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.

Treatment modalities and drug survival in a systemic sclerosis real-life patient cohort.

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

Regional cerebral perfusion correlates with anxiety in neuropsychiatric SLE: evidence for a mechanism distinct from depression.

The study examined the hypothesis that hypoperfusion in brain areas known to be involved in emotional disturbances in primary psychiatric disorders is also linked to emotional difficulties in systemic lupus erythematosus (SLE) and that these are not secondary to the physical and social burden incurred by the disease. Nineteen SLE patients without overt neuropsychiatric manifestations (non-NPSLE), 31 NPSLE patients, and 23 healthy controls were examined. Dynamic susceptibility contrast MRI was used and cerebral blood flow and cerebral blood volume values were estimated in six manually selected regions of interest of brain regions suspected to play a role in anxiety and depression (dorsolateral prefrontal cortex, ventromedial prefrontal cortex, anterior cingulate cortex, hippocampi, caudate nuclei and putamen). NPSLE patients reported high rates of anxiety and depression symptomatology. Significantly reduced cerebral blood flow and cerebral blood volume values were detected in the NPSLE group compared to healthy controls in the dorsolateral prefrontal cortex and ventromedial prefrontal cortex, bilaterally. Within the NPSLE group, anxiety symptomatology was significantly associated with lower perfusion in frontostriatal regions and in the right anterior cingulate gyrus. Importantly, the latter associations appeared to be specific to anxiety symptoms, as they persisted after controlling for depression symptomatology and independent of the presence of visible lesions on conventional MRI. In conclusion, hypoperfusion in specific limbic and frontostriatal regions is associated with more severe anxiety symptoms in the context of widespread haemodynamic disturbances in NPSLE.

Is systemic lupus erythematosus different in urban versus rural living environment? Data from the Cretan Lupus Epidemiology and Surveillance Registry.

BACKGROUND: Examining urban-rural differences can provide insights into susceptibility or modifying factors of complex diseases, yet limited data exist on systemic lupus erythematosus (SLE). OBJECTIVE: To study SLE risk, manifestations and severity in relation to urban versus rural residence. METHODOLOGY: Cross-sectional analysis of the Crete Lupus Registry. Demographics, residency history and clinical data were obtained from interviews and medical records ( N=399 patients). Patients with exclusively urban, rural or mixed urban/rural residence up to enrolment were compared. RESULTS: The risk of SLE in urban versus rural areas was 2.08 (95% confidence interval: 1.66-2.61). Compared with rural, urban residence was associated with earlier (by almost seven years) disease diagnosis - despite comparable diagnostic delay - and lower female predominance (6.8:1 versus 15:1). Rural patients had fewer years of education and lower employment rates. Smoking was more frequent among urban, whereas pesticide use was increased among rural patients. A pattern of malar rash, photosensitivity, oral ulcers and arthritis was more prevalent in rural patients. Residence was not associated with organ damage although moderate/severe disease occurred more frequently among rural-living patients (multivariable adjusted odds ratio: 2.17, p=0.011). CONCLUSION: Our data suggest that the living environment may influence the risk, gender bias and phenotype of SLE, not fully accounted for by sociodemographic factors.

[Segmental testicular infarction]. / Segmentaler Hodeninfarkt.

Segmental testicular infarction is a rare cause of acute scrotum and only a few cases have been reported. Torsion of the testis, testicular tumor and infection are important differential diagnoses. The present case report describes a 61-year-old man with left-sided testicular pain increasing over 24 h. The diagnosis of segmental testicular infarction was considered after color Doppler ultrasound of the left scrotum and it was confirmed by surgical exploration and pathological examination. Although it is uncommon, segmental testicular infarction should be taken into consideration when acute scrotal pain is encountered, especially for younger patients, since a testis-sparing treatment strategy can be performed.

Investigation of the genetic overlap between rheumatoid arthritis and psoriatic arthritis in a Greek population.

OBJECTIVES: Several rheumatoid arthritis (RA) susceptibility loci have also been found to be associated with psoriatic arthritis (PsA), demonstrating that there is a degree of genetic overlap between various autoimmune diseases. We sought to investigate whether single nucleotide polymorphisms (SNPs) mapping to previously reported RA and/or PsA susceptibility loci, including PLCL2, CCL21, REL, STAT4, CD226, PTPN22, and TYK2, are associated with risk for the two diseases in a genetically homogeneous Greek population. METHOD: This study included 392 RA patients, 126 PsA patients, and 521 healthy age- and sex-matched controls from Greece. Genotyping of the SNPs was performed with Taqman primer/probe sets. Bioinformatic analysis was performed using BlastP, PyMOL, and Maestro and Desmond. RESULTS: A significant association was detected between the GC genotype of rs34536443 (TYK2) in both the PsA and RA cohorts. The C allele of this SNP was associated with PsA only. Evidence for association with PsA was also found for the GG genotype and G allele of the rs10181656 SNP of STAT4. The TC genotype of the rs763361 SNP of CD226 was associated with PsA only. CONCLUSIONS: Genetic overlap between PsA and RA was detected for the rs34536443 SNP of the TYK2 gene within a Greek population. An association of STAT4 (rs10181656) with PsA was confirmed whereas CD226 (rs763361) was associated with PsA but not with RA, in contrast to previous reports. The different findings of this study compared to previous ones highlights the importance of comparative studies that include various ethnic or racial populations.

Clinical and financial burden of active lupus in Greece: a nationwide study.

Analyses of the medical and economic burden of chronic disorders such as systemic lupus erythematosus (SLE) are valuable for clinical and health policy decisions. We performed a chart-based review of 215 adult SLE patients with active autoantibody-positive disease at the predefined ratio of 30% severe (involvement of major organs requiring treatment) and 70% non-severe, followed at seven hospital centres in Greece. We reviewed 318 patients consecutively registered over three months (sub-study). Disease activity, organ damage, flares and healthcare resource utilization were recorded. Costs were assessed from the third-party payer perspective. Severe SLE patients had chronic active disease more frequently (22.4% vs 4.7%), higher average SLE disease activity index (SLEDAI) (10.5 vs 6.1) and systemic lupus international collaborating clinics (SLICC) damage index (1.1 vs 0.6) than non-severe patients. The mean annual direct medical cost was €3741 for severe vs €1225 for non-severe patients. Severe flares, active renal disease and organ damage were independent cost predictors. In the sub-study, 19% of unselected patients were classified as severe SLE, and 30% of them had chronic active disease. In conclusion, this is the first study to demonstrate the significant clinical and financial burden of Greek SLE patients with active major organ disease. Among them, 30% display chronic activity, in spite of standard care, which represents a significant unmet medical need.

Cyclophosphamide in combination with glucocorticoids for severe neuropsychiatric systemic lupus erythematosus: a retrospective, observational two-centre study.

Cyclophosphamide (CYC) is used in severe neuropsychiatric systemic lupus erythematosus (NPSLE), but long-term data regarding its efficacy and safety are lacking. We identified NPSLE cases who received CYC from two centres during the period 1999-2013 and had regular follow-up. General and neuropsychiatric outcome at last follow-up visit were determined, and major complications were documented. CYC was administered in 50 neuropsychiatric events. Median age was 45.0 years and 46% of patients were positive for antiphospholipid antibodies. Most frequent indications were psychosis (11 cases), polyneuropathy (six cases), and cerebrovascular disease, seizure disorder and cranial neuropathy (five cases). CYC was mainly administered as monthly pulses (median number: 8.0 (range 3-26), median cumulative dose: 7.2 g (range 2.4-33.8)). Cases were followed for a median of 46.5 months (range 5-408). At last follow-up, partial or complete response of NPSLE was observed in 84% of events; 10% had stable disease, whereas the remaining 6% failed to improve or worsened and were rescued with rituximab. In events that responded to CYC, maintenance therapy consisted of azathioprine in 31 events (65.9%), bimonthly or quarterly pulses of intravenous CYC in nine (19.1%), and mycophenolate mofetil in five (10.6%). Relapses were observed in six events (12%) at median eight months after initial response. No malignancies were observed, yet there were three cases of severe infections. Amenorrhea was recorded in three patients, who had not received gonadal protection. In conclusion, cyclophosphamide was efficacious and led to sustained response of severe NPSLE in a cohort with long follow-up.

Association of the PTPN22 R620W polymorphism with increased risk for SLE in the genetically homogeneous population of Crete.

Autoimmune diseases affect approximately 5% of the population, but much work remains to define the genetic risk factors and pathogenic mechanisms underlying these conditions. There is accumulating evidence that common genetic factors might predispose to multiple autoimmune disorders. Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are complex autoimmune disorders with multiple susceptibility genes. The functional R620W (C1858T) polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, a member of the PTPs that negatively regulate T-cell activation, has been recently associated with susceptibility to various autoimmune diseases. The aim of this study was to assess whether the C1858T polymorphism of PTPN22 also confers increased risk for SLE and RA in the genetically homogeneous population of Crete. It was found that the minor T allele of the PTPN22 C1858T SNP was more common in SLE patients than in control individuals (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.11 to 3.9, p = 0.017). No significant difference was observed in the frequency of this allele when RA patients were compared with controls (OR = 1.14, 95% CI = 0.65 to 1.9, p = 0.64). Although the PTPN22 1858 T allele is found at decreased frequency in Southern Europe, including Crete, an association was found between this allele and SLE in the population studied.

Air trapping in Wegener's granulomatosis: an additional finding on expiratory chest HRCT.

PURPOSE: This study was undertaken to assess the presence and extent of air trapping (AT) on high-resolution computed tomography (HRCT) in patients with Wegener's granulomatosis (WG) and to correlate the finding with the inspiratory pattern and bronchial/bronchiolar involvement. MATERIALS AND METHODS: Twenty-one patients (7 M/14 F) with WG underwent inspiratory and expiratory HRCT. Images were evaluated for the presence and extent of AT and for airway involvement (bronchi/bronchioles); the predominant HRCT pattern was also documented. The attenuation difference was measured between the areas of AT on expiration and the same areas on inspiration in order to verify the finding of AT. The extent of AT was calculated by visual scoring and correlated with the predominant inspiratory patterns and bronchial/bronchiolar involvement. RESULTS: AT was found in seven patients (33.3%) and its extent ranged between 3% and 70% (mean 15.8±7). Two patients showed no lesions on inspiratory HRCT, and the only finding was AT on expiration. The attenuation difference between areas of AT on expiration and the same areas on inspiration ranged between 32 and 89 HU. Inspiratory HRCT was pathological in 19 patients (90.4%), and the principal lung patterns were nodular, cavitary or noncavitary (n=7, 38.9%); ground-glass opacities (n=5, 26.3%); masses (n=3, 15.8%); fibrotic (n=3, 15.8%); and consolidation with air bronchogram (n=1, 5.3%). Bronchial and bronchiolar involvement was found in 14 and five patients, respectively. No statistically significant correlation was found between AT extent and the findings on inspiration. In addition, there were no specific patterns that caused higher or lower scores of AT. Moreover, when bronchial or bronchiolar involvement was absent, the mean AT score was statistically significantly higher. CONCLUSIONS: Areas of AT represent a new and indirect HRCT finding--and in rare cases the only finding--of pulmonary WG. The nonsignificant correlation between AT extent and inspiratory findings may suggest AT as an additional HRCT finding in patients with WG.

Pulse cyclophosphamide treatment for severe refractory cutaneous lupus erythematosus.

Cutaneous lupus erythematosus includes a variety of lupus erythematosus specific skin lesions that, in some cases, can be disfiguring and refractory to conventional therapy. This short report describes our experience in treating six patients with severe, refractory subacute cutaneous lupus erythematosus with monthly cyclophosphamide pulses, followed by azathioprine as maintenance therapy. Significant clinical improvement of the subacute cutaneous lupus erythematosus lesions was achieved in all patients, with four patients in complete remission and two in partial remission. Mean time to clinical response was 4.33 +/- 1.36 months. Minor adverse events and no relapses were noted in a follow-up period of more than 3 years.

EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis.

OBJECTIVES: To develop evidence-based EULAR recommendations for cardiovascular (CV) risk management in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). METHODS: A multidisciplinary expert committee was convened as a task force of the EULAR Standing Committee for Clinical Affairs (ESCCA), comprising 18 members including rheumatologists, cardiologists, internists and epidemiologists, representing nine European countries. Problem areas and related keywords for systematic literature research were identified. A systematic literature research was performed using MedLine, Embase and the Cochrane library through to May 2008. Based on this literature review and in accordance with the EULAR's "standardised operating procedures", the multidisciplinary steering committee formulated evidence-based and expert opinion-based recommendations for CV risk screening and management in patients with inflammatory arthritis. RESULTS: Annual CV risk assessment using national guidelines is recommended for all patients with RA and should be considered for all patients with AS and PsA. Any CV risk factors identified should be managed according to local guidelines. If no local guidelines are available, CV risk management should be carried out according to the SCORE function. In addition to appropriate CV risk management, aggressive suppression of the inflammatory process is recommended to further lower the CV risk. CONCLUSIONS: Ten recommendations were made for CV risk management in patients with RA, AS and PsA. The strength of the recommendations differed between RA on the one hand, and AS and PsA, on the other, as evidence for an increased CV risk is most compelling for RA.

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: results of the Hellenic working group of the 3E Initiative in Rheumatology.

OBJECTIVE: The 3E (Evidence, Experts and Exchange) Initiative is a multi-national effort that involves a large number of experts and practicing rheumatologists addressing specific questions relevant to everyday clinical practice, concerning the management of Ankylosing Spondylitis. Within this multinational group, the Hellenic working group, addressed specific issues complementary to the international ones, and formulated evidence-based recommendations, in order to improve everyday clinical practice for patients with Ankylosing Spondylitis. METHODS: A scientific committee of rheumatologists specializing in AS formulated a set of 7 questions in three domains: diagnosis, monitoring and treatment. Literature search in MedLine for papers published up to August 2006 was conducted. The evidence to support each proposition was evaluated and scored. To avoid any conflict of interest with the sponsor issues related to the use of biologics were not discussed. After extensive discussion among 50 rheumatologists and one Delphi round of votes, the final recommendations were formulated. RESULTS: A literature search resulted in a total of 320 relevant papers of which 29 were evaluated. A total of seven recommendations were formulated: two concerning diagnosis (role of HLA-B27 and MRI) and prognosis, one concerning monitoring for extra-articular manifestations and four concerning treatment (analgesics, disease modifying agents and physical therapy) were made. The level of evidence and the strength of recommendation were reported. The compiled agreement among experts ranged from 90% up to 100%. CONCLUSION: Recommendations for the management of AS were developed using an evidence-based approach followed by physicians' consensus with high level of agreement. These are complementary to existing ones, and address specific domains of everyday clinical practice.

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.

Familial Mediterranean Fever in Crete: a genetic and structural biological approach in a population of 'intermediate risk'.

Familial Mediterranean Fever (FMF) is an autosomal, recessively inherited disease, characterized by recurrent and short attacks of fever with serosal inflammation that are caused by mutations in MEFV gene that encodes pyrin protein. To date, more than 70 disease-associated mutations have been identified, almost all of them representing missense nucleotide changes. FMF is very common among patients with Mediterranean ancestry, although the exact prevalence is not yet known, Greeks are considered to be at 'intermediate risk'. In the present study, we studied FMF patients in natives of Crete, a population sharing a common genetic and cultural background. The spectrum of MEFV gene mutations in 71 patients as well as 158 healthy controls was studied by performing a molecular analysis focused on the 12 most frequent FMF-associated mutations. We found that 59 of 71 (83.1%) FMF patients had at least one MEFV mutation, five patients were homozygotes and 54 heterozygotes for FMF-associated mutations. No mutations were detected in 12 patients (16.9%). As in high-risk populations, common MEFV mutations were found in Cretan FMF patients, with the M694V being the most penetrant. M694V and M694I mutations were associated with severe phenotypes, with many patients presenting with uncommon clinical manifestations such as erysipelas-like erythema or renal disturbances. Of interest, 20 (37%) of our heterozygous FMF patients presented with a severe phenotype. Population genetics analysis showed an FMF carrier frequency in healthy Cretan population of approximately 6% (1:17) and places Cretans closer to the Western rather than Eastern populations of the Mediterranean basin. Finally, we constructed a three-dimensional model showing the interaction of the PRYSPRY domain of pyrin with caspase-1 onto which we mapped MEFV mutations, classified according to disease severity. In this model, the 'flexible loops' of caspase-1 appear to have no access to some positions that have been previously associated with mild disease, suggesting that alternative pathogenic pathways leading to FMF need to be explored.

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.