The real-world safety profile of sodium-glucose co-transporter-2 inhibitors among older adults (≥ 75 years): a retrospective, pharmacovigilance study.

BACKGROUND: As indications for sodium-glucose co-transporter-2 inhibitors (SGLT2i) are expanding, a growing number of older adults have become candidates for treatment. We studied the safety profile of SGLT2i among older adults. METHODS: A retrospective, pharmacovigilance study of the FDA's global database of safety reports. To assess reporting of pre-specified adverse events following SGLT2i among adults (< 75 years) and older adults (≥ 75), we performed a disproportionality analysis using the sex-adjusted reporting odds ratio (adj.ROR). RESULTS: We identified safety reports of 129,795 patients who received non-insulin anti-diabetic drugs (NIAD), including 24,253 who were treated with SGLT2i (median age 60 [IQR: 51-68] years, 2,339 [9.6%] aged ≥ 75 years). Compared to other NIAD, SGLT2i were significantly associated with amputations (adj.ROR = 355.1 [95%CI: 258.8 - 487.3] vs adj.ROR = 250.2 [79.3 - 789.5]), Fournier gangrene (adj.ROR = 45.0 [34.5 - 58.8] vs adj.ROR = 88.0 [27.0 - 286.6]), diabetic ketoacidosis (adj.ROR = 32.3 [30.0 - 34.8] vs adj.ROR = 23.3 [19.2 - 28.3]), genitourinary infections (adj.ROR = 10.3 [9.4 - 11.2] vs adj.ROR = 8.6 [7.2 - 10.3]), nocturia (adj.ROR = 5.5 [3.7 - 8.2] vs adj.ROR = 6.7 [2.8 - 15.7]), dehydration (adj.ROR = 2.5 [2.3 - 2.8] vs adj.ROR = 2.6 [2.1 - 3.3]), and fractures (adj.ROR = 1.7 [1.4 - 2.1] vs adj.ROR = 1.5 [1.02 - 2.1]) in both adults and older adults, respectively. None of these safety signals was significantly greater in older adults (Pinteraction threshold of 0.05). Acute kidney injury was associated with SGLT2i in adults (adj.ROR = 1.97 [1.85 - 2.09]) but not in older adults (adj.ROR = 0.71 [0.59 - 0.84]). Falls, hypotension, and syncope were not associated with SGLT2i among either adults or older adults. CONCLUSION: In this global post-marketing study, none of the adverse events was reported more frequently among older adults. Our findings provide reassurance regarding SGLT2i treatment in older adults, although careful monitoring is warranted.

Safety of the BNT162b2 mRNA COVID-19 vaccine in patients with familial Mediterranean fever.

OBJECTIVES: Evidence suggests a possible association between the COVID-19 vaccine and autoimmune disease flares or new onset of various autoinflammatory manifestations, such as pericarditis and myocarditis. The objective of this study was to assess the safety of an mRNA-based BNT162b2 anti-COVID-19 vaccine in individuals with FMF, a prototypic autoinflammatory disease. METHODS: Patients participating in this study fulfilled the criteria for diagnosis of FMF, were older than 18 years and received at least one dose of the vaccine. Data on baseline characteristics, features of FMF, post-vaccination side effects, and disease flares were acquired using electronic medical files and telephone interviews. RESULTS: A total of 273 FMF patients were recruited for the study. >95% were vaccinated with two doses of the vaccine. The rates of local reactions following the first and second vaccine doses were 65.5% and 60%, respectively, and 26% and 50.4%, respectively, for systemic adverse events. These rates are lower than those reported for the general population from real-world and clinical trial settings. Postvaccination FMF activity remained stable in most patients. None of the patients reported an attack of pericarditis or myocarditis, considered the most serious vaccine-associated adverse events. Patients with a more active FMF disease and patients harboring the M694V mutation had a significantly higher rate of post-vaccination systemic side effects and attacks. CONCLUSION: The BNT162b2 mRNA COVID-19 vaccine is safe in patients with FMF. Our results support the administration of this vaccine to FMF patients according to guidelines applicable to the general population.

CHA2DS2-VASC Score Predicts the Risk of Stroke in Patients Hospitalized to the Internal Medicine Department Without Known Atrial Fibrillation.

BACKGROUND: The CHA2DS2-VASC score is used to assess the risk of cerebrovascular accident (CVA) in patients with atrial fibrillation (AF) or atrial flutter (AFL). OBJECTIVES: We aimed to determine whether this score can determine the risk of CVA during the first year after hospitalization, in patients without known AF/AFL. DESIGN: Single-center retrospective cohort. PATIENTS: We included all patients aged ≥ 50 who were hospitalized between January 1, 2008, and December 31, 2018, to the internal medicine departments at the Chaim Sheba Medical Center, Israel. Exclusion criteria included history or new diagnosis of CVA, TIA, and AF/AFL and use of anticoagulation at any time. MAIN MEASURES: Patients were stratified into 3 groups according to their CHA2DS2-VASC score (0-1, 2, or ≥ 3). The primary outcome was hospitalization with CVA/TIA within one year of the index hospitalization. KEY RESULTS: Of the patients, 52,206 were included in the study. CVA/TIA occurred in 0.7%, 1.3%, and 1.7% of patients with a CHA2DS2-VASC score of 0-1, 2, and ≥ 3, respectively. Compared to a CHA2DS2-VASC score of 0-1, the HR for CVA/TIA occurrence for CHA2DS2-VASC scores of 2 and ≥ 3 was 1.77 (CI 1.42, 2.22) and 2.33 (CI 1.9, 2.85), respectively (p < 0.001 for both comparisons). Each additional CHA2DS2-VASC point increased the probability for readmission with CVA/TIA within 1-year by 26% (HR 1.26, CI 1.19, 1.32, p < 0.001). Similar trends were seen in subgroup analyses by gender, age, and renal function. CONCLUSIONS: The CHA2DS2-VASC score is a predictor for CVA/TIA during the first year after hospitalization in patients without AF. High CHA2DS2-VASC scores warrant work-up for occult AF/AFL and other risk factors for CVA/TIA.

Clinical and prognostic significance of elevated ferritin levels in hospitalised adults.

PURPOSE OF THE STUDY: Elevated ferritin levels are associated with a variety of infectious, malignant and inflammatory diseases. We aimed to investigate the prognostic value of markedly elevated ferritin levels in hospitalised patients with various medical conditions. STUDY DESIGN: Retrospective analysis of patients with a ferritin level higher than 2000 ng/mL hospitalised in Sheba Medical Center between 1 January 2007 and 31 December 2015. Medical conditions of these patients were recorded. In-hospital, 30-day and 1-year mortality rates were evaluated according to ferritin ranges and clinical categories. RESULTS: The study included 722 patients (63.4% men) with a mean age of 63.9±16.7 years. The most common clinical conditions associated with markedly elevated ferritin were infectious diseases and malignancies. The highest mean ferritin levels were associated with rheumatological/inflammatory conditions (16 241.3 ng/dL), particularly in patients with macrophage activation syndrome (MAS) (96 615.5 ng/dL). In-hospital, 30-day and 1-year mortality rates were 32.3%, 46.7% and 70.8%, respectively. The highest in-hospital, 30-day and 1-year mortality rates were observed among patients with solid malignancies (40.1%, 64.7% and 90.3%, respectively), whereas the lowest rates were found among patients with rheumatological/inflammatory conditions, including MAS (21.4%, 38.1% and 45.2%, respectively). Ferritin levels were not associated with mortality. CONCLUSIONS: In hospitalised patients, ferritin levels higher than 2000 ng/mL are mainly associated with infectious and malignant diseases but do not predict mortality.

The Preferential Use of Anakinra in Various Settings of FMF: A Review Applied to an Updated Treatment-Related Perspective of the Disease.

Familial Mediterranean fever (FMF), the most frequent monogenic autoinflammatory disease, is manifested with recurrent and chronic inflammation and amyloid A (AA) amyloidosis, driven by overproduction of interleukin 1 (IL-1) through an activated pyrin inflammasome. Consequently, non-responsiveness to colchicine, the cornerstone of FMF treatment, is nowadays addressed by IL-1- blockers. Each of the two IL-1 blockers currently used in FMF, anakinra and canakinumab, has its own merits for FMF care. Here we focus on anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist, and explore the literature by using PubMed regarding the utility of anakinra in certain conditions of FMF. Occasionally we enrich published data with our own experience. To facilitate insights to anakinra role, the paper briefs some clinical, genetic, pathogenetic, and management aspects of FMF. The clinical settings of FMF covered in this review include colchicine resistance, AA amyloidosis, renal transplantation, protracted febrile myalgia, on- demand use, leg pain, arthritis, temporary suspension of colchicine, pediatric patients, and pregnancy and lactation. In many of these instances, either because of safety concerns or a necessity for only transient and short-term use, anakinra, due to its short half-life, is the preferred IL-1 blocker.

Amyloid storm: acute kidney injury and massive proteinuria, rapidly progressing to end-stage kidney disease in AA amyloidosis of familial Mediterranean fever.

OBJECTIVE: Amyloid A nephropathy of FMF usually progresses over many years to end-stage renal disease (ESRD). We aim to describe an acute condition, termed here 'amyloid storm', typically manifesting with a rapid (≤2 weeks) increase in serum creatinine and urine protein, that has never been characterized in FMF amyloidosis. METHODS: This retrospective analysis features amyloid storm by comparing between FMF amyloidosis patients who have experienced an episode of amyloid storm (study group) and matched patients who have not (control group). The primary outcome was ESRD or death within 1 year from study entry. Featured data were retrieved from hospital files. RESULTS: The study and control groups, each comprising 20 patients, shared most baseline characteristics. However, they differed on the time from FMF onset to reaching serum creatinine of 1.2 mg/dl [26.5 years (s.d. 15.15) vs 41.55 (10.98), P = 0.001] and the time from the onset of proteinuria to study entry [8.8 years (s.d. 6.83) vs 15.75 (13.05), P = 0.04], culminating in younger age at study entry [39.95 years (s.d. 16.81) vs 48.9 (9.98), respectively, P = 0.05] and suggesting an accelerated progression of kidney disease in the study group. Within 1 year from study entry, 16 patients in the study and 3 in the control groups reached the primary endpoint (P = 0.000). The major triggers of amyloid storm were infections, occurring in 17 of 20 patients. CONCLUSION: Amyloid storm is a complication of FMF amyloidosis, induced by infection and associated with poor prognosis and death.

Lasing in 15 atm CO2 cell optically pumped by a Fe:ZnSe laser.

10 µm lasing is studied in a compact CO2-He cell pressurized up to 15 atm when optically pumped by a ∼50 mJ Fe:ZnSe laser tunable around 4.3 µm. The optimal pump wavelength and partial pressure of CO2 for generating 10 µm pulses are found to be ∼4.4 µm and 0.75 atm, respectively. Without cavity optimization, the optical-to-optical conversion efficiency reached ∼10% at a total pressure of 7 atm. The gain lifetime is measured to be ∼1 µs at pressures above 10 atm, indicating the feasibility of using high-pressure optically pumped CO2 for the efficient amplification of picosecond 10 µm pulses.

Effect of interleukin-1 inhibition in a cohort of patients with colchicine-resistant familial Mediterranean fever treated consecutively with anakinra and canakinumab.

OBJECTIVES: To evaluate the efficacy of IL-1 blockers in a cohort of patients with colchicine-resistant familial Mediterranean fever (crFMF) treated consecutively with anakinra and canakinumab. METHODS: Patients with crFMF treated with anakinra and canakinumab in any order were identified using the computerised database of Sheba Medical Centre. Background characteristics of the patients, reason for switching IL-1 inhibitor, and frequency of attacks under colchicine only, anakinra, and canakinumab were extracted from the computerised patient files. Patients were then interviewed for patient-reported outcomes. RESULTS: A total of 46 patients in our clinic were prescribed canakinumab for crFMF after previous anakinra treatment, whereas no patients who switched treatment from canakinumab to anakinra were identified. Of those, 23/46 patients (50%) discontinued anakinra due to inadequate response (11 of them with secondary failure after a good initial response). Frequency of flares was significantly decreased following switch to canakinumab from anakinra treatment (p<0.01). After the switch to canakinumab, the median duration of flares, the severity of pain during a flare, and the patient's global assessment of disease activity were all significantly decreased (p≤0.01), according to the reports from the patients. CONCLUSIONS: Canakinumab is an effective treatment for FMF after failure of anakinra due to any cause.

Measurements of nonlinear absorption of intense 10 µm laser pulses in n-Ge, GaAs, and ZnSe.

We study the nonlinear absorption of high-power 10 µm radiation propagating through n-Ge, GaAs, and ZnSe materials widely used in the long-wave infrared range. Measurements are performed using both nanosecond and picosecond CO2 laser pulses providing intensities up to 100MW/cm2 and 5GW/cm2, respectively. Nonlinear absorption coefficients in optical quality n-Ge are found to be the same for both pulse durations. The nonlinear absorption coefficient of these materials scales inverse proportionally to their bandgap energies, indicating increased photoionization in the smaller bandgap materials.

Macrophage activation syndrome complicating rheumatic diseases in adults: case-based review.

Macrophage activation syndrome (MAS) is a life-threatening complication of rheumatologic diseases. Data regarding the clinical course, management and outcome of adults with MAS is limited. Therefore, we aimed to describe the clinical features, treatment and outcome of adult patients with MAS, and review the literature for previous cohorts. We retrospectively reviewed patients with MAS complicating rheumatologic diseases between the years 2007 and 2017. Through Pubmed, Medline and Scopus literature search we identified previous cases of adult patients with MAS. We identified 7 patients with MAS complicating rheumatologic diseases (5 females and 2 males). The median age of diagnosis was 32 (range 26-57) years. The median follow-up was 30 months (range 6.95-36.5) months. The underlying rheumatologic disease was adult onset Still's disease (AOSD) in 3 patients, systemic juvenile idiopathic arthritis (sJIA) in 2 patients, systemic lupus erythematosus (SLE) in 1 patient, and systemic vasculitis in 1 patient. Four patients developed MAS concurrently with the clinical development of the rheumatologic disease. All the patients were treated with systemic corticosteroids. Five patients were treated with cyclosporine A, one of which received combination therapy with anakinra, and one received tocilizumab. Two patients deceased during the hospitalization. We identified 92 patients from literature cohorts, 73 (79%) of them with AOSD. MAS developed concurrently with the underlying rheumatologic disease in 25 (27%) patients, and 30 (33%) patients deceased. Our cohort and previous cohorts demostrate that MAS often presents concurrently with the underlying rheumatologic disease and is associated with a high mortality rate. Further larger prospective studies are needed to determine the optimal management of MAS.

Cytokine expression in temporal arteries: comparative analysis between patients with biopsy-positive giant cell arteritis, biopsy-negative giant cell arteritis and biopsy-negative without arteritis.

OBJECTIVES: To investigate whether expression of pro-inflammatory cytokines in the temporal artery may aid in differentiating biopsy-negative giant cell arteritis (GCA) patients from those with a negative biopsy without arteritis. METHODS: We investigated cytokine expression in temporal artery biopsy (TAB) of 54 consecutive patients: 17 with biopsy-positive GCA, 17 with biopsy-negative GCA, and 20 biopsy-negative without arteritis. We compared the expression rate of the following cytokines among these 3 groups of patients: interleukin-6 (IL-6), osteopontin (OPN), COX-2, and TNF-α. RESULTS: IL-6 was expressed in 13 (76%) patients with biopsy-positive GCA, 0 patients in biopsy-negative GCA, and 1(5%) patient with biopsy-negative without arteritis (p<0.05). OPN was expressed in 17 (100%) patients with biopsy-positive GCA, 2 (12%) patients with biopsy-negative GCA, and 0 patients with biopsy-negative without arteritis (p<0.05). Cox-2 was expressed in 16 (94%) patients with biopsy-positive GCA, 0 patients with biopsy-negative GCA, and 3 (15%) patients with biopsy-negative without arteritis (p<0.05). TNF- α was expressed in 17 (100%) patients with biopsy-positive GCA, 14 (82%) patients with biopsy-negative GCA, and 8 (40%) patients with biopsy-negative without arteritis (p<0.05). CONCLUSIONS: IL-6, COX-2 and OPN are significantly more expressed in the presence of a positive TAB compared to a negative TAB. TNF-α is significantly more expressed in GCA patients compared to non-GCA patients. Thus, TNF-α expression may suggest a diagnosis of GCA despite a negative TAB. Further larger studies are needed to confirm these findings.

Kidney disease and plasma cell dyscrasias: ambiguous cases solved by serum free light chain dimerization analysis.

BACKGROUND: Plasma cell dyscrasias (PCD) comprise a wide spectrum of disorders, which may adversely affect the kidney. However, in some PCD cases associated with kidney disease, the routine laboratory tests may be incapable to determine precisely the form of PCD, i.e., benign or malignant. Moreover, the kidney biopsy needed for precise diagnosis may be risky or declined. To overcome these limitations, we have developed and reported a new non-invasive technique based on serum free light chains (FLC) monomer (M) and dimer (D) pattern analysis (FLC MDPA), which allowed differentiation between malignant and benign PCD forms. The objective of our retrospective study was to demonstrate the utility of FLC MDPA in solving ten puzzling PCD cases complicated with kidney disease (patients 1-10). METHODS: Ten patients with uncertain form of PCD or with a questionable response to treatment were studied. In addition to routine laboratory tests and clinical evaluation of the PCD patients, our previously developed FLC MDPA in sera and biochemical amyloid typing in biopsy tissues were applied. RESULTS: The FLC MDPA aided the diagnosis of the PCD underlying or accompanying the kidney disease in patients 1-5, and helped to interpret properly the response to treatment in patients 1, 6-10. The FLC MDPA findings were confirmed by a biochemical analysis of tissue amyloid deposits and subsequently by the outcome of these patients. CONCLUSIONS: FLC MDPA is a non-invasive diagnostic test useful in the management of ambiguous cases of PCD associated with kidney disease.

Efficacy and safety of long-term treatment with intravenous colchicine for familial Mediterranean fever (FMF) refractory to oral colchicine.

Colchicine is the mainstay of treatment for familial Mediterranean fever (FMF). Intravenous (IV) colchicine, administered over several months, has been shown to be effective for FMF patients unresponsive to oral colchicine. The objective of this study was to evaluate the efficacy and safety of long-term IV colchicine treatment in oral colchicine-resistant FMF. We analyzed data of 15 patients with frequent FMF attacks, despite a maximal tolerated dose of oral colchicine (2-3 mg/day), who were treated with weekly IV injections of 1 mg of colchicine for at least 12 months. Treatment efficacy was determined by changes in frequency, duration and severity of FMF attacks. Safety was assessed according to adverse events. The mean duration of IV colchicine treatment was 5.16 ± 2.85 years. Decreases were observed from pre-treatment period in the monthly mean rates of abdominal attacks (from 5.6 ± 3.7 to 1.9 ± 3.3, p = 0.0009), joint attacks (from 6.5 ± 5.1 to 1.6 ± 1.6, p = 0.01) and overall attacks (from 22.3 ± 16.2 to 7.4 ± 5.7, p = 0.002) as well as in the mean duration (from 3.8 ± 1.5 to 2.4 ± 1.1 days per attack, p = 0.008) and severity of attacks (from 9.9 ± 0.3 to 5.7 ± 2.6, on a scale of 0-10, p < 0.05). The rate of adverse events was low, and they were mainly gastrointestinal. No severe or serious adverse events were recorded. Long-term treatment with IV colchicine in patients unresponsive to oral colchicine therapy is effective and safe.

Inflammation and cardiovascular disease in familial Mediterranean fever. An analysis of hospital admissions for acute cardiovascular event.

OBJECTIVES: Patients, suffering from inflammatory disorders, are at an increased risk to develop cardiovascular disease (CVD). Here, we examine whether in familial Mediterranean fever (FMF), a model of inflammatory diseases, inflammation also increases the risk to develop cardiovascular (CV) disease. METHODS: To explore the role of inflammation in the occurrence of CVD in FMF, we identified all FMF patients ≤55 years old with CVD, admitted to our center over a 15-year period. Correlates of inflammation, such as severity of FMF and dose of colchicine, as well as the presence of traditional CV risk factors were compared between the FMF patients with CVD (FMF- CVD) and control FMF patients with- out CVD. RESULTS: Twenty-three FMF-CVD and 40 control patients were compared. The severity of FMF, and the dose of colchicine, were similar in the 2 study groups; therefore, not associated with CVD. Compared with FMF patients without CVD, the FMF-CVD group comprised a higher proportion of men (78 vs. 40% p=0.005), and of patients with diabetes (31 vs. 7%, p=0.016) and inflammatory comorbidities such as Behçet's disease (30 vs. 7%, p=0.005). Multivariate analysis revealed that only diabetes mellitus and inflammatory comorbidities were independent factors associated with FMF-CVD. CONCLUSIONS: In FMF patients treated with colchicine, CVD is not associated with FMF-related inflammation.

The prevalence and clinical effect of immunogenicity of TNF-α blockers in patients with axial spondyloarthritis.

OBJECTIVES: To evaluate the prevalence of immunogenicity of TNF-α blockers in axial spondyloarthritis (SpA) patients and to assess the effect of immunogenicity on drug levels and clinical response. METHPDS: Patients with axial SpA treated with either infliximab (INF), adalimumab (ADA) or etanercept (ETN) were recruited to our observational cross-sectional study. Demographic and clinical data were collected and disease activity scores were assessed. Drug trough levels and anti-drug antibodies were measured in serum samples and collected before the next administration. RESULTS: Thirty-nine patients with axial SpA with a mean age of 46.3±12.7 (10 women) were recruited to the study (14 receiving INF, 16 ADA and 9 ETN). Patients' mean therapy duration was 50.6 months (±46.4) and 6 (15%) of them were using MTX concomitantly with the TNF-α blockers. Anti-drug antibodies were found in 6 (15%) patients (4 with INF and 2 with ADA), all of which had undetectable drug level. No anti-drug antibodies were detected in patients treated with ETN. Immunogenicity was associated with higher BASDAI (Bath Ankylosing Spondylitis Disease Index), ASDAS-CRP (Ankylosing Spondylitis Disease Activity Score) and ASDAS-ESR. CONCLUSIONS: Axial SpA patients failure to respond to TNF-α blockers may be at least partially related to immunogenicity. Measurement of anti-drug antibodies and drug levels in these patients may assist in determining further treatment strategies.

Hematological malignancies mimicking rheumatic syndromes: case series and review of the literature.

It is well established that some rheumatic syndromes (RS) are associated with several hematological malignancies. We aimed to describe the clinical course of patients with hematological malignancies mimicking RS. We studied a series of four patients presenting with apparent RS who were eventually diagnosed with hematological malignancies, and reviewed the relevant literature. Our series consisted of 4 patients, with a mean age of 62.8 ± 20.3 years, who presented to our rheumatology unit between December 2012 and March 2018. Two patients were initially diagnosed with polyarthritis. One of these patients was eventually diagnosed with multiple myeloma and amyloidosis and the other was diagnosed with angioimmunoblastic T-cell lymphoma. The third patient was initially diagnosed with migratory arthritis and was eventually diagnosed with acute myeloid leukemia. The fourth patient was initially diagnosed with giant cell arteritis and eventually diagnosed with anaplastic large T-cell lymphoma. All the patients displayed a very good response to corticosteroid treatment. Vigilance for occult malignancy is essential in the diagnostic workup of RS. A good response to corticosteroids may constitute a major diagnostic pitfall in patients with hematological malignancies presenting with an apparent RS. In these cases, subtle clinical and laboratory features should elicit the clinician to seek for an occult malignancy.

Colchicine intoxication in familial Mediterranean fever patients using clarithromycin for the treatment of Helicobacter pylori: a series of six patients.

Familial Mediterranean fever is a hereditary disease, characterized by recurrent episodes of inflammation. Colchicine, the mainstay of therapy, is administered continuously to all diagnosed FMF patients. Drug-drug interaction between colchicine and clarithromycin, resulting in colchicine intoxication, has been noted, mainly in association with gout and pneumonia. In FMF, this adverse event has been scarcely described. We present and characterize six patients with clarithromycin-related colchicine intoxication, aiming mainly at characterizing the FMF-specific features of this event. This study is a retrospective analysis, based on clinical and hospital records of all FMF patients admitted to one hospital during 2002-2015, for colchicine intoxication, precipitated by consumption of clarithromycin. All six patients were women who received colchicine for FMF, and clarithromycin for Helicobacter pylori (HBP) gastric infection. Their daily dosages of colchicine ranged from 1.5 to 2.5 mg. Two had mild FMF, two moderate and two severe diseases. Colchicine intoxication occurred despite intact kidney function and was characterized by abdominal pain, diarrhea, weakness, rhabdomyolysis, hepatitis, kidney impairment and bone marrow injury. It is concluded that clarithromycin-induced colchicine intoxication is a hazard in FMF. It occurs despite normal kidney function and standard colchicine dose and is associated with female sex and moderate to severe FMF.

Gender disparities in the functional significance of anemia among apparently healthy adults.

BACKGROUND: Data on the functional impact of anemia on cardiorespiratory fitness (CRF) and survival in healthy individuals are limited. Our aim was to evaluate the association between anemia thresholds, low CRF, and survival in otherwise healthy adults. METHODS: Study population included 16 334 apparently healthy subjects attending annual periodic health screening examinations (71 200 annual visits), including exercise stress testing (EST). Anemia was defined by the World Health Organization (WHO) or Beutler and Waalens' (BW) criteria. Low CRF was defined as the lowest fitness quintile according to the Bruce protocol. RESULTS: The mean age was 46±10 years, and 70% were men. Mean Hb levels were 13±1 and 15±1 among women and men, respectively, with higher proportion of anemia among women. The majority of anemic subjects had mild anemia. When analyzing repeated annual visits, anemia was associated with a significant 39% and 64% increased risk of low CRF according the WHO and BW criteria only in women (n=18 672). Baseline anemia at first visit was associated with 2.6- and 1.9-fold increased risk of all-cause mortality using the WHO and BW criteria, exclusively in men (n=11 511). CONCLUSIONS: Overall, the functional and prognostic impact of anemia is gender dependent, based on the WHO and BW arbitrary criteria, suggesting differing mechanism and responses.

Risk factors for severe cranial ischaemic events in patients with giant cell arteritis.

OBJECTIVES: Cranial ischaemic events constitute a significant component in the clinical spectrum of giant cell arteritis (GCA). Our aim was to investigate whether cardiovascular risk factors, specific medications and baseline clinical features are associated with the development of severe cranial ischaemic events in GCA patients. METHODS: Retrospective analysis of GCA patients. Information collected included baseline clinical and laboratory data, comorbidities, cardiovascular risk factors and medications. GCA Patients with and without severe cranial ischaemic complications were compared. RESULTS: A total of 83 patients with GCA were included in the study. Among them, 24 (29%) patients developed severe cranial ischaemic events. Compared with patients without severe cranial ischaemic events, those with severe cranial ischaemic events had lower erythrocyte sedimentation rate (ESR) levels at diagnosis (81±17 vs. 93±21, p=0.018) and were more likely to have jaw claudication (37.5% vs. 17%, p=0.043). Rate of cardiovascular risk factors and rate of use of anti-platelets and statins were similar between the two groups. The use of ß-blockers was higher among patients with severe ischaemic events (46% vs. 20%, p=0.019). Logistic regression analysis showed that lower ESR levels (OR=0.967, 95% CI, 0.94, 0.99) and ß-blockers use (OR=4.35, 95% CI, 1.33, 14.2) predicted development of severe cranial ischaemic complications. CONCLUSIONS: The present study demonstrated that GCA patients with severe cranial ischaemic events had lower inflammatory responses and were more likely to have been treated with ß-blockers. Cardiovascular risk factors and antiplatelet therapy had no effect on the occurrence of severe cranial ischaemic events.

Normal arterial stiffness in familial Mediterranean fever. Evidence for a possible cardiovascular protective role of colchicine.

OBJECTIVES: Familial Mediterranean fever (FMF) is an autoinflammatory disorder with episodic and persistent inflammation, which is only partially suppressed by continuous colchicine treatment. While chronic inflammation is considered an important cardiovascular risk factor in many inflammatory disorders, its impact in FMF is still disputed. We measured arterial stiffness, a marker of atherosclerotic cardiovascular disease, in a group of FMF patients, in order to evaluate the cardiovascular consequences of inflammation in FMF and the role of colchicine in their development. METHODS: Eighty colchicine treated FMF patients, without known traditional cardiovascular risk factors, were randomly enrolled in the study. Demographic, genetic, clinical and laboratory data were retrieved from patient files and examinations. Arterial stiffness was measured using pulse wave velocity (PWV). The recorded values of PWV were compared with those of an age and blood pressure adjusted normal population, using internationally endorsed values. RESULTS: FMF patients displayed normal PWV values, with an even smaller than expected proportion of patients deviating from the 90th percentile of the reference population (5% vs. 10%, p=0.02). The lowest PWV values were recorded in patients receiving the highest dose of colchicine (≥2 mg vs. 0-1 mg, p=0.038), and in patients of North African Jewish origin, whose disease was typically more severe than that of patients of other ethnicities; both observations supporting an ameliorating colchicine effect (p=0.043). CONCLUSIONS: Though subjected to chronic inflammation, colchicine treated FMF patients have normal PWV. Our findings provide direct evidence for a cardiovascular protective role of colchicine in FMF.