Treatment of rheumatoid arthritis patients with anti-TNF-alpha monoclonal antibody is accompanied by down-regulation of the activating Fcgamma receptor I on monocytes

OBJECTIVES: To study the effect of anti-TNF-alpha therapy on activating IgG Fc receptor (FcgammaR) expression on monocytes of RA patients in relation to changes in disease activity. METHODS: RA patients were treated with anti-TNF-alpha mAb (infliximab). At baseline, 2 and 14 weeks after the start of anti-TNF-alpha treatment, FcgammaR expression levels on circulating monocytes were evaluated. Changes in expression were correlated to changes in disease parameters. To study the direct effects of TNF-alpha blockade on monocytic FcgammaR expression levels, monocytes were isolated and cultured with anti-TNF-alpha mAb. The effects were compared with those induced by TNF-alpha. RESULTS: Two weeks after the start of anti-TNF-alpha mAb therapy, monocytic FcgammaRI expression levels were decreased, whereas FcgammaRIIa and IIIa expression levels were unchanged. At 14 weeks, 8 weeks after the last gift of anti-TNF-alpha mAb, FcgammaRI expression levels returned to baseline levels. FcgammaRIIa and IIIa expression levels remained unchanged. The change in FcgammaRI correlated with changes in CRP and ESR levels. In vitro, anti-TNF-alpha mAb treatment did not alter expression of FcgammaRI on monocytes, but increased FcgammaRIIa and IIIa. TNF-alpha down-regulated all activating FcgammaRs, mainly FcgammaRIIa and IIIa, but also the inhibitory FcgammaRIIb. CONCLUSION: Anti-TNF-alpha mAb treatment of RA patients is accompanied by down-regulation of FcgammaRI expression levels on monocytes. This is likely an indirect effect of TNF-alpha blockade on disease activity, since in vitro anti-TNF-alpha mAb does not directly change FcgammaRI expression on monocytes. In contrast, TNF-alpha down-regulated all activating FcgammaRs. Thus, blocking TNF-alpha may relieve the negative feedback mechanism of TNF-alpha as down-regulator of FcgammaRs. Strategies to reduce activating FcgammaRs may have additional value in the treatment of RA patients with TNF-alpha blockade by diminishing immune complex-mediated activation of monocytes/macrophages.     

The effect of tumor necrosis factor blockade on the response to pneumococcal vaccination in patients with rheumatoid arthritis and ankylosing spondylitis

OBJECTIVE: To assess the effect of anti-tumor necrosis factor (TNF) alpha therapies on the immunogenicity of pneumococcal vaccination in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). METHODS: A group of 16 consecutive patients (11 with RA and 5 with AS) treated either with infliximab or etanercept, and a control group of 17 age-matched RA patients treated with disease-modifying medications other than anti-TNF-alpha, received intradeltoid injection with 0.5 mL of pneumococcal vaccine. Pneumococcal polysaccharide (PPS)-specific IgG to 7 vaccine PPS (representing high- and low-prevalence serotypes) was measured by enzyme-linked immunosorbent assay in sera obtained before and 1 month after pneumococcal immunization. RESULTS: One month after vaccination, both groups had significant increases in the geometric mean concentration of capsule PPS-specific antibody and in the mean fold increase in antibody levels to all 7 serotypes, compared with prevaccination levels. However, compared with the control group, the TNF-alpha blockade-treated patients tended to have lower antibody increases for all the serotypes tested except serotype 14. In addition, lower proportions of TNF-alpha blockade-treated patients responded to pneumococcal vaccination compared with patients on other therapies. Similarly, more TNF-alpha blockade-treated patients were poor responders compared with patients not on anti-TNF-alpha treatment. CONCLUSION: Treatment of groups of patients with etanercept or infliximab does not impair their mean antibody responses to pneumococcal vaccination. However, a larger proportion of RA patients may not respond adequately to pneumococcal vaccination once on TNF-alpha blockade therapies. Consequently, pneumococcal vaccination before starting TNF-alpha blockade therapy is recommended.     

Anti-tumor necrosis factor-alpha blockade improves insulin resistance in patients with rheumatoid arthritis

OBJECTIVE: Systemic inflammation, insulin resistance, and endothelial dysfunction have been implicated in the development of cardiovascular disease in rheumatoid arthritis (RA). Since insulin resistance can promote endothelial dysfunction and anti-TNF-alpha blockade yield a rapid improvement of endothelial function, we have sought to assess whether TNF-alpha blockade may also result in a reduction of insulin serum levels and improvement of insulin resistance in RA patients who require this therapy because of severe and refractory disease. METHODS: We recruited patients with RA seen over a period of 1 month at Hospital Xeral-Calde, Lugo, Spain, that were on treatment with anti-TNF-alpha monoclonal antibody-infliximab. Patients with diabetes mellitus or plasma glucose > 110 mg/dl were excluded. Fasting blood samples were taken for determination of plasma glucose and serum insulin levels immediately prior to and after infliximab infusion. RESULTS: Twenty-seven RA patients (21 women; mean age: 57.1 years; mean DAS28: 4.43) fulfilled the inclusion criteria. Dramatic reduction in the serum insulin levels and insulin/glucose index was observed following infliximab infusion. Also, a significant improvement of insulin resistance and insulin sensitivity was found. CONCLUSION: Our study confirms a rapid beneficial effect of infliximab on insulin resistance and insulin sensitivity in RA patients treated periodically with this drug. It may support the long-term use of drugs that act blocking TNF-alpha function to reduce the mechanisms implicated in the development of atherosclerosis in patients with RA.     

Peripheral blood lymphocytes from patients with rheumatoid arthritis are differentially sensitive to apoptosis induced by anti-tumour necrosis factor-alpha therapy

OBJECTIVE: The efficacy of anti-tumour necrosis factor-alpha (TNF-alpha) therapies in rheumatoid arthritis (RA) has been mainly attributed to TNF-alpha neutralisation. Other mechanism as immune cell apoptosis, which is impaired in RA, may also be induced by anti-TNF-alpha therapies. The aim of our study was to investigate whether TNF-alpha inhibitors could induce apoptosis in vitro of the peripheral blood lymphocytes of RA patients. METHODS: Peripheral blood mononuclear cells (PBMC) isolated from 24 patients with RA and 18 healthy donors were incubated with anti-TNF-alpha agents, infliximab or etanercept, in comparison with no agent and including an isotypic control, for 48 hours. Apoptosis was detected and quantified by annexin V labelling of phosphatidylserine externalization using cytofluorometric analysis and compared with PBMC production TNF-alpha in vitro. RESULTS: In healthy donors, induced apoptosis was observed in 0.3% to 3.8% of lymphocytes with both therapies. In RA patients the treatment induced lymphocyte apoptosis in 17 of 24 patients with a percentage of annexin V-positive lymphocytes ranging from 0.1% to 25%. Among these 17 RA patients, a significant in vitro lymphocyte apoptosis (> 4%) was observed in 11 patients (46%) compared with healthy donors (p < 0.01). The variability of the response to anti-TNF-alpha within the RA population was not dependent on TNF-alpha synthesis or disease activity. CONCLUSION: In vitro induction of lymphocyte apoptosis by anti-TNF-alpha was observed in a subgroup of RA patients. Based on these data, it would be of interest to further study the interindividual variations of sensitivity to apoptosis induced by TNF alpha inhibitors in relation to treatment efficacy or resistance observed in RA patients.     

Serious bacterial infections in patients with rheumatoid arthritis under anti-TNF-alpha therapy

OBJECTIVE: With rising numbers of anti-tumour necrosis factor alpha (TNF-alpha) treatments for rheumatoid arthritis (RA), Crohn's disease and other conditions, physicians unaware of potential pitfalls are increasingly likely to encounter associated severe infections. Our purpose was to assess the incidence and nature of severe infections in our RA patients under anti-TNF-alpha therapy. METHODS: We reviewed patient charts and records of the Infectious Disease Unit for serious infections in patients with RA in the 2 yr preceding anti-TNF-alpha therapy and during therapy. RESULTS: Serious infections affected 18.3% of patients treated with infliximab or etanercept. The incidence was 0.181 per anti-TNF-alpha treatment year vs 0.008 in the 2 yr preceding anti-TNF-alpha therapy. In several cases, only a few signs or symptoms indicated the severity of developing infections, including sepsis. CONCLUSIONS: A high level of suspicion of infection is necessary in patients under anti-TNF-alpha therapy. We suggest additional strategies for the prevention, rapid identification and pre-emptive therapy of such infections.     

Induction of hyperadiponectinemia following long-term treatment of patients with rheumatoid arthritis with infliximab (IFX), an anti-TNF-alpha antibody

Tumor necrosis factor-alpha (TNF-alpha) plays an important role in forming atherosclerosis based on chronic inflammatory condition in vivo and animal models. In human system, it is not clear the involvement of TNF-alpha to atherosclerosis. To clarify the relevance of TNF-alpha to atherosclerotic factors in human, We performed a prospective cohort study to investigate the inhibition of TNF-alpha with anti-TNF-alpha antibody infliximab may contribute to increase serum adiponectin levels, adipocyte-derived hormone with antiatherogenic properties, in patients with RA. 97 patients with active RA had been treated every 8 weeks for 1 year(13 men and 84 women, 54.2 +/- 12.6 years, disease duration; 8.5 +/- 1.5 years). They received a fixed dose of infliximab of 3 mg/kg every 8 weeks for 52 weeks. We evaluated changes of inflammatory markers, high molecular weight form of adiponectin levels and blood lipid levels. We also studied the association between increment rate of serum adiponectin and improvement of disease activity and inflammatory markers. Infliximab were strikingly dropped inflammatory markers (p<0.01), increased total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) (p<0.05). Besides, serum adiponectin significantly increased, independent of RA activity and clinical backgrounds, suggesting that TNF-alpha and adiponectin exhibit opposite effects in human body. TNF-alpha blockade may interfere in the atherosclerosis directly or indirectly, by increasing serum adiponectin levels, therefore TNF-alpha blockade may improve cardiovascular morbidity and mortality in chronic inflammatory disease such as RA.     

Protein biomarker analysis by mass spectrometry in patients with rheumatoid arthritis receiving anti-tumor necrosis factor-alpha antibody therapy

OBJECTIVE: To investigate the mechanism of action of anti-tumor necrosis factor-alpha (TNF-alpha) antibody in patients with rheumatoid arthritis (RA), we analyzed serum or plasma proteins by mass spectrometry system. METHODS: Ten RA patients who received treatment with anti-TNF-alpha antibody were studied. Samples obtained before and after therapy were analyzed by a two-dimensional liquid chromatography tandem mass spectrometry (2D LC-MS/MS) system after pretreatment by a recently developed method to remove high molecular weight proteins. RESULTS: Using this system, certain proteins were identified after treatment with anti-TNF-alpha antibody, including proteins related to the TNF-alpha-mediated pathway for nuclear factor kappa B (NF-kappaB) activation and/or to the metabolism (including regeneration) of articular cartilage. CONCLUSION: Our mass spectrometry system appears to be useful for proteomic analysis. The efficacy of anti-TNF-alpha antibody therapy for RA may be related to various consequence of the inhibition of TNF-alpha activity.     

Tumor necrosis factor-alpha antagonists for the treatment of rheumatic diseases

Tumor necrosis factor-alpha (TNF-alpha) antagonists have rapidly emerged as a valuable class of antirheumatic agents. Etanercept, a dimerized version of the soluble tumor necrosis factor receptor II, and infliximab, a chimeric anti-TNF-alpha monoclonal antibody, are currently approved for the treatment of rheumatoid arthritis (RA) based on their proven beneficial effects in clinical trials. New insights into the role of TNF-alpha in disease pathogenesis have expanded our understanding about the possible mechanisms by which these agents reduce synovial inflammation and inhibit bone and cartilage degradation. The enlarging safety experience has revealed growing concerns about TNF-alpha inhibition and increased risk for opportunistic infection, most notably the reactivation of latent Mycobacterium tuberculosis infection. Recent recommendations have addressed this risk by calling for pretreatment screening for previous exposure to tuberculosis. The success of etanercept and infliximab therapy for RA has prompted the development of other TNF-alpha antagonists and extended the investigation of this therapeutic approach to other inflammatory diseases. TNF-alpha antagonists promise to shape the care of RA and other rheumatic diseases for many years to come.     

Drug survival, efficacy and toxicity of monotherapy with a fully human anti-tumour necrosis factor-alpha antibody compared with methotrexate in long-standing rheumatoid arthritis

OBJECTIVES: To compare the 48-week drug survival, efficacy and toxicity of monotherapy with a fully human anti-tumour necrosis factor-alpha (TNF-alpha) monoclonal antibody (moAb) and methotrexate (MTX) in patients with active long-standing rheumatoid arthritis (RA). Secondary aims were to identify potential predictors for clinical response. METHODS: Patients with RA, enrolled in phase I trials with a human anti-TNF-alpha moAb and followed for at least 48 weeks at our centre, were compared with patients receiving MTX monotherapy without folate supplementation. The first 6 weeks of anti-TNF therapy were placebo-controlled and followed by an open-label study. Patients treated with MTX participated in a 48-week, double-blind, phase III study of MTX alone vs MTX with folate supplementation, which was co-ordinated by our department. The studies with anti-TNF-alpha and MTX were performed in the same period and had very similar inclusion, exclusion, response and stop criteria. RESULTS: Sixty-one patients treated with anti-TNF-alpha moAb were compared with 137 receiving MTX monotherapy. At baseline, patients in the anti-TNF-alpha group had a longer disease duration (median 108 vs 50 months, P=0.0001) and a more protracted history of second-line anti-rheumatic drugs than those treated with MTX (median 4 vs 1, P=0.0001). The 48-week dropout rate was lower among patients treated with anti-TNF (23 vs 45% in the MTX group, P<0.005). Proportional hazard analysis showed a significantly lower dropout risk among anti-TNF-treated patients [relative risk (95% confidence interval): 0.28 (0.12-0.6) uncorrected and 0.17 (0.06-0.45) corrected for confounders). The 48-week area under the curve for the disease activity score (DAS) was smaller in the anti-TNF-alpha group than in the MTX group (P=0.005). The percentage of responders was higher in the anti-TNF-alpha group over the whole study period. The median percentage of visits in which a patient fulfilled the European League Against Rheumatism (EULAR) response criteria was 83% in the anti-TNF-alpha group vs 40% in the MTX group (P=0.0001). Clinical and demographic characteristics were, in general, poor predictors for response to therapy at week 48. The clinical response after the first anti-TNF-alpha dose tended to increase the chance of prolonged efficacy of this approach [relative risk (95% confidence interval): 2 (0.75-6.0)]. The previous number of second-line drugs was the only predictive variable for response to MTX to which it was inversely related [relative risk (95% confidence interval): -0.71 (-0.57 to -0.88)]. CONCLUSIONS: In patients with active, long-standing RA, blocking TNF-alpha is more effective and better tolerated than MTX monotherapy. An early response increases the chance of a sustained effect of anti-TNF-alpha. In contrast to MTX, the response to anti-TNF-alpha is not affected by previous disease-modifying anti-rheumatic drug history.     

The role of TNF-alpha in the pathogenesis of inflammation and joint destruction in rheumatoid arthritis (RA): a study using a human RA/SCID mouse chimera

OBJECTIVE: In order to elucidate which cytokine preferentially stimulates the synovium in patients with rheumatoid arthritis (RA), we investigated the roles of tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) using SCID mice engrafted with human RA tissue (SCID-HuRAg). METHODS: The SCID-HuRAg mice were prepared according to our previously described method. First, SCID-HuRAg mice were treated with chimeric anti-TNF-alpha monoclonal antibody (mAb, 100 microg/mouse) and histological changes were examined 4 weeks after the initial treatment. Secondly, a total of 100 microg of recombinant TNF-alpha or IL-6 (0.6 microg/h) was administered daily to mice using an osmium pump. The histological changes and serum cytokine levels were examined 4 weeks after the initial administration. Human immunoglobulin G (IgG) was administered to mice as a control. RESULTS: Synovial inflammatory cells were significantly decreased after the anti-TNF-alpha mAb treatment; conversely, the degree of synovial inflammation was significantly exacerbated by TNF-alpha administration. The levels of both IL-6 and TNF-alpha in sera were significantly increased by recombinant TNF-alpha administration, while TNF-alpha levels were unchanged by IL-6 administration. This suggests that TNF-alpha controls IL-6 production. Despite the profound changes in inflammation, we found no effects on bone and no articular cartilage damage was produced by TNF-alpha. CONCLUSION: This study provides strong evidence that TNF-alpha is a key molecule in the control of the inflammatory changes that occur in the RA synovium. In addition, TNF-alpha regulates IL-6 production. However, other inflammatory pathways independent of TNF-alpha may contribute to the bone and cartilage damage seen in RA.     

Vitamin D derivatives induce apoptosis and downregulate ICAM-1 levels in peripheral blood mononuclear cells of inflammatory bowel disease patients

BACKGROUND: Lymphocytes are crucial in the pathogenesis of inflammatory bowel disease (IBD) and are an important target for drug development. Our aim was to verify whether 2 vitamin D derivatives, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and EB 1089, could induce cell apoptosis and affect cell-cell interaction by regulating adhesion molecule levels. METHODS: Peripheral blood mononuclear cell (PBMC) proliferation was studied by [3H]thymidine incorporation and apoptosis was determined using an enzyme-linked immunosorbent assay (ELISA) kit. (Poly(ADP-ribose)polymerase (PARP) cleavage, caspase-3, and ICAM-1 protein levels were determined by Western blot analysis. RESULTS: Our results indicate that 1,25(OH)2D3 or EB 1089 or anti-TNF-alpha (infliximab) induce apoptosis in PBMC obtained from healthy subjects. In IBD patients apoptosis is induced by vitamin D derivatives and by anti-TNF-alpha only in CD patients. Caspase-3 activation and PARP cleavage are registered when PBMC were treated with vitamin D derivatives. ICAM-1 levels remarkably increase when PBMC was incubated with lipopolysaccharide (LPS) or TNF-alpha. The treatment with the vitamin D derivatives, alone or in combination with LPS or TNF-alpha, significantly decreases ICAM-1 levels both in healthy subjects and IBD patients. In HUVEC cocultured with PBMC, previously incubated with LPS or TNF-alpha associated with 1,25(OH)2D3, ICAM-1 levels decrease both in healthy subjects and IBD patients. CONCLUSIONS: 1,25(OH)2D3 and EB 1089 inhibit PBMC proliferation, induce apoptosis in PBMC of healthy subjects and IBD patients, and affect ICAM-1 expression on PBMC and on HUVEC cocultured with PBMC, suggesting that the ICAM-1 downregulation could provide a new target for controlling the recruitment of leukocytes at the sites of inflammation in IBD.     

Toxoplasmic chorioretinitis and antitumor necrosis factor treatment in rheumatoid arthritis

OBJECTIVES: To present the data supporting the possible relationship of ocular toxoplasmosis to antitumor necrosis factor-alpha (TNF-alpha) therapy in patients with rheumatoid arthritis (RA). METHODS: A Medline search was performed using the words "toxoplasmosis, anti-TNF-alpha antagonists, chorioretinitis." We report 2 RA patients who developed ocular toxoplasmosis while receiving anti-TNF-alpha therapy. RESULTS: In addition to our patients with toxoplasmic chorioretinitis, there are 2 published cases of cerebral toxoplasmosis during treatment with anti-TNF-alpha agents. CONCLUSION: The risk of serious toxoplasmic infection during anti-TNF-alpha therapy for RA should be recognized.     

Recommendations for the diagnosis and treatment of latent and active tuberculosis in patients with inflammatory joint diseases treated with tumour necrosis factor alpha inhibitors

The Portuguese Society of Rheumatology (SPR) and the Portuguese Society of Pulmonology (SPP) have developed guidelines for the diagnosis and treatment of latent tuberculosis infection (LTBI) and active tuberculosis (AT) in patients with inflammatory joint diseases (IJD), namely rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, treated with tumour necrosis factor alpha (TNF-alpha) antagonists. Due to the high risk of tuberculosis (TB) in patients with IJD, LTBI and AT screening should be performed as soon as possible, ideally at the moment of IJD diagnosis. Even if TB screening was performed at the beginning of the disease, the evaluation should be repeated before starting anti-TNF-alpha therapy. When TB (LTBI orAT) treatment is indicated, it should be performed before the beginning of anti-TNF-alpha therapy. If the IJD activity requires urgent anti-TNF-alpha therapy, these drugs can be started after two months of antituberculosis therapy in AT cases, or after one month in LTBI cases. Chest X-ray is mandatory for all patients. If abnormal, e.g. Gohn complex, the patient should be treated as LTBI; residual lesions require the exclusion of AT and patients with history of untreated or incomplete TB treatment should be treated as LTBI. In cases of suspected active lesions, AT diagnosis should be confirmed and adequate therapy initiated. Tuberculin skin test (TST), with two units of RT23, should be performed in all patients. If induration is less than 5 mm, the test should be repeated after 1 to 2 weeks, on the opposite forearm, and should be considered negative if the result is again inferior to 5 mm. Positive TST implicates LTBI treatment. IfTST is performed in immunosupressed IJD patients, LTBI treatment should be offered to the patient before starting anti-TNFalpha therapy, even in the presence of a negative test.     

Tumor necrosis factor-α inhibits chondrogenic differentiation of synovial fibroblasts through p38 mitogen activating protein kinase pathways

We previously reported that synovial fibroblast-like cells (SFs) can be differentiated into chondrocytes through activin receptor-like kinase (ALK) 3 activation. The aim of this study was to clarify the effect and signaling pathways of tumor necrosis factor (TNF)-alpha on the chondrogenic differentiation of SFs. Primary SFs from patients with rheumatoid arthritis (RA) were treated with recombinant human bone morphogenetic protein-2 or transduced with a constitutively active mutant of the ALK3 gene (ALK3(CA)) with or without TNF-alpha, and then cultured in pellets. Expression of chondrocyte-specific genes was analyzed by real-time polymerase chain reaction or by histological analysis. Inhibitors of mitogen-activating protein kinase (MAPK) pathways or adenovirus vectors carrying a dominant-negative mutant of the IkappaB kinase 2 gene (AxIKK2(DN)) were used to analyze the signaling pathways of TNF-alpha. Expression of chondrocyte-specific genes was induced in SFs either by rhBMP-2 treatment or by ALK3(CA) transduction, which was strongly suppressed by TNF-alpha treatment. TNF-alpha markedly increased the p38 MAPK pathways in SFs, and inhibition of p38 MAPK activation partially restored the inhibitory effect of TNF-alpha on the chondrogenic differentiation of SFs. Combination therapy BMP-2 and anti-TNF-alpha agents especially targeting p38 MAPK might be a good approach to stimulating neochondrogenesis in the damaged joints in RA.     

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.     

Value of anti-TNF-alpha molecules in inflammatory and infectious diseases

INTRODUCTION: The pathophysiological interest of tumor necrosis factor-alpha (TNF-alpha) has been recently reported in inflammatory and infectious diseases. Thus, TNF-alpha blockade has become a new field of therapeutical research. CURRENT KNOWLEDGE AND KEY POINTS: Several biological agents specifically directed against TNF-alpha are available: anti-TNF-alpha monoclonal antibodies on the one hand--either mainly murine sequence (cA2), partially humanized (CDP 571) or fully human (D2E7)--and TNF-alpha soluble receptors on the other hand (lenercept or etanercept). The first clinical studies reveal interesting results. In rheumatoid arthritis (cA2, etanercept), these molecules may be used either alone or in synergistic combination with methotrexate. They produce a significant response compared to placebo or methotrexate alone, without loss of efficacy in medium-term treatment. In Crohn's disease (cA2 CDP571), they reduce significantly the activity of the disease, compared to placebo, and cA2 makes it possible to accelerate closure of the fistulas. The studies of severe sepsis did not reveal a significant efficacy, however, and only one study has been published on malignant disease, with a possible interesting effect. Even if these medications are usually well tolerated, the frequency of infections is slightly increased. The development of anti-DNA antibodies has also been reported, but drug-induced lupus is highly unusual. FUTURE PROSPECTS AND PROJECTS: Further studies will define the place of anti-TNF-alpha biological agents among the other available treatments of rheumatoid arthritis and Crohn's disease. Because of their high cost, these drugs will probably be limited to patients with active inflammatory disease despite more conventional treatments.     

New-onset psoriatic palmoplantaris pustulosis following infliximab therapy: a class effect?

Reports of induction or exacerbation of psoriatic palmoplantaris pustulosis (PPPP) after anti-tumor necrosis factor-alpha (TNF-alpha) treatment are few. We describe 2 new cases of PPPP induced by infliximab. In 1999, a total of 442 patients in our department received anti-TNF-alpha treatment for a variety of chronic rheumatic conditions and were regularly followed. Medical records for 166 given infliximab were retrospectively reviewed for disease [rheumatoid arthritis (RA), spondylarthropathies (SpA) including psoriatic arthritis], disease duration, clinical characteristics, skin side-effects, and use of other potentially relevant medications. PPPP was observed in 2 patients treated with infliximab for symmetrical rheumatoid factor-positive RA; the patients had no personal or family history of psoriasis. In both cases, pustulosis appeared after several months of infliximab administration. There was no clinical, biological, or radiological evidence to support a diagnosis of psoriatic SpA. Both patients fulfilled ACR criteria for RA, and there was no reason to suspect previously unidentified psoriasis. Comorbid RA and psoriasis are unusual, and our patients exhibited a clear link between anti-TNF-alpha administration and cutaneous lesions, suggesting a direct effect in both cases. The 28 published cases of PPPP induced by anti-TNF-alpha treatment report lesions that tend towards pustulosis and palmoplantar localization. The mechanisms involved remain elusive. Disappearance of lesions in our second patient when switched to a soluble receptor suggests a molecule-specific side effect, while the literature describing variable reaction to switching anti-TNF agents, and/or their discontinuation and reintroduction, indicates otherwise. Given the rarity of this side effect, its elucidation will require systematic study.     

Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti-tumor necrosis factor-alpha antibody therapy

Circumstantial evidence has implicated tumor necrosis factor alpha (TNF-alpha) in the pathogenesis of anemia of chronic disease (ACD) in rheumatoid arthritis (RA). We investigated the role of TNF-alpha in erythropoiesis of patients with active RA (n = 40) and the effect of anti-TNF-alpha antibody administration (cA2). Patients with RA had lower numbers of CD34+/CD71+ and CD36-/glycophorin A+ (glycoA+) bone marrow (BM) cells and increased proportions of apoptotic cells within the CD34+/CD71+ and CD36+/glycoA+ cell compartments, compared to healthy controls (n = 24). Erythroid burst-forming units (BFU-Es) obtained by BM mononuclear or purified CD34+ cells were significantly lower in RA patients compared to controls. These abnormalities were more pronounced among patients with ACD. Increased TNF-alpha levels in patient long-term BM culture supernatants inversely correlated with BFU-Es and hemoglobin levels and positively with the percentage of apoptotic CD34+/CD71+ and CD36+/glycoA+ cells. Following cA2 therapy, a normalization was documented in the number of CD34+/CD71+ and CD36-/glycoA+ cells, the number of BFU-Es, and the proportion of apoptotic CD34+/CD71+ and CD36+/glycoA+ cells, which was associated with a significant increase in hemoglobin levels compared to baseline. Recovery from anemia was more prominent in patients with ACD. The exogenous addition of an anti-TNF-alpha antibody in the cultures increased BFU-E number in patients prior to cA2 treatment but not after treatment, further substantiating the inhibitory role of TNF-alpha on patients' erythropoiesis. We conclude that TNF-alpha-mediated apoptotic depletion of BM erythroid cells may account for ACD in RA and that cA2 administration may ameliorate ACD in these patients by down-regulating the apoptotic mechanisms involved in erythropoiesis.     

Psoriasis induced by tumor necrosis factor-alpha antagonist therapy: a case series

OBJECTIVE: Although tumor necrosis factor-alpha (TNF-alpha) antagonists are effective in the treatment of refractory psoriasis, some cases have suggested that psoriasis might be induced as a result of treatment prescribed mainly for rheumatoid arthritis, ankylosing spondylitis, and Crohn's disease. To investigate anti-TNF-alpha induced psoriasis, we conducted a systematic analysis of the 6 cases we observed among our inflammatory patient cohort treated with anti-TNF-alpha (infliximab or etanercept). METHODS: We report 6 cases of psoriasis with onset during TNF-alpha antagonist therapy (infliximab and etanercept); characteristics and skin lesions are described. RESULTS: No patient had a personal or family history of psoriasis. The development of psoriasis was seen in all the types of inflammatory diseases we treated with TNF-alpha antagonists. There was great variation in the age of affected patients and in the onset of psoriasis after initiation of TNF-alpha antagonists. Both TNF-alpha antagonists studied were associated with development of psoriasis. In 2 cases psoriasis was associated with 2 different TNF-alpha antagonists in the same patient. In half our patients, skin lesions started in the inguinal and pubic regions, but palmoplantar pustulosis was also common. In half the cases, skin lesions responded favorably with topical agents despite continuation of TNF-alpha antagonist therapy. CONCLUSION: In light of previously published cases describing psoriasis or psoriasiform lesions after TNF-alpha antagonist therapy, our series strongly confirms that TNF-alpha antagonists may induce psoriasis in some patients. Further studies are needed to identify risk factors for TNF-alpha antagonist induced psoriasis.