Vitamin D3 metabolism in patients with rheumatic diseases: low serum levels of 25-hydroxyvitamin D3 in patients with systemic lupus erythematosus.

1,25-dihydroxyvitamin D3 (1,25(OH)2 D3) has been shown to modulate lymphocyte activation in vitro. Through binding to specific receptors 1,25-(OH)2 D3 inhibits proliferation, immunoglobulin production and the release of cytokines. Moreover, 1,25-(OH)2 D3 is efficiently produced by activated monocytes. These findings suggest that 1,25-(OH)2 D3 may play a role as a regulator of immunological activation. Consequently, we found it of interest to study the serum levels of the two major metabolites of vitamin D3 in patients with systemic lupus erythematosus (SLE) (n = 21), rheumatoid arthritis (RA) (n = 29) and osteoarthritis (n = 12). In patients with SLE the levels of 25-OH D3 were below those of the healthy controls (p = 0.0008) and OA (p = 0.0168). The levels 1,25-(OH)2 D3 corresponded to normal levels. There were no significant correlations between 25-OH D3 levels and clinical or paraclinical disease manifestations. Further, the phenotypic distribution of Gc-globulin, which binds vitamin D3 metabolites in circulation, was normal. The serum concentrations of 1,25-(OH)2 D3 and 25-OH D3 in patients with RA and OA corresponded to those of the controls. Although the cause of the reduced 25-OH D3 levels in SLE patients is unclear, possible beneficial effects of administration of vitamin D to these patients should be considered.

Follow-up of 151 patients with high-titer U1RNP antibodies.

We performed a longitudinal follow-up study of clinical findings in 151 patients with high-titer antibodies against U1 ribonucleoprotein (U1RNP) as measured by haemagglutination. Formal connective tissue disease (CTD) diagnoses were assigned and diagnostic transitions analysed. One-hundred eighteen females and 33 males entered the study; the mean duration of follow-up was 7.1 years. Mean age at entry was 34.7 years; 73% of the patients had early disease (duration < 2 years). Fifty-six patients (37%) presented with a definite diagnosis, most often mixed connective tissue disease (MCTD, n = 40), followed by systemic lupus erythematosus (SLE, n = 11) and systemic sclerosis (SSc, n = 5). Of 84 patients (56%) presenting with nonspecific symptoms of possible, "undifferentiated" CTD, 58 developed MCTD, 4 SSc and 2 SLE. By the end of the follow-up period. 127 patients had developed a well-defined CTD; final diagnoses were: MCTD (n = 97), SLE (n = 18), SSc (n = 12). We conclude that CTD in the context of high-titer anti-U1RNP antibodies may be transitive and sequential in nature, although the diagnostic criteria for MCTD previously proposed by our group seem to delimit a clinically stable condition in most patients in this subgroup.

[Systemic lupus erythematosus. 1. Disease manifestations, infections, thrombotic episodes, causes of death and survival in a case load of 173 patients followed for 13.9 years]. / Systemisk lupus erythematosus. 1. Sygdomsmanifestationer, infektioner, trombotiske episoder, dødsåger og overlevelse i et materiale bestående patienter fulgt i gennemsnitlig 13,9 år.

One hundred and seventy-three patients had systemic lupus erythematosus according to the 1982-ARA-criteria. The mean disease duration at the time of the study was 16.4 years, and the patients were followed by three Copenhagen clinics for a mean of 13.9 years until 1987/88 or death. Half of the patients had nephropathy, 61 patients developed severe infections, and 39 patients had thrombotic episodes. Fifty-six patients died during the observation period, 24 due to active lupus (12 of kidney failure), 12 because of infections, and 11 because of atherosclerotic cardio-vascular disease. The patients had 10-, 15- and 20-year survival rates of 80, 65 and 48 per cent. The deaths were evenly distributed throughout the observation period.

[Systemic lupus erythematosus. 2. Factors of predictive significance for survival]. / Systemisk lupus erythematosus. 2. Faktorer med praediktiv betydning for overlevelsen.

Sixty-one of 173 patients with systemic lupus erythematosus followed for a mean of 13.9 years had severe infections which influenced their survival more than could be accounted for by the mortality (20 per cent) caused by the infections. Patients with infections had more SLE manifestations than patients without infections, and they died of lupus manifestations more often than patients without infections. Patients who went into a permanent remission and patients who died of lupus differed most markedly by the rates of infection. The rate of infection was increased more than tenfold in patients treated with high dosages of glucocorticoid compared with patients who received low dosages. Treatment with cytostatics influenced the rate of infections to a moderate degree. Nephropathy also influenced survival but half of the patients with nephropathy maintained a normal plasma creatinine in spite of the long observation period. 16 per cent of the patients with nephropathy died of kidney failure or are receiving chronic hemodialysis.

6-Thioguanine nucleotide accumulation in erythrocytes during azathioprine treatment for systemic connective tissue diseases: a possible index for monitoring treatment.

BACKGROUND: Owing to adverse pharmacokinetics, azathioprine treatment may fail to induce a satisfactory clinical response in systemic connective tissue diseases. The major intracellular cytotoxic metabolites of azathioprine are 6-thioguanine nucleotides (6TGNs). METHODS: To assess whether the erythrocyte accumulation of 6TGN is a clinically applicable index for monitoring azathioprine treatment, erythrocyte accumulation of 6TGN was measured in patients with rheumatoid arthritis (n = 12), systemic lupus erythematosus (n = 7), polyarteritis nodosa (n = 2), myositis (n = 1), or leukocytoclastic vasculitis (n = 1). Ages ranged from 28 to 75 (median 58) years. RESULTS: Erythrocyte accumulation of 6TGN varied among the patients from 20 to 303 (median value 95) nmol/mmol haemoglobin. No significant correlation was found between erythrocyte accumulation of 6TGN and the dose of azathioprine/kg body weight, the age of the patients, the duration of treatment, or the presence of myelotoxicity or hepatotoxicity. The interindividual coefficient of variation (CV) in the erythrocyte accumulation of 6TGN/mg azathioprine/kg body weight was 0.65. The median intraindividual CV in erythrocyte accumulation of 6TGN at an unchanged dose of azathioprine was 0.09 (19 patients; range 0.03-0.27). CONCLUSIONS: The low intraindividual variation compared with the high interpatient variation in erythrocyte accumulation of 6TGN implies that erythrocyte accumulation of 6TGN may be clinically applicable for monitoring azathioprine treatment. Prospective studies are needed to clarify the relation between the erythrocyte accumulation of 6TGN and the clinical response to treatment, and to establish recommendations for dose modifications.

Keratoconjunctivitis sicca in patients with primary Sjögren's syndrome. A longitudinal study of ocular parameters.

Thirty-four patients, all fulfilling the Copenhagen criteria for Primary Sjögren's Syndrome, were examined retrospectively in order to evaluate possible longitudinal alterations in Schirmer-1-test results, Rose-bengal score, break-up time and level of ocular score. Twenty-three of the patients were characterized as Bromhexine responders according to their initially positive response to systemic treatment (16 mg x 3 daily) and 11 patients were Bromhexine non-responders. All patients were treated with tear substitutes during the entire observation period of 27 to 76 months (mean 53 months), and all eye examinations were carried out by the same ophthalmologist. The responder group had, both in the start as well as at the end of the observation period, a better ocular status compared to the non-responder group. The latter group had a significantly (P less than 0.02) lower Schirmer-1-test at the start and at the end of the period, and a significantly (P less than 0.02) higher Rose-bengal score at the end of the period. Moreover, the responder group improved in Rose-bengal score (P less than 0.001), whereas the non-responder group improved both in break-up time (P less than 0.05) and Rose-bengal score (P less than 0.05). The use of a score combining results from all three tests, i.e. the ocular score, seems to be a useful tool when evaluating longitudinal variations i dry eye states. Considerable variation was seen between successive results of each ocular test, also in the periods without systemic treatment.

A follow-up study of pulmonary function in patients with primary Sjögren's syndrome.

Twenty-seven patients (25 women, 2 men) with primary Sjögren's syndrome, previously reported to have reduced pulmonary diffusing capacities were reexamined in a 7-year follow-up in order to evaluate longitudinal alterations in pulmonary function. Primary Sjögren's syndrome was diagnosed according to the Copenhagen criteria. The present examination revealed normal and unchanged values for vital capacity, forced expiratory volume in 1 s, maximal expiratory flow at 50% of expired vital capacity (MEF50), and diffusing capacity per liter alveolar volume. Total diffusing capacity (P less than 0.01) and MEF75 (P less than 0.05), were, however, significantly reduced compared with the predicted values, indicating pulmonary involvement primarily affecting the small airways. The longitudinal examination, furthermore, showed increasing values for total diffusing capacity (P less than 0.02), diffusing capacity per liter alveolar volume (P less than 0.001), and MEF75 (P less than 0.02), suggesting an improvement in lung status in the course of time. No correlation was found between MEF75 and diffusing capacities, nor between alterations in pulmonary function and complaints of dyspnoea, tiredness, cough, expectoration, tobacco smoking, or medical treatment with bromhexine, glucocorticosteroids, essential fatty acids, or nonsteroid antiinflammatory drugs.

Antibodies to urinary tract pathogens in patients with spinal cord lesions.

Chronic or recurrent urinary tract infection (UTI) is a significant problem or patients with spinal cord lesions (SCL). UTIs are thought to be a major factor in the development of reduced renal function. To investigate the pathogenesis 151 patients with SCL were included in this study during a 7 year period. Results of intravenous pyelography and isotope renography were recorded as well as the bladder emptying methods. One to seven blood samples were obtained from each patient and tested for plasma creatinine, and the presence of precipitating antibodies against Escherichia coli, Klebsiella pneumonia, Klebsiella ozaenae, Proteus mirabilis, Enterococcus faecalis and Pseudomonas aeruginosa. We found significant correlation between duration of SCL and precipitating antibodies against urinary tract pathogens (PAU) (r = 0.23, P < 0.005), between plasma creatinine and PAU in patients with spina bifida (r = 0.64, P < 0.01), between PAU and the number of positive urine cultures (r = 0.17; P < 0.05) and a relation between abnormal urological findings and PAU. In addition, the PAU was significantly higher in patients with indwelling urethral catheters (P < 0.001). Thus it seems that PAU can be of prognostic value in SCL patients, and PAU might be an indicator for intensified treatment of recurrent UTI.

An 8-year follow-up study of pulmonary function in patients with rheumatoid arthritis.

To evaluate longitudinal alterations in pulmonary function, 63 patients suffering from rheumatoid arthritis (RA) with previously reported reduced pulmonary diffusing capacity were re-examined in an 8-year follow-up study. Cross-sectional examination revealed normal values for vital capacity (VC), forced expiratory volume in 1 s (FEV1) and diffusing capacity per litre alveolar volume (KCO). Total diffusing capacity (DLCO; P < 0.0001), maximal expiratory flow at 75% of expired VC (MEF75; P < 0.0001) and MEF50 (P < 0.01) were decreased. Longitudinal evaluation revealed unchanged MEF50, MEF75 and FEV1, whereas increases in DLCO (P < 0.0001) and KCO (P < 0.0001) and a decrease in VC (P < 0.05) were found. The longitudinal changes in diffusing capacity were unrelated to patient age, disease duration, disease activity in the study period or pulmonary function at the first examination. Thus, in patients suffering from RA, the most prominent functional pulmonary abnormality, decreased diffusing capacity, appeared to improve in the course of time, despite a slight decrease in VC and continued articular disease activity.

Rose bengal score--a possible key parameter when evaluating disease level and progression in primary Sjögren's syndrome.

The rose bengal score is one of the most commonly used tests for evaluation of ocular surface epithelial damage. The test is used in most Sjögren's syndrome criteria. We examined 24 female and four male patients with primary Sjögren's syndrome (primary SS) in order to evaluate possible correlation between the various tests for keratoconjuncivitis sicca (KCS), and for possible correlations to xerostomia and p-IgG levels. Among the KCS tests a high rose bengal score appeared to be the key parameter, being correlated to low break-up time (P less than 0.01), low tear lysozyme (P less than 0.01), appearance of snake-like chromatin in conjunctival imprints (P less than 0.05), low sialometry (P greater than 0.01) and high p-IgG (P less than 0.01). We followed another group of patients with primary SS (30 females and four males) for a mean period of 53 (range 27-76) months. The patients were divided according to their initial response to systemic treatment with bromhexine. KCS parametres and p-IgG were measured repeatedly during the observation period. Patients responding to and continuously treated with bromhexine (2/3 of patients) improved significantly (P less than 0.05) in rose bengal score, but had increasing levels of p-IgG. Non-responders kept their low tear-production rate and had also increasing p-IgG levels. However, when subdivided according to p-IgG level, the group of patients with relatively low p-IgG improved in rose begal score, whereas the high p-IgG-group increased in rose bengal score. The rose bengal score appears to be a useful key parameter when evaluating disease level and progression.

A follow-up study of the progress of keratoconjunctivitis sicca and response to treatment in primary Sjögren's syndrome.

Thirty-four patients with Sjögren's syndrome were retrospectively examined in order to evaluate longitudinal alterations in objective ocular disease parameters and their possible relation to systemic bromhexine treatment. Twenty-three patients (68%) were initially found to respond to peroral bromhexine treatment and were subsequently treated with this agent in addition to tear substitutes. The other 11 patients (32%) were considered bromhexine non-responders and were treated with topical agents only. The bromhexine non-responders had a significantly (p less than 0.02) more reduced tear gland function, evaluated by the Schirmer-1 test, than the responder group. At the end of the follow-up period the conjunctival surface cells were significantly (p less than 0.02) more damaged in the bromhexine non-responders than in the responders. The bromhexine non-responders improved in both break-up time and van Bijsterveld score in the course of time while the responders improved in the van Bijsterveld score only. No differences as regards extraglandular disease manifestations, serological abnormalities or treatment with other systemic agents were found between the bromhexine responders and non-responders.