Drug Profile
Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nyu Medical Center on 06/05/15 For personal use only.
Ustekinumab for the treatment of psoriatic arthritis Expert Rev. Clin. Immunol. 10(2), 189–202 (2014)
Jay Wofford1 and Alan Menter*1,2 1 Division of Dermatology, Baylor University Medical Center, Dallas, TX, USA 2 Baylor Research Institute, Dallas, TX, USA *Author for correspondence: Tel.: +1 214 820 9115 Fax: +1 972 715 1469 [email protected]
Ustekinumab is a fully human monoclonal antibody directed against the p40 subunit shared by interleukin 12 and interleukin 23, two naturally occurring protein regulators that play an important role in immune-mediated inflammatory diseases, including psoriatic arthritis (PsA). In September of 2009, the US FDA approved ustekinumab for the treatment of adult patients with moderate to severe plaque psoriasis. Beginning in November of 2009, Janssen Biotech (formerly Centocor Biotech), the developer of ustekinumab, initiated clinical trials to investigate the efficacy of ustekinumab in the treatment of other inflammatory disorders, including PsA. Phase II and Phase III studies showed both a good safety profile and significant efficacy for ustekinumab in the treatment of PsA, leading to the drug’s approval in both Europe and the USA. In an immunotherapy market currently dominated by anti-TNF-a drugs for the treatment of PsA, ustekinumab offers an alternative option for patients with PsA, including those unresponsive to methotrexate and the TNF-a inhibitory agents currently approved for this potentially debilitating disease. KEYWORDS: biologic therapy . IL-12 . IL-23 . immunotherapy . inflammatory arthritis . monoclonal antibody . psoriatic arthritis . ustekinumab
Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis affecting up to 30% of patients with psoriasis [1,2]. PsA impacts men and women with equal frequency, with an estimated incidence of approximately 6/100,000/year and a prevalence of about 1–2/1000 people [3–6]. Assuming a US population of 314 million, PsA afflicts an estimated 314,000–628,000 people across the USA. A 2008 systematic review encompassing reports from 1987 to 2006 showed considerable variation in reported incidence and prevalence for PsA and highlighted multiple factors as contributors to this variability [7]. A multicenter European trial of 1560 patients with psoriasis estimated that 31% of psoriasis patients would go on to develop PsA up to 30 years after the onset of their psoriasis [8]. Another German study of 1511 patients from dermatology practices identified 21% of psoriasis patients as having concomitant psoriatic joint disease [9]. In 2006, an internationally agreed upon new set of classification criteria were proposed for PsA, termed the Classification criteria for psoriatic arthritis (CASPAR) www.expert-reviews.com
10.1586/1744666X.2014.878649
(TABLE 1).
The CASPAR require established inflammatory articular disease with the presence of at least three points from the following features: current psoriasis, a history of psoriasis without current active psoriasis, a family history of psoriasis, dactylitis, juxta-articular new bone formation, rheumatoid factor negativity and nail dystrophy [10]. Using these new criteria, a large study from the UK estimated the prevalence of PsA among psoriasis patients to be 14% [11]. Also, based upon the CASPAR, the incidence of newly diagnosed PsA among patients with psoriasis who lacked a diagnosis of PsA at initial presentation was found to be 2% per year in one prospective study [12]. Though the precise pathophysiological mechanism behind PsA has not been clearly elucidated, it is likely that multiple immunological factors play a contributing role. Evidence suggests that the early phase of PsA is primarily mediated by tissue-specific factors and innate immune mechanisms [13]. In the established phase of PsA, both the innate and adaptive immune systems play important roles. In PsA, the pattern of inflammatory cytokines
2014 Informa UK Ltd
ISSN 1744-666X
189
Drug Profile
Wofford & Menter
Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nyu Medical Center on 06/05/15 For personal use only.
Table 1. Classification criteria for psoriatic arthritis. Category
Description
Points
Current psoriasis OR Personal or family history of psoriasis
Current psoriasis: skin disease confirmed by rheumatologist or dermatologist Personal History: obtained from patient, family physician, dermatologist, rheumatologist or other qualified health provider Family history: presence of psoriasis in a primary or secondary relative as reported by patient
2 (current) OR 1 (history)
Psoriatic nail dystrophy on current examination
Onycholysis, pitting, hyperkeratosis
1
Negative rheumatoid factor
Any method except latex, but preferably ELISA or nephelometry, using local laboratory reference range
1
Dactylitis (current or on history as recorded by a rheumatologist)
Swelling of an entire digit
1
Radiographic evidence of juxtaarticular new-bone formation
Ill-defined ossification near joint margins but excluding osteophyte formation on plain X-ray films of the hand or foot
1
A patient must have inflammatory articular disease (joint, spine or enthesis) and ‡3 points from the above categories for a diagnosis of psoriatic arthritis. Data taken from [10].
†
seen in the synovium and synovial fluid is similar to that seen in rheumatoid arthritis and includes elevated levels of TNF-a, IL-1, IL-6, IL-8, IL-10, IL-13 and IFN-a among other inflammatory markers [14,15]. In addition, elevated levels of activated type 1 CD4+ Th1 cells have been found in affected joints of patients with PsA. However, the T cells found in synovial fluid of PsA patients are predominantly CD8+ T cells [16,17]. Several studies have shown that cytokines secreted from activated Th1 cells and other proinflammatory cells induce proliferation and activation of synovial fibroblasts, contributing to psoriatic joint disease. The role of IL-12 and IL-23 in the pathogenesis of PsA is highlighted by multiple well-studied immunological mechanisms. For example, IL-12 is known to be involved in the differentiation of naı¨ve T cells into the Th1 cell subset. IL-12 is also known to stimulate the production of IFN-g and TNF-a from Th1 cells. Finally, IL-12 plays an important role in enhancing the cytotoxic activity of NK cells and CD8+ cytotoxic T cells. Studies have also found elevated levels of type 17 T (Th17) cells in psoriatic joint synovial fluid [16,18]. It is thought that IL-23 stimulates naı¨ve CD4+ T cells to differentiate into this novel subset of cells called Th17 cells. Th17 cells produce IL-17, a proinflammatory cytokine that enhances the production of other proinflammatory cytokines, such as IL-1, IL-6 and TNF-a [18]. This complex interaction of proinflammatory cells and cytokines emphasizes the integral role of IL-12 and IL-23. Currently, there are numerous approaches to the treatment of PsA. The treatment of PsA usually begins with NSAIDs, such as meloxicam, piroxicam, ibuprofen and celecoxib mainly to control symptoms and disease-modifying antirheumatic drugs (DMARDs) to control inflammation. Methotrexate (a DMARD) is the most commonly used drug worldwide in clinical practice for treating both psoriasis and PsA [19]. Other DMARDs used in treating PsA include leflunomide, cyclosporine, sulfasalazine, hydroxychloroquine, gold compounds, azathioprine and retinoic acid derivatives [20–23]. Numerous studies 190
have confirmed the efficacy of these agents in achieving significant clinical improvement in patients with PsA. However, it should be noted that none of these medications has ever been shown to prevent or retard the progression of joint damage in PsA patients. With the advent of the TNF-a inhibitory agents, the treatment of PsA has shifted. TNF-a inhibitors, in multiple large studies, have shown considerable efficacy in controlling joint disease and symptoms in PsA patients [24,25]. The TNF-a inhibitors currently used in the treatment of PsA include etanercept, infliximab, adalimumab, golimumab and certolizumab pegol [26–29]. In addition to their clinical efficacy in treating the symptoms and inflammation associated with psoriatic joint disease, these agents have also been shown to prevent the radiographic progression of PsA [30,31]. Despite the array of treatment options targeting multiple different cytokines in the inflammatory pathway of psoriatic joint disease, there exists a subset of patients who fail to respond adequately to currently available treatment options including the TNF-a inhibitors. Thus, the recent approval of ustekinumab by both the US FDA and the EMA for PsA is an important advance. Body of review Overview of the market
Due to the central role that TNF-a plays in driving the inflammatory process of PsA, currently approved biologic therapies for PsA are directed against this target. Currently, there are five biologic agents on the market that target TNF-a with FDA approval for the treatment of PsA. These include etanercept, infliximab, adalimumab, golimumab and certolizumab pegol. Etanercept is a fusion protein that is produced from recombinant DNA. This fusion protein combines the soluble human TNF receptor 2 to the constant Fc domain of human IgG1. In vivo, etanercept functions as a ‘decoy receptor’ that binds circulating TNF-a, preventing it from interacting with its receptor. Adalimumab and golimumab are both fully human Expert Rev. Clin. Immunol. 10(2), (2014)
Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nyu Medical Center on 06/05/15 For personal use only.
Ustekinumab for the treatment of PsA
monoclonal antibodies directed against TNF-a, while infliximab is a human–mouse chimeric monoclonal antibody directed against TNF-a. Certolizumab pegol is a PEGylated Fab fragment of a humanized (from mouse) monoclonal antibody against TNF-a. Together, these five biologic agents represent the mainstays of treatment for PsA patients who either fail to be controlled on traditional DMARDs or who show early radiographic progression of their joint disease. These agents vary in their route of administration and dosing intervals. Etanercept is administered subcutaneously once or twice weekly depending on the dose. Adalimumab and golimumab are administered subcutaneously every 2 weeks and every month, respectively. Infliximab is administered by intravenous infusion every 8 weeks, while certolizumab pegol is administered subcutaneously every 2 weeks [32–35,29]. In practice, however, clinicians frequently have to adjust the dosing intervals of these biologic agents to achieve maximal disease control with the most convenient dosing schedule. Also, clinicians often combine biologic agents with additional methotrexate, low-dose prednisone and/or NSAIDs for enhanced benefit. In multiple large, randomized, placebocontrolled trials, each of these anti-TNF-a therapies has shown significant efficacy in the treatment of PsA with ACR20 responses in the 60–70% range. These agents invariably show efficacy specifically in patient populations who exhibited prior inadequate response to traditional DMARDs. In addition to improvement in the clinical signs and symptoms of PsA, each of these agents has also been shown to reduce the radiographic progression of psoriatic joint disease [30]. Another key player in the inflammatory milieu of PsA that has emerged as a target for drug developers is IL-17. Three monoclonal antibodies targeting IL-17 are currently being studied for the treatment of PsA. Secukinumab (a fully human monoclonal antibody) and ixekizumab (a humanized monoclonal antibody) are currently undergoing Phase III clinical trials, while brodalumab (another fully human monoclonal antibody) is in Phase II clinical trials. Preliminary findings have revealed that two of these three therapeutic agents (secukinumab and ixekizumab) show significant clinical efficacy in the treatment of PsA, with efficacy results for brodalumab yet to be reported. However, in patients with psoriatic skin disease, Phase III trials of brodalumab have shown excellent clinical responses. These agents, if approved by the FDA, exist as future potential options for treating PsA patients who are unresponsive to traditional DMARDs or poorly controlled on anti-TNF medications [36–38]. Abatacept is a therapeutic agent with FDA approval for the treatment of rheumatoid arthritis and is currently being examined for efficacy in PsA. Abatacept is a fusion protein composed of the Fc region of human IgG1 fused to the extracellular domain of CTLA-4. This fusion protein binds with high affinity to B7 (CD80), a crucial molecule located on the surface of antigen-presenting cells that is required as a costimulator in the activation of T cells. Thus, abatacept acts as an inhibitor of the costimulation of T cells, preventing activation of T cells in vivo. In a small Phase II trial, abatacept has been shown to be efficacious in controlling PsA symptoms in www.expert-reviews.com
Drug Profile
patients previously unresponsive to traditional DMARDs and anti-TNF agents. Abatacept treatment also demonstrated improvements in the MRI findings of affected psoriatic joints in this trial [39]. Apremilast, a novel, orally administered inhibitor of phosphodiesterase-4, has been shown to suppress multiple proinflammatory mediators and cytokines involved in both innate and adaptive immunity. It is currently undergoing Phase III clinical trials for three different indications, one of which is PsA. This agent is distinct from other agents currently being investigated in that, rather than targeting a specific inflammatory mediator, it works by intracellular mechanisms to decrease the production of multiple inflammatory molecules. In addition to its divergent mechanism, apremilast has the advantage of oral administration. Lastly, tofacitinib, an oral inhibitor of the JAK 3 enzyme, is being investigated as a potential treatment for PsA. This agent, already FDA approved for the treatment of rheumatoid arthritis, interferes with the JAK-STAT signaling pathway, which transmits cell surface signals into the nucleus. Interference with this signaling pathway suppresses the expression of STAT1-dependent genes, and thus, the production of proinflammatory mediators. Like apremilast, this agent is orally administered and targets the production pathway of numerous proinflammatory molecules, rather than interfering with a single, specific target. Clearly, the pharmaceutical industry is currently in the process of rapidly expanding the repertoire of biologic and immunomodulatory agents available for treating patients with PsA (TABLE 2). Introduction to ustekinumab
Ustekinumab (Stelara) is a fully human monoclonal antibody that targets the p40 subunit common to both IL-12 and IL-23. On 21 November 2008 and 25 September 2009, ustekinumab was approved by the EMA and FDA, respectively, for the treatment of adult patients with moderate-to-severe plaque psoriasis. Ustekinumab is administered by subcutaneous injection at a dose of either 45 mg (for body weight
Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nyu Medical Center on 06/05/15 For personal use only.
Ustekinumab for the treatment of psoriatic arthritis Expert Rev. Clin. Immunol. 10(2), 189–202 (2014)
Jay Wofford1 and Alan Menter*1,2 1 Division of Dermatology, Baylor University Medical Center, Dallas, TX, USA 2 Baylor Research Institute, Dallas, TX, USA *Author for correspondence: Tel.: +1 214 820 9115 Fax: +1 972 715 1469 [email protected]
Ustekinumab is a fully human monoclonal antibody directed against the p40 subunit shared by interleukin 12 and interleukin 23, two naturally occurring protein regulators that play an important role in immune-mediated inflammatory diseases, including psoriatic arthritis (PsA). In September of 2009, the US FDA approved ustekinumab for the treatment of adult patients with moderate to severe plaque psoriasis. Beginning in November of 2009, Janssen Biotech (formerly Centocor Biotech), the developer of ustekinumab, initiated clinical trials to investigate the efficacy of ustekinumab in the treatment of other inflammatory disorders, including PsA. Phase II and Phase III studies showed both a good safety profile and significant efficacy for ustekinumab in the treatment of PsA, leading to the drug’s approval in both Europe and the USA. In an immunotherapy market currently dominated by anti-TNF-a drugs for the treatment of PsA, ustekinumab offers an alternative option for patients with PsA, including those unresponsive to methotrexate and the TNF-a inhibitory agents currently approved for this potentially debilitating disease. KEYWORDS: biologic therapy . IL-12 . IL-23 . immunotherapy . inflammatory arthritis . monoclonal antibody . psoriatic arthritis . ustekinumab
Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis affecting up to 30% of patients with psoriasis [1,2]. PsA impacts men and women with equal frequency, with an estimated incidence of approximately 6/100,000/year and a prevalence of about 1–2/1000 people [3–6]. Assuming a US population of 314 million, PsA afflicts an estimated 314,000–628,000 people across the USA. A 2008 systematic review encompassing reports from 1987 to 2006 showed considerable variation in reported incidence and prevalence for PsA and highlighted multiple factors as contributors to this variability [7]. A multicenter European trial of 1560 patients with psoriasis estimated that 31% of psoriasis patients would go on to develop PsA up to 30 years after the onset of their psoriasis [8]. Another German study of 1511 patients from dermatology practices identified 21% of psoriasis patients as having concomitant psoriatic joint disease [9]. In 2006, an internationally agreed upon new set of classification criteria were proposed for PsA, termed the Classification criteria for psoriatic arthritis (CASPAR) www.expert-reviews.com
10.1586/1744666X.2014.878649
(TABLE 1).
The CASPAR require established inflammatory articular disease with the presence of at least three points from the following features: current psoriasis, a history of psoriasis without current active psoriasis, a family history of psoriasis, dactylitis, juxta-articular new bone formation, rheumatoid factor negativity and nail dystrophy [10]. Using these new criteria, a large study from the UK estimated the prevalence of PsA among psoriasis patients to be 14% [11]. Also, based upon the CASPAR, the incidence of newly diagnosed PsA among patients with psoriasis who lacked a diagnosis of PsA at initial presentation was found to be 2% per year in one prospective study [12]. Though the precise pathophysiological mechanism behind PsA has not been clearly elucidated, it is likely that multiple immunological factors play a contributing role. Evidence suggests that the early phase of PsA is primarily mediated by tissue-specific factors and innate immune mechanisms [13]. In the established phase of PsA, both the innate and adaptive immune systems play important roles. In PsA, the pattern of inflammatory cytokines
2014 Informa UK Ltd
ISSN 1744-666X
189
Drug Profile
Wofford & Menter
Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nyu Medical Center on 06/05/15 For personal use only.
Table 1. Classification criteria for psoriatic arthritis. Category
Description
Points
Current psoriasis OR Personal or family history of psoriasis
Current psoriasis: skin disease confirmed by rheumatologist or dermatologist Personal History: obtained from patient, family physician, dermatologist, rheumatologist or other qualified health provider Family history: presence of psoriasis in a primary or secondary relative as reported by patient
2 (current) OR 1 (history)
Psoriatic nail dystrophy on current examination
Onycholysis, pitting, hyperkeratosis
1
Negative rheumatoid factor
Any method except latex, but preferably ELISA or nephelometry, using local laboratory reference range
1
Dactylitis (current or on history as recorded by a rheumatologist)
Swelling of an entire digit
1
Radiographic evidence of juxtaarticular new-bone formation
Ill-defined ossification near joint margins but excluding osteophyte formation on plain X-ray films of the hand or foot
1
A patient must have inflammatory articular disease (joint, spine or enthesis) and ‡3 points from the above categories for a diagnosis of psoriatic arthritis. Data taken from [10].
†
seen in the synovium and synovial fluid is similar to that seen in rheumatoid arthritis and includes elevated levels of TNF-a, IL-1, IL-6, IL-8, IL-10, IL-13 and IFN-a among other inflammatory markers [14,15]. In addition, elevated levels of activated type 1 CD4+ Th1 cells have been found in affected joints of patients with PsA. However, the T cells found in synovial fluid of PsA patients are predominantly CD8+ T cells [16,17]. Several studies have shown that cytokines secreted from activated Th1 cells and other proinflammatory cells induce proliferation and activation of synovial fibroblasts, contributing to psoriatic joint disease. The role of IL-12 and IL-23 in the pathogenesis of PsA is highlighted by multiple well-studied immunological mechanisms. For example, IL-12 is known to be involved in the differentiation of naı¨ve T cells into the Th1 cell subset. IL-12 is also known to stimulate the production of IFN-g and TNF-a from Th1 cells. Finally, IL-12 plays an important role in enhancing the cytotoxic activity of NK cells and CD8+ cytotoxic T cells. Studies have also found elevated levels of type 17 T (Th17) cells in psoriatic joint synovial fluid [16,18]. It is thought that IL-23 stimulates naı¨ve CD4+ T cells to differentiate into this novel subset of cells called Th17 cells. Th17 cells produce IL-17, a proinflammatory cytokine that enhances the production of other proinflammatory cytokines, such as IL-1, IL-6 and TNF-a [18]. This complex interaction of proinflammatory cells and cytokines emphasizes the integral role of IL-12 and IL-23. Currently, there are numerous approaches to the treatment of PsA. The treatment of PsA usually begins with NSAIDs, such as meloxicam, piroxicam, ibuprofen and celecoxib mainly to control symptoms and disease-modifying antirheumatic drugs (DMARDs) to control inflammation. Methotrexate (a DMARD) is the most commonly used drug worldwide in clinical practice for treating both psoriasis and PsA [19]. Other DMARDs used in treating PsA include leflunomide, cyclosporine, sulfasalazine, hydroxychloroquine, gold compounds, azathioprine and retinoic acid derivatives [20–23]. Numerous studies 190
have confirmed the efficacy of these agents in achieving significant clinical improvement in patients with PsA. However, it should be noted that none of these medications has ever been shown to prevent or retard the progression of joint damage in PsA patients. With the advent of the TNF-a inhibitory agents, the treatment of PsA has shifted. TNF-a inhibitors, in multiple large studies, have shown considerable efficacy in controlling joint disease and symptoms in PsA patients [24,25]. The TNF-a inhibitors currently used in the treatment of PsA include etanercept, infliximab, adalimumab, golimumab and certolizumab pegol [26–29]. In addition to their clinical efficacy in treating the symptoms and inflammation associated with psoriatic joint disease, these agents have also been shown to prevent the radiographic progression of PsA [30,31]. Despite the array of treatment options targeting multiple different cytokines in the inflammatory pathway of psoriatic joint disease, there exists a subset of patients who fail to respond adequately to currently available treatment options including the TNF-a inhibitors. Thus, the recent approval of ustekinumab by both the US FDA and the EMA for PsA is an important advance. Body of review Overview of the market
Due to the central role that TNF-a plays in driving the inflammatory process of PsA, currently approved biologic therapies for PsA are directed against this target. Currently, there are five biologic agents on the market that target TNF-a with FDA approval for the treatment of PsA. These include etanercept, infliximab, adalimumab, golimumab and certolizumab pegol. Etanercept is a fusion protein that is produced from recombinant DNA. This fusion protein combines the soluble human TNF receptor 2 to the constant Fc domain of human IgG1. In vivo, etanercept functions as a ‘decoy receptor’ that binds circulating TNF-a, preventing it from interacting with its receptor. Adalimumab and golimumab are both fully human Expert Rev. Clin. Immunol. 10(2), (2014)
Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nyu Medical Center on 06/05/15 For personal use only.
Ustekinumab for the treatment of PsA
monoclonal antibodies directed against TNF-a, while infliximab is a human–mouse chimeric monoclonal antibody directed against TNF-a. Certolizumab pegol is a PEGylated Fab fragment of a humanized (from mouse) monoclonal antibody against TNF-a. Together, these five biologic agents represent the mainstays of treatment for PsA patients who either fail to be controlled on traditional DMARDs or who show early radiographic progression of their joint disease. These agents vary in their route of administration and dosing intervals. Etanercept is administered subcutaneously once or twice weekly depending on the dose. Adalimumab and golimumab are administered subcutaneously every 2 weeks and every month, respectively. Infliximab is administered by intravenous infusion every 8 weeks, while certolizumab pegol is administered subcutaneously every 2 weeks [32–35,29]. In practice, however, clinicians frequently have to adjust the dosing intervals of these biologic agents to achieve maximal disease control with the most convenient dosing schedule. Also, clinicians often combine biologic agents with additional methotrexate, low-dose prednisone and/or NSAIDs for enhanced benefit. In multiple large, randomized, placebocontrolled trials, each of these anti-TNF-a therapies has shown significant efficacy in the treatment of PsA with ACR20 responses in the 60–70% range. These agents invariably show efficacy specifically in patient populations who exhibited prior inadequate response to traditional DMARDs. In addition to improvement in the clinical signs and symptoms of PsA, each of these agents has also been shown to reduce the radiographic progression of psoriatic joint disease [30]. Another key player in the inflammatory milieu of PsA that has emerged as a target for drug developers is IL-17. Three monoclonal antibodies targeting IL-17 are currently being studied for the treatment of PsA. Secukinumab (a fully human monoclonal antibody) and ixekizumab (a humanized monoclonal antibody) are currently undergoing Phase III clinical trials, while brodalumab (another fully human monoclonal antibody) is in Phase II clinical trials. Preliminary findings have revealed that two of these three therapeutic agents (secukinumab and ixekizumab) show significant clinical efficacy in the treatment of PsA, with efficacy results for brodalumab yet to be reported. However, in patients with psoriatic skin disease, Phase III trials of brodalumab have shown excellent clinical responses. These agents, if approved by the FDA, exist as future potential options for treating PsA patients who are unresponsive to traditional DMARDs or poorly controlled on anti-TNF medications [36–38]. Abatacept is a therapeutic agent with FDA approval for the treatment of rheumatoid arthritis and is currently being examined for efficacy in PsA. Abatacept is a fusion protein composed of the Fc region of human IgG1 fused to the extracellular domain of CTLA-4. This fusion protein binds with high affinity to B7 (CD80), a crucial molecule located on the surface of antigen-presenting cells that is required as a costimulator in the activation of T cells. Thus, abatacept acts as an inhibitor of the costimulation of T cells, preventing activation of T cells in vivo. In a small Phase II trial, abatacept has been shown to be efficacious in controlling PsA symptoms in www.expert-reviews.com
Drug Profile
patients previously unresponsive to traditional DMARDs and anti-TNF agents. Abatacept treatment also demonstrated improvements in the MRI findings of affected psoriatic joints in this trial [39]. Apremilast, a novel, orally administered inhibitor of phosphodiesterase-4, has been shown to suppress multiple proinflammatory mediators and cytokines involved in both innate and adaptive immunity. It is currently undergoing Phase III clinical trials for three different indications, one of which is PsA. This agent is distinct from other agents currently being investigated in that, rather than targeting a specific inflammatory mediator, it works by intracellular mechanisms to decrease the production of multiple inflammatory molecules. In addition to its divergent mechanism, apremilast has the advantage of oral administration. Lastly, tofacitinib, an oral inhibitor of the JAK 3 enzyme, is being investigated as a potential treatment for PsA. This agent, already FDA approved for the treatment of rheumatoid arthritis, interferes with the JAK-STAT signaling pathway, which transmits cell surface signals into the nucleus. Interference with this signaling pathway suppresses the expression of STAT1-dependent genes, and thus, the production of proinflammatory mediators. Like apremilast, this agent is orally administered and targets the production pathway of numerous proinflammatory molecules, rather than interfering with a single, specific target. Clearly, the pharmaceutical industry is currently in the process of rapidly expanding the repertoire of biologic and immunomodulatory agents available for treating patients with PsA (TABLE 2). Introduction to ustekinumab
Ustekinumab (Stelara) is a fully human monoclonal antibody that targets the p40 subunit common to both IL-12 and IL-23. On 21 November 2008 and 25 September 2009, ustekinumab was approved by the EMA and FDA, respectively, for the treatment of adult patients with moderate-to-severe plaque psoriasis. Ustekinumab is administered by subcutaneous injection at a dose of either 45 mg (for body weight
