Primary adrenal insufficiency due to bilateral adrenal hemorrhage-adrenal infarction in a patient with systemic lupus erythematosus and antiphospholipid syndrome: case presentation and review of the literature.

Primary adrenal insufficiency (PAI) is a rare disease which represents the end stage of a destructive process involving the adrenal cortex. Occasionally it may be caused by bilateral adrenal hemorrhagic infarction in patients with antiphospholipid syndrome (APS). We herein report the challenging case of a 30-year-old female patient with systemic lupus erythematosus (SLE) and secondary APS who was admitted to the emergency department (ED) due to fever, lethargy, and syncopal episodes. Hyponatremia, hyperkalemia, hyperpigmentation, shock, altered mental status, and clinical response to glucocorticoid administration were features highly suggestive of an acute adrenal crisis. The patient's clinical status required admission to the intensive care unit (ICU), where steroid replacement, anticoagulation, and supportive therapy were provided, with a good outcome. Imaging demonstrated bilateral adrenal enlargement attributed to recent adrenal hemorrhage. This case highlights the fact that bilateral adrenal vein thrombosis and subsequent hemorrhage can be part of the thromboembolic complications seen in both primary and secondary APS and which, if misdiagnosed, may lead to a life-threatening adrenal crisis. High clinical suspicion is required for its prompt diagnosis and management. A literature search of past clinical cases with adrenal insufficiency (AI) in the setting of APS and SLE was conducted using major electronic databases. Our aim was to retrieve information about the pathophysiology, diagnosis, and management of similar conditions.

High prevalence of metabolic syndrome and cardiovascular risk factors in men with ankylosing spondylitis on anti-TNFalpha treatment: correlation with disease activity.

OBJECTIVE: Ankylosing spondylitis (AS) may be associated with an increased risk for cardiovascular diseases (CVD). We investigated the prevalence of cardiovascular risk factors and metabolic syndrome (MetS) in men with AS and assessed any correlation with AS-related factors. METHODS: This was a cross-sectional study of 63 men with AS, median age 40 (19-69) years, and 126 age-matched controls. Patients were on anti-TNFalpha treatment because of considerable disease activity at some time during the course of the disease. MetS was assessed according to the modified National Cholesterol Education Program Adult Treatment Panel III criteria. The risk for CVD event within the next 10 years was estimated using the Framingham equation. RESULTS: Patients had lower high-density lipoprotein cholesterol (HDL-C) (p<0.001), higher systolic (p=0.001) and diastolic (p<0.01) blood pressure compared with controls. The prevalence of the MetS was higher in patients compared to controls (34.9% vs. 19.0%; p<0.05). AS patients with MetS were older (p<0.01), with higher Framingham risk score (p=0.001), had longer disease duration (p<0.05) and higher BASDAI (5.1 vs. 3.7; p<0.05) than those without MetS, while both BASFI and CRP had an inverse correlation with HDL-C levels. CONCLUSIONS: Men with AS have a higher prevalence of cardiovascular risk factors and MetS compared with controls. The presence of MetS was associated with increased 10 year CVD risk in these patients. The association of AS disease activity with MetS suggests that CVD in AS patients may, at least in part, be attributed to the inflammatory burden of the disease.

Sustained improvement of vascular endothelial function during anti-TNFalpha treatment in rheumatoid arthritis patients.

OBJECTIVES: Vascular endothelial function and common carotid artery intima-medial thickness (CCA-IMT) are well-established surrogate markers for early atherosclerotic disease, which accounts for 30-40% of excess mortality in rheumatoid arthritis (RA) patients. Our aim was to investigate whether long-term treatment with anti-tumour necrosis factor (TNF)alpha agents can modulate endothelial function and CCA-IMT. METHODS: Twelve patients with RA (mean age 54.8+/-15 years) on anti-TNFalpha treatment (seven adalimumab, five infliximab) due to uncontrolled disease activity, with mean Disease Activity Score (DAS28) 5.7 (range 4.6-6.9) despite disease-modifying anti-rheumatic drugs (DMARDs), were studied prospectively. Patients were assessed at baseline and after 3 and 18 months for endothelial-dependent vasodilatation, assessed by flow-mediated vasodilatation (FMD), endothelial-independent vasodilatation and CCA-IMT. RA disease activity and response to therapy were assessed by the DAS28 index. RESULTS: After 18 months of treatment, 67% of the patients were responders according to European League Against Rheumatism (EULAR) response criteria. Anti-TNFalpha treatment improved FMD (from 7+/-4.3% to 11.1+/-3.8%, p = 0.026) whereas CCA-IMT did not change significantly [from 0.67 (0.4-1) to 0.68 (0.39-1.2) mm; mean change 0.01 (-0.06 to 0.08) mm]. Endothelial-independent vasodilatation remained stable (20.4+/-7.3% to 22.9+/-6.5%, p = 0.4). CONCLUSIONS: In this small cohort of patients with RA and no clinically overt cardiovascular disease (CVD), after 18 months of treatment with anti-TNFalpha agents, endothelial function improved significantly while CCA-IMT remained stable. Longitudinal studies using more patients are needed to determine the clinical significance of these findings in relation to the risk of atherosclerosis.

Evidence-based recommendations for the management of ankylosing spondylitis: systematic literature search of the 3E Initiative in Rheumatology involving a broad panel of experts and practising rheumatologists.

OBJECTIVE: Recommendations and/or guidelines represent a popular way of integrating evidence-based medicine into clinical practice. The 3E Initiatives is a multi-national effort to develop recommendations for the management of rheumatic diseases, which involves a large number of experts combined with practising rheumatologists addressing specific questions relevant to clinical practice. METHODS: Ten countries participated in three rounds of discussions and votes concerning the management of AS. A set of nine questions was formulated in the domains of diagnosis, monitoring and treatment, after a Delphi procedure. A literature search in MedLine was conducted. Predefined outcome parameters for the domains of diagnosis, monitoring and treatment were assessed. The evidence to support each proposition was evaluated and scored. After discussion and votes, the final recommendations were presented using brief statements by each national group, following which the final international recommendations were formulated. RESULTS: A total of 2699 papers were found and 467 were selected for analysis. Twelve key recommendations were developed: three in the domain of diagnosis addressing general diagnostic considerations, early AS diagnosis and general practitioners' referral recommendations; three concerning monitoring of AS disease activity, severity and prognosis; six concerning pharmacological treatment (except biologics): non-steroidal anti-inflammatory drugs/COX-II inhibitors, bisphosphonates and treatment of enthesitis. The compiled agreement among experts ranged from 72% to 93%. CONCLUSION: Recommendations for the management of AS were developed using an evidence-based approach followed by expert/physician consensus with high level of agreement. Involvement of a larger and more representative group of rheumatologists may improve their dissemination and implementation in daily clinical practice.

Inflammasomes and rheumatic diseases: evolving concepts.

The realisation that the production of inflammatory cytokines in inflammatory rheumatic diseases may be induced by non-infectious endogenous signals has encouraged researchers to explore mechanisms of innate immunity and their contribution to the pathogenesis of these diseases. The nucleotide-binding and oligomerisation domain (NOD)-like receptors (NLRs) sense pathogens, products of damaged cells or endogenous metabolites and could potentially be involved in the initiation, amplification and progression of the inflammatory response in rheumatic diseases. NLRs are involved in the regulation of innate immune responses with some of them promoting the activation of inflammatory caspases within multiprotein complexes, called inflammasomes. A typical inflammasome consists of a sensor, an NLR protein, an adaptor protein such as ASC (for apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD)) and an effector protein that is a caspase that activates pro-inflammatory cytokines such as interleukin (IL)1beta and IL18. Recent data suggest a role of the inflammasome in the pathogenesis of autoinflammatory as well as inflammatory rheumatic diseases such as juvenile chronic arthritis, adult onset Still disease, rheumatoid arthritis and gout. Modulation of these pathways may be a potential therapeutic target for inflammatory rheumatic diseases.

Chronic alcohol consumption as a predisposing factor for multiple tendon ruptures in unusual sites in a patient with rheumatoid arthritis.

Simultaneous bilateral patellar tendon ruptures are a rare complication of rheumatoid arthritis (RA). Systemic inflammatory diseases (RA, systemic lupus erythematosus (SLE), chronic renal failure, primary and secondary hyperparathyroidism, diabetes mellitus, obesity, sports activity, older age (>50) and drugs (prolonged use of high doses of steroids, local steroid injections and quinolones) are considered as potent predisposing factors for tendon rupture. We report a case of an alcoholic patient with RA and bilateral spontaneous tendon ruptures of the knees. Circumstantial evidence suggest that in this patient, chronic alcohol consumption, a very frequent cause of toxicity to striated and cardiac muscle, contributed to the injury.

Metabolic syndrome is common among middle-to-older aged Mediterranean patients with rheumatoid arthritis and correlates with disease activity: a retrospective, cross-sectional, controlled, study.

OBJECTIVES: Patients with rheumatoid arthritis have an increased risk for cardiovascular disease (CVD). The prevalence of metabolic syndrome (MetS)-a major contributor to CVD-in a cohort of patients with rheumatoid arthritis and its relationship with rheumatoid arthritis related factors is investigated here. METHODS: 200 outpatients with rheumatoid arthritis (147 women and 53 men), with a mean (standard deviation (SD)) age of 63 (11) years, and 400 age and sex-matched controls were studied. MetS was assessed according to the adult treatment panel III criteria and rheumatoid arthritis disease activity by the disease activity score of 28 joints (DAS28). A standard clinical evaluation was carried out, and a health and lifestyle questionnaire was completed. RESULTS: The overall prevalence of MetS was 44% in patients with rheumatoid arthritis and 41% in controls (p = 0.5). Patients with rheumatoid arthritis were more likely to have low high-density lipoprotein cholesterol compared with controls (p = 0.02), whereas controls were more likely to have increased waist circumference or raised blood pressure (p = 0.001 and 0.003, respectively). In multivariate logistic regression analysis adjusting for demographics and rheumatoid arthritis treatment modalities, the risk of having moderate-to-high disease activity (DAS28>3.2) was significantly higher in patients with MetS compared with those with no MetS components (OR 9.24, 95% CI 1.49 to 57.2, p = 0.016). CONCLUSION: A high, albeit comparable to the control population, prevalence of MetS was found in middle-to-older aged patients with rheumatoid arthritis. The correlation of rheumatoid arthritis disease activity with MetS suggests that the increased prevalence of coronary heart disease in patients with rheumatoid arthritis may, at least in part, be attributed to the inflammatory burden of the disease.

An open label, single dose study to evaluate the safety, efficacy, and effects on CD25 expression of ciclosporin in patients with active rheumatoid arthritis despite treatment with methotrexate and infliximab.

OBJECTIVE: To explore the safety, efficacy, and lymphocyte activation of a triple therapeutic regimen with infliximab, methotrexate (MTX), and ciclosporin A (CsA) by an open label, pilot study. PATIENTS AND METHODS: 19 patients (mean age 52.9 years) with active rheumatoid arthritis (mean DAS28 7.3) after a mean of 16.8 infliximab infusions and dose adjustments of both infliximab and MTX were enrolled. CsA was added to a stable therapeutic regimen. Disease activity was evaluated by the DAS28. Lymphocyte activation was evaluated by assessing CD25 expression on peripheral blood mononuclear cells (PBMCs). Primary end points were safety and efficacy according to the EULAR response criteria at 24 weeks. RESULTS: Eight patients (42%) discontinued treatment: adverse events (3), inefficacy (2) or non-compliance (2). One patient had a stroke and died. 5/11 (45%) patients who completed 24 weeks' treatment were moderate responders. CD25 expression, both on unstimulated and phytohaemagglutinin stimulated PBMCs in five patients assessed, was reduced (mean (SD) values from 37 (34)% to 15 (10)% and from 50 (15)% to 29 (20)%, respectively). CONCLUSION: In this group of patients with refractory, highly active disease, addition of CsA reduced lymphocyte activation, and resulted in a modest response and a high rate of discontinuation. In such patients, other new approaches need to be explored.

Lupus nephritis flares.

The clinical course of lupus nephritis varies remarkably among SLE patients, even between those with the same histological type. Current immunosuppressive agents induce remission in the majority of the patients with proliferative lupus nephritis, but a substantial proportion of them - ranging in different studies from 27% to 66% - will flare. Flares represent a significant problem because of the potential for cumulative damage that may lead to deterioration of renal function as well as toxicity due to the additional immunosuppression. Maintenance therapy with azathioprine, mycophenolate mofetil or quarterly pulses of cyclophosphamide is usually recommended. Renal flares can be characterized as nephritic or nephrotic and can be mild or severe. The majority of the patients that flare restore renal function, if diagnosed early and treated promptly. However, current immunosuppressive agents have limitations concerning efficacy and toxicity profiles. Unresolved management issues include the value of repeat renal biopsy and issues related to optimal strategy/regimen to prevent flares. Renal flares are an important feature of the natural history of lupus nephritis and provide an opportunity for additional preventive strategies, as well as measures of efficacy in future therapeutic trials.

Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients.

The CD40-CD40L system has pleiotropic effects in a variety of cells and biological processes including immune response, thrombosis and atherogenesis. Within the immune system, these molecules represent a critical link between its humoral and cellular arms. As a result of these attributes and based on preclinical data in animals, anti-CD40L antibodies were tested in a variety of immunologic diseases including idiopathic thrombocytopenic purpura, psoriasis, Crohn's disease, systemic lupus erythematosus and transplantation. Phase I/II studies in humans with lupus nephritis demonstrated reduction of anti-double-stranded DNA (anti-dsDNA) antibodies but not of protective antibodies. Reduction of anti-DNA was associated with increased serum complement levels and reduced glomerular inflammation. As a result of thrombotic effects, observed even in patients negative for anti-cardiolipin antibodies, there is a temporary halt on further human studies. The reasons for the prothrombotic effects are not clear at present but may represent effects on platelets and/or the endothelium. In view of the significant immunomodulatory effects of anti-CD40L treatment in patients with lupus nephritis, the increasing realization of the importance of premature atherosclerosis in lupus and an increasing amount of data supporting a role for the CD40-CD40L interactions in this process, inhibition of this pathway deserves further exploration in lupus.