Performance capacity evaluated using the 6-minute walk test: 5-year results in patients with diffuse systemic sclerosis and initial interstitial lung disease.

OBJECTIVES: To identify factors indicating exercise-induced oxygen desaturation during the 6-minute walk test (6MWT) in patients with diffuse systemic sclerosis (SSc) and initial interstitial lung disease (ILD). METHODS: The study involved 121 consecutive adult anti-Scl 70 autoantibody-positive SSc patients with initial ILD, 93 of whom were followed up for five years. Before enrolment and then annually, the patients underwent high-resolution computed tomography (HRCT), functional lung tests, with carbon monoxide diffusion capacity of the lung (DLCO) and its components (alveolar-capillary membrane [Dm] and pulmonary blood volume [Vc]), the evaluation of dyspnea before and after the 6MWT using the Borg scale, and transthoracic echocardiography. A decrease in peripheral capillary oxygen saturation (SpO2) of ≥4% during the 6MWT was used to define desaturation, the appearance of which led to the patient being withdrawn from follow-up. RESULTS: There were no significant differences in HRCT score during the follow-up, but 32 patients (35%) desaturated during the 6MWT, including 12 (37%) who experienced a severe decrease SpO2 to ≤88%, indicating a high risk of mortality. At baseline, there was no statistically significant difference in any considered clinical characteristics between the desaturating and non-desaturating patients but, at the time of desaturation, the desaturators had lower minimum SpO2% levels during the 6MWT (p<0.0001), and lower DLCO (p<0.0001) and Dm (p<0.0001). Comparison of the desaturators defined on the basis of a reduction in SpO2 to ≤88% and those defined on the basis of a decrease in SpO2 of ≥4% showed that, at baseline, the former had lower minimum SpO2% levels during 6MWT (p<0.001), lower DLCO (p=0.01), a lower DLCO/VA ratio (p=0.05), lower Dm (p<0.005) and Vc values (p<0.5), and higher RVsystP (p=0.01). At the time of desaturation, the desaturators' minimum SpO2 levels during the 6MWT correlated with their DLCO (r=0.78; p<0.001), Dm (r=0.65; p<0.01), Vc (r=0.52;p<0.05) and RV-systP values (r = -0.53; p<0.05). CONCLUSIONS: Our data seem to confirm the close interdependence between pulmonary diffusion and oxygen desaturation during exercise. In SSc combined 6MWT, DLCO and its components may indicate patients at increased risk of developing pulmonary hypertension.

Evidence of NLRP3-inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3-inflammasome complex in relation to susceptibility to RA and response to anti-TNF treatment.

BACKGROUND: The NLRP3-inflammasome, implicated in the pathogenesis of several inflammatory disorders, has been analysed in rheumatoid arthritis (RA). METHODS: Relative gene expression of NLRP3-inflammasome components was characterised in PBMCs of 29 patients receiving infliximab. A total of 1278 Caucasian patients with RA from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) cohort receiving tumour necrosis factor (TNF) antagonists (infliximab, adalimumab and etanercept) were genotyped for 34 single nucleotide polymorphisms (SNPs), spanning the genes NLRP3, MEFV and CARD8. Regression analyses were performed to test for association between genotype and susceptibility and treatment response (disease activity score across 28 joints (DAS28) and EULAR improvement criteria) at 6 months, with secondary expression quantitative trait loci (eQTL) analyses. RESULTS: At baseline, gene expression of ASC, MEFV, NLRP3-FL, NLRP3-SL and CASP1 were significantly higher compared with controls whereas CARD8 was lower in the patients. Caspase-1 and interleukin-18 levels were significantly raised in patients with RA. SNPs in NLRP3 showed association with RA susceptibility and EULAR response to anti-TNF in the BRAGGSS cohort, and in monocytes but not B cells, in eQTL analysis of 283 healthy controls. CARD8 SNPs were associated with RA susceptibility and DAS28 improvement in response to anti-TNF and eQTL effects in monocytes and B cells. CONCLUSIONS: This study found evidence of modulation of the NLRP3-inflammasome in patients with RA prior to receiving infliximab and some evidence of association for SNPs at NLRP3 and CARD8 loci with RA susceptibility and response to anti-TNF. The SNPs associated with susceptibility/response are not the main eQTL variants for either locus, and the associations with treatment response require replication in an independent cohort.

Standard and pocket-size lung ultrasound devices can detect interstitial lung disease in rheumatoid arthritis patients.

OBJECTIVES: Interstitial lung disease (ILD) is a frequent extra-articular manifestation of RA associated with increased mortality. High-resolution CT (HRCT) is used for diagnosis and follow-up, but its accuracy is counterbalanced by high costs and radiological risk. In the presence of ILD, lung US (LUS) detects vertical artefacts called B-lines. The aims of the present study were to evaluate the accuracy of LUS in the diagnosis of ILD in RA and to validate the use of a pocket-size US device (PS-USD) as a screening tool. METHODS: LUS was performed with standard equipment by a trained physician through longitudinal scans following anatomical lines: 72 segments were considered (28 anteriorly and 44 posteriorly) and B-lines were counted in each segment. A B-lines score >10 identified a positive examination (presence of ILD). A second LUS session for positive/negative judgment was performed by a short-trained physician using a PS-USD. RESULTS: Thirty-nine patients were studied. The sensitivity and specificity of standard LUS vs HRCT were 92% and 56%, respectively. The B-line score was significantly correlated with HRCT score (r = 0.806). A total of 29 patients were studied with a PS-USD. Sensitivity and specificity for PS-USD vs HRCT were 89% and 50%. CONCLUSION: The sensitivity of LUS in the detection of ILD supports its use as a screening test for ILD in RA patients, even in the ambulatory setting with a PS-USD. The strong correlation between echographic and HRCT scores indicates LUS is a valid tool for grading and follow-up of ILD.

Familial Mediterranean fever and related periodic fever syndromes/autoinflammatory diseases.

PURPOSE OF REVIEW: The spectrum of periodic fever syndromes (PFS)/autoinflammation diseases is continuously expanding. This review provides an overview of the primary research and an update on the main clinical developments in these disorders published in the past 12-18 months. RECENT FINDINGS: IL-1ß is pivotal to the pathogenesis of most of the PFS. In familial Mediterranean fever (FMF) MEFV mutations lead to gain of pyrin function, resulting in inappropriate IL-1ß release that is dependent on ASC but not the NLRP3 inflammasome. Anti-IL-1 therapy is effective in tumour necrosis factor receptor-associated periodic syndrome (TRAPS), whilst both spontaneous and pathogen-associated molecular patterns (PAMPs) induced IL-1ß release have been demonstrated in NLRP12-associated periodic syndrome (NAPS12). Somatic NLRP3/CIAS1 mosaicism is a significant cause of cryopyrin-associated periodic syndromes (CAPS). Close connections have also been established between metabolic and inflammatory pathways. In TRAPS increased reactive oxygen species (ROS) of mitochondrial origin leads to production of pro-inflammatory cytokines, whilst NLRP3 inflammasome activation in type 2 diabetes (T2D) is induced by oligomers of islet amyloid polypeptides (IAPP). SUMMARY: Caspase 1 activation and IL-1ß release is central to the pathogenesis of many autoinflammatory syndromes. This is supported by the effectiveness of anti-IL-1 biologics in treatment of these disorders.

Hiccups and Inappropriate ADH Secretion Syndrome as Presentations of Tick-Borne Disease.

Tick-borne diseases (Lyme disease and tick-borne encephalitis) are becoming a major public health concern. Rapid and correct diagnosis is crucial for complicated cases but is often delayed because of low suspicion or unusual clinical presentation. In this paper the authors describe two atypical presentations of Lyme disease and tick-borne encephalitis in order to help clinicians resolve diagnostic challenges. LEARNING POINTS: Tick -borne diseases canould have atypical presentations.In endemic areas, patients with unexplained and refractory hyponatremiaaemia, should be screened for Lyme disease even in the absence of elevatedion of inflammatory markers or other specific symptoms.Persistent hiccups could be an atypical clinical presentation of tick-borne encephalitis (TBE).

Coronary flow reserve and asymmetric dimethylarginine levels: new measurements for identifying subclinical atherosclerosis in patients with psoriatic arthritis.

OBJECTIVE: To identify the presence of subclinical atherosclerosis in patients with psoriatic arthritis (PsA) and healthy controls using intima-media thickness (IMT), coronary flow reserve (CFR), and the plasma concentration of asymmetric dimethylarginine (ADMA), to evaluate the correlations among ADMA, IMT, and CFR. METHODS: The study involved 22 patients who fulfilled the ClASsification of Psoriatic ARthritis study group criteria for PsA and a cohort of 35 healthy controls with no history or current signs of coronary artery disease (CAD). Common carotid IMT was measured using high-resolution B-mode ultrasonography. Dipyridamole transthoracic stress echocardiography was used to evaluate CFR. Blood samples were obtained to assess ADMA levels. The clinical manifestations were recorded. All patients were treated with disease-modifying antirheumatic drug, but none had received any biological or steroid therapy. RESULTS: Plasma ADMA levels were significantly higher in the patients with PsA (0.71 ± 0.07 µmol/l vs 0.48 ± 0.07 µmol/l; p = 0.00) and CFR was significantly reduced in that group (2.86 ± 0.70 vs 3.3 ± 0.43; p < 0.01) compared to controls. Common carotid IMT was greater in the patients with PsA, but the difference was not significant (0.64 ± 0.26 mm vs 0.62 ± 0.5 mm; p = 0.65). There was a significant correlation between CFR and plasma ADMA levels in the PsA group (R = 0.28; p < 0.01), but no correlation between plasma ADMA levels and IMT (R = 0.02; p = 0.32), Disease Activity Score 28 (p = 0.52), or Psoriasis Area and Severity Index (p = 0.98). CONCLUSION: Our patients with PsA showed a profile of subclinical atherosclerosis. ADMA may be a useful marker of endothelial dysfunction in PsA.

Is it antiphospholipid syndrome?

The diagnosis of bacterial endocarditis remains a challenge, as nearly half of cases develop in the absence of preexistent heart disease and known risk factors. Not infrequently, a blunted clinical course at onset can lead to erroneous diagnoses. We present the case of a 47-year-old previously healthy man in which a presumptive diagnosis of antiphospholipid syndrome was made based on the absence of echocardiographically detected heart involvement, a negative blood culture, normal C-reactive protein (CRP) levels, a positive lupus anticoagulant (LAC) test, and evidence of splenic infarcts. The patient eventually developed massive aortic endocarditic involvement, with blood cultures positive for Streptococcus bovis, and was referred for valvular replacement. This case not only reminds us of the diagnostic challenges of bacterial endocarditis, but also underlines the need for a critical application of antiphospholipid syndrome diagnostic criteria.