Anti-tumor Necrosis Factor Treatment Research Articles

A new low-field extremity magnetic resonance imaging and proposed compact MRI score: evaluation of anti-tumor necrosis factor biologics on rheumatoid arthritis

Magnetic resonance imaging (MRI) is a useful tool for evaluating disease activity and therapeutic efficacy in rheumatoid arthritis (RA). However, conventional whole-body MRI is inconvenient on several levels. We have therefore developed a new low-field extremity MRI (compact MRI, cMRI) and examined its clinical utility. Thirteen RA patients treated with anti-tumor necrosis factor (TNF) biologics were included in the study. The MRI was performed twice using a 0.21-T extremity MRI system. The MRI images were scored using our proposed cMRI scoring system, which we devised with reference to the Outcome Measures in Rheumatology Clinical Trials RA MRI score (OMERACT RAMRIS). In our cMRI scoring system, synovitis, bone edema, and bone erosion are separately graded on a scale from 0 to 3 by imaging over the whole hand, including the proximal interphalangeal joint. The total cMRI score (cMRIS) is then obtained by calculating the total bone erosion score × 1.5 + total bone edema score × 1.25 + total synovitis score. In this study, one patient showed a progression of bone destruction even under low clinical activity, as assessed by the disease activity score on 28 joints (DAS28); however, another patient’s cMRIS decreased concurrently with the decrease in DAS28, with the positive correlation observed between ΔDAS28 and ΔcMRIS (R = 0.055, P < 0.05). We conclude that cMRI and cMRIS are useful for assessing total disease activity and as a method linking MRI image evaluation to clinical evaluation.

Successful Treatment of Hidradenitis Suppurativa with Infliximab in a Patient Who Failed to Respond to Etanercept

Hidradenitis suppurativa (HS) is a devastating chronic scarring disease of the axillae, groins, and submammary tissue occurring predominantly in women, with onset at puberty. Multiple treatments have been attempted, with limited success. The association of HS with Crohn disease, psoriasis (PSO), and pyoderma gangrenosum, as well as the seronegative arthropathies, suggests a common immunopathogenesis and has motivated attempts at treatment with anti-tumor necrosis factor (TNF)-alpha agents, already demonstrated to be efficacious in major inflammatory diseases. To report on the clinical evolution of a patient with HS and PSO treated with infliximab who had failed to respond to etanercept and to discuss the possible mechanism responsible for the outcome. We describe the medical history, diagnostic tests, and clinical evolution of a 25-year-old woman with HS and psoriasis treated with infliximab. The patient demonstrated a rapid and complete response with infliximab for the HS and PSO, sustained for 24 months. The success of anti-TNF agents such as infliximab in managing HS offers a new therapeutic option and supports an underlying immunologic basis for the disease. The differential response to HS observed with infliximab and etanercept in this patient could be related to differences in structure, binding specificities, or gene suppression.

Relapsing Cutaneous Leishmaniasis in a Patient with Ankylosing Spondylitis Treated with Infliximab

A 31-year-old man with ankylosing spondylitis, receiving treatment with infliximab, presented with a large progressive cutaneous ulcer at the right knee. Biopsies showed Leishmania amastigotes, and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis showed Leishmania infantum as the causative agent. After treatment with miltefosine, the ulcer resolved completely, and infliximab was reinstituted because of progression of spondylitis. After 1 year, there was a recurrent ulcer at the same site being positive for Leishmania DNA by PCR. Local treatment with sodium stibogluconate resulted in complete regression. Cutaneous leishmaniasis should be added to the list of opportunistic infections associated with anti-tumor necrosis factor (TNF) treatment. Despite recurrences, antileish-manial treatment may be effective in cases without alternatives to anti-TNF therapy.

Tuberculosis screening in patients with psoriasis before antitumour necrosis factor therapy: comparison of an interferon-γ release assay vs. tuberculin skin test

Antitumour necrosis factor (anti-TNF) treatments may reactivate latent tuberculosis infection (LTBI). For detecting LTBI, the tuberculin skin test (TST) has low sensitivity and specificity. Interferon-gamma release assays (IGRA) have been shown to be more sensitive and specific than TST. To compare the TST and the T-SPOT.TB IGRA for identifying LTBI in patients with psoriasis before anti-TNF treatment. A retrospective study was carried out over a 4-year period on patients with psoriasis requiring anti-TNF treatment. All were subjected to the TST, T-SPOT.TB and chest X-ray. Risk factors for LTBI and history of bacillus Calmette-Guérin (BCG) vaccination were recorded. The association of T-SPOT.TB and TST results with risk factors for LTBI was tested through univariate logistic regression models. Agreement between tests was quantified using kappa statistics. Treatment for LTBI was started 1 month before anti-TNF therapy when indicated. Fifty patients were included; 90% had prior BCG vaccination. A positive T-SPOT.TB was strongly associated with a presumptive diagnosis of LTBI (odds ratio 7.43; 95% confidence interval 1.38-39.9), which was not the case for the TST. Agreement between the T-SPOT.TB and TST was poor, kappa = 0.33 (SD 0.13). LTBI was detected and treated in 20% of the patients. In 20% of the cases, LTBI was not retained in spite of a positive TST but a negative T-SPOT.TB. All patients received an anti-TNF agent for a median of 56 weeks (range 20-188); among patients with a positive TST/negative T-SPOT.TB, no tuberculosis was detected with a median follow-up of 64 weeks (44-188). One case of disseminated tuberculosis occurred after 28 weeks of adalimumab treatment in a patient with LTBI in spite of treatment with rifampicin. This study is the first to underline the frequency of LTBI in patients with psoriasis (20%), and to support the use of IGRA instead of the TST for its detection. Nevertheless, there is still a risk of tuberculosis under anti-TNF therapy, even if LTBI is correctly diagnosed and treated.

Real-World Anti-Tumor Necrosis Factor Treatment in Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis: Cost-Effectiveness Based on Number Needed to Treat to Improve Health Assessment Questionnaire

To determine the effectiveness and cost-effectiveness of anti-tumor necrosis factor (anti-TNF) medications in a real-world environment for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) using the Health Assessment Questionnaire (HAQ). We created a database of patients with RA, PsA, or AS treated with anti-TNF agents (etanercept, infliximab, or adalimumab) at a large outpatient rheumatology clinic. Patient characteristics, baseline HAQ prior to treatment, subsequent yearly HAQ, and reasons for termination were collected. The cost based on percentage of patients achieving >or= 0.2 improvement in HAQ (minimal clinically important difference, MCID) was calculated using the 2008 direct cost (Cdn) of the medication. Data were available on 297 patients (206 with RA, 57 PsA, 34 AS). The mean age was 55 years, with 12 years of disease, and the mean baseline HAQ (standard error, SE) was 1.37 (0.04). The changes in HAQ (SE) at Years 1, 2, and 3 were -0.31 (0.04), -0.24 (0.06), and -0.27 (0.07) for annual cost to achieve MCID of $41,636, $42,077, and $42,147, respectively. The number needed to treat (NNT) was 1.94 (RA), 1.88 (PsA), and 2.30 (AS). There were no statistical differences between the diseases studied. We obtained data on the effectiveness and cost-effectiveness of anti-TNF drugs using the HAQ score, which is known to be an excellent predictor of work disability, morbidity, and mortality. HAQ scores decreased with treatment and were sustained throughout the 3-5 years of followup. The NNT of approximately 2 seems favorable and was similar between diseases.

Improvement of lipid profile is accompanied by atheroprotective alterations in high‐density lipoprotein composition upon tumor necrosis factor blockade: A prospective cohort study in ankylosing spondylitis

Cardiovascular mortality is increased in ankylosing spondylitis (AS), and inflammation plays an important role. Inflammation deteriorates the lipid profile and alters high-density lipoprotein cholesterol (HDL-c) composition, reflected by increased concentrations of serum amyloid A (SAA) within the particle. Anti-tumor necrosis factor (anti-TNF) treatment may improve these parameters. We therefore undertook the present study to investigate the effects of etanercept on lipid profile and HDL composition in AS. In 92 AS patients, lipid levels and their association with the inflammation markers C-reactive protein (CRP), erythrocyte sedimentation rate, and SAA were evaluated serially during 3 months of etanercept treatment. HDL composition and its relationship to inflammation markers was determined in a subgroup of patients, using surface-enhanced laser desorption/ionization time-of-flight analysis. With anti-TNF treatment, levels of all parameters of inflammation decreased significantly, whereas total cholesterol, HDL-c, and apolipoprotein A-I (Apo A-I) levels increased significantly. This resulted in a better total cholesterol:HDL-c ratio (from 3.9 to 3.7) (although the difference was not statistically significant), and an improved Apo B:Apo A-I ratio, which decreased by 7.5% over time (P=0.008). In general, increases in levels of all lipid parameters were associated with reductions in inflammatory activity. In addition, SAA was present at high levels within HDL particles from AS patients with increased CRP levels and disappeared during treatment, in parallel with declining plasma levels of SAA. Our results show for the first time that during anti-TNF therapy for AS, along with favorable changes in the lipid profile, HDL composition is actually altered whereby SAA disappears from the HDL particle, increasing its atheroprotective ability. These findings demonstrate the importance of understanding the role of functional characteristics of HDL-c in cardiovascular diseases related to chronic inflammatory conditions.

A new low-field extremity magnetic resonance imaging and proposed compact MRI score: evaluation of anti-tumor necrosis factor biologics on rheumatoid arthritis

Magnetic resonance imaging (MRI) is a useful tool for evaluating disease activity and therapeutic efficacy in rheumatoid arthritis (RA). However, conventional whole-body MRI is inconvenient on several levels. We have therefore developed a new low-field extremity MRI (compact MRI, cMRI) and examined its clinical utility. Thirteen RA patients treated with anti-tumor necrosis factor (TNF) biologics were included in the study. The MRI was performed twice using a 0.21-T extremity MRI system. The MRI images were scored using our proposed cMRI scoring system, which we devised with reference to the Outcome Measures in Rheumatology Clinical Trials RA MRI score (OMERACT RAMRIS). In our cMRI scoring system, synovitis, bone edema, and bone erosion are separately graded on a scale from 0 to 3 by imaging over the whole hand, including the proximal interphalangeal joint. The total cMRI score (cMRIS) is then obtained by calculating the total bone erosion score × 1.5 + total bone edema score × 1.25 + total synovitis score. In this study, one patient showed a progression of bone destruction even under low clinical activity, as assessed by the disease activity score on 28 joints (DAS28); however, another patient’s cMRIS decreased concurrently with the decrease in DAS28, with the positive correlation observed between ΔDAS28 and ΔcMRIS (R = 0.055, P < 0.05). We conclude that cMRI and cMRIS are useful for assessing total disease activity and as a method linking MRI image evaluation to clinical evaluation.

Interpreting lipid levels in the context of high-grade inflammatory states with a focus on rheumatoid arthritis: a challenge to conventional cardiovascular risk actions

In severe untreated rheumatoid arthritis (RA), reductions in high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol and total cholesterol have been noted; this is in line with findings in other pathologies/conditions associated with inflammation...

Patient’s Perspectives Important for Early Anti-Tumor Necrosis Factor Treatment in Inflammatory Bowel Disease

Background/Aim: We hypothesized that limited information is given to patients on the risks and benefits of individual therapy, and feedback is lacking to verify if patients correctly interpreted the given information. We assessed the perspectives of patients with inflammatory bowel disease (IBD) concerning the treatment-associated risks/benefits of infliximab. Methods: Patients were asked to complete a survey regarding the benefits and risks of infliximab. Results are reported as descriptive statistics. Comparisons between groups were analyzed using independent t tests and the Kruskal-Wallis test. Results: In total, 152 IBD patientscompleted the questionnaire. Fifty-seven percent (78/138) estimated the 1-year remission rate from infliximab to be >50%. Seventy-one percent (104/146) indicated they would not take a drug with risks reflecting those estimated for infliximab if the 1-year remission rate was <75%. Crohn’s disease patients and those recalling a discussion regarding the risks/benefits of infliximab treatment had higher estimates of the 1-year remission rate with infliximab than ulcerative colitis patients (p = 0.03) and patients who did not recall previous information (p = 0.03). Perceptions were independent of age and disease duration. Conclusion: IBD patients misperceive the risks and benefits of infliximab. The majority of patients would not accept treatment-related risks if the 1-year remission rate was <75%. Counseling on treatment-associated risks and benefits should be ameliorated.

Intradermal influenza vaccination in immunocompromized patients is immunogenic and feasible

Background Many strategies, including intradermal vaccination, have been tested to augment antibody responses upon vaccination. This strategy has not been evaluated in different groups of immunocompromized patients. We conducted a prospective, randomized study to compare the humoral response upon standard intramuscular influenza vaccination with the response upon reduced-dose intradermal vaccination in patients treated with anti-tumor necrosis factor (TNF)-alpha, human immunodeficiency virus (HIV)-infected patients, hematologic stem cell transplantation (HSCT) patients, and healthy controls. Methods In total 156 immunocompromized patients and 41 healthy controls were randomized to receive either 0.5 mL of the 2005/2006 trivalent influenza vaccine intramuscular or 0.1 mL intradermal. Humoral responses, determined by hemagglutination inhibition assay, were measured before and 28 days postvaccination. Geometric mean titers (GMTs) and protection rates (PRs) are reported as primary outcomes, adverse events as a secondary outcome. Results Reduced-dose intradermal vaccination leads to similar GMTs and PRs, within all tested groups, compared to the standard intramuscular vaccination. Healthy controls yielded significantly better GMTs and PRs than immunocompromized patients. Local skin reactions after intradermal vaccination occurred less frequent and were milder in immunocompromized patients than in healthy subjects and were predictive for a positive vaccination outcome for individual subjects. Conclusions Intradermal influenza vaccination is a feasible alternative for standard intramuscular vaccination in several groups of immunocompromized patients, including those treated with anti-TNF, HIV-infected patients and HSCT patients. The occurrence of a local skin reaction after intradermal vaccination is predictive of a response to at least one of the vaccine antigens.

Six and 12 Weeks Treatment Response Predicts Continuation of Tumor Necrosis Factor Blockade in Rheumatoid Arthritis: An Observational Cohort Study from Southern Sweden

To investigate if treatment response predicts continuation of anti-tumor necrosis factor (TNF) treatment in patients with rheumatoid arthritis (RA). We investigated if treatment response and/or achieving a certain activity state at 6 weeks or 3 months predicts continuation of treatment in an observational cohort of 1789 anti-TNF-naive patients with established RA disease from southern Sweden. Response to treatment at 6 weeks at overall/American College of Rheumatology (ACR20) or good/major level (except ACR70) significantly predicted drug continuation. Response according to all criteria sets at overall/ACR20 and at good/major/ACR70 level predicted drug continuation at 3 months, as did achieving low disease activity at 3 months irrespective of activity index applied. Remaining in a high disease activity state predicted drug discontinuation at both timepoints and according to all criteria sets. Response criteria may be useful aids in deciding on continuation of TNF blockade in RA as early as after 6 weeks of treatment. The various criteria sets perform similarly.

Sustained improvement of vascular endothelial function during anti‐TNFα treatment in rheumatoid arthritis patients

Objectives: Vascular endothelial function and common carotid artery intima–medial thickness (CCA‐IMT) are well‐established surrogate markers for early atherosclerotic disease, which accounts for 30–40% of excess mortality in rheumatoid arthritis (RA) patients. Our aim was to investigate whether long‐term treatment with anti‐tumour necrosis factor (TNF)α agents can modulate endothelial function and CCA‐IMT.Methods: Twelve patients with RA (mean age 54.8±15 years) on anti‐TNFα treatment (seven adalimumab, five infliximab) due to uncontrolled disease activity, with mean Disease Activity Score (DAS28) 5.7 (range 4.6–6.9) despite disease‐modifying anti‐rheumatic drugs (DMARDs), were studied prospectively. Patients were assessed at baseline and after 3 and 18 months for endothelial‐dependent vasodilatation, assessed by flow‐mediated vasodilatation (FMD), endothelial‐independent vasodilatation and CCA‐IMT. RA disease activity and response to therapy were assessed by the DAS28 index.Results: After 18 months of treatment, 67% of the patients were responders according to European League Against Rheumatism (EULAR) response criteria. Anti‐TNFα treatment improved FMD (from 7±4.3% to 11.1±3.8%, p = 0.026) whereas CCA‐IMT did not change significantly [from 0.67 (0.4–1) to 0.68 (0.39–1.2) mm; mean change 0.01 (−0.06 to 0.08) mm]. Endothelial‐independent vasodilatation remained stable (20.4±7.3% to 22.9±6.5%, p = 0.4).Conclusions: In this small cohort of patients with RA and no clinically overt cardiovascular disease (CVD), after 18 months of treatment with anti‐TNFα agents, endothelial function improved significantly while CCA‐IMT remained stable. Longitudinal studies using more patients are needed to determine the clinical significance of these findings in relation to the risk of atherosclerosis.

Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not carriage of shared epitope or PTPN22 susceptibility variants, with anti-tumour necrosis factor response in rheumatoid arthritis

Objective:To determine whether rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibodies, or carriage of shared epitope (SE) and PTPN22 genetic susceptibility variants predict response to therapy in patients with rheumatoid...

The safety of anti-tumour necrosis factor treatments in rheumatoid arthritis: meta and exposure-adjusted pooled analyses of serious adverse events

Objective:To evaluate the safety of biological treatments for rheumatoid arthritis (RA) using results from randomised controlled trials (RCT).Methods:The literature was searched to December 2007 for RCT evaluating inhibitors of tumour...

Cardiovascular, rheumatologic, and pharmacologic predictors of stroke in patients with rheumatoid arthritis: A nested, case–control study

To determine the risk of stroke in patients with rheumatoid arthritis (RA) and risk factors associated with stroke. We performed nested case-control analyses within a longitudinal databank, matching up to 20 controls for age, sex, and time of cohort entry to each patient with stroke. Conditional logistic regression was performed as an estimate of the relative risk of stroke in RA patients compared with those with noninflammatory rheumatic disorders, and to examine severity and anti-tumor necrosis factor (anti-TNF) treatment effects in RA. We identified 269 patients with first-ever all-category strokes and 67 with ischemic stroke, including 41 in RA patients. The odds ratio (OR) for the risk of all-category stroke in RA was 1.64 (95% confidence interval [95% CI] 1.16-2.30, P = 0.005), and for ischemic stroke was 2.66 (95% CI 1.24-5.70, P = 0.012). Ischemic stroke was predicted by hypertension, myocardial infarction, low-dose aspirin, comorbidity score, Health Assessment Questionnaire score, and presence of total joint replacement, but not by diabetes, smoking, exercise, or body mass index. Adjusted for cardiovascular and RA risk factors, ischemic stroke was associated with rofecoxib (P = 0.060, OR 2.27 [95% CI 0.97-5.28]), and possibly with corticosteroid use. Anti-TNF therapy was not associated with ischemic stroke (P = 0.584, OR 0.80 [95% CI 0.34-1.82]). RA is associated with increased risk of stroke, particularly ischemic stroke. Stroke is predicted by RA severity, certain cardiovascular risk factors, and comorbidity. Except for rofecoxib, RA treatment does not appear to be associated with stroke, although the effect of corticosteroids remains uncertain.

Heart rate variability predicts anti-tumor necrosis factor therapy response for inflammatory arthritis

To consider autonomic status as a predictor of anti-tumor necrosis factor (TNF) treatment response for inflammatory arthritis, we conducted an exploratory, double-blind, 52-week study with 33 patients with rheumatoid (25) or psoriatic (8) arthritis using heart rate variability (HRV). All were assessed for parasympathetic, sympathetic, total power and tension index measures of autonomic reactivity at initiation of anti-TNF therapy with etanercept (15) or adalimumab (18). Clinical response was assessed at 6, 12, 26 and 52 weeks by internationally accepted outcome criteria (ACR20/50/70 and DAS28 response). Predictive value was demonstrated for all HRV assessments ( p-value range 0.001–0.032), except sympathetic ( p-value range 0.06–0.22), for ACR20, ACR50 and ACR70 at 52 weeks and at as early as 6 weeks for some measures. Only parasympathetic and tension index predicted DAS28 outcome ( p-value range 0.009–0.024). Poor anti-TNF response was associated with low parasympathetic, low total power, high sympathetic and high tension index measures, a profile also predominant in the prior anti-TNF failure subset (12). In conclusion, this unique, exploratory study suggests that HRV may be a novel, useful predictor of response to anti-TNF therapy in patients with inflammatory arthritis, and emphasizes the importance of autonomic influence of autoimmune disease expression.

Evaluating guidelines on continuation of anti-tumour necrosis factor treatment after 3 months: clinical effectiveness and costs of observed care and different alternative strategies

Objective:To study the adherence of rheumatologists to the Dutch guidelines for anti-tumour necrosis factor alpha (TNF-α) treatment. The secondary objective was to evaluate alternatives to the present guidelines with regard...

Research and development round-up: June 2008

Findings from a novel, randomized, double-blind, placebo-controlled Phase III study showed that patients with moderately-to-severely active rheumatoid arthritis (RA) who were previously treated with anti-tumor necrosis factor (TNF)-alpha agents, experienced significant improvements aft er receiving anti TNF-alpha therapy golimumab.

BDNF in RA: Downregulated in plasma following anti-TNF treatment but no correlation with inflammatory parameters

The involvement of brain-derived neurotrophic factor (BDNF) in rheumatoid arthritis (RA) is largely unknown. The distribution of BDNF and its associated receptors, TrkB and p75, in the synovial tissue of patients with RA was examined and contrasted with that in patients with osteoarthritis (OA). Additionally, levels of BDNF in both synovial tissue and synovial fluid were measured. Furthermore, the effects of anti-tumour necrosis factor (anti-TNF; infliximab) treatment on BDNF levels in the plasma of RA patients were analysed. Cells in the synovium showed immunoreactivity for BDNF and BDNF-, p75- and TrkB-receptor immunoreactions were seen in nerve fibres of nerve fascicles and in association with sensory corpuscles. The levels of BDNF in synovial tissue were not correlated with the number of inflammatory cells observed microscopically or with levels of TNFalpha. Nor did the BDNF levels in synovial fluid correlate with erythrocyte sedimentation rate (ESR) or white blood cell counts. Anti-TNF treatment lead to a decrease in plasma levels of BDNF 14 weeks after the initiation of anti-TNF therapy, i.e., 8 weeks after the last infusion. Higher levels of BDNF were observed in RA patients at baseline compared with those for healthy individuals. However, the levels of BDNF in plasma of patients treated with anti-TNF did not correlate with the changes in ESR or a disease activity score. The clinical significance of this study is that anti-TNF treatment influences plasma levels of BDNF although there was no evidence that BDNF levels correlate with inflammatory parameters in either infliximab-treated or non-infliximab-treated patients with RA. Instead it is likely that sources other than inflammatory cells, including nerve structures, are important sources of BDNF and that the effects of anti-TNF treatment on BDNF levels may be related to effects on circulating and various local cells and/or BDNF-containing neurons.

Preferential decrease in IgG4 anti-citrullinated protein antibodies during treatment with tumour necrosis factor blocking agents in patients with rheumatoid arthritis

Objective:To investigate the dynamics of IgG1 and IgG4 anti-citrullinated protein antibody (ACPA) subclasses during anti-tumour necrosis factor (TNF) treatment in patients with rheumatoid arthritis (RA).Methods:IgG, IgG1 and IgG4 ACPA levels...