Antinuclear and antiphospholipid antibodies in patients with multiple sclerosis.

The prevalence of autoantibodies in multiple sclerosis (MS) patients and their clinical associations differ between various studies. This study investigated antiphospholipid and antinuclear antibodies in 85 patients with multiple sclerosis (MS) and clinically isolated syndrome (CIS) with regard to their association with demographic features, MS specific clinical features and symptoms of connective tissue diseases. Autoantibodies tested included antinuclear antibodies (ANA) with their specificities and anticardiolipin (aCL) and anti-beta-2-glycoprotein I (anti-ß2GPI) antibodies. Antinuclear antibodies were more prevalent in MS patients than in controls (63.5% vs. 3.3%; p < 0.01) and in 19% of patients specific antinuclear antibodies were detected. Anti-ß2GPI IgM antibodies were more frequent in MS patients than in the control group (20% vs. 3.3%; p < 0.05). The frequency of anticardiolipin antibodies did not differ between MS patients and controls. MS patients seropositive for ANA and extractable nuclear antigens (ENA) had significantly shorter disease duration than seronegative patients (p < 0.05) and a lower disability score (Expanded Disability Status Score; EDSS) (p < 0.05). Anti-ß2GPI antibodies were more frequent in patients with secondary progressive MS (SP-MS) and specific ANA antibodies were more frequent in patients with clinically isolated syndrome (CIS) (p < 0.05). The presence of autoantibodies was not associated with the predominant site of neurological involvement or the clinical features of connective tissue diseases.

Rheumatoid arthritis in a patient with common variable immunodeficiency: difficulty in diagnosis and therapy.

Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency syndrome in adults with equal sex prevalence. The syndrome typically presents as recurrent infections, with onset in childhood or young adulthood (between 20 and 30 years). CVID patients also have a higher prevalence of autoimmune diseases. A 38-year-old woman presented to the Rheumatology Department with polyarthralgia and fever of 39 degrees C of several months' duration. She had recurrent respiratory and gastrointestinal tract infections and pernicious anemia. Immunological studies showed decreased levels of IgG, IgM, complete IgA deficiency, increased percentage of CD8 lymphocytes, and a reduced CD4:CD8 ratio. HLA-DR typing was performed and we identified HLA-DRB1*01. Adequate intravenous immune globulin substitution as well as antibiotic and anti-inflammatory treatment resulted in the remission of arthritis. Hand radiograms repeated after 12 months showed narrowing of the intra-articular space in the right metacarpophalangeal and radiocarpal joints with multiple bone cysts and erosions. Erosions were found in both humeral heads as well. This prompted the diagnosis of rheumatoid arthritis. Arthritis can be a presenting symptom of primary immunodeficiency in adults, especially when accompanied by recurrent infections or autoimmune diseases. These patients require more advanced diagnostic procedures and therapeutic cooperation of different specialists.

Carotid sinus reflexes in rats given small doses of lead.

The effect of low level lead poisoning on the carotid sinus reflex in rats was studied. The reflex was evoked by carotid artery clamping, in control and lead-poisoned animals. Wistar rats were given lead acetate trihydrate (50 mg/kg) via stomach tube once weekly for 5 weeks; control animals were given equimolar amounts of sodium acetate. Both groups were fed a regular animal food diet. At the end of the 6th week, and under urethane anesthesia, mean arterial blood pressure and heart rate were continuously recorded for both groups, before and after clamping, and after unclamping the left common carotid artery. In other experiments, some animals were pre-treated with dopamine, 0.040 mg/kg; practolol, 3 mg/kg; propranolol, 0.1 mg/kg; or atropine, 0.1 mg/kg. In animals not given drugs, lead produced a less pronounced rise in mean arterial blood pressure after clamping, and a more pronounced decrease in heart rate after unclamping, compared to control animals. Some drugs altered this response pattern. Atropine led to a more pronounced tachycardia in the lead-poisoned rats, whereas practolol led to a more pronounced bradycardia in the lead-poisoned rats. Propranolol pretreatment led to a less pronounced decrease in heart rate for lead-poisoned rats, again as compared to the controls. Atropine and beta-adrenergic receptor blocking agents produced similar carotid sinus reflex responses in control and lead-poisoned animals.

Response of the cardiovascular system to catecholamines in rats given small doses of lead.

Experiments were done in order to assess the influence of low level lead poisoning in rats upon the responses of the rat cardiovascular system to perturbation by norepinephrine, epinephrine, and isoproterenol administration. Wistar rats were given lead acetate (50.0 mg/kg) via stomach tube once weekly for 5 weeks. Control rats were given sodium acetate similarly; both groups of rats were on a regular animal food diet during the experiment. At the end of the sixth week 2 types of responses were determined. Under urethane anesthesia, the response of mean arterial pressure and heart rate in control and lead-poisoned animals to various catecholamines was measured. Also the response of perfusion pressure in isolated mesenteric vessels, to catecholamines, was measured for vessels having been obtained from control and lead poisoned animals. Our results indicate that lead-treated rats, as compared to controls, have augmented and prolonged pressor responses to epinephrine and norepinephrine; less pronounced depression of arterial pressure in response to epinephrine and isoproterenol; and more pronounced tachycardia in response to isoproterenol. In the lead-treated rats, more pronounced vasoconstriction was observed in the perfusion studies upon administration of exogenous norepinephrine. Small doses of lead intensified alpha receptor response, diminished beta receptor response in blood vessels, and increased positive chronotropic action of isoproterenol.

Renal function in rheumatoid arthritis patients treated with methotrexate and infliximab.

OBJECTIVE: This study was aimed at monitoring the early and late effects of infliximab on renal proximal function in RA patients treated with methotrexate. N-acetyl-3-D-glucosaminidase (NAG) activity in urine served as an indicator of proximal tubular damage METHODS: NAG activity was estimated in 21 patients during the course of treatment with infliximab and methotrexate. In every patient NAG-enzymuria was estimated directly before and 60 min after infliximab infusions and 62 weeks after starting the therapy. RESULTS: The total of mean NAG activities observed before each infusion of infliximab was significantly lower (p < 0.02) than NAG-enzymuria before the start of infliximab treatment (7.4 UI/g vs 11.8 UI/g). The proportion of patients in whom NAG activity rose by more than 50% during treatment ranged from 5.3% to 25%. Administration of infliximab did not significantly change the mean serum creatinine levels or creatinine clearance. No significant differences were observed in the mean values of NAG values before and 60 min after infliximab infusion. Patients who demonstrated elevated NAG activities during the course of the whole treatment demonstrated significantly more pronounced NAG enzymuria before treatment and one hour after the first infusion (p < 0.0005), as well as higher RA activity (p < 0.05). There was no observed influence of NSAIDs or prednisone on the frequency of elevated NAG activities. Raised creatinine concentrations (> 1.3 mg/dL) were noted before and during the course of infliximab treatment in 3 patients. In 16 patients abdominal fat aspiration biopsy was performed and in 3 the presence of amyloid deposits was demonstrated. In these patients NAG activity exceeded twice the upper normal limit. CONCLUSION: The introduction of infliximab during methotrexate therapy demonstrated no early or delayed nephrotoxicity of the drug in patients with rheumatoid arthritis.

The effect of adrenal steroids on human erythrocyte phosphofructokinase.

Phosphofructokinase isolated from human erythrocytes incubated with cortisol showed alterations in regulatory properties. The enzyme was more sensitive to the inhibition by ATP and citrate. This effect was abolished by alanine. Similar changes in phosphofructokinase properties were found after incubation with aldosterone and corticosterone.

N-acetyl-beta-D-glucosaminidase enzymuria as an indicator in monitoring the therapy of some rheumatic diseases with potentially nephrotoxic drugs.

The measurement of NAG enzymuria by the spectrofluorimetric assay according to Merle et al. enables an early diagnosis of tubular dysfunction. Urinary NAG activity was determined in 13 patients with various rheumatic diseases during administration of potentially nephrotoxic drugs like nonsteroidal anti-inflammatory drugs (NSAID), aminoglycosides, gold salts, cyclosporin and steroids. The significant decrease of urinary NAG activity was common in patients with recently diagnosed rheumatic diseases, who received steroids. The decrease of NAG enzymuria was correlated with biochemical indices of inflammation like ESR or hemoglobin. The use of two types of potentially nephrotoxic drugs, like NSAID and gentamicin or NSAID with cyclosporin induced significant augmentation of NAG excretion. This occurrence may precede azotemia. The recognition of high NAG enzymuria permits to reduce dosage or discontinue treatment with potentially nephrotoxic drug prior to irreversible renal insufficiency as shown in the case of a patient with psoriatic arthritis treated with simultaneously administered cyclosporin and diclofenac.

Monitoring methotrexate therapy in patients with rheumatoid arthritis.

OBJECTIVE: The aim of this work was to study methotrexate (MTX) kinetics and their relation to the effectiveness of the therapy in patients with rheumatoid arthritis (RA). Other aims were to analyze the influence of MTX on liver, kidney, hematopoietic function and to determine the possibility of using early drug concentrations to predict the subsequent value of the treatment. MATERIAL AND METHODS: The observations were carried out in 49 patients with RA after the first dose of MTX and after 7 months of treatment. Methotrexate concentrations in blood serum and urine were determined using fluorescence polarization immunoassay applying a TDx Abbott analyzer. RESULTS: No correlation between concentrations, pharmacokinetic parameters and the duration of the disease, its activity, clinical symptoms, observations pertaining to the disease made by physician and patients and morning stiffness of joints was seen. Of those tests for the evaluation of liver, kidney and hematopoietic function, only the mean activity of N-acetyl-beta-D-glucosaminidase (NAG) in urine was significantly elevated both before and after treatment with MTX when compared to corresponding values in the control group of healthy subjects. We have formulated equations allowing for the early recognition of patients with a risk of adverse effects due to impaired elimination of MTX from the body. CONCLUSION: Our results show that monitoring MTX therapy using concentrations in patients with RA does not significantly improve the effectiveness of the treatment, but it can play an important role in increasing the safety of this drug.

N-acetyl-beta-D-glucosaminidase urinary excretion as an early indicator of kidney damage in rheumatoid arthritis patients starting on parenteral gold and Depo-Medrone/placebo injections.

The purpose of the study was to determine the effect of initiation of gold therapy on glomerular and tubular integrity. Urine albumin was used as a marker of glomerular damage. N-acetyl-beta-D-glucosaminidase (NAG) urinary excretion served as an indicator of proximal tubular damage. This study was an adjunct to a clinical trial that investigated the safety and the efficacy of Depo-Medrone during the induction phase of gold therapy. The NAG activities and albumin levels in the urine of 36 patients with active rheumatoid arthritis treated with sodium aurothiomalate weekly up to a total of 1 g were investigated. NAG was assayed in 565 early morning urine samples of these patients at weekly intervals for 24 weeks. The mean NAG level rose from 50.2 nmol/mg of creatinine on entry to peak NAG excretion of 120.4 nmol/mg of creatinine at week 4 and then fell to 56.3 nmol/mg of creatinine at week 24. Urinary albumin was assayed in 252 early morning urine samples at monthly intervals during gold treatment. Values greater than 20 mg/l were observed in 7.5% of urine samples. Microalbuminuria was present in 9% of patients at baseline. Two patients who were withdrawn because of proteinuria and macroalbuminuria had normoalbuminuria on entry. We conclude that raised levels of NAG associated with tubular damage are more frequent than glomerular damage on entry to, and during, treatment with gold salts.

Femoral neck and intertrochanteric fractures: radiographic indicators of fracture healing.

Serial hip radiographs from 280 patients with proximal femoral fractures were analyzed retrospectively by 3 radiologists to evaluate conventional radiographic healing patterns. Patients with hemiarthroplasty or insufficient follow-up were excluded. In the remaining 41 patients, the fracture line and callus was assessed. Intertrochanteric fractures demonstrated increasing callus and sclerosis at the fracture site. No such association was seen in femoral neck fractures. Traditional indicators of fracture healing cannot be readily applied at the hip. Radiographic features relate more to fracture type and fixation method.

[Endemic occurrence of lyme disease in the forested areas of the Pila district]. / Endemiczne wystepowanie choroby Lyme na terenach lesnych województwa pilskiego.

Lyme disease (L.D.) caused by Borrelia burgdorferi and spread by Ixodes ticks arouses great interest with more and more clinicians and other scientists. It may be very difficult to diagnose a disease as L.D. because of its various clinical symptoms expressions. This is why it is often called "the great imitator". There are three phases in the natural history of the disease. Diagnostic problems come from the fact that early phases are often lacking. The disease may begin with any symptom of any stage. In our paper we present the endemicity of Lyme disease among a group of 28 people who spent their summer holidays on a forest camp near Pila (in the north-western part of Poland) in July 1991. We diagnosed 15 of them as having early stages of L.D.

[Ankylosing spondylitis in Central and Eastern Europe. Cross-sectional study on treatment modalities, disease activity and quality of life]. / Ankylosierende Spondylitis in Mittel- und Osteuropa. Querschnittsstudie zu Behandlungsmustern, Krankheitsaktivität und Lebensqualität.

OBJECTIVES: To obtain information on the profile of patients with ankylosing spondylitis (AS), disease activity, previous and current treatments, and the proportion and profile of patients treated with conventional medications but considered eligible for anti-tumour necrosis factor (TNF) therapy. METHODS: Participants were rheumatologists from seven Central and Eastern European countries who were considered experts in the treatment of AS and were to include 3-5 patients who had never received anti-TNF therapy. Rheumatologists were asked to decide whether they considered their patients candidates for anti-TNF therapy. RESULTS: A total of 1506 patients were analysed. Overall, 61% of AS patients who had never received anti-TNF therapy until the time of the survey were considered candidates for anti-TNF therapy based on the clinical judgement of their rheumatologists. This proportion ranged from 40% in Slovakia to 84% in Romania. Candidates had higher levels of disease activity and functional impairment, and they were more likely to report a lower quality of life. Only 38% of candidates fulfilled the Assessment in Ankylosing Spondylitis (ASAS) recommendations with respect to a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) of at least 4 combined with previous use of at least two non-steroidal anti-inflammatory drugs, ranging from 18% in Poland to 57% in Hungary. CONCLUSION: More than half of AS patients currently treated with other medications may be eligible for anti-TNF therapy. Also, rheumatologists regarded disease activity as the determining factor for starting anti-TNF drugs, but their decision did not always fully comply with the ASAS recommendations, confirming the need for continued exchange among the medical community to increase awareness of the ASAS recommendations.

Synovial fibronectin fragmentation and domain expressions in relation to rheumatoid arthritis progression.

OBJECTIVE: To determine whether the expression of some fibronectin (FN) domains and a degree of FN degradation are associated with the progression of rheumatoid arthritis (RA). METHODS: Based on the radiographs of the hands of RA patients, three groups of synovial fluid and plasma samples were distinguished: (i) those with early radiological changes, (ii) established and (iii) late progressive radiological changes. The expressions of FN domains were determined by ELISA using appropriate domain-specific monoclonal antibodies. FN fragmentation was analysed by immunoblotting. RESULTS: In the early RA group, synovial FN was found to be totally degraded to a mixture of FN fragments. In the established group, it consisted of a portion of intact FN molecules and a smaller part of FN fragments, whereas in the late group the synovial FN immunoblotting pattern was similar to that of intact FN. The FN fragmentation was accompanied by decreases in FN immune reactivity with monoclonal antibodies specific to the collagen, fibrin and C-terminal FN domains. In the blood plasma of all studied groups of RA patients, the FN immunopattern was analogous to that in normal plasma. However, the expressions of the plasma FN domains were higher than those of healthy individuals. CONCLUSIONS: Profound degradation of FN and low collagen, fibrin and C-terminal domain expressions in FN were only associated with early destructive changes observed in radiographs of the RA patients' hands.

Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate.

OBJECTIVE: To establish the safety and efficacy of repeat infusions of tocilizumab (previously known as MRA), a humanized anti-interleukin-6 (IL-6) receptor antibody, alone and in combination with methotrexate (MTX), for the treatment of rheumatoid arthritis (RA). METHODS: The study group comprised 359 patients with active RA in whom the response to MTX was inadequate. During a stabilization period, these patients received their current dose of MTX for at least 4 weeks. Following stabilization, they were randomized to 1 of 7 treatment arms, as follows: tocilizumab at doses of 2 mg/kg, 4 mg/kg, or 8 mg/kg either as monotherapy or in combination with MTX, or MTX plus placebo. RESULTS: A 20% response (improvement) according to the American College of Rheumatology criteria (ACR20 response) was achieved by 61% and 63% of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy, respectively, and by 63% and 74% of patients receiving those doses of tocilizumab plus MTX, respectively, compared with 41% of patients receiving placebo plus MTX. Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX (P < 0.05). A dose-related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward, in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab. In the majority of patients who received 8 mg/kg of tocilizumab, the C-reactive protein level/erythrocyte sedimentation rate normalized, while placebo plus MTX had little effect on these laboratory parameters. Tocilizumab was mostly well tolerated, with a safety profile similar to that of other biologic and immunosuppressive therapies. Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern (rising and falling between infusions). There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high-density lipoprotein cholesterol and neutrophil levels. There were 2 cases of sepsis, both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX. CONCLUSION: These results indicate that targeted blockade of IL-6 signaling is a highly efficacious and promising means of decreasing disease activity in RA.

Etanercept 50 mg once weekly is as effective as 25 mg twice weekly in patients with ankylosing spondylitis.

OBJECTIVE: To compare the efficacy, pharmacokinetics and safety of etanercept 50 mg once weekly with 25 mg twice weekly and placebo in patients with ankylosing spondylitis. METHODS: A 12-week, double-blind, placebo-controlled study compared the effects of etanercept 50 mg once weekly, etanercept 25 mg twice weekly and placebo in 356 patients with active ankylosing spondylitis (3:3:1 randomisation, respectively). The primary end point was the proportion of patients achieving a response at week 12 based on the Assessment in Ankylosing Spondylitis Working Group criteria (ASAS 20). The pharmacokinetics of etanercept 50 mg once weekly and 25 mg twice weekly were analysed. RESULTS: Baseline characteristics and disease activity were similar among the three groups: etanercept 50 mg once weekly, etanercept 25 mg twice weekly and placebo. The percentage of patients discontinuing therapy was 9.0%, 9.3% and 13.7% for the three respective groups. ASAS 20 response at 12 weeks was achieved by 74.2% of patients with etanercept 50 mg once weekly and 71.3% of those with etanercept 25 mg twice weekly, both significantly higher than the percentage of patients taking placebo (37.3%, p<0.001). Percentages of patients with ASAS 5/6 response (70.3%, 72.0% and 27.5%, respectively; p<0.001) and those with ASAS 40 response (58.1%, 53.3% and 21.6%, respectively; p<0.001) followed a similar pattern. Significant improvement (p<0.05) was seen in measures of disease activity, back pain, morning stiffness and C reactive protein levels as early as 2 weeks. Serum etanercept exposure was similar between the etanercept groups. Incidence of treatment-emergent adverse events, including infections, was similar among all three groups, and no unexpected safety issues were identified. CONCLUSIONS: Patients with ankylosing spondylitis can expect a comparable significant improvement in clinical outcomes with similar safety when treated with etanercept 50 mg once weekly or with 25 mg twice weekly.

A randomised, placebo controlled, comparative trial of the gastrointestinal safety and efficacy of AZD3582 versus naproxen in osteoarthritis.

OBJECTIVE: To evaluate the gastrointestinal safety and efficacy of the COX inhibiting nitric oxide donator AZD3582 in patients with hip or knee osteoarthritis. METHODS: 970 patients were randomised (7:7:2) to AZD3582 750 mg twice daily, naproxen 500 mg twice daily, or placebo twice daily in a double blind study. The primary end point was the six week incidence of endoscopic gastroduodenal ulcers (diameter > or =3 mm). Overall damage measured on the Lanza scale was a secondary end point. Safety and tolerability assessments included endoscopic upper gastrointestinal erosions and the gastrointestinal symptom rating scale (GSRS). Efficacy was primarily assessed by WOMAC. RESULTS: The incidence of ulcers with AZD3582 was 9.7% and with naproxen 13.7% (p = 0.07, NS), v 0% on placebo. The incidence of Lanza scores >2 was higher with naproxen (43.7%) than with AZD3582 (32.2%) (p<0.001). Compared with baseline, significantly fewer ulcers and erosions developed in stomach and stomach/duodenum combined, and fewer erosions developed in stomach, duodenum, and both combined on AZD3582 than on naproxen. GSRS reflux and abdominal pain subscale scores were lower for AZD3582 than for naproxen but there was no difference for indigestion, constipation, and diarrhoea. AZD3582 was as effective as naproxen at improving WOMAC scores. Both agents were well tolerated, with no significant effects on blood pressure. CONCLUSIONS: At doses with similar efficacy in relieving osteoarthritis symptoms, the primary end point of six week endoscopic gastroduodenal ulcer incidence was not significantly different between AZD3582 and naproxen. Most secondary endoscopic gastrointestinal end points favoured AZD3582.

Our experience with Lyme arthritis.

Since 1975, when first described, Lyme disease becomes more and more interesting and complicated medical problem. One of the "classical features" of the disease is arthritis. Based upon our own experience we described and discuss the diagnosis, treatment and outcome of three patients with Lyme arthritis.