18F-FDG PET/MRI compared with clinical and serological markers for monitoring disease activity in patients with aortitis and chronic periaortitis.

OBJECTIVES: We compared the diagnostic value of fully integrated 18F-FDG PET/MRI to that of clinical and serological markers for monitoring disease activity in patients with aortitis/chronic periaortitis (A/CPA) during immunosuppressive therapy. METHODS: Patients positive for A/CPA at the initial and at least 2 consecutive PET/MRI studies were included for retrospective analysis. Imaging (qualitative and quantitative analysis), clinical, and serologic (C-reactive protein, erythrocyte sedimentation rate) assessments were determined at each visit, and their findings compared. Differences in various PET/MRI parameters, clinical symptoms, and serologic markers during therapy between first and second visits were tested for statistical significance. Spearman's rank correlation coefficient was calculated to relate imaging to serologic marker changes between the first 2 visits. RESULTS: Serial assessments were performed in 12 patients with A/CPA, over 34 visits. PET/MRI suggested active disease in 22/34 (64.7%) studies, whereas clinical assessment and serological analysis were positive in only 18/34 (52.9%) and 17/34 (50%) cases, respectively. Disease activity assessment differed between PET/MRI, and clinical and serological markers, in 8/34 (23.5%) and 9/34 (26.5%) cases, respectively. Imaging and serologic parameters (p < 0.009) and clinical symptoms (p = 0.063) predominantly improved at the second visit. Changes from the first to the second visit were not correlated between PET/MRI and serologic markers. CONCLUSIONS: Fully integrated 18F-FDG PET/MRI provides a comprehensive imaging approach with data on vascular/perivascular inflammation that is complementary to clinical and laboratory assessments. This highlights the potential value of imaging-based disease activity monitoring, which might have a crucial impact on clinical management in patients with A/CPA.

Mortality prediction in stable hemodialysis patients is refined by YKL-40, a 40-kDa glycoprotein associated with inflammation.

Chronic inflammation contributes to increased mortality in hemodialysis (HD) patients. YKL-40 is a novel marker of inflammation, tissue remodeling, and highly expressed in macrophages inside vascular lesions. Elevated levels of YKL-40 have been reported for HD patients but how it integrates into the proinflammatory mediator network as a predictor of mortality remains elusive. We studied serum YKL-40, Interleukin-6 (IL-6), high-sensitivity C-reactive protein, monocyte chemotactic protein-1 (MCP-1), and interferon-gamma induced protein-10 (IP-10) in 475 chronic hemodialysis patients. Patients were followed for mortality for a median of 37 [interquartile range: 25-49] months and checked for interrelation of the measured mediators. To plot cumulative incidence functions, patients were stratified into terciles per YKL-40, IL-6, MCP-1, and IP-10 levels. Multivariable Cox regression models were built to examine associations of YKL-40, IP-10, and MCP-1 with all-cause and cause-specific mortality. Net reclassification improvement was calculated for the final models containing YKL-40 and IL-6. Increased YKL-40 was independently associated with age, IP-10, and IL-6 serum levels. After adjustment for demographic and laboratory parameters, comorbidities, and IL-6, only YKL-40 significantly improved risk prediction for all-cause (hazard ratio 1.4; 95% confidence interval 1.1-1.8) and cardiovascular mortality (hazard ratio 1.5; 95% confidence interval 1.03-2.2). Thus, in contrast to other biomarkers of aberrant macrophage activation, YKL-40 reflects inflammatory activity, which is not covered by IL-6. Mechanistic and prospective studies are needed to test for causal involvement of YKL-40 and whether it might qualify as a therapeutic target.

Imaging large vessel vasculitis with fully integrated PET/MRI: a pilot study.

PURPOSE: The aim of this study was to evaluate the feasibility of hybrid [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET)/MRI in patients with large vessel vasculitis (LVV) by comparing visual and quantitative parameters to that of PET/CT. Furthermore, the value of PET/MRI in disease activity and extent of LVV was assessed. METHODS: A total of 16 [(18)F]FDG PET/MRI and 12 [(18)F]-FDG PET/CT examinations were performed in 12 patients with LVV. MRI of the vessel wall by T1-weighted and T2-weighted sequences was used for anatomical localization of FDG uptake and identification of morphological changes associated with LVV. In addition, contrast-enhanced (CE) magnetic resonance angiography (MRA) was performed. The vascular FDG uptake in the vasculitis group was compared to a reference group of 16 patients using a four-point visual score. Visual scores and quantitative parameters [maximum standardized uptake value (SUVmax) and target to background ratio (TBR)] were compared between PET/MRI and PET/CT. Furthermore, correlations between C-reactive protein (CRP) and quantitative PET results, as well the extent of vasculitis in PET, MRI/CE-MRA and combined PET/MRI, were analysed. RESULTS: TBRs, SUVmax values and visual scores correlated well between PET/MRI and PET/CT (r = 0.92, r = 0.91; r = 0.84, p < 0.05). There was no significant difference between both modalities concerning SUVmax measurements and visual scores. In PET/MRI, PET alone revealed abnormal FDG uptake in 86 vascular regions. MRI/CE-MRA indicated 49 vessel segments with morphological changes related to vasculitis, leading to a total number of 95 vasculitis regions in combination with PET. Strong and significant correlations between CRP and disease extent in PET alone (r = 0.75, p = 0.0067) and PET/MRI (r = 0.92, p < 0.0001) in contrast to MRI/CE-MRA only were observed. Regarding disease activity, no significant correlations were seen between quantitative PET results and CRP, although there was a trend towards significance (r = 0.55, p = 0.0651). PET/MRI also showed active LVV in 15/16 examinations. CONCLUSION: Hybrid PET/MRI is feasible in LVV and holds promise for precisely determining disease extent and disease activity.

Diagnostic utility of Acoustic Radiation Force Impulse (ARFI) imaging in primary Sjoegren`s syndrome.

OBJECTIVES: The purpose of the study was to assess the diagnostic utility of acoustic radiation force impulse (ARFI) imaging in primary Sjögren's syndrome (pSS). METHODS: One hundred fifty-seven patients with sicca symptoms and/or salivary gland swelling were included. Sicca symptoms, Schirmer test, unstimulated whole saliva (UWS), SS-A/B antibodies, and histology were assessed according to American-European Consensus group (AECG) criteria. All patients underwent high-resolution ultrasound and ARFI imaging of the parotid (PG) and submandibular glands (SMG). RESULTS: Seventy patients were classified as having pSS. The remaining 87 patients suffered from idiopathic sicca (n = 24), rheumatoid arthritis (n = 12), sarcoidosis (n = 9), cutaneous/systemic lupus erythematosus (n = 7), scleroderma (n = 2), dermatomyositis (n = 1), HBV/HCV (n = 2), and panarteritis nodosa (n = 1), and disorders in 29 patients were classified as not otherwise specified. ARFI values of the PG were significantly higher in the pSS versus non-pSS groups (2.86 ± 0.07 m/s vs. 2.15 ± 0.11 m/s, p < 0.0001). ARFI imaging demonstrated diagnostic sensitivity and specificity of 81 % and 67 %, respectively. CONCLUSIONS: In addition to histology, ARFI imaging was the most important diagnostic tool for identifying early pSS. KEY POINTS: • Early stages in Sjögren's syndrome become apparent with major salivary gland enlargements. • Schirmer and unstimulated whole saliva tests demonstrated insufficient sensitivity/specificity for early-stage diagnosis. • Acoustic radiation force impulse imaging is a reliable tool for diagnosing early disease stages.

Clinical aspects of granulomatosis with polyangiitis affecting the head and neck.

There are many controversies in head and neck granulomatosis with polyangiitis (HN-GPA). Diagnostic/therapeutic regimens vary due to limited knowledge about the special properties of HN-GPA. 28 patients were diagnosed with GPA accordingly. Anti-neutrophil-cytoplasmatic-antibody (ANCA), anti-peroxidase-antibody (anti-PR3) and biopsies were performed for all patients and set into clinical context. 14 patients had sinonasal symptoms. Otological (n = 8) and laryngeal (n = 2) symptoms were usually associated with complex disease activity. Pulmonary and/or renal impairment was present in 14 patients at the time of diagnosis and developed in a further nine patients within 1 year. 21 patients with systemic disease displayed elevated ANCA/anti-PR3. In contrast, those with persistent isolated HN manifestations (n = 6) lacked auto-antibodies. These patients underwent multiple biopsies to diagnose GPA. Interestingly, five patients without clinical HN manifestations but elevated auto-antibodies were identified by nasal "blind" biopsy. Clinical examination, auto-antibody testing, and histology are effective diagnostic tools in HN-GPA. Histological diagnosis remains the gold standard in patients with persistent isolated head and neck manifestations but missing auto-antibodies. Based on our findings, we suggest early and sufficient systemic therapy for all HN-GPA. Nasal mucosal "blind" biopsy should be performed in patients with elevated auto-antibodies but lacking clinical head and neck manifestations.

Fluorescence-aided tomographic imaging of synovitis in the human finger.

PURPOSE: To propose and evaluate indocyanine green (ICG)-enhanced tomographic optical imaging for detection and characterization of synovitis in affected finger joints of patients with rheumatoid arthritis and differentiation from healthy joints in comparison to 3-T magnetic resonance (MR) imaging. MATERIALS AND METHODS: This prospective pilot study was approved by the institutional ethics committee. Six arthritic proximal interphalangeal (PIP) joints in six patients (five women and one man; mean age ± standard deviation, 62.6 years ± 13.3) with clinically determined rheumatoid arthritis and six healthy PIP joints from six volunteers (four women and two men; mean age, 41.5 years ± 20.2) were examined with an ICG-enhanced fluorescence molecular tomography (FMT) system and 3-T MR imaging as the standard of reference. The degree of inflammation was graded semiquantitatively on a four-point ordinate scale according to the Outcome Measures in Rheumatology Clinical Trials Rheumatoid Arthritis MR Imaging Score, or OMERACT RAMRIS. FMT reconstructions were coregistered with the MR images. Groups were compared by using a two-sided t test, and a weighted κ coefficient was used for comparing FMT and MR imaging semiquantitative scores, as well as assessing intrareader agreement. RESULTS: FMT was used to detect synovitis in all arthritic joints. The reconstructed FMT signal correlated with MR imaging findings in intensity and spatial, transverse profile. Semiquantitative scoring of FMT correlated well with MR imaging findings (weighted κ coefficient = 0.90). The reconstructed quantitative FMT signal, denoting synovial hyperperfusion, was used to differentiate between synovitis and healthy joints (healthy joints, 1.25 ± 0.59; arthritic joints, 3.13 ± 1.03; P < .001). CONCLUSION: FMT enhanced with ICG provided depth-resolved imaging of synovitis in PIP joints. FMT may help detect synovitis in patients with rheumatoid arthritis.

Haemostasis in chronic kidney disease.

The coagulation system has gained much interest again as new anticoagulatory substances have been introduced into clinical practice. Especially patients with renal failure are likely candidates for such a therapy as they often experience significant comorbidity including cardiovascular diseases that require anticoagulation. Patients with renal failure on new anticoagulants have experienced excessive bleeding which can be related to a changed pharmacokinetic profile of the compounds. However, the coagulation system itself, even without any interference with coagulation modifying drugs, is already profoundly changed during renal failure. Coagulation disorders with either episodes of severe bleeding or thrombosis represent an important cause for the morbidity and mortality of such patients. The underlying reasons for these coagulation disorders involve the changed interaction of different components of the coagulation system such as the coagulation cascade, the platelets and the vessel wall in the metabolic conditions of renal failure. Recent work provides evidence that new factors such as microparticles (MPs) can influence the coagulation system in patients with renal insufficiency through their potent procoagulatory effects. Interestingly, MPs may also contain microRNAs thus inhibiting the function of platelets, resulting in bleeding episodes. This review comprises the findings on the complex pathophysiology of coagulation disorders including new factors such as MPs and microRNAs in patients with renal insufficiency.

Management of Rheumatic Diseases During Pregnancy and Breastfeeding: Position Paper of the Working Group for Obstetrics and Prenatal Medicine in the German Society for Gynecology and Obstetrics e. V. (AGG - Section Maternal Diseases in Pregnancy).

Purpose These recommendations issued by the AGG (Section Maternal Diseases in Pregnancy) were developed as a rapid orientation on maternal rheumatic diseases for counselling and disease management in pregnancy and breastfeeding. Methods The standard literature, consensus and position papers, guidelines and recommendations by other specialist associations were evaluated by a task force of the Section and summarized in these recommendations following a joint consensus process. Recommendations This paper provides an orientating overview of the physiology, pathophysiology and definitions of rheumatic diseases which is relevant for gynecologists and obstetricians. The recommendations focus on the maternal, fetal and neonatal diagnostic workup in cases with underlying maternal rheumatic disease.

Detection of synovitis in the hands of patients with rheumatologic disorders: diagnostic performance of optical imaging in comparison with magnetic resonance imaging.

OBJECTIVE: To prospectively compare an indocyanine green (ICG)-enhanced optical imaging system with contrast-enhanced magnetic resonance imaging (MRI) for the detection of synovitis in the hands of patients with rheumatologic disorders. METHODS: Forty-five patients (30 women [67%], mean ± SD age 52.6 ± 13.4 years) in whom there was a clinical suspicion of an inflammatory arthropathy were examined with a commercially available device for ICG-enhanced optical imaging as well as by contrast-enhanced 3T MRI as the standard of reference. Three independent readers graded the degree of synovitis in the carpal, metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints of both hands (1,350 joints), using a 4-point ordinate scale (0 = no synovitis, 1 = mild, 2 = moderate, 3 = severe). Statistical analyses were performed using a logistic generalized estimating equation approach. Agreement of optical imaging ratings made by the different readers was estimated with a weighted kappa coefficient. RESULTS: When MRI was used as the standard of reference, optical imaging showed a sensitivity of 39.6% (95% confidence interval [95% CI] 31.1-48.7%), a specificity of 85.2% (95% CI 79.5-89.5%), and accuracy of 67.0% (95% CI 61.4-72.1%) for the detection of synovitis in patients with arthritis. Diagnostic accuracy was especially limited in the setting of mild synovitis, while it was substantially better in patients with severely inflamed joints. Moderate interreader and intrareader agreement was observed. CONCLUSION: The evaluated ICG-enhanced optical imaging system showed limitations for the detection of inflamed joints of the hand in comparison with MRI.

Evaluation of smell and taste in patients with Wegener's granulomatosis.

Although a reduced olfactory/gustatory function affects patients in all parts of life, this problem has not received much attention in Wegener's granulomatosis (WG). The aim of this study was to assess the smell/taste function of WG patients. Demographic data of 16 WG patients (9 males, 7 females) were obtained. They all subjectively assessed their taste/smell function on visual analogue scale. Olfactory/gustatory functions of the patients were tested with 'Sniffin' Sticks and 'Taste' strips, respectively. The results were then compared with those from sex and age-matched control group (n = 16) and normative data. WG patients subjectively assessed their olfactory (p = 0.03) and gustatory (p = 0.02) function to be lower than control group. All the olfactory scores (odour identification, odour discrimination and threshold) in both genders were significantly below the scores in the control group. WG patients were hyposmic. For taste (total taste score, as well as scores for the qualities sweet, sour, salty and bitter), WG patients did not significantly differ from controls and were normogeusic. However, the gustatory scores showed the tendency of reduction as compared to the control group. In conclusion, WG patients truly suffer from olfactory/taste dysfunction, but this is worse with olfaction. It is, therefore, imperative that physicians should make their patients to be aware of these sensory dysfunctions and educate them on methods to cope with it for better quality of life.

Rheumatic disorders affecting the head and neck: underestimated diseases.

OBJECTIVES: To describe the clinical manifestations of rheumatic disorders with isolated head and neck (H&N) affection and to introduce a novel diagnostic pathway. METHODS: From 2004 to 2010, 90 patients presented with isolated H&N symptoms of a rheumatic disorder were included in the study. Rheumatic disorders were classified according to the ACR criteria. In 2008, we introduced a novel diagnostic pathway to reduce under-diagnosis of primary rheumatic disorders in the H&N. Disease-related data were assessed retrospectively and set into clinical context. RESULTS: The majority of patients suffered from SS (n = 42), granulomatosis with polyangiitis (Wegener's) (n = 13) and sarcoidosis (n = 18) with predominance for female patients (n = 65). Enlargement of the major salivary glands (n = 47), sicca symptoms (n = 41) and cervical lymphadenopathy (n = 25) represented the most frequent symptoms. Interestingly, 3% of all enlargements of salivary glands and 4% of all cervical lymphadenopathy could be contributed to rheumatic disorders. The mean time to diagnosis was 20.71 months for SS, 8.4 months for granulomatosis with polyangiitis and 57.5 months for sarcoidosis. After implementation of the newly developed diagnostic pathway in 2008, the annually diagnosed rheumatic disorders increased 5-fold. CONCLUSIONS: The majority of rheumatic diseases of the H&N can be related to SS, granulomatosis with polyangiitis and sarcoidosis. However, the lack of specific symptoms and the clinical variability of H&N manifestation may contribute to a prolonged time to diagnosis. Our retrospective study points out the variability of symptoms and suggests a diagnostic pathway to reduce the cases of undetected H&N affection in rheumatic disorders.

Fetuin-A pretransplant serum levels, kidney allograft function and rejection episodes: a 3-year posttransplantation follow-up.

BACKGROUND: Fetuin-A is a negative acute-phase protein, which acts as a potent calcification inhibitor and an antagonist of transforming growth factor-ß. Thus, fetuin-A levels are influenced by chronic inflammation and actively affect fibrosis and calcification processes, respectively. Graft rejection, interstitial fibrosis and tubular atrophy, chronic inflammation and calcification are common causes for kidney allograft loss. This study evaluated whether pretransplant fetuin-A levels predict long-term graft survival and rejection episodes in patients after kidney transplantation. METHODS: In 206 renal transplant recipients pretransplant fetuin-A levels were measured in serum by ELISA. During the 36 months' active follow-up (median 1,249 days) 13 patients died (94% patient survival) and renal allograft failure was reported in 18 patients (91% graft survival). RESULTS: Pretransplant fetuin-A levels did not differ among patients with incident graft failures as compared to patients with functional graft after long-term follow-up or rejection episodes (fetuin-A: 393.6 ± 46 vs. 384.4 ± 69 vs. 405 ± 27.4 µg/ml). In logistic regression analysis, pretransplant fetuin-A levels did not correlate with graft failure after 3 years' follow-up (p = 0.895). In COX regression analysis, fetuin-A levels were not associated with the time to graft loss. Moreover, fetuin-A levels correlated neither with renal and metabolic parameters nor with cellular or humoral rejection episodes. CONCLUSION: Pretransplant levels of fetuin-A are not a predictor for renal allograft loss or rejection episodes after 36 months' follow-up in transplant recipients.

Treatment of severe intravenous phenytoin overdose with hemodialysis and hemoperfusion.

BACKGROUND: Phenytoin is a widely used anticonvulsant agent responsible for a number of intentional and unintentional overdoses. However, besides supportive care, specific treatment recommendations to enhance elimination of the parent compound have been discussed controversially and effectiveness of hemoperfusion is under debate. CASE REPORT: A women with a prehistory of cerebral seizures was presented following a severe iatrogenic phenytoin overdose with a peak plasma concentration of 117 mg/L. A Phenytoin overdose could be contributed to both inadequate dosing and missed repeated drug monitoring. Native phenytoin body clearance failed to relevantly lower phenytoin concentration. Thus, three sessions of a four-hour long combination of activated charcoal hemoperfusion and high-flux hemodialysis were performed resulting in considerably reduced half-life during these measures of about 7-13 hours compared to the native half-life wavering between 40-100 hours. This resulted in a substantial clinical improvement in terms of central nervous system toxicity. CONCLUSIONS: Hemodiaperfusion with activated charcoal seems to be a reasonable measure for forced lowering of highly toxic phenytoin plasma concentration and should be considered especially in circumstances following intravenous overdose (e.g. inadequate iatrogenic dosing). Its narrow therapeutic range enforces strictly adequate dosing and subsequent repeated drug monitoring of phenytoin.