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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. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-021-01610-1.

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

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.

Summary 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.

ObjectiveTo 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).MethodsORAL 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.ResultsSubstantial 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.ConclusionTreatment 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 numberNCT02187055.

Background: Tofacitinib is an oral JAK inhibitor for the treatment of RA. Greater improvements in efficacy outcomes have been reported with tofacitinib 5 mg BID ± csDMARDs in patients (pts) with early vs established RA.1,2 Objectives: This post hoc analysis of ORAL Strategy data evaluated the efficacy and safety of tofacitinib monotherapy, tofacitinib + methotrexate (MTX) and adalimumab (ADA) + MTX, stratified by baseline (BL) RA duration. Methods: ORAL Strategy (NCT02187055) was a P3b/4, 1-yr, double–blind, triple-dummy, active comparator-controlled study. MTX inadequate-responder pts were randomised 1:1:1 to receive tofacitinib 5 mg BID (tofa mono), tofacitinib 5 mg BID + MTX (tofa+MTX), or ADA SC 40 mg Q2W + MTX (ADA+MTX); MTX was dosed at 15–25 mg/wk except in cases of intolerance/toxicity. In this analysis, pts were stratified by BL RA duration as having early (≤2 yrs) or established (>2 yrs) RA. Efficacy outcomes (Months [M]3, 6 and 12): ACR20/50/70; change from BL (Δ) in DAS28–4(ESR), SDAI and CDAI; and rates of DAS28-4(ESR)-, SDAI- and CDAI–defined LDA (≤3.2, ≤11 and ≤10, respectively) and remission ( Results: 241 pts had early RA (tofa mono: N=80; tofa+MTX: N=83; ADA+MTX: N=78; mean RA duration: 1.0–1.1 yrs); 905 pts had established RA (tofa mono: N=304; tofa+MTX: N=293; ADA+MTX: N=308; mean RA duration: 9.4–10.4 yrs). BL demographics and disease characteristics were generally comparable for early vs established RA pts, with some expected differences (the latter were slightly older, and a greater proportion had received prior bDMARDs); RF+ and anti-CCP+ rates were higher for established RA pts (Table). ACR50 and ΔDAS28-4(ESR) were generally similar for tofa mono and tofa+MTX up to M12 in early RA but significantly greater with tofa+MTX in established RA (p Conclusion: Efficacy was similar for tofa mono and tofa+MTX in early RA, and significantly higher with tofa+MTX in established RA. ADA+MTX was numerically but not always significantly more effective than tofacitinib in early RA. AE rates were generally similar regardless of BL RA duration. These findings, especially in established RA, are consistent with the conclusion of the primary analysis.3 Limitations to this post hoc analysis include low numbers of early RA pts. References: [1] Hall S, et al. Arthritis Rheum2016; 68(S10): 1999-2001. [2] Fleischmann RM, et al. RMD Open2016; 2: e000262. [3] Fleischmann RM, et al. Lancet2017; 390: 457-468. Acknowledgement: Study sponsored by Pfizer Inc. Medical writing support was provided by Christina Viegelmann of CMC Connect and funded by Pfizer Inc. Disclosure of Interests: Tsutomu Takeuchi Grant/research support from: Astellas Pharma Inc, Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., AbbVie GK, Asahikasei Pharma Corp., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Eisai Co., Ltd., AYUMI Pharmaceutical Corporation, Nipponkayaku Co. Ltd., Novartis Pharma K.K., Grant/research support from: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Grant/research support from: Astellas Pharma Inc., Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahi Kasei Pharma Corp., Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd., Janssen Pharmaceutical K.K., Celltrion Inc., Nipponkayaku Co. Ltd., and UCB Japan, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Abbivie GK, Nipponkayaku Co.Ltd, Janssen Pharmaceutical K.K., Astellas Pharma Inc., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Taisho Toyama Pharmaceutical Co. Ltd., GlaxoSmithKline K.K., UCB Japan Co. Ltd., Consultant for: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Asahi Kasei Medical K.K., AbbVie GK, Daiichi Sankyo Co., Ltd., Bristol Myers Squibb, and Nipponkayaku Co. Ltd., Speakers bureau: Astellas Pharma Inc., Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahi Kasei Pharma Corp., Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd., Janssen Pharmaceutical K.K., Celltrion Inc., Nipponkayaku Co. Ltd., and UCB Japan, Speakers bureau: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Astellas Pharma Inc, Diaichi Sankyo Co. Ltd., Eisai Co. Ltd., Sanofi K.K., Teijin Pharma Ltd., Takeda Pharmaceutical Co. Ltd., Novartis Pharma K.K., Yoshiya Tanaka Grant/research support from: Abbvie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, MSD, Ono, Taisho-Toyama, Takeda, Speakers bureau: Abbvie, Asahi-kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Eisai, Glaxo-Smithkline, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer Japan Inc, Sanofi, Takeda, UCB, YL Biologics, Naonobu Sugiyama Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Noriko Iikuni Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Koshika Soma Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Harry Shi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Eduardo Mysler Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Pfizer, Novartis, Janssen, Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lily, Janssen, Medimmune, Pfizer Inc, and Roche, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lily, Janssen, Medimmune, Pfizer Inc, and Roche, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Pfizer, Novartis, Janssen, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lily, Janssen, Medimmune, Pfizer Inc, and Roche, Robert J Moots Grant/research support from: Biogen, Bristol-Myers Squibb, Chugai, Novartis, Pfizer Inc, Roche, Sandoz, and UCB, Consultant for: Biogen, Bristol-Myers Squibb, Chugai, Novartis, Pfizer Inc, Roche, Sandoz, and UCB, Speakers bureau: Biogen, Bristol-Myers Squibb, Chugai, Novartis, Pfizer Inc, Roche, Sandoz, and UCB, Josef S. Smolen Grant/research support from: AbbVie, Eli Lilly, Janssen, MSD, Pfizer Inc, Roche, Consultant for: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Eli Lilly, GlaxoSmithKline, ILTOO, Janssen, Medimmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, UCB, Speakers bureau: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Eli Lilly, GlaxoSmithKline, ILTOO, Janssen, Medimmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, UCB, Roy Fleischmann Grant/research support from: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celtrion, Genentech, GSK, Janssen, Lilly, Novartis, Pfizer Inc, Sanofi-Aventis, UCB, Consultant for: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celtrion, Genentech, GSK, Janssen, Lilly, Novartis, Pfizer Inc, Sanofi-Aventis, UCB

Background Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). The impact of methotrexate (MTX) withdrawal in patients (pts) with RA who achieve low disease activity (LDA) or remission following treatment with tofacitinib in combination with MTX is unclear. Objectives To compare the efficacy and safety of tofacitinib modified-release (MR) 11 mg once daily (QD) with and without MTX in pts with RA who have achieved LDA with tofacitinib and MTX. Methods ORAL Shift (NCT02831855) was a global Phase 3b/4 study in pts aged ≥18 years with moderate to severe RA and an inadequate response to MTX. Pts received open-label (OL) tofacitinib MR 11 mg QD with MTX (tofacitinib + MTX) for 24 weeks. Pts achieving LDA (CDAI ≤10) at Week (W)24 entered the 24-week double-blind (DB) MTX withdrawal phase and were randomised 1:1 to receive tofacitinib MR 11 mg QD with placebo (tofacitinib monotherapy; ie underwent blinded MTX withdrawal) or continue tofacitinib + MTX. The primary endpoint was least squares mean change from W24 to W48 (Δ; DB phase) in DAS28 4(ESR). Non inferiority of tofacitinib monotherapy vs tofacitinib + MTX was declared if the upper bound of the 95% two-sided confidence interval (CI) for the difference in ΔDAS28-4(ESR) between arms was Results Of 694 pts in the OL phase, 530 achieved CDAI-defined LDA at W24 and were treated in the DB phase (tofacitinib monotherapy: n=264; tofacitinib + MTX: n=266). Demographics and pt characteristics at OL-phase baseline were similar between treatment arms. The difference (95% CI) between arms in ΔDAS28 4(ESR) (primary endpoint) was 0.30 (0.12, 0.48; Table 1) at W48, demonstrating that tofacitinib monotherapy was non-inferior to tofacitinib + MTX. Consistent with the primary endpoint, ΔDAS28-4(CRP)/SDAI/CDAI were greater for tofacitinib monotherapy vs tofacitinib + MTX, but these differences were not clinically meaningful; ACR/HAQ-DI response and LDA rates were generally similar between arms (Table). Remission rates were also similar between arms and generally did not change after MTX withdrawal. In the DB phase, rates of AEs, serious AEs, discontinuations due to AEs and AEs of special interest were generally comparable between arms (Table 1). Conclusion Pts receiving tofacitinib MR 11 mg QD + MTX who achieve LDA may withdraw MTX up to W48 without significant worsening of disease activity. Pts in remission tend to remain in remission after MTX withdrawal. Safety appeared consistent with the known profile of tofacitinib. Reference [1] Felson DT et al. Arthritis Rheum 2011;63:573-586 Acknowledgement Study sponsored by Pfizer Inc. Medical writing support was provided by C Viegelmann of CMC Connect and funded by Pfizer Inc. Disclosure of Interests Stanley B. Cohen Grant/research support from: AbbVie, Eli Lilly, Genentech, Gilead, Pfizer Inc, Consultant for: AbbVie, Eli Lilly, Genentech, Gilead, Pfizer Inc, Janet Pope Grant/research support from: Bristol-Myers Squibb, Roche, Seattle Genetics, UCB, Consultant for: AbbVie, Actelion, Amgen, Bayer, Bristol-Myers Squibb, Lilly, Merck, Novartis, Pfizer Inc, Roche, Sandoz, Sanofi, UCB, Boulos Haraoui Grant/research support from: AbbVie, Pfizer Inc, Consultant for: AbbVie, Amgen, Eli Lilly, Merck, Pfizer Inc, UCB, Fedra Irazoque-Palazuelos Consultant for: Bristol-Myers Squibb, Janssen, Pfizer Inc, Roche, UCB, Mariusz Korkosz Consultant for: AbbVie, Lilly, MSD, Novartis, Roche, UCB, Annette Diehl Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Jose Luis Rivas Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Tatjana Lukic Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Shixue Liu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lori Stockert Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Noriko Iikuni Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Edward Keystone Grant/research support from: AbbVie, Amgen, Lilly Pharmaceuticals, Pfizer Inc, PuraPharm, Sanofi-Aventis, Consultant for: AbbVie, Amgen, AstraZeneca, Biotest, Bristol-Myers Squibb, Celltrion, Crescendo Bioscence, F. Hoffman-La Roche, Genentech, Gilead, Janssen, Lilly Pharmaceuticals, Merck, Pfizer Inc, Sandoz, Sanofi-Genzyme, Samsung Bioepis, UCB, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb Canada, F. Hoffman-La Roche, Janssen, Merck, Pfizer Inc, Sanofi-Genzyme, UCB

Background: Tofacitinib is an oral JAK inhibitor for the treatment of RA. Pain is the most common symptom reported by patients (pts) with RA,1,2 thus reduction of pain is an important treatment goal. Objectives: To evaluate the effect of tofacitinib monotherapy ± pain medication on pain in pts with RA. Methods: This pooled post hoc analysis included pts who received tofacitinib 5 mg BID monotherapy (ie without csDMARDs) in Phase (P)2 (NCT00550446), P3 (ORAL Solo; NCT00814307) and P3b/4 (ORAL Strategy; NCT02187055) studies. Pts were stratified by concomitant use of ‘any pain therapy’ (opioids, plain analgesics [eg acetaminophen], NSAIDs or glucocorticoids [GC; ≤10 mg of prednisone or equivalent per day]), ‘pure analgesics’ (opioids or plain analgesics) and ‘adjuvant analgesics’ (NSAIDs or GC). Pts receiving pain medication at baseline (BL) maintained a stable dose during the studies; opioid and/or acetaminophen dose could be increased as rescue therapy. Efficacy outcomes were assessed at Month (M)3 and M6: change from BL (δ) in Pt Assessment of Pain (Pain; visual analogue scale [VAS]) and δPain stratified by DAS28-4(ESR)-defined low disease activity (LDA; ≤3.2) status at M3 and M6. Results: Of 676 pts who received tofacitinib 5 mg BID monotherapy, 604 (89%) received ‘any pain therapy’, 141 (21%) received ‘pure analgesics’ and 589 (87%) received ‘adjuvant analgesics’. Demographics and BL disease characteristics, including disease activity and Pain VAS, were generally similar when stratified by use/type of pain medication. Reductions in pain (δPain VAS) at M3 and M6 were generally similar for pts who received tofacitinib with ‘any pain therapy’ vs those who did not receive ‘any pain therapy’ (Figure 1a). There was a trend for a numerically greater reduction in pain at M3 and M6 in pts who received tofacitinib with ‘any pain therapy’ and who achieved LDA at M3 and M6 vs those who received tofacitinib with ‘any pain therapy’ and did not achieve LDA (95% CI overlapped; Figure 1b). By contrast, pain reductions were similar for pts who received tofacitinib without ‘any pain therapy’, irrespective of LDA status. Similar trends were seen when pts were stratified by use of ‘pure analgesics’ and ‘adjuvant analgesics’ (data not shown). Conclusion: In this pooled post hoc analysis, pain reduction was similar in pts with RA receiving tofacitinib, regardless of pain medication use. Pain reduction was similar in pts receiving tofacitinib without ‘any pain therapy’, irrespective of LDA status. These results should be interpreted with caution, as pain medication could be used as rescue therapy, few pts received tofacitinib without ‘any pain therapy’, and confounding by indication cannot be excluded. Further analyses are required to explore the impact of tofacitinib on the relationship between reductions in pain and disease activity. References [1] Walsh DA, McWilliams DF. Curr Pain Headache Rep 2012; 16: 509-17. [2] American College of Rheumatology Pain Management Task Force. Arthritis Care Res (Hoboken) 2010; 62: 590-9. Acknowledgement: Study sponsored by Pfizer Inc. Medical writing support was provided by Sarah Piggott of CMC Connect and funded by Pfizer Inc. Disclosure of Interests: Peter C. Taylor Grant/research support from: Celgene, Galapagos, Eli Lilly, UCB, Consultant for: AbbVie, Galapagos, Gilead, Eli Lilly, Pfizer Inc, Mart van de Laar Grant/research support from: AbbVie, Eli Lilly, Janssen-Cilag, Merck Inc, Pfizer Inc, Sanofi Genzyme, Speakers bureau: Eli Lilly, Pfizer Inc, Jeffrey R. Curtis Grant/research support from: Abbvie, Amgen, BMS, Corrona, Janssen, Lilly, Myriad, Pfizer, Roche/Genentech, UCB, Crescendo Bioscience Inc., Consultant for: Abbvie, Amgen, BMS, Corrona, Janssen, Lilly, Myriad, Pfizer, Roche/Genentech, UCB, Crescendo Bioscience Inc., Valderilio F Azevedo Grant/research support from: AbbVie, GSK, Janssen, Merck Serono, Novartis, Pfizer Inc, UCB, Consultant for: AbbVie, GSK, Janssen, Merck Serono, Novartis, Pfizer Inc, UCB, Jose Luis Rivas Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Palle Dahl Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lisy Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Noriko Iikuni Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Harry Shi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, John Woolcott Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Salim Benkhalifa Shareholder of: Pfizer SAS, Employee of: Pfizer SAS, Juan Jose Gomez-Reino Grant/research support from: Biogen, Gilead, Eli Lilly, Merck Sharp & Dohme, Pfizer, Roche, Consultant for: Biogen, Gilead, Eli Lilly, Merck Sharp & Dohme, Pfizer, Roche, maxime dougados Grant/research support from: Eli Lilly and Company, Pfizer, AbbVie, and UCB Pharma, Consultant for: Eli Lilly and Company, Pfizer, AbbVie, and UCB Pharma

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Glucocorticoids (GC) are an established therapy in RA that are often used to rapidly reduce pain and inflammation while awaiting the effects of disease-modifying antirheumatic drugs. Objectives: A post hoc analysis to describe the impact of background GC on the efficacy and safety of tofacitinib with and without methotrexate (MTX) and adalimumab (ADA) with MTX in ORAL Strategy. Methods: ORAL Strategy (NCT02187055) was a 1-year, double-blind, Phase 3b/4, head-to-head, non-inferiority randomised controlled trial in adult patients (pts) with active RA despite MTX therapy. Pts were randomised 1:1:1 to receive tofacitinib 5 mg twice daily (BID; tofa mono), tofacitinib 5 mg BID + MTX (tofa+MTX) or subcutaneous ADA 40 mg every other week + MTX (ADA+MTX). Pts receiving low-dose GC (≤10 mg/day prednisone or equivalent) before enrolment maintained a stable dose throughout the study period. The following efficacy endpoints were assessed through Month 12 for pts receiving tofa mono, tofa+MTX and ADA+MTX with/without GC: ACR20, ACR50 and ACR70 response rates, proportions of patients achieving low disease activity (LDA; DAS28–4[ESR]≤3.2) and remission (DAS28–4[ESR] Results: 1146 patients were randomised and treated; low-dose BL GC were received by 228/384 (59.4%) pts receiving tofa mono (mean [SD] BL GC dose: 7.5 [13.7] mg/day), 215/376 (57.2%) pts receiving tofa+MTX (mean [SD] BL GC dose: 6.5 [2.5] mg/day) and 223/386 (57.8%) pts receiving ADA+MTX (mean [SD] BL GC dose: 6.4 [2.6] mg/day). BL demographics and disease characteristics were generally similar across treatment groups, regardless of BL GC use. Efficacy endpoints (ACR50 response rate, LDA and remission rates, ΔHAQ-DI) were generally similar for each treatment group when stratified by GC use (figure 1, table 1; similar results were seen for ACR20/70 response rates – data not shown). GC use did not appear to be associated with higher rates of AEs, discontinuations due to AEs, SIEs and SAEs; some AE rates were higher with MTX than without MTX (table 2). SIEs in pts using GC included herpes zoster (HZ; tofa mono, n=2) and tuberculous meningitis (tofa+MTX, n=1); in pts not using GC, there was 1 event each of cytomegalovirus chorioretinitis (tofa+MTX), pulmonary TB (tofa+MTX), HZ (ADA+MTX) and varicella (ADA+MTX). Conclusions: In pts with RA, concomitant stable GC use did not appear to impact the efficacy of tofacitinib 5 mg BID±MTX or ADA+MTX. The finding that GC use was not associated with higher AE rates was unexpected and of interest. Acknowledgements: Study sponsored by Pfizer Inc. Medical writing support was provided by C Viegelmann of CMC and funded by Pfizer Inc. Disclosure of Interest: R. Fleischmann Grant/research support from: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celltrion, Eli Lilly, Genentech, GSK, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, UCB, Consultant for: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celltrion, Eli Lilly, Genentech, GSK, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, UCB, J. Wollenhaupt Consultant for: Pfizer Inc, Speakers bureau: Pfizer Inc, S. Cohen Grant/research support from: AbbVie, Amgen, Astellas, Bristol-Meyers Squibb, Eli Lilly, Genentech, Gilead, Janssen, Novartis, Pfizer Inc, Roche, Sandoz, Consultant for: AbbVie, Amgen, Astellas, Bristol-Meyers Squibb, Eli Lilly, Genentech, Gilead, Janssen, Novartis, Pfizer Inc, Roche, Sandoz, J. Smolen Grant/research support from: AbbVie, Eli Lilly, Janssen, MSD, Pfizer Inc, Roche, Consultant for: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celltrion, Eli Lilly, GSK, ILTOO, Janssen, MedImmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, UCB, Speakers bureau: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celltrion, Eli Lilly, GSK, ILTOO, Janssen, MedImmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, UCB, P. Dahl Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, N. Iikuni Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, H. Shi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Tatulych Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Takiya Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Patients (pts) with RA are at increased risk for herpes zoster (HZ) and this risk is further increased with tofacitinib treatment.1 Objectives: To evaluate the effect of live zoster vaccination (LZV) on HZ rates in a subset of methotrexate inadequate responder (MTX-IR) pts with RA who received tofacitinib with or without MTX, or adalimumab (ADA) with MTX in the ORAL Strategy randomised controlled trial (RCT).2 Methods: ORAL Strategy (NCT02187055) was a Phase 3b/4, 1-year, triple-dummy active-comparator-controlled RCT. Pts were randomised 1:1:1 to receive tofacitinib 5 mg twice daily (BID; tofa mono), tofacitinib 5 mg BID+MTX (tofa+MTX), or subcutaneous ADA 40 mg every other week + MTX (ADA+MTX); target MTX dose was 15–25 mg/week. In countries where LZV was available, pts aged ≥50 years received LZV at the investigator’s discretion, 28 days before the first dose of study drug. HZ incidence rates (IR; pts with events per 100 pt-years) and 95% confidence intervals (CI) were calculated for each treatment arm and for vaccinated vs non-vaccinated pts. Results: Of 1146 pts who received study drug (mean age: 50.1 years), 216 received LZV (proportion of pts who received LZV by treatment group: tofa mono: 18.0%; tofa+MTX: 19.9%; ADA+MTX: 18.7%) 28 days before randomisation in this RCT; 30 pts self-reported prior vaccination (Table). No pts had zoster-like lesions within 42 days of vaccination; 1 pt had vaccination site erythema. In the overall study population, HZ IR was similar between tofa mono and ADA+MTX and numerically higher (overlapping CI) with tofa+MTX. IRs were generally similar for pts who received LZV (18.8% of pts were vaccinated) vs those who did not (81.2%) (Table). Overall, 18/1146 pts had HZ. Among vaccinated pts, 3 (1.4%) had HZ: no events were serious and 1 (0.5%) event was multidermatomal (tofa mono). Among pts not vaccinated, 15 (1.6%) had HZ: there were 2 (0.2%) serious HZ events (tofa+MTX: n=1; ADA+MTX: n=1), 2 (0.2%) multidermatomal events (tofa mono: n=1; ADA+MTX: n=1) and 1 (0.1%) disseminated event (ADA+MTX). Conclusions: In MTX-IR pts with RA, LZV was well-tolerated. HZ IR was numerically similar between tofa mono and ADA+MTX and higher with tofa+MTX. HZ rates were generally similar in pts who received LZV vs those not vaccinated. LZV has shown efficacy in prevention of HZ in 51% (pts ≥60 years old) and 70% (50–59 years old) of immunocompetent adults.3 Efficacy of LZV could not be fully evaluated as a minority ( References [1]Winthrop, et al. Arthritis Rheumatol2014;66:2675–84. [2]Fleischmann, et al. Lancet2017;390:457–68. [3]Hales, et al. MMWR Morb Mortal Wkly Rep2014;63:729–31. Acknowledgements: Study sponsored by Pfizer Inc. Medical writing support was provided by D Binks of CMC and funded by Pfizer Inc. Disclosure of Interest: L. Calabrese Grant/research support from: Celgene, Crescendo, Consultant for: Celgene, Crescendo, Speakers bureau: Celgene, Crescendo, C. Abud-Mendoza Consultant for: Bristol-Myers Squibb, Pfizer Inc, Roche, Speakers bureau: Bristol-Myers Squibb, Merck-Serono, Pfizer Inc, Roche, UCB, S. Lindsey Speakers bureau: Pfizer Inc, S.-H. Lee: None declared, L. Takiya Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, N. Iikuni Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Soma Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Z. Luo Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Fleischmann Grant/research support from: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celltrion, Genentech, GSK, Janssen, Lilly, Novartis, Pfizer Inc, Sanofi-Aventis, and UCB, Consultant for: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celltrion, Genentech, GSK, Janssen, Lilly, Novartis, Pfizer Inc, Sanofi-Aventis, and UCB

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). ORAL Strategy (NCT02187055), a 12-month, global, Phase 3b/4 study, demonstrated that in patients with RA and an inadequate response to methotrexate (MTX), tofacitinib + MTX was non-inferior to adalimumab + MTX, while tofacitinib monotherapy was not non-inferior to either combination based on American College of Rheumatology (ACR)50 response rates at Month 6. 1 Objectives: To assess clinical and functional efficacy across treatments in the ORAL Strategy trial using cumulative probability plots. Methods: Efficacy was evaluated between patients who received tofacitinib 5 mg twice daily (BID) as monotherapy (N=384), tofacitinib 5 mg BID + MTX (N=376) and adalimumab 40 mg subcutaneously once every 2 weeks + MTX (N=386) based on ACR responses and changes from baseline in Health Assessment Questionnaire-Disability Index (ΔHAQ-DI) score at Month 12. Cumulative probability plots for ACR-n (where ACR is the % improvement from baseline in ACR components, and n represents the mimimum % achieved by each patient) and ΔHAQ-DI are presented. The area under the curve (AUC) was calculated for ACR-n up to Month 12 (in months), and an analysis of covariance model was used to assess treatment effects in terms of the AUC of ACR-n at Month 12; there was no adjustment for multiplicity for this post hoc analysis. Results: The cumulative probability plots of ACR responses at Month 12 indicated that the proportion of patients who achieved responses of ACR20, ACR50 and ACR70 was similar for tofacitinib + MTX and adalimumab + MTX, but was numerically smaller for tofacitinib monotherapy (figure, A). Responses of approximately ≥ACR80 were achieved by a similar proportion of patients in each treatment group. Least squares mean (standard error) AUC of ACR-n up to Month 12 (in months) was similar for tofacitinib + MTX (437 [35]) and adalimumab + MTX (402 [35]), but was smaller for tofacitinib monotherapy (319 [35]; p Figure 1 Cumulative probability plot of A) ACR response and B) VHAQ-DI at Month 12 Two outlets for ACR response are not shown: tofacitinib 5 mg BID monotherapy, ACR-n-1700, cumulative probability-0.0003; adailmumab 40 mg SC Q2W + MTX, ACR-n-463, cumulative probability-0.003 Conclusions: These data support the primary ORAL Strategy findings, 1 indicating that in patients with RA, clinical efficacy, based on ACR response, was generally similar for tofacitinib + MTX and adalimumab + MTX, while a smaller proportion of patients who received tofacitinib monotherapy achieved ACR response in general, and particularly for Reference [1]Fleischmann R, et al. Lancet2017;390:457–68. Acknowledgements: Study sponsored by Pfizer Inc. Medical writing support was provided by A MacLachlan of CMC and funded by Pfizer Inc. Disclosure of Interest: T. Takeuchi Grant/research support from: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Consultant for: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Speakers bureau: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, J. Smolen Grant/research support from: AbbVie, Eli Lilly, Janssen, MSD, Pfizer Inc, Roche, Consultant for: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Eli Lilly, GSK, ILTOO, Janssen, MedImmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, UCB, Speakers bureau: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Eli Lilly, GSK, ILTOO, Janssen, MedImmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, UCB, R. Fleischmann Consultant for: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celltrion, Eli Lilly, Genentech, GSK, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, UCB, N. Iikuni Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, H. Fan Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Soma Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, E. Akylbekova Consultant for: Pfizer Inc, Employee of: IQVIA, T. Hirose Shareholder of: Pfizer Japan Inc, Employee of: Pfizer Japan Inc

To assess changes in quality of life (QOL) and pain in raloxifene-treated Japanese women with postmenopausal osteoporosis.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.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 include the lack of a control group, the possibility of the changes being due to the natural disease course, and potential selection bias.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.

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.

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.

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.

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.

Objectives The impact of corticosteroids on the risk of organ damage in the context of clinical end points endorsed in some systemic lupus erythematosus (SLE) clinical trials is underexplored. Methods We analysed data from the Hopkins Lupus Cohort using Cox proportional hazards models to understand the impact of exposure to different corticosteroid doses on the risk of developing any new organ damage or any new organ damage at the individual organ systems over time. Results Mean prior prednisone dose, recent disease activity and immunosuppressant use during follow-up, as well as organ damage score at cohort entry, were significant independent predictors of the risk of developing any new organ damage. Even after adjustment for recent disease activity, there was a dose-response relationship across the different levels of exposure to prednisone during follow-up and the risk of developing any new organ damage. The risk more than doubled in patients exposed to a mean prior prednisone dose of ≥20 mg/day versus

Objectives To study the role of monocyte chemoattractant protein-4 (MCP-4)/CCL13 in the pathogenesis of rheumatoid arthritis (RA), we analysed the expression of MCP-4/CCL13 in chondrocytes, synovial fluid and serum from patients with RA and investigated the effect of MCP-4/CCL13 on the proliferation of synovial cells. Methods Human articular cartilage specimens were obtained from joints from RA and osteoarthritis (OA) patients and normal joints (controls). Transcript levels of MCP-4 in cartilage were determined by real-time polymerase chain reaction. Protein levels were measured by enzyme-linked immunoassay. Cultured fibroblast-like synoviocytes (FLS) were treated with various concentrations of recombinant MCP-4/CCL13 protein, and cell proliferation was evaluated with a viability assay. Results The gene expression of MCP-4 was significantly higher in cartilage from RA patients than in that from OA patients (P = 0.00902) and in normal cartilage (P = 0.00902). The concentration of MCP-4/CCL13 protein in serum from RA patients (mean 94.7 +/- 37.6 pg/ml) was significantly higher than in serum from OA patients (mean 49.2 +/- 31.2 pg/ml, P = 0.0051) and controls (mean 32.6 +/- 23.9 pg/ml, P = 0.0001). The concentration of MCP-4/CCL13 protein in synovial fluid from RA patients (mean 247.2 +/- 161.2 pg/ml) was also significantly higher than in that from OA patients (mean 29.6 +/- 50.5 pg/ml, P = 0.000019). Moreover, MCP-4/CCL13 enhanced the proliferation of FLS in a dose-dependent manner. Conclusions MCP-4/CCL13 is highly expressed in RA joints at the mRNA and protein levels. Our results suggest that MCP-4/CCL13 is secreted from chondrocytes and activates the proliferation of rheumatoid synovial cells, thereby leading to joint destruction in RA.

Background: The major histocompatibility complex (MHC) class II transactivator (CIITA) is a master switch of antigen presentation and activates expression of the MHC II gene. Insufficient up regulation of MHC class II molecules is reported to be one of the major immunological mechanisms in systemic lupus erythematosus (SLE). Objective: To examine the association between single nucleotide polymorphisms (SNPs) in the human CIITA gene ( MHC2TA ) and SLE. Methods: Promoters and coding regions of MHC2TA were evaluated for polymorphisms in 100 patients with SLE and 100 healthy donors. Eight oligonucleotide primer sets that covered the coding region and each promoter region were used for genomic analysis of SNPs. Results: Allele frequencies of previously reported SNPs did not differ between healthy donors and patients with SLE. Additionally, a new polymorphism in an intronic region at nt 485 (A→A/G) was identified, which is close to the polymorphism at nt 474 that has been associated with one of the disease causing CIITA cDNA mutations in bare lymphocyte syndrome. This SNP was found in 11% of patients with SLE and in 3% of healthy donors, suggesting it may have a role in the pathogenesis of SLE. Conclusions: A newly identified polymorphism in an intronic region at nt 485 (A→A/G) may have an important role in the pathogenesis of 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 Ca2+ 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.

We report the case of a 54-year-old woman with systemic sclerosis and Sjögren's syndrome, followed by a simultaneous onset of Graves' disease and primary biliary cirrhosis. Eight years after the patient was diagnosed with systemic sclerosis and secondary Sjögren's syndrome, she complained of thirst and lower extremity muscle weakness. Initially, these symptoms were thought to be due to her original diseases, but laboratory data revealed thyroid dysfunction as well as liver dysfunction, and further tests confirmed the diagnoses of Graves' disease and primary biliary cirrhosis. The patient was treated with thiamazole and ursodeoxycholic acid. Following treatment, her symptoms were relieved, and laboratory data improved. Although a combination of these diseases is rare, it is important to keep in mind that various autoimmune diseases can occur simultaneously, and early detection and therapy are important.

Objective. Corticosteroids constitute one of the most common treatments of RA. The purpose of this study is to investigate whether long-term corticosteroid use suppresses the progression of disability in RA patients with low disease activity state. Methods. Data collected from a large observational cohort of RA patients at our institution were analysed for 214 RA patients whose disease activity score (DAS) 28 and HAQ were available consecutively from October 2000 to October 2004. All 214 patients had average DAS 28

Objectives. To examine whether a seasonal fluctuation exists with rheumatoid arthritis (RA) activity and to analyse seasonal effects of varying components that express disease activity in RA patients. Methods. A group of 1665 RA patients (mean age 57.2yrs, mean disease duration 9.9yrs) whose data were available for 10 consecutive phases from a large observational cohort study conducted at our institution from October 2000 to April 2005, bi-annually, were evaluated. Ten criteria were analysed to assess RA disease activity. Results. All criteria revealed decrease in disease activity during fall and increase in disease activity during spring, except for the physician’s global assessment of disease activity in which significant differences were not observed between the two seasons. Conclusions. We found definite seasonal differences in RA patients, both subjectively and objectively. RA disease activity was higher in spring and lower during fall. Seasonal changes may play an important role in evaluating disease activity of RA patients and should be taken into account when examining these patients.

Spontaneous Achilles' tendon rupture associated with systemic lupus erythematosus (SLE) is rare complication in literature review. We encountered two patients with neglected spontaneous ruptures of Achilles' tendons who had been on corticosteroid therapy to treat SLE. The ages of these patients were 43 and 49 years, and both were women. One of them was a case of bilateral Achilles' tendons rerupture. Achilles' tendons of both patients were reconstructed by surgery because of delay in their diagnosis. Histological section of the both ruptured Achilles' tendon revealed fibrotic scar tissue and little existence of inflammatory change. We concluded that careful diagnosis, surgical suture, and careful treatment after operation are necessary for Achilles' tendon rupture in those patients with SLE.

Proinflammatory cytokines increase in concentration in the cerebrospinal fluid (CSF) of patients with neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE), and some reports have shown that cytokines are elevated intrathecally.1–3 Recently, levels of Th1 chemokines, monocyte chemotactic protein 1 (MCP-1; CCL2) and interferon inducible protein-10 (IP-10; CXCL10) have been reported to be raised in the CSF of patients with NPSLE, implicating important roles for these chemokines in the pathogenesis of NPSLE.4,5 Here we study the role of soluble fractalkine (CX3CL1) in NPSLE. A total of 165 patients (161 women and 4 men, aged 16–58 years; mean age 32.4 years) fulfilling the criteria of the American College of Rheumatology for systemic lupus erythematosus (SLE) classification were selected. NPSLE was diagnosed under the American College of Rheumatology criteria for neuropsychiatric lupus syndromes.1 In all, 84 patients were diagnosed with NPSLE and 81 patients did not fulfill our criteria …

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.

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

Atherosclerosis is accelerated in people with systemic lupus erythematosus, and the presence of dysfunctional, pro-inflammatory high-density lipoproteins is a marker of increased risk. We developed a mouse model of multigenic lupus exposed to environmental factors known to accelerate atherosclerosis in humans — high-fat diet with or without injections of the adipokine leptin. BWF1 mice were the lupus-prone model; BALB/c were non-autoimmune controls. High-fat diet increased total serum cholesterol in both strains. In BALB/c mice, non-high-density lipoprotein cholesterol levels increased; they did not develop atherosclerosis. In contrast, BWF1 mice on high-fat diets developed increased quantities of high-density lipoproteins as well as elevated high-density lipoprotein scores, indicating pro-inflammatory high-density lipoproteins; they also developed atherosclerosis. In the lupus-prone strain, addition of leptin increased pro-inflammatory high-density lipoprotein scores and atherosclerosis, and accelerated proteinuria. These data suggest that environmental factors associated with obesity and metabolic syndrome can accelerate atherosclerosis and disease in a lupus-prone background.

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 α-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.

Treatment of (NZB × NZW)F1 (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.

Objective:The primary aim of this study was to investigate the association of polymorphisms of TRAF1-C5, a newly identified rheumatoid arthritis (RA) risk locus in Caucasians, with susceptibility to RA and systemic lupus erythematosus (SLE) in Japanese populations. Gene expression levels of TRAF1 and C5 to assess the functional significance of genotypes were also analysed.Methods:A multicentre association study consisting of 4 RA case-control series (4397 cases and 2857 controls) and 3 SLE case-control series (591 cases and 2199 shared controls) was conducted. Genotyping was performed using TaqMan genotyping assay for two single nucleotide polymorphisms (SNPs) that showed the best evidence of association in the previous Caucasian studies. Quantifications of TRAF1 and C5 expression were performed with TaqMan expression assay.Results:Significant differences in allele frequency for both SNPs were observed between RA and control subjects (combined odds ratio = 1.09), while no significant difference was detected between patients with SLE and controls. Interestingly, alleles rs3761847 A and rs10818488 G had increased the risk for RA in the present study, while they decreased the risk in the original studies. A significant difference was found between risk allele carriers and non-carriers of rs10818488 for the expression level of TRAF1 in phorbol myristate acetate-stimulated lymphoblastoid cell lines (p = 0.04).Conclusion:Association of TRAF1-C5 locus with RA susceptibility was detected in the Japanese populations with modest magnitude, while no significant association was observed for SLE. Significant positive effect of genotype on the expression of TRAF1 might support the genetic association between TRAF1 and RA.

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.

An imbalance in cytokine homoeostasis is thought to have a key role in the neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE), and recently, a role for chemokines has been noted.To compare concentrations of monocyte chemotactic protein-1 (MCP-1)/CCL2 in cerebral spinal fluid (CSF) of patients with SLE, and with and without neuropsychiatric symptoms.CSF was obtained from 185 patients with SLE: 96 with NPSLE and 89 patients with SLE without neuropsychiatric symptoms (non-NPSLE patients). MCP-1/CCL2 concentrations were measured with an ELISA.The average concentration of CSF MCP-1/CCL2 in patients with NPSLE was 1959 pg/ml, and in non-NPSLE patients 712 pg/ml. The average MCP-1/CCL2 concentration was significantly higher in the NPSLE group than in the non-NPSLE group (p0.001). In one representative patient with NPSLE, MCP-1/CCL2 levels in the CSF decreased in parallel with a decline in neuropsychiatric symptoms.CSF MCP-1/CCL2 levels are higher in patients with NPSLE than in non-NPSLE patients. MCP-1/CCL2 may have an important role in the expression of NPSLE. These results indicate that CSF MCP-1/CCL2 reflects an inflammatory activity in the brain, suggesting that it might be used as a diagnostic tool and a monitor for therapeutic responses in patients with NPSLE.

A 58-year-old woman was admitted to our hospital for repeated episodes of dry cough, low-grade fever, and gradual development of dyspnea on exertion. Chest computed tomography showed diffuse ground-glass opacities in both lung fields. Bronchoalveolar lavage fluid (BALF) showed an increased number of lymphocytes, and transbronchial lung biopsy revealed alveolitis and epithelioid cell granuloma. The acute onset and the patient's living environment suggested summer-type hypersensitivity pneumonitis. However, anti-Trichosporon antibody was negative and a definitive diagnosis could not be made. The patient's condition improved with corticosteroid treatment and, after discharge from the hospital, she moved to a new home. The following year, however, her symptoms returned, and she was readmitted to our hospital. Recurrence of the disease despite the change in environment ruled out summer-type hypersensitivity pneumonitis. Given the patient's history of budgerigar breeding five years earlier, bird breeder's lung was suspected. Anti-bird excreta antibody found in the patient's serum and BALF, along with a positive lymphocyte stimulation test against pigeon serum, strongly suggested an acute onset of bird breeder's lung. We report a rare case of acute bird breeder's lung with radiologic findings of ground-glass opacities, a one-year disease-free period and an acute relapse.

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.

Many diseases have increased expression of both major histocompatibility complex (MHC) class I and II molecules, and in particular the class II genes in the human leucocyte antigen region in particular are known to influence many chronic inflammatory diseases. Recently, a −168A→G polymorphism (rs3087456) in the type III promoter of MHC2TA, which has a pivotal role in MHC class II regulation, was found to be associated with increased susceptibility to rheumatoid arthritis in a Swedish population.1 However, most replication studies in other populations did not reproduce this finding, except a Spanish study.2–6 The purpose of this study was to see if the reported association could be observed in a Japanese population. DNA samples were …