Patient-tailored dose reduction of TNF-α blocking agents in ankylosing spondylitis patients with stable low disease activity in daily clinical practice.

OBJECTIVES: Tumour necrosis factor-alpha (TNF-α) blocking agents are very effective in controlling systemic inflammation and improving clinical assessments in ankylosing spondylitis (AS). In view of potential side effects and high costs of long-term treatment, our aim was to investigate whether dose reduction of TNF-α blocking agents is possible without loss of effectiveness in AS patients in daily clinical practice. METHODS: Patients from the prospective observational GLAS cohort, fulfilling the modified New York criteria for AS, with active disease before start of TNF-α blocking therapy and stable (≥6 months) low disease activity on the conventional dose regimen, who started with dose reduction of TNF-α blocking therapy before June 2011 were studied. Dose reduction was patient-tailored (step-by-step approach) and consisted of lowering the dose and/or extending the interval between doses. RESULTS: Between June 2005 and March 2011, 58 AS patients started dose reduction of etanercept (n=39), infliximab (n=10), or adalimumab (n=9). Of all patients, 74%, 62%, and 53% maintained their reduced dose or dosing frequency after 6, 12, and 24 months, respectively. The mean dose of TNF-α blocking therapy over time corresponded to 62% of the standard dose regimen. Disease activity remained low in the majority of patients who maintained dose reduction after 24 months (94% had BASDAI<4). If there was recurrence of disease symptoms, patients achieved good clinical response after returning to the conventional regimen (88% reached BASDAI<4). CONCLUSIONS: In this observational cohort, patient-tailored dose reduction of TNF-α blocking agents was successful preserving stable low disease activity over 24 months in approximately half of the AS patients.

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

INTRODUCTION: The 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). METHODS: For 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. RESULTS: IPAQ 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. CONCLUSIONS: Both 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.

Validity and reliability of the Dutch adaptation of the Psoriatic Arthritis Quality of Life (PsAQoL) Questionnaire.

OBJECTIVE: The Psoriatic Arthritis Quality of Life (PsAQoL) questionnaire is a disease- specific instrument developed to measure quality of life (QoL) in patients with psoriatic arthritis (PsA). The aim of this study was to translate the measure into Dutch and to determine its psychometric properties. METHOD: Translation of the original English PsAQoL into Dutch was performed by bilingual and lay panel. Ten field-test interviews with PsA patients were performed to assess face and content validity. In total, 211 PsA patients were included in a test-retest postal survey to investigate the reliability and construct validity of the Dutch adaptation of the PsAQoL. The PsAQoL, Health Assessment Questionnaire (HAQ) and Skindex-17 were administered on two different occasions approximately two weeks apart. RESULTS: The Dutch version of the PsAQoL was found to be relevant, understandable and easy to complete in only a few minutes. It correlated as expected with the HAQ (Spearman's ρ = 0.72) and the 2 subscales of the Skindex-17 (ρ = 0.40 for the psychosocial and ρ = 0.46 for the symptom scale). Furthermore, the measure had good internal consistency (Cronbach's α = 0.92) and test-retest reliability (ρ = 0.89). The PsAQoL was able to define groups of patients based on self-reported general health status, self-reported severity of PsA and flare of arthritis. Duration of PsA did not influence PsAQoL scores. CONCLUSIONS: The Dutch version of the PsAQoL is a valid and reliable questionnaire suitable for use in clinical or research settings to asses PsA-specific QoL.

The effect of three years of TNFα 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.

INTRODUCTION: The 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). METHODS: This 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. RESULTS: After 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 physician's 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. CONCLUSIONS: Three 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.

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.

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

INTRODUCTION: Identifying 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. METHODS: AS 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. RESULTS: Between 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 patient's 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. CONCLUSIONS: Besides 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.

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.

A comparison of an interferon-gamma release assay and tuberculin skin test in refractory inflammatory disease patients screened for latent tuberculosis prior to the initiation of a first tumor necrosis factor α inhibitor.

Treatment with TNFα inhibitors increases risk of reactivating a latent tuberculosis\infection (LTBI). Therefore screening, prior to therapy with TNFα inhibitors, has been recommended, even in low-endemic areas such as well-developed Western Europe countries. We evaluated interferon-gamma release assay (IGRA), as opposed to tuberculin skin test (TST), for detection of LTBI in refractory inflammatory disease patients prior to the initiation of a first TNFα inhibitor. In addition, we evaluated the impact of impaired cellular immunity on IGRA. Patients starting on TNFα inhibition were screened for LTBI by TST and IGRA (Quantiferon-TB Gold). Data on tuberculosis exposure and Bacillus Calmette-Guérin (BCG) vaccination were obtained. Cellular immunity was assessed by CD4(+) T lymphocyte cell count. Nine out of 56 patients (16.1%) tested positive for LTBI. A concordant positive result was present in three patients with a medical history of tuberculosis exposure. Six patients with discordant test results had either: (1) a negative TST and positive IGRA in combination with a medical history of tuberculosis exposure (n = 1) or (2) a positive TST and negative IGRA in combination with BCG vaccination (n = 3) or a medical history of tuberculosis exposure (n = 2). CD4(+) T lymphocyte cell counts were within normal limits, and no indeterminate results of IGRA were present. IGRA appears reliable for confirming TST and excluding a false positive TST (due to prior BCG vaccination) in this Dutch serie of patients. In addition, IGRA may detect one additional case of LTBI out of 56 patients that would otherwise be missed using solely TST. Immune suppression appears not to result significantly in lower CD4(+) T lymphocyte cell counts and indeterminate results of IGRA, despite systemic corticosteroid treatment in half of the patients. Confirmation in larger studies, including assessment of cost-effectiveness, is required.

Rituximab in cryoglobulinaemic vasculitis, evidence for its effectivity: a case report and review of literature.

Cryoglobulinaemia associated with systemic vasculitis mediated by immune complexes is a rare combination. These immune complexes are composed of immunoglobulins and precipitate when exposed to cold temperature. Cryoglobulinaemic vasculitis, treated or untreated, may lead to substantial morbidity and even mortality. Novel targeted therapies may well provide new therapeutic options following or perhaps even prior to the classical cytotoxic therapies. Systemic B cell depletion with rituximab, a chimeric monoclonal antibody against CD20 antigen, is commonly applied in patients with non-Hodgkin's lymphoma or in refractory rheumatoid factor-positive rheumatoid arthritis. Since B cell clones are the source of cryoglobulins, therapeutic effectiveness of rituximab in cryoglobulinaemic vasculitis may be expected. We describe a 72-year-old woman with mixed cryoglobulinaemia type 2, who has successfully been treated with rituximab infusions after failing on prednisone and azathioprine. We reviewed the literature and found 142 cases of cryoglobulinaemic vasculitis, 138 mixed (type 2 or 3) and four, type 1. Rituximab was applied mostly after failure on other treatments. Significant reduction in levels of rheumatoid factor, cryoglobulins and IgM were reported after rituximab therapy. Of the total 142, cases 119 could be evaluated for the response on rituximab therapy, the other 23 cases only regarding side effects. Of the 119 evaluated patients, 71 (60%) had complete response; 28 (23%), partial response and 20 patients (17%), no response. Data were not blinded or placebo-controlled. Side effects were seen in 27 of the 142 patients. Occurrence of the side effects was associated with high baseline levels of cryoglobulins, with a high dose of rituximab infusion of 1,000 mg and with a high level of complement activation. Death was reported four times and was related with the disease.

Biochemical effectiveness of allopurinol and allopurinol-probenecid in previously benzbromarone-treated gout patients.

In 2003, the uricosuric drug benzbromarone was withdrawn from the market. The first alternative drug of choice was the xanthine oxidase inhibitor allopurinol. The purpose was to (1) investigate the efficacy of allopurinol (standard dosage) compared with previous treatment with benzbromarone; and (2) investigate the combination therapy allopurinol-probenecid as an effective alternative treatment compared with previous benzbromarone treatment. A prospective, open study was carried out in a cohort of 51 gout patients who discontinued benzbromarone therapy because of market withdrawal. Patients were given 200-300 mg allopurinol (stage 1). When allopurinol failed to attain the target serum urate (sUr) levels