Serum golimumab concentration and anti-drug antibodies are associated with treatment response and drug survival in patients with inflammatory joint diseases: data from the NOR-DMARD study.

Objectives: This study aimed to identify the therapeutic target concentration and frequency of anti-drug antibodies (ADAbs) in golimumab-treated patients with inflammatory joint disease (IJD).Method: Associations between golimumab concentration, ADAbs, and treatment response were examined in 91 patients with IJD [41 axial spondyloarthritis (axSpA), 20 rheumatoid arthritis (RA), and 30 psoriatic arthritis (PsA)] included in the NOR-DMARD study. Treatment response was defined by Ankylosing Spondylitis Disease Activity Score (ASDAS) clinically important improvement in axSpA, European League Against Rheumatism (EULAR) good/moderate response in RA, and improvement of ≥ 50% in modified Disease Activity index for PSoriatic Arthritis (DAPSA) (28 swollen/tender joint counts) in PsA. Serum drug concentrations and ADAbs were analysed using automated in-house assays.Results: At inclusion, 42% were biological disease-modifying anti-rheumatic drug naïve and 42% used concomitant synthetic disease-modifying anti-rheumatic drug. The median golimumab concentration was 2.2 (interquartile range 1.0-3.5) mg/L. The proportions of responders after 3 months among patients with golimumab concentration < 1.0, 1.0-3.9, and ≥ 4.0 mg/L were 19%, 49%, and 74%, respectively. A higher rate of treatment discontinuation was seen in patients with serum golimumab concentration < 1.0 compared to ≥ 1.0 mg/L (hazard ratio 3.3, 95% confidence interval 1.8-6.0, p < 0.05). ADAbs were detected in 6%, and were associated with lower drug concentrations and both reduced treatment response and drug survival.Conclusions: Golimumab concentrations ≥ 1.0 mg/L were associated with improved treatment response and better drug survival, although some patients may benefit from higher concentrations. This study suggests a rationale for dosing guided by therapeutic drug monitoring in golimumab-treated patients with IJD. The results should be confirmed in larger studies including trough samples, and the efficacy of such a strategy must be examined in randomized controlled trials.

4ß-Hydroxycholesterol Level in Patients With Rheumatoid Arthritis Before vs. After Initiation of bDMARDs and Correlation With Inflammatory State.

Systemic inflammation has been linked to suppressed CYP3A(4) activity. We determined 4ß-hydroxycholesterol (4ßOHC), an endogenous CYP3A4 metabolite, in patients with rheumatoid arthritis (RA) before and after treatment with biological disease-modifying antirheumatic drugs (bDMARDs). The 4ßOHC was compared in 41 patients before and 2-5 months after initiating TNFα inhibitors (n = 31), IL-6 inhibitors (n = 5), or B-cell inhibitors (n = 5). Correlations between 4ßOHC and inflammatory markers (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) were also tested before and after bDMARDs. 4ßOHC did not differ following bDMARD treatment (P = 0.6), nor in patients who started with IL-6 inhibitors (median 51.6 vs. 50.6 nmol/L). The 4ßOHC and CRP/ESR did not correlate before treatment (P > 0.5), but correlated significantly after bDMARDs (CRP = Spearman r -0.40; P < 0.01; ESR = r -0.34; P = 0.028) suggesting that mainly non-CYP3A4-suppressive cytokines were reduced during treatment. Thus, this study does not support a generally regained CYP3A4 phenotype in patients with RA following initiation of bDMARDs.

Cerebrospinal fluid biomarkers of white matter lesions - cross-sectional results from the LADIS study.

BACKGROUND AND PURPOSE: White matter lesions (WMLs) caused by small vessel disease are common in elderly people and contribute to cognitive impairment. There are no established biochemical markers for WMLs. We aimed to study the relation between degree of WMLs rated on magnetic resonance imaging of the brain and cerebrospinal fluid (CSF) levels of structural biomarkers associated with Alzheimer's disease (AD) and subcortical vascular dementia. METHODS: Fifty-three non-demented elderly individuals with WMLs were subjected to lumbar puncture. Degree of WMLs was rated using the Fazekas scale. Volumetric assessment of WMLs was performed. CSF samples were analyzed for the 40 and 42 amino acid fragments of amyloid beta, alpha- and beta-cleaved soluble amyloid precursor protein, total tau (T-tau), hyperphosphorylated tau (P-tau(181)), neurofilament light protein (NFL), sulfatide and CSF/Serum-albumin ratio. RESULTS: Fifteen subjects had mild, 23 had moderate and 15 had severe degree of WMLs. CSF-NFL levels differed between the groups (P < 0.001) and correlated with the volume of WMLs (r = 0.477, P < 0.001). CSF sulfatide concentration displayed similar changes but less strongly. T-tau, P-tau(181) and the different amyloid markers as well as CSF/S-albumin ratio did not differ significantly between the groups. CONCLUSIONS: The association of increased CSF-NFL levels with increasing severity of WMLs in non-demented subjects suggests that NFL is a marker for axonal damage in response to small vessel disease in the brain. This manifestation may be distinct from or earlier than the neurodegenerative process seen in AD, as reflected by the lack of association between WMLs and AD biomarkers.

Prediction of radiographic progression in rheumatoid arthritis and the role of antibodies against mutated citrullinated vimentin: results from a 10-year prospective study.

OBJECTIVES: Anti-citrullinated peptide antibodies (ACPAs) are established as useful predictors of radiographic progression in rheumatoid arthritis (RA). The main objective of this study was to test the prognostic capacity of the recently developed test for anti-mutated citrullinated vimentin (anti-MCV). METHODS: A cohort of 238 patients with RA was followed longitudinally for 10 years; 125 patients with complete x ray sets were included in the main analyses. Radiographs were scored according to the van der Heijde modified Sharp score (SHS). Patients were analysed for anti-MCV and anti-cyclic citrullinated peptide (CCP), and were genotyped for human leukocyte antigen (HLA)-DRB1 "shared epitope" (SE) and protein tyrosine phosphatase, non-receptor type 22 (PTPN22) 1858T. RESULTS: Anti-MCV and anti-CCP were strongly associated with regard to status and level. Both antibodies were associated with SE, but only anti-MCV was significantly associated with PTPN22 1858T. A positive anti-MCV test increased the odds of radiographic progression by 7.3 (95% confidence interval (CI) 3.2 to 16.5) compared to 5.7 (95% CI 2.6 to 12.5) for a positive anti-CCP. Presence of MCV antibodies gave an average increase in the total SHS of 30 U compared to an average increase of 25 U for the presence of CCP antibodies. Anti-MCVs were more strongly associated to progression in erosions than joint space narrowing. Associations remained after adjustment for other predictors of radiographic progression. The odds of progression increased with increasing anti-MCV level. CONCLUSIONS: Presence of anti-MCV predicted joint damage, and the strength of this prediction was at least as strong as for anti-CCP. Antibody status showed a stronger association to bone than to cartilage destruction. This study also indicates that higher anti-MCV levels add prognostic information compared to their mere presence or absence.

Calprotectin (a major S100 leucocyte protein) predicts 10-year radiographic progression in patients with rheumatoid arthritis.

BACKGROUND: Plasma levels of calprotectin, a major S100 leucocyte protein, are cross-sectionally associated with clinical and laboratory markers of inflammation and with radiographic damage in rheumatoid arthritis (RA). High amounts of calprotectin are found in synovial fluid from patients with RA. OBJECTIVE: To examine whether calprotectin might be an independent predictor of joint destruction over time. METHODS: 124 patients with RA were assessed at baseline and after 10 years with inflammatory markers (calprotectin, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)), serological variables (antibodies to cyclic citrullinated peptide (anti-CCP), IgA rheumatoid factor (RF) and IgM RF) and radiographic and clinical assessments of joint damage (hand radiographs and Rheumatoid Arthritis Articular Damage (RAAD) score). Progression of radiographic damage was assessed according to the van der Heijde modified Sharp score. RESULTS: At both examinations the highest calprotectin levels were found in patients positive for anti-CCP, IgA and IgM RF. Calprotectin had moderate to good correlations with inflammatory and serological markers (r = 0.41-0.67). Patients with normal baseline calprotectin levels had a lower degree of joint damage. High univariate associations were found between baseline calprotectin levels and progression in the Sharp score as well as the RAAD score. Baseline calprotectin was independently associated with progression in the Sharp score and with the RAAD score in multiple linear regression analyses, including baseline levels of CRP, ESR, anti-CCP in addition to demographic variables. CONCLUSION: Calprotectin was an independent predictor of clinical and radiographic joint damage after 10 years. These findings support the proposal that calprotectin may be a prognostic biomarker for erosive disease in patients with RA.

Cortical hand bone loss after 1 year in early rheumatoid arthritis predicts radiographic hand joint damage at 5-year and 10-year follow-up.

OBJECTIVE: To examine 1-year hand bone loss in early rheumatoid arthritis (RA) as a predictor of radiographic damage at 5-year and 10-year follow-up METHODS: A total of 136 patients with RA (disease duration 0-4 years) were followed for 10 years with clinical data and hand radiographs. Joint damage was scored according to the van der Heijde modification of the Sharp method (vdH Sharp score) and hand bone mineral density (BMD) was measured by digital x ray radiogrammetry (DXR). Group comparisons, correlation analyses and multivariate analyses were performed to evaluate the relationship between hand bone loss and radiographic joint damage. RESULTS: Patients with hand BMD loss at 1 year had a higher median increase in vdH Sharp score compared to patients without loss at 5 years (12 vs 2, p = 0.001) and 10 years (22 vs 4, p = 0.002). In a linear regression model adjusting for age, gender, baseline C-reactive protein (CRP), anti-cyclic citrullinated peptide (CCP), IgM rheumatoid factor (RF) and radiographic damage, absolute hand DXR-BMD loss at 1 year was an independent predictor of radiographic outcome at 5 years (p<0.01) and 10 years (p = 0.02). In a logistic regression model the odds ratio (95% CI) for radiographic progression among patients with hand BMD loss was 3.5 (1.4 to 8.8) and 3.5 (1.4 to 8.4) at 5 and 10 years, respectively. CONCLUSION: Early hand bone loss measured by DXR-BMD is an independent predictor of subsequent radiographic damage. Our findings support that quantitative hand bone loss in RA precedes radiographic joint damage and may be used as a tool for assessment of bone involvement in RA.

High anti-cyclic citrullinated peptide levels and an algorithm of four variables predict radiographic progression in patients with rheumatoid arthritis: results from a 10-year longitudinal study.

OBJECTIVES: New effective therapies with particularly good effect on joint destruction have highlighted the need for reliable predictors of radiographic progression in rheumatoid arthritis (RA). Our objective was to assess the combined predictive role of a set of laboratory markers with regard to 10-year radiographic progression, and to examine the effect of anti-cyclic citrullinated peptide (anti-CCP) level. METHODS: A cohort of 238 patients with RA was followed longitudinally for 10 years with the collection of clinical data and serum samples. 125 patients with radiographs of the hands available at both baseline and after 10 years were included in this study. Radiographs were scored according to the van der Heijde modified Sharp score. Baseline sera were analysed for C-reactive protein, erythrocyte sedimentation rate (ESR), anti-CCP, IgA rheumatoid factor (RF) and IgM RF. Logistic regression analyses were used to identify predictors of radiographic progression and to examine the effect of anti-CCP level. RESULTS: Anti-CCP (OR 4.0; 95% CI 1.6 to 10.0) was the strongest independent predictor of radiographic progression. Female gender (OR 3.3; 95% CI 1.3 to 7.6), high ESR (OR 3.2; 95% CI 1.2 to 7.6) and a positive IgM RF (OR 3.1; 95% CI 1.2 to 7.9) were also independent predictors. Compared with the anti-CCP-negative patients, patients with low to moderate levels of anti-CCP (OR 2.6; 95% CI 0.9 to 7.2) and patients with high levels of anti-CCP (OR 9.9; 95% CI 2.7 to 36.7) were more likely to develop radiographic progression. CONCLUSIONS: Anti-CCP, IgM RF, ESR and female gender were independent predictors of radiographic progression and could be combined into an algorithm for better prediction. Patients with high levels of anti-CCP were especially prone to radiographic progression, indicating that the anti-CCP level may add prognostic information.

The effect of simvastatin treatment on the amyloid precursor protein and brain cholesterol metabolism in patients with Alzheimer's disease.

During the last years, several clinical studies have been published trying to elucidate the effect of statin treatment on amyloid precursor protein (APP) processing and metabolism of brain cholesterol in Alzheimer's disease (AD) in humans. We present an open biochemical study where 19 patients with AD have been treated with simvastatin (20 mg/day) for 12 months. The aim was to further investigate the effect of simvastatin treatment on cerebrospinal fluid (CSF) biomarkers of APP processing, AD biomarkers as total tau and tau phosphorylated at threonine 181, brain cholesterol metabolism as well as on cognitive decline in patients with AD. Despite biochemical data suggesting that treatment with 20 mg/day of simvastatin for 12 months does affect the brain cholesterol metabolism, we did not find any change in CSF or plasma levels of beta-amyloid (Abeta)(1-42). However, by analysis of APP isoforms, we found that statin treatment may favor the nonamyloidogenic pathway of APP processing. The relevance and mechanism between statin treatment and AD has to be further elucidated by using statins of different lipophility in different dosages over a longer period of time.

A controlled multicenter clinical study of citalopram and placebo in elderly depressed patients with and without concomitant dementia.

A total of 149 patients in 7 centers in Denmark, Norway and Sweden entered a 6-week double-blind trial intended to assess the antidepressant effect and safety of citalopram vs placebo in depressed elderly patients (65 years of age or older) who might also suffer from somatic disorders and/or senile dementia. Results of ratings on the Hamilton Rating Scale for Depression, the Montgomery-Asberg Depression Rating Scale and the Clinical Global Impression Scale provided consistent evidence that the citalopram-treated patients improved more than the placebo-treated patients. Results of ratings on the Gottfries-Bråne-Steen dementia rating scale indicated that both cognitive and emotional functioning improved significantly more in the citalopram-treated subgroup of patients with dementia than in the placebo-treated subgroup.

Bending and rotational stability of femoral neck osteotomies. An experimental study.

The bending and rotational stability of experimental cadaveric femoral neck osteotomies fixed by Thornton's triflanged nail. McLaughlin's nail and plate and the Ullevål hip compression screw are reported. The bending stability of the three implants tested is statistically equal whereas the rotational stability of the Thornton nail is lower. However, the rotational stability of all three implants tested is sufficient under normal clinical circumstances. The bending stability achieved by the three implants is insufficient for the forces acting upon the femoral head in vivo and is the most obvious reason for the high rate of nonunion in femoral neck fractures.

Dysphagia after proximal gastric vagotomy.

Ten patients were examined before and after proximal gastric vagotomy with videotape recordings of barium passage in esophagus, esophageal pressure recordings, and the insulin test. Four of the patients complained of dysphagia after the operation. The dysphagia subsided spontaneously after 1--2 months. Patients with dysphagia showed dilatation of the body of the esophagus and a tapered narrowing in the distal segment. The pressure recordings showed increased frequency and strength of rhythmic pressure waves compared with the preoperative findings. Our results support the theory of a neuromuscular dysfunction.

Overgrowth of the femur after fracture of the shaft in childhood.

Twenty-six children conservatively treated for fracture of the femoral shaft have been reviewed with regard to differences in limb length seven to ten years after the injury. In nine patients the clinical measurements were checked against radiographic measurements of both femora and tibiae. The following conclusions were reached. Nearly two-thirds of the patients had overgrowth of the femur of 10 millimetres or more. Shortening of 15 to 20 millimetres at the fracture site was well compensated for by accelerated growth. Growth acceleration seemed to take place during the healing period and the difference at the end of healing was permanent. Overgrowth was promoted by comminuted and long oblique fractures and by overriding of the fracture ends, but was not influenced by the age at fracture, the duration of treatment or the level of fracture of the shaft. Growth of the tibia was not affected by the femoral fracture.