CD4+ T-cell-directed antibody responses are maintained in patients with psoriasis receiving alefacept: results of a randomized study

BACKGROUND: Alefacept, human LFA-3/IgG(1) fusion protein, selectively reduces memory-effector (CD45RO(+)) T cells, a source of the pathogenic mediators of psoriasis. OBJECTIVE: To evaluate the effect of alefacept on immune function, T-cell-dependent humoral responses to a neoantigen (PhiX174) and recall antigen (tetanus toxoid) were assessed. METHODS: Patients with psoriasis were randomized to the control group or to receive alefacept (7.5 mg intravenously weekly for 12 weeks). The alefacept group received PhiX174 immunizations at weeks 6, 12, 20, and 26 and tetanus toxoid at week 21; control subjects received PhiX174 at weeks 6 and 12 and tetanus at week 10. RESULTS: Mean anti-PhiX174 titers were comparable in both groups. There was no difference in the percentage of responders (anti-PhiX174 IgG >/=30% of the total anti-PhiX174) between the alefacept group and the control group (86% and 82%, respectively; P =.73). The percentage of patients with anti-tetanus toxoid titer increases >/=2 times baseline also was similar (alefacept, 89%; control 91%). CONCLUSION: A single 12-week course of alefacept did not impair primary or secondary antibody responses to a neoantigen or memory responses to a recall antigen. The selective immunomodulatory effect of alefacept against a potentially pathogenic T-cell subset is associated with maintenance of a significant aspect of immune function (antibody response) to fight infection and respond to vaccinations.     

Blockade of CD11a by efalizumab in psoriasis patients induces a unique state of T-cell hyporesponsiveness

Efalizumab (anti-CD11a) interferes with LFA-1/ICAM-1 binding and inhibits several key steps in psoriasis pathogenesis. This study characterizes the effects of efalizumab on T-cell activation responses and expression of surface markers on human circulating psoriatic T cells during a therapeutic trial. Our data suggest that efalizumab may induce a unique type of T-cell hyporesponsiveness, directly induced by LFA-1 binding, which is distinct from conventional anergy described in animal models. Direct activation of T cells through different activating receptors (CD2, CD3, CD3/28) is reduced, despite T cells being fully viable. This hyporesponsiveness was spontaneously reversible after withdrawal of the drug, and by IL-2 in vitro. In contrast to the state of anergy, Ca(+2) release is intact during efalizumab binding. Furthermore, lymphocyte function-associated antigen-1 (LFA-1) blockade resulted in an unexpected downregulation of a broad range of surface molecules, including the T-cell receptor complex, co-stimulatory molecules, and integrins unrelated to LFA-1, both in the peripheral circulation and in diseased skin tissue. These observations provide evidence for the mechanism of action of efalizumab. The nature of this T-cell hyporesponsiveness suggests that T-cell responses may be reduced during efalizumab therapy, but are reversible after ceasing efalizumab treatment.     

Efalizumab-associated papular psoriasis

BACKGROUND: Efalizumab is a human anti-CD11a monoclonal antibody used in the treatment of patients with moderate to severe plaque psoriasis. Some of the patients develop new papular lesions during treatment, which are predominantly located in the flexural regions. OBSERVATION: Four patients with recalcitrant psoriasis undergoing treatment with efalizumab presented with erythematous, partly scaly papules and small plaques on previously unaffected areas after 4 to 10 weeks of efalizumab therapy. Tissue sections of biopsy specimens were stained with hematoxylin-eosin, and immunohistochemical staining was performed using monoclonal antibodies against CD3, CD4, CD8, T-cell-restricted intracellular antigen 1, granzyme B, neutrophil elastase, CD68, CD1a, CD11c, HLA-DR, CD25, CD20, and CD56. Histopathological and immunohistochemical examination of the lesions showed features consistent with psoriasis and activation of various leukocyte subtypes including T cells, dendritic cells, macrophages, and neutrophils. CONCLUSIONS: Papular eruptions appearing during efalizumab therapy represent new psoriatic lesions and could be referred to as efalizumab-associated papular psoriasis (EAPP). They usually do not necessitate termination of efalizumab therapy and may optionally be treated with topical corticosteroids. Dermatologists should be aware of these lesions and inform their patients accordingly.     

Efalizumab,a reversible T-cell modulator for psoriasis

The humanized monoclonal antibody (MAb) efalizumab (Raptiva®) was developed to meet a longstanding need for specific, safe, and effective anti-psoriatic treatments. Efalizumab, which is directed at the lymphocyte surface protein LFA-1, prevents multiple interactions between T cells and other cell types. Here, we review the inflammatory pathway that drives the development of psoriasis, and we discuss several mechanisms by which efalizumab suppresses skin inflammation in psoriasis. Efalizumab reversibly increases circulating T-cell counts, as T cells—including pathogenic CD8 memory T cells that are prominent in psoriatic lesions— are specifically restrained from leaving the bloodstream and entering the skin. Within two weeks of the onset of efalizumab treatment, cell surface and intracellular LFA-1 pools are substantially cleared by lysosomal degradation. Residual surface LFA-1 molecules remain saturated with bound efalizumab for some weeks following cessation of treatment. Efalizumab’s pharmacodynamic properties are consistent with its profound and reversible beneficial effects on the histopathology of psoriatic skin.     

New-onset, debilitating arthritis in psoriasis patients receiving efalizumab

Efalizumab is a humanized anti-CD11a monoclonal IgG(1) antibody approved for the treatment of moderate-to-severe plaque psoriasis. This case report describes two cases of new-onset debilitating psoriatic arthritis in patients with plaque psoriasis on long-standing efalizumab therapy, despite the fact that their skin disease was in remission. Although during the clinical trials, involving over 2,700 study subjects, arthralgia was seen only at a rate of 1-2% higher than in those subjects receiving placebo, the cases presented here are interesting in that it appears that efalizumab treatment 'uncoupled' the psoriatic arthritic component from the cutaneous disease. It can be speculated that a possible mechanism for efalizumab-induced psoriatic arthritis is related to the blockade of regulatory T cells from joint tissue.     

Efalizumab,a reversible T-cell modulator for psoriasis

The humanized monoclonal antibody (MAb) efalizumab (Raptiva®) was developed to meet a longstanding need for specific, safe, and effective anti-psoriatic treatments. Efalizumab, which is directed at the lymphocyte surface protein LFA-1, prevents multiple interactions between T cells and other cell types. Here, we review the inflammatory pathway that drives the development of psoriasis, and we discuss several mechanisms by which efalizumab suppresses skin inflammation in psoriasis. Efalizumab reversibly increases circulating T-cell counts, as T cells—including pathogenic CD8 memory T cells that are prominent in psoriatic lesions— are specifically restrained from leaving the bloodstream and entering the skin. Within two weeks of the onset of efalizumab treatment, cell surface and intracellular LFA-1 pools are substantially cleared by lysosomal degradation. Residual surface LFA-1 molecules remain saturated with bound efalizumab for some weeks following cessation of treatment. Efalizumab’s pharmacodynamic properties are consistent with its profound and reversible beneficial effects on the histopathology of psoriatic skin.

     

Efalizumab

Efalizumab is a humanized monoclonal antibody that binds to CD11a, the alpha-subunit of lymphocyte function-associated antigen-1, and consequently inhibits T-cell activation. In randomized, double-blind, placebo-controlled trials, efalizumab 1.0 mg/kg, administered subcutaneously once weekly for 12 weeks, significantly reduced disease activity in patients with chronic, moderate-to-severe plaque psoriasis. Significantly more efalizumab recipients had a > or =75% decrease in the Psoriasis Area and Severity Index (PASI) score [22.4-38.9%] than placebo recipients (2.4-4.9%); an additional 12 weeks of treatment resulted in sustained or increased PASI responses. The efficacy of weekly subcutaneous efalizumab was maintained during 15 months of treatment. Efalizumab significantly improved health-related quality of life in patients with chronic plaque psoriasis, with significant improvements in all the Dermatology Life Quality Index domains. Efalizumab was generally well tolerated in patients with chronic, moderate-to-severe plaque psoriasis, with few serious adverse events or treatment withdrawals. The most common adverse events were headache, chills, myalgia, pain, and fever; these most often occurred within 2 days of administration of the drug, were most frequent after the first or second dose, and decreased in frequency over time.     

The lymphocyte: protagonism in the new era of the biological therapies

Psoriasis is a systemic type T cell mediated immune system chronic inflammatory skin disease. These cells play an important role in the immune system and in the inflammatory response that determines the development and maintenance of the psoriasis lesions. However, greater understanding of the pathophysiology of this disease has led to the development of specific and selective biological treatments. Efalizumab is a humanized IgG1 monoclonal antibody that binds to the Leukocyte-Function-Associated Antigen 1 (LFA-1). When it binds to the CD11a--alpha subunit of LFA1--it inhibits the binding of this ligand to the intercellular adhesion molecule 1. This inhibits several processes related with the T cells that are fundamental in the pathogenesis of psoriasis: activation of the T cells in the lymph nodes, the migration of the T cells towards the dermis and epidermis and finally the reactivation of these in the inflammatory focus. The clinical studies have demonstrated that efalizumab, administered subcutaneously only once a week, provides a clinical benefit as well as improvement in the quality of life in patients with psoriasis with chronic, moderate or severe plaques. Long-term treatment studies suggest that continuous therapy with efalizumab is more beneficial in the maintenance of the improvement of the response and demonstrate that efalizumab may be administered safely for prolonged periods. Given its efficacy, rapid onset action, safety profile due to its selective action mechanism and convenience in its subcutaneous self-administration weekly, efalizumab offers a new therapeutic option, especially of interest for the treatment of psoriasis.     

Defective IgG2 response to Pneumovax in HIV seropositive patients.

OBJECTIVE--To determine whether HIV (Human Immunodeficiency Virus) antibody positive adults are capable of mounting an effective immune response when immunized with polyvalent pneumococcal vaccine. DESIGN--28 patients (nine homosexual men, one bisexual man, three heterosexual females, 10 injecting drug abusers, five haemophiliacs) and 11 healthy volunteers, were immunised with Pneumovax II and titres of IgG1 and IgG2 specific antibody measured before and 1 month after immunisation. Magnitude of immune response was related to CD4 T-lymphocyte count at time of immunisation to establish whether responses are better in early disease. MAIN OUTCOME MEASURES--Based on our data in healthy volunteers we defined an adequate response to Pneumovax II as a post immunisation IgG2 antibody level at least 50% greater than the pre immunisation level. RESULTS--The magnitude of the response was significantly higher in the normal volunteers (U = 95; p = 0.0328). Adequate IgG2 responses were seen in 11/11 normals but in only 14/28 HIV seropositives (chi 2 = 8.58; p < 0.01). Poor responses were unrelated to the CD4 T-lymphocyte count at immunisation. Absolute IgG2 deficiency accounted for the poor response in only 1 HIV patient. CONCLUSION--50% of HIV antibody seropositive individuals fail to mount adequate immune responses to polyvalent pneumococcal vaccine. Non responders are unlikely to be protected.     

El linfocito: protagonista en la nueva era de los biológicos

Psoriasis is a systemic type T cell mediated immune system chronic inflammatory skin disease. These cells play an important role in the immune system and in the inflammatory response that determines the development and maintenance of the psoriasis lesions. However, greater understanding of the pathophysiology of this disease has led to the development of specific and selective biological treatments. Efalizumab is a humanized IgG1 monoclonal antibody that binds to the Leukocyte-Function-Associated Antigen 1 (LFA-1). When it binds to the CD11a –alpha subunit of LFA1– it inhibits the binding of this ligand to the intercellular adhesion molecule 1. This inhibits several processes related with the T cells that are fundamental in the pathogenesis of psoriasis: activation of the T cells in the lymph nodes, the migration of the T cells towards the dermis and epidermis and finally the reactivation of these in the inflammatory focus. The clinical studies have demonstrated that efalizumab, administered subcutaneously only once a week, provides a clinical benefit as well as improvement in the quality of life in patients with psoriasis with chronic, moderate or severe plaques. Long-term treatment studies suggest that continuous therapy with efalizumab is more beneficial in the maintenance of the improvement of the response and demonstrate that efalizumab may be administered safely for prolonged periods. Given its efficacy, rapid onset action, safety profile due to its selective action mechanism and convenience in its subcutaneous self-administration weekly, efalizumab offers a new therapeutic option, especially of interest for the treatment of psoriasis.     

Current concepts and review of efalizumab in the treatment of psoriasis

Efalizumab is a recombinant humanized monoclonal IgG1 antibody that targets CD11a, a cell surface protein that plays a key role in the T-cell-mediated steps leading to the pathogenesis of psoriasis. The efficacy and safety of efalizumab have been studied extensively in patients with moderate to severe chronic plaque psoriasis. Clinical trial data developed in several large phase 3 studies have demonstrated that efalizumab rapidly improves both physician- and patient-assessed measures of clinical efficacy, and that the observed changes are sustainable over extended periods of continuous treatment, with a favorable safety profile. Efalizumab represents a new therapeutic option for the long-term management of moderate to severe chronic plaque psoriasis.     

Exacerbation of pityriasis rubra pilaris under efalizumab therapy

A 60-year-old woman, diagnosed as having psoriasis vulgaris in 2004 and unresponsive to standard therapies, received weekly subcutaneous injections with efalizumab. Within 9 weeks of treatment a massive aggravation of skin lesions occurred with widespread orange-tinged erythroderma, islands of normal skin on the back and the inner side of the forearms and palmoplantar hyperkeratosis. A biopsy confirmed the clinical diagnosis of pityriasis rubra pilaris. After discontinuation of efalizumab and treatment with oral corticosteroids, acitretin (30 mg/day) and PUVA therapy, the skin lesions continuously improved. Efalizumab, a fully humanized monoclonal antibody against CD11a, inhibits various T cell processes important in the pathogenesis of psoriasis. Efalizumab has been approved for the treatment of moderate to severe psoriasis, but there are no reports in the literature on the use of efalizumab for pityriasis rubra pilaris.     

Efficacy of short-term cyclosporine treatment to control psoriasis-related events during efalizumab therapy

Efalizumab is a recombinant humanized anti-CD11a monoclonal antibody that blocks the activation, adhesion and trafficking of T cells and has been approved for the treatment of moderate-to-severe plaque psoriasis. To document management of the fluctuations in symptom control that patients with psoriasis sometimes experience during treatment, we performed a retrospective analysis of our experience using cyclosporine as an intercurrent treatment to control psoriasis-related adverse events (AEs) in 10 patients who had received continuous efalizumab therapy for 20-200 weeks prior to recurrence of symptoms. Combination therapy with cyclosporine and efalizumab was generally well tolerated and controlled the relapse effectively. There were no reports of severe AEs during combination treatment, and no clinically significant changes were noted in clinical and laboratory values. Although mild, localized psoriasis recurred in most of these patients after cyclosporine termination, no patient experienced rebound or psoriasis flare and all continued with long-term efalizumab treatment.     

Psoriasis as a model for T-cell-mediated disease: immunobiologic and clinical effects of treatment with multiple doses of efalizumab,an anti-CD11a antibody

BACKGROUND: Leukocyte function-associated antigen 1 (LFA-1), consisting of CD11a and CD18 subunits, plays an important role in T-cell activation and leukocyte extravasation. OBJECTIVE: To test whether blocking CD11a decreases immunobiologic and clinical activity in psoriatic plaques. DESIGN: Open-label, multicenter, dose escalation study. PATIENTS: Thirty-nine patients with moderate-to-severe psoriasis. INTERVENTION: Intravenous infusions of efalizumab, a humanized anti-CD11a monoclonal antibody, for 7 weeks at doses of 0.1 mg/kg every other week or 0.1 mg/kg weekly (category 1), 0.3 mg/kg weekly (category 2), and 0.3 increasing to 0.6 or 1.0 mg/kg weekly (category 3). Skin biopsies were performed on days 0, 28, and 56. MAIN OUTCOME MEASURES: Serum efalizumab levels, levels of total and unoccupied T-cell CD11a, T cell counts, epidermal thickness, cutaneous intercellular adhesion molecule 1 (ICAM-1) and keratin 16 (K16) expression, Psoriasis Area and Severity Index (PASI) scores. RESULTS: Dose-response relationships were observed for pharmacokinetics and pharmacodynamic measures. Category 1 failed to maintain detectable serum efalizumab or T cell CD11a down-modulation between doses. Category 2 achieved both. Category 3 achieved both and additionally maintained sustained T-cell CD11a saturation between doses. A dose-response relationship was also observed clinically and histologically. The mean decrease in the PASI score was 47% in category 3, 45% in category 2, and 10% in category 1 (P<.001). Epidermal and dermal T-cell counts, epidermal thickness, and ICAM-1 and K16 expression decreased in categories 2 and 3 but not in category 1. Circulating lymphocyte counts increased in categories 2 and 3. CONCLUSIONS: At doses of 0.3 mg/kg or more per week, intravenous efalizumab produced significant clinical and histologic improvement in psoriasis, which correlated with sustained serum efalizumab levels and T-cell CD11a saturation and down-modulation.     

Efalizumab in the treatment of discoid lupus erythematosus

BACKGROUND: Discoid lupus erythematosus is a chronic inflammatory condition in which the pathogenesis and the role of cell-mediated immunity remains unclear. Currently, the most effective treatments for severe disease are thalidomide, methotrexate, and cyclosporin, although the evidence for this is limited. Efalizumab is a monoclonal antibody directed against CD11a, the alpha-subunit of the leukocyte-functioning antigen 1, with a current license for use in psoriasis. Because discoid lupus erythematosus is known to be predominantly T-cell mediated, our aim was to use efalizumab as a T-cell modulator in patients with recalcitrant disease. OBSERVATIONS: Thirteen patients received efalizumab, with treatment responses varying from good to excellent in 12 of 13 patients. There was a significant reduction in the cutaneous lupus activity and severity score (CLASS) score after therapy with efalizumab (P = .002). CONCLUSIONS: We have presented efalizumab as a novel alternative treatment for patients with difficult discoid lupus erythematosus. The response to treatment in 12 patients was very encouraging, with the mean time to response being 5.5 weeks. However, patient numbers were small, and many remain in the early stages of therapy. A prospective randomized study with a long-term follow-up is required, especially in light of recent findings to evaluate both the effectiveness and safety profile of this monoclonal antibody.     

Profiling lymphocyte subpopulations in peripheral blood under efalizumab treatment of psoriasis by multi epitope ligand cartography (MELC) robot microscopy

CD11a-blocking efalizumab has recently been approved as a systemic treatment of moderate to severe chronic plaque psoriasis. When treating 6 psoriasis patients with efalizumab over 12 weeks in the present study, we observed an overall good tolerability and 5 treatment responders characterized by a decrease of PASI from 21.3 +/- 5.4 to 3.9 +/- 0.6. The accompanying significant increase of peripheral blood lymphocytes from 1.9 +/- 0.7 to 4.3 +/- 1.0 x 10(9)/L (p < 0.05) was analyzed by multi epitope ligand cartography (MELC) robot microscopy. Thereby a high-dimension simultaneous multiplex immunophenotyping was pursued using 39 fluorophore-labeled antibodies including labeled efalizumab and 3 other affinity reagents such as lectins. Due to efalizumab treatment there was a substantial decrease of the cellular expression of CD11a (detected by mab clone 25.3.1) and efalizumab binding sites (EfaBSs). This was paralleled by an increase of the number of EfaBS- and EfaBS+ lymphocytes by a factor of 2.4x and 2.2x, respectively. The latter effect was mainly derived from a subpopulation showing a low degree of EfaBS expression. Efalizumab treatment led furthermore to an increase of the numbers of CD3+, CD4+, CD8+, CD44+, CD45+, CD45R0+, CD45 RA+, CD52+, CD58+, CD247+, HLA-DR+ and Sambucus nigra lectin-reactive lymphocytes (by factors from 2.0 to 3.3x). In terms of a combinatorial molecular phenotype we identified a CD3+/CD4+/CD44+/CD52+ lymphocyte subpopulation which accumulated most predominantly from 0.824 +/- 0.270 x 10(9)/L up to 1.616 +/- 0.152 x 10(9)/L under efalizumab treatment (p < 0.01). Thus, the current study extends the knowledge of efalizumab-dependent perturbations of recirculating blood lymphocyte subpopulations in psoriasis patients.     

Efalizumab for severe refractory atopic eczema: retrospective study on 11 cases

Background Efalizumab is a recombinant humanized murine monoclonal antibody against CD11a, approved for the treatment of plaque psoriasis. However, recent reports suggest that it also may be effective in the treatment of severe atopic dermatitis (AD). Objective To evaluate the clinical effect of efalizumab in AD. Methods A systematic retrospective study of the medical files of patients treated with efalizumab for AD in Danish dermatology departments. Positive outcome was defined as improvement of the disease registered in the patient's file over a period exceeding 6 months. Results Two of eleven patients had a positive outcome. Nine patients stopped treatment due to progression of AD or lack of effect. Limitations Retrospective study. Conclusions Only a minority of patients with severe AD responded to efalizumab treatment in a standard dose.     

Efalizumab, a reversible T-cell modulator for psoriasis

The humanized monoclonal antibody (MAb) efalizumab (Raptiva) was developed to meet a longstanding need for specific, safe, and effective anti-psoriatic treatments. Efalizumab, which is directed at the lymphocyte surface protein LFA-1, prevents multiple interactions between T cells and other cell types. Here, we review the inflammatory pathway that drives the development of psoriasis, and we discuss several mechanisms by which efalizumab suppresses skin inflammation in psoriasis. Efalizumab reversibly increases circulating T-cell counts, as T cells--including pathogenic CD8 memory T cells that are prominent in psoriatic lesions-- are specifically restrained from leaving the bloodstream and entering the skin. Within two weeks of the onset of efalizumab treatment, cell surface and intracellular LFA-1 pools are substantially cleared by lysosomal degradation. Residual surface LFA-1 molecules remain saturated with bound efalizumab for some weeks following cessation of treatment. Efalizumab's pharmacodynamic properties are consistent with its profound and reversible beneficial effects on the histopathology of psoriatic skin.     

Efalizumab: results of a 3-year continuous dosing study for the long-term control of psoriasis

BACKGROUND: Efalizumab, a T-cell-targeted, recombinant, humanized, monoclonal IgG1 antibody, inhibits key T-cell-mediated steps in the pathogenesis of psoriasis. Efalizumab is approved for the treatment of moderate-to-severe chronic plaque psoriasis in adults in more than 50 countries. OBJECTIVES: To evaluate the efficacy and safety of long-term, continuous efalizumab therapy in patients with psoriasis. METHODS: This open-label, multicentre phase III study enrolled 339 patients with moderate-to-severe chronic plaque psoriasis. During the initial 3-month phase, patients received subcutaneous efalizumab 2 mg kg(-1) weekly with randomization to receive concomitant fluocinolone acetonide or placebo ointment during month 3. The second phase was a long-term observational period; patients achieving a >or=50% improvement in the Psoriasis Area and Severity Index (PASI) score were eligible to receive efalizumab 1 mg kg(-1) weekly for up to 33 months. The final 3-month treatment period was an optional transition period for patients who completed the 33-month segment before efalizumab became commercially available. RESULTS: After 3 months, 41.3% of patients achieved a >or=75% improvement in PASI (PASI-75) and 13.0% achieved a >or=90% improvement (PASI-90). Continued improvement was observed: 45.4% and 24.5% achieved PASI-75 and PASI-90, respectively, at the end of the observational phase. The safety profile was stable, with no new or no increase in common events over 36 months of treatment. CONCLUSIONS: This was the longest continuous study using a biologic therapy for psoriasis. Clinical benefit of efalizumab improved over the first 18 months and was maintained during 36 months of continuous therapy. Long-term efalizumab therapy is appropriate for many patients with plaque psoriasis.     

Efalizumab in the treatment of psoriasis: mode of action, clinical indications, efficacy, and safety

Efalizumab is a humanized monoclonal antibody directed against the CD11a subunit of the lymphocyte function-associated antigen 1. It has been approved for the treatment of moderate-to-severe plaque psoriasis. Efalizumab has been shown in several clinical trials to be effective and well tolerated in the treatment of patients with moderate-to-severe psoriasis. The safety profile of continuous therapy with efalizumab—as far as it is currently available—is favorable. Mode of action, pharmacological profile, clinical indications and efficacy, safety, and tolerability as well as practical considerations of efalizumab are reviewed in this article.