Objective To verify the hypothesis that in rheumatoid arthritis (RA), tumor necrosis factor α (TNFα) plays a critical role in regulating leukocyte trafficking and chemokine levels. Methods Ten patients with longstanding RA received a single 10 mg/kg infusion of anti-TNFα monoclonal antibody (cA2). The articular localization of autologous granulocytes, separated in vitro and labeled with 111In, was studied by analysis of gamma-camera images both before and 2 weeks after treatment. At the same sequential time points, synovial biopsy samples were assessed for infiltrating CD3+ T cells, CD22+ B cells, and CD68+ macrophages. Synovial tissue expression of the chemokines interleukin-8 (IL-8), monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, Groα, and RANTES was also determined. Serum IL-8 and MCP-1 concentrations were measured by enzyme-linked immunosorbent assay. Results Anti-TNFα therapy in RA significantly reduced 111In-labeled granulocyte migration into affected joints. There was a simultaneous and significant reduction in the numbers of infiltrating synovial CD3+ T cells, CD22+ B cells, and CD68+ macrophages and in the expression of IL-8 and MCP-1, with a trend toward a reduction in serum concentrations of these chemokines. Conclusion TNFα blockade reduces synovial expression of the chemokines IL-8 and MCP-1 and diminishes inflammatory cell migration into RA joints.
The efficacy and tolerability of rIFN‐α has been evaluated in 17 selected patients with symptomatic polycythaemia vera, diagnosed according to the PRV Study Group criteria. Complete disease control (CR) was achieved, after 1–12 months, in nine patients, with partial control in a further five cases. Three patients failed to respond. Pruritus significantly improved in 83% (10/12) of cases, following 1–28 weeks of treatment. Six patients (35%), however, were unable to tolerate rIFN‐α, on account of weight loss, myalgia and mental changes. Overall, α‐interferon therapy significantly improved venesection requirements, MCV and PCV values, platelet counts, pruritus scores and the degree of splenomegaly. Analysis of pooled published data (100 evaluable patients, including the present study) revealed an overall CR of 60%, a PR of 27%, and a failure rate of 13%. Significant pruritus control (>50% improvement) occurred in 77% of cases. rIFN‐α appears to be an effective therapy for PV‐associated myeloproliferation and/or pruritus, although side‐effects remain a concern. Long‐term studies are now indicated to determine if the natural history of the disease is altered, in particular whether the incidence of myelofibrosis and/or leukaemic transformation is reduced.
Pain reduction with baricitinib was assessed in patients with rheumatoid arthritis (RA) who either used opioids or did not use opioids during three randomized, double-blind phase 3 trials.Analysis populations were as follows: i) baricitinib 4 mg once daily versus placebo groups integrated from RA-BEAM (NCT01710358) for patients with inadequate response (IR) to methotrexate, RA-BUILD (NCT01721057) with IR to conventional disease-modifying antirheumatic drugs, and RA-BEACON (NCT01721044) with IR to at least one tumor necrosis factor inhibitors; ii) baricitinib 2 mg versus placebo from RA-BUILD and RA-BEACON; and iii) adalimumab 40 mg every other week versus placebo from RA-BEAM. Pain was measured by the Patient Assessment of Pain Visual Analog Scale. Analysis of covariance modeling assessed differences in pain reduction between treatments at each time point through Week 24, with an interaction term to test heterogeneous treatment effects across opioid users and nonusers.Baricitinib 4 mg had greater pain reduction versus placebo in opioid users and nonusers (P < 0.05) at all time points starting from Week 1; the pain reduction was similar between opioid users and nonusers. Baricitinib 2 mg had greater pain reduction versus placebo in opioid users and nonusers starting at Week 4. A significant difference in pain reduction was not observed for adalimumab versus placebo in the opioid users but was observed in nonusers at all time points.Pain reduction was observed and was similar between opioid users and nonusers with baricitinib 2 mg and 4 mg but not adalimumab in this post hoc analysis.
Summary A joint working group established by the H aemato‐oncology subgroup of the B ritish C ommittee for S tandards in H aematology ( BCSH ) and the B ritish S ociety for B one M arrow T ransplantation ( BSBMT ) has reviewed the available literature and made recommendations for the diagnosis and management of acute graft‐versus‐host disease. This guideline includes recommendations for the diagnosis and grading of acute graft‐versus‐host disease as well as primary treatment and options for patients with steroid‐refractory disease. The goal of treatment should be effective control of graft‐versus‐host disease while minimizing risk of toxicity and relapse.
Background: Inflammation, local joint destruction and systemic bone loss are common complications in patients with rheumatoid arthritis (RA).We have identified that localised pre-receptor activation of glucocorticoids (GC) by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11b-HSD1) is increased within sites of inflammation and surrounding tissues, such as synovium and bone.Whilst this greatly increases local bioavailability of cortisol, which supports resolution of inflammation, in chronic disease, GCs drive may drive catabolic pathways that contribute to joint destruction and systemic bone loss.Methods: To determine the contribution of 11b-HSD1 activated glucocorticoids to joint destruction and inflammatory bone loss, we crossed an 11b-HSD1 null mouse onto a transgenic murine model of chronic polyarthritis (TNF-Tg) to generate TNF-tg 11bKO mice.Clinical measures of joint inflammation, mobility and behaviour were collected between four and nine weeks of age.Paw swelling was determined using calliper measurements.Histology was assessed in formalin fixed sections following staining with haematoxylin and eosin, safranin O or TRAP staining.Juxta articular and systemic bone losses were measured by micro-Ct.synovitis was determined by Image J analysis of histology sections.Results: 11b-HSD1 was completely knocked out within sites of inflammation in the TNF-tg 11bKO mouse.At nine weeks, both clinical and inflammation scores were markedly exacerbated in TNF-tg 11bKO animals relative to TNF-tg counterparts (inflammation score; TNF-tg, 4.3 AE 2.26 versus TNF-tg 11bKO , 11.08 AE 0.86; p < 0.001).This was supported by marked increases in joint swelling and juxta articular bone loss from these animals (erosion scores, TNFtg, 5.2 AE 0.61 versus TNF-tg 11bKO , 9.0 AE 0.66; p < 0.005).Closer examination of joint destruction revealed that the pannus was larger and more extensive within subchondral bone, whilst evidence of cartilage degradation was significantly worse in the TNF-tg 11bKO mouse (synovitis size, TNFtg, 26763 (AU) AE 3200 versus TNF-tg 11bKO , 530276 AE 3225; p < 0.005).Systemic bone loss determined by bone volume to tissue volume (BV/ TV), trabecular thickness (TT) and trabecular number (TN) was also greatly exacerbated within the TNF-tg 11bKO mouse (TNF-tg, BV/TV 5.7 AE 0.75, TT 73.5 AE 6.4, TN 0.00077 AE 0.00004 versus TNF-tg 11bKO BV/ TV 1.8 AE 0.36, TT 7359.77AE 3.7, TN 0.0003 AE 0.00005; P < 0.001, P < 0.005, P < 0.001 respectively).Conclusion: This study demonstrates that rather than contributing to catabolic pathways of tissue destruction, local GC activation by 11b-HSD1 is critical in mediating the suppression inflammation, joint destruction, synovitis and inflammatory bone loss in this murine model of chronic polyarthritis.
treatment options for patients with rheumatoid arthritis (RA) who have failed a first TNFi.The risk of serious infection (SI) is similar between these two treatments during the first year.However, long-term data on risk of SI for RTX are scarce but required, in light of reports of reduction in IgG following repeated dosing.We compared the risk of SI over five years of treatment in patients with RA who had failed a first TNFi and then received either RTX or TNFi.Methods: This study used patients with RA registered with the BSRBR-RA, a large national prospective study in the UK established primarily to assess the long-term safety of exposure to biologic therapies in patients with RA.This analysis included patients treated with either a second TNFi or RTX after failing a first TNFi.Patients were followed until first SI, 90 days or nine months following last dose of TNFi or RTX respectively if treatment was discontinued, last recorded follow-up or the end of the fifth year after the switch, which ever came first.SI was defined as infection requiring intravenous antibiotics, hospitalisation or resulting in death.The risk of first SI was compared between TNFi and RTX using unadjusted, adjusted for sex and age, and propensity score adjusted Cox proportional hazard models.Results: This analysis included 3,419 TNFi-treated patients contributing 9,527 person-years (pyrs), median (IQR) exposure time per person 2.0 (0.8-3.3) years; and 1,396 RTX patients contributing 3,570 pyrs, median (IQR) exposure time 2.9 (1.7-3.9)years.A total of 362 and 135 first SI were reported in TNFi and RTX patients respectively, giving a crude incidence rate (95% CI) of 38 (34-42) SI/1,000 pyrs (TNFi) and 38 (32-45) SI/1,000 pyrs (RTX).The unadjusted, adjusted for sex and age, and propensity score adjusted hazard ratios (95%CI) for SI were 0.9 (0.8-1.1), 0.9 (0.7-1.0) and 0.9 (0.7-1.1) respectively.Conclusion: The risk of serious infections was comparable over five years of treatment between TNFi and RTX treatment in patients who had failed a single prior TNFi.
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