Efficacy of methotrexate and tumor necrosis factor inhibitors in Japanese patients with active psoriatic arthritis

Abstract

Objective. The aim of this study was to assess the efficacy of oral methotrexate and tumor necrosis factor inhibitors in Japanese patients with active psoriatic arthritis.

Methods. We retrospectively investigated 51 patients who fulfilled the ClASsification criteria for Psoriatic ARthritis (CASPAR) criteria for the efficacy of tumor necrosis factor inhibitors and methotrexate. We assessed the visual analog scale score, psoriasis area and severity index score, C-reactive protein-based disease activity score in 28 joints (DAS28), swollen joint count (0–66), tender joint count (0–68), health assessment questionnaire score, C-reactive protein level, erythrocyte sedimentation rate, and matrix metalloproteinase 3, at both baseline and week 24.

Results. Of the 51 patients, 34 were male and 17 were female, with a mean age of 50.3 ± 13.2 years. The duration of psoriasis to onset of arthritis was 10.2 ± 9.1 years. At week 24, in the group treated with the tumor necrosis factor inhibitor plus methotrexate, the tender joint count declined from 6.05 ± 5.84 to 0.43 ± 1.03, the swollen joint count declined from 6.42 ± 4.36 to 0.00 ± 0.00, and the DAS28 declined from 4.35 ± 0.82 to 2.04 ± 0.68. In the group treated with methotrexate alone, the tender joint count declined from 3.70 ± 1.76 to 0.60 ± 0.86, the swollen joint count declined from 5.26 ± 4.00 to 0.27 ± 0.70, and the DAS28 declined from 3.91 ± 0.82 to 1.94 ± 0.53. There were no significant differences in the mean reduction in clinical measurements between the two groups.

Conclusion. Our study demonstrated that methotrexate and tumor necrosis factor inhibitors are effective for the treatment of active psoriatic arthritis in Japanese patients.     

Role of leptin in the progression of psoriatic,rheumatoid and osteoarthritis

Leptin, an adipokine responsible for body weight regulation, may be involved in pathological processes related to inflammation in joint disorders including rheumatoid arthritis (RA), osteoarthritis, and psoriatic arthritis (PsA). These arthropathies have been associated with a wide range of systemic and inflammatory conditions including cardiovascular disease, obesity, and metabolic syndrome. As a potent mediator of immune responses, leptin has been found in some studies to play a role in these disorders. Furthermore, current potent biologic treatments effectively used in PsA including ustekinumab (an interleukin 12/23 blocker) and adalimumab (a tumor necrosis factor-alpha blocker also used in RA) have been found to increase leptin receptor expression in human macrophages. This literature review aims to further investigate the role leptin may play in the disease activity of these arthropathies.     

Cutaneous immunohistochemical expression of interleukin-23 receptor (IL-23R) in psoriasis and psoriatic arthritis patients: Relation to musculoskeletal ultrasound findings

Aim of the workTo assess the immunohistochemical expression of cutaneous interleukin-23 receptor (IL-23R) in psoriasis and psoriatic arthritis (PsA) patients and study its relation to musculoskeletal ultrasound (MSUS) findings.Patients and methodsThe study was conducted on 40 patients: 20 with PsA and 20 with psoriasis only. The psoriasis area severity index (PASI) was estimated. Synovitis was assessed by Power Doppler ultrasound and enthesitis by Glasgow Ultrasound Enthesitis Scoring System (GUESS).ResultsThe mean age of PsA and psoriasis only patients (49.9 ± 11.6 and 44.9 ± 13 years) and gender (12 males and 8 females each) were comparable. IL-23R expression in the epidermal keratinocytes and dermal inflammatory cells of PsA patients scored 5 in 40% and 4 in 45% respectively while in psoriasis only the highest frequency of cases (40%) scored 2 in both. In psoriasis only, dermal and epidermal IL-23R were significantly associated to effusion (5 ± 0 vs 2.2 ± 0.7 and 4 ± 0 vs 1.5 ± 0.5, p < 0.001 respectively) and synovitis (5 ± 0 vs 2.4 ± 1 and 4 ± 0 vs 1.7 ± 0.8, p < 0.001 respectively) (p < 0.001) and both significantly correlated with erosions (r = 0.64, p = 0.002 and r = 0.64, p = 0.003) and GUESS (r = 0.68, p = 0.001 and r = 0.61, p = 0.005). Dermal IL-23R was significantly associated with the PASI score in PsA patients (r = 0.59, p = 0.01). On regression, IL-23R significantly predicted PsA (epidermal: p = 0.001 and dermal: p = 0.018).ConclusionIL-23R is highly expressed in psoriatic skin and strongly associated with psoriatic skin, joints and entheses findings. MSUS is valuable in the detection of subclinical arthritis. Cutaneous IL-23R expression may refer to early joint affection and with MSUS may allow early prediction and management.     

A comparison study of a recombinant tumor necrosis factor receptor:Fc fusion protein (rhTNFR:Fc) and methotrexate in treatment of patients with active rheumatoid arthritis in China

The objective of this study is to evaluate the efficacy and safety of rhTNFR:Fc: a recombinant tumor necrosis factor receptor:Fc fusion protein compared with methotrexate (MTX) in patients with rheumatoid arthritis in China. We treated 238 patients with active rheumatoid arthritis with either twice weekly subcutaneous injection rhTNFR:Fc (25 mg) or weekly oral MTX (mean 15 mg per week) for 24 weeks (registration number: 2003L01264). Clinical responses were defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology (ACR-N). As compared with MTX-treated patients, more patients who received rhTNFR:Fc had ACR20 improvement in disease activity during the first 2 weeks (P < 0.05). Similarly, more patients treated with rhTNFR:Fc having ACR20, ACR50, ACR70 improvement in disease activity during 8 weeks (P < 0.05). At the end of 12-week treatment, patients received rhTNFR:Fc also had significant improvement at ACR20 (P < 0.05). Compared with oral MTX, patients received rhTNFR:Fc also had significant improvement at ACR70 at the end of 24 weeks treatment (P < 0.05). In conclusion, compared with oral MTX subcutaneous injection, rhTNFR:Fc acted more rapidly to release symptoms and signs of active RA in Chinese patients, and well tolerated in patients with rheumatoid arthritis in China.     

Quantifying harmful effects of psoriatic diseases on quality of life: Cardio-metabolic outcomes in psoriatic arthritis study (COMPASS)

ObjectiveUp to 30% of patients with psoriasis suffer from concurrent psoriatic arthritis, and both the diseases have worse quality-of-life outcomes compared to the general population. There is limited literature comparing quality-of-life outcomes between these diseases. We seek to compare quality-of-life outcomes between both these groups.MethodsThe current study is a cross-sectional analysis of a cohort of 252 patients with psoriatic diseases, who were recruited from 2 tertiary-care centers. A self-administered questionnaire was used to collect demographic and validated quality-of-life data using short form-12 (SF 12), health assessment questionnaire (HAQ), and dermatology life quality index (DLQI). Univariate and multivariate analyses were conducted to compare the quality-of-life outcomes.ResultsWe included 107 (42.5%) psoriatic arthritis and 145 (57.5%) psoriasis patients in the cohort. The groups had comparable gender distribution and co-morbid diseases prevalence, but arthritis patients were older and received biologics/DMARDs more frequently than psoriasis patients. The physical indices (identified by HAQ and SF 12 PCS) were worse for psoriatic arthritis, whereas the mental/psychometric indices (identified by DLQI and SF 12 MCS) were comparable between both the groups.ConclusionsDespite aggressive therapy, physical quality of life was worse in psoriatic arthritis patients compared to psoriasis patients. The mental quality-of-life indices were comparable in both the groups and were still below the population norm. These results suggest need for screening for psoriatic arthritis in patients with psoriasis to reduce the burden of physical quality of life and screening for early signs of psychiatric illnesses in both these disease populations.     

Response of early active rheumatoid arthritis to tumor necrosis factor inhibitors: evaluation by magnetic resonance imaging

Inflammatory changes (synovitis and bone marrow edema) and destructive changes (bone erosion) were evaluated by magnetic resonance imaging (MRI) in patients with rheumatoid arthritis (RA), and their relations with disease activity were assessed during treatment with tumor necrosis factor (TNF) inhibitors. Ten patients with early active RA underwent MRI at 0 and 16 weeks of TNF-inhibitor treatment. The carpal bones of the dominant hand were evaluated by the outcome measures in rheumatology clinical trials MRI score for RA. After 16 weeks, the mean disease activity score (DAS 28) decreased significantly from 5.54 to 2.70, while the number of tender joints, number of swollen joints, and inflammatory parameters were also significantly improved. The mean synovitis and marrow edema scores determined by MRI showed a significant decrease from 6.1 to 2.2 and 12.8 to 6.2, respectively, while the annual bone-erosion progression score decreased from 12.6 to 2.0. Although synovitis persisted in some patients, imaging remission was achieved in two patients. In conclusion, TNF-inhibitor therapy achieved an early decrease of disease activity and MRI revealed amelioration of joint destruction. The MRI score for RA is useful for assessing the early response to TNF inhibitors.     

Nail affection as a central part of the entheseal organ in psoriasis patients for early detection of psoriatic arthritis

Aim of the workTo evaluate nail unit and detect subclinical enthesitis at extensor tendons in psoriatic patients for early detection of psoriatic arthritis (PsA).Patients and methodsThe study included 60 PsO patients and 60 matched healthy controls. Patients underwent history, clinical examination, assessment of Psoriasis Area and Severity Index (PASI), Nail Psoriasis Severity Index (NAPSI), Leeds Enthesitis Index (LEI), musculoskeletal ultrasound (MSUS) both grey and power Doppler (PD) for measuring nail bed thickness (NBT), nail vessels resistive index (NVRI), extensor digitorum tendon insertion for enthesitis and distal interphalangeal joints for synovitis.ResultsPatients were 38 females and 22 males (F:M 1.7:1) with mean age 45.1 ± 13.5 years. Nail irregularities were in all cases. The mean NBT of right thumb and index were significantly increased in patients (2.3 ± 0.6 and 1.9 ± 0.4) compared to control (1.5 ± 0.2 and 1.2 ± 0.2; p < 0.001 respectively). The mean NVRI was significantly increased (0.7 ± 0.1) in cases compared to control (0.4 ± 0.1; p < 0.001). NBT > 1.8 mm would differentiate cases from control (sensitivity 76.7% and specificity 100%). Frequency of tendons hypoechogenicity and thickness were significantly increased (73% and 93.3%) in patients. A significant correlation was found between disease duration and NAPSI (r = 0.4, p = 0.04). Enthesophyte with PD significantly correlated with PASI (r = 0.6, p = 0.02). Enthesophyte without PD significantly correlated with PASI (r = 0.6, p = 0.001) and with tendon thickness (r = 0.5, p = 0.01). A significant correlation was found between NBT and LEI (r = 0.7, p = 0.01).ConclusionMSUS is an important tool for examining nail as part of the entheses in psoriasis. There is a significantly increased frequency of extensor tendon enthesopathy in fingers with involved nails.     

Tumor necrosis factor antagonist responsiveness in a United States rheumatoid arthritis cohort

Objective

The study objective was to investigate responsiveness according to whether patients satisfy eligibility criteria from randomized controlled trials of tumor necrosis factor (TNF) antagonists in a multicentered US cohort.

Methods

Biologic-naïve patients with rheumatoid arthritis who were prescribed TNF antagonists (n = 465) in the Consortium of Rheumatology Researchers of North America registry were included. Patients were stratified by whether they met eligibility criteria from 3 major TNF antagonist trials. Two cohorts were examined: Cohort A (n = 336) included patients with complete American College of Rheumatology response criteria except acute phase reactants, and cohort B (n = 129) included patients with complete response criteria. Study outcomes included modified American College of Rheumatology 20% and 50% improvement responses (cohort A) and standard American College of Rheumatology improvement (cohort B).

Results

A minority of patients (5.4%-19.4%) prescribed TNF antagonists met trial eligibility criteria and predominantly had high disease activity (78.5%-100%). For patients who met eligibility criteria in cohort A, rates of 20% improvement (52.3%-63.6%) and 50% improvement (30.8%-45.5%) were achieved. Among patients failing to meet eligibility criteria, rates of 20% improvement (16.2%-20.4%) and 50% improvement (8.9%-10.8%) were consistently inferior (P <.05 all comparisons). For cohort B, similar differences were observed.

Conclusion

This multicentered US cohort study demonstrates that the majority of patients receiving TNF antagonists would not meet trial eligibility criteria and achieve lower clinical responses. These findings highlight the tradeoff between defining treatment responsive populations and achieving results that can be generalized for broader patient populations.     

糖尿病患者血浆肿瘤坏死因子的变化

用生物活性法测定了４４例糖尿病患者血浆ＴＮＦ－α水平，并与２０倒正常健康人进行了比较。结果发现：４４例糖尿病患者ＴＮＦ－α水平显著升高。糖尿病患者中，血糖控制越差者，病程越长者，ＴＮＦ－α水平越高。伴有血管并发症的糖尿病患者ＴＮＦ－α水平明显高于不伴有血管并发症者。作者对ＴＮＦ－α与糖尿病血管并发症的关系进行了讨论。     

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.     

Intra-articular methotrexate in the treatment of rheumatoid arthritis and psoriatic arthritis: a clinical and sonographic study

The aim of our study was to evaluate the effects of intra-articular methotrexate (MTX) in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Twenty-three consecutive patients, 10 with RA and 13 with PsA, with prevalent or unique arthritic involvement of one knee, were treated with intra-articular injections of MTX 10 mg every 7 days for 8 weeks. Before the beginning of the treatment and after 9 and 17 weeks, the patients underwent a clinical evaluation measuring maximal knee flexion angle, visual analog scale (VAS) and erythrocyte sedimentation rate (ESR). On the same days, an ultrasonographic examination of the involved knee was performed by two independent experienced operators. Synovial thickness in the suprapatellar bursa and the presence of joint effusion and Bakers cyst were assessed. An increase of the mean value of maximal knee flexion angle and a reduction of the mean values of ESR and VAS between T0, T9 and T17 were demonstrated. Ultrasonographic evaluation showed significant reduction of synovial thickness and joint effusion. No differences were detected for the presence of Bakers cyst. We may conclude that repeated intra-articular injections of MTX resulted in a decrease of local as well as systemic inflammatory signs. As far as we know, this is the first study that explores the effects of intra-articular MTX in RA and PsA both clinically and by ultrasonography.     

Rheumatoid factor and anti-citrullinated protein antibodies (ACPA) in psoriatic arthritis (PsA), and skin psoriasis: Relevance and clinical implications

Aim of the workAnti-citrullinated protein antibodies (ACPAs), is a highly specific markers for rheumatoid arthritis, can also be found in psoriatic arthritis (PsA). This work aimed to look into the frequency of rheumatoid factor (RF) and ACPA in PsA and psoriasis patients without clinical evidence of arthritis (PSO), and to correlate findings with demographics, disease characteristics, laboratory findings, and radiological damage in PsA. Patients and methods: The study included 78 PsA patients, 47 PSO patients, and 69 normal controls. Full clinical assessments, RF and ACPA assays, and modified radiological Steinbroker score (Mss) for PsA were performed. Results: The age of the patients was 45.6 ± 8.7 years and the M:F 59:66 (M:F 0.9:1). Positive RF was not significantly different between PsA and PSO groups (p = 0.35), but positive ACPA was significantly more common in PsA patients (p < 0.001) than in PSO and controls. No significant difference was observed between the PSO and controls (p = 0.08). In PsA, RF titers correlated significantly with ESR (p = 0.002), swollen joint count (SJC)(p = 0.02), tender joint count (TJC)(p = 0.02), and mSS (p = 0.001), while in the PSO RF correlated significantly with ESR (p = 0.011) and CRP levels (p = 0.02). In the PsA, ACPA titer significantly correlated with CRP levels (p < 0.001), SJC (p = 0.002), TJC (p = 0.003), mSS (p < 0.001) and PASI (p < 0.001), but with none of these in the PSO. Conclusion: PsA patients have more frequent positive RF and ACPA than PSO patients. ACPA values are significantly correlated with markers of inflammation, swollen and tender joint count and radiological damage in PsA and not in PSO patients.     

Study of tumor necrosis factor receptor in the inflammatory bowel disease

Ulcerative colitis(UC) and Crohn’s disease(CD) are part of Inflammatory Bowel Diseases(IBD) and have pathophysiological processes such as bowel necrosis and enteric neurons and enteric glial cells.In addition,the main inflammatory mediator is related to the tumor necrosis factor-alpha(TNF-α).TNF-α is a mediator of the intestinal inflammatory processes,thus being one of the main cytokines involved in the pathogenesis of IBD,however,its levels,when measured,are present in the serum of patients wit...     

重型肝炎患者血清肿瘤坏死因子α与白细胞介素10和15水平的研究

重型肝炎肝细胞损伤的病理机制与机体的免疫应答和免疫调节紊乱密切相关。细胞因子是一类由免疫活性细胞产生的小分子多肽或蛋白质,其异常分泌和生成能引起机体许多病理性紊乱,细胞因子在病毒性肝炎发病机制中的作用愈来愈被重视,我们应用ELISA法检测了重型乙型肝炎患者血清TNFα,IL-10及IL-15水平,探讨它们在重型肝炎免疫发病机制中的意义。一、资料与方法1.对象:1999年3月-2004年2月我院感染内科住院     

Tumor necrosis factor receptor 2 M196R polymorphism in rheumatoid arthritis and osteoarthritis: relationship with sTNFR2 levels and clinical features

We investigate the clinical association of tumor necrosis factor receptor 2 (TNFR2) M196R polymorphism with rheumatoid arthritis (RA) and knee osteoarthritis (OA). Acute phase reactants, lipid profile, sTNFR2 levels, disease activity–disability indexes, and TNFR2 M196R polymorphism were analyzed in 50 RA, 50 knee OA patients, and 120 healthy subjects (HS). The M/M genotype frequency was 0.74 (RA), 0.80 (OA), and 0.64 (HS). The M/R genotype frequency was RA (0.26), OA (0.20), and HS (0.29). The R/R genotype was observed only in HS (0.07). The M allele was associated with OA (P = 0.0137, OR = 2.43). Total cholesterol, triglyceride levels, apolipoprotein A-I and B showed significant differences (P < 0.05). The highest sTNFR2 levels were observed in RA and OA (P = 0.001), however M/M and M/R carriers do not correlate with sTNFR2 production. Our findings suggest an association of the M allele with knee OA. In addition, high sTNFR2 levels in RA and OA were found.     

白三烯促进类风湿关节炎患者滑膜细胞的IL-1β和TNF-αmRNA表达

目的探讨在类风湿关节炎(RA)患者滑膜细胞中,白三烯B4(LTB4)对肿瘤坏死因子(TNF-α)和白细胞介素-1β(IL-1β)mRNA表达的作用。方法在RA患者滑膜细胞培养体系中,加入LTB4、脂多糖(LPS)、MK-886(5-脂氧化酶激动蛋白的抑制剂),采用实时定量聚合酶链反应(PCR)检测RA患者滑膜细胞中TNF-α和IL-1βmRNA表达的改变。结果原代培养的RA滑膜细胞表达基本的IL-1β和TNF-α[IL-1β/糖酵解甘油醛-3-磷酸脱氢酶(GAPDH)和TNF-α/GAPDH],分别为0.16±0.09和0.02±0.00(n=6)。加入外源性的LTB410-9～10-8mol/L后,使TNF-α和IL-1β的mRNA表达显著增高。LPS刺激内源性的LTB4增高后,也使IL-1β和TNF-αmRNA表达显著增高。在LPS存在时,MK-8861μmol/L和10μmol/L使TNF-α的mRNA表达分别下降了15%和66%(n=7,P<0.05),使IL-1βmRNA表达下降了41%和71%(n=6,P<0.01)。结论LTB4可以调节RA滑膜细胞TNF-α和IL-1βmRNA的表达。     

Inflammatory infiltrate and interleukin-8 expression in the synovium of psoriatic arthritis – an immunohistochemical and mRNA analysis

Psoriatic arthritis is an inflammatory arthropathy that ultimately can lead to joint destruction. In this study, we investigated the immunophenotype of the inflammatory cells and the expression of interleukin-8 (IL-8), which is the hallmark chemoattractant cytokine of psoriasis in synovial membranes from patients exhibiting active psoriatic synovitis (n=9). The tissue samples were examined by immunohistochemistry, Western blot analysis and in situ hybridisation. The inflammatory infiltrate consisted predominantly of CD3⁺ T lymphocytes, with a higher proportion of CD4⁺ than CD8⁺ T lymphocytes in six cases. CD3⁺ T lymphocytes were focally distributed near small blood vessels and the enlarged synovial intima. CD1⁺ interdigitating reticulum cells were not detected. CD22⁺ B lymphocytes and plasma cells were found in small aggregates without KiM4⁺ follicular dendritic cells. KiM8⁺ macrophages were located in the synovial intima and were distributed in a diffuse pattern near the synovial lining cells. CD15⁺ neutrophil granulocytes were detected in four cases. They were preferentially located in the vicinity of blood vessels and the synovial intima. IL-8 was found at a high level in the synovial lining cells and to a lesser extent in cells located in the perivascular areas. Immunofluorescence double staining showed IL-8 to be expressed in KiM8⁺ multinucleated giant cells, KiM8⁺ macrophages and CD3⁺ T lymphocytes. IL-8 receptor A was demonstrated in the synovial lining and in macrophages and lymphocytes. IL-8 was detected by immunoblot analysis of the synovial tissue at 8.4 kD. Employing in situ hybridisation, IL-8 mRNA was strongly and preferentially expressed in the synovial intima, as well as in macrophages and lymphocytes. The immunophenotype of the psoriatic arthritis inflammatory cells shows great similarity to the inflammatory infiltrate found in the synovial tissue of patients with rheumatoid arthritis. The preferential expression of IL-8 and IL-8 mRNA in the enlarged synovial intima and in lymphocytes and macrophages suggests that IL-8 exerts its action through activated mononuclear cells and T lymphocytes. It seems to play a role in regulating leucocyte traffic into the enlarged synovial intima and may contribute to the aggressive synovitis of patients with psoriatic arthritis. Received: 14 August 1997 / Accepted: 25 August 1997     

Efficacy of add-on tacrolimus on methotrexate to maintain clinical remission after rediscontinuation of a tumor necrosis factor inhibitor in rheumatoid arthritis patients who relapsed shortly after discontinuation of the same tumor necrosis factor inhibitor due to clinical remission

Objectives: To describe the efficacy of adding tacrolimus to maintain remission in patients with rheumatoid arthritis (RA) on methotrexate after discontinuation of tumor necrosis factor inhibitor (TNFi) therapy.

Methods: Consecutive patients with RA, who resumed a TNFi to treat flares after initial TNFi-free remission and discontinued a TNFi again after achieving remission and adding tacrolimus were enrolled. The lengths of remission after discontinuation of TNFi without or with tacrolimus were analyzed.

Results: Thirteen TNFi-free periods in six patients, in which seven were without and six were with tacrolimus were analyzed. All were seropositive females with a median age of 46 years and symptom duration of 1.2 years at the onset of TNFi therapy. Two were treated with infliximab and four were with etanercept. The median dose of tacrolimus was 2?mg/day with trough level of 4.5?ng/ml. The length of time to flare after discontinuation of TNFi therapy with tacrolimus was significantly longer than those without tacrolimus (median 107 weeks [range 4–207] versus 13 weeks [2–36]). After adding tacrolimus, only one patient resumed TNFi therapy and three had no flare until final observation.

Conclusions: Add-on tacrolimus was effective in maintaining TNFi-free remission in patients with RA who ever relapsed after TNFi-free remission.     

Influence of hexadecylphosphocholine on the release of tumor necrosis factor and nitroxide from peritoneal macrophages in vitro

Hexadecylphosphocholine (HPC) has been investigated intensively for its cancerostatic properties. One explanation for the mechanism of action of HPC assumes that it plays a role in stimulation of the immune system. In particular, its potency to activate macrophages has already been recognised for different lyso- and ether lipids. Important steps in the cascade for developing cytotoxic effects of macrophages on tumor cells are the release of nitric oxide radicals (NO) and/or tumor necrosis factor (TNF). The aim of our study was to examine the role of HPC as primer and/or trigger for macrophage activation to cytotoxicity. In our experiments we used HPC in free (micellar) or liposomal form in different primer/trigger combinations with lipopolysaccharide (LPS). A weak change in morphology was revealed by electron microscopy, if macrophages were harvested from mice previously treated with HPC or HPC multilamellar vesicles. This observation was quantified by the measurement of NO, TNF and cytotoxic activity of the peritoneal macrophages. A specific release of NO was induced by the combination of in vivo treatment with liposomal HPC and subsequent stimulation by LPS in vitro. This process started only after 12 h of in vitro incubation of macrophages with the endotoxin. The release of TNF was dependent of the primer/trigger combination used. A moderate priming effect was obtained with HPC in liposomal form independently of the trigger. On the other hand, liposomes as priming agents were found to induce a dramatic increase in TNF release after in vitro coculture with the trigger LPS. The high release of NO and TNF is accompanied by only a weak increase in tumor cytostasis. The best results were once more found with macrophages primed with liposomal HPC and then triggered with LPS.Abbreviations HPC hexadecylphosphocholine - MLV multilamellar vesicle - TNF tumor necrosis factor - IFN interferon - LPS lipopolysaccharide This work was supported by a grand from the Federal Ministry for Research and Technology of Germany (0319564A)