Serum type-III-procollagen and laminin concentration after interferon therapy in chronic myeloproliferative disorders

Serum procollagen-III-peptide (P-III-P) and laminin P 1 (LP1) concentrations were measured in 24 patients with various chronic myeloproliferative diseases, viz., essential thrombocythaemia (ET), chronic myelogenous leukaemia (CML) and myelofibrosis (MF). The highest P-III-P values were found in myelofibrosis. As compared to the controls, the serum laminin concentration was higher in all there groups of patients. No significant difference was found between the groups of patients. After three months of alpha-IFN therapy the P-III-P values became significantly higher, the laminin concentration slightly decreased in all investigated patients. Longitudinal follow-up myeloproliferative patients should be carried out in order to prove whether P-III-P and laminin determinations provide a useful test to monitor the progression of the disease and the effect of the therapy.     

Liver biopsies from psoriatics related to methotrexate therapy. 2. Findings before and after methotexate therapy in 88 patients. A blind study.

Eightyeight patients with severe, recalcitrant psoriasis had liver biopsies performed before and after Methotrexate (MTX) therapy. MTX was given for an average of 26 months as a single, weekly, oral dose of 25 mg maximum. The mean cumulative dose was 1733 mg (range 175-4590 mg). A statistically significant increase in the number of pathological post-MTX liver biopsies was found (p less than 0.0001). Of the 88 patients 6 developed cirrhosis and another 5 developed fibrosis, in all 12.5 per cent, during MTX therapy (95 per cent confidence limits for cirrhosis: 3-14 per cent). There was no statistically significant correlation between the number of pathological post-MTX liver biopsy findings in the 88 patients and the following variables one by one: cumulative dose of MTX, duration of MTX therapy and admitted alcoholic intake during MTX therapy. Cirrhosis and fibrosis did not develop statistically more frequently from pathological than normal pre-MTX liver histology (p = 0.062). The liver damage appeared to be due to a multifactorial interaction of straining factors on the liver during MTX therapy. A multifactorial index comprising: cumulative dose of MTX, admitted alcoholic intake during MTX therapy, age, obesity and, if available, pre-MTX liver histology gave an estimate of the probability of developing cirrhosis or fibrosis during treatment of psoriasis with weekly, oral doses of MTX. For use of MTX therapy in psoriasis the following precautions are suggested: MTX therapy should be used only in disabling cases; a pre-MTX liver biopsy and repeat liver biopsies at regular intervals of 1/2-1 year should be performed, alcohol should be prohibited and frequent inquiries should be made about the patient's alcoholic intake; and strong reliance should not be placed on the SGOT as an indicator of abnormal liver histology.     

Polymorphisms in the thymidylate synthase and methylenetetrahydrofolate reductase genes and sensitivity to the low-dose methotrexate therapy in patients with rheumatoid arthritis

Methotrexate (MTX), widely used in the treatment of rheumatoid arthritis (RA), inhibits dihydrofolate reductase (DHFR) and folate-dependent enzymes. Thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) are key enzymes in the folate metabolism and both have been shown to be polymorphic affecting the enzyme activity. To clarify the association between these genetic variations and MTX-related toxicity and efficacy in the treatment of RA, a total of 167 Japanese individuals with RA, including 52 and 63 patients treated with low-dose MTX with or without adverse effects, respectively, and 52 patients without MTX administration were analyzed. Among the 93 patients treated with MTX for >2 months, significantly more patients homozygous for the triple-repeat allele of the polymorphism in the promoter region of the TYMS gene required higher dose of MTX compared to those having at least a double-repeat allele (P=0.033). The incidence of > or =50% improvement in the serum CRP level was significantly higher in patients homozygous for the deletion allele of the polymorphism in the 3'-untranslated region (UTR) of the TYMS gene (P=0.0383). The allele frequency of the insertion/deletion polymorphism in the TYMS 3'UTR in Japanese was significantly different from that in Caucasians (P<0.0001), as was the tandem-repeat polymorphism in its promoter region. On the other hand, MTHFR C677T and A1298C polymorphisms showed no association with MTX-related toxicity or efficacy. Our results suggest that the genotyping for the TYMS polymorphisms may become a useful indicator in determining the appropriate dose of MTX in patients with RA.     

The Immunosuppressive Effect of Methotrexate in Active Rheumatoid Arthritis Patients vs. its Stimulatory Effect in Nonactive Patients,as Indicated by Cytometric Measurements of CD4 + T Cell Subpopulations

This cytometric study assesses the effects of methotrexate (MTX) on the expanded CD4 + lymphocyte population in active and nonactive rheumatoid arthritis (RA) patients. In the active patients, MTX was found to reduce the predominant CD4 + CD28+ subpopulation (by 30%), and the minor subpopulation of CD4 + CD28? (by 34%). The incidence of CD25 phenotype was downregulated by 15%. These reductions can be attributed to immunosuppression through apoptosis, which was demonstrated by MTX‐induced fluorescein diacetate (FDA) hyperpolarization (an established indicator of early apoptosis). In contrast, in nonactive RA patients, the major CD4 + CD28+ subpopulation of small lymphocytes appeared to be activated by MTX, subsequently transforming into a major hyperblast population, whereas the minor CD4 + CD28? subpopulation was not affected by MTX treatment. The activation by MTX in this group of patients is evidenced by MTX‐induced FDA depolarization (an indicator of early activation). Thus, MTX immunosuppressive effect on CD4 + subsets was found in active patients, whereas immunostimulation by MTX was shown in non‐active patients. The found discriminative effect of MTX may suggest a higher effectiveness of low‐dose MTX therapy in active RA patients.     

Plasma from rheumatoid patients taking low dose methotrexate enhances platelet aggregation

Methotrexate (MTX) in low doses is commonly used to treat rheumatoid arthritis (RA). At least 36 deaths have been attributed to bone marrow cytotoxicity associated with low dose MTX. The goal was to determine if plasma from arthritis patients taking low dose MTX induces platelet aggregation in platelet rich plasma from healthy volunteers. Plasma from patients on MTX alone caused a 3-fold increase in aggregation vs plasma from controls (P<0.05). Plasma from patients not taking MTX or taking MTX with diclofenac caused aggregation to a lesser extent. Diclofenac, along with several others NSAIDs and cyclooxygenase inhibitors, depressed aggregation produced by arachidonic acid in platelet rich plasma from healthy volunteers. A precise mechanism for amplification of aggregation by MTX plasma and its relationship to MTX toxicity remains unknown. However, a serum factor may be produced by MTX that modulates the activity of cyclooxygenase, thereby influencing aggregation.     

Additive triple DMARD combination therapy of a low dose of sulfhydryl compounds, sulfasalazine and methotrexate in the treatment of rheumatoid arthritis: a clinical trial

To evaluate the efficacy and safety of additive triple disease modifying anti-rheumatic drug (DMARD) combination therapy of a low dose of sulfhydryl compounds ?D-penicillamine, bucillamine or tiopronin?, sulfasalazine (SSZ) and methotrexate (MTX) as a treatment for rheumatoid arthritis (RA) patients, we studied a total of 33 Japanese RA patients (6 males, 27 females). At 1 or 2 months after simultaneous administration of the 3 above-mentioned DMARDs was begun, significant improvements were seen in markers of joint inflammation, i.e., erythrocyte sedimentation rate and C-reactive protein in sera. At 6 months, clinical improvement judged by the physicians' overall assessment of joint symptoms and laboratory data was observed in 29 (88%) of the 33 RA patients. No marked effect was observed in the other 4 (12%) patients, however. We observed no significant adverse reaction to this therapy. This suggests that additive triple DMARD combination therapy of a low dose of sulfhydryl compounds, SSZ and MTX could be a useful drug therapy for the treatment of RA patients, even those who are refractory.     

Drug-loaded gold/iron/gold plasmonic nanoparticles for magnetic targeted chemo-photothermal treatment of rheumatoid arthritis

We have developed methotrexate (MTX)-loaded poly(lactic-co-glycolic acid, PLGA) gold (Au)/iron (Fe)/gold (Au) half-shell nanoparticles conjugated with arginine-glycine-aspartic acid (RGD), which can be applied for magnetic targeted chemo-photothermal treatment, and in vivo multimodal imaging of rheumatoid arthritis (RA). Upon near-infrared (NIR) irradiation, local heat is generated at the inflammation region due to the NIR resonance of Au half-shells and MTX release from PLGA nanoparticles is accelerated. The Fe half-shell layer embedded between the Au half-shell layers enables in vivo T₂-magnetic resonance (MR) imaging in addition to NIR absorbance imaging. Furthermore, the delivery of the nanoparticles to the inflammation region in collagen-induced arthritic (CIA) mice, and their retention can be enhanced under external magnetic field. When combined with consecutive NIR irradiation and external magnetic field application, these nanoparticles provide enhanced therapeutic effects with an MTX dosages of only 0.05% dosage compared to free MTX therapy for the treatment of RA.     

Adenosine abolishes MTX-induced suppression of osteoclastogenesis and inflammatory bone destruction in adjuvant-induced arthritis

Methotrexate (MTX) is widely utilized for the treatment of patients with rheumatoid arthritis (RA); however, recent observation of the MTX-resistant patients proposed some difficulty in MTX-dependent therapeutic approach for RA. To access cellular events related to MTX resistance in RA in respect to inflammatory bone destruction, we investigated on an involvement of the potent inflammatory mediator adenosine in the regulation of osteoclastogenesis and inflammatory bone destruction. In rats with adjuvant-induced arthritis (AA rats), MTX efficiently suppressed bone destruction when it was administrated within 3 days after adjuvant injection, while it could not suppress inflammatory bone destruction if MTX was injected at the time of onset of inflammation (at day 10 after adjuvant injection). Time-course change in the level of plasma adenosine of AA rats was estimated by use of high-performance liquid chromatography and elucidated that adenosine level was markedly elevated till 10 days after adjuvant injection. In vitro bone marrow culture system for evaluating osteoclastogenesis, MTX markedly suppressed osteoclastogenesis in a stromal cell-dependent manner. This MTX-induced suppression of osteoclastogenesis was abrogated by the addition of adenosine. MTX suppressed the expression of mRNA for the receptor activator NF-κB ligand (RANKL), but it did not suppress the expression of osteoprotegerin (OPG). The addition of MTX and adenosine together markedly suppressed the level of OPG expression. Abolishment of MTX action by adenosine was significantly blocked by MRS1754, a highly selective antagonist for the A(2b) adenosine receptor (A(2b)AR), but not by caffeine, an antagonist for A?, A(2a), A? AR (A?AR, A(2a)AR, and A?AR), which suggests that adenosine acts through A(2b)AR. Immunohistochemical studies showed abundant expression of A(2b)AR in cells localized in the bone-bone marrow boundary of the distal tibia in AA rats but not in control rats. When adenosine was injected in the ankle joints of MTX-treated AA rats, the suppressive effects of MTX on bone destruction was abolished. The current data therefore suggest that upregulation of adenosine production abolished the suppressive effect of MTX on osteoclastic bone destruction. Involvement of the adenosine-A(2b)AR system may explain MTX resistance in RA.     

The immunosuppressive effect of methotrexate in active rheumatoid arthritis patients vs. its stimulatory effect in nonactive patients, as indicated by cytometric measurements of CD4+ T cell subpopulations

This cytometric study assesses the effects of methotrexate (MTX) on the expanded CD4+ lymphocyte population in active and nonactive rheumatoid arthritis (RA) patients. In the active patients, MTX was found to reduce the predominant CD4+ CD28+ subpopulation (by 30%), and the minor subpopulation of CD4+ CD28- (by 34%). The incidence of CD25 phenotype was downregulated by 15%. These reductions can be attributed to immunosuppression through apoptosis, which was demonstrated by MTX-induced fluorescein diacetate (FDA) hyperpolarization (an established indicator of early apoptosis). In contrast, in nonactive RA patients, the major CD4+ CD28+ subpopulation of small lymphocytes appeared to be activated by MTX, subsequently transforming into a major hyperblast population, whereas the minor CD4+ CD28- subpopulation was not affected by MTX treatment. The activation by MTX in this group of patients is evidenced by MTX-induced FDA depolarization (an indicator of early activation). Thus, MTX immunosuppressive effect on CD4+ subsets was found in active patients, whereas immunostimulation by MTX was shown in nonactive patients. The found discriminative effect of MTX may suggest a higher effectiveness of low-dose MTX therapy in active RA patients.     

Different effects of biological drugs in rheumatoid arthritis

Biological drugs have brought new hope to patients with rheumatoid arthritis (RA) in whom previously existing treatments could not control inflammation, joint destruction, or the progression of disability. The five currently available TNF blockers are approved for treating RA patients, but they have different structures, morphology, pharmacokinetic properties, and activity.Randomised clinical trials (RCTs) have shown that they improve the signs and symptoms of both early and long-standing RA and other inflammatory arthritides, prevent radiographic progression, and improve the patients’ health-related quality of life. However, they are more effective in combination with methotrexate (MTX) than alone. Combined treatment is generally well tolerated, and seems to be relatively safe in the short term, as confirmed by RCTs, long-term observational studies and in clinical practice. Patients who fail to respond or develop adverse effects - when treated with one anti-TNF agent can be successfully treated with a second TNF antagonist. However, in the case of primary failure, it is possible that biological agents with a different mechanism of action may be more successful. Tocilizumab alone or in combination with MTX is more effective than MTX monotherapy in reducing disease activity over 24 weeks. Abatacept is well tolerated and retains its efficacy over time, as does rituximab in non-responders to other anti-TNF drugs. Finally, although these drugs improve the quality of life of RA patients, they considerably increase direct medical costs.     

The Immunosuppressive Effect of Methotrexate in Active Rheumatoid Arthritis Patients vs. its Stimulatory Effect in Nonactive Patients, as Indicated by Cytometric Measurements of CD4 T Cell Subpopulations

This cytometric study assesses the effects of methotrexate (MTX) on the expanded CD4 + lymphocyte population in active and nonactive rheumatoid arthritis (RA) patients. In the active patients, MTX was found to reduce the predominant CD4 + CD28+ subpopulation (by 30%), and the minor subpopulation of CD4 + CD28- (by 34%). The incidence of CD25 phenotype was downregulated by 15%. These reductions can be attributed to immunosuppression through apoptosis, which was demonstrated by MTX-induced fluorescein diacetate (FDA) hyperpolarization (an established indicator of early apoptosis). In contrast, in nonactive RA patients, the major CD4 + CD28+ subpopulation of small lymphocytes appeared to be activated by MTX, subsequently transforming into a major hyperblast population, whereas the minor CD4 + CD28- subpopulation was not affected by MTX treatment. The activation by MTX in this group of patients is evidenced by MTX-induced FDA depolarization (an indicator of early activation). Thus, MTX immunosuppressive effect on CD4 + subsets was found in active patients, whereas immunostimulation by MTX was shown in non-active patients. The found discriminative effect of MTX may suggest a higher effectiveness of low-dose MTX therapy in active RA patients.     

Methotrexate for the treatment of rheumatoid arthritis in the biologic era: Still an “anchor” drug?

The improvement of rheumatoid arthritis (RA) management has been strictly related to methotrexate (MTX) long-term effectiveness, safety profile and its widespread use in clinical practice over the last decades. According to the results of several head-to-head comparative trials against other synthetic DMARDs, MTX has been recognised as the “anchor drug” for the treatment of RA at the end of the 1990s. The subsequent increasing knowledge in the area of RA pathophysiology has progressively expanded the arsenal of available therapeutic tools, especially by the introduction of novel drugs such as biological DMARDs. The introduction of therapies targeted to key molecules and cells involved in RA pathogenesis has significantly changed the strategies for disease management, possibly modifying the key role of MTX. This review first analyses data supporting the evolution of MTX towards the role of “anchor drug” for RA in the pre-biologic era. We will then examine how the introduction and progressive spreading of biological agents could have modified the central role of MTX in the approach to RA.     

Differential effects of infliximab on absolute circulating blood leucocyte counts of innate immune cells in early and late rheumatoid arthritis patients

Anti-tumour necrosis factor (TNF) biologics have revolutionized therapy of rheumatoid arthritis (RA). We compared the effects of infliximab on numbers of circulating leucocyte subsets in early RA (disease/symptom duration of ≤1 year) and late RA patients (>1 year). A control group consisted of early RA patients treated with a combination of methotrexate (MTX) and methylprednisolone. Blood samples were obtained at baseline (pre-therapy) from all RA patients, divided into three groups: (i) late RA receiving infliximab/MTX, (ii) early RA-infliximab/MTX, (iii) early RA-steroid/MTX, and also from follow-up patients at 2 and 14 weeks. Significant differences in absolute counts of monocytes and granulocytes were observed between healthy controls and RA patients. At baseline CD14(bright) monocytes and CD16(+) granulocytes were increased in both early RA and late RA patients. CD4(+) T cells, CD8(+) T cells and B cells were all increased at baseline in early RA, but not in late RA. At 2 weeks following infliximab treatment decreased granulocytes were observed in both early and late RA and decreased natural killer (NK) cells in late RA. CD16(+) granulocytes and NK cells were also decreased at 14 weeks post-infliximab in early RA. Biotinylated infliximab was used to detect membrane-associated TNF (mTNF)-expressing leucocytes in RA patients. CD16(+) granulocytes, NK cells and CD14(dim) monocytes all expressed higher levels of mTNF in RA patients. In summary infliximab is associated with decreased CD16(+) granulocyte and NK cell counts, possibly through binding of mTNF. Differential effects of infliximab between early and late RA suggest that pathogenic mechanisms change as disease progresses.     

Tumour necrosis factor (TNF) production by T cell receptor-primed T lymphocytes is a target for low dose methotrexate in rheumatoid arthritis.

Methotrexate (MTX) is an effective immunosuppressive agent in various chronic inflammatory diseases such as rheumatoid arthritis (RA). However, its mechanisms of action are only partially understood. In this study, we assessed the effects of MTX on the differentiation of peripheral blood (PB) CD4+CD45RA 'naive' and CD4+CD45RO 'memory' T cells from healthy controls and patients with RA. Accordingly, purified T cells were primed and restimulated in vitro via the T cell receptor (TCR) in the presence of IL-2 to generate effector T cells secreting large amounts of Th1 and Th2 cytokines. We observed that low doses of MTX strongly suppress TNF and to a lesser extent interferon-gamma (IFN-gamma) production by T cells from both healthy donors and RA patients when present during T cell priming via the TCR. Similar data were obtained for TCR-primed synovial fluid mononuclear cells in RA. In contrast, production of IL-4 by TCR-primed CD45RA T cells was significantly increased upon MTX treatment. Interestingly, MTX did not enhance IL-4 production when present during restimulation of effector CD45RO T cells, although it still suppressed TNF production. The results indicate that MTX effects depend on the stage of T cell activation and identify TNF production by TCR-primed T lymphocytes as a target for low-dose MTX treatment in RA. These findings could explain the delayed clinical effects of MTX and may contribute to its potent anti-inflammatory and immunoregulatory properties.     

Combined steroid-cyclosporin treatment of chronic autoimmune diseases

Summary Twenty-one patients suffering from different autoimmune diseases (14 from systemic lupus erythematosus, 4 from rheumatoid arthritis, one from Sjögren's syndrome, one from systemic hypersensitivity vasculitis, and one from diffuse proliferative glomerulonephritis) were treated with a combined immuno-suppressive regimen. Cyclosporin was given at a dose of 5 mg/kg/day together with steroids. In addition, the rheumatoid arthritis patients also received methotrexate. In all patients a kidney biopsy was performed after a treatment period of 17 to 42 months (mean duration 21.7 months). The cumulative cyclosporin dose at the time of biopsy varied from 1.071 to 4.587 mg/kg. Patients suffering from systemic lupus erythematosus and rheumatoid arthritis were assessed according to a scoring system set up for this purpose. The combined therapy proved useful in these patients as reflected in the diminution of the respective activity scores, improvement of kidney function, and diminution of proteinuria. Histological examination of the kidney biopsy specimens showed only minimal activity in patients with systemic lupus erythematosus. No unequivocal signs of renal toxicity could be detected. In the last group, the condition of the patient with Sjögren's syndrome was stabilized and the patient with systemic vasculitis improved clinically. Neither patient had signs of kidney lesions. The patient with diffuse proliferative glomerulonephritis, in whom kidney biopsy was performed before and after treatment, showed improvement of kidney function, diminution of proteinuria, and diminution of inflammatory activity within the kidney, and no signs of cyclosporin toxicity.Abbreviations CyA Cyclosporin - MTX Methotrexate - NSAID Nonsteroidal antiinflammatory drugs - RA Rheumatoid arthritis - SLE Systemic lupus erythematosus - TFA index Index of extent of tubular atrophy, intersitital fibrosis, and arteriolopathy     

Predictive Factors for Rheumatoid Arthritis Flare After Switching From Intravenous to Subcutaneous Formulation of Tocilizumab in Real-World Practice

BackgroundTo evaluate the incidence and related factors of rheumatoid arthritis (RA) flares after switching from intravenous tocilizumab (TCZ-IV) to subcutaneous tocilizumab (TCZ-SC) injection in stable RA patients.MethodsWe retrospectively evaluated the medical records of stable RA patients who used TCZ-IV for more than 6 months and switched to TCZ-SC between January 2013 and April 2020. RA flare was defined as an increase of more than 1.2 in the RA disease activity as assessed by the disease activity score in 28 joints. The factors associated with RA flare were evaluated by logistic regression analysis.ResultsAmong 106 patients treated with TCZ-IV for > 6 months, 37 patients were switched to TCZ-SC after the acquisition of remission or low disease activity. RA flares occurred in 11 (29.7%) of patients who switched TCZ-SC. Results from the multivariable logistic analysis revealed that the dose of TCZ-IV per weight at switching (odds ratio [OR], 20.70; 95% confidence interval [CI], 2.22–192.84; P = 0.008) and methotrexate (MTX) non-use (OR, 8.53; 95% CI, 1.21–60.40; P = 0.032) were associated with the risk of RA flares after switching to TCZ-SC. Interestingly, most patients who switched back to TCZ-IV had their RA activity controlled again.ConclusionMTX non-use and high dose of TCZ-IV per weight were associated with a risk of RA flare after switching to TCZ-SC. RA patients with these factors need to be carefully observed for flare after switching from TCZ-IV to TCZ-SC.     

The Prospect of Treating Rheumatoid Arthritis with Recombinant Human Interleukin-1 Receptor Antagonist

The prospect of introducing a potent novel therapy that specifically targets a pivotal mediator of disease offers new hope to patients with rheumatoid arthritis (RA). There is convincing evidence that interleukin-1 (IL-1) plays a critical role in the pathogenesis of RA. In RA, the inadequate production of IL-1 receptor antagonist (IL-1Ra), the natural inhibitor of IL-1, results in increased IL-1-mediated pathophysiological activity. Unregulated IL-1-mediated effects produce enhanced tissue inflammation and progressive degradation of cartilage and bone matrix. Recombinant IL-1Ra treatment in experimental models of arthritis results in profound suppression of synovial inflammation and joint damage. Recombinant human IL-1Ra (rhu-IL-1Ra) has been evaluated in RA in several randomised clinical trials and was shown to significantly reduce both the clinical manifestations of arthritis and the rate of progressive joint damage. Firstly, in a 6-month placebo-controlled study, 43% of the patients who received the highest dose of rhu-IL-1Ra (150 mg/day) demonstrated a 20% improvement (American College of Rheumatology clinical criteria) compared to 27% of the patients who received placebo. In addition, the patients who received rhu-IL-1Ra demonstrated 46% less joint damage (Larsen scores). Secondly, in a 6-month extension of the placebo-controlled study, the treated patients maintained their clinical improvement and there was further significant reduction in the rate of progressive joint damage. The patients who had originally received placebo demonstrated both clinical and radiological responses that were similar to those observed in the treated patients during the initial phase of the study. Finally, in a combination study with methotrexate (MTX), 42% of patients who received MTX and the optimal dose of rhu-IL-1Ra (1.0 mg/kg/day) demonstrated an ACR 20% clinical response, compared to 23% of those receiving MTX and placebo. rhu-IL-1Ra was well tolerated in all studies and adverse events were uncommon. The most frequently reported adverse event causing withdrawal of treatment was an injection site reaction, occurring in approximately 5% of patients. In conclusion, targeted IL-1 inhibition significantly reduced both the clinical manifestations and the rate of progressive joint damage in patients with RA. These observations suggest that rhu-IL-1Ra has a potential role as a novel therapeutic modality in the future management of RA.     

Is rheumatoid arthritis a risk factor for oral bisphosphonate-induced osteonecrosis of the jaws?

Bisphosphonate-related osteonecrosis of the jaws is a relevant side-effect of these drugs that has been generating a great concern through increasing reports, worldwide, of this bone necrosis. Among several BRONJ hypothetical co-factors that could play a role in BRONJ pathogenesis, rheumatoid arthritis (RA) has been included as a relevant risk factor for BRONJ; however, until now the relationship between these diseases has not been fully explained. Thus, the purpose of this paper is to establish hypothetical factors that could link these two diseases, considering mainly inflammatory components and the organism effects of medicines used to treat RA, particularly steroids and methotrexate (MTX).     

类风湿性关节炎滑膜成纤维细胞骨保护素和骨形态发生蛋白-2的表达及干预

目的 探讨甲氨蝶呤（MTX）及白细胞介素-6受体（IL-6R）抗体对类风湿关节炎（RA）滑膜成纤维细胞增殖的干预及对骨保护素（OPG）、骨形态发生蛋白-2（BMP-2）的影响.方法 获取RA患者滑膜组织,消化并传代培养成纤维细胞.CCK-8法检测IL-6R抗体、甲氨蝶呤（MTX）对RA滑膜成纤维细胞活性影响;荧光定量（qRT）-PCR检测OPG和BMP-2表达.结果 与空白组相比,MTX组、IL-6R抗体组成纤维细胞的活性受到抑制（F=29.30,34.22,P＜0.05）,MTX联合IL-6R抗体组成纤维细胞的活性显著受到抑制（F=52.04,P ＜0.01）.qRT-PCR显示与空白组相比,IL-6R抗体组、MTX联合IL-6R抗体组OPG、BMP-2的表达均上升（P＜0.05）.与MTK组相比,IL-6R抗体组OPG、BMP-2的表达增加（P＜0.05）.结论 IL-6R抗体单独或联合MTK使用均能明显抑制RA滑膜成纤维细胞的活性,与MTX相比,IL-6R抗体能升高OPG、BMP-2的表达.本研究为应用IL-6R抗体预防和治疗RA关节破坏提供实验依据.