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Erythema multiforme during treatment with interleukin-12 and interleukin-23 inhibitor
P6505
P6408
Effect of tumor necrosis factorealfa inhibitor and methotrexate therapy on total cholesterol, high-density lipoprotein, and low-density lipoprotein in psoriasis/psoriatic arthritis and rheumatoid arthritis patients Jashin Wu, MD, Jashin Wu, Los Angeles, CA, United States; Anny Xiang, PhD, Kaiser Permanente Southern California, Pasadena, CA, United States; Christopher Rowan, PhD, Outcome, A Quintiles Company, Cambridge, MA, United States; Kwun-Yee Poon, MS, Kaiser Permanente Southern California, Pasadena, CA, United States; Mary Anthony, PhD, Amgen, Inc, Thousand Oaks, CA, United States
Efficacy and safety of topical janus kinase inhibitor tofacitinib in the treatment of chronic plaque psoriasis: Results of a phase IIA randomized clinical trial William Ports, Pfizer Inc, Groton, CT, United States; Chantal Bolduc, Innovaderm Research/The University of Montreal, Montreal, Quebec, Canada; Kim Papp, Probity Medical Research and K. Papp Clinical Research Inc, Waterloo, Ontario, Canada; Manisha Lamba, Pfizer Inc, Groton, CT, United States; Robert Bissonnette, Innovaderm Research, Montreal, Quebec, Canada; Shahbaz Khan, Pharmanet/i3, Princeton, Princeton, NJ, United States; Shuping Lan, Pfizer Inc, Groton, CT, United States
Objective: To understand the impact of treatment with a TNF inhibitor (TNFi) or methotrexate (MTX) on total cholesterol (TC), HDL, and LDL in psoriasis (PsO), psoriatic arthritis (PsA), and rheumatoid arthritis (RA) patients. Methods: The study population consists of adult patients diagnosed with prevalent or incident PsO/PsA/RA between January 1, 2002 and July 31, 2011 from a large HMO. Patients exposed to a TNFi (etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol) 6 MTX exposure comprised the TNFi group. Patients in the TNFi group were matched to patients exposed to MTX but not a TNFi (MTX group). Drug exposure status was determined based on exposure status within 1545 days before the laboratory measurements. The groups were matched on inflammatory condition (PsO/PsA/RA), diabetes status, and the date of TNFi initiation/prevalent MTX exposure (index date). All patients had metabolic factor measurements within 1-year before and after the index date. Unadjusted median percent change from baseline and interquartile ranges (IQR) in TC, HDL, and LDL was determined in both exposure groups. Results: There were 1249 PsO patients, 725 PsA patients, and 4962 RA patients. The TC median percent change was +0.4% in TNFi (IQR: -10.5, 10.8, n ¼ 1122) and -0.9% in MTX (IQR: -9.8, 9.2, n ¼ 4575) (P ¼.24). The HDL median percent change was 0% in TNFi (IQR: -10.2, 11.8, n ¼ 1115) and 0% in MTX (IQR: -9.5, 12.3, n ¼ 4577) (P ¼ .26). The LDL median percent change was -2.2% in TNFi (IQR: 13.3-15.7, n ¼ 937) and -1.2% in MTX (IQR: -14.7, 13.4, n ¼ 4103) (P ¼ .53). Conclusion: Although TC was numerically higher in the TNFi group and lower in the MTX group, these changes were not statistically significant. HDL was unchanged in both groups. LDL was numerically lower in both groups, but these changes were not statistically significant. Analysis of other metabolic factors and comparisons between treatment groups and amongst the separate diseases while accounting for differences in medications and demographic and clinical factors are in process. This study was 100% sponsored by a research grant from Amgen.
Objective: To assess efficacy, safety and pharmacokinetics (PK) of tofacitinib ointments in subjects with plaque psoriasis. Methods: In a double-blind, vehicle-controlled phase IIA trial (NCT01246583), 2 ointment formulations of 2% tofacitinib were evaluated in adults with mild to moderate plaque psoriasis. Subjects (N ¼ 71) were randomized 2:1:2:1 to ointment 1 (n ¼ 23), vehicle 1 (n ¼ 13), ointment 2 (n ¼ 25) or vehicle 2 (n ¼ 10). Study drug was applied BID for 4 weeks to a single fixed 300 cm2 treatment area containing a target plaque 6 one or more nontarget plaques and normal skin. The primary endpoint was Target Plaque Severity Score (TPSS) percent change from baseline at week 4. Secondary endpoints included treatment area Physician’s Global Assessment (PGA), Target Plaque Area (TPA), safety and PK. Statistical significance was claimed if the upper 1-sided 90% confidence limit was \0. Exploratory biomarker analyses of baseline and week 4 plaque biopsies for ointment 1 (n ¼ 5) and vehicle 1 (n ¼ 3) were performed by immunohistochemistry. Results: The primary endpoint (week 4 TPSS % change from baseline) showed statistically significant improvement for ointment 1 vs vehicle 1 (least squares mean [LSM] -54.4% vs -41.5%), but not for ointment 2 vs vehicle 2 (LSM -24.2% vs -17.2%). Secondary efficacy endpoints (treatment area PGA and TPA) improved similarly for tofacitinib ointment vs corresponding vehicle. Adverse event (AE) occurrence was similar across treatment groups. All-causality AEs were reported for 25/71 subjects; all AEs were mild or moderate and none were serious or led to subject discontinuation. One application site AE (erythema) was reported. Week 4 plasma tofacitinib levels were below the quantification limit in 40% of ointment 1 and 74% of ointment 2 subjects. Tofacitinib mean systemic exposure was low; ointment 1 exposure was greater than ointment 2. Epidermal pSTAT3 and Ki67 mean percent decrease from baseline was greater for ointment 1 (-56% and -50%, respectively) vs vehicle 1 (-3% and -18%, respectively); dermal pSTAT3 and Ki67 mean percent decrease from baseline for ointment 1 did not differ from vehicle 1. Epidermal K16 and CD3, and dermal CD3 increased from baseline for both ointment 1 and vehicle 1. Conclusion: In this small phase IIA study, tofacitinib ointment 1 was efficacious as compared to vehicle and well tolerated for the treatment of plaque psoriasis. Further study of tofacitinib for topical plaque psoriasis therapy is warranted. Supported 100% by Pfizer Inc.
P6633 Effects of golimumab on the dermatologic manifestations of psoriatic arthritis: 5-year results from the long-term extension of the randomized, placebo-controlled, GO-REVEAL study G. G. Krueger, MD, University of Utah, Salt Lake City, UT, United States Objective: To report dermatologic responses from the long-term extension through 5 yrs of treatment with two doses of golimumab (GLM) 50 mg and 100 mg. Methods: Adult PsA pts with active joint and skin disease were randomized to injections of PBO (group [Group]1, n ¼ 113), GLM 50 mg (Group2, n ¼ 146), or GLM 100 mg (Group3, n ¼ 146) q4wks through week 20. Concomitant MTX was allowed. At week 16, PBO pts with \10% improvement in joints disease received GLM 50 mg, all pts received GLM 50 mg from week 24 forward. After week 52, investigator judgement permitted dose change of GLM 50 mg to 100 mg; after week 104, reduction from GLM 100 mg to GLM 50 mg. Efficacy was assessed at week 256 based on randomized group and completer analyses using PASI response, nail PGA, and target nail NAPSI. Safety included all pts who received [1 GLM dose through 5 years. Results: Of 405 pts randomized, 140 pts (48%) received MTX at baseline; 279 pts (69%) continued GLM through week 252. 34% of pts in group 1 increased dose from 50 to 100 mg, with 8% decreasing the dose to 50 mg through 5 years. In group 2, 29% of pts increased the dose from 50 to 100 mg, with 8% decreasing the dose to 50 mg through 5 years. In group 3, 25% of pts decreased the dose from 100 mg to 50 mg through 5 years. Baseline characteristics (mean), for groups 1, 2 and 3, respectively, were: PsO duration (yrs)- 19, 18., 18; PASI scores- 7.7, 9.4, 11.2; BSA [3%- 70%, 75%, 74%; NAPSI score of target fingernail- 4.7, 4.6, 4.6;. At week 256, among pts with [3% BSA, PASI responses for Groups1, 2 and 3, respectively were: PASI 50, 91% (50/55), 83% (58/70), 95% (75/79); PASI 75 73% (40/55), 69% (48/70), 79% (62/79); PASI 90 51% (28/55), 46% (32/70), 65% (51/79). MTX did not affect PASI responses. Mean % changes from baseline in NAPSI score at week 256 were: 79, 76, and 77 for groups 1, 2 and 3 respectively. Proportions achieving nail PGA improvement were 81% (48/59), 87% (55/63), 81.0% (64/79) for groups 1, 2, and 3, respectively. 88% and 21% GLM-treated pts experienced AE and SAE, respectively. 12% of pts discontinued GLM because of AE, and 4% pts experienced a serious infection(s). Malignancies were observed in 5% of pts (incidence per 100 ptyr 1.28 [95% CI: 0.80, 1.96]); for NMSC (10 events of BCC and 1 event of SCC) occurred in 2.5 % of pts (incidence per 100 pt yr 0.61 [95% CI: 0.29, 1.12]). Conclusion: GLM resulted in long-term improvement in skin and nail psoriasis. No apparent differences between long-term safety and efficacy of GLM doses administered q4wks were observed. Supported by Janssen Research and Development, LLC.
APRIL 2013
P6867 Erythema multiforme during treatment with interleukin-12 and interleukin-23 inhibitor Pawel Bogucki, MBBS, Department of Dermatology, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom; Anthony Downs, MBBS, Department of Dermatology, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom The mechanism of erythema multiforme (EM) is not well understood. It can be druginduced or follow viral infection, such as HSV. EM has previously been reported following treatment with antieTNF-a agents including infliximab, etanercept, and adalimumab, but not ustekinumab. We know that in drug-induced EM the level of tissue TNF-a is increased, which would be paradoxical in the context of therapy with antieTNF-a inhibitors; hence reactivation of HSV because of immunosuppression has been suggested as more likely cause of EM secondary to these biologic agents. We report a case of a 49-year-old woman with a 34-year history of psoriasis treated unsuccessfully with etanercept, and developed widespread EM after 2 years of initially uneventful treatment with adalimumab. This skin eruption resolved shortly after adalimumab was stopped and 3 months later the patient was given the starting dose (45 mgs) of ustekinumab. Within 3 weeks she developed targetoid lesions on her arms, face and trunk, and shallow, eroded areas on the mucosal surfaces of her mouth. These clinical findings were consistent with yet another episode of EM, most likely induced by reactivation of latent HSV (despite swabs taken from the eroded areas failing to confirm that). The patient displayed positive IgG titers for HSV type 1 (IgM titer was not checked because of local guidelines). Serology for varicella zoster virus and mycoplasma pneumoniae was negative as well as IgE radioallergosorbent test for latex. A skin biopsy, due to a clear clinical picture of EM, was not undertaken. Symptoms resolved on antihistamine tablets alone. The patient was established on acyclovir 400 mg twice daily for 1 month then rechallenged and maintained on ustekinumab. After 2 months the acyclovir was halved, and then stopped a month later. No recurrence of EM or cold sores has been seen. To our knowledge, EM triggered by therapy with IL-12 and -23 has not been previously reported in the literature, but because of interactions between these cytokines and TNF-a, similar complications are not surprising. We believe that the empirical treatment with acyclovir of our patient will help to progress the understanding of the mechanism behind EM secondary to biologic agents and will become a recognized treatment option for those who were unfortunate to develop EM while being on such effective therapy for psoriasis. Commercial support: None identified.
J AM ACAD DERMATOL
AB199
P6408
Effect of tumor necrosis factorealfa inhibitor and methotrexate therapy on total cholesterol, high-density lipoprotein, and low-density lipoprotein in psoriasis/psoriatic arthritis and rheumatoid arthritis patients Jashin Wu, MD, Jashin Wu, Los Angeles, CA, United States; Anny Xiang, PhD, Kaiser Permanente Southern California, Pasadena, CA, United States; Christopher Rowan, PhD, Outcome, A Quintiles Company, Cambridge, MA, United States; Kwun-Yee Poon, MS, Kaiser Permanente Southern California, Pasadena, CA, United States; Mary Anthony, PhD, Amgen, Inc, Thousand Oaks, CA, United States
Efficacy and safety of topical janus kinase inhibitor tofacitinib in the treatment of chronic plaque psoriasis: Results of a phase IIA randomized clinical trial William Ports, Pfizer Inc, Groton, CT, United States; Chantal Bolduc, Innovaderm Research/The University of Montreal, Montreal, Quebec, Canada; Kim Papp, Probity Medical Research and K. Papp Clinical Research Inc, Waterloo, Ontario, Canada; Manisha Lamba, Pfizer Inc, Groton, CT, United States; Robert Bissonnette, Innovaderm Research, Montreal, Quebec, Canada; Shahbaz Khan, Pharmanet/i3, Princeton, Princeton, NJ, United States; Shuping Lan, Pfizer Inc, Groton, CT, United States
Objective: To understand the impact of treatment with a TNF inhibitor (TNFi) or methotrexate (MTX) on total cholesterol (TC), HDL, and LDL in psoriasis (PsO), psoriatic arthritis (PsA), and rheumatoid arthritis (RA) patients. Methods: The study population consists of adult patients diagnosed with prevalent or incident PsO/PsA/RA between January 1, 2002 and July 31, 2011 from a large HMO. Patients exposed to a TNFi (etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol) 6 MTX exposure comprised the TNFi group. Patients in the TNFi group were matched to patients exposed to MTX but not a TNFi (MTX group). Drug exposure status was determined based on exposure status within 1545 days before the laboratory measurements. The groups were matched on inflammatory condition (PsO/PsA/RA), diabetes status, and the date of TNFi initiation/prevalent MTX exposure (index date). All patients had metabolic factor measurements within 1-year before and after the index date. Unadjusted median percent change from baseline and interquartile ranges (IQR) in TC, HDL, and LDL was determined in both exposure groups. Results: There were 1249 PsO patients, 725 PsA patients, and 4962 RA patients. The TC median percent change was +0.4% in TNFi (IQR: -10.5, 10.8, n ¼ 1122) and -0.9% in MTX (IQR: -9.8, 9.2, n ¼ 4575) (P ¼.24). The HDL median percent change was 0% in TNFi (IQR: -10.2, 11.8, n ¼ 1115) and 0% in MTX (IQR: -9.5, 12.3, n ¼ 4577) (P ¼ .26). The LDL median percent change was -2.2% in TNFi (IQR: 13.3-15.7, n ¼ 937) and -1.2% in MTX (IQR: -14.7, 13.4, n ¼ 4103) (P ¼ .53). Conclusion: Although TC was numerically higher in the TNFi group and lower in the MTX group, these changes were not statistically significant. HDL was unchanged in both groups. LDL was numerically lower in both groups, but these changes were not statistically significant. Analysis of other metabolic factors and comparisons between treatment groups and amongst the separate diseases while accounting for differences in medications and demographic and clinical factors are in process. This study was 100% sponsored by a research grant from Amgen.
Objective: To assess efficacy, safety and pharmacokinetics (PK) of tofacitinib ointments in subjects with plaque psoriasis. Methods: In a double-blind, vehicle-controlled phase IIA trial (NCT01246583), 2 ointment formulations of 2% tofacitinib were evaluated in adults with mild to moderate plaque psoriasis. Subjects (N ¼ 71) were randomized 2:1:2:1 to ointment 1 (n ¼ 23), vehicle 1 (n ¼ 13), ointment 2 (n ¼ 25) or vehicle 2 (n ¼ 10). Study drug was applied BID for 4 weeks to a single fixed 300 cm2 treatment area containing a target plaque 6 one or more nontarget plaques and normal skin. The primary endpoint was Target Plaque Severity Score (TPSS) percent change from baseline at week 4. Secondary endpoints included treatment area Physician’s Global Assessment (PGA), Target Plaque Area (TPA), safety and PK. Statistical significance was claimed if the upper 1-sided 90% confidence limit was \0. Exploratory biomarker analyses of baseline and week 4 plaque biopsies for ointment 1 (n ¼ 5) and vehicle 1 (n ¼ 3) were performed by immunohistochemistry. Results: The primary endpoint (week 4 TPSS % change from baseline) showed statistically significant improvement for ointment 1 vs vehicle 1 (least squares mean [LSM] -54.4% vs -41.5%), but not for ointment 2 vs vehicle 2 (LSM -24.2% vs -17.2%). Secondary efficacy endpoints (treatment area PGA and TPA) improved similarly for tofacitinib ointment vs corresponding vehicle. Adverse event (AE) occurrence was similar across treatment groups. All-causality AEs were reported for 25/71 subjects; all AEs were mild or moderate and none were serious or led to subject discontinuation. One application site AE (erythema) was reported. Week 4 plasma tofacitinib levels were below the quantification limit in 40% of ointment 1 and 74% of ointment 2 subjects. Tofacitinib mean systemic exposure was low; ointment 1 exposure was greater than ointment 2. Epidermal pSTAT3 and Ki67 mean percent decrease from baseline was greater for ointment 1 (-56% and -50%, respectively) vs vehicle 1 (-3% and -18%, respectively); dermal pSTAT3 and Ki67 mean percent decrease from baseline for ointment 1 did not differ from vehicle 1. Epidermal K16 and CD3, and dermal CD3 increased from baseline for both ointment 1 and vehicle 1. Conclusion: In this small phase IIA study, tofacitinib ointment 1 was efficacious as compared to vehicle and well tolerated for the treatment of plaque psoriasis. Further study of tofacitinib for topical plaque psoriasis therapy is warranted. Supported 100% by Pfizer Inc.
P6633 Effects of golimumab on the dermatologic manifestations of psoriatic arthritis: 5-year results from the long-term extension of the randomized, placebo-controlled, GO-REVEAL study G. G. Krueger, MD, University of Utah, Salt Lake City, UT, United States Objective: To report dermatologic responses from the long-term extension through 5 yrs of treatment with two doses of golimumab (GLM) 50 mg and 100 mg. Methods: Adult PsA pts with active joint and skin disease were randomized to injections of PBO (group [Group]1, n ¼ 113), GLM 50 mg (Group2, n ¼ 146), or GLM 100 mg (Group3, n ¼ 146) q4wks through week 20. Concomitant MTX was allowed. At week 16, PBO pts with \10% improvement in joints disease received GLM 50 mg, all pts received GLM 50 mg from week 24 forward. After week 52, investigator judgement permitted dose change of GLM 50 mg to 100 mg; after week 104, reduction from GLM 100 mg to GLM 50 mg. Efficacy was assessed at week 256 based on randomized group and completer analyses using PASI response, nail PGA, and target nail NAPSI. Safety included all pts who received [1 GLM dose through 5 years. Results: Of 405 pts randomized, 140 pts (48%) received MTX at baseline; 279 pts (69%) continued GLM through week 252. 34% of pts in group 1 increased dose from 50 to 100 mg, with 8% decreasing the dose to 50 mg through 5 years. In group 2, 29% of pts increased the dose from 50 to 100 mg, with 8% decreasing the dose to 50 mg through 5 years. In group 3, 25% of pts decreased the dose from 100 mg to 50 mg through 5 years. Baseline characteristics (mean), for groups 1, 2 and 3, respectively, were: PsO duration (yrs)- 19, 18., 18; PASI scores- 7.7, 9.4, 11.2; BSA [3%- 70%, 75%, 74%; NAPSI score of target fingernail- 4.7, 4.6, 4.6;. At week 256, among pts with [3% BSA, PASI responses for Groups1, 2 and 3, respectively were: PASI 50, 91% (50/55), 83% (58/70), 95% (75/79); PASI 75 73% (40/55), 69% (48/70), 79% (62/79); PASI 90 51% (28/55), 46% (32/70), 65% (51/79). MTX did not affect PASI responses. Mean % changes from baseline in NAPSI score at week 256 were: 79, 76, and 77 for groups 1, 2 and 3 respectively. Proportions achieving nail PGA improvement were 81% (48/59), 87% (55/63), 81.0% (64/79) for groups 1, 2, and 3, respectively. 88% and 21% GLM-treated pts experienced AE and SAE, respectively. 12% of pts discontinued GLM because of AE, and 4% pts experienced a serious infection(s). Malignancies were observed in 5% of pts (incidence per 100 ptyr 1.28 [95% CI: 0.80, 1.96]); for NMSC (10 events of BCC and 1 event of SCC) occurred in 2.5 % of pts (incidence per 100 pt yr 0.61 [95% CI: 0.29, 1.12]). Conclusion: GLM resulted in long-term improvement in skin and nail psoriasis. No apparent differences between long-term safety and efficacy of GLM doses administered q4wks were observed. Supported by Janssen Research and Development, LLC.
APRIL 2013
P6867 Erythema multiforme during treatment with interleukin-12 and interleukin-23 inhibitor Pawel Bogucki, MBBS, Department of Dermatology, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom; Anthony Downs, MBBS, Department of Dermatology, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom The mechanism of erythema multiforme (EM) is not well understood. It can be druginduced or follow viral infection, such as HSV. EM has previously been reported following treatment with antieTNF-a agents including infliximab, etanercept, and adalimumab, but not ustekinumab. We know that in drug-induced EM the level of tissue TNF-a is increased, which would be paradoxical in the context of therapy with antieTNF-a inhibitors; hence reactivation of HSV because of immunosuppression has been suggested as more likely cause of EM secondary to these biologic agents. We report a case of a 49-year-old woman with a 34-year history of psoriasis treated unsuccessfully with etanercept, and developed widespread EM after 2 years of initially uneventful treatment with adalimumab. This skin eruption resolved shortly after adalimumab was stopped and 3 months later the patient was given the starting dose (45 mgs) of ustekinumab. Within 3 weeks she developed targetoid lesions on her arms, face and trunk, and shallow, eroded areas on the mucosal surfaces of her mouth. These clinical findings were consistent with yet another episode of EM, most likely induced by reactivation of latent HSV (despite swabs taken from the eroded areas failing to confirm that). The patient displayed positive IgG titers for HSV type 1 (IgM titer was not checked because of local guidelines). Serology for varicella zoster virus and mycoplasma pneumoniae was negative as well as IgE radioallergosorbent test for latex. A skin biopsy, due to a clear clinical picture of EM, was not undertaken. Symptoms resolved on antihistamine tablets alone. The patient was established on acyclovir 400 mg twice daily for 1 month then rechallenged and maintained on ustekinumab. After 2 months the acyclovir was halved, and then stopped a month later. No recurrence of EM or cold sores has been seen. To our knowledge, EM triggered by therapy with IL-12 and -23 has not been previously reported in the literature, but because of interactions between these cytokines and TNF-a, similar complications are not surprising. We believe that the empirical treatment with acyclovir of our patient will help to progress the understanding of the mechanism behind EM secondary to biologic agents and will become a recognized treatment option for those who were unfortunate to develop EM while being on such effective therapy for psoriasis. Commercial support: None identified.
J AM ACAD DERMATOL
AB199