The Future of Treatment for Psoriatic Arthritis
The Future of Treatment for Psoriatic Arthritis
Ustekinumab is a fully human monoclonal IgG antibody directed against the common p40 chain of both IL-12 and IL-23 and administered subcutaneously. IL-12 facilitates differentiation of CD4 T cells into Th-1 T cells, which produce TNF-α while IL-23 stimulates CD4 cell differentiation into IL-17, IL-22 and TNF-α-producing Th-17 T cells. Both IL-12 and IL-23 are produced by antigen-presenting cells, such as dendritic cells. Monotherapy with ustekinumab in moderate-to-severe psoriasis has been shown to have a sustained benefit over 3 years, with over two-thirds of study participants experiencing a 75% decrease in the Psoriasis Area Severity Index (PASI75) compared with 3–4% of those in the placebo arms.
The PSUMMIT 1 trial (Phase III RCT) examined outcomes of ustekinumab (n = 409) compared with placebo (n = 206) over 1 year of treatment in PsA patients with primary failure of DMARDs. Those taking ustekinumab had significantly better outcomes on all primary and secondary end points, with 42.4% of those taking the 45-mg dose and 49.5% of those receiving 90 mg achieving an ACR20 response at week 24 compared with 22.8% in the placebo arm (p < 0.0001). These responses were maintained until week 52. Significant response in axial disease was also found with 49 and 58% of those taking 45 and 90 mg of ustekinumab, respectively, having at least a 20% improvement in the Bath Ankylosing Spondylitis Disease Activity Index, compared with 26% of those taking placebo (p = 0.01 and 0.0005, respectively). Response to cutaneous disease was impressive with 59.9% of those taking ustekinumab achieved a PASI75 compared with 11% on placebo (p < 0.0001). Adverse event rates were similar in the placebo and treatment arms.
While the ACR20 responses in peripheral arthritis were not as impressive as those reported from the original TNFi trials, the findings are noteworthy. Future studies regarding its use in clinical practice will need to address maintenance of efficacy beyond 52 weeks, its effect on radiographic damage, efficacy in those who have failed TNFi treatment and whether concomitant DMARD prescription enhances response.
Apremilast is an orally administered inhibitor of phosphodiesterase 4 (PDE4), which has downstream effects on inflammatory cytokine expression through increased levels of intracellular cAMP resulting in reduced levels of TNF-α, IL-12 and IL-23.
The efficacy and safety of apremilast in PsA was evaluated in a Phase II multicenter, randomized, double-blind, placebo-controlled trial in patients with active disease despite treatment with DMARD or TNFi. Two doses of apremilast were administered: 20-mg two-times a day (n = 69) and 40-mg once daily (n = 67) with 68 patients in the placebo arm. A significant ACR20 response at week 12 in the apremilast-treated groups was reported, with 43.5 and 35.8% of patients (taking 20 mg two-times a day and 40 mg, respectively) meeting the primary end point compared with 11.8% receiving placebo (p = 0.002). Treatment response was maintained at 24 weeks. Concomitant MTX use was not associated with a significant augmentation in the ACR20 response in either group, nor was it associated with additional adverse effects. In that regard, the safety profile was encouraging.
Future studies on apremilast will include the Phase III PALACE study which will examine efficacy over 12 months and will separately examine the response in DMARD-naive and DMARD-exposed patients. Once again, its effect on axial disease, psoriasis, dactylitis and enthesitis would be useful to examine, as well as its role with concomitant TNFi therapy.
Abatacept. T cells have a central role in the pathogenesis of PsA, and blockade of T-cell activation may be a therapeutic strategy with significant outcomes. Activation of T cells requires costimulatory signals, including that between the MHC and the T-cell receptor, and between either CD80 or CD86 and CD28 on the T cell. Once activated, the T cell attempts to downregulate its activity through production of CTLA-4, which competes with CD28 for either CD80 or CD86.
Abatacept is an intravenously administered fusion protein with the extracellular domain of CTLA-4 linked to the Fc portion of a human IgG1, inhibiting T-cell activation with a decrease in inflammatory cytokine production. A Phase II double-blind RCT assessing its safety and efficacy in PsA over 6 months was conducted in patients with DMARD or TNFi treatment failure. Patients were randomized to placebo (n = 42) and to one of three different dose of abatacept. The ACR20 response was significantly greater in the abatacept 10 mg/kg group and those who received 30 mg/kg on days 1 and 15 followed by 10 mg/kg thereafter compared with placebo (48 and 42% vs 19%, p = 0.006 and 0.022, respectively), while response was greater in the TNFi-naive (56%) compared with those previously treated with TNFi (31%). Abatacept was not found to have a significant effect on psoriasis; however, the study suggests that it has use in treatment of joint disease, particularly in those with a history of DMARD failure.
IL-17 is an inflammatory cytokine, found to be elevated in cutaneous psoriatic lesions, as well as the synovium of those with PsA. IL-23 has been shown to play a key role in the polarization of CD4 T cells to become IL-17-producing, or Th-17 cells. IL-17 can also induce the production of other proinflammatory cytokines including IL-6, TNF-α and IL-1β. Based on this evidence, blockade of this cytokine, or its associated receptors, could have therapeutic implications for the treatment of both psoriasis and PsA.
Secukinumab is a fully human anti-IL-17A monoclonal antibody that is currently under trial in moderate-to-severe PsA. In a Phase II proof-of-concept study, 42 patients were randomized to receive either two intravenous doses of secukinumab 21 days apart (n = 28) or placebo (n = 14). Unfortunately, the primary end point, the ACR20 response at 6 weeks, was achieved in only 39% of the secukinumab groups versus 23% for placebo (p = 0.27), while nonsignificant differences in the ACR20 response at weeks 12 (39 vs 15%; p = 0.13) and 24 (42 vs 18%; p = 0.14) were also found. However, the study size was small and a signal of potential benefit remained. CRP, ESR and HAQ scores all significantly improved compared with placebo. Of note, 62% of the TNFi-naive patients in the secukinumab arm achieved an ACR20 response at week 6, compared with 10% with TNFi exposure. Leukopenia occurred in eight secukinumab-treated patients compared with one in the placebo arm, while infection rates and other adverse events were similar between the two groups.
These findings are of interest and suggest that secukinumab may have a therapeutic role in future treatment of PsA.
Ixekizumab, an anti-IL-17 monoclonal antibody and brodalumab, an anti-IL-17 receptor antibody, are currently under trial in moderate-to-severe plaque psoriasis and PsA. The results of both Phase II trials show very encouraging effects in terms of cutaneous manifestations. While improvement in joint disease was not specifically examined, treatment with the highest dose of ixekizumab resulted in significant reductions in joint pain scores at week 12, compared with placebo. An ACR20 response at 12 weeks was reportedly achieved in 37 and 39% of PsA patients assigned 140 and 280 mg of brodalumab, respectively, compared with 18% of those receiving placebo. Peer-reviewed publications regarding both of these treatments in PsA are pending.
Janus kinases (JAKs) are intracellular tyrosine kinases that participate in the cytokine signaling pathway by associating with specific cytokine receptors. Tofacitinib is an oral JAK inhibitor that can suppress IL-23 receptor expression, thereby affecting Th-17 cell differentiation while also interrupting signaling by IL-6 and IFN-γ. A Phase IIb trial in active RA has shown efficacy. A Phase IIb trial in moderate-to-severe plaque psoriasis (n = 197) has recently shown significant results by week 12 compared with placebo; however, analysis examining effect on joint disease was not performed. Infection rates and adverse events were similar in both groups. A trial in PsA is now underway.
With the exponential increase in knowledge of the immunopathology of psoriatic disease, the 'bench-to-bedside' approach in the development of targeted biologic medications is set to continue to provide rheumatologists and patients with therapeutic options. As with the introduction of TNFi into routine practice, new biologic treatments will need to be monitored over time, particularly in regards to long-term safety.
Failure of Anti-TNF Therapy: What Next?
Ustekinumab
Ustekinumab is a fully human monoclonal IgG antibody directed against the common p40 chain of both IL-12 and IL-23 and administered subcutaneously. IL-12 facilitates differentiation of CD4 T cells into Th-1 T cells, which produce TNF-α while IL-23 stimulates CD4 cell differentiation into IL-17, IL-22 and TNF-α-producing Th-17 T cells. Both IL-12 and IL-23 are produced by antigen-presenting cells, such as dendritic cells. Monotherapy with ustekinumab in moderate-to-severe psoriasis has been shown to have a sustained benefit over 3 years, with over two-thirds of study participants experiencing a 75% decrease in the Psoriasis Area Severity Index (PASI75) compared with 3–4% of those in the placebo arms.
The PSUMMIT 1 trial (Phase III RCT) examined outcomes of ustekinumab (n = 409) compared with placebo (n = 206) over 1 year of treatment in PsA patients with primary failure of DMARDs. Those taking ustekinumab had significantly better outcomes on all primary and secondary end points, with 42.4% of those taking the 45-mg dose and 49.5% of those receiving 90 mg achieving an ACR20 response at week 24 compared with 22.8% in the placebo arm (p < 0.0001). These responses were maintained until week 52. Significant response in axial disease was also found with 49 and 58% of those taking 45 and 90 mg of ustekinumab, respectively, having at least a 20% improvement in the Bath Ankylosing Spondylitis Disease Activity Index, compared with 26% of those taking placebo (p = 0.01 and 0.0005, respectively). Response to cutaneous disease was impressive with 59.9% of those taking ustekinumab achieved a PASI75 compared with 11% on placebo (p < 0.0001). Adverse event rates were similar in the placebo and treatment arms.
While the ACR20 responses in peripheral arthritis were not as impressive as those reported from the original TNFi trials, the findings are noteworthy. Future studies regarding its use in clinical practice will need to address maintenance of efficacy beyond 52 weeks, its effect on radiographic damage, efficacy in those who have failed TNFi treatment and whether concomitant DMARD prescription enhances response.
Apremilast
Apremilast is an orally administered inhibitor of phosphodiesterase 4 (PDE4), which has downstream effects on inflammatory cytokine expression through increased levels of intracellular cAMP resulting in reduced levels of TNF-α, IL-12 and IL-23.
The efficacy and safety of apremilast in PsA was evaluated in a Phase II multicenter, randomized, double-blind, placebo-controlled trial in patients with active disease despite treatment with DMARD or TNFi. Two doses of apremilast were administered: 20-mg two-times a day (n = 69) and 40-mg once daily (n = 67) with 68 patients in the placebo arm. A significant ACR20 response at week 12 in the apremilast-treated groups was reported, with 43.5 and 35.8% of patients (taking 20 mg two-times a day and 40 mg, respectively) meeting the primary end point compared with 11.8% receiving placebo (p = 0.002). Treatment response was maintained at 24 weeks. Concomitant MTX use was not associated with a significant augmentation in the ACR20 response in either group, nor was it associated with additional adverse effects. In that regard, the safety profile was encouraging.
Future studies on apremilast will include the Phase III PALACE study which will examine efficacy over 12 months and will separately examine the response in DMARD-naive and DMARD-exposed patients. Once again, its effect on axial disease, psoriasis, dactylitis and enthesitis would be useful to examine, as well as its role with concomitant TNFi therapy.
T-cell Activation Inhibitors
Abatacept. T cells have a central role in the pathogenesis of PsA, and blockade of T-cell activation may be a therapeutic strategy with significant outcomes. Activation of T cells requires costimulatory signals, including that between the MHC and the T-cell receptor, and between either CD80 or CD86 and CD28 on the T cell. Once activated, the T cell attempts to downregulate its activity through production of CTLA-4, which competes with CD28 for either CD80 or CD86.
Abatacept is an intravenously administered fusion protein with the extracellular domain of CTLA-4 linked to the Fc portion of a human IgG1, inhibiting T-cell activation with a decrease in inflammatory cytokine production. A Phase II double-blind RCT assessing its safety and efficacy in PsA over 6 months was conducted in patients with DMARD or TNFi treatment failure. Patients were randomized to placebo (n = 42) and to one of three different dose of abatacept. The ACR20 response was significantly greater in the abatacept 10 mg/kg group and those who received 30 mg/kg on days 1 and 15 followed by 10 mg/kg thereafter compared with placebo (48 and 42% vs 19%, p = 0.006 and 0.022, respectively), while response was greater in the TNFi-naive (56%) compared with those previously treated with TNFi (31%). Abatacept was not found to have a significant effect on psoriasis; however, the study suggests that it has use in treatment of joint disease, particularly in those with a history of DMARD failure.
Anti-IL-17 Antibodies
IL-17 is an inflammatory cytokine, found to be elevated in cutaneous psoriatic lesions, as well as the synovium of those with PsA. IL-23 has been shown to play a key role in the polarization of CD4 T cells to become IL-17-producing, or Th-17 cells. IL-17 can also induce the production of other proinflammatory cytokines including IL-6, TNF-α and IL-1β. Based on this evidence, blockade of this cytokine, or its associated receptors, could have therapeutic implications for the treatment of both psoriasis and PsA.
Secukinumab is a fully human anti-IL-17A monoclonal antibody that is currently under trial in moderate-to-severe PsA. In a Phase II proof-of-concept study, 42 patients were randomized to receive either two intravenous doses of secukinumab 21 days apart (n = 28) or placebo (n = 14). Unfortunately, the primary end point, the ACR20 response at 6 weeks, was achieved in only 39% of the secukinumab groups versus 23% for placebo (p = 0.27), while nonsignificant differences in the ACR20 response at weeks 12 (39 vs 15%; p = 0.13) and 24 (42 vs 18%; p = 0.14) were also found. However, the study size was small and a signal of potential benefit remained. CRP, ESR and HAQ scores all significantly improved compared with placebo. Of note, 62% of the TNFi-naive patients in the secukinumab arm achieved an ACR20 response at week 6, compared with 10% with TNFi exposure. Leukopenia occurred in eight secukinumab-treated patients compared with one in the placebo arm, while infection rates and other adverse events were similar between the two groups.
These findings are of interest and suggest that secukinumab may have a therapeutic role in future treatment of PsA.
Ixekizumab, an anti-IL-17 monoclonal antibody and brodalumab, an anti-IL-17 receptor antibody, are currently under trial in moderate-to-severe plaque psoriasis and PsA. The results of both Phase II trials show very encouraging effects in terms of cutaneous manifestations. While improvement in joint disease was not specifically examined, treatment with the highest dose of ixekizumab resulted in significant reductions in joint pain scores at week 12, compared with placebo. An ACR20 response at 12 weeks was reportedly achieved in 37 and 39% of PsA patients assigned 140 and 280 mg of brodalumab, respectively, compared with 18% of those receiving placebo. Peer-reviewed publications regarding both of these treatments in PsA are pending.
Janus Kinase Inhibitors
Janus kinases (JAKs) are intracellular tyrosine kinases that participate in the cytokine signaling pathway by associating with specific cytokine receptors. Tofacitinib is an oral JAK inhibitor that can suppress IL-23 receptor expression, thereby affecting Th-17 cell differentiation while also interrupting signaling by IL-6 and IFN-γ. A Phase IIb trial in active RA has shown efficacy. A Phase IIb trial in moderate-to-severe plaque psoriasis (n = 197) has recently shown significant results by week 12 compared with placebo; however, analysis examining effect on joint disease was not performed. Infection rates and adverse events were similar in both groups. A trial in PsA is now underway.
With the exponential increase in knowledge of the immunopathology of psoriatic disease, the 'bench-to-bedside' approach in the development of targeted biologic medications is set to continue to provide rheumatologists and patients with therapeutic options. As with the introduction of TNFi into routine practice, new biologic treatments will need to be monitored over time, particularly in regards to long-term safety.
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