Synergy between anti-CD4 and anti-tumor necrosis factor in the amelioration of established collagen-induced arthritis.

Anti-CD4 treatment is reported to prevent collagen-induced arthritis if administered before the onset of clinical disease but has relatively little effect on established arthritis. In contrast, we have recently shown that anti-tumor necrosis factor alpha/beta (TNF) treatment reduces the severity of established arthritis. We now study the effect of combined administration of anti-CD4 monoclonal antibody (YTS 191.1.2/YTA 3.1.2) and anti-TNF monoclonal antibody (TN3-19.12) in established arthritis. Anti-CD4 treatment caused some reduction in paw-swelling but did not significantly prevent joint erosion. A suboptimal dose of anti-TNF alone had no significant effect on arthritis. In contrast, anti-CD4 plus suboptimal anti-TNF significantly reduced paw-swelling, limb involvement, and joint erosion. As previously reported, an optimal dose of anti-TNF alone inhibited paw-swelling, limb involvement, and joint erosion. However, optimal anti-TNF combined with anti-CD4 caused significantly greater reductions in paw-swelling and joint erosion than those achieved by optimal anti-TNF alone. Coadministration of anti-CD4 was also effective in preventing an antibody response to the hamster anti-TNF antibody, which may have implications for long-term therapy in human disease. Thus anti-CD4 acts synergistically with anti-TNF in ameliorating established collagen-induced arthritis and this combined therapeutic approach may provide effective long-term control of rheumatoid arthritis.     

Long‐term amelioration of established collagen‐induced arthritis achieved with short‐term therapy combining anti‐CD3 and anti–tumor necrosis factor treatments

Objective

The goal of rheumatoid arthritis (RA) treatment is to achieve clinical remission in order to limit structural damage and physical disability. To this end, recent emphasis has been placed on aggressive treatment early in the course of disease with drugs such as anti–tumor necrosis factor (anti‐TNF) agents. As T cells are also thought to play an important role in the initiation of RA, we hypothesized that targeting both TNF and T cells would result in better outcomes. The aim of this study was to examine the efficacy of combined therapy with anti‐CD3 and anti‐TNF in experimental RA.

Methods

Two anti‐mouse antibodies were developed as surrogate reagents for anti‐TNF and anti‐CD3 therapies. Collagen‐induced arthritis (CIA) was induced in DBA/1 mice, and antibodies were injected intraperitoneally, either alone on in combination, at predetermined subtherapeutic doses. The frequency and number of pathogenic and regulatory CD4+ T cell subsets in the draining lymph nodes were determined in order to investigate the mechanisms of action.

Results

Strikingly, the combination of the two antibodies demonstrated a potent synergy in established CIA, with long‐term inhibition of disease progression and protection from joint destruction. The results did not demonstrate any enhancement of CD25+FoxP3+ regulatory T cells, but a profound depletion of pathogenic T cells from the draining lymph nodes was associated with reduced numbers of T cells in the joints.

Conclusion

A short course of combination therapy with anti‐CD3 and anti‐TNF efficiently depletes pathogenic T cells from the draining lymph nodes, reducing the numbers of T cells in the joints and affording long‐lasting inhibition of established CIA.

     

A comparative study into the mechanisms of action of anti-tumor necrosis factor alpha, anti-CD4, and combined anti-tumor necrosis factor alpha/anti-CD4 treatment in early collagen-induced arthritis

OBJECTIVE: Anti-tumor necrosis factor alpha (anti-TNFalpha) therapy is very effective in rheumatoid arthritis (RA), whereas depleting anti-CD4 therapy is relatively ineffective. To explain the differences in efficacy between these 2 therapies, we used an animal model of RA to compare their effects on different aspects of the disease process. METHODS: Mice with collagen-induced arthritis were treated with depleting anti-CD4 monoclonal antibodies (mAb), anti-TNFalpha mAb, or phosphate buffered saline. Another group was given a combination of anti-TNFalpha plus anti-CD4. The treatments were compared for their ability to down-regulate the expression of proinflammatory cytokines and adhesion molecules, reduce the cellularity of the joint, and inhibit Th1 activity. RESULTS: Anti-TNFalpha significantly reduced the numbers of cells expressing TNFalpha, interleukin-1beta (IL-1beta), very late activation antigen 4 (VLA-4), vascular cell adhesion molecule 1 (VCAM-1), and numbers of CD4+ T cells and macrophages in the joint. Anti-CD4 treatment led to a small reduction in the expression of TNFalpha, IL-1beta, VLA-4, and VCAM-1, but this did not reach statistical significance. Depleting anti-CD4 was also surprisingly ineffective in eliminating CD4+ T cells from the joint. Anti-TNFalpha therapy was also more effective than anti-CD4 in reducing Thl activity, as assessed by the production of interferon-gamma in lymph node cell cultures. There was a synergistic relationship between anti-TNFalpha and anti-CD4 in the reduction of histologic score and inhibition of TNFalpha/IL-1beta expression in the joints. CONCLUSION: The efficacy of the 3 treatments correlated with their ability to modulate the expression of inflammatory cytokines and adhesion molecules in the joint, reduce the cellularity of the joint, and inhibit Th1 activity. This kind of analysis may prove useful in the testing of novel therapies for RA.     

Systemic anti-tumor necrosis factor alpha therapy in rheumatoid arthritis down-regulates synovial tumor necrosis factor alpha synthesis

OBJECTIVE: To investigate the hypothesis that tumor necrosis factor alpha (TNFalpha) blockade in rheumatoid arthritis (RA) diminishes synovial synthesis of TNFalpha, interleukin-1alpha (IL-1alpha), and IL-1beta. METHODS: Patients with active RA received a single 10 mg/kg infusion of infliximab. Multiple synovial biopsy specimens were obtained from a knee the day before infusion and 14 days later. A modified immunohistochemical method detecting cytokine-producing rather than cytokine-binding cells was applied to determine synthesis of TNFalpha, IL-1alpha, and IL-1beta in fixed, cryopreserved sections. Computerized image analysis using two different methodologies was performed by independent observers blinded to the identity of samples. RESULTS: All 8 patients met the American College of Rheumatology 20% improvement response criteria (ACR 20) at 2 weeks, and half of these patients met the ACR 50. With a few exceptions, there was concordance between both image analysis methodologies regarding the direction of change in immunopositive area fraction for all cytokines analyzed. TNFalpha synthesis was significantly reduced after treatment (P = 0.05 at the Karolinska Institute, Stockholm, Sweden; P = 0.008 at the Kennedy Institute, London, UK). Patients meeting the ACR 50 were those with the highest baseline levels of TNFalpha synthesis. There was a significant correlation between baseline levels of TNFalpha expression and change in TNFalpha levels in response to therapy. Both IL-1alpha and IL-1beta synthesis were reduced in 3 patients; IL-1alpha synthesis alone was reduced in 2 patients and IL-1beta synthesis alone was reduced in 2 patients. In 1 patient, neither IL-1alpha nor IL-1beta synthesis was reduced. CONCLUSION: Analysis of synovial tissue by means of immunomorphology and image analysis in a clinical trial setting may allow the drawing of biologically meaningful conclusions. Synovial TNFalpha synthesis was reduced 2 weeks after infliximab treatment. Reductions in IL-1alpha and IL-1beta synthesis were demonstrated in a subgroup of patients. High levels of synovial TNFalpha production prior to treatment may predict responsiveness to therapy.     

Update on anti-tumor necrosis factor therapy in the spondyloarthropathies including psoriatic arthritis

PURPOSE OF REVIEW: The introduction of the macromolecule tumor necrosis factor inhibitors etanercept, infliximab, and adalimumab has proven very successful for patients with spondyloarthropathies. The greatest experience has accrued in ankylosing spondylitis and psoriatic arthritis. This paper reviews data from clinical trials with tumor necrosis factor inhibitors in ankylosing spondylitis and psoriatic arthritis. RECENT FINDINGS: Treatment with tumor necrosis factor inhibitors has not only resulted in substantial improvement in the signs and symptoms of arthritis but has also improved functional status and quality of life in ankylosing spondylitis and psoriatic arthritis. Improvements in associated inflammatory features, such as enthesitis in psoriatic arthritis and uveitis in ankylosing spondylitis, have also been observed. Moreover, treatment has been shown to inhibit the progression of radiographic joint damage in psoriatic arthritis and to attenuate spinal inflammation in ankylosing spondylitis. The notable success of tumor necrosis factor inhibitors has not only changed the treatment paradigms for these conditions but has also stimulated studies aimed at improving diagnosis, prognostic stratification, and other aspects of clinical care. SUMMARY: The introduction of tumor necrosis factor inhibitors for patients with ankylosing spondylitis and psoriatic arthritis has had a tremendous impact on daily clinical care.     

Long-term anti-tumor necrosis factor antibody therapy in rheumatoid arthritis patients sensitizes the pituitary gland and favors adrenal androgen secretion

OBJECTIVE: New insights into the role of tumor necrosis factor (TNF) in the pathogenesis of rheumatoid arthritis (RA) have expanded our understanding about the possible mechanisms by which anti-TNF antibody therapy reduces local synovial inflammation. Beyond local effects, anti-TNF treatment may modulate systemic antiinflammatory pathways such as the hypothalamic-pituitary-adrenal (HPA) axis. This longitudinal anti-TNF therapy study was designed to assess these effects in RA patients. METHODS: RA patients were given 5 infusions of anti-TNF at weeks 0, 2, 6, 10, and 14, with followup observation until week 16. We measured serum levels of interleukin-6 (IL-6), adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17[OH]progesterone), cortisol, cortisone, androstenedione (ASD), dehydroepiandrosterone (DHEA), and DHEA sulfate in 19 RA patients. RESULTS: Upon treatment with anti-TNF, we observed a fast decrease in the levels of serum IL-6, particularly in RA patients who did not receive parallel prednisolone treatment (P = 0.043). In these RA patients who had not received prednisolone, the mean serum ACTH levels sharply increased after every injection of anti-TNF, which indicates a sensitization of the pituitary gland (not observed for the adrenal gland). During treatment, the ratio of serum cortisol to serum ACTH decreased, which also indicates a sensitization of the pituitary gland (P < 0.001), and which was paralleled by constant cortisol secretion. The adrenal androgen ASD significantly increased relative to its precursor 17(OH)progesterone (P = 0.013) and relative to cortisol (P = 0.009), which indicates a normalization of adrenal androgen production. The comparison of patients previously treated with prednisolone and those without previous prednisolone revealed marked differences in the central and adrenal level of this endocrine axis during long-term anti-TNF therapy. CONCLUSION: Long-term therapy with anti-TNF sensitizes the pituitary gland and improves adrenal androgen secretion in patients who have not previously received prednisolone treatment. These changes are indicative of normalization of the HPA axis and must therefore be considered as evidence of an additional antiinflammatory influence of anti-TNF treatment in patients with RA.     

Power Doppler ultrasonographic monitoring of response to anti-tumor necrosis factor therapy in patients with rheumatoid arthritis

OBJECTIVE: To evaluate the validity, responsiveness, and predictive value of power Doppler ultrasonography (PDUS) monitoring of response to tumor necrosis factor (TNF) blocking agents in rheumatoid arthritis (RA). METHODS: Three hundred sixty-seven RA patients were prospectively recruited at 25 Spanish centers; complete clinical, laboratory, and PDUS data were obtained on 278 patients. The patients underwent clinical, laboratory, and PDUS assessment at baseline and after 1, 3, 6, and 12 months of anti-TNF treatment, and radiographic assessment of the hands and feet at baseline and 12 months. The Disease Activity Score in 28 joints (DAS28) was recorded at each visit. PDUS examination included 86 intraarticular and periarticular sites in 28 joints. US synovial fluid (SF), synovial hypertrophy (SH), and PD signal were scored in all synovial sites. US count and index for SF, SH, and PD signal were obtained. Sensitivity to change of the PDUS variables was assessed by estimating the smallest detectable difference (SDD) from the intraobserver variability. RESULTS: A significant parallel improvement in DAS28 and PDUS parameters was found at followup assessment (P < 0.0005 for within-subject between-visit changes). The SDD for PDUS parameters was lower than the mean changes throughout followup. Time-integrated values of US joint count for PD signal and rheumatoid factor (RF) showed predictive value in relation to progression of radiographic erosion (R = 0.64), and time-integrated values of US joint count for PD signal, RF, and erythrocyte sedimentation rate were predictors of progression of the total radiographic score (R = 0.59). CONCLUSION: These findings indicate that PDUS is a valid method for monitoring response to anti-TNF therapy in RA; results obtained by PDUS are reproducible and sensitive to change. PDUS findings may have predictive value in relation to radiologic outcome.     

Long-term effects of anti-tumour necrosis factor therapy on weight in patients with rheumatoid arthritis

In patients with rheumatoid arthritis (RA), weight is an important prognostic factor. Preliminary evidence has indicated that treatment with anti-tumour necrosis factor (TNF) therapy can affect the weight of patients with RA, but the relationship between improved prognosis and weight changes remains to be clarified. Our aim was to investigate the effects of anti-TNF therapy on the weight of patients with RA following 24 months of treatment. Patients (n = 168) were selected for this retrospective analysis on the basis of having received anti-TNF therapy for the first time. Change in body weight after 12 and 24 months of treatment was calculated and analysed by multiple regression analysis using age, sex, baseline body mass index (BMI), baseline DAS28 score, disease-modifying antirheumatic drug use, steroid use and specific anti-TNF drug as explanatory variables. The mean weight change of the patient group after 12 months of treatment was +1.58 kg (95% CI 0.71 to 2.46 kg) and after 24 months was +1.80 kg (95% CI 0.69 to 2.67 kg). After 24 months, 64.3% of patients had gained weight. There was no statistically significant association between weight gain at 12 or 24 months and age, sex, steroid use at baseline, anti-TNF drug or baseline DAS28 score. Baseline BMI had a statistically significant negative association with weight gain at 12 and 24 months. RA patients with lower BMIs tend to gain weight with anti-TNF therapy. Further studies are required to determine if the weight gained is fat and/or muscle and the effects upon general health outcomes.     

A tumor necrosis factor receptor loop peptide mimic inhibits bone destruction to the same extent as anti-tumor necrosis factor monoclonal antibody in murine collagen-induced arthritis

OBJECTIVE: The cyclic peptide WP9QY (YCWSQYLCY) was designed to mimic the most critical tumor necrosis factor alpha (TNFalpha) recognition loop on TNF receptor I, and it prevents interactions of TNFalpha with its receptor. We undertook this study to compare the effects of the WP9QY peptide on collagen-induced arthritis (CIA) in mice with those of anti-TNFalpha monoclonal antibody. METHODS: CIA was induced by primary and secondary immunizations. Osmotic minipumps were implanted in the backs of all mice on the day of the booster injection (day 21), and vehicle, anti-TNF antibody (4 mg/kg/day), or WP9QY peptide (2 mg/kg/day or 4 mg/kg/day) was continuously infused until the mice were killed (day 40). Thereafter, clinical, radiographic, and histologic assessments were performed. RESULTS: WP9QY treatment inhibited CIA-induced increases in the arthritis score, but onset of disease was not delayed by the peptide. The inhibitory effect of WP9QY on inflammation was definitely weaker than that of anti-TNF antibody. Microfocal computed tomography analyses, however, revealed that WP9QY blocked CIA-induced bone destruction at the knee joints to the same extent as did anti-TNF antibody. In addition, WP9QY inhibited synovial pannus infiltration and reduced osteoclast number. Furthermore, inhibition of CIA-induced systemic bone loss by WP9QY was more apparent than that by anti-TNF antibody. CONCLUSION: The TNFalpha antagonist WP9QY would be a useful template for the development of small molecular inhibitors to prevent both inflammatory bone destruction and systemic bone loss in rheumatoid arthritis.     

Scoring evaluation for histopathological features of synovium in patients with rheumatoid arthritis during anti-tumor necrosis factor therapy

The present study was performed to evaluate the synovium in patients with rheumatoid arthritis (RA) treated with anti-tumor necrosis factor α agents (anti-TNFα). Synovial tissue specimens were obtained during total knee arthroplasty (TKA) from 42 RA patients (12 men, 30 women). Twenty-one RA patients were given anti-TNFα agents (infliximab, n = 12; etanercept, n = 9), while the remaining 21 RA patients were given no such agents. The histopathological findings were compared between specimens from these groups using the histological scoring system reported by Rooney, which consists of six items: degree of synovial hyperplasia, fibrosis, number of blood vessels, perivascular lymphocyte infiltration, focal aggregates of lymphocytes, and diffuse infiltrates of lymphocytes. Clinical laboratory data including C-reactive protein (CRP), matrix metalloproteinase-3 (MMP-3), and disease activity scores including a 28-joint count (DAS28), disease duration, methotrexate (MTX) dose, and glucocorticoid dose were also assessed before surgery. There were no significant differences in total score between anti-TNFα and no anti-TNFα groups. However, significant differences were observed in scores of synoviocyte hyperplasia and perivascular infiltrates of lymphocytes between the groups. These results suggested that these agents have a suppressive effect on cell proliferation in the lining layer and on perivascular lymphocyte infiltration. However, further studies are necessary to elucidate the mechanisms of these effects.     

Anti-C5 monoclonal antibody therapy prevents collagen-induced arthritis and ameliorates established disease.

Activated components of the complement system are potent mediators of inflammation that may play an important role in numerous disease states. For example, they have been implicated in the pathogenesis of inflammatory joint diseases including rheumatoid arthritis (RA). To target complement activation in immune-mediated joint inflammation, we have utilized monoclonal antibodies (mAbs) that inhibit the complement cascade at C5, blocking the generation of the major chemotactic and proinflammatory factors C5a and C5b-9. In this study, we demonstrate the efficacy of a mAb specific for murine C5 in the treatment of collagen-induced arthritis, an animal model for RA. We show that systemic administration of the anti-C5 mAb effectively inhibits terminal complement activation in vivo and prevents the onset of arthritis in immunized animals. Most important, anti-C5 mAb treatment is also highly effective in ameliorating established disease. These results demonstrate a critical role for activated terminal complement components not only in the induction but also in the progression of collagen-induced arthritis and suggest that C5 may be an attractive therapeutic target in RA.     

Efficacy of anti-tumor necrosis factor therapy in patients with ulcerative colitis

OBJECTIVES: Tumor necrosis factor-alpha (TNF-alpha) is an important cytokine involved in the pathogenesis of inflammatory bowel disease. The monoclonal antibody to TNF-alpha, infliximab, is effective in treating Crohn's disease. Preclinical studies suggest the importance of TNF-alpha in treating ulcerative colitis (UC). We report the effectiveness of infliximab for UC and examine factors predictive of response to medication. METHODS: Data from all UC patients receiving infliximab at four institutions were analyzed. Disease activity was determined by the Disease Activity Index. RESULTS: A total of 27 patients with active UC received inpatient (37%) and outpatient (63%) infliximab as single (52%) or multiple (two to 15) infusions (48%). Twelve patients (44%) achieved remission and six patients (22%) had partial response. Nine patients had no response; five subsequently underwent total colectomy. The median time to achieve response and remission was 4 days and the median duration 8 wk. Nine of the 18 patients who responded experienced 19 relapses; 18 of these relapses (95%) were successfully treated with repeat infusions. Steroid-refractory patients were less likely to respond to infliximab therapy than were steroid-responsive patients (33% vs 83%; p = 0.026). No other factors were predictive of response to infliximab. Two patients developed serious adverse events, including death in one case. CONCLUSIONS: Preliminary evidence suggest effectiveness of infliximab in the treatment of UC, including medically refractory severe disease. Individuals who are refractory to corticosteroids, however, may be unlikely to respond to infliximab. A randomized controlled trial is necessary to further investigate the efficacy of infliximab in patients with UC.