Development of new extra-glandular manifestations or associated auto-immune diseases after establishing the diagnosis of primary Sjögren's syndrome : A long-term study of the Antonius Nieuwegein Sjögren (ANS) cohort.

To investigate in a long-term study, the development of new extra-glandular manifestations (EGM) or associated auto-immune diseases (AID) from 1 year after establishing the diagnosis of primary Sjögren's syndrome (pSS). The primary goal was to examine the frequency and type of these manifestations and to find out which demographic, clinical and serological profile was most at risk. All outpatients diagnosed with primary Sjögren's syndrome were included in a retrospective study, with at least one check-up per year, from June 1991 until August 2015. Patients also fulfilling the criteria for concomitant connective tissue disorders were excluded. Data were collected with respect to the cumulative prevalence of a new EGM or associated AID. 140 patients were included in the final analysis. After 10 years of follow-up, the cumulative incidence of a new EGM or associated AID was 30.7%. The most frequent events were polyneuropathy, interstitial lung disease, (poly)arthritis, discoid lupus erythematosus (LE)/subacute cutaneous LE and Hashimoto's disease. Non-Hodgkin lymphoma was not diagnosed during the follow-up. Patients without chronic benign pain syndrome (CBP) (HR 2.13; 95% CI [0.94-4.76]; p = 0.061), but in particular those with cryoglobulins (HR 2.87; 95% CI [1.20-6.86]; p = 0.013), developed more events. Age at diagnosis, gender, the presence of ANA, anti-Ro/SSA, anti-La/SSB, IgM-RF, decreased levels of C3 or C4, or hypergammaglobulinaemia did not show any statistically significant differences. The burden of disease in pSS is higher than expected due to the development of EGM or associated AID. Therefore, we recommend long-term follow-up of all pSS patients, particularly those with cryoglobulinaemia.

Lower prevalence of extra-glandular manifestations and anti-SSB antibodies in patients with primary Sjögren's syndrome and widespread pain: evidence for a relatively benign subset.

OBJECTIVES: To investigate in primary Sjögren's syndrome, the differences between patients with and without widespread pain (WSP) with respect to the cumulative prevalence of extra-glandular manifestations (EGMs) and systemic auto-antibodies. METHODS: All outpatients diagnosed with primary Sjögren's syndrome (2) were included in a prospective follow-up, with at least one check up each year, from June 1991 until November 2011. Patients who also fulfilled criteria for concomitant connective tissue disorders were excluded. Widespread pain was defined as the presence of long-lasting (>one year) diffuse pain in all four body quadrants. Data were collected with respect to the cumulative prevalence of systemic auto-antibodies (anti-nuclear antibodies [ANA], anti-Sjögren syndrome A antigen [anti-SSA], anti-Sjögren syndrome B antigen [anti-SSB] and immunoglobulin M-Rheumatoid factor [IgM-RF]) and EGMs related to primary Sjögren's syndrome. RESULTS: Eighty-three patients were included in the final analysis. Thirty-nine (34.9%) patients had widespread pain. Anti-SSB was found less frequently (p<0.05) in patients with WSP than in patients without WSP. The WSP-positive patients were more frequently negative for all four tested autoantibodies (p<0.05). The patients with WSP had fewer EGMs than the patients without WSP (p<0.01); more specifically, polyneuropathy occurred less frequently (p<0.05) in the patients with WSP. Cytopenia, uveitis, pericarditis, pleuritis, interstitial lung disease, vasculitis, monoclonal gammapathy of unknown significance and non-Hodgkin lymphoma only occurred in the patients without WSP. CONCLUSIONS: Primary Sjögren's patients with WSP form a benign subgroup, with a lower prevalence of anti-SSB and EGMs (in particular polyneuropathy). We suggest a shorter period of follow-up for this subset than for the WSP-negative patients.

An index for breathlessness and leg fatigue.

The features of perceived symptoms causing discontinuation of strenuous exercise have been scarcely studied. The aim was to characterize the two main symptoms causing the discontinuation of heavy work in healthy persons as well as describe the growth of symptoms during exercise. Breathlessness (b) and leg fatigue (l) were assessed using the Borg CR10 Scale and the Borg CR100 (centiMax) Scale, during a standardized exercise test in 38 healthy subjects (24-71 years). The b/l-relationships were calculated for terminal perceptions (ERI(b/l)), and the growth of symptoms determined by power functions for the whole test, as well as by growth response indexes (GRI). This latter index was constructed as a ratio between power levels corresponding to a very strong and a moderate perception. In the majority (71%) of the test subjects, leg fatigue was the dominant symptom at the conclusion of exercise (P<0.001) and the b/l ratio was 0.77 (CR10) and 0.75 (CR100), respectively. The GRI for breathlessness and leg fatigue was similar, with good correlations between GRI and the power function exponent (P<0.005). In healthy subjects, leg fatigue is the most common cause for discontinuing an incremental exercise test. The growth functions for breathlessness and leg fatigue during work are, however, almost parallel.

Candidate gene association study for noise-induced hearing loss in two independent noise-exposed populations.

Millions of people are daily exposed to high levels of noise. Consequently, noise-induced hearing loss (NIHL) is one of the most important occupational health hazards worldwide. In this study, we performed an association study for NIHL based on a candidate gene approach. 644 Single Nucleotide Polymorphisms (SNPs) in 53 candidate genes were analyzed in two independent NIHL sample sets, a Swedish set and part of a Polish set. Eight SNPs with promising results were selected and analysed in the remaining part of the Polish samples. One SNP in PCDH15 (rs7095441), resulted in significant associations in both sample sets while two SNPs in MYH14 (rs667907 and rs588035), resulted in significant associations in the Polish sample set and significant interactions with noise exposure level in the Swedish sample set. Calculation of odds ratios revealed a significant association of rs588035 with NIHL in the Swedish high noise exposure level group. Our studies suggest that PCDH15 and MYH14 may be NIHL susceptibility genes, but further replication in independent sample sets is mandatory.

Rituximab in life threatening antisynthetase syndrome.

This case study reports a patient with severe interstitial pneumonitis, mild polyarthritis and polymyositis, accompanied by the presence of anti-Jo-1 antibodies diagnosed as antisynthetase syndrome. The concurrence of anti-Jo-1 with anti-Ro/SSA antibodies leads to a more severe form of interstitial lung disease. This patient was referred to our hospital because of life threatening respiratory failure. He was refractory to glucocorticoids and cyclophosphamide, but was successfully treated with two sequential infusions of rituximab. Clinical condition improved very rapidly. Response to treatment was well correlated with a fall of levels of serum soluble IL2-receptor. A decrease in pulmonary disease activity was visualized on PET-scans before and after two sequential rituximab infusions.

Relationship between histological subtypes and clinical characteristics at presentation and outcome in biopsy-proven temporal arteritis. Identification of a relatively benign subgroup.

Temporal arteritis (TA) may offer major complications, whilst high dosage of prednisone may result in serious side effects. We tried to identify a subgroup of TA, which can be treated with a lower dosage of prednisone. Retrospectively, clinical and laboratory data were studied at presentation, as well as the outcome in 44 consecutive patients with biopsy-proven temporal arteritis. These data were related to three particular histological subgroups, (a) classical giant cell arteritis, (b) atypical arteritis, and (c) 'healed arteritis', defined according to Allsop and Gallagher (The American Journal of Surgical Pathology 5:317-332, 1981). At presentation in subgroup c, erythrocyte sedimentation rate was lower and the level of haemoglobin was higher than in the other two subgroups. During follow-up in the healed arteritis group, reactivation, recurrence, or early death were not observed, whilst prednisone dosage after 2 and 3 years was lower compared to subgroup b. Major complications (permanent blindness and cerebrovascular accident) were only observed in subgroups a and b. We believe that the healed arteritis subgroup represents a relatively benign subgroup with a mild clinical presentation and a good prognosis. Therefore, a much lower initial prednisone dosage (15 mg/day) is suggested for patients in subgroup c than in the other two subgroups (40-60 mg/day).

Extremely high serum ferritin levels as diagnostic tool in adult-onset Still's disease.

The diagnosis of adult-onset Still's disease (ASD) is difficult to establish due to the nonspecific clinical and laboratory findings. A markedly raised serum ferritin level is a typical finding, although it is not well understood why ferritin levels are extremely high in ASD. We discuss several possible explanations leading to the extremely high levels of ferritin.

Nocardiosis: a case series and a mini review of clinical and microbiological features.

Infections caused by Nocardia species are uncommon and have a wide variety of clinical manifestations in immunocompetent and immunocompromised patients. The diagnosis of nocardiosis can easily be missed because there are no characteristic symptoms. We present one case of a Nocardia infection in detail and give a brief description of eight other cases, including a relatively unique type of Nocardia veterana, diagnosed in our hospital during a five-year period. The diversity of clinical manifestations, microbiological identification and general principles of treatment of nocardiosis are reviewed.

Polyarthritis in primary Sjögren's syndrome represents a distinct subset with less pronounced B cell proliferation a Dutch cohort with long-term follow-up.

The primary goal was to investigate the differences in patients with and without polyarthritis (PA) in primary Sjögren's syndrome (pSS) in a clinical-based (real-life) setting, with respect to demographic characteristics, cumulative prevalence of other extra-glandular manifestations (EGM), hypergammaglobulinaemia and serological profile. The secondary goal was to describe the characteristics of polyarthritis in our pSS cohort. Patients diagnosed with pSS and polyarthritis but without rheumatoid arthritis (RA)-like changes on X-rays were followed up prospectively from June 1991 until August 2014, with at least one check-up each year. Patients fulfilling the criteria for concomitant connective tissue disorders were excluded. Data were collected with respect to the prevalence of systemic auto-antibodies (anti-nuclear antibodies (ANA), anti-Sjögren's syndrome-related antigen A (anti-SSA), anti-Sjögren's syndrome type B (anti-SSB) and immunoglobulin M-rheumatoid factor (IgM-RF)) and other EGM related to pSS. A total of 134 patients were included for the final analysis. The median follow-up was 86 months (range 0-368 months). Twenty-two patients (16.4 %) had polyarthritis. The prevalence of systemic auto-antibodies including rheumatoid factor did not differ between the two groups. Anti-cyclic citrullinated peptide (CCP) occurred much more frequently in the polyarthritis-positive (PA+) patients (13.7 vs 0.9 %; p = 0.015). Hypergammaglobulinaemia (p = 0.002) and increased levels of IgG (p = 0.013) occurred much less frequently in the PA+ group compared to the polyarthritis-negative (PA-) group. The mean total number of EGM or of any specific EGM did not differ between the two groups. Most patients had a mild, symmetrical PA predominantly involving the finger joints (proximal interphalangeal joints/metacarpophalangeal joints (PIP/MCP)) and/or wrists and/or metatarsophalangeal (MTP) joints. Significant morning stiffness lasting ≥1 h was found infrequently (32 %). All patients were treated with a classic (c) disease-modifying antirheumatic drug (DMARD), but in two cases, treatment was necessary with a tumour necrosis factor (TNF) inhibitor. PA+ pSS patients are more frequently anti-CCP positive and have a less pronounced B cell proliferation than PA- patients. PSS patients with PA seem to have a relatively mild articular expression with a favourable course.

[A patient with sclerosing autoimmune pancreaticocholangitis as the cause of recurrent cholangitis following a pylorus-sparing pancreaticoduodenectomy]. / Een patient met scleroserende auto-immune pancreaticocholangitis als oorzaak van recidiverende cholangitis na pylorussparende pancreaticoduodenectomie.

A pylorus-sparing pancreaticoduodenectomy was performed in a 67-year-old man because of indications for a carcinoma of the distal common bile duct. Histology of the postoperative specimen, however, revealed a sclerosing inflammation of the distal common bile duct and the surrounding pancreatic parenchyma. Initial postoperative recovery was followed by recurrent cholangitis. Stenosis of the choledocho-jejunostomy could not be demonstrated. Instead, repeated endoscopic retrograde cholangiopancreaticography revealed extensive sclerosis of the intrahepatic bile ducts, which suggested a sclerosing cholangitis associated with an autoimmune pancreatitis: sclerosing autoimmune pancreaticocholangitis. This disorder was recently described; it is characterised by a disorder in the pancreas that is indistinguishable from malignancy by imaging techniques and that is followed by a sclerosing inflammation of the bile ducts. The disease responds well to steroids. The patient described demonstrated a complete clinical and biochemical recovery after initiation ofprednisone therapy.

Hearing loss from the acoustic artifact of the coil used in extracranial magnetic stimulation.

The stimulating coil used in extracranial magnetic field stimulation (EMFS) emits a high intensity impulse sound artifact that causes permanent threshold shifts in the unprotected ears of experimental animals. At magnetic stimulation levels of 50 to 100%, the magnetic coil acoustic artifact (MCAA) ranged from 145 to 157 dB peak sound pressure level at the eardrum. The magnetic field alone did not appear to cause hearing impairment since no threshold shifts were observed in ears that were plugged with ear protectors during exposure to the MCAA. These findings suggest that the acoustic artifact produced by EMFS in the clinic may pose some risk for hearing loss in patients and clinicians when held in close proximity to the unprotected ear. We recommend the use of ear protectors for the patient and clinician during EMFS as a precautionary measure to prevent hearing loss.

Pulmonary diffusing capacity disturbances are related to nailfold capillary changes in patients with Raynaud's phenomenon with and without an underlying connective tissue disease.

PURPOSE: The aim of this study was to evaluate whether pulmonary microvascular damage is part of a more generalized involvement of the microvasculature in the spectrum of scleroderma (Scl)-like syndromes. PATIENTS AND METHODS: We studied four groups of patients, all with Raynaud's phenomenon (RP), distinguished by the extent and nature of their underlying connective tissue disease. Twenty-two patients had primary RP (pRP), another 22 patients had RP and an undifferentiated connective tissue disease (uCTD), 15 patients had Scl, and eight patients had the CREST syndrome (CREST). Pulmonary vascular damage in these groups was assessed by measuring the pulmonary diffusing capacity (T1,CO) and its components: the diffusing capacity of the alveolocapillary membrane (Dm) and the pulmonary capillary blood volume (Vc). Results were compared with morphologic abnormalities of the nailfold capillaries, as determined by nailfold capillary microscopy, and related to the presence of antinuclear antibodies. RESULTS: Vc was below normal in 38% and 43% of patients with pRP and uCTD, respectively (versus 52% in patients with Scl or CREST combined). In contrast, Dm was below normal in only 5% and 26% of patients with pRP and uCTD, respectively (versus 61% in patients with Scl or CREST combined). In patients with Scl and CREST, Dm was significantly decreased as compared with the former groups (p less than 0.01). Dm was also the pulmonary function parameter that correlated most strongly with both nailfold capillary abnormalities and the presence of antinuclear antibodies, whereas Vc did not. CONCLUSION: Early pulmonary involvement in Scl syndromes is functionally characterized by a lowered Dm, correlating with morphologic changes of the nailfold capillaries. Decreased Vc is probably a reflection of RP of the pulmonary vasculature.

Pulmonary function in systemic lupus erythematosus is related to distinct clinical, serologic, and nailfold capillary patterns.

PURPOSE: The purpose of this study was to investigate whether systemic lupus erythematosus (SLE) patients with interstitial lung disease represent a particular subset of patients characterized by the presence of clinical, serologic, and nailfold capillary patterns overlapping scleroderma. PATIENTS AND METHODS: In 57 consecutive patients with SLE, a standardized detailed history was obtained and a physical examination performed, directed at signs and symptoms of connective tissue diseases, in particular scleroderma. Additionally, pulmonary function testing, chest radiography, radionuclide transit studies of the esophagus, nailfold capillary microscopy, and detailed serologic studies directed at the antigenic specificities of antinuclear antibodies were performed. Patients were divided into three groups based on the results of pulmonary function testing, i.e., normal lung function, restriction, or isolated impairment of diffusion. Clinical, serologic, and nailfold capillary microscopic findings were compared among these three groups. RESULTS: Twenty patients had normal lung function, 19 had restrictive lung function loss, and 9 had an isolated impairment of the diffusing capacity (T1,CO). Patients with obstructive lung disease (n = 9) were excluded from analysis. Sclerodermatous changes of the hands were associated with a restrictive lung function pattern. Interstitial changes on chest radiograph were associated with isolated impairment of T1,CO. Nailfold capillary abnormalities correlated with decreased T1,CO and Dm, the component of T1,CO representing the diffusing capacity of the alveolocapillary membrane. Antibodies to U1-RNA were associated with restrictive lung function and decreased T1,CO. CONCLUSION: We conclude that interstitial lung disease is present in a subset of SLE patients characterized by an increased prevalence of scleroderma traits and anti-(U1)RNA antibodies. Microvascular changes may contribute to the development of interstitial lung disease in SLE as well as in scleroderma.

Serial nailfold capillary microscopy in primary Raynaud's phenomenon and scleroderma.

Eighty-four patients with long-standing Raynaud's phenomenon (RP) were evaluated by nailfold capillary microscopy (NCM) in a cross-sectional and longitudinal study. The patients were classified in five diagnostic groups: primary familial RP (n = 16), primary nonfamilial RP (n = 20), possible scleroderma (n = 27), scleroderma (n = 16), and the CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome (n = 8). In the cross-sectional study, NCM showed gradually decreasing numbers of capillary loops and increasing numbers of widened and giant loops in the following order: primary RP, possible scleroderma, and scleroderma/CREST, suggesting that these diseases are part of a continuing spectrum of RP. In the longitudinal study there was a decrease in the total number of nailfold capillary loops in scleroderma/CREST but not in primary RP and possible scleroderma.

Clinical associations of antiribonucleoprotein antibodies in patients with systemic lupus erythematosus.

The authors undertook a cross-sectional study to investigate the clinical associations of antiribonucleoprotein (anti-RNP) antibodies in 49 patients with systemic lupus erythematosus (SLE) without other concomitant connective tissue disorders. The traditional counterimmunoelectrophoresis (CIE) and the immunoblotting (IB) technique were compared. Clinically, special attention was given to the identification of sclerodermalike features. All patients completed a detailed questionnaire, physical examination, and additional investigations including pulmonary function tests, chest roentgenogram, radionuclide transit studies of the esophagus, and nailfold capillary microscopy. Pulmonary function testing and radionuclide transit studies of the esophagus were very sensitive for the detection of (subclinical) pulmonary and esophageal involvement, respectively. Within the relatively homogeneous SLE population, a subset was recognized that was characterized clinically by the presence of sclerodermalike features such as Raynaud's phenomenon, sclerodactyly, interstitial changes on chest roentgenogram, and decreased numbers of nailfold capillary loops, and serologically by the presence of anti-RNP antibodies. IB was somewhat more sensitive than CIE for the detection of anti-RNP (anti-Sm/anti-nRNP) antibodies but did not identify other clinical associations. Thus, anti-RNP antibodies in SLE are associated with scleroderma-associated features. For clinical practice, CIE is the technique recommended for their detection.

Magnetic resonance imaging of the cochlea, spiral ganglia and eighth nerve of the guinea pig.

The membranous labyrinth of the guinea pig cochlea and retrocochlear neural structures were investigated by magnetic resonance imaging (MRI) using an experimental system with a field strength of 4.7T and a single turn surface coil 25 mm in diameter, or standard resonators of 34 or 70 mm in diameter and gradient field strengths of 950 mTm and 200 mTm. High-resolution 2-D and 3-D images of 0.3-1.0 mm slice thickness were acquired by a rapid acquisition with relaxation enhancement (RARE) sequence and a standard multi-echo technique. Structural and dimensional aspects of the cochlea were resolved in vitro and in vivo down to <50 microm, showing the scala vestibule, scala media, scala tympani, spiral ganglia and the cochlear (eighth) nerve. In vivo perfusions with the gadodiamide (GdDTPA-BMA) chelate-bound paramagnetic gadolinium ion resulted in dynamic temporal enhancement of the scala vestibule and scala tympani, but did not penetrate the scala media.

Magnetic resonance imaging of the membranous labyrinth during in vivo gadolinium (Gd-DTPA-BMA) uptake in the normal and lesioned cochlea.

MRI with a T1 contrast agent was used to investigate the normal and noise-damaged cochlea. The time course and distribution of the in vivo uptake of the gadodiamide chelate bound paramagnetic Gd ion (GdDTPA-BMA) throughout the membranous labyrinth of normal and impulse noise-damaged guinea pig cochleae were measured by MRI at 4.7T. Simultaneous signal enhancement of the basal, medial and apical scala tympani (ST) and scala vestibuli (SV) was observed within 10 min following i.v. injection, reaching maximum levels at around 100 min. ANOVA and post hoc paired t-tests showed statistically significant differences in the levels and rates of Gd uptake-enhancement between the scalae. The ST revealed the most rapid and extensive enhancement throughout the period of active Gd uptake, while the SV showed comparatively slower and less enhancement, and the intact scala media (SM) indicated insignificant enhancement. The in vivo Gd penetration and enhancement of the membranous SM increased significantly in the noise-damaged cochlea, suggesting lesioning of the cochlear membranes.

Processing of intensity-correlated information in an acoustic-autonomic reflex system.

The extraction and utilization of sound level changes in acoustic-autonomic reflex systems were studied on a vasoconstriction response in the tail of nonanesthetized rats. The vasoconstriction was found to depend on sound level and changes of level in the following ways. (a) It increased as a linear function of sound level (in dB) of short noise bursts. (b) It habituated during stimulation with a constant sound. (c) It was re-elicited by changes in the level of ongoing sound. (d) Its size, in response to a 10 dB increase in an on-going sound, was determined by the total level reached, and not by the size of the change. (e) Its size, in response to an increase varying from 5 to 50 dB, was equal if the total level reached was the same. (f) It gradually decreased if the stimulus steps were of less than 5 dB. The results are interpreted to show the existence of sound level specific information channels and level-specific habituation phenomena.

Stapedius reflex thresholds in relation to tails of auditory nerve fiber frequency tuning curves.

The acoustic stapedius reflex (ASR) threshold on non-anesthetized rabbits was compared to some measures of the single auditory nerve fiber activity of rabbits. The observations were made on normal-hearing animals, with some additional data from noise-exposed individuals. The results showed that the ASR threshold was reached at a sound level above saturation of discharge rate for individual neurons at their characteristic frequency (CF) in normal animals. It was found, on the other hand, that the ASR threshold measured across frequencies from 0.25 to 12.0 kHz were at a level similar to that of the tails of the frequency tuning curves (FTCs). Cochlear lesions-induced changes in FTC tail levels were paralleled by changes in ASR threshold levels. The raise of ASR threshold was, however, somewhat larger than the raise of the tails which might be explained by the significant relative decrease in the total number of units found in the frequency region corresponding to the lesion. There was also a decrease in the high spontaneous rate (SR) compared to the low and medium SR fibers for higher frequencies. It is concluded that the FTC tails can be a major eighth-nerve correlate to ASR activation.

Ultrastructural changes in the presynaptic region of outer hair cells after acoustic stimulation.

Protection against noise trauma results by sound-conditioning animals to a low-level, long-term acoustic stimulus prior to a damaging exposure. It is known that the outer hair cells are selectively protected by sound-conditioning. The aim of the present study was to determine if the intrinsic properties of the outer hair cell had been modified by sound-conditioning. A stimulus-related increase in the vesicle content in the presynaptic region was found. It is suggested that the outer hair cells are involved in sound conditioning and that changes in the presynaptic region can be one correlate to the protection against noise trauma by sound-conditioning.