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Daniel E Furst

Publications and source records attributed to Daniel E Furst.

At least 55 records · Page 3Linked to original sources
PubMed2004

High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial: lessons learned.

OBJECTIVES: To review important findings, or lessons, that were learned about measures of response, design, conduct, and analysis of a randomized, controlled trial (RCT), even though the trial failed to demonstrate efficacy of d-penicillamine. METHODS: One hundred thirty-four patients with early (< or =18 months), diffuse systemic sclerosis (SSc) were entered into an RCT (high-dose [822 mg daily] vs low-dose [120 mg every other day] D-penicillamine) and were followed up regularly for up to 4 years. Because analysis failed to show efficacy for D-penicillamine in early diffuse SSc, all data were pooled for additional secondary analyses. RESULTS: This RCT showed that trials of potential disease-modifying interventions can be completed in SSc using the American College of Rheumatology guidelines. This RCT used an active control. After analysis, we were not able to tell whether either dose was effective or ineffective. That experience argues in favor of using placebo controls until such time as an active control can be found that truly modifies the disease. Skin score and the disability index of the Health Assessment Questionnaire (HAQ-DI) were valid predictors of outcome. Along with the physician global assessment, they also were valid measures of response. CONCLUSIONS: Even in studies that are therapeutically "negative," careful evaluation of the data can examine other hypotheses and thereby provide important insights into other aspects of trial design, outcome measures, patient function, and trial conduct.

Adult↗
PubMed2004

Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis.

We investigated whether polymorphisms in reduced folate carrier (SLC19A1 G80A) and gamma-glutamyl-hydrolase (GGH-401C/T) are predictive of methotrexate polyglutamate (MTXPG) levels in patients with rheumatoid arthritis treated with weekly low-dose methotrexate (MTX). Adult patients treated with MTX were enrolled in a multicentred study. Blood was drawn at the time of the visit, DNA was extracted and red blood cell (RBC) MTXPG levels (up to the penta-order of glutamation) were measured by high-performance liquid chromatography-fluorometry. A G80A polymorphism in SLC19A1 and a -401C/T promoter polymorphism in GGH were measured by polymerase chain reaction-restriction fragment length polymorphism. Multivariate linear and logistic regressions were used to predict long-chain RBC MTXPG3-5. In 226 adult patients receiving MTX (median 15 mg range: 5-25 mg) median RBC long-chain MTXPG3-5 was 56 nmol/l (range < 5-224 nmol/l). A total of 35 patients carried the SLC19A1 80AA genotype whereas 36 patients carried the GGH-401TT genotype. Weekly MTX dose, age, presence of the SLC19A1 80AA and GGH-401TT genotypes predicted independently and significantly MTXPG3-5 levels (global r = 0.38; P < 0.0001). Patients with the GGH-401TT genotype were 4.8-fold [odds ratio (OR) 95% confidence interval (CI) 1.8-13.0; P = 0.002] more likely to have MTXPG3-5 below the group median compared to patient carriers of the GGH-401CC or CT genotype. Conversely, those with the SLC19A1 80AA genotype were 3.4-fold more likely to have MTXPG3-5 levels above the group median compared to those with the SLC19A1 80GG or 80GA genotype (OR CI 95% 1.4-8.4; P = 0.007). These data demonstrate that polymorphisms in SLC19A1 and GGH affect polyglutamation of MTX.

Adult↗
PubMed2004

Safety of tumour necrosis factor-alpha antagonists.

Tumour necrosis factor-alpha (TNFalpha) is a proinflammatory cytokine that is synthesised by a variety of cell types in response to infectious or inflammatory stimuli. Although TNFalpha plays an adaptive role in immune protection and wound healing at 'physiological' levels, excess TNFalpha production can lead to adverse consequences. TNFalpha is a pivotal cytokine involved in the pathogenesis and progression of rheumatoid arthritis (RA). TNFalpha antagonists have been shown to be effective in the treatment of signs and symptoms of RA and the US FDA has approved three TNFalpha antagonists, etanercept, infliximab, and most recently, adalimumab, for the treatment of RA. However, differences have emerged, with respect to their demonstrated efficacy in other diseases (e.g. Crohn's disease). Worldwide, over half a million patients have been treated with TNFalpha antagonists and concerns regarding their safety have been raised. There is a risk of reactivation of granulomatous diseases, especially tuberculosis, with all three agents and appropriate measures should be taken for detection and treatment of latent infections. An association between non-Hodgkin's lymphoma and treatment with TNFalpha antagonists has been reported, although patients with active, long-standing RA are already known to have an increased incidence of non-Hodgkin's lymphoma. No associations with solid tumours have been found to date. The biological plausibility of lymphomas associated with immunomodulatory agents raises concern and vigilance is appropriate until the relationship is fully characterised. Large phase II and III trials have shown a detrimental effect of TNFalpha antagonists in advanced heart failure and these agents should be avoided in this population. Rare case reports of drug-induced lupus, seizure disorder, pancytopenia and demyelinating diseases have been noted after TNFalpha antagonists and continued vigilance is warranted in patients on TNFalpha antagonists for the development of these diseases. At present there is no evidence implicating TNFalpha antagonists with embryotoxicity, teratogenicity or increased pregnancy loss.

Animals↗
PubMed2004

Combination leflunomide and methotrexate (MTX) therapy for patients with active rheumatoid arthritis failing MTX monotherapy: open-label extension of a randomized, double-blind, placebo controlled trial.

OBJECTIVE: To obtain additional safety and efficacy data on leflunomide (LEF) treatment in combination with methotrexate (MTX) therapy in an open-label extension study in patients with rheumatoid arthritis (RA). METHODS: Following a 24 week, randomized, double-blind trial of adding placebo (PLA) or LEF to stable MTX therapy, patients could enter a 24 week extension. Subjects randomized to LEF and MTX continued treatment [(LEF/LEF) + MTX]. Subjects randomized to PLA and MTX switched to LEF (10 mg/day, no loading dose) and MTX [(PLA/LEF) + MTX]. The double-blind regarding initial randomization was maintained. RESULTS: For subjects in the extension phase, American College of Rheumatology 20% (ACR20) responder rates for the (LEF/LEF) + MTX group were maintained from Week 24 (57/96, 59.4%) to Week 48 (53/96, 55.2%). ACR20 responder rates improved in patients switched to LEF from PLA at Week 24 [(PLA/LEF) + MTX] from 25.0% (24/96) at Week 24 to 57.3% (55/96) at Week 48. Patients in the extension who switched from PLA to LEF without a loading dose exhibited a lower incidence of elevated transaminases compared to patients initially randomized to LEF. Diarrhea and nausea were less frequent during the open-label extension in patients who did not receive a LEF loading dose. CONCLUSION: Response to therapy was maintained to 48 weeks of treatment in patients who continued to receive LEF and MTX during the extension. Importantly, ACR20 response rates after 24 weeks of LEF therapy were similar between patients switched from PLA to LEF without loading dose, and those who received a loading does of LEF (100 mg/day x 2 days) at randomization. Fewer adverse events were reported in patients switched to LEF without a loading dose.

Antirheumatic Agents↗
PubMed2003

Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial.

OBJECTIVE: To evaluate the efficacy and safety of adalimumab (D2E7), a fully human monoclonal tumor necrosis factor alpha antibody, in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite treatment with MTX. METHODS: In a 24-week, randomized, double-blind, placebo-controlled study, 271 patients with active RA were randomly assigned to receive injections of adalimumab (20 mg, 40 mg, or 80 mg subcutaneously) or placebo every other week while continuing to take their long-term stable dosage of MTX. The primary efficacy end point was the American College of Rheumatology criteria for 20% improvement (ACR20) at 24 weeks. RESULTS: An ACR20 response at week 24 was achieved by a significantly greater proportion of patients in the 20-mg, 40-mg, and 80-mg adalimumab plus MTX groups (47.8%, 67.2%, and 65.8%, respectively) than in the placebo plus MTX group (14.5%) (P < 0.001). ACR50 response rates with the 20-mg, 40-mg, and 80-mg adalimumab dosages (31.9%, 55.2%, and 42.5%, respectively) were significantly greater than that with placebo (8.1%) (P = 0.003, P < 0.001, and P < 0.001, respectively). The 40-mg and 80-mg doses of adalimumab were associated with an ACR70 response (26.9% and 19.2%, respectively) that was statistically significantly greater than that with placebo (4.8%) (P < 0.001 and P = 0.020). Responses were rapid, with the greatest proportion of adalimumab-treated patients achieving an ACR20 response at the first scheduled visit (week 1). Adalimumab was safe and well tolerated; comparable numbers of adalimumab-treated patients and placebo-treated patients reported adverse events. CONCLUSION: The addition of adalimumab at a dosage of 20 mg, 40 mg, or 80 mg administered subcutaneously every other week to long-term MTX therapy in patients with active RA provided significant, rapid, and sustained improvement in disease activity over 24 weeks compared with MTX plus placebo.

Adalimumab↗
PubMed2003

Efficacy and safety of tacrolimus in patients with rheumatoid arthritis: a double-blind trial.

OBJECTIVE: To evaluate the efficacy and safety of tacrolimus as monotherapy in controlling the signs and symptoms of patients with rheumatoid arthritis (RA). METHODS: This was a 6-month, phase III, double-blind, multicenter study. Patients with active RA who had discontinued all disease-modifying antirheumatic drugs (DMARDs) for an appropriate washout period (at least 1 month) and who, after the washout period, had a stable joint count (at least 10 tender/painful joints and 7 swollen joints) were stratified according to DMARD intolerance or DMARD resistance, and randomized to receive a single daily oral dose of placebo, tacrolimus 2 mg, or tacrolimus 3 mg. RESULTS: A total of 464 patients received at least 1 dose of study drug. Baseline characteristics were similar among the 3 treatment groups. American College of Rheumatology 20% improvement (ACR20) success (defined as completion of 6 months of treatment and an ACR20 response at the month 6 visit) for the placebo, tacrolimus 2 mg, and tacrolimus 3 mg groups was 10.2%, 18.8% (P < 0.05 versus placebo), and 26.8% (P < 0.0005 versus placebo), respectively. At the end of treatment, the ACR20 and ACR50 response rates in the 3-mg group were 32.0% (P < 0.005 versus placebo) and 11.8% (P < 0.05 versus placebo), respectively. DMARD-intolerant patients had better ACR response rates than did DMARD-resistant patients. Although serum creatinine levels increased by >/=40% from baseline at some time during the trial in 20% and 29% of patients receiving tacrolimus 2 mg/day and 3 mg/day, respectively, the serum creatinine level remained within the normal range throughout the trial in approximately 90% of patients. CONCLUSION: Tacrolimus, at dosages of both 2 mg/day and 3 mg/day, is efficacious and safe as monotherapy for patients with active RA, but treatment with the 3-mg dose of tacrolimus resulted in generally better ACR response rates.

Administration, Oral↗
PubMed2003

Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully human anti-tumor necrosis factor-alpha monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant methotrexate: a pilot study.

BACKGROUND: Because traditional therapies for rheumatoid arthritis (RA) such as methotrexate (MTX) do not produce an adequate response in many patients, newer therapies that block the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) are increasingly being used in combination with MTX. OBJECTIVE: This study evaluated the efficacy, pharmacokinetics, and safety profile of adalimumab, a fully human anti-TNF alpha monoclonal antibody, when added to continuing MTX therapy. METHODS: This Phase I, randomized, dose-titration study consisted of a 4-week, double-blind, placebo-controlled treatment phase and a 26-month, open-label continuation phase. Patients with RA who had been taking stable doses of MTX (mean dose, 17 mg/wk) for > or =3 months before enrollment with an inadequate response were randomly assigned to receive 2 single doses of either adalimumab 0.25, 0.5, 1, 3, or 5 mg/kg i.v. or placebo in the double-blind phase. In the open-label phase, patients received treatment with 1 of the doses of adalimumab every other week or monthly for 18 months; patients were then switched to adalimumab 40 mg i.v. or SC every other week or monthly. The main efficacy end point was 20% improvement in American College of Rheumatology response criteria (ACR20). Other efficacy end points included 50% (ACR50) and 70% improvements in ACR response criteria. Pharmacokinetic parameters were analyzed for adalimumab and MTX during both phases of the study. Serum adalimumab concentrations were analyzed using a validated enzyme-linked immunosorbent assay relying on the double-antigen principle. Peak and trough concentrations were determined from observed concentration-time data, and a modeling approach was used to estimate total serum clearance, mean apparent terminal half-life, apparent volume of distribution at steady state, and area under the concentration-time curve. RESULTS: Sixty patients entered the double-blind phase, 45 receiving adalimumab and 15 receiving placebo; 1 placebo recipient chose not to continue into the open-label phase. Overall, the study population included 47 (78.3%) women and 13 (21.7%) men. The mean age was 52.9 years (range, 24-73 years), and the mean body weight was 69.7 kg (range, 43-98 kg). ACR20 and ACR50 responses were achieved on at least 1 assessment during the 4-week double-blind phase by a respective 29 (64.4%) and 11 (24.4%) of 45 patients receiving active treatment and by 4 (26.7%) and none of the 15 patients receiving placebo. Responses to adalimumab were rapid, with 10 (22.2%) of 45 patients achieving an ACR20 response within 24 hours of dosing. Of 29 adalimumab recipients who had an ACR20 response, 18 (62.1%) had a duration of response (time from first occurrence of a response to first occurrence of a nonresponse) of 1 to 2 weeks, and 11 (37.9%) had a duration of response of 3 to 13 weeks. The pharmacokinetic properties of adalimumab appeared to be linear. The mean apparent terminal half-life after a single intravenous dose of adalimumab ranged from 15 to 19 days in the 5 dose groups. Repeated administration of adalimumab had no statistically significant effect on the pharmacokinetics of MTX, indicating that dose adjustment of MTX is not necessary. Adalimumab was well tolerated, and there were no dose-related adverse events. CONCLUSIONS: Among patients with active RA who had not had an adequate response to MTX, addition of adalimumab to MTX achieved statistically significant, long-term improvement compared with placebo plus MTX (P < or = 0.05), as indicated by ACR responses at 26 months. The combination was well tolerated. Adalimumab exhibited linear pharmacokinetics. In this selected patient population, adalimumab's long half-life of 15 to 19 days supports every-other-week dosing. Coadministration of adalimumab did not alter serum levels of MTX.

Adalimumab↗
PubMed2003

Update on disease-modifying antirheumatic drugs in the treatment of systemic sclerosis.

Treatment of systemic sclerosis has been somewhat haphazard and treatment has often been "borrowed" from the experience gained from treating other connective tissue diseases. There was a period of time that was focused mainly on organ-specific manifestations of systemic sclerosis and some advance in preventing vital organ damage (such as renal crisis) was achieved. The vast improvement in mortality from the use of ACE inhibitors raises one's hopes for other effective therapeutic interventions. At this juncture, the evidence is strong that the ACE inhibitors that are used in scleroderma renal crisis are disease-modifying, even without proving it by a randomized controlled trial. The evidence is strong that the use of epoprostenol for primary pulmonary hypertension is life-saving; however, whether epoprostenol is life-saving in the pulmonary hypertension in scleroderma remains to be proven. There are suggestions that bosentan (for the pulmonary hypertension of scleroderma), cyclophosphamide (for SSc alveolitis), stem cell transplant, interferon-gamma (for interstitial pulmonary fibrosis), and methotrexate (for the skin thickening of diffuse scleroderma) may improve organ function or functional activities, but whether they are truly disease-modifying remains to be proven. As we increase our understanding of the pathophysiology of systemic sclerosis and we learn how better to design trials for systemic sclerosis, we may be more successful in developing optimal disease-modifying therapy. Although the treatment of systemic sclerosis remains difficult, there are an increasing number of potentially effective regimens that are undergoing clinical investigations. A rational approach to therapy seems possible, based on a hypothesis of the pathogenesis of systemic sclerosis. Thus, there is accumulating evidence that supports the use of prostacyclin derivatives to treat systemic sclerosis, some evidence that antifibrotic regimens may be effective, and moderate evidence that immunosuppression also may be effective in certain stages of this disease.

Antirheumatic Agents↗
PubMed2003

Epstein-Barr virus-associated posttransplantation lymphoproliferative disorder after high-dose immunosuppressive therapy and autologous CD34-selected hematopoietic stem cell transplantation for severe autoimmune diseases.

High-dose immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) is currently being evaluated for the control of severe autoimmune diseases. The addition of antithymocyte globulin (ATG) to high-dose chemoradiotherapy in the high-dose immunosuppressive therapy regimen and CD34 selection of the autologous graft may induce a higher degree of immunosuppression compared with conventional autologous HSCT for malignant diseases. Patients may be at higher risk of transplant-related complications secondary to the immunosuppressed state, including Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disorder (PTLD), but this is an unusual complication after autologous HSCT. Fifty-six patients (median age, 42 years; range, 23-61 years) with either multiple sclerosis (n = 26) or systemic sclerosis (n = 30) have been treated. The median follow-up has been 24 months (range, 2-60 months). Two patients (multiple sclerosis, n = 1; systemic sclerosis, n = 1) had significant reactivations of herpesvirus infections early after HSCT and then developed aggressive EBV-PTLD and died on days +53 and +64. Multiorgan clonal B-cell infiltrates that were EBV positive by molecular studies or immunohistology were identified at both autopsies. Both patients had positive screening skin tests for equine ATG (Atgam) and had been converted to rabbit ATG (Thymoglobulin) from the first dose. Of the other 54 patients, 2 of whom had partial courses of rabbit ATG because of a reaction to the intravenous infusion of equine ATG, only 1 patient had a significant clinical reactivation of a herpesvirus infection (herpes simplex virus 2) early after HSCT, and none developed EBV-PTLD. The T-cell count in the peripheral blood on day 28 was 0/microL in all 4 patients who received rabbit ATG; this was significantly less than in patients who received equine ATG (median, 174/microL; P =.001; Mann-Whitney ranked sum test). Although the numbers are limited, the time course and similarity of the 2 cases of EBV-PTLD and the effect on day 28 T-cell counts support a relationship between the development of EBV-PTLD and the administration of rabbit ATG. The differences between equine and rabbit ATG are not yet clearly defined, and they should not be considered interchangeable in this regimen without further study.

Adult↗
PubMed2003

Plasmapheresis for rheumatic diseases in the twenty-first century: take it or leave it?

As is often the case, one cannot give a simple answer to the question: plasmapheresis-take it or leave it? A thorough review of the current data on the possible mechanisms of action, the efficacy, and the safety of plasmapheresis in rheumatic diseases demonstrates that the answer depends on the disease and the patients involved.

Arthritis, Rheumatoid↗
PubMed2003

Current status of outcome measure development for clinical trials in systemic sclerosis. Report from OMERACT 6.

Systemic sclerosis (SSc), also known as scleroderma, is a complex, multisystem disease that results in severe morbidity, disability, and life-threatening complications. The wide range of biological systems clinically involved, and the large spectrum of disease activity and damage that occurs in this disease have limited clinical investigation of SSc, especially therapeutic trials. The OMERACT 6 Workshop on Systemic Sclerosis was conceived as a starting point for the process of assessing the current state of the science in outcome assessment in SSc and then setting a realistic research agenda and priorities for future work in this area This article reviews the current status of assessment tools for research in SSc within the main fundamental domains of illness in SSc, including problems related to skin, pulmonary, cardiac, peripheral vascular (Raynaud's phenomenon and digital ulceration), renal, and musculoskeletal systems as well as health-related quality of life and physical functioning. The current level of validation of outcome measures in SSc is assessed according to the guidelines set forth by prior OMERACT meetings.

Clinical Trials as Topic↗
PubMed2003

Intravenous human recombinant tumor necrosis factor receptor p55-Fc IgG1 fusion protein, Ro 45-2081 (lenercept): results of a dose-finding study in rheumatoid arthritis.

OBJECTIVE: To determine the optimal dose regimen of intravenous (IV) Ro 45-2081 (lenercept), a tumor necrosis factor receptor p55-Fc IgG1 fusion protein, in patients with active rheumatoid arthritis (RA) METHODS: In a double-blind, placebo-controlled, parallel-group, multicenter trial, adult patients with long-standing active RA stabilized on conventional therapy were randomly assigned to receive 3 IV infusions, one every 4 weeks, of one of the following: (a) placebo, (b) lenercept 0.01 mg/kg (maximum 1 mg), (c) lenercept 0.05 mg/kg (maximum 5 mg), (d) lenercept 0.2 mg/kg (maximum 20 mg), or (e) lenercept 0.5 mg/kg (maximum 50 mg). The material utilized in the study had a lower relative bioavailability [lower area under the time-concentration curve (AUC) per mg infused] than that used in a recent similar trial. Efficacy variables included change from baseline in number of swollen joints and tender joints, scores on physician and patient assessments of disease activity, and patient assessment of pain. RESULTS: Patients treated with lenercept exhibited improvement as early as one day after the first IV infusion. The treatment benefit, however, was modest, maximized by 2 weeks and then diminished or vanished as non-neutralizing anti-lenercept antibody concentrations increased. The majority of adverse experiences were mild or moderate and not considered related to study drug. CONCLUSION: Our results showed that lenercept administered by IV infusion every 4 weeks is well tolerated, but only transiently effective in patients with long-standing RA, likely due to both the low relative bioavailability of the material used in the study and the formation of non-neutralizing anti-lenercept antibodies.

Adult↗
PubMed2003

Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis).

OBJECTIVE: This study, known as STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis), evaluated the safety and efficacy of adalimumab (Humira), a fully human monoclonal tumor necrosis factor-alpha (TNF-a) antibody, when given with standard antirheumatic therapy in patients with active rheumatoid arthritis (RA) not adequately responding to such therapies. Standard antirheumatic therapy included traditional disease modifying antirheumatic drugs (DMARD), low dose corticosteroids, nonsteroidal antiinflammatory drugs (NSAID), and/or analgesics. METHODS: In this 24-week, double-blind, placebo-controlled study, 636 patients with RA were randomly assigned to receive adalimumab 40 mg subcutaneously (sc) every other week (n = 318) or placebo (n = 318) while continuing standard antirheumatic therapy. The frequencies of adverse events, serious adverse events, severe or life-threatening adverse events, adverse events leading to withdrawal, infection, or serious infection were the primary endpoints. Secondary endpoints were determined by American College of Rheumatology (ACR) response criteria. RESULTS: During the study, the majority of patients received concomitant traditional DMARD (83.5%) and/or corticosteroids, NSAID, and/or analgesics (97.3%). Overall, 56.0% of patients continued treatment with one, 23.6% with 2, and 3.9% with > or = 3 traditional DMARD. At 24 weeks, there were no statistically significant differences between the adalimumab and placebo groups in their respective rates of adverse events (86.5% vs 82.7%), serious adverse events (5.3% vs 6.9%), severe or life-threatening adverse events (11.9% vs 15.4%), or those leading to withdrawal (2.8% vs 2.2%). There were also no statistically significant differences in the rates of infections (52.2% vs 49.4%) or serious infections (1.3% vs 1.9%) between the groups. The incidence and types of adverse events did not vary between adalimumab- and placebo-treated patients by the number of concomitant traditional DMARD (0, 1, or 2). Adalimumab-treated patients compared with placebo-treated patients achieved statistically superior ACR20 (52.8% vs 34.9%), ACR50 (28.9% vs 11.3%), and ACR70 (14.8% vs 3.5%) response rates at Week 24 (p < or = 0.001). CONCLUSION: This study demonstrated that addition of adalimumab 40 mg given sc every other week to concomitant standard antirheumatic therapy is well tolerated and provides significant improvements in signs and symptoms of RA. The data indicate that adalimumab is a safe and effective therapeutic option in patients with active RA who have an inadequate response to standard antirheumatic therapy, including one or more traditional DMARD, corticosteroids, NSAID, and analgesics.

Adalimumab↗