Thrombocytopaenia in antiphospholipid syndrome: a free radical perspective.

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.

Subjective loss of clinical response to TNFi in axSpA relates to recurrence of MRI bone marrow oedema particularly with long-acting agents.

OBJECTIVES: Subjective loss of response immediately prior to routine TNFi therapy can occur in axial spondyloarthritis (axSpA). We investigated clinical outcomes in patients taking the first three licenced TNFis and correlated this with recurrence of MRI bone marrow oedema (MRI-BMO). METHODS: Proof-of-concept study including axSpA patients established on etanercept (ETA), adalimumab (ADA) or infliximab (IFX) reporting symptom deterioration prior to next dose. MRI/clinical data were collected prior to scheduled dose (v1), 4 days post-dose (v2) and at the time of patient-reported symptom return (v3). MRI spine/sacroiliac joints utilizing 3 T were scored using the semi-quantitative Leeds MRI scoring system. RESULTS: A total of 113 clinical assessments and MRIs were performed in 38 participants (ADA = 16, ETA = 12, IFX = 10), mean age 42.1 years ± 24.4(2SD, n = 38), 71.1% male (n = 27/38), 69.7% HLA-B27 positive (n = 23/33). At v1, all patients had high disease activity [ASDAS-CRP = 3 (2.7-3.7)] and 57.9% had MRI-BMO (number of MRI-BMO: ETA = 26, ADA = 59, IFX = 28). Improved clinical responses were seen at v2 [ASDAS-CRP -0.41(-0.81 - 0.30), P =0.018; BASDAI -0.58(-2.2 - 0.52), P =0.024]. Despite just a 4-day interval between v1 and v2, a numerical reduction in MRI-BMO lesions between v1/v2 was observed (ETA = -6, ADA = -10, IFX = -3). By v3, comparatively fewer new BMO lesions were detected in the ETA and ADA groups compared with IFX (ETA = -1, ADA = +3, IFX = +8), although the numbers were too small to enable testing for statistical significance. CONCLUSIONS: Short-lived fluctuations in MRI-BMO were commoner with longer-acting agents and corresponded with subjective loss of clinical response before next scheduled TNFi dose. Larger studies are needed to confirm the possible pathogenic implications of this phenomenon.

Antiphospholipid Antibodies and Autoimmune Haemolytic Anaemia: A Systematic Review and Meta-Analysis.

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.

Isoprostane in systemic sclerosis: A systematic review and meta-analysis.

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 (I2 = 75%). Subgroup analysis on urinary isoprostane favoured excess excretion in SSc (p = .009) with slightly lower heterogeneity (I2 = 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 (I2 = 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.

A review of current management of vasculo-Behcet's.

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.

The problem in differentiation between psoriatic-related polyenthesitis and fibromyalgia.

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.

Antiphospholipid syndrome: an update.

BACKGROUND: Antiphospholipid syndrome (APS) or 'Hughes syndrome' is a prothrombotic disease characterized by thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). More than three decades have passed, and experts are still uncovering new pieces of this disease complex pathogenesis and management. MATERIALS AND METHODS: We searched in literature using MEDLINE and PubMed databases focusing on the latest development on disease pathogenesis, risk assessment of thrombosis and treatment of APS. RESULTS: The phosphatidylinositol 3-kinase (PI3K)-AKT-mTORC pathway was most recently identified to have a crucial role in activating inflammation among endothelial vessel wall causing vascular lesions in APS. Additionally, new variables are being implemented to assess the risk of thrombosis in patients with APS. Global APS Score (GAPSS) utilizes cardiovascular risk factors and new autoimmune antibodies as part of the score assessment and is the most valid so far. It can be a promising tool in the future for prediction of thrombosis. Anticoagulation remains the cornerstone in APS; however, many new potential therapeutic agents are developing and are currently under investigation. CONCLUSIONS: The most recent advances in pathogenesis, risk stratification and treatment provide a platform for high yield studies with the ultimate goal of providing the optimal management to patients with APS.

Seronegative antiphospholipid syndrome.

APS is an autoimmune disease that leads to arterial and/or venous thrombosis, recurrent pregnancy loss and persistently positive aPLs. Patients with clinical manifestations highly suggestive of APS but persistently negative conventional aPLs are classified as having seronegative APS. Ongoing research has revealed the existence of non-criteria antibodies proposed to be relevant to APS and that can be potentially included in the disease's classification criteria. We present a literature review on the most promising antibodies of this heterogeneous aPL family, which includes antibodies to a zwitterionic phospholipid, namely phosphatidylethanolamine, phospholipid-binding plasma proteins, phospholipid-protein complexes and anionic phospholipids other than cardiolipin. Although these molecules can increase the diagnostic yield of APS, their clinical relevance is still debatable and needs to be confirmed by interlaboratory efforts toward standardizing diagnostic tools, in addition to experimental data and larger longitudinal studies.

The Prevalence of Behçet's Disease in a Thrombosis Clinic.

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.

Tocilizumab in the Treatment of Eosinophilic Fasciitis: A Case Study and Review of Literature.

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.

Systemic Mastocytosis: A Mimicker of Reactive Arthritis.

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.

Subclinical atherosclerosis in Behcet's disease and its inverse relation to azathioprine use: an updated meta-analysis.

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 (I2 = 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.

Relevance of vein wall thickness in Behcet's disease: A systematic review and meta-analysis.

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 (I2 = 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.

Expert Opinion Guidance on the Detection of Early Connective Tissue Diseases in Interstitial Lung Disease.

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.

Intima media thickness of carotid arteries in familial Mediterranean fever: a systematic review and meta-analysis.

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 (I2 = 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.

Plasma Homocysteine in Behcet's Disease: A Systematic Review and Meta-Analysis.

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.