Human anti-TNF Monoclonal Antibody Research Articles

33431 Efficacy of 80 mg/week dose of adalimumab (Humira) in treatment of hidradenitis suppurativa

Hidradenitis suppurativa (HS) is an inflammatory skin condition involving the apocrine gland-bearing regions, such as the axillae, groin, anogenital, and inframammary areas. Though its etiology is unknown, disease manifests when hair follicles become obstructed, leading to the release of inflammatory mediators, such as TNF-α and IL-17. Levels of TNF-α have been found to be elevated in lesions of HS, providing a basis for the use of biologics in treatment of severe HS. Adalimumab is a recombinant human IgG1 anti-TNF monoclonal antibody which acts via antagonism of TNF-α.

33431 Efficacy of 80 mg/week dose of adalimumab (Humira) in treatment of hidradenitis suppurativa

Hidradenitis suppurativa (HS) is an inflammatory skin condition involving the apocrine gland-bearing regions, such as the axillae, groin, anogenital, and inframammary areas. Though its etiology is unknown, disease manifests when hair follicles become obstructed, leading to the release of inflammatory mediators, such as TNF-α and IL-17. Levels of TNF-α have been found to be elevated in lesions of HS, providing a basis for the use of biologics in treatment of severe HS. Adalimumab is a recombinant human IgG1 anti-TNF monoclonal antibody which acts via antagonism of TNF-α. Although adalimumab has been studied in phase 2 and 3 trials and has been approved as a treatment modality for HS at a 40 mg weekly dose, numerous patients still suffer on a day-to-day basis due to the severity of their disease and do not respond to this conventional dosing. We present a series of 6 such patients whose response to an 80 mg/week dose of adalimumab has been positive, with a decrease in severity and number of HS lesions, leading to improvement in the Hidradenitis Suppurativa Clinical Response (HiSCR) in the absence of serious adverse effects. Although this dosing regimen has not been well-documented in literature, it is important to consider the lasting benefits of treatment with a higher dose in individuals afflicted with treatment-resistant HS, including a decreased likelihood of comorbidities and complications and an improved quality of life.

Evaluation of golimumab for the treatment of patients with active rheumatoid arthritis

ABSTRACTIntroduction: Golimumab is a human anti-TNF monoclonal antibody that was derived from human antibody-transgenic mice. Golimumab demonstrated meaningful clinical benefit and tolerable safety in patients with active rheumatoid arthritis (RA) who were methotrexate (MTX)-naïve, or who inadequately responded to MTX or who had previously been treated with a TNF inhibitor.Areas covered: This review summarizes published data on the clinical efficacy and safety for golimumab (including its pharmacodynamic and pharmacokinetic characteristics) from multiple global phase III and Japanese phase II/III clinical trials. In the long term extension of three Phase III studies with subcutaneous golimumab, the reported retention rate is high.Expert opinion: Golimumab binds TNF with high affinity and can be delivered subcutaneously every 4 weeks. Like other IgG1 antibodies, FcγR functions suggests that antibody dependent cellular cytotoxicity is observed but the contribution of cell lysis to efficacy is unclear. Although anti-TNFα agents made it possible to achieve clinical remission in RA patients, there is still an unmet need to develop treatments that will enable them to discontinue all RA medication and maintain drug-free remission.

FRI0205 Golimumab administered subcutaneously every four weeks in patients with active rheumatoid arthritis despite methotrexate therapy: long-term clinical, radiographic and safety results, including evaluation of remission using the new acr/eular criteria

BackgroundGolimumab (GLM), a human anti-TNF monoclonal antibody that binds with high affinity and specificity to soluble and transmembrane TNF antagonizes the effects of TNF. GLM plus methotrexate (MTX) has demonstrated...

FRI0176 Golimumab, a human anti-TNF monoclonal antibody, administered subcutaneously every four weeks as monotherapy in patients with active rheumatoid arthritis despite dmard therapy: 52-week results of clinical, radiographic and pharmacokinetic assessments

ObjectivesTo assess the efficacy and safety of golimumab (GLM) as monotherapy in Japanese patients (pts) with active rheumatoid arthritis (RA) despite DMARD therapy.MethodsGO-MONO is a multicenter, randomized, double-blind, placebo (PBO)-controlled...

FRI0177 52-week results of clinical, radiographic and pharmacokinetic assessments: Golimumab, a human anti-TNF monoclonal antibody, administered subcutaneously every four weeks in patients with active rheumatoid arthritis despite methotrexate therapy

ObjectivesTo assess the efficacy and safety of golimumab (GLM) in Japanese patients (pts) with active RA despite MTX therapy.MethodsGO-FORTH is a multicenter, randomized, double-blind, placebo (PBO)-controlled study in pts with...

FRI0324 Experience with adalimumab in 123 patients with juvenile idiopathic arthritis (JIA)

BackgroundAdalimumab is a fully human anti-TNF monoclonal antibody approved for the treatment of resistant polyarticular juvenile idiopathic arthritis at a dosage of 24 mg/kg/m2. every other week in children below...

AB0513 Safety and efficacy of golimumab, a human anti-tnf monoclonal antibody injected subcutaneously every 4 weeks, in chinese patients with active ankylosing spondylitis: one-year results of a phase 3, randomized, placebo-controlled study

BackgroundA multicenter, randomized, placebo (PBO)-controlled study of golimumab (GLM) was performed in Chinese pts with ankylosing spondylitis (AS).ObjectivesTo assess efficacy and safety of golimumab (GLM) through wk56 in Chinese pts...

Adalimumab therapy for refractory uveitis: results of a multicentre, open-label, prospective trial

ObjectiveTumour necrosis factor (TNF) blockers have been demonstrated to be effective in the treatment of systemic and ocular inflammatory diseases. We conducted a prospective, multicentre, open-label Phase II clinical trial...

Adalimumab, a human anti-TNF monoclonal antibody, outcome study for the prevention of joint damage in Japanese patients with early rheumatoid arthritis: the HOPEFUL 1 study

ObjectivesTo evaluate the efficacy and safety of adalimumab+methotrexate (MTX) in Japanese patients with early rheumatoid arthritis (RA) who had not previously received MTX or biologics.MethodsThis randomised, double-blind, placebo-controlled, multicentre study...

Influence of psoriatic arthritis on the efficacy of adalimumab and on the treatment response of other markers of psoriasis burden: subanalysis of the BELIEVE study

Adalimumab is a fully human anti-TNF monoclonal antibody with demonstrated efficacy and safety in patients with moderate to severe psoriasis and psoriatic arthritis (PsA). This study examined the effect of PsA on adalimumab treatment response in patients from the Phase IIIb BELIEVE trial (NCT00574249, ClinicalTrials.gov registry), and response of other markers of disease burden to adalimumab treatment. In this post hoc analysis, patients with or without a history of PsA and with moderate to severe psoriasis were randomized to adalimumab plus adjunctive topical therapy (calcipotriol/betamethasone dipropionate) or monotherapy (adalimumab plus matching topical vehicle). Regardless of baseline PsA, improvement at Week 16 was seen in PASI 75, pruritus, PSSI, and DLQI (all patients), and mean NAPSI scores. Patients with PsA had HAQ improvement at Week 16, and compared to patients without PsA, had higher VAS pain scores. This analysis represents the first publication of the influence of PsA and PsA plus body weight on patient response to adalimumab, and response of scalp psoriasis, nail psoriasis, and patient-reported outcomes to adalimumab. The incidence of AEs was similar among all patients (62%), those with PsA (65%) and without PsA (60%). The most common AEs were infections (27%); 4.2% of all patients reported serious AEs. Adalimumab treatment resulted in comprehensive, clinically relevant improvements from baseline PsA status, in skin, nails, quality of life, pain and pruritus. Despite having more severely affected disease and quality of life, patients with PsA did not respond to adalimumab significantly differently from patients without PsA.

Reduced Inflammation and Lymphoid Tissue Immunopathology in Rhesus Macaques Receiving Anti–Tumor Necrosis Factor Treatment During Primary Simian Immunodeficiency Virus Infection

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections induce robust, generalized inflammatory responses that begin during acute infection and lead to pathological systemic immune activation, fibrotic damage of lymphoid tissues, and CD4⁺ T-cell loss, pathogenic processes that contribute to disease progression. To better understand the contribution of tumor necrosis factor (TNF), a key regulator of acute inflammation, to lentiviral pathogenesis, rhesus macaques newly infected with SIVmac239 were treated for 12 weeks in a pilot study with adalimumab (Humira), a human anti-TNF monoclonal antibody. Adalimumab did not affect plasma SIV RNA levels or measures of T-cell immune activation (CD38 or Ki67) in peripheral blood or lymph node T cells. However, compared with untreated rhesus macaques, adalimumab-treated rhesus macaques showed attenuated expression of proinflammatory genes, decreased infiltration of polymorphonuclear cells into the T-cell zone of lymphoid tissues, and weaker antiinflammatory regulatory responses to SIV infection (ie, fewer presumed alternatively activated [ie, CD163⁺] macrophages, interleukin 10-producing cells, and transforming growth factor β-producing cells), along with reduced lymphoid tissue fibrosis and better preservation of CD4⁺ T cells. While HIV/SIV replication drives pathogenesis, these data emphasize the contribution of the inflammatory response to lentiviral infection to overall pathogenesis, and they suggest that early modulation of the inflammatory response may help attenuate disease progression.

Identifying Hepatitis B Carriers at Low Risk for Hepatocellular Carcinoma

Identifying Hepatitis B Carriers at Low Risk for Hepatocellular Carcinoma

Resolution of Flare or Nonresponse in Patients with Crohnʼs Disease Achieved in Most Adalimumab-Treated Patients without a Dosage Increase

Purpose: CHARM was a 56-week, randomized, double-blinded, placebo-controlled, Phase III trial that confirmed the sustained efficacy and safety of the fully human anti-TNF monoclonal antibody adalimumab (ADA) in maintaining clinical remission in patients (pts) with moderately to severely active Crohn's disease (CD).1 Methods: The objective of this analysis was to assess the clinical benefits to pts in CHARM who changed from ADA every other week (eow) to open-label (OL) ADA eow. All pts received OL induction of ADA 80 mg at Week 0 and ADA 40 mg eow starting at Week 2. Patients were then randomized to ADA 40 mg eow, ADA 40 mg weekly, or placebo at Week 4. At ≥12 weeks patients were allowed to switch stepwise to OL ADA eow and then to OL weekly for protocol-defined flares or nonresponse. This analysis determined the percentages of pts among those initially randomized to eow therapy who achieved clinical remission (CDAI < 150) or a clinical response of CR-70 (drop from baseline CDAI of 70) or CR-100 (drop from baseline CDAI of 100) after changing to OL ADA eow therapy. Results: Of the 260 pts randomized to ADA eow, 102 completed 56 weeks of blinded eow therapy, 38 withdrew, and 120 switched to OL eow for flares or nonresponse. Of these, 120 pts, 71 moved to OL weekly for repeat flares or non-response. 49 pts continued on ADA OL eow without the need for dosage increase to weekly. Of the 49 pts, a majority gained CR-70 response (32/49, 65%), with a median time to response of 29 days. In addition, 20 pts (41%) achieved clinical remission, and 59% achieved CR-100. 28 of the 49 pts were Week-4 responders. Among these pts, a majority regained CR-70 response (21/28, 75%), with a median time to response of 31 days. The clinical remission and CR-100 rates for this population were 46% and 64%, respectively. Conclusion: A majority of blinded pts on ADA eow therapy who switched to OL eow upon flares or nonresponse achieved or regained response in a short time period without the need for dosage increase to weekly therapy. Among pts regaining response, >85% of patients did it by at least 100 points or remission. These findings demonstrate the need to evaluate all options including continuation of unchanged dosing before increasing the dosage of ADA. This research was funded by Abbott Laboratories, Abbott Park, IL.

T1139 The ACT Trials: Incremental Benefit of Second and Third Induction Doses of Infliximab in Patients with Moderately-to-Severely Active Ulcerative Colitis (UC)

BACKGROUND Adalimumab (ADA), a fully human anti-TNF monoclonal antibody, is approved for treating patients (pts) with moderately to severely active Crohn's disease (CD) who have had an inadequate response to conventional therapy or who have lost response to or are intolerant of infliximab. OBJECTIVE To assess overall ADA safety across CD randomized pivotal trials, open-label extensions (OLE), and phase IIIb studies CHOICE (US) and CARE (EU). METHODS All participants in these trials were evaluated for safety at regular intervals. Rates of adverse events (AE) of interest to physicians prescribing antiTNF therapy were assessed per 100-pt-years (E/100-PY). Standard mortality ratios were calculated using the World Health Organization 2002 US mortality data as comparator. RESULTS As of Apr 15, 2007 the ADA CD clinical trial safety database contained data for 2,228 pts [2,373.7 patient-years (PYs) of ADA exposure]. The table compares rates observed in all CD clinical trials as of Apr 15, 2007 to those from the Feb 14, 2006 safety update. The rate of serious infection was comparable to those observed in Feb 2006 and to rates in published reports of other-TNF antagonists.[1,2] AE rates in ADA CD and rheumatoid arthritis clinical trials were comparable. In CD trials, the calculated standardized mortality ratio, 0.31 (95% CI, 0.03, 1.11), was lower than published rates.[3] CONCLUSIONS The safety profile of adalimumab in the Crohn's clinical trials was similar to that reported previously and to safety reports of other TNF antagonists in CD populations. Rates of AE were stable or lower over time, adalimumab was well-tolerated, and no new safety signals were identified. REFERENCES 1. Colombel JF, et al. Gastroenterology. 2004;126(1):19-31. 2. Lichtenstein GR, et al. Clin Gastroenterol Hepatol. 2006;4(5):621-630. 3. Canavan C, et al. Aliment Pharmacol Ther. 2007;25(8):861-870. Rates of Adverse Events of Interest

Mode of function of biological anti-TNF agents in the treatment of inflammatory bowel diseases

TNF-α has been identified as a major mediator in the pathophysiology of inflammation. Anti-TNF agents, either as a neutralising antibody or a soluble TNF receptor, have markedly influenced the clinical management of several chronic inflammatory disorders. Whereas it seems likely that neutralisation of soluble and membrane-bound TNF might be a key mechanism of any anti-TNF agent, the potential of the anti-TNF antibody infliximab to induce lymphocyte/monocyte apoptosis in Crohn's disease has been considered an additional important mechanism. Other potential mode of actions include induction of the anti-inflammatory cytokines IL-10 or TGF-β via retrograde signalling or induction of a certain subset of regulatory T cells. Certolizumab, a pegylated fully human anti-TNF monoclonal antibody also effective in Crohn's disease, lacks the capacity to induce apoptosis. Therefore, the capacity to induce apoptosis and neutralisation of TNF alone are insufficient to explain clinical efficacy of anti-TNF agents in human inflammatory bowel diseases.

Tumor Necrosis Factor Blockade: Mechanism of Action

Modulation of the immune response with tumor necrosis factor (TNF) blockers is not a new treatment strategy for many inflammatory disorders; however, relatively little is known about their specific mechanism of action. Understanding the mode of action, pharmacology, and pharmacokinetics of the monoclonal TNF antibodies, infliximab and adalimumab, and the soluble TNF receptor, etanercept, may therefore enable us to account for their differing clinical profiles. The aim of this supplement is to explore the roles and mechanisms of TNF and TNF blockade using in vitro pharmacological and in vivo animal modeling experiments, and in vivo studies of the effects of etanercept on the inflammatory cascade in patients with psoriasis.

Rheumatic Manifestations Associated with Inflammatory Bowel Diseases

Rheumatic manifestations, in particular joint complaints, are frequent features in inflammatory bowel disease (IBD), with a prevalence varying from 10 to 35%. Their spectrum is almost wide, involving bone, tendons, entheses and joints. Joint manifestations may be seen as arthralgia and/or inflammatory arthropathies. These latter may in turn be found in three principal forms: the peripheral, the axial or spondylitis and that overlapping between these two varieties. Peripheral arthritis may be classified in oligoarticular (type I) and polyarticular (type II) forms. Oligoarthritis is the most frequent. Usually asymmetric, involving large joints of lower limbs, it is transient, commonly associated with IBD flares, and may disappear after few weeks, although in 10% of cases it may evolves to chronic arthritis. Type II arthritis is polyarticular and symmetric, involving hands and feet but also large joints. The prevalence is about 2-4% of IBD patients, its course is independent from IBD flares and usually evolves in chronic disease. Peripheral arthritis is classically nondeforming, non erosive, and seronegative for the rheumatoid factor. Axial involvement is equally frequent in both CD and UC and varies in different studies from 10 to 30% for sacroiliitis and from 3 to 10% for ankylosing spondylitis. Its course is independent from IBD state, the extension of IBD involvement and the occurrence of flares. The treatment of rheumatic manifestations in IBD is frequently problematic, due to the possibility of frequent side effects. Among drugs used for IBD, corticosteroids, also effective in joint complaints, may have osteopenic effects; sulfasalazine, sometimes able to control peripheral arthritis, is ineffective for the axial involvement. A potential gut toxicity is associated with the use of NSAIDs, which in some patients may induce asymptomatic lesions causing small gut bleeding and loss of proteins. Local injections with steroid may be used for tendonitis, monoarthritis or isolated sacroiliac inflammation. In patients with peripheral arthritis, especially when involving several joints and/or refractory to other therapies, disease modifying drugs for rheumatoid arthritis (DMARDs) should be used. Among these, methotrexate is also useful for CD while it seems inefficacious in UC. Cyclosporin, administrated alone or in association, may contain flares of steroid refractory UC. Azathioprine is commonly used to induce and maintain remission in refractory CD while its role on arthritis is marginal. Aminobisphosphonates seem effective for both axial and peripheral involvements and probably, it may represent a good option for the future in the management of enteropathic arthritis, because of their anti-osteopenic effect. Finally, the most promising opportunities derive from the recently introduced biologic agents, in particular anti-tumour necrosis factor (TNF) . Infliximab, a chimeric anti-TNFα monoclonal IgGI antibody, has largely demonstrated its efficacy in refractory CD and in all rheumatic manifestations. Other biologic agents are proposed, including the human anti-TNF monoclonal antibody adalimumab, antibodies to integrins (anti-α 4 β7), anti-ICAM-1 (intracellular adhesion molecule 1) and IL-10. Concerning the surgical options, the colectomy may be protective on type I peripheral arthritis but is not influent on the course of axial disease, while the surgery on small intestine usually do not prevent the appearance of peripheral arthritis. In the case of destructive arthritis, like coxitis, joint prosthesis may be necessary. Keywords: Inflammatory bowel disease, Crohn's disease, ulcerative colitis, enteroarthritis, arthritis, heumatic manifestations, anti-TNF therapy

Adalimumab Induces and Maintains Clinical Response and Remission in Patients With Active Crohn’s Disease: Results of the CHARM Trial

Adalimumab Induces and Maintains Clinical Response and Remission in Patients With Active Crohn’s Disease: Results of the CHARM Trial

Adalimumab Rapidly Induces Clinical Remission and Response in Patients with Moderate to Severe Crohnʼs Disease Who Had Secondary Failure to Infliximab Therapy

Purpose: To assess the safety and efficacy of adalimumab (ADA), a self-injectable, fully human anti-TNF monoclonal antibody, in the induction of clinical remission (CDAI < 150) and response in patients with active Crohn's disease (CD) who had secondary failure to infliximab (IFX) therapy. Methods: Patients with moderate to severe CD (CDAI 220–450) and secondary failure to IFX therapy were enrolled in GAIN, a Phase III, double-blind, placebo-controlled study, and were randomized to receive ADA, 160 mg sc at Wk 0 (BL) and 80 mg sc at Wk 2, or placebo (PBO) at both time points. Primary endpoint was remission at Wk 4. Secondary endpoints were clinical response (CR) defined as a decrease from BL CDAI of ≥70 or 100 (CR70/100) at Wk 4. Safety was assessed throughout the study. Results: Patients were randomized to receive ADA (N = 159) or PBO (N = 166). Baseline characteristics were similar between the two arms: mean age, 38 yrs; female, 65%; mean CDAI, 313 (± 62 SD); median CRP, 0.8 mg/dL; immunosuppressant use, 48%. Clinical remission and response rates observed in the ADA arm were significant vs. PBO. Serious adverse events (SAE) were observed in 4.8% of PBO patients (abscess, 3; sepsis, 1; CD flare, 1; dehydration, 1; abdominal pain, 1) and in 1.3% of ADA patients (CD flare, 1; dehydration, 1). No delayed-hypersensitivity (serum sickness) reactions or deaths occurred. The overall safety profile of ADA was consistent with prior CD trials and the existing RA database. Conclusions: Adalimumab rapidly and significantly induced clinical remission and response in patients with moderate to severe CD who had secondary failure to IFX. Adalimumab was well-tolerated.Table: Clinical Remission and Response in GAIN.