This review will summarize all the literature data relevant to this topic., Methods: We searched all the articles through PubMed and Embase databases from 1963 until 2017 addressing the relationship between AS and FMF patients., Results: The prevalence of AS among FMF patients is highly variable. However, a significant relationship was found to exist between MEFV gene mutations and AS. Most patients with coexistent MEFV gene mutations and AS were human leucocyte antigen B27 (HLA-B27) negative. The effect of these mutations on AS severity and prognosis was not significant., Conclusion: Large based population studies are needed to further assess the existence of MEFV gene mutations among AS patients and their effect on the clinical course of the disease in addition to assessment of AS prevalence in patients with FMF., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The recognition of the primacy of enthesitis in animal models of spondyloarthritis and the prevalence of clinically occult enthesopathy in psoriatic subjects and of persistent joint pain in PsA subjects who have ostensibly good reduction of joint swelling under biological therapy has highlighted the potential impact of polyenthesitis in psoriatic disease. In daily practice, the formal demonstration of enthesitis is challenging for the following reasons: the relatively avascular nature of enthesis, often leading to the absence of overt clinical inflammatory signs; the frequent lack of elevation of inflammatory markers; and finally, the limitations of current imaging techniques to provide supportive evidence for inflammation in these areas. Consequently, enthesitis may present as widespread pain indistinguishable from FM or may emerge as the dominant feature after successful biological therapy for suppression of synovitis. The unmet needs in the differentiation between FM and enthesitis in psoriatic disease patients are highlighted and critically evaluated in this article., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose of Review: To give an overview of recently published articles about the management of vasculo-Behcet's with particular emphasis on anticoagulation., Recent Findings: Biologic agents are emerging as a potential therapeutic option in refractory vasculo-Behcet with a good safety profile. Evidence further shows that following nonpulmonary aneurysm repair, there is a reduced risk of recurrent aneurysmal formation at the operative site in patients treated with immunosuppressants in addition to their surgery, than those undergoing surgical intervention alone., Summary: Behcet disease patients are at risk of developing multiple vascular complications including thrombosis and aneurysms. Treatment should focus on reducing inflammation; and the role of anticoagulation is still debatable.

Background: The relationship between antiphospholipid antibodies (aPL) and multiple sclerosis (MS) is unclear., Objectives: To evaluate a link between aPL and MS., Methods: EMBASE and PubMed search to August 2016; Peto's odds ratio (OR) meta-analysis., Results: The pooled prevalence of participants positive for IgG and IgM anticardiolipin (aCL) from 12 case-control studies was superior in MS than controls (6.8% vs 1.8%, p = 0.01 and 8.58% vs 2.18%, p = 0.001) with medium and high heterogeneities respectively (I 2 = 48.55% and 68.13%). The pooled prevalence of participants positive for IgG anti-beta 2 glycoprotein-I (aβ 2 GPI) from seven case-control studies was lower in MS than controls (0.93% vs 4.02%) with high heterogeneity (I 2 = 53.92%) though the pooled prevalence of participants positive for IgM aβ 2 GPI was similar (7.24% vs 6.13%) with high heterogeneity (I 2 = 52.85%). Five cohorts compared IgG/IgM aCL and IgM aβ 2 GPI in stable/remission vs active/relapsing MS: the pooled prevalence of IgG aCL was similar in active/relapsing and stable/remission MS (19% vs 18.9%) but the pooled prevalence of IgM aCL was higher in active than in stable MS (36.9% vs 21%, p < 0.0001) as well as that of IgM β 2 GPI (40.5% vs 3.2%, p < 0.0001) with no heterogeneity., Conclusion: Data from case-control studies do not support a link between IgG/IgM aPL and MS. Data from cohort studies comparing active vs stable MS indicate a strong link between aPL of IgM isotype and active/relapsing MS but in the absence of aPL titres to comment upon this may either represent an epiphenomenon of active neuro-inflammation or natural autoantibodies devoid of pathogenic potential. Data expressed as frequency of aPL positive participants rather than average titres preclude further assumptions., (Copyright © 2017. Published by Elsevier Inc.)

Objective: To evaluate the clinical relevance of antiphospholipid antibodies (aPL) in systemic sclerosis (SSc)., Methods: A systematic search of EMBASE and PubMed databases from January 1983 to July 2016 was carried out according to PRISMA guidelines whereas Peto׳s odds ratio (OR) for rare events was used for the meta-analysis., Results: The pooled prevalence of participants positive for IgG and IgM anticardiolipin (aCL) antibodies was higher in SSc than controls (12.8% vs 1.6% and 7.8% vs 0.6%; p < 0.0001 for both) as was that of IgG and IgM anti-beta-2-glycoprotein-I antibodies (aβ 2 GPI) (6.1% vs 0.58%, p < 0.0001; 3.5% vs 0.3%, p = 0.001). The pooled prevalence of pulmonary arterial hypertension (PAH) was more common in SSc positive than negative patients for aCL (IgG/IgM combined) (26.5% vs 10.9%, p < 0.0001) whereas the pooled prevalence of renal disease (RD) was more common in IgG aCL positive than negative patients (36.3% vs 10.9%, p = 0.02). The pooled prevalence of thrombosis was higher in IgG aCL, IgM aCL, and IgM aβ 2 GPI positive than negative SSc patients (12.6% vs 1.4%, p < 0.0001), (15.1% vs 2.7%, p = 0.002) and (15% vs 0.78%, p = 0.009), respectively. The pooled prevalence of digital infarction/ischemia (DI) was higher in IgG aCL and IgM positive than negative SSc (52.8% vs 39.8%, p = 0.002) and (68.1% vs 29%, p = 0.07)., Conclusions: A strong relationship exists between aCL and aβ 2 GPI of IgG/IgM isotype and SSc; patients positive for these antibodies are more likely to suffer from PAH, RD, thrombosis, and DI. However, data expressed as frequency of aPL positive patients rather than average antibody titers preclude further insight into the relevance of these assumptions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The vascular mortality of antiphospholipid syndrome (APS) ranges from 1.4 % to 5.5 %, but its predictors are poorly known. It was the study objective to evaluate the impact of baseline lupus anticoagulant assays, IgG anticardiolipin (aCL), plasma fibrinogen (FNG) and von Willebrand factor (VWF), platelets (PLT) and of genetic polymorphisms of methylenetetrahydrofolate reductase C677T, of prothrombin G20210A and of paraoxonase-1 Q192R on survival in primary APS (PAPS). Cohort study on 77 thrombotic PAPS and 33 asymptomatic carriers of aPL (PCaPL) seen from 1989 to 2015 and persistently positive for aPL as per annual review. At baseline all participants were tested twice for the ratios of kaolin clotting time (KCTr), activated partial thromboplastin time (aPTTr), dilute Russell viper venom time (DRVVTr), IgG aCL, FNG, VWF and once for PLT. All thrombotic PAPS were on warfarin with regular INR monitoring. During follow-up 11 PAPS deceased (D-PAPS) of recurrent thrombosis mostly arterial, despite adequate anticoagulation yielding an overall vascular mortality of 10 %. D-PAPS had the strongest baseline aPTTr and DRVVTr and the highest mean baseline IgG aCL, FNG, VWF and PLT. Cox proportional hazards model identified baseline DRVVTr and FNG as main predictors of mortality with adjusted hazard ratios of 5.75 (95 % confidence interval [CI]: 1.5, 22.4) and of 1.03 (95 %CI: 1.01, 1.04), respectively. In conclusion, plasma DRVVTr and FNG are strongly associated with the risk of vascular death in PAPS; while FNG lowering agents exist further research should be directed at therapeutic strategies able to dampen aPL production.

The scope of clinical and laboratory manifestations of the antiphospholipid syndrome (APS) has increased dramatically since its discovery in 1983, where any organ system can be involved. Musculoskeletal complications are consistently reported in APS patients, not only causing morbidity and mortality, but also affecting their quality of life. We reviewed all English papers on APS involvement in the musculoskeletal system using Google Scholar and Pubmed; all reports are summarized in a table in this review. The spectrum of manifestations includes arthralgia/arthritis, avascular necrosis of bone, bone marrow necrosis, complex regional pain syndrome type-1, muscle infarction, non-traumatic fractures, and osteoporosis. Some of these manifestations were reported in good quality studies, some of which showed an association between aPL-positivity and the occurrence of these manifestations, while others were merely described in case reports., (© The Author(s) 2016.)

Objective: To evaluate subclinical atherosclerosis in Behcet disease (BD), we performed a systematic review and meta-analysis of studies where atherosclerosis was determined by flow-mediated dilatation (FMD) and endothelial-mediated dilatation (EMD) and by measurement of intima media thickness (IMT) of carotid arteries., Methods: Systematic search of EMBASE and PubMed databases from January 2000 to January 2014 according to PRISMA guidelines., Results: Nine studies met the inclusion criteria on FMD/EMD, 11 on IMT and 4 on both. BD had lower FMD than controls (SMD = -0.89, 95% CI: -0.660 to -1.11, p < 0.001), which was confirmed by subgroup analyses on active and inactive patients (SMD = -1.17, 95% CI: -1.45 to -0.89 and SMD = -0.72, 95% CI: -0.97 to -0.46, p = 0.0001 for both). EMD was lower in BD but with a large estimate (SMD = 0.38, 95% CI: -0.79 to -0.03, p = 0.06, I(2) = 82.2%). IMT was greater in BD and the large estimate (SMD = 0.95, 95% CI: 0.63-1.28, p < 0.0001, I(2) = 87.6%) persisted after subgroup analysis on active and inactive patients (I(2) = 88.4% and 86.7%, respectively). Pooling IMT studies by a Newcastle Ottawa Scale of 5 and 6/7 yielded lower estimates (SMD = 0.54, 95% CI: 0.32-0.75, p < 0.0001, I(2) = 58.7% and SMD = 1.72, 95% CI: 1.35-2.09 p < 0.05, I(2) = 48.6%)., Conclusions: FMD is impaired in BD even in inactive state and IMT is greater despite a degree of statistical heterogeneity that reflects the clinical heterogeneity of BD. Future prospective studies should account for risk stratification of atherosclerosis in BD., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)