Quantitative assessment of betamethasone dual-acting formulation in urine of patients with rheumatoid arthritis and ankylosing spondylitis after single-dose intramuscular administration and its application to long-term pharmacokinetic study.

Quantitative evaluation and assessment of pharmacokinetic parameters of Diprospan® (suspension for injection 7mg/mL (2mg+5mg/mL) of betamethasone) were performed in urine samples taken from patients with rheumatoid arthritis or ankylosing spondylitis for 28days after systemic intramuscular administration in routine clinical practice in an open-comparative prospective cohort study. The maximum betamethasone concentration was reached at day 4 of the follow-up; in some cases, ß-phase of elimination of the drug was appeared at day 14 or at day 21 of the follow-up. The deferred ß-phase elimination was likely a consequence of the physiological characteristics of the patients or of the influence of non-steroidal agents. The half-life of betamethasone was 8.5days. The elimination rate constant was 2.49h-1; the mean clearance was 4.72L/d. The recommended frequency of the drug administration to its complete elimination was estimated up to 48days. Mann-Whitney test showed no significant differences in pharmacokinetic characteristics between male and female subjects. The prolonged elimination phase was observed in patients with deviations in their body mass index, continual treatment by diclofenac and nimesulide or, possibly, after consuming an alcohol. The study was recorded in Clinical Trials open source with identifier NCT03119454.

Risk factors for urolithiasis in patients with ankylosing spondylitis: a prospective case-control study.

It has been reported that renal stone formation increased in patients with ankylosing spondylitis (AS). However, its reason remains unclear. The aim of this study was to evaluate serially the possible risk factors for renal stone formation in AS patients. Two groups consisted of AS patients with renal stone (n = 30), AS patients without renal stone (n = 30), and 20 healthy controls (HC) were included to the study. Parathyroid hormone, calcium, magnesium, phosphorus and immunoglobulin A levels and 24 h urine were evaluated at baseline, and three times monthly. Serum calcium levels were higher in AS patients with urolithiasis than those without at baseline and third-month evaluation (baseline: 9.53 ± 0.3 vs 9.32 ± 0.3 mg/dl; p < 0.03; at third-month evaluation: 9.74 ± 0.2 vs 9.56 ± 0.3 mg/dl; p < 0.01). No significant differences were found between groups in terms of PTH and magnesium levels. In all evaluation times, although urinary calcium excretion was higher in AS patients with urolithiasis than in those without, it did not reach a statistical significance. IgA levels were significantly higher in renal stone sufferers than HC patients in all evaluation times.AS patients with urolithiasis also had high IgA levels compared with AS patients without renal stone at the second-month evaluation time (276 ± 102 vs 219 ± 104 mg/dl, p < 0.002). Increased levels of serum calcium and IgA levels as well as family history for urolithiasis may be an indicator of the development of urolithiasis in AS patients.

Relationship of environmental exposures and ankylosing spondylitis and spinal mobility: US NHAENS, 2009-2010.

It was aimed to study the relationships of different sets of urinary environmental chemical concentrations and ankylosing spondylitis in a national and population-based setting. Data were extracted from United States National Health and Nutrition Examination Surveys, 2009-2010. Information on demographics was obtained by household interview and ankylosing spondylitis clinical measures and urines were taken at examination. People with abnormal occiput-to-wall distance were found to have higher urinary cadmium (OR 2.17, 95 % CI 1.34-3.52, p = 0.004), antimony (OR 1.74, 95 % CI 1.15-2.62, p = 0.012), tungsten (OR 1.91, 95 % CI 1.39-2.64, p = 0.001), uranium (OR 1.49, 95 % CI 1.03-2.15, p = 0.036), and trimethylarsine oxide (OR 5.01, 95 % CI 2.34-10.71, p < 0.001) concentrations. Moreover, people who resided in older households tended to have abnormal ankylosing spondylitis clinical measures, compared to those who resided in households that were built in 1990 or after. The odds were 1.74 for households built in 1978-1989 and 1.81 for those built in 1940 or earlier.

Beneficial effects of adalimumab on biomarkers reflecting structural damage in patients with ankylosing spondylitis.

OBJECTIVE: We analyzed the effects of adalimumab on biomarkers predictive of structural damage in inflammatory arthritis. METHODS: In a 24-week randomized controlled trial, patients with active ankylosing spondylitis (AS) received adalimumab 40 mg or placebo every other week. Efficacy measures included ASsessment in Ankylosing Spondylitis International Working Group response, Bath AS Disease Activity Index (BASDAI), Total Back Pain, Bath AS Functional Index, C-reactive protein (CRP), and patient's global assessment of disease activity. Urinary type II collagen C-telopeptides (CTX-II), serum type I collagen N-telopeptides (NTX), and serum metalloproteinase-3 (MMP-3) were assessed using ELISA for treatment-group differences at baseline, 12, and 24 weeks. We determined correlations between changes in biomarkers and AS efficacy outcomes. RESULTS: A total of 82 patients (38 adalimumab, 44 placebo) enrolled. At 12 and 24 weeks, significant reductions in urinary CTX-II and MMP-3, but not NTX concentrations, were observed for adalimumab versus placebo (p<0.001). Significant baseline correlations were noted between CRP and CTX-II (r=0.71), MMP-3 (r=0.45), and NTX (r=0.37) (p

Association of markers of bone- and cartilage-degradation with radiological changes at baseline and after 2 years follow-up in patients with ankylosing spondylitis.

OBJECTIVE: There is a lack of knowledge on factors that reliably can predict radiological changes in patients with AS. We have investigated whether urinary C-terminal cross-linking telopeptide of type I (CTX-I) and type II (CTX-II) collagen, as specific biochemical markers of bone and cartilage degradation, respectively, are associated with radiological damage and progression, and with BMD in patients with AS. METHODS: Eighty-three patients with AS [mean (s.d.) age: 50.4 (12) yrs, 65% male, mean (s.d.) disease duration after diagnosis: 16.7 (10) yrs] who participate in an ongoing cohort study of patients with AS [Outcome in AS International Study (OASIS) cohort] were assessed for urinary CTX-I and -II. Results of both biochemical markers were compared with baseline scores for radiological damage (modified modified Stoke Ankylosing Spondylitis Spine Score, primarily reflecting syndesmophyte-formation and -growth), and with scores for radiological progression after 2 yrs follow-up. Markers were also associated with disease activity parameters and BMD. RESULTS: Mean duration of complaints was 28.6 yrs. At that time, 54% of patients had signs of radiological damage, and 35% of them showed radiological progression after 2 yrs. Baseline radiological damage (rho = 0.24; P

Factors modifying collagen catabolism in patients with ankylosing spondylitis.

OBJECTIVE: We quantified the total excretion of the collagen crosslinks (CL) pyridinoline (PYD) and deoxypyridinoline (DPD) in 108 ankylosing spondylitis (AS) patients (29 f, 79 m) in correlation to different characteristics of disease to evaluate different mechanism contributing to development of osteoporosis in AS. METHODS: PYD and DPD were measured by HPLC. RESULTS: AS patients show a highly significant positive correlation between PYD and inflammatory activity. In cases involving peripheral joints, significantly higher CL levels in urine were found. Patients with syndesmophytes excreted significantly more CL vs. those without. In the more advanced stages of sacroiliitis (stage III and IV), CL levels tended to be higher. Among those patients treated with NSAIDs, a tendency to decreased levels of DPD and consecutive raised levels of the quotient PYD/DPD were observed. No significant correlation was found between restricted spine mobility or duration of disease and amount of excreted CL. CONCLUSIONS: Our investigations show that the inflammatory process, the involvement of the peripheral joints, the presence of syndesmophytes and the stage of sacroiliitis all have an influence on the extent of collagen degradation in AS patients. NSAIDs do not increase but appear to reduce collagen I catabolism.

[Collagen breakdown in ankylosing spondylitis-relationship to disease related parameters]. / Kollagenabbauaktivität bei Spondylitis ankylosans in Beziehung zu krankheitsrelevanten Daten.

OBJECTIVE: Patients with ankylosing spondylitis (AS) often develop osteoporosis particularly of the axis skeleton. To investigate disease-related or therapeutic influence on bone catabolism, we quantified the total excretion of the collagen crosslinks (CL) pyridinoline (Pyd) and deoxypyridinoline (Dpyd) in 91 AS patients (26 f, 65 m) in relation to disease activity or stage and therapy with NSAID. METHODS: CL were determined by HPLC (High Performance Liquid Chromatography). RESULTS: The AS patients show a highly significant positive correlation between Pyd and the inflammatory activity (CrP, r = 0.36, p < 0.001: ESR, r = 0.379, p < 0.001). Also the quotient Pyd/Dpyd correlates positively to the inflammatory activity (CrP, r = 0.262, p < 0.001: ESR, r = 0.325, p < 0.002). In the case of increased inflammatory disease activity (CrP > or = 10 mg/l vs CrP < 10 mg/l or ESR > or = 10 30 mm vs ESR < 30 mm), Pyd excretion is raised significantly (p < 0.042 for CrP and p < 0.009 for ESR). Among those patients treated with NSAID therapy, significantly reduced levels for Dpyd (p < 0.001) and raised levels for the quotient Pyd/Dpyd (p < 0.002) appear. In the case of advanced radiological changes with evidence of syndesmophytes, Pyd (p = 0.014) and Dpyd (p < 0.004) were significantly raised in urine. Regarding the movement function (finger-floor distance, schober test), no significant correlation to crosslink excretion could be proven. CONCLUSION: From our investigations, we assume that osteoporosis in AS is primarily caused by an inflammatory-mediated degradation of bone.

Bilateral hip arthroplasty for ochronotic arthropathy.

Ochronosis is a musculoskeletal manifestation of alkaptonuria, a rare hereditary metabolic disorder characterised by the absence of the enzyme homogentisic acid oxidase and associated with various systemic abnormalities related to the deposition of homogentisic acid pigment (ochronotic pigment). In this report, we describe a 53-year-old, HLA-B27(+) woman with ochronotic arthropathy. In addition to the typical clinical features of the disorder, she had bilateral hip involvement, which was improved by cementless total hip prosthesis.

Prevalence of Chlamydia trachomatis in urine of male patients with ankylosing spondylitis is not increased.

OBJECTIVE: To compare the prevalence of Chlamydia trachomatis infections in ankylosing spondylitis (AS) patients with controls, using DNA amplification assays in urine specimens. METHODS: The prevalence of C trachomatis infections was assessed in 32 male AS patients and 120 age and sex matched controls. Urine specimens were tested by ligase chain reaction and polymerase chain reaction. In addition, blood samples of AS patients were tested on serum antibodies to C trachomatis (IgA and IgG) by a specific peptide based solid phase enzyme immunoassay. A questionnaire was used to assess the differences in sexual behaviour and ethnic origin between the two groups. AS patients were also asked about disease characteristics. RESULTS: No significant differences were found between cases and controls in the prevalence of C trachomatis infections. No associations were found between C trachomatis antibodies and disease characteristics, except for acute anterior uveitis (AAU). Four of eight (50%) AS men positive for IgG had a history of AAU in comparison with three of 24 (12.5%) IgG negative men (OR = 7.0; 95% confidence intervals: 1.1, 44.1). CONCLUSION: The prevalence of Chlamydia trachomatis infections, as detected by commercially available DNA amplification assays in urine specimens, in AS patients is not higher compared with male controls of the same age. However, there seems to be an association between specific antibodies to C trachomatis and AAU.

Relationship between urinary pyridinium cross-links, disease activity and disease subsets of ankylosing spondylitis.

OBJECTIVE: In this study, we aimed to determine the urinary levels of pyridinium cross-links and urinary beta-isomerized fragments derived from the C-telopeptide of the alpha1 chain of type I collagen (beta-CTX) as markers of bone resorption in patients with ankylosing spondylitis (AS), and to study their relationship to markers of disease activity [erythrocyte sedimentation rate (ESR)] and to disease subsets of this condition. METHODS: The serum calcium, osteocalcin (OC), parathormone (PTH), 25 OHD3 levels, beta-CTX and the urinary combined free pyridinolines (f-Pyr + f-Dpyr), urinary free deoxypyridinoline (f-Dpyr) and urinary free pyridinoline (f-Pyr) were evaluated and compared in 32 AS patients and 25 controls. Bone mineral density (BMD) was evaluated at the lumbar spine and the femoral neck. RESULTS: The serum markers of bone metabolism (serum calcium, PTH, 25 OHD3 and OC) were in the normal range in the AS group. AS patients had a lowered lumbar spine BMD (P = 0.01) (corresponding T score: P = 0.03), but femoral neck BMD did not differ significantly between AS and controls (P = 0.08) (corresponding T score: P = 0.11). There was no difference in the urinary levels of pyridinium cross-links and beta-CTX between AS patients and controls. A positive correlation between ESR, (f-Pyr + f-Dpyr) (r = 0.42; P = 0.018) and f-Dpyr (r = 0.49; P = 0.005) was observed. In the different disease subsets of AS, we found that patients with peripheral involvement had higher (f-Pyr + f-Dpyr) (P = 0.04) and f-Dpyr levels (P = 0.04), patients with early disease had elevated (f-Pyr + f-Dpyr) (P = 0.01), f-Dpyr (P = 0.02) and f-Pyr (P = 0.01) levels, and that those with raised ESR had enhanced f-Dpyr (P = 0.009) excretion. Patients were then stratified according to disease duration, peripheral involvement and sex, and this allowed us to observe that only urinary f-Dpyr remained elevated in patients independently from these variables and that raised ESR is the more relevant parameter for explaining this high level of excretion. CONCLUSION: We conclude that there was no difference in the levels of urinary pyridinium cross-links and beta-CTX between AS and controls. However, urinary excretion of some of these collagen compounds was enhanced in subgroups of AS, mainly in patients with raised ESR. Thus, AS patients with laboratory evidence of active disease could have a higher risk of bone loss.

Urinary glucaric acid excretion in rheumatoid arthritis: influence of disease activity and disease modifying drugs.

OBJECTIVE: To examine if a correlation exists between cytochrome P-450 enzyme induction and disease activity in patients with rheumatoid arthritis (RA), measuring urinary excretion of D-glucaric acid (GA) as an index of phase II drug metabolism. METHODS: Patients with RA were treated with sulphasalazine, sodium aurothiomalate, or D-penicillamine in standard dose regimens, for 24 weeks. Patients with ankylosing spondylitis (AS) or non-inflammatory arthritis (NIA) acted as controls. The urinary GA:creatinine ratio was measured at 0, 12, and 24 weeks of treatment. RESULTS: Patients with RA had a slightly greater urinary GA:creatinine ratio than patients with AS or NIA at baseline; this increased during treatment with disease modifying antirheumatic drugs (DMARDs). Sulphasalazine treatment had a greater effect on GA excretion than sodium aurothiomalate or D-penicillamine; this difference was statistically significant between weeks 0 and 12 (p = 0.01). Gamma glutamyltranspeptidase concentration showed a weak correlation with GA excretion between weeks 0 and 12 (p = 0.03), but all other measurements of changes in disease activity (plasma viscosity, C reactive protein, platelets, and articular index) were found not to correlate with GA excretion between weeks 0-12 or 0-24. CONCLUSION: The increased excretion of GA in patients with RA receiving DMARD treatment is probably the result of an indirect effect on hepatic metabolism bearing no relationship to disease activity.

Evidence of impaired cartilage/bone turnover in patients with active ankylosing spondylitis.

OBJECTIVES: To compare serum markers of bone formation with the urinary excretion of pyridinium crosslinks (PYR) as a possible measure of bone and cartilage degradation which would detect changes in bone metabolism in patients with ankylosing spondylitis (AS) and to relate them to influences of inflammatory disease activity, and to treatment. METHODS: In 62 patients with AS, serum osteocalcin, alkaline phosphatase (ALP), and skeletal ALP isoenzyme levels were evaluated concurrently in comparison with urinary excretion of pyridinium cross links and were compared with values in 50 healthy controls. RESULTS: Osteocalcin concentrations in AS patients were in the middle normal range (3.5 (SD 1.2) ng/ml) and did not differ significantly from those in control subjects (4.2 (1.3) ng/ml); the same was true for ALP and skeletal ALP isoenzyme fraction (AS: ALP 149 (50.3) U/l, skeletal ALP 12.8 (4.1) micrograms/l; controls: ALP 133 (25.2) U/l, skeletal ALP 11.9 (4.3) micrograms/l). The urinary levels of PYR in AS (51.2 (25.2) nmol PYR/mmol creatinine) were significantly increased compared with controls (33.9 (12.4) nmol PYR/mmol creatinine (p < 0.001)). In the AS group there was a positive correlation between urinary excretion of PYR and inflammatory disease activity (erythrocyte sedimentation rate (ESR)) (r = 0.6, p < 0.0001) and C reactive protein (CRP) (r = 0.3, p = 0.02), but no significant correlation was found with ESR, CRP, and markers of bone formation. CONCLUSIONS: Bone metabolism in patients with AS is characterised by normal bone formation and enhanced cartilage/bone degradation, suggesting that impaired bone turnover is pronounced in active disease. The results clearly indicate that this comparison can be used to demonstrate impairment of cartilage/bone metabolism which correlates with disease activity. The data obtained further emphasise the importance of measuring both serum variables and urinary excretion of PYR crosslinks to obtain adequate evaluation of cartilage/bone metabolism in patients with AS.

Urinary glycosaminoglycan excretion in rheumatic diseases.

We used Alcian Blue (AB) and dimethylmethylene blue (DMB) methods to measure glycosaminoglycan (GAG) excretion in the first morning urine specimens of patients with osteoarthritis (OA), ankylosing spondylitis (AS), and rheumatoid arthritis (RA) in different stages of disease. By the AB method, urinary GAG excretion in patients with RA was not different from healthy control subjects. However, the DMB method showed significant differences (in milligrams of GAG per gram of creatinine) for OA (median 25.4, range 14.3-44.0, P less than 0.01, n = 23) and RA patients (median 33.0; range 10.0-147.6; P less than 0.001, n = 63) in comparison with unaffected individuals (median 20.2; range 8.9-41.4, n = 38). We noted a significant difference in urinary GAG excretion between RA and OA patients (P less than 0.01) and between RA and AS (P less than 0.01) patients. The DMB method was further investigated by clinical decision analysis. The DMB method is simple and rapid and may be useful in diagnosing RA by distinguishing between RA and OA or AS.

Osteoporosis in early ankylosing spondylitis: a primary pathological event?

Patients with severe ankylosing spondylitis of long duration often have spinal osteoporosis secondary to ankylosis and immobility. Bone mineral density of defined regions of the lumbar spine, femoral neck, and carpus was measured in 25 men who met accepted diagnostic criteria for ankylosing spondylitis but had early disease, with normal mobility and no, or very minor, radiological evidence of lumbar spine involvement. Compared with age-matched male controls, patients with ankylosing spondylitis had a significantly lower hydroxyapatite density in the lumbar spine (mean [SD] 0.82 g/cm2 [0.12] vs 0.91 g/cm2 [0.11]) and in the femoral neck (0.83 g/cm2 [0.11] vs 0.92 g/cm2 [0.11]). There was no significant difference in carpal bone mineralisation density. The pattern of bone loss in these patients indicates early loss of trabecular bone in ankylosing spondylitis, possibly from a systemic cause, but biochemical indices of calcium turnover were similar in patients and controls.

[Hyaluronic acid and N-terminal procollagen-III-peptide in the urine in inflammatory and degenerative joint diseases]. / Hyaluronsäure und N-terminales Prokollagen-III-Peptid im Urin bei entzündlichen und degenerativen Gelenkerkrankungen.

In a cross-sectional study of 130 patients (main diagnosis: rheumatoid arthritis, n = 41, osteoarthritis, n = 39; ankylosing spondylitis, n = 28) we measured the concentrations of hyaluronan (HA) and the N-terminal propeptide of type-III collagen (NP III P) in urine and evaluated the relationship with their serum levels. Increased HA levels in serum correlated with increased urinary excretion (r = 0.69 for patients with active rheumatoid arthritis). Only patients with rheumatoid arthritis showed significantly elevated HA concentrations in urine (mean = 1,493 micrograms/mmol creatinine). Because of relatively wide fluctuations in urinary HA in normals (mean = 944, standard deviation 818 micrograms/mmol creatinine) and only modest differences between groups, the diagnostic accuracy of urinary HA measurements is inferior to serum determinations. NP III P showed no significant differences between patients and controls (means 10.5 to 15 micrograms/mmol creatinine). Obviously, renal excretion is of minor importance in the metabolism of HA and NP III P. The possible diagnostic usefulness of determinations of these parameters in serum is not enhanced by measurements in urine.

Renal affection in patients with ankylosing spondylitis and psoriatic arthritis.

In a retrospective study of 148 patients with well-defined ankylosing spondylitis (AS), psoriatic arthritis (PSA) or reactive arthritis (ReA) an 11% prevalence of idiopathic hematuria, proteinuria, or cylinduria was found in the former two groups. None of the patients with ReA had unexplained pathological urinary findings. Such findings were associated with raised ESR and presence of peripheral arthritis in AS and with the duration of disease in PSA. No patient lacking sacroiliitis showed pathological urinary findings. We believe that such findings may reflect nephropathy associated with AS and PSA.

[Calcium, phosphorus, hydroxyproline and nitrogen in inflammatory joint diseases]. / Zum Studium des Calciums, Phosphors, Oxyprolins und Stickstoffs bei entzündlichen Gelenkerkra nkungen

The elimination of calcium, phosphorus, hydroxyproline and nitrogen was studied in 127 patients with inflammatory joint diseases and )6 healthy controls for 4 days. On the third day, 186 mg of calcium was administered intravenously. Provoked hypercalciuria tests were made in 35 males, 116 females with rheumatiod arthritis (RA), 18 males with ankylosing spondylitis (ASp), 8 postinfectious arthritis (PA) and 18 healthy controls (C). In 120 patients comparison was made between the ratios of eliminated P/hydroxyproline, Ca/hydroxyproline and P/Ca with regards to the results obtained in healthy controls. The kinetics of 47Ca were studied in 7 males with ASp and 4 C. The ratios Ca/P in serum and P/Ca in urine were studied in the same patients and compared with 21 C. The results show that the bone symptomatology of PA manifests itself by elimination of elevated amounts of all of the indicators studied, especially phosphorus. In RA there may be considerable oscillations of flow of urine due to the perspiration of patients. RA differs from decompensated coxarthrosis and gonarthrosis in that the patients eliminate significantly less calcium and phosphorus. Corticosteroids stimulate the elimination of hydroxyproline. Younger patients with RA (25-44) show changes compatible with osteoporosis, older females (45-64) display changes similar to those seen in osteomalacia, the oldest female patient (65-84) appear to have insufficient binding capacity for calcium. The hyposthesis is proposed that at the disease onset RA is characterized by an extremely marked syndrome of osteopathy. ASp is characterized by significantly reduced elimination of hydraxyproline, higher metabolic pool of calcium, lower elimination of calcium in urine and faeces and lower accretion to bone.