Disease activity and damage accrual during the early disease course in a multinational inception cohort of patients with systemic lupus erythematosus.

An inception cohort of patients with systemic lupus erythematosus from 14 European centres was followed for up to 5 years in order to describe the current early disease course. At inclusion patients (n = 200, 89% female, mean age 35 years, 97% Caucasian, mean SLEDAI 12.2) fulfilled a mean of 6.5 ACR classification criteria. The most prevalent criteria were antinuclear Ab presence (97%) followed by anti-dsDNA Ab (74%), arthritis (69%), leukocytopenia (54%) and malar rash (53%), antiphospholipid Ab (48%) and anti-synovial membrane Ab (21.6%). Clinical signs of lupus nephritis (LN) were present in 39% with biopsy-confirmed LN seen in 25%. Frequent additional findings were hypocomplementaemia (54%), anti-SSA Ab (49%), alopecia (26%) and Raynaud's phenomenon (31%). There were few regional differences in disease presentation and management. One and 5-year survival rates were 99% and 97% respectively. During the mean follow-up of 4.1 years 25% entered a state of early disease quiescence by global physician assessment, but the overall risk of subsequent flare was 60%. Maximum SLEDAI scores decreased over time, but 45% of patients accrued damage (SDI >or=1) for which baseline presence of proteinuria and persistent disease activity were independent predictors. The results indicate minor differences in SLE presentation and treatment within various regions of Europe and a high diagnostic reliance on anti-dsDNA Ab. Despite early reductions in disease activity and improved mortality, the risk for disease flare and damage development is, however, still substantial, especially in patients not entering an early remission.

Manometric assessment of impaired esophageal motor function in primary Sjögren's syndrome.

OBJECTIVE: To evaluate by manometry the esophageal motility changes in patients with primary Sjögren's syndrome (SS). METHODS: Esophageal manometry was carried out in 25 (F/M: 22/3) primary SS patients with systemic manifestations and in 42 control subjects. The primary SS patients also completed a dysphagia scoring questionnaire and underwent whole salivary flow measurements. RESULTS: As compared with the controls the primary SS patients exhibited a decreased lower esophageal sphincter (LES) pressure (P < 0.01) and a prolongation of LES relaxations (P < 0.02). In the esophageal body (EB) a decreased peristaltic velocity (p < 0.01), an increased duration of contractions (p < 0.01) and a higher occurrence of simultaneous waves (p < 0.01) were detected. Since decreased peristaltic velocity was the most frequent motor abnormality (11/25 cases), two groups of patients were formed for further analysis: patients with a decreased (group I, n = 11) and patients with a normal (group II, n = 14) peristaltic velocity. The SS patients with a decreased EB propagation velocity (< or = 2.7 cm/s, group I) displayed more significantly decreased pressures (p < 0.01) and more prolonged relaxation times (p < 0.05) in the LES, with higher rates of simultaneous contractions on dry swallows (p = 0.05) in the EB, as compared with those who had a normal peristaltic velocity (group II). Of the clinical parameters, the decreased EB peristaltic velocity was associated with a smaller whole saliva production both in the basal state and after stimulation. Furthermore, this group of patients had a significantly higher liquid requirement for swallowing than those who had normal peristaltic velocities (p = 0.05). CONCLUSIONS: Primary SS patients with systemic manifestations exhibit several esophageal motility abnormalities. In this study, a decreased EB peristaltic velocity was the most common manometric change, and showed an association with impaired saliva production and higher liquid requirement for swallowing, but not with the laboratory parameters or with the systemic manifestations of the disease.

Primary Sjögren's syndrome with secondary hyperparathyroidism.

The case history of a 43-year-old woman with primary Sjögren's syndrome is presented: in 1970, xerostomia and keratoconjunctivitis sicca; in 1980, arthritis; in 1982, chronic tubulointerstitial nephritis with renal tubular acidosis and vasopressin-resistant hyposthenuria. The renal function gradually deteriorated. Chronic atrophic gastritis with vitamin B12 deficiency and chronic duodenitis with diminished disaccharidase activity in the mucosa were also diagnosed. From 1985, repeated multiple fractures of the ribs occurred, with secondary hyperparathyroidism in the background. The renal and intestinal involvement suggests that, besides the elevated parathyroid hormone level, an acquired vitamin D deficiency plays a pathogenetic role in severe osteopenia. The patient is being treated at present by haemodialysis, and subtotal parathyroidectomy and renal transplantation are planned.

Autonomic nervous system dysfunction involving the gastrointestinal and the urinary tracts in primary Sjögren's syndrome.

OBJECTIVE: Antibodies reacting with the m3 subtype muscarinic acetylcholine receptor appear to be an important pathogenic factor in primary Sjögren's syndrome (pSS). As this receptor subtype is functionally important in the gastrointestinal and urinary tracts, and very little is known about the autonomic nervous system function in these organs in pSS patients, the occurrence and clinical significance of an autonomic nervous system dysfunction involving the gastrointestinal and urinary tracts were investigated. METHODS: Data on clinical symptoms attributable to an autonomic dysfunction were collected from 51 pSS patients. Gastric emptying scintigraphy and urodynamic studies were performed on 30 and 16 patients, respectively, and the results were correlated with patient characteristics and with the presence of autonomic nervous system symptoms. RESULTS: Gastric emptying was abnormally slow in 21 of the 30 examined patients (70%). Urodynamic findings, compatible with a decreased detrusor muscle tone or contractility were found in 9 of the 16 patients tested (56%). Various symptoms of an autonomic nervous system dysfunction were reported by 2-16% of the patients. CONCLUSION: Signs of an autonomic nervous system dysfunction involving the gastrointestinal and the urinary systems can be observed in the majority of pSS patients. This high occurrence is rarely associated with clinically significant symptoms. The authors presume a role of autoantibodies reacting with the m3 muscarinic acetylcholine receptor in the elicitation of the autonomic dysfunction.

[Secondary membranous glomerulonephritis]. / Secunder membranosus glomerulonephritis.

Following 689 percutaneous renal biopsies, membranous glomerulonephritis was proved in 68 patients. In 16 (23.5%) an underlying primary disease was verified, and thus the glomerulonephritis the secondary form. The primary disease was SLE in 5 cases, diabetes mellitus in 5 cases, rheumatoid arthritis in 3 cases, chronic active hepatitis in 2 cases, an ulcerative colitis and eosinophilic angiolymphoid hyperplasia in 1 patient. As initial sign, nephrotic syndrome emerged in 87.5% of the 16 cases. Microscopic haematuria was observed in half of the patients, as was hypertension, while acute renal failure presented in only 1 case. Histologically, in 13 cases the predominance of early glomerular alterations was characteristic, while in 9 cases the picture proved to be equivocal and accompanied by some degree of interstitial alterations. During combined treatment, remission was achieved in 75%. Two patients with SLE died, but not as a consequence of renal failure. Transient side-effects of the treatment were registered in 5 cases. The principal pathogenetic and clinical differences between the individual secondary nephritis forms, and the difficulty of their differentiation from the idiopathic cases, even on repeated examination, are emphasized. In 3 patients the possibility of secondary renal processes was suggested by the histological picture, and this was proved by the detailed clinical findings.

[Diffuse alveolar hemorrhage in systemic lupus erythematosus]. / Diffúz alveolaris haemorrhagia szisztémás lupus erythematosusban.

Of the 120 systemic lupus erythematosus (SLE) patients treated by the authors, two have developed diffuse alveolar haemorrhage. The authors' objective is to present this rare, but severe manifestation. Patients 1 and 2 were 66- and 22-year old women, respectively. Both had SLE with multi-organ involvements including diffuse proliferative lupus nephritis. Before the diagnosis of the disease, both patients had experienced pneumonitis that resolved on corticosteroid treatment. Soon after the diagnosis, respiratory failure, haemoptoea and acute anaemia developed, accompanied by a rapid deterioration in the general condition. Chest radiographs revealed bilateral, diffuse, alveolar infiltrates. The pulmonary haemorrhage temporarily ceased in response to corticosteroid treatment, but both patients later died in consequence of active SLE and mixed bacterial and fungal sepsis. Post mortem examination demonstrated fibrosing alveolitis and alveolar bleeding in Patient 1, and an immune complex deposition-induced alveolocapillary inflammation with alveolar haemorrhage in Patient 2. Diffuse alveolar haemorrhage is a life-threatening manifestation of SLE. Its onset may be preceded by episodes of pneumonitis resolving on corticosteroid treatment. An active diagnostic workup, intensive observation and aggressive immunosuppressive treatment are the cornerstones of the management. The early detection and the active treatment of secondary infections are obligatory. The authors consider the most difficult challenge to be the optimum coordination of the above treatment modalities.

Current causes of death in systemic lupus erythematosus in Europe, 2000--2004: relation to disease activity and damage accrual.

Current therapeutic and diagnostic resources have turned systemic lupus erythematosus (SLE) into a chronic disease by reducing mortality rates. The exact contribution of disease activity and disease related damage to mortality is not well studied. The aim of this study was to describe the current causes of death (COD) in a multinational European cohort of patients with SLE in relation to quantified measures of disease activity and damage. Prospective five-year observational study of case fatalities in SLE patients at 12 European centres was performed. Demographics, disease manifestations, interventions and quantified disease activity (by ECLAM and SLEDAI) and damage (by SLICC-DI) at the time of death were related to the various COD. Ninety-one case fatalities (89% females) occurred after median disease duration of 10.2 years (range 0.2-40) corresponding to a annual case fatality of one for each of the participating cohorts. Cumulative mortality correlated linearly with disease duration with nearly 10% of fatalities occurring in the first year and 40% after more than 10 years of disease. Death occurred during SLE remission in one third of cases. In the remaining cases a mixture of disease activity (median ECLAM 5.5, median SLEDAI 15) and accrued damage (median SLICC-DI 5.0) with opposing relationships to disease duration contributed to death. Infections and cardiovascular events were the most frequent COD in both early and late fatalities with no gender differences for type of COD, disease activity, damage or comorbidity. In Europe, case fatalities have become uncommon events in dedicated SLE cohorts. The bimodal mortality curve has flattened out and deaths now occur evenly throughout the disease course with infectious and cardiovascular complications as the main direct COD in both early and late fatalities. Accrued damage supplants disease activity over time as the main SLE specific contributor to death over time.

Clinical associations of autoantibodies to human muscarinic acetylcholine receptor 3(213-228) in primary Sjogren's syndrome.

OBJECTIVES: The authors have previously identified a peptide of the human muscarinic acetylcholine receptor-3 (m3AChR) as a suitable antigen for the immunodetection of antimuscarinic acetylcholine receptor autoantibodies in primary Sjögren's syndrome (pSS). The aim of this study was to assess the clinical correlations and disease specificity of these antibodies. METHODS: Seventy-three pSS, 40 rheumatoid arthritis (RA), 19 systemic lupus erythematosus (SLE), 14 secondary Sjögren's syndrome (sSS) patients, 22 subjects in whom pSS was suspected but in whom the diagnosis not could eventually be established (suspSS) and 40 healthy subjects were investigated. An enzyme-linked immunosorbent assay system developed by the authors using a 16-mer peptide of the m3AChR (m3AChR(213-228)) in a recombinant fusion peptide form was used as the antigen. RESULTS: Anti-m3AChR(213-228) antibody positivity was observed in 66 (90%) of the pSS patients. The antibody levels correlated positively with the number of extraglandular organ manifestations. Both the mean antibody levels and the occurrence of anti-m3AChR(213-228) positivity were significantly higher in pSS than in the comparison groups. The test discriminated the pSS patients from the various comparison groups with specificities of 65, 68, 71 and 50% for RA, SLE, sSS and suspSS, respectively. CONCLUSIONS: The presence of m3AChR(213-228) antibodies is a common feature in pSS. Although it is significantly more common in pSS than in the comparison groups, anti-m3AChR(213-228) positivity is not exclusive to pSS.

Laser-nephelometric detection of soluble immune complexes.

A new method for the detection of soluble immune complexes has been worked out by combining the polyethylene glycol (PEG) precipitation method with laser nephelometry. Experiences achieved by measurements on in vitro immune complexes are presented. The method was found suitable for the detection of immune complexes development in vivo. The optimum concentration of PEG was found to be 3.51%. Results were compared to those achieved by the traditional PEG precipitation technique in 88 cases. The laser nephelometric method was found to be more sensitive and is recommended for use in clinical laboratories.

Primary Sjögren's syndrome from the viewpoint of an internal physician.

The characteristics of primary Sjögren's syndrome are described on the basis of the follow-up of 65 patients with extraglandular symptoms at the onset and during the disease. The mean age of the patients at onset was 41.8 years and at the time of definite diagnosis was 45.8 years. Articular (32 cases), lacrimal (30 cases) and salivary (30 cases) manifestations were the most frequent initial symptoms. In only 22 of the 65 patients could Sjögren's syndrome be diagnosed at the onset. In most cases, the articular symptoms observed observed in 56 patients during the course corresponded to true polyarthritis, as verified by joint scintigraphy. Most frequently the wrists and ankles were affected. Chronic atrophic gastritis was found in 35 patients. In the young patients (13 cases), both the antrum and the corpus were affected more frequently than in the controls. In middle-aged patients (21 cases), atrophy of the antrum, and in the elderly (10 cases) atrophy of the corpus was more frequent than in the controls. All three types of chronic atrophic gastritis occurred in the disease. The decreased gastric acid secretion was characteristic of types A and AB gastritis, but the hypergastrinaemia only of type A. It was verified that chronic duodenitis and jejunitis occur in the disease. The pancreatic lesions were mild. Renal involvement was detected in 15 patients, vascular symptoms in 22 and lower-airway changes in 21. The variety of the different symptoms proved that primary Sjögren's syndrome can involve many organs.

Types of atrophic gastritis in patients with primary Sjögren's syndrome.

Histological examination of the gastric mucosa was performed in 44 patients with primary Sjögren's syndrome with extraglandular symptoms (mean age 51.9, range 22-76). Biopsy specimens were taken from each of three separate regions: the antrum, the corpus, and the transitional zone between the antrum and the corpus. The incidence of chronic atrophic gastritis was considerably higher in patients with Sjögren's syndrome than in the controls. In the young patients with Sjögren's syndrome atrophic lesions were more common both in the antrum and in the corpus than in the control group. In middle aged patients, however, only the antrum, and in the elderly only the corpus, was much more commonly affected than in the controls. All three types of chronic atrophic gastritis occurred in patients with Sjögren's syndrome. Decreased gastric acid secretion was associated mainly with atrophic gastritis of types A and AB, whereas hypergastrinaemia occurred almost exclusively in gastritis of type A.

Cardiac manifestations in primary Sjögren's syndrome.

OBJECTIVE: To determine cardiac manifestations in primary Sjögren's syndrome (SS). METHODS: Echocardiographic examination was undertaken in 64 patients (62 women, two men) with primary SS (54 definite (DSS) and 10 probable (PSS)) who had systemic symptoms. Twenty one healthy women volunteers of similar age acted as controls. RESULTS: Acute exudative pericarditis occurred in only one patient. An echogenic pericardium was demonstrated in 21 patients (19 DSS, two PSS) (33%) who had a previous symptom free pericarditis, but in none of the controls. Pulmonary pressure was significantly greater in the patients than in the controls (31 (SD 8) mm Hg compared with 24 (7) mm Hg), but there was no significant difference between the DSS and PSS groups. Left ventricular (LV) systolic function was similar in patients and controls. Twenty two patients (20 DSS, two PSS) and one control subject were excluded from LV diastolic function evaluation because of conditions likely to influence the parameters. Of the remaining 42 patients with SS (34 DSS, eight PSS), 21 (17 DSS, four PSS) had impaired diastolic function, confirmed by several diastolic parameters. LV diastolic dysfunction and echogenic pericardium occurred independently of each other, and there was no correlation between the occurrence of these silent cardiac abnormalities and the clinical and laboratory findings. CONCLUSIONS: Obvious cardiac involvement is rare in primary SS, but clinically silent manifestations (symptom free pericarditis and LV diastolic dysfunction) are common. The clinical and prognostic significance of these changes cannot yet be defined.

Parotid gland ultrasonography as a diagnostic tool in primary Sjögren's syndrome.

The diagnostic value of parotid gland ultrasonography (Acuson 128, 7 MHz transducer) was studied in 62 patients with primary Sjögren's syndrome (SS) and in 69 controls of similar age and sex distribution. Different degrees (mild, evident or gross) of parenchymal inhomogeneity (PIH) were the most important sonographic changes in SS; they occurred in 83.9% of the patients. The sonographic results (the presence or absence of PIH) were in accordance with the parotid sialographic and scintigraphic findings and the histology of the minor salivary glands in 87.3, 84.7 and 84.3% of the cases, respectively. Of the degrees of PIH, only evident and gross PIH are thought to be of true diagnostic value for SS. On the basis of the good agreement between the sonographic and sialographic results, consideration of the introduction of parotid sonography as an alternative to sialography is suggested in SS if the latter method cannot be performed.

Impaired microvascular response to cholinergic stimuli in primary Sjögren's syndrome.

OBJECTIVE: Signs of a parasympathetic dysfunction have been revealed in primary Sjögren's syndrome (SS). Its role in the pathogenesis and the clinical picture of the disease is not clear. To investigate the responsiveness of SS patients to a cholinergic agonist, a model was used involving examination of the cutaneous microcirculation. The microvascular response to the administration of carbachol was measured, a muscarinic cholinergic agonist. METHODS: Twenty two SS patients and 12 controls were examined. Carbachol and 0.9% saline solution were administered intracutaneously into the forearm skin at two distinct places. Skin blood flow (SBF) in the injected areas was measured continuously before and for 10 minutes after the injections by means of a laser Doppler perfusion monitor. The increase in SBF in response to carbachol (dSBF), reflecting vasodilatation, was calculated by a formula including the baseline and the maximum SBF values after the injections of carbachol and saline solution. RESULTS: The vasodilatation was significantly lower in SS patients than in the controls (mean dSBF: 2.1 (range: 1.0-4.5) versus 3.3 (range: 1.7-7.6), p=0.02). With non-responder patients defined as those in whom a smaller response was observed than in any of the controls, 11 of the 22 SS patients proved to be non-responders to carbachol. Comparisons of demographic, clinical and laboratory characteristics and HLA class II genotypes between responder and non-responder SS patients did not show any significant differences. CONCLUSIONS: A diminished or absent response to carbachol indicates a cholinergic dysfunction in SS patients. A disturbance in the neurotransmission at a receptorial or postreceptorial level is hypothesised. Unresponsiveness to cholinergic stimuli may contribute to exocrine insufficiency.