Biologic Therapy for Psoriatic Arthritis




Biologic medications, therapeutic proteins that inhibit or modulate proinflammatory immune cells and cytokines, have significantly altered clinicians’ ability to effectively treat psoriatic arthritis (PsA). The first widely used biologics have been those targeting tumor necrosis factor alpha. Five agents (etanercept, infliximab, adalimumab, golimumab, and certolizumab) have shown significant benefit in all clinical domains of PsA as well as inhibiting progressive joint destruction. Treatment strategies such as treating PsA early in the disease course, treating to target and tight control, use of background methotrexate to reduce immunogenicity, and various cost-saving strategies are all being tested with biologic medicines for PsA.


Key points








  • Biologic medicines target specific cells and cytokines in the immunologic pathway of inflammation, inhibiting and modulating proinflammatory processes.



  • Tumor necrosis factor (TNF) alpha is a key proinflammatory cytokine that drives inflammation and tissue destruction in autoimmune diseases, including psoriatic arthritis (PsA). Medicines that target and diminish the activity of this cytokine show significant benefit in curtailing arthritis, enthesitis, dactylitis, spondylitis, and skin and nail disease; inhibiting progressive structural damage; and improving function and quality of life.



  • TNF inhibitors may not work in all patients and may lose effectiveness over time, partly because of immunogenicity. Agents with different mechanisms of action, including the interleukin (IL)-12/23 inhibitor ustekinumab, IL-17 inhibitors such as secukinumab, ixekizumab, and brodalumab, and potentially other emerging therapies such as abatacept and IL-23 inhibitors, show effectiveness in clinical domains of PsA.



  • Adoption of treatment strategies such as treatment early in the course of disease, tight control, and treating to target, and the emerging use of biosimilars to reduce cost of therapy may improve outcomes and broaden availability of these medicines for patients.



  • Serious safety issues can arise with biologic therapy, so cost-benefit risk must be weighed in decision making about use of biologic medications.






Introduction


Biologic therapies are parenteral (administered subcutaneously or intravenously) complex proteins biologically manufactured in mammalian or yeast cell lines that typically function by binding to proinflammatory cytokines or cell receptor sites to diminish immunologic cell function. Before the introduction of biologic therapy in the late 1990s, therapy for psoriatic arthritis (PsA) consisted primarily of synthetic medicinals such as methotrexate, sulfasalazine, nonsteroidal antiinflammatory medications, along with adjunctive approaches, including physical and occupational therapy. Although partially effective, these medicines were not able to achieve low disease activity or remission states and often were not well tolerated. The first biologic therapies approved for the treatment of PsA were the tumor necrosis factor alpha (TNFα) inhibitors. These agents have revolutionized the ability to effectively treat all of the clinical manifestations of PsA, including arthritis, enthesitis, dactylitis, spondylitis, skin and nail disease, as well as associated inflammatory bowel disease and uveitis. PsA treatment recommendations developed by international groups such as the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) and the European League Against Rheumatism (EULAR) recommend biologic agents as therapy for patients with moderate to severe disease, noting that the biologics are highly effective in all disease domains of PsA, including arthritis, enthesitis, dactylitis, spondylitis, and skin and nail disease. Sustained remission or a low disease activity state is now achievable with these agents. With time, effectiveness may diminish and be lost, necessitating cycling between TNFα inhibitors or switching to agents with a different mechanism of action. This article addresses all biologic therapies for PsA, albeit with a greater emphasis on newer therapies.




Introduction


Biologic therapies are parenteral (administered subcutaneously or intravenously) complex proteins biologically manufactured in mammalian or yeast cell lines that typically function by binding to proinflammatory cytokines or cell receptor sites to diminish immunologic cell function. Before the introduction of biologic therapy in the late 1990s, therapy for psoriatic arthritis (PsA) consisted primarily of synthetic medicinals such as methotrexate, sulfasalazine, nonsteroidal antiinflammatory medications, along with adjunctive approaches, including physical and occupational therapy. Although partially effective, these medicines were not able to achieve low disease activity or remission states and often were not well tolerated. The first biologic therapies approved for the treatment of PsA were the tumor necrosis factor alpha (TNFα) inhibitors. These agents have revolutionized the ability to effectively treat all of the clinical manifestations of PsA, including arthritis, enthesitis, dactylitis, spondylitis, skin and nail disease, as well as associated inflammatory bowel disease and uveitis. PsA treatment recommendations developed by international groups such as the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) and the European League Against Rheumatism (EULAR) recommend biologic agents as therapy for patients with moderate to severe disease, noting that the biologics are highly effective in all disease domains of PsA, including arthritis, enthesitis, dactylitis, spondylitis, and skin and nail disease. Sustained remission or a low disease activity state is now achievable with these agents. With time, effectiveness may diminish and be lost, necessitating cycling between TNFα inhibitors or switching to agents with a different mechanism of action. This article addresses all biologic therapies for PsA, albeit with a greater emphasis on newer therapies.




Tumor necrosis factor inhibition


TNFα was one of the first proinflammatory cytokines implicated in the pathogenesis of numerous inflammatory/autoimmune diseases. It is produced by several types of immune cells and activates several key effector cells involved in tissue inflammation and destruction in psoriasis and PsA, including lymphocytes, macrophages, chondroctyes, osteoclasts, and keratinoctyes. Five agents that inhibit TNFα are now US Food and Drug Administration (FDA) approved, including etanercept, infliximab, adalimumab, golimumab, and certolizumab. These agents were first shown to be effective in the treatment of rheumatoid arthritis, and subsequently showed effectiveness in PsA and ankylosing spondylitis (AS). With the exception of etanercept, these agents are monoclonal antibodies with demonstrated effectiveness in inflammatory bowel disease, whereas etanercept has not. Etanercept, infliximab, and adalimumab are approved for the treatment of psoriasis. The effects of these agents in PsA are reviewed later and American College of Rheumatology (ACR) 20/50/70 responses are summarized in Table 1 .



Table 1

Anti-TNF therapies in PsA: ACR responses






























































Trial n ACR20% ACR50% ACR70%
Rx P Rx P Rx P
Adalimumab a , 315 58 14 36 4 20 1
Certolizumab a , 409 58 24 36 11 25 3
Etanercept a , 205 59 15 38 4 11 0
Golimumab b , 405 52 8 32 3.5 18 0.9
Infliximab b , 200 58 11 36 3 15 1

Abbreviations: Rx, Treatment Arm; P, placebo.

a 12 weeks.


b 14 weeks.



Etanercept


Etanercept is a soluble receptor antibody administered subcutaneously at 50 mg per week. Its efficacy in PsA was first shown in an investigator-initiated trial of 60 patients, later confirmed in a phase 3 trial in 205 patients (see Table 1 ). Dosing in PsA is 50 mg subcutaneously weekly. This anti-TNFα agent was the first to be approved for PsA and was the first of this class to show the ability to inhibit progressive joint damage as measured by serial radiographs of hands and feet. Ability to improve enthesitis and dactylitis with this agent was shown in the PRESTA (Psoriasis Randomized Etanercept Study in Patients with Psoriatic Arthritis) study, an observational study in which the 50-mg weekly regimen was compared with 50 mg twice weekly for 12 weeks followed by 50 mg weekly in patients with moderate to severe arthritis and severe skin disease. The latter regimen is the approved regimen for this agent in psoriasis. Improvement of musculoskeletal domains (arthritis, enthesitis, and dactylitis) was similar between these two dosage regimens. However, skin manifestations of psoriasis were more effectively treated in the initial higher-dose arm of the study. Etanercept can be administered with or without background methotrexate and durability of effectiveness does not seem to be affected by background methotrexate use, implying a lesser tendency to immunogenicity.


Infliximab


Infliximab, an intravenously administered anti-TNFα agent, showed effectiveness in a 200-patient study using 5 mg/kg every 2 months after a loading dose regimen. As with other anti-TNFα agents, the multiple clinical domains of PsA improve significantly, including inhibition of structural damage (see Table 1 ). This agent has murine sequences, and may generate more immunogenicity with subsequent neutralization of effect over time. Thus, although it can be administered without background methotrexate, its efficacy may be more sustained if methotrexate is used concomitantly.


Adalimumab


Adalimumab is a fully human subcutaneously administered anti-TNFα antibody given at a dose of 40 mg every other week. Its efficacy in PsA was established in the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT) trial of 313 patients (see Table 1 ). Sustained effectiveness has been shown in various PsA clinical domains, including inhibition of structural damage and patient-reported outcomes of function, quality of life, and fatigue, as it has for other anti-TNFα agents. Durability of effectiveness has been shown with or without background methotrexate. Antidrug antibodies have been noted in patients with PsA treated with adalimumab, which may decrease drug levels and effectiveness of the agent, and may be abrogated with concomitant use of methotrexate.


Golimumab


Golimumab is an anti-TNFα antibody with a prolonged half-life, allowing monthly subcutaneous administration, approved for PsA, in 50-mg doses based on a 405-patient study. It is also available in intravenous formulation, although that is only approved for rheumatoid arthritis (RA). Effectiveness in all clinical domains of PsA, including inhibition of structural damage, as well as long-term efficacy through 5 years has been noted (see Table 1 ). In RA, 1 study with golimumab showed its efficacy after previous anti-TNF therapy.


Certolizumab


Certolizumab is a unique antibody composed of the Fab portion of an immunoglobulin molecule attached to 2 polyethylene glycol moieties to prolong half-life. It is administered subcutaneously at a dose of 200 mg every 2 weeks or 400 mg every 4 weeks. In the RAPID (RA Prevention of structural Damage)-PsA trial, at 12 and 24 weeks, 405 patients were evaluated with both doses versus placebo, showing statistically significant benefit in ACR responses (see Table 1 ) as well as significant improvement in Disease Activity Score (DAS28), Health Assessment Questionnaire (HAQ)-DI, enthesitis, dactylitis, skin and nail measures, inhibition of radiologic damage progression, as well as improvement in Short Form 36 and work productivity measures. Uniquely, in this study 20% of patients had previously been exposed to anti-TNFα therapy and similar degrees of response were seen in this group compared with anti-TNFα–naïve patients. Safety results were similar to other agents of this class.




Costimulatory blockade modulating T-lymphocyte function


Abatacept


Abatacept is a costimulatory blockade agent that inhibits T-cell activation through second signal inhibition and is approved for RA. A phase 2 study of 170 patients with PsA, using various doses of its intravenous formulation, showed significant improvement of ACR20 response. MRI study of hands or feet at 24 weeks showed improved synovitis, erosion, and osteitis scores. Skin psoriasis responses were low. In patients who had previously taken anti-TNF agents, responses in ACR scores were lower than in patients naive to anti-TNF therapy. This agent is now in phase 3 development in its subcutaneous form in PsA.




Interleukin-6 inhibition


Like TNFα, interleukin (IL)-6 is a pleiotropic proinflammatory cytokine that has a significant role in RA and has been shown to be at increased levels in psoriasis skin lesions and PsA synovium. Tocilizumab is an IL-6 receptor blocker approved for RA. There have been mixed results from case reports about its efficacy in PsA.


Clazakizumab


Clazakizumab is a direct IL-6 inhibitor that has shown efficacy in RA. This agent was studied in a phase 2 dose ranging trial with 165 patients with PsA, 70% of whom were on background methotrexate. ACR20 response was observed in 29%, 46%, 52%, and 39% of patients in the placebo, 25-mg, 100-mg, and 200-mg monthly groups, respectively, at the week 16 primary end point, which was statistically significant in the 100-mg group. A reduction of 75% in the Psoriasis Area and Severity Index (PASI75) responses were observed in 12%, 15%, 17%, and 5% of placebo, 25-mg, 100-mg, and 200-mg groups. Improvements in enthesitis and dactylitis were most noted in the 100-mg group. The safety profile was that expected for an IL-6–inhibiting agent. Thus, this trial did show an effect in musculoskeletal inflammation domains, supporting the concept that IL-6 inhibition may be helpful for this set of domains, but it showed minimal effect for treatment of psoriasis lesions. The trial also lacked a true dose effect given the underperformance of the 200-mg group, partly because of the use of nonresponder imputation analysis and a greater number of adverse effects and dropouts in the higher-dose group.




B-lymphocyte inhibition


Rituximab, a B-lymphocyte ablating agent, has been approved for the treatment of RA and vasculitis. In RA, B lymphocytes play a prominent role and subsets of patients with RA have significant B-cell aggregation in synovial tissue, denoting a more severe phenotype. Although some B-cell aggregation has been noted in PsA symovium, in general B cells are not considered to be important players in psoriasis or PsA pathogenesis. Small series of patients have been treated with rituximab and, in general, although modest efficacy in arthritis has been shown in such open-label use, not enough efficacy has been shown in joints or psoriasis skin lesions to lead to placebo-controlled studies of this agent in PsA.




Targeting the T-helper 17 cell axis in psoriatic arthritis


The cytokine IL-17A was discovered in 1993. Since then, a family of related cytokines, IL-17A-F, has been characterized, which led to the discovery, in 2005, of a distinct form of T cells, T-helper (TH) 17, distinguished by their ability to produce a distinct repertoire of cytokines, including IL-17s, IL-21, and IL-22, and not interferon-gamma (IFN γ) or IL-4, which are reflective of TH1 and TH2 lineage cells ( Fig. 1 ). Since then, new discoveries regarding the functional and immunologic significance of this T-cell lineage have been published, including front-line antimicrobial defense via the innate immune response as well as a prominent role in several immunologic diseases, such as psoriasis; the spondyloarthritides, including PsA and axial spondyloarthritis; inflammatory bowel disease (IBD); and RA.




Fig. 1


T-cell differentiation pathways. IFN, interferon; TGF, transforming growth factor; TNF, tumor necrosis factor; T reg , T regulatory cell.

( From Patel DD, Lee DM, Kolbinger F, et al. Effect of IL-17A blockade with secukinumab in autoimmune diseases. Ann Rheum Dis 2013;72(Suppl 2):ii116–23; with permission.)


TH17 cell differentiation is induced by IL-1β plus IL-23, and possibly transforming growth factor beta, in the presence of inflammatory cytokines such as IL-6, IL-21, and IL-23. Human TH17 cells produce IL-17A through IL-17F, IL-22, IL-26, and the chemokine CCL20. IL-17A is more potent than IL-17F, IL-17E (also known as IL-25) is involved in TH2 responses, and IL-17B, IL-17C, and IL-17D are less well characterized in terms of their biological significance. In the quiescent state, IL-17A and F are primarily observed in spleen and small intestine lamina propria cells. In inflammatory states, activated T cells, particularly TH17 cells, are the main producers of both isoforms of IL-17, but CD8+, natural killer T cells, gamma and delta T cells, neutrophils, myeloid cells, and type 3 innate lymphoid cells may synthesize and release these cytokines.


The IL-17 receptor is broadly expressed in the immune cell pathway by a wide array of cell types, including endothelium, epithelium, fibroblasts, keratinocytes, osteoblasts, monocytes, and macrophages. In a pioneering murine study, Sherlock and colleagues found that IL-23 encased in minicircles preferentially gravitated to entheseal insertion sites and the aortic root, where a local inflammatory reaction occurred involving a unique group of resident lymphocytes (CD3+CD-CD8-ROR-γt+IL-23R+). The enthesitis inflammatory response was primarily driven by IL-17 produced by these cells, whereas IL-22 expression activated signal transducer and activator of transcription 3 (STAT3)-dependent osteoblast-mediated bone remodeling. Lories and McInnes subsequently proposed the model that, in humans, a variety of factors such as microbial antigens, alterations in the gut microbiome, the human leukocyte antigen (HLA)-B27 unfolded protein response, and biomechanical stress may lead to expression of IL-23 ( Fig. 2 ). IL-23 then incites differentiation and activation of specific populations of T cells, including TH17 cells, which in turn produce cytokines such as IL-17 and IL-22, with IL-17 driving an inflammatory response that may result in such consequences as bone erosion, in addition to clinical features such as inflammation in synovium and skin, whereas IL-22 may, among other inflammatory activities, lead to osteoproliferation, as is seen in the periostitis and ankylosis of PsA and ankylosis of AS. Such a model could help explain why both osteolysis and osteoproliferation, seemingly opposite processes, are both seen in parallel in the spondyloarthritis conditions, including PsA. This model also posits a greater role for the innate immune system relative to the adaptive immune system, distinct from some other autoimmune diseases, such as RA.


Sep 28, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Biologic Therapy for Psoriatic Arthritis
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