Tumor necrosis factor alpha (TNF-α) is an inflammatory cytokine that has been implicated in a variety of rheumatic and inflammatory diseases. New understanding of the importance of TNF-α in the pathophysiology of rheumatoid arthritis and Crohn's disease led to the development of a new class of targeted anti-TNF therapies. Anti-TNF-α agents including etanercept (a fusion protein of the p75 TNF receptor and IgG1) and infliximab (a chimeric monoclonal antibody specific for TNF-α) have been approved for the treatment of rheumatoid arthritis. In addition, infliximab has been approved in the treatment of patients with active or fistulating Crohn's disease. A new appreciation of the importance of TNF-α in other rheumatic and inflammatory diseases has led to a broadening of the application of anti-TNF agents. Both etanercept and infliximab have been used in open-label and randomized studies in patients with psoriatic arthritis. Although larger randomized trials are needed to confirm early results, both these anti-TNF-α agents, etanercept and infliximab, have demonstrated activity in improving the signs and symptoms of psoriatic arthritis and psoriasis. Infliximab has also been shown to be effective in patients with other rheumatic diseases, including ankylosing spondylitis, and may be effective in adult-onset Still's disease, polymyositis, and Behçet's disease. Further investigations will fully elucidate the role of infliximab in these and other rheumatic diseases.
anti-tumor necrosis factor; cytokine; infliximab; rheumatic disease; tumor necrosis factor
Infliximab was the first monoclonal antibody to human necrosis factor alpha (TNFα) developed for treating rheumatoid arthritis (RA). This chimeric antibody binds with high affinity to both soluble and trans-membrane TNF and is able to reduce synovial inflammation, bone resorption and cartilage degradation. The efficacy of infliximab has been observed in active RA despite treatment with multiple disease modifying anti-rheumatic drugs (DMARDs), and in early disease with no prior treatment by methotrexate (MTX). Infliximab has been shown to reduce joint inflammation and to slow radiographic progression, in both clinical and non-clinical responders. Recent data suggest that using infliximab early in RA treatment increases the percentage of clinical remission and allows infliximab discontinuation. The recommended dosage of 3 mg/kg could be increased up to 10 mg/kg with partial efficacy of the dose escalation. Antibodies to infliximab have been observed in 7% to 61% of patients and are associated with a low trough level of infliximab and secondary response failure. Their occurrence could be prevented by co-medication with MTX. The combination of DMARDs other than MTX with infliximab was found to be safe and efficacious. Infections, principally tuberculosis, are increased in treated patients, and the risk is greater at higher dose. Even if the treatment is generally safe and well tolerated, patients treated with infliximab should be closely monitored.
infliximab; rheumatoid arthritis; disease modifying anti-rheumatic drugs
Tumour necrosis factor-alpha (TNFα) has an important role in the pathogenesis of inflammatory conditions such as rheumatoid arthritis, Crohn’s disease, ulcerative colitis and psoriasis. Infliximab, a chimeric anti-TNFα monoclonal antibody, has been shown to reduce the severity of symptoms or induces remission of active disease. Infusions have generally been limited to the hospital setting due to cost and concerns for patient safety. Studies defining its efficacy and safety have, therefore, originated almost exclusively from hospital settings.
To evaluate the safety of infliximab in a community clinic environment, across all types of patients.
A retrospective chart review of 3161 patients who received a combined 20,976 infusions at a network of community clinics over 16.5 months was conducted. Adverse drug reaction (ADR) information was retrieved and coded for time of onset, severity and outcome. Only ADRs that occurred during or within the first 24 h of the infusion were included.
A total of 524 (2.5% of all infusions) acute ADRs in 353 patients (11.2%) were recorded. Most reactions (ie, ADRs) were mild (n=263 [50.2%, 1.3% of all infusions]) or moderate (n=233 [44.5%, 1.1% of all infusions]). Twenty-eight reactions (5.3%, 0.1% of all infusions) were severe. Emergency medical services were called to transport patients to hospital for seven of the severe reactions, of which none required admission. As per pre-established medical directives, adrenaline was administered three times.
Infliximab infusions are safe in the community setting. Severe ADRs were rare. None required active physician intervention; nurses were able to treat all reactions by following standardized medical directives.
Adverse events; Community setting; Infliximab; Safety
Tumor necrosis factor-α (TNFα) was cloned over 2 decades ago and its identification in part led to the discovery of a super family of tumor necrosis factors (TNFs) and their receptors. TNFα signals through two transmembrane receptors, TNFR1 and TNFR2, and regulates a number of critical cell functions including cell proliferation, survival, differentiation, and apoptosis. Macrophages are the major producers of TNFα and interestingly are also highly responsive to TNFα. Aberrant TNFα production and TNF receptor signaling have been associated with the pathogenesis of several diseases, including rheumatoid arthritis, Crohn’s disease, atherosclerosis, psoriasis, sepsis, diabetes, and obesity. TNFα has been shown to play a pivotal role in orchestrating the cytokine cascade in many inflammatory diseases and because of this role as a “master-regulator” of inflammatory cytokine production, it has been proposed as a therapeutic target for a number of diseases. Indeed anti-TNFα drugs are now licensed for treating certain inflammatory diseases including rheumatoid arthritis and inflammatory bowel disease. In this review we discuss the discovery of TNFα and its actions especially in regulating macrophage biology. Given its importance in several human diseases, we also briefly discuss the role of anti-TNFα therapeutics in the treatment of inflammatory diseases.
TNFα; disease; inflammation; macrophage; arthritis; inflammatory bowel disease
We prepared and characterized golimumab, a human IgG1 tumor necrosis factor alpha (TNFα) antagonist monoclonal antibody chosen for clinical development based on its molecular properties. Golimumab was compared with infliximab, adalimumab and etanercept for affinity and in vitro TNFα neutralization. The affinity of golimumab for soluble human TNFα, as determined by surface plasmon resonance, was similar to that of etanercept (18 pM versus 11 pM), greater than that of infliximab (44 pM) and significantly greater than that of adalimumab (127 pM, p = 0.018). The concentration of golimumab necessary to neutralize TNFα-induced E-selectin expression on human endothelial cells by 50% was significantly less than those for infliximab (3.2-fold; p = 0.017) and adalimumab (3.3-fold; p = 0.008) and comparable to that for etanercept. The conformational stability of golimumab was greater than that of infliximab (primary melting temperature [Tm] 74.8°C vs. 69.5°C) as assessed by differential scanning calorimetry. In addition, golimumab showed minimal aggregation over the intended shelf life when formulated as a high concentration liquid product (100 mg/mL) for subcutaneous administration. In vivo, golimumab at doses of 1 and 10 mg/kg significantly delayed disease progression in a mouse model of human TNFα-induced arthritis when compared with untreated mice, while infliximab was effective only at 10 mg/kg. Golimumab also significantly reduced histological scores for arthritis severity and cartilage damage, as well as serum levels of pro-inflammatory cytokines and chemokines associated with arthritis. Thus, we have demonstrated that golimumab is a highly stable human monoclonal antibody with high affinity and capacity to neutralize human TNFα in vitro and in vivo.
TNF; golimumab; neutralization; affinity; bioassay; arthritis; stability; solubility
Tumour necrosis factor α (TNFα) antagonists are effective for the treatment of rheumatoid arthritis (RA), but concerns remain about their safety in the presence of hepatitis C virus (HCV) infection. The influence of treatment with the TNFα antagonist infliximab on levels of HCV viraemia and serum transaminases in a 38-year-old patient with RA and HCV was examined to assess the safety of the drug. After starting infliximab treatment, the patient’s clinical symptoms improved significantly (28-joint Disease Activity Score (DAS28) of less than 3) and levels of transaminases were normal. At the 14th injection of infliximab, the levels of HCV viraemia and transaminases were significantly elevated. After stopping the infliximab injections, the levels of transaminases returned to normal with infusion of glycyrrhizinate derivatives within 3 months. Evidence is provided of aggravation of serum transaminases and progression of viraemia during treatment with infliximab in a patient with RA and HCV infection.
Patients with Crohn’s disease (CD) have a high risk of developing osteoporosis, but the mechanisms underlying bone mass loss are unclear. Elevated proinflammatory cytokines, such as tumour necrosis factor-alpha (TNFα), have been implicated in the pathogenesis of bone resorption.
To assess whether suppression of TNFα with infliximab treatment has a beneficial effect on lumbar bone mass.
Adult CD patients who had received infliximab treatment, and who underwent lumbar densitometric evaluation before and during treatment, were selected. Adult CD patients who had never received infliximab treatment were selected as controls. Information regarding age, sex, weight, duration of CD, use of glucocorticoids and bisphosphonates, and signs of disease activity between both densitometric measurements were collected.
Data from 45 patients were analyzed. The control group (n=30, mean [± SD] 26.7±9 years of age) had a significantly higher increase in body weight between both evaluations (6.26%±8%) than the infliximab group (n=15, 30.6±13 years), which had an increase of 0.3%±7.4%. There was a strong correlation between the final weight and lumbar bone mineral content (BMC) in both groups. The infliximab group had a significant increase in lumbar bone area (4.15%±6.6%), BMC (12.8%±13.6%) and bone mineral density (8.13%±7.7%) between both evaluations (interval 22.6±11 months) compared with the control group. The increase in BMC in patients who had received infliximab treatment was significant when compared with control patients who had received glucocorticoids (n=8) or had evidence of disease activity (n=13).
Infliximab therapy improved lumbar bone mass independent of nutritional status. This finding suggests that TNFα plays a role in bone loss in CD.
Bone mass; Crohn’s disease; Infliximab; Osteopenia; Osteoporosis
The anti-tumor necrosis factor (TNF)α medications demonstrate efficacy in the induction of remission and its maintenance in numerous chronic inflammatory conditions. With the increasing number of patients receiving anti-TNFα agents, however, less common adverse reactions will occur. Cutaneous eruptions complicating treatment with an anti-TNFα agent are not uncommon, occurring in around 20% of patients. Adalimumab, a fully humanized antibody against TNFα, may be expected to cause minimal immune-mediated skin reactions compared to the chimeric monoclonal antibody, infliximab. We, however, report a case of Stevens-Johnson syndrome that required hospitalization and cessation of adalimumab in a patient with Crohn’s disease (CD). In this case report, a 29-year-old male with colonic and perianal CD with associated erythema nodosum and large joint arthropathy developed severe mucositis, peripheral rash and desquamation, fevers and respiratory symptoms concomitant with a second dose of 40 mg adalimumab after a 2 mo break from adalimumab therapy. Skin biopsies of the abdominal wall confirmed erythema multiforme and the patient was on no other drugs and infective etiologies were excluded. The patient responded rapidly to IV hydrocortisone and was able to be commenced on infliximab without recurrence of the Stevens-Johnson syndrome. Desquamating skin reactions have now been described in three of the TNFα antagonists (infliximab, etanercept and adalimumab). These reactions can be serious and prescribers need to be aware of the potential mucocutaneous side effects of these agents, especially as Stevens-Johnson syndrome is associated with significant morbidity and mortality.
Stevens-Johnson syndrome; Crohn’s disease; Adalimumab; Serious adverse effect
Objective: To evaluate the efficacy and tolerability of anti-tumour necrosis factor α (TNFα) monoclonal antibody (infliximab) in the treatment of spondyloarthropathy (SpA) associated with active and inactive Crohn's disease (CD).
Methods: Twenty four patients with SpA associated with active or inactive CD (16 active, 8 quiescent) were treated with anti-TNFα monoclonal antibody (infliximab) with repeated infusions for a period of 12–18 months. The treatment aimed at ameliorating the general musculoskeletal and spinal pain, controlling peripheral arthritis and enthesitis, decreasing the BASDAI score, modifying acute phase reactants, and reducing CD activity.
Results: Infliximab improved both gastrointestinal (p<0.01) and overall articular symptoms (BASDAI, p<0.01; general musculoskeletal and spinal pain, p<0.01; peripheral arthritis, p<0.01) in patients with active CD. Additionally, infliximab effectively controlled not only axial involvement and peripheral arthritis but also enthesitis (p<0.01) and prevented inflammatory bowel disease reactivation in patients with inactive CD and low inflammatory markers. Amelioration of gut and musculoskeletal involvement persisted for up to 12 months.
Conclusion: Infliximab may act on the inflammation of entheses and of periarticular structures, which usually does not cause a change in the haematological markers that are the main indicators of pain and joint ankylosis in SpA. Infliximab induces and maintains remission of CD while at the same time treating active and severe SpA, suggesting that it should be the preferred drug for the treatment of active and severe SpA associated with active or quiescent CD.
Regulatory T cells have been clearly implicated in the control of disease in murine models of autoimmunity. The paucity of data regarding the role of these lymphocytes in human autoimmune disease has prompted us to examine their function in patients with rheumatoid arthritis (RA). Regulatory (CD4+CD25+) T cells isolated from patients with active RA displayed an anergic phenotype upon stimulation with anti-CD3 and anti-CD28 antibodies, and suppressed the proliferation of effector T cells in vitro. However, they were unable to suppress proinflammatory cytokine secretion from activated T cells and monocytes, or to convey a suppressive phenotype to effector CD4+CD25− T cells. Treatment with antitumor necrosis factor α (TNFα; Infliximab) restored the capacity of regulatory T cells to inhibit cytokine production and to convey a suppressive phenotype to “conventional” T cells. Furthermore, anti-TNFα treatment led to a significant rise in the number of peripheral blood regulatory T cells in RA patients responding to this treatment, which correlated with a reduction in C reactive protein. These data are the first to demonstrate that regulatory T cells are functionally compromised in RA, and indicate that modulation of regulatory T cells by anti-TNFα therapy may be a further mechanism by which this disease is ameliorated.
T lymphocytes; tolerane; autoimmune disease; TNFα; cytokines
Background: Tumour necrosis factor α (TNFα) antagonists are effective for the treatment of rheumatoid arthritis (RA), but concerns remain about the safety of these agents in the presence of chronic infections, including hepatitis C virus (HCV) infection.
Objective: To examine the influence of treatment with TNFα antagonists on levels of HCV viraemia and serum transaminases in patients with RA and HCV.
Methods: In a retrospective survey the course of 16 HCV infected patients with RA who had received the TNFα antagonists etanercept or infliximab was analysed. Eight additional patients with RA and HCV were also enrolled into a three month prospective trial of etanercept. Serum concentrations of albumin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and HCV were followed.
Results: Viraemia was measured in 22 patients receiving a TNFα antagonist at the start of treatment and after 1–34 months (median 9 months follow up). Twenty four patients had serial tests of liver related enzymes and albumin. None of the differences between liver related tests at baseline and at follow up achieved significance (p>0.05). Similarly, the mean HCV measurement at 1–3, 4–6, 7–12, and 13–34 months did not differ significantly from baseline (p>0.05).
Conclusion: In this study, liver related blood tests and HCV viral load measurements did not change substantially. These findings suggest that TNFα antagonists merit further study for the treatment of RA in HCV infected patients. Larger and longer term studies are still needed.
Tumor necrosis factor alpha (TNFα) is the most widely studied pleiotropic cytokine of the TNF superfamily. In pathophysiological conditions, generation of TNFα at high levels leads to the development of inflammatory responses that are hallmarks of many diseases. Of the various pulmonary diseases, TNFα is implicated in asthma, chronic bronchitis (CB), chronic obstructive pulmonary disease (COPD), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In addition to its underlying role in the inflammatory events, there is increasing evidence for involvement of TNFα in the cytotoxicity. Thus, pharmacological agents that can either suppress the production of TNFα or block its biological actions may have potential therapeutic value against a wide variety of diseases. Despite some immunological side effects, anti-TNFα therapeutic strategies represent an important breakthrough in the treatment of inflammatory diseases and may have a role in pulmonary diseases characterized by inflammation and cell death.
Infliximab, a chimeric monoclonal immunoglobulin antibody to tumor necrosis factor-α, has been established as a safe and effective treatment of rheumatoid arthritis, active and fistulising crohn's disease. Infliximab is generally well tolerated drug. The commonly reported cardiac side effects of Infliximab include exacerbation of congestive heart failure, hypotension and syncope. Symptomatic disorders of cardiac rhythm have been reported only rarely in few case reports and to the best of our knowledge, no tachyarrhythmia has been reported in past.
We report the case of a supraventricular tachycardia that occurred within three hours of Infliximab infusion in a patient with rheumatoid arthritis.
It is interesting to note that prior infusions in this patient did not precipitate similar consequences, thus, emphasising the importance of careful monitoring of patients on Infliximab therapy for possible reactions, even if prior exposures have been uneventful.
To assess the efficacy of one course of rituximab (two 1-g doses) compared to an alternative tumor necrosis factor-α (TNFα) blocker in rheumatoid arthritis patients who had experienced one previous TNFα blocker failure (eg, etanercept, adalimumab, or infliximab).
Patients and methods
The efficacy of both treatments was studied in this retrospective, multicenter, noninterventional cohort study with 196 patients. All patients had active rheumatoid arthritis defined by a Disease Activity Score-28 of ≥3.2 despite having TNFα blocker therapy, and were followed over 6.6 months on average after switching to rituximab versus a second TNFα blocker (ie, switching to etanercept, adalimumab, or infliximab) at baseline.
At baseline, both cohorts showed similar demographic and disease-related characteristics (including Disease Activity Score-28). At the end of observation, mean Disease Activity Score-28 was significantly lower after treatment with rituximab than with a second TNFα blocker (−1.64 [95% confidence interval: −1.92; −1.36] versus −1.19 [95% confidence interval: −1.42; −0.96], P = 0.013). This difference between the two groups was even more pronounced when patients were seropositive for rheumatoid factor (−1.66 versus −1.17, P = 0.018) and anti-cyclic citrullinated peptide antibodies (−1.75 versus −1.06, P = 0.002). More rituximab-treated patients achieved good European League Against Rheumatism response than TNFα blocker-treated patients (30% versus 15%), and less patients were nonresponders (22% versus 35%) according to European League Against Rheumatism criteria (P = 0.022, chi-squared test).
Treatment with rituximab was more effective than a second TNFα blocker therapy in rheumatoid arthritis patients after failure of the first TNFα blocker. It was found that anti-cyclic citrullinated peptide antibodies may be a useful predictive biomarker for response to rituximab in patients with TNFα blocker treatment failure.
rheumatoid arthritis; rituximab; anti-cyclic citrullinated peptide antibodies; rheumatoid factor
Objectives: To analyse immunological changes during treatment with a monoclonal anti-tumour necrosis factor α (TNFα) antibody, infliximab, in patients with rheumatoid arthritis (RA).
Methods: 25 patients with RA and 5 patients with other arthritides were studied during the first 6 weeks of treatment with infliximab. At the start of treatment and after 2 and 6 weeks, spontaneous expression of CCR3 and CCR5 on peripheral blood T cells and monocytes was studied by flow cytometry. The secretion and mRNA expression of interferon γ (IFNγ), interleukin (IL)4, IL5, and TNFα from phytohaemagglutinin (PHA) stimulated peripheral blood mononuclear cells was measured with an ELISA and RT-PCR. Plasma levels of C reactive protein, serum amyloid protein A, rheumatoid factor, and antibodies to filaggrin and citrullinated cyclic peptide were measured with an ELISA.
Results: The number of CD4 T cells and CD14 monocytes expressing CCR3 (p = 0.013, p = 0.009, respectively) and CD8 T cells expressing CCR5 (p = 0.040) as well as PHA stimulated secretion of IL4 and IFNγ (p<0.05) increased during treatment in patients with RA. 15 (60%) patients with RA achieved clinical response (at least ACR20) during the first 2 weeks. The number of T cells expressing CCR3 and CCR5 was higher before treatment in non-responders than in responders (p<0.05). The number of T cells increased in responders.
Conclusion: Increase in secretion of Th1 and Th2 cytokines together with induced expression of chemokine receptors on T cells and monocytes suggest restoration of peripheral cell mediated immunity and blockade of the accumulation of inflammatory cells in joints as response to treatment.
Biologics targeting TNF have brought about a paradigm shift in the treatment of rheumatoid arthritis (RA) and infliximab, anti-TNF-α chimeric monoclonal antibody, was marketed in 2003 in Japan. We previously reported on the RECONFIRM study, a retrospective clinical study on the efficacy of infliximab therapy in a RA management group in Japan, where we evaluated the clinical response after 22 weeks of the therapy in 258 patients. The study reported here was aimed at reconfirming the clinical efficacy of the infliximab therapy and demographic factors related to the efficacy over a 54-week study period in 410 RA patients in the same study group. Infliximab was infused according to the domestically approved method, and the clinical response was evaluated following 54 weeks of infliximab therapy using the European League Against Rheumatism (EULAR) response criteria. Disease activity was assessed by DAS28-CRP (Disease Activity Score including a 28-joint count/C-reactive protein). Infliximab was discontinued in 24.4% of the 410 patients at 54 weeks and 9.3% and 8.1% discontinued the therapy due to adverse events and inefficiency, respectively. Average DAS28-CRP decreased from 5.5 at week 0 to 3.1 at week 54 after the therapy. Patients in remission and those showing low-, moderate-, and high-disease activity changed from 0.0, 1.0, 9.0 and 90.0%, respectively, at the start of the study to 27.6, 11.7, 34.4 and 26.3%, respectively, at week 54. Younger age, RF-negativity and low scores of DAS28-CRP showed significant correlations with remission at week 54. EULAR response criteria—good, moderate, and no response to infliximab—were 37.0, 41.7 and 21.2%, respectively. In conclusion, we reconfirmed the clinical efficacy of infliximab and demographic factors related to the efficacy over a 54-week study period in 410 Japanese patients with RA using DAS28-CRP and EULAR response criteria.
Rheumatoid arthritis; Infliximab; EULAR response; Retrospective study
Tumor necrosis factor-alpha (TNF-α) inhibitors, such as etanercept, infliximab, and adalimumab, bind to TNF-α and thereby act as anti-inflammatory agents. This group of drugs has been approved for the treatment of rheumatoid arthritis, psoriatic arthritis, moderate to severe plaque psoriasis, ankylosing spodylitis, Crohn disease, and juvenile idiopathic arthritis. We describe a 56-year-old woman who developed an erythematous pruritic rash on both arms—diagnosed as granuloma annulare by skin biopsy—approximately 22 months after initiating adalimumab for treatment of rheumatoid arthritis. On stopping adalimumab there was total clearance of the skin lesions, but a similar rash developed again when her treatment was switched to another anti-TNF agent (etanercept). This clinical observation supports a link between TNF inhibition and the development of granuloma annulare.
Adverse effect; anti-TNF therapy; granuloma annulare
Psoriatic arthritis (PsA) is a rheumatoid factor (RF)-seronegative systemic inflammatory disorder associated with psoriasis. Current treatment for PsA in China is still focused on disease modifying anti-rheumatic drugs (DMARDs). In this paper, we report two Chinese patients with active longstanding PsA treated with infliximab, a human-mouse chimeric monoclonal antibody against tumor necrosis factor alpha (TNF-α). The results show that infliximab acted quickly and effectively in relieving peripheral and axial symptoms and refractory skin lesions, even in recombinant human TNF-α receptor (rhTNFR)-resistant case. The take-home message from our cases is that infliximab is a useful therapeutic option for refractory PsA, especially when a patient has a combination of psoriasis and psoriatic arthritis. Further local evidence and experience must be accumulated in order to make anti-TNF-α therapy more accessible to PsA patients in China.
Refractory psoriatic arthritis; Skin lesions; Infliximab; Anti-tumor necrosis factor alpha (TNF-α) treatment
Various demyelinating disorders have been reported in association with anti‐tumour necrosis factor α (TNFα) agents. The objective of this study was to review the occurrence, clinical features and outcome of optic neuritis (ON) during treatment with anti‐TNFα agents.
A PubMed search was conducted to identify literature addressing the potential association between anti‐TNFα agents and ON, following our experience with a patient having rheumatoid arthritis in whom ON developed while being treated with infliximab.
15 patients including the case presented here with ON in whom the symptoms developed following TNFα antagonist therapy were evaluated. Eight of these patients had received infliximab, five had received etanercept and two patients had received adalimumab. Among them, nine patients experienced complete resolution, and two patients had partial resolution, while four patients continued to have symptoms.
Patients being treated with a TNFα antagonist should be closely monitored for the development of ophthalmological or neurological signs and symptoms. Furthermore, consideration should be given to avoiding such therapies in patients with a history of demyelinating disease. If clinical evaluation leads to the diagnosis of ON, discontinuation of the medication and institution of steroid treatment should be a priority.
Patients with rheumatoid arthritis (RA) have increased cardiovascular mortality. Tumour necrosis factor α (TNFα)-blocking therapy has been shown to reduce RA disease activity measures and joint damage progression. Some observational studies suggest that TNFα blockade reduces mortality and incidence of first cardiovascular events. The mechanisms contributing to these outcomes are unclear. This study assessed the effects of infliximab treatment on vascular stiffness and structure in patients with RA.
A post hoc analysis of longitudinal data from a randomised placebo controlled study evaluated the effect of infliximab on vascular assessments. 26 patients received intravenous infliximab (3 mg/kg) at weeks 0, 2, 6 and every 8 weeks thereafter to week 54. Patients were followed up to 56 weeks of infliximab therapy with assessments of RA disease activity, cardiovascular risk factors, vascular stiffness (pulse wave velocity (PWV)), carotid intima media thickness (CIMT) and carotid artery plaque (CAP). Univariate analyses of changes over time by repeated measures analysis of variance (ANOVA) were followed by multivariate time-series regression analysis (TSRA) if changes were seen.
PWV was significantly lower (better) after 56 weeks of treatment with infliximab (ANOVA p<0.01, TSRA p<0.01). However, CIMT (ANOVA p = 0.50) and CAP (χ2 = 4.13, p = 0.88) did not change over the study period. Multiple cardiovascular risk measures did not change with treatment and did not correlate with changes in measures of vascular structure.
Arterial stiffness improves with infliximab treatment in RA. This change may help explain the improved cardiovascular disease survival in patients with RA receiving TNFα-blocking therapy.
Ankylosing spondylitis (AS) is a chronic, progressive disease characterized by inflammation in the spine and sacroiliac joints which causes pain, stiffness and the potential for spinal ankylosis. It is associated with significant functional impairment. It is common and since onset is often in young people, the burden of disease is considerable. Conventional treatment including non-steroidal antiinflammatory drugs (NSAIDs) and physiotherapy have proven but limited efficacy in controlling symptoms and preventing progression of spinal manifestations. Infliximab, a chimeric monoclonal antibody which binds to and inhibits tumor necrosis factor alpha (TNFα), is highly effective in controlling disease activity in AS. In AS, infliximab 5 mg/kg body weight is usually given as an infusion at weeks 0, 2 and 6, and then every 6–8 weeks. When infliximab is used in combination with NSAIDs a rapid improvement in disease activity by at least 50% is seen in as many as 50% of AS patients. Infliximab has been shown to have ongoing efficacy for as long as regular infusions continue and is safe in the medium term. Magnetic resonance studies show major reductions in spinal inflammation during treatment with infliximab, however ongoing studies will assess if infliximab has disease modifying effect in AS.
infliximab; ankylosing spondylitis; tumour necrosis factor inhibitors
To determine whether the heterogeneous clinical response to tumour necrosis factor (TNF)α blocking therapy in rheumatoid arthritis (RA) can be predicted by TNFα expression in the synovium before initiation of treatment.
Prior to initiation of infliximab treatment, arthroscopic synovial tissue biopsies were obtained from 143 patients with active RA. At week 16, clinical response was evaluated using the 28-joint Disease Activity Score (DAS28). Immunohistochemistry was used to analyse the cell infiltrate as well as the expression of various cytokines, adhesion molecules and growth factors. Stained sections were evaluated by digital image analysis. Student t tests were used to compare responders (decrease in DAS28 ⩾1.2) with non-responders (decrease in DAS28 <1.2) and multivariable regression was used to identify the independent predictors of clinical response.
Synovial tissue analysis confirmed our hypothesis that the baseline level of TNFα expression is a significant predictor of response to TNFα blocking therapy. TNFα expression in the intimal lining layer and synovial sublining were significantly higher in responders than in non-responders (p = 0.047 and p = 0.008, respectively). The numbers of macrophages, macrophage subsets and T cells (all able to produce TNFα) were also significantly higher in responders than in non-responders. The expression of interleukin (IL)1β, IL6, IL18, IL10, E-selectin, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) was not associated with response to anti-TNFα treatment.
The effects of TNFα blockade are in part dependent on synovial TNFα expression and infiltration by TNFα producing inflammatory cells. Clinical response cannot be predicted completely, indicating involvement of other as yet unknown mechanisms.
A 27-year-old patient of mine with rheumatoid arthritis has been treated with
infliximab for the last 5 years. She is planning her first pregnancy. How
should I advise her regarding use of infliximab during pregnancy, bearing in
mind that infliximab substantially improved her medical condition?
Infliximab (Remicade) has not been tested in pregnant animals because it does
not interact with non–human tumour necrosis factor (TNF) alpha.
Several case reports describing women who used infliximab during pregnancy
do not suggest a strong association with adverse pregnancy outcomes. More
studies are required to determine infliximab’s safety during pregnancy.
The use of TNF-alpha antagonists (infliximab, etanercept, adalimumab) has changed the course of many rheumatic diseases including rheumatoid arthritis (RA). Since their approval, some questions regarding their safety including infections have been observed. The aim of the study was to evaluate the changes in cytokines levels and cells subsets in patients with RA during anti TNF blocking agents treatment and the possible effect on infections’ development. We evaluated in 89 RA patients [39 treated with etanercept (ETN), 29 with adalimumab (ADA) and 21 with infliximab (IFN)] at baseline and after 6 months the following parameters: procalcitonin, ESR, CRP, cytokines as TNF, IL-6, IL-10, IL-8 and the TNF/IL-10 ratio, and peripheral mononuclear cells as CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD3- /CD16+/56+, CD14+HLADR+, CD20+, CD19+/CD38+. Peripheral mononuclear cells were detected by flow cytometric system Cytomics FC500 and cytokines circulating levels by a quantitative sandwich enzyme immunoassay technique (Human IL-8 Instant ELISAe Bioscience, Human IL-6 Instant ELISA e Bioscience, Human IL-10 Instant ELISAe Bioscience and Human TNF-a Quantikine immunoassay RD system). A lower reduction of CD14+HLADR+ in ADA group 54.6±10.4% vs ETA 48.4±15.7% vs INF 40.7±16.5%, p<0.039 was found. No differences in all three groups on peripheral mononuclear cells CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD 20+, CD19+/CD38+, CD3-/CD16+/56+, and cytokine circulating levels were found. The number of infections at 6 months was: 10.3% in ADA group, 12.8% in ETN group and 19.04% in IFN group. A correlation was found between the reduction in CD14+HLADR+ cells and IFN treatment. Our data showed that the level of CD14+HLADR+ cells was reduced during therapy with IFN. ADA and ETN don’t reduce lymphocyte populations and their subsets such as CD14+HLADR+ cells that play an important role host defence.
Infections; TNF blocking agents; peripheral mononuclear cells.
Ankylosing spondylitis (AS) is a member of the family of spondyloarthropathies, which are inflammatory arthritides largely involving the axial skeleton and commonly accompanied by peripheral arthritis. Genetic factors, particularly the presence of HLA-B27, are major contributors to the susceptibility for AS. Despite some therapeutic advances, the treatment options for patients with AS and related disorders have been limited. Several lines of evidence have led to the hypothesis that patients with AS might benefit from treatment with tumor necrosis factor (TNF). Specifically, TNF concentrations are known to be significantly elevated in the synovium of patients with rheumatoid arthritis (RA), in the inflamed gut of patients with inflammatory bowel disease, and in the inflamed sacroiliac joints of patients with AS. The anti-TNF agents have been shown to be of benefit in, and currently have indications for, RA (etanercept, infliximab, adalimumab), Crohn's disease (infliximab), and psoriatic arthritis (etanercept). Because the spondyloarthropathies share pathogenetic mechanisms with the above-specified disease states, studies have been conducted to evaluate the effectiveness of anti-TNF agents in several disorders, including AS. Data from clinical trials so far with infliximab and etanercept show that patients with AS and related disorders achieve significant improvement in clinical signs and symptoms based on validated outcomes measures. Computed tomography and magnetic resonance imaging (MRI) can facilitate the early diagnosis of AS. Studies with infliximab using MRI together with updated scoring methods demonstrated significant decreases in associated spinal inflammation. TNF antagonist therapy is well tolerated in patients with AS, with a side effect profile consistent with the prior experience of patients with RA.
efficacy; etanercept; infliximab; spondyloarthropathies; tumor necrosis factor