Steroid therapy improves endothelial function in patients with biopsy-proven giant cell arteritis

OBJECTIVE: Endothelial dysfunction has been found to be present in subjects with both small and medium-size blood vessel vasculitides. We assess whether endothelial dysfunction was also present in patients with biopsy-proven giant cell arteritis (GCA) and whether it might be improved following steroid treatment. METHODS: Endothelial function was determined in cross-sectional and longitudinal studies of 6 patients with biopsy-proven GCA diagnosed between January and May 2002 by measuring flow-mediated endothelial-dependent and independent vasodilatation (EDV and EIV) by brachial ultrasonography. Patients were assessed for endothelial function within 48 hours after the onset of steroid therapy, 4 weeks after the onset of steroid therapy, and 2 years after the disease diagnosis. RESULTS: EDV was significantly impaired in patients with GCA compared with 12 matched controls [mean 2.9%, median 2.45% (range 2.1% to 4.7%) vs mean 6.5%, median 6.6% (range 3.9% to 9.3%) in matched controls; p = 0.002]. However, no significant difference existed between patients and controls in EIV. Significant improvement of EDV after the suppression of inflammation was achieved. At Week 4 after the onset of steroid therapy all 6 patients showed enhanced responses (p = 0.028). This improvement of EDV was still present when steroid treatment was ended, 2 years after diagnosis. CONCLUSION: Endothelial function is significantly impaired in individuals with active biopsy-proven GCA. The results highlight the importance of steroid therapy to improve endothelial function after suppression of the inflammation of GCA.     

Short-term adalimumab therapy improves endo-thelial function in patients with rheumatoid arthritis refractory to infliximab

OBJECTIVE: Endothelial dysfunction has been found in patients with rheumatoid arthritis (RA). In this study we aimed to assess whether adalimumab, a fully human monoclonal antibody directed against TNF-alpha, was able to improve endothelial function in RA patients with long-standing disease refractory to infliximab. METHODS: Eight RA patients (7 women; range: 24- 74 years) were studied. They had been treated with the chimeric monoclonal anti-TNF-alpha antibody-infliximab for at least 1 year and were switched to adalimumab therapy because of loss of efficacy following periodical treatment with infliximab. Endothelial dependent (EDV) and independent vasodilatation (EIV) were measured by brachial ultrasonography. Patients were assessed prior to (day 0) and at day 2, and weeks 2 and 12 after the onset of adalimumab therapy. RESULTS: Following adalimumab administration a rapid increase in the percentage (%) of EDV was found in all patients (mean +/- SD: 10.1 +/- 5.1% at day 2 compared to 5.8 +/- 4.1% at day 0). At weeks 2 and 12 the %EDV was also significantly increased compared to day 0. All patients showed decrease in the disease activity score 28 and C-reactive protein levels (P = 0.012). Moreover, at week 12 the atherogenic index was reduced in all patients (P = 0.012). CONCLUSION: Our study confirms that short-term adalimumab therapy yields an active and positive effect on endothelial function in long-standing RA patients with severe disease. This observation emphasizes the potential role of the TNF-alpha blockade in the mechanisms implicated in the development of atherogenesis in RA.     

Infliximab treatment shifts the balance between stimulatory and inhibitory Fcgamma receptor type II isoforms on neutrophils in patients with rheumatoid arthritis

OBJECTIVE: Human neutrophils express both activating and inhibitory Fcgamma receptors (FcgammaR), and their relative expression determines the inflammatory response to immune complexes. Tumor necrosis factor alpha (TNFalpha) up-regulates the expression of stimulatory FcgammaRIIa on neutrophils in vitro, and amplifies immune complex-induced activation of neutrophils in vivo. This study was undertaken to determine whether TNFalpha blockade in patients with rheumatoid arthritis (RA) alters the balance of activating FcgammaR and inhibitory FcgammaR and thereby decreases inflammation. METHODS: We used fluorescence-activated cell sorting and Western blotting to examine FcgammaR expression on neutrophils in 24 patients with RA, preceding their first infusion of infliximab and immediately prior to >or=3 subsequent infusions. RESULTS: In 13 of 24 patients (54.2%), there was a decrease in the expression of the predominant activating FcgammaR, FcgammaRIIa, after treatment with infliximab, an effect that persisted over >or=3 months of treatment. Although prior to initiation of infliximab therapy the inhibitory FcgammaR, FcgammaRIIb, was undetectable in neutrophils from 23 of 24 patients with RA, FcgammaRIIb protein was detected by Western blotting in 9 patients (37.5%) at the time of the third infliximab infusion. The induction of inhibitory FcgammaRIIb was always associated with decreased levels of FcgammaRIIa, and improvement following infliximab therapy, measured using the Health Assessment Questionnaire, was significantly associated with down-regulation of FcgammaRIIa. CONCLUSION: Our findings indicate that TNFalpha inhibition may reduce inflammation in patients with RA by restoring the balance of activating and inhibitory FcgammaR and thereby raising the threshold for immune complex-mediated activation of neutrophils.     

Ambulatory blood pressure and endothelium-dependent vasodilation in hypertensive patients

Endothelial function is important for local vascular regulation and an abnormal endothelium-dependent vasodilatation (EDV) has been observed in subjects with essential hypertension. As ambulatory blood pressure (ABP) is more closely related to target organ damage than office blood pressure, this study investigated also if 24-h ABP is more closely related to an impaired EDV than office blood pressure recordings. In a group of 25 untreated patients with essential hypertension and an age- and sex-matched control group (n = 21) endothelial function was evaluated by measurements of forearm blood flow (FBF) during local intra-arterial infusions of metacholine (evaluating EDV) and sodium nitroprusside (evaluating endothelium independent vasodilation, EIDV). FBF was measured with venous occlusion plethysmography. Both office mean artery pressure (MAP; r= -0.57, p < 0.001) and 24-h ABP (r = 0.40, p < 0.01) were related to the endothelial vasodilator function (EDV to EIDV ratio) in an inverse way, but ABP was not superior to office blood pressure recordings. Within the hypertensive group, pronounced white-coat effect (office minus daytime ABP) was associated with a reduced,EDV (r= 0.41, p < 0.05). The degree of night-time decline in blood pressure ("dipping") showed no correlation to EDV. In conclusion, the finding that ABP was no more closely related to the endothelial vasodilator function than office blood pressure recordings might be due to an increased mental alertness affecting EDV in some hypertensive subjects, as suggested by the finding of a reduced EDV in those with a pronounced white-coat effect.     

Intravenous cyclophosphamide plus methylprednisolone in treatment of systemic rheumatoid vasculitis

Systemic vasculitis in rheumatoid arthritis shows similarities to polyarteritis nodosa and may require equally aggressive therapy. Forty-five patients with systemic rheumatoid vasculitis were studied during treatment with either cyclophosphamide plus methylprednisolone given by intermittent bolus intravenous injection (21 patients) or a variety of other more conventional drug regimens (24 patients). In this open study, the intravenous treatment group had more severe initial disease, a higher incidence of neuropathy, and more frequent evidence of necrotizing arteritis on biopsy than the other treatment group. Despite this, intravenous cyclophosphamide plus methylprednisolone resulted in more frequent healing of vasculitic lesions including leg ulcers and neuropathy, a lower incidence of relapse, fewer serious complications, and a lower mortality than did other treatments. Toxic effects were similar in both study groups. Intravenous cyclophosphamide plus methylprednisolone is a useful early treatment for systemic rheumatoid vasculitis.     

Low dose of infliximab is inadequate in most patients with spondylarthropathies

OBJECTIVES: The recommended starting dose for infliximab for ankylosing spondylitis 5mg/kg is higher than that for rheumatoid arthritis. Because of the high expense of the drug lower doses may be considered. We report our experience with lower initial doses. METHODS: Thirty patients with active SpA (16 psoriatic arthritis, 12 ankylosing spondylitis and 2 undifferentiated) received 6 infliximab infusions. Patients had substantial axial disease (mean BASDAI at baseline 5.5). Concomitant therapy (methotrexate or prednisolone) remained stable throughout treatment period. The mean initial dose of infliximab was 3.5 mg/kg/infusion. Clinical efficacy was assessed by BASDAI. The criterion for dose adjustment was a BASDAI improvement of less than 50%. The primary end-points were the proportion of patients requiring a dose adjustment and the percentage of patients achieving 50% improvement in BASDAI after 6 infusions. RESULTS: In this cohort, 2 patients discontinued therapy, 1 for pulmonary infection and 1 for allergic reaction. Twelve patients (40%) showed 50% improvement in BASDAI between baseline and prior to the 7th infusion, while 15 patients (50%) had an improvement > 2 points. To achieve clinical response the frequency and/or the dose of infliximab infusions were increased in 63% of patients. The mean infliximab dose increased from 3.5 mg/kg at the first infusion to 4.3 mg/kg (p < 0.001) at the 7th infusion, resulting in a cumulative dose at the end of the study period comparable to the recommended one. CONCLUSIONS: In the majority of our SpA patients low starting doses of infliximab required subsequent adjustment. In these patients infliximab should be administered at the recommended dose of 5mg/kg/infusion.     

TNF-alpha blockade induces a reversible but transient effect on endothelial dysfunction in patients with long-standing severe rheumatoid arthritis

Considerable evidence indicates that patients with rheumatoid arthritis (RA) are at greater risk of developing atherosclerosis and cardiovascular disease. Recent studies support the predictive ability of endothelial function measures for subsequent atherosclerotic events. We have investigated the effects of infliximab, a chimeric monoclonal anti-tumor necrosis factor (TNF) antibody, on endothelial vasodilation, measured by brachial ultrasonography and on the levels of inflammatory biomarkers and adhesion molecules in ten consecutive patients with severe long-standing RA, despite methotrexate therapy, during the loading phase of infliximab therapy. Flow-mediated dilation (FMD) in RA patients at baseline was significantly impaired compared with healthy controls (7.71 +/- 2.78% vs 14.91 +/- 6.41%; p = 0.008) and improved significantly after infliximab infusion (12.63 +/- 1.63% vs 7.71 +/- 2.78%; p = 0.005). At baseline, a statistically significant correlation between C-reactive protein levels and FMD was found (r = -0.69, p = 0.026). However, this improvement was transitory, as FMD values returned to baseline values before each infliximab infusion at weeks 2, 6 and 14. There were no significant differences in baseline brachial artery diameter between visits, although at each time, the diameter was increased. According to European League Against Rheumatism response criteria, all ten patients were good responders. No significant differences were observed in intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, vascular endothelial growth factor and E-selectin plasma levels before and after each infusions. This study demonstrates that endothelial dysfunction is a reversible phenomenon in RA. The addition of anti-TNFalpha treatment reduces inflammatory symptoms in patients with severe RA. The improvement of endothelial function during the loading phase of therapy is transitory, suggesting an enhanced and persistent TNF-alpha generation within the arterial wall.     

Continuation of treatment with infliximab in ankylosing spondylitis: 2-yr open follow-up

OBJECTIVE: To evaluate the continuation and safety of treatment with infliximab in ankylosing spondylitis (AS) over a 2-yr period. METHODS: This study was an open, observational, 2-yr extension study of an open-label study of three induction infusions of infliximab in refractory AS. The fourth infusion was performed only in case of relapse. Thereafter, infliximab was to be administered as needed according to the rheumatologist's opinion; however, for some patients, infusions were performed systematically. RESULTS: None of the 50 recruited patients was lost to follow-up. Thirteen patients (26%) interrupted their treatment by infliximab: four for inefficacy, seven for adverse events, of which four were for allergic reactions to the infusion, and two for other reasons. For all of the 46 patients who had had three infusions judged efficacious and well tolerated, a fourth infusion was performed because of a flare of the disease, after a mean interval of 20.3+/-9.9 weeks (range 7.3-57.9). Over the 24 months, the mean interval between infusions was 11.6+/-9.0 weeks. This interval was longer when patients were treated only as needed (mean 14.3+/-12.1 weeks) than systematically (mean 9.8+/-5.7 weeks). Side-effects were similar to those noted in shorter-term studies; seven patients suffered serious adverse events. There were no deaths, no malignancies and no tuberculosis. CONCLUSION: This study confirms the long-term treatment continuation of infliximab in AS, and shows an acceptable safety profile. It appears that for some patients the disease can be controlled with long intervals between infusions; these findings warrant further studies.     

Successful treatment of active ankylosing spondylitis with the anti-tumor necrosis factor alpha monoclonal antibody infliximab

OBJECTIVE: Tumor necrosis factor alpha (TNFalpha) has been detected in sacroiliac joint biopsy specimens from patients with spondylarthropathy. The present open pilot study was undertaken to test the efficacy of the anti-TNFalpha monoclonal antibody infliximab in the treatment of active ankylosing spondylitis (AS). METHODS: Eleven patients with AS of short duration (median 5 years, range 0.5-13 years) that had been active for at least 3 months (range 3-72 months) were treated with 3 infusions of infliximab (at weeks 0, 2, and 6), in a dosage of 5 mg/kg. Ten of the 11 patients had elevated C-reactive protein (CRP) levels (>6 mg/liter) before treatment; these elevations were known to have had persisted > 1 year in at least 3 patients. The Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index (BASFI), pain as measured on a visual analog scale, and the Bath AS Metrology Index (BASMI) were assessed. Quality of life was assessed using the Short Form 36 instrument. Laboratory markers of disease activity, including interleukin-6 (IL-6) levels, were determined. Dynamic magnetic resonance imaging (MRI) of the spine was performed in 5 patients. RESULTS: One patient withdrew from the study due to the occurrence of urticarial xanthoma 8 days after the first infusion. At study enrollment, 3 of 5 patients had evidence of spinal inflammation (spondylitis and spondylodiscitis) as detected by MRI; followup MRI 2-6 weeks after the third infusion revealed improvement in 2. Improvement of > or = 50% in activity, function, and pain scores was documented in 9 of 10 patients; the median improvement in the BASDAI after 4 weeks was 70% (range 41-94%). This clear-cut benefit lasted for 6 weeks after the third infusion in 8 of 10 patients. The median CRP level decreased from 15.5 mg/liter (range <6-90.8) to normal, and the median IL-6 level from 12.4 mg/liter (range 0-28.4) to normal (<5). There was improvement in all 9 SF-36 concepts; the improvement was significant for 6 concepts. CONCLUSION: These data suggest that anti-TNFalpha therapy is very effective for several weeks in AS. Whether this therapy, in addition to its antiinflammatory effect, prevents ankylosis remains to be determined.     

The effect of acute hyperglycaemia on brachial artery flow mediated dilatation in normal volunteers

Abstract Background : Endothelial function is known to be abnormal in patients with diabetes and acute hyperglycaemia may play an aetiological role.
Aims : The aim of this randomised controlled study was to determine if acute systemic hyperglycaemia impairs endothelial function in normal subjects.
Methods : Endothelial function was assessed by the change in brachial artery diameter in response to forearm ischaemia using B-mode ultrasound in ten healthy subjects (eight male) aged 19–35 years. Brachial artery blood flow velocity and diameter were measured before and after five minutes of forearm ischaemia. Measurements were performed in the supine position after an overnight fast, before and after 60 minute infusions of 0.9% saline or 10% dextrose. Measurements were made on two separate occasions at least 24 hours apart, and subjects were randomised to saline first or dextrose first. The largest diameter measured after ischaemia was divided by the resting arterial diameter to calculate percent dilatation of the artery from baseline, and is reported as flow-mediated dilatation (FMD).
Results : Dextrose infusion resulted in a significant rise in mean (SD) serum glucose 5.2 (0.1) to 9.2 (0.3) mmol/L and insulin concentration 6.3 (1.4) to 20.6 (3.7) mU/L p <0.002. Brachial artery blood flow velocity and diameter increased significantly from baseline after ischaemia ( p <0.002). Mean FMD (SEM) before and after infusion were not, however, significantly different ( p =0.4) (pre-saline 7.3 [1.0]%, post saline 5.2 [1.5]% and predextrose 8.1 [2.0]%, post dextrose 5.9 [1.7]%).
Conclusions : These data suggest that acute hyperglycaemia does not impair FMD in normal subjects.     

Soluble intercellular adhesion molecule-1 is related to endothelial vasodilatory function in healthy individuals

OBJECTIVE: To investigate the associations between markers of systemic and vascular inflammation, and indicators of vascular morphology and function. METHODS: In 59 apparently healthy individuals, we measured serum levels of highly sensitive C-reactive protein (hsCRP), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. Endothelium-dependent (EDV) and -independent (EIDV) vasodilatation was evaluated in the forearm by venous occlusion plethysmography and local infusions of methacholine and sodium nitroprussid. Endothelial function index (EFI) was expressed as the EDV/EIDV ratio. The intima-media thickness (IMT) of the common carotid artery was investigated with ultrasound (far wall). RESULTS: EFI was inversely related only to ICAM-1 (r=-0.31, P<0.02) by univariate analysis. This association remained significant after adjustment for age, sex, blood pressure, smoking and serum cholesterol. EFI did not relate to hsCRP, VCAM-1 or E-selectin. Neither hsCRP, nor the adhesion molecules were significantly related to carotid artery IMT. CONCLUSION: ICAM-1 was related to endothelial vasodilatory function, but not to IMT, suggesting that endothelial inflammatory activation is related to an impaired vascular relaxation in apparently healthy individuals.     

Effect of anti TNFalpha therapy on arterial diameter and wall shear stress and HDL cholesterol

It has been recently hypothesized that both TNFalpha and anti TNFalpha treatment have a stimulating effect on nitric oxide synthesis and release. Moreover, an in vitro experiment has demonstrated that HDL-cholesterol binds TNFalpha. Aims of our study were to investigate wall shear stress of peripheral arteries and endothelial function of brachial artery in subjects with Rheumatoid Arthritis (RA) at baseline and after infliximab. Moreover, we evaluated the effect of anti TNFalpha therapy on lipid profile. Ten patients with RA received infliximab therapy at weeks 0, 2 and 6. Lipids and vascular parameters were measured before and the day after each infusion. After the first treatment, FMD increased (3.7 +/- 1.9% versus 17.5 +/- 2.9%, P <0.01) and common carotid and brachial artery diameters decreased (5.9 +/- 0.2 mm versus 5.5 +/- 0.2 mm; 3.5 +/- 0.4 mm versus 3.1 +/- 0.4 mm, respectively, P <0.005). Common carotid and brachial artery wall shear stress increased (21.1 +/- 1.1 dynes/cm2 versus 23.9 +/- 1.4 dynes/cm2; 42.0 +/- 4.7 dynes/cm2 versus 51.6 +/- 5.7 dynes/cm2, P <0.01). Similar results were observed after the second and third infusion. All these parameters returned to pre-treatment level at the following infusion. HDL-cholesterol and apolipoprotein AI significantly decreased after each treatment (1st treatment: 1.4 +/- 0.05 mmol/L versus 1.2 +/- 0.06 mmol/L, P <0.01; 1.73 +/- 0.05 g/L versus 1.57 +/- 0.02 g/L, P <0.03). The present data show vasoconstriction and an increase of wall shear stress in studied arteries after infliximab. HDL cholesterol is reduced by treatment and does not seem to influence FMD.     

Active but transient improvement of endothelial function in rheumatoid arthritis patients undergoing long-term treatment with anti-tumor necrosis factor alpha antibody

OBJECTIVE: Cardiovascular disease is the major cause of excessive mortality in rheumatoid arthritis (RA). Atherosclerosis and RA share similar inflammatory mechanisms that include involvement of tumor necrosis factor alpha (TNF alpha). Anti-TNF alpha antibody improved endothelial function in RA patients after a 12-week treatment. The aim of the present study was to assess whether improvement of endothelial function is still effective in long-term infliximab-treated RA patients. METHODS: Seven RA patients (5 women; age range 25-73 years) were studied. They had been treated with infliximab for at least 1 year and were currently being treated with this drug every 8 weeks. Endothelial-dependent and independent vasodilatation were measured by brachial ultrasonography. RESULTS: Following infliximab infusion, a rapid increase in the percentage of endothelial-dependent vasodilatation was found in all patients (mean +/- SD 9.4 +/- 5.5% 2 days postinfusion compared with 2.8 +/- 2.5% 2 days before infusion). However, values returned to baseline by 4 weeks after infusion. There were no differences in the percentage of endothelial-independent vasodilatation prior to and after infusion. A decrease in the individual disease activity score for each patient was observed at day 7 postinfusion (P = 0.02). CONCLUSION: Our study confirms an active but transient effect of infliximab on endothelial function in RA patients treated periodically with this drug. It may support long-term use of drugs that block TNF alpha function to reduce the high incidence of cardiovascular complications in RA.     

Effects of short-term infliximab therapy on autoantibodies in systemic lupus erythematosus

OBJECTIVE: To analyze changes in autoantibodies occurring in patients with systemic lupus erythematosus (SLE) treated with 4 infusions of the chimeric anti-tumor necrosis factor alpha (TNFalpha) antibody infliximab. METHODS: In an open-label safety study, 7 patients with SLE were treated with infliximab at weeks 0, 2, 6, and 10 in combination with azathioprine or methotrexate. Antibodies to double-stranded DNA (dsDNA) were determined by radioimmunoassay and the Crithidia luciliae indirect immunofluorescence assay; anticardiolipin antibodies (aCL) and antibodies to histone and chromatin were measured by enzyme-linked immunosorbent assay. Antihistone antibodies were also analyzed by immunoblotting. Peripheral blood mononuclear cells from healthy individuals and SLE patients were incubated for 2 weeks with or without TNFalpha. TNFalpha was removed by washing and by the addition of infliximab. Apoptotic cells were stained with annexin V and analyzed by flow cytometry. RESULTS: Autoantibodies to dsDNA increased in 5 of 7 patients. Histone, chromatin, and IgM aCL levels were increased in 4 of 7, 6 of 7, and 4 of 7 patients, respectively, peaking 4-10 weeks after the last infliximab infusion, but falling to baseline levels or lower thereafter. In the in vitro experiments, TNF withdrawal after long-term incubation with recombinant human TNF led to increased percentages of apoptotic cells. CONCLUSION: While TNF blockade was clinically effective, the majority of SLE patients treated with infliximab showed an increase in autoantibodies to nuclear antigens and phospholipids. These increases were transient and were not associated with disease flares. Increased availability of apoptotic antigens after TNF blockade may play a role in the autoantibody formation induced by TNF blockade.     

Infliximab in patients with primary Sjögren's syndrome: a pilot study

OBJECTIVE: Tumor necrosis factor alpha (TNFalpha) is a proinflammatory cytokine involved in the pathogenesis of Sj?gren's syndrome (SS), and blockade of TNFalpha may reduce the activity of the disease. The purpose of this study was to evaluate the safety and potential efficacy of infliximab, a chimeric human-mouse anti-TNFalpha monoclonal antibody, in patients with active primary SS. METHODS: This was a single-center, open-label pilot study. Sixteen patients with active primary SS received 3 infusions of infliximab (3 mg/kg) at 0, 2, and 6 weeks. Standard clinical assessment, complete ophthalmologic testing, and functional evaluation of salivary flow were performed at baseline and at weeks 2, 6, 10, and 14. RESULTS: All patients completed the study. There was statistically significant improvement in all clinical and functional parameters, including global assessments (patient's global assessment, patient's assessment of pain and fatigue, physician's global assessment), erythrocyte sedimentation rate, salivary flow rate, the Schirmer I test, tender joint count, fatigue score, and dry eyes and dry mouth. This clinical benefit was observed at week 2 and was maintained throughout the study and the 2-month followup period. The treatment was well tolerated in all patients, and no significant adverse events were seen. No lupus-like syndrome was observed, and no anti-double-stranded DNA antibodies were observed that were attributable to infliximab therapy. CONCLUSION: In patients with active primary SS, a loading-dose regimen of 3 infusions of infliximab provided a fast and significant clinical benefit without major adverse reactions. It was possible to maintain statistically significant improvement for up to 8 weeks after the third infusion.     

Infusion-related reactions to infliximab in patients with rheumatoid arthritis in a clinical practice setting: relationship to dose, antihistamine pretreatment, and infusion number

OBJECTIVE: We describe infusion-related reactions to infliximab (during infusion or within 1 hour postinfusion) in patients with active rheumatoid arthritis (RA) treated in a quaternary care center. METHODS: We followed 113 patients for a mean of 60.6 +/- 28.9 weeks, obtaining 10.5 +/- 4.9 infusions per patient. RESULTS: We observed 1183 infusions resulting in 104 infusion reactions (8.8%). All reactions resolved within several hours following cessation of the infusion and none was serious enough to warrant hospitalization. Reactions included allergic reactions (pruritis, urticaria) in 4.2% of infusions, cardiopulmonary (hypotension, hypertension, tachycardia) in 3.0%, and miscellaneous reactions (headache, nausea, vomiting) in 2.0%. Reactions occurred in 8.0% of 3 mg/kg infusions and in 10.3% of 5 mg/kg infusions. Reactions occurred in 13.2% of infusions that involved antihistamine pretreatment compared to only 7.5% of infusions that involved no pretreatment. At both infliximab doses, there was a similar frequency of infusion reactions in patients pretreated due to a previous infusion (12.6%) compared to those pretreated strictly based on infusion number (14.7%). A number of the reactions involving antihistamine pretreatment may be explained by known side effects of diphenhydramine, including headache, dizziness, nausea, and palpitations. CONCLUSION: Infusion-related reactions to infliximab were infrequent, rarely severe, and easily manageable. The frequency of reactions was equivalent in patients treated with 3 mg/kg compared to 5 mg/kg. Reactions were significantly more frequent in infusions where patients were pretreated with the antihistamine diphenhydramine, compared to those not involving pretreatment.     

Active but transient improvement of endothelial function in rheumatoid arthritis patients undergoing long‐term treatment with anti–tumor necrosis factor α antibody

Objective

Cardiovascular disease is the major cause of excessive mortality in rheumatoid arthritis (RA). Atherosclerosis and RA share similar inflammatory mechanisms that include involvement of tumor necrosis factor α (TNFα). Anti‐TNFα antibody improved endothelial function in RA patients after a 12‐week treatment. The aim of the present study was to assess whether improvement of endothelial function is still effective in long‐term infliximab‐treated RA patients.

Methods

Seven RA patients (5 women; age range 25–73 years) were studied. They had been treated with infliximab for at least 1 year and were currently being treated with this drug every 8 weeks. Endothelial‐dependent and independent vasodilatation were measured by brachial ultrasonography.

Results

Following infliximab infusion, a rapid increase in the percentage of endothelial‐dependent vasodilatation was found in all patients (mean ± SD 9.4 ± 5.5% 2 days postinfusion compared with 2.8 ± 2.5% 2 days before infusion). However, values returned to baseline by 4 weeks after infusion. There were no differences in the percentage of endothelial‐independent vasodilatation prior to and after infusion. A decrease in the individual disease activity score for each patient was observed at day 7 postinfusion (P = 0.02).

Conclusion

Our study confirms an active but transient effect of infliximab on endothelial function in RA patients treated periodically with this drug. It may support long‐term use of drugs that block TNFα function to reduce the high incidence of cardiovascular complications in RA.

     

Open label study to assess infliximab safety and timing of onset of clinical benefit among patients with rheumatoid arthritis

OBJECTIVE: To assess the timing of onset of clinical benefit following the initial infusion of infliximab and to obtain additional safety experience of infliximab when given in an office setting to patients with rheumatoid arthritis (RA). In addition, the safety of reducing the infusion time from 2 hours to 1 hour was evaluated. METHODS: Patients (n = 553) with active RA despite receiving methotrexate (MTX) were treated with infliximab 3 mg/kg given over 2 h at baseline (Week 0), and Weeks 2, 6, and 14 in this multicenter open-label trial. Patients continued to receive a stable dose of MTX (> or = 7.5 mg/wk). At selected sites, patients tolerating the first 4 infusions were eligible to receive 2 additional infusions at twice the usual infusion rate (given over 1 h). Patients returned for efficacy assessments at 48 h following the initial infusion and several times throughout study participation. RESULTS: By 48 h following the first infusion, significant (p < 0.001) improvements were observed in duration of morning stiffness (34% mean improvement), physician's global disease assessment scores (30%), patient's global disease assessment scores (25%), and patient's pain assessment scores (30%). By Week 16, 52 to 63% mean improvements in these efficacy variables were observed (p < 0.001), the significant improvement was maintained through the end of study participation in the subset of patients who received the additional 1 h infliximab infusions. Through 16 weeks, 10% (54/553) of patients reported an adverse event associated with at least 1 of the 4 infusion procedures; the majority were mild and transient in nature. In the subset of 197 patients who received 2 additional infusions over 1 h, no increase in the frequency or severity of infusion-related adverse events was observed compared to the 2 h infusion. CONCLUSION: Infliximab administered to patients with RA in an outpatient setting resulted in significant clinical improvement within 48 h that was sustained with additional infusions. Approximately 10% of patients experienced an infusion reaction, highlighting the need for direct supervision over patient treatment. Patients who tolerated infliximab infusions given over 2 h also tolerated a 1 h infusion.     

Analysis of efficacy and safety of multiple intravenous infusion of anti-tumor necrosis factor-alpha monoclonal antibody (Remicade) combined with methotrexate compared with sodium aurothiomalate and intramuscular depot methylprednisolone in rheumatoid arthritis

The objective of the paper was compare the effects and tolerability of combined therapy of multiple intravenous infusions of anti-tumour necrosis factor-alfa (TNF-alfa) monoclonal antibody (Remicade) with methotrexate versus treatment with sodium aurothiomalate and intramuscular depot methylprednisolone in rheumatoid arthritis (RA). We investigate also the interval necessary to obtain the improvement in both treatment groups. 36 patients commencing intramuscular sodium aurothiomalate therapy with intramuscular depot methylprednisolone acetate at weeks 0, 4, 8 and 12 in addition to chrysotherapy were compared in retrospective analysis with 32 patients starting with multiple intravenous infusions of infliximab, anti-TNF-alfa monoclonal antibody (Remicade) and methotrexate at a stable dose. Patients were assessed by composite clinical score (DAS 28) and C-reactive protein during 22 weeks of therapy. At week 2 and 6 a significantly greater percentage of infliximab-treated than gold-treated RA patients achieved improvement in each clinical measurement of disease activity. At 22 week of treatment moderate and good response according to EULAR criteria was achieved in 91% of infliximab-treated patients and 58% gold treated patients (p < 0.001). Adverse events were more frequently observed in infliximab-treated patients, but only gold-treated patients discontinued treatment because adverse events (2 patients due to proteinuria, 2 patients due to mucocutaneous changes and one patient due to leucopenia). The higher percentage of adverse events in infliximab-treated patients was caused mainly by the occurrence of infusion reactions (23 reactions out of 160 infusions); most of them were mild (somnolentia and headache) and transient. Viral infections (including herpes simplex and zoster) were more common in patients treated with infliximab and methotrexate. Combination therapy of infliximab and methotrexate is more effective in reducing clinical and biochemical disease activity than gold with methylprednisolone treatment in RA patients during 22 weeks of treatment, especially in the first 6 weeks.