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Fatigue is a hallmark symptom of systemic lupus erythematosus (SLE), often associated with flares, side effects of treatment, and extensive organ damage and may have a significant impact on health-related quality of life (HrQoL). To date, the experience of fatigue in patients with SLE is underexplored. This study explored the experience of fatigue in patients with SLE and its impact on their lives through qualitative interviews.This cross-sectional qualitative study was conducted with 22 adult patients with SLE, recruited from two clinical sites in the United States. In-person semi-structured interviews were conducted and thematic analysis was performed focusing on the experience of fatigue in SLE.Results indicated that 21 out of 22 patients experienced fatigue due to SLE. Patients reported that fatigue was variable in nature in terms of both severity and frequency. Fatigue was described as having an impact on multiple aspects of a patient’s life: emotions, cognition, work, activities of daily living, leisure activities, social activities, and family activities.Understanding how patients with SLE describe the symptom of fatigue and how it impacts their lives is the key to better understanding how to measure fatigue in clinical studies evaluating new treatments for SLE. [ABSTRACT FROM AUTHOR]

Abstract Objective: To assess changes in quality of life (QOL) and pain in raloxifene-treated Japanese women with postmenopausal osteoporosis. Research design and methods: This prospective, postmarketing observational study was conducted at 60 Japanese hospitals from September 2007 to February 2009 and included Japanese women with postmenopausal osteoporosis who were new to standard treatment with raloxifene (60 mg/day). Primary outcome measures (QOL and pain) were assessed using the Short Form-8 (SF-8), European Quality of Life Instrument (EQ-5D), osteoporosis-specific Japanese Osteoporosis Quality of Life Questionnaire (JOQOL), a visual analogue scale (VAS-pain), and a pain frequency survey. Assessments were performed at baseline and 8 (except JOQOL) and 24 weeks after first administration of raloxifene. Adverse drug reactions were recorded. Japan Pharmaceutical Information Center registration number: JapicCTI-070465. Results: A total of 506 participants, mean (±standard deviation [SD]) age = 70.7 ± 8.7 years, completed >=1 follow-up assessment and were included in the analyses. All QOL scores increased from baseline during follow-up. All SF-8 domain scores increased significantly from baseline after 8 and 24 weeks (P < 0.001). Mean (±SD) EQ-5D scores increased significantly from baseline (0.70 ± 0.17) by 0.05 ± 0.15 after 8 weeks and 0.07 ± 0.17 after 24 weeks (P < 0.001). The mean (±SD) total JOQOL score increased significantly from baseline (66.8 ± 16.5) by 3.8 ± 11.3 after 24 weeks (P < 0.001). The percentage of participants with a >=20 mm reduction in VAS-pain was 32.6% (120/368) and 39.5% (115/291) after 8 and 24 weeks, respectively. The frequency of pain reported by participants decreased after 8 and 24 weeks. Forty adverse drug reactions were reported by 34 participants. Limitations: Limitations include the lack of a control group, the possibility of the changes being due to the natural disease course, and potential selection bias. Conclusions: Our findings suggest that standard treatment with raloxifene improves QOL and relieves pain in Japanese women with postmenopausal osteoporosis in a real-world clinical setting. [ABSTRACT FROM AUTHOR]

Objectives: This exploratory analysis investigated the potential use of the multibiomarker disease activity (MBDA) score to support biosimilarity assessments using data from two randomised controlled trials (RCTs) of biosimilar infliximab (IFX-qbtx) and biosimilar adalimumab (ADL-afzb) versus EU-sourced infliximab (Remicade; IFX-EU) and adalimumab (Humira; ADL-EU) reference products, respectively, both conducted in adult patients with active rheumatoid arthritis., Methods: In one study, patients (N=650) were randomised 1:1 to IFX-qbtx or IFX-EU (3 mg/kg intravenous at weeks 0, 2 and 6, then every 8 weeks). In the other, patients (N=597) were randomised 1:1 to ADL-afzb or ADL-EU (40 mg subcutaneous every other week). All treatments were given with MTX. Mean values of MBDA scores were calculated at baseline (BL), based on the concentrations of 12 serum proteins using the Vectra disease activity algorithm, and at timepoints throughout treatment period 1 (TP1) of the IFX (weeks 6, 14, 30) and ADL (weeks 6, 12, 26) studies. Data were summarised using descriptive statistics for the intent-to-treat population, without imputation for missing data., Results: At BL, mean (±SD) MBDA scores were 61.3 (±12.5) and 58.8 (±13.2) for IFX-qbtx (n=236) and IFX-EU (n=248), respectively, and 57.2 (±14.44) and 58.3 (±15.34) for ADL-afzb (n=292) and ADL-EU (n=293), respectively. Mean MBDA scores were highly comparable between IFX-qbtx and IFX-EU and between ADL-afzb and ADL-EU at all measured timepoints during TP1 in each study., Conclusions: These RCTs are the first to incorporate MBDA score as an exploratory assessment of biosimilarity. MBDA scores may provide objective, quantitative evidence of biosimilarity using an assessment of disease activity that is independent of the potential subjectivity inherent in joint counts, or in patient or physician global assessments., Trial Registration Numbers: NCT02222493 and NCT02480153., Competing Interests: Competing interests: JK reports grant support (paid to his institution) from Aker BioMarine, Alliance for Lupus Research, AMPEL BioSolutions, Gilead Sciences, Inc., Novartis Pharmaceuticals Corp., Pfizer and UCB Inc; royalty fees from UpToDate; consulting fees from AbbVie, Alvotech Suisse AG, Arena Pharmaceuticals, Inc., Boehringer Ingelheim GmbH, Celltrion Healthcare Co. Ltd., Horizon Therapeutics PLC, Jubilant Radiopharma, Merck Sharp & Dohme Corp., Mylan Inc., Novartis AG, Pfizer, Samsung Bioepis, Sandoz Inc., Scipher Medicine, and UCB Inc.; and fees for participation in data monitoring boards from Bristol Myers Squibb Co., Inmagene Biopharmaceuticals and Kolon TissueGene Inc. DFA, AEB, MR and MZ are full-time employees of, and declare shareholdings, stock holdings and/or stock options from, Pfizer. NI was a full-time employee of Pfizer at the time of the studies and declares shareholdings, stock holdings and/or stock options from Pfizer. WZ is a full-time employee of Pfizer and declares shareholdings, stock holdings and/or stock options from Abbot, AbbVie and Pfizer., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Over time, clinicians have become increasingly comfortable embracing the prescription of biosimilars-highly similar versions of innovator or reference biological agents-for their patients with inflammatory diseases. Although a switch from a reference product to a licensed biosimilar version (or vice versa) is a medical decision robustly supported by the stepwise accumulation of clinical trial evidence concerning comparable safety, immunogenicity, and efficacy between these products, a switch from one biosimilar to another biosimilar of the same reference product, or a cross-switch, is not. Similarity among biosimilars of a reference product is not a regulatory agency concern and therefore is unlikely to be investigated in randomized controlled trials in the foreseeable future. Yet in clinical practice, across a diverse range of patients, the option to cross-switch from one biosimilar to another can and does arise for valid reasons such as convenience or tolerability issues, or driven by third parties (e.g., payers). In the absence of clinical trial data, clinicians must attempt to objectively evaluate the emerging real-world cross-switching evidence within the context of what is known about the science underpinning a designation of biosimilar. That knowledge then needs to be integrated with what clinicians know about their patients and their disease on a case-by-case basis. This review aims to consolidate relevant emerging real-world data and other key information about biosimilar-to-biosimilar cross-switching for prescribing clinicians. In the absence of clear clinical guidelines addressing this topic at present, this review may serve to facilitate discretionary and educated treatment decision making., (© 2021. The Author(s).)

Background: This post hoc analysis assessed clinical and functional responses to tofacitinib monotherapy, tofacitinib + methotrexate (MTX), and adalimumab + MTX, in patients with rheumatoid arthritis enrolled in the ORAL Strategy study, including evaluation of patient-level data using cumulative probability plots., Methods: In the 12-month, phase IIIb/IV ORAL Strategy study, patients with rheumatoid arthritis and an inadequate response to MTX were randomized to receive tofacitinib 5 mg twice daily (BID), tofacitinib 5 mg BID + MTX, or adalimumab 40 mg every other week + MTX. In this post hoc analysis, cumulative probability plots were generated for mean percent change from baseline (%∆) in the Clinical Disease Activity Index (CDAI; clinical response) and mean change from baseline (∆) in the Health Assessment Questionnaire-Disability Index (HAQ-DI; functional response) at month 12. Median C-reactive protein (CRP) levels by time period were summarized by CDAI remission (≤ 2.8) status at months 6 and 12., Results: Data for 1146 patients were analyzed. At month 12, cumulative probability plots for %∆CDAI and ∆HAQ-DI were similar across treatments in patients with greater response. At lower levels of response, patients receiving tofacitinib monotherapy did not respond as well as those receiving combination therapies. With tofacitinib + MTX, numerically higher baseline CRP levels and numerically larger post-baseline CRP reductions were seen in patients achieving CDAI remission at months 6 and 12 vs those who did not., Conclusions: These results suggest that patients with a greater response did well, irrespective of which therapy they received. Patients with lesser response had better outcomes with combination therapies vs tofacitinib monotherapy, suggesting they benefitted from MTX. High pre-treatment CRP levels may be associated with better response to tofacitinib + MTX., Trial Registration: ClinicalTrials.gov, NCT02187055. Registered on 08 July 2014., (© 2021. The Author(s).)

Objective: To explore herpes zoster (HZ) rates and live zoster vaccine (LZV) safety in a subset of patients with rheumatoid arthritis who received LZV before tofacitinib ± methotrexate (MTX), or adalimumab (ADA) plus MTX in the ORAL Strategy., Methods: ORAL Strategy was a 1-year, phase IIIb/IV, randomized, triple-dummy, active-comparator-controlled study. MTX-inadequate responder patients received tofacitinib 5 mg twice daily (BID), tofacitinib 5 mg BID plus MTX, or ADA 40 mg every other week plus MTX (1:1:1 randomization). Eligible patients age ≥50 years could opt to receive LZV 28 days before initiating study treatment. HZ incidence rates (IRs; patients with events per 100 patient-years) were calculated. Opportunistic HZ infections (multidermatomal/disseminated), serious HZ events, and LZV-related adverse events were monitored., Results: In ORAL Strategy, 216 of 1,146 patients (18.8%) received LZV. Overall, 18 patients (1.6%) developed HZ (vaccinated: n = 3; nonvaccinated: n = 15). HZ IRs were 1.1 (95% confidence interval [95% CI] 0.3-2.9), 2.3 (95% CI 1.0-4.6), and 1.7 (95% CI 0.6-3.7) for tofacitinib monotherapy, tofacitinib plus MTX, and ADA plus MTX, respectively, and were generally similar between vaccinated and nonvaccinated patients. Three multidermatomal, 1 disseminated, and 2 serious HZ events occurred. No vaccinated patients had zoster-like lesions within 42 days of vaccination; 1 patient had vaccination-site erythema., Conclusion: LZV was well tolerated, and HZ IRs were generally similar between treatment groups and vaccinated versus nonvaccinated patients. However, ORAL Strategy was not powered for comparisons between vaccinated and nonvaccinated patients because <20% of all patients were vaccinated. Furthermore, LZV has been shown to be effective only in ~50% of individuals., (© 2019 Pfizer Inc. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objective: To provide the first direct comparison of patient-reported outcomes (PROs) following treatment with tofacitinib monotherapy versus tofacitinib or adalimumab (ADA) in combination with methotrexate (MTX) in patients with rheumatoid arthritis (RA) with inadequate response to MTX (MTX-IR)., Methods: ORAL Strategy (NCT02187055), a phase IIIB/IV, head-to-head, randomised controlled trial, assessed non-inferiority between tofacitinib 5 mg two times per day monotherapy, tofacitinib 5 mg two times per day+MTX and ADA 40 mg every other week+MTX. PROs assessed included the following: Patient Global Assessment of disease activity (PtGA), Pain, Health Assessment Questionnaire-Disability Index, Functional Assessment of Chronic Illness Therapy-Fatigue and 36-Item Short-Form Health Survey (SF-36) summary and domain scores., Results: Substantial improvements from baseline were reported across all PROs in all treatment arms, which, in the majority, met or exceeded minimum clinically important differences. Compared with tofacitinib monotherapy, tofacitinib+MTX combination treatment conferred significantly greater improvements in PtGA, Pain and SF-36 physical component summary scores at month 6. Statistically or numerically greater improvements were often, but not uniformly, reported for combination treatments compared with tofacitinib monotherapy at other time points., Conclusion: Treatment with tofacitinib+MTX, ADA+MTX and tofacitinib monotherapy resulted in clinically meaningful improvements in PROs in MTX-IR patients with RA. These were comparatively greater with combination treatments versus tofacitinib monotherapy, although differences between treatment arms were small, limiting our ability to confer clinical meaning., Trial Registration Number: NCT02187055., Competing Interests: Competing interests: VS has received consulting fees from AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Corrona, Eli Lilly, Genentech/Roche, GSK, Janssen, Merck, Novartis, Pfizer Inc, Regeneron, Samsung, Sandoz, Sanofi and UCB. EM has received research grants, consulting fees or other remuneration from, and is a member of the speakers’ bureau for, AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, MedImmune, Pfizer Inc and Roche. RJM has received research grants and consulting fees from, or is a member of the speakers’ bureau for, AbbVie, AKL Pharma, Biogen, Bristol-Myers Squibb, Chugai, Eli Lilly, Novartis, Pfizer Inc, Roche, Sandoz, Sanofi and UCB. DG, KS and NI are employees and shareholders of Pfizer Inc. GVW and RD were employees and shareholders of Pfizer Inc at the time of the analysis. JSS has received consulting fees, speaking fees and honoraria from AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celltrion, Eli Lilly, GSK, ILTOO, Janssen, MedImmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi and UCB Pharma; and has received institutional grants from AbbVie, Eli Lilly, Janssen, MSD, Pfizer Inc and Roche. RF has received research grants or consulting fees from AbbVie, ACEA, Amgen, AstraZeneca, Bristol-Myers Squibb, Celltrion, Eli Lilly, Genentech, GSK, Janssen, Novartis, Pfizer Inc, Samsung, Sanofi-Aventis, Tahio and UCB., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Tofacitinib is an oral Janus kinase (JAK) inhibitor used for the treatment of rheumatoid arthritis. We assessed the efficacy and safety of tofacitinib after methotrexate withdrawal in patients who achieved low disease activity (LDA) with tofacitinib in combination with methotrexate., Methods: ORAL Shift was a phase 3b/4 non-inferiority trial in patients aged at least 18 years with moderate-to-severe rheumatoid arthritis and an inadequate response to methotrexate done in 109 centres across 16 countries. After 24 weeks of open-label tofacitinib modified-release 11 mg once daily plus methotrexate, patients who achieved LDA (clinical disease activity index [CDAI] ≤10) were randomly assigned 1:1 via an automated web-based response system to receive tofacitinib plus placebo (tofacitinib monotherapy; ie, masked methotrexate withdrawal) or continue tofacitinib plus methotrexate for 24 weeks in a double-blind manner. The primary endpoint was the least squares mean change from week 24 to week 48 in disease activity score in 28 joints with four variables, including erythrocyte sedimentation rate (DAS28-4[ESR]). The primary analysis was done in all patients who received at least one dose of study treatment in both phases, and safety was assessed in all patients who received at least one dose of study treatment since enrolment. Non-inferiority of tofacitinib monotherapy versus tofacitinib plus methotrexate was declared if the upper bound of the 95% CI for the difference in change in DAS28-4(ESR) between treatment groups was less than 0·6. Safety was assessed in both phases. The trial is registered with ClinicalTrials.gov, NCT02831855, and is complete., Findings: Between Sept 1, 2016, and Nov 1, 2017, 694 patients were enrolled in the open-label phase and 623 received study treatment for 24 weeks. 533 achieved CDAI-defined LDA and were randomly assigned into the double-blind phase (267 in the tofacitinib monotherapy group and 266 in the tofacitinib plus methotrexate group). Three participants in the monotherapy group did not start treatment so were not included in the primary analysis. Non-inferiority was demonstrated (difference 0·30 [95% CI 0·12-0·48]). 107 (41%) of 264 patients in the tofacitinib monotherapy group and 109 (41%) of 266 in the tofacitinib plus methotrexate group had adverse events; five patients from each group discontinued because of adverse events; two patients died in the tofacitinib plus methotrexate group. No new safety findings were reported up to 48 weeks., Interpretation: Patients with rheumatoid arthritis who achieve LDA with a combination of tofacitinib plus methotrexate may consider withdrawing methotrexate without significant worsening of disease activity or unexpected safety issues., Funding: Pfizer., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

In systemic lupus erythematosus (SLE), the availability of self-antigen promotes and fuels self-reactive immune responses. Apoptotic cells represent a major source of self-antigens, and an impairment of the removal of apoptotic material containing self-antigen can contribute to the development of autoimmunity. To address whether the adipocytokine leptin--which favors autoimmune responses through little understood mechanisms--could modulate the handling of apoptotic cells in SLE, we evaluated the ability of leptin to modulate the capacity of macrophages to phagocytose apoptotic bodies in (NZB × NZW)F1 lupus mice. It was found that leptin promoted phagocytosis of apoptotic cells by macrophages by modulating cAMP levels in macrophages. This finding associated with an increased availability of antigen that favored the development of T cell responses to apoptotic-derived antigen. As leptin promotes macrophage phagocytosis of apoptotic bodies in SLE and subsequent availability of apoptotic-derived antigen to T cells, an inhibition of this process via leptin blockade might have a therapeutic potential in SLE.

To prevent autoimmunity, anergy of autoreactive B cells needs to be maintained, together with the suppression of hyperactive B cells. We previously reported that CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) can directly suppress autoantibody-producing autoreactive B cells in systemic lupus erythematosus. In this article, we show that Tregs can also reduce the production of autoantibodies in (NZB × NZW)F1 mouse lupus B cells by promoting B cell anergy, both in vitro and in vivo. This phenomenon associated with a reduction in Ca(2+) flux in B cells, and CTLA-4 blockade inhibited the effects of Tregs on anergic lupus B cells. These findings identify a new mechanism by which Tregs can control production of autoantibodies in lupus B cells and, more generally, B cell activity in physiopathological conditions.

In systemic lupus erythematosus (SLE), the impairment in apoptosis can facilitate the initiation and maintenance of autoimmune responses to self antigens. Here we show that the adipocytokine leptin, which is abnormally elevated in SLE, promotes the survival and proliferation of autoreactive T-cells in mice with an autoreactive T-cell repertoire, including (NZB x NZW)F1 lupus-prone mice. This ability of leptin to promote lupus T-cell autoimmunity suggests the possibility of a therapeutic targeting of leptin in SLE., (© 2013.)

This large-scale postmarketing surveillance of raloxifene (60 mg/day) was conducted to assess the safety and effectiveness of raloxifene for long-term use in postmenopausal Japanese women with osteoporosis. The baseline examination included 6,967 women (mean age, 70.4 years). Participants completed observation after 6, 12, 24, and 36 months of therapy. Adverse drug reactions (ADR) were reported in 776 participants (11.14 %), with a total of 87 serious ADR cases occurring in 76 participants (1.09 %). The most frequently reported ADRs were edema peripheral (45/6,967, 0.65 %) and venous thromboembolism (11/6,967, 0.16 %). Of the 6,967 participants, 2,784 were included in the effectiveness analysis. Lumbar spine bone mineral density (BMD) increased significantly (p < 0.001, paired t test) compared with baseline at 6, 12, 24, and 36 months (2.51 %, 2.85 %, 4.76 %, and 3.51 %, respectively). Significant decreases in serum and urinary cross-linked amino-terminal telopeptide of type I collagen (NTX) and urinary deoxypyridinoline levels from baseline were observed at 3 months, followed by a significant decrease of serum bone alkaline phosphatase at 6 months [p < 0.001 for all comparisons except serum NTX (p = 0.011), Wilcoxon signed-rank test]. Early reductions in the biochemical markers of bone turnover (BTM) observed at 3 months with raloxifene treatment correlated negatively with subsequent increases in lumbar spine BMD at 1 year (r = -0.347, p = 0.008). The incidence of any new clinical fractures within 3 years was 1.18 % (82/6,967 participants). In summary, no new signals in safety were observed in the daily use of raloxifene. Moreover, the effectiveness profile of raloxifene was confirmed in practical use by this large-scale, long-term, postmarketing surveillance.

We investigated the effect of long-term corticosteroid usage in suppressing the progression of functional disability in patients with early rheumatoid arthritis (RA). We studied 3,982 RA patients, who had continuous enrollment for at least 3 years, among 9,132 RA patients enrolled in an observational cohort study, IORRA, in Tokyo, Japan, from 2000 to 2007. The DAS28 and Japanese version of Health Assessment Questionnaire (J-HAQ) scores were collected at 6-month intervals (each phase). Among these patients, those with DAS28 values under 3.2 in all phases and RA disease duration under 2 years at study entry were selected as "early RA patients with well-controlled disease". These patients were further classified into 3 groups based on average months of steroid usage per year: Non-users, Medium-users, and Frequent-users. Multiple linear regression analysis was used to study the relationship between steroid usage and the final J-HAQ scores. Among the 3,982 patients, 109 had DAS28 values under 3.2 in all the phases and were selected as study cohort. The average Final J-HAQ in Non-user (N = 64), in Medium-user (N = 25), in Frequent-user group (N = 20) was 0.04, 0.06, and 0.33, respectively. Multiple linear regression analysis after adjusting for all potential covariates confirmed that frequent steroid usage was the most significant factor associated with higher final J-HAQ scores (P < 0.05). Frequent steroid usage was associated with significantly higher final J-HAQ scores in early RA patients, even though their disease was managed efficiently by maintaining the DAS28 values under 3.2 over a long-term period.

Introduction: The purpose of this study was to evaluate the effects of L-4F, an apolipoprotein A-1 mimetic peptide, alone or with pravastatin, in apoE-/-Fas-/-C57BL/6 mice that spontaneously develop immunoglobulin G (IgG) autoantibodies, glomerulonephritis, osteopenia, and atherosclerotic lesions on a normal chow diet., Methods: Female mice, starting at eight to nine weeks of age, were treated for 27 weeks with 1) pravastatin, 2) L-4F, 3) L-4F plus pravastatin, or 4) vehicle control, followed by disease phenotype assessment., Results: In preliminary studies, dysfunctional, proinflammatory high-density lipoproteins (piHDL) were decreased six hours after a single L-4F, but not scrambled L-4F, injection in eight- to nine-week old mice. After 35 weeks, L-4F-treated mice, in the absence/presence of pravastatin, had significantly smaller lymph nodes and glomerular tufts (PL, LP<0.05), lower serum levels of IgG antibodies to double stranded DNA (dsDNA) (PL<0.05) and oxidized phospholipids (oxPLs) (PL, LP<0.005), and elevated total and vertebral bone mineral density (PL, LP<0.01) compared to vehicle controls. Although all treatment groups presented larger aortic root lesions compared to vehicle controls, enlarged atheromas in combination treatment mice had significantly less infiltrated CD68+ macrophages (PLP<0.01), significantly increased mean alpha-actin stained area (PLP<0.05), and significantly lower levels of circulating markers for atherosclerosis progression, CCL19 (PL, LP<0.0005) and VCAM-1 (PL<0.0002)., Conclusions: L-4F treatment, alone or with pravastatin, significantly reduced IgG anti-dsDNA and IgG anti-oxPLs, proteinuria, glomerulonephritis, and osteopenia in a murine lupus model of accelerated atherosclerosis. Despite enlarged aortic lesions, increased smooth muscle content, decreased macrophage infiltration, and decreased pro-atherogenic chemokines in L-4F plus pravastatin treated mice suggest protective mechanisms not only on lupus-like disease, but also on potential plaque remodeling in a murine model of systemic lupus erythematosus (SLE) and accelerated atherosclerosis.

In systemic lupus erythematosus (SLE), adaptive CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) suppress Th cells that help autoantibody (autoAb)-producing B cells. It is not known whether naturally occurring Tregs can directly suppress B cells in SLE without an intermediate suppression of Th cells. This aspect is important for its implications in the natural course of SLE, because most if not all of the clinical and pathologic effects in SLE are associated with a dysregulated production of autoAbs. In this study, we show that natural Tregs can inhibit B cell activity in vitro and in vivo in SLE through cell contact-mediated mechanisms that directly suppress autoAb-producing B cells, including those B cells that increase numerically during active disease. These results indicate that one way by which natural Tregs attempt to limit humoral autoimmunity in SLE is by directly targeting autoreactive B cells.

Treatment of (NZB x NZW)F(1) (NZB/W) lupus-prone mice with the anti-DNA Ig-based peptide pConsensus prolongs the survival of treated animals and effectively delays the appearance of autoantibodies and glomerulonephritis. We have previously shown that part of these protective effects associated with the induction of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) that suppressed autoantibody responses. Because the effects of pConsensus appeared secondary to qualitative rather than quantitative changes in Tregs, we investigated the molecular events induced by tolerance in Tregs and found that signaling pathways including ZAP70, p27, STAT1, STAT3, STAT6, SAPK, ERK, and JNK were not significantly affected. However, peptide tolerization affected in Tregs the activity of the MAPK p38, whose phosphorylation was reduced by tolerance. The pharmacologic inhibition of p38 with the pyridinyl imidazole inhibitor SB203580 in naive NZB/W mice reproduced in vivo the effects of peptide-induced tolerance and protected mice from lupus-like disease. Transfer experiments confirmed the role of p38 in Tregs on disease activity in the NZB/W mice. These data indicate that the modulation of p38 activity in lupus Tregs can significantly influence the disease activity.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that is characterized by pathologic manifestations in multiple organs and elevated morbidity. Traditional management of SLE has included the use of non-steroidal anti-inflammatory drugs, anti-malarials and immunosuppressive drugs such glucocorticoids, azathioprine, cyclophosphamide, and mycophenolate mofetil. Although many of these therapies have shown great efficacy, they often associate with adverse effects, due to their systemic activity. The development of safer therapies for SLE has led to recent emphasis on targeting selected pathways that can be important in the inflammatory response in SLE. In this context, the use of biological agents such as monoclonal antibodies has seen a rapidly increasing progress, and is poised to be some part of the clinical practice for SLE in a near future. This review provides an update on the ongoing clinical trials and the promise and obstacles in the use of biologics in SLE.

Objective: To compare the sex differences of various components of rheumatoid arthritis (RA)., Methods: Data of 4823 patients from a large observational cohort study were analyzed. Remarkable differences were noted between the sexes, and overall, women had significantly higher disease activity., Results: When variables were adjusted using sex, age, and duration, Health Assessment Questionnaire, rather than Disease Activity Score, contributed most to sex difference. Further analysis showed evidence that progression of disability was approximately 3 times more rapid in female patients compared to male patients., Conclusion: Women overall have higher RA disease activity and are prone to greater and faster progression of disability over time.

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with elevated morbidity and multi-organ involvement. While many strategies have shown efficacy and improved management of SLE, they have often been associated with adverse effects. Some patients may not respond well to some treatments because of inter-individual variability of the disease. More specific and safer therapies are needed., Objective/methods: To review literature on peptide-based therapy of SLE., Results/conclusions: Recently, emphasis has been placed on targeting molecules and pathways involved in the inflammatory response in SLE, including the use of immunogenic peptides derived from anti-DNA antibodies. Encouraging data from murine models of SLE have led to tests in initial clinical trials in humans--which have unfortunately not met the primary endpoints. The current challenge is to design improved strategies for immunotherapeutic use of anti-DNA peptides in SLE.

The past few years of research on leptin have provided important information on the link between metabolism and immune homeostasis. Adipocytes influence not only the endocrine system but also the immune response through several cytokine-like mediators known as adipokines, which include leptin. It is widely accepted that leptin can directly link nutritional status and pro-inflammatory T helper 1 immune responses, and that a decrease of leptin plasma concentration during food deprivation can lead to an impaired immune function. Additionally, several studies have implicated leptin in the pathogenesis of chronic inflammation, and the elevated circulating leptin levels in obesity appear to contribute to the low-grade inflammatory background which makes obese individuals more susceptible to increased risk of developing cardiovascular diseases, type II diabetes, or degenerative disease including autoimmunity and cancer. Conversely, reduced levels of leptin such as those found in malnourished individuals have been linked to increased risk of infection and reduced cell-mediated immune responses. We discuss here the functional influences of leptin in the physiopathology of inflammation, and the effects of leptin in the modulation of such responses.

This study aims to reconfirm the clinical efficacy and related factors of infliximab therapy, the first biological agent introduced to Japanese patients with rheumatoid arthritis (RA). Data of 351 RA patients with infliximab were collected retrospectively from three major centers for management of rheumatic diseases in Japan. Infliximab was infused according to the approved method, and the clinical response was evaluated following 22 weeks of infliximab therapy in 258 patients using the European League Against Rheumatism (EULAR) response criteria. DAS28-CRP (Disease Activity Score including a 28-joint count/C-reactive protein) with a threshold of 4.1 or 2.7 for the high or low disease activity cut-off was also used. A total of 90.3% of patients exhibited high disease activity before infliximab therapy. After 22 weeks of infliximab therapy, the proportions of patients exhibiting high activity, moderate activity, low activity, or in clinical remission were 27.9%, 33.3%, 10.9%, or 27.9%, respectively, thereby indicating good overall efficacy of infliximab therapy. A good or moderate overall response to therapy was achieved in 84.5% of patients. Male sex, rheumatoid factor (RF) negativity, low CRP, lower swollen joint count and a low prednisolone dose were significantly related to the clinical response. Furthermore, male sex, older age, and a high tender joint count had a significant correlation with treatment discontinuation as a result of adverse reactions. In conclusion, we have reconfirmed the effectiveness of infliximab in Japanese patients with RA by using DAS28-CRP and EULAR response criteria. These data will facilitate more efficacious use of this expensive biological agent in the daily practice of rheumatology in Japan.