P. M. Houtman

Baseline predictors of response and discontinuation of tumor necrosis factor-alpha blocking therapy in ankylosing spondylitis: a prospective longitudinal observational cohort study

IntroductionIdentifying ankylosing spondylitis (AS) patients who are likely to benefit from tumor necrosis factor-alpha (TNF-α) blocking therapy is important, especially in view of the costs and potential side effects of these agents. Recently, the AS Disease Activity Score (ASDAS) has been developed to assess both subjective and objective aspects of AS disease activity. However, data about the predictive value of the ASDAS with respect to clinical response to TNF-α blocking therapy are lacking. The aim of the present study was to identify baseline predictors of response and discontinuation of TNF-α blocking therapy in AS patients in daily clinical practice.MethodsAS outpatients who started TNF-α blocking therapy were included in the Groningen Leeuwarden Ankylosing Spondylitis (GLAS) study, an ongoing prospective longitudinal observational cohort study with follow-up visits according to a fixed protocol. For the present analysis, patients were excluded if they had previously received anti-TNF-α treatment. Predictor analyses of response and treatment discontinuation were performed using logistic and Cox regression models, respectively.ResultsBetween November 2004 and April 2010, 220 patients started treatment with infliximab (n = 32), etanercept (n = 137), or adalimumab (n = 51). At three and six months, 68% and 63% of patients were Assessments in Ankylosing Spondylitis (ASAS)20 responders, 49% and 46% ASAS40 responders, and 49% and 50% Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)50 responders, respectively. Baseline predictors of response were younger age, male gender, higher ASDAS score, higher erythrocyte sedimentation rate (ESR) level, higher C-reactive protein (CRP) level, presence of peripheral arthritis, higher patients global assessment of disease activity, and lower modified Schober test. In August 2010, 64% of patients were still using their TNF-α blocking agent with a median follow-up of 33.1 months (range 2.4 to 68.2). Baseline predictors of discontinuation of TNF-α blocking therapy were female gender, absence of peripheral arthritis, higher BASDAI, lower ESR level, and lower CRP level.ConclusionsBesides younger age and male gender, objective variables such as higher inflammatory markers or ASDAS score were identified as independent baseline predictors of response and/or continuation of TNF-α blocking therapy. In contrast, higher baseline BASDAI score was independently associated with treatment discontinuation. Based on these results, it seems clinically relevant to include more objective variables in the evaluation of anti-TNF-α treatment.

The relation between bone mineral density, bone turnover markers, and vitamin D status in ankylosing spondylitis patients with active disease: a cross-sectional analysis

SummaryOsteoporosis is a well recognized complication of ankylosing spondylitis (AS). This study indicates that increased bone turnover, inflammation, and low vitamin D levels are important in the pathophysiology of AS-related osteoporosis, and that bone turnover markers (BTM) are valuable markers to detect bone loss in AS.IntroductionThe aim of this study was to elucidate the pathophysiology of AS-related osteoporosis by investigating the relation between bone mineral density (BMD), BTM, vitamin D, and clinical assessments of disease activity and physical function, as well as to identify parameters that are related to low BMD (osteopenia or osteoporosis) in AS patients with active disease.MethodsOne hundred twenty-eight consecutive Dutch AS outpatients were included in this cross-sectional study. Bath AS Disease Activity Index (BASDAI), erythrocyte sedimentation rate (ESR), C-reactive protein, ASAS-endorsed disease activity score (ASDAS), Bath AS Functional Index (BASFI), bone formation markers procollagen type 1 N-terminal peptide (PINP) and osteocalcin (OC), bone resorption marker serum C-telopeptides of type I collagen (sCTX), 25-hydroxyvitamin D (25OHvitD), lumbar spine and hip BMD, and vertebral fractures were assessed. Z-scores of BTM were calculated using matched 10-year cohorts of a Dutch reference group to correct for the normal influence that age and gender have on bone turnover.ResultssCTX Z-score, OC Z-score, BASDAI, age, and gender were independently related to low BMD. In addition, PINP Z-score, ESR, 25OHvitD, age, and gender were independently related to sCTX and/or OC Z-score.ConclusionsThis study indicates that increased bone turnover, inflammation, and low vitamin D levels are important in the pathophysiology of AS-related osteoporosis. Furthermore, sCTX and OC Z-scores seem to be valuable markers to detect bone loss in AS patients in daily clinical practice where BMD of the lumbar spine, measured by DXA, may be overestimated due to osteoproliferation in patients with advanced AS.

Hepatic injury caused by benzbromarone

This case study describes a woman who developed a predominantly hepatocellular injury, approximately 3 months after starting treatment with 100 mg benzbromarone daily. She had also taken 250 mg methyldopa daily for several years. Infections with hepatitis A and B were excluded serologically, no autoantibodies were demonstrated, and ultrasonography and endoscopic retrograde cholangiopancreatography did not show extrahepatic obstruction. The patient recovered after discontinuation of both drugs. Two years later, readministration of benzbromarone was followed by a relapse. Later, methyldopa was used without problems. We conclude that hepatic injury in this patient was caused by benzbromarone.

The prevalence of clinical remission in RA patients treated with anti-TNF: results from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry

OBJECTIVES To evaluate the prevalence of clinical remission and minimal disease activity according to the ACR/European League Against Rheumatism (EULAR) remission, DAS-28 <2.6 and minimal disease activity (MDA) criteria, and to compare the extent of residual disease activity with disability in RA patients after 6 months of treatment with anti-TNF. METHODS In the Dutch Rheumatoid Arthritis Monitoring (DREAM) biologic registry the prevalence of DAS-28 <2.6, MDA and ACR/EULAR remission criteria was assessed. Residual disease activity during MDA or remission was assessed as the percentage of patients with swollen and tender joints, elevated acute-phase reactants and general health on a visual analogue scale (VAS). Disability was evaluated with the HAQ score. RESULTS Prevalence of DAS-28 <2.6 was 27%, prevalence of MDA was 34% and ACR/EULAR remission was reached by 6% of patients. Residual disease activity was present mostly in the most lenient criteria and occurred most frequently on the level of swollen joint count and VAS score: at least one swollen joint in DAS-28 <2.6, MDA and ACR/EULAR remission was present in, respectively, 51, 54 and 34% of the patients. VAS >1 occurred in, respectively, 67, 69 and 0% of the patients. Modification of the cut-point of the patient-reported outcome increased the prevalence of ACR/EULAR remission, but also the level of disability. CONCLUSION MDA and DAS-28 <2.6 are reachable treatment targets in RA with anti-TNF, although residual disease activity might still be present. In turn, ACR/EULAR remission criteria leave little residual disease activity, but might be too stringent for use in daily clinical practice due to the strict cut-point in the patient-reported outcome.

Serum MMP-3 Level as a Biomarker for Monitoring and Predicting Response to Etanercept Treatment in Ankylosing Spondylitis

Objective. To investigate whether level of serum matrix metalloproteinase-3 (MMP-3) can serve as a biomarker for monitoring and predicting response to etanercept treatment in patients with ankylosing spondylitis (AS) in daily clinical practice. Methods. Ninety-two consecutive AS outpatients with active disease who started etanercept treatment were included in this longitudinal observational study. Clinical data were collected prospectively at baseline and after 3 and 12 months of treatment. At the same timepoints, serum MMP-3 levels were measured retrospectively by ELISA. Results. Since baseline serum MMP-3 levels were significantly higher in male compared to female patients with AS, data analysis was split for gender. Changes in serum MMP-3 levels after etanercept treatment correlated positively with changes in clinical assessments of disease activity and physical function in both male and female patients. Receiver operating characteristic analysis in male patients showed that baseline serum MMP-3 levels had poor accuracy (AUC < 0.7) to discriminate between Assessments in Ankylosing Spondylitis 20 (ASAS20) or ASAS40 responders and nonresponders after 3 or 12 months of treatment. The accuracy of change in serum MMP-3 levels from baseline to 3 months in predicting response after 3 or 12 months of treatment was poor for ASAS40 (AUC < 0.7) or moderate for ASAS20 (AUC = 0.752 and 0.744, respectively), and was not superior to the accuracy of change in the currently used objective biomarkers, erythrocyte sedimentation rate and C-reactive protein. Conclusion. Although significant changes in serum MMP-3 levels were found after etanercept treatment, data analysis indicates that serum MMP-3 levels are not very useful for monitoring and predicting response to etanercept treatment in patients with AS in daily clinical practice.

The effect of three years of TNF alpha blocking therapy on markers of bone turnover and their predictive value for treatment discontinuation in patients with ankylosing spondylitis: a prospective longitudinal observational cohort study

IntroductionThe aim of this study was to investigate the effect of three years of tumor necrosis factor-alpha (TNF-α) blocking therapy on bone turnover as well as to analyze the predictive value of early changes in bone turnover markers (BTM) for treatment discontinuation in patients with ankylosing spondylitis (AS).MethodsThis is a prospective cohort study of 111 consecutive AS outpatients who started TNF-α blocking therapy. Clinical assessments and BTM were assessed at baseline, three and six months, as well as at one, two, and three years. Z-scores of BTM were calculated to correct for age and gender. Bone mineral density (BMD) was assessed yearly.ResultsAfter three years, 72 patients (65%) were still using their first TNF-α blocking agent. In these patients, TNF-α blocking therapy resulted in significantly increased bone-specific alkaline phosphatase, a marker of bone formation; decreased serum collagen-telopeptide (sCTX), a marker of bone resorption; and increased lumbar spine and hip BMD compared to baseline. Baseline to three months decrease in sCTX Z-score (HR: 0.394, 95% CI: 0.263 to 0.591), AS disease activity score (ASDAS; HR: 0.488, 95% CI: 0.317 to 0.752), and physicians global disease activity (HR: 0.739, 95% CI: 0.600 to 0.909) were independent inversely related predictors of time to treatment discontinuation because of inefficacy or intolerance. Early decrease in sCTX Z-score correlated significantly with good long-term response regarding disease activity, physical function and quality of life.ConclusionsThree years of TNF-α blocking therapy results in a bone turnover balance that favors bone formation, especially mineralization, in combination with continuous improvement of lumbar spine BMD. Early change in sCTX can serve as an objective measure in the evaluation of TNF-α blocking therapy in AS, in addition to the currently used more subjective measures.

Decreased nailfold capillary density in Raynaud's phenomenon: a reflection of immunologically mediated local and systemic vascular disease?

Nailfold capillary patterns were studied in 107 patients with Raynauds phenomenon (RP), including patients wih (n = 39) and without (n = 68) connective tissue disease (CTD). Capillary density was decreased in patients with sclerodactyly, digital ulcers, tuft resorption, and telangiectasia, compared with patients without these symptoms. In addition, an inverse relationship was found between the severity of RP at first presentation (as graded by photoelectric plethysmography during cooling) and the capillary density in patients with CTD (r = -0.45; p less than 0.05). In the total group of patients nailfold capillary density was inversely related to organ system involvement (r = -0.52; p less than 0.01). Decreased nailfold capillary density was observed, in particular, in patients with oesophageal hypomotility and in patients with chest x-rays compatible with interstitial fibrosis. As to factors supposedly involved in the pathogenesis of vascular changes in CTD, the presence of autoantibodies, increased levels of circulating immune complexes, and increased levels of acute phase reactants were all associated with a decreased number of nailfold capillaries. We conclude that loss of nailfold capillaries as observed by microscopy is a reflection of local and systemic vascular disease.

Fluctuations in anti-nRNP levels in patients with mixed connective tissue disease are related to disease activity as part of a polyclonal B cell response.

In a follow up study of 11 patients with mixed connective tissue disease the levels of antibodies to nuclear ribonucleoprotein (nRNP) as measured by an enzyme linked immunosorbent assay (ELISA) were related to clinical activity of disease. To assess the relation between anti-nRNP levels and disease activity the levels of total immunoglobulin G, IgM rheumatoid factor (IgM RF), and antibodies to an unrelated antigen (tetanus toxoid) were determined simultaneously. No significant changes in anti-nRNP levels were noted in four patients with minor activity of disease. Major flares of disease were observed in seven patients. Clinical symptoms were preceded by a rise in anti-nRNP level in these patients unless they received immunosuppressive agents before the exacerbation. Conversely, when a rise in anti-nRNP level occurred a major flare of disease was followed in all but one case. Anti-nRNP levels fell during clinical improvement whether or not immunosuppressive treatment was given. All patients showed parallel fluctuations in anti-nRNP, IgM RF, and total immunoglobulin G levels. Furthermore, parallel fluctuations were seen in the levels of anti-nRNP and antibodies to tetanus toxoid except in one patient. We conclude that measurement of anti-nRNP by ELISA may be a guide for disease activity in connective tissue disease. Fluctuations of anti-nRNP are not restricted to this antibody, however, but are part of a more polyclonal activity of the B lymphocyte system.

QUANTITATION OF ANTIBODIES TO NUCLEORIBONUCLEOPROTEIN BY ELISA - RELATION BETWEEN ANTIBODY-LEVELS AND DISEASE-ACTIVITY IN PATIENTS WITH CONNECTIVE-TISSUE DISEASE

We describe a solid-phase enzyme-linked immunosorbent assay (ELISA) for quantitation of antibodies to nucleoribonucleoprotein (nRNP/Sm). nRNP/Sm was purified from rabbit thymus acetone powder by immunoaffinity chromatography and characterized by counterimmunoelectrophoresis (CIE) and immunoblotting using sera with well-known specificities. The purified antigen was used in ELISA. Positive results in ELISA were obtained only in sera with anti-nRNP or anti-Sm specificity as determined in CIE. Levels of anti-nRNP/Sm as quantitated by ELISA were higher in the sera of patients with active connective tissue disease (n = 7) than in those with inactive disease (n = 6) (P less than 0.01). Differences in anti-nRNP/Sm levels were also found between patients with mildly active disease (n = 19) and those with active disease (P less than 0.01). Fluctuations of anti-nRNP/Sm levels related to disease activity were seen in longitudinal observation. Although anti-nRNP/Sm levels as quantitated by ELISA correlated with titres of antinuclear antibodies as determined by immunofluorescence (r = 0.46, P less than 0.05), quantitation of anti-nRNP/Sm by ELISA is superior since the assay is antigen-specific and its quantitation independent of titration-related inaccuracies.

Daily physical activity in ankylosing spondylitis: validity and reliability of the IPAQ and SQUASH and the relation with clinical assessments.

IntroductionThe aim of this study was to investigate the construct validity and test-retest reliability of the International Physical Activity Questionnaire (IPAQ; long form) and the Short QUestionnaire to Assess Health-enhancing physical activity (SQUASH) and to investigate the relation between daily physical activity and clinical assessments in patients with ankylosing spondylitis (AS).MethodsFor validity, the self-report questionnaires IPAQ and SQUASH were compared with daily physical activity assessed with the ActiGraph accelerometer during 7 consecutive days in 63 AS outpatients. For reliability, the IPAQ and SQUASH were administered twice approximately 1 week apart in 52 AS outpatients. In all 115 patients, clinical assessments were performed at the outpatient clinic.ResultsIPAQ and SQUASH total scores correlated significantly with accelerometer outcome: ρ = 0.38 and r = 0.35, respectively. Intraclass correlation coefficients between first and second assessments of the IPAQ and SQUASH were 0.83 and 0.89, respectively. Bland-Altman analyses showed no systemic bias, but in particular for the IPAQ the 95% limits of agreement were wide. Daily physical activity assessed by accelerometer, IPAQ, and SQUASH correlated significantly with disease activity, physical activity, and quality of life. A relation with spinal mobility was found only for the accelerometer and SQUASH. The direction of these correlations indicates that higher daily physical activity is related to lower disease activity and better physical function, spinal mobility and quality of life.ConclusionsBoth physical activity questionnaires showed modest construct validity. The SQUASH showed good test-retest reliability, superior to the IPAQ. These results indicate that the SQUASH is more suitable than the IPAQ to assess daily physical activity in AS population studies. However, it is desirable to add questions on AS-specific physical activity. Further studies are needed to investigate the causality of the relation between daily physical activity and clinical assessments.